Title of Invention

"CINNAMIDE COMPOUND"

Abstract The present invention relates to a compound represented by Formula (I): [Formula 1] or a pharmacologically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising the said compuond.
Full Text DESCRIPTION CINNAMIDE COMPOUND
Technical F'ield [0001]
The present invention relates to a
pharmaceutical agent, particularly an agent of reducing amyloid beta (hereinafter referred to as Ap) production, which is effective in the treatment of neurodegenerative diseases caused by Ap, such as Alzheimer's disease and Down syndrome.
Background Art [0002]
Alzheimer's disease is a disease
characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary change. Presently, treatment of Alzheimer's disease is limited to symptomatic therapies with a symptom-improving agent represented by an acetylcholinesterase inhibitor, and the basic remedy which prevents progress of the disease has not been developed. A method of controlling the cause of onset of pathologic conditions needs to be developed for creation of the basic remedy of Alzheimer's disease.
AP protein, which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is

considered to be greatly involved in degeneration and loss of neurons as well as onset of demential conditions (for example, see Non-Patent Document 1 and Non-Patent Document 2). The main components of AP protein are Ap40 consisting of 40 amino acids and AP42 having two additional amino acids at the C-terminal. The Ap40 and AP42 tend to aggregate (for example, see Non-Patent Document 3) and constitute main components of senile plaques (for example, Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5), and furthermore, it is known that mutations of APP and presenelin genes, which is observed in familial Alzheimer's disease, increase production of AP40 and AP42 (for example, see Non-Patent Document 6, Non-Patent Document 7 and Non-Patent Document 8). Therefore, compounds which reduce production of AP40 and Ap42 are expected as an agent for controlling progress of Alzheimer's disease or for preventing the disease.
These Aps are produced when APP is cleaved by beta secretase and subsequently clipped by gamma secretase. In consideration of this, creation of inhibitors of y secretase and P secretase has been attempted for the purpose of reducing production of Aps. Many of these secretase inhibitors already known are peptides or peptidomimetics such as L-685,458 (for example, see Non-Patent Document 9) and LY-411575 (for example, see Non-Patent Document 10, Non-Patent

Document 11 and Non-Patent Document 12).
Non-Patent Document 1: Klein WL, and seven others, Related Articles, Links Alzheimer's disease-affected brain: presence of oligomeric A(3 ligands (ADDLs) suggests a molecular basis for reversible memory loss, Proceeding National Academy of Science USA, 2003, Sep 2, 100(18), p. 10417-10422;
Non-Patent Document 2: Nitsch RM, and 16 others, Antibodies against |3-amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22, 38(4), p. 547-554;
Non-Patent Document 3: Jarrett JT, and 2 others, The carboxy terminus of the (3 amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry, 1993, May 11, 32(18), p. 4693-4697;
Non-Patent Document 4: Glenner GG, and another, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, 1984, May 16, 120(3), p. 885-890;
Non-Patent Document 5: Masters CL, and six others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, 1985, Jun, 82(12), p. 4245-4249;
Non-Patent Document 6: Gouras GK, and eleven

others, Intraneuronal A|342 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156(1), p. 15-20;
Non-Patent Document 7: Scheuner D, and twenty others, Secreted amyloid (3-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2(8), p. 864-870;
Non-Patent Document 8: Forman MS, and 4 others, Differential effects of the Swedish mutant amyloid precursor protein on p-amyloid accumulation and secretion in neurons and nonneuronal cells, Journal of Biological Chemistry, 1997, Dec 19, 272(51), p. 32247-32253;
Non-Patent Document 9: Shearman MS, and nine others, L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid (3-protein precursor Y~secretase activity, Biochemistry, 2000, Aug 1,39(30), p. 8698-8704;
Non-Patent Document 10: Shearman MS, and six others, Catalytic site-directed Y~secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and |3-APP cleavages, Biochemistry, 2003, Jun 24, 42(24), p. 7580-7586;
Non-Patent Document 11: Lanz TA, and three others, Studies of Ap pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free)

Tg2576 mice using the v~secretase inhibitor N2-[(2S)-2- (3,5-difluorophenyl)-2-hydroxyethanoyl]-Nl-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575), Journal of Pharmacology and Experimental Therapeutics, 2004, Apr, 309(1), p. 49-55;
Non-Patent Document 12: Wong GT, and twelve others, Chronic treatment with the Y~secretase inhibitor LY-411,575 inhibits p-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation, Journal of Biological Chemistry, 2004, Mar 26, 279(13), p. 12876-12882.
Disclosure of the Invention
Problems to be Solved by the Invention
[0003]
As mentioned above, compounds which prevent production of AP40 and A(342 from APP are expected as an preventive or therapeutic agent for diseases caused by A(5 represented by Alzheimer's disease. However, non-peptide compounds which prevent production of AP40 and AP42 and have an excellent medicinal effect have not been known. Therefore, a novel low molecular compound that inhibits production of AP40 and AP42 is demanded.
Means for Solving the Problems [0004]
The present inventors have conducted intensive studies and first discovered non-peptidic

cinnamide compounds which inhibit production of AP40 and Ap42 from APP and discovered preventive or therapeutic agents for diseases caused by AP, represented by Alzheimer's disease, thereby completed the present invention. [0005]
That is, the present invention relates to the followings:
1) A compound or a pharmacologically acceptable salt thereof represented by Formula (I): [0006] [Formula 1]
(Figure Remove)

(wherein ArL represents an imidazolyl group which may be substituted with 1 to 3 substituents selected from Substituent Group Al shown below; Ar2 represents a pyridinyl group, a pyrimidinyl group, or a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A2 shown below; Xi represents (I) -C=C- or (2) -CR3=CR4- (wherein R3 and R4 represents a Substituent selected from Substituent Group A3 shown below); and
(1) R1 and R2 represent groups selected from Substituent Group A4 shown below or

R1 and R2, together with a nitrogen atom to which they bind, form one of the following groups: (2-1) a 5- to 11-membered non-aromatic heterocyclic group represented by Formula (II): [Formula 2]
(CH2)ma
/ \ ---- N Y! (II)
(CH2jmb
(wherein YI represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2~, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5=CR6- (wherein R5 and R6 represent substituents selected from Substituent Group A4 shown below), (11) a single bond or (12) >C=CR13R14 (wherein R13 arid R14 represent substituents selected from Substituent Group A4 shown below) ; and
ma and nib represent an integer of 0 to 4) which may be substituted with 1 to 4 substituents selected from Substituent Group A4 ;
(2-2) a 6- to 20-membered non-aromatic heterocyclic group represented by Formula (III) : [Formula 3]
(CH2)ma /CH2)mc

(CH2)nfb CH2
(wherein Y2 represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -S0?.-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9)

-NHCO-, (10) -CR5= CR6- (wherein R5 and R6 represent substituents selected from Substituent Group A4 shown below or R5 and R6, together with a carbon atom to which they bind, form a 6- to 14-membered aromatic hydrocarbon ring group or a 6- to 14-membered non-aromatic hydrocarbon ring group) or (11) a single bond; and
ma/ mb, mc and md represent an integer of 0 to 4) which may be substituted with 1 to 4 substituents selected from Substituent Group A4;
(2-3) a 9- to 16-membered non-aromatic heterocyclic group represented by Formula (IV): [Formula 4]
(CH:)ma
(wherein Y3 represents (1) -NH-, (2) -0-, (3) -S-, (4;
-SO-, (5) -S02~, (6) ~CH2-, (7) -CO-, (8) -CONH-, (9)
-NHCO- or (10) a single bond; and
ma and mb are the same as defined above) which may be
substituted with 1 to 4 substituents selected from
Substituent Group A4;
(2-4) a group represented by the following formula:

[formula b
(Figure Remove)



which may be substituted with 1 to 4 substituents selected from Substituent Group A4 shown below; (2-5) a group represented by the following formula [Formula 6]
(Figure Remove)









which may be substituted with 1 to 4 substituents selected from Substituent Group A4 shown below; or R1 and R2, together with -Xi-CO-N-, form one of the following ring structures:
(wherein Z;L represents (1) -NH-, (2) -0-, (3) -S-, (4)
(3--1) a cyclic group represented by Formula (V) : [Formula 7]
(Figure Remove)


-SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO- or (10) a single bond; Z2 represents (1) a methine group or (2) a nitrogen atom; R7 represents a substituent selected from Substituent Group A3 shown below; and na, nt) and nc represent an integer of 0 to 4) which may be substituted with 1 to 4 substituents selected from Substituent Group A4 ; (3-2) a cyclic group represented by Formula (VI): [Formula 8]
R7
(Figure Remove)
(VI)
(wherein Zs represents (1) a single bond, (2) -CO-, (3)
-(Cf-bjnd- (wherein nd represents an integer of 1 to 3) or
(4) -CR8R9- (wherein R8 and R9 represent a substituent
selected from Substituent Group A4 shown below;
Z4 represents (1) a single bond, (2) -0-, (3) -NRCO-,
(4) -CONR-, (5) -CSNR- ( 6) -NRCS- (wherein R represents a
substituent selected from Substituent Group A4 shown
below) or (7) -S-;
Zs represents (1) a single bond, (2) an imino group
which may be substituted with a substituent selected
from Substituent Group A4 shown below, (3) -(CH2)ne-
(wherein ne represents an integer of 1 to 3), (4)
-CR8R9- (wherein R8 and R9 are the same as defined above)
or (5) -0-; and
R1 and R7 are the same as defined above) ;or


(3-3) a cyclic group represented by the following formula: [Formula 9]
(Figure Remove)


(wherein R1 and R7 are the same as defined above) which may be substituted with 1 to 4 substltuents selected 5 from Substituent Group A4 shown below.
Substituent Group Al: (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a nitro group, (5) a C3-8 cycloalkyl group, (6) a C2-6 alkenyl group, (7) a C2-6 alkynyl group, (8) a Cl-6 alkoxy group, (9) a
C3-8 cycloalkoxy group, (10) a formyl group, (11) a Cl-6 alkylcarbonyl group, and (12) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substltuents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a
Cl-6 alkoxy group, a C3-8 cycloalkyl group and a Cl-6 alkylcarbonyl group).
Substituent Group A2: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group
may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a Cl-6 alkoxy group, a C2-6 alkeny group, a C2-6


alkyny group and a C3-8 cycloalkyl group), (6) a C3-8 cycloalkoxy group, (7) a C2-6 alkenyloxy group and (8) a C2-6 alkyriyloxy group.
Substituent Group A3: (1) a hydrogen atom, (2) a 5 halogen atom, (3) a 6- to 14-membered aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents
selected from Substituent Group A4, (5) a Cl-6 alkyl
group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting
group, a cyano group, a C2-6 alkenyl group, a C2-6
alkynyl group, a C3-8 cycloalkyl group, a Cl-6 alkoxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group, a Cl-6 alkylsulfonyl group, a Cl-6 alkylcarbonyl group, an amino group (wherein said amino group may be
substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-mernbered aromatic heterocyclic group which may
be substituted with 1 to 3 substituents selected from Substituent Group A4, a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a


5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -0- or -S- and A represents 5 a 6- to 14-membered aromatic hydrocarbon ring group or
- to 14-membered aromatic heterocyclic group which may
be substituted with 1 to 3 substituents selected from
Substituent Group A4) and (6) a Cl-6 alkoxyl group.
Substituent Group A4: (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a Cl-6 alkylcarbonyl group,
(13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a
Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (22) a
6- to 14-membered aromatic hydrocarbon ring group which
may be substituted with 1 to 5 substituents selected
from Substituent Group A4, (23) a 5- to 14-membered


aromaitic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 5 to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkeriyloxy group, (27) a C2-6 alkynyloxy group, (28) a
C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may
be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).
2) The compound or pharmacologically acceptable
salt thereof according to above 1) wherein Ari is an
imidazolyl group which may be substituted with 1 to 2 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8 cycloalkyl group, (4) a C2-6 alkeny group, (5) a C2-6 25 alkyny group, (6) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 halogen atoms).
3) The compound or pharmacologically acceptable


salt thereof according to above 1) wherein Ar2 is a pheriyl group which may be substituted with 1 to 3 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl 5 group, (4) a cyano group, (6) a Cl-6 alkoxy group
(wherein said Cl-6 alkoxy group may be substituted with 1 to 3 substituents selected from a C2-6 alkenyl group, a C2-6 alkyriy group and a C3-8 cycloalkyl group), (7) a C2-6 alkenyloxy group and (8) a C2-6 alkynyloxy group.
4) The compound or pharmacologically acceptable salt thereof according to above 2) wherein Arx is an imidazolyl group which may be substituted with 1 to 2 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8
cycloalkyl group and (4) a Cl-6 alkyl group.
5) The compound or pharmacologically acceptable
salt thereof according to above 3) wherein Ar2 is a
phenyl group which may be substituted with 1 to 3
substituents selected from the group consisting of (1)
a hydrogen atom, (2) a halogen atom, (3) a cyano group and (4) a Cl-6 alkoxy group.
6) The compound or pharmacologically acceptable
salt thereof according to above 1) wherein Xi is -C=C-.
7) The compound or pharmacologically acceptable
salt thereof according to above 1) wherein Xi is -
CRJ=CR4- (wherein R3 and R4 represent substituents selected from Substituent Group A3 shown below). Substituent Group A3: (1) a hydrogen atom, (2) a


halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a - to 14-membered aromatic heterocyclic group 5 which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a
hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a Cl-6 alkoxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group, a Cl-6 alkylsulfonyl group, a Cl-6 alkylcarbonyl
group, an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a
5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a
5- to 14-memberecl non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -0- or -S- and A represents

17 a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may
be substituted with 1 to 3 substituents selected from
Substituent Group A4) and (6) a Cl-6 alkoxy group.
Substituent Group A4: (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,
(11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a
carbamoyl group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (22) a
6- to 14-membered aromatic hydrocarbon ring group which
may be substituted with 1 to 3 substituents selected
from Substituent Group A4, (23) a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1


to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 5 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).
8) The compound or pharmacologically acceptable salt thereof according to above 7) wherein Xi is -CR3l=CR41- (wherein R31 is a group selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a Cl-6 alkyl group and (4) a Cl-6 alkoxy
group; and R41 represents a group selected from the
group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A5, (4) a 5- to 14-
membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5 and (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with

1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a Cl-6 alkyl group, a Cl-6 alkoxy group, an amino group (wherein said amino group 5 may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A5, a 5- to 14-membered aromatic
heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5, a 5-to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5 and -0-A1 (wherein A1
represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A5 or a 5-to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from
Substituent Group A5))).
Substituent Group A5: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a Cl-6 alkyl group (wherein said Cl-6 alkyl
group may be substituted with 1 to 5 halogen atoms),
(8) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen atoms) and (9) an amino group (wherein said amino group may be


substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms).
9) The compound or pharmacologically acceptable
salt thereof according to above 8) wherein Xi is
-CR32-=CR42- (wherein R32 represents a hydrogen atom or a halogen atom, and R42 represents a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with a C3-8 cycloalkyl group or a 10 phenyl group) and a phenyl group).
10) The compound or pharmacologically acceptable
salt thereof according to above 1) wherein R1 and R2 are
groups selected from substituents selected from
Substituent Group A4.
Substituent Group A4 : (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyL group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,
(11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amlno group which may be substituted with 1 to 2

1

substituents selected from Substituent Group A4, (21) a
carbarnoyl group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which 5 may be substituted with 1 to 3 substituents selected from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6
alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).
11) The compound or pharmacologically acceptable salt thereof according to above 10) wherein R1 is a group selected from Substituent Group A8 shown below and R~ is a group selected from Substituent Group A6


shown below.
Substituerit Group A6: (1) a hydrogen atom, (2) a C3-8 cycloalkyl group, (3) a C3-8 cycloalkoxy group, (4) a C1--6 alkyl group (wherein said Cl-6 alkyl group may be 5 substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkylthio group, a hydroxyiraino group, a Cl-6 alkoxyimino group,
a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from
Substituent Group A7 shown below, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A7 shown below and -0-A2 (wherein A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below)) and (5) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with

1 to 3 substituents selected from the group consisting
of a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkylthio group, a hydroxyimino 5 group, a Cl-6 alkoxyimino group, a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1
to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered non-aromatic heterocyclic group which may
be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below and -0-A2 (wherein A2 is the same as defined above)).
Substituent Group A7: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group,
(5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a Cl-6 alkylcarbonyl group, (8) a Cl-6 alkylthio group, (9) a Cl-6 alkylsulfinyl group, (10) a Cl-6 alkylsulfonyl group, (11) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with
1 to 5 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group, a 6- to 14-membered aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group and -0-A3 (wherein


A3 represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group)), (12) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen 5 atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), (13) an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), (14) a 6- to 14-membered aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (15) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (16) a 5- to 14-
membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 and (17) -CO-A3 (wherein A3 is the same as defined above). Substituent Group A8: (1) a hydrogen atom, (2) Cl-6
alkyl group (wherein said Cl-6 alkyl group may be
substituted with 1 to 3 substituents selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkyl
group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form a cyclic group


(wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl 5 group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected from Substituent Group A7, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A7, a 5-to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A 7 and -X-A2 (wherein X represents an imino group, -0- or -S- and A2 represents
a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected from Substituent Group A7 or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from
Substituent Group A7)), (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A7 and (5) -X-A2 (wherein X and A2 are the same as defined above). 12) The compound or pharmacologically acceptable salt thereof according to above 11) wherein R1 is a Cl-6


alkyl group (wherein said Cl-6 alkyl group is a hydrogen atom, a C3-8 cycloalkoxy group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene 5 group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)) , a Cl-6 alkoxy group, a 6- to 14-membered
aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from Substituent Group A9, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and -0-
A4 (wherein A4 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected
from Substituent Group A9)), and R2 is (1) a hydrogen
atom or (2) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a
Cl-6 alkylthio group, an amino group (wherein said
amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be


substituted with 1 to 3 substituents selected from Substituent Group A9, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and a 5 - to 14-membered non-aromatic heterocyclic group which, may be substituted with 1 to 3 substituents selected from Substituent Group A9).
Substituent Group A9: (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8 cycloalkyl group, (4) a C3-8
cycloalkoxy group, (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom and a Cl-6 alkyl group), (6) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be
substituted with 1 to 5 halogen atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), (7) an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms),
(8) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9, (9) -CO-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group), (10) a 6- to 14-membered aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and (11) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents


selected from Substituent Group A9.
13) The compound or pharmacologically acceptable salt thereof according to above 1) wherein R1 and R2, together with a nitrogen atom to which they bind, form 5 a 5- to 11-membered heterocyclic group represented by Formula (II): [Formula 10]
(CH2)ma
/ N Y1 (II)
\CH2K
(wherein YI represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR6=CR6- (wherein R5 and R6 represent 10 groups selected from Substituent Group A4 shown below),
(11) a single bond or (12) >C=CR13R14 (wherein R13 and R14 represent substituents selected from Substituent Group A4 shown below); and; ma and mb represent an integer of 0 to 4) which may be substituted with 1 to 4 15 substituents selected from Substituent Group A4 shown below.
Substituent Group A4: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group,
(5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a 20 C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,
(11) a formyl group, (12) a Cl-6 alkylcarbonyl group,
(13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl

group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a 5 Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted
with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic
group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X
represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from


Subst.ituent Group A4} , (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).
14) The compound or pharmacologically acceptable 5 salt thereof according to above 13) wherein a 5- to 11-membered heterocyclic group is a piperidinyl group, a pyrrolidinyl group, an azepinyl group, an azocanyl group, a piperazinyl group, a 1, 4-diazepanyl group, a morpholinyl group or a thiomorpholinyl group.
15) The compound or pharmacologically acceptable salt thereof according to above 14) wherein R1 and R2, together with a nitrogen atom to which they bind, form a piperidinyl group, a pyrrolidinyl group, an azepinyl group, an azocanyl group, a piperazinyl group, a 1,4-
diazepanyl group, a morpholinyl group or a
thiomorpholinyl group which may be substituted with 1 to 3 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a formyl group, (5) a hydroxyimino group,
(6) a Cl-6 alkoxyimino group, (7) a Cl-6 alkyl group
(wherein said Cl-6 alkyl group may be substituted with I to 3 hydroxyl groups or 1 to 3 substituents selected from the group consisting of a 6- to 14-membered aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from
Substituent Group A7 shown below or a 5- to 14-membered aromatic heterocyclic group which may be substituted with I to 3 substituents selected from Substituent


Group A7 shown below), (8) 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from substituents of A7 shown below, (9) a 5- to 14-membered aromatic 5 heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, (10) -0-A2 (wherein A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from
Substituent Group A7 shown below or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below), (11) -CO-A2 (wherein A2 is the same as defined above) and (12) =CH-A2 (wherein A2 is
the same as defined above).
Substituent Group A7: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a Cl-6 alkylcarbonyl group, (8) a Cl-6
alkylthio group, (9) a Cl-6 alkylsulfinyl group, (10) a Cl-6 alkylsulfonyl group, (11) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group, a 6- to 14-
membered aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group and -0-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic


group)), (12) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), 5 (13) an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to halogen atoms), (14) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7,
(15) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (16) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from
Substituent Group A7 and (17) -CO-A3 (wherein A3 is the same as defined above).
16) The compound or pharmacologically acceptable salt thereof according to above 15) wherein R1 and R2, together with a nitrogen atom to which they bind, form
a piperidinyl group, a pyrrolidinyl group, an azepinyl group, an azocanyl group, a piperazinyl group, a 1,4-diazepanyl group, a morpholinyl group or a thiomorpholinyl group which may be substituted with 1 to 4 substituents selected from the group consisting of
(1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 hydroxyl groups or 1 to 3 substituents selected from the group consisting


of a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A10 shown below), (5) a 6- to 14-membered aromatic hydrocarbon ring group which 5 may be substituted with 1 to 3 substituents selected from substituents of A10 shown below, (6) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A10 shown below, (7) -0-A6 (wherein A6
represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group AID shown below), (8) =CH-A6 (wherein A6 has the same above). Substituent Group Aid: (1) a hydrogen atom, (2) a
halogen atom, (3) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 5 halogen atoms), (4) a Cl-6 alkoxy group and (5) a 6- to 14-membered aromatic hydrocarbon ring group. 17) The compound or pharmacologically acceptable
salt thereof according to above 1) wherein R1 and R2, together with a nitrogen atom to which they bind, form a 6- to 20-membered non-aromatic heterocyclic group represented by Formula (III): [Formula 11)
(CH2)ma /CH2)mc
(CH2


(wherein Y2 represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5= CR6- (wherein R5 and R6 represent groups selected from Substituent Group A4 shown below 5 or R5 and Rb, together with a nitrogen atom to which they bind, form a 6- to 14-membered aromatic hydrocarbon ring group or a 6- to 14-membered non-aromatic hydrocarbon ring group) or (11) a single bond; and ma, mb, mc and md represent an integer of 0 to 4)
which may be substituted with 1 to 4 substituents selected from Substituent Group A4 shown below. Substituent Group A4: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a
C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a
hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20)
an amino group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (22) a


6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted 5 with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic
group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X
represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the
same as defined above) and (32) =CH-A (wherein A is the same as defined above).
18) The compound or pharmacologically acceptable salt thereof according to above 1) wherein R1 and R2, together with a nitrogen atom to which they bind, form
a 9- to 16-rnembered non-aromatic heterocyclic group represented by Formula (IV):


[Formula 12] (Figure Remove)


(wherein Y3 represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -SO,-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO- or (10) a single bond; and ma and mb represent an integer of 0 to 4) which may be substituted with 1 to 4 5 substituents selected from Substituent Group A4. Substituent Group A4: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group,
(5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-10 8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,
(11) a forinyl group, (12) a Cl-6 alkylcarbonyl group,
(13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) 15 a Cl-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 20 substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which


may be substituted with 1 to 3 substituents selected from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent 5 Group A4 , (24) a 6- to 14-membered non-aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents
selected from Substituent Group A4 , (26) a C2-6
alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents
a 6- to 14-inembered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 ) , (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the
same as defined above) .
19) The compound or pharmacologically acceptable salt thereof according to above 1) wherein R1 and R2, together with a nitrogen atom to which they bind, form a group represented by the following formula:
[Formula 13] (Figure Remove)





which may be,1 substituted with 1 to 4 substituents selected from Substituent Group A4. Substituent Group A4: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, 5 (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl
group, (15) a Cl-6 alkylsulfonyl group, (16) a
hydroxyimi.no group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyi group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3
substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (22) a
6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent
Group A4, (24) a 6- to 14-membered non-aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and (25) a 5- to 14-membered non-aromatic heterocyclic


group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkeriyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 5 cycloalkylsulfonyl group, (30) -X-A (wherein X
represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from
Substituent Group A4), (31) -CO-A (wherein A is the
same as defined above) and (32) =CH-A (wherein A is the same as defined above).
20) The compound or pharmacologically acceptable salt thereof according to above 1) wherein R1 and R2,
together with a nitrogen atom to which they bind, form a group represented by the following formula: [Formula 14j
(Figure Remove)











which may be substituted with 1 to 4 substituents
selected from Substituent Group A4.
Substituent Group A4: (1) a hydrogen atom, (2) a


halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2--6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, 5 (11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a
carbarnoyl group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected from Substituent Group A4, (23) a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4,
(25) a 5- to 14-membered non-aromatic heterocyclic
group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a


C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4) , (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).
21) The compound or pharmacologically acceptable salt thereof according to above 20) wherein R1 and R2, together with a nitrogen atom to which they bind, form a group represented by the following formula: [Formula 15]
(Figure Remove)







which may be substituted with 1 to 4 substituents
selected from Substituent Group A4.
Substituent Group A4: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-
2.0 8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,
(11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) 5 a Cl-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected
from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1
to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a
C3-8 cycloalkylsulfinyl group, (29) a C3-8
cyclodlkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or

- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent: Group A4) , (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the 5 same as defined above).
22) The compound or pharmacologically acceptable
salt thereof according to above 21) wherein the group
formed by R1 and R2, together with a nitrogen atom to
which they bind, may be substituted with 1 to 4
fluorine atoms.
23) The compound or pharmacologically acceptable
salt thereof according to above 1) wherein R1 and R2,
together with -X.-CO-N-, form a cyclic group represented
by Formula (V):
[Formula 16] (Figure Remove)

(wherein Zx represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO- or (10) a single bond; Z2 represents (1) a methine group or (2) a nitrogen atom; R7 represents a substituent selected from Substituent Group A3 shown
below; and nd, nb and nc represent an integer of 0 to 4 which may be substituted with 1 to 4 substituents selected from Substituent Group A4. Substituent Group A3: (1) a hydrogen atom, (2) a

halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group 5 which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a
hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a Cl-6 alkoxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group, a Cl-6 alkylsulfonyl group, a Cl-6 alkylcarbonyl
group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group, which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a
- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a
5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -0- or -S- and A represents 45 a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may
be substituted with 1 to 3 substituents selected from
Substituent Group A4)) and (6) a Cl-6 alkoxy group.
Substituent Group A4: (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,
(11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a
carbamoyl group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (22) a
6- to 14-membered aromatic hydrocarbon ring group which
may be substituted with 1 to 5 substituents selected
from Substituent Group A4, (23) a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1
If
to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 5 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above) .
24) The compound or pharmacologically acceptable salt thereof according to above 1) wherein R1 and R2, together with -Xi-CO-N-, form a cyclic group represented by Formula (VI) : [Formula 17]

(Figure Remove)
(wherein Z3 represents (1) a single bond, (2) -CO-, (3) 20 -(CH2)nd- (wherein nd represents an integer of 1 to 3) or (4) -CR8R9- (wherein R8 and R9 represent a Substituent selected from Substituent Group A4 shown below; Z4 represents (1) a single bond, (2) -0-, (3) -NRCO-,


(4) -CONR-, (5) -CSNR-, (6)-NRCS-(wherein R represents a substituent selected from Substituent Group A4 shown below) or (7) -S-;
Z5 represents (1) a single bond, (2) an imino group 5 which may be substituted with a substituent selected from Substituent Group A4 shown below, (3) -(CH2)ne-(wherein ne represents an integer of 1 to 3), (4) -CR8R9- (wherein R8 and R9 are the same as defined above) or (5) -0-; and R1 represents a substituent selected
from Substituent Group A4 and R7 represents a substituent selected from Substituent Group A3) which may be substituted with 1 to 4 substituents selected from Substituent Group A4. Substituent Group A3: (1) a hydrogen atom, (2) a
halogen atom, (3) a 6- to 14-membered aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents
selected from Substituent Group A4, (5) a Cl-6 alkyl
group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting
group, a cyano group, a C2-6 alkenyl group, a C2-6
alkynyl group, a C3-8 cycloalkyl group, a Cl-6 alkoxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group, a Cl-6 alkylsulfonyl group, a Cl-6 alkylcarbonyl


group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 5 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1
to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -0- or -S- and A represents
a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (6) a Cl-6 alkoxy group. Substituent Group A4: (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a Cl-6 alkylcarbonyl group,
(13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3


substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 5 substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected
from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1
to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a
C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group, which
may be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).


25) The compound or pharmacologically acceptable salt thereof according to above 24) wherein Formula (VI) is a cyclic group: [Formula 18]
(Figure Remove)









(wherein R1 and R5i represents a substituent selected from Substituent Group A4 and R7 represents a substituent selected from Substituent Group A3) which may be substituted with 1 to 4 substituents selected from Substituent Group A7.
Substituent Group A3: (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituents
selected from Substituent Group A4, (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a

hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a Cl-6 alkoxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl 5 group, a Cl-6 alkylsulfonyl group, a Cl-6 alkylcarbonyl group, an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1
10 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1
to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -0- or -S- and A represents
a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (6) a Cl-6 alkoxy group. Substituent Group A4: (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,i
(11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimi.no group, (17) a Cl-6 alkoxyimino group, (18) 5 a Cl-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected
from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1
to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a
C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the 5 same as defined above).
Substituent Group A7: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a Cl-6 alkylcarbonyl group, (8) a Cl-6
alkylthio group, (9) a Cl-6 alkylsulfinyl group, (10) a Cl-6 alkylsulfonyl group, (11) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group, a 6- to 14-
membered aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group and -0-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group)), (12) a Cl-6 alkoxy group (wherein said Cl-6
alkoxy group may be substituted with 1 to 5 halogen
atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), (13) an amirio group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1
to 5 halogen atoms), (14) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (15) a 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (16) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from 5 Substituent Group A7 and (17) -CO-A3 (wherein A3 is the same as defined above).
26) The compound or pharmacologically acceptable salt thereof according to above 1) wherein R1 and R2, together with -Xi-CO-N-, form a cyclic group represented 10 by the following formula: [Formula 19] (Figure Remove)





(wherein R1 and R7 are the same as defined above) which may be substituted with 1 to 4 substituents selected from Substituent Group A4. Substituent Group A4: (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a Cl-6 alkylcarbonyl group,
(13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl gro-up, (15) a Cl-6 alkylsulfonyl group, (16) a

hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 5 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (22) a
6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent
Group A4, (24) a 6- to 14-membered non-aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents
selected from Substituent Group A4, (26) a C2-6
alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents
a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the
same as defined above) and (32) =CH-A (wherein A is the same as defined above).
27) The compound or pharmacologically acceptable salt thereof according to any one of above 24) and 26) 5 wherein R1 is a substituent selected from Substituent Group A8.
Substituent Group A8: (1) a hydrogen atom, (2) Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the
group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene
group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, an amino group (wherein
said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, a 5- to 14-membered aromatic
heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, a 5-to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected
from Substituent Group A7 and -X-A2 (wherein X represents an imino group, -0- or -S- and A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents 5 selected from Substituent Group A7 or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7)), (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from
Substituent Group A7, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 and (5) -X-A2 (wherein X and A2 are the same as defined above) .
Substituent Group A7: (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a Cl-6 alkylcarbonyl group, (8) a Cl-6 alkylthio group, (9) a Cl-6 alkylsulfinyl group, (10) a
Cl-6 alkylsulfonyl group, (11) a Cl-6 alkyl group
(wherein said Cl-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group, a 6- to 14-membered aromatic hydrocarbon ring group, a 5- to 14-
membered aromatic heterocyclic group and -0-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group), (12) a Cl-6 alkoxy group (wherein said Cl-6

alkoxy group may be substituted with 1 to 5 halogen atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), (13) an amino group (wherein said amino group may be 5 substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), (14) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (15) a 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituents
selected from Substituent Group A7, (16) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 and (17) -CO-A3 (wherein A3 is the
same as defined above).
28) The compound or pharmacologically acceptable salt thereof according to above 27) wherein R1 is a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the
group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene
group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen

atom)), a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may 5 be substituted with 1 to 3 substituents selected from Substituent Group A9, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9, a 5-to 14-membered non-aromatic heterocyclic group which
may be substituted with 1 to 3 substituents selected from Substituent Group A9 and -X-A4 (wherein X represents an imino group, -0- or -S- and A4 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents
selected from Substituent Group A9 or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9)). Substituent Group A9: (I) a hydrogen atom, (2) a
halogen atom, (3) a C3-8 cycloalkyl group, (4) a C3-8 cycloalkoxy group, (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom and a Cl-6 alkyl group), (6) a Cl-6 alkoxy
group (wherein said Cl-6 alkoxy group may be
substituted with 1 to 5 halogen atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), (7) an amino group

(wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), (8) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents 5 selected from Substituent Group A9, (9) -CO-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group), (10) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9
and (11) a 5- to 14-membered aromatic heterocyclic
group which may be substituted with 1 to 3 substituents selected from Substituent Group A9.
29) The compound or pharmacologically acceptable salt thereof according to any one of above 10), 24) and
26) wherein R1 is -X2i-X22-Ar3 (wherein X2i represents 1) a Cl-6 alkylene group (wherein said Cl-6 alkylene group may be substituted with 1 to 3 substituents selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8
cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form
a cyclic group (wherein a rnethylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with
a Cl-6 alkyl), a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7) or 2) a single bond, and X22 represents a single bond, an 5 imino group which may be substituted with a substituent selected from Substituent Group A7, -0- or -S- and Ar^ represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 or a 5-
to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7).
Substituent Group A7: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group,
(5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a Cl-6 alkylcarbonyl group, (8) a Cl-6 alkylthio group, (9) a Cl-6 alkylsulfinyl group, (10) a Cl-6 alkylsulfonyl group, (11) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with
1 to 5 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group, a 6- to 14-membered aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group and -0-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon
ring group or a 5- to 14-membered aromatic heterocyclic group), (12) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen atoms or may, together with a carbon atom to which said
adjacent Cl-6 alkoxy groups bind, form a cyclic group), (13) an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), (14) a 6- to 14-membered aromatic 5 hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (15) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (16) a 5- to 14-
membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 and (17) -CO-A3 (wherein A3 is the same as defined above). 30) The compound or pharmacologically acceptable
salt thereof according to above 29) wherein R1 is -X2ia-X22a~Araa (wherein X2ia represents a Cl-6 alkylene group (wherein said Cl-6 alkylene group may be substituted with 1 to 3 substituents selected from the group consisting of a hydrogen atom, a halogen atom, a
hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene group and said two Cl-6 alkyl groups may, together with
the carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, an amino group (wherein
said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from 5 Substituent Group A9), and Xa2a represents a single bond or an oxygen atom and Araa represents a 6- to 14-membered aromatic hydrocarbon ring group which may be 'substituted with 1 to 3 substituents selected from Substituent Group A9 or a 5- to 14-membered aromatic
heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9). Substituent Group A9: (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8 cycloalkyl group, (4) a C3-8 cycloalkoxy group, (5) a Cl-6 alkyl group (wherein said
Cl-6 alkyl group may be substituted with 1 to 5
substituents selected from the group consisting of a halogen atom and a Cl-6 alkyl group), (6) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen atoms or may, together
with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), (7) an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), (8) a 5- to 14-membered non-aromatic heterocyclic group
which may be substituted with 1 to 3 substituents
selected from Substituent Group A9, (9) -CO-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group), (10) a 6- to 14-membered aromatic


hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and (11) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents 5 selected from Substituent Group A9.
31) The compound or pharmacologically acceptable salt thereof according to above 30) wherein Arsa is a 6-to 14-membered aromatic hydrocarbon ring group selected from the group consisting of a phenyl group, a naphthyl
group and a fluorenyl group or a 5- to 14-membered aromatic heterocyclic group selected from the group consisting of a thienyl group, a pyridyl group, a guinolyl group, an isoquinolyl group, an indolyl group, a benzothiazolyl group, a benzoxazolyl group and a
furyl group, which may be substituted with 1 to 3 substituents selected from Substituent Group A9. Substituent Group A9: (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8 cycloalkyl group, (4) a C3-8 cycloalkoxy group, (5) a Cl-6 alkyl group (wherein said
Cl-6 alkyl group may be substituted with 1 to 5
substituents selected from the group consisting of a halogen atom and a Cl-6 alkyl group), (6) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen atoms or may, together
with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), (7) an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms),


(8) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9, (9) -CO-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon 5 ring group), (10) a 6- to 14-membered aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and (11) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents
selected from Substituent Group A9.
32) The compound or pharmacologically acceptable salt thereof according to above 1) wherein R1 is a 6- to 14-membered non-aromatic hydrocarbon ring group or a 5-to 14-membered non-aromatic heterocyclic group
represented by Formula (VII): [Formula 20] (Figure Remove)



(wherein R8 to R12 represent 1) a single bond, 2) -CO-, 3) a methylene group which may be substituted with 1 or 2 substituents selected from Substituent Group A4, 4) -0-, 5) an imino group which may have a Substituent 20 selected from Substituent Group A4 or 6) -S-, and Ar4 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3


substituents selected from Substituent Group A4 shown below or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 shown below). 5 Substituent Group A4 : (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,
(11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a
carbamoyl group which may be substituted with 1 to 2
substituents selected from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected from Substituent Group A4, (23) a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1


to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 5 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).
33) The compound or pharmacologically acceptable salt thereof according to above 32) wherein Ar4 represents a phenyl group or a 5- to 14-membered aromatic heterocyclic group selected from the group consisting of a pyridinyl group, a pyrimidinyl group, a
pyrazinyl group, a thienyl group, an oxazolyl group, a pyrrolyl group, a thiazolyl group and a furyl group, which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be
substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a Cl-6 alkyl group), a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 3 halogen atoms), an


amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 5 to 3 substituents selected from Substituent Group A7, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A7 and -CO-A2 (wherein A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below).
Substituent Group A7: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group,
(5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a Cl-6 alkylcarbonyl group, (8) a Cl-6 alkylthio group, (9) a Cl-6 alkylsulfinyl group, (10) a Cl-6 alkylsulfonyl group, (11) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with
1 to 5 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group, a 6- to 14-membered aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group and -0-A3 (wherein


A3 represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group), (12) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen 5 atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group), (13) an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), (14) a 6- to 14-membered aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (15) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (16) a 5- to 14-
membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 and (17) -CO-A3 (wherein A3 is the same as defined above). 34) The compound or pharmacologically acceptable
salt thereof according to above 33) wherein R1 is an indanyl group, an azaindanyl group, a tetrahydronaphthyl group, an azatetrahydronaphthyl group, a chromanyl group, an azachromanyl group, a tetrahydrobenzofuranyl group or a
tetrahydrobenzothienyl group, which may be substituted with 1 to 3 substituents selected from the group consisting of (1) a halogen atom, (2) a hydroxyl group, (3) a cyano gro-up, (4) a C3-8 cycloalkyl group, (5) a


C3-8 cycloalkoxy group, (6) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 halogen atoms or Cl-6 alkyl groups), (7) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be 5 substituted with 1 to 3 halogen atoms), (8) an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), and (9) a 5- to 14-membered non-aromatic heterocyclic group.
35) The compound or pharmacologically acceptable salt thereof according to above 1) selected from the following group:
1) (E)-N-biphenyl-3-ylmethyl-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylamide,
2) (E)-N-((lS)-indan-l-yl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl)acrylamide,
3) (E)-N-(chroman-4-yl)-3-(3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl)acrylamide,
4) (E)-1-(3,4-difluorobenzyl)-3-(3-methoxy-4-(4-methyl-
IH-imidazol-l-yl)benzylidene)piperidin-2-one,
5) (E)-l-indan-2-yl-3-(3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene)piperidin-2-one,
6) (E)-1-(chroman-4-yl)-3-(3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene)piperidin-2-one,
7) (E)-1-((lS)-l-(4-fluorophenyl)ethyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)piperidin-2-one, 8) (E)-1-((6-chloropyridin-2-yl)methyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)piperidin-2-one,


9) (E)-1- (4-tert-butylbenzyl)-3-(3-methoxy-4-(4-methyl-
IH-imidazol-l-yl)benzylidene)piperidin-2-one,
10) (E)-l-(3,4-difluorobenzyl)-3-((5-methoxy-6-(4-
methyl-lH-imidazol-1-yl)pyridin-3-yl) methylene)
piperidin-2-one,
11) (E)-1-( (lH-indol-3-yl)ethyl)-3-(3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene)piperidin-2-one,
12) (E)-l-(5-fluoroindan-2-yl)-3-(3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene)piperidin-2-one,
13) (E)-1-(7-fluorochroman-4-yl)-3-(3-methoxy-4- (4-methyl-lH-imidazol-1-yl)benzylidene)piperidin-2-one, 14) (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-1-(1,2,3,4-tetrahydronaphthalen-2-yl) piperidin-2-one and
15) (E)-l-((2,4-difluorophenyl)ethyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)piperidin-2-one.
36) A preventive or therapeutic agent for a
disease resulting from amyloid betas comprising a
compound represented by general formula (I) or
pharmacologically acceptable salt thereof as an active ingredient.
37) The preventive or therapeutic agent according
to above 36) wherein the disease resulting from amyloid
betas is Alzheimer's disease, senile dementia, Down
syndrome or amyloidosis.
The compound of the general formula (I) of the present invention or pharmacologically acceptable salt thereof and preventive or therapeutic agent of


diseases caused by Afis are new inventions not described in documents. [0007]
Hereinbelow, symbols, terms and the like used 5 in the present specification are explained and the present invention is described in detail. [0008]
Although a structural formula of a compound may express a certain isomer for the sake of 10 convenience in the present specification, the present invention encompasses all the isomers such as geometric isomers which can be generated from the structure of a compound, optical isomers based on chiral carbon (s), stereoisomers and tautomers and a mixture of isomers 15 and the invention is not limited to the formula
described for the sake of convenience and may be either one of isomers or mixtures thereof. Therefore, although some molecules may have a chiral carbon atom therein and there may be an optically-active substance 20 and racemate, the present invention is not limited to a certain one of them and includes either one of them. Furthermore, crystal polymorphs, which may exist, are not limited, and may be either one of single crystal type thereof or a mixture thereof, and may be hydrate 25 or may be an anhydride. [0009]
The term "disease (s) caused by A(3" encompasses a wide variety of diseases includeing

Alzheimer's disease (for example, see Klein WL, and seven others, Alzheimer's disease-affected brain: presence of oligomeric AP ligands (ADDLs) suggests a molecular basis for reversible memory loss, Proceeding 5 National Academy of Science USA, 2003, Sep 2, 100(18), p. 10417-10422;
Nitsch RM, and 16 others, Antibodies against p-amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22, 38(4), p. 547-554;
Jarrett JT, and 2 others, The carboxy terminus of the p amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry, 1993, May 11, 32(18), p. 4693-4697;
Glenner GG, and another, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem Biophys Res Commun, 1984, May 16, 120(3), p. 885-890; Masters CL, and six others, Amyloid plaque core protein
in Alzheimer disease and Down syndrome, Proceeding
National Academy of Science USA, 1985, Jun, 82(12), p.
4245-4249;
Gouras GK, and eleven others, Intraneuronal Ap42
accumulation in human brain, American Journal of
Pathology, 2000, Jan, 156(1), p. 15-20;
Scheuner D, and twenty others, Secreted amyloid p-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the


presenilin I and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2(8), p. 864-870; and
Forman MS, and 4 others, Differential effects of the 5 Swedish mutant amyloid precursor protein on (3-amyloid accumulation and secretion in neurons and nonneuronal cells, Journal of Biological Chemistry, 1997, Dec 19, 272(51), p. 32247-32253.), senile dementia (for example, see Blass JP, Brain metabolism and brain
disease: is metabolic deficiency the proximate cause of Alzheimer dementia? Journal of Neuroscience Research, 2001, Dec 1, 66(5), p. 851-6.), frontotemporal dementia (for example, see Evin G, and eleven others, Alternative transcripts of presenilin-1 associated with
frontotemporal dementia, Neuroreport, 2002, Apr 16, 13(5), p. 719-723.), Pick disease (for example, see Yasuhara 0, and three others, Accumulation of amyloid precursor protein in brain lesions of patients with Pick disease, Neuroscience Letters, 1994, Apr 25,
171(1-2), p. 63-66.), Down syndrome (for example, see Teller JK, and ten others, Presence of soluble amyloid p-peptide precedes amyloid plaque formation in Down's syndrome, Nature Medicine, 1996, Jan, 2(1), p. 93-95; and
Tokuda T, arid six others, Plasma levels of amyloid p proteins A|31-40 and A(31-42(43) are elevated in Down's syndrome, Annals of Neurology, 1997, Feb, 41(2), p. 271-273.), cerebral amyloid angiopathy (for example,

see Hayashi Y, and nine others, Evidence for presenilin-1 involvement in amyloid angiopathy in the Alzheimer's disease-affected brain, Brain Research, 1998, Apr 13, 789(2), p. 307-314;
Barelli H, and fifteen others, Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid (3 peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease
and cerebral amyloid angiopathy cases, Molecular Medicine, 1997, Oct, 3(10), p. 695-707; Calhoun ME, and ten others, Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid, Proceeding
National Academy of Science USA, 1999, Nov 23, 96(24), p. 14088-14093; and
Dermaut B, and ten others, Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation, Brain, 2001, Dec, 124(Pt
12), p. 2383-2392.), hereditary cerebral hemorrhage with amyloidosis-Dutch type (for example, see Cras P, and nine others, Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly
mutation, Acta Neuropathologica (Berl), 1998, Sep, 96(3), p. 253-260;
Herzig MC, and fourteen others, A(3 is targeted to the vasculature in a mouse model of hereditary cerebral


hemorrhage with amyloidosis, Nature Neuroscience, 2004, Sep, 7(9), p. 954-960;
Van Duinen SG, and five others, Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin 5 is related to Alzheimer disease, Proceeding National Academy of Science USA, 1987, Aug, 84(16), p. 5991-5994; and
Levy E, and eight others, Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage,
Dutch type, Science, 1990, Jun 1, 248(4959), p. 1124-1126.), cognitive impairment (for example, see Laws SM, and seven others, Association between the presenilin-1 mutation Glu318Gly and complaints of memory impairment, Neurobiology of Aging, 2002, Jan-Feb, 23(1), p. 55-
58.), memory disorder/ learning disorder (for example, see Vaucher E, and five others, Object recognition memory and cholinergic parameters in mice expressing human presenilin 1 transgenes, Experimental Neurology, 2002, Jun, 175(2), p. 398-406;
Morgan D, and fourteen others, A|3 peptide vaccination prevents memory loss in an animal model of Alzheimer's disease, Nature, 2000, Dec 21-28, 408(6815), p. 982-985; and Moran PM, and three others, Age-related learning
deficits in transgenic mice expressing the 751-amino acid isoform of human (3-amyloid precursor protein, Proceeding National Academy of Science USA, 1995, Jun 6, 92(12), p. 5341-5345.), amyloidosis, cerebral


ischemia (for example, see Laws SM, and seven others, Association between the presenilin-1 mutation Glu318Gly and complaints of memory impairment, Neurobiology of Aging, 2002, Jan-Feb, 23(1), p. 55-58; 5 Koistinaho M, and ten others, (3-amyloid precursor
protein transgenic mice that harbor diffuse A(3 deposits but do not form plaques show increased ischemic vulnerability: role of inflammation, Proceeding National Academy of Science USA, 2002, Feb 5, 99(3), p.
1610-1615; and
Zhang F, and four others, Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein, Journal of Neuroscience, 1997, Oct 15, 17(20), p. 7655-7661.), vascular dementia
(for example, see Sadowski M, and six others, Links between the pathology of Alzheimer's disease and vascular dementia, Neurochemical Research, 2004, Jun, 29(6), p. 1257-1266.), ophthalmoplegia(eye muscle paralysis) (for example, see O'Riordan S, and seven
others, Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities, Neurology, 2002, Oct 8, 59(7), p. 1108-1110.), multiple sclerosis (for example, see Gehrmann J, and four others, Amyloid precursor protein (APP)
expression in multiple sclerosis lesions, Glia, 1995, Oct, 15(2), p. 141-151; and
Reynolds, WF, and six others, Myeloperoxidase polymorphism is associated with gender specific risk


for Alzheimer's disease, Experimental Neurology, 1999, Jan, 155(1), p. 31-41.), head trauma, cranial damage (for example, see Smith DH, and four others, Protein accumulation in traumatic brain injury, Neuromolecular 5 Medicine, 2003, 4(1-2), p. 59-72.), apraxia (for example, see Matsubara-Tsutsui M, and seven others, Molecular evidence of presenilin 1 mutation in familial early onset dementia, American Journal of Medical Genetics, 2002, Apr 8, 114(3), p. 292-298.), prion
disease, familial amyloid neuropathy, triplet repeat disease (for example, see Kirkitadze MD, and two others, Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies, Journal of Neuroscience
Research, 2002, Sep 1, 69(5), p. 567-577;
Evert BO, and eight others, Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains, Journal of Neuroscience, 2001, Aug 1, 21(15), p. 5389-5396; and
Mann DM, and another, Deposition of amyloid (A4)
protein within the brains of persons with dementing disorders other than Alzheimer's disease and Down's syndrome, Neuroscience Letters, 1990, Feb 5, 109(1-2), p. 68-75.), Parkinson's disease (for example, see
Primavera J, and four others, Brain Accumulation of Amyloid-p in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, Oct, 1(3), p. 183-193.), Dementia with Lewy bodies (for example, see Giasson BI,


and two others, Interactions of amyloidogenic proteins, Neuromolecular Medicine, 2003, 4(1-2), p. 49-58; Masliah E, and six others, (3-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a 5 transgenic mouse model linking Alzheimer's disease and Parkinson's disease, Proceeding National Academy of Science USA, 2001, Oct 9, 98(21), p. 12245-12250; Barrachina M, and six others, Amyloid-p deposition in the cerebral cortex in Dementia with Lewy bodies is
accompanied by a relative increase in A|3PP mRNA
isoforms containing the Kunitz protease inhibitor, Neurochemistry International, 2005, Feb, 46(3), p. 253-260; and Primavera J, and four others, Brain Accumulation of
Amyloid-p in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, Oct, 1(3), p. 183-193.), Parkinsonism-dementia complex (PDC) (for example, see Schmidt ML, and six others, Amyloid plaques in Guam amyotrophic lateral sclerosis/parkinsonism-dementia
complex contain species of A(3 similar to those found in the amyloid plaques of Alzheimer's disease and pathological aging, Acta Neuropathologica (Berl), 1998, Feb, 95(2), p. 117-122; and Ito H, and three others, Demonstration of (3 amyloid
protein-containing neurofibrillary tangles in
parkinsonism-dementia complex on Guam, Neuropathology and Applied Neurobiology, 1991, Oct, 17(5), p. 365-373.), frontotemporal dementia-parkinsonism linked to


chromosome 17 (FTDP-17) (for example, see Rosso SM, and three others, Coexistent tau and amyloid pathology in hereditary frontotemporal dementia with tau mutations, Annals of the New York Academy of Science, 2000, 920, 5 p. 115-119.), dementia with argyrophilic grains (for example, see Tolnay M, and four others, Low amyloid (A(3) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease, Neuropathology and Applied
Neurobiology, 1999, Aug, 25(4), p. 295-305.), Niemann-Pick disease (for example, see Jin LW, and three others, Intracellular accumulation of amyloidogenic fragments of amyloid-p precursor protein in neurons with Niemann-Pick type C defects is associated with
endosomal abnormalities, American Journal of Pathology, 2004, Mar, 164(3), p. 975-985.), amyotrophic lateral scleraosis (for example, see Sasaki S, and another, Immunoreactivity of (3-amyloid precursor protein in amyotrophic lateral sclerosis, Acta Neuropathologica
(Berl), 1999, May, 97(5), p. 463-468;
Tamaoka A, and four others, Increased amyloid p protein in the skin of patients with amyotrophic lateral sclerosis, Journal of Neurology, 2000, Aug, 247(8), p. 633-635;
Hamilton RL, and another, Alzheimer disease pathology in amyotrophic lateral sclerosis, Acta Neuropathologica (Berl), 2004, Jun, 107(6), p. 515-522; and Turner BJ, and six others, Brain (3-amyloid accumulation


in transgenic mice expressing mutant superoxide dismutase 1, Neurochemical Research, 2004, Dec, 29(12), p. 2281-2286.), hydrocephalus (for example, see Weller RO, Pathology of cerebrospinal fluid and interstitial 5 fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis, Journal of Neuropathology and Experimental Neurology, 1998, Oct, 57 (10), p. 885-894; Silverberg GD, and four others, Alzheimer's disease,
normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis, Lancet Neurology, 2003, Aug, 2(8), p. 506-511; Weller RO, and three others, Cerebral amyloid angiopathy: accumulation of A3 in interstitial fluid
drainage pathways in Alzheimer's disease, Annals of the New York Academy of Sciences, 2000, Apr, 903, p. 110-117;
Yow HY, and another, A role for cerebrovascular disease in determining the pattern of (3-amyloid deposition in
Alzheimer's disease, Neurology and applied neurobiology, 2002, 28, p. 149; and
Weller RO, and four others, Cerebrovascular disease is a major factor in the failure of elimination of A from the aging human brain, Annals of the New York Academy
of Sciences, 2002, Nov, 977, p.162-168.), incomplete parapalegia (for example, see O'Riordan S, and seven others, Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter


abnormalities, Neurology, 2002, Oct 8, 59(7), p. 1108-10;
Matsubara-Tsutsui M, and seven others, Molecular evidence of presenilin 1 mutation in familial early 5 onset dementia, American Journal of Medical Genetics, 2002, Apr 8, 114(3), p. 292-8;
Smith MJ, and eleven others, Variable phenotype of Alzheimer's disease with spastic paraparesis, Ann Neurol. 2001 Jan, 49(1), p. 125-129; and
Crook R, and seventeen others, A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1, Nature Medicine, 1998, Apr, 4(4), p.452-455.), progressive supranuclear palsy (PSP) (for example, see Masliah E,
and six others, p-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease, Proceeding National Academy of Science USA, 2001,Oct 9, 98(21), p. 12245-12250; and
Primavera J, and four others, Brain Accumulation of Amyloid-p in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, Oct, 1(3), p. 183-193.), cerebral hemorrhage (for example, see Atwood CS, and three others, Cerebrovascular requirement for sealant,
anti-coagulant and remodeling molecules that allow for the maintenance of vascular integrity and blood supply, Brain Research Review, 2003 Sep, 43(1), p. 164-178; and Lowenson JD, and 2 others, Protein Aging: Extracellular


amyloid formation and intracellular repair, Trends in Cirdiovascular medicine, 1994, 4(1), p. 3-8.), spasm (for example, see Singleton AB, and thirteen others, Pathology of early-onset Alzheimer's disease cases 5 bearing the Thrll3-114ins presenilin-1 mutation, Brain, 2000, Dec, 123 Pt 12, p. 2467-2474.), mild cognitive impairment (for example, see Gattaz WF, and four others, Platelet phospholipase A(2) activity in Alzheimer's disease and mild cognitive impairment,
Journal of Neural Transmission, 2004, May, 111(5), p. 591-601; and
Assini A, and four others, Plasma levels of amyloid (3-protein 42 are increased in women with mild cognitive impairment, Neurology, 2004, Sep 14, 63(5), p. 828-
831.), atherosclerosis (for example, see De Meyer GR, and eight others, Platelet phagocytosis and processing of p-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis, Circulation Research, 2002, Jun 14, 90(11), p. 1197-1204.), etc.
[0010]
The "6- to 14-membered aromatic hydrocarbon ring group," "5- to 14-membered aromatic heterocyclic group," "6- to 14-membered non-aromatic hydrocarbon ring group" and "5- to 14-membered non-aromatic
heterocyclic group" in the above-mentioned formula (I) contained in the therapeutic or preventive agent of diseases caused by Aps according to the present invention have the following meanings.

[0011]
The "6- to 14-membered aromatic hydrocarbon ring group" means a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon 5 atoms and preferable groups include a monocyclic, bicyclic or tricyclic 6- to 14-membered aromatic hydrocarbon ring group, for example, a phenyl group, an indenyl group, a naphthyl group, an azulenyl group, a heptalenyl group, a biphenyl group, a fluorenyl group,
a phenalenyl group, a phenanthrenyl group, an anthracenyl group, etc. [0012]
The "5- to 14-membered aromatic heterocyclic group" refers to a monocyclic, bicyclic or tricyclic
aromatic heterocyclic group having 5 to 14 atoms and preferable groups include, for example, (1) nitrogen-containing aromatic heterocyclic groups such as a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a pyrazolinyl
group, an imidazolyl group, an indolyl group, an isoindolyl group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl group, a naphthylizinyl group, a quinoxalinyl group, a
quinazolinyl group, a cinnolinyl group, a pteridinyl
group, an imidazotriazinyl group, a pyrazinopyridazinyl group, an acridinyl group, a phenantholizinyl group, a carbazolyl group, a perimidinyl group, a


phenanthrolinyl group and a phenacyl group; (2) sulfur-containing aromatic heterocyclic groups such as a thienyl group and a benzothienyl group; (3) oxygen-containing aromatic heterocyclic groups such as a furyl 5 group, a pyranyl group, a cyclopentapyranyl group, a benzofuranyl group and an isobenzofuranyl group; (4) aromatic heterocyclic groups containing two or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom such
as a thiazolyl group, an isothiazolyl group, a
benzothiazolyl group, a benzothiadiazolyl group, a phenothiazinyl group, an isoxazolyl group, a furazanyl group, a phenoxazinyl group, a pyrazoloxazolyl group, imidazothiazolyl group, a thienofuryl group, a
furopyrrolyl group, a pyridoxazinyl group, etc. [0013]
The "6- to 14-membered non-aromatic
hydrocarbon ring group" refers to a cyclic, aliphatic hydrocarbon group having 6 to 14 carbon atoms, and
means, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a spiro[3.4]octanyl group, a decanyl group, an indanyl group, 1-acenaphthenyl group, a cyclopentacyclooctenyl
group, a benzocyclooctenyl group, an indenyl group, a tetrahydronaphthyl group, a 6,7,8,9-tetrahydro-5H-benzocycloheptenyl group, 1,4-dihydronaphthalenyl group and the other cyclic, aliphatic hydrocarbon groups


having 6 to 14 carbon atoms. [0014]
The "5- to 14-membered non-aromatic
heterocyclic group" means not only a 5- to 14-membered 5 non-aromatic hetero monocyclic group but also a
saturated heterocyclic group condensed with aromatic hydrocarbon ring groups, or a saturated hydrocarbon ring group or a saturated heterocyclic group condensed with aromatic heterocyclic group(s), which 1) has 5 to 10 14 ring-constituting atoms, 2) contains 1 to 5 hetero atoms such as a nitrogen atom, -0- or -S- in the ring-constituting atoms and 3) may contain one or more carbonyl groups, double bonds, or triple bonds in the ring. Specific examples of 5- to 14-membered non-15 aromatic heterocyclic group include an azetidinyl ring, a pyrrolidinyl ring, a piperidinyl ring, an azepanyl ring, an azocanyl ring, a tetrahydrofuranyl ring, a tetrahydropyranyl ring, a morpholinyl ring, a thiomorpholinyl ring, a piperazinyl ring, a
thiadiazolidinyl ring, a dioxanyl ring, an imidazolinyl ring, a thiadiazolinyl ring, 1,2-benzopyranyl ring, an isochromanyl ring, a chromanyl ring, an indolinyl ring, an isoindolinyl ring, an azaindanyl group, an azatetrahydronaphthyl group, an azachromanyl group, a 25 tetrahydrobenzofuranyl group, a tetrahydrobenzothienyl group, a 2,3,4,5- tetrahydrobenzo[b]thienyl group, a 3,4-dihydro-2H--benzo [b] [1,4] dioxepinyl group, an indan-1-onyl group, a 6,7-dihydro-5H-

cyclopentapyrazinyl group, a 6,7-dihydro-5H-[1]-pyridinyl group, a 6,7-dihydro-5H-[1]-pyridinyl group, a 5,6-dihydro-4H-cyclopenta[b]thienyl group, a 4,5,6,7-tetrahydro-benzo[b]thienyl group, a 3,4-dihydro-2H-5 naphthale-1-onyl group, a 2,3-dihydro-isoindol-l-onyl group, a 3,4-dihydro-2H-isoquinoline-l-onyl group, a 3,4-dihydro-2H-benzo[1,4]oxapinyl group, etc. [0015]
The substituent group Al, substituent group
A2, substituent group A3, substituent group A4,
substituent group A5, substituent group A6, substituent group A7, substituent group A8, substituent group A9 and substituent group A10 represent the following groups.
Substituent Group Al refers to (I) a hydrogen
atom, (2) a halogen atom, (3) a cyano group, (4) a nitro group, (5) a C3-8 cycloalkyl group, (6) a C2-6 alkenyl group, (7) a C2-6 alkynyl group, (8) a Cl-6 alkoxy group, (9) a C3-8 cycloalkoxy group, (10) a
formyl group, (11) a Cl-6 alkylcarbonyl group, or (12) a Cl-6 alkyl group (wherein the above described Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a Cl-6 alkoxy group, a
C3-8 cycloalkyl group and a Cl-6 alkylcarbonyl group).
Substituent Group A2 refers to (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a Cl-6 alkoxy group (wherein the Cl-6


alkoxy group may be substituted with I to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a Cl-6 alkoxy group, a C2-6 alkeny group, a C2-6 alkyny group and a C3-8 5 cycloalkyl group), (6) a C3-8 cycloalkoxy group, (7) a C2-6 alkenyloxy group or (8) a C2-6 alkynyloxy group.
Substituent Group A3 refers to (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from
Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be
substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a Cl-6 alkoxy
group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl
group, a Cl-6 alkylsulfonyl group, a Cl-6 alkylcarbonyl group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from


Substituent Group A4, a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which 5 may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may
be substituted with 1 to 3 substituents selected from Substituent Group A4)) or (6) a Cl-6 alkoxy group.
Substituent Group A4 refers to (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl
group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl
group, (16) a hydroxyimino group, (17) a Cl-6
alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituents selected
from Substituent Group A4, (20) an amino group which may be substituted with 1 to 2 substituents selected from Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituents selected


from Substituent Group A4, (22) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituents selected from Substituent Group A4, (23) a 5- to 14-membered aromatic 5 heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (25) a 5- to 14-
membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) -X-A (wherein X
represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from
Substituent Group A4), (31) -CO-A (wherein A is the
same as defined above) or (32) =CH-A (wherein A is the same as defined above).
Substituent Group A5 refers to (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a
cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8
cycloalkoxy group, (7) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 5 halogen atoms) (8) a Cl-6 alkoxy group (wherein said alkoxy


group may be substituted with 1 to 5 halogen atoms) or (9) an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms).
Substituent Group A6 refers to (1) a hydrogen
atom, (2) a C3-8 cycloalkyl group, (3) a C3-8 cycloalkoxy group, (4) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a
halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkylthio group, a hydroxyimino group, a Cl-6 alkoxyimino group, a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with
Cl-6 alkyl groups optionally having 1 to 5 halogen
atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered aromatic heterocyclic group which may be
substituted with 1 to 3 substituents selected from
Substituent Group A7 shown below, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below and -0-A2 (wherein A2
represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below or a 5- to 14-membered aromatic heterocyclic


group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below)) or (5) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 3 substituents selected from 5 the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkylthio group, a hydroxyimino group, a Cl-6 alkoxyimino group, a Cl-6 alkoxy group, an amino group (wherein said amino
group may be substituted with Cl-6 alkyl groups
optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown
below and -0-A2 (wherein A2 is the same as defined above)).
Substituent Group A7 refers to (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8
cycloalkoxy group, (7) a Cl-6 alkylcarbonyl group, (8) a Cl-6 alkylthio group, (9) a Cl-6 alkylsulfinyl group, (10) a Cl-6 alkylsulfonyl group, (11) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted


with 1 to 5 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group, a 6-to 14-membered aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group and -0-A3 5 (wherein AJ represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group)), (12) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen atoms or may, together with a carbon atom to
which said adjacent Cl-6 alkoxy groups bind, form a
cyclic group), (13) an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), (14) a 6- to 14-membered aromatic hydrocarbon ring group which may
be substituted with 1 to 3 substituents selected from Substituent Group A7, (15) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (16) a 5- to 14-membered non-aromatic heterocyclic group which
may be substituted with 1 to 3 substituents selected from Substituent Group A7 or (17) -CO-A3 (wherein A3 is the same as defined above).
Substituent Group A8 refers to (1) a hydrogen atom, (2) Cl-6 alkyl group (wherein said Cl-6 alkyl
group may be substituted with 1 to 3 substituents
selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl


group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form 5 a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen
atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent
Group A7, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 and -X-A2 (wherein X represents an imino group, -0- or -S- and A2 represents a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7)), (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from
Substituent Group A7, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 or (5) -X-A2 (wherein X and A2 are the same as defined above) .


Substituent Group A9 refers to (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8 cycloalkyl group,
(4) a C3-8 cycloalkoxy group, (5) a Cl-6 alkyl group
(wherein said Cl-6 alkyl group may be substituted with
1 to 5 substituents selected from the group consisting of a halogen atom and a Cl-6 alkyl group), (6) a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy
groups bind, form a cyclic group), (7) an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), (8) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents
selected from Substituent Group A9, (9) -CO-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group), (10) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 or
(11) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9.
Substituent Group A10 refers to (1) a hydrogen atom, (2) a halogen atom, (3) a Cl-6 alkyl
group (wherein said Cl-6 alkyl group may be substituted with 1 to 5 halogen atoms), (4) a Cl-6 alkoxy group and
(5) a 6- to 14-membered aromatic hydrocarbon ring
group.

[0016]
The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., and preferably a fluorine atom, a chlorine atom 5 and a bromine atom. [0017]
The term "Cl-6 alkyl group" refers to an alkyl group having 1 to 6 carbon atoms and preferable groups include linear or branched alkyl groups, for 10 example, methyl group, ethyl group, n-propyl group,
iso-propyl group, n-butyl group, iso-butyl group, tert-butyl group, n-pentyl group, iso-pentyl group, neopentyl group, n-hexyl group, 1-methylpropyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, 1-15 methyl-2-ethylpropyl group, l-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group, 3-20 methylpentyl group, etc. [0018]
The term "Cl-6 alkoxy group" refers to a group in which a hydrogen atom has been substituted with an oxygen atom in an alkyl group having 1 to 6 25 carbon atoms and preferable groups include, for
example, methoxy group, ethoxy group, n-propoxy group, an i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group,


i-pentoxy group, sec-pentoxy group, tert-pentoxy group, n-hexoxy group, i-hexoxy group, 1,2-dimethylpropoxy group, 2-ethylpropoxy group, l-methyl-2-ethylpropoxy group, l-ethyl-2-methylpropoxy group, 1,1,2-5 trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group, 3-methylpentoxy group, a hexyloxy group, etc.
10 [0019]
The term "Cl-6 alkylsulfonyl group" refers to a group in which a hydrogen atom has been substituted with a sulfonyl group in an alkyl group having 1 to 6 carbon atoms and preferable groups include, for
example, methanesulfonyl group, ethanesulfonyl group, etc. [0020]
The term "amino group which may be substituted with Cl-6 alkyl groups" refers to an amino
group which may be substituted with alkyl groups having I to 6 carbon atoms and preferable groups include, for example, amino group, methylamino group, ethylamino group, propylamino group, dimethylamino group, etc. [0021]
The term "C2-6 alkenyl group" refers to an
alkenyl group having 2 to 6 carbon atoms and preferable groups include linear or branched alkenyl groups, for example, vinyl group, allyl group, 1-propenyl group,


isopropenyl group, 1-buten-l-yl group, l-buten-2-yl group, l-buten-3-yl group, 2-buten-l-yl group, 2-buten-2-yl group, etc. [0022]
The term "C2-6 alkynyl group" refers to an
alkynyl group having 2 to 6 carbon atoms and preferable groups include linear or branched alkynyl groups, for example, ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group, hexynyl group,
etc. [0023]
The term "C3-8 cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms and preferable groups include, for example, cyclopropyl
group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc. [0024]
The term "Cl-6 alkylthio group" refers to a group in which a hydrogen atom has been substituted
with a sulfur atom in an alkyl group having 1 to 6 carbon atoms and preferable groups include, for example, methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, tert-butylthio group, n-
pentylthio group, i-pentylthio group, neopentylthio group, n-hexylthio group, 1-methylpropylthio group, etc. [0025]


The term "Cl-6 alkylsulfinyl group" refers to a group in which a hydrogen atom has been substituted with a sulfinyl group in an alkyl group having 1 to 6 carbon atoms and preferable groups include, for 5 example, methylsulfinyl group, ethyl methylsulfinyl group, n-propylsulfinyl group, i-propylsulfinyl group, n-butylsulfinyl group, i-butylsulfinyl group, tert-butylsulfinyl group, n-pentylsulfinyl group, i-pentylsulfinyl group, neopentylsulfinyl group, n-
hexylsulfinyl group, 1-methyl propyl sulfinyl group, etc. [0026]
The term "Cl-6 alkylcarbonyl group" refers to a group in which a hydrogen atom has been substituted
with a carbonyl group in an alkyl group having 1 to 6 carbon atoms and preferable groups include, for example, acetyl group, propionyl group, butyryl group, etc. [0027]
The term "C3-8 cycloalkoxy group" refers to a
group in which a hydrogen atom has been substituted with an oxygen atom in a cyclic alkyl group having 3 to 8 carbon atoms and preferable groups include, for example, cyclopropoxy group, cyclobutoxy group,
cyclopentoxy group, cyclohexoxy group, cycloheptyloxy group, cyclooctyloxy group, etc. [0028]
The term "C3-8 cycloalkylthio group" refers


to a group in which a hydrogen atom has been substituted with a sulfur atom in a cyclic alkyl group having 3 to 8 carbon atoms and preferable groups include, for example, cyclopropylthio group, 5 cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cycloheptylthio group, cyclooctylthio group, etc. [0029]
The term "Cl-6 alkoxyimino group" refers to a
group in which a hydrogen atom, has been substituted with a Cl-6 alkoxy group in an imino group and preferable groups include, for example, methoxyimino group, ethoxyimino group, etc. [0030]
The term "C2-6 alkenyloxy group" refers to a
group in which a hydrogen atom has been substituted with an oxygen atom in an alkenyl group having 2 to 6 carbon atoms and preferable groups include linear or branched alkenyloxy groups, for example, vinyloxy
group, allyloxy group, 1-propenyloxy group,
isopropenyloxy group, 1-buten-l-yloxy group, l-buten-2-yloxy group, l-buten-3-yloxy group, 2-buten-l-yloxy group, 2-buten-2-yloxy group. [0031]
The term "C2-6 alkynyloxy group" refers to a
group in which a hydrogen atom has been substituted with an oxygen atom in an alkynyl group having 2 to 6 carbon atoms and preferable groups include linear or


branched alkynyloxy groups, for example, ethynyloxy group, 1-propynyloxy group, 2-propynyloxy group, butynyloxy group, pentynyloxy group, hexynyloxy group, etc. 5 [0032]
The term "C3-8 cycloalkylsulfinyl group" refers to a group in which a hydrogen atom has been substituted with a sulfinyl group in a cyclic alkyl group having 3 to 8 carbon atoms and preferable groups
include, for example, cyclopropylsulfinyl group,
cyclobutylsulfinyl group, cyclopentylsulfinyl group, cyclohexylsulfinyl group, cycloheptylsulfinyl group, cyclooctylsulfinyl group, etc. [0033]
The term "C3-8 cycloalkylsulfonyl group"
refers to a group in which a hydrogen atom has been substituted with a sulfonyl group in a cyclic alkyl group having 3 to 8 carbon atoms and preferable groups include, for example, cyclopropylsulfonyl group,
cyclobutylsulfonyl group, cyclopentylsulfonyl group, cyclohexylsulfonyl group, cycloheptylsulfonyl group, cyclooctylsulfonyl group, etc. [0034]
Preferable examples of "hydroxyl group having
a protecting group" include methoxymethyl ether group, tetrahydropyranyl ether group, tert-butyl ether group, allyl ether group, benzoate group, acetate group, formate group, crotonate group, p-phenylbenzoate group


or pivaloate group, tert-butydimethyl silyl group, tert-butyldiphenyl silyl group, trityl group, benzyl group, etc. [0035]
Preferable examples of Cl-6 alkoxy group in
"Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 5 halogen atoms or may, together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind, form a cyclic group)" include a Cl-
6 alkoxy group substituted with 1 to 5 halogen atoms or a cyclic group can be formed together with a carbon atom to which said adjacent Cl-6 alkoxy groups bind. The expression "a cyclic group can be formed together with a carbon atom to which said adjacent Cl-6 alkoxy
groups bind" means, for example, a methylenedioxy group, ethylenedioxy group, etc. and it can be specifically illustrated by, for example, a formula: [0036] [Formula 21]
and the like.
[0037]
The substituent in a "Cl-6 alkyl group
(wherein I or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene group and said two Cl-6 alkyl groups may, together with the


carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom))" can be specifically illustrated by, for 5 example, a formula: [0038] [Formula 22]
(Figure Remove)





and the like. [0039]
Next, the compound of Formula (I) of the present invention is described.
Among the compounds represented by Formula
(I), preferred is a compound or a pharmacologically acceptable salt thereof in which Ari is an imidazolyl group which may be substituted with 1 to 2 substituents selected from Substituent Group Al;
more preferred is a compound or a pharmacologically acceptable salt thereof in which Ari is an imidazolyl group which may be substituted with 1 to 2 substituents selected from a hydrogen atom, a halogen atom, a C3-8 cycloalkyl group, a C2-6 alkeny group, a C2-6 alkyny
group and a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 halogen atoms); and the most preferred is a compound or a pharmacologically


acceptable salt thereof in which Ari is an imidazolyl group which may be substituted with 1 to 2 substituents selected from the group consisting of a hydrogen atom, a halogen atom, a C3-8 cycloalkyl group and a Cl-6 5 alkyl group. [0040]
Among the compounds represented by Formula (I), preferred is a compound or a pharmacologically acceptable salt thereof in which Ar2 is a pyridinyl
group, a pyrimidinyl group, or a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A2;
more preferred is a compound or a pharmacologically acceptable salt thereof in which Ar2 is a pyridinyl
group, a pyrimidinyl group or a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be
substituted with 1 to 3 substituents selected from a C2-6 alkeny group, a C2-6 alkyny group and a C3-8 cycloalkyl group), a C2-6 alkenyloxy group and a C2-6 alkynyloxy group; and the most preferred is a compound or a pharmacologically
acceptable salt thereof in which Ar2 is a pyridinyl
group, a pyrimidinyl group or a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of (1) a hydrogen atom, (2) a


halogen atom, (3) a cyano group and (4) a Cl-6 alkoxy group. [0041]
Among the compounds represented by Formula (I), preferred is a compound or a pharmacologically
acceptable salt thereof in which Xi represents (1) -C=C-or (2) -CR3=CR4- (wherein R3 and R4 represents a substituent selected from Substituent Group A3; more preferred is a compound or a pharmacologically 10 acceptable salt thereof in which Xi is -CR31=CR41-(wherein R31 is a group selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a Cl-6 alkyl group and (4) a Cl-6 alkoxyl group; and R41 represents a group selected from the group 15 consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A5, (4) a 5- to 14-membered aromatic heterocyclic group which may be 20 substituted with 1 to 3 substituents selected from Substituent Group A5 and (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a 25 C3-8 cycloalkyl group, a Cl-6 alkyl group, a Cl-6
alkoxy group, an amino group (wherein said amino group may be substituted with Cl-6 alkyl groups optionally having 1 to 5 halogen atoms), a 6- to 14-membered


aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A5, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 5 substituents selected from Substituent Group A5, a 5-to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5 and -0-A1 (wherein A1 represents a 6- to 14-membered aromatic hydrocarbon
ring group which may be substituted with 1 to 3
substituents selected from Substituent Group A5 or a 5-to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5))); and
the most preferred is a compound or a pharmacologically acceptable salt thereof in which Xi is -CR32=CR42-(wherein R32 represents a hydrogen atom or a halogen atom, and R42 represents a Substituent selected from the group consisting of a hydrogen atom, a halogen atom and
a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with a C3-8 cycloalkyl group or a phenyl group) and a phenyl group). [0042]
Among the compounds represented by Formula
(I), a compound or a pharmacologically acceptable salt thereof in which R1 and R2 represent groups selected from Substituent Group A4 or the group formed by R1 and R2, together with a nitrogen atom is a 5- to 11-membered


heterocyclic group represented by Formula (II) which may be substituted with 1 to 4 substituents selected from Substituent Group A4;, a 6- to 20-membered non-aromatic heterocyclic group represented by Formula 5 (III) which may be substituted with 1 to 4 substituents selected from Substituent Group A4, a 9- to 16-membered non-aromatic heterocyclic group represented by Formula (IV) which may be substituted with 1 to 4 substituents selected from Substituent Group A4, a group represented 10 by the following formula: [Formula 23]
(Figure Remove)





which may be substituted with 1 to 4 substituents selected from Substituent Group A4, a group represented by the following formula: [Formula 24] (Figure Remove)











which may be substituted with 1 to 4 substituents selected from Substituent Group A4, a cyclic group represented by Formula (V) which may be substituted with 1 to 4 substituents selected from Substituent 5 Group A4, a cyclic group represented by Formula (VI) which may be substituted with 1 to 4 substituents selected from Substituent Group A4 and a cyclic group represented by the following formula:
[Formula 25] (Figure Remove)


which may be substituted with 1 to 4 substituents 10 selected from Substituent Group A4 can be exemplified
as a preferable compound.
[0043]
Among the compounds represented by Formula
(I), preferred is a compound or a pharmacologically 15 acceptable salt thereof in which R1 and R2 are groups
selected from Substituent Group A4;
more preferred is a compound or a pharmacologically
acceptable salt thereof in which R1 is a group selected
from Substituent Group A8 and R2 is a group selected 20 from Substituent Group A6; and
the most preferred is a compound or a pharmacologically
acceptable salt thereof in which R1 is a Cl-6 alkyl


group (wherein said Cl-6 alkyl group is a hydrogen atom, a C3-8 cycloalkoxy group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene group and 5 said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, a 6- to 14-membered 10 aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from Substituent Group A9, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and -CD-IS A4 (wherein A4 represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9)}, and R2 is (1) a hydrogen atom or (2) a Cl-6 alkyl group 20 (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a Cl-6 alkylthio group, an amino group (wherein said amino group may be substituted with 25 a Cl-6 alkyl group optionally having 1 to 5 halogen atoms) , a 6- to 14-rnembered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9, a 5- to 14-membered


aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 5 substituents selected from Substituent Group A9). [0044]
Among the compounds represented by Formula (I), a 5- to 11-membered heterocyclic group represented by Formula (II) formed by R1 and R2, together with a
nitrogen atom to which they bind, refers to a hetero atom containing cyclic group having 5 to 11 total members and preferable examples include a piperidinyl group, a pyrrolidinyl group, an azepinyl group, an azocanyl group, a piperazinyl group, a 1,4-diazepanyl
group, a morpholinyl group or a thiomorpholinyl group.
Among the compounds represented by Formula (I), preferred is a compound or a pharmacologically acceptable salt thereof in which R1 and R2 form a 5- to 11-membered heterocyclic group represented by Formula
(II), together with a nitrogen atom to which they bind, which may be substituted with 1 to 4 substituents selected from Substituent Group A4;
more preferred is a compound or a pharmacologically acceptable salt thereof in which R1 and R2 form a 5- to
11-membered heterocyclic group represented by Formula (II), together with a nitrogen atom to which they bind, which may be substituted with 1 to 4 substituents selected from the group consisting of a hydrogen atom,


a halogen atom, a hydroxyl group, a formyl group, a hydroxyimino group, a Cl-6 alkoxyimino group, a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the 5 group consisting of a hydroxyl group, a 6- to 14-
membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered aromatic heterocyclic group which may be substituted
with 1 to 3 substituents selected from Substituent Group A7 shown below), 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from substituents of A7 shown below, a 5- to 14-membered aromatic heterocyclic
group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, -0-A2 (wherein A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7
shown below or a 5- to 14-membered aromatic
heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below), -CO-A2 (wherein A2 is the same as defined above) and =CH-A2 (wherein A2 is the same as defined above) ;
and
the most preferred is a compound or a pharmacologically acceptable salt thereof in which R1 and R2 form a 5- to 11-membered heterocyclic group represented by Formula


(II), together with a nitrogen atom to which they bind, which may be substituted with 1 to 4 substituents selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a Cl-6 alkyl group 5 (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group or a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A10),
a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from substituents of A10, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent
Group A10, -0-A6 (wherein A6 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group AID shown below) and =CH-A6 (wherein A6 is the same as defined above).
[0045]
Among the compounds represented by Formula (I), the "6- to 20-membered non-aromatic heterocyclic group" represented by Formula (III) formed by R1 and R2' together with a nitrogen atom to which they bind, refers
to a hetero atom containing spiro cyclic group having 6 to 20 total members and preferable examples include


[Formula 26]
(Figure Remove)






and the like.
In addition, among the compounds represented by Formula (I), preferred is a compound or a pharmacologically acceptable salt thereof in which R1 5 and R2 form a 6- to 20-membered non-aromatic
heterocyclic group represented by Formula (III), together with a nitrogen atom to which they bind, which may be substituted with 1 to 4 substituents selected from Substituent Group A4.
[0046]
Among the compounds represented by Formula (I), preferred is a compound in which the group formed by R1 and R2, together with a nitrogen atom to which they bind is a 9- to 16-membered non-aromatic
heterocyclic group represented by Formula (IV) which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4 or a pharmaceutically acceptable salt thereof.
The "9- to 16-membered non-aromatic
heterocyclic group" represented by Formula (IV) refers


to a hetero atom containing cyclic group having 9 to 16 members in total. [0047]
Among the compounds represented by Formula 5 (I), preferred is a compound in which the group formed by R1 and R2, together with a nitrogen atom to which they bind, is a group represented by the following formula : [Formula 27] (Figure Remove)



which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4 or a
pharmaceutically acceptable salt thereof.
[0048]
Among the compounds represented by Formula
(I) , preferred is a compound in which the group formed by R1 and R2, together with a nitrogen atom to which
they bind, is a group represented by the following
formula:

[Formula 28]
(Figure Remove)






which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4 or a pharmaceutically acceptable salt thereof.
Among the compounds represented by Formula 5 (I), more preferred is a compound in which R1 and R2, together with a nitrogen atom to which they bind, form a group represented by the following formula: [Formula 29]
(Figure Remove)




which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4 or a 10 pharmaceutically acceptable salt thereof.
Among the compounds represented by Formula (I), preferred is a compound in which the group formed

by R1 and R2, together with a nitrogen atom to which
they bind, may be substituted with 1 to 4 substituent
groups selected from Substituent Group A4 or a
pharmaceutically acceptable salt thereof.
Among the compounds represented by Formula
(I), more preferred is a compound in which the group formed by R1 and R2, together with a nitrogen atom to which they bind, may be substituted with 1 to 4 fluorine atoms and the like or a pharmaceutically
acceptable salt thereof. [0049]
Among the compounds represented by Formula (I), preferred is a compound in which the group formed by R1 and R2, together with -Xr-CO-N, is a cyclic group
(wherein R7 represents a substituent selected from substituent Group A3) represented by Formula (V) in which may be substituted with 1 to 4 substituents selected from Substituent Group A4 or a pharmaceutically acceptable salt thereof.
[0050]
Among the compounds represented by Formula (I), preferred is a compound in which the group formed by R1 and R2, together with -Xi-CO-N, is a cyclic group represented by Formula (VI) in which may be substituted
with 1 to 4 substituents selected from Substituent
Group A4 (wherein Rl represents a substituent selected from Substituent Group A4, and R7 represents a substituent selected from Substituent Group A3) or a
pharmaceutically acceptable salt thereof.
Among the compounds represented by Formula (I), more preferred is a compound in which the group formed by R1 and R2, together with -Xi-CO-N, is a cyclic 5 group represented by the following formula: [Formula 30]
(Figure Remove)





which may be substituted with 1 to 4 substituent groups selected from Substituent Group A7 (wherein, Rl represents a substituent selected from Substituent Group A4, and R7 represents Substituent Group A3) or a
pharmaceutically acceptable salt thereof.
Among the compounds represented by Formula (I), preferred is a compound in which R1 in the above described cyclic group is a substituent selected from Substituent Group A4 or a pharmaceutically acceptable
salt thereof.
Among the compounds represented by Formula (I), more preferred is a compound in which R1 in the above described cyclic group is a substituent selected from Substituent Group A8 or a pharmaceutically118 acceptable salt thereof.
Among the compounds represented by Formula (I), the most preferred is a compound in which R1 in the above described cyclic group is a substituent selected 5 from the group consisting of a Cl-6 alkyl group
(wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituent groups selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group,
a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form a cyclic group
(wherein a methylene group in the cyclic group which
constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to
14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9,
a 5- to 14-membered non-aromatic heterocyclic group
which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9 and -X-A4 (wherein X represents an imino group, -0- or -S- and A4 represents
a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9 or 5- to 14-membered aromatic heterocyclic group which may be substituted 5 with 1 to 3 substituent groups selected from
Substituent Group A9)) or a pharmaceutically acceptable
salt thereof.
[0051]
Among the compounds represented by Formula 10 (I)/ preferred is a compound in which the group formed by R1 and R2, together with -Xi-CO-N, is a cyclic group represented by the following formula: [Formula 31]
(Figure Remove)




which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4 or a 15 pharmaceutically acceptable salt thereof.
Among the compounds represented by Formula (I), preferred is a compound in which R1 in the above described cyclic group is a substituent selected from Substituent Group A4 or a pharmaceutically acceptable 20 salt thereof.
Among the compounds represented by Formula120
(I), more preferred is a compound in which R1 in the
above described cyclic group is a substituent selected
from Substituent Group A8 or a pharmaceutically
acceptable salt thereof.
Among the compounds represented by Formula
(I), the most preferred is a compound in which R1 in the above described cyclic group is a substituent selected from the group consisting of a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with
1 to 3 substituent groups selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may
substitute the same carbon atom in the Cl-6 alkylene
group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen
atom)), a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected
from Substituent Group A9, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9, a 5- to 14-membered non-aromatic heterocyclic group

which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9 and -X-A4 (wherein X represents an imino group, -0- or -S- and A4 represents a 6- to 14-membered aromatic hydrocarbon ring group 5 which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9 or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9)) or a pharmaceutically acceptable
10 salt thereof. [0052]
Among the compounds represented by Formula (I), preferred is a compound in which R1 in Formula (I), R1 in Formula (VI) and R1 in the cyclic group
represented by the following formula: [Formula 32]
(Figure Remove)





is -X2i
wherein X2i represents a Cl-6 alkylene group (wherein said Cl-6 alkylene group may be substituted with 1 to 3 substituent groups selected from the group consisting 20 of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8

cycloalkoxy group, a formyl group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the Cl-6 alkylene group and said two Cl-6 alkyl groups may, together with the 5 carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, an amino group (wherein said amino group may be substituted with a Cl-6 alkyl),
a 5- to 14-membered non-aromatic heterocyclic group
which may be substituted with 1 to 3 substituent groups selected from Substituent Group A7) or a single bond, and X22 represents a single bond, an imino group which may be substituted with a substituent selected from
Substituent Group A7, -0- or -S- and Ar3 represents a 6-to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A7 or a 5- to 14-membered aromatic heterocyclic group which may be
substituted with 1 to 3 substituent groups selected from Substituent Group A7 or a pharmaceutically acceptable salt thereof.
Among the compounds represented by Formula (I), more preferred is a compound in which R1 is
-X2ia-X22a~Ar3a wherein X2ia represents a Cl-6 alkylene group (wherein said Cl-6 alkylene group may be substituted with 1 to 3 substituent groups selected from the group consisting of a hydrogen atom, a halogen

atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a Cl-6 alkyl group (wherein 1 or 2 of said Cl-6 alkyl group may substitute the same carbon atom in the 5 Cl-6 alkylene group and said two Cl-6 alkyl groups may, together with the carbon atom to which they bind, form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a Cl-6 alkoxy group, an amino
group (wherein said amino group may be substituted with a Cl-6 alkyl having 1 to 5 halogen atoms), a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9), and X22a represents a single
bond or an oxygen atom and Ar3a represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A9 or a 5- to 14-membered aromatic heterocyclic group which may be substituted
with 1 to 3 substituent groups selected from
Substituent Group A9 or a pharmaceutically acceptable salt thereof.
Furthermore, Ar3a in "-X2ia-X22a-Ar3a" represents a 6- to 14-membered aromatic hydrocarbon ring group or
a 5- to 14-membered aromatic heterocyclic group and preferably a group selected from a phenyl group, a naphthyl group and a fluorenyl group or a group selected from a thienyl group, a pyridinyl group, a

quinolinyl group, an isoquinolinyl group, an indolyl group, a benzothiazolyl group, a benzoxazolyl group and a furyl group. [0053]
Among the compounds represented by Formula
(I), preferred is a compound in which R1 is a 6- to 14-membered non-aromatic hydrocarbon ring group or a 5- to 14-membered non-aromatic heterocyclic group represented by Formula (VII) or a pharmaceutically acceptable salt
thereof.
Among the compounds represented by Formula (I), preferred is a compound in which R1 is represented by Formula (VII) wherein Ar4 represents a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazinyl
group, a thienyl group, an oxazolyl group, a pyrrolyl group, a thiazolyl group and a furyl group, which may be substituted with 1 to 3 substituent groups selected from the group consisting of a halogen atom, a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be
substituted with 1 to 3 substituent groups selected
from the group consisting of a halogen atom and a Cl-6 alkyl group), a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 3 halogen atoms), an amino group (wherein said amino group may be
substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group

A7, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A7, a 5- to 14-membered non-aromatic heterocyclic group which may be 5 substituted with 1 to 3 substituent groups selected from Substituent Group A7 and -CO-A2 (wherein A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A7
or a 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituent groups selected from Substituent Group A7) or a pharmaceutically acceptable salt thereof.
Among the compounds represented by Formula
(I), the most preferred is a compound in which R1 is represented by Formula (VII) wherein R1 is an indanyl group, an azaindanyl group, a tetrahydronaphthyl group, an azatetrahydronaphthyl group, a chromanyl group, an azachromanyl group, a tetrahydrobenzofuranyl group or a
tetrahydrobenzothienyl group, which may be substituted with 1 to 3 substituent groups selected from the group consisting of, for example, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a Cl-6 alkyl group (wherein said Cl-
6 alkyl group may be substituted with 1 to 3 halogen atoms or Cl-6 alkyl groups), a Cl-6 alkoxy group (wherein said Cl-6 alkoxy group may be substituted with 1 to 3 halogen atoms), an amino group (wherein said

amino group may be substituted with a Cl-6 alkyl having 1 to 5 halogen atoms), and a 5- to 14-membered non-aromatic heterocyclic group or a pharmaceutically acceptable salt thereof. 5 [0054]
Particularly, preferred are compounds selected from the following group, for example, or a pharmaceutically acceptable salt thereof, which are useful as a preventive or therapeutic agent for
diseases caused by amyloid beta, for example,
Alzheimer's disease, senile dementia, Down syndrome, amyloidosis, etc.
1) (E)-N-Biphenyl-3-ylmethyl-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylamide,
2) (E)-N-((IS)-Indan-1-yl)-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylamide,
3) (E)-N-(Chroman-4-yl)-3[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl]acrylamide,
4) (E)-1-(3,4-Difluorobenzyl)-3-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one,
5) (E)-l-Indan-2-yl-3[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one,
6) (E)-1-(Chroman-4-yl)-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one,
7) (E)-l-[(1S)-1-(4-Fluorophenyl)ethyl]-3-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one, 8) (E)-1-[(6-Chloropyridin-2-yl)methyl]-3-[3-methoxy-

4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one,
9) (E)-1-(4-Tert-butylbenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one, 5 10) (E)-l-(3,4-Difluorobenzyl)-3-{[5-methoxy-6-(4-methyl-lH-imidazol-1-yl)pyridin-3-yljmethylene}piperidin-2-one,
11) (E)-1-[(lH-Indole-3-yl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one, 10 12) (E)-l-(5-Fluoroindan-2-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one,
13) (E)-1-(7-Fluorochroman-4-yl)-3-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one,
14) (E)-3-[3-Methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzyliden]-1-(1,2,3,4-tetrahydronaphthalen-2-
yl)piperidin-2-one and,
15) (E)-1-[(2,4-Difluorophenyl)ethyl]-3-[3-methoxy-4-
(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one.
[0055]
Although the above are preferable embodiments
of the compound of the above-mentioned general formula (I), the active ingredient of a pharmaceutical agent according to the present invention is not limited to a specific compound described in this specification, and
any embodiment can be selected from the full extent contained in the range of the compound of general formula (I) . [0056]

The production process of the compound of the general formula (I) of the present invention is described below.
The compound represented by the general 5 formula (I) [0057] [Formula 33] (Figure Remove)
(wherein Arif At2, Xi, R1 and R'2 have the same meanings as above and if necessary, Ari and AiC2 may contain protecting group(s) for functional groups such as hydroxy group(s), amino group(s) or carboxylic acid
group(s).) can be synthesized according to the following General Production Processes 1 to 5. [0058] (General Production Process 1)
A typical production process (General
Production Process 1) of the compound of the general formula (I) according to the present invention is described below.

[0059] [Formula 34;
(Figure Remove)
(wherein Ari, Ar2 and Xi is the same as defined above; V represents a protecting group for carboxyl group such as a methyl group, an ethyl group, a benzyl group, an allyl group, a triphenylmethyl group, a tert-butyl 5 group, a methoxymethyl group or a tert-butyldimethylsilyl group, and (1) R1 and R2 represent groups selected from Substituent Group A4 shown below or
R1 and R2, together with a nitrogen atom to which they 10 bind, form one of the following groups:
(2-1) a 5- to 11-membered non-aromatic heterocyclic
group represented by Formula (II):
[0060]
[Formula 35] (CH2)ma
-N \1 (II)
Jn»b
(wherein YI represents (1) -NH-, (2) -0-, (3) -S-, (4; -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9)


-NHCO-, (10) -CR5=CR6- (wherein R5 and R6 represent groups selected from Substituent Group A4 shown below), (11) a single bond or (12) >C==CR13R14 (wherein R13 and R14 represent groups selected from Substituent Group A4 5 shown below); and
ma and nib represent an integer of 0 to 4) which may be substituted with 1 to 4 Substituent groups selected from Substituent Group A4;
(2-2) a 6- to 20-membered non-aromatic heterocyclic 10 group represented by Formula (III): [0061] [Formula 36]
(CH2)ma /CH2)mc
\ V2 m
(CH2 (CH2)rnd
(wherein Y2 represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2~, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5= CR6- (wherein R5 and R6 represent groups selected from Substituent Group A4 shown below
or R5 and R6, together with a carbon atom to which they bind, form a 6- to 14-membered aromatic hydrocarbon ring group or a 6- to 14-membered non-aromatic hydrocarbon ring group) or (11) a single bond; and ma, mb/ mc and ntd represent an integer of 0 to 4) which
may be substituted with 1 to 4 Substituent groups selected from Substituent Group A4; (2-3) a 9- to 16-membered non-aromatic heterocyclic


group represented by Formula (IV) [0062] [Formula 37]
(Figure Remove)


(wherein Y3 represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO- or (10) a single bond; and
ma and 1% represent an integer of 0 to 4) which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4;
(2-4) a group represented by the following formula: [0063] [Formula 38]
(Figure Remove)


which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4;
(2-5) a group represented by the following formula:
[0064] [Formula 39; (Figure Remove)












which may be substituted with 1 to 4 substituent groups selected from. Substituent Group A4 shown below. Substituent group A4: (I) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, 5 (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl
group, (15) a Cl-6 alkylsulfonyl group, (16) a
hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) a Cl-6 alkyl group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with
1 to 3 substituent groups selected from Substituent
Group A4, (20) an amino group which may be substituted with 1 to 2 substituent groups selected from Substituent Group A4, (21) a carbamoyl group which may


be substituted with 1 to 2 substituent groups selected from Substituent Group A4, (22) 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 5 substituent groups selected 5 from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituent groups selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (26) a C2-6 alkenyloxy
group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or
5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).
[0065]
The above described "General Production Process 1" is an example of production process of the compound of the general formula (I) in which an ester

IL

compound (la) is subjected to deprotection reaction in "step 1-1" to be converted into a carboxylic acid compound (2) and subsequently the carboxylic acid compound (2) is subjected to amidation reaction 5 together with an amine compound (3). [0066] (Preparation of carboxylic acid compound (2))
The carboxylic acid compound (2) can be prepared, for example, by subjecting an ester compound
(la) to the "step 1-1". That is, although the
deprotection reaction in "step 1-1" may vary depending on the starting material, no particular limitation is imposed upon it as long as the reaction is conducted under conditions similar to those in this reaction by
methods known in the art (for example, methods as
described in T.W. Green. "Protective Groups in Organic Synthesis" John Wiley & Sons. Inc., 1981, p!54-186) can be employed. Preferably, it is a hydrolysis reaction of an ester compound, and techniques described in many
known references can be used (for example, such methods are described in "Composition and Reaction of Organic Compound [II]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p.930-943). Preferably, a
desired carboxylic acid compound (2) can be obtained by reacting an ester compound (la) using a water-containing solvent (mixed solvent of water with, for example, methanol, ethanol and/or tetrahydrofuran,


etc.) at room temperature to 100°C in the presence of 1.0 to 5.0 equivalents of metal hydroxide (preferably, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide etc.). Moreover, depending on a 5 corresponding ester compound (la), a carboxylic acid compound (2) can also be suitably obtained under an acidic condition (preferably with trifluoroacetic acid). Under a preferable reaction condition, the reaction completes in 1 to 24 hours, and the progress
of reaction can be monitored by known chromatography technology. Undesirable by-products can be removed by techniques in the art such as conventional chromatography technology, extraction procedure and/or crystallization.
[0067]
(Preparation of compound of general formula (I))
The compound of general formula (I) can be prepared, for example, by subjecting carboxylic acid compound (2) to the "step 1-2". That is, although the
amidation reaction of "step 1-2" may vary depending on the starting material, no particular limitation is imposed upon it as long as the reaction is conducted under conditions similar to those in this reaction by known techniques described in many references (for
example, such methods are described in "Composition and Reaction of Organic Compound [II]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978,


p.1136-1162) can be employed. Preferable examples include i) a process comprising converting a carboxylic acid compound (2) to an acid halide followed by reacting the acid halide with an amine compound under a 5 basic condition (for example, such a process is described in "Composition and Reaction of Organic Compound [II]," New Experiment Chemistry Series,, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p.1142-1145), ii) a process
comprising reacting a carboxylic acid compound (2) and an amine compound using a condensation agent (for example, such a process is described in "Guide to Organic Chemistry Experiment (4)," KagakuDojin, September, 1990, p.27-52), etc.
[0068]
In the case of above i), the base, solvent and reaction temperature to be used may vary depending on the starting material and are not particularly limited, and (i) a technique using, for example,
pyridine, lutidine, quinoline, isoquinoline, etc. as a basic solvent; (ii) a technique using, for example, pyridine, triethylamine, N,N-diisopropylethylamine etc. as a base and preferably, for example, tetrahydrofuran, 1,4-dioxane etc. as a solvent which dissolves the
starting substance(s) to some extent but does not prevent the reaction or a mixed solvent thereof; or (iii) a technique using a two-layer distribution system comprising of an alkali solution, preferably, for


example, an aqueous solution of a base, such as sodium hydroxide, potassium hydroxide, etc., and a halogenated solvent preferably, for example, methylene chloride, 1,2-dichloroethane, etc. can be used. The reaction 5 temperature should be a temperature which is sufficient for completing the reaction without promoting formation of undesired by-products and is preferably an ice-cooling temperature to 100°C. In preferable reaction conditions, the reaction completes in 1 to 24 hours,
and the progress of the reaction can be monitored by known chromatography technology. Although the technique of converting the carboxylic acid compound (2) to an acid halide may vary depending on the starting material, no particular limitation is imposed
upon it as long as the reaction is conducted under
conditions similar to those in this reaction by methods known in the art can be used. Preferably, a chlorination agent such as thionyl chloride and oxalyl chloride can be used in an inert solvent such as
methylene chloride, toluene and tetrahydrofuran. A
catalytic amount of N,N-dimethylformamide, etc. may be suitably added to advance the reaction. The reaction temperature should be a temperature which is sufficient for completing the reaction without promoting formation
of undesired by-products and is an ice-cooling temperature to 100°C preferably. [0069]
In the case of above ii), the condensation


agent to be used may vary depending on the starting material and is not particularly limited, and it is preferable to use suitably 1.0 equivalent to 2.0 equivalents of 1,3-dicyclohexylcarbodiimide, l-ethyl-3-5 (3'-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate etc., for example, to the carboxylic acid compound (2). In order to advance the reaction efficiently, 1.0 equivalents to 2.0
equivalents of N-hydroxysuccinimide, N-
hydroxybenzotriazol, etc., for example, may be added. It is preferable from a viewpoint of operativity and stirring efficiency to perform this reaction in the presence of a solvent, and although the solvent to be
used may vary depending on the starting material and the condensation agent to be used and is not particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the reaction, a halogen solvent such as
methylene chloride and 1,2-dichloroethane, or a polar solvent such as tetrahydrofuran and N,N-dimethylformamide are preferable. The reaction temperature should be a temperature which is sufficient for completing the reaction without promoting formation
of undesired by-products and is an ice-cooling
temperature to 100°C preferably. In preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the reaction can be monitored by


known chromatography technique. Undesirable byproducts can be removed by any technique known in the art, such as conventional chromatography technique and/or crystallization. It is also possible to obtain 5 a desired compound of the general formula (I) by
forming an amide bond and subsequently converting R1 and R2 by a usual method using a technique known and it is also possible to obtain a desired compound of the general formula (I) by suitably modifying the
substituent groups of Ari, Ar2 and Xi. [0070] (Preparation of amine compound (3))
The amine compound (3) is commercially available or can be obtained by a technique known in
the art. Preferable examples thereof include i) a
method of converting a corresponding alcohol compound or alkyl halide compound to the amine compound by a known technique; ii) a method of converting a corresponding nitro compound, nitrile compound, oxime
compound, azide compound or acid amide compound by a
known reduction reaction, iii) a method of converting a corresponding carbonyl compound by a known reductive amidation reaction, iv) a method of obtaining amine compound by subjecting the nitrogen atom protected by a
protecting group to deprotection reaction, etc. [0071]
In the case of above i), conversion can be effected by methods described in many known references,


and for example, methods of obtaining the amine compound from a corresponding alcohol compound by Mitsuriobu method (see, for example, 0. Mitsunobu, "Synthesis," p.l, 1981) or from a alkyl halide compound 5 by Gabriel method (see, for example, M.M.S. Gibson et al., "Angew. Chem.," vol. 80, p.986, 1968) are preferable. In the case of Mitsunobu method, the desired amine compound can be efficiently obtained preferably by a two-step reaction comprising condensing
a corresponding alcohol compound with an imide compound using 1.0 to 3.0 equivalents of diethyl azodicarboxylate under the coexistence of 1.0 to 3.0 equivalents of triphenylphosphine and treating a product obtained from the first step with 1.0 to 3.0
equivalents of hydrazine, for example. The reaction
temperature should be a temperature which is sufficient for completing the reaction without promoting formation of undesired by-products and it is preferably an ice-cooling temperature to 100°C for the condensation
reaction with an imide compound at the first step and 50°C to 100°C for the hydrazine treatment at the second step. Although the solvent to be used in this reaction may vary depending on the starting material and the condensation agent to be used and is not particularly
limited as long as it dissolves the starting
substance(s) to some extent but does not prevent the reaction, diethyl ether, tetrahydrofuran, etc., for example, are preferable for the reaction of the first


step and methanol, ethanol, etc., for example, are preferable for the reaction of the second step. In preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the reaction can 5 be monitored by known chromatography technigue.
Undesirable by-products can be removed by any technigue known in the art such as conventional chromatography technigue and/or crystallization. In the case of Gabriel method, the desired amine compound can be
efficiently obtained preferably by a two-step reaction comprising condensing a corresponding alkyl halide compound with an imide compound by any technigue known in the art and treating a product obtained from the first step with 1.0 to 3.0 eguivalents of hydrazine for
example. The reaction temperature should be a
temperature which is sufficient for completing the reaction without promoting formation of undesired byproducts and it is preferably an ice-cooling temperature to 100°C for the condensation reaction with
an imide compound in the first step and 50°C to 100°C for the hydrazine treatment in the second step. Although the solvent to be used in this reaction may vary depending on the starting material and the condensation agent to be used and is not particularly
limited as long as it dissolves the starting
substance(s) to some extent but does not prevent the reaction, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, etc., for example, are preferable


for the reaction of the first step and methanol, ethanol, etc., for example, are preferable for the reaction of the second step. In preferable reaction conditions, the reaction completes in 1 to 24 hours, 5 and the progress of the reaction can be monitored by known chromatography technique. Undesirable byproducts can be removed by any technique known in the art such as conventional chromatography technique and/or crystallization.
[0072]
In the case of above ii), reduction processes described in many known references can be used (for example, such a process is described in "Composition and Reaction of Organic Compound [III]," New Experiment
Chemistry Series, vol. 14, edited by the Chemical
Society of Japan, Maruzen Co., Ltd., February, 1978, p. 1333-1341) , and the desired amine compound can be efficiently obtained by catalytic hydrogenation method which preferably uses, for example, a metal catalyst, a
reduction method using a metal hydride, etc. The
catalytic hydrogenation method is preferably conducted at ordinary pressure to 100 atm under hydrogen atmosphere. The metal catalysts usable in this reaction are preferably, for example, platinum,
platinum oxide, platinum black, Raney nickel,
palladium-carbon, etc. Although the solvent to be used in this reaction may vary depending on the starting material and is not particularly limited as long as it


dissolves the starting substance(s) to some extent but does not prevent the reaction, methanol, ethanol, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, etc., for example, are 5 preferable. In order to advance the reaction
efficiently, acidic substances such as acetic acid or hydrochloric acid may be added. As for the reduction method using a metal hydride, the desired amine compound (3) will be obtained efficiently by preferably
using lithium aluminum hydride or diborane. The
solvent to be used in this reaction may vary depending on the starting material and is not particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the
reaction, diethyl ether, tetrahydrofuran, etc. are preferable, for example. The temperature for the reduction reaction of ii) should be a temperature which is sufficient for completing the reaction without promoting formation of undesired by-products, and it is
preferably an ice-cooling temperature to 100°C. In
preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the reaction can be monitored by known chromatography technique. Undesirable by-products can be removed by any technique
known in the art such as conventional chromatography technique and/or crystallization. [0073]
In the case of above iii), reductive


amination reaction known in the art (for example, such a process is described in "Composition and Reaction of Organic Compound [III]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of 5 Japan, Maruzen Co., Ltd., February, 1978, p.1380-1384) can be used, and a preferable process comprises obtaining an imine compound by dehydration reaction from a corresponding carbonyl compound and an amine compound by heat-refluxing in the presence of an acid
catalyst (preferably, for example, an inorganic acid such as hydrochloric acid or sulfuric acid, an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid or an organic acid salt such as pyridinium p-toluenesulfonate) and reducing the
imine compound with a metal hydride such as lithium
aluminum hydride, sodium borohydride, etc. to obtain a desired amine compound. Alternatively, a process comprising treating an imine compound in an inert solvent such as tetrahydrofuran in the presence of a
Lewis acid catalyst (preferably titanium (IV)
isopropoxide) and reducing the imine compound with a metal hydride such as sodium borohydride is also preferable. Alternatively, for example, a technique of reducing a carbonyl compound and 0.5 to 5.0 equivalents
of an amine compound with a metal hydride such as sodium triacetoxy borohydride and sodium cyano borohydride in an inert solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, methanol


and ethanol to obtain a desired amine compound is also preferable. It is preferable to suitably add an acidic substance such as acetic acid or hydrochloric acid in order to advance the reaction efficiently. The 5 progress of the reductive amination reaction iii) can be monitored by known chromatography technique. Undesirable by-products can be removed by any technique known in the art such as conventional chromatography technique and/or crystallization.
[0074]
In the case of above iv), deprotection reactions described in many known references can be used (see, for example, T.W. Green, "Protective Groups in Organic Synthesis," John Wiley & Sons. Inc., 1981),
and a method of obtaining a desired amine compound from a corresponding carbamate compound (preferably, for example, a tert-butylcarbamate compound, a benzylcarbamate compound, a 9-fluorenylmethylcarbamate compound etc.), or a method of obtaining such a desired
amine compound from a corresponding amide compound (preferably, for example, a formamide compound, an acetamide compound, a trifluoroacetamide compound, etc.) are preferable. Alternatively, a method of deprotecting a corresponding imide compound according
to the above described Gabriel method to obtain a
desired amine compound is also preferable. Although the conditions of deprotecting reaction may vary depending on the starting material and no particular


limitation is imposed upon it as long as the reaction is conducted under conditions similar to those in this reaction and any known method can be used. In preferable reaction conditions, the reaction completes 5 in 1 to 24 hours, and the progress of the reaction can be monitored by known chromatography technique. Undesirable by-products can be removed by any technique known in the art such as conventional chromatography technique and/or crystallization. 10 [0075]
(Preparation-1 of an ester compound (la))
[0076]
[Formula 40]
(Figure Remove)




(wherein Ai'i, Ar2, Xi and V represent the same meaning
as above;
V, Vi and V2 are the same or different and represent
protecting groups for a carboxyl group such as a methyl group, an ethyl group, a benzyl group, an allyl group,
a triphenylmethyl group, a tert-butyl group or a tert-
butyldimethylsilyl group;
LI, L2, LS and L$ represent leaving groups such as a
hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a sulfonate such as
triflate, a trialkyltin group, boronic acid or boronic
acid ester (B(OVi)2) ;
L7 represents ester groups such as methylester,
ethylester or benzylester, or cyano group; 15 W represents a diethylphosphonyl group, a diphenyl
phosphonyl group or a bis(2,2,2-
trifluoroethyl)phosphonyl group;
R13 and R14 represent groups selected from Substituent
Group Al shown below; and 20 R11 and R12 represent groups selected from Substituent
Group A3 shown below.
Substituent group Al: (1) a hydrogen atom, (2) a
halogen atom, (3) a cyano group, (4) a nitro group, (5)
a C3-8 cycloalkyl group, (6) a C2-6 alkenyl group, (7) a C2-6 alkynyl group, (8) a Cl-6 alkoxy group, (9) a
C3-8 cycloalkoxy group, (10) a formyl group, (11) a Cl-
6 alkylcarbonyl group, and (12) a Cl-6 alkyl group
(wherein said Cl-6 alkyl group may be substituted with


1 to 3 substituent groups selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a Cl-6 alkoxy group, a C3-8 cycloalkyl group and a Cl-6 alkylcarbonyl group).
Substituent group A3: (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted with 1 to 3 substituent groups selected from the group consisting of a formyl group, a halogen atom, a
hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a Cl-6 alkoxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group, a Cl-6 alkylsulfonyl group, a Cl-6 alkylcarbonyl
group, an amino group (wherein said amino group may be substituted with Cl-6 alkyl group(s) optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group
A4, a 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, a 6- to 14-membered non-aromatic hydrocarbon ring group which may be


substituted with 1 to 3 substituent groups selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from 5 Substituent; Group A4 and -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted group with 1 to 3 substituted groups
selected from Substituent Group A4) and (6) a Cl-6 alkoxyl group. [0077]
Although the ester compound (la) may vary depending on the starting material, it can be obtained
by a technique known in the art. Preferably, for example, the ester compound (la) can be prepared as shown in the above-mentioned reaction formula, but the preparation is not limited thereto. That is, the ester compound (la) can be prepared, for example, by reacting
a compound (4a) and a compound (5a) at "Step 2-1" to obtain a carbonyl compound (6a), and subjecting the carbonyl compound to Horner-Emmons reaction at "Step 2-2" to yield the ester compound (la). Alternatively, starting from a carbonyl compound (6a) through "step 2-
9" to obtain a compound (6c), and subjecting the
compound (6c) to Horner-Emmons reaction with a compound (7a') at "Step 2-2" to yield the ester compound (la). Alternatively, the ester compound (la) can be also


prepared through a three-step reaction of "step 2-4" using an amino compound (5b) as the starting material to build Ari of a compound (6b) followed by a coupling reaction with a compound (7b) or (7b') according to 5 "step 2-5". The ester compound (la) can be also prepared by using a compound (5d) as the starting material and converting it into a compound (6b) according to "Step 2-1" to yield an ester compound (la) at "Step 2-5".
[0078]
(Preparation of carbonyl compound (6a))
The carbonyl compound (6a) is commercially available or can be acquired with technique known in the art. When not marketed, the carbonyl compound (6a)
can be prepared according to "Step 2-1" by using a
compound (5a), for example, as the starting material. That is, the reaction of "Step 2-1" may vary depending on the starting material and no particular limitation is imposed upon it as long as the reaction is conducted
under conditions similar to those in this reaction and any method known in the art can be used. For example, it is preferable to conduct a coupling reaction of a compound (4a) and a compound (5a) under neutral or basic conditions (see, for example, D.D. Davey et al.,
"J. Med. Chem.," vol. 39, p.2671-2677, 1991). That is, it is preferable to use 1.0 to 5.0 equivalents of compound (4a) to compound (5a). In order to perform the reaction efficiently, the base is preferably used

in 1.0 to 5.0 equivalents, and preferable examples include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, barium carbonate, etc. The solvent 5 to be used in this reaction may vary depending on the starting material and is not particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the reaction, acetonitrile, tetrahydrofuran, dimethylsulfoxide, N,N-
10 dimethylformamide, N-methylpyrrolidine, etc. are preferable, for example. The reaction temperature should be a temperature which is sufficient for completing the reaction without promoting formation of undesired by-products and it is preferably 50°C to
200°C. In preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the reaction can be monitored by known chromatography technique. Undesirable by-products can be removed by any technique known in the art such as conventional
chromatography technique and/or crystallization. [0079]
The carbonyl compound (6a) can be prepared according to "Step 2-8" by using a compound (6b) as the starting material. That is, the reaction of "Step 2-8"
may vary depending on the starting material and no
particular limitation is imposed upon it as long as the reaction is conducted under conditions similar to those in this reaction and any method known in the art can be


used. For example, a two-step technique comprising subjecting a compound (6b) (wherein L2 is preferably a chlorine atom, a bromine atom, an iodine atom, and a sulfonate such as triflate) and a vinyl tin compound to 5 Stille coupling reaction to convert the former to a vinyl compound and subjecting the vinyl compound to ozone oxidation reaction (see, for example, S.S. Chandran et al., "Bioorg. Med. Chem. Lett.," vol. 11, p.1493-1496, 2001) can also be used. Alternatively,
carbon monoxide insertion reaction (see, for example, T. Okano et al., "Bull. Chem. Soc. Jpn.," vol. 67, p.2329-2332, 1994) using a transition metal catalyst can also be used.
Additionally, for example, in case the
carbonyl compound (6b) has L7 group, the compound 6a
can be prepared by reductive reaction which methods are
known in the art.
[0080]
(Preparation of a compound (5a))
The compound (5a) used in this step is
commercially available, or can be obtained by a technique known in the art. When not marketed, a preferable compound (5a) (wherein, LI represents a fluorine atom, a chlorine atom or a bromine atom) can
be obtained as a corresponding alcohol by an oxidation reaction known in the art, and an ester can be subjected to a known reduction reaction to yield a carbonyl compound.

[0081] (Preparation of a compound (4a))
The compound (4a) used at this step is commercially available, or can be obtained by a 5 technique known in the art (see, for example, M. Komoto et al., "Agr. Biol. Chem.," vol. 32, p.983-987, 1968 or J.M. Kokosa et al., "J. Org. Chem.," vol. 48, p.3605-3607, 1983). [0082]
(Conversion of carbonyl compound (6a) to ester compound (la))
Although the conversion of the carbonyl compound (6a) to an ester compound (la) may vary depending on the starting material, known technique 15 described in many references can be used (such a process is described, for example, in H.O. House, "Modern synthetic reactions," W.A. Benjamin Inc., p629-733, 1972, or W. Carrthers, "Some modern methods of organic synthesis," Cambridge University press, p.125-20 144, 1986). For example, an ester compound (la) can be prepared by converting a carbonyl compound (6a) according to "Step 2-2". That is, although the Horner-Emmons reaction of "Step 2-2" may vary depending on the starting material, no particular limitation is imposed 25 upon it as long as the reaction is conducted under conditions similar to those in this reaction and methods known in the art (see, for example, W.S. Wadsworth, Jr. "Org. Reactions.," vol. 25, p.73, 1997)


can be used. That is, the carbonyl compound (6a) and the phosphonic acid ester compound (7a) can be subjected to a reaction condensation and converted into a corresponding ester compound (la) under basic 5 conditions. The base is preferably used in 1.0 to 2.0 equivalents to carbonyl compound (6a), and preferable examples include sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, n-butyl lithium, lithium diisopropyl amide, lithium
bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, etc. The solvent to be used in this reaction may vary depending on the starting material and is not particularly limited as long as it
dissolves the starting substance(s) to some extent but does not prevent the reaction, diethyl ether, tetrahydrofuran, dimethylsulfoxide, toluene, benzene, ethanol, methanol, etc. are preferable, for example. The reaction temperature should be a temperature which
is sufficient for completing the reaction without
promoting formation of undesired by-products and it is preferably -78°C to 100°C, and more preferably -78°C to room temperature. In preferable reaction conditions, the reaction completes in 1 to 24 hours, and the
progress of the reaction can be monitored by known
chromatography technique. As for the geometric isomers formed during this reaction, the desired geometric isomer can be selectively prepared by a suitable


selection of a phosphonic acid ester compound (la), base, reaction temperature and/or solvent, and undesirable by-products and geometric isomers can be removed by any technique known in the art such as 5 conventional chromatography technique and/or crystallization. [0083]
For example, conversion of a carbonyl compound (6a) to an ester compound (la) can be effected
through a compound (6c) by subjecting the compound
(la') to Horner-Emmons reaction of "Step 2-2" to yield an ester compound (la). For example, well-known technique described in many references can be used in the "Step 2-9" to prepare the compound (6c) (for
example, as described in 0. Pamies et al., J. Org. Chem., p.4815-4818, 2003, etc.). That is, it is preferable to use a carbonyl compound (6a) and a phosphate compound such as diethyl phosphite, etc. under basic conditions. As a base, it is preferable to
use 1.0 to 2.0 equivalent to the carbonyl compound (6a), preferable examples of which include 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, piridine, sodium methoxide, etc. The solvent used for this reaction may vary depending on the starting
material, and is not particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the reaction. Preferable examples include diethyl ether, tetrahydrofuran,


dimethylsulfoxi.de, toluene, benzene, ethanol, methanol, etc. The reaction temperature should be a temperature which is sufficient for completing the reaction without promoting formation of undesired by-product and it is 5 preferably -78°C to 100°C, and more preferably -78°C to room temperature. In preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the reaction can be monitored by known chromatography technique. Undesirable by-products
formed in this reaction can be removed by any technique known in the art such as conventional chromatography technique and/or crystallization. Moreover, the prepared compound (6c) can be modified by a technology well-known to those skilled in the art into a desired
compound (for example, as described in T.-J.Tsai.
Tetrahedron Letters, vol. 37, No. 5, p.629-632, 1996).
[0084]
(Preparation of compound (7a'))
The compound (7af) used at this step is
commercially available, or can be obtained by a technique known in the art. When not marketed, a preferable compound (7a') can be obtained by subjecting a corresponding alcohol to an oxidation reaction well-known to those skilled in the art or by subjecting a
corresponding ester to well-known oxidation reaction to obtain an a-ketoester compound. [0085] (Preparation of amine compound (5b))


The amine compound (5b) is commercially available, or can be obtained by a technique known in the art. Preferably, it can be prepared according to "Step 2-3" using a nitro compound (5c) as the starting 5 material. That is, although the reduction reaction of "Step 2-3" may vary depending on the starting material, no particular limitation is imposed upon it as long as the reaction is conducted under conditions similar to those in this reaction and methods known in the art
(for example, such a process is described in
"Composition and Reaction of Organic Compound [III]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p.1333-1341) can be used. Preferably, they are
catalytic hydrogenation method which preferably uses, for example, a metal catalyst, or a reduction method using a metal, etc. The catalytic hydrogenation method is preferably conducted at ordinary pressure to 100 atm under hydrogen atmosphere. The metal catalysts usable
in this reaction are preferably, for example, platinum, platinum oxide, platinum black, Raney nickel, palladium-carbon, etc. Although the solvent to be used in this reaction may vary depending on the starting material and is not particularly limited as long as it
dissolves the starting substance(s) to some extent but does not prevent the reaction, methanol, ethanol, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, etc., for example, are


preferable. In order to advance the reaction efficiently, acidic substances such as acetic acid or hydrochloric acid may be added. As for the reduction method using a metal, it is preferable to use zinc, 5 iron, tin, etc. and to carry out under acidic
conditions using, for example, hydrochloric acid, acetic acid, and ammonium chloride, preferably. Although the solvent to be used in this reaction may vary depending on the starting material and is not
particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the reaction, methanol, ethanol, 2-propanol, etc. are preferable, for example. The reaction temperature should be a temperature which is sufficient
for completing the reaction without promoting formation of undesired by-products and it is preferably room temperature to 100°C. In preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the reaction can be monitored by
known chromatography technique.. Undesirable byproducts can be removed by any technique known in the art such as conventional chromatography technique and/or crystallization. [0086]
The preferable amine compound (5b) can also
be prepared according to the coupling reaction in "Step 2-6" by using as a starting material the compound (5d) which is commercially available or can be obtained by a


technique known in the art. That is, although the coupling reaction of "Step 2-6" may vary depending on the starting material, no particular limitation is imposed upon it as long as the reaction is conducted 5 under conditions similar to those in this reaction and methods known in the art can be used. Preferably, two-step technique of carrying out known de-benzophenone reaction processing after coupling reaction of benzophenone imine using a transition metal catalyst
can be used (see, for example, S.L. Buchwald et al.,
"Tetrahedron Lett.," vol. 38, p.6367-6370, 1997 or J.F. Hartwig et al., " J. Am. Chem. Soc.," vol. 120, p.827-828, 1998). In the coupling reaction of benzophenone imine, a catalytic amount (0.01 to 0.2 equivalents to
compound (5d)) of a conventional palladium catalyst such as palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(O) or tris(dibenzylideneacetone)dipalladium(O), or a
conventional nickel catalyst such as (1,5-
cyclooctadien) nickel (0), etc. can be preferably used as a catalyst. In addition, it is also preferable to suitably add a phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphine, tri-
tert-butylphosphine, 2-(di-tert-butylphosphino)-
biphenyl, 2,2'- bis(diphenylphosphino)-1,1'-binaphthyl,
1,2- bis(diphenylphosphino)ethane, or 1,1'-
bis(diphenylphosphino) ferrocene, etc. in order to


advance the reaction efficiently. Moreover, the reaction may give a preferable result in the presence of a base, and although the base to be used is not particularly limited as long as it can be used in a 5 similar coupling reactions as this reaction, and
preferable examples include sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium tert-butoxide, etc. This
reaction is preferably conducted in the presence of a solvent from a viewpoint of operativity and stirring efficiency, and although the solvent to be used in this reaction may vary depending on the starting material and the transition metal catalyst to be used and is not
particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the reaction, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone, N,N-dimethylformamide
etc. are preferable, for example. The reaction
temperature should be a temperature which is sufficient for completing the coupling reaction and it is preferably room temperature to 100°C. It is preferable to carry out this reaction under an inactive gas
atmosphere, and more preferably under nitrogen or argon atmosphere. Post-processing of the second step can use a technique known in the art (see, for example, T.W. Green. "Protective Groups in Organic Synthesis" John


Wiley & Sons. Inc., 1981). Undesirable by-products can be removed by any technique known in the art such as conventional chromatography technique and/or crystallization. 5 [0087]
As for the preferable amine compound (5b), L2 can be modified by a technique known in the art, and preferably conversion from a hydrogen atom to a halogen substituent group is possible at La (for example, as
described in "Composition and Reaction of Organic
Compound [I]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., November, 1977, p. 354-360). [0088]
(Preparation of nitro compound (5c))
The nitro compound (5c) used at this step is commercially available, or can be obtained by a technique known in the art. When not marketed, a preferable compound (5c) (wherein L2 represents a
fluorine atom, a chlorine atom, a bromine atom, or iodine) can be efficiently obtained by subjecting a corresponding precursor to a nitration known to those skilled in the art (for example, as described in "Composition and Reaction of Organic Compound [III],"
New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1978, p. 1261-1300) . [0089]

(Preparation of a compound (6b))
A compound (6b) can be obtained by a
technique known in the art. It is preferably prepared through the above "Step 2-1," using a compound (5d) as 5 the starting material, or it can also be prepared
according to "step 2-4" using an amine compound (5b) as the starting material. For example, the "step 2-4" can be conducted by treating the compound (5b) with a mixed solvent of acetic anhydride and formic acid in the
first phase, effecting condensation with an a-
haloketone (in which 1,4 is a chlorine atom, a bromine atom, or iodine) under a basic condition in the second phase, and heat-treating with ammonium acetate and acetic acid in the third phase to efficiently convert
into a compound (6b). It is preferable in the first phase to conduct treatment with a mixed solvent of 2.0 to 10.0 equivalents of acetic anhydride and 10.0 to 20.0 equivalents of formic acid to the compound (5b) at a temperature of ice-cooling temperature to 50°C. The
base used in the second phase is preferably used in 1.0 to 5.0 equivalents to the compound (5b), and, for example, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, n-butyl lithium, lithium diisopropyl amide, lithium bis(trimethylsilyl)amide,
sodium bis(trimethylsilyl)amide, etc. are preferable. Although the solvent to be used in this reaction may vary depending on the starting material and is not particularly limited as long as it dissolves the


starting substance(s) to some extent but does not prevent the reaction, diethyl ether, tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, etc. are preferable, for example. It is preferable to suitably 5 add, for example, potassium iodide, sodium iodide, etc. in order to advance the reaction efficiently. The reaction temperature should be a temperature which is sufficient for completing the reaction without promoting formation of undesired by-products and it is
preferably room temperature to 100°C. It is preferable in the third phase to conduct treatment with a mixed solvent of 5.0 to 10.0 equivalents of ammonium acetate and 10.0 to 20.0 equivalents of acetic acid to the compound (5b) at a temperature of 50°C to 150°C. In
preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the reaction can be monitored by known chromatography technique. Undesirable by-products can be removed by any technique known in the art such as conventional chromatography
technique and/or crystallization. [0090]
The a-haloketone used in the second phase of this step is commercially available, or can be acquired with technique known in the art. When not marketed,
preferable a-haloketone (in which 1^ is a chlorine atom, a bromine atom, or iodine) can be efficiently obtained by subjecting a corresponding precursor to a halogenation reaction known to those skilled in the art


(for example, as described in "Composition and Reaction of Organic Compound [I]," New Experiment Chemistry Series, vol. 14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., February, 1977, p. 307-450). 5 [0091]
As for the compound (6b), L2 can be modified by a technique known in the art, and preferably conversion to an iodine group (see, for example, S.L. Buchwald et al. "J. Am. Chem. Soc.," vol. 124, p.14844-
14845, 2002), to a lower alkyl tin group (see, for example, J. Marti et al., "Synth. Commun.," vol. 30, p.3023-3030, 2000), and to a boron group (see, for example, N. Miyaura et al., " J. Org. Chem.," vol. 60, p.7508-7510, 1995), etc. is possible.
[0092]
(Conversion from compound (6b) to ester compound (la))
The conversion from a compound (6b) to an ester compound (la) can be conducted by using a known technique in the art. For example, an ester compound
(la) can be prepared by subjecting a compound (6b) to "Step 2-5" together with a compound (7b) or a compound (7b')_ That is, although the coupling reaction of "Step 2-5" may vary depending on the starting material, no particular limitation is imposed upon it as long as
the reaction is conducted under conditions similar to those in this reaction and methods known in the art can be used, and Mizoroki-Heck reaction (see, for example, R.F. Heck, "Org, Reactions.," vol. 27, p.345, 1982),


Suzuki-Miyaura reaction (see, for example, A. Suzuki, "Chem. Rev.," vol. 95, p.2457, 1995), Sonogashira reaction (see, for example, K. Sonogashira, "Comprehensive Organic Synthesis," vol. 3, p.521, 5 1991), Stille coupling reaction (J.K. Stille, "Angew. Chem. Int. Ed. Engl.," vol. 25, p.508,1986), etc. are preferable. [0093]
In Mizoroki-Heck reaction preferably
performed is a coupling reaction of a halide, a
triflate compound (6b) (wherein L2 represents a chlorine atom, a bromine atom, an iodine atom, or a triflate), with an alkene compound (7b; La is a hydrogen atom) in 1.0 to 5.0 equivalents to the compound (6b) in the
presence of 0.01 to 0.2 equivalents of a transition metal catalyst, for example. This reaction is preferably conducted in the presence of a solvent from a viewpoint of operativity and stirring efficiency, and although the solvent to be used in this reaction may
vary depending on the starting material and the transition metal catalyst to be used and is not particularly limited as long as it dissolves the starting substance (s) to some extent but does not prevent the reaction, acetonitrile, tetrahydrofuran,
1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene,
xylene, l-methyl-2-pyrrolidone, N,N-dimethylformamide, etc. are preferable, for example. The reaction temperature should be a temperature which is sufficient


for completing the coupling reaction and it is preferably room temperature to 150°C. It is preferable to carry out this reaction under an inactive gas atmosphere, and more preferably under nitrogen or argon 5 atmosphere. The transition metal catalyst is
preferably a palladium complex, for example, and more preferably includes a conventional palladium complex such as palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II),
tetrakis(triphenylphosphine)palladium(O) or
tris(dibenzylideneacetone)dipalladium(0). In addition, it is also preferable to suitably add a phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, 2-(di-
tert-butylphosphino)biphenyl, etc.) in order to advance the reaction efficiently. Moreover, the reaction may give a preferable result in the presence of a base, and although the base to be used is not particularly limited as long as it can be used in a similar coupling
reactions as this reaction, and preferable examples
include triethylamine, N,N-diisopropylethylamine, N,N-dicyclohexylmethylamine, tetrabutylammonium chloride, etc. In preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the
reaction can be monitored by known chromatography technique. [0094]
Suzuki-Miyaura reaction is preferably carried

out by coupling, for example, a halide or a triflate compound (6b), wherein La represents a chlorine atom, a bromine atom, an iodine atom or a triflate, with, for example, a boronic acid compound or a boronic ester 5 compound (7b), wherein La represents B(OH)2 or B(OVi)2, in the presence of 0.01 to 0.5 equivalent of a transition metal catalyst based on the triflate compound. This reaction is preferably carried out in the presence of a solvent in order to achieve easy
operation and stirring. The solvent used differs
according to the starting material and the transition metal catalyst used, and is not specifically limited insofar as the solvent does not inhibit the reaction and allows the starting material to be solved therein
to a certain extent. Preferable examples include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, l-methyl-2-pyrrolidone and N,N-dimethylformamide, and mixtures of water with these solvents. The reaction temperature
should be a temperature that can complete the coupling reaction, and is preferably room temperature to 200°C. The reaction is carried out preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. Under preferable reaction conditions, the
reaction is completed in 1 to 24 hours, and the
progress of the reaction can be monitored using a known chromatography technology. The transition metal catalyst is preferably a known palladium catalyst, and


more preferably a known palladium catalyst such as, for example, palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or 5 tris(dibenzylideneacetone)dipalladium (0). In order to proceed the reaction efficiently, a phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine or tri-tert-butylphosphine) or the like may be appropriately added.
Further, in order to proceed the reaction efficiently, a quaternary ammonium salt, preferably, for example, tetrabutylammonium chloride or tetrabutylammonium bromide may be appropriately added. This reaction can bring about preferable results in the presence of a
base. The base used in this case differs according to the starting material, the solvent used, and the like, and is not specifically limited. Preferable examples include sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate, potassium
carbonate, cesium carbonate and potassium phosphate. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored using a known chromatography technology. In this reaction, even if the compound
(7b) is, for example, a halide or a triflate compound (7b) , wherein L$ represents a chlorine atom, a bromine atom, an iodine atom or a triflate, and the compound (6b) is, for example, a boronic acid compound or a


boronic ester compound (6b), wherein L2 represents
B(OH)2 or B(OVi)2f a desired coupling product (la) can
be efficiently obtained.
[0095]
The reaction conditions for Sonogashira
reaction differ according to the starting material, the solvent and the transition metal catalyst, but are not specifically limited insofar as the reaction conditions are those used in a reaction like this reaction. A
technique known to a person skilled in the art may be used for the reaction. As the starting material, an alkyne compound (7bf) is preferably used. Examples of preferable solvents include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,
benzene, toluene, xylene, l-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide. Examples of more preferable solvents include tetrahydrofuran, 1,4-dioxane, l-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction temperature should be
a temperature that can complete the coupling reaction, and is preferably room temperature to 100°C. The reaction is carried out preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. Under preferable reaction conditions, the
reaction is completed in 1 to 24 hours, and the
progress of the reaction can be monitored using a known chromatography technology. The transition metal catalyst is preferably, for example, a known palladium


catalyst, and more preferably a known palladium catalyst such as, for example, palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or 5 tris(dibenzylideneacetone)dipalladium (0). In order to proceed the reaction efficiently, a phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphine or tri-tert-butylphosphine) may be appropriately added, for example. In this reaction, a
metal halide, a quaternary ammonium salt, or the like, preferably, for example, copper (I) iodide, lithium chloride, tetrabutylammonium fluoride or silver (I) oxide may be added. The reaction can bring about preferable results in the presence of a base. The base
used in this case is not specifically limited insofar as the base can be used in a coupling reaction like this reaction. Preferable examples include basic solvents such as diethylamine, triethylamine, N,N-diisopropylethylamine, piperidine and pyridine.
[0096]
Stille coupling reaction is preferably carried out by reacting 1.0 equivalent or more of a trialkyltin compound (6b), wherein L2 represents (Vi)Sn, with a halide or a triflate compound (7b), wherein L3
represents a chlorine atom, a bromine atom, an iodine atom or a triflate, in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst. In order to proceed the reaction efficiently, it is preferable to


use 0.1 to 5.0 equivalents of copper (I) halide and/or lithium chloride appropriately. Examples of preferable solvents used in this reaction include toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-5 2-pyrrolidone and dimethyl sulfoxide. The reaction temperature should be a temperature that can complete the coupling reaction, and is preferably room temperature to 100°C. The transition metal catalyst is preferably a palladium catalyst, more preferably a
known palladium catalyst such as, for example, palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0), and still
more preferably, for example,
tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium (0). The reaction is carried out preferably in an inert gas atmosphere, and more preferably in a nitrogen or argon
atmosphere. Under preferable reaction conditions, the reaction is completed in 1 to 24 hours, and the progress of the reaction can be monitored using a known chromatography technology. [0097]
[Preparation of compound (7b) and compound (7b')]
The compound (7b) and the compound (7b') used in this step are commercially available or can be obtained by a technique known to a person skilled in


the art. When such a compound is not commercially available, a preferable compound (7b), wherein L^ represents B(OH)2 or B(OVi)2, and Vi represents the same as defined above, can be efficiently obtained, for 5 example, from a corresponding precursor by a coupling reaction known to a person skilled in the art (as described in, for example, C.R. Deloge et al., "Bull. Soc. Chim. Fr.", 1992, vol.129, pp. 285-290). Alternatively, a preferable compound (7b), wherein Io is
a triflate, can be efficiently obtained from, for
example, a corresponding precursor by a method known to a person skilled in the art (as described in, for example, B. Dupre et al., "J. Org. Chem.", 1991, vol.56, pp. 3197-3198.
[0098]
(Preparation of phosphonic acid ester compound (7a))
[0099]
[Formula 41]
(Figure Remove)






















(wherein V2 and R12 is the same as defined above, W represents (EtO)2PO, (PhO)2PO or (CF3CH20) 2PO, and L3 represents a chlorine atom, a bromine atom or an iodine atom.)
The above-mentioned formula shows an example
of the method of preparing a phosphonic acid ester compound (la). That is, a phosphonic acid ester compound (7a) is commercially available or can be obtained by a method known to those skilled in the art
shown above as "Step 3-1" to "Step 3-3" (see, for example, C.Patois et al., Synth.Commun., vol. 22, p.2391, 1991 or J.A.Jackson et al., J.Org.Chem., vol. 20, p.5556, 1989). For example, "Step 3-1" is a process in which a desired phosphonic acid ester
compound (7a) is obtained by processing a phosphonic acid ester compound (9a) with an alkyl halide compound (8a) 1.0 to 2.0 equivalent to the phosphonic acid ester compound (9a) under basic conditions and introducing R12. "Step 3-2" is a process in which a desired
phosphonic acid ester compound (7a) is obtained by
processing a phosphonic acid ester compound (8b) with a halogenated formic acid ester compound (9b) 1.0 to 2.0 equivalent to the phosphonic acid ester compound (8b) under basic conditions. "Step 3-3" is a process in
which a desired phosphonic acid ester compound (7a) is obtained by processing a phosphonic acid halide (8c) with an ester compound (9c) 1.0 to 2.0 equivalent to the phosphonic acid halide (8c) under basic conditions.


"Step 3-4" is a process in which a desired phosphonic acid ester compound (7a) is obtained by processing on ct-haloester compound (9d) with trialkylphosphite 1.0 to 10.0 equivalent to the a-haloester compound (9d). 5 Although the base compounds used at this step vary depending on the starting materials, it is preferable to use sodium hydride, n-butyl lithium, lithium diisopropyl amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide etc., in an amount of
1.0 to 1.5 equivalent, for example. Although the
trialkyl phosphites used at this step vary depending on the starting materials, it is preferable to use trimethyl phosphite, triethylphosphite etc., in an amount of 1.0 to 10.0 equivalent, for example. The
solvent used for this reaction may vary depending on the starting material, and is not particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the reaction. Preferable examples include hexane, toluene, diethyl
ether, tetrahydrofuran, N,N-dimethylformamide,
hexamethyl phosphoric acid triamide, or a mixed solvent of thereof. Reaction temperature should be a temperature which is sufficient for completing the reaction without promoting formation of undesired by-
products and is preferably -78°C to 150°C. In
preferable reaction conditions, the reaction completes in 1 to 24 hours, and the progress of the reaction can be monitored by known chromatography technique.


Undesirable by-products formed in this reaction can be removed by any technique known in the art such as conventional chromatography technique and/or crystallization. Moreover, as for the phosphonic acid 5 ester compound (7a), R12 can be modified by a technology well-known to those skilled in the art into a desired phosphonic acid ester compound (7a) efficiently. [0100]
The alkyl halide compound (8a), phosphonic
acid ester compound (8b), phosphonic acid halide (8c), phosphonic acid ester compound (9a), halogenated formic acid ester compound (9b) ester compound (9c) and a-habester compound (9d) used at this step are commercially available or can be obtained by a
technique known in the art. [0101]
(Preparation-2 of ester compound (la)) [0102] [Formula 42]
(Figure Remove)

(wherein Ar2, Xi, V and LI have the same meaning as in formula (I) ;
V represents an methyl group, an ethyl group, a benzyl group, an allyl group, a triphenylmethyl group, a tert-5 butyl group, or a protecting group such as a tert-butyldimethylsilyl group, a methoxymethyl group; LI represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and a triflate such as a sulfonate, a trialkyltin group,
boronic acid or boronic acid ester (B(OVi)2.)
The above described formula shows an example of the method of preparing an ester compound (la) as an alternative method. That is, it is (i) a process in which the above described compound (5a) is used as a
starting material, which is converted to an ester
compound (Ib) following the above described "Step 2-2" to prepare an ester compound (la) in the above-mentioned "Step 2-1"; (ii) a process in which an ester compound (Ib) is converted to an amine compound (Id) at
"Step 2-6" from which an ester compound (la) is
prepared according to the above described "Step 2-4" or (iii) a process in which the above described nitro compound (5c) is used as a starting material, which is subjected to the three of the above "Step 2-5", "Step
2-3" and "Step 2-4" to prepare an ester compound (la). In addition, it is shown that the amine compound (Id) can be also converted to an ester compound (Ib) at the Sandmeyer reaction of "Step 2-7" and then converted to
an ester compound (la) according to the above "Step 2-1".
[0103]
(Conversion from ester compound (Ib) to amine compound (Id))
The conversion to an amine compound (Id) from an ester compound (Ib) can be effected using a technique known in the art. Preferably, the same technique as the above "Step 2-6" can be used. 10 (Conversion from amine compound (Id) to ester compound (Ib)) [0104]
The conversion from an amine compound (Id) to an ester compound (Ib) may vary depending on the 15 starting material, and is not particularly limited as long as it can be effected under similar conditions as in this process and processes known in the art can be used. Preferably, the Sandmeyer reaction of "Step 2-7" etc. can be used, and a preferable ester compound (Ib) 20 can be efficiently obtained by the technique known in the art (for example, as described in "Composition and Reaction of Organic Compound [I]", New Experiment Chemistry Series, vol.14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., November, 1977, p. 25 383-388) [0105] (General preparing process 2)
The "general preparing process 2" for
preparing typical compound of general formula (I) is explained below. [0106] [Formula 43]
(Figure Remove)




Arir Ar2, Xi, R1, R2, R11, R12 and L3 is the same as defined above; 5 Wi has the same meaning as W and LS represents a
hydroxyl group, a chlorine atom and a bromine atom). The compound of general formula (I) can be prepared by, for example, converting a compound (7c) to a compound (7d) according to the above "Step 1-2", and 10 then performing "Step 2-2" with a carbonyl compound (6a) as described above, or by converting a compound (7e) to a compound (7f) according to the above "Step 1-2", and then performing "Step 2-5" with a carbonyl compound (6b) as described above.
[0107] (Preparation of compound (7d))
The compound (7d) is commercially available or can be prepared by subjecting a compound (7c) to a 5 similar step as the above "Step 1-2" with an amine compound (3) as described above. [0108] (Preparation of compound (7c))
The compound (7c) is commercially available 10 or can be prepared by a technique known in the art. Preferably, compound (7c) can be efficiently obtained by using the above described phosphonic acid ester (7a) as the starting material and subjecting it to a similar deprotection reaction as in above "step 1-1". 15 [0109]
(Preparation of compound (7f))
The compound (If) is commercially available or can be prepared by subjecting a compound (7e) to a similar step as in above "Step 1-2" together with an 20 amine compound (3) as described above. [0110] (Preparation of compound (7e))
The compound (7e) is commercially available or can be obtained by a technique known in the art. 25 Preferably, compound (7e) can be efficiently obtained by using the above described compound (7b) as the starting material and subjecting it to a similar deprotection reaction as in above "step 1-1".

[0111]
(General manufacturing process 3)
The typical (general manufacturing process 3; of the compound of general formula (I) is explained 5 below. [0112] [Formula 44]
(Figure Remove)






(wherein, Arx, Ar2 and Xi is the same as defined above; R1 and R2, together with -Xi-CO-N-, form one of the following ring structures:
10 (3-1) a cyclic group represented by Formula (V): [0113] [Formula 45] (Figure Remove)
(wherein Zi represents (1) -NH-, (2) -0-, (3) -S-, (4) -SO-, (5) -S02-f (6) -CH2-, (7) -CO-, (8) -CONH-, (9)
NHCO- or (10) a single bond; Z2 represents (1) a methine group or (2) a nitrogen atom; R7 represents a substituent selected from Substituent Group A3 shown below; and na, nb and nc represent an integer of 0 to 4) 5 which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4; (3-2) a cyclic group represented by Formula (VI): [0114] [Formula 46]
(Figure Remove)




(wherein Z3 represents (1) a single bond, (2) -CO-, (3) -(CH2)nd- (wherein nd represents an integer of 1 to 3)
or (4) -CR8R9- (wherein R8 and R9 represent a substituent selected from Substituent Group A4 shown below; Z4 represents (1) a single bond, (2) -0-, (3) -NRCO-, (4) -CONR-, (5) -CSNR- or (6)-NRCS-(wherein R represents a substituent selected from Substituent
Group A4 shown below) or (7) -S-;
Zs represents (1) a single bond, (2) an imino group which may be substituted with a substituent selected from Substituent Group A4 shown below, (3) -(CH2)ne-(wherein ne represents an integer of 1 to 3), (4) -
CR8R9- (wherein R8 and R9 is the same as defined above) or (5) -0-; and

R l to R7 are the same as defined above); or (3-3) a cyclic group represented by the following formula: [0115] [Formula 47]
(Figure Remove)
(wherein R1 and R7 are the same as defined above) 5 which may be substituted with 1 to 4 substituent groups selected from Substituent Group A4 shown below. Substituent group A3: (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1
to 3 substituent groups selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (5) a Cl-6 alkyl group (wherein said Cl-6 alkyl group may be substituted
with 1 to 3 substituent groups selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6183
alkynyl group, a C3-8 cycloalkyl group, a Cl-6 alkoxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group, a Cl-6 alkylsulfonyl group, a Cl-6 alkylcarbonyl group, an amino group (wherein said amino group may be 5 substituted with a Cl-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group 10 which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, a 6- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, a 5- to 14-membered non-15 aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-20 membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4) and (6) a Cl-6 alkoxyl group.
Substituent group A4: (1) a hydrogen atom, (2) a 25 halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio group,

(11) a formyl group, (12) a Cl-6 alkylcarbonyl group, (13) a Cl-6 alkylthio group, (14) a Cl-6 alkylsulfinyl group, (15) a Cl-6 alkylsulfonyl group, (16) a hydroxyimino group, (17) a Cl-6 alkoxyimino group, (18) 5 a Cl-6 alkyl group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (19) a Cl-6 alkoxy group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (20) an amino group which may be substituted 10 with 1 to 2 substituent groups selected from
Substituent Group A4, (21) a carbamoyl group which may be substituted with 1 to 2 substituent groups selected from Substituent Group A4, (22) 6- to 14-membered aromatic hydrocarbon ring group which may be 15 substituted with 1 to 3 substituent groups selected from Substituent Group A4, (23) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected from Substituent Group A4, (24) a 6- to 14-membered non-20 aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituent groups selected from Substituent Group A4, (25) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected 25 from Substituent Group A4, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) -X-A (wherein X

represents an imino group, -0- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituent groups selected 5 from Substituent Group A4), (31) -CO-A (wherein A is the same as defined above) and (32) =CH-A (wherein A is the same as defined above).
The above-mentioned formula is given to illustrate an example of a process using a compound
(lOa), a compound (lOb), a compound (lOc) or a compound (lOd) as starting materials, and subjecting them to a dehydration reaction of "Step 4-1" with a carbonyl compound (6a') to prepare the compound of general formula (I). That is, although the dehydration
reaction of "Step 4-1" may vary depending on the
starting material, and is not particularly limited as long as it can be effected under similar conditions as in this process and processes known in the art can be used (for example, as described in H.0.House."Modern
synthetic reactions" W.A.Benjamin, Inc., p.629-653,
1972). Preferably, the compound of Formula (I) can be efficiently obtained by carrying out dehydrating condensation reaction of the acidic hydrogen of a compound (lOa), a compound (lOb), a compound (lOc) or a
compound (lOd) and the oxygen atom of a carbonyl compound (6a') on basic conditions. Preferable examples of base usable in this reaction include piperidine, pyrrolidine, sodium methoxide, sodium
ethoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, n-butyl lithium, 5 lithium diisopropyl amide, lithium bis(trimethylsllyl)amide, sodium
bis(trimethylsllyl)amide, etc. The equivalent of the base may vary depending on the base to be used, starting material and the solvent to be used, and is
not limited. The solvent used for this reaction may vary depending on the starting material and base, and is not particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the reaction. Preferable examples include
diethyl ether, tetrahydrofuran, benzene, toluene, xylene, methanol, ethanol or tert-butyl alcohol. Reaction temperature should be a temperature which is sufficient for completing the reaction without promoting formation of undesired by-products and is
preferably -78°C to 150°C. In preferable reaction conditions, the reaction completes in I to 24 hours, and the progress of the reaction can be monitored by known chromatography technique. [0116]
In addition, the compound of general formula
(I) can also be obtained two-step process wherein compounds (lOa), (lOb), (lOc) or (lOd) which have been processed under basic conditions and a carbonyl


compound (6a') form an alcohol compound through aldol reaction and then the hydroxyl group thereof is eliminated by a known technique. As a base used at the first step of this technique, sodium hydride, n-butyl 5 lithium, lithium diisopropyl amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium ethoxide, tert-butoxide, etc. are mentioned preferably. The equivalent of these bases may vary depending on the
starting material, and although it is not limited, 1.0 to 2.0 equivalent is preferable. In order to advance the reaction efficiently, titanium (IV) isopropoxide or boron trifluoride may be added, for example. The solvent used for the first step may vary depending on
the starting material and base and is not particularly limited as long as it dissolves the starting substance(s) to some extent but does not prevent the reaction. Preferable examples include diethyl ether, tetrahydrofuran, etc. Reaction temperature should be a
temperature which is sufficient for completing the
reaction without promoting formation of undesired byproducts and is preferably -78°C to room temperature. As the second step of this reaction any technique known in the art can be used (for example, as described in
"Composition and Reaction of Organic Compound [I]", New Experiment Chemistry Series, vol.14, edited by the Chemical Society of Japan, Maruzen Co., Ltd., November, 1977, p. 115-127). The progress of the reaction can be


monitored by known chromatography technique. Undesirable by-products formed in this reaction can be removed by any technique known in the art such as conventional chromatography technique and/or 5 crystallization. [0117] (Preparation of carbonyl compound (6a'))
The carbonyl compound (6a!) can be prepared by the same technique as for the above described 10 carbonyl compound (6a), for example. [0118]
(Preparation of compound (lOa), compound (lOb), compound (lie) and compound (lid))
The compound (lOa), compound (lOb), compound 15 (lie) and compound (lid) are commercially available or can be prepared by the technique known in the art. Preferably, they can be prepared efficiently by introducing R1 group into the secondary amide nitrogen under basic conditions (see J. A.Campbell et al., J. 20 Org. Chem., vol. 60, p.4602-4616, 1995). [0119] (General manufacturing process 4)
The typical (general manufacturing process 4) of the compound of general formula (I) is explained 25 below.
[0120] [Formula 48] (Figure Remove)











(wherein, Ari, Ar2, Xi, R1, R2, R7, Zx, Z2, Z3, Z4/ Z5, na, nb, nc and Wi is the same as defined above).
The above described formula illustrates an 5 example of a process using a compound (lla), a compound (lib), a compound (lie) or a compound (lid) as starting materials, and subjecting them to the reaction of "Step 2-2" with a carbonyl compound (6a') to prepare the compound of general formula (I).
[0121]
(Preparation of compound (lla), compound (lib), compound (lie), and compound (lid))
The compound (lla), the compound (lib), the compound (lie), and the compound (lid) are commercially
available, or can be prepared by the technique known in the art. Preferably, according to the "Step 3-3" of the above (Preparation of a phosphonic acid ester compound (la)), they can be prepared efficiently by using a corresponding amide compound as starting materials.
[0122]
(General manufacturing process 5)
The typical (general manufacturing process 5] of the compound of general formula (I) is explained 5 below.
[Formula 49]
(Figure Remove)

(wherein, Ari, Ar2, Xi, R1, R2, R7, Z3, Z4, Z5f Wi and V2 is the same as defined above and
Lg is selected from the above-mentioned substituent group A4).
The above described formula illustrates an
example of a process using an ester compound (12a) as the starting material, and subjecting it to the reaction of "Step 4-1" with a carbonyl compound (6a') to convert to a compound (13) which is then converted


to a compound of general formula (I) by cyclization reaction of "Step 5-1" or a process using a compound (12b) as the starting material, and subjecting it to the reaction of "Step 2-2" with a carbonyl compound 5 (6a') to convert to a compound (13) which is then
subjected to "Step 5-1". For example, the cyclization of "Step 5-1" may vary depending on the starting material, and is not particularly limited as long as it can be effected under similar conditions as in this
process and processes known in the art can be used. For example, cyclization can be effected by (i) reacting the compound (13) with an amine compound (3b) through two of the above "step 1-1" and "Step 1-2" to form an amide bond and cyclize while eliminating the
substituent group L6 or (ii) introducing an amine compound (3b) into the substituent group Le and subjecting the product to the above "step 1-1" and 2 of "Step 1-2" to form an intramolecular amide bond to effect cyclization. The substituent groups L6 or Va may
be preferably suitably modified using a technique known to those skilled in the art in order to advances the reaction efficiently at each step. [0123J (Preparation of compound (12a))
The compound (12a) is commercially available
or can be prepared by the technique known in the art. When the carboxylic acid compound is not marketed, a corresponding compound, for example, can be obtained by


subjecting a corresponding carboxylic acid compound to a protection reaction known in the art (see T.W. Green."Protective Groups in Organic Synthesis" John Wiley & Sons. Inc., 1981). 5 [0124]
(Preparation of the amine compound (3b))
The amine compound (3b) is commercially available or can be prepared by the technique known in the art. Preferably, it can be prepared by the same 10 technique as in the above (Preparation of the amine compound (3)) . [0125] (Preparation of compound (12b))
The compound (12b) is commercially available 15 or can be prepared by the technique known in the art. Preferably, it can be prepares by the same technique as in the above (phosphonic acid ester compound (7a)) .
Effect of the Invention 20 [0126]
The present inventors performed the following
tests in order to demonstrate the usefulness of the
compound of the general formula (I) of the present
invention. [0127]
Test Example 1 [Quantification of Ap Peptide in
Neuronal Culture From Rat Fetus Brain]
(1)

Rat Primary Neuronal Culture
Primary neuronal cultures were prepared from cerebral cortices from embryonic day 18 Wistar rat (Charles River Japan, Yokohama, Japan). The embryos 5 were aseptically removed from a pregnant rat under ether anesthesia. The brain was isolated from the embryo, and immersed in ice-cold L-15 medium (for example, Invitrogen Corp. Cat #11415-064, Carlsbad, CA, USA, or SIGMA L1518, St. Louis. MO, USA). The cerebral
cortex was collected under a stereoscopic microscope from the brain. The cerebral cortex fragments collected were subjected to enzyme treatment in an enzyme solution containing 0.25% trypsin (for example, Invitrogen Corp., Cat #15050-065, Carlsbad, CA, USA)
and 0.01% DNase (for example, Sigma D5025, St. Louis. MO, USA) at 37C for 30 minutes to allow for cell dispersion. The enzyme reaction was terminated by addition of same volume of heat-inactivated horse serum. After centrifugation at 1500 rpm for 5 minutes,
the supernatant was removed and 5-10 ml of medium was added to the cell pellet. Neurobasal medium™ (Invitrogen Corp., Carlsbad, CA, USA) supplemented with 2% B-27 supplement (Invitrogen Corp., Carlsbad, CA, USA), 25 uM 2-mercaptoethanol (2-ME, WAKO, 139-06861,
Osaka, Japan), 0.5 mM L-glutamine (for example,
Invitrogen Corp., Cat # 25030-081, Carlsbad, CA, USA), and 1% antibiotics-antimycotics (Invitrogen Corp., Cat # 15240-062, Carlsbad, CA, USA) was used as the culture


medium (Neurobasal/B27/2-ME). At the compound evaluation, the medium of the same composition not to add 2-ME alone (Neurobasal/B27) was used. The cell pellet was triturated by mild pipetting. Remaining 5 cell pellet was removed by filtering through a 40-um nylon mesh (Cell Strainer, Cat # 35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) and a neuronal cell suspension was obtained. The neuronal cell suspension was diluted with the Neurobasal/B27/2-
ME medium and then plated in a volume of 100 ^I/well to obtain an initial cell density of 5 x 105 cells/cm2 in a 96-well polystyrene plate pre-coated with poly-L or D-lysine (for example, Falcon MICROTEST™ Tissue culture plate 96 well flat bottom with low evaporation lid (Cat
# 35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA) coated with poly-L-lysine using the method shown below, or BIOCOAT™ cell environments Poly-D-lysine cell ware 96-well plate, Cat # 35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, USA). Poly-L-
lysine coating was carried out as follows. Poly-L-lysine (SIGMA P2636, St. Louis, MO, USA) solution at 100 fig/ml was prepared aseptically with 0.15 M Borate buffer (pH 8.5). The solution was added to a 96-well polystyrene incubator at 50-100 (il/well and incubated
at room temperature for one hour or more, or at 4C
overnight or longer. This was rinsed 4 or more times with sterile water, and then dried or rinsed with, for example, sterile PBS or medium, and used for plating


cells. Cells were cultured for one day in an incubator of 5% C02-95% air at 37C, the entire amount of the medium was exchanged with fresh Neurobasal/B27/2-ME, and the cells were then cultured for further 3 days.
Addition of Compounds
Drugs were added on day 4 of culture as follows. The entire amount of the medium was removed from culture well, and Neurobasal/B27 medium was added at 180 ul/well. The test compound dimethyl sulfoxide
(hereinafter abbreviated as DMSO) solution was diluted with Neurobasal/B27 so than it would be 10-fold of the desired final concentration. A diluent was added at 20 ul/well and mixed well. The final concentration of DMSO was 1 % or less. Only DMSO was added to the
control group.
Sampling
After incubation for 3 days, the entire amount of the medium was collected as ELISA sample. This was used without any dilution for Apx-42 20 measurement, and diluted to 5-fold with the diluent
supplied with ELISA kit for A(3x-40 measurement, before subjecting to respective ELISA assays.
Evaluation of Cell Survival
Cell survival was evaluated by MTT assay. 25 MTT assay was carried out according to the following


protocols. Pre-warmed medium of 100 fil/well was added to the wells after collecting the medium. A solution of 8 mg/ml of MTT (SIGMA M2128, St. Louis, MO, USA) dissolved in D-PBS(-) (Dulbecco's phosphate buffered 5 Saline, SIGMA D8537, ST. Louis, MO, USA) was added at 8 ul/well, and this was incubated in an incubator of 5% C02-95% air at 37C for 20 minutes. MTT solubilizing buffer was added to this at 100 fj,l/well, MTT formazan crystals were dissolved well in an incubator of 5% CO2-
95% air at 37C, and absorbance was measured at 550 nm. MTT solubilizing buffer was prepared as follows. N, N'-dimethylformamide (for example, WAKO 045-02916, Osaka, Japan) and distilled water 250 ml each were mixed together. To this 100 g of SDS (sodium dodecyl
sulfate (for example, sodium lauryl sulfate, WAKO 191-07145, Osaka, Japan)) was dissolved. Cone. HC1 and cone. Acetic acid 350 ul each were added to allow for a final pH of about 4.7.
Upon measurement, wells without plating any
cells containing only the medium and MTT solution were set as background (bkg). Individual measured values were subjected to the following formula and calculate the proportion against the control group (group without treatment with drugs, CTRL) (% of CTRL), to compare and
evaluate cell survival.
% of CTRL = (A550_sample - A550_bkg) / (A550_CTRL -A550_bkg) x 100 (A550 sample: absorbance at 550 nm of sample well,


A550_bkg: absorbance at 550 nm of background well, A550_CTRL: absorbance at 550 nm of control group well)
Ap ELISA
For AP ELISA, Human Amyloid beta (1-42) Assay 5 Kit (#17711 or #27711) and Human Amyloid beta (1-40) Assay Kit (#17713 or #27713) from Immune-Biological Laboratories, Co., Ltd. (IBL Co., Ltd.) were used. The methods were as described in the protocols recommended by the manufacturer (methods described in the attached
document), except that Ap calibration curve was created using beta-amyloid peptide 1-42, rat and beta-amyloid peptide 1-40, rat (Calbiochem, #171596 [AP42], #171593[Ap40]). The results are shown as percentage to the Ap concentration in the medium of control group (%
of CTRL). The results are shown in Table 1.
(2) Accordingly, the compound of the present invention was proved to have effect to reduce Ap42 production.
[0128]
Consequently, as the compound of the general formula (I) or a pharmaceutically acceptable salt thereof have effect to reduce AP42 production, according to the present an invention, they can provide
a preventive or therapeutic agent particularly for neurodegenerative diseases caused by Ap such as Alzheimer's disease and Down syndrome.


[0129] [Table 1-1]
Test Compound Effect to Reduce AP42 Production IC50 (nM)
Example 153 190
Example 121 70
Example 173 190
Example 175 60
Example 186 190
Example 86 320
Example 122 190
Example 139 200
Example 398 220
Example 96 220
Example 338 330
Example 90 240
Example 402 70
Example 403 90
Example 366 330
Example 353 220
[0130] [Table 1-2]
Test Compound Effect to Reduce A042 IC50(nM) Production
Example 414 130
Example 416 100 .
Example 418 109
Example 420 120
Example 425 80

[0131] [Table 1-3]




Test Compound Effect to Reduce Ap42 Production IC50(nM)
Example 427 780
Example 430 119
Example 611 265
Example 639 56
Example 908 68
Example 976 80
Example 1014 60
Example 1027 71
Example 965 87
Example 991 60
Example 1025 70
Example 621 100
[0132]
"Salt" indicates a pharmaceutically acceptable salt, and is not particularly limited provided that it forms a pharmaceutically acceptable 5 salt with a compound of the general formula (I) which would be a preventive or therapeutic agent for diseases caused by Ap. Particular examples which can be mentioned are, for example, preferably hydrohalic acid salts (such as for example hydrofluorides,
hydrochlorides, hydrobromides, and hydroiodides), inorganic acid salts (such as for example sulfates, nitrates, perchlorates, phosphates, carbonates, and bicarbonates), organic carboxylates (such as for example acetates, oxalates, maleates, tartrates,
fumarates, and citrates), organic sulfonates (such as


for example methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, and camphorsulfonates), amino acid salts (such as for 5 example aspartates and glutamates), quaternary amine salts, alkaline metal salts (such as for example sodium salts and potassium salts), alkaline earth metal salts (such as for example magnesium salts and calcium salts) etc.
[0133]
The preventive agent for diseases caused by Ap according to the present invention can be formulated by customary methods. Preferred dosage forms are, for example, tablets, powders, subtle granules, granules,
coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, ophthalmic solutions, ophthalmic ointments, nasal drops, ear drops, cataplasms, lotions, etc. For formulation, commonly used excipients, such as for example binders,
lubricants, colorants, and correctives, and where
necessary stabilizers, emulsifiers, absorbefacients, surfactants, pH adjusters, preservatives, and antioxidants, can be used, and components generally used as ingredients for Pharmaceuticals can be blended
to formulate by customary methods. Such components which can be mentioned are animal and plant oils such as for example soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as for example liquid


paraffin, squalane, solid paraffin; ester oils such as for example octyldodecyl myristate, isopropyl myristate; higher alcohols such as for example cetostearyl alcohol, behenyl alcohol; silicone resin; 5 for example silicone oil; surfactants such as
polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerine fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block
copolymer; water-soluble polymers such as for example hydroxyethylcellulose, polyacrylate, carboxyvinyl polymer, polyethyleneglycol, polyvinylpyrrolidone, methylcellulose; lower alcohols such as for example ethanol, isopropanol; polyols such as for example
glycerine, propylene glycol, dipropylene glycol,
sorbitol; sugars such as glucose, sucrose; inorganic powders such as for example silicic anhydride, aluminium magnesium silicate, aluminium silicate; and purified water, etc. Excipients used are for example
lactose, corn starch, white soft sugar, dextrose,
mannitol, sorbitol, crystalline cellulose, and silicone dioxide etc. Binders used are for example polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arable, tragacanth, gelatin,
shellac, hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene block polymer, and meglumine etc. Disintegrators used are for example


starch, agar, gelatin powders, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium etc. Lubricants used are for example magnesium 5 stearate, talc, polyethyleneglycol, silica, and hydrogenated plant oils etc. As colorants, those approved as additives to Pharmaceuticals are used. Correctives used are cocoa powder, peppermint camphor, empasm, mentha oil, borneol, and cinnamon powder etc.
[0134]
Oral formulations, for example, are formulated by adding a compound which is an active ingredient or a salt thereof or a hydrate thereof and excipients, and further for example binders,
disintegrators, lubricants, colorants, and correctives etc. as necessary, then by customary methods formulating into for example powders, subtle granules, granules, tablets, coated tablets, and capsules etc. In case of tablets/granules, needless to say, it is
acceptable to coat them accordingly as necessary with for example sugar coating. In case of syrups or injection formulation, for example pH adjusters, solubilizers, and tonicity adjusting agents etc., and when necessary solubilization facilitators and
stabilizers etc. are added, and formulated by customary methods. In case of external preparations, formulation methods are not particularly limited and can be manufactured by customary methods. As base materials


used, various materials commonly used such as for Pharmaceuticals, quasi drugs, and cosmetics can be used. Examples of such which can be mentioned are animal and plant oils, mineral oils, ester oils, waxes, 5 higher alcohols, fatty acids, silicone oils,
surfactants, phospholipids, alcohols, polyols, water-soluble polymers, clay minerals, and purified water etc., and pH adjuster, antioxidants, chelators, preservatives and fungicides, colorants, and fragrances
etc. can also be added as necessary. In addition, ingredients having differentiation inducing effect, such as for example blood flow facilitating agents, bactericides, anti-inflammatory agents, cell stimulants, vitamins, amino acids, humectants, and
keratolytic agents can be formulated as necessary.
Amount of the therapeutic/preventive agents according to the present invention administered varies according to for example degree of symptoms, age, gender, .weight, mode of administration, type of salt, and particular
type of disease etc. A typical amount for an adult is about 30 \ig to 10 g, preferably 100 jag to 5g, more preferably 100 \iq to 3 g per day for oral administration, and about 30 ^g to 1 g, preferably 100 |ig to 500 mg, more preferably 100 (J,g to 30 mg for
injection administration, which are either administered in a single or multiple dose(s).
Best Mode for Carrying out the Invention

[0135]
The present invention will now be described
in further detail with reference to Examples. These
are illustrative, and are in no means to limit the 5 preventive or therapeutic agents for diseases caused by
Ap of the present invention to the particular Examples
below. Those having ordinary skills in the art are
capable of applying different variations to the
reference examples and Examples below as well as Claims according to the present invention to carry out the
invention to its full. Such variations are within the
scope of Claims according to the present invention.
[0136]
The following symbols are used in the following Examples.
DMF: N,N'-dimethylformamide
THF: tetrahydrofuran
LAH: lithium aluminum hydride
EDC: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
HOBT: 1-hydroxybenzotriazol
IPEA: diisopropylethylamine
TEA: triethylamine
DPPF: 1,1-bis(diphenylphosphino)ferrocene CDI: N,N'-carbonyldiimidazole
TBAF: tetrabutylammonium fluoride
PYBOP: benzotriazol-1-
yloxytris(pyridino)phosphoniumhexafluorophosphonic acid


ester
DBU: 1, 8-diazabicyclo [5.4.0] uridec-7-ene
DAST: diethylamino sulfur trifluoride
BOP: benzotriazol-1-yloxy-5 tris(dimethylamino)phosphoniumhexafluorophosphate
DIBAL-H: diisobutyl aluminum hydride
Dess-Martin reagent: Dess-Martin Periodinane
Chromatography was conducted using BW-300
(product of Fuji Silysia Chemical Ltd.) as a carrier 10 unless otherwise stated.
LC-MS: High-performance liquid Chromatography for
preparative isolation of the object compound using mass
spectrometry. As an elution solvent, 10 to 99% of
linear gradient system of water containing 0.1% 15 trifluoroacetic acid and acetonitrile containing 0.1%
trifluoroacetic acid was used.
[0137]
Example 1
Synthesis of (E)-N-indan-l-yl-3-[3-methoxy-4-(4-methyl- IH-imidazol-l-yl)phenyl]acrylamide
[138]
[Formula 50]
O
(Figure Remove)
^0139
Synthesis of 3-methoxy-4-(4-methyl-lH-imidazol-l-


yl) benzaldehyde and 3-methoxy-4-(5-methyl-lH-imidazol-1-yl)benzaldehyde
To a DMF (50 mL) solution of 4-fluoro-3-methoxybenzaldehyde (3.00 g) and 4-methylimidazole 5 (3.307 g) , potassium carbonate (4.05 g) was added and the reaction mixture was agitated at 100°C overnight. The obtained reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned.
The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system), and 3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)benzaldehyde (856 mg) and 3-methoxy-4-(5-methyl-lH-imidazol-1-yl)benzaldehyde (44 mg) were obtained.
The physical properties of 3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzaldehyde:
1H-NMR (CDC13) 8 (ppm): 2.31 (s, 3H), 3.97 (s, 3H), 7.02 (brs, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.55 (dd, J=1.6 Hz, 8.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H) , 7.84 (brs, 1H), 10.00 (s, 1H) . The physical properties of 3-methoxy-4-(5-methyl-lH-
imidazol-1-yl)benzaldehyde:
^-NMR (CDC13 ) 8 (ppm): 2.10 (s, 3H) , 3.90 (s, 3H) , 6.91 (brs, 1H), 7.40 (d, J=8.0 Hz, 1H) , 7.50 (d, J=1.2 Hz, 1H), 7.57-7.59 (m, 1H), 7.84 (s, 1H) , 10.05 (s, 1H) .


In addition, 3-methoxy-4-(4-methy-lH-
limidazol-1-yl)benzaldehyde can be synthesized also in the following alternative method. [0140] 5 Synthesis of 3-methoxy-4-nitrobenzoic acid methyl ester
Methyl iodide (463 g) was dropped to a mixture of 3-hydroxy-4-nitrobenzoic acid (199 g) and potassium carbonate (450 g) in DMF (1 L) at room temperature. After agitating the reaction solution at 10 room temperature overnight, methyl iodide (230 g) was further added to the reaction mixture, and the reaction mixture was further agitated at room temperature for 6 hours. The reaction mixture was added to ice water and the deposited solids were obtained by filtration. 178 15 g of the title compound was obtained by drying the obtained solid at 50°C overnight. The physical properties was in agreement with the reported values (CAS#5081-37-8). [0141] 20 Synthesis of 4-amino-3-methoxybenzoic acid methyl ester
To a solution of 3-methoxy-4-nitroberizoic acid methyl ester (150 g) in methanol (600 mL) and THF (300 mL), 10% palladium-carbon (15 g) was added and the reaction mixture was agitated at 50°C to 64°C under 25 hydrogen pressure of 0.9 MPa(s) for 6.5 hours. After allowing cool the reaction solution to room temperature, 134 g of the title compound was obtained by filtering the reaction solution on celite and


condensing the obtained filtrate under reduced pressure. The physical properties was in agreement with the reported values (CAS#41608-64-4). [0142]
Synthesis of 4-formylamino-3-methoxybenzoic acid methyl ester
Anhydrous acetic acid (268 mL) was added dropwise to formic acid (401 mL) at room temperature, and the reaction solution was agitated for 40 minutes 10 at room temperature. To this reaction solution, a THF (600 mL) solution of 4-amino-3-methoxybenzoic acid methyl ester (134 g) was added dropwise at room temperature, and the reaction solution was agitated for 1 hour. 3.8 L of iced water was added to the reaction solution, and the deposited solids were separated by filtering, and further washed with water (2 L). Ill g of the title compound was obtained by drying the obtained solid at 50°C overnight. The physical properties was in agreement with the reported values (CAS#700834-18-0) . [0143]
Synthesis of 4-[formyl-(2-oxopropyl)amino]-3-methoxybenzoic acid methyl ester
Chloroacetone (84.5 mL) was added dropwise to the DMF (497 mL) mixture of 4-formylamino-3-
methoxybenzoic acid methyl ester (111 g), cesium carbonate (346 g), and potassium iodide (8.78 g) at room temperature, and the reaction mixture was agitated


for 3 hours. Cesium carbonate (173 g) and chloroacetone (42.0 mL) were added to the reaction mixture, and the reaction mixture was agitated at room temperature for 2 hours. Iced water and ethyl acetate 5 were added to the reaction mixture, and the organic layer was partitioned. Ethyl acetate was added to the aqueous layer and the organic layer was partitioned. The organic layers were combined, washed with water and a saturated saline solution in this order, and the
obtained organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with toluene and the solution was concentrated under reduced pressure. Tert-butylmethyl ether and heptane were added to the
resulted residue and the deposited solids were
separated by filtering and washed with a 50% heptane solution of tert-butylmethyl ether. 118 g of the title compound was obtained by air-drying the obtained solids overnight.
XH-NMR (CDC13) 6 (ppm) : 2.19 (s, 3H) , 3.91 (s, 3H), 3.94 (s, 3H), 4.49 (s, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.69 (dd, J=8.0, 2.0 Hz, 1H), 8.33 (s, 1H) . [0144]
Synthesis of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzoic acid methyl ester
An acetic acid (255 mL) solution of 4-(formyl-(2-oxopropyl)amino)-3-methoxybenzoic acid


methyl ester (118 g) and ammonium acetate (172 g) was heated under stirring at 140°C for 1 hour. The reaction solution was neutralized with an ammoniac solution under ice-cooling after the reaction completed. Ethyl 5 acetate was added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was filtered with a silica gel pad after dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Tert-butylmethyl
ether and heptane were added to the residue and the
deposited solids were separated by filtering and washed with a 50% heptane solution of tert-butylmethyl ether. 68.4 g of the title compound was obtained by air-drying the obtained solids overnight. Furthermore,
crystallization mother liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), and 22.3 g of the title compound was obtained.
^-NMR (CDC13) 5 (ppm) : 2.30 (s, 3H) , 3.94 (s, 3H) , 3.96 (s, 3H) , 6.98 (brs, 1H), 7.32 (d, J=8.4 Hz, 1H) , 7.71-7.73 (m, 2H), 7.79 (brs, 1H). [0145] Synthesis of 3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzaldehyde
To a THF (60 mL) solution of sodium bis (2-methoxyethoxy) aluminum hydride (65% toluene solution, 56 mL), a THF (45 mL) solution of pyrrolidine (18 mL)


was added dropwise for 15 minutes at -5°C or less. The reaction solution was agitated at room temperature for 1 hour, a THF (15 mL) suspension of tert-butoxide (2.10 g) was added dropwise to the reaction solution at room 5 temperature and the reaction mixture was agitated for 15 minutes. The reaction mixture was added dropwise to a THF (50 mL) solution of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzoic acid methyl ester (20 g) under ice-cooling for 30 minutes. The reaction mixture was
agitated at room temperature for 2 hours and a 5N
sodium hydroxide solution (150 mL) was added dropwise to the reaction solution. Ethyl acetate was added to the reaction solution and the organic layer was partitioned. The organic layer was washed with a
saturated ammonium chloride solution and a saturated saline solution in this order. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure after filtration with a silica gel pad. The residue was
diluted with ethyl acetate and the deposited solids were separated by filtering. 7.10 g of the title compound was obtained by air-drying the obtained solids overnight. Furthermore, crystallization mother liquid was concentrated under reduced pressure, the residue
was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate-2-propanol system), and 2.65 g of the title compound was obtained. [0146]


Synthesis of indan-1-ylcarbamoylmethylphosphonic acid diethyl ester
After adding thionyl chloride (6.07 g) to a methylene chloride (20 mL) solution of
diethoxyphosphoryl acetic acid (5.00 g), this reaction mixture was agitated at room temperature for 2 hours and the reaction solution was concentrated under reduced pressure. THF (40 mL) solution of the obtained residue was added dropwise to a THF (80 mL) solution of
1-aminoindane (3.40 g) and TEA (3.5 mL) under ice-cooling, and the reaction solution was agitated at the temperature. Water and ethyl acetate were added to this reaction mixture, and the organic layer was partitioned. The organic layer was washed with a
saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system), and 4.2 g of the title compound was
obtained.
^-NMR (CDC13) 5 (ppm) : 1.31-1.36 (m, 6H) , 1.79-1.89 (m, 1H), 2.56-2.63 (m, 1H), 2.83-3.03 (m, 4H), 4.09-4.18 (m, 4H), 5.47 (q, J=7.6 Hz, 1H), 6.83-6.89 (brd, 1H), 7.19-7.32 (m, 4H).
[0147]
Synthesis of (E)-N-indan-l-yl-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylamide
Lithium hydroxide monohydrate (9 mg) was

added to a THF (2 mL) solution of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (21 mg) and indan-1-ylcarbamoylmethylphosphonic acid diethyl ester (30 mg) obtained above, and the reaction solution was 5 agitated at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: hexane-ethyl acetate system), and 13 mg of the
title compound was obtained.
VH-NMR (CDC13) 6 (ppm): 1.86-1.95 (m, 1H), 2.29 (s, 3H), 2.63-2.72 (m, 1H) , 2.88-3.06 (m, 2H), 3.88 (s, 3H), 5.65 (q, J=7.6 Hz, 1H) , 5.88 (d, J=8.4 Hz, 1H) , 6.41 (d, J=15.4 Hz, 1H) , 6.92 (t, J=1.2 Hz, 1H), 7.13-7.35
(m, 7H), 7.67 (d, J=15.4 Hz, 1H) , 7.71 (d, J=l.6 Hz, 1H) . [0148]
Example 1-1 Synthesis of (E)-3-[4-(4-bromo-lH-imidazol-l-yl)-3-
methoxyphenyl]-N-(9H-fluoren-9-yl)acrylamide [0149] [Formula 51]
(Figure Remove)


Synthesis of 4-(4-bromo-lH-imidazol-l-yl)-3-methoxybenzaldehyde
Potassium carbonate (1.74 g) was added to a DMF solution of 4-fluoro-3-methoxybenzaldehyde (1.94 g) 5 and 4-bromoimidezole(1.85 g) , and the reaction solution was agitated at 100°C overnight. The obtained reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the obtained residue, and the organic layer was partitioned. The organic
layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane: ethyl acetate system), and 1.21 g of the title
compound was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 3.93 (s, 3H) , 7.24 (s, 1H) , 7.43 (d, J=7.6 Hz, 1H), 7.52-7.55 (m, 2H), 7.74 (s, 1H), 9.97 (s, 1H).
[0150]
Synthesis of (E) -3- [4- (4-bromo-lH-imidazol-l-yl) -3-methoxyphenyl] -N-(9H-fluoren-9-yl)acrylamide
By the same method as in Example 121, the title compound was synthesized from 3-(4-(4-bromo-lH-
imidazol-1-yl)-3-methoxyphenyl)acrylic acid (100 mg) obtained from 4-(4-bromo-lH-imidazol-l-yl)-3-methoxybenzaldehyde and 9-fluoren-9-ylamine hydrochloride (81 mg).


XH-NMR (CDC13) 6 (ppm) : 1.83-1.97 (m, 1H) , 2.60-2.74 (m, 1H), 2.84-3.08 (m, 2H) , 3.89 (s, 3H) , 5.64 (q, J=7 . 6 Hz, 1H), 6.05 {d, J=8.4 Hz, 1H) , 6.46 (d, J=15.2 Hz, 1H), 7.10-7.30 (m, 7H) , 7.34 (d, J=6.8 Hz, 1H) , 7.61 5 (d, J=6.0 Hz, 1H) , 7.67 (d, J=15.6 Hz, 1H) . [0151] Example 2 Synthesis of (E) -3- [3-ethoxy-4- (4-methyl-lH-imidazol-l-
yl) phenyl] -N-indan-1-yl-acrylamide
(Figure Remove)
Synthesis of 4-fluoro-3-hydroxybenzaldehyde
Boron tribromide (1M methylene chloride solution, 100 mL) was gradually added dropwise to a methylene chloride (100 mL) solution of 3-methoxy-4-fluoro benzaldehyde (4.4 g) under ice-cooling. The
reaction solution was agitated at room temperature for 2 hours after the dropping ended. The reaction solution was again cooled with ice, iced water was gradually added to the reaction solution to terminate the reaction, and further 5N hydrochloride solution was
added until the pH reached 1. After condensing the reaction solution under reduced pressure, water and ethyl acetate were added to the residue, and the

organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. 5 The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 4:1), and 3.18 g (79%) of 4-fluoro-3-hydroxybenzaldehyde was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8(ppm):5.70 (s, 1H) , 7.24 (dd, J=8.4, 10.0 Hz, 1H), 7.40-7.50 (m, 1H), 7.55 (dd, J=2.0, 8.4 Hz, 1H), 9.91 (s, 1H) . [0153] Synthesis of 3-ethoxy-4-fluorobenzaldehyde
Sodium hydride (171 mg) was added to a DMF
(10 mL) solution of 4-fluoro-3-hydroxybenzaldehyde (300 mg) obtained above at room temperature, and the reaction solution was agitated for 30 minutes. Then, iodoethane (0.26 mL) was added dropwise to the reaction
solution, and the reaction mixture was agitated at room temperature for 1 hour. After the reaction ended, water and ethyl acetate were added to the reaction solution under ice-cooling and the organic layer was separated. The obtained organic layer was washed with
a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution

solvent: heptane-ethyl acetate 5:1), and 250 mg (70%) 3-ethoxy-4-fluorobenzaldehyde was obtained. The physical properties of the compound are as follows. XH-NMR (CDC13) 6(ppm): 1.49 (t, J=6.8 Hz, 3H) , 4.19 (q, 5 J=6.8 Hz, 2H), 7.23 (dd, J=8.0, 10.4 Hz, 1H), 7.43 (m, 1H), 7.50 (dd, J=2.0, 8.0 Hz, 1H) , 9.91 (s, 1H) . [0154]
Synthesis of 3-ethoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde
4-methylimidazole (244 mg) was added to a DMF
(3 mL) solution of 3—ethoxy-4-fluorobenzaldehyde (250 mg) obtained above, and the reaction solution was agitated at 150°C for 4 hours. The reaction solution was concentrated as it was after the reaction ended,
water and ethyl acetate were added to the obtained
reaction residue, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over
anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 1:4), and 60 mg (18%) of 3-ethoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde was obtained. The physical properties of the compound are
as follows.
XH-NMR (CDC13) 5(ppm): 1.46 (t, J=8.4 Hz, 3H), 2.31 (s, 3H), 4.20 (q, J=8.4 Hz, 2H), 7.00-7.06 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.53 (dd, J=1.6, 8.0 Hz, 1H), 7.55
(d, J=1.6 Hz, 1H), 7.90 (d, J=l.2 Hz, 1H), 9.99 (s, 1H) . [0155]
Synthesis of (E)-3-[3-ethoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl]-N-indan-1-yl-acrylamide
To a THF (8 mL) solution of 3-ethoxy-4- (4-methyl-lH-imidazole-1-yl)benzaldehyde (60 ing), (indan-1-ylcarbamoylmethyl)phosphonic acid diethyl ester (81 mg) and lithium hydroxide monohydrate (22 mg) were
added, and the reaction mixture was agitated at room
temperature for 14 hours. Water and ethyl acetate were added to the reaction solution after the reaction ended, and the organic layer was separated. The obtained organic layer was washed with a saturated
sodium chloride solution, and the solvent was
evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 1:4), and 23 mg (23%) of
the title compound was obtained. The physical properties of the compound are as follows. ESI-MS; m/z388 [M++H]. 1H-NMR (CDC13) 8(ppm): 1.41 (t, J=6.8 Hz, 3H), 1.82-1.97 (m, 1H), 2.30 (s, 3H), 2.60-2.74 (m, 1H), 2.84-3.10 (m, 2H), 4.10 (q, J=6.8 Hz,
2H), 5.64 (q, J=7.6 Hz, 1H), 5.88 (d, J=8.4 Hz, 1H), 6.39 (d, J=15.6 Hz, 1H), 6.95 (s, 1H), 7.10-7.19 (m, 2H), 7.20-7.31 (m, 4H), 7.34 (d, J=6.8 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.78 (d, J=l.6 Hz, 1H). [0156] Example 3
Synthesis of (E)-3-[3-cyclopropyl methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]-N-indan-1-yl-acrylamide [0157] [Formula 53]
(Figure Remove)
By the same method as in Example 2, 22 mg
(3.6%) of the title compound was obtained from 4-fluoro-3-hydroxybenzaldehyde (200 mg). The physical properties of the compound are as follows. ESI-MS; m/z414 [M++H]. XH-NMR (CDC13) 8(ppm): 0.24-0.38
(m, 2H), 0.56-0.70 (m, 2H) , 1.16-1.32 (m, 1H), 1.82-1.98 (m, 1H), 2.30 (s, 3H), 2.60-2.74 (m, 1H), 2.84-3.10 (m, 2H),3.87 (d, J=6.8 Hz, 2H), 5.63 (q, J=7.6 Hz, 1H), 5.93 (d, J=8.4 Hz, 1H), 6.39 (d, J=15.6 Hz, 1H), 6.98 (s, 1H), 7.11 (d, J=1.7 Hz, 1H) , 7.16 (dd, J=1.7,
8.4 Hz, 1H), 7.19-7.30 (m, 4H), 7.34 (d, J=6.8 Hz, 1H), 7.65 (d, J=15.2 Hz, 1H) , 7.84 (m, 1H) . [0158] Example 4 Synthesis of (E)-3-[3-(2-butynyloxy)-4-(4-methyl-lH-
imidazol-1-yl)phenyl]-N-indan-1-yl-acrylamide [0159] (Figure Remove)
[Formula 54]
(Figure Remove)
By the same method as in Example 2, 58 mg (7.8%) of the title compound was obtained from 4-fluoro-3-hydroxybenzaldehyde (250 mg). The physical properties of the compound are as follows. 5 ESI-MS; m/z412 [M++H]. 1H-NMR (CDC13) 8(ppm): 1.85 (t, J=3.0 Hz, 3H), 1.82-1.98 (m, 1H) , 2.45 (s, 3H), 2.62-2.74 (m, 1H), 2.86-3.10 (m, 2H) , 4.71 (d, J=3.0 Hz, 2H), 5.65 (q, J=7.6 Hz, 1H), 5.93 (d, J=8.0 Hz, 1H), 6.41 (d, J=15.6 Hz, 1H), 6.92-6.97 (m, 1H), 7.18-7.32
(m, 6H), 7.35 (d, J=7.6 Hz, 1H), 7.69 (d, J=15.6 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H). [0160] Example 5 Synthesis of (E)-N-indan-2-yl-3-[4-(4-methyl-lH-
imidazol-1-yl)-3-(2-propynyloxy)phenyl]acrylamide

[0161] [Formula 55] (Figure Remove)











[0162]
By the same method as the Example 2, 96 mg
(9.5%) of the title compound was obtained from 4-
fluoro-3-hydroxybenzaldehyde (350 mg). The physical 5 properties of the compound are as follows.
ESI-MS; m/z398 [M++H]. lH-NMR (CDC13) 8(ppm): 2.29 (d,
J=1.0 Hz, 3H), 2.55 (t, J=2.0 Hz, 1H), 2.99 (dd, J=4.0,
16.4 Hz, 2H), 3.39 (dd, J=6.8, 16.4 Hz, 2H), 4.73 (d,
J=2.0 Hz, 2H), 4.85-4.95 (m, 1H), 5.94 (d, J=8.0 Hz, 10 1H), 6.33 (d, J=15.6 Hz, 1H), 6.91-6.95 (m, 1H), 7.16-
7.32 (m, 7H), 7.63 (d, J=15.6 Hz, 1H), 7.71 (d, J=l.6
Hz, 1H).
[0163]
Example 6 15 Synthesis of (E)-N-indan-l-yl-3-[4-(4-methyl-lH-
imidazol-1-yl)-3-vinyloxyphenyl]acrylamide
[0164]
[Formula 56]
(Figure Remove)



Synthesis of 3-(2-bromoethoxy)-4-fluoro benzaldehyde Sodium hydride (1.14 g) was added to a DMF (30 mL) solution of 4-fluoro-3-hydroxybenzaldehyde (2.00 g) at room temperature, and the reaction solution 5 was agitated for 30 minutes. Then, dibromoethane (2.46 mL) was added dropwise to the reaction solution, and the reaction solution was heated at 140°C for 3 hours after the dropping ended. Water and ethyl acetate were added to the reaction solution under ice-cooling, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 6:1), and 606 mg (20%) 3-(2-bromoethoxy)-4-fluoro benzaldehyde was obtained. The physical properties of the compound are as follows.
'•H-NMR (CDC13) 8(ppm): 3.69 (t, J=6.4 Hz, 2H) , 4.42 (t, 20 J=6.4 Hz, 2H), 7.27 (dd, J=8.4, 9.6 Hz, 1H), 7.46-7.56 (m, 2H), 9.92 (s, 1H). [0165] Synthesis of 4-fluoro-3-vinyloxybenzaldehyde
A 50% sodium hydroxide solution (5 mL) and
tetrabutylammonium hydrogen sulfate (859 mg) were added to the toluene (8 mL) solution of 3-(2-bromoethoxy)-4-fluorobenzaldehyde derivative (606 mg) obtained above, and the reaction solution was agitated at room


temperature for 1 hour. Water and ethyl acetate were added to the reaction solution after the reaction ended, and the organic layer was separated. The obtained organic layer was washed with a saturated 5 sodium chloride solution, and the solvent was
evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 6:1), and 200 mg (49%)
of 4-fluoro-3-vinyloxybenzaldehyde was obtained. The physical properties of the compound are as follows. VH-NMR (CDC13) 8(ppm): 4.60 (dd, J=2.0, 6.0 Hz, 1H) , 4.84 (dd, J=2.0, 13.6 Hz, 1H), 6.67 (dd, J=6.0, 13.6 Hz, 1H), 7.30 (dd, J=8.4, 10.0 Hz, 1H), 7.50-7.70 (m,
2H), 9.93 (sf 1H). [0166]
Synthesis of 4-(4-methyl-lH-imidazol-l-yl)-3-vinyloxybenzaldehyde
By the same method as in Example 2, 66 mg
(24%) of 4-(4-methyl-lH-imidazol-l-yl)-3-
vinyloxybenzaldehyde was obtained from 4-fluoro-3-vinyloxybenzaldehyde (200 mg) obtained above. The physical properties of the compound are as follows. XH-NMR (CDC13) 5(ppm): 2.31 (s, 3H) , 4.64 (dd, J=2.0,
6.0 Hz, 1H), 4.87 (dd, J=2.0, 13.6 Hz, 1H) , 6.63 (dd, J=6.0, 13.6 Hz, 1H), 7.03 (s, 1H), 7.50 (d, J=8 . 4 Hz, 1H), 7.64-7.74 (m, 2H), 7.85 (s, 1H), 10.00 (s, 1H) . [0167]


Synthesis of (E)-N-indan-l-yl-3-[4-(4-methyl-lH-
imidazol-1-yl)-3-vinyloxyphenyl]acrylamide
By the same method as in Example 2, 60 mg (54%) of (E)-N-indan-l-yl-3-(4-(4-methyl-lH-imidazol-l-5 yl)-3-vinyloxyphenyl)acrylamide was obtained from 4-(4-
methyl-lH-imidazol-1-yl)-3-vinyloxybenzaldehyde (66 mg)
obtained above. The physical properties of the
compound are as follows.
ESI-MS; m/z386 [M++H]. 1H-NMR (CDC13) 8(ppm): 1.89-1.98 (m, 1H), 2.30 (s, 3H) , 2.60-2.74 (m, 1H) , 2.84-3.10 (m,
2H), 4.53 (dd, J=2.8, 5.6 Hz, 1H) , 4.76 (dd, J=2.8,
14.0 Hz, 1H), 5.64 (q, J=7.2 Hz, 1H), 5.91 (d, J=8.4
Hz, 1H), 6.41 (d, J=15.6 Hz, 1H) , 6.55 (dd, J=6.4, 14.0
Hz, 1H), 6.95 (s, 1H), 7.20-7.37 (m, 6H), 7.34 (d, 15 J=6.8 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.73 (d, J=l.6
Hz, 1H).
[0168]
Example 7
Synthesis of (E)-3-[3-ethoxy-4-(4-methyl-lH-imidazol-l- yl)phenyl]-1-(4-indol-l-yl-piperidin-l-yl)propenone
[0169]
By the same method as in Example 121, 60 mg
[Formula 57]
(Figure Remove)



(26%) of the title compound was obtained from (E)-(3-ethoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (140 mg). The physical properties of the compound are as follows.
ESI-MS; m/z477 [M++Na]. lH-NMR (CDC13) 8(ppm): 1.42 (t, J=6.8 Hz, 3H), 1.90-2.10 (m, 2H), 2.19-2.29 (m, 2H), 2.30 (s, 3H), 2.80-3.06 (m, 1H) , 3.25-3.50 (m, 1H), 4.12 (q, J=6.8 Hz, 2H), 4.24-4.40 (m, 1H), 4.46-4.60 (m, 1H), 4.90-5.08 (m, 1H) , 6.54 (dd, J=0.8, 3.2 Hz,
1H), 6.92-6.97 (m, 1H), 7.08-7.30 (m, 7H), 7.39 (d,
J=8.0 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H) , 7.68 (d, J=15.6 Hz, 1H) , 7.78 (d, J=1.6 Hz, 1H) . [0170] Example 8
Synthesis of (E)-3-[3-allyloxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-indan-2-yl-acrylamide [0171] [Formula 58]
(Figure Remove)
By the same method as in Example 121, 48 mg (17%) of the title compound was obtained from (E)-(3-allyloxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic 20 acid (512 mg). The physical properties of the compound are as follows.


XH-NMR (CDC13) 8: 2.29 (s, 3H) , 2.89 (dd, J=4.0, 16.0 Hz, 2H), 3.38 (dd, J=6.8, 16.13 Hz, 2H) , 4.58 (d, J=5.2 Hz, 2H), 4.82-4.98 (m, 1H), 5.27 (dd, J=1.2, 10.8 Hz, 1H), 5.35 (dd, J=1.2, 15.6 Hz, 1H), 5.90-6.10 (m, 1H) , 5 6.04 (d, J=8.0 Hz, 1H), 6.32 (d, J=15.2 Hz, 1H), 6.94 (s, 1H), 7.07-7.17 (m, 2H), 7.18-7.30 (m, 5H), 7.59 (d, J=15.6 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H). [0172] Example 9
Synthesis of (E)-3-[3-cyano-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-indan-1-ylacrylamide [0173] [Formula 59]
O
(Figure Remove)
Synthesis of 5-bromo-2-(4-methyl-lH-imidazol-l-yl)benzonitrile and 5-bromo-2-(5-methyl-lH-imidazol-l-yl)benzonitrile
Potassium carbonate (2.07 g) was added to a
DMF (20 mL) solution of 5-bromo-2-fluorobenzonitrile (2.00 g) and 4-methylimidazole (1.23 g) and the reaction solution was agitated at 100°C for 4.5 hours. The reaction mixture was concentrated under reduced
pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The


organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution 5 solvent: hexane-ethyl acetate system), and 5-bromo-2-(4-methyl-lH-imidazol-l-yl)benzonitrile (962 mg) and 5-bromo-2-(5-methyl-lH-imidazol-l-yl)benzonitrile (60 mg) were obtained. The physical properties of 5-bromo-2-(4-methyl-lH-
imidazol-1-yl)benzonitrile are as follows.
XH-NMR (CDC13) 5 (ppm) : 2.32 (s, 3H) , 7.05 (t, J=1.2 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H) , 7.74 (d, J=1.2 Hz, 1H) , 7.83 (dd, J=2 Hz, 8.8 Hz, 1H) , 7.93 (d, J=1.2 Hz, 1H) . The physical properties of 5-bromo-2-(5-methyl-lH-
imidazol-1-yl)benzonitrile are as follows.
^-NMR (CDC13) 8 (ppm): 2.15 (s, 3H) , 6.97 (t, J=1.2 Hz, 1H) , 7.28 (d, J [0174]
Synthesis of N-indan-1-yl-acrylamide
A THF (10 mL) solution of acrylic acid chloride (2.04 g) was added dropwise to a THF (30 mL) solution of 1-aminoindane (3.00 g) and TEA (2.28 g)
under ice-cooling, and the reaction solution was
agitated for 20 minutes at the temperature. Water and ethyl acetate were added to this reaction mixture, and the organic layer was partitioned. The organic layer


was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 2.23 g of the title compound was obtained by adding ether to the residue and filtering 5 insoluble matter.
^-NMR (CDC13) 5 (ppm) : 1.81-1.90 (m, 1H) , 2.61-2.69 (m, 1H) , 2.86-3.05 (m, 2H), 5.58 (q, J=7.6 Hz, 1H), 5.68 (dd, J=1.6 Hz, 10.4 Hz, 1H) , 5.70-5.78 (brs, 1H), 6.10 (dd, J=10.4 Hz, 17.2 Hz, 1H) , 6.34 (dd, J=1.6 Hz, 17.2
Hz, 1H), 7.20-7.32 (m, 4H). [0175]
Synthesis of (E)-3-[3-cyano-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-indan-1-ylacrylamide
To a DMF (2 mL) solution of 5-bromo-2-(4-
methyl-lH-imidazol-1-yl)benzonitrile (50 mg) and N-
indan-1-yl-acrylamide (43m g) obtained above, palladium acetate (2.2 mg), ortho-tritolylphosphine (6 mg) and TEA (0.5 mL) were added, and the reaction solution was agitated at 70°C under nitrogen atmosphere overnight.
The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: ChromatorexONH, elution solvent:hexane-ethyl acetate system}, and 31 mg of the title compound was obtained.


(CDC13) 5 (ppm) : 1.86-1.95 (m, 1H) , 2.32 (s, 3H) , 2.64-2.72 (m, 1H) , 2.89-3.08 (m, 2H), 5.64 (q, J=7.6 Hz, 1H), 5.96 (d, J=8.4 Hz, 1H), 6.44 (d, J=16 Hz, 1H) , 7.10 (t, J=1.2 Hz, 1H), 7.22-7.30 (m, 3H), 7.34 (d, 5 J=7.6 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.69 (d, J=16 Hz, 1H), 7.78-7.80 (m, 2H), 7.90 (d, J=2 Hz, 1H). [0176] Example 10
Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-cyano-4-(4-10 methyl-lH-imidazol-1-yl)phenyl]acrylamide [0177] [Formula 60]
(Figure Remove)
Synthesis of (E)-3-[3-cyano-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid
To a DMF (10 mL) solution of 5-bromo-2-(4-methyl-lH-imidazol-l-yl)benzonitrile (700 mg) and
acrylic acid ethyl ester (362 mg), palladium acetate (31 mg), tri-ortho-tolylphosphine (85 mg) and TEA (2 mL) were added, and the reaction solution was agitated at 80°C under nitrogen atmosphere overnight. The reaction mixture was concentrated under reduced
pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The


organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution 5 solvent: hexane-ethyl acetate system), fractions of the object substance were combined, and concentrated under reduced pressure. The obtained substance was dissolved by 5N sodium hydroxide solution (5 mL) and ethanol (30 mL), and the reaction mixture was agitated at 60°C for 3
hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and was made neutral with 5N hydrochloric acid. Insoluble matter consequently deposited was separated by filtering, washed with ether, and 498 mg of the title
compound was obtained. ESI-MS; m/z254 [M++H]. [0178]
Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-cyano-4- (4-methyl-lH-imidazol-1-yl)phenyl]acrylamide
To a DMF (0.2 mL) solution of (E)-3-[3-cyano-
4- (4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (15 mg) and 3-phenylbenzylamine monohydrochloride (16 mg), TEA (0.007 mL), HOBT (10 mg) and EDC (14 mg) were added one by one, and the reaction mixture was agitated at
room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Carrier: Chromatorex®NH, elution solvent:hexane-ethyl acetate


system), and 5 mg of the title compound was obtained. ^-NMR (CDC13) 5 (ppm) : 2.32 (s, 3H) , 4.67 (d, J=6 Hz, 2H), 6.04-6.08 (m, 1H), 6.49 (d, J=15.6 Hz, 1H), 7.09 (s, 1H), 7.32-7.60 (m, 10H) , 7.68 (d, J=15.6Hz, 1H), 5 1.16-1.19 (m, 2H), 7.89 (d, J=2 Hz, 1H). [0179] Example 11
Synthesis of (E)-3-[3-chloro-4-(IH-imidazol-l-yl-phenyl]-N-indan-1-yl-acrylamide [0180] [Formula 61]

(Figure Remove)
Synthesis of 3-chloro-4-(lH-imidazol-1-yl)benzaldehyde
To a DMF (20 mL) solution of 3-chloro-4-fluorobenzaldehyde (500 mg), potassium carbonate (1.20 g) and imidazole (275 mg) were added one by one, and the reaction solution was agitated at 80°C overnight.
Water and ethyl acetate were added to the reaction
solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The
obtained residue was purified by silica gel
chromatography (elution solvent: ethyl acetate -> ethyl acetate : methanol = 10:1), and 548 mg of the title


compound was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 10.0 (s, 1H) , 8.09 (d, J=2.0 Hz, 1H), 7.91 (dd, J=2.0, 8.0 Hz, 1H), 7.80 (s, 1H), 7.54 5 (d, J=8.0 Hz, 1H), 7.24-7.27 (m, 2H) . [0181]
Synthesis of (E)-3-[3-chloro-4-(IH-imidazol-l-yl-phenyl]acrylic acid
To a THF (13 mL) solution of 3-chloro-4-(1H-
imidazol-1-yl)benzaldehyde (545 mg)
dimethylphosphonoacetic acid methyl ester (513 ^L) and lithium hydroxide monohydrate (133 mg) were added one by one, and the reaction solution was agitated overnight. After confirming disappearance of the
starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under
reduced pressure to obtain 442 mg of crude ester
product. 2N sodium hydroxide solution (5.0 mL) was added to the reaction solution obtained by which dissolving the obtained ester product in THF (5.0 mL), and the reaction solution was agitated at room
temperature overnight. The reaction solution was
cooled to 0°C, 2N hydrochloric acid was added to the reaction solution, and the deposited precipitation was separated by filtering with Kiriyama funnel. The


obtained precipitation was washed with water and ethyl
acetate, and 218 mg of the title compound was obtained.
The physical properties of the compound are as follows.
^-NMR (DMSO-d6) 8 (ppm) : 8.08 (d, J=2.0 Hz, 1H) , 7.93 (s, 1H), 7.82 (dd, J=2.0, 8.4 Hz, 1H) , 7.61 (d, J=16
Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7,11 (s,
1H), 6.70 (d, J=16 Hz, 1H).
[0182]
Synthesis of (E)-3-[3-chloro-4-(IH-imidazol-l- yl)phenyl]-N-indan-1-yl-aery1amide
17.0 mg of the title compound was obtained
from (E)-3-[3-chloro-4-(IH-imidazol-l-yl)phenyl]
acrylic acid (20.0 mg) and 1-aminoindan (15.0 fj.L) by
the same method as in Example 324. The physical properties of the compound are as follows.
ESI-MS; m/z364[M++H].
[0183]
Example 12
Synthesis of (E)-3-[4(IH-imidazol-l-yl)phenyl]-N-indan- 1-yl-acrylamide
[0184]
Synthesis of (E)-3-[4(IH-imidazol-l-yl)phenyl]acrylic acid
[Formula 62]
(Figure Remove)


To a THF (3.0 mL) solution of 4-imidazol-l-yl-benzaldehyde (100 mg), dimethylphosphonoacetic acid methyl ester (103 p.L) and lithium hydroxide monohydrate (27.0 mg) were added to one by one, and the reaction 5 solution was agitated overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 143 mg of crude ester product. 2N sodium hydroxide solution (2.0 mL) was added to a THF (2.0 mL) solution of the obtained ester product, and the reaction
solution was agitated at room temperature overnight. The reaction solution was cooled to 0°C, and 2N hydrochloric acid was added to the reaction solution, and the deposited precipitation was separated by filtering with Kiriyama funnel. The obtained
precipitation was washed with water and ethyl acetate, and 98.0 mg of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (DMSO-d6) 6 (ppm) : 8.35 (s, 1H) , 7.83 (d, J=8.4 Hz, 2H), 7.82 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.60 (d,
J=16 Hz, 1H) , 7.11 (s, 1H), 6.58 (d, J=16 Hz, 1H) . [0185]
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)phenyl]-N-indan-1-yl-acrylamide


11.0 mg of the title compound was obtained from (E)-3-[4-(IH-imidazol-l-yl)phenyl]acrylic acid (20.0 mg) and 1-aminoindan (17.0 f^L) by the same method as in Example 324. The physical properties of the 5 compound are as follows.
^-NMR (CDC13) 5 (ppm) : 7.91 (s, 1H) , 7.70 (d, J=16 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H) , 7.40 (d, J=8.4 Hz, 2H), 7.22-7.37 (m, 5H), 7.20 (s, 1H) , 6.43 (d, J=16 Hz, 1H), 5.88 (d, J=7.2 Hz, 1H) , 5.64 (q, J=7.2 Hz, 1H) , 3.03
(ddd, J=4.4, 8.8, 16 Hz, 1H) , 2.92 (td, J=8.0, 16 Hz, 1H), 2.64-2.72 (m, 1H), 1.86-1.95 (m, 1H) [0186]
Example 12-1 Synthesis of (E)-N-(9H-fluoren-9-yl)-3-[4-(IH-imidazol-
1-yl)phenyl]acrylamide [0187] [Formula 63]
(Figure Remove)
By the same method as in Example 12, 3.6 mg of the title compound was obtained from (E)-3-[4-(1H-imidazol-1-yl-phenyl)acrylic acid (13 mg) and 9-aminofluorene hydrochloride (20 mg). The physical 20 properties of the compound are as follows. ESI-MS; m/z378 [M++H].

[0188] Example 13
Synthesis of (E)-3-[4-(lH-imidazol-1-yl)-3-trifluoromethylphenyl] -N-indari-1-yl-acrylamide [0189] [Formula 64]
(Figure Remove)
To a DMF (2.0 mL) solution of 4-fluoro-3-
trifluoromethylbenzaldehyde (400 mg), potassium carbonate (414 mg) and imidazole (136 mg) were added one by one, and the reaction solution was agitated at 80°C for 6 hours. Water and ethyl acetate were added to
the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica
gel chromatography (elution solvent: hexane : ethyl acetate 3:1 -> ethyl acetate) and 13.7 mg of 4-(lH-imidazol-1-yl)-3-trifluoromethylbenzaldehyde was obtained. Next, malonic acid (11.0 mg) and piperidine (53.0 mg) were added to an ethanol (1.0 mL) solution of
the obtained aldehyde compound (13.0 mg), and the
reaction solution was refluxed for 5 hours. Pyridine (2.0 mL) and malonic acid (11.0 mg) were added to the


reaction solution, and the reaction solution was refluxed for one and a half hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained 5 organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and 15.0 mg of crude carboxylic acid was obtained by condensing under reduced pressure. By the same method as in Example 324, 10.7 mg of the title compound was
obtained from the obtained carboxylic acid and 1-
aminoindan. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 7.94 (dd, J=2.0, 8.4 Hz, 1H) , 7.76 (d, J=16 Hz, 1H), 7.75-7.78 (m, 1H),7.64 (s, 1H),
7.41 (d, J=8.4 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.26-7.31 (m, 3H), 7.21 (s, 1H), 7.13 (s, 1H), 6.53 (d, J=16 Hz, 1H), 5.97 (brs, 1H), 5.65 (q, J=7.6 Hz, 1H), 3.04 (ddd, J=4.4, 8.8, 16 Hz, 1H), 2.95 (td, J=8.0, 16 Hz, 1H), 2.69 (dtd, 4.4, 8.0, 13 Hz, 1H), 1.87-1.96 (m, 1H)
[0190]
Example 14
Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-hydroxy-4-
(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid amide
[0191]
[Formula 65]
(Figure Remove)


To a methylene chloride solution (3 mL) of (E)-N-biphenyl-3-ylmethyl-3-(3-methoxy-4-(4-methyl-lH-imidazol-l~yl)phenyl)acrylic acid amide (100 mg) obtained in Example 121, boron tribromide (1M pentane 5 solution, 1.18 mL) was added dropwise at -78°C and the reaction solution was agitated at room temperature for 6 hours. The reaction solution was diluted with a saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was partitioned. The
organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: chloroform-methanol system), and 16.5 mg of the title compound was
obtained.
ESI-MS; m/z410 [M++H]. 1H-NMR (DMSO-d6) 5(ppm): 2.15 (s, 3H), 4.49 (d, J=6.0 Hz, 1H) , 6.63 (d, J=15.6 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.19-7.20 (m, 2H) , 7.30-7.66 (m, 11H), 7.86 (s, 1H) , 8.72 (t, J=6.0 Hz, 1H) , 10.43
(s, 1H). [0192] Example 15
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)-2-methoxyphenyl]-N-indan-1-yl-acrylamide

(Figure Remove)
Synthesis of 4-(IH-imidazol-l-yl)-2-methoxybenzoic acid methyl ester
To an acetone (10 mL) solution of 4-fluoro-2-hydroxy benzoic acid methyl ester (1.0 g), potassium 5 carbonate (1.2 g) and iodomethane (732 (J.L) were added one by one, and the reaction solution was concentrated under reduced pressure, after refluxing for 4 hours. Potassium carbonate (1.20 g) and imidazole (479 mg) were added to a DMF (10 mL) solution of the obtained
residue (1.08 g) one by one, and the reaction solution was agitated at 80°C overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it
was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane : ethyl acetate = 3:1 -> ethyl acetate : methanol = 10:1), and 370 mg of the title compound was
obtained. The physical properties of the compound are as follows.


!H-NMR (CDC13) 6 (ppm) : 7.92-7.96 (m, 2H), 7.34 (s, 1H) , 7.23 (s, 1H), 6.97-7.04 (m, 2H), 3.98 (s, 3H), 3.91 (s, 3H)
[0194]
Synthesis of (E)-3-[4-(lH-imidazol-l-yl-2-methoxyphenyl]-N-indan-1-yl-acrylamide
DIBAL-H (l.OM toluene solution, 3.27 mL) was added to a methylene chloride (5.0 mL) solution of 4-(IH-imidazol-l-yl)-2-methoxybenzoic acid methyl ester
(253 mg) at -78°C, and the reaction solution was
agitated for 1 hour. Saturated Rochelle salt aqueous solution was added to the reaction solution, and the reaction solution was agitated at room temperature overnight. Ethyl acetate was added to the reaction
solution and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and 216 mg of crude alcohol compound was obtained by condensing under reduced pressure.
To a methylene chloride (4.0 mL) solution of
oxalyl chloride (277 |j,L) , dimethylsulfoxide (451 [J.L) was added at -78°C and the reaction solution was agitated for 15 minutes. Next, a methylene chloride (3.0 mL) solution of alcohol compound (216 mg) obtained
at a precedent step was added to the above-mentioned
reaction solution at -78°C, and was agitated for 25 more minutes. Then, TEA (1.0 mL) was added to the reaction solution, heated to 0°C, and agitated for 3 hours.


Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium 5 sulfate and obtained 214 mg of crude aldehyde compounds by condensing under reduced pressure. To a THF (2.0 m.L) solution of the obtained aldehyde (25.5 mg) , sodium hydride (8.0 mg) and (indan-1-ylcarbamoylmethyl)phosphonic acid diethyl ester (63.0
mg) obtained in Example 1 were added at 0°C, and the reaction solution was agitated at room temperature for one hour and 40 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane : ethyl acetate = 1:1 -> ethyl acetate -> ethyl acetate :
methanol = 10:1), and 28.4 mg of the title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 7.89 (d, J=16 Hz, 1H) , 7.88 (s, 1H), 7.56 (d, J=8.4 Hz, 1H) , 7.35 (d, J=6.4 Hz, 1H),
7.20-7.30 (in, 5H) , 6.98 (dd, J=2.0, 8.4 Hz, 1H) , 6.89 (d, J=2.0 Hz, 1H) , 6.57 (d, J=16 Hz, 1H), 5.93 (brd, J=8.0 Hz, 1H), 5.65 (q, J=8.0 Hz, 1H), 3.94 (s, 3H), 3.02 (ddd, J=4.4, 8.8, 16 Hz, 1H) , 2.87-2.96 (m, 1H),


2.67 (dtd, J=4.4, 8.0, 16 Hz, 1H) , 1.85-1.95 (m, 1H) [0195] Example 16
Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)-5-5 methoxyphenyl]-N-indan-1-yl-acrylamide [0196] [Formula 67]
(Figure Remove)
Synthesis of 1- (4-bromo-2-f luoro-6-methoxyphenyl) -1H-imidazole
To an acetone (10 mL) solution of 5-bromo-
2,3-difluoro phenol (600 H-L) , potassium carbonate (1.10 10 g) and iodomethane (654 (4.L) were added one by one, and the reaction solution was refluxed for 4 hours. The reaction solution was concentrated under reduced pressure and the crude bromo compound was obtained. Potassium carbonate (1.10 g) and imidazole (429 mg) 15 were added to a DMF (10 mL) solution of the obtained bromo compound (1.17 g) one by one, and the reaction solution was agitated at 80°C overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained 20 organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate


and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate= 3:1 -> ethyl acetate:ethanol = 10:1), and 510 mg of the title 5 compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 7.82 (s, 1H) , 7.24 (s, 1H) , 7.21 (s, 1H), 7.05-7.08 (m, 2H), 3.98 (s, 3H). [0197]
Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)-5-methoxyphenyl]-N-indan-1-yl-acrylamide
By the same method as in Example 9, 3.80 mg of the title compound was obtained from 1-(4-bromo-2-fluoro-6-methoxyphenyl)-IH-imidazole (86.0 mg) and N-
indan-1-yl-acrylamide (90.0 mg). The physical properties of the compound are as follows. ^-NMR (CDC13) 6 (ppm): 7.84 (s, 1H) , 7.64 (d, J=16 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.23-7.29 (m, 5H), 7.11 (t, J=8.0 Hz, 1H), 6.40 (d, J=16.0 Hz, 1H), 5.95 (d,
J=8.0 Hz, 1H), 5.64 (q, J=8.0 Hz, 1H), 3.98 (s, 3H), 3.04 (ddd, J=4.4, 8.8, 16.0 Hz, 1H), 2.93 (td, J=8.0, 16.0 Hz, 1H), 2.64-2.72 (m, 1H) , 1.86-1.95 (m, 1H) . [0198] Example 17
Synthesis of (E)-3-[3-(IH-imidazol-l-yl)-4-methoxyphenyl]-N-indan-1-yl-acrylamide

(Figure Remove)
Synthesis of 3-(lH-imidazol-l-yl-4-methoxybenzaldehyde
To an aqueous solution (15 mL) of imidazole (5.69 g), 3-bromo-4-methoxybenzaldehyde (3.00 g) and
copper powder (86 mg) were added, and the reaction 5 solution was agitated for three days at 100°C under
nitrogen atmosphere. A concentrated ammonia water and
ethyl acetate were added to the reaction mixture, and
the organic layer was partitioned. The organic layer
was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica
gel column chromatography (elution solvent: ethyl
acetate), and 321 mg of the title compound was
obtained. 15 XH-NMR (CDC13) 8 (ppm) : 3.98 (s, 3H) , 7.11-7.28 (m, 3H) ,
7.84-7.93 (m, 3H), 9.94 (s, 1H)
[0200]
Synthesis of (E)-3-[3-(IH-imidazol-l-yl)-4-
methoxyphenyl]-N-indan-1-yl-acrylamide
By the same method as in Example 1, 44 mg of
the title compound was obtained from 3-imidazol-l-yl-4-
methoxybenzaldehyde (33 mg)


(CDC13 ) 5 (ppm) : 1.84-1.93 (m, 1H) , 2.60-2.68 (m, 1H), 2.85-3.04 (m, 2H) , 3.87 (s, 3H), 5.61 (q, J=7.6 Hz, 1H), 6.28 (d, J=8 Hz, 1H) , 6.37 (d, J=15.6 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H) , 7.13-7.34 (m, 6H) , 7.41 (d, J=2 5 Hz, 1H), 7.47 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.64 (d, J=15.6 Hz, 1H), 7.72 (s, 1H). [0201] Example 18
Synthesis of (E)-3-[2-fluoro-5-methoxy-4-(4-methyl-lH-10 imidazol-1-yl)phenyl]-N-indan-1-yl-acrylamide [0202] [Formula 69]
(Figure Remove)
Synthesis of 4-bromo-5-fluoro-2-methoxyaniline
To a THF (20 mL) solution of 5-fluoro-2-methoxyaniline (1.76 g), a THF (30 mL) solution of pyridinium bromide perbromide (4.36 g) was added
dropwise under ice-cooling, and the reaction solution was agitated for 30 minutes at room temperature. The solid which deposited from the reaction mixture was separated by filtering and the solid was washed by THF. After the obtained solid was dissolved with water and
ethyl acetate, the aqueous layer was neutralized with a saturated sodium bicarbonate water, and the organic


layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was 5 purified by silica gel chromatography (elution solvent: hexane-ethyl acetate system), and 1.83 mg of the title compound was obtained.
^-NMR (CDC13) 5 (ppm) : 3.82 (s, 3H) , 3.91 (brs, 2H) , 6.50 (d, J=9.6 Hz, 1H), 6.84 (d, J=6.0 Hz, 1H).
[0203]
Synthesis of 1-(4-bromo-5~fluoro-2-methoxyphenyl)-4-methyl-lH-imidazole
By the same method as in Example 23, 326 mg of the title compound was obtained from 4-bromo-5-
fluoro-2-methoxyaniline (500 mg).
XH-NMR (CDC13) 5 (ppm): 2.29 (s, 3H), 3.85 (s, 3H), 6.89 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.19 (d, J=6.0 Hz, 1H), 7.70 (s, 1H). [0204]
Synthesis of (E) -3-[2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-indan-1-yl-acrylamide
By the same method as in Example 9, 31 mg of the title compound was obtained from 1-(4-bromo-5-fluoro-2-methoxyphenyl)-4-methyl-lH-imidazole (44 mg).
XH-NMR (CDC13) 6 (ppm): 1.86-1.95 (m, 1H), 2.29 (s, 3H), 2.63-2.72 (m, 1H), 2.88-3.07 (m, 2H), 3.86 (s, 3H), 5.65 (q, J=7.6 Hz, 1H), 5.97 (d, J=8 . 4 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.93 (s, 1H) , 7.05 (d, J=10.4 Hz,


1H), 7.08 (d, J=6.8 Hz, 1H), 7.21-7.27 (m, 3H), 7.34 (d, J=6.4 Hz, 1H), 7.71 (d, J=15.6 Hz, 1H), 7.76 (s, 1H) . [0205] Example 19
Synthesis of (E)-3-[2-fluoro-3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-indan-1-yl-acrylamide [0206] [Formula 70]
(Figure Remove)
Synthesis of 2,4-difluoro-3-methoxybenzaldehyde
Lithium diisopropyl amide (1.5M cyclohexane
solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2, 6-difluoroanisole (1.00 g) at -72°C under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated
for 30 minutes at -78°C, and then agitated at room
temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel


column chromatography (elution solvent: hexane-ethyl
acetate system) and 433 mg of the title compound was
obtained.
XH-NMR (CDC13) 6 (ppm) : 4.05 (s, 3H) , 6.99-7.05 (m, 1H) , 7.54-7.60 (m, 1H) , 10.27 (s, 1H) .
[0207]
Synthesis of (E)-3-[2-fluoro-3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl]-N-indan-1-yl-acrylamide
By the same method as in Example 1, 5 mg of 10 the title compound was obtained from 2,4-difluoro-2-
methoxybenzaldehyde (443 mg).
XH-NMR (CDC13) 6 (ppm): 1.86-1.95 (m, 1H), 2.30 (s, 3H),
2.64-2.73 (rn, 1H) , 2.89-3.07 (m, 2H) , 3.81 (s, 3H) ,
5.65 (q, J=7.6 Hz, 1H), 5.88 (d, J=8.4 Hz, 1H), 6.54 15 (d, J-15.6 Hz, 1H) , 6.98 (s, 1H) , 7.08 (dd, J=2 Hz, 8.4
Hz, 1H), 7.21-7.27 (m, 4H) , 7.35 (d, J=7. 6 Hz, 1H) ,
7.76 (d, J=15.6 Hz, 1H), 7.78 (s, 1H).
[0208]
Example 20 20 Synthesis of (E)-3-[4-(2-chloro-lH-imidazol-l-yl)-3-
methoxyphenyl]-N-indan-1-ylacrylamide
[0209]
[Formula 71]
O
(Figure Remove)

Synthesis of 4-(2-chloro-lH-imidazol-l-yl)-3-methoxybenzaldehyde and 4-(5-chloro-lH-imidazol-l-yl)-3-methoxybenzaldehyde
To a chloroform (3 mL) solution of the 4-(lH-5 imidazol-1-yl)-3-methoxybenzaldehyde (50 mg) obtained in Example 111, N-chlorosuccinimide (35 mg) was added, and the reaction solution was heated to reflux for 1.5 hours. The reaction mixture was allowed to be cooled and then purified by silica gel column chromatography
(elution solvent: hexane-ethyl acetate system), and 4-(2-chloro-lH-imidazol-l-yl)-3-methoxybenzaldehyde (13 mg) and 4-(5-chloro-lH-imidazol-l-yl)-3-methoxybenzaldehyde (14 mg) were obtained. The physical properties of 4-(2-chloro-lH-imidazol-l-
yl)-3-methoxybenzaldehyde are as follows.
XH-NMR (CDC13) 5 (ppm) : 3.92 (s, 3H) , 7.04 (d, J=1.4 Hz, 1H), 7.10 (d, J=1.4 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.57-7.59 (m, 2H), 10.6 (s, 1H). The physical properties of 4-(5-chloro-lH-imidazol-l-
yl)-3-methoxybenzaldehyde are as follows.
XH-NMR (CDC13) 5 (ppm): 3.92 (s, 3H), 7.10 (s, 1H), 7.47
(d, J=8 Hz, 1H), 7.58-7.60 (m, 3H) , 10.6 (s, 1H)
[0210]
Synthesis of (E)-3-[4-(2-chloro-lH-imidazol-l-yl)-3-
methoxyphenyl]-N-indan-1-ylacrylamide
By the same method as in Example 1, 18 mg of the title compound was obtained from 4-(2-chloro-lH-imidazol-1-yl)-3-methoxybenzaldehyde (13 mg).


(CDC13) 8 (ppm) : 1.86-1.96 (m, 1H) , 2.63-2.72 (m, 1H), 2.88-3.07 (m, 2H), 3.84 (s, 3H) , 5.64 (q, J=7.6 Hz, 1H), 5.94 (d, J=8.4 Hz, 1H) , 6.46 (d, J=15.4 Hz, 1H), 7.00 (d, J=1.0 Hz, 1H), 7.06 (d, J=l.0 Hz, 1H) , 5 7.14-7.36 (m, 7H), 7.70 (d, J=15.4 Hz, 1H). [0211] Example 21
Synthesis of (E)-3-[4-(5-chloro-lH-imidazol-l-yl)-3-methoxyphenyl]-N-indan-1-ylacrylamide [0212] [Formula 72]
(Figure Remove)
By the same method as in Example 1, 19 mg of
the title compound was obtained from 4-(5-chloro-lH-imidazol-1-yl)-3-methoxybenzaldehyde (14 mg). XH-NMR (CDC13) 6 (ppm): 1.86-1.96 (m, 1H), 2.63-2.72 (m, 1H), 2.86-3.07 (m, 2H), 3.84 (s, 3H) , 5.65 (q, J=7.6
Hz, 1H) , 6.01 (d, J=8.4 Hz, 1H) , 6.47 (d, J=15.4 Hz, 1H), 7.05 (s, 1H), 7.15-7.36 (m, 7H), 7.53 (s, 1H), 7.70 (d, J=15.4 Hz, 1H) . [0213] Example 22
Synthesis of (E)-N-indan-l-yl-3-[5-methoxy-6-(4-methyl-IH-imidazol-l-yl)pyridine-3-yl]acrylamide

(Figure Remove)

Synthesis of (E)-3-(5-methoxy-6-nitropyridin-3-yl)acrylic acid ethyl ester
To a DMF (20 mL) solution of 5-bromo-3-methoxy-2-nitropyridine (726 mg) synthesized according 5 to the method described in Acta Chemica Scandinavica vol.47, p.805, 1993, ethyl acrylate (0.44 mL), palladium acetate (35 mg) , 2-(di-tert-butylphosphino) biphenyl (93 mg) and TEA (0.87 mL) were added, and the reaction solution was agitated at 80°C for 3 hours.
After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution to separate an organic layer. After the obtained organic layer was dried over anhydrous
magnesium sulfate, solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 787 mg (69%) of (E)-3-(5-methoxy-6-riitropyridin-3-yl) acrylic acid ethyl ester was
obtained. The physical properties of the compound are as follows.


XH-NMR (CDC13) 8 (ppm) : 1.35 (t, J=7 . 6 Hz, 3H) , 4.01 (s, 3H), 4.28 (q, J=7 . 6 Hz, 2H), 6.58 (d, J=16.4 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.67 (d, J=16.4 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H). 5 [0215]
Synthesis of (E)-3-(6-amino-5-methoxypyridin-3-yl)acrylic acid ethyl ester
Iron (1.6 g) and ammonium chloride (3 g) were added to the suspension of (E)-3-(5-methoxy-6-
nitropyridin-3-yl)acrylic acid ethyl ester (787 mg) in ethanol (40 mL) and water (8 mL) obtained above, and the reaction solution was heated to reflux for 1 hour. After the reaction solution was allowed to be cooled to room temperature, deposited substance was filtered by
celite. Ethyl acetate and saturated sodium bicarbonate water were added to the filtrate, and the organic layer was partitioned. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate 2:1), and 506 mg (66%) (E)-3-(6-amino-5-methoxypyridin-3-yl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
1H-NMR (CDC13) 5 (ppm): 1.33 (t, J=7 .2 Hz, 3H), 3.88 (s, 3H), 4.25 (q, J=7.2 Hz, 2H), 5.02 (brs, 2H), 6.23 (d, J=16.0 Hz, 1H), 7.06 (d, J=l.6 Hz, 1H), 7.60 (d, J=16.0 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H).

[0216]
Synthesis of (E)-3-(6-chloro-5-methoxypyridin-3-yl)acrylic acid ethyl ester
Sodium nitrite (124 mg) was. added to a
concentrated hydrochloric acid (10 mL) solution of (E)-3- (6-chloro-5-methoxypyridin-3-yl)acrylic acid ethyl ester (200 mg) obtained above at 0°C. The reaction solution was agitated for 1 hour and 30 minutes at 0°C and further for 1 hour and 30 minutes at room
temperature. Then, the reaction solution was
neutralized with 8N sodium hydroxide solution, and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate 2:1), and 57 mg (26%) (E) -3-(6-chloro-5-methoxypyridin-3-yl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 1.35 (t, J=7.2 Hz, 3H), 3.96 (s, 3H), 4.28 (q, J=7.2 Hz, 2H) , 6.48 (d, J=16.4 Hz, 1H) , 7.29 (d, J=1.6 Hz, 1H), 7.64 (d, J=16.4 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H). [0217]
Synthesis of (E)-3-[5-methoxy-6-(4-methyl-lH-imidazol-1-yl)pyridine-3-yl]acrylic acid ethyl ester
4-methylimidazole (39 mg) and potassium carbonate (65 mg) were added to a DMF (5 mL) solution


of (E)-3-[5-methoxy-6-(4-methyl-lH-imidazol-l-yl)pyridin-3-yl]acrylic acid ethyl ester (57 mg) obtained above, and agitated at 120°C for 32 hours. After the reaction solution was allowed to be cooled to 5 room temperature, ethyl acetate was added to the
reaction solution and the organic layer was washed with a saturated sodium bicarbonate water. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The
obtained residue was purified by silica gel column
chromatography (elution solvent: ethyl acetate), and 12 mg (18%) (E)-3-[5-methoxy-6-(4-methyl-lH-imidazol-l-yl)pyridine-3-yl]acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
^-H-NMR (CDC13) 8 (ppm) : 1.35 (t, J=7.2 Hz, 3H) , 2.29 (s, 3H), 4.04 (s, 3H), 4.29 (q, J=7.2 Hz, 2H) , 6.48 (d, J=15.6 Hz, 1.H) , 7.45 (d, J=l.6 Hz, 1H), 7.56 (s, 1H), 7.67 (d, J=15.6 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 8.39 (s, 1H).
[0218]
Synthesis of (E)-N-indan-l-yl-3-[5-methoxy-6-(4-methyl-IH-imidazol-l-yl)pyridine-3-yl]acrylamide
IN sodium hydroxide solution (0.2 mL) was added to a methanol (0.5 mL) solution of (E)-3-[5-
methoxy-6-(4-methyl-lH-imidazol-l-yl)pyridine-3-
yl]acrylic acid ethyl ester (12 mg) obtained above, and agitated at room temperature for 12 hours. After adding IN hydrochloric acid water (0.2 mL) to the


reaction solution for neutralizing the reaction solution, it was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and 11 mg (100%) of (E)-3-[5-methoxy-6-(4-5 methy-lH-limidazol-1-yl)pyridine-3-yl]acrylic acid was obtained for by evaporating the solvent under reduced pressure. 4 mg (23%) of the title compound was obtained for by condensing 1-aminoindane (7.5 mg) with an acrylic acid compound obtained by the same method as
in Example 121. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 1.86-1.97 (m, 1H), 2.29 (s, 3H), 2.63-2.74 (m, 1H) , 2.88-3.09 (m, 2H), 3.99 (s, 3H), 5.65 (q, J=7.6 Hz, 1H) , 5.87 (brd, J=7.6 Hz, 1H), 6.46
(d, J=15.6 Hz, 1H) , 7.20-7.35 (m, 4H), 7.42 (d, J=1.6 Hz, 1H), 7.56 (s, 1H), 7.68 (d, J=15.6 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 8.39 (s, 1H) . [0219] Example 23
Synthesis of (E) -N-indan-l-yl-3-[6-methoxy-5-(4-methyl-l.H-imidazol-1-yl) pyridin-2-yl] acrylamide [0220] [Formula 74]
(Figure Remove)

256 Synthesisof 6-chloro-2-methoxy-3-nitropyridine
Sodium methoxide (1.40 g) was gradually added to a THF (50 mL) solution of 2,6-dichloro-3-nitropyridine (5.00 g) over 30 minutes under ice-5 cooling. Then, the reaction solution was agitated at 0°C for 1 hour, and agitated at room temperature for further 12 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate. After drying the
organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 2.90 g (58%) of 6-chloro-2-methoxy-3-
nitropyridine was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 4.16 (s, 3H) , 7.03 (d, J=8.8 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H) . [0221]
Synthesis of (E)-3-(6-methoxy-5-nitropyridin-2-yl)acrylic acid tert-butyl ester
To a DMF (10 mL) solution of 6-chloro-2-methoxy-3-nitropyridine (440 mg) obtained above, acrylic acid tert-butyl ester (0.44 mL), palladium
acetate (26 mg) , 2-(di-tert-butylphosphino)biphenyl (70 mg) and TEA (0.65 mL) were added, and the reaction solution was agitated at 120°C for 3 hours. After the reaction solution was allowed to be cooled to room


temperature, ethyl acetate and a saturated ammonium chloride solution were added and the reaction solution was partitioned. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated 5 under reduced pressure. The obtained residue was
purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 491 mg (75%) (E)-3-(6-methoxy-5-nitropyridin-2-yl)acrylic acid tert-butyl ester was obtained. The physical properties of
the compound are as follows.
1H-NMR (CDC13) 5 (ppm) : 1.55 (s, 9H) , 4.16 (s, 3H) , 6.93 (d, J=15.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H) , 7.47 (d, J=15.6 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H) . [0222]
Synthesis of (E)-3-(5-amino-6-methoxypyridin-2-yl)acrylic acid tert-butyl ester
Iron (780 mg) and ammonium chloride (1.5 g) were added to a suspension of (E)-3-(5-amino-6-methoxypyridin-2-yl)acrylic acid tert-butyl ester (491
mg) obtained above in ethanol (40 mL) and water (8 mL), and heating refluxing of the reaction solution was carried out for 7 hours. After the reaction solution was allowed to be cooled to room temperature, deposited substance was filtered by celite. Ethyl acetate and
saturated sodium bicarbonate water were added to the filtrate and the organic layer was partitioned. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced


pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 340 mg (78%) (E)-3-(5-amino-6-methoxypyridin-2-yl)acrylic acid tert-butyl ester was 5 obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.56 (s, 9H) , 4.01 (s, 3H) , 4.03 (brs, 2H), 6.63 (d, J=15.6 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 7.40 (d, J=15.6 Hz, 1H) .
[0223]
Synthesis of (E)-3-(5-formylamino-6-methoxypyridin-2-yl)acrylic acid tert-butyl ester
A methylene chloride (3 mL) solution of (E)-3-(5-formylamino-6-methoxypyridin-2-yl)acrylic acid
tert-butyl ester (136 mg) obtained above was added
dropwise to a mixed solution of acetic anhydride (0.2 mL) and formic acid (0.4 mL) agitated at room temperature for 10 minutes. After agitating reaction solution at room temperature for 20 minutes, ethyl
acetate and a saturated sodium bicarbonate water were added to the reaction solution and the organic layer was partitioned. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 1:1), and 151 mg (69%) (E) -3- (5-forrnylamino-6-methoxypyridin-2-yl) acrylic acid tert-butyl ester was obtained. The physical properties


of the compound are as follows.
XH-NMR (CDC13) S (ppm) : 1.54 (s, 9H) , 4.06 (s, 3H) , 6.76 (d, J=15.6 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.79 (brs, 1H) , 8.50 (s, 1H), 8.57 (d, 5 J=8.8 Hz, 1H). [0224]
Synthesis of (E)-3-{5-[formyl(2-oxopropyl)amino]-6-methoxypyridin-2-yl}acrylic acid tert-butyl ester
Cesium carbonate (490 mg), potassium iodide
(13 mg) and chloroacetone (0.12 mL) were added to a DMF (2 mL) solution of (E)-3-{5-formyl(2-oxopropyl)amino]-6-methoxypyridin-2-yl}acrylic acid tert-butyl ester (104 mg) obtained above, and the reaction solution was agitated at room temperature for 10 hours. Then, ethyl
acetate and saturated sodium bicarbonate water were added to the reaction solution and the organic layer was partitioned, and the solvent was evaporated under reduced pressure after the organic layer was dried over anhydrous magnesium sulfate. The obtained residue was
purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate = 1:1), and 116 mg (93%) of (E)-3-{5-[formyl(2-oxopropyl)amino]-6-methoxypyridin-2-yl}acrylic acid tert-butyl ester was obtained. The physical properties of the compound are
as follows.
^-NMR (CDC13) 5 (ppm): 1.53 (s, 9H) , 2.16 (s, 3H) , 4.00 (s, 3H), 4.50 (s, 2H), 6.81 (d, J=15.6 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.43 (d, J=15.6 Hz, 1H), 7.55 (d,


J=8.8 Hz, 1H), 8.28 (s, 1H) . [0225]
Synthesis of (E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-
l-yl)pyridin-2-yl]acrylic acid tert-butyl ester
Ammonium acetate (130 mg) was added to an
acetic acid (2 mL) solution of (E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyridin-2-yl]acrylic acid tert-butyl ester (116 mg) obtained above, and the reaction solution was agitated at 120°C for 3 hours.' Then, after
the reaction solution was allowed to be cooled to room temperature, the reaction solution was diluted with ethyl acetate and the resultant mixture was neutralized with a saturated sodium bicarbonate water. After separating and drying the organic layer with anhydrous
magnesium sulfate, the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and 40 mg (37%) (E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyridin-2-yl]acrylic acid tert-
butyl ester was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 1.55 (s, 9H) , 2.30 (s, 3H) , 4.06 (s, 3H), 6.86 (d, J=15.6 Hz, 1H), 6.99 (s, 1H), 7.05 (d, J=8.8 Hz, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.52 (d,
J=8.8 Hz, 1H), 7.82 (s, 1H). [0226]
Synthesis of (E)-N-indan-l-yl-3-[6-methoxy-5-(4-methyl-IH-imidazol-l-yl)pyridin-2-yl]acrylamide


An ethyl acetate solution (3 mL) of 4N hydrochloric, acid was added to (E)-N-indan-l-yl-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]acrylamide (20 mg) obtained above, and the reaction 5 solution was agitated at room temperature for 3 hours. Then, the reaction solution was concentrated under reduced pressure. 20 mg (69%) of the title compound was obtained by condensing the obtained crude acrylic acid compound with 1-aminoindane (0.015 mL) by the same
method as in Example 121. The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 1.86-1.97 (m, 1H) , 2.30 (s, 3H) , 2.64-2.74 (m, 1H), 2.88-3.09 (m, 2H), 4.04 (s, 3H), 5.65 (q, J=7.6 Hz, 1H) , 5.95 (brd, J=7.6 Hz, 1H), 6.95
(d, J=15.6 Hz, 1H) , 6.98 (brs, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.20-7.39 (m, 4H), 7.56 (d, J=8.8 Hz, 1H), 7.60 (d, J=15.6 Hz, 1H), 7.81 (brs, 1H). [0227] Example 24
Synthesis of (E)-N-indan-l-yl-3-[4-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyridin-2-yl]acrylamide [0228] [Formula 75]
(Figure Remove)



262 Synthesis of 5-bromo-4-methoxypyridine-2-carbaldehyde
Dess-Martin reagent (1.14 g) was added at 0°C to a methylene chloride (5 mL) solution of (5-bromo-4-methoxypyridin-2-yl)methanol (450 mg) synthesized by 5 the method described in Organic Process Research & Development 2000 4,473. The reaction solution was agitated at 0°C for 1 hour and further agitated at room temperature for 1 hour. IN sodium hydroxide solution was added to the reaction solution, the organic layer
was separated, and washed with a saturated sodium
chloride solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate 1:1), and 300 mg (67%) 5-bromo-4-methoxypyridine-2-carbaldehyde was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13 ) 8 (ppm) : 4.04 (s, 3H) , 7.48 (s, 1H) , 8.75
(s, 1H), 10.1 (s, 1H). [0229]
Synthesis of (E)-3-(5-bromo-4-methoxypyridin-2-yl)acrylic acid tert-butyl ester
Diethylphosphonoacetic acid tert-butyl ester
(0.26 mL) was added to a THF (4 mL) suspension of
sodium hydride (45 mg), and the reaction solution was agitated at room temperature for 1 hour. Then, the reaction solution was cooled to 0°C, and a THF (1 mL)


solution of 5-bromo-4-methoxypyridine-2-carbaldehyde (200 mg) obtained above was added dropwise to the reaction solution. The reaction solution was agitated for Ih at 0°C and further agitated for 12h at room 5 temperature. A saturated ammonium chloride solution was added to the reaction solution after the reaction ended, and the reaction solution was extracted with ethyl acetate to separate an organic layer. After drying the organic layer over anhydrous magnesium
sulfate, the solvent was evaporated under reduced
pressure. The obtained residue was purified by silica gel column chrornatography (elution solvent: heptane-ethyl acetate 2:1), and 116 mg (40%) (E)-3-(5-bromo-4-methoxypyridin-2-yl)acrylic acid tert-butyl ester was
obtained. The physical properties of the compound are as follows.
1H-NMR (CDC13) 8 (ppm): 1.53 (s, 9H), 3.98 (s, 3H), 6.82 (d, ,7=15.6 Hz, IH) , 6.92 (s, IH) , 7.49 (d, J=15.6 Hz, IH), 8.56 (s, IH).
[0230]
Synthesis of (E)-3-(5-amino-4-methoxypyridin-2-yl)acrylic acid tert-butyl ester
Benzophenone imine (0.04 mL), sodium tert-butoxide (26 mg) and DPPF (13 mg), and bis(1,5-
cyclooctadiene) nickel (0) were added to a toluene (3 mL) solution of (E)-3-(5-bromo-4-methoxypyridin-2-yl)acrylic acid tert-butyl ester (70 mg) obtained above, and heating refluxing of the solution was


carried out for 14 hours. After the reaction solution was allowed to be cooled to room temperature, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column 5 chromatography (elution solvent: heptane-ethyl acetate 3:1), and 45 mg of (49%) imine compound was obtained. Hydroxylamine hydrochloride (15 mg) and sodium acetate (30 mg) were added to a methanol (3 mL) solution of the obtained imine compound, and the reaction solution was
agitated at room temperature for 1 hour. A saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution after the reaction ended, and the organic layer was separated. After drying the organic layer with anhydrous magnesium sulfate, the
solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate = 1:2), and 20 mg (73%) (E)-3-(5-amino-4-methoxypyridin-2-yl)acrylic acid tert-butyl ester was
obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.52 (s, 9H) , 3.91 (s, 3H) , 3.93 (brs, 2H), 6.54 (d, J=15.6 Hz, 1H), 6.88 (s, 1H), 7.49 (d, J=15.6 Hz, 1H) , 8.00 (s, 1H) .
[0231]
Synthesis of (E)-3-[4-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyridin-2-yl]acrylic acid tert-butyl ester
By the same method as in Example 23, 15 mg


(60%) of (E)-3-(4-methoxy-5-(4-methylimidazol-l-yl)pyridin-2-yl)acrylic acid tert-butyl ester was obtained from (E)-3-(5-amino-4-methoxypyridin-2-yl)acrylic acid tert-butyl ester (20 mg) obtained 5 above. The physical properties of the compound are as follows.
XH-NMR (CDC13) 6: 1.54 (s, 9H) , 2.31 (s, 3H), 3.97 (s, 3H), 6.83 (d, J=15.6 Hz, 1H), 6.93 (s, 1H), 7.07 (s, 1H), 7.55 (d, J=15.6 Hz, 1H), 7.74 (s, 1H), 8.45 (s,
1H) .
[0232]
Synthesis of (E)-N-indan-l-yl-3-[4-methoxy-5-[4-methyl-
IH-imidazol-l-yl)pyridin-2-yl]acrylamide
By the same method as in Example 23, 4 mg
(27%) (E)-N-indan-l-yl-3-[4-methoxy-5-(4-
methylimidazol-1-yl)pyridin-2-yl)acrylamide was obtained from (E)-3-(4-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyridin-2-yl)acrylic acid tert-butyl ester (15 mg) obtained above and 1-aminoindan. The physical
properties of the compound are as follows.
^H-NMR (CDC13) S (ppm): 1.84-1.96 (m, 1H), 2.30 (s, 3H), 2.65-2.74 (m, 1H), 2.88-3.08 (m, 2H), 3.98 (s, 3H), 5.65 (q, J=7.6 Hz, 1H), 6.00 (brd, J=7.6 Hz, 1H), 6.93 (s, 1H), 7.01 (d, J=15.6 Hz, 1H), 7.05 (s, 1H), 7.21-
7.37 (m, 4H), 7.66 (d, J=15.6 Hz, 1H) , 7.72 (s, 1H), 8.43 (s, 1H). [0233] Example 24-1


Synthesis of (E)-N-(9H-fluoren-9-yl)-3-(3-fluoro-4-(1H imidazol-1-yl)phenyl]acrylamide [0234] [Formula 76]
(Figure Remove)
By the same method as in Example 12, 7.6 mg of the title compound was obtained from (E)-3-(3-5 fluoro-4-(IH-imidazol-l-yl)phenyl]acrylic acid (14 mg) and 9-aminofluorene hydrochloride (20 mg). The physical properties of the compound are as follows. ESI-MS; m/z396 [M++H] [0235]
According to the Example 1, the combination
of an imidazole derivative and a benzaldehyde derivative was changed, and the compounds shown in Table 2 were synthesized. The structural formulae and physicochemical properties are shown in Table 2,
respectively.

[0236] [Table 2-1;
(Figure Remove)

Example Ei E2 E3 E4 Data:MS m/z
M++H:344
25 Me H H H (ESI)
26 F Me H H (ESI)
M++H:362
27 F H Me H (ESI)
r^Y* M++H:424
28 F H LJ H (ESI)
M++H:393
29 F H N02 H (ESI)
M++H:378
30 F H HOCH2- H (ESI)
M++H:374
31 MeO H H Me (ESI)
M++H:426
32 F H Br H (ESI)
M++H:376
33 F H Me Me (ESI)
M++H:438
34 MeO H Br H (ESI)
M++H:374
35 MeO Me H H (ESI)
M++H:388
36 MeO H Et H (ESI)
M++H:428
37 MeO H CF3 H (ESI)
M++H:385
38 MeO H NC- H (ESI)
.""V^ M+-fH:436
39 u H H H (ESI)
fV"* M++H:422
40 U H H H (ESI)
- Continued

[0237] [Table 2-2]
(Figure Remove)

Example Ei E2 E3 E4 DATA: MS m/z
41 X%TX~Xx'0-* H H H M++H:450 (ESI)
42 Br H H H M++H:408 (ESI)
43 Cl H Me H M++H:378 (ESI)
44 Br H Me H M++H:422 (ESI)
45 MeO H HOCH2- H M++H:390 (ESI)
46 MeO H (X* H M++H:450 (ESI)
47 MeO H F H M">H:378 (ESI)
48 MeO H H*C*Y-*
Me H M++H:400 (ESI)
49 MeO H i-Pr H M++H:402 (ESI)
50 MeO H °Y
Me H M++H:402 (ESI)
51 H Me Me H M++H:358 (ESI)
52 H H Me H M++H:344 (ESI)
53 MeO H Cl H M'1"+H:394 (ESI)
- Continued -


[0238] [Table 2-3]
(Figure Remove)

Example Ei E2 E3 E4 DATA: MS m/z
54 O~ H H H M++H:400 (ESI)
55 SMe H H H M++H:376 (ESI)
56 S02Me H H H M++H:408 (ESI)
57 N
°x. H Me H M++H:398 (ESI)
58 o^^Sss-^' NS* H Me H M++H:418 (ESI)
59 9
°x. H Me H M++H:428 (ESI)
60 F3CO-^ H Me H M++H:428 (ESI)
61 s
°x. H Me H M++H:400 (ESI)
62 °v. H Me H M++H:402 (ESI)
63 MeO H ± H M++H:416 (ESI)
64 MeO H ^ H M++H:400 (ESI)
65 MeO H * H M++H:486 (ESI)
- Continued -

[0239]
The compound shown in Table 3 were synthesized as in Example 10. These structural formulae and physicochemical properties are shown in Table 3, respectively.

[0240] [Table 3;



(Table Remove)
[0241] Example 75
Synthesis of N-(9H-fluoren-9-yl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl)propiolic acid amide [0242] [Formula 77]
O
(Figure Remove)
Synthesis of N-(4-bromo-2-methoxyphenyl)-2,2,2-
trifluoroacetamide
[0243]
Trifluoroacetic anhydride (24 mL) was added
dropwise to a pyridine (48 mL) solution of 4-bromo-2-10 methoxyaniline (23.4 g) under ice-cooling. The
reaction solution was stirred for an hour and iced
water was added thereto. Crystals deposited were
separated by filtering, and air-dried overnight. 32.4
g of the title compound was obtained. 15 ^H-NMR (CDC13) 8(ppm): 3.93 (s, 3H) , 7.07 (d, J=2.4 Hz,
1H), 7.16 (dd, J=8.8, 2.4 Hz, 1H), 8.21 (d, J=8.8 Hz,
1H), 8.47 (brs, 1H).
[0244]
Synthesis of 1-(4-bromo-2-methoxyphenyl)aminopropan-2- one
Chloroacetone (20 g) was added dropwise to a
DMF (160 mL} suspension of N-(4-bromo-2-methoxyphenyl)-


2,2,2-trifluoroacetamide (32.4 g), cesium carbonate (71 g) and potassium iodide (1.8 g) , and the reaction solution was agitated at room temperature for 2 hours. Then, The reaction solution was stirred for 1 hour and 5 iced water was added thereto. Crystals deposited were separated by filtering. The obtained crystal was suspended in methanol (360 mL) and 2N sodium hydroxide solution (55 mL), and the suspension was agitated for 30 minutes. An iced water was added thereto. Crystals
deposited were separated by filtering, and air-dried overnight. 25.2 g of the title compound was obtained. ^-NMR (CDC13) 5(ppm): 2.25 (s, 3H) , 3.85 (s, 3H) , 3.97 (d, J=5.2 Hz, 2H), 5.05 (brs, 1H) , 6.29 (d, J=8.4 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H) , 6.94 (dd, J=8.4, 2.0 Hz,
1H) . [0245]
Synthesis of N-(4-bromo-2-methoxyphenyl)-N- (2-oxopropyl)acetamide
A mixture of acetic anhydride (40 g) and
formic acid (90 g) was agitated under ice-cooling for 30 minutes. A methylene chloride (65 mL) solution of 1-(4-bromo-2-methoxyphenyl)propan-2-one(25.2 g) was added dropwise to the solution, and the reaction solution was agitated for 30 minutes. The reaction
solution was extracted with ether after neutralized with a sodium hydroxide solution. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under


reduced pressure. The residue was filtered, washed with ether and air-dried, and 23.4 g of the title compound was obtained.
'•H-NMR (CDC13) 5(ppm): 2.17 (s, 3H) , 3.84 (s, 3H) , 4.43 5 (s, 2H), 7.09 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.0, 2.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 8.23 (s, 1H) . [0246]
Synthesis of 1-(4-bromo-2-methoxyphenyl)-4-methyl-lH-imidazole
A mixture of N-(4-bromo-2-methoxyphenyl)-N-
(2-oxopropyl)acetamide (23.4 g), ammonium acetate (31.5 g), and acetic acid (49 g) was agitated under heating at 120°C for 30 minutes. After the reaction solution was neutralized with sodium hydroxide under ice-
cooling, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: hexane-ethyl acetate system), and 19.4 g of the title compound was obtained. ^H-NMR (CDC13) 5(ppm): 2.29 (s, 3H) , 3.85 (s, 3H), 6.87 (s, 1H) , 7.10-7.18 (m, 3H), 7.65 (s, 1H) . [0247]
Synthesis of 1-(4-iodine-2-methoxyphenyl)-4-methyl-lH-imidazole
A 1,4-dioxane (50 mL) suspension of l-(4-bromo-2-methoxyphenyl)-4-methyl-lH-imidazole (10.0 g)


and copper iodide (I) (I) (7.13 g), sodium iodide (11.2 g) and N,N'-dimethyl ethylene diamine (6.59 g) was agitated at 110°C for 9 hours. Ethyl acetate and a saturated ammonium chloride solution were added to the 5 reaction solution after cooling reaction solution to room temperature, and the reaction solution was agitated for 30 minutes. After celite filtration, the organic layer of the filtrate was washed with a saturated saline solution, and the reaction solution
was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), and 4.07 g of the title compound was obtained.
^-NMR (CDC13) 8(ppm): 2.29 (s, 3H) , 3.86 (s, 3H) , 6.82 (s, 1H), 6.97 (d, J=8.0 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.36 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (s, 1H). [0248] Synthesis of tert-butyl(3-methoxy-4-(4-methyl-lH-
imidazol-l-yl)phenyl]propiolic acid ester
A DMF (17 mL) suspension of 1-(4-iodine-2-methoxyphenyl)-4-methyl-lH-imidazole (2.67 g) and tert-butyl propiolate (2.14 g), dichlorobis(triphenylphosphine)palladium(II) (300 mg),
potassium carbonate (2.35 g) and iodation copper (I) (162 mg) was agitated under heating at 100°C for 20 minutes. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution


after cooling reaction solution to room temperature, and the reaction solution was agitated for 30 minutes. After washed with a saturated saline solution, reaction solution was dried over anhydrous magnesium sulfate and 5 the separated organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system), and 2.45 g of the title compound was obtained. XH-NMR (CDC13) 5(ppm): 1.56 (s, 9H) , 2.29 (s, 3H), 3.87
(s, 3H), 6.93 (s, 1H), 7.21-7.24 (m, 3H), 7.78 (s, 1H). [0249]
Synthesis of [3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]propiolic acid
Trifluoroacetic acid (6.0 mL) was added to a
methylene chloride (30 mL) solution of tert-butyl (3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl)propiolic acid ester (2.45 g) under ice-cooling, and the reaction solution was agitated at room temperature overnight. The reaction solution was concentrated under reduced
pressure and diluted with ethyl acetate. Crystals deposited were separated by filtering, and air-dried overnight. 1.45 g of the title compound was obtained. XH-NMR (DMSO-d6) 5(ppm): 2.32 (s, 3H) , 3.92 (s, 3H) , 7.44 (dd, J=8.0, 1.6 Hz, 1H), 7.61 (d, J=l.6 Hz, 1H),
7.66 (d, J=8.0 Hz, 1H), 7.71 (s, 1H) , 9.18 (s, 1H) . [0250]
Synthesis of N-(9H-fluoren-9-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]propiolic acid amide


A DMF (2 mL) solution of [3-methoxy-4- (4-methyl-lH-imidazol-l-yl)phenyl]propiolic acid (74 mg) and 9-aminofluorene (65 mg) and BOP (133 mg) and N, N'-IPEA (77f.iL) was agitated at room temperature overnight. 5 Water and chloroform were added to the reaction solution, the organic layer was partitioned and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex NH, elution solvent: heptane-ethyl acetate
system), and 45 mg of the title compound was obtained. ESI-MS; m/z420 [M++H].
^-NMR (DMSO-de) 6(ppm): 2.14 (s, 3H) , 3.86 (s, 3H) , 6.11 (d, J=8.0 Hz, 1H) , 7.18 (s, 1H), 7.26 (d, J=6.4 Hz, 1H), 7.34-7.47 (m, 6H), 7.55 (d, J=7.6 Hz, 2H),
7.84 (s, 1H), 7.88 (d, J=7 . 6 Hz, 2H), 9.47 (d, J=8.0' Hz, 1H).
ESI-MS; m/z420 [M++H]. [0251]
The compounds shown in Table 4 were
synthesized as in Example 75. The structural formulae and physicochemical properties are shown in Table 4, respectively.

[0252] [Table 4]
(Table Remove)
[0253] Example 85
Synthesis of (E)-2-fluoro-N-[(IR)-hydroxymethyl-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-5 yl)phenyl]acrylamide [0254] [Formula 78]
(Figure Remove)
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylic acid ethyl ester
To a THF (15 mL) solution of sodium hydride (814 mg) triethylphosphonoacetic acid (4.1 mL) was
added at 0°C, and the reaction solution was agitated at 0°C for 30 minutes and at room temperature for 1 hour. After cooling the reaction solution at 0°C, the THF (5 mL) solution of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (4.0 g) synthesized in Example 1 was
added dropwise to the reaction solution. The reaction solution was further agitated at 0°C for 30 minutes and then at room temperature for 2 hours. Ethyl acetate and water was added to the reaction solution, and the organic layer was separated and washed with a saturated
ammonium chloride solution. After drying with
anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. By re-crystallizing the


obtained solid using a mixed solution of hexane and ethyl acetate, the 4.55 g (86%) title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8(ppm): 1.71 (t, J=7.8 Hz, 3H) , 2.60 (s, 3H), 3.79 (s, 3H), 4.58 (q, J=7.8 Hz, 2H), 6.45 (d, J=16.2 Hz, 1H), 6.95 (m, 1H), 7.17 (d, J=l.6 Hz, 1H), 7.19 (dd, J=8.4, 1.6 Hz, 1H), 7.28 (d, J=8.4 Hz.lH), 7.68 (d, J=16.2 Hz, 1H) , 7.72 (d, J=1.2 Hz, 1H) .
[0255]
Synthesis of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylic acid ethyl ester
2-fluoro malonic acid diethyl ester (670 jiL) was added to a THF (8 mL) suspension of sodium hydride
(170 mg) under ice-cooling, and the reaction solution was agitated under ice-cooling for 20 minutes and further agitated at room temperature for 1 hour. After dropping the THF (2 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid ethyl
ester (1 g) obtained above to the reaction solution
over 10 minutes and the reaction solution was agitated at room temperature for 30 minutes, and heated to reflux for 8 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate
and water was added and the organic layer was washed with a saturated ammonium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced


pressure. The obtained residue was purified by silica gel column chromatography (Carrier : Chromatorex™ NH, elution solvent: from hexane to hexane : ethyl acetate = 1:1), and 593 mg (56%) of (E)-2-fluoro-3-(3-methoxy-5 4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
ESI-MS; m/z305 [M++H].lH-NMR (CDC13) 8(ppm): 1.42 (t, J=7.8 Hz, 3H), 2.31 (s, 3H) , 3.89 (s, 3H) , 4.38 (q,
J=7.8 Hz, 2H), 6.92 (d, J=36 Hz, 1H), 6.95 (m, 1H), 7.26 (d, J=8.4 Hz, 1H) , 7.31 (dd, J=8.4, 1.6 Hz, 1H), 7.37 (brs, 1H), 7.76 (d, J=l.6 Hz, 1H). [0256] Synthesis of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl]acrylic acid
2N sodium hydroxide solution (2 mL) was added to a solution of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylic acid diethyl ester (593 mg) in THF (1 mL) and ethanol (4 mL). The reaction
solution was agitated at room temperature for 15 hours, neutralized with 2N hydrochloric acid (2 mL). The solid deposited from the reaction solution was separated by filtering and 512 mg (95%) of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]acrylic acid was obtained by washing the solid with ethanol. The physical properties of the compound are as follows. 1H-NMR (DMSO-d6) 6(ppm): 2.15 (s, 3H), 3.85 (s, 3H),


7.06 (d, J=36.0 Hz, 1H), 7.18 (m, 1H) , 7.38 (dd, J=8.4,
1.6 Hz, 1H), 7.44 (dd, J=8.4, 1H), 7.51 (brs, 1H), 7.84
(d, J=1.6 Hz, 1H).
[0257] 5 Synthesis of (E)-2-fluoro-N-[(IR)-hydroxymethyl-2-
phenylethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]acrylamide
71 mg (74%) of the title compound was
obtained from (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-lH- imidazol-1-yl)phenyl)acrylic acid (65 mg) and D-
phenylalanilol (43 mg) which were obtained by the same
method as in Example 121. The physical properties of
the compound are as follows.
ESI-MS; m/z410 [M++H].lH-NMR (CDC13) 6: 2.30 (s, 3H), 15 2.98 (d, J=7.2 Hz, 2H), 3.69 (dd, J=6.8, 4.8 Hz, 1H),
3.77 (dd, J=6.8, 4.8 Hz, 1H), 3.87 (s, 3H), 4.30-4.39
(m, 1H), 6.64 (brd, 1H), 6.90 (d, J=36.0 Hz, 1H), 6.94
(brs, 1H), 7.38 (dd, J=8.4, 1.6 Hz, 1H) , 7.25-7.38 (m,
8H) , 7.74 (d, J=1.6 Hz, 1H) . 20 [0258]
Example 86
Synthesis of N-(9H-fluoren-9-yl)-2-fluoro-3-[3-methoxy-
4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylamide
[0259]
[Formula 79]
(Figure Remove)



By the same method as in Example 86, 46 mg (36%) of the title compound was obtained from the 2-fluoro-3-(3-methoxy~4-(4-methyl-imidazol-l-yl)phenyl)acrylic acid (80 mg) obtained in the Example 5 85 and 9-aminofluorene hydrochloride (64 mg). The physical properties of the compound are as follows. ^-NMR (DMSO-de) 8(ppm): 2.15 (s, 3H) , 3.85 (s, 3H) , 6.17 (brd, 1H), 7.10 (d, J=38.0 Hz, 1H), 7.18 (brs, 1H), 7.28-7.55 (m, 9H), 7.83 (d, J=1.6Hz, 1H), 7.88
10 (d, J=7.6, 2H), 9.30 (d, J=8.8 Hz, 1H) . [0260] Example 87
Synthesis of (E)-2-fluoro-N-(4-fluoro-3-morpholin-4-yl-benzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]acrylamide [0261] [Formula 80]

(Figure Remove)
By the same method as in Example 85, 43.8 mg of the title compound was obtained from (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (40.0 mg) and 4-fluoro-3-morpholin-4-yl-20 benzylamine (32.0 mg). The physical properties of the compound are as follows.


(CDC13) $ (ppm) : 7.74 (d, J=l. 6 Hz, 1H) , 7.27-7.29 (m, 3H), 7.00-7.05 (m, 2H) , 6.89-6.95 (m, 3H) , 6.61-6.67 (br, 1H), 4.54 (d, J=6.0 Hz, 2H), 3.88 (s, 3H), 3.86-3.89 (m, 4H), 3.09-3.11 (m, 4H), 2.30 (s, 5 3H) . [0262] Example 88
Synthesis of (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)-phenyl]-N-methyl-N-(2-morpholin-4-yl-l-10 phenylethyl)acrylamide [0263] [Formula 81]
(Figure Remove)
By the same method as in Example 85, 51.5 mg of the title compound was obtained from (E)-2-fluoro-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylic acid (45.0 mg) and methyl-(2-morpholin-4-yl-
phenylethyl) amine (1M DMF solution, 245 \iL) . The physical properties of the compound are as follows. XH-NMR (CDC13) 6 (ppm): 7.74 (s, 1H), 7.30-7.42 (m, 4H) , 7.21-7.28 (m, 4H), 6.94 (s, 1H), 6.62 (d, J=38 Hz.lH), 3.88 (s, 3H), 3.64-3.74 (m, 4H), 2.94-3.20 (m, 1H),
2.80-2.90 (m, 4H) , 2.62-2.74 (br, 2H) , 2.43-2.50 (m,


3H), 2.30 (s, 3H) [0264] Example 89
Synthesis of (E)-2-1luoro-N-[(IR, 2S)-2-hydroxy-indan-l-5 yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-methyl-acrylamide [0265] [Formula 82]
(Figure Remove)
By the same method as in Example 85, 76.0 mg
of the title compound was obtained from (E)-2-fluoro-3-
[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (60.0 mg) and (IR,2S)l-methylamino-indan-2-ol
(42.5 mg). The physical properties of the compound are
as follows.
XH-NMR (CDC13) 5 (ppm) : 7.74 (s, 1H) , 7.24-7.34 (m, 7H),
6.95 (s, 1H), 6.73 (d, J=37 Hz, 1H), 5.66-5.74 (m, 1H) , 4.90-4.96 (m, 1H), 3.89 (s, 3H), 3.35 (dd, J=7.2, 17
Hz, 1H), 2.94-3.02 (m, 1H), 2.86-2.90 (m, 3H), 2.30 (s,
3H) .
[0266]
Example 90 20 Synthesis of (E)-2-fluoro-N-[(IR,2S)-2-hydroxy-indan-l-
yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-



yl)phenyl]acrylamide [0267] [Formula 83] (Figure Remove)






By the same method as in Example 85, (E)-2-
fluoro-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl)acrylic acid (60.0 mg) and 76.0 mg of 5 (IR,23)l-amino-2-indanol (38.8 mg) title compounds were
obtained. The physical properties of the compound are
as follows.
XH-NMR (CDC13) 8 (ppm) : 7.72 (s, 1H), 7.25-7.35 (m, 7H) ,
7.16 (d, J=8.4 Hz, 1H), 6.98 (d, J=38 Hz, 1H), 6.94 (s, 1H), 5.54 (dd, J=5.2, 8.4 Hz, 1H), 4.77 (dt, J=2.0, 5.2
Hz, 1H), 3.86 (s, 3H), 3.26 (dd, J=5.2, 16 Hz, 1H),
3.05 (dd, J=2.0, 16 Hz, 1H) , 2.29 (s, 3H)
[0268]
Example 91 15 Synthesis of (E)-3-(4-imidazol-yl-3-methoxyphenyl)-N-
indan-yl-2-methyl-acrylamide
[0269] [Formula 84]

(Figure Remove)


Triethyl-2-phosphonopropionic acid ester (116 \iL) and sodium hydride (43.0 mg) were added at 0°C one by one to a DMF (5.0 mL) solution of 4-(IH-imidazol-l-yl)-3-raethoxybenzaldehyde (100 mg) obtained in the 5 Example 111. The reaction solution was warmed to room temperature and agitated overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and 68.0 mg of crude carboxylic acid was obtained by condensing under reduced pressure. Next, 25.3 mg of the title compound was obtained from the obtained carboxylic acid (30.5 mg) and 1-aminoindan (24.0 jaL) by
the same method as in Example 324. The physical properties of the compound are as follows. ^-NMR (CDC13) 6 (ppm) : 7.82 (s, 1H) , 7.41 (s, 1H) , 7.37 (d, J=6.0 Hz, 1H), 7.247.30 (m, 4H), 7.23 (s, 1H) , 7.18 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 7.01 (s, IE), 6.14 (d,
J=7.6 Hz, 1H), 5.64 (q, J=7.6 Hz, 1H), 3.86 (s, 3H) , 3.05 (ddd, J=4.0, 8.8, 16 Hz, 1H), 2.94 (td, J=8.0, 16 Hz, 1H), 2.71 (dtd, J=4.0, 8.0, 12 Hz, 1H), 2.16 (s, 3H), 1.86-1.96 (m, 1H) [0270]
Example 92
Synthesis of (E)-2-cyano-3-[4-(IH-imidazol-l-yl)-3-methoxyphenyl)-N-indan-1-yl-acrylamide [0271]

[Formula 85]
o
(Figure Remove)
Cyano ethyl acetate (76.0 jaL) and piperidine were added one by one to an ethanol solution (5.0 mL) of 4-(lH-imidazol-l-yl-3-methoxybenzaldehyde (144 mg) obtained in Example 111 (35.0 \iL) . The reaction 5 solution was refluxed for 3.5 hours, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to obtain the crude ester product. 2N sodium hydroxide solution (1.0 mL) was added to a THF (2 mL) solution of the obtained ester product, and the reaction solution was agitated for 45 minutes at room temperature. Then, the reaction
solution was warmed up to 50°C, it was agitated for
further 9 hours. Crude carboxylic acid sodium salt was obtained by condensing the reaction solution as it was under reduced pressure. 1.0 mg of the title compound was obtained from the obtained carboxylic acid sodium
salt and 1-aminoindan (41.0 (J.L) by the same method as in Example 324. The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 8.11 (s, 1H), 7.68 (s, 1H),


7.24-7.38 (m, 9H) , 6.41 (d, J=7.6 Hz, 1H), 5.73 (q, J=7.6 Hz, 1H), 3.96 (s, 3H) , 3.08 (ddd, J=4.0, 8.8, 16 Hz, 1H) , 2.88-3.00 (m, 1H) , 2.75 (tdt, J=4.0, 8.0, 13 Hz, 1H) , 1.93-2.02 (m, 1H) . 5 [0272]
Example 93
Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)-phenyl]-2-butenone acid indan-1-ylamide [0273] [Formula 86]
O
(Figure Remove)
Synthesis of 1-[3-fluoro-4-(IH-imidazol-l-yl)-
phenyl]ethanone
Imidazole (543 mg) and potassium carbonate (1.80 g) were added to a DMF (15 mL) solution of 3,4-difluoroacetophenone (1.0 mL). After agitating reaction solution at 80°C for 4 hours, water and ethyl
acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (elution
solvent: hexane: ethyl acetate = 5:1 -> ethyl acetate), and 1.40 g of the title compound was obtained. The


physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm) : 7.95 (s, 1H) , 7.86-7.92 (m, 2H) , 7.52-7.59 (m, 1H), 7.39 (s, 1H), 7.25 (s, 1H), 2.65 (s, 3H) . 5 [0274]
Synthesis of (E)-3-(3-fluoro-4-(IH-imidazol-l-yl)-phenyl]crotonic acid indan-1-ylamide
Dimethylphosphonoacetic acid methyl ester (308 \iL) and sodium hydride (44.0 mg) were added to a
THF (5.0 mL) solution of 1-[3-fluoro-4-(IH-imidazol-l-yl)phenyl]ethanone (390 mg), and the reaction solution was refluxed for 2 hours. Sodium hydride (40.0 mg) was further added to the reaction solution, the reaction solution was refluxed for 5 hours. Water and ethyl
acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield 525 mg
of crude ester product as an isomer mixture
(E:Z=2.4:1). 2N sodium hydroxide solution (3.0 mL) was added to a THF (3.0 mL) solution of the obtained ester product (260 mg). The reaction solution was warmed to 50°C, and was agitated for 1 hour and 40 minutes. By
condensing reaction solution under reduced pressure, 235 mg of crude carboxylic acid sodium salt was obtained as an isomer mixture. 22.0 mg of the title compound was obtained from the obtained carboxylic acid


sodium salt and 1-aminoindan (234 jj,L) by the same method as in Example 324. The physical properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm) : 7.80 (s, 1H) , 7.31-7.38 (m, 4H) , 5 7.20-7.28 (m, 5H), 6.30 (d, J=7 . 6 Hz, 1H), 6.12-6.13 (m, 1H), 5.58 (q, J=7.6 Hz, 1H) , 3.01 (ddd, J=4.8, 8.8, 16 Hz, 1H), 2.93 (td, J=8.0, 16 Hz, 1H), 2.60-2.69 (m, 1H), 2.60 (s, 3H), 1.85-1.94 (m, 1H) [0275] 10 Example 94
Synthesis of (E)-N-[(IR, IS)-2-hydroxy-indan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-2-methyl acrylamide trifluoroacetic acid salt [0276] [Formula 87]
(Figure Remove)


Synthesis of (E)-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]-2-methyl-acrylic acid
250 mg of the title compound was obtained from 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (200 mg) obtained in Example 1 and diethyl-2-phosphonopropionic acidethyl ester (238 \iL)
by the same method as in Example 111. The physical properties of the compound are as follows.


(DMSO-d6) 8 (ppm) : 7.80 (d, J=l. 2 Hz, 1H) , 7.61 (d, J=1.2 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.29 (d, J=1.6 Hz, 1H), 7.16 (dd, J=1.6 Hz, 7.4 Hz, 1H), 7.14-7.15 (m, 1H), 3.85 (s, 3H) , 2.15 (s, 3H), 2.07 (s, 3H). 5 [0277]
Synthesis of (E)-N-[(1R, 2S)-2-hydroxy-indan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)-phenyl]-2-methylacrylamide trifluoroacetic-acid salt
To a DMF (3 itiL) solution of (E)-[3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)phenyl]-2-methylacrylic acid (60.0 mg), (IR,2S)-l-amino-2-indanol (39.4 mg), IPEA (0.05 mL), EDC (58 mg) and HOBT (41 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. 55.5 mg of the title compound
was obtained by purifying reaction solution by LC-MS as it was. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm): 8.66 (s, 1H) , 7.48 (s, 1H) , 7.24-7.39 (m, 5H), 7.02-7.15 (m, 3H), 6.68 (d, J=7.6
Hz, 1H), 5.53-5.57 (m, 1H), 4.76 (brs, 1H), 3.90 (s, 3H), 3.27 (dd, J=4.8, 16 Hz, 1H) , 3.02 (d, J=16 Hz, 1H), 2.48 (s, 3H), 2.18 (s, 3H) . [0278] Example 95
Synthesis of (E)-N-[(IR,2S)-2-hydroxy-indan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene] butyl amide trifluoroacetic acid salt

(Figure Remove)

Synthesis of (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]butyric acid
269 mg of the title compound was obtained
from (348 mg) by the same method as in Example 111 from 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde
(200 mg) and 2-(diethoxyphosphoryl)butyric acid ethyl
ester obtained in Example 1. The physical properties
of the compound are as follows.
^-NMR (DMSO-d6) 8 (ppm) : 7.81 (d, J=l. 2 Hz, 1H) , 7.59 (s, 1H), 7.43 (d, J=8.0 Hz, 1H) , 7.25 (d, J=l. 2 Hz,
1H), 7.16 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 3.86 (s,
3H), 2.16 (s, 3H), 1.11-1.19 (m, 5H)
[0280]
Synthesis of (E)-N-[(1R,2S)-2-hydroxy-indan-l-yl]-3- [3- methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]butylamide trifluoroacetic acid salt
26.0 mg of the title compound was obtained by
the same method as in Example 111 from (E)-2-(3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)butyl acid (20.0 mg) and (1R,2S)-l-amino-2-indanol (15.6 mg).


The physical properties of the compound are as follows ^-NMR (CDC13) 6 (ppm) : 8.69 (d, J=l. 6 Hz, 1H) , 7.28-7.36 (m, 6H), 7.04-7.06 (m, 3H), 6.68 (brd, J=7.6 Hz, 1H), 5.56 (dd, J-4.8, 7.6 Hz, 1H) , 4.76 (dt, J=2.0, 4.f 5 Hz, 1H), 3.90 (s, 3H), 3.28 (dd, J=4.8, 16 Hz, 1H), 3.01 (dd, J=2.0, 16 Hz, 1H), 2.56-2.65 (m, 2H), 2.48 (s, 3H), 1.21 (t, J=7.6 Hz, 3H). [0281] Example 96
Synthesis of (E)-2-benzyl-N-[(IR,2S)-2-hydroxy-indan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yDphenyl]acrylamide trifluoroacetic acid salt [0282] [Formula 89]
(Figure Remove)
Synthesis of (E) -2-benzyl-3- [3-methoxy-4- (4-methyl-lH-imidazol-1-yl)phenyl]acrylic acid
315 mg of the title compound was obtained by
the same method as in Example 111 from 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (200 mg) and 2-(diethoxyphosphoryl)-3-phenylpropionic acid ethyl ester (434 mg) obtained in Example 1. The physical
properties of the compound are as follows.

(DMSO-d6) 6 (ppm) : 7.92 (s, 1H) , 7.64 (s, 1H) ,
7.56 (d, J=7.6 Hz, 1H), 7.28-7.35 (m, 3H), 7.16-7.23
(m, 5H), 3.92 (s, 2H) , 3.69 (s, 3H), 2.30 (s, 3H) .
[0283] 5 Synthesis of (E)-2-benzyl-N[(IR,2S)-2-hydroxy-indan-l-
yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]acrylamide trifluoroacetic acid salt
19.3 mg of the title compound was obtained
from (E)-2-benzyl-3-[3-methoxy-4-(4-methyl-lH-imidazol- 1-yl)phenyl]acrylic acid (25.0 mg) and (IR, 2S)1-amino-
2-indanol (16.1 mg) by the same method as in Example
94. The physical properties of the compound are as
follows.
XH-NMR (CDC13) 5 (ppm): 8.64 (s, 1H), 7.76 (s, 1H), 15 7.22-7.37 (m, 8H), 7.15 (td, J=3.6, 7.6 Hz, 1H), 7.10
(d, J=8.4 Hz, 1H), 7.02-7.06 (m, 2H), 6.93 (d, J=7.2
Hz, 1H), 6.49 (brd, J=8.0 Hz, 1H), 5.44 (dd, J=5.2, 8.0
Hz, 1H), 4.59 (dt, J=1.6, 5.2 Hz, 1H), 4.00 (d, J=17
Hz, 1H), 3.99 (d, J=17 Hz, 1H), 3.71 (s, 3H), 3.16 (dd, J=5.2, 16 Hz, 1H), 2.90 (dd, J=1.6, 16 Hz, 1H), 2.46
(s, 3H).
[0284]
Example 97
Synthesis of (E)-2-cyclopropylmethyl-N-[(IR,2S)-2-25 hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl]acrylamide trifluoroacetic acid
salt
[0285]

(Figure Remove)
Synthesis of (E)-2-cyclopropylmethyl-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylic acid
102 mg of the title compound was by the same method as in Example 111 from 3-methoxy-4-(4-5 methylimidazol-l-yl)benzaldehyde (200 mg) obtained in Example 1 and 3-cyclopropyl-2-
(diethoxyphosphoryl)propionic acid ethyl ester (384 mg). The physical properties of the compound are as follows.
^-NMR (DMSO-d6) 8 (ppm) : 7.82 (s, 1H) , 7.61 (s, 1H) , 7.43 (d, J=8.0 Hz, 1H) , 7.31 (s, 1H) , 7.17-7.18 (m, 2H), 3.86 (s, 3H), 2.15 (s, 3H), 2.45-2.50 (m, 2H), 0.90-0.98 (m, 1H), 0.39-0.43 (m, 2H), 0.12-0.16 (m, 2H) .
[0286]
Synthesis of (E)-2-cyclopropylmethyl-N-[(1R,2S)-2-hydroxy-indan-1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylamide trifluoroacetic acid salt
11.5 mg of the title compound was obtained
from (E)-2-cyclopropylmethyl-3-(3-methoxy-4-(4-methyl-


IH-imidazol-l-yl)phenyl)acrylic acid (20.0 mg) and (IR,2S)l-amino-2-indanol (11.5 mg) by the same method as in Example 94. The physical properties of the compound are as follows.
5 ^-NMR (CDC13) 8 (ppm) : 8.72 (s, 1H) , 7.28-7.40 (m, 6H) , 7.07-7.10 (m, 3H), 6.79 (d, J=8. 4 Hz, 1H) , 5.56 (dd, J=5.2, 8.4 Hz, 1H), 4.77 (dt, J=2.4, 5.2 Hz, 1H), 3.91 (s, 3H), 3.28 (dd, J=5.2, 16 Hz, 1H) , 3.02 (dd, J=2.4, 16 Hz, 1H), 2.54 (d, J=6.4 Hz, 2H), 2.48 (s, 3H), 0.88-10 0.96 (m, 1H), 0.50-0.60 (m, 2H), 0.18-0.26 (m, 2H) . [0287] Example 98
Synthesis of (E)-2-benzyl-N-(2-hydroxy ethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide 15 trifluoroacetic acid salt [0288] [Formula 91]
(Figure Remove)
15.3 mg of the title compound was obtained from (E)-2-benzyl-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl)acrylic acid (25.0 mg) and ethanolamine (8.8 mg) by the same method as in Example 94. The 20 physical properties of the compound are as follows. ESI-MS; m/z392 [M++H].

[0289] Example 99
Synthesis of (E)-1-(4-indol-l-yl-piperidin-l-yl)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y1)benzylidene]butan-5 1-one [0290] [Formula 92]
(Figure Remove)
76.8 mg of the title compound was obtained from (E)-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)butyric acid (60.0 mg) and 4-(l-indole)piperidine hydrochloride (74.6 mg) by the same
method as in Example 111. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 7.69 (s, 1H) , 7.64 (d, J=8 .0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.18-7.25 (m, 3H), 7.12 (t, J=7.6 Hz, 1H), 6.92-6.96 (m, 3H), 6.53 (d, J=10 Hz,
2H), 4.65-4.95 (brs, 1H), 4.49-4.55 (m, 1H), 4.20-4.50 (br, 1H), 3.85 (s, 3H), 2.80-3.40 (br, 2H), 2.62-2.67 (m, 2H), 2.99 (s, 3H), 2.22-2.25 (m, 2H) , 1.80-2.10 (br, 2H), 1.18 (t, J=7.2 Hz, 3H) [0291]
Example 100
Synthesis of (E)-N-indan-l-yl-2-[3-methoxy-4-(4-methyl-


IH-imidazol-l-yl]benzylidene)butyl amide trifluoroacetic acid salt
[0292] [Formula 93;
(Figure Remove)
6.95 mg of the title compound was obtained from (E)-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-5 yl)benzylidene)butyric acid (13.8 mg) and 1-aminoindane (9.6 mg) by the same method as in Example 111. The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 8.63 (s, 1H) , 7.22-7.35 (m, 5H) , 7.17 (s, 1H), 7.00-7.02 (m, 3H), 6.08 (brd, J=7.6 Hz,
1H), 5.63 (q, J=7.6 Hz, 1H), 3.48 (s, 3H), 3.05 (ddd, J=4.0, 8.8, 16 Hz, 1H), 2.94 (dt, J=7.6, 16 Hz, 1H), 2.71 (dtd, J=4.0, 7.6, 16 Hz, 1H), 2.51-2.59 (m, 2H), 2.47 (s, 3H), 1.86-1.95 (m, 1H), 1.20 (t, J=7.6 Hz, 3H).
[0293]
Example 101
Synthesis of (E)-2-cyclopropyl methyl-N-indan-l-yl-3-
[3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)phenyl]acrylamide trifluoroacetic acid salt

[0294] [Formula 94]
O
(Figure Remove)
6.23 mg of the title compound was obtained from (E)-2-cyclopropyl methyl-3-(3-methoxy-4- ( 4-methyl-IH-imidazol-l-yl)phenyl)acrylic acid (15.0 mg) and 1-aminoindane (9.6 mg) by the same method as in Example 5 94. The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 8.67 (s, 1H) , 7.22-7.36 (m, 5H) , 7.18 (s, 1H), 7.04-7.05 (m, 3H), 6.24 (brd, J=7.6 Hz, 1H), 5.62 (q, J=7.6 Hz, 1H) , 3.89 (s, 3H), 3.05 (ddd,
J=4.0, 8.4, 16 Hz, 1H), 2.93 (dt, J=8.0, 16 Hz, 1H), 2.71 (dtd, J=4.0, 7.6, 16 Hz, 1H), 2.50 (d, J=6.4 Hz, 2H), 2.47 (s, 3H), 1.88-1.97 (m, 1H), 0.82-0.91 (m, 1H), 0.52-0.56 (m, 2H) , 0.18-0.22 (m, 2H) [0295]
Example 102
Synthesis of (E)-2-benzyl-N-indan-l-yl-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide trifluoroacetic acid salt

[0296] [Formula 95;
(Figure Remove)
6.76 mg of the title compound was obtained from (E)-2-benzyl-3-(3-methoxy-4-(4-methyl-lH-imidazol-5 l-yl)phenyl)acrylic acid (17.0 mg) and 1-aminoindane (9.6 mg) by the same method as in Example 94. The physical properties of the compound are as follows. XH-NMR (CDC13) 6 (ppm): 8.61 (d, J=2.0 Hz, 1H) , 7.71 (s, 1H), 7.20-7.37 (m, 7H), 7.05-7.13 (m, 3H), 6.99-7.01 10 (m, 2H), 6.87 (d, J=7.2 Hz, 1H) , 5.95 (brd, J=7.6 Hz, 1H), 5.50 (q, J=7.6 Hz, 1H), 3.98 (d, J=16 Hz, 1H), 3.88 (d, J=16 Hz, 1H), 3.68 (s, 3H) , 2.80-2.94 (m, 2H), 2.59 (dtd, J=4.0, 7.2, 13 Hz, 1H) , 2.46 (s, 3H), 1.62-1.71 (m, 1H) . 15 [0297]
The compounds shown in Table 5 were synthesized as in Example 85.
The structural formulae and physicochemical properties are shown in Table 5, respectively.


[ [Table 5] (Table Remove)
[0299]
The compounds shown in Table 6 were
synthesized as in Example 474. The structured formulae and physicochemical properties are shown in Table 6, 5 respectively.


[0300] [Table 6]
(Table Remove)
[0301]
Example 111
Synthesis of (E)-N-(9H-fluoren-9-yl) -3-[4-(IH-imidazol-1-yl)-3-methoxyphenyl]acrylamide [0302J fFormula 961
(Figure Remove)
Synthesis of 4-(IH-imidazol-l-yl)-3-methoxybenzaldehyde
Potassium carbonate (6.70 g) and imidazole (2.60 g) were added to a DMF (30 mL) solution of 4-fluoro-3-methoxybenzaldehyde (5.00 g) one by one, and the reaction solution was agitated at 130°C overnight.
After confirming disappearance of the starting
materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried
over anhydrous magnesium sulfate and 4.76 g of crude aldehyde compounds was obtained by condensing under reduced pressure. The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 10.01 (s, 1H) , 7.92 (s, 1H) ,
7.57-7.60 (m, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.29 (s, 1H) , 7.21 (s, 1H), 3.98 (s, 3H) .

[0303]
Synthesis of (E)-3-[4-(lH-imidazol-1-yl)-3-methoxyphenyl)acrylic acid
Dimethylphosphonoacetic acid methyl ester 5 (3.80 mL) and lithium hydroxide monohydrate (1.20 g) were added one by one to a THF (20 mL) solution of the crude aldehyde compound (4.76 g) obtained above, and the reaction solution was agitated overnight at the room temperature. 2N sodium hydroxide solution was
added to the reaction solution after confirming
disappearance of the starting materials (20 mL), and the reaction solution was agitated at 50°C for 2 hours. The reaction solution was cooled to 0°C, 2N hydrochloric acid was added to the reaction solution (20 mL), and
deposited precipitation was separated by filtering with Kiriyama funnel. The obtained precipitation was washed with water and ethyl acetate, and 4.2 g of the title compound was obtained. The physical properties of the compound are as follows.
^-H-NMR (DMSO-d6) 8 (ppm) : 7.96 (s, 1H) , 7.63 (d, J=16 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H) , 7.48 (s, 1H) , 7.45 (d, J=8.0 Hz, 1H) , 7.39 (dd, J=1.6, 8.0 Hz, 1H), 7.06 (s, 1H), 6.68 (d, J=16 Hz, 1H), 3.90 (s, 3H). [0304]
(E)-N-(9H-fluoren-9-yl)-3-[4-(IH-imidazol-l-yl)-3-methoxyphenyl]acrylicamide
To a DMF (70 mL) solution of (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl)acrylic acid (3.50 g),


9-aminofluorene (2.40 g), IPEA (7.5 mL), EDC (3.00 g) and HOBT (2.10 g) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the 5 starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane : ethyl acetate = 1:1 -> ethyl acetate -> ethyl acetate : ethanol = 10:1), and 2.20 g of the title compound was obtained. The physical properties of the compound are
as follows.
^-NMR (CDC13) 6 (ppm) : 7.80 (s, 1H) , 7.76 (d, J=16 Hz, 1H), 7.72 (d, J=7.2 Hz, 2H), 7.63 (d, J=7.2 Hz, 2H), 7.42 (t, J=7.2 Hz, 2H), 7.32 (dt, J=1.2 Hz, 7.2 Hz, 2H) , 7.28 (d, J 7.17 (m, 2H), 6.47 (d, J=16 Hz, 1H), 6.39 (d, J=8.8 Hz, 1H) , 6.00 (d, J=8.8 Hz, 1H), 3.88 (s, 3H) . [0305]
Example 112 Synthesis of (E)-{3-[4-(IH-imidazol-l-yl)-3-
methoxyphenyl]acryloylamino}-(S)-phenylacetic acid tert-butyl ester trifluoroacetic acid salt [0306] [Formula 97]





(Figure Remove)


By the same method as in Example 94, 14.0 mg of the title compound was obtained from (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (20.0 mg) and (S)-2-phenylglycine-tert-butyl ester (25.0 mg). 5 The physical properties of the compound are as follows. ^-NMR (CD3OD) 8 (ppm) : 9.19 (t, J=l. 6 Hz, 1H) , 7.79 (t, J=1.6 Hz, 1H), 7.63 (t, J=1.6 Hz, 1H), 7.52 (d, J=16 Hz, 1H) , 7.50 (d, J=8.4 Hz, 1H) , 7.40 (d, J=l. 6 Hz, 1H), 7.26-7.36 (m, 6H), 7.32 (d, J=16 Hz, 1H), 5.38 (s, 10 1H), 3.88 (s, 3H), 1.32 (s, 9H) . [0307]
Example 113
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)-3-methoxyphenyl]-N-(3-iodo-benzyl)acrylamide [0308] [Formula 98] (Figure Remove)




N'

15

By the same method as in Example 111, 1.40 g


of the title compound was obtained from (E)-3-(4-lH-imidazol-l-yl-3-methoxyphenyl)acrylic acid (1.00 g) and 3-iodobenzylamine (550 jiL) . The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 7.76 (s, 1H), 7.65 (s, 1H), 7.64 (d, J=15.2 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.20 (t, J=1.6 Hz, 1H), 7.11-7.16 (m, 3H), 7.04 (t, J=8.0 Hz, 1H), 6.94 (brs, 1H), 6.54 (d, J=15.2 Hz, 1H) , 4.51 (d, J=6.0
Hz, 2H), 3.84 (s, 3H) . [0309]
Example 114
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)-3-methoxyphenyl]-N-(3-phenethyl-benzyl)acrylamide
trifluoroacetic acid salt [0310] [Formula 99]

(Figure Remove)
O


By the same method as in Example 94, 2.30 mg of the title compound was obtained from (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (10.0 mg) and 3-phenethyl-benzylamine hydrochloride (14.0 mg). 20 The physical properties of the compound are as follows. (CD3OD) S (ppm): 9.29 (t, J=1.6 Hz, 1H) , 7.89 (t,


J=1.6 Hz, 1H), 7.73 (t, J=1.6 Hz, 1H) , 7.62 (d, J=16 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.40 (dd, J=1.2, 8.0 Hz, 1H), 7.08-7.25 (m, 9H), 6.78 (d, J=16 Hz, 1H), 4.48 (s, 2H), 3.98 (s, 3H), 2.90 5 (s, 4H). [0311]
Example 115
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)-3-methoxyphenyl]-N-(5-methyl-6-oxo-6,7-dihydro-5H-10 dibenzo[b,d]azepin-7-yl)acrylamide trifluoroacetic acid salt [0312] [Formula 100]

(Figure Remove)

By the same method as in Example 94, 2.7 mg of the title compound was obtained from (E)-3-(4-lH-imidazol-l-yl-3-methoxyphenyl)acrylic acid (6.20 mg)
and 7-amino~5-methyl-5H,7H-dibenzo[b,d]azepin-6-one
(6.00 mg). The physical properties of the compound are as follows.
'•H-NMR (CD3OD) 8 (ppm) : 9.31 (t, J=1.6 Hz, 1H) , 7.90 (t, J=1.6 Hz, 1H), 7.74 (t, J=1.6 Hz, 1H) , 7.71 (d, J=8.0
Hz, 1H), 7.67 (d, J=3.6, 5.6 Hz, 1H) , 7.62 (d, J=8.0 Hz, 1H), 7.61 (d, J=16 Hz, 1H), 7.55-7.58 (m, 3H),


7.40-7.50 (m, 5H), 7.20 (d, J=16 Hz, 1H) , 5.46 (s, 1H) , 4.00 (s, 3H), 3.37 (s, 3H) . [0313]
Example 116
Synthesis of (E)-N-(2-benzylbenzyl)-3-[4-(IH-imidazol-1-yl)-3-methoxyphenyl]acrylamide trifluoroacetic acid salt [0314] [Formula 101]
(Figure Remove)
By the same method as in Example 94, 7.2 mg of the title compound was obtained from (E)-3-[4-(1H-
imidazol-1-yl)-3-methoxyphenyl]acrylic acid (10.0 mg) and 2-benzylbenzylamine (12.0 mg). The physical properties of the compound are as follows. ^-NMR (CD3OD) 8 (ppm) : 9.29 (t, J=l. 6 Hz, 1H) , 7.88 (t, J=1.6 Hz, 1H), 7.73 (t, J=1.6 Hz, 1H), 7.58 (d, J=8.0
Hz, 1H), 7.55 (d, J=16 Hz, 1H), 7.45 (d, J=l.6 Hz, 1H), 7.36 (dd, J-1.6, 8.0 Hz, 1H), 7.32-7.34 (m, 1H), 7.19-7.27 (m, 5H), 7.12-7.15 (m, 3H), 6.65 (d, J=16 Hz, 1H), 4.49 (s, 2H), 4.10 (s, 2H), 3.97 (s, 3H). [0315]
Example 117


Synthesis of (E)-N-(9H-fluoren-1-yl)-3-[4-(IH-imidazol-1-yl)-3-methoxyphenyl]acrylamide trifluoroacetic acid salt [0316] [Formula 102]
(Figure Remove)
By the same method as in Example 94, 14.0 mg 5 of the title compound was obtained from (E)-3-[4-(1H-
imidazol-1-yl)-3-methoxyphenyl]acrylic acid (20.0 mg)
and 1-aminofluorene (22 mg). The physical properties
of the compound are as follows.
^-NMR (CD3OD) 5 (ppm) : 9.29 (s, 1H) , 7.98 (s, 1H) , 7.89 (t, J=1.6 Hz, 1H), 7.72-7.80 (m, 3H) , 7.74 (t, J=1.6
Hz, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.53-7.54 (m, 2H),
7.46 (d, J=8.0 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.26
(dt, J=1.2, 7.6 Hz, 1H), 6.96 (d, J=16 Hz, 1H), 4.01
(s, 3H), 3.92 (s, 2H). [0317]
Example 118
Synthesis of (E)-N-(lH-benzoimidazol-2-ylmethyl)-3-[4-
(1H-imidazol-1-yl)-3-methoxyphenyl]acrylamide
nitrilofluoroacetic acid salt
[0318]
[Formula 103]



(Figure Remove)


By the same method as in Example 94, 3.00 mg of the title compound was obtained from (E)-3-[4-(1H-imidazol-1-yl)-3-methoxyphenyl]acrylic acid (20.0 mg) and 2-(aminomethyl)benzimidazole dihydrochloride (26.0 5 mg). The physical properties of the compound are as follows.
^-NMR (CD3OD) 8 (ppm) : 9.28 (d, J=l. 6 Hz, 1H) , 7.89 (t, J=1.6 Hz, 1H), 7.55-7.61 (m, 2H) , 7.74 (t, J=l.6 Hz, 1H), 7.70 (d, J=16 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H),
7.73-7.78 (m, 2H), 7.53 (d, J=1.6, 1H), 7.44 (dd, J=1.6, 8.0 Hz, 1H), 6.90 (d, J=16 Hz, 1H), 4.98 (s, 2H), 3.99 (s, 3H). [0319] Example 119
Synthesis of (E)-3- [4-(IH-imidazol-l-yl)-3-
methoxyphenyl]-N-naphthalen-1-ylmethyl-acrylamide [0320] [Formula 104]

(Figure Remove)
O



By the same method as in Example 111, 1.90 mg of the title compound was obtained from (E)-3-[4-(1H-iiuidazol-1-yl) -3-methoxyphenyl] acrylic acid (20.0 mg) and 1-naphthalenemethylamine (19.0 mg) . The physical 5 properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 8.06 (d, J=8 . 4 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.86 (d, J=12.4 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J=15.6 Hz, 1H), 7.42-7.58 (m, 4H), 7.11-7.30 (m, 5H), 6.38 (d, J=15.6 Hz, 1H), 5.86 (brs, 1H), 5.05
(d, J=5.2 Hz, 2H), 3.85 (s, 3H) [0321]
Example 120
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)-3-methoxyphenyl]-N-(lH-imidazole-2-ylmethyl)acrylamide
nitrilofluoroacetic acid salt [0322] [Formula 105]
(Figure Remove)
15.7 mg of the title compound was obtained from (E)-3-[4-(IH-imidazol-l-yl)-3-
methoxyphenyl]acrylic acid (15.0 mg) and (IH-imidazole-2-yl)-methylamine dihydrochloride (15.3 mg) by the same 20 method as in Example 94. The physical properties of


the compound are as follows.
^-NMR (CD3OD) 8 (ppm) : 9.29 (t, J=l. 6 Hz, 1H) , 7.88 (t, J=1.6 Hz, 1H), 7.74 (t, J=1.6 Hz, 1H), 7.66 (d, J=16 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.51 (d, J=1.6 Hz, 5 1H), 7.48 (s, 2H), 7.42 (dd, J=1.6, 8.0 Hz, 1H), 6.84 (d, J=16 Hz, 1H) , 4.78 (s, 2H), 3.99 (s, 3H) [0323]
Example 121
Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-methoxy-4-10 (4-methyl-lH-imidazol-l-yl)phenyl]acrylamide [0324] [Formula 106]
O
(Figure Remove)
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylic acid
To a THF (40 mL) solution of 3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzaldehyde (4.00 g) obtained
in Example 1, diethylphosphonoacetic acid ethyl ester (4.00 mL) and lithium hydroxide monohydrate (932 mg) were added one by one, and the reaction solution was agitated overnight at room temperature. 2N sodium hydroxide solution (30 mL) and ethanol (5 mL) were
added to the reaction solution after confirming disappearance of the starting materials, and the


reaction solution was agitated at room temperature overnight. The reaction solution was cooled to 0°C, 2N hydrochloric acid (30 mL) was added to the reaction solution, arid the precipitation consequently deposited 5 was separated by filtering with Kiriyama funnel. The obtained precipitation was washed with water and ethyl acetate, and 4.61 g of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (DMSO~d6) 5 (ppm) : 7.81 (s, 1H) , 7.60 (d, J=16
Hz, 1H), 7.56 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 6.66 (d, J=16 Hz, 1H), 3.88 (s, 3H), 2.15 (s, 3H). [0325] Synthesis of (E)-N-biphenyl-3-ylmethyl-3-[3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide
To a DMF (30 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (2.20 g), 3-phenylbenzylamine hydrochloride (2.30 g), IPEA (4.57 mL), EDC (1.96 g) and HOST (1.38 g) were
added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After
the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography


(elution solvent: ethyl acetate -> ethyl acetate : ethanol = 10:1), and 3.30 g of the title compound was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 7.71 (d, J=1.2 Hz, 1H) , 7.67 (d, J=16 Hz, 1H), 7.52-7.60 (m, 4H), 7.42-7.46 (m, 3H), 7.37 (td, J-1.2, 7.6 Hz, 1H), 7.33 (brd, J=7.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.17 (dd, J=1.6 Hz, 6.4 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 6.93 (t, J=l.2 Hz, 1H),
6.45 (d, J=16 Hz, 1H), 6.09 (brs, 1H), 4.67 (d, J=5.6 Hz, 2H), 3.87 (s, 3H), 2.29 (s, 3H) . [0326]
Example 122 Synthesis of (E)-N-[(IS)-indan-1-yl]-3-[3-methoxy-4-(4-
methyl-lH-imidazol-l-yl)phenyl]acrylamide trifluoroacetic acid salt [0327] [Formula 107]
(Figure Remove)
To a DMF (0.8 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (15.0 mg), (S)-(+)-1-aminoindan (12.0 mg), IPEA 20 (30 (J.L) , EDC (16.7 mg) , and HOBT (11.8 mg) were added one by one, and the reaction solution was agitated at


room temperature for 3 hours. After confirming disappearance of the starting materials, the reaction solution was purified by LC-MS, and 6.6 mg of the title compound was obtained. The physical properties of the 5 compound are as follows.
XH-NMR (CDC13) 8 (ppm): 9.15 (d, J=2.0 Hz, 1H), 8.57 (d, J=8.4 Hz, 1H), 7.65 (d, J=16 Hz, 1H), 7.59 (t, J=1.2 Hz, 1H) , 7.56 (d, J=8.0 Hz, 1H), 7.48 (d, J=l.6 Hz, 1H), 7.34 (dd, J=1.6, 6.8 Hz, 1H), 7.18-7.29 (m, 4H),
6.77 (d, J=16 Hz, 1H), 5.50-5.55 (m, 1H), 3.97 (s, 3H), 3.05 (ddd, J=4.4, 8.8, 16 Hz, 1H) , 2.90 (td, J=7.6, 16 Hz, 1H), 2.57 (dtd, J=4.4, 7.6, 16 Hz, 1H), 2.43 (s, 3H) , 1.88-1.97 (m, 1H) . [0328]
Example 123
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)phenyl]-N-(2-pheoxy ethyl)acrylamide
trifluoroacetic acid salt
[0329]
[Formula 108]
(Figure Remove)
By the same method as in Example 94, 5.3 mg 20 of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic


acid (15.0 mg) and 2-pheoxyethylamine (13.0 juL) . The physical properties of the compound are as follows. XH-NMR (CD3OD) 8 (ppm): 9.13 (d, J=1.6 Hz, 1H), 8.50 (t, J=5.6 Hz, 1H), 7.54-7.61 (m, 3H), 7.47 (d, J=2.0 Hz, 5 1H), 7.37 (dd, J=2.0, 8.4 Hz, 1H), 7.20-7.31 (m, 2H), 6.90-6.98 (m, 3H), 6.79 (d, J=15.6 Hz, 1H), 4.12 (t, J=5.6 Hz, 2H), 3.97 (s, 3H), 3.69-3.74 (m, 2H), 2.43 (s, 3H). [0330] 10 Example 124
Synthesis of (E)-N-[(IR)-l-hydroxymethyl-2-phenylethyl] -3-[3-methoxy-4- (4-methyl-lH-imidazol-l-yl)phenyl]acrylamide [0331] [Formula 109]
(Figure Remove)


By the same method as in Example 121, 262 mg 15 of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (200 mg) and D-phenylalanilol (176 mg). The physical properties of the compound are as follows. ^-NMR (CDC13 ) 8 (ppm): 7.69 (d, J=1.6 Hz, 1H) , 7.56 (d, 20 J=15.6 Hz, 1H), 7.20-7.33 (m, 5H) , 7.18 (d, J=8.0 Hz, 1H), 7.06-7.10 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 6.34


(d, J=15.6 Hz, 1H), 6.18 (d, J=7.6 Hz, 1H), 4.31-4.36 (m, 1H), 3.84 (s, 3H) , 3.79 (dd, J=3.2, 11 Hz, 1H), 3.68 (dd, J=4.8, 11 Hz, 1H), 2.98 (d, J=7.2 Hz, 2H), 2.29 (s, 3H}. 5 [0332]
Example 125
Synthesis of (E)-N-[2-(3-fluoro-pheoxy)-ethyl]-3- [3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide
trifluoroacetic acid salt
[0333]
[Formula 110]




(Figure Remove)

By the same method as in Example 94, 2.10 mg
of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylic acid (15.0 mg) and 2-(3-fluoropheoxy) ethyl amine (13.0 mg). The physical properties of the compound are as
follows.
^i-NMR (CD3OD) 6 (ppm) : 8.89 (s, 1H) , 7.59 (d, J=16 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.49 (m, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.36 (dd, J=1.6, 8.4 Hz, 1H), 7.26 (dt, J-6.8, 8.0 Hz, 1H), 6.76-6.79 (m, 1H), 6.65-6.75 (m,
3H), 4.12 (t, J=5.2 Hz, 2H), 3.96 (s, 3H), 3.72 (t, J==5.2 Hz, 2H) , 2.39 (s, 3H) .

[0334]
Example 126
Synthesis of (E)-N-[(IS, 2R)-2-hydroxy-indan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)-phenyl]acrylamide 5 trifluoroacetic acid salt [0335] [Formula 111]
(Figure Remove)
By the same method as in Example 94, 8.40 mg of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (15.0 mg) and (IS, 2R)-l-amino-2-indanol (13.0
mg). The physical properties of the compound are as follows.
^-NMR (CD3OD) 8 (ppm) : 9.14 (d, J=l. 2 Hz, 1H) , 8.26 (d, J=8.8 Hz, 1H), 7.67 (d, J=16 Hz, 1H), 7.59 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.52 (d, J=l.6 Hz, 1H), 7.41
(dd, J=1.2, 8.8 Hz, 1H), 7.21-7.29 (m, 3H) , 6.98 (d, J=16 Hz, 1H), 5.47 (q, J-5.6 Hz, 1H) , 4.63 (dt, J=2.0, 5.6 Hz, 1H), 3.98 (s, 3H), 3.20 (dd, J=5.6, 16 Hz, 1H), 2.87 (dd, J=2.0/ 16 Hz, 1H), 2.44 (s, 3H). [0336]
Example 127


Synthesis of (E)-N-[(IR)-l-hydroxymethyl-2-phenyl-ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-(2-morpholin-4-yl-ethyl)acrylamide [0337] [Formula 112]
(Figure Remove)
Synthesis of (2R)-2-(2-morpholin-4-yl-ethylamino)-3-5 phenylpropan-1-ol
Sodium iodide (84.5 mg) and sodium hydride (676 mg) and 4-(2-chloroethyl)morpholine hydrochloride (2.1 g) were added to a DMF (20 mL) solution of (R)-4-benzyl-2-oxazolidinone (1.0 g) at 0°C, and the reaction
solution was warmed to 60°C and agitated for 3 hours. After agitating the reaction solution at room temperature overnight, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate = 2:1), and 1.62
g of oxazolidinone compound was obtained. Next,
lithium hydroxide (1.61 g) was added to a solution of


the obtained oxazolidinone in ethanol (14 mL) and water (6.0 mL), and the reaction solution was refluxed for 6 hours and 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer 5 was partitioned. The obtained organic layer was washed with a saturated salt solution, dried over anhydrous magnesium sulfate, and 549 mg of crude amine compounds was obtained by condensing under reduced pressure. The physical properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm) : 7.14-7.32 (m, 5H) , 3.67-3.76 (m, 1H), 3.64 (dd, J=4.8, 10 Hz, IE) , 3.51-3.62 (m, 3H) , 3.39 (dd, J=5.6, 10 Hz, 1H), 2.86-2.92 (m, 1H), 2.70-2.80 (m, 2H), 2.62-2.68 (m, 2H), 2.42-2.54 (m, 2H) , 2.28-2.36 (m, 6H).
[0338]
Synthesis of (E)-N-[(IR)-l-hydroxymethyl-2-phenyl-ethylJ-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-(2-morpholin-4-yl-ethyl)-acrylamide
18.1 mg of the title compound was obtained
by the same method as the in Example 111 from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (15.0 mg) and (2R)-2-(2-morpholin-4-yl-ethylamino)-3-phenyl-propan-l-ol (23.0 mg). The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 7.71 (d, J=l.2 Hz, 1H), 7.25-7.29 (m, 1H), 7.14-7.22 (m, 4H), 6.92-7.05 (m, 5H), 6.48 (d, J=15 Hz, 1H), 4.27-4.36 (m, 1H), 3.87 (s, 3H) , 3.60-3.86 (m, 7H) , 3.52-3.58 (m, 1H), 3.06-3.26 (m,


2H), 2.63-2.76 (m, 4H) , 2.42-2.54 (m, 3H), 2.30 (s, 3H) . [0339]
Example 128
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-[3-(morpholin-4-yl-benzyl)acrylamide [0340] [Formula 113]

(Figure Remove)
O


By the same method as in Example 121, 12.0 mg of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic
acid (15.0 mg) and (3-morpholin-4-yl)benzylamine (17.0 mg). The physical properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 7.70 (d, J=1.2 Hz, 1H), 7.65 (d, J=16 Hz, 1H), 7.23-7.27 (m, 2H) , 7.16 (dd, J=1.6, 8.4
Hz, 1H), 7.11 (d, J=1.6 Hz, 1H) , 6.91 (t, J=1.2 Hz, 1H), 6.836.88 (m, 3H), 6.40 (d, J=16 Hz, 1H), 5.93 (brs, 1H), 4.54 (d, J=5.6 Hz, 2H), 3.87 (s, 3H), 3.85 (t, J=4.8 Hz, 4H), 3.16 (t, J=4.8 Hz, 4H), 2.29 (s, 3H) [0341]
Example 129
Synthesis of (E)-N-(4-fluoro-3-morpholin-4-yl-benzyl)-


3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide oxalic acid salt [0342] [Formula 114]
(Figure Remove)
By the same method as in Example 121, free compound of the title compound was obtained from (E)-3-5 [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (200 mg) and 4-fluoro-3-morpholin-4-yl-benzylamine (165 mg). 221 mg of the title compound was obtained by adding 1 equivalent of oxalic acid to a methanol (2 mL) solution of the obtained free compound, and reaction
solvent was removed. The physical properties of the compound are as follows.
VH-NMR (DMSO-d6) 8 (ppm): 8.59 (t, J=6.0 Hz, 1H) , 8.07 (brs, 1H), 7.50 (d, J=15.6 Hz, 1H), 7.427.44 (m, 2H) , 7.27 (dd, J=1.6, 8.4 Hz, 1H), 7.26-7.28 (m, 1H), 7.09
(dd, J=8.4, 12.8 Hz, 1H), 6.98 (dd, J=1.6, 8.4 Hz, 1H), 6.88-6.91 (m, 1H), 6.75 (d, J=15.6 Hz, 1H) , 4.35 (d, J=5.6 Hz, 2H), 3.87 (s, 3H), 3.74 (t, J=4.8 Hz, 4H), 2.99 (t, J=4.8 Hz, 4H), 2.18 (s, 3H). [0343]
Example 130
Synthesis of (E)-N-[2-(3-fluorophenyl)ethyl]-3-[3-


methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide trifluoroacetic acid salt [0344] [Formula 115]

(Figure Remove)
O
OH


By the same method as in Example 94, 3.1 mg of the title compound was obtained from (E)-3-[3-5 methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (15.0 mg) and 2-(3-fluorophenyl)ethyl amine (12.0 (J.L) . The physical properties of the compound are as follows. ^-NMR (CD3OD) 8 (ppm) : 9.05 (s, 1H) , 7.56 (d, J=15.6
Hz, 1H), 7.54 (dd, J=8.4 Hz, 1H), 7.45 (d, J=l.6 Hz,
1H), 7.35 (dd, J=1.6, 8.4 Hz, 1H), 7.29 (dd, J=6.0, 8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.00 (d, J=10.0 Hz, 1H), 6.94 (dt, J=1.6, 8.0 Hz, 1H), 6.68 (d, J=15.6 Hz, 1H), 3.96 (s, 3H), 3.56 (t, J=7.2 Hz, 2H), 2.89 (t,
J=7.2 Hz, 2H), 2.41 (s, 3H). [0345]
Example 131
Synthesis of (E)-N-(benzo[B]thiophen-3-ylmethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide
trifluoroacetic acid salt
[0346]


[Formula 116]

(Figure Remove)


By the same method as in Example 94, 1.40 mg of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (15.0 mg) and 1-benzo[B]thiophen-3-ylmethylamine 5 hydrochloride (17.0 mg). The physical properties of the compound are as follows.
^-NMR (CD3OD) 6 (ppm) : 9.05 (s, 1H) , 7.86-7.90 (m, 2H) , 7.64 (d, J=16 Hz, 1H), 7.51-7.54 (m, 3H) , 7.46 (d, J=1.2 Hz, 1H), 7.35-7.42 (m, 3H), 6.75 (d, J=16 Hz,
1H), 4.78 (s, 2H), 3.96 (s, 3H), 2.41 (s, 3H). [0347]
Example 132
Synthesis of (E)-N-(biphenyl-3-ylmethyl)-3-[3-fluoro-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide 1/2 oxalic
acid salt [0348] [Formula 117]

(Figure Remove)
O
1/2 (COOH)2



By the same method as in Example 121, 118 mg of the title compound was obtained from (E)-3-[3-fluoro-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (60.0 mg) and 3-phenylbenzylamine hydrochloride 5 (80.0m). The physical properties of the compound are as follows.
^-NMR (CD3OD) 8 (ppm) : 8.75 (t, J=4.8 Hz, 1H) , 8.48 (s, 1H), 7.527.68 (m, 8H), 7.41-7.44 (m, 4H), 7.31-7.35 (m, 2H), 6.76 (d, J=16 Hz, 1H) , 4.86 (s, 3H), 4.58 (d,
J=4.8 Hz, 2H). [0349]
Example 133
Synthesis of (E) -3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-methyl-N-(2-pheoxy ethyl)acrylamide
trifluoroacetic acid salt [0350] [Formula 118]
(Figure Remove)
By the same method as in Example 94, 41.0 mg of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (70.0 mg) and methyl-(2-pheoxy ethyl)amine (61.0 20 mg). The physical properties of the compound are as

follows.
XH-NMR (CD3OD) 6 (ppm): 9.12 (s, 1H), 7.21-7.63 (m, 8H), 6.87-6.95 (m, 3H), 4.20-4.24 (m, 2H), 4.02 (t, J=4.8 Hz, 1H), 3.98 (s, 1.5H), 3.95 (s, 1.5H), 3.89 (t, J=5.6 5 Hz, 1H), 3.38 (s, 1.5H), 3.15 (s, 1.5H), 2.42 (s, 3H). [0351]
Example 134
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-methyl-N-(2-morpholin-4-yl-l-10 phenylethyl)acrylamide trifluoroacetic acid salt [0352] [Formula 119]
(Figure Remove)
By the same method as in Example 94, 139 mg of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (70.0 mg) and a DMF solution (405 (J.L) of methyl-15 (2-morpholin-4~yl-phenylethyl)amine of 10mM(s). The physical properties of the compound are as follows. ^-NMR (CD3OD) 8 (ppm): 9.16 (d, J=l. 2 Hz, 1H) , 7.74 (d, J=16 Hz, 1H), 7.56-7.59 (m, 3H), 7.35-7.47 (m, 6H), 7.2 (d, J=15 Hz, 1H), 6.49 (dd, J=2.8, 12 Hz, 1H), 4.16 (t,


J=12 Hz, 1H), 3.98 (s, 3H), 3.83 (dd, J=2.8, 12 Hz, 1H), 3.81-4.20 (m, 8H), 2.94 (s, 3H) , 2.43 (s, 3H) [0353]
Example 135
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-methyl-N-(3-morpholin-4-yl-l-benzyl)acrylamide 1/2 oxalic acid salt [0354] [Formula 120]

(Figure Remove)
O
1/2 (COOH)2


By the same method as in Example 121, 132 mg of the title compound was obtained from (E)-3-[3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (68.0 mg) and N-methyl-N-[3-morpholin-4-yl)benzyl]amine (76.0 mg). The physical properties of the compound are as follows. 1H-NMR (DMSO-d6) 6 (ppm): 8.01 (brs, 1H), 7.55-7.60 (m,
2H), 7.40-7.44 (m, 2H), 7.32-7.36 (m, 1H), 7.18-7.26
(m, 2H), 6.84-6.86 (m, 2H), 6.65-6.71 (m, 1H), 4.78 (s, 1H), 4.58 (s, 1H), 3.90 (s, 1.5H), 3.87 (sr 1.5H), 3.69-3.74 (m, 4H), 3.12 (s, 1.5H), 3.07-3.10 (m, 4H), 2.93 (s, 1.5H), 2.18 (s, 3H)
[0355]


Example 136
Synthesis of (E)-N-[3-(2-hydroxy-ethoxy)-benzyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-methyl-acrylamide trifluoroacetic acid salt [0356] [Formula 121]
(Figure Remove)
By the same method as in Example 94, 36.1 mg
of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (20.0 mg) and 2-(3-methylaminomethylpheoxy) ethanol (21.0 mg). The physical properties of the
compound are as follows.
^-NMR (CDC13) 6 (ppm) : 8.72 (s, 0.5H), 8.69 (s, 0.5H), 7.75 (d, J=12 Hz, 0.5H), 7.72 (d, J=12 Hz, 0.5H), 7.28-7.36 (m, 2H), 7.20-7.21 (m, 1H), 6.97-7.12 (m, 2H) , 6.79-6.91 (m, 4H), 4.71 (s, 1H), 4.69 (s, 1H), 4.07-
4.12 (m, 2H), 3.96-4.00 (m, 2H), 3.95 (s, 1.5H), 3.90 (s, 1.5H), 3.13 (s, 1.5H), 3.12 (s, 1.5H), 2.48 (s, 1.5H), 2.47 (s, 1.5H). [0357] Example 137
Synthesis of (E)-N-[1-(3-fluorophenyl)ethyl]-3-[3-
methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylamide

(Figure Remove)
trifluoroacetic acid salt
[0358]
[Formula 122]
By the same method as in Example 94, 17.3 mg of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic 5 acid (20.0 mg) and 1-(3-fluorophenyl)ethyl amine (16.2 mg). The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 8.68 (d, J=l. 6 Hz, 1H) , 7.63 (d, J=16 Hz, 1H), 7.30-7.35 (m, 2H), 7.22-7.26 (m, 1H),
7.19 (d, J=1.6 Hz, 1H), 7.15 (dd, J=1.2, 8.4 Hz, 1H), 6.99-7.08 (m, 2H), 6.97 (dt, J=2.4, 8.4 Hz, 1H), 6.55 (d, J=16 Hz, 1H), 6.02-6.08 (brs, 1H), 5.27 (qu, J=7.2 Hz, 1H), 3.99 (s, 3H), 2.47 (s, 3H), 1.57 (d, J=7.2 Hz, 3H) .
[0359]
Example 139
Synthesis of (E)-N-[(IR)-fluoromethyl-2-phenylethyl]-3-
[3-methoxy-4- (4-inethyl-lH-imidazol-l-yl) phenyl] acrylic
acid amide
[0360]
[Formula 360]

O
MeO II


F _

Synthesis of (R)-2-(1-fluoromethyl-2-phenylethyl)isoindol-1,3-dione
(R)-2-(l-hydroxymethyl-2-
phenylethyl)isoindole-1,3-dione (1.20 g) was added to a 5 methylene chloride (20 mL) solution of DAST (825 mg) at -78°C and the reaction solution was agitated at room temperature. DAST (500 mg) was added to the reaction solution after 2 hours, and the reaction solution was agitated at 50°C for 3 hours. Saturated sodium
bicarbonate solution was added for reaction solution to the reaction solution after allowing the reaction solution to be cooled to room temperature, and the organic layer was partitioned. The organic layer was concentrated under reduced pressure after dried over
anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system), and 52 mg of the title compound was obtained. ^-NMR (CDC13 ) 5(ppm): 3.16 (dd, J=14.0, 6.4 Hz, 1H) ,
3.28 (dd, J=14.0, 9.6 Hz, 1H), 4.67 (ddd, J=40.8, 8.8, 4.8 Hz, 1H), 4.82-4.94 (m, 1H), 4.98 (dt, J=47.2, 8.8 Hz, 1H), 7.13-7.24 (m, 5H), 7.67-7.70 (m, 2H), 7.77-7.79 (m, 2H). [0361]
Synthesis of (R)-1-fluoromethyl-2-phenylethylamine on


A mixture of (R)-2-(l-fluoromethyl-2-phenylethyl)isoindol-1,3-dione (52 mg) and hydrazine hydrate (two drops) and ethanol (1 mL) was heated to reflux for 2 hours. The reaction solution was allowed 5 to be cooled to room temperature, and the deposited crystal was separated by filtration and concentrated under reduced pressure. The residue was purified by LC-MS and 6.0 mg of the title compound was obtained. ^-NMR (CDC13) 8(ppm): 2.61 (dd, J=13.2, 8.4 Hz, 1H) ,
2.82 (dd, J=13.2, 5.6 Hz, 1H) , 3.23-3.39 (m, 1H), 4.20-4.47 (m, 2H), 7.20-7.34 (m, 5H). ESI-MS; m/z!54 [M++H]. [0362] Synthesis of (R)-(E)-[(IR)-fluoromethyl-2-phenylethyl]-
3- [3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylic acid amide
By the same method as in Example 121, 1.38 mg of the title compound was obtained from 3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (10.0
mg) and (R)-l-fluoromethyl-2-phenylethylamine (6.0 mg). ESI-MS; m/z394 [M++H]. XH-NMR (CDC13) 8(ppm): 2.29 (s, 3H), 2.92-3.06 (m, 2H) , 3.89 (s, 3H) , 4.34-4.56 (m, 3H), 5.85 (d, J=8.2 Hz, 1H), 6.38 (d, J=15.2 Hz, 1H), 6.92 (s, 1H), 7.11-7.17 (m, 2H), 7.23-7.27 (m, 4H),
7.31-7.35 (m, 2H), 7.60 (d, J=15.2 Hz, 1H), 7.71 (s, 1H) . [0363] Example 140


Synthesis of (E) -3- [3-methoxy-4- (4-methyl-lH-imidazol-1-yl) phenyl] — N- ( 6-phenylpyridin-2-ylmethyl) acrylic acid amide [0364] [Formula 124]
(Figure Remove)


By the same method as in Example 121, the 5 title compound (83 mg) was obtained from (E)-3-[3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic
acid (71 mg) and (6-phenylpyridin-2-ylmethyl)amine (61
mg) .
ESI-MS; m/z425 [M++H]. 1H-NMR (CDC13) 5(ppm): 2.30 (s, 10 3H), 3.90 (s, 3H), 4.79 (d, J=4.8 Hz, 2H), 6.57 (d,
J=15.6 Hz, 1H), 6.94 (s, 1H), 7.10-7.29 (m, 5H), 7.43-
7.56 (m, 3H), 7.64-7.80 (m, 4H), 8.01 (d, J=15.6 Hz,
1H), 8.03 (s, 1H).
[0365] 15 Example 141
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)phenyl]-N-methyl-N-(quinoline-4-ylmethyl)acrylic
acid amide
[0366]
[Formula 125]
(Figure Remove)




By the same method as in Example 121 The title compound (18 mg) was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (71 mg) and N-(methylquinoline -4-yl)methylamine 5 (57 mg).
ESI-MS; m/z413 [M++H] . lH-NMR (CDC13) 5(ppm): 2.26 (s, 0.9H), 2.30 (s, 2.1H), 3.17 (s, 2.1H), 3.24 (s, 0.9H), 3.75 (s, 0.9H), 3.91 (s, 2.1H), 5.20 (s, 0.6H), 5.24 (s, 1.4H), 6.60-7.29 (m, 6H), 7.59-7.83 (m, 4H), 8.08-
8.25 (m, 2H), 8.88-8.94 (m, 1H). [0367]
Example 142-1 and Example 142-2
Synthesis of (E)-N-[(1R,2S) and (IS, 2R)-(2-fluoroindan-1-yl)]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]-N-methyl acrylic acid amide [0368] [Formula 126]
(Figure Remove)
Synthesis of methylamine(IR*,2S*)-(2-fluoroindan-1-yl) To a THF (1.0 mL) solution of 2-fluoroindan-l-one(100 mg) synthesized according to the method described in Tetrahedron Letters, vol.37, No. 20, p. 20 3591, 1996, 2M methylamine THF solution (0.67 mL),
acetic acid (400 mg) and triacetoxy sodium borohydride (282 mg) were agitated under ice-cooling and the reaction solution was agitated at room temperature


after addition. After 5 hours, 2M methylamine THF solution (0.67 mL) was added to the reaction solution, and the reaction solution was agitated overnight. The organic layer was diluted with a saturated sodium 5 bicarbonate solution and ethyl acetate and partitioned. After drying the organic layer over anhydrous magnesium sulfate the organic layer was washed with a saturation sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (elution solvent: from ethyl acetate to ethyl acetate : methanol = 20:1), and the title compound (57 mg) was obtained.
ESI-MS; m/z!66 [M++H]. lH-NMR (CDC13) 8(ppm): 2.67 (s, 3H), 3.09 (ddd, J=37.6, 17.2, 4.4 Hz, 1H), 3.22 (dd,
J=23.2, 17.2 Hz, 1H) , 4.12 (dd, J=23.2, 4.0 Hz, 1H),
5.48 (dt, J=54.0, 4.0 Hz, 1H), 7.23-7.27 (m, 3H), 7.41-
7.45 (m, 1H).
[0369]
Synthesis of (E)-N-[(1R*,2S*)-(2-fluoroindan-1-yl)]-3-
[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-methyl acrylamide
By the same method as the in Example 121, the title compound (81 mg) was obtained from (E)-3-(4-lH-imidazol-l-yl-3-methoxyphenyl)acrylic acid (74 mg) and
(1R*,2S*)(2-fluoroindan-l-yl)methylamine (57 mg).
ESI-MS; m/z406 [M++H].xH-NMR (CDC13) 8(ppm): 2.31 (s, 3H), 3.10 (s, 3H), 3.18-3.28 (m, 2H), 3.92 (s, 3H), 5.46-5.63 (m, 1H) , 6.29 (dd, J=27.2, 4.8 Hz, 1H), 6.95


(s, 1H), 7.04 (d, J=15.2 Hz, 1H), 7.18-7.24 (m, 2H) , 7.25-7.38 (m, 5H) 7.75 (s, 1H), 7.81 (d, J=15.2 Hz, 1H) . [0370]
Synthesis of (E)-N-[(1R,2S) and (IS,2R)-(2-fluoroindan-l-yl] 3- [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-methyl acrylic acid amide
N-[ (1R*,2S*)-(2-fluoroindan-l-yl))-3-(3-methoxy-4-(4-methyl-IH-imidazol-1-yl)phenyl]-N-methyl 10 acrylic acid amide racemate (80 mg) was separated by
CHIRALCEL OD available from Daicel Chemical Industries, Ltd. (2 cmx25 cm : mobile phase; ethanol). The title optically-active substance with a retention time of 17 minutes (Example 142-1: 35.8 mg; 99%e.e) and the title 15 optically-active substance with a retention time of 22 minutes (Example 142-2: 30.9 mg; 99%e.e) were obtained. [0371]
Example 143
By the same method as in Example 121, the
Synthesis of (E)-N-[(1R*,2S*)-(2-fluoroindan-1-yl)]-3-20 [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid amide [0372] [Formula 127]
(Figure Remove)


title compound (6.2 mg) was obtained from (E)-3-(4-methyl-lH-imidazol-l-yl-3-methoxyphenyl)acrylic acid (24 mg) and (1R*,2S*)-(2-fluoroindan-1-yl)amine (17 mg) .
ESI-MS; m/z392 [M++H].1H-NMR (CDC13) 6(ppm): 2.31 (s, 3H), 3.14-3.29 (m, 2H), 3.91 (s, 3H), 5.43 (dt, J=53.6, 4.0 Hz, 1H), 5.80 (ddd, J=25.6, 9.2, 4.0 Hz, 1H), 6.21 (d, J=9.2 Hz, 1H), 6.54 (d, J=15.6 Hz, 1H), 6.95 (s, 1H), 7.18-7.34 (m, 7H), 7.74 (s, 1H), 7.75 (d, J=15.6
Hz, 1H). [0373]
Example 144
Synthesis of (E)-N-[(1R*,2S*)-(2-fluoroindan-1-yl)]-N-(4-methoxybenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)phenyl]acrylic acid amide [0374] [Formula 128]
(Figure Remove)

MeO


By the same method as in Example 121, the title compound (18.2 mg) was obtained from (E)-3-(4-methyl-lH-imidazol-l-yl-3-methoxyphenyl)acrylic acid (24 mg) and (1R*,2S*)-(2-fluoroindan-1-yl)-(4-20 methoxybenzyl)amine (15 mg).
ESI-MS; m/z512 [M++H].lH-NMR (CDC13) 6(ppm): 2.28 (s, 3H), 3.24 (d, J=28.4 Hz, 2H), 3.75 (s, 3H), 3.79 (s, 3H), 4.53 (d, J=18.0 Hz, 1H), 4.68 (d, J=18.0 Hz, 1H),


5.59 (d, J=50.0 Hz, 1H), 6.40 (dd, J=25.6, 4.8 Hz, 1H), 6.67 (d, J=15.6 Hz, 1H), 6.82 (s, 1H) , 6.87-6.96 (m, 4H), 7.10-7.34 (m, 7H) 7.67 (s, 1H) , 7.73 (d, J=15.6 Hz, 1H). 5 [0375]
Example 145-1 and Example 145-2
Synthesis of (E)-N-[(1R,2S) and (1S,2R) -(1-
fluoroindan-2-yl)]-3-[3-methoxy-4-(4-methyl-1H-
imidazol-1-yl)phenyl]-N-methyl acrylic acid amide
[0376]
[Formula 129]
(Figure Remove)
By the same method as in Example 121, the
title compound (228 mg) was obtained from (E)-3-(4-methyl-lH-imidazol-l-yl-3-methoxyphenyl)acrylic acid (190 mg) and (1R*,2S*)-(1-fluoroindan-2-yl)methylamine (146 mg).
ESI-MS; m/z406 [M++H].:H-NMR (CDC13) 6(ppm): 2.30 (s, 3H), 3.07-3.14 (m, 1H), 3.27 (s, 3H), 3.36-3.46 (m, 1H), 3.91 (s, 3H), 5.52 (d, J=31.2 Hz, 1H) , 5.90 (d, J=57.6 Hz, 1H), 6.94 (s, 1H), 6.98 (d, J=15.6 Hz, 1H), 7.17 (s, 1H), 7.19-7.46 (m, 5H) 7.50-7.55 (m, 1H), 7.73
(s, 1H), 7.74 (d, J=15.6 Hz, 1H). [0377]
N-[(lR*,2S*)-(1-fluoroindan-2-yl)]-3-[3-


methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-N-methyl acrylic acid amide (270 mg) racemate obtained in the Example 145 was separated by CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm : 5 mobile phase; ethanol). The title optically-active substance with a retention time of 28 minutes (Example 145-1: 105 mg; 99%e.e) and the title optically-active substance with a retention time of 37 minutes (Example 145-2: 124 mg;86%e.e) were obtained.
[0378]
Example 146
Synthesis of (E)-N-[(1R*,2S*)-(1-fluoroindan-2-yl)]-3-
[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic
acid amide
[0379]
[Formula 130]
(Figure Remove)
The title compound (9.05 mg} was obtained by
the same method as in Example 121 from (E)-3-(4-methyl-lH-imidazol-l-yl-3-methoxyphenyl)acrylic acid (14.3 mg) and (1R*,2S*) - (1-f luoroindan-2-yl) amine (10.1 ing). ESI-MS; m/z392 [M++H].1H-NMR (CDC13) 6: 2.30 (s, 3H),
2.96-2.30 (m, 1H), 3.43 (dd, J=15.2, 8.4 Hz, 1H), 3.91 (s, 3H), 4.90-5.01 (m, 1H), 5.77 (dd, J=58.4, 4.4 Hz, 1H), 6.28 (d, J=8.8 Hz, 1H), 6.51 (d, J=15.6 Hz, 1H),


6.94 (s, 1H), 7.17-7.34 (m, 5H), 7.41-7.44 (m, 1H) ,
7.52-7.54 (m, 1H) , 7.69 (d, J=15.6 Hz, 1H), 7.74 (s,
1H) .
[0380] 5 Example 147
Synthesis of (E)-N-[(2S)-(2-fluoro-2-phenylethyl)]-3-
[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic
acid amide
[0381]
[Formula 131J
o MeO^^tS't
-so- H
N:'
-J
To a methylene chloride (1.0 mL) solution of 10 the N-((2R)-(2-hydroxy-2-phenylethyl))-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid amide (36.5 mg) obtained in the Example 195, DAST (23 mg) was added at -78°C, and the reaction solution was agitated for two hours at room temperature. After 2hrs, the 15 reaction solution was diluted with saturated sodium bicarbonate solution and chloroform, and the organic layer was partitioned. The organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified 20 by column chromatography (Carrier: Chromatorex™ NH, an elution solvent : heptane-ethyl acetate system), and 5.7 mg of the title compound was obtained. ESI-MS; m/z380 [M++H].lH-NMR (CDC13) 5(ppm): 2.30 (s,

^
3H), 3.50-3.61 (m, 1H), 3.90 (s, 3H) , 4.04-4.19 (m, 1H), 5.63 (ddd, J=48.8, 8.8, 2.8 Hz, 1H), 6.12 (brs, 1H), 6.45 (d, J=15.6 Hz, 1H) , 6.94 (s, 1H), 7.14-7.20 (m, 2H), 7.25-7.27 (m, 1H), 7.36-7.46 (m, 5H), 7.65 (d, 5 J=15.6 Hz, 1H), 7.73 (s, 1H). [0382]
Example 148-1 and Example 148-2 Synthesis of (E)-N-[(2R) and (2S) -fluoro-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-10 yl)phenyl]-N-methylacrylic acid amide [0383] [Formula 132]
^O (*Jj
WJ
By the same method as in Example 147, 100 mg of the racemate of the title compound was obtained from the N-(2-hydroxy-2-phenylethyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl)-N-methylacrylic acid
amide (310 mg) obtained in the Example 202.
ESI-MS; m/z394 [M++H].1H-NMR (CDC13) 8(ppm): 2.31 (s, 3H), 3.11 (s, 0.9H), 3.32 (s, 2.1H), 3.38-3.48 (m, 1H), 3.90 (s, 3H), 4.24 (ddd, J=34.8, 14.4, 2.4 Hz, 1H), 5.81 (ddd, J=49.2, 9.2, 2.4 Hz, 1H) , 6.68 (d, J=15.2
Hz, 0.3H), 6.90-6.95 (m, 1.7H), 7.05-7.48 (m, 8H), 7.58 (d, J=15.2 Hz, 0.3H), 7.69-7.74 (m, 1.7H). [0384]
(E)-N-(2-fluoro-2-phenylethyl-3-[3-methoxy-4-


(4-methyl-lH-imidazol-l-yl)phenyl]-N-methylacrylic acid amide (100 mg) racemate obtained above was separated by CHRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (cm: 2 cmx25 mobile phase; ethanol). 5 The title optically active substance with a retention time of 15 minutes (Example 148-1: 49 mg; 99%e.e) and the title optically active substance with a retention time of 22 minutes (Example 148-2: 35 mg; 99%e.e) were obtained. 10 [0385]
Example 149
Synthesis of N-[(1R, 2R)-(2-fluoroindan-1-yl)]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid amide
[0386]
[Formula 133]
(Figure Remove)

MeO


By the same method as in Example 147, 3.20 mg
of the title compound was obtained from the N-[(1R,2S)-(2-hydroxyindan-l-yl)]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylic acid amide (50 mg) obtained in the Example 198.
ESI-MS; m/z392 [M++H]. xH-NMR (CDC13) 8(ppm): 2.30 (s, 3H), 3.13-3.24 (m, 1H), 3.36-3.49 (m, 1H), 3.88 (s, 3H), 5.28 (d, J=48.0 Hz, 1H), 5.65 (ddd, J=17.2, 7.2, 2.8 Hz, 1H), 5.77 (d, J=7.2 Hz, 1H), 6.41 (d, J=15.2


Hz, 1H), 6.93 (s, 1H), 7.12-7.20 (m, 2H), 7.24-7.38 (m, 5H), 7.70 (d, J=15.2 Hz, 1H), 7.74 (s, 1H) . [0387]
The compounds shown in Table 7 were synthesized as in Example 121.
The structural formulae and physicochemical properties are shown in Table 7, respectively.


[0388] [Table 1-1.
(Table Remove)

[0406] Example 320
Synthesis of (E)-3-[4-(lH-imidazol-1-yl)-3-nitro phenyl]-N-(indan-1-yl)acrylamide [0407] [Formula 134]
(Figure Remove)
[0408]
Synthesis of 1-(4-bromo-2-nitro phenyl)-IH-imidazole Potassium carbonate (1.80 g) and imidazole 5 (667 mg) were added to a DMF (10 mL) solution of 4-
bromo-1-fluoro-2-nitro benzene (1.0 mL) one by one, and the reaction solution was agitated at 80°C for 3 hours and 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was
partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and 1.04 g of crude bromo compounds was obtained by condensing under reduced pressure. The physical properties of the
compound are as follows.
^-NMR (CDC13) 8 (ppm) : 8.15 (d, J=2.0 Hz, 1H) , 7.86 (dd, J=2.0, 8.4 Hz, 1H) , 7.62 (s, 1H), 7.36 (d, J=8.4 Hz, 1H) , 7.22-7.23 (m, 1H), 7.05 (m, 1H) . [0409]364
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)-3-
nitrophenyl]-N-(indan-1-yl)acrylamide
21.0 mg of the title compound was obtained
from 1-(4-bromo-2-nitrophenyl)-IH-imidazole (40.0 mg) 5 and N-(indan-1-yl)acrylamide (42.0 mg) obtained in the
Example 9. The physical properties of the compound are
as follows.
]-H-NMR (CDC13) 5 (ppm) : 8.11 (d, J=2 . 0 Hz, 1H) , 7.79
(dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=16 Hz, 1H), 7.63 10 (s, 1H) , 7.47 (d, J=8.0 Hz, 1H) , 7.34 (d, J=7.2 Hz,
1H), 7.22-7.29 (m, 4H), 7.07 (s, 1H), 6.56 (d, J=16Hz,
1H), 6.13 (brd, J=8.0 Hz, 1H), 5.64 (q, J=8.0 Hz, 1H),
3.04 (ddd, J=4.4, 8.8, 16 Hz, 1H), 2.93 (td, J=8.0, 16
Hz, 1H), 2.68 (dtd, J=4.4, 8.0, 12 Hz, 1H), 1.87-1.36 15 (m, 1H) .
[0410]
Example 321
Synthesis of (E)-3-[3-cyano-4-(IH-imidazol-l-yl)-
phenyl]-N-(indan-1-yl)acrylamide
[0411]
[Formula 135]

(Figure Remove)


Synthesis of 5-bromo-2-(IH-imidazol-yl)-benzonitrile Potassium carbonate (1.80 g) and imidazole
(667 mg) were added to a DMF (10 mL) solution of 5-bromo-2-fluorobenzonitrile (1.78 g) one by one, and the reaction solution was agitated at 80°C for 3 hours and 30 minutes. Water and ethyl acetate were added to the 5 reaction solution, and the organic layer was
partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and 1.07 g of crude bromo compounds was obtained by condensing under
reduced pressure. The physical properties of the compound are as follows.
XH-NMR (CDCl-j) 8 (ppm) : 7.95 (d, J=2.4 Hz, 1H) , 7.84-7.88 (m, 2H), 7.34-7.36 (m, 2H), 7.29 (brs, 1H) [0412]
Synthesis of (E)-3-[3-cyano-4-(IH-imidazol-l-yl)-phenyl)-N-indan-1-yl-acrylamide
By the same method as in Example 9, 5.20 mg of the title compound was obtained from 5-bromo-2-(1H-imidazol-1-yl)benzonitrile (38.0 mg) and N-indan-1-yl-
acrylamide (42.0 mg). The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm): 7.91 (d, J=l. 6 Hz, 1H) , 7.85 (s, 1.H) , 7.81 (dd, J=2.0, 8.4 Hz, 1H) , 7.66 (d, J=16 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d,
J=4.8 Hz, 1H), 7.20-7.28 (m, 4H), 6.54 (d, J=16 Hz,
1H) , 6.33 (brs, 1H), 5.63 (g, J=8.4 Hz, 1H), 3.02 (ddd, J=4.8, 8.4, 16 Hz, 1H), 2.88-2.99 (m, 1H), 2.62-2.71 (m, 1H), 1.86-1.96 (m, 1H).
[0413]
Example 322
Synthesis of (E)-3-[3-amino-4-(IH-imidazol-l-ylj phenyl]-N-indan-1-yl-acrylamide [0414] [Formula 136]
(Figure Remove)
Synthesis of 5-bromo-2-(lH-imidazol-1-yl)-phenylamine
To a solution of 1-(4-bromo-2-nitro phenyl)-IH-imidazole (500 mg) in methylene chloride (10 mL) and methanol (10 mL) at 0°C nickel hexahydrate (22.0 mg) and sodium borohydride (177 mg) were added one by one, and
the reaction solution was agitated for 20 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH; elution solvent:hexane:ethyl acetate -1:1 -> ethyl acetate), and 431 mg of the title compound was obtained. The physical properties of the
compound are as follows.
]H-NMR (CDC13) 8 (ppm): 7.61 (s, 1H), 7.25 (s, 1H), 7.09


(s, 1H), 6.99-6.70 (m, 1H) , 6.97 (d, J=8.4 Hz, 1H), 6.94 (m, 1H), 3.78 (brs, 2H). [0415]
Synthesisof (E)-3-[3-amino-4-(IH-imidazol-l-yl)-5 phenyl)-N-indan-1-yl-acrylamide
By the same method as in Example 9, 249 mg of the title compound was obtained from 5-bromo-2-(1H-imidazol-1-yl)-phenylamine (200 mg) and N-indan-1-yl-acrylamide (236 mg). The physical properties of the
compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 7.64 (s, 1H) , 7.62 (d, J=16 Hz, 1H), 7.34 (d, J=6.8 Hz, 1H), 7.22-7.29 (m, 4H), 7.13 (s, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.94-6.98 (m, 2H) , 6.39 (d, J=16 Hz, 1H), 5.93 (d, J=8.0 Hz, 1H), 5.64 (q,
J=8.0 Hz, 1H), 3.77 (brs, 2H), 3.03 (ddd, J=4.4, 8.8, 16 Hz, 1H), 2.93 (td, J=8.0, 16 Hz, 1H), 2.67 (dtd, J=4.4, 8.0, 13 Hz, 1H), 1.85-1.94 (m, 1H) . [0416] Example 323
To a THF (7.0 mL) solution of 4-(IH-imidazol-
Synthesis of (Z)-3-[4-(IH-imidazol-l-yl)-3-methoxyphenyl]-N-indan-1-yl-acrylamide [0417] [Formula 137]
(Figure Remove)

^
1-yl)-3-methoxy benzaldehyde (300 mg) obtained in Example 328, 18-crown-6 (2.0 g) and potassium bis(trimethylsilyl)amide (0.5M toluene solution, 4.4 mL) and (bis-(2,2,2,-trifluoroethoxy)phosphoryl)ethyl 5 acetate ester (470 p.L) were added at -78°C, and the reaction solution was agitated overnight at room temperature. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the
obtained organic layer was washed with a saturated
saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH and elution
solvent:hexane:ethyl acetate =1:1 -> ethyl acetate), and 306 mg of ester product was obtained as an isomer mixture (E:Z=1:5.5). 2N sodium hydroxide solution (5.0 mL) was added to a THF (5.0 mL) solution of the obtained ester product, and the reaction solution was
agitated at room temperature overnight. The isomer compound impurities were separated by cooling the reaction solution at 0°C, adding 2N hydrochloric acid to the reaction solution, and filtering off the deposited precipitation by Kiriyama funnel. The obtained
filtrate was concentrated under reduced pressure and
253 mg of crude carboxylic acid was obtained. TEA (507 p.L) , 1-aminoindane (133 (4.L) , and PYBOP (812 mg) were added to a DMF (5.0 mL) solution of the obtained


carboxylic acid one by one, and the reaction solution was agitated at room temperature for 1 hour. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction 5 solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography
(elution solvent: hexane: ethyl acetate = 1:1 -> ethyl acetate), and 9.0 mg of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13 ) 6 (ppm) : 7.81 (s, 1H) , 7.41 (s, 1H) ,
7.21-7.29 (m, 5H), 7.13-7.18 (m, 3H), 6.79 (d, J=12 Hz, 1H), 6.09 (d, J=12 Hz, 1H), 5.83 (brd, J=7.6 Hz, 1H), 5.52 (q, J=7.6 Hz, 1H) , 3.87 (s, 3H), 2.82-2.96 (m, 2H), 2.59 (dtd, J=4.8, 7.6, 12 Hz, 1H), 1.70-1.79 (m, 1H) .
[0418]
Example 324
Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)-
phenyl] -N-indan-l-yl-acrylamide
[0419]
[Formula 138]
(Figure Remove)


Synthesis of 3-fluoro-4-(IH-imidazol-l-yl)-benzaldehyde
Potassium carbonate (1.71 g) and imidazole (847 mg) were added to a DMF (20 mL) solution of 3,4-difluorobenzaldehyde (2.0 g) . The reaction solution 5 was agitated at 100°C overnight, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane : ethyl acetate =1:1 -> ethyl acetate), and 1.11 g of the title compound was obtained. The physical properties of the compound are as follows.
The physical properties of the compound are
as follows.
^-NMR (CDC13) 6 (ppm) : 10.0 (s, 1H) , 7.96 (s, 1H) , 7.82 (d, J=7.2 Hz, 2H), 7.61 (t, J=7.2 Hz, 1H) , 7.36 (s, 1H), 7.27 (s, 1H).
[0420]
Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)phenyl)acrylic acid
By the same method as in Example 111, 1.66 g of the title compound was obtained from 3-fluoro-4-(1H-
imidazol-1-yl)-benzaldehyde (1.40 g) and
dimethylphosphonoacetic acid methyl ester (1.40 mL). The physical properties of the compound are as follows. XH-NMR (DMSO-d6) 6 (ppm): 8.10 (s, 1H) , 7.93 (d, J=13


Hz, 1H), 7.70-7.71 (m, 2H), 7.63 (s, 1H) , 7.62 (d, J=16 Hz, 1H), 7.15 (s, 1H), 6.69 (d, J=16 Hz, 1H). [0421]
Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l- yl)phenyl)-N-(indan-1-yl)acrylamide
To a DMF (4.0 mL) solution of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)phenyl]acrylic acid (100 mg) , TEA (167 jj.L) , 1-aminoindane (83.0 ^L) and PYBOP (448 mg) were added one by one, and the reaction
solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane : ethyl acetate =1:1 -> ethyl acetate), and 95.0 mg of the
title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 7.82 (s, 1H), 7.64 (d, J=16 Hz, 1H), 7.40 (s, 1H), 7.37-7.38 (m, 2H), 7.32 (d, J=7.2 Hz, 1H), 7.20-7.28 (m, 5H), 6.43 (d, J=16 Hz, 1H),
6.02-6.14 (br, 1H), 5.62 (q, J=7.2 Hz, 1H), 3.02 (ddd, J=4.4, 8.8, 16 Hz, 1H), 2.91 (td, J=8.0, 16 Hz, 1H), 2.62-2.70 (m, 1H), 1.85-1.94 (m, 1H) [0422]


Example 325
Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)phenyl)-N-methylacrylamide [0423] [Formula 139]
(Figure Remove)
By the same method as in Example 324, 17.5 mg of the title compound was obtained from (E)-3-[3-
fluoro-4-(IH-imidazol-l-yl)phenyl]acrylic acid (60.0
mg) and methylamine (650 (J.L) . The physical properties
of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 7.86 (s, 1H) , 7.61 (d, J=16 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.36-7.42 (m, 2H), 7.23-
7.29 (m, 2H), 6.40 (d, J=16 Hz, 1H), 5.66 (brs, 1H),
2.97 (d, J=4.8 Hz, 3H) .
'[0424]
Example 326 15 Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-
yl)phenyl)-N-phenylacrylamide
[0425]
[Formula 140]
(Figure Remove)


By the same method as in Example 324, 32 mg of the title compound was obtained from (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)phenyl]acrylic acid (50.0 mg) and aniline (29.0 \iL) . The physical properties of 5 the compound are as follows.
^-NMR (CDC13) 8 (ppm): 7.94 (brs, 1H) , 7.88 (s, 1H) , 7.72 (d, J=16 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.41-7.45 (m, 3H), 7.37 (t, J=8.0 Hz, 1H), 7.30 (d, J=1.2 Hz, 1H), 7.24-7.27 (m, 3H), 7.16 (t, J=8.0 Hz, 1H), 10 6.64 (d, J=16 Hz, 1H). [0426]
Example 327
Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)phenyl)-N-(4-methoxybenzyl)acrylamide [0427] [Formula 141]
(Figure Remove)
By the same method as in Example 324, 55.0 mg
of the title compound was obtained from 3-[3-fluoro-4-(IH-imidazol-l-yl)phenyl]acrylic acid (50.0 mg) and 4-methoxybenzylamine (42.0 nD. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 7.86 (s, 1H) , 7.63 (d, J=16 Hz, 1H), 7.35-7.42 (m, 3H), 7.23-7.28 (m, 4H), 6.88 (td, J=2.0, 8.8 Hz, 2H), 6.43 (d, J=16Hz, 1H), 6.05 (brs,


1H), 4.52 (d. J=6.0 Hz, 2H), 3.80 (s, 3H). [0428]
Example 328
Synthesis of (E)-3-[4-(lH-imidazol-1-yl)-3-5 methoxyphenyl]-N-indan-1-yl-aery1amide [0429] [Formula 142]
(Figure Remove)
Synthesis of 4-(IH-imidazol-l-yl)-3-methoxybenzaldehyde
Potassium carbonate (2.0 g) and imidazole (662 mg) were added to a DMF (20 mL) solution of 4-
fluoro-3-methoxybenzaldehyde (1.50 g). The reaction
solution was agitated at 80°C overnight, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane : ethyl acetate = 3:1 -> ethyl acetate -> ethyl acetate : methanol = 10:1), and 960 mg of the
title compound was obtained. The physical properties of the compound are as follows. aH-NMR (CDC13) 6 (ppm): 10.0 (s, 1H), 7.92 (s, 1H),


7.56-7.60 (m, 2H) , 7.48 (d, J=7.6 Hz, 1H), 7.30 (s,
1H), 7.21 (s, 1H), 3.98 (s, 3H). [0430]
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)-3-5 methoxyphenyl. ] acrylic acid
11.9 g of the title compound was obtained
from 4-(IH-imidazol-l-yl)-3-methoxybenzaldehyde (13.2
g) by the same method as in Example 111. The physical
properties of the compound are as follows. 10 ^-NMR (DMSO-d6) 8 (ppm) : 7.96 (t, J=1.2 Hz, 1H) , 7.63
(d, J=16 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.48 (t,
J=1.2 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.38 (dd, J=l.6
Hz, 8.0 Hz, 1H), 7.06 (t, J=1.2 Hz, 1H), 6.68 (d, J-16
Hz, 1H), 3.89 (s, 3H). [0431]
Synthesis of (E) -3-[4-(IH-imidazol-l-yl)-3-
methoxyphenyl]-N-indan-1-yl-acrylamide
By the same method as in Example 111, 142 mg
of the title compound was obtained from (E)-3-[4-(1H-20 imidazol-1-yl)-3-methoxyphenyl]acrylic acid (100 mg)
and 1-aminoindane (53.0 ^L). The physical properties
of the compound are as follows.
^•H-NMR (CDC13) 8 (ppm): 7.85 (s, 1H) , 7.69 (d, J=16 Hz,
1H), 7.35 (d, J=6.8 Hz, 1H), 7.16-7.29 (m, 8H), 6.44 25 (d, J=16 Hz, 1H), 5.92 (d, J=8.4 Hz, 1H), 5.65 (q,
J=8.4 Hz, 1H) , 3.88 (s, 3H) , 3.04 (ddd, J=4.0, 8.8, 16
Hz, 1H), 2.91-2.96 (m, 1H), 2.64-2.72 (m, 1H), 1.86-
1.95 (m, 1H).

[0432]
Example 329
Synthesis of (E)-N-{3-[1-(4-fluorophenyl)-6-methyl-indan-1-yl]propyl}-3-[3-methoxy-4-(4-methyl-lH-5 imidazol-1-yl)phenyl]acrylamide and (E)-N-{3-[1- (4-
fluorophenyl)-4-methyl-indan-l-yl]propyl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide [0433]
[Formula 143] O
(Figure Remove)
p-Toluenesulfonate monohydrate (95 mg) was added to a toluene (10 mL) solution of l-[4-(4-
fluorophenyl)-4-hydroxyazepan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]propenone (45 mg) obtained in Example 350. Heating refluxing of the reaction solution was carried out for 3 hours. Water was added to the reaction solution after the reaction
ended, and the reaction solution extracted with ethyl acetate, and the organic layer was washed with a saturated sodium bicarbonate and also a saturated sodium chloride solution. The partitioned organic layer the solvent was dried over anhydrous magnesium
sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column


chromatography (elution solvent: ethanol : ethyl acetate = 1:10), and 10 mg (19%) of the title compound was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 5(ppm): 1.50 (m, 2H) , 2.04 (m, 1H) , 2.13 (m, 1H), 2.24 (m, 1H), 2.36 (m, 1H), 2.30 (s, 3H), 2.35 (s, 3H), 2.83 (m, 2H), 3.36 (m, 2H), 3.87 (s, 3H), 5.79 (br.s, 1H), 6.36 (d, J=16.0 Hz, 1H) , 6.92 (m, 1H), 6.925 (m, 1H), 6.93 (m, 1H), 7.04 (d, J=8.0 Hz, 1H),
7.11 (br.s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.20 (m, 2H) ,7.23 (d, J=8.0 Hz, 1H), 7.59 (d, J=16.0 Hz, 1H), 7.71 (s, 1H).
ESI-MS; m/z524 [M++H].1H-NMR (CDC13) 5: 1.50 (m, 2H), 2.04 (m, 1H), 2.13 (m, 1H), 2.24 (m, 1H), 2.36 (m, 1H),
2.26 (s, 3H), 2.30 (s, 3H), 2.78 (m, 1H), 2.82 (m, 1H), 3.36 (m, 2H), 3.87 (s, 3H), 5.79 (br.s, 1H), 6.35 (d, J=16.0 Hz, 1H), 6.925 (m, 1H), 6.93 (m, 2H), 6.98 (m, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.11 (br.s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H) , 7.20 (m, 2H),
7.23 (d, J=8.0 Hz, 1H), 7.59 (d, J=16.0 Hz, 1H), 7.71 (s, 1H) . [0434]
Example 330 Synthesis of (E)-3-[3-fluoro-4-(IH-imidazol-l-
yl)phenyl)-N-indan-l-yl-N-methyl-acrylamide [0435] [Formula 144]

(Figure Remove)
To a DMF (1.0 mL) solution of (E)-3-[3-fluoro-4-(IH-imidazol-l-yl)phenyl]-N-indan-1-yl-acrylamide (30.0 mg) obtained in Example 324, sodium hydride was added at 0°C (10.0 mg) , and the reaction 5 solution was allowed to be warmed to room temperature, lodomethane (54.0 ^L) was added to the reaction solution, the reaction solution was agitated at room temperature for 3 hours, water and ethyl acetate were added to the reaction solution, and the organic layer
was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex NH, elution
solvent heptane-ethyl acetate = 1:1), and 8.5 mg of the title compound was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 7.86 (s, 0.5H), 7.85 (s, 0.5H), 7.74 (d, J=16 Hz, 0.5H), 7.68 (d, J=16 Hz, 0.5H), 7.38-
7.47 (m, 3H), 7.13-7.28 (m, 6H), 7.06 (d, J=16 Hz,
0.5H), 6.95 (d, J=16 Hz, 0.5 Hz), 6.41 (t, J=8.0 Hz, 0.5H), 5.67 (t, J=8.0 Hz, 0.5H), 3.00-3.12 (m, 1H), 2.94 (td, J=8.4 Hz, 16 Hz, 1H), 2.80 (s, 1.5H), 2.88 (s, 1.5H), 2.43-2.55 (m, 1H), 2.10-2.20 (m, 0.5H),


1.89-2.00 (m, 0.5H). [0436]
Example 331
Synthesis of (E)-N-((IR)-formyl-2-phenylethyl)-3-[3-5 methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide [0437] [Formula 145]
(Figure Remove)
Dimethylsulfoxide (136 (iL) was added to a methylene chloride (3 mL) solution of oxalyl chloride (100 |iL) at -78°C and the reaction solution was agitated for 15 minutes. Next, the methylene chloride (2.0 mL)
solution of (E)-N-[(IR)-l-hydroxymethyl-2-phenylethyl)-3-(3-methoxy~4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylamide (150 mg) obtained in Example 124 was added to this reaction solution, and the reaction solution was agitated for 15 minutes, then, TEA (534
\iL) was added to this reaction solution to warm the reaction solution up to 0°C, it was agitated for 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under


reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate : ethanol = 10:1), and 62.0 mg of the title compound was obtained. The physical properties 5 of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 9.72 (s, 1H) , 7.73 (s, 1H) , 7.64 (d, J=16 Hz, 1H), 7.25-7.34 (m, 4H), 7.16-7.20 (m, 3H) , 7.14 (s, 1H), 6.93 (s, 1H), 6.45 (d, J=16 Hz, 1H), 6.33 (brs, 1H), 4.92 (dd, J=5.6, 7.2 Hz, 1H), 3.89 (s, 3H),
3.32 (dd, J=5.6, 14 Hz, 1H) , 3.25 (dd, J=7.2, 14 Hz, 1H) , 2.30 (s, 3H) . [0438]
Example 332 Synthesis of (E)-3-[3-methoxy-4-(4-(IH-methylimidazol-
1-yl)-phenyl]-N-((IR)-morpholin-4-ylmethyl-2-phenylethyl)acrylamide [0439] [Formula 146]
(Figure Remove)
To a methylene chloride (1.0 mL) solution of (E)-N-((IR)-formyl-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylamide (39.0 mg) 20 obtained in Example 331, morpholine (13.0 p.L) , acetic


acid (1.0 mL) and sodium triacetoxy borohydride (64.0 mg) were added one by one. After agitating the reaction solution at room temperature overnight, a saturated sodium bicarbonate water and ethyl acetate 5 were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (Carrier:
Chromatorex™ NH, an elution solvent: ethyl acetate -> ethyl acetate : ethanol = 10:1), and 13.9 mg of the title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 7.70 (s, 1H) , 7.59 (d, J=16 Hz, 1H), 7.14-7.32 (m, 7H), 7.12 (s, 1H) , 6.92 (s, 1H), 6.38 (d, J=16 Hz, 1H), 5.88 (d, J=7.2 Hz, 1H), 4.39-4.47 (m, 1H), 3.88 (s, 3H), 3.64-3.71 (m, 4H), 3.03 (dd, J=4.8, 14 Hz, 1H), 2.97 (dd, J=6.4, 14 Hz, 1H),
2.48-2.55 (m, 2H), 2.31-2.42 (m, 4H), 2.30 (s, 3H). [0440]
Example 333
Synthesis of (E)-N-[(1R)-1-(cis-2,6-dimethylmorpholin-4-ylmethyl)-2-phenylethyl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl]acrylamide

(Figure Remove)
5.2 mg of the title compound was obtained by the same method as in Example 332 from (E)-N-((1R)-formyl-2-phenylethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylamide (25.0 mg) and cis-2 and 5 6-dimethylmorpholine (23.7 jaL) obtained in Example 331. The physical properties of the compound are as follows. XH-NMR (CDC13) 6 (ppm): 7.72 (d, J=l.2 Hz, 1H), 7.61 (d, J=16 Hz, 1H) , 7.29-7.33 (m, 2H) , 7.17-7.26 (m, 5H), 7.13 (d, J=1.2 Hz, 1H), 6.93 (t, J=l.2 Hz, 1H), 6.38
(d, J=16 Hz, 1H), 5.82 (d, J=6.8 Hz, 1H), 4.38-4.46 (m, 1H), 3.89 (s, 3H) , 3.58-3.69 (m, 2H), 3.05 (dd, J=4.8, 14 Hz, 1H), 2.97 (dd, J=6.4, 14 Hz, 1H), 2.67-2.71 (m, 2H), 2.39 (dd, J=9.2, 13 Hz, 1H), 2.28-2.33 (m, 1H), 2.30 (s, 3H), 1.85 (t, J=12 Hz, 1H), 1.67 (t, J=12 Hz,
1H), 1.13-1.16 (m, 6H). [0442]
Example 334
Synthesis of (E)-N-(l-benzyl-2-hydroxy propyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide [0443]

(Figure Remove)

To a THF (3.0 mL) solution of the (E)-N-( (IR)l-formyl-2-phenylethyl)-3-[(3-methoxy-4-(4-methy1-IH-imidazol-l-yl)phenyl]acrylamide (100 mg) obtained in Example 331, methyl magnesium chloride (3MTHF solution, 5 0.17 mL) was added at -78°C. After warming the reaction solution to room temperature, it was agitated for 3 hours and 30 minutes, and methyl magnesium chloride (3MTHF solution, 0.51 mL) was added to the reaction solution. The reaction solution was agitated at room
temperature overnight, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate : ethanol = 10:1), and 33.0 mg of the title compound was obtained as an isomer mixture. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 7.70 (m, 1H), 7.59 (d, J=16H, 0.5H), 7.53 (d, J=16 Hz, 0.5H), 7.06-7.35 (m, 8H), 6.92-6.93 (m, 1H), 6.42 (d, J=16 Hz, 0.5H), 6.32 (d,


J=16 Hz, 0.5H), 5.92-6.30 (br, 1H), 4.30-4.39 (m, 0.5H), 4.19-4.28 (m, 0.5H), 4.00-4.10 (m, 0.5H), 3.90-3.99 (m, 0.5H), 3.86 (s, 1.5H), 3.83 (s, 1.5H), 2.92-3.02 (m, 2H), 2.29 (s, 3H), 1.10-1.30 (m, 3H) . [0444]
Example 335
Synthesis of (E)-N-(l-benzyl-2-oxopropyl)-3- [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide [0445] [Formula 149]
(Figure Remove)
To a methylene chloride (2.0 mL) solution of 10 (E)-N-(l-benzyl-2-hydroxy propyl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylamide (29.0 mg), Dess-Martin reagent (60.7 mg) was added. After agitating the reaction solution at room temperature for 4 hours and 30 minutes, a saturated sodium bicarbonate 15 water and ethyl acetate were added to the reaction
solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The 20 residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate :


ethanol = 10:1), and 15.4 mg of the title compound was obtained. The physical properties of the compound are as follows.
:H-NMR (CDC13) 5 (ppm): 7.73 (s, 1H), 7.60 (d, J=16 Hz, 5 1H), 7.27-7.33 (m, 3H), 7.25 (s, 1H), 7.14-7.18 (m, 4H), 6.93 (s, 1H), 6.42 (d, J=16 Hz, 1H), 6.34 (d, J=6.8 Hz, 1H), 5.03 (td, J=5.2, 6.8 Hz, 1H), 3.89 (s, 3H), 3.25 (dd, J=6.8, 14 Hz, 1H), 3.16 (dd, J=5.2, 14 Hz, 1H), 2.30 (s, 3H), 2.23 (s, 3H). 10 [0446]
Example 336
Synthesis of (E)-N-(l-benzyl-2-hydroxy-2-methylpropyl)-
3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)-
phenyl]acrylamide
[0447]
[Formula 150]
(Figure Remove)
To a THF (1.0 mL) solution of (E)-N-(l-
benzyl-2-oxopropyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylamide (12.0 mg), methyl magnesium chloride (3MTHF solution, 198 (J.L) was added at -78°C, the reaction solution was allowed to be warmed
to room temperature and agitated for further 1 hour. Water and ethyl acetate were added to the reaction


solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The 5 residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate : ethanol = 10:1), and 6.8 mg of the title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 7.70 (s, 1H) , 7.48 (d, J=16 Hz, 1H), 7.18-7.30 (m, 6H), 7.10 (d, J=9.6 Hz, 1H), 7.07 (s, 1H), 6.92 (s, 1H), 6.29 (d, J=16 Hz, 1H), 5.84 (d, J=8.8 Hz, 1H), 4.16-4.23 (m, 1H), 3.86 (s, 3H), 3.20 (dd, J=9.6, 14 Hz, 1H), 2.80 (dd, J=ll, 14 Hz, 1H),
2.29 (s, 3H), 1.39 (s, 3H), 1.34 (s, 3H). [0448]
Example 337
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-1-(3-phenylpyrrolidine-l-yl)propenone [0449] [Formula 151]

(Figure Remove)
By the same method as in Example 121, 65 mg
(62%) of the title compound was obtained from (E)-3-[3-


methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (70 mg) and 3-phenylpyrrolidine (40 mg). The physical properties of the compound are as follows. ESI-MS; m/z388 [M++H].lH-NMR (DMSO-d6) 8: 1.99-2.22 (m, 5 1H), 2.28 (s, 1.5H), 2.29 (s, 1.5H), 2.30-2.51 (m, 1H), 3.38-3.81 (m, 3H), 3.85 (s, 1.5H), 3.87 (s, 1.5H), 3.88-4.20 (m, 2H), 6.73 (d, J=15.6 Hz, 0.5H), 6.77 (d, J=15.6Hz, 0.5H), 6.91 (brs, 0.5H), 6.93 (brs, 0.5H), 7.12-7.39 (m, 8H), 7.68-7.76 (m, 2H). 10 [0450]
Example 338
Synthesis of (E)-l-{4-(lH-indol-2-yl)piperidin-1-yl}-3-
[3-methoxy-4-(4-methyl-IH-imidazol-1-
yl)phenyl]propenone
[0451]
[Formula 152]
(Figure Remove)
By the same method as in Example 121, 47 mg
(43%) of the title compound was obtained from (E)-3-[3-methoxy-4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (65 mg) and 2-piperidine-4-yl-lH-indol (50 mg). The physical properties of the compound are as follows. 20 ESI-MS; m/z441 [M++H].1H-NMR (DMSO-d6) 8(ppm): 1.70-1.88 (m, 2H), 2.12-2.23 (m, 2H), 2.30 (s, 3H), 2.83-3.11 (m, 2H), 3.27-3.43 (m, 1H), 3.89 (s, 3H) , 4.17-4.28 (m,


1H), 4.76-4.87 (m, 1H), 6.27 (s, 1H) , 6.93 (brs, 1H), 6.94 (d, J=15.6 Hz, 1H), 7.05-7.28 (m, 5H), 7.33 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.67 (d, J=15.6H, 1H), 7.74 (s, 1H), 8.25 (brs, 1H). 5 [0452]
Example 339
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)phenyl]-1-(4-pheoxypiperidin-l-yl)propenone
[0453]
[Formula 153]
(Figure Remove)




By the same method as in Example 121, 74 mg (91%) of the title compound was obtained from (E)-3-[3-
methoxy-4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid
(50 mg) and 4-pheoxypiperidine hydrochloride (42 mg).
The physical properties of the compound are as follows,
^-NMR (DMSO-d6) 8(ppm): 1.70-2.10 (m, 4H) , 2.30 (s, 15 3H), 3.62-3.71 (m, 1H), 3.82-3.95 (m, 3H), 3.90 (s,
3H), 4.58-4.65 (m, 1H), 6.88-7.03 (m, 5H), 7.19-7.36
(m, 5H), 7.66 (d, J=15.2 Hz, 1H) , 7.73 (s, 1H) .
[0454]
Example 340 20 Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)phenyl]-1- (6-phenyl-3, 4-dihydro-lH-pyrrolo[1,2-
a]pyrazine-2-yl)propenone


[0455] [Formula 154

(Figure Remove)


By the same method as in Example 121, 112 mg (94%) of the title compound was obtained from (E)-3-[3-methoxy-4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (70 mg), 6-phenyl 1, 2, and 3, and 4-tetrahydropyrrolo 5 [1,2-a] pyrazine (54 mg). The physical properties of the compound are as follows.
^-NMR (CDC13) S(ppm): 2.31 (s,3H), 3.92 (s, 3H) , 3.95-4.22 (m, 4H), 4.96-5.03 (m, 2H), 6.11 (d, J=3.2 Hz, 1H), 6.28 (d, J=3.2 Hz, 1H), 6.86-6.97 (m, 2H), 7.17
(brs, 1H), 7.21-7.45 (m, 7H), 7.73 (d, J=15.6 Hz, 1H), 7.74 (brs, 1H). [0456]
Example 341 Synthesis of (E)-3-[3-methoxy-4-methyl-lH-imidazol-l-
yl)phenyl]-1-(1-phenyl-octahydropyrrolo[3,2c]pyridine-5-yl)propenone [0457] [Formula 155]
o
(Figure Remove)


By the same method as in Example 121, 46 mg (90%) of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (30 mg) and 1-phenyloctahydropyrrolo[3,2-c] 5 pyridine (24 mg). The physical properties of the compound are as follows.
ESI-MS; m/z.443 [M++H]. l H-NMR (CDC13 ) 6 (ppm) : 1.50-1.91 (m, 1H) , 1.91-2.25 (iru3H), 2.30 (s, 3H) , 2.49-2.64 (m, 1H), 3.01-3.12 (m, 0.5H), 3.24-3.55 (m, 3H), 3.65-3.77 10 (m, 0.5H), 3.89 (s, 3H), 3.90-4.00 (m, 2H) , 4.23-4.42 (m, 1H), 6.54-6.63 (m, 2H), 6.68 (t, J=7.2 Hz, 1H), 6.87 (d, J=15.2 Hz, 1H), 6.92 (brs, 1H), 7.12 (s, 1H), 7.17-7.28 (m, 4H), 7.67 (d, J=15.2 Hz, 1H), 7.72 (s, 1H) -15 [0458]
Example 342
Synthesis of (S)-1-(4-indol-l-yl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenylpropenone [0459] [Formula 156]
(Figure Remove)

By the same method as in Example 121, 86 mg
(82%) of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (50 mg) and l-piperidin-4-yl-lH-indol (46 mg).


The physical properties of the compound are as follows. ESI-MS; m/z441 [M++H]. lH-NMR (CDC13) 8(ppm): 1.93-2.10 (nu2H), 2.19-2.29 (m.2H), 2.30 (s, 3H) , 2.83-2.97 (m, 1H), 3.34-3.46 (m, 1H) , 3.91 (s, 3H) , 4.26-4.43 (m, 5 1H), 4.48-4.58 (m, 1H) , 4.90-5.10 (m, 1H), 6.55 (d, J=3.2 Hz, 1H), 6.94 (s, 1H) , 6.96 (d, J=15.6 Hz, 1H), 7.11-7.19 (m, 3H), 7.21-7.29 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.71 (d, J=15.6 Hz, 1H), 7.73 (s, 1H). 10 [0460]
Example 343
Synthesis of (E)-1-[4-(4-fluorophenyl)piperazin-1-yl]-
3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]propenone 2 trifluoroacetic acid salt
[0461]
[Formula 157]
(Figure Remove)
5.30 mg of the title compound was obtained
from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (15.0 mg) and l-(4-fluorophenyl)piperazine (16.0 mg) by the same method as in Example 94. The physical properties of the compound
are as follows.
XH-NMR (CD3OD) 5 (ppm) : 9.16 (d, J=l. 6 Hz, 1H) , 7.64 (d,


J=15.6 Hz, 1H), 7.607.61 (m, 2H) , 7.58 (d, J=8.4 Hz, 1H), 7.45 (dd, J=1.6 Hz, 8.4 Hz, 1H) , 7.38 (d, J=15.6 Hz, 1H), 6.80-7.03 (m, 4H), 4.00 (s, 3H), 3.95 (brs, 2H), 3.88 (brs, 2H), 3.17 (brs, 4H) , 2.43 (s, 3H) . [0462]
Example 344
Synthesis of (E)-1-[4-(2-fluorophenyl)piperazin-1-yl]-3-[3-methoxy-4-(4-(IH-imidazol-l-yl)phenyl]propenone 2 trifluoroacetic acid salt [0463] [Formula 158]
(Figure Remove)
By the same method as in Example 94, 7.5 mg
of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]acrylic acid (15.0 mg) and 1-(2-fluorophenyl)piperazine monohydrochloride (19.0 mg) . The physical properties
of the compound are as follows.
^-NMR (CD3OD) 8 (ppm) : 9.16 (d, J=1.6 Hz, 1H) , 7.64 (d, J=15.6 Hz, 1H), 7.60-7.61 (m, 2H) , 7.58 (d, J=8.4 Hz, 1H), 7.45 (dd, J=1.6 Hz, 8.4 Hz, 1H) , 7.38 (d, J=15.6 Hz, 1H), 6.80-7.03 (m, 4H), 4.00 (s, 3H), 3.95 (brs,
2H), 3.88 (brs, 2H), 3.17 (brs, 4H), 2.43 (s, 3H). [0464]


Example 345
Synthesis of (E)-1-[4-(2,4-difluorobenzyl)piperazin-1-
yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]propenone 2 trifluoroacetic acid salt
[0465]
[Formula 159]
(Figure Remove)








By the same method as in Example 94, 4.00 mg
of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (15.0 mg) and l-(2, 4-difluorobenzyl)piperazine dihydrochloride (25.0 mg). The physical properties of
the compound are as follows.
XH-NMR (CD3OD) 8 (ppm): 9.16 (d, J=l.6 Hz, 1H) , 7.68 (d, J=16 Hz, 1H), 7.59-7.67 (m, 3H), 7.57 (d, J=8.0 Hz, 1H), 7.45 (dd, J=1.6 Hz, 8.4 Hz, 1H), 7.34 (d, J=16 Hz, 1H), 7.12-7.21 (m, 2H), 4.44 (s, 2H), 3.80-4.20 (brs,
4H), 3.99 (s, 3H), 3.40 (brs, 4H), 2.43 (s, 3H). [0466]
Example 346
Synthesis of (E)-1-(3,4-dihydro-lH-isoquinoline-2-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]propenone trifluoroacetic acid salt [0467]


[Formula 160] (Figure Remove)



By the same method as in Example 94, 4.90 mg of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (15.0 mg) and 1,2,3,4-tetrahydroisoquinoline (12.0 5 mg). The physical properties of the compound are as follows.
XH-NMR (CD3OD) S (ppm): 9.16 (d, J=1.6 Hz, 1H), 7.65 (d, J=16 Hz, 1H), 7.60-7.63 (m, 2H) , 7.57 (d, J=8.0 Hz, 1H), 7.397.48 (m, 2H), 7.20 (brs, 4H), 4.96 (s, 1H),
4.82 (s, 1H), 4.01 (s, 3H) , 4.01 (t, J=5.6 Hz, 1H), 3.91 (t, J=5.6 Hz, 1H), 3.00 (t, J=5.6 Hz, 1H), 2.93 (t, J=5.6 Hz, 1H), 2.43 (s, 3H). [0468] Example 347
Synthesis of (E)-1-(3,4-dihydro-lH-isoquinoline-2-yl)-3- [3-fluoro-4-(IH-imidazol-l-yl)-phenyl]propenone [0469] [Formula 161] (Figure Remove)




By the same method as in Example 324, 16.0 mg of the title compound was obtained from (E)-3-[3-fluoro-4- (IH-imidazol-l-yl)-phenyl]acrylic acid (20.0 mg} and 1, 2, 3, 4-tetrahydroisoquinoline (22.0 JJ.L) . The 5 physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 7.91 (s, 1H) , 7.63 (d, J=16 Hz, 1H), 7.38-7.45 (m, 3H) , 7.27 (s, 1H) , 7.14-7.24 (m, 4H), 7.13 (s, 1H), 6.96-7.01 (m, 1H), 4.82 (s, 2H), 3.86-3.92 (m, 2H), 2.92-3.00 (m, 2H). 10 [0470]
Example 348, Example 348-1 and Example 348-2
Synthesis of (E)-1-(3-benzyl-3-hydroxymethylpiperidin-
1-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]propenone
[0471]
[Formula 162]
(Figure Remove)
Synthesis of (±) - (E)-1_-(3-benzyl-3-hydroxymethyl-
piperidin-1-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone
To a DMF (5 mL) solution of (E)-3-[4-methyl -IH-imidazol-l-yl]-3-methoxyphenyl)acrylic acid (250 mg)
obtained in Example 121 and (3-benzyl-piperidin-3-
yljmethanol (200 mg), isopropyl ethylamine (0.34 mL) , HOBT (158 mg), and EDC (230 mg) were added, and the


reaction solution was agitated at room temperature for 12 hours. Ethyl acetate and a saturated sodium bicarbonate water were added to the reaction solution after the reaction ended, and the organic layer was 5 separated. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: from ethyl acetate to
ethyl acetate : methanol = 9:1), and 310 mg (71%) of (±)-(E)-1-(3-benzyl-3-hydroxymethylpiperidin-l-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone was obtained. The physical properties of the compound are as follows.
ESI-MS; m/z446 [M++H]. [0472]
Synthesis of (+)-(E)-1-(3-benzyl-3-hydroxvmethyl-piperidin-1-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone and (-)-(E)-1-(3-benzyl-3-
hydroxymethyl-piperidin-1-yl)-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl]propenone
(±)-(E)-1-(3-benzyl-3-hydroxymethyl-
piperidin-1-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone (310 mg) was separated using
CHIRALPAK™AD-H (25 cm x 2 cm; mobile phase hexane: isopropanol 7:3) available from Daicel Chemical Industries, Ltd. 30 mg of (-)-(E)-1-(3-benzyl-3-hydroxymethylpiperidin-1-yl)-3-[3-methoxy-4-(4-methyl—


IH-imidazol-l-yl)phenyl]propenone having a shorter retention time (retention time: 12.9 minutes) was obtained by 99%e.e., and 29 mg of (+)-(E)-1-(3-benzyl-3-hydroxymethylpiperidin-l-yl)-3-[3-methoxy-4- (4-5 methyl-lH-imidazol-1-yl)phenyl]propenone having a longer retention time (retention time: 13.5 minutes) was obtained by 94%e.e. [0473]
Example 349, Example 349-1 and Example 349-2 10 Synthesis of (+)-(E)-1-[3-(4-fluorophenyl)-3-
hydroxypiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl]phenyl]propenone [0474] [Formula 163]
F
(Figure Remove)
Synthesis of (±)-(E)-1-[3-(4-fluorophenyl)-3-
hydroxypiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-lH-15 imidazol-1-yl)phenyl]propenone
Isopropylethylamine (0.07 mL) , HOBT (45 mg)
and EDC (64 mg) were added to a DMF (3 mL) solution of
(E)-3-[4-methyl-lH-imidazol-l-yl-3-
methoxyphenyl)acrylic acid (71 mg) obtained in Example 121 and 3-(4-fluorophenyl)piperidin-3-ol (54 mg), and
the reaction solution was agitated at room temperature
for 12 hours. Ethyl acetate and a saturated sodium


bicarbonate water were added to the reaction solution after the reaction ended, and the organic layer was separated. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was 5 evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: from ethyl acetate to ethyl acetate : methanol 9:1) and 91 mg (75%) of (±)-(E)-I-[3-(4-fluorophenyl)-3-hydroxypiperidin-l-yl]-3-
[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl) pheriyl] propenone was obtained. The physical properties of the compound are as follows. ESI-MS; m/z436 [M++H]. 1H-NMR (CDC13) 5(ppm): 1.55-2.20 (nu3H), 2.32 (s,3H), 2.68-2.76 (nulH), 3.12-3.50 (nu2H),
3.89 (s,3H), 4.08-4.22 (m, 1H) , 4.55-90) m, 1H) , 6.84-7.04 (m, 2H), 7.05-7.33 (m, 5H) , 7.50-5.57 (m, 2H) , 7.64-7.78 (m, 2H). [0475] Synthesis of (+)-(E)-1-[3-(4-fluorophenyl)-3-
hydroxypiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]propenone and (-)-(E)-1-[3-(4-fluorophenyl)-3-hydroxypiperidin-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone (±)-(E)-1-(3-(4-fluorophenyl)-3-
hydroxypiperidin-1-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]propenone (80 mg) obtained above was separated by CHIRALPAK™AD-H (25 cm x 2 cm; mobile phase hexane: isopropanol 7:3) available from Daicel


Chemical Industries, Ltd. 14 mg of (-)-(E)-1-[3-(4-fluorophenyl)-3-hydroxypiperidin-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone having a short retention time (retention time: 16.3 minutes) was 5 obtained by 99%e.e. and 13 mg of ( + )-(E)-1-[3-(4-fluorophenyl) -3-hydroxypiperidin-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone having a longer retention time (retention time: 20.4 minutes) of-(E)-1-(3-(4-fluorophenyl)-3-hydroxypiperidin-l-yl)-
3-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl)propenone was obtained by 89%e.e.
[0476]
Example 350
Synthesis of (E)-1-[4-(4-fluorophenyl)-4-hydroxyazepan-
1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone [0477] [Formula 164]
O MeO
(Figure Remove)
Synthesis of l-{3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)-phenyl]acryloyl}azepan-4-one
The method of Example 121 was followed to 20 synthesize 1-{3-[3-methoxy-4-(4-methylimidazol-l-yl)phenyl]acryloyl)azepan-4-one. The physical


properties of the compound are as follows. ESI-MS; m/z354 [M++H] [0478]
Synthesis of (E)-1-[4-(4-fluorophenyl)-4-hydroxyazepan-5 1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone
Fluorobenzene magnesium bromide (l.OM THF solution, 0.85 mL) was added to a THF (7 mL) solution of the amide (100 mg) obtained above under ice-cooling.
The reaction solution was allowed to be warmed to room temperature and agitated for further 2 hours. An ice-cooled water was added after the reaction ended, extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution.
After the organic layer was dried over anhydrous
magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethanol : ethyl acetate = 1:4), and 63 mg (50%) of the
title compound was obtained. The physical properties of the compound are as follows.
ESI-MS; m/z450 [M++H].lH-NMR (CDC13) 5(ppm): 1.87 (m, 1H), 1.88 (m, 2H), 2.01 (m, 2H), 2.12 (m, 1H) , 2.23 (s, 3H), 3.45 (m, 1H), 3.79 (m, 1H), 3.93 (s, 3H), 3.95 (m,
1H), 4.11 (m, 1H), 7.00 (dd, J=9.0/ 9.0 Hz, 2H), 7.08 (br.d, J=7.0 Hz, 1H) , 7.19 (d, J=15.0 Hz, 1H), 7.32 (m, 1H), 7.36 (m, 1H), 7.44 (m, 1H), 7.47 (m, 2H), 7.61 (d, J=15.0 Hz, 1H), 7.81 (br.d, J=7.0 Hz, 1H).

[0479]
Example 351
Synthesis of (E)-1-[4-fluoro-4-(4-fluorophenyl)azepan-1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-5 yl)phenyl]propenone [0480] [Formula 165]
O MeO
(Figure Remove)
To a methylene chloride (4 mL) solution of (E)-1-[4-(4-fluorophenyl)-4-hydroxyazepan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone (50 mg) obtained in Example 350, DAST (0.022 mL) was
added at -78°C, and the reaction solution was allowed to be warmed to room temperature and the reaction solution was agitated for 7 hours. Water was added to the reaction solution after the reaction ended, extracted with ethyl acetate, and the organic layer was washed
with a saturated sodium chloride solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethanol :
ethyl acetate = 1:10), and 43 mg (86%) of the title
compound was obtained. The physical properties of the


compound are as follows.
ESI-MS; m/z452 [M++H].1H-NMR (CDC13) 8(ppm): 2.03 (m, 2H), 2.16 (m, 2H), 2.22 (s, 3H), 2.72 (m, 1H), 2.85 (m, 1H), 3.46 (br.dd, J=14.0, 14.0 Hz, 1H), 3.55 (ddd, 5 J=7.0, 7.0, 14.0 Hz, 1H), 3.93 (s, 3H), 3.99 (m, 1H), 4.14 (ddd, J=7.0, 7.0, 14.0 Hz, 1H), 7.06 (dd, J=7.0, 9.0 Hz, 2H), 7.09 (d, J=7.0 Hz, 1H) , 7.18 (d, J=15.0 Hz, 1H) , 7.32 (m, 1H), 7.37 (m, 1H), 7.39 (m, 2H), 7.46 (br.s, 1H), 7.62 (d, J=15.0 Hz, 1H), 7.83 (d, J=7.0 Hz,
1H). [0481]
Example 352
Synthesis of (E)-1-[5-(4-fluorophenyl)-2,3, 4, 7-tetrahydroazepin-1-yl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl]propenone and (E)-l-[4-(4-
fluorophenyl)-2,3,6,7-tetrahydroazepin-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone [0482] [Formula 166]
(Figure Remove)

MeO


Synthesis of 4-(4-fluorophenyl)-4-hydroxyazepane-l-carboxylic acid tert-butyl ester
To a THF (60 mL) solution of tert-butyl ester
of 4-oxoazepane-l-carboxylic acid (5 g), fluoro benzene

magnesium bromide (1.OM THF solution, 82 mL) was added under ice-cooling, and the reaction solution was allowed to be warmed to room temperature and agitated for 1 hour. Water was added to the reaction solution 5 under ice-cooling after the reaction ended, extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution. The organic layer separated was dried over anhydrous magnesium sulfate and then the solvent was evaporated under
reduced pressure. The obtained residue is purified by silica gel column chromatography (elution solvent: heptane : ethyl acetate = 2:1), and 3.73 g (52%) of 4-(4-fluorophenyl)-4-hydroxyazepane-l-carboxylic acid tert-butyl ester was obtained. The physical properties
of the compound are as follows.
^-NMR (CDC13) 8(ppm): 1.47 (s, 9H) , 1.62-2.26 (m, 6H) , 3.22-3.44 (m, 2H), 3.37-3.89 (m, 3H) ,6.95-7.07 (m, 2H), 7.36-7.48 (m, 2H). ESI-MS; m/z332 [M++Na]
[0483]
Synthesis of 4-(4-fluorophenyl)-2,3,6,7-tetrahydroazepin-1-carboxylic acid tert-butyl ester and 5-(4-fluorophenyl)-2,3,4,7-tetrahydroazepin-l-carboxylic acid 4-(4-fluorophenyl)-4-hydroxy-azepane-l-
carboxylic acid tert-butyl ester
To a methylene chloride (20 mL) solution of 4-(4-fluorophenyl)-4-hydroxyazepane-l-carboxylic acid tert-butyl ester (500 mg) obtained above, TEA (1.13 mL)

and methane sulfonylchloride (0.15 mL) were added under ice-cooling, and the reaction solution was agitated at room temperature for 1 hour. Water is added to the reaction solution under ice-cooling liquid after the 5 reaction ended, extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution. The organic layer separated was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel column
chromatography (elution solvent: heptane : ethyl acetate 2:1) and 3.73 g (52%) of the olefin compound as an isomer mixture was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5(ppm): 1.46 (s, 9H) , 1.90 (br.s, 1H) , 2.44br.s, 1H) , 2.60-2.80 (m, 2H), 3.46-3.70 (m, 3H) , 3.92-4.14 (m, 1H), 5.95 (t, J=5.6 Hz, 1H), 6.97 (t, J=8.8 Hz, 2H), 7.20-7.32 (m, 2H) . ESI-MS; m/z314 [M++Na].xH-NMR (CDC13) 6: 1.48 (s, 9H),
1.90 (br.s, 1H), 2.44br.s, 1H), 2.60-2.80 (m, 2H),
3.46-3.70 (m, 3H) , 3.92-4.14 (m, 1H), 5.95 (t, J=5.6
Hz, 1H), 6.97 (t, J=8.8 Hz, 2H), 7.20-7.32 (m, 2H).
[0484]
Synthesis of 4-(4-fluorophenyl)-2,3,6,7-tetrahydro-lH-
azepine hydrohloride salt and 5-(4-fluorophenyl)-2,3,4,7-tetrahydro-lH-azepine hydrohloride salt
To an ethyl acetate (5 mL) solution of the olefin (250 mg) obtained above, 4N hydrochloric acid

was added at room temperature, and the reaction solution was agitated for 2 hours. It was concentrated under reduced pressure after the reaction ended and used for the next reaction as it was without 5 purification. [0485]
Synthesis of (E)-1-[5-(4-fluorophenyl)-2,3,4,7-tetrahydroazepin-1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)-phenyl]propenone and (E)-l-[4-(4-
fluorophenyl)-2,3,6,7-tetrahydroazepin-1-yl]-3- [3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)-phenyl]propenone By the same method as in Example 121, 157 mg (55%) of the title compound was obtained from crude amine (150 mg) obtained above and (E)-3-[3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid. The physical properties of the compound are as follows. ESI-MS; m/z454 [M++Na].lH-NMR (CDC13) 5(ppm): 2.00-2.12 (m, 2H), 2.30 (s, 3H), 2.54-2.63 (m, 1.5H), 2.66-2.77 (m, 1H) , 2.80-2.90 (m, 1.5H), 3.80-3.98 (m, 3H), 3.90
(s, 3H), 4.33 (d, J=5.6 Hz, 1H) , 5.95 (t, J=5.6 Hz, 0.5H), 6.09 (t, J=5.6 Hz, 0.5H), 6.82-7.04 (m, 2H) , 7.08-7.18 (m, 1H) , 7.19-7.34 (m, 4H), 7.62-7.77 (m, 2H) . 1H-NMR (CDC13) S(ppm): 2.00-2.12 (m, 2H), 2.30 (s, 3H),
2.54-2.63 (m, 1.5H), 2.66-2.77 (m, 1H), 2.80-2.90 (m, 1.5H), 3.80-3.98 (m, 3H), 3.88 (s, 3H), 4.26 (d, J=5.2 Hz, 1H) , 5.98-6.06 (m, 1H) , 6.82-7.04 (m, 2H), 7.08-7.18 (m, 1H), 7.19-7.34 (m, 4H), 7.62-7.77 (m, 2H) .


[0486]
Example 353
Synthesis of (E)-1-[4-(4-fluorophenyl)
[3-methoxy-4-(4-methyl-IH-imidazol-l- yl)phenyl]propenone
[0487]
[Formula 167]

azepan-1-yl]-3-

(Figure Remove)
Synthesis of 4-(4-fluorophenyl)azepane-1-carboxylic acid tert-butyl ester
To a methanol (10 mL) solution of 4-(4-fluorophenyl)-4-hydroxyazepane-l-carboxylic acid tert-
butyl ester (100 mg) obtained in Example 352, 10% Pd-C (100 mg) was added, and the reaction solution was agitated in hydrogen stream at room temperature for 1 hour. Suction filtration of the reaction solution was carried out using celite after the reaction ended, and
the filtrate was concentrated under reduced pressure. The obtained crude product of 4-(4-
fluorophenyl)azepane-1-carboxylic acid tert-butyl ester was used for the next reaction, without further purifying.
[0488]
Synthesis of 4-(4-fluorophenyl)azepane


By the same method as in Example 352, 4-(4-fluorophenyl)azepane was obtained from 4-(4-fluorophenyl)azepane-1-carboxylic acid tert-butyl ester (80 mg) obtained above. The obtained crude product was 5 used for the next reaction without further purifying. [0489]
Synthesis of (E)-1-[4-(4-fluorophenyl)azepan-1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone
By the same method as in Example 121, 75 mg
(66%) of the title compound was obtained from 4-(4-fluorophenyl)azepane (60 mg) obtained above and (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid. The physical properties of the compound are as 15 follows.
ESI-MS; m/z456 [M++Na].1H-NMR (CDC13) S(ppm): 1.62-2.03 (m, 4H), 2.04-2.20 (m, 2H), 2.29 (s, 1.5H), 2.30 (s, 1.5H), 2.62-2.76 (m, 1H), 3.44-3.72 (m, 2H), 3.73-3.96 (m, 1.5H), 3.88 (s, 1.5H), 3.90 (s, 1.5H), 3.97-4.07 20 (m, 0.5H), 6.82-7.00 (m, 4H), 7.06-7.16 (m, 3H), 7.17-7.29 (m, 2H), 7.68-7.76 (m, 2H). [0490]
Example 354
Synthesis of (E)-1-[3-(4-fluorophenyl)-4-hydroxyazepan-25 1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone


[0491] [Formula 168
(Figure Remove)
Synthesis of 3-(4-fluorophenyl)-3-hydroxyazepane-l-carboxylic acid tert-butyl ester
By the same method as in Example 352, 528 mg (72%) of 3-(4-fluorophenyl)-3-hydroxyazepane-l-5 carboxylic acid tert-butyl ester was obtained from 3-oxoazepine-1-carboxylic acid tert-butyl ester (507 mg). The physical properties of the compound are as follows. ESI-MS; m/z332 [M++Na].lH-NMR (CDC13) 8(ppm): 1.50 (s, 9H), 1.60-1.74 (m, 2H) , 1.80-2.10 (m, 4H), 2.90-3.40
(m, 2H), 3.80-4.10 (m, 1H) , 4.03 (d, J=15.2 Hz, 1H), 4.66 (s, 1H), 6.94-7.08 (m, 2H) , 7.40-7.54 (m, 2H) . [0492] Synthesis of 3-(4-fluorophenyl)azepan-3-ol
By the same method as in Example 352, 3-(4-
fluorophenyl)azepan-3-ol was obtained from the 3-(4-fluorophenyl)-3-hydroxyazepane-l-carboxylic acid tert-butyl ester (150 mg) obtained above. The obtained crude product was used for the next reaction, without purifying further.
[0493]


Synthesis of (E)-1-[3-(4-fluorophenyl)-4-hydroxyazepan-1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone
By the same method as in Example 121, 160 mg 5 (74%) of the title compound was obtained from the 3-(4-fluorophenyl)azepan-3-ol (119 mg) obtained above and (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid. The physical properties of the compound are as follows.
ESI-MS; m/z472 [M++Na]. 1H-NMR (CDC13) 6: 1.64-2.26 (m, 6H), 2.24 (s, 3H), 3.50-3.79 (m, 2H) , 3.93 (s, 3H), 3.98-4.32 (m, 2H), 7.00-7.15 (m, 3H) , 7.20-7.31 (m, 2H), 7.32-7.44 (m, 2H) , 7.46-7.73 (m, 3H), 7.87 (dd, J=1.0, 6.8 Hz, 1H).
[0494]
Example 355
Synthesis of (E)-1-[3-fluoro-3-(4-fluorophenyl)azepan-
1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)phenyl]propenone
[0495]
[Formula 169]
(Figure Remove)


Synthesis of (E)-1-[3-fluoro-3-(4-fluorophenyl)azepan-1-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone
To a methylene chloride (5 mL) solution of 5 (E)-1-[3-(4-fluorophenyl)-4-hydroxyazepan-l-yl]-3- [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]propenone (50 mg) obtained in Example 354, DAST (0.022 mL) was added at -78°C, and the reaction solution was allowed to be warmed to room temperature and agitated for 13
hours. Water was added to the reaction solution after the reaction ended, extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was
evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethanol : ethyl acetate = 1:5), and 30 mg (60%) of the title compound was obtained. The physical properties of the compound
are as follows.
ESI-MS; m/z474 [M++Na]. lH-NMR (CDC13) 6(ppm): 1.68-2.40 (m, 5H), 2.30 (s, 3H) , 3.15-3.30 (m, 1H) , 3.52-3.80 (m, 2H), 3.90 (s, 3H), 4.00-4.45 (m, 2H), 6.82-6.98 (m, 2H), 7.00-7.18 (m, 3H) , 7.20-7.34 (m, 2H) , 7.36-7.54
(m, 2H), 7.66 (d, J=15.6 Hz, 1H), 7.74 (d, J=7.0 Hz, 1H) . [0496] Example 356


(Figure Remove)
Synthesis of (E)-1-[6-(4-fluorophenyl)-2,3,4,5-tetrahydroazepin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone [0497] [Formula 170]
MeC>

Synthesis of (E)-1-[6-(4-fluorophenyl)-2,3,4,5-5 tetrahydroazepin-1-yl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl]propenone
By the same method as in Example 352, 5 mg
(6%) of the title compound was obtained from (E)-l-[3-
(4-fluorophenyl)-4-hydroxyazepan-l-yl]-3-[3-methoxy-4- (4-methyl-lH-imidazol-l-yl)phenyl]propenone (52 mg)
obtained in Example 354. The physical properties of
the compound are as follows.
ESI-MS; m/z432 [M++H]. l H-NMR (CDC13) 5: 1.80 (m, 2H),
1.94 (m, 2H), 2.30 (s, 3H), 2.68 (m, 2H) , 3.89 (s, 3H), 3.91 (m, 2H), 6.75 (s, 1H) , 6.87 (d, J=15.0 Hz, 1H),
6.92 (m, 1H), 7.06 (m, 2H) , 7.11 (s, 1H), 7.24 (d,
J=6.0 Hz, 1H), 7.27 (d, J=6.0 Hz, 1H), 7.34 (ddd,
J=2.0, 5.0, 9.0 Hz, 2H) , 7.70 (d, J=15.0 Hz, 1H), 7.76
(m, 1H). [0498]
Example 357


Synthesis of (E)-1-(3-hydroxymethyl-4-phenylpyrrolidine-1-yl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-l-yl)phenyl]propenone [0499] [Formula 171]
(Figure Remove)
By the same method as in Example 121, 368 mg 5 (76%) of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (290 mg) and trans-(4-phenylpyrrolidine-3-yl)methanol (200 mg). The physical properties of the compound are as follows.
XH-NMR (CDC13) 5(ppm): 2.28 (d, J=0.8 Hz, 1.5H), 2.30 (d, J-0.8 Hz, 1.5H), 2.55-2.73 (m, 1H), 3.17 (td, J=10.0, 8.0 Hz, 0.5H), 3.35 (td, J=10.0, 8.0 Hz, 0.5H), 3.50-3.82 (m, 4H) , 3.87 (s, 1.5H)/3.91 (s, 1.5H), 4.09-4.22 (m, 2H), 6.68 (d, J=15.2 Hz, 0.5H), 6.78 (d,
J=15.2 Hz, 0.5H), 6.91 (brt, 0.5H), 6.93 (brt, 0.5H), 7.11-7.40 (m, 8H), 7.70 (d, J-0.8 Hz, 0.5H), 7.71 (d, J=15.2 Hz, 0.5H), 7.72 (d, J=15.2 Hz, 0.5H), 7.73 (d, J=0.8 Hz, 0.5H). [0500]
Example 358
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-1-(trans-3-phenyl-4-piperidin-l-


ylmethylpyrrolidin-1-yl)propenone [0501] [Formula 172]
(Figure Remove)

To a methylene chloride (3 mL) solution of (E)-1-(3-hydroxymethyl-4-phenyl-pyrrolidine-l-yl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)propenone 5 (65 mg) obtained in Example 357, Dess-Martin reagent (128 mg) was added at 0°C, the reaction solution was agitated at the temperature for 1 hour, and then agitated at room temperature for 1 hour. The reaction solution was washed with a saturated sodium bicarbonate
water, and after drying the organic layer over
anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained aldehyde compound was used for the following reaction, without carrying out further purifying. Piperidine (5.9 |iL) and acetic
acid (4.5 p,L) were added to the methylene chloride (2 ml) solution of the above-mentioned aldehyde compound (17 mg). Furthermore, sodium triacetoxy borohydride (17 mg) was added to the solution, and the reaction solution was agitated at room temperature for 12 hours.
Ethyl acetate was added to the reaction solution after the reaction ended, and the reaction solution was


washed with a saturated sodium bicarbonate water. After drying the separated organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by 5 silica gel column chromatography (Carrier: Chromatorex™ NH, an elution solvent: from ethyl acetate to ethyl acetate : methanol 9:1), and 19.7 mg (76%) of the title compound was obtained. The physical properties of the compound are as follows.
ESI-MS; m/z507 [M+Na+] . ^-NMR (CDC13 ) 5(ppm): 1.35-1.60 (m, 6H), 2.15-2.48 (m, 9H) , 2.55-2.72 (m, 1H) , 3.01 (q, J=9.6 Hz, 0.5H), 3.15 (q, J=9.6 Hz, 0.5H), 3.38 (dd, J=12.8, 9.2 Hz, 0.5H), 3.52 (t, J=10.0 Hz, 0.5H), 3.61 (dd, J=12.8, 9.2 Hz, 0.5H), 3.67 (t, J=10.0 Hz, 0.5H),
3.87 (s, 1.5H), 3.93 (s, 1.5H), 4.06-4.21 (m, 2H), 6.70 (d, J=15.6 Hz, 0.5H), 6.80 (d, J=15.6 Hz, 0.5H), 6.92 (brt, 0.5H), 6.95 (brt, 0.5H), 7.11 (d, J=l.6 Hz, 0.5H), 7.15-7.40 (m, 7.5H), 7.70 (d, J=15.6 Hz, 0.5H), 7.72 (d, J=1.6 Hz, 0.5H), 7.73 (d, J=15.6 Hz, 0.5H),
7.74 (d, J=1.6 Hz, 0.5H). [0502]
Example 359
Synthesis of (E) -1-{3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl]phenyl}acryloyl)-4-phenylpyrrolidine-3-
carbaldehyde oxime

(Figure Remove)

To an ethanol (2 ml) solution of (E)-l-{3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acryloyl}-4-phenylpyrrolidine-3-carbaldehyde (34 mg) obtained in Example 358, hydroxylamine hydrochloride and sodium 5 acetate were added, and the reaction solution was agitated at room temperature for 12 hours. After condensing reaction solution under reduced pressure, ethyl acetate and saturated sodium bicarbonate water were added, and the organic layer was partitioned. The
obtained organic layer was dried over anhydrous
magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, an elution solvent: ethyl acetate : methanol =
10:1), and 16.2 mg (46%) of the title compound was obtained as a mixture of oxime moiety Z:E=1:2. The physical properties of the compound are as follows. ^-NMR (CDC13) 6(ppm): 2.28 (s, 1.5H), 2.29 (s, 1.5H), 3.19-3.77 (m, 4H) , 3.87 (s, 1.5H), 3.90 (s, 1.5H),
4.08-4.37 (m, 2H), 6.67-6.79 (m, 1.3H), 6.92 (brs, 0.5H), 6.94 (brs, 0.5H), 7.11-7.42 (m, 8.7H), 7.71


(brs, 0.5H), 7.72 (brs, 0.5H), 7.75 (brs, 1H), 8.70 (brs, 0.35H), 9.01 (brs, 0.15H), 9.20 (brs, 0.35H), 9.64 (brs, 0.15H). [0504] 5 Example 360
Synthesis of (E)-l-{3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acryloyl}-4-phenylpyrrolidine-3-carbonitrile [0505] 10 [Formula 174]
(Figure Remove)
To a THF (3 ml) solution of (E)-l-{3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acryloyl}-4-phenylpyrrolidine-3-carbaldehyde oxime (17.8 mg) obtained in Example 359, GDI (32.4 mg) was added at
room temperature, and heat-refluxing was carried out for 3 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was
partitioned. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column


chromatography (elution solvent: ethyl acetate :
methanol 10:1), and the 14.6 mg (86%) title compound
was obtained. The physical properties of the compound
are as follows. 5 ESI-MS; m/z413 [M++H].lH-NMR (CDC13) (ppm): 2.30 (s,
1.8H), 2.31 (s, 1.2H), 3.18-3.34 (m, 1H), 3.65-3.87 (m,
2.6H), 3.89 (s, 1.8H), 3.92 (s, 1.2H), 4.03 (t, J=9.2
Hz, 0.4H), 4.24-4.35 (m, 2H), 6.67 (d, J=15.6 Hz,
0.6H), 6.68 (d, J=15.6 Hz, 0.4H), 6.93 (brs, 0.6H), 10 6.95 (brs, 0.4H), 7.13-7.46 (m, 8H), 7.73 (brs, 0.6H),
7.74 (brs, 0.4H), 7.75 (d.J=15.6 Hz, 0.6H), 7.76 (d,
J=15.6 Hz, 0.4H).
[0506]
Example 361 15 Synthesis of-(E) trans-1-[4-(4-fluoropheoxy)-2-
hydroxymethyl-piperidin-1-yl]-3-[3-methoxy-4-(4-methyl-
IH-imidazol-l-yl)phenyl]propenone
[0507]
[Formula 175]
(Figure Remove)

o -


By the same method as in Example 121, 78 mg (68%) of the title compound was obtained from (E)-3-[3-20 methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic
acid (63 mg) and trans-(4-(4-fluoropheoxy)piperidine-2-yl)methanol (55 mg). The physical properties of the418
compound are as follows.
ESI-MS; m/z466 [M++H]. ^-NMR (CDC13 ) 8(ppm): 1.76-1.86 (nulH), 2.16-2.35 (rruSH), 2.82-2.99 (nulH) , 3.41-3.58 (nulH), 3.76-4.13 (nu5H), 4.75-5.06 (rru3H), 6.85 (dd, 5 J=9.2, 4.4 Hz, 2H), 6.93 (brs, 1H), 6.98 (t, J=9.2 Hz, 2H), 7.11 (brs, 1H), 7.14-7.28 (m, 3H), 7.64 (d, J=15.2 Hz, 1H), 7.72 (brs, 1H) . [0508]
The racemates or racemic compounds shown in 10 Table 8 were synthesized as in Example 358, 359 and 360.
The structural formulae and physicochemical properties are shown in Table 8, respectively. [0509] [Table 8]
O X
(Figure Remove)

Example X DATA: MS m/z
362 M++H:461 (ESI)

* -ii N

363 N oxrv/xOMe M++H:493 (ESI)
364 X3 M++H:533 (ESI)

[0510] Example 365
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-1-[4-(l-methyl-lH-indol-2-5 yl)piperidin-1-yl]propenone [0511] [Formula 176]
(Figure Remove)
To a THF (1 mL) solution of (E)-l-{4-(1H-indol-2-yl)piperidin-1-yl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]propenone (20 mg) obtained in Example 338 and iodomethane (0.04 mL), sodium hydride
(2.2 mg) was added at room temperature. The reaction solution was agitated at room temperature for 7 hours. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution after the reaction ended, and the organic layer was partitioned.
After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, an elution solvent: ethyl acetate), and 10 mg (49%)
of the title compound was obtained. The physical properties of the compound are as follows. *H-NMR (CDC13) 6(ppm): 1.72-1.85 (m, 2H), 2.09-2.18 (m,


2H), 2.30 (s, 3H), 2.80-2.96 (m, 1H), 2.99-3.07 (m,
1H), 3.28-3.44 (m, 1H), 3.75 (s, 3H), 3.91 (s, 3H),
4.22-4.35 (m, 1H) , 4.86-4.95 (m, 1H), 6.23 (s, 1H) ,
6.94 (s, 1H), 6.95 (d, J=15.6 Hz, 1H), 7.07-7.32 (m, 5 6H), 7.55 (d, J=7.6 Hz, 1H), 7.68 (d, J=15.6 Hz, 1H),
7.73 (brs, 1H) .
[0512]
Example 366
Synthesis of (E)-l-{4-[1-(2-hydroxy ethyl)-lH-indol-2- yl]piperidin-l-yl}-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)phenyl]propenone
[0513]
[Formula 177]
(Figure Remove)
By the same method as in Example 365, (E)-l-{4-(lH-indol-2-yl)piperidine-l-yl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]propenone (6 mg) a
obtained in Example 338 and (2-bromoethoxy)tert-butyldimethylsilane (0.04 mL) ,
(E)-l-{4-[1-(2-tert-butyldimethylsiloxyethyl)-IH-indol-2-yl]piperidin-l-yl}-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]propenone was obtained. TBAF (1M
THF solution, 0.02 mL) was added to a THF (1 mL)
solution of the obtained silyl protected compound, and the reaction solution was agitated at room temperature


for 3 hours. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution after the reaction ended, and the organic layer was separated. After drying the obtained organic layer 5 with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate : methanol = 9:1), and 0.9 mg (14%) of the title compound
was obtained. The physical properties of the compound are as follows.
ESI-MS; m/z485 [M++H]. XH-NMR (CDC13) 8(ppm): 1.75-1.83 (m, 2H), 2.09-2.18 (m, 2H), 2.280 (s, 3H), 2.79-2.94 (m, 1H), 3.10-3.20 (m, 1H), 3.23-3.40 (m, 1H), 3.91 (sf
3H), 4.00 (t, J=5.6 Hz, 2H), 4.22-4.33 (m, 1H) , 4.34 (t, J=5.2 Hz, 2H), 4.84-4.95 (m, 1H), 6.30 (s, 1H), 6.94 (t, J=1.2 Hz, 1H), 6.95 (d, J=15.6 Hz, 1H), 7.08-7.34 (m, 6H), 7.56 (d, J=7.6 Hz, 1H), 7.68 (d, J=15.6 Hz, 1H) , 7.72 (d, J=1.2 Hz, 1H) .
[0514]
The compounds shown in Table 9 were synthesized as in Example 121. The structural formulae and physicochemical properties are shown in Table 9, respectively.


[0515] [Table (Figure Remove)
as follows.
*H-NMR (CDC13) 8 (ppm): 4.09-4.18 (m, 4H), 3.66-3.72 (m, 1H), 3.54 (dt, J=5.2, 9.2 Hz, 1H) , 3.15 (ddd, J=3.6, 11, 22 Hz, 1H), 1.97-2.17 (m, 2H), 1.47 (s, 9H) , 1.31-5 1.36 (m, 6H), 0.89 (s, 9H), 0.04 (s, 6H). [0520]
Synthesis of (E)-4-(tert-butyldimethylsilanyloxy)-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl) -benzylidene]butyric acid tert-butyl ester
To a solution of 3-methoxy-4-(4-methyl-1H-
imidazol-l-yl)benzaldehyde (295 mg) obtained in Example 1 in THF (5.0 mL) and ethanol (5.0 mL) , 4-(tert-butyldimethylsilanyloxy) -2-(diethoxyphosphoryl)butyric acid tert-butyl ester (509 mg) and lithium hydroxide
monohydrate (104 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was
partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (heptane-ethyl acetate = 2:!->!:!),
and 395 mg of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm): 7.73 (s, 1H) , 7.69 (s, 1H) , 7.22-7.30 (m, 2H), 7.24 (s, 1H) , 6.94 (s, 1H), 3.91 (t,


J=6.4 Hz, 2H), 3.87 (s, 3H) , 2.77 (t, J=6.4 Hz, 2H), 2.30 (s, 3H), 1.56 (s, 9H) , 0.87 (s, 9H) , 0.03 (s, 6H) . [0521]
Synthesis of (E)-4-hydroxy-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester
To a THF (10 mL) solution of (E)-4-(tert-butyldimethylsilanyloxy) -2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)butyric acid tert-butyl ester (122 rag), TBAF (1M THF solution, 318 faL) was added, and
the reaction solution was agitated at room temperature for 1 hour. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate : ethanol = 10:1), and 49.7 mg of the
title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 7.72 (s, 1H), 7.69 (s, 1H), 7.20-7.25 (m, 3H) , 7.07 (d, J=8.0 Hz, 1H) , 6.93 (s, 1H), 3.88-3.94 (m, 2H), 3.86 (s, 3H), 2.76-2.84 (s,
2H), 2.30 (s, 3H), 1.56 (s, 9H) [0522]
Synthesis of (E)-4-(1,3-dioxo-l, 3-dihydro-isoindol-2-yl)-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-

yl)benzylidene]butyric acid tert-butyl ester
To an anhydrous THF (3.0 mL) solution of (E) -4-hydroxy-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]butyric acid tert-butyl ester (100 mg), 5 triphenylphosphine (87.8 mg) , phthalimide (49.3 mg) and diisopropyl azodicarboxylate (77.0 fiL) were added one by one. After agitating reaction solution at room temperature for 1.5 hours, reaction solution was concentrated under reduced pressure as it was, the
residue was purified by silica gel chromatography (elution solvent: ethyl acetate), and 119 mg of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 7.72-7.76 (m, 2H) , 7.63-7.68 (m,
4H) , 7.13 (d, J=8.0 Hz, 1H) , 6.99 (d, J=7 .2 Hz, 1H) , 6.90 (s, 1H), 6.86 (s, 1H), 3.91 (t, J=6.8 Hz, 2H), 3.77 (s, 3H), 2.95 (t, J=6.8 Hz, 2H), 2.30 (s, 3H), 1.60 (s, 9H). [0523]
Synthesis of (E)-4-amino-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester
To an ethanol (2.0 mL) solution of (E)-4-(1,3-dioxo-l,3-dihydroisoindol-2-yl)-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene] butyric acid tert-
butyl ester (119 mg), hydrazine monohydrate (48.9 mg) was added. The white precipitation was filtered off, after refluxing the reaction solution for 30 minutes and confirming disappearance of the starting materials.


The obtained filtrate was concentrated under reduced pressure and 86 mg of crude amino compounds was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 7.71 (d, J=1.2 Hz, 1H) , 7.63 (s, 1H), 7.24 (d, J=8.0 Hz, 1H) , 7.10 (d, J=l. 2 Hz, 1H) , 7.04 (dd, J=1.2, 8.0 Hz, 1H) , 6.92 (t, J=1.2 Hz, 1H), 3.86 (s, 3H), 2.92 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.30 (s, 3H), 1.56 (s, 9H).
[0524]
Synthesis of (E)-4-(3-fluorobenzylamino)-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]butyric acid tert-butyl ester
To a methylene chloride (2.0 mL) solution of
(E)-4-amino-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]butyric acid tert-butyl ester (71 mg), 3-fluorobenzaldehyde (21.1 |IL) , acetic acid (0.1 mL) and sodium triacetoxy borohydride (63.3 mg) were added one by one. After agitating reaction solution at room
temperature for 5.5 hours, a saturated sodium
bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried
over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate : ethanol = 20:1), and 47.5 mg


of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 7.72 (s, 1H) , 7.62 (s, 1H) , 7.22-7.28 (m, 2H), 7.10 (s, 1H) , 7.00-7.06 (m, 3H), 5 6.90-6.96 (m, 2H), 3.82 (s, 3H) , 3.78 (s, 2H), 2.84 (t, J=6.8 Hz, 2H), 2.74 (t, J=6.8 Hz, 2H), 2.30 (s, 3H), 1.53 (s, 9H). [0525] Synthesis of (E)-1-(3-fluorobenzyl)-3-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]pyrrolidin-2-one
To a methylene chloride (0.5 mL) solution of (E) -4-(3-fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]butyric acid tert-butyl ester (4.50 mg) , trifluoroacetic acid (500 jj,L) was
added. After agitating reaction solution at room
temperature for 1.5 hours and agitating that materials disappeared, reaction solution was concentrated under reduced pressure as it was. The residue was dissolved in DMF (0.5 mL) , IPEA (17.0 jiL) , EDC (5.58 mg) , and
HOBT (3.93 mg) were added to the reaction solution one by one, and the reaction solution was agitated at room temperature for 1.5 hours. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and
the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue


was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate : ethanol = 20:1), and 2.30 mg of the title compound was obtained. The physical properties of the compound are as follows. 5 ^H-NMR (CDC13) § (ppm) : 7.74 (s, 1H) , 7.42 (t, J=2.8 Hz, 1H), 7.28-7.35 (m, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.70-7.30 (m, 2H), 6.94 (s, 1H), 4.69 (s, 2H), 3.88 (s, 3H), 3.44 (t, J=6.8 Hz, 2H) , 3.09 (dt, J=2.8, 10 6.8 Hz, 2H), 2.30 (s, 3H). [0526]
Example 398
Synthesis of (E)-1-(3-fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0527] [Formula 179]
(Figure Remove)
Synthesis of 2-(diethoxyphosphoryl)-4-[1,3]dioxolan-2-yl-butyric acid ethyl ester
To a DMF (25 mL) solution of diethylphosphono ethyl acetate ester (10.0 mL), sodium hydride (3.02 g) was added at 0°C, and the reaction solution was heated
to 70°C and was agitated for 70 minutes. Next, after adding 2-(2-bromo ethyl)-1,3-dioxolane (14.8 mL) to the reaction solution and the reaction solution was


agitated at 80°C for 15 hours, and sodium hydride (1.40 g) and 2-(2-bromo ethyl)-1,3-dioxolane (7.70 ml) were further added to the reaction solution, and the reaction solution was agitated for 4 hours. Water and 5 ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (elution solvent; heptane-ethyl acetate =1:1 ->1:2 -> ethyl acetate), and 3.58 g of the title compound was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 4.87 (t, J=4.4 Hz, 1H) , 4.10-4.25 (m, 6H), 3.93-3.99 (m, 2H), 3.81-3.88 (m, 2H) , 3.03 (ddd, J=4.4, 11, 23 Hz, 1H), 1.94-2.16 (m, 2H), 1.64-1.84 (m, 2H), 1.30-1.36 (m, 9H) [0528]
Synthesis of (E)-4-[1,3]dioxolan-2-yl-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]butyric acid ethyl ester
To a THF (20 mL) solution of (1.75 g) of the 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde
obtained in Example 1, 2-(diethoxyphosphoryl)-4-
[1,3]dioxolan-2-yl-butyric acid ethyl ester (2.50 g) and lithium hydroxide monohydrate (388 mg) were added one by one, and the reaction solution was agitated at


room temperature overnight. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained 5 organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; heptane-ethyl acetate =1:2 -> ethyl acetate),
and 1.05 g of the title compound as an isomer mixture (E:Z=4:1) was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 7.74 (s, 1H) , 7.66 (s, 1H) , 7.27 (d, J=8.4 Hz, 1H) , 7.13 (s, 1H) , 7.09 (d, J=8.4 Hz,
1H), 6.95 (s, 1H), 4.95 (t, J=4.4, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.92-4.00 (m, 2H), 3.90 (s, 3H), 3.82-3.88 (m, 2H), 2.71-2.75 (m, 2H), 2.31 (s, 3H), 1.96-2.10 (m, 2H) , 1.37 (t, J=7.2 Hz, 3H) . [0529]
Synthesis of (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-5-oxovaleric acid ethyl ester
To an aqueous solution of (243 mg) of (E)-4-[l,3]dioxolan-2-yl-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]butyric acid ethyl ester,
acetic acid (2 mL) and trifluoroacetic acid (2.0 mL) were added one by one, and the reaction solution was agitated at room temperature for 4 hours. After confirming disappearance of the starting materials, a


saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it 5 was dried over anhydrous magnesium sulfate and 110 mg of the title compound was obtained by condensing under reduced pressure. The physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm) : 9.81 (s, 1H) , 7.72-7.74 (m, 2H) ,
7.27 (d, J=8.0 Hz, 1H) , 6.94-7.01 (m, 3H), 4.30 (q, J=7.2 Hz, 2H), 3.87 (s, 3H), 2.89 (t, J=8.0 Hz, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.30 (s, 3H) , 1.37 (t, J=7.2 Hz, 3H). [0530]
Synthesis of (E)-5-(3-fluorobenzylamino)-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]valeric acid ethyl ester
To a methylene chloride (2.0 mL) solution of (E)-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)-5-oxo-valeric acid ethyl ester (142
mg) , 3-f luorobenzylamine (141 jj,L) , acetic acid (1.0 mL) and sodium triacetoxy borohydride (105 mg) were added one by one. After agitating reaction solution at room temperature overnight, a saturated sodium bicarbonate
water and ethyl acetate were added to the reaction
solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium


sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, an elution solvent: ethyl acetate -> ethyl acetate : ethanol = 10:1), and 81 mg 5 of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13) 6 (ppm) : 7.72 (s, 1H) , 7.66 (s, 1H) , 7.23 (d, J-8.4 Hz, 1H), 6.89-7.07 (m, 7H), 4.29 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 2H) , 2.69 (t, J=6.8 Hz,
2H), 2.62 (t, J=8.0 Hz, 2H), 2.30 (s, 3H), 1.74-1.83 (m, 2H), 1.36 (t, J=7.2 Hz, 3H). [0531]
Synthesis of (E)-1-(3-fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
An acetic acid (3 mL) solution of (E)-5-(3-
fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid ethyl ester (81 mg) was heated to reflux overnight. After cooling the reaction solution to 0°C, it was neutralized with IN
sodium hydroxide solution, and then a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried
over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate =1:5 -> ethyl acetate),


and 21 mg of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13) 6 (ppm) : 7.88 (s, 1H) , 7.73 (s, 1H) , 7.25-7.34 (m, 3H), 7.09 (d, J=7.2 Hz, 1H) , 6.94-7.05 (m, 4H), 4.73 (s, 2H), 3.87 (s, 3H) , 3.39 (t, J=6.0 Hz, 2H), 2.84 (dt, J=2.0, 6.4 Hz, 2H), 2.30 (s, 3H), 1.89 (m, 2H). [0532]
Example 399
Synthesis of (E) -3-[3-methoxy-4-(4-methyl-lH-imidazol-5 1-yl)benzylidene]-1-[(IS)-1-phenylethyl]piperidin-2-one [0533] [Formula 180]
(Figure Remove)
To a methylene chloride (2 mL) solution of (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-5-oxovaleric acid ethyl ester (162 mg), (S) - (-) -alpha-methylbenzylamine (183 jaL) , acetic acid
(1.0 mL) and sodium triacetoxy borohydride (120 mg) were added one by one. After agitating reaction solution at room temperature overnight, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was
partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried


over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in acetic acid (2 mL), and heat-refluxing of the reaction solution was carried out overnight. After 5 cooling reaction solution to 0°C, neutralized with a saturated sodium bicarbonate water, ethyl acetate was added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried
over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate =1:1 -> ethyl acetate : ethanol = 10:1), and 13.7 mg of the title compound was
obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 7.90 (s, 1H) , 7.72 (d, J=1.2 Hz, 1H), 7.24-7.29 (m, 6H) , 7.04-7.06 (m, 2H), 6.94 (t, J=1.2 Hz, 1H), 6.26 (q, J=7.2 Hz, 1H), 3.85 (s, 3H),
3.25 (ddd, J=3.6, 8.4, 12 Hz, 1H), 2.96 (ddd, J=4.4,
6.8, 11 Hz, 1H), 2.72-2.85 (m, 2H), 2.30 (s, 3H), 1.79-1.83 (m, 1H), 1.68-1.74 (m, 1H), 1.58 (d, J=7.2 Hz, 3H). [0534]
Example 400
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-1-[1-(3-morpholin-4-ylphenyl)ethyl]piperidin-2-one

[0535] [Formula 181] (Figure Remove)
Synthesis of (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)-benzylidene]-5-[1-(3-morpholin-4-ylphenyl)ethylamino] valeric acid ethyl ester
To a methylene chloride (10 mL) solution of 5 (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)-
benzylidene]-5-oxovaleric acid ethyl ester (173 mg) obtained in Example 398, 1-(3-morpholin-4-yl-phenyl)ethyl amine (157 mg) and acetic acid (0.1 mL) and sodium triacetoxy borohydride (214 mg) were added
one by one. The reaction solution was agitated at room temperature for 1 hour, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated
saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex NH, elution solvent:heptane-ethyl acetate = 1:2), and 205 mg of the title compound was
obtained. The physical properties of the compound are as follows.



(CDC13) 6 (ppm) : 7.72 (s, 1H) , 7.62 (s, 1H) , 7.19-7.23 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.98 (s, 1H), 6.93 (s, 1H), 6.87 (s, 1H) , 6.78-6.81 (m, 2H) , 4.27 (q, J=7.2 Hz, 2H), 3.82-3.86 (m, 4H), 3.81 (s, 5 3H), 3.70 (q, J=6.8 Hz, 1H), 3.14 (t, J=4.8 Hz, 4H), 2.43-2.61 (m, 4H), 2.30 (s, 3H), 1.62-1.80 (m, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H). [0536] Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]-1-[1-(3-morpholin-4-ylphenyl)ethyl]piperidin-2-one
To a solution of (E)-2-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]-5-[1-(3-morpholin-4-ylphenyl)ethylamino] valeric acid ethyl ester (55.0
mg) in THF (1.0 mL) and ethanol (1.0 mL), 2N sodium hydroxide solution (1.0 m) was added. The reaction solution was agitated at room temperature overnight, 2N hydrochloric acid and ethyl acetate were added, and the organic layer was partitioned. After the obtained
organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and 50.0 mg of crude carboxylic acid compound was obtained by condensing under reduced pressure. To a DMF (2.0 mL) solution of the obtained carboxylic acid
compound, IPEA (51.8 jiL) , EDC (38.0 mg) and HOBT (26.8 mg) were added one by one, and the reaction solution was agitated at room temperature for 1 hour. After confirming disappearance of the starting materials,


water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium 5 sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex NH, elution solvent: ethyl acetate =1:1 -> heptane-ethyl acetate), and 6.00 mg of the title compound was obtained. The physical
properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm) : 7.89 (s, 1H) , 7.72 (d, J=l.6 Hz, 1H), 7.22-7.28 (m, 2H) , 7.05-7.07 (m, 2H), 6.93 (s, 1H), 6.83-6.90 (m, 3H), 6.21 (q, J=7.2 Hz, 1H), 3.85-3.87 (m, 7H) , 3.24 (dd, J=4.0, 8.4, 12 Hz, 1H), 3.16
(t, J=4.8 Hz, 4H), 2.95-3.01 (m, 1H), 2.76-2.82 (m, 2H), 2.30 (s, 3H), 1.76-1.84 (m, 1H), 1.67-1.73 (m, 1H), 1.55 (d, J=7.2 Hz, 3H). [0537] Example 401
Synthesis of (E)-1-[(IR,2S)-2-hydroxyindan-l-yl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one [0538] [Formula 182]
(Figure Remove)


Synthesis of (E)-5-[(1R,2S)-2-hydroxyindan-l-ylamino]-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]valeric acid ethyl ester
To a methylene chloride (2.0 mL) solution of (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]-5-oxovaleric acid ethyl ester (110 mg), (1R,2S)-amino-2-indanol (63.2 mg), acetic acid (0.1 mL) and sodium triacetoxy borohydride (81.7 mg) were added one by one. After agitating reaction solution at room
temperature overnight, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: ethyl acetate =1:1 -> heptane-ethyl acetate), and 120 mg of the title compound was obtained. The physical
properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 7.71 (d, J-l. 6 Hz, 1H) , 7.68 (s, 1H), 7.17-7.27 (m, 5H), 7.05 (dd, J=l.6 Hz, 1H), 7.01 (d, J=1.6 Hz, 1H), 6.93 (t, J=1.6 Hz, 1H), 4.39 (dt, J=2.8, 5.2 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 4.03 (d,
J=5.2 Hz, 1H), 3.85 (s, 3H) , 3.04 (dd, J=5.2 Hz, 1H), 2.92-2.99 (m, 2H), 2.75-2.83 (m, 1H), 2.61-2.73 (m, 2H), 2.30 (s, 3H), 1.84 (qu, 7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H) .

[0539]
Synthesis of (E)-1-[(IR,2S)-2-hydroxyindan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
To an ethanol (2.0 mL) solution of (E)-5-
[(IR,2S)-2-hydroxyindan-l-ylamino]-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene] valeric acid ethyl ester (120 mg), 2N sodium hydroxide solution (1.0 mL) was added. After carrying out heat-refluxing of the
reaction solution for 30 minutes and confirming
disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate =1:1 -> ethyl acetate -> ethyl acetate : ethanol =
10:1), and 78.9 mg of the title compound was obtained. The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 7.82 (s, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.22-7.30 (m, 5H), 7.02 (d, J=7.2 Hz, 1H), 7.01 (s, 1H), 6.92 (s, 1H), 6.01 (d, J=7.2 Hz, 1H) , 4.91 (q,
J=7.2 Hz, 1H), 3.84 (s, 3H), 3.30 (dd, J=7.2, 16 Hz, 1H), 3.11-3.22 (m, 2H), 2.96 (dd, J=7.2, 16 Hz, 1H), 2.75-2.86 (m, 2H), 2.30 (s, 3H), 1.70-1.90 (m, 2H). [0540]


Example 402
Synthesis of (E)-1-(3-iodobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one monotrifluoroacetic acid salt [0541] [Formula 183]
(Figure Remove)



F
By the same method as in Example 398, (E)-2-
[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-5-oxovaleric acid ethyl ester (197 mg) and 3-iodobenzylamine (310 (aL) were reacted. 7.8 mg of the title compound was obtained by purifying the obtained
crude product by LC-MS. The physical properties of the compound are as follows.
TH-NMR (CDC13) 6 (ppm) : 8.72 (s, 1H) , 7.88 (s, 1H), 7.63-7.66 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.07-7.12 (m, 4H), 4.68 (s, 2H), 3.91
(s, 3H), 3.39 (t, J=5.6 Hz, 2H), 2.80-2.83 (m, 2H), 2.48 (s, 3H) , 1.86-1.92 (m, 2H) . [0542]
Example 403 Synthesis of (E)-1-(2,6-dichloropyridine-4-ylmethyl)-3-
[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one


;0543]
; Formula 184]
(Figure Remove)



By the same method as in Example 398, 7.4 mg of the title compound was obtained from (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)-benzylidene]-5-oxovaleric acid ethyl ester (130 mg) and C-(2,6-5 dichloro-pyridin-4-yl)methylamine (101 mg). The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 7.87 (s, 1H) , 7.73 (s, 1H) , 7.27 (d, J=8.4 Hz, 1H), 7.20 (s, 2H) , 7.05 (d, J=8.4 Hz, 1H), 7.04 (s, 1H), 6.95 (s, 1H) , 4.69 (s, 2H), 3.87 (s,
3H), 3.44 (t, J=5.6 Hz, 2H) , 2.89 (t, J=5.6 Hz, 2H), 2.05 (s, 3H), 1.92-1.98 (m, 2H). [0544]
Example 404 Synthesis of (E)-1-(3-fluorobenzyl)-3-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]azepan-2-one [0545] [Formula 185]
(Figure Remove)


Synthesis of 2-(diethoxyphosphoryl)-5-[1,3]dioxolan-2-yl valeric acid ethyl ester
To a DMF (50 mL) solution of diethylphosphono ethyl acetate ester (2.65 mL), sodium hydride (643 mg) 5 and 2-(3-chloropropyl)-1,3-dioxolane (2.6 g) were added at 0°C one by one, and the reaction solution was allowed to be warmed to 60°C and agitated overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained
organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (heptane-ethyl acetate = from 1:2 to
1:5 to ethyl acetate), and 1.62 g of the title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 4.84 (t, J=4.8 Hz, 1H) , 4.10-4.25 (m, 6H), 3.93-3.97 (m, 2H), 3.80-3.85 (m, 2H),
2.88-2.90 (m, 1H), 1.97-2.10 (m, 1H) , 1.82-1.94 (m, 1H), 1.64-1.71 (m, 2H) , 1.40-1.57 (m, 2H), 1.21-1.35 (m, 9H). [0546] Synthesis of (E)-5-[1, 3]dioxolan-2-yl-2-[3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)benzylidene]valeric acid ethyl ester
To a solution of 3-methoxy-4-(4-methyl-lH-imidazol-1-yl)-benzaldehyde (580 mg) obtained in


Example 1 in THF (10 mL) and ethanol (10 mL), 2-(diethoxyphosphoryl)-5-[1,3]dioxolan-2-yl valeric acid ethyl ester (826 mg) and lithium hydroxide monohydrate (205 mg) were added one by one, and the reaction 5 solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was
(
partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate : ethanol = 20:1), and it was obtained
485 mg, the title compound was obtained as an isomer mixture (E:Z=4:1). The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 7.72 (s, 1H) , 7.64 (s, 1H) , 7.24-7.26 (m, 1H) , 7.01-7.04 (m, 2H), 6.93 (s, 1H),
4.89 (t, J=4.0 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.92-3.95 (m, 2H), 3.87 (s, 3H), 3.81-3.85 (m, 2H), 2.57-2.61 (m, 2H), 2.30 (s, 3H), 1.66-1.78 (m, 4H), 1.36 (t, J=7.2 Hz, 3H). [0547]
Synthesis of (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-6-oxohexanoic acid ethyl ester
To an aqueous solution (2.0 mL) of (E)-5-[1,3] dioxolan-2-yl-2-[3-methoxy-4-(4-methyl-lH-


imidazol-1-yl)benzylidene] valeric acid ethyl ester (480 mg), acetic acid (1.0 mL) and trifluoroacetic acid (1.0 mL) were added one by one, and the reaction solution was agitated at room temperature for 2.5 5 hours. A saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate : ethanol = 10:1), and 400 mg of the title compound was obtained.
The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 9.78 (s, 1H) , 7.50-7.80 (brs, 1H), 7.69 (s, 1H), 7.28-7.31 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.90-6.96 (m, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.89 (s, 3H), 2.47-2.61 (m, 4H), 2.31
(s, 3H), 1.86-1.93 (s, 2H), 1.37 (t, J=7.2 Hz, 3H). [0548]
Synthesis of (E)-6-(3-fluorobenzylamino)-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]hexanoic acid ethyl ester
To a methylene chloride (6 mL) solution of
(E)-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-6-oxohexanoic acid ethyl ester (231 mg) , 3-fluorobenzylamine (88.7 jj,L) , acetic acid (0.5


mL) and sodium triacetoxy borohydride (165 mg) were added one by one. After agitating the reaction solution at room temperature overnight, a saturated sodium bicarbonate water and ethyl acetate were added 5 to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica
gel chromatography (Carrier: Chromatorex NH, elution
solvent; heptane-ethyl acetate =1:1 -> ethyl acetate -> ethyl acetate : ethanol = 10:1), and 173 mg of the title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 7.71 (s, 1H) , 7.62 (s, 1H) , 7.20-7.25 (m, 2H), 6.98-7.08 (m, 4H), 6.86-6.93 (m, 2H), 4.27 (q, J=7.2 Hz, 2H) , 3.84 (s, 3H) , 3.77 (s, 2H), 2.60-2.70 (m, 2H), 2.52-2.60 (m, 2H), 2.30 (s, 3H) , 1.76-1.87 (m, 4H), 1.35 (t, J=7.2 Hz, 3H) .
[0549]
Synthesis of (E)-1-(3-fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]azepan-2-one
To a to ethanol (2.0 mL) solution of (E)-6-(3-fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene)hexanoic acid ethyl ester (173 mg), 2N sodium hydroxide solution (2.0 mL) was added. After refluxing the reaction solution for 1 hour and confirming disappearance of the starting


materials, 2N hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried 5 over anhydrous magnesium sulfate and concentrated under reduced pressure. IPEA (134 (iL) , EDC (98.2 mg) , and HOBT (69.2 mg) were added to a DMF (5.0 mL) solution of the obtained carboxylic acid compound (112 mg) one by one, and the reaction solution was agitated at room
temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried
over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate), and 70.3 mg of the title compound was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 7.72 (d, J=1.2 Hz, 1H) , 7.28-
7.34 (m, 1H), 7.23 (d, J=26 Hz, 1H), 6.95-7.15 (m, 6H), 6.94 (t, J=1.2 Hz, 1H), 4.67 (s, 2H), 3.86 (s, 3H), 3.36 (t, J=5.2 Hz, 2H), 2.62 (t, J=5.2 Hz, 2H), 2.30 (s, 3H) , 1.82-1.88 (m, 2H), 1.61-1.68 (m, 2H) .
[0550]
Example 405
Synthesis of 3-[4-(IH-imidazol-l-yl)-3-
methoxybenzylidene]-1-naphtha1en-1-ylmethyl-piperidin-

2-one trifluoroacetic acid salt [0551] [Formula 186]
(Figure Remove)

Synthesis of l-naphthalen-l-ylmethyl-piperidin-2-one
To a DMF (20 mL) solution of 8-valerolactam (1.0 g), sodium hydride (404 mg) , 1-
(chloromethyl)naphthalene (1.78 g) and sodium iodide (151 mg) were added one by one at 0°C, and the reaction solution was allowed to be warmed to 60°C, and was agitated for 6 hours. 2N hydrochloric acid and THF were added to the reaction solution, and the organic
layer was partitioned. After the obtained organic
layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (heptane: elution
solvent; ethyl acetate =1:2 -> ethyl acetate), and 2.42 g of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13) § (ppm) : 8.08-8.11 (m, 1H) , 7.83-7.85 (m, 1H), 7.78 (d, J=8.4 Hz, 1H) , 7.45-7.53 (m, 2H), 7.40
(dd, J=6.8, 8.0 Hz, 1H), 7.31 (d, J=6.8 Hz, 1H), 5.08


(s, 2H) , 3.09 (t, J=6.0 Hz, 2H) , 2.50 (t, J=6.0 Hz, 2H), 1.67-1.79 (ra, 4H). [0552]
Synthesis of 3-[4-(IH-imidazol-l-yl)-3-
methoxybenzylidene]-l-naphthalen-l-ylmethylpiperidin-2-one trifluoroacetic acid salt
To a THF (7.0 mL) solution of 1-naphthalen-l-ylmethylpiperidin-2-one (800 mg), lithium bis (trimethylsilyl)amide (1.5M THF capacity, 6.68 mL)
was added at 0°C, and the reaction solution was agitated for 20 minutes. A THF (2 mL) solution of 4-(lH-imidazol-1-yl)-3-methoxy benzaldehyde (676 mg) obtained in Example 1 was added dropwise to the reaction solution, and the reaction solution was agitated at
room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: elution solvent: ethyl acetate = one -> ethyl acetate -> ethyl acetate : ethanol 10:1), and 330 mg of alcoholic compounds was obtained. Next, methane sulfonyl chloride
(31 nL) and TEA were added to a methylene chloride (1.0 mL) solution of the obtained alcoholic compound at 0°C (113 juiL) , and the reaction solution was agitated for 3 hours and 30 minutes. Water and ethyl acetate were


added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under 5 reduced pressure. DBU (24.7 mg) was added to the methylene chloride (1.0 mL) solution of the obtained residue, and the reaction solution was agitated at room temperature overnight. The reaction solution was purified in LC-MS as it was, and 3.1 mg of the title
compound was obtained. The physical properties of the compound are as follows.
^-NMR (CD3OD) 8 (ppm) : 9.24 (s, 1H) , 8.10-8.12 (m, 1H) , 7.89-7.92 (m, IE), 7.83-7.85 (m, 2H), 7.72 (s, 1H) , 7.51-7.55 (m, 2H), 7.44-7.47 (m, 2H), 7.36 (d, J=6.4
Hz, 1H), 7.25 (s, 1H) , 7.08 (d, J=8.0 Hz, 1H), 5.19 (d, J=15 Hz, 1H), 5.07 (d, J=15 Hz, 1H), 3.89 (s, 3H), 3;.41 (dd, J=4.0, 13 Hz, 1H) , 3.14-3.24 (m, 2H), 2.95 (dd, J=9.2, 14 Hz, 1H), 2.78-2.84 (m, 1H) , 1.78-1.88 (m, 2H), 1.66-1.76 (m, 1H), 1.51-1.60 (m, 1H) .
[0553]
Example 406
Synthesis of 3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-l-naphthalen-l-ylmethylpyrrolidin-2-one trifluoroacetic acid salt

[0554] [Formula 187]
(Figure Remove)
Synthesis of l-naphthalen-l-ylmethy-pyrrolidin-2-one
By the same way as Example 405, 2.32 g of the title compound was obtained from 2-pyrrolidone (767 jiL) and 1-(chloromethyl)naphthalene (1.78 g). The physical 5 properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 9.41 (s, 1H) , 8.15-8.17 (m, 1H) , 8.00 (s, 1H), 7.94-7.97 (m, 1H) , 7.87 (d, J=8 . 0 Hz, 1H), 7.85 (s, 1H), 7.78 (s, 1H) , 7.64 (d, J=8.0 Hz, 1H), 7.47-7.57 (m, 3H), 7.40-7.42 (m, 2H), 7.23 (d,
J=8.4 Hz, 1H), 5.14 (s, 2H), 3.89 (s, 3H), 3.32 (t, J=5.6 Hz, 2H), 2.81 (t, J=5.6 Hz, 2H), 1.78 (t, J=5.6 Hz, 2H). [0555] Synthesis of 3- [3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]-l-naphthalen-l-ylmethyl-pyrrolidin-2-one mono(trifluoroacetic-acid) salt
By the same method as in Example 405, 1-naphthalen-l-ylmethylpyrrolidin-2-one (300 mg) obtained in Example 1, 3.4 mg of the title compound was obtained
from the 3-methoxy-4-(4-methyl-lH-imidazol-l-

yl)benzaldehyde (431 mg). The physical properties of the compound are as follows.
XH-NMR (CD3OD) 6 (ppm): 9.14 (t, J=1.2 Hz, 1H) , 8.16-8.18 (m, 1H), 7.88-7.93 (m, 2H) , 7.46-7.58 (m, 7H), 5 7.38-7.41 (m, 1H) , 7.32 (d, J=7.6 Hz, 1H), 5.11 (s, 2H), 3.95 (s, 3H), 3.37 (t, J=6.8 Hz, 2H), 3.05-3.10 (m, 2H), 2.42 (s, 3H) [0556]
Example 407
Synthesis of 3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-l-naphthalen-l-ylmethylazepan-2-one trifluoroacetic acid salt [0557] [Formula 188]
(Figure Remove)
Synthesis of l-naphthalen-l-ylmethylazepan-2-one
By the same method as in Example 405, 2.53 g
of the title compound was obtained from e-caprolactam (1.14 g) and 1-(chloromethyl)naphthalene (1.78 g). The physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm): 8.12 (d, J=8. 4 Hz, 1H) , 7.85-7.87 (m, 1H), 7.80 (d, J-8.4 Hz, 1H), 7.48-7.56 (m,
2H), 7.42 (t, J=8.4 Hz, 1H), 7.35 (d, J=6.4 Hz, 1H),


5.06 (s, 2H), 3.26-3.29 (m, 2H), 2.62-2.65 (m, 2H),
1.58-1.70 (m, 4H), 1.21-1.26 (m, 2H) .
[0558]
Synthesis of 3- [3-methoxy-4- (4-methyl-lH-iitiidazol-l-5 yl)benzylidene]-l-naphthalen-l-ylmethylazepan-2-one the
trifluoroacetic acid salt
By the same method as in Example 405, 1.0 mg
of the title compound was obtained from the 3-methoxy-
4- (4-methyl-lH-imidazol-l-yl)benzaldehyde (383 mg) obtained in Example 1 and 1-naphthalen-l-ylmethyl-
azepin-2-one(300 mg). The physical properties of the
compound are as follows.
XH-NMR (CD3OD) 5 (ppm): 9.08 (d, J=1.2 Hz, 1H), 8.18 (d,
J=9.2 Hz, 1H), 7.92 (dd, J=2.0, 7.6 Hz, 1H), 7.88 (d, 15 J=7.6 Hz, 1H), 7.44-7.57 (m, 6H) , 7.31 (d, J=l. 2 Hz,
1H), 7.23 (dd, J=1.6, 8.4 Hz, 1H), 7.04 (s, 1H), 5.16
(s, 2H), 3.94 (s, 3H), 3.44 (t, J=5.6 Hz, 2H), 2.59 (t,
J=5.6 Hz, 2H), 2.43 (s, 3H), 1.63-1.69 (m, 2H), 1.22-
1.25 (m, 2H). [0559]
Example 408
Synthesis of (Z)-3-benzyl-5-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]imidazolidine-2,4-dione
[0560]
[Formula 189]

(Figure Remove)


Synthesis of (Z)-2-benzyloxycarbonylamino--3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid methyl ester
To a methylene chloride (10 mL) suspension of 5 potassium tert-butoxide (290 mg), a methylene chloride (3 mL) solution of
benzyloxycarbonylamino(diethoxyphosphono)acetic acid methyl ester (850 mg) was added dropwise at -70°C. After agitating the reaction solution at -70°C for 2
hours, a methylene chloride (7 mL) solution of 3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (500 mg) obtained in Example 1 was added dropwise. The reaction solution was agitated at -70°C for I hour, and then agitated at room temperature for 4 hours. Ethyl
acetate and a saturated ammonium chloride solution were added to the reaction solution after the reaction ended, and the organic layer was separated. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate 4:1 -> elution solvent: hexane : ethyl acetate), and 433 mg (45%) of (Z)-2-benzyloxycarbonylamino-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid methyl
ester was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8(ppm): 2.37 (s, 3H) , 3.68 (s, 3H) , 3.86 (s, 3H), 5.11 (s, 2H), 6.50 (brs, 1H), 6.91 (s, 1H),


7.11-7.35 (m, 9H), 7.70 (s, 1H) . [0561]
Synthesis of (Z)-(l-benzylcarbamoyl-2-[3-methoxy-4- (4-methyl-lH-imidazol-1-yl)phenyl]vinyl)carbamic acid 5 benzyl ester
To a solution of (Z)-2-
benzyloxycarbonylamino-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid methyl ester (433 mg) obtained at the above step in THF (1 mL) and methanol
(2 mL), 2N sodium hydroxide solution (1.5 mL) was
added, and the reaction solution was agitated at room temperature for 12 hours. After the reaction ended, 2N hydrochloric acid (1.5 mL) was added to the reaction solution to neutralize it, and the reaction solution
was extracted with ethyl acetate. After the organic layer was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. By adding ether to the obtained residue, 363 mg (87%) of carboxylic acid
compound was obtained as a solid. Diethyliso
propylamine (0.05 mL), HOBT (30 mg) , and EDC (40 mg) were added to a DMF (3 mL) solution of the obtained carboxylic acid (66 mg) and benzylamine (0.018 mL) , and the reaction solution was agitated at room temperature
for 12 hours. Ethyl acetate and saturated sodium
bicarbonate water were added to the reaction solution after the reaction ended, and after separating the organic layer and drying the obtained organic layer


with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane : ethyl acetate 5 = 4:1 -» ethyl acetate), and 448 mg (60%) of (Z)-(l-benzylcarbamoyl-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]vinyl)carbamic acid benzyl ester was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5(ppm): 2.30 (s, 3H), 3.68 (s, 3H), 4.55 (d, J=7.2 Hz, 2H), 5.15 (s, 2H) , 6.22-6.38 (m, 1H), 6.55 (brt, J=7.2 Hz, 1H), 6.91 (s, 1H) , 7.03-7.39 (m, 14H), 7.68 (s, 1H). [0562]
Synthesis of (Z)-3-benzyl-5-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]imidazolidine-2, 4-dione
To a THF (3 mL) solution of (Z)-{1-
benzylcarbamoyl-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]vinyl}carbamic acid benzyl ester (48 mg)
obtained above, TBAF (1M THF solution, 0.01 mL) was added and heat-refluxing of the reaction solution was carried out for 3 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate was added and washed with a saturated ammonium
chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution

'
solvent: from hexane: ethyl acetate 1:1 to ethyl
acetate), and 28 mg (75%) of (Z)-3-benzyl-5-[3-methoxy-
4-(4-methyl-lH-imidazol-l-yl)benzylidene]imidazolidine-
2,4-dione was obtained. The physical properties of the compound are as follows.
hi-NMR (CDC13) 8(ppm): 2.31 (s, 3H) , 3.78 (s, 3H) , 4.79
(s, 2H), 6.72 (s, 1H), 6.88 (brs, 1H) , 7.03-7.45 (m,
9H), 9.95 (s, 1H) , 12.7 (brs, 1H) .
[0563] 10 Example 409
Synthesis of (Z)-5-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]-3-(4-methoxyphenyl)-2-
thioxsoimidazolidine-4-one
[0564]
[Formula 190]
(Figure Remove)
Synthesis of (Z)-5-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]-3-(4-methoxyphenyl)-2-thioxoimidazolidine-4-one
Piperidine (0.019 mL) was added to an ethanol (2 mL) solution of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (20 mg) obtained in Example 1 and 3-(4-
methoxyphenyl)-2-thioxoimidazolidine-4-one (21 mg), and heat-refluxing of the reaction solution was carried out for 12 hours. The reaction solution was allowed to be


cooled to room temperature and the solid deposited was separated by filtering, and 18 mg (47%) of the title compound was obtained by washing with ethanol and ether. The physical properties of the compound are as 5 follows.
^-NMR (DMSO-d6) 6(ppm): 2.15 (s, 3H) , 3.81 (s, 3H), 3.93 (s, 3H), 6.69 (s, 1H) , 7.22 (d, J=9.2 Hz, 2H), 7.20 (s, 1H), 7.38 (d, J=9.2 Hz, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.54 (brs, 1H), 7.56 (brd, J=8.0 Hz, 1H), 7.85
(brs, 1H). [0565]
The compounds shown in Table 9 were
synthesized as in Example 409. The structural formulae and physicochemical properties are shown in Table 9,
respectively. [0566] [Table 10]
(Figure Remove)

Example X Y DATA: MS m/ z
410 *-\ H M + +H : 4 3 5 (E S I
OMe
411 * .1.1. H M + +H : 4 0 5 (ESI
o
412 *-O°- M e M + + H : 4 3 5 (ESI

[0567]
Example 413 and Example 414
Synthesis of (E)-N-[(4R) and (4S)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylamide [0568] [Formula 191]
(Figure Remove)


N

I O
~N

To a DMF (4 mL) solution of (E)-3-[3-methoxy-
4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylic acid (70 mg) obtained in Example 121, chroman-4-ylamine (CAS#53981-38-7) (49 mg), EDC (62 mg) and HOST (44 mg) were added at room temperature under nitrogen
atmosphere, and the reaction solution was agitated at room temperature for 17 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with a saturated sodium chloride solution, and the
organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (elution solvent: methanol-ethyl acetate system), and (E)-N-(chroman-4-yl)-3-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)phenyl]acrylamide racemate (90 mg) was obtained. This compound (50 mg) was separated
by CHIRALPAK™ AD-H (2 cmx25 cm : mobile phase; hexane-ethanol 20%) available from Daicel Chemical Industries, Ltd., and the title optically-active substance with a retention time of 22 minutes (16 mg;>99%ee) and the 5 title optically-active substance with a retention time of 28 minutes (19 mg;>98%ee) were obtained. The physical properties of the title optically-active substance with a retention time of 22 minutes (Example 413) are as follows.
^-NMR (CDC13) 6 (ppm) : 2.11-2.21 (m, 1H) , 2.26-2.36 (m, 1H), 2.29 (s, 3H), 3.88 (s, 3H), 4.15-4.23 (m, 1H), 4.27-4.35 (m, 1H), 5.25-5.32 (m, 1H), 5.88 (d, J=7.2 Hz, 1H), 6.39 (d, J=15.6 Hz, 1H), 6.83-6.95 (m, 3H) , 7.11-7.28 (m, 5H), 7.67 (d, J=15.2 Hz, 1H) , 7.71 (d,
J=1.2 Hz, 1H) .
The physical properties of the title
optically-active substance with a retention time of 22 minutes (Example 414) are as follows, ^-NMR (CDC13) 8 (ppm): 2.11-2.21 (m, 1H) , 2.26-2.36 (m,
1H), 2.29 (s, 3H), 3.88 (s, 3H), 4.15-4.23 (m, 1H), 4.27-4.35 (m, 1H), 5.25-5.32 (m, 1H), 5.88 (d, J=7.2 Hz, 1H), 6.39 (d, J=15.6 Hz, 1H), 6.83-6.95 (m, 3H), 7.11-7.28 (m, 5H), 7.67 (d, J=15.2 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H).
[0569]
Example 415
Synthesis of (E)-N-[1-(4-fluorophenyl)-1-methyl ethyl]-
3-[3-methoxy-4-(4-methyl-lH-imidazol-l-


yl)phenyl]acrylamide [0570] [Formula 192] (Figure Remove)

To a DMF (5 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (60 mg) obtained in Example 121, 1-(4-fluorophenyl)-1-5 methylethylamine (CAS#17797-10-3) (43 mg), EDC (53 mg) and HOBT (38 mg) were added at room temperature under nitrogen atmosphere, and the reaction solution was agitated at room temperature for 12 hours. Water and ethyl acetate were added to the reaction solution, and
the organic layer was partitioned. The organic layer was washed with a saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel
chromatography (elution solvent: methanol-ethyl acetate system), and the title compound (60 mg) was obtained. ^-NMR (CDC13) 8 (ppm) : 1.77 (s, 6H) , 2.29 (d, J=0.8 Hz, 3H), 3.87 (s, 3H), 5.90 (brs, 1H), 6.41 (d, J=15.2 Hz, 1H), 6.90-6.94 (m, 1H), 6.97-7.05 (m, 2H), 7.09 (d,
J=2.0 Hz, 1H), 7.14 (dd, J=2.0, 8.0 Hz, 1H), 7.20-7.28 (m, 1H), 7.35-7.43 (m, 2H) , 7.54 (d, J=15.2 Hz, 1H) , 7.71 (d, J=1.2 Hz, 1H) .

[0571]
Example 416
Synthesis of (E)-1-(3,4-difluorobenzyl)-3-[3-methoxy-4-(4 -methyl- IH-iitiidazol-l-yl) benzylidene] piper idin-2 -one [0572] [Formula 193]
(Figure Remove)
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
To a sodium hydride suspension (40% mineral oil content, 2.77 g) in THF (50 mL) and DMF (200 mL), a solution of 3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzaldehyde (10 g) obtained in Example 1 and 1-acetylpiperidin-2-one (7.17 g) in THF (50 mL) and DMF (200 mL) were added dropwise over 20 minutes at 5°C. This reaction solution was agitated at 0°C for 2 hours. The reaction solution was added to iced water and the
reaction solution was extracted with ethyl acetate.
The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The deposited solids were separated by
filtering and 5.0 g of the title compound was obtained


by washing with diethyl ether. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.86-1.96 (m, 2H) , 2.30 (s, 3H) , 2.81-2.87 (m, 2H) , 3..42-3.50 (m, 2H) , 3.86 (s, 3H) , 5 5.97 (brs, 1H), 6.93 (s, 1H), 7.00-7.08 (m, 2H), 7.22-7.28 (m, 1H) , 7.71 (d, J=1.2 Hz, 1H) , 7.79 (s, 1H) . [0573]
Synthesis of (E)-1-(3,4-difluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
To a DMF (6.0 mL) solution of (E) -3-(3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)piperidin-2-one (100 mg) obtained above, lithium bis(trimethylsilyl)amide (1M hexane solution, 0.60 mL) was added dropwise at 0°C, and the reaction
solution was agitated at 0°C for 30 minutes. 3,4-difluorobenzylbromide (0.06 mL) was added to this solution at 0°C, and the reaction solution was agitated at room temperature for 1 hour. The reaction solution was added to iced water and the reaction solution was
extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system), and 110 mg of the title compound was obtained. The physical properties of the compound are as follows. (CDC13) 6 (ppm): 1.83-1.92 (m, 2H) , 2.30 (s, 3H) ,


2.80-2.87 (m, 2H), 3.34-3.41 (m, 2H), 3.86 (s, 3H), 4.66 (s, 2H), 6.91-6.95 (m, 1H) , 7.00-7.07 (m, 3H), 7.07-7.18 (m, 2H) , 7.22-7.28 (m, 1H), 7.71 (d, J=l. 6 Hz, 1H), 7.86 (s, 1H). [0574]
Example 417
Synthesis of (E) -1-[1-(3, 4-difluorobenzyl)- (3S) -pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0575] [Formula 194]
(Figure Remove)

Synthesis of 5-chloro-2-(diethoxyphosphoryl)valeric acid ethyl ester
Sodium hydride (40% mineral oil content, 9.8 g) was washed with hexane (50 mL) 3 times to remove oily substances. A THF (100 mL) solution of
phosphonoacetic acid triethyl (50 g) was added dropwise to a THF (400 mL) suspension of this sodium hydride at 0°C for 30 minutes. Then, the reaction solution was allowed to be warmed to room temperature and agitated for further 1 hour. l-bromo-3-chloropropane (70.2 g)
was added dropwise to this reaction solution for 30 minutes. Heating refluxing of the reaction solution was carried out after the dropping end for 15 hours.


This reaction solution was allowed to be cooled to room temperature, ethyl acetate (1 L) and saturated ammonium chloride water (1 L) were added, and the organic layer was partitioned. 61.2 g of the title compound was 5 obtained by drying with anhydrous magnesium sulfate and condensing the obtained organic layer under reduced pressure. The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 1.26-1.38 (m, 9H) , 1.55-2.36 (m,
4H), 2.89-3.01 (m, 1H), 3.54 (t, J=6.4 Hz, 2H), 4.23-4.58 (m, 6H). [0576]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid ethyl ester
To a solution of 3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzaldehyde (5 g) obtained in Example 1 in THF (60 mL) and ethanol (20 mL), 5-chloro-2-(diethoxyphosphoryl)valeric acid ethyl ester (7.6 g) and lithium hydroxide monohydrate (2.9 g) were added
one by one, and the reaction solution was agitated at room temperature overnight. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained
organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 3.76 g of the title compound was obtained by purifying the residue by


silica gel chromatography (heptane: elution solvent: ethyl acetate = 1:1), and re-crystallizing the obtained solid from a mixed solvent of ethyl acetate and hexane. The physical properties of the compound are as follows. 5 LH-NMR (CDC13) 8 (ppm): 1.37 (t, J=7.6 Hz, 3H), 2.02-2.09 (m, 2H), 2.30 (s, 3H), 2.70-2.76 (m, 2H), 3.60 (t, J=6.4 Hz, 2H), 3.88 (s, 3H) , 4.29 (q, J=7.6 Hz, 2H), 6.94 (m, 1H), 7.02 (d, J=1.2 Hz, 1H), 7.06 (dd, J=8.4, 1.2 Hz, 1H), 7.26 (d, J=8 . 4 Hz, 1H) , 7.68 (s, 1H), 7.72
(d, J=1.2 Hz, 1H) . [0577]
Synthesis of [(3S)-1-(3,4-difluorobenzyl)pyrrolidine-3-yljcarbamic acid tert-butyl ester
To a methylene chloride (10 mL) solution of
(3S)-3-(tert-butoxycarbonylamino) pyrrolidine (916 mg), 3,4-difluorobenzylbromide (0.7 mL) and IPEA (2.2 mL) were added one by one, and the reaction solution was agitated at room temperature for 20 hours. A saturated sodium bicarbonate water was added to the reaction
solution after the reaction ended, and the organic layer was partitioned. It was dried over anhydrous magnesium sulfate and the obtained organic layer was concentrated under reduced pressure. 1.55 g of the title compound was obtained by purifying the residue by
silica gel chromatography (elution solvent: heptane: ethyl acetate = 1:1). The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 1.44 (s, 9H), 1.55-1.64 (m, 1H),


2.18-2.22 (m, 2H), 2.46-2.81 (m, 3H), 3.52 (d, J=13.6
Hz, 1H), 3.55 (d, J=13.6 Hz, 1H) , 4.11-4.23 (m, 1H),
4.82 (brs, 1H), 6.97-7.19 (m, 3H).
[0578] 5 Synthesis of [(3S)-1-(3,4-difluorobenzyl)pyrrolidine-3-
yl]amine dihydrochloride
To an ethyl acetate solution (5 mL) of (3S)-
(1-(3,4-difluorobenzyl)pyrrolidin-3-yl)carbamic acid
tert-butyl ester (1.55 g) , an ethyl acetate (5 mL) solution of 4N hydrochloric acid was added, and the
reaction solution was agitated at room temperature.
Deposited substances in the reaction solution was
separated by filtering after 10 hours, and 904 mg of
the title compound was obtained by further washing with ether. The physical properties of the compound are as
follows.
ESI-MS; m/z213 [M++H].
[0579]
Synthesis of (E)-1-[1-(3,4-difluorobenzyl)-(3S)-20 pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]piperidin-2-one
To a solution of (E)-5-chloro-2-(3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid
ethyl ester (200 mg) and ((3S)-l-(3, 4-25 difluorobenzyl)pyrrolidine-3-yl)amine dihydrochloride
(315 mg) in acetonitrile (8 mL) and water (2 mL),
potassium carbonate (228 mg) and sodium iodide (831 mg)
were added. After carrying out heat-refluxing of the


reaction solution for 12 hours, the reaction solution allowed to be cooled to room temperature and concentrated under reduced pressure. A 2N sodium hydroxide solution (1 mL) in ethanol (5 mL) was added 5 to the obtained residue. After agitating the reaction mixture at room temperature for 12 hours, it was neutralized with a 5N hydrochloric acid solution, and the reaction solution was extracted with ethyl acetate. After the obtained organic layer was washed with a
saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 200 mg of the title compound was obtained by purifying the residue by silica gel chromatography (Carrier: Chromatorex™ NH; elution solvent: ethyl
acetate). The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.75-1.93 (m, 3H) , 2.22-2.33 (m, 2H), 2.29 (s, 3H), 2.50 (dd, J=10.4, 8.4 Hz, 1H), 2.70 (dd, J=10.4, 3.6 Hz, 1H), 2.77-2.95 (m, 3H), 3.45-3.62
(m, 4H), 3.84 (s, 3H) , 5.17-5.45 (m, 1H) , 6.92 (s, 1H) , 6.98-7.27 (m, 6H), 7.70 (d, J=1.2 Hz, 1H), 7.78 (s, 1H) . [0580] Example 418
Synthesis of (E)-l-indan-2-yl-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one [0581] [Formula 195]


(Figure Remove)
Synthesis of 5-chloro-2-(diethoxyphosphoryl)valeric acid tert-butyl ester
Sodium hydride (40% mineral oil content, 17.4 g) was washed with hexane (100 mL) 3 times to remove 5 oily substances. A THF (100 mL) solution of
diethylphosphonoacetic acid tert-butyl ester (100 g) was added dropwise to a THF (500 mL) suspension of this sodium hydride at 0°C for 30 minutes. Then, the reaction solution was allowed to be warmed to room
temperature and agitated for further 1 hour. A THF (100 mL) solution of l-bromo-3-chloropropane (125 g) was added dropwise to this reaction solution for 30 minutes. Heating refluxing of the reaction solution was carried out after the dropping end for 15 hours.
This reaction solution was allowed to be cooled to room temperature, ethyl acetate (1 L) and saturated ammonium chloride water (1 L) were added, and the organic layer was partitioned. 113.4 g of the title compound was obtained by drying with anhydrous magnesium sulfate and
condensing the obtained organic layer under reduced
pressure. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 1.31-1.48 (m, 6H) , 1.48 (s, 9H) , 1.79-2.14 (m, 4H), 2.73-2.91 (m, 1H), 3.55 (t, J=6.4


Hz, 2H), 4.10-4.19 (m, 4H) . [0582]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-
imidazol-l-yl)benzylidene]valeric acid tert-butyl ester
To a solution of 3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzaldehyde (50 g) in THF (600 mL) and ethanol (200 mL), 5-chloro-2-
(diethoxyphosphoryl)valeric acid tert-butyl ester (83.5 g) and lithium hydroxide monohydrate (29.1 g) were
added to the one by one, and the reaction solution was agitated at room temperature overnight. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained
organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 54.9 g of the title compound was obtained by purifying the residue by silica gel chromatography (elution
solvent:heptane:ethyl acetate = 1:1), and re-crystallizing the obtained solid from the mixed-solution of ethyl acetate and hexane. The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 1.55 (s, 9H), 1.99-2.08 (m, 2H),
2.30 (s, 3H), 2.63-2.71 (m, 2H) , 3.59 (t, J=6.4 Hz, 2H), 3.87 (s, 3H), 6.93 (m, 1H) , 7.00 (d, J=1.2 Hz, 1H), 7.09 (dd, J=8.4, 1.2 Hz, 1H) , 7.27 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.72 (m, 1H).

[0583]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid trifluoroacetic acid salt
To a methylene chloride (20 mL) solution of
(E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid tert-butyl ester (5 g), trifluoroacetic acid (10 mL) was added and the reaction solution was agitated at room temperature for 2 hours.
After confirming disappearance of the starting
materials, the reaction solution was concentrated under reduced pressure. The resulted solids were separated by filtering and 5.7 g of the title compound was obtained by washing with ethyl acetate further. The
physical properties of the compound are as follows. ^-NMR (DMSO-de) 8 (ppm) : 1.93-2.03 (m, 2H) , 2.35 (s, 3H), 2.58-2.66 (m, 2H) , 3.70 (t, J=6.4 Hz, 2H), 3.91 (s, 3H) , 7.24 (dd, J=8.4, 1.2 Hz, 1H) , 7.37 (d, J=1.2 Hz, 1H), 7.64 (d, J=8.4, 1H), 7.66 (m, 1H), 7.76 (s,
1H), 9.36 (m, 1H). [0584]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid indan-2-ylamide To a DMF solution (200 mL) of (E)-5-chloro-2-
(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt (13 g) and 2-amino indan hydrochloride (7.8 g), IPEA (24.1 mL), HOBT (9.4 g) and EDC (13.3 g) were added one


by one, and the reaction solution was agitated at room temperature. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution after 15 hours, and the organic layer was partitioned. 5 After the obtained organic layer was washed with a saturated sodium chloride solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 6.93 g of the title compound was obtained by purifying the residue by silica gel
chromatography (elution solvent: ethyl acetate). The physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm) : 1.93-2.04 (m, 2H) , 2.28 (s, 3H) , 2.67-2.73 (m, 2H), 2.90 (dd, J=16.0, 4.4 Hz, 2H) , 3.40 (dd, J=16.0, 7.2 Hz, 2H) , 3.56 (t, J=5.6 Hz, 2H), 3.84
(s, 3H), 4.81-4.95 (m, 1H), 6.29 (d, J=7.2 Hz, 1H), 6.90-6.94 (m, 3H), 7.10 (s, 1H), 7.18-7.27 (m, 5H), 7.68 (d, J=1.6 Hz, 1H) . [0585] Synthesis of (E)-l-indan-2-yl-3-[3-methoxy-4-(4-methyl-
IH-imidazol-l-yl)benzylidene]piperidin-2-one
To a DMF (50 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid indan-2-ylamide (6.9 g), sodium hydride (40% mineral oil content, 740 mg) was
added at room temperature, and the reaction solution was agitated at room temperature for 1 hour and 30 minutes. The reaction solution was poured into iced water after the reaction ended, and the deposited


solids were separated by filtering. 4.9 g of the title compound was obtained by recrystallizing the obtained solid from a mixed solvent of ethyl acetate, ethanol, and hexane. The physical properties of the compound 5 are as follows.
:H-NMR (CDC13) 8 (ppm): 1.81-1.88 (m, 2H) , 2.30 (s, 3H), 2.77-2.84 (m, 2H), 3.00 (dd, J=16.4, 6.0 Hz, 2H), 3.24-3.32 (m, 4H), 3.86 (s, 3H), 5.75-5.83 (m, 1H), 6.93 (d, J=1.2 Hz, 1H), 7.02-7.07 (m, 2H) , 7.17-7.28 (m, 5H),
7.71 (d, J=1.2 Hz, 1H), 7.85 (s, 1H). [0586]
Example 419 and Example 420
Synthesis of (E)-1-[(4R) and (4S)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one [0587] [Formula 196]
(Figure Remove)



N

To a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid ethyl ester (50 mg) obtained in Example 417 in acetonitrile (2 mL) and water (0.2 mL), chroman-4-20 ylamine (CAS#53981-38-7) (31 mg) and cesium carbonate (90 mg) were added at room temperature, and the mixture was reacted in a microwave synthesizing equipment


(80W;150°C) for 1 hour. The reaction solution was allowed to be cooled to room temperature, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer 5 was washed with a saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, an elution
solvent: heptane-ethyl acetate system), and (E)-5-(chroman-4-ylamino)-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid ethyl ester (25 mg) was obtained. 2N sodium hydroxide solution (1 mL) was added to an ethanol (3 mL) solution of the (E)-5-
(chroman-4-ylamino)-2-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene] valeric acid ethyl ester (59 mg) obtained by repeating the above-mentioned operation at room temperature, the reaction solution was agitated at room temperature for 12 hours, and heat-refluxing
was carried out for further 1 hour. The reaction
solution was allowed to be cooled to room temperature, 2N hydrochloric acid (1 mL) was added to the reaction solution under ice-cooling, and the reaction solution was concentrated under reduced pressure. EDC (50 mg)
and HOBT (36 mg) were added to a DMF (3 mL) suspension of the obtained residue, and the reaction solution was agitated at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution, and


the organic layer was partitioned. The organic layer was washed with a saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. 5 The obtained residue was purified by silica gel
chromatography (Carrier: Chromatorex™ NH, an elution solvent: heptane-ethyl acetate system), and (E)-l-(chroman-4-yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one racemate (21 mg) was
obtained. This compound (21 mg) was separated in CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm : mobile phase; ethanol), and the title optically-active substance with a retention time of 45 minutes (7 mg;>99%ee) and the
title optically-active substance with a retention time of 61 minutes (6 mg;>99%ee) were obtained. The physical properties of the title optically-active substance with a retention time of 45 minutes (Example 419) is as follows.
^-NMR (CDC13) 8 (ppm) : 1.70-1.95 (m, 2H) , 2.00-2.28 (m, 2H), 2.30 (s, 3H), 2.74-2.85 (m, 1H), 2.87-2.98 (m, 1H) , 3.05-3.14 (m, 1H) , 3.15-3.26 (m, 1H), 3.87 (s, 3H) , 4.20-4.30 (m, 1H), 4.31-4.40 (m, 1H), 6.23 (dd, J=6.4, 9.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.89 (dd,
J-7.2, 7.6 Hz, 1H), 6.94 (s, 1H) , 7.02-7.10 (m, 3H), 7.12-7.18 (m, 1H), 7.23-7.29 (m, 1H), 7.72 (s, 1H), 7.91 (s, 1H). The physical properties of the title optically-active


substance with a retention time of 61 minutes (Example
420) are as follows.
XH-NMR (CDC13) 8 (ppm): 1.70-1.95 (m, 2H), 2.00-2.28 (m,
2H), 2.30 (s, 3H), 2.74-2.85 (m, 1H), 2.87-2.98 (m, 5 1H), 3.05-3.14 (m, 1H) , 3.15-3.26 (m, 1H), 3.87 (s,
3H), 4.20-4.30 (m, 1H), 4.31-4.40 (m, 1H), 6.23 (dd,
J=6.4, 9.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.89 (dd,
J=7.2, 7.6 Hz, 1H), 6.94 (s, 1H), 7.02-7.10 (m, 3H) ,
7.12-7.18 (m, 1H), 7.23-7.29 (m, 1H), 7.72 (s, 1H) , 10 7.91 (s, 1H).
[0588]
Example 421 and Example 422
Synthesis of (E)-1-[(R) and (S)-6-methoxyindan-l-yl]-3-
[3-methoxy-4-(4-methyl-lH-imidazol-l- yl)benzylidene]piperidin-2-one
[0589]
[Formula 197]
(Figure Remove)




To a DMF (2 mL) suspension of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene] valeric acid trifluoroacetic acid salt (50 mg) obtained in Example 418 and 6-methoxyindan-l-ylamine 20 (CAS#103028-81-5) (27 mg), IPEA (0.06 mL), EDC (64 mg) and HOBT (45 mg) were added at room temperature, and the reaction solution was agitated at room temperature

for 12 hours. Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed one by one with a saturated ammonium 5 chloride solution and water, and also saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (elution solvent:
methanol-ethyl acetate system) and (E)-5-chloro-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]valeric acid (6-methoxyindan-l-yl)amide (29 mg) was obtained. To a DMF (2 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid (6-methoxyindan-l-yl)amide (29 mg) obtained, sodium hydride (40% mineral oil content, 20 mg) was added at room temperature, and the reaction solution was agitated for 10 minutes at room temperature. Saturated sodium bicarbonate solution and
ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed one by one in a saturated ammonium chloride solution and water, and also saturated sodium chloride solution, and the organic layer was concentrated under
reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (elution solvent: methanol-ethyl acetate system), and (E)-1-(6-methoxyindan-l-yl)-3-[3-

methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one racemate (17 mg) was obtained. This compound (17 mg) was separated by CHIRALCEL™ AD-H available from Daicel Chemical 5 Industries, Ltd. (2 cmx25 cm : mobile phase; ethanol), and the title optically-active substance with a retention time of 36 minutes (6 mg;>99%ee) and the title optically-active substance with a retention time of 43 minutes (6 mg;>95%ee) were obtained. The 10 physical properties of the title optically-active
substance with a retention time of 36 minutes (Example
421) is as follows.
^-NMR (CDC13) 6 (ppm) : 1.73-1.90 (m, 2H) , 1.94-2.03 (m, 1H), 2.30 (s, 3H), 2.45-2.56 (m, 1H), 2.74-3.02 (m,
4H), 3.04-3.21 (m, 2H), 3.77 (s, 3H) , 3.86 (s, 3H), 6.47 (dd, J=7.6, 8.4 Hz, 1H) , 6.70 (d, J=2.4 Hz, 1H), 6.80 (dd, J=2.4, 8.4 Hz, 1H) , 6.94 (s, 1H) , 7.03-7.10 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.22-7.28 (m, 1H), 7.72 (s, 1H), 7.90 (s, 1H).
The physical properties of the title optically-active substance with a retention time of 43 minutes (Example
422) are as follows.
^-NMR (CDC13) 8 (ppm): 1.73-1.90 (m, 2H) , 1.94-2.03 (m, 1H), 2.30 (s, 3H), 2.45-2.56 (m, 1H), 2.74-3.02 (m, 25 4H), 3.04-3.21 (m, 2H), 3.77 (s, 3H), 3.86 (s, 3H), 6.47 (dd, J=7.6, 8.4 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.80 (dd, J-2.4, 8.4 Hz, 1H) , 6.94 (s, 1H), 7.03-7.10 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.22-7.28 (m, 1H),

7.72 (s, 1H) , 7.90 (s, 1H). [0590]
Example 423 and Example 424
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-5 1-yl)benzylidene]-1-[(R)and(S)-7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl]piperidin-2-one [0591] [Formula 198]
(Figure Remove)




To a solution of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid ethyl ester (50 mg) obtained in Example 417 in
acetonitrile (3 mL) and water (0.3 mL), 7-methoxy-
1,2,3, 4-tetrahydronaphthalen-l-ylamine (CAS#50399-51-4) (25 mg), potassium carbonate (57 mg) and sodium iodide (21 mg) were added at room temperature, and heat-refluxing of the reaction solution was carried out
for two days. The reaction solution was allowed to be cooled to room temperature, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with a saturated sodium chloride solution, and the
organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, an elution solvent: heptane-ethyl acetate system), and (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-5-(7-methoxy-5 1,2,3,4-tetrahydronaphthalen-l-ylamino)valeric acid ethyl ester (24 mg) was obtained. 2N sodium hydroxide solution (0.3 mL) was added to an ethanol (1 mL) solution of obtained (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-5-(7-methoxy-l,2,3,4-
tetrahydronaphthalen-1-ylamino)valeric acid ethyl ester (24 mg) at room temperature, and the reaction solution was agitated at room temperature for 16 hours. 2N hydrochloric acid (0.3 mL) was added to the reaction solution under ice-cooling, and the reaction solution
was concentrated under reduced pressure. EDC (25 mg) and HOBT (18 mg) were added to a DMF (2 mL) suspension of the obtained residue, and the reaction solution was agitated at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution, and
the organic layer was partitioned. The organic layer was washed with a saturated sodium chloride solution, and the organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel chromatography
(Carrier: Chromatorex™ NH, an elution solvent: heptane-ethyl acetate system), and (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-l-yl)piperidin-2-one

racemate (19 mg) was obtained. This compound (19 mg) was separated in CHIRALCEL™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm : mobile phase; ethanol), and the title optically-active substance with 5 a retention time of 17 minutes (7 mg;>99%ee) and the title optically-active substance with a retention time of 25 minutes (6 mg;>99%ee) were obtained. The physical properties of the title optically-active substance with a retention time of 17 minutes (Example
423) are as follows.
^-NMR (CDC13) 8 (ppm) : 1.72-1.82 (m, 4H) , 1.96-2.14 (m, 2H), 2.31 (s, 3H), 2.68-2.84 (m, 3H), 2.88-2.98 (m, 1H), 3.05-3.13 (m, 1H), 3.18-3.26 (m, 1H), 3.75 (s, 3H), 3.87 (s, 3H), 6.07-6.15 (m, 1H), 6.66 (d, J=2.8
Hz, 1H), 6.75 (dd, J=2.8, 8.4 Hz, 1H) , 6.95 (s, 1H) , 7.02-7.11 (m, 3H), 7.24-7.30 (m, 1H) , 7.73 (d, J=1.2 Hz, 1H), 7.92 (s, 1H).
The physical properties of the title optically-active substance (Example 424) for retention time 25 minutes
are as follows.
XH-NMR (CDC13) 5 (ppm): 1.72-1.82 (m, 4H), 1.96-2.14 (m, 2H), 2.31 (s, 3H), 2.68-2.84 (m, 3H), 2.88-2.98 (m, 1H), 3.05-3.13 (m, 1H), 3.18-3.26 (m, 1H), 3.75 (s, 3H), 3.87 (s, 3H), 6.07-6.15 (m, 1H) , 6.66 (d, J=2.8
Hz, 1H), 6.75 (dd, J=2.8, 8.4 Hz, 1H) , 6.95 (s, 1H) , 7.02-7.11 (m, 3H), 7.24-7.30 (m, 1H) , 7.73 (d, J=1.2 Hz, 1H), 7.92 (s, 1H). [0592]

Example 425
Synthesis of (E)-1-[(IS)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0593] [Formula 199]
(Figure Remove)
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid ((lS)-l-(4-fluorophenyl)ethyl)amide
To a DMF (50 mL) solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt (8.00 g) and (S)-1-(4-fluorophenyl)ethylamine (2.60 g), IPEA (12.4 mL), EDC (6.82 g) and HOST (4.81 g) were added one by one, and the reaction solution was agitated at room temperature overnight. After
confirming disappearance of the starting materials, the solvent was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. After the organic layer was washed with a saturated saline solution, it was
dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent:

heptane-ethyl acetate =2:3 ->1:1 -> ethyl acetate), and 3.90 g of the title compound was obtained. The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 1.56 (d, J=6.8 Hz, 3H), 1.95-5 2.02 (m, 2H), 2.30 (s, 3H), 2.70-2.74 (m, 2H) , 3.58 (t, J=6.0 Hz, 2H), 3.85 (s, 3H), 5.17-5.24 (m, 1H), 6.15 (d, J=6.8 Hz, 1H), 6.92-6.96 (m, 3H), 7.02-7.07 (m, 2H), 7.17 (s, 1H), 7.23-7.25 (m, 1H), 7.32-7.36 (m, 2H), 7.70-7.71 (s, 1H).
[0594]
Synthesis of (E)-1-[(IS)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-1-yl)benzylidene]piperidin-2-one
To a DMF (30 mL) solution of (E)-5-chloro-2-
[3-methoxy-4-(4-methyl-lH-imidazol-l-yl]benzylidene valeric acid ((S)-1-(4-fluorophenyl)ethyl)amide (3.90 g), sodium hydride (40% mineral oil content, 410 mg) was added at 0°C, the reaction solution was allowed to be warmed to room temperature and agitated overnight.
The reaction solution was cooled to 0°C after confirming disappearance of the starting materials, and water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; ethyl acetate -> ethyl acetate : ethanol

10:1). The obtained solid was washed with diethyl ether and 2.60 g of the title compound was obtained by further performing recrystallization with ethyl acetate. The physical properties of the compound are 5 as follows.
Hi-NMR (CDC13) 8 (ppm) : 1.50 (d, J=7.2 Hz, 3H) , 1.65-1.74 (m, 1H), 1.78-1.87 (m, 1H) , 2.30 (s, 3H), 2.71-2.85 (m, 2H), 2.91-2.97 (m, 1H) , 3.24 (ddd, J=3.6, 8.8, 12.0 Hz, 1H), 3.86 (s, 3H), 6.23 (q, J=7.2 Hz, 1H),
6.93 (t, J=1.2 Hz, 1H), 7.00-7.06 (m, 4H), 7.24-7.26 (m, 1H), 7.31-7.34 (m, 2H), 7.72 (d, J=1.2 Hz, 1H), 7.89 (s, 1H). [0595] Example 426
Synthesis of (E) -1-[3-fluoro-4-(morpholin-4-yl)benzyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0596] [Formula 200]
(Figure Remove)
Synthesis of 3-fluoro-4-(morpholin-4-yl)benzonitrile
To a DMF (20 mL) solution of 3,4-
difluorobenzonitrile (3.00 g), morpholine (2.82 g) and potassium carbonate (5.97 g) were added, and the


reaction solution was allowed to be warmed to 100°C and agitated for 5.5 hours. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the 5 organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and 4.41 g of the title compound was obtained by condensing under reduced pressure. The physical
properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 3.19-3.22 (m, 4H), 3.86-3.88 (m, 4H), 6.92 (t, J=8.4 Hz, 1H), 7.29 (dd, J=2.0, 13.0 Hz, 1H), 7.37-7.40 (m, 1H). [0597]
Synthesis of 3-fluoro-4-(morpholin-4-yl)benzylamine
To a THF (30 mL) suspension of lithium
aluminum hydride (975 mg), a THF (10 mL) solution of 3-fluoro-4-(morpholin-4-yl)benzonitrile (4.41 g) was added dropwise at -78°C. Then, the reaction solution
was allowed to be warmed to room temperature and
agitated overnight. The reaction solution was cooled to 0°C after confirming disappearance of the starting materials, water and 5N sodium hydroxide solution, and also ethyl acetate were added to the reaction solution
one by one, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced


pressure. The obtained residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: ethyl acetate =1:1 -> heptane-ethyl acetate), and 3.60 g of the title compound was obtained. The 5 physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 3.06-3.08 (m, 4H) , 3.81 (s, 2H) , 3.87-3.89 (m, 4H), 6.91 (t, J=8.8 Hz, 1H), 7.01-7.05 (m, 2H). [0598]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid[3-fluoro-4-(morpholin-4-yl)benzyl]amide
To a DMF (4.0 mL) solution of 5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-
valeric acid trifluoroacetic acid salt (200 mg)
obtained in Example 418 and 3-fluoro-4-(morpholin-4-yDbenzylamine (112 mg) , IPEA (231 mg) , EDC (171 mg) and HOBT (120 mg) were added one by one, and the reaction solution was agitated at room temperature
overnight. After confirming disappearance of the
starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried
over anhydrous magnesium sulfate and concentrated under reduced pressure. 135 mg of the title compound was obtained by purifying the obtained residue by silica gel chromatography (elution solvent: ethyl acetate ->


ethyl acetate : methanol = 90:10). The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 1.99-2.06 (m, 2H) , 2.29 (s, 3H), 2.72-2.76 (m, 2H) , 3.06-3.09 (m, 4H), 3.58 (t, J=6.0 5 Hz, 2H), 3.85 (s, 3H), 3.84-3.88 (m, 4H) , 4.49 (d, J=5.6 Hz, 2H), 6.28-6.38 (m, 1H), 6.88-6.98 (m, 4H) , 7.01-7.06 (m, 2H), 7.17 (s, 1H), 7.22-7.25 (m, 1H) , 7.70 (s, 1H). [0599]
Synthesis of (E)-1-[3-fluoro-4-(morpholin-4-yl)benzyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
To a DMF (4 mL) solution of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-
yl]benzylidene)valeric acid [3-fluoro-4-(morpholin-4-yDbenzyl] amide (135 mg) , sodium hydride was added at 0°C (40% mineral oil content, 35.6 mg) was added, and the reaction solution was allowed to be warmed to room temperature and agitated for 45 minutes. The reaction
solution was cooled to 0°C after confirming
disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After washed with a saturated saline solution the organic layer, it was
dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 113 mg of the title compound was obtained by purifying the obtained residue by silica gel chromatography (elution solvent; ethyl


acetate -> ethyl acetate : ethanol 90:10). The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm) : 1.82-1.90 (m, 2H) , 2.30 (s, 3H) , 2.83 (t, J=5.6 Hz, 2H), 3.07-3.09 (m, 4H), 3.37 (t, 5 J=5.6 Hz, 2H), 3.86 (s, 3H) , 3.86-3.88 (m, 4H), 4.66 (s, 2H), 6.90 (t, J=8.0 Hz, 1H) , 6.94 (s, 1H), 7.02-7.05 (m, 4H), 7.25-7.27 (m, 1H), 7.72 (S, 1H), 7.82 (S, 1H) . [0600] 10 Example 427
Synthesis of (E)-1-[(6-chloropyridin-2-yl)methyl]-3- [3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]piperidin-2-one
[0601]
[Formula 201]
(Figure Remove)
To a suspension of (E)-5-chloro-2-[3-methoxy-15 4- (4-methyl-lH-imidazol-l-yl]benzylidene)valeric acid ethyl ester (200 mg) obtained in Example 417 and 2-(aminomethyl)-6-chloropyridine (CA 188637-75-4) hydrochloride (100 mg) in ethanol (3 mL) and DMF (3 mL), anhydrous potassium carbonate (100 mg) was added 20 and the reaction mixture was agitated at 100°C for 8


hours. After the reaction mixture was allowed to be cooled to room temperature, the reaction mixture was poured into iced water and the reaction solution was extracted with ethyl acetate. The obtained organic 5 layer was washed with a saturated sodium chloride
solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. Ethanol (10 mL) and sodium hydroxide (1.0 g) aqueous solution (5 mL) were added to the residue, and the reaction
solution was agitated at room temperature for 1 hour. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and it concentrated under
reduced pressure after dried over anhydrous magnesium sulfate. 23 mg of the title compound was obtained by the residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system). ^-NMR (CDC13) 8 (ppm) : 1.88-1.96 (m, 2H) , 2.30 (s, 3H) ,
2.82-2.89 (m, 2H), 3.54-3.62 (m, 2H), 3.85 (s, 3H) , 4.78 (s, 2H), 6.92 (s, 1H), 6.99-7.05 (m, 2H), 7.20-7.28 (m, 2H), 7.31 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.83 (s, 1H) . [0602]
Example 428
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-1-[(6-(morpholin-4-yl)pyridine-3-yl)methyl]piperidin-2-one

[0603] [Formula 202]
(Figure Remove)
Synthesis of 2-[6-(morpholin-4-yl)pyridin-3-yl]methylisoindol-l,3-dione
To a THF (200 mL) solution of (6-(morpholin-4-yl) pyridine-3-yl)methanol (CA 388088-73-1) (3.2 g), 5 phthalimide (3.64 g) and triphenylphosphine (6.49 g), diisopropylazodicarboxylate (5.43 mL) was added at 0°C for 5 minutes. The reaction solution was concentrated under reduced pressure after 12-hour stirring at room temperature. 3.8 g of the title compound was obtained
by the residue was purified by silica gel
chromatography (heptane-ethyl acetate system). ^-NMR (CDC13) 6 (ppm): 3.42-3.50 (m, 4H) , 3.74-3.82 {m, 4H) , 4.73 (s, 2H), 6.56 (d, J=8.4 Hz, 1H), 7.42-7.72 (m, 1H), 7.64-7.72 (m, 2H) , 7.78-7.84 (m, 2H), 8.29 (d,
J=2.0 Hz, 1H). [0604]
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl]benzylidene)-1-[(6-(morpholin-4-yl)pyridine-3-yl]methyl)piperidin-2-one
To an ethanol (50 mL) solution of 2-[6-


(morpholin-4-yl)pyridine-3-yl]methylisoindoindol-l,3-dione (3.8 g) obtained above, hydrazine monohydrate (2.95 mL) was added, and heat-refluxing of the reaction solution was carried out for 2 hours. The reaction 5 solution was allowed to be cooled to room temperature, diethyl ether (100 mL) was added to the reaction solution, and the reaction solution was agitated for 30 minutes at room temperature. C-[6-(morpholin-4-yl)pyridine-3-yl]methylamine (3.0 g) was obtained by
filtering off insoluble solids in the reaction solution and condensing the obtained filtrate under reduced pressure. To a DMF (30 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetic acid salt
(0.20 g) obtained in Example 418 and C-[6-(morpholin-4-yl)pyridine-3-yl]methylamine (0.30 g), HOBT (0.181 g), IPEA (0.388 mL) and EDC (0.257 g) were added at room temperature, and the reaction solution was agitated at room temperature for 12 hours. The reaction solution
was added to water and the reaction solution was
extracted with ethyl acetate. The obtained organic layer was washed with a saturated salt solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified
by silica gel column chromatography (elution solvent: from heptane-ethyl acetate system to methanol-ethyl acetate system) and 0.21 g of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-


yl)benzylidene]valeric acid [6-(morpholin-4-yl)pyridine-3-yl]methyl amide was obtained.
To a DMF (30 mL) solution of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-5 yl)benzylidene]valeric acid [6-(morpholin-4-
yl)pyridine-3-yl]methyl amide (0.21 g) obtained above, sodium hydrite (40% mineral oil content, 29.7 mg) was added at room temperature, and the reaction solution was agitated for 30 minutes at the temperature. The
reaction solution was added to water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated salt solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. 0.125 g of the
title compound was obtained by the residue was purified by silica gel chromatography (elution solvent: from heptane-ethyl acetate system to methanol-ethyl acetate system). ^-NMR (CDC13) 8 (ppm) : 1.78-1.88 (m, 2H) , 2.30 (s, 3H) ,
2.75-2.83 (m, 2H), 3.32-3.39 (m, 2H), 3.44-3.54 (m, 4H), 3.76-3.88 (m, 4H), 3.85 (s, 3H), 4.59 (s, 2H), 6.62 (d, J=8.8 Hz, 1H), 6.92 (s, 1H) , 6.98-7.04 (m, 2H), 7.20-7.28 (m, 1H), 7.57 (dd, J=2.0, 8.8 Hz, 1H), 7.70 (s, 1H), 7.84 (s, 1H), 8.12 (d, J=2.0 Hz, 1H) .
[0605]
Example 429
Synthesis of (E)-1-[(5-chloro-2-methylpyridin-3-
yl)methyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-


yl)benzylidene]piperidin-2-one [0606] [Formula 203]
(Figure Remove)
Synthesis of (5-chloro-2-methylpyridin-3-yl)methanol
To a THF (30 mL) solution of 5-chrolo-2-methyl nicotinic acid methyl ester (CAS# 350597-49-8) 5 (1.0 g), boron lithium hydride (0.153 g) was added at 0°C. The reaction solution was agitated at room temperature for 2 hours. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic
layer was washed with a saturated salt solution, and it concentrated under reduced pressure after dried over anhydrous magnesium sulfate. 0.26 g of the title compound was obtained by the residue was purified by silica gel chromatography (elution solvent: heptane-
ethyl acetate system).
XH-NMR (CDC13) 5 (pprn) : 2.47 (s, 3H) , 4.70 (s, 2H) , 7.74
(d, J=2.4 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H).
[0607]
Synthesis of 2-[(5-chloro-2-methylpyridin-3-
yl]methyl)isoindole-1,3-dione


To a THF (10 mL) solution of (5-chloro-2-methylpyridin-3-yl)methanol (0.26 g) obtained above, phthalimide (0.364 g) and triphenylphosphine (0.649 g), diisopropylazodicarboxylate (0.585 mL) were added at 0°C 5 for 5 minutes. The reaction solution was agitated for three days at room temperature and concentrated under reduced pressure. 0.20 g of the title compound was obtained by the residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate
system).
XH-NMR (CDC13) 8 (ppm): 2.68 (s, 3H), 4.83 (s, 2H), 7.55 (s, 1H), 7.70-7.80 (m, 2H) , 7.80-7.95 (m, 2H), 8.35 (s, 1H) . [0608]
Synthesis of (E)-1-[(5-chloro-2-methylpyridin-3-yl)methyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
To an ethanol (10 mL) solution of 2-((5-chloro-2-methyl-pyridine-3-yl)methyl)isoindole-1,3-
dione (0.20 g), hydrazine monohydrate (0.50 mL) was
added, and heat-refluxing of the reaction solution was carried out for 2 hours. The reaction solution was allowed to be cooled to room temperature, diethyl ether (50 mL) was added to the reaction solution, and the
reaction solution was agitated for 30 minutes at room temperature. C-(5-chloro-2-methylpyridin-3-yl)methylamine (0.13 g) was obtained by filtering off insoluble matters in the reaction solution and


condensing the obtained filtrate under reduced pressure.
To a DMF (20 mL) solution of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]valeric acid trifluoroacetic acid salt (0.20 g) obtained according to Example 418 and C-(5-chloro-2-methylpyridin-3-yl)methylamine (0.13 g), HOBT (0.301 g), IPEA (0.397 mL), and EDC (0.428 g) were added, and the reaction solution was agitated under 10 room temperature for 12 hours. The reaction solution was added to water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated salt solution, and concentrated under reduced pressure after dried over 15 anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and 0.14 g of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]valeric acid (5-chloro-2-methylpyridin-20 3-yl)methyl amide was obtained.
To a DMF (10 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid (5-chloro-2-methylpyridin-3-yl)methyl amide (0.14 g) obtained above, sodium 25 hydride (40% mineral oil content, 47.4 mg) was added at room temperature, and the reaction solution was agitated at that temperature for 1 hour. The reaction solution was added to water and the reaction solution


was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. 0.027 g of the 5 title compound was obtained by the residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system).
^-NMR (CDC13) 6 (ppm) : 1.90-2.00 (m, 2H) , 2.30 (s, 3H) , 2.54 (s, 3H), 2.85-2.92 (m, 2H) , 3.34-3.41 (m, 2H),
3.87 (s, 3H), 4.72 (s, 2H) , 6.92-6.95 (m, 1H), 7.02-7.08 (m, 2H), 7.24-7.30 (m, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H) , 7.87 (s, 1H) , 8.37 (d, J=2.4 Hz, 1H) . [0609]
Example 430
Synthesis of (E)-1-(4-tert-butylbenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0610] [Formula 204]
O
(Figure Remove)
To a DMF (2 mL) solution of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-20 one (70 mg) obtained in Example 416, lithium
bis(trimethylsilyl)amide (1M THF solution, 0.47 mL) was


added dropwise under ice-cooling, and the reaction solution was agitated for 30 minutes under ice-cooling. Subsequently, l-tert-butyl-4-chloromethylbenzene (0.073 mL) was added to the reaction solution, and the 5 reaction solution was agitated for 30 minutes under ice-cooling. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried with magnesium sulfate and was concentrated under reduced
pressure. The residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate system), and 37.8 mg of the title compound was obtained. The physical properties are as follows. ^-NMR (CDC13) 8 (ppm) : 1.31 (s, 9H) , 1.86 (m, 2H) , 2.30
(s, 3H), 2.82 (m, 2H), 3.38 (m, 2H), 3.85 (s, 3H), 4.70 (s, 2H), 6.92 (t, J=1.2 Hz, 1H), 7.01 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 7.22-7.26 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 7.70 (d, J=1.2 Hz, 1H), 7.86 (s, 1H). [0611]
Example 431
Synthesis of (E)-3-[4-(4-fluoromethyl-lH-imidazol-1-
yl)-3-methoxyphenyl]-N-indan-1-ylacrylamide
[0612]
[Formula 205]
(Figure Remove)

By the same as in Example 147, 11 mg of the title compound was obtained from (E)-3-[4-(4-hydroxymethyl-lH-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-ylacrylamide (20 mg) obtained in Example 45. 5 aH-NMR (CDC13) 8 (ppm): 1.87-1.96 (m, 1H), 2.65-2.73 (m, 1H), 2.90-2.98 (m, 1H), 3.01-3.08 (m, 1H), 3.90 (s, 3H), 5.40 (d, J=49.2 Hz, 2H), 5.66 (q, J=7.6 Hz, 1H), 5.99 (d, J=8 Hz, 1H), 6.46 (d, J=15.6 Hz, 1H), 7.17-7.37 (m, 8H), 7.70 (d, J=15.6 Hz, 1H), 7.79 (s, 1H). 10 [0613]
Example 432
Synthesis of (E)-3-[4-(4-formyl-lH-imidazol-l-yl)3-methoxyphenyl]-N-indan-1-ylacrylamide [0614] [Formula 206]

(Figure Remove)
To a chloroform (5 mL) solution of (E)-3-(4-15 (4-hydroxymethyl-lH-imidazol-l-yl)-3-methoxyphenyl)-N-indan-1-ylacrylamide (15 mg) obtained in Example 45, activated manganese dioxide (280 mg) was added, and the reaction mixture was agitated at room temperature overnight. The reaction solution was filtered through 20 a filter paper and the filtrate was concentrated under reduced pressure. The residue was purified by silica


gel column chromatography (elution solvent: ethyl acetate) , and 30 mg of the title compound was obtained. ^-NMR (CDC13) § (ppm) : 1.86-1.96 (m, 1H) , 2.63-2.73 (m, 1H), 2.89-2.97 (m, 1H), 3.00-3.07 (m, 1H) , 3.91 (s, 5 3H), 5.65 (q, J=7 . 6 Hz, 1H) , 5.94 (d, J=8.8 Hz, 1H) , 6.47 (d, J=15.6 Hz, 1H), 7.19-7.36 (m, 6H), 7.70 (d, J=15.6 Hz, 1H), 7.84 (d, J=l Hz, 1H), 7.92 (d, J=l Hz, 1H), 9.96 (s, 1H) . [0615] 10 Example 433
Synthesis of (E)-3-[4-(4-difluoromethyl-lH-imidazol-1-yl)-3-methoxyphenyl]-N-indan-1-ylacrylamide [0616] [Formula 207]

(Figure Remove)


6 mg of the title compound was obtained from the above (E)-3-(4-(4-formyl-lH-imidazol-l-yl)3-
methoxyphenyl)-N-indan-1-ylacrylamide (9 mg) and DAST (0.012 mL) in a similar way as in the synthesis in Example 147.
^-NMR (CDC13) 8 (ppm): 1.86-1.96 (m, 1H) , 2.65-2.73 (m, 1H), 2.89-2.97 (m, 1H), 3.01-3.08 (m, 1H), 3.90 (s,
3H), 5.65 (q, J=7.6 Hz, 1H) , 5.85 (d, J=8.8 Hz, 1H), 6.44 (d, J=15.6 Hz, 1H), 6.74 (t, J=56 Hz, 1H), 7.17-7.36 (m, 6H), 7.46 (s, 1H) , 7.70 (d, J=15.6 Hz, 1H) ,


7.80 (s, 1H) . [0617]
Example 434
Synthesis of (E)-N-indan-l-yl-3-[3-methoxy-4- (4-5 methoxymethyl-lH-imidazol-1-yl]phenyl)acrylamide [0618] [Formula 208]
O
(Figure Remove)
MeO
A thionyl chloride (0.4 mL) solution of (E)-3-[4-(4-hydroxymethyl-lH-imidazole-l-yl)-3-methoxyphenyl]-N-indan-1-ylacrylamide (15 mg) obtained in Example 45 was agitated for 40 minutes at 50°C, and
then the reaction solution was concentrated under
reduced pressure. A solution of sodium methoxide (40% methanol solution, 2 mL) was added to the obtained residue, and the reaction solution was agitated for 90 minutes at room temperature. After the reaction
solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH,


elution solvent:hexane-ethyl acetate system), and 4 mg of the title compound was obtained.
:H-NMR (CDC13) 5 (ppm): 1.86-1.95 (m, 1H), 2.64-2.73 (m, 1H), 2.89-2.97 (m, 1H) , 3.00-3.07 (m, 1H) , 3.47 (s, 5 3H), 3.88 (s, 3H), 4.48 (s, 2H) , 5.65 (q, J=7.6 Hz, 1H), 5.85 (d, J=8.4 Hz, 1H) , 6.42 (d, J=15.6 Hz, 1H), 7.15-7.29 (m, 7H) , 7.35 (d, J=7. 6 Hz, 1H), 7.69 (d, J=15.6 Hz, 1H), 7.78 (s, 1H). [0619] 10 Example 435
Synthesis of (E)-5-hydroxy-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid (biphenyl-3-ylmethyl)amide [0620] [Formula 209] (Figure Remove)
Synthesis of (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol- 1-yl)benzylidene] 5-(tetrahydropyran-2-yloxy) valeric
acid ethyl ester
To a DMF (30 mL) suspension of sodium hydride
(40% mineral oil content, 1.25 g),
triethylphosphonoacetic acid (4.89 mL) was added 20 dropwise at room temperature. After agitating the
reaction solution at room temperature for 3 hours, a


DMF (10 mL) solution of 2-(3-bromopropoxy)tetrahydro-2H-pyran was added dropwise to the solution. The reaction solution was agitated at 60°C for 6 hours. The reaction solution was allowed to be cooled to room 5 temperature and concentrated under reduced pressure. Ethyl acetate and a saturated ammonium chloride solution were added to the residue, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it
was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue is purified by silica gel chromatography (elution solvent: hexane: ethyl acetate = 2:1 -> ethyl acetate), and 2.9 g of 2-(diethoxyphosphoryl)-5-(tetrahydropyran-2-yloxy)
valeric acid ethyl ester was obtained.
To a THF (5 mL) solution of 3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzaldehyde (283 mg) obtained in Example 1 and 2-(diethoxyphosphoryl)-5-(tetrahydropyrari-2-yloxy) valeric acid ethyl ester (480
mg), lithium hydroxide monohydrate (110 mg) was added, and the reaction solution was agitated at room temperature for 19 hours. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution, and the organic layer was
partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica


gel chromatography (Carrier: Chromatorex™ NH and elution solventrhexane:ethyl acetate =1:1 -> ethyl acetate), and 186 mg of the title compound was obtained. The physical properties of the compound are 5 as follows.
*H-NMR (CDC13) 8 (ppm) : 1.36 (t, J=7.2 Hz, 3H) , 1.47-1.93 (m, 10H), 2.31 (s, 3H), 2.62-2.76 (m, 2H), 3.39-3.53 (m, 2H), 3.76-3.87 (m, 2H) , 3.88 (s, 3H), 4.29 (q, J=7.2 Hz, 2H), 4.54 (brs, 1H), 6.94 (brs, 1H), 7.05
(brs, 1H), 7.13 (brd, J=7.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.66 (brs, 1H), 7.72 (brs, 1H) . [0621]
Synthesis of (E)-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-5-(tetrahydropyran-2-yloxy)valeric
acid (biphenyl-3-ylmethyl)amide
To a methanol (3 mL) solution of (E)-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)5-(tetrahydropyran-2-yloxy)valeric acid ethyl ester (186 mg), 2N sodium hydroxide aqueous solution (0.5 mL) was
added and the reaction solution was agitated at room temperature for 19 hours. 2N hydrochloric acid (0.5 mL) was added to the reaction solution, and the solution was concentrated under reduced pressure. 3-phenylbenzylamine (87 mg) , HOBT (86 mg), EDC (108 mg),
and IPEA (0.15 mL) were added to a DMF (5 mL) solution of the residue one by one, and the reaction solution was agitated at room temperature for 12 hours. Ethyl acetate and a saturated ammonium chloride solution were

*
added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under 5 reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate: methanol = 9:1), and 168 mg of the title compound was obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.32-1.71 (m, 6H) , 1.84-1.95 (m, 2H), 2.30 (s, 3H), 2.64-2.77 (m, 2H), 3.40-3.47 (m, 2H), 3.70-3.84 (m, 2H), 3.85 (s, 3H) , 4.48 (brs, 1H), 4.63 (dd, J=10.4, 5.6 Hz, 1H), 4.70 (dd, J=10.4, 4.5 Hz, 1H), 6.71 (t, J=5.6 Hz, 1H), 6.92 (brs, 1H), 6.98
(brs, 1H), 7.02 (brd, J=8.0 Hz, 1H) , 7.23 (d, J=8.0 Hz, 1H), 7.33-7.62 (m, 10H), 7.71 (brs, 1H). [0622]
Synthesis of (E)-5-hydroxy-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylldene]valeric acid (biphenyl-3-
ylmethyl)amide
To the methanol (5 mL) solution of (E) -2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-5-(tetrahydropyran-2-yloxy) valeric acid (biphenyl-3-ylmethyl)amide (168 mg), Dow- X™50W X-8 (300 mg) was
added, and the reaction solution was agitated at 45°C for 5 hours. The resin was filtered off, the ammonia water (1 mL) was added to the filtrate, and the solution was concentrated under reduced pressure. The


residue was purified by silica gel chromatography (elution solvent: ethyl acetate -> ethyl acetate:
methanol = 9:1), and 120 mg of the title compound was
obtained. The physical properties of the compound are as follows.
ESI-MS; m/z482 [M++H] . ^-NMR (CDC13) 8 (ppm) : 1.81
(quintet, J=6.8 Hz, 2H), 2.30 (s, 3H), 2.73 (t, J=6.8
Hz, 2H) , 3.67 (t, J=6.8 Hz, 2H), 3.85 (s, 3H), 4.65 (d,
J=5.6 Hz, 2H), 6.63 (t, J=5.6 Hz, 1H), 6.92 (brs, 1H), 6.98-7.02 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 7.33-7.62
(m, 10H), 7.71 (brs, 1H).
[0623]
Example 436
Synthesis of (E)-3-[4-(4-ethyl-lH-imidazol-l-yl)-3-15 methoxyphenyl]-N-((IS)-l-hydroxymethyl-2-
phenylethyl)acrylamide
[0624]
[Formula 210]
(Figure Remove)
Synthesis of (E)-3-[4-(4-ethyl-lH-imidazol-l-yl)-3-methoxyphenyl]acrylic acid
By the same method as in Example 121, 3.05 g 20 of the title compound was obtained from 4-(4-ethyl-lH-imidazol-1-yl)-3-methoxybenzaldehyde (2.72 g) obtained in Example 637 and diethylphosphono ethyl acetate ester

(3.17 g). The physical properties of the compound are
as follows.
:H-NMR (DMSO-d6) 5 (ppm) : 0.46 (t, J=7 . 6 Hz, 3H) , 1.83 (q, J=7.6 Hz, 2H), 3.13 (s, 3H) , 5.76 (d, J=16 Hz, 1H), 5 6.35 (s, 1H), 6.50 (dd, J=2 Hz, 8.4 Hz, 1H), 6.61 (d,
J=8.4 Hz, 1H), 6.62 (d, J=l.6 Hz, 1H) , 6.61 (d, J=8.4
Hz, 1H), 6.86 (d, J=16 Hz, 1H) , 7.18 (s, 1H) .
[0625]
Synthesis of (E)-3-[4-(4-ethyl-lH-imidazol-l-yl)-3- methoxyphenyl]-N-((IS)-l-hydroxymethyl-2-
phenylethyl)acrylamide
[0626]
By the same method as in Example 121, 58 mg
of the title compound was obtained from (E)-3-(4-(4-15 ethyl-lH-imidazol-1-yl)-3-methoxyphenyl)acrylic acid
(116 mg) and D-phenylalaninol (78 mg). The physical
properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm): 1.28 (t, J=7. 6 Hz, 3H) , 2.66 (q,
J=7.6 Hz, 2H), 3.68 (dd, J=4.4 Hz, 11.2 Hz, 1H), 3.79 (dd, J=3.6 Hz, 11.2 Hz, 1H) , 3.83 (s, 3H), 4.33-4.37
(m, 2H), 6.31 (d, J=7.6 Hz, 1H), 6.38 (d, J=16 Hz, 1H),
6.92 (s, 1H), 7.06 (s, 1H), 7.08 (dd, J=l.6 Hz, 8 Hz,
1H), 7.18-7.33 (m, 6H), 7.57 (d, J=16 Hz, 1H), 7.72 (d,
J=1.2 Hz, 1H). [0627]
Example 437
Synthesis of (E)-3-[3-formyl-4-(IH-imidazol-l-
yl)phenyl]-N-indan-1-ylacrylamide

[0628] [Formula 211]

(Figure Remove)
Synthesis of 5-bromo-2-(lH-imidazol-1-yl)benzaldehyde
By the same method as in Example 11, 2.8 g of the title compound was obtained from 5-bromo-2-fluorobenzaldehyde (5 g) and imidazole(2 g). 5 :H-NMR (CDC13) 5 (ppm): 7.21 (t, J=1.2 Hz, 1H) , 7.28-7.29 (m, 1H), 7.34 (d, J=8 . 4 Hz, 1H) , 7.71 (t, J=1.2 Hz, 1H), 7.86 (dd, J=2.8 Hz, 8.4 Hz, 1H), 8.17 (d, J=2.8 Hz, 1H), 9.75 (s, 1H). [0629]
Synthesis of (E)-3-[3-formyl-4-(IH-imidazol-l-yl)phenyl]-N-indan-1-ylacrylamide
By the same method as in Example 9, 44 mg of the title compound was obtained from 5-bromo-2-(1H-imidazol-1-yl)benzaldehyde (50 mg) and N-indan-1-yl-
acrylamide (45 mg).
XH-NMR (CDC13) 8 (ppm): 1.87-1.96 (m, 1H), 2.64-2.72 (m, 1H), 2.90-3.07 (m, 2H), 5.64 (q, J=7.6 Hz, 1H), 6.19 (d, J=8.4 Hz, 1H), 6.60 (d, J=15.6 Hz, 1H), 7.21-7.35 (m, 5H), 7.44 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 7.75 (d,
J=15.6 Hz, 1H), 7.81 (dd, J=2 Hz, 15.6 Hz, 1H), 8.18 (d, J=2 Hz, 1H) , 9.82 (s, 1H) .

[0630]
Example 438
Synthesis of (E)-3-[5-bromo-2-(lH-imidazol-1-yl)phenyl]-N-indan-l-ylacrylamide [0631] [Formula 212]
(Figure Remove)
Br
By the same method as in Example 1, 49 mg of
the title compound was obtained from 5-bromo-2-(1H-imidazol-1-yl)benzaldehyde (30 mg} and indan-1-ylcarbamoyl methylphosphonic acid diethyl ester (37 mg) .
^-NMR (CDC13) 5 (ppm) : 1.80-1.89 (m, 1H) , 2.58-2.66 (m, 1H), 2.85-2.93 (m, 1H), 2.96-3.03 (m, 1H), 5.55 (q, J=7.6 Hz, 1H), 5.99 (d, J=8.4 Hz, 1H) , 6.20 (d, J=15.6 Hz, 1H), 7.06 (t, J=1.2 Hz, 1H), 7.16-7.28 (m, 5H), 7.38 (d, J=15.6 Hz, 1H), 7.55-7.58 (m, 2H), 7.79 (d,
J=2 Hz, 1H) . [0632]
Example 439
Synthesis of (E)-3-[3-hydroxymethyl-4-(IH-imidazol-l-yl)phenyl]-N-indan-l-ylacrylamide

;0633]
;Formula 213]

Sodium borohydride (2 mg) is added to an ethanol (1 mL) solution of (E)-3-(3-formyl-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-ylacrylamide (17 mg) obtained in Example 437 and the reaction mixture was 5 agitated for 30 minutes at room temperature. After the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline
solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:methanol-ethyl acetate system), and 1.8 mg of the title compound was obtained.
XH-NMR (CDC13) 5 (ppm) : 1.86-1.95 (m, 1H) , 2.63-2.72 (m, 1H), 2.89-2.97 (m, 1H), 3.00-3.07 (m, 1H), 4.55 (s, 2H), 5.65 (q, J=7.6 Hz, 1H), 5.89 (d, J=8.4 Hz, 1H), 6.48 (d, J=15.6 Hz, 1H), 7.18-7.35 (m, 7H), 7.54 (dd, J=2.4 Hz, 8 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.79 (d,
J=2 Hz, 1H). [0634] Example 440


Synthesis of (E)-3-[3-(1-hydroxy ethyl)-4-(IH-imidazol-1-yl)phenyl]-N-indan-1-ylacrylamide [0635]
[Formula 214]
O
(Figure Remove)
To a THF (0.5 mL) solution of (E)-3-(3-formyl-4-(IH-imidazol-l-yl)phenyl)-N-indan-1-5 ylacrylamide (23 mg) obtained in Example 437, methyl magnesium bromide (3M ether solution, 0.04 mL) was added under nitrogen atmosphere under ice-cooling and the reaction mixture was agitated for 1 hour. A saturated ammonium chloride water and ethyl acetate
were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (Carrier: Chromatorex™ NH,
elution solvent:methanol-ethyl acetate system), and 10 mg of the title compound was obtained. XH-NMR (CDC13) 6 (ppm): 1.40 (d, J=6.4 Hz, 3H), 1.86-1.95 (m, 1H), 2.66-2.73 (m, 1H), 2.89-2.97 (m, 1H),
3.00-3.07 (m, 1H) , 4.79 (q, J=6.4 Hz, 1H), 5.65 (q,
J=7.6 Hz, 1H), 5.90 (d, J=8.4 Hz, 1H), 6.50 (d, J=15.6 Hz, 1H), 7.09 (t, J=1.2 Hz, 1H), 7.20-7.35 (m, 5H),


7.49 (dd, J=1.6 Hz, 8 Hz, 1H) , 7.61 (s, 1H), 7.73 (d, J=15.6 Hz, 1H), 7.89 (d, J=2 Hz, 1H). [0636]
Example 441
Synthesis of (E)-3-[3-acetyl-4-(IH-imidazol-l-yl)phenyl]-N-indan-1-ylacrylamide [0637]
[Formula 215]
0 O
(Figure Remove)
To a chloroform (0.5 mL) solution of (E)-3-(3- (1-hydroxyethyl)-4-(IH-imidazol-l-yl)phenyl)-N-indan-1-ylacrylamide (3 mg) obtained in Example 440,
activated manganese dioxide (14 mg) was added and the reaction mixture was agitated at room temperature overnight. The reaction solution was filtered through a filter paper and the filtrate was concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (elution solvent: ethyl acetate), and 3.8 mg of the title compound was obtained.
:H-NMR (CDC13) 8 (ppm): 1.86-1.96 (m, 1H) , 2.02 (s, 3H) , 2.65-2.73 (m, 1H), 2.89-2.97 (m, 1H), 3.00-3.08 (m,
1H) , 5.64 (q, J=7. 6 Hz, 1H) , 5.88 (d, J=8.4 Hz, 1H) ,
6.49 (d, J=15.6 Hz, 1H), 7.12 (t, J=1.2 Hz, 1H), 7.22-7.39 (m, 6H), 7.64 (t, J=l.2 Hz, 1H) , 7.70 (dd, J=1.6


Hz, 8 Hz, 1H), 7.78 (d, J=l. 6 Hz, 1H) . [0638]
Example 442
Synthesis of (E)-3-[4-(IH-imidazol-l-yl)-3-5 methoxymethylphenyl]-N-indan-1-ylacrylamide [0639] [Formula 216]
(Figure Remove)
Sodium borohydride (127 mg) was added to an ethanol (10 mL) solution of the 5-bromo-2-(iH-imidazol-1-yl)benzaldehyde (420 mg) obtained in Example 437, and the reaction mixture was agitated at room temperature
for 1 hour. After the reaction solution was
concentrated under reduced pressure, water and ethyl acetate was added to the residue and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous
magnesium sulfate, and concentrated under reduced
pressure. Sodium methoxide (40% methanol solution, 10 mL) was added to a methanol (2 mL) solution of the obtained crude alcohol compound, and the reaction mixture was agitated at room temperature overnight.
After the reaction solution was concentrated under
reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned.


The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and a crude methoxymethyl compound (211 mg) was obtained. By the 5 same method as in Example 9, 15 mg of the title
compound was obtained from this crude methoxymethyl compound (23 mg) and N-indan-1-yl-acrylamide (16 mg). ^-NMR (CDC13) 5 (ppm) : 1.86-1.97 (m, 1H) , 2.63-2.72 (m, 1H), 2.90-2.96 (m, 1H), 3.00-3.07 (m, 1H), 3.39 (s,
3H), 4.23 (s, 2H) , 5.65 (q, J=7.6 Hz, 1H), 5.89 (d,
J=8.4 Hz, 1H), 6.47 (d, J=15.6 Hz, 1H), 7.17 (t, J=1.2 Hz, 1H) , 7.22-7.35 (m, 7H), 7.54 (dd, J=2 Hz, 8.4 Hz, 1H), 7.70-7.75 (m, 2H). [0640]
Example 443
Synthesis of (E) -3-[3-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-indan-1-ylacrylamide [0641] [Formula 217]
(Figure Remove)
By the same method as in Example 9, 32 mg of the title compound was obtained from 1-(4-bromo-2-20 fluoro-6-methoxyphenyl)-4-methyl-lH-imidazole (30 mg) and N-indan-1-yl-acrylamide (24 mg) synthesized by the same method as in Example 16. The physical properties


of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 1.85-1.94 (m, 1H), 2.29 (s, 3H), 2.62-2.70 (m, 1H), 2.87-2.95 (m, 1H), 2.98-3.06 (m, 1H), 3.96 (s, 3H), 5.62 (q, J=7.6 Hz, 1H), 6.02 (d, 5 J=8.4 Hz, 1H), 6.39 (d, J=15.6 Hz, 1H), 6.96 (d, J=0.8 Hz, 1H), 7.04-7.08 (m, 2H), 7.20-7.34 (m, 4H), 7.61 (d, J=15.6 Hz, 1H), 7.70 (t, J=1.6 Hz, 1H). [0642]
Example 444
Synthesis of (E)-3-[2,5-dimethoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-indan-1-ylacrylamide [0643]
[Formula 218]
(Figure Remove)
35 mg of the title compound was obtained from 1-(4-bromo-2,5-dimethoxyphenyl)-4-methyl-lH-imidazole (58 mg) prepared by a similar method as in Example 18 and N-indan-1-yl-acrylamide (44 mg) by the same method as in Example 9. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm): 1.86-1.95 (m, 1H) , 2.30 (s, 3H) , 2.63-2.72 (m, 1H), 2.88-2.96 (m, 1H), 2.99-3.05 (m, 1.H) , 3.81 (s, 3H), 3.86 (s, 3H) , 5.65 (q, J=7. 6 Hz, 15 1H), 5.92 (d, J=8.4 Hz, 1H) , 6.59 (d, J=15.6 Hz, 1H), 6.81 (s, 1H), 6.94-6.95 (m, 1H), 7.13 (s, 1H), 7.21-


7.29 (m, 3H), 7.36 (d, J=6.8 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 7.86 (d, J=15.6 Hz, 1H). [0644]
Example 445
Synthesis of (E)-3-[2-chloro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-indan-1-ylacrylamide [0645] [Formula 219] (Figure Remove)
MeO,
19 mg of the title compound was obtained by the same method as in Example 9 from 1-(4-bromo-5-chloro-2-methoxyphenyl)-4-methyl-lH-imidazole (72 mg)
prepared by a similar method as in Example 18 and N-indan-1-yl-acrylamide (49 mg).
The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 1.87-1.96 (m, 1H), 2.29 (s, 3H) ,
2.64-2.73 (m, 1H), 2.89-2.97 (m, 1H), 3.00-3.07 (m, 1H) , 3.88 (s, 3H), 5.65 (q, J=7.6 Hz, 1H) , 5.96 (d, J=8.4 Hz, 1H), 6.45 (d, J=15.6 Hz, 1H), 6.92 (t, J=1.2 Hz, 1H), 7.17 (s, 1H), 7.22-7.29 (m, 3H), 7.33 (s, 1H), 7.36 (d, J=6.8 Hz, 1H), 7.73 (d, J=l.6 Hz, 1H), 7.98
(d, J=15.6 Hz, 1H). [0646] Example 446


Synthesis of (E)-3-[3-cyano-4-(5-methyl-lH-imidazol-l-yl)phenyl]-N-indan-1-ylacrylamide [0647] [Formula 220]
(Figure Remove)
By the same method as in Example 9, 9 mg of the title compound was obtained from 5-bromo-2-(5-5 methyl-lH-imidazol-1-yl)benzonitrile (30 mg).
XH-NMR (CDC13) 6 (ppm): 1.87-1.97 (m, 1H), 2.18 (s, 3H), 2.65-2.74 (m, 1H), 2.90-2.98 (m, 1H), 3.01-3.08 (m, 1H), 5.65 (q, J=7.6 Hz, 1H), 5.91 (d, J=8 . 4 Hz, 1H), 6.50 (d, J=16 Hz, 1H), 6.98 (t, J=l.2 Hz, 1H), 7.22-
7.30 (m, 3H), 7.34 (d, J=7.6 Hz, 1H) , 7.41 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H) 7.73 (d, J=16 Hz, 1H) , 7.83 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.94 (d, J=2 Hz, 1H). [0648] Compounds shown in Table 11 were synthesized in which
Example 447 to Example 450 followed the method of
Example 434, Example 451 to Example 455 followed the method of Example 20 and Example 456 and Example 457 followed the method of Example 1 changing the substitutent groups on the imidazolering ring and the
benzene ring. The structural formulae and physical properties are shown in Table 11, respectively.

[0649] [Table 11]
(TableRemove)
50]
The compounds shown in Table 12 were
synthesized as in Example 85. The structural formulae and physical properties are shown in Table 12, respectively. 5 [0651]
[Table 12-1]
(Table Remove) [0653]
Example 474
Synthesis of (Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-(6-phenylpyridin-2-5 ylmethyl)acrylic acid amide [0654] [Formula 221]

(Figure Remove)


Synthesis of (Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]acrylic acid
By the same method as in Example 111, 4.52 g
of the title compound was obtained from 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (4.0 g) synthesized in Example 1, 2-fluoro -2-phosphonoacetic acid triethyl ester (5.82 g) and lithium hydroxide
monohydrate (0.664 g) . The physical properties of the compound are as follows.
^-NMR (DMSO-de) 6 (ppm) : 2.16 (s, 3H) , 3.82 (s, 3H) , 7.02 (d, J=24 Hz, IE), 7.20 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.36 (d, J-8.0 Hz, 1H), 7.59 (s, 1H), 7.93 (s,
1H). [0655]
Synthesis of (Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl]-N-(6-phenylpyridin-2-ylmethyl)acrylic acid amide

By the same method as in Example 111, 12.1 mg of the title compound was obtained from (Z)-2-fluoro-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylic acid (10 mg) and (6-phenylpyridin-2-yl)methylamine (10 5 mg). The physical properties of the compound are as follows.
ESI-MS;m/z443[M++H]. [0656]
The following compounds in Table 13 were 10 synthesized as in Example 474. The structural formulae and physicochemical properties are shown in Table 13, respectively.
[0657] [Table 13; (Table Remove)
'0658
The following compounds in Table 14 were synthesized as in Example 23. The structural formulae and physicochemical properties are shown in Table 14, 5 respectively. [0659] [Table 14] (Table Remove)
[0660]
The following compounds in Table 15 were synthesized as in Example 121. The structural formulae and physicochemical properties are shown in Table 15, respectively. [0661] [Table 15-1]
(Table Remove)
[0667]
Example 538
Synthesis of (E)-1-(3,4-difluorobenzyl)-3-[3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)benzylidene]pyrrolidin-2-one
[0668]
[Formula 222]
(Figure Remove)
Synthesis of (E)-l-acetyl-3-[3-methoxy-4-(4-methyl-lH-
imidazol-l-yl)benzylidene] pyrrolidin-2-one
Triethylamine (45 mL) was added to an ethanol
(80 mL) solution of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (3.0 g) and (l-acetyl-2-oxopyrrolidin-3-yl)triphenylphosphonyl bromide (8.4 g) synthesized by the method described in Journal of
Medicinal Chemistry, vol.30, No. 11, p.1995, 1987. The reaction solution was made to react at 60°C for 2 hours. The reaction solution was cooled to room temperature and was added to a mixed-solution of ethyl acetate and iced water. The deposited solids were dried under
reduced pressure after separated by filtration, and 3.3 g of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (DMSO-d6) 6 (ppm) : 2.15 (s, 3H) , 2.46-3.54 (m, 3H), 3.08-3.16 (m, 2H), 3.74-3.80 (m, 2H), 3.89 (s,
3H), 7.18 (t, J=1.2 Hz, 1H), 7.28-7.34 (m, 1H), 7.42-

7.50 (m, 3H), 7.84 (d, J=l.2 Hz, 1H). [0669]
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene] pyrrolidin-2-one
A mixed solution of ethanol (100 mL) and
methanol (100 mL) of (E)-l-acetyl-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]pyrrolidin-2-one (7.5 g) and potassium carbonate (1.6 g) was agitated at room temperature for 2 hours. After condensing reaction
solution to 1/3, added to iced water and ethyl acetate and deposited solids were separated by filtration to obtain 4.7 g of the title compound. Furthermore, the filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium
sulfate after washed with a saturated saline solution. This solution was concentrated and the deposited solids was obtained by filtration to yield 2.7 g of the title compound. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 2.30 (s, 3H) , 3.15-3.25 (m, 2H) , 3.55-3.63 (m, 2H), 3.88 (s, 3H), 5.97 (brs, 1H), 6.94 (d, J=1.2 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.15 (dd, J=l.6,8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.35 (t, J=2.8 Hz, 1H), 7.72 (d, J=l.6 Hz, 1H).
[0670]
Synthesis of (E)-1-(3, 4-difluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]pyrrolidin-2-one To a DMF (6.0 mL) solution of (E)-3-(3-

methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)pyrrolidin-2-one (100 mg), lithium bis(trimethylsilyl)amide (1M hexane solution, 0.53 mL) was added at 0°C, and the reaction solution was agitated 5 for 30 minutes at 0°C. 3, 4-difluorobenzylbromide (0.060 mL) was added to this solution at 0°C, and that reaction solution was agitated at room temperature for 1 hour. The reaction solution was added to iced water and ethyl acetate, and the organic layer was partitioned. The
obtained organic layer was washed with a saturated salt solution, and it concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate
system), and 80 mg of the title compound was obtained. The physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm) : 2.30 (s, 3H) , 3.05-3.13 (m, 2H) , 3.38-3.45 (m, 2H), 3.88 (s, 3H), 4.58 (s, 2H), 6.91-6.95 (m, 1H) , 6.99-7.05 (m, 1H), 7.08-7.17 (m, 4H) ,
7.27 (d, J=8.0 Hz, 1H) , 7.40 (t, J=2.8 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H) . [0671]
The following compounds in Table 16 were synthesized as in Example 538. The structural formulae
and physicochemical properties are shown in Table 16, respectively.


[0672] [Table (Table Remove)
[0674]
Example 554, Example 555 and Example 556 Synthesis of (E)-1-[1-(3,4-difluorobenzyl)- (4R)-hydroxy-(3R)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-5 IH-imidazol-l-yl)benzylidene]piperidin-2-one and (E)-l-[1- (3,4-difluorobenzyl)-(4S)-hydroxy-(35)-pyrrolidine-3-yl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0675]
(Figure Remove)


[Formula 223]

HO,,

Synthesis of (E)-trans-3-hydroxy-4-(3-[3-methoxy-4-(4-10 methyl-lH-imidazol-1-yl)benzylidene]-2-oxopiperidin-l-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
By the same method as in Example 418, 2.61 g of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-
yl)benzylidene)valeric acid trifluoroacetic acid salt (3.66 g) and trans-3-amino-4-hydroxypyrrolidin~l-carbamic acid tert-butyl ester (1.5 g) synthesized according to the method described in The Journal of Organic Chemistry, vol. 62, No. 12, p.4197, 1997. The 20 physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 1.47 (s, 9H), 1.83-2.02 (m, 2H), 2.30 (s, 3H), 2.70-2.88 (m, 2H), 3.25-3.63 (m, 4H),

3.79-3.83 (m, 2H), 3.85 (s, 3H) , 4.33-4.43 (m, 1H) , 4.87-4.95 (m, 1H), 6.92 (brs, 1H), 7.00 (brs, 1H), 7.01 (dd, J=9.6, 1.2 Hz, 1H), 7.24 (d, J=9.6 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.80 (brs, 1H). 5 [0676]
Synthesis of (E)-1-[1-(3, 4-difluorobenzyl)-trans-4-hydroxy-3-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
Trifluoroacetic acid (1 mL) was added to a
methylene chloride (1 mL) solution of tert-butyl ester (100 mg) of
(E)-trans-3-hydroxy-4(3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)-2-oxopiperidin-l-yl)pyrrolidine-1-carboxylic acid and the reaction
solution was agitated at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved with methylene chloride (3 mL), and 3,4-difluorobenzaldehyde (0.046 mL) and sodium triacetoxyborohydride (132 mg) were
added to the solution. After agitating the reaction
solution at room temperature for 6 hours, ethyl acetate and a saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 100 mg of the title compound was obtained by purifying the residue by silica gel

chromatography (Carrier: Chromatorex™ NH and elution solvent:heptane:ethyl acetate =1:1 -> ethyl acetate). The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 1.79-1.89 (m, 1H) , 1.93-2.02 (m, 5 1H), 2.30 (s, 3H), 2.39-2.45 (m, 1H), 2.63-2.97 (m, 4H), 3.08-3.13 (m, 1H) , 3.34-3.42 (m, 1H), 3.49 (d, J=13.2 Hz, 1H), 3.50-3.58 (m, 1H), 3.63 (d, J=13.2 Hz, 1H), 3.72 (brs, 1H), 3.85 (s, 3H), 4.18-4.24 (m, 1H), 4.55-4.61 (m, 1H), 6.92 (brs, 1H), 7.00 (brs, 1H), 7.01
(brd, J=8.0 Hz, 1H), 7.05-7.19 (m, 3H), 7.24 (d, J=8.0 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.77 (brs, 1H) . [0677]
Synthesis of (E)-1-[1-(3,4-difluorobenzyl)-(4R)-hydroxy-(3R)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-
IH-imidazol-l-yl)benzylidene]piperidin-2-one and (E)-l-[1-(3,4-difluorobenzyl)-(4S)-hydroxy-(3S)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
The above-mentioned racemate (10 mg) was
separated by CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase; hexane:iso propanol= 30:70). The title optically active substance with a retention time of 13 minutes (4 mg;>99%ee) and the title optically active substance
with a retention time of 16 minutes (4 mg;>99%ee) were obtained. The physical properties of the title optically active substance with a retention time of 13 minutes (Example 555) are as follows.

(CDC13) 5 (ppm) : 1.79-1.89 (m, 1H) , 1.93-2.02 (m, 1H), 2.30 (s, 3H), 2.39-2.45 (m, 1H), 2.63-2.97 (m, 4H), 3.08-3.13 (m, 1H), 3.34-3.42 (m, 1H), 3.49 (d, J=13.2 Hz, 1H), 3.50-3.58 (m, 1H) , 3.63 (d, J=13.2 Hz, 5 1H), 3.72 (brs, 1H), 3.85 (s, 3H), 4.18-4.24 (m, 1H), 4.55-4.61 (m, 1H), 6.92 (brs, 1H), 7.00 (brs, 1H), 7.01 (brd, J=8.0 Hz, 1H), 7.05-7.19 (m, 3H), 7.24 (d, J=8.0 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H) , 7.77 (brs, 1H) . The physical properties of the title optically active
substance with a retention time of 16 minutes (Example 556) are as follows.
^-NMR (CDC13) 6 (ppm): 1.79-1.89 (m, 1H) , 1.93-2.02 (m, 1H), 2.30 (s, 3H), 2.39-2.45 (m, 1H), 2.63-2.97 (m, 4H), 3.08-3.13 (m, 1H), 3.34-3.42 (m, 1H), 3.49 (d,
J=13.2 Hz, 1H) , 3.50-3.58 (m, 1H) , 3.63 (d, J=13.2 Hz, 1H), 3.72 (brs, 1H) , 3.85 (s, 3H), 4.18-4.24 (m, 1H), 4.55-4.61 (m, 1H), 6.92 (brs, 1H), 7.00 (brs, 1H), 7.01 (brd, J=8.0 Hz, 1H), 7.05-7.19 (m, 3H), 7.24 (d, J=8.0 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.77 (brs, 1H).
[0678]
The following compounds in Table 17 were synthesized as in Example 554, Example 555 and Example 556. The structural formulae and physicochemical properties are shown in Table 17, respectively.
[0679] [Table 17-1] (Table Remove)
[0682]
Example 576
Synthesis of (E)-cis-3-hydroxy-4-{3-(3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]-2-oxopiperidin-l-
yl}pyrrolidine-l-carboxylic acid tert-butyl ester
[0683]
To a THF (5 mL) solution of (E)-trans-3-
[Formula 224]
(Figure Remove)

hydroxy-4-(3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-2-oxopiperidin-l-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg) obtained in Example 554, diisopropylazodicarboxylate (0.024 mL), 5 triphenylphosphine (33 mg) and acetic acid (0.007 mL) were added, and the reaction solution was agitated at room temperature for 3 hours. Ethyl acetate and a saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was
partitioned. After the obtained organic layer was
washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 10 mg of the title compound was obtained by purifying the residue by silica gel
chromatography (Carrier: Chromatorex™ NH, elution
solvent:ethyl acetate). The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 1.49 (s, 9H) , 1.91-1.99 (m, 2H) , 2.31 (s, 3H), 2.75-2.90 (m, 2H), 3.20-3.84 (m, 6H) ,
3.86 (s, 3H), 4.61-4.71 (m, 1H), 4.73-4.80 (m, 1H) ,
6.93 (brs, 1H), 7.01 (brs, 1H), 7.03 (dd, J=10.0,1-2 Hz, 1H) , 7.25 (d, J=10.0 Hz, 1H) , 7.72 (d, J=l. 6 Hz, 1H) , 7.80 (brs, 1H). [0684]
Example 577
Synthesis of (E)-l-benzoyl-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-[1,4'] bipiperidinyl-2-one trifluoroacetic acid salt
[0685]
[Formula 225]

(Figure Remove)

To methylene chloride (1 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-2-oxo-[1,4']bipiperidinyl-l'-carboxylic acid tert-butyl ester (20 mg) obtained in Example 716, trifluoroacetic 5 acid (1 mL) was added, and the reaction solution was agitated at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and IPEA (0.022 mL) and benzoyl chloride (0.01 mL) were added to the methylene chloride (2 mL) solution of the
residue. The reaction solution was agitated at room temperature for 12 hours, a saturated sodium bicarbonate water was added to the reaction solution, and the organic layer was partitioned. 9.4 mg of the title compound was obtained by condensing the obtained
organic layer and purifying by LC-MS. The physical properties of the compound are as follows. ESI-MS; m/z485 [M++H]. [0686] Example 578
Synthesis of (E)-l-trifluoroacetyl-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-[1,4'] bipiperidinyl-2-one trifluoroacetic acid salt [0687] [Formula 226]
P


F

By the same method as in Example 577, 11 mg of the title compound was obtained from (E)-3-(3-methoxy--4- (4-methyl-lH-imidazol-l-yl)benzylidene)-2-oxo-[1,4']bipiperidinyl-l'-carboxylic acid tert-butyl 5 ester (20 mg) and a trifluoroacetic acid anhydride
(0.02 rnL). The physical properties of the compound are as follows. ESI-MS;m/z477 [M++H]. [0688] 10 Example 579
Synthesis of (E)-3-[4-(4-ethyl-lH-imidazol-l-yl)-3-methoxybenzylidene]-1-(7-methoxy-l,2,3 4-tetrahydronaphthalen-1-yl)piperidin-2-one [0689] [Formula 227]

(Figure Remove)


Synthesis of 4-(4-ethyl-lH-imidazol-l-yl)-3-methoxy benzaldehyde

7.3 g of the title compound was obtained via series of steps starting from 4-formylamino-3-methoxybenzoic acid methyl ester (24.8 g) in a similar method from 4-formylamino-3-methoxybenzoic acid methyl b ester to 3-inethoxy-4- (4-methyl-lH-imidazol-l-yDbenzaldehyde as in Example 1 except that chloroacetone was changed to l-bromo-2-butanone. ^-NMR (CDC13) 8: 1.30 (t, J=7. 6 Hz, 3H) , 2.69 (q, J=7.6 Hz, 2H), 3.97 (s, 3H), 7.00 (q, J=1.2 Hz, 1H), 7.46 (d,
J=7.6 Hz, 1H), 7.55 (dd, J=l.6 Hz, 7.6 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 10.01 (s, 1H) . [0690] Synthesis of (E)-5-chloro-2-[4-(4-ethyl-lH-imidazol-l-
yl)-3-methoxybenzylidene]valeric acid tert-butyl ester
By the same method as in Example 418, 3.2 g of the title compound was obtained from 4-(4-ethyl-lH-imidazol-1-yl)-3-methoxybenzaldehyde (7.3 g) and 5-chloro-2-(diethoxyphosphoryl)valeric acid tert-butyl
ester (12.5 g). The physical properties of the compound are as follows.
^-NMR (CDC13 ) 5 (ppm) : 1.29 (t, J=7. 6 Hz, 3H) , 1.60 (s, 9H), 2.00-2.07 (m, 2H), 2.65-2.71 (m, 4H), 3.60 (t, J=6.4 Hz, 2H), 3.88 (s, 3H), 6.94 (s, 1H), 7.01 (s,
1H), 7.03 (d, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.60 (s, 1H), 7.76 (d, J=0.8 Hz, 1H). [0691] Synthesis of (E)-5-chloro-2-[4-(4-ethyl-lH-imidazol-l-
r
yl)-3-methoxybenzylidene]valeric acid trifluoroacetic acid salt
By the same method as in Example 418 and following the synthesis method of (E)-5-chloro-2-(3-5 methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt, 3.5 g of the title compound was obtained from (E)-5-chloro-2-(4-(4-ethyl-lH-imidazol-l-yl)-3-methoxybenzylidene)valeric acid tert-butyl ester (3.2
g). The physical properties of the compound are as follows.
^-NMR (DMSO-d6) 8 (ppm) : 1.25 (t, J=7. 6 Hz, 3H) , 1.94-2.01 (m, 2H), 2.60-2.64 (m, 2H), 2.71 (q, J=7.6 Hz, 2H), 3.70 (t, J=6 Hz, 2H) , 3.91 (s, 3H), 7.24 (dd, J=8,
1.6 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.64 (d, J=8 Hz, 1H) , 7.69 (sf 1H) , 7.75 (d, J=1.2 Hz, 1H) , 9.27 (s, 1H) . [0692] Synthesis of (E)-3-[4-(4-ethyl-lH-imidazol-l-yl)-3-
methoxybenzylidene]-1-(7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)piperidin-2-one
By the same method as in Example 418, 159 mg of the title compound was obtained from (E)-5-chloro-2-(4-(4-ethyl-lH-imidazol-l-yl)-3-
methoxybenzylidene)valeric acid trifluoroacetic acid salt (200 mg) and (S)-7-methoxy-l,2,3,4-tetrahydronaphthalen-1-ylamine (144 mg). The physical properties of the compound are as follows.


(CDC13) 8 (ppm) : 1.30 (t, J=7.0 Hz, 3H) , 1.58-
1.89 (m, 4H), 1.98-2.05 (m, 1H) , 2.08-2.12 (m, 1H) ,
2.66-2.82 (m, 5H) , 2.90-2.96 (m, 1H), 3.07-3.12 (m,
1H), 3.18-3.25 (m, 1H), 3.75 (s, 3H) , 3.88 (s, 3H),
6.08-6.12 (m, 1H), 6.65 (s, 1H), 6.75 (d, J=4.4 Hz,
1H), 6.94 (s, 1H), 7.03-7.10 (m, 3H), 7.26-7.29 (m,
1H) , 7.75 (s, 1H), 7.92 (s, 1H) .
The following compounds in Table 18 were
synthesized as in Example 579. The structural formulae and physicochemical properties are shown in Table 18, respectively.

ftl

[0693] [Table
(Table Remove)
[0695]
Example 596
Synthesis of (E)-3-[4-(2-chloro-lH-imidazol-l-yl)-3-
methoxybenzylidene]-1-(indan-2-yl)piperidin-2-one
[0696]
[Formula 228] (Figure Remove)
Synthesis of 1-(4-[1,3]dioxolan-2-yl-2-methoxyphenyl)-IH-imidazole
To a toluene (70 mL) solution of 4-(lH-
imidazol-l-yl-3-methoxybenzaldehyde (4.3 g) and ethylene glycol (6.5 g), para-toluenesulfonic acid monohydrate (4.8 g) was added, Dean- Stark equipment was attached and heat-refluxing was carried out for 4
hours. After allowing cool the reaction mixture to
room temperature, a saturated sodium bicarbonate water and ethyl acetate were added, and the organic layer was partitioned. The organic layer was washed with a saturated salt solution and concentrated under reduced
pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system), and 3.15 g of the title compound was obtained. The physical properties of the compound are as follows.

XH-NMR (CDC13) 8 (ppm) : 3.88 (s, 3H) , 4.06-4.18 (m, 4H) , 5.85 (s, 1H), 7.15-7.17 (m, 2H), 7.19-7.20 (m, 2H) , 7.29 (d, J=7.6 Hz, 1H), 7.78 (t, J=l Hz, 1H). [0697]
Synthesis of 2-chloro-l-(4-[1,3]dioxolan-2-yl-2-methoxyphenyl)-IH-imidazole
To a THF (50 mL) solution of l-(4-
[1,3]dioxolan-2-y1-2-methoxyphenyl)-IH-imidazole (3.85 g), n-butyllithium (1.6M hexane solution, 12 mL) was
added dropwise under nitrogen atmosphere at -78°C, and the reaction solution was agitated for 30 minutes. THF (10 mL) solution of hexachloroethane (6.1 g) was added to the reaction solution and the reaction solution was agitated at room temperature for 1 hour after agitating
for 30 minutes at -78°C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel
column chromatography (elution solvent: hexane-ethyl acetate system), and 3.19 g of the title compound was obtained. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 3.84 (s, 3H), 4.07-4.19 (m, 4H), 5.85 (s, 1H), 6.98 (d, J=l.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.17 (dd, J=1.6 Hz, 8.0 Hz, 1H) , 7.19 (d, J=1.6 Hz, 1H), 7.27 (d, J=8 Hz, 1H).


[0698]
Synthesis of 4-(2-chloro-lH-imidazol-l-yl)-3-methoxybenzaldehyde
To a THF (40 mL) solution of 2-chloro-l-(4-5 [1,3]dioxolan-2-yl -2-methoxyphenyl)-IH-imidazole (3.19 g), 5N hydrochloric acid (15 mL) was added and the reaction solution was agitated for 2 hours. The reaction mixture was made basic with 5N sodium hydroxide aqueous solution, ethyl acetate was added and
the organic layer was partitioned. The organic layer obtained was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 2.69 g of the title compound. The physical properties of the compound are
as follows.
XH-NMR (CDC13) 5 (ppm) : 3.91 (s, 3H) , 7.04 (d, J=1.6 Hz, 1H) , 7.10 (d, J=1.6 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.57-7.59 (m, 2H), 10.06 (s, 1H). [0699]
Synthesis of (E)-5-chloro-2-[4-(2-chloro-lH-imidazol-l-yl)-3-methoxybenzylidene]valeric acid tert-butyl ester
4.55 g of the title compound was obtained from 4-(2-chloro-lH-imidazol-l-yl)-3-methoxy benzaldehyde (3.19 g) and 5-chloro-2-
(diethoxyphosphoryl)valeric acid tert-butyl ester (5.32 g) in a similar way as in the synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]valeric acid tert-butyl ester in Example


418. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 1.60 (s, 9H), 2.00-2.07 (m, 2H), 2.67-2.71 (m, 2H) , 3.60 (t, J=6.4 Hz, 2H) , 3.84 (s, 5 3H), 6.70-7.08 (m, 4H), 7.26-7.29 (m, 1H), 7.27 (s, 1H) . [0700]
Synthesis of (E)-5-chloro-2-[4-(2-chloro-lH-imidazol-l-yl)-3-methoxybenzylidene]valeric acid
A trifluoroacetic acid (15 mL) solution of 5-
chloro-2-(4-(2-chloro-lH-imidazol-l-yl)-3-methoxybenzylidene)valeric acid tert-butyl ester (1.35 g) was agitated under ice-cooling. The reaction solution was concentrated under reduced pressure after
2 hours. When the residue was purified in LC-MS, 0.99 g of the title compound was obtained. The physical properties of the compound are as follows. '•H-NMR (DMSO-d6) 8 (ppm): 1.96-2.00 (m, 2H) , 2.60-2.64 (m, 2H), 3.70 (t, J=6.4 Hz, 2H) , 3.83 (s, 3H) , 7.04 (s,
1H), 7.17 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.40 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.68 (s, 1H). [0701]
Synthesis of (E)-5-chloro-2-[4-(2-chloro-lH-imidazol-l-yl)-3-methoxybenzylidene]valeric acid indan-2-ylamide
By the same method as in Example 418, 11 mg
of the title compound was obtained from (E)-5-chloro-2-(4- (2-chloro-lH-imidazol-l-yl)-3-methoxybenzylidene)valeric acid (50 mg} and 2-


aminoindan hydrochloride salt (36 mg). The physical properties of the compound are as follows. Hi-NMR (CDC13) 6: 1.83-1.87 (m, 2H) , 2.79-2.83 (m, 2H) , 2.98-3.04 (m, 2H), 3.25-3.32 (m, 4H), 3.82 (s, 3H), 5 5.76-5.81 (m, 1H), 7.01-7.02 (m, 2H), 7.04-7.07 (m, 2H), 7.16-7.26 (m, 5H), 7.87 (s, 1H). [0702]
The compounds shown in Table 19 were
synthesized as in Example 596. The structural formulae 10 and physicochemical properties are shown in Table 19, respectively. [0703] [Table 19-1]
(Table Remove) [0705]
Example 611
Synthesis of (E)-1-(3,4-difluorobenzyl)-3-{[5-methoxy-6-(4-methyl-lH-imidazol-l-yl)pyridin-3-5 yljmethylene}piperidin-2-one

[0706] [Formula 229]
(Figure Remove)
Synthesis of 5-methoxy-6-(4-methyl-lH-imidazol-l-yl) pyridin-3-carbaldehyde
Ozone was boubled into a methanol (5 mL) solution of (E)-3-(6-chloro-5-methoxypyridin-3-5 yl)acrylic acid ethyl ester (123 mg) synthesized by the method of Example 22 under agitation at -78°C. After 10 minutes, introduction of ozone was stopped, dimethylsulfide (1 mL) was added to the reaction solution and the reaction mixture was allowed to be
warmed to room temperature for 1 hour and 30 minutes under agitation. The reaction solution was concentrated under reduced pressure and 4-methylimidazole(125 mg) was added to a DMF (1 mL) solution of the residue. The reaction solution was
agitated at 120°C for 3 hours. After the reaction
solution was allowed to be cooled to room temperature, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was partitioned. After the obtained organic
layer was washed with a saturated sodium bicarbonate water, it was dried over anhydrous magnesium sulfate


and concentrated under reduced pressure. 50 mg of the
title compound was obtained by purifying the residue by
silica gel chromatography (elution solvent heptane:
ethyl acetate =9:1 to ethyl acetate). The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 2.31 (s, 3H) , 4.05 (s, 3H) , 7.65 (s, 1H), 7.78 (s, 1H), 8.52 (s, 2H) , 10.07 (s, 1H) .
[0707]
Synthesis of (E)-5-chloro-2-[5-methoxy-6-(4-methyl-lH-10 imidazol-l-yl)pyridin-3-ylmethylene]valeric acid tert-
butyl ester
By the same method as in Example 418, 35 mg
of the title compound was obtained from 5-methoxy-6-(4-
methyl-lH-imidazol-1-yl)pyridine-3-carbaldehyde (50 mg) and 5-chloro-2-(diethoxyphosphoryl)valeric acid tert-
butyl ester (83 mg). The physical properties of the
compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.56 (s, 9H), 1.78-1.90 (m, 2H) ,
2.30 (s, 3H), 2.66-2.73 (m, 2H), 3.58-3.64 (m, 2H) , 20 3.98 (s, 3H), 7.35 (s, 1H) , 7.54 (s, 2H), 8.06 (s, 1H),
8.37 (S, 1H).
[0708]
Synthesis of (E)-1-(3,4-difluorobenzyl)-3-[5-methoxy-6-
(4-methyl-lH-imida2ol-l-yl)pyridin-3-25 ylmethylene]piperidin-2-one
By the same method as in Example 418, 15 mg
of the title compound was obtained from (E)-5-chloro-2-
[5-methoxy-6-(4-methyl-lH-imidazol-l-yl)pyridin-3-


ylmethylene] valeric acid tert-butyl ester (35 mg) and
3,4-difluorobenzylamine (0.02 mL). The physical
properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 1.76-1.83 (m, 2H), 2.30 (s, 3H),
5 2.81-2.87 (m, 2H), 3.36-3.41 (m, 2H), 3.97 (s, 3H),
4.66 (s, 2H), 7.02-7.18 (m, 3H), 7.31 (d, J=1.2 Hz,
1H), 7.54 (brs, 1H) , 7.82 (brs, 1H), 8.09 (d, J=1.2 Hz,
1H), 8.36 (d, J=1.2 Hz, 1H).
[0709]
The compounds shown in Table 20 were
synthesized as in Example 611. The structural formulae
and physicochemical properties are shown in Table 20,
respectively.
[0710]
[Table 20] (Table Remove)
[0711]
Example 616 and Example 617
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-one-[(R)and(S)-(5-morpholin-4-yl-indan-1-yl))piperidin-2-one [0712] [Formula 230] (Figure Remove)

[0713] 5 Synthesis of 5-morpholin-4-yl-indan-l-one
A l-methyl-2-pyrrolidone (10 mL) solution of 5-fluoroindanone (1.97 g) and morpholine (1.71 g) was agitated at 100°C for 26 hours and 30 minutes. Water and ethyl acetate were added to the reaction solution,
and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography
(elution solvent: heptane-ethyl acetate system), and

2.20 g of the title compound was obtained. The physical properties of the compound are as follows. XH-NMR (CDC13) 6 (ppm) : 2.64-2.67 (m, 2H) , 3.03-3.07 (m, 2H), 3.34 (t, J=4.8 Hz, 4H) , 3.86 (t, J=4.8 Hz, 4H), 5 6.82 (s, 1H), 6.88 (dd, J=2.0, 8.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H) . [0714] Synthesis of 5-morpholin-4-yl-indan-l-on-oxime
An ethanol (5.0 mL) solution of 5-morpholin-
4-yl-indan-l-one(2.20 g) , hydroxyl ammonium chloride (1.05 g) and the triethylamine (4.22 mL) was refluxed for 3 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed
with a saturated sodium chloride solution, and 2.28 g of the title compound was obtained by condensing under reduce pressure after drying over anhydrous magnesium sulfate. The physical properties of the compound are as follows.
^-NMR (CDC13) d (ppm): 2.92-2.96 (m, 2H) , 2.98-3.04 (m, 2H), 3.20-3.26 (m, 4H), 3.85 (t, J=4.8 Hz, 4H), 6.78-6.85 (m, 2H), 7.53 (d, J=8.8 Hz, 1H). [0715] Synthesis of 5-morpholin-4-yl-indan-l-ylamine
An ethanol (20 mL) suspension of 5-morpholin-
4-yl-indan-l-on-oxime (2.76 g) and 10% palladium carbon (48% water content, 1.0 g) was agitated at room temperature under 0.4 MPa hydrogen atmosphere for 6

hours. After filtering the reaction solution and condensing the filtrate under reduced pressure, 1.64 g of the title compound was obtained by purifying the obtained residue by silica gel chromatography (Carrier: 5 Chromatorex™ NH, elution solvent:heptane-ethyl acetate system -> ethyl acetate- methanol system). The physical properties of the compound are as follows. 1H-NMR (CDC13) 8 (ppm) : 1.65-1.70 (m, 1H) , 2.47-2.53 (m, 1H), 2.78 (td, J=8.4, 16 Hz, 1H) , 2.92 (ddd, J=3.6,
8.8, 16 Hz, 1H), 3.13 (t, J=4.8 Hz, 4H), 3.85 (t, J=4.8 Hz, 4H), 4.31 (t, J=7.2 Hz, 1H), 6.79-6.81 (m, 2H), 7.21 (d, J=8.8 Hz, 1H). [0716] Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]valeric acid (5-morpholin-4-y 1 -_i n dan-l-yl)amide
To a DMF (5.0 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetic acid salt
(3.0 g) obtained in Example 418 and 5-morpholin-4-yl-indan-1-ylamine (1.80 g), IPEA (5.18 mg) , EDC (3.84 g) and HOBT (2.71 g) were added one by one, and the reaction solution was agitated at room temperature for 1 hour. After confirming disappearance of the starting
materials, the solvent was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. After washed with a saturated saline solution the organic
layer, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2.80 g of the title compound was obtained by purifying the obtained residue by silica gel chromatography (elution solvent: 5 heptane-ethyl acetate system). The physical properties of the compound are as follows.
^-NMR (CDC13 ) 5 (ppm) : 1.88-1.97 (m, 1H) , 2.00-2.08 (m, 2H), 2.30 (s, 3H), 2.63-2.72 (m, 1H), 2.74 (t, J=7.2 Hz, 2H), 2.82-2.94 (m, 1H) , 2.87-3.05 (m, 1H), 3.10-
3.18 (m, 4H), 3.59 (t, J=6.0 Hz, 2H), 3.82-3.84 (m, 4H), 3.85 (s, 3H) , 5.52 (q, J=7.6 Hz, 1H) , 6.10 (d, J=7.6 Hz, 1H), 6.80-6.83 (m, 2H), 6.92-6.96 (m, 3H), 7.14 (s, 1H), 7.23-7.25 (m, 2H), 7.70 (s, 1H). [0717]
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-1-[(R) and (S)-(5-morpholin-4-yl-indan-1-yl)]-piperidin-2-one
To a DMF (5.0 mL) solution of ((E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid (5-morpholin-4-yl-indan-l-yl)amide (2.80 g) , sodium hydride (40% mineral oil content, 267 mg) was added at 0°C, and the reaction solution was agitated for 15 minutes. Water and ethyl acetate were added to the reaction solution after
confirming disappearance of the starting materials, and the organic layer was partitioned. After the organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and

concentrated under reduced pressure. By purifying the obtained residue by silica gel chromatography (elution solvent: a heptane-ethyl acetate system, ethyl acetate-ethanol system), 2.12 g of (E)-3-(3-methoxy-4-(4-5 methyl-lH-imidazol-l-yl)benzylidene)-1-(5-morpholin-4-yl-indan-l-yl)piperidin-2-one racemate was obtained. Next, this compound (140 mg) was separated in CHRIALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm mobile phase; ethanol),
and the title optically active substance with a
retention time of 14 minutes (64 mg;>99%ee) and the title optically active substance with a retention time of 16 minutes (58 mg;>97%ee) were obtained. The physical properties of the title optically active
substance with a retention time of 14 minutes are as follows.
1H-NMR (CDC13) 8 (ppm): 1.72-1.86 (m, 2H), 1.90-2.00 (m, 1H), 2.30 (s, 3H), 2.44-2.56 (m, 1H), 2.78-2.86 (m, 2H), 2.86-3.00 (m, 2H), 3.02-3.14 (m, 2H), 3.14-3.17
(m, 4H), 3.85-3.86 (m, 4H), 3.86 (s, 3H), 6.41 (t,
J=6.8 Hz, 1H), 6.78-6.80 (m, 2H), 6.93 (s, 1H), 7.04-7.08 (m, 3H), 7.24-7.25 (m, 1H), 7.71 (s, 1H), 7.88 (s, 1H) . The physical properties of the title optically active
substance with a retention time of 16 minutes are as follows.
XH-NMR (CDC13) 8 (ppm): 1.72-1.86 (m, 2H), 1.90-2.00 (m, 1H), 2.30 (s, 3H), 2.44-2.56 (m, 1H), 2.78-2.86 (m,

2H), 2.86-3.00 (m, 2H), 3.02-3.14 (m, 2H), 3.14-3.17 (m, 4H), 3.85-3.86 (m, 4H), 3.86 (s, 3H), 6.41 (t,
J=6.8 Hz, 1H), 6.78-6.80 (m, 2H) , 6.93 (s, 1H), 7.04-
7.08 (m, 3H), 7.24-7.25 (m, 1H), 7.71 (s, 1H), 7.88 (s, 1H) .
[0718]
Example 618 and Example 619
Synthesis of (E)-1-[(R) and (S)-1-(4-fluoro -2-
morpholin-4-ylphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-10 IH-imidazol-l-yl)benzylidene]piperidin-2-one
[0719]
[Formula 231]
(Figure Remove)
[0720]
Synthesis of 1-(4-fluoro-2-morpholin-4-ylphenyl)-
ethanone
A DMF (5.0 mL) solution of 2,4-
difluoroacetophenone (1.0 g) and morpholine (558 mg) 15 was agitated at 110°C for 6 hours and 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium

sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system), and 642 mg of the title compound was obtained. The 5 physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 2.64 (s, 3H) , 2.98-3.00 (m, 4H) , 3.84-3.87 (m, 4H), 6.71-6.77 (m, 2H), 7.44-7.48 (m, 1H) . [0721]
Synthesis of 1- (4-fluoro-2-morpholin-4-ylphenyl)ethane oxime
An ethanol (5.0 mL) solution of l-(4-fluoro-2-morpholin-4-ylphenyl)ehanone (630 mg) , hydroxylammonium chloride (294 mg) and the
triethylamine (1.18 mL) was refluxed for 5 hours. Water was added to the reaction solution and precipitation generated was filtered and air-dried to yield 642 mg of the title compound. The physical properties of the compound are as follows.
1H-NMR (CDC13) 8 (ppm): 2.24 (s, 0.75H), 2.27 (s,
2.25H), 2.96-2.99 (t, J=4.8 Hz, 4H) , 3.81 (t, J=4.8 Hz, 4H), 6.70-6.79 (m, 2H), 7.14 (t, J=6.8 Hz, 0.25H), 7.22 (t, J=6.8 Hz, 0.75H), 7.97 (brs, 0.25H), 8.24 (brs, 0.75H) .
[0722]
Synthesis of 1- (4-fluoro-2-morpholin-4-ethylamine An ethanol (5.0 mL) suspension of l-(4-


fluoro-2-morpholin-4-ylphenyl)ethane oxime (548 mg) and 10% palladium carbon (48% water content, 548 mg) was agitated for 32 hours and 30 minutes at room temperature under 0.4 MPa hydrogen atmosphere. After 5 filtering the reaction solution and condensing the filtrate under reduced pressure, 155 mg of the title compound was obtained by purifying the obtained residue by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system -> ethyl
acetate- methanol system). The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 1.38 (d, J=6.4 Hz, 3H), 1.68 (brs, 2H), 2.88 (t, J=4.4 Hz, 4H), 3.85 (t, J=4. 4 Hz, 4H), 4.54 (q, J=6.4 Hz, 1H), 6.81-6.85 (m, 2H), 7.35-
7.39 (m, 1H), [0723]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid [1-(4-fluoro-2-morpholin-4-ylphenyl]ethyl)amide
To a DMF (3.0 mL) solution (E)-5-chloro-2-(3-
methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt (280 mg) obtained in the Example 418 and 1-(4-fluoro-2-morpholin-4-ylphenyl)ethylamine (155 mg), IPEA (484 mg)
and EDC (359 mg) and HOST (253 mg) were added one by one, and the reaction solution was agitated at room temperature for 1 hour and 20 minutes. After confirming disappearance of the starting materials, the


solvent was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. After the organic layer was washed with a saturated saline solution, it was 5 dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent: from heptane : ethyl acetate system to ethyl acetate-methanol system), and 270 mg of the title compound was
obtained. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.49 (d, J=6.8 Hz, 3H) , 1.95-2.01 (m, 2H), 2.29 (s, 3H), 2.70-2.74 (m, 2H), 2.78-2.82 (m, 2H), 3.13-3.17 (m, 2H), 3.58 (t, J=6.0 Hz,
2H), 3.85 (s, 3H), 3.82-3.93 (m, 4H), 5.53-5.60 (m, 1H), 6.68-6.74 (m, 1H), 6.83-6.95 (m, 4H), 7.15 (s, 1H), 7.23-7.30 (m, 3H), 7.70 (s, 1H). [0724] Synthesis of (E)-1-[(R) and (S)-1-(4-fluoro-2-
morpholin-4-ylphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one To a DMF (3.0 mL) solution of (E)-5-chloro-2-(3-methoxy-4- (4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (1-(4-fluoro -2-morpholin-
4-ylphenyl)-ethyl)amide (270 mg), sodium hydride (40% mineral oil content, 50 mg) was added at 0°C, the reaction solution was allowed to be warmed to room temperature and agitated for 5 hours and 20 minutes.


The reaction solution was cooled to 0°C after confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained 5 organic layer was washed with a saturated saline
solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system -> ethyl acetate-
methanol system) 223 mg of (E)-1-(1-(4-fluoro-2-
morpholin-4-ylphenyl)ethyl)-3-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)piperidin-2-one racemate was obtained. Next, this compound (150 mg) was separated in CHIRALPAK™ AD-H available from Daicel
Chemical Industries, Ltd. (2 cmx25 cm: mobile phase;
ethanol), and the title optically active substance with a retention time of 6 minutes (63.6 mg;>99%ee) and the title optically active substance with a retention time of 7 minutes (54.0 mg;>98%ee) were obtained. The
physical properties of the title optically active substance with a retention time of 6 minutes is as follows.
XH-NMR (CDC13) 5 (ppm): 1.52 (d, J=7.2 Hz, 3H), 1.74-1.82 (m, 2H), 2.30 (s, 3H), 2.59-2.72 (m, 1H), 2.79-
2.94 (m, 6H), 3.21 (td, J=5.6, 12 Hz, 1H), 3.77-3.88 (m, 4H), 3.86 (s, 3H), 6.27 (q, J=7.2 Hz, 1H), 6.83-6.93 (m, 3H), 7.01-7.03 (m, 2H), 7.22-7.25 (m, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.70 (s, 1H) , 7.84 (s, 1H) .


The physical properties of the title optically active substance with a retention time of 7 minutes is as follows.
XH-NMR (CDC13) 6 (ppm): 1.52 (d, J=7 . 2 Hz, 3H), 1.74-5 1.82 (m, 2H), 2.30 (s, 3H), 2.59-2.72 (m, 1H) , 2.79-2.94 (m, 6H), 3.21 (td, J=5.6, 12 Hz, 1H) , 3.77-3.88 (m, 4H), 3.86 (s, 3H), 6.27 (q, J=7.2 Hz, 1H), 6.83-6.93 (m, 3H), 7.01-7.03 (m, 2H) , 7.22-7.25 (m, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.70 (s, 1H) , 7.84 (s, 1H) .
[0725]
Example 620 and Example 621
Synthesis of (E)-1-[(1R) and (lS)-l-(2,4-
difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one
[0726]
[Formula 232]
(Figure Remove)
To a DMF (5 mL) solution of (E)-5-chloro-2-
(3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt (250 mg) obtained in Example 418 and l-(2,4-difluorophenyl)ethylamine (CAS#603951-43-5,141 mg),
IPEA (0.5 mL), EDC (430 mg) and HOBT (303 mg) were added one by one, and the reaction solution was


agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried with anhydrous magnesium 5 sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system). (E)-5-chloro-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]valeric acid [l-(2, 4-
difluorophenyl)ethyl]amide was obtained. Sodium
hydride (40% mineral oil content, 20 mg) was added to a DMF (5 mL) solution of this compound, and that reaction solution was agitated at room temperature for 5 minutes. Water and ethyl acetate were added to the
reaction solution, and the organic layer was
partitioned. The obtained organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: heptane-
ethyl acetate system) 151 mg of (E)-1-(1-(2,4-difluorophenyl)ethyl)-3-(3-methoxy-4-(methyl-lH-imidazol-1-yl)benzylidene)piperidin-2-one racemate was obtained. This compound (25 mg) was separated in CHIRALPAK™ AD-H available from Daicel Chemical
Industries, Ltd. (2 cmx25 cm: mobile phase;
hexane:ethanol = 7:3), and the title optically active substance with a retention time of 25 minutes (Example 620:11.8 mg;>99%ee) and the title optically active


substance with a retention time of 45 minutes (Example 621:11.2 mg;>99%ee) were obtained. The physical properties of the title optically active compound with a retention time of 25 minutes are as follows. 5 ^-NMR (CDC13) 5 (ppm) : 1.59 (d, J=7 .2 Hz, 3H) , 1.77-1.84 (m, 2H), 2.30 (s, 3H), 2.71-2.83 (m, 2H), 2.99-3.05 (m, 1H), 3.27-3.33 (m, 1H), 3.85 (s, 3H), 6.18 (q, J=7.2 Hz, 1H), 6.79-6.85 (m, 1H), 6.86-6.92 (m, 1H), 6.93 (t, J=1.6 Hz, 1H), 7.02 (s, 1H), 7.02 (d, J=8.0
Hz, 1H) , 7.24 (d, J=8.0 Hz, 1H), 7.33-7.39 (m, 1H) , 7.71 (d, J=1.2 Hz, 1H), 7.86 (s, 1H).
The physical properties of the title optically active compound with a retention time of 45 minutes are as follows.
XH-NMR (CDC13) 8 (ppm): 1.59 (d, J=7.2 Hz, 3H), 1.77-1.84 (m, 2H), 2.30 (s, 3H), 2.71-2.83 (m, 2H), 2.99-3.05 (m, 1H), 3.27-3.33 (m, 1H), 3.85 (s, 3H), 6.18 (q, J=7.2 Hz, 1H), 6.79-6.85 (m, 1H) , 6.86-6.92 (m, 1H) , 6.93 (t, J=1.6 Hz, 1H), 7.02 (s, 1H), 7.02 (d, J=8.0
Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.33-7.39 (m, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.86 (s, 1H). [0727]
Example 622 Synthesis of (E)-1-[1-(4-fluorophenyl)-trans-4-
hydroxypyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0728] [Formula 233]

(Figure Remove)
Synthesis of 3- (4-fluorophenyl)-6-oxa-3-azabicyclo[3.1.0]hexane
To a methanol (5 mL) solution of l-(4-fluorophenyl)-2,5-dihydro-lH-pyrrole (300 mg) 5 synthesized according to the method described in The Journal of Organic Chemistry vol. 25, p.2230, 1960, acetonitrile (0.8 mL), potassium hydrogen carbonate (221 mg) and 20% hydrogen peroxide (0.8 mL) were added one by one, and the reaction solution was agitated at
room temperature for 10 hours. Ethyl acetate and
saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated sodium bicarbonate water, it
was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. 75 mg of the title compound was obtained by purifying the residue by silica gel chromatography (heptane: elution solvent; ethyl acetate = 3:1). The physical properties of the
compound are as follows.
^-NMR (CDC13) 5 (ppm) : 3.25 (d, J=8.1 Hz, 2H) , 3.69 (d, J=8.1 Hz, 2H), 3.87 (brs, 2H), 6.37-6.43 (m, 2H), 6.88-6. 96 (m, 2H) .

[0729]
Synthesis of trans-4-amino-l-(4-fluorophenyl)pyrrolidine-3-ol
To a 1,4-dioxane (3 mL) solution of 3-(4-
fluorophenyl)-6-oxa-3-azabicyclo[3.1.0]hexane (75 mg), an aqueous (1 mL) solution of sodium azide (82 mg) was added, and the reaction solution was agitated at 100°C for 7 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and a
saturated sodium chloride solution were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 10% Palladium carbon (48% water
content, 10 mg) was added to an ethanol (5 mL) solution of the residue, and the reaction solution was agitated at room temperature under a hydrogen current for 3 hours. 61 mg of the title compound was obtained by carrying out celite filtration of the reaction
solution, and condensing the filtrate under reduced
pressure. The physical properties of the compound are as follows.
^-NMR (CD3OD3) 8 (ppm) : 3.05-3.17 (m, 2H) , 3.38-3.44 (m, 1H), 3.57-3.67 (m, 2H), 4.10-4.14 (m, 1H), 6.44-
6.49 (m, 2H), 6.87-6.94 (m, 2H).
Synthesis of (E)-1-[1-(4-fluorophenyl)-trans-4-hydroxypyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one


By the same method as in Example 418, 70 mg of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt 5 (175 mg) and trans-4-amino-l-(4-
fluorophenyl)pyrrolidine-3-ol (61 mg). The physical properties of the compound are as follows. XH-NMR (CDC13) 6 (ppm) : 1.83-2.00 (m, 2H), 2.30 (s, 3H) , 2.72-2.96 (m, 2H), 3.22 (dd, J=10.0, 5.6 Hz, 1H), 3.41-
3.48 (m, 3H), 3.62 (dd, J=10.0, 8.0 Hz, 1H), 3.70 (dd, J=10.0, 6.8 Hz, 1H), 3.86 (s, 3H) , 4.50-4.56 (m, 1H), 5.03-5.10 (m, 1H), 6.50-6.55 (m, 2H), 6.92-7.05 (m, 5H), 7.25 (d, J=8.6 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.82 (brs, 1H).
[0730]
Example 623, Example 624 and Example 625
Synthesis of (E)-1-[1-(4-fluorophenyl)-(3S) and (3R)-
pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]piperidin-2-one
[0731]
Synthesis of 1-(4-fluorophenyl)-3-pyrrolidinol of l-(4-fluorophenyl)pyrrolidin-3-ylamine
[Formula 234]
(Figure Remove)


Sodium azide (722 mg) was added to a DMSO (10 mL) solution of methane sulphonate (CAS#618068-72-7, 289 mg). The reaction solution was agitated at 50°C for 15 hours. The reaction solution was allowed to be 5 cooled to room temperature, ether and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated sodium bicarbonate water, it was dried over anhydrous
magnesium sulfate and concentrated under reduced
pressure. 10% Palladium carbon (48% water, 10 mg) was added to the ethanol (5 mL) solution of the obtained residue, and the reaction solution was agitated at room temperature under a hydrogen stream for 20 hours. 187
mg of the title compound was obtained by carrying out celite filtration of the reaction solution, and condensing filtrate under reduced pressure. The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm) : 1.75-1.85 (m, IE) , 2.18-2.28 (m,
1H), 2.96-3.01 (m, 1H), 3.25-3.32 (m, 1H), 3.38-3.50 (m, 2H), 3.68-3.75 (m, 1H), 6.43-6.49 (m, 2H), 6.90-6.97 (m, 2H). [0732'] Synthesis of (E)-1-(1-(4-fluorophenyl)-pyrrolidin-3-
yl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one (Example 623)
By the same method as in Example 418, 82 mg of the title compound was obtained from (E)-5-chloro-2-


(3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt (278 rng) and 1-(4-f luorophenyl) pyrrolidin-3-ylamine (142 mg). The physical properties of the compound are 5 as follows.
XH-NMR (CDC13) 5 (ppm): 1.83-1.97 (m, 2H), 2.11-2.21 (m, 1H), 2.30 (s, 3H), 2.31-2.39 (m, 1H), 2.75-2.90 (m, 2H), 3.23-3.30 (m, 2H), 3.39-3.55 (m, 4H), 3.86 (s, 3H), 5.53-5.61 (m, 1H), 6.48-6.54 (m, 2H), 6.91-7.05
(m, 5H), 7.24 (dd, J=8.0, 2.0 Hz, 1H) , 7.71 (s, 1H) , 7.83 (brs, 1H). [0733]
Synthesis of (E)-1-[1-(4-fluorophenyl)-(3S) and (3R)-pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]piperidin-2-one
the above-mentioned racemate (14 mg) was separated in CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase; hexane:ethanol = 70:30). The title optically active
substance with a retention time of 36 minutes (4.6 mg;>99%ee) and the title optically active substance with a retention time of 39 minutes (4.3 mg;>88%ee) were obtained. The physical properties of the title optically active substance with a retention time of 36
minutes (Example 624) are as follows.
^-NMR (CDCIs ) 8 (ppm): 1.83-1.97 (m, 2H) , 2.11-2.21 (m, 1H), 2.30 (s, 3H), 2.31-2.39 (m, 1H), 2.75-2.90 (m, 2H), 3.23-3.30 (m, 2H), 3.39-3.55 (m, 4H), 3.86 (s,


3H), 5.53-5.61 (m, 1H), 6.48-6.54 (m, 2H), 6.91-7.05 (m, 5H), 7.24 (dd, J=8.0, 2.0 Hz, 1H), 7.71 (s, 1H),
7.83 (brs, 1H).
The physical properties of the title optically active 5 substance with a retention time of 39 minutes (Example
625) are as follows.
^-NMR (CDC13) 6 (ppm) : 1.83-1.97 (m, 2H) , 2.11-2.21 (m,
1H), 2.30 (s, 3H), 2.31-2.39 (m, 1H), 2.75-2.90 (m,
2H), 3.23-3.30 (m, 2H), 3.39-3.55 (m, 4H), 3.86 (s, 10 3H), 5.53-5.61 (m, 1H), 6.48-6.54 (m, 2H), 6.91-7.05
(m, 5H), 7.24 (dd, J=8.0, 2.0 Hz, 1H), 7.71 (s, 1H),
7.83 (brs, 1H).
[0734]
Example 626 and Example 627 15 Synthesis of (E)-1-[(R) and (S)-cyclopropyl-(4-
fluorophenyl)methyl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one
[0735]
[Formula 235]
(Figure Remove)
By the same method as in Example 418, 133 mg of (E)-1-cyclopropyl-(4-fluorophenyl)methyl)-3- (3-20 methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)piperidin-2-one racenate was obtained


from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (250 mg) and cyclopropyl-(4-fluorophenyl)methylamine (CAS#705-14-6, 187 mg). Next, this compound (8.0 mg) 5 was separated by CHIRALCEL™ OJ available from Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase; hexane:ethanol = 80:20), the title optically active substance with a retention time of 9 minutes (0.9 mg;>87%ee) and the title optically active substance
with a retention time of 12 minutes (0.8 mg;>88%ee) were obtained.
The physical properties of the title
optically active substance with a retention time of 9 minutes are as follows.
XH-NMR (CDC13) 8 (ppm): 0.50-0.68 (m, 3H), 0.86-0.92 (m, 1H), 1.29-1.38 (m, 1H) , 1.68-1.78 (m, 1H), 1.86-1.94 (m, 1H), 2.30 (s, 3H), 2.75-2.82 (m, 1H), 2.91 (td, J=4.8, 16 Hz, 1H), 3.10-3.16 (m, 1H), 3.51 (ddd, J=3.6, 10, 12 Hz, 1H), 3.86 (s, 3H) , 5.22 (d, J=10 Hz, 1H) ,
6.94 (s, 1H), 7.00-7.07 (m, 4H), 7.25-7.27 (m, 1H), 7.44 (dd, J=5.6, 6.8 Hz, 2H), 7.73 (s, 1H), 7.89 (s, 1H).
The physical properties of the title optically active substance with a retention time of 12 minutes are as
follows.
^-NMR (CDC13) S (ppm): 0.50-0.68 (m, 3H) , 0.86-0.92 (m, 1H), 1.29-1.38 (m, 1H), 1.68-1.78 (m, 1H), 1.86-1.94 (m, 1H), 2.30 (s, 3H), 2.75-2.82 (m, 1H), 2.91 (td,


J=4.8, 16 Hz, 1H), 3.10-3.16 (m, 1H), 3.51 (ddd, J=3.6, 10, 12 Hz, 1H), 3.86 (s, 3H) , 5.22 (d, J=10 Hz, 1H), 6.94 (s, 1H), 7.00-7.07 (m, 4H) , 7.25-7.27 (m, 1H), 7.44 (dd, J=5.6, 6.8 Hz, 2H) , 7.73 (s, 1H), 7.89 (s, 5 1H) . [0736]
Example 628
Synthesis of (E)-1-[2-fluoro-4-morpholin-4-ylbenzyl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-10 yl)benzylidene]piperidin-2-one [0737] [Formula 236]
(Figure Remove)
Synthesis of 2-fluoro-4-morpholin-4-ylbenzylamine
By the same method as in Example 426, 740 mg of the title compound was obtained using 2-fluoro-4-morpholin-4-ylbenzonitrile (CAS#554448-62-3, 1.0 g).
The physical properties of the compound are as follows. ^-NMR (CDC13) 6 (ppm) : 1.55 (brs, 2H) , 3.13 (t, J=4.8 Hz, 4H), 3.80 (s, 2H), 3.84 (t, J=4.8 Hz, 4H), 6.56 (dd, J=2.4, 13 Hz, 1H), 6.63 (dd, J=2.4, 8.4 Hz, 1H), 7.17 (t, J=8.8 Hz, 1H).
Synthesis of (E)-1-[2-fluoro-4-morpholin-4-ylbenzyl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-


yl)benzylidene]piperidin-2-one
By the same method as in Example 418, 126 mg
of the title compound was obtained from (E)-5-chloro-2-
(3-methoxy-4-(4-methyl-lH-imidazol-1-5 yl)benzylidene)valeric acid trifluoroacetic acid salt
(200 mg) and 2-fluoro -4-morpholin-4-ylbenzylamine (141
mg). The physical properties of the compound are as
follows.
XH-NMR (CDC13) 8 (ppm) : 1.82-1.88 (m, 2H) , 2.30 (s, 3H) , 2.78-2.81 (m, 2H) , 3.15 (t, J=3.6 Hz, 4H) , 3.41 (t,
J=5.6 Hz, 2H), 3.83-3.86 (m, 4H), 3.84 (s, 3H), 4.69
(s, 2H), 6.56 (dd, J=2.4, 13 Hz, 1H) , 6.64 (dd, J=2.4,
8.8 Hz, 1H), 6.92 (s, 1H) , 7.00-7.02 (m, 2H), 7.23 (d,
J=8.4, 1H), 7.32 (t, J=8.8 Hz, 1H), 7.70 (s, 1H) , 7.83 (s, 1H) .
[0738]
Example 629
Synthesis of (E)-1-[(IR)-(4-fluorophenyl)-2-hydroxy
ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l- yl)benzylidene]piperidin-2-one
[0739]
[Formula 237]
(Figure Remove)

Synthesis of (2R)-amino-2-(4-fluorophenyl)ethanol
A THF (5.0 mL) solution of D-(-)-4-
fluorophenylglycine (500 mg) was cooled to 0°C. Sodium borohydride (246 mg) and iodine (751 mg) were added to 5 the reaction solution. After refluxing the reaction solution overnight, methanol was added to the reaction solution and the reaction solution was concentrated under reduced pressure. Next, 5N sodium hydroxide solution and ethyl acetate were added to the reaction
solution, and the organic layer was partitioned. 389 mg of the title compound was obtained by drying with anhydrous magnesium sulfate and condensing under reduced pressure, after the obtained organic layer was washed with a saturated sodium chloride solution. The
physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 2.24 (brs, 3H) , 3.52 (dd, J=8.0, 11 Hz, 1H), 3.70 (dd, J=4.0, 11 Hz, 1H) , 4.04 (dd, J=4.0, 8.0 Hz, 1H), 7.00-7.04 (m, 2H), 7.27-7.31 (m, 2H) .
Synthesis of (E)-1-[(1R)-(4-fluorophenyl)-2-
hydroxyethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
By the same method as in Example 418, 25 mg of the title compound was obtained from (E)-5-chloro-2-
(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt (250 mg) and (2R)-amino-2-(4-fluorophenyl)ethanol (104 mg). The physical properties of the compound are as


follows.
^-NMR (CDC13) 6 (ppm) : 1.72-1.90 (m, 2H) , 2.30 (s, 3H) , 2.79-2.84 (m, 2H), 3.09 (ddd, J=4.4, 7.6, 12 Hz, 1H), 3.33 (ddd, J=4.4, 8.0, 12 Hz, 1H), 3.85 (s, 3H) , 4.17-5 4.25 (m, 2H), 5.86 (dd, J=6.0, 8.0 Hz, 1H), 6.92-6.93 (m, 1H), 7.02-7.08 (m, 4H), 7.20-7.32 (m, 3H) , 7.71 (d, J=1.2 Hz, 1H), 7.87 (s, 1H). [0740]
Example 630 and Example 631 10 Synthesis of (E)-1-[(1R) and (IS)- (3,4-
difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0741] [Formula 238]
(Figure Remove)
Synthesis of (E)-1-((1R) and (IS)-(3,4-difluorophenyl)-ethyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)piperidin-2-one
By the same method as in Example 418, 150 mg of (E)-l-(l-(3,4-difluorophenyl)-ethyl-3-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)piperidin-2-one racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetic acid salt (250 mg) and l-(3,4-


difluorophenyl)ethylamine (CAS#276875-21-9, 140 mg). Next, this compound (150 mg) was separated by CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase : ethanol), 5 and the title optically active substance with a
retention time of 6 minutes (68.0 mg;>99%ee) and the title optically active substance with a retention time of 7 minutes (66.2 mg;>91%ee) were obtained. The physical properties of the title optically active
substance with a retention time of 6 minutes is as follows.
^-NMR (CDC13) 5 (ppm) : 1.54 (d, J=7.2 Hz, 3H) , 1.62-1.76 (m, 1H), 1.80-1.90 (m, 1H), 2.30 (s, 3H), 2.72-2.80 (m, 1H), 2.83-2.90 (m, 1H), 2.92-2.98 (m, 1H),
3.26 (ddd, J=3.6, 8.8, 12 Hz, 1H), 3.86 (s, 3H) , 6.19 (q, J=7.2 Hz, 1H), 6.92 (s, 1H) , 7.03-7.18 (m, 5H) , 7.24-7.25 (m, 1H), 7.71 (s, 1H), 7.88 (s, 1H). The physical properties of the title optically active substance with a retention time of 7 minutes is as
follows.
XH-NMR (CDC13) 8 (ppm): 1.54 (d, J=7.2 Hz, 3H), 1.62-1.76 (m, 1H), 1.80-1.90 (m, 1H) , 2.30 (s, 3H) , 2.72-2.80 (m, 1H), 2.83-2.90 (m, 1H), 2.92-2.98 (m, 1H), 3.26 (ddd, J=3.6, 8.8, 12 Hz, 1H), 3.86 (s, 3H), 6.19
(q, J=7.2 Hz, 1H), 6.92 (s, 1H), 7.03-7.18 (m, 5H) , 7.24-7.25 (m, 1H), 7.71 (s, 1H) , 7.88 (s, 1H) . [0742] Example 632. and Example 633


Synthesis of (E)-1-[ (1R) and (lS)-(4-
fluorophenyl)propyl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one
[0743]
[Formula 239]
(Figure Remove)
Synthesis of (E)-1-[(1R) and (lS)-(4-5 fluorophenyl)propyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
By the same method as in Example 418, 21.9 mg of (E)-l-(l-(4-fluorophenyl)propyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)piperidin-2-one
racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetic acid salt (150 mg) and l-(4-fluorophenyl)propylamine (CAS#74877-10-4, 76.8 mg). Next, this compound (20.0 mg) was separated by
CHIRALPAK™ AD-H available from Daicel Chemical
Industries, Ltd. (2 cmx25 cm:mobile phase : ethanol), and the title optically active substance with a retention time of 6 minutes (6.10 mg;>99%ee) and the title optically active substance with a retention time
of 7 minutes (5.10 mg;>92%ee) were obtained. The physical properties of the title optically active


substance with a retention time of 6 minutes is as follows.
XH-NMR (CDC13) 6 (ppm): 1.02 (t, J=7.2 Hz, 3H), 1.57-1.70 (m, 1H), 1.76-1.88 (m, 1H), 1.89-1.97 (m, 1H), 5 1.99-2.07 (m, 1H), 2.30 (s, 3H) , 2.71-2.84 (m, 2H) , 2.92-2.97 (m, 1H), 3.21 (ddd, J=3.6, 8.4, 12 Hz, 1H) , 3.85 (s, 3H), 6.01 (dd, J=6.0, 10 Hz, 1H), 6.92 (s, 1H), 6.99-7.04 (m, 4H), 7.23-7.25 (m, 1H), 7.31-7.35 (m, 2H), 7.71 (s, 1H), 7.87 (s, 1H).
The physical properties of the title optically active substance with a retention time of 7 minutes is as follows.
:H-NMR (CDC13) 5 (ppm): 1.02 (t, J=7.2 Hz, 3H), 1.57-1.70 (m, 1H), 1.76-1.88 (m, 1H), 1.89-1.97 (m, 1H),
1.99-2.07 (m, 1H), 2.30 (s, 3H) , 2.71-2.84 (m, 2H), 2.92-2.97 (m, 1H), 3.21 (ddd, J=3.6, 8.4, 12 Hz, 1H), 3.85 (s, 3H), 6.01 (dd, J=6.0, 10 Hz, 1H) , 6.92 (s, 1H), 6.99-7.04 (m, 4H), 7.23-7.25 (m, 1H) , 7.31-7.35 (m, 2H), 7.71 (s, 1H), 7.87 (s, 1H).
[0744]
Example 634
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]-1-(2-piperidin-l-ylbenzyl)piperidin-
2-one

[0745] [Formula 240]
(Figure Remove)

By the same method as in Example 641, 8.40 mg
of the title compound was obtained from (E)-5-chloro-2-
(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid tert-butyl ester (50 mg) 5 and 2-piperidin-l-ylbenzylamine (1M DMF solution, 256
|iL) . The physical properties of the compound are as
follows.
XH-NMR (CDC13) d (ppm) : 1.52-1.74 (m, 6H) , 1.82-1.88 (m,
2H), 2.30 (d, J=1.2 Hz, 3H), 2.82-2.86 (m, 6H), 3.28-10 3.31 (m, 2H), 3.86 (S, 3H), 4.86 (s, 2H) , 6.93 (m, 1H),
7.02-7.06 (m, 3H), 7.09 (dd, J=1.2, 8.4 Hz, 1H), 7.20-
7.26 (m, 3H), 7.79 (d, J=l. 2 Hz, 1H), 7.88 (S, 1H).
[0746]
Example 635 15 Synthesis of (E)-1-[(IS)-(4-chlorophenyl)ethyl]-3-[3-
methoxy-4-(4-methylimidazole-2-
yl)benzylidene]piperidin-2-one

[0747] [Formula 241]
(Figure Remove)

By the same method as in Example 641, 10.5 mg
of the title compound was obtained from (E)-5-chloro-2-
(3-methoxy~4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid tert-butyl ester (50 mg) 5 and (S)-1-(4-chlorophenyl)ethylamine (32.0 mg). The
physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.55 (d, J=6.8 Hz, 3H), 1.64-
1.73 (m, 1H), 1.76-1.88 (m, 1H), 2.30 (s, 3H), 2.71-
2.85 (m, 2H), 2.91-2.96 (m, 1H) , 3.24 (dtd, J=4.0, 8.8, 12 Hz, 1H), 3.85 (s, 3H), 6.21 (q, J=6.8 Hz, 1H), 6.92-
6.93 (m, 1H), 7.03-7.05 (m, 2H), 7.22-7.32 (m, 5H),
7.70 (d, J=1.6 Hz, 1H), 7.88 (s, 1H).
[0748]
Example 636 15 Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]-1-(4-trifluoromethylbenzyl)piperidin-
2-one trifluoroacetic acid salt

[0749] [Formula 242] (Figure Remove)








By the same method as in Example 416, 12.5 mg of the
title compound was obtained from (E)-5-chloro-2-(3-
methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid tert-butyl ester (50 mg) 5 and 4-(trifluoromethyl)benzylamine (36.0 mg). The
physical properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 1.87-1.93 (m, 2H), 2.48 (S, 3H),
2.82 (t, J=5.6 Hz, 2H), 3.41 (t, J=6.0 Hz, 2H), 3.90
(s, 3H), 4.78 (s, 2H), 7.06 (d, J=6.4 Hz, 2H), 7.09 (d, J=8.0 Hz, 1H) , 7.33 (d, J=8.0 Hz, 1H) , 7.42 (d, J=8.0
Hz, 1H), 7.60 (d, J=8.0 Hz, 2H) , 7.87 (s, 2H), 8.71 (d,
J=1.2 Hz, 1H).
[0750]
Example 637 15 Synthesis of (E)-3-[4-(4-ethyl-lH-imidazol-l-yl)-3-
methoxybenzylidene]-1-(7-methoxy-l,2,3,4-
tetrahydronaphthalen-1-yl)piperidin-2-one
[0751]
[Formula 243]
(Figure Remove)
Synthesis of (E)-5-chloro-2-[4-(4-ethyl-lH-imidazol-l-yl)-3-methoxybenzylidene]valeric acid trifluoroacetic acid salt
By the same method as in Example 418, 3.5 g 5 of the title compound was obtained from (E)-5-chloro-2-(4- (4-ethyl-lH-imidazol-l-yl) -3-methoxybenzylidene) valeric acid tert-butyl ester (3.2 g) obtained above. The physical properties of the compound are as follows.
^-NMR (DMSO-d6) 8 (ppm) : 1.25 (t, J=7 . 6 Hz, 3H) , 1.94-2.01 (m, 2H), 2.60-2.64 (m, 2H), 2.71 (q, J=7.6 Hz, 2H), 3.70 (t, J=6 Hz, 2H), 3.91 (s, 3H), 7.24 (dd, J=1.6 Hz, 8 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.69 (s, 1H), 7.75 (d, J=1.2 Hz, 1H), 9.27
(s, 1H). [0752]
Synthesis of (E)-3-[4-(4-ethyl-lH-imidazol-l-yl)-3-methoxybenzylidene]-1-(7-methoxy-l,2,3,4-tetrahydronaphthalen-1-yl)piperidin-2-one
By the same method as in Example 641, 159 mg
of the title compound was obtained from (E)-5-chloro-2-(4-(4-ethyl-lH-imidazol-l-yl)-3-
methoxybenzylidene)valeric acid trifluoroacetic acid salt (200 mg) and (S)-7-methoxy-l,2,3,4-
tetrahydronaphthalen-lylamine (144 mg). The physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm): 1.30 (t, J=7.0 Hz, 3H) , 1.58-1.89 (m, 4H), 1.98-2.05 (m, 1H), 2.08-2.12 (m, 1H),

2.66-2.82 (m, 5H), 2.90-2.96 (m, 1H), 3.07-3.12 (m, 1H), 3.18-3.25 (m, 1H), 3.75 (s, 3H), 3.88 (s, 3H), 6.08-6.12 (m, 1H) , 6.65 (s, 1H) , 6.75 (d, J=4 . 4 Hz, 1H), 6.94 (s, 1H)., 7.03-7.10 (m, 3H) , 7.26-7.29 (m, 5 1H), 7.75 (s, 1H), 7.92 (s, 1H). [0753]
Example 638
Synthesis of (E)-1-[(1R)-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-10 yl)benzylidene]piperidin-2-one [0754] [Formula 244]
(Figure Remove)
By the same method as Example 418, 1.0 g of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetic acid salt
(1.6 g) and (R)-1-(4-fluorophenyl)ethylamine (495 mg). The physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm) : 1.50 (d, J=7 .2 Hz, 3H) , 1.65-1.74 (m, 1H), 1.78-1.87 (m, 1H), 2.30 (s, 3H), 2.71-2.85 (m, 2H), 2.91-2.97 (m, 1H), 3.24 (ddd, J=3.6, 8.8,
12.0 Hz, 1H), 3.86 (s, 3H), 6.23 (q, J=7.2 Hz, 1H), 6.93 (t, J=1.2 Hz, 1H), 7.00-7.06 (m, 4H), 7.24-7.26

(m, 1H) , 7.31-7.34 (m, 2H) , 7.72 (d, J=1.2 Hz, 1H) , 7.89 (s, 1H). [0755]
Example 639
Synthesis of (E)-1-[4-(4-fluorophenyl)tetrahydropyran-4-yl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0756] [Formula 245]
(Figure Remove)
By the same method as in Example 418, 1.15 g of the title compound was obtained from (E)-5-chloro-2-
(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt (2.1 g) and 4-(4-fluorophenyl)tetrahydropyran-4-ylamine (833 mg) synthesized according to the method described in Journal of Medicinal Chemistry, vol.10, No. 1 p.128
1967. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.75-1.84 (m, 2H) , 2.30 (s, 3H) , 2.32-2.38 (m, 2H) , 2.74-2.88 (m, 4H), 3.34-3.39 (m, 2H), 3.71-3.78 (m, 2H), 3.80-3.88 (m, 5H), 6.92 (brs,
1H), 6.99-7.07 (m, 4H), 7.23 (d, J=8.0 Hz, 1H), 7.44-7.50 (m, 2H), 7.68 (brs, 1H), 7.72 (s, 1H).

[0757]
Example 640 Synthesis of (E)-1-[1-(3,4-difluorobenzyl)-

3R)-

pyrrolidin-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-5 1-yl)benzylidene]piperidin-2-one [0758] [Formula 246]
(Figure Remove)
By the same method as in Example 417, 12 mg of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)valeric acid ethyl ester (50 mg) and
(3R)-l-(3, 4-difluorobenzyl)pyrrolidin-3-ylamine dihydrochloride (40 mg)
The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm) : 1.75-1.93 (m, 3H) , 2.22-2.33 (m, 2H) , 2.29 (s, 3H), 2.50 (dd, J=10.4, 8.4 Hz, 1H), 2.70
(dd, J=10.4, 3.6 Hz, 1H), 2.77-2.95 (m, 3H), 3.45-3.62 (m, 4H) , 3.84 (s, 3H) , 5.17-5.45 (m, 1H) , 6.92 (s, 1H) , 6.98-7.27 (m, 6H) , 7.70 (d, J=1.2 Hz, 1H), 7.78 (s, 1H) . [0759]
Example 641
Synthesis of (E)-4-{(3S)-(3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-2-oxopiperidin-l-


yl)pyrrolidine-l-yl}benzonitrile [0760] [Formula 247]
(Figure Remove)
Synthesis of [(IS)-(4-silanophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester
DMF (10 mL) suspension of (3S)-3-
(tertbutoxycarbonylamino)pyrrolidine (837 mg) and 4-fluorobenzonitrile (544 mg) and potassium carbonate (1.24 g) was agitated at 120°C for 22 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and saturated sodium
bicarbonate water were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried over anhydrous magnesium sulfate and was concentrated under reduced pressure. 320 mg of the title compound was obtained by re-
crystallizing the residue from the mixed-solution of ethyl acetate and hexane. The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 1.45 (s, 9H) , 1.94-2.05 (m, 1H) , 2.25-2.37 (m, 1H) , 3.16-3.67 (m, 4H), 4.36 (brs, 1H),
4.67 (brs, 1H) , 6.49 (d, J=6.8 Hz, 2H), 7.45 (d, J=6.8 Hz, 2H).

»
[0761]
Synthesis of 4-[(3S)-aminopyrrolidin-1-yl]benzonitrile 2 trifluoroacetic-acid salt
Trifluoroacetic acid (1 mL) was added to a methylene 5 chloride (3 mL) solution of ((IS)-(4-
silanophenyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (100 mg), and the reaction solution was agitated at room temperature for 15 hours. 144 mg of the title compound was obtained by condensing reaction solution
under reduced pressure. The physical properties of the compound are as follows.
^-NMR (CD3OD) 6 (ppm) : 2.18-2.28 (m, 1H) , 2.45-2.56 (m, 1H), 3.43-3.75 (m, 4H), 3.99-4.07 (m, 1H), 6.67 (d, J=6.8 Hz, 2H), 7.53 (d, J=6.8 Hz, 2H).
[0762]
Synthesis of (E)-4-{(3S)-{(3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-2-oxopiperidin-l-yl}pyrrolidin-l-yl}benzonitrile
To a mixed solution of 4-((3S)-
aminopyrrolidin-1-yl)benzonitrile 2 trifluoroacetic-acid salt (144 mg) and (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid tert-butyl ester (136 mg) in acetonitrile (5 mL) and water (0.5 mL), potassium carbonate (239 mg) and sodium
iodide (52 mg) were added, and heat-refluxing of the reaction mixture was carried out for 34 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and water were added to the


reaction solution, and the organic layer was partitioned. The obtained organic layer was dried over anhydrous magnesium sulfate and was concentrated under reduced pressure. Trifluoroacetic acid (I mL) was added 5 to a methylene chloride (3 mL) solution of the residue, and the reaction solution was agitated at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and HOBT (188 mg), EDC (266 mg), and IPEA (0.36 mL) were added to a DMF (3
mL) solution of the obtained residue. The reaction mixture was agitated at room temperature for 6 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was
dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 47 mg of the title compound was obtained by purifying the residue by silica gel chromatography (Carrier: Chromatorex™ NH and elution solvent:heptane:ethyl acetate =1:1 -> ethyl acetate).
The physical properties of the compound are as follows. ^-NMR (CDC13) 6 (ppm) : 1.86-2.00 (m, 2H) , 2.19-2.38 (m, 5H), 2.75-2.92 (m, 2H), 3.29-3.4 (m, 4H), 3.53-3.67 (m, 2H), 3.86 (s, 3H), 5.48-5.57 (m, 1H) , 6.53 (d, J=6.8 Hz, 2H), 6.93 (brs, 1H), 7.01 (brs, 1H), 7.04 (brd,
J=7.0 Hz, 1H), 7.25 (d, J=7.0 Hz, 1H), 7.47 (d, J=6.8 Hz, 2H), 7.70 (s, 1H), 7.83 (brs, 1H) . [0763] Example 642


Synthesis of (E)-4-{3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-2-oxopiperidin-l-yl}piperidin-l-yl)benzonitrile [0764] [Formula 248]
(Figure Remove)
By the same method as in Example 641, 72 mg of the title compound was obtained from 4-(4-
aminopiperidin-1-yl)benzonitrile (142 mg) and (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid tert-butyl ester (129 mg). The physical properties of the compound are as follows.
'•H-NMR (DMSO-d6) 8 (ppm) : 1.60-1.81 (m, 6H) , 2.14 (s, 3H), 2.73-2.78 (m, 2H), 2.92-3.02 (m, 2H), 3.24-3.30 (m, 2H), 3.84 (s, 3H), 4.01-4.10 (m, 2H), 4.60-4.71 (m, 1H), 7.04 (d, J=9.2 Hz, 2H), 7.08 (dd, J=9.2, 1.6 Hz, 1H), 7.14 (s, 1H), 7.23 (d, J=l.6 Hz, 1H), 7.38 (d,
J=9.2 Hz, 1H), 7.55 (d, J=9.2 Hz, 2H), 7.62 (brs, 1H), 7.77 (dd, J=1.2 Hz, 1H). [0765]
Example 643
Synthesis of (E)-1-[4-(1-methoxy-l-methylethyl)benzyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one

(Figure Remove)
[0766] [Formula 249]
By the same method as in Example 418, 100 mg of the title compound was obtained from (E)-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt 5 (250 mg) and 4-(1-methoxy-l-methylethyl)benzylamine (174 mg). The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.52 (s, 6H) , 1.84-1.91 (m, 2H) , 2.30 (s, 3H), 2.82-2.85 (m, 2H), 3.07 (s, 3H), 3.38-
3.41 (m, 2H), 3.86 (s, 3H) , 4.73 (s, 2H) , 6.94 (t,
J=1.2 Hz, 1H), 7.03 (s, 1H), 7.03-7.05 (m, 1H), 7.25-7.30 (m, 3H), 7.38 (d, J=8.0 Hz, 2H) , 7.72 (d, J=1.2 Hz, 1H), 7.89 (s, 1H) . [0767]
Example 644
Synthesis of (E)-1-[3-fluoro-4-(1-methoxy-l-methylethyl) benzyl] -3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0768] [Formula 250]

(Figure Remove)
By the same method as in Example 418, 57 mg of the title compound was obtained from (E)-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-
yl)benzylidene)valeric acid trifluoroacetic acid (250 mg) and 3-fluoro 4-(1-methoxy-l-methyl-
ethyl)benzylamine (132 mg). The physical properties of the compound are as follows.
aH-NMR (CDC13) 6 (ppm): 1.59 (s, 6H) , 1.86-1.92 (m, 2H), 2.30 (s, 3H), 2.81-2.86 (m, 2H), 3.18 (s, 3H),
3.38-3.42 (m, 2H), 3.86 (s, 3H) , 4.70 (s, 2H), 6.92 (s, 1H), 6.97 (d, J=12 Hz, 1H) , 7.02 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H) , 7.24 (m, 1H) , 7.37 (t, J=8.0 Hz, 1H), 7.71 (1H, s, 1H), 7.86 (1H, s, 1H) .
[0769]
Example 645
Synthesis of (E)-1-[2-fluoro-4-(1-methoxy-l-
methylethyl)benzyl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one
[0770]
[Formula 251]

(Figure Remove)
By the same method as Example 418, 110 mg of
the title compound was obtained from (E)-chloro-2-(3-
methoxy-4-(4-methyl-IH-imidazol-1-
yl)benzylidene)valeric acid trifluoroacetic acid salt 5 (250 mg) and 3-fluoro 4-(1-methoxy-l-methyl-
ethyl)benzylamine (154 mg). The physical properties of
the compound are as follows.
^-NMR (CDC13 ) 8 (ppm) : 1.50 (s, 6H) , 1.86-1.92 (m,
2H), 2.30 (s, 3H), 2.81-2.85 (m, 2H) , 3.08 (s, 3H), 10 3.45-3.48 (m, 2H), 3.85 (s, 3H), 4.76 (s, 2H) , 6.92 (t,
J=1.2 Hz, 1H), 7.00 (s, 1H), 7.00-7.03 (m, 1H), 7.09-
7.15 (m, 2H), 7.22-7.24 (m, 1H), 7.36 (t, J=8.0 Hz,
1H), 7.70 (d, J=1.2 Hz, 1H), 7.85 (s, 1H).
[0771] 15 Example 646
Synthesis of (E)-1-(4-chloro-3-fluorobenzyl)-3-[3-
methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
[0772]
[Formula 252]
(Figure Remove)

V

By the same method as in Example 416, 100 mg
of the title compound was obtained from (E)-3-(3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)piperidin-2-one (80 mg) and 4-chloro-3-5 fluorobenzylbromide (0.070 mL). The physical
properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.84-1.92 (m, 2H), 2.30 (s, 3H),
2.80-2.88 (m, 2H), 3.34-3.42 (m, 2H), 3.86 (s, 3H),
4.68 (s, 2H), 6.93 (s, 1H), 7.00-7.08 (m, 3H), 7.11 (d, J=8.8 Hz, 1H), 7.22-7.30 (m, 1H) , 7.35 (t, J=8.4 Hz,
1H), 7.71 (s, 1H), 7.86 (s, 1H).
[0773]
Example 647
Synthesis of (E)-1-[4-methyl-2-(4-15 trifluoromethylphenyl)-1,3-thioazol-5-ylmethyl]-3- [3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]piperidin-2-one
[0774]
[Formula 253]
(Figure Remove)
By the same method as in Example 416, 24 mg of the title compound was obtained from (E)-3-(3-20 methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)piperidin-2-one (80 mg) and 5-(chloromethyl)-4-methyl-2-(4-trifluoromethylphenyl)-


1,3-thiazole (94.2 mg). The physical properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm) : 1.85-1.95 (m, 2H), 2.30 (s, 3H) , 2.55 (s, 3H), 2.80-2.85 (m, 2H), 3.45-3.54 (m, 2H) , 5 3.85 (s, 3H), 4.83 (s, 2H) , 6.91-6.93 (m, 1H), 6.98-7.05 (m, 2H), 7.22-7.27 (m, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.70 (d, J=1.2 Hz, 1H), 7.86 (s, 1H), 8.00 (d, J=8.4 Hz, 2H). [0775] 10 Example 648
Synthesis of (E)-1-(3,4,5-trifluorobenzyl)-3-[3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]piperidin-2-one
[0776]
[Formula 254]
(Figure Remove)
By the same method as in Example 416, 55 mg 15 of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one (50 mg) and 3, 4,5-trifluorobenzylchloride (0.027 mL). The physical properties of the compound are as follows.
20 :H-NMR (CDC13) 5 (ppm): 1.86-1.94 (m, 2H) , 2.30 (s, 3H) , 2.80-2.88 (m, 2H), 3.35-3.42 (m, 2H), 3.86 (s, 3H), 4.64 (s, 2H), 6.90-6.98 (m, 3H), 7.00-7.05 (m, 2H),


7.22-7.28 (m, 1H), 7.69-7.73 (m, 1H), 7.85 (s, 1H) . [0777]
Example 649
Synthesis of (E)-1-(3,4-dichlorobenzyl)-3-[3-methoxy-4-5 (4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one [0778] [Formula 255]
(Figure Remove)
By the same method as in Example 416, 30 mg of the title compound was obtained from (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one (30 mg) and 3,4-
dichlorobenzylchloride (0.020 mL). The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 1.84-1.92 (m, 2H), 2.30 (s, 3H), 2.80-2.88 (m, 2H), 3.34-3.41 (m, 2H), 3.86 (s, 3H), 4.67 (s, 2H), 6.90-6.95 (m, 1H), 7.00-7.06 (m, 2H),
7.17 (dd, J-2.0, 8.4 Hz, 1H), 7.23-7.27 (m, 1H), 7.40 (d, J=2.0 Hz, 1H) , 7.40 (d, J=8.4 Hz, 1H) , 7.71 (d, J=1.2 Hz, 1H), 7.86 (s, 1H) . [0779] Example 650
Synthesis of (E)-1-[6-chloro-2-(morpholin-4-yl)pyridin-3-ylmethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-


yl)benzylidene]piperidin-2-one [0780] [Formula 256]
(Figure Remove)
By the same method as in Example 418, 27 mg of the title compound was obtained from (E)-5-chloro-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]valeric acid trifluoroacetic acid salt (200 mg) and (6-chloro-2-(morpholin-4-yl)-pyridin-3-yl)methylamine (250 mg). The physical properties of the compound are as follows. ^•H-NMR (CDC13) 6 (ppm) : 1.82-1.92 (m, 2H) , 2.31 (s, 3H) ,
2.82-2.90 (m, 2H), 3.12-3.20 (m, 4H) , 3.22-3.30 (m, 2H), 3.80-3.90 (m, 4H), 3.87 (s, 3H) , 4.71 (s, 2H) , 6.90-7.00 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 7.04 (s, 1H) , 7.05 (d, J=8.4 Hz, 1H), 7.20-7.30 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.74 (brs, 1H), 7.88 (s, 1H).
[0781]
Example 651
Synthesis of (E)-(2,2-difluorobenzo[1,3] dioxol-5-ylmethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one

v

[0782] [Formula 257.


(Figure Remove)
By the same method as in Example 427, 44 mg
of the title compound was obtained from (E)-5-chloro-2-
[3-methoxy-4-(4-methyl-lH-imidazol-1-
yl)benzylidene]valeric acid ethyl (100 mg) and 5 methylamine (2,2-difluorobenzo [1,3]dioxol-5-
ylmethyl)(77.5 mg). The physical properties of the
compound are as follows.
XH-NMR (CDC13) 6 (ppm) : 1.83-1.92 (m, 2H), 2.30 (s, 3H) ,
2.80-2.86 (m, 2H), 3.35-3.41 (m, 2H), 3.86 (s, 3H), 4.68 (s, 2H), 6.91-6.94 (m, 1H), 6.98-7.05 (m, 4H),
7.07-7.10 (m, 1H), 7.22-7.27 (m, 1H), 7.71 (d, J=1.2
Hz, 1H), 7.86 (s, 1H).
[0783]
Example 652 15 Synthesis of (E)-1- (3-chloro-4-fluorobenzyl)-3-[3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]piperidin-2-one

[0784] [Formula 258]
(Figure Remove)
By the same method as in Example 427, 27 mg of the title compound was obtained from (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]valeric acid ethyl (100 mg) and 3-5 chloro-4-fluorobenzylamine (100 mg). The physical properties of the compound are as follows. ^-NMR (CDC13) 6 (ppm) : 1.84-1.92 (m, 2H) , 2.30 (s, 3H) , 2.80-2.87 (m, 2H), 3.34-3.41 (m, 2H), 3.88 (s, 3H), 4.66 (s, 2H), 6.91-6.94 (m, 1H) , 7.00-7.05 (m, 2H), 10 7.10 (t, J=8.8 Hz, 1H), 7.17-7.23 (m, 1H), 7.23-7.28 (m, 1H), 7.36 (dd, J=2.0, 6.8 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.86 (s, 1H). [0785]
The compounds shown in Table 21 were 15 synthesized as in Example 418.
The structural formulae and physical properties are shown in Table 21, respectively.
The separation conditions in the notes to Table 21 are as follows:
Separation Condition A: CHIRALPAK™ AD-H (2 cmx25 cm: mobile phase : hexane-ethanol system)


Separation Condition B: CHIRALPAK™ OJ-H (2 cmx25 cm: mobile phase : hexane-ethanol system) [0786] [Table 21-1]
(Table Remove)
[0809]
The compound shown in Table 24 was
synthesized as in Example 1. The structural formulae and physical properties are shown in Table 24, 5 respectively. [0810] [Table 24]
(Figure Remove)




Example Rt1 E, DATA: MS m/z Note
MeQ optically
851 Me TO M+4-H : 4 0 4 (ESI) active substance
852 Et 7b M+ + H : 4 1 8 (ESI) optically active substance
[0811]
The compounds shown in Table 25 were
synthesized as in Example 121. The structural formulae and physical properties are shown in Table 25, 10 respectively.

[0812] [Table 25-1]
(Table Remove)
[0814]
The compounds shown in Table 26 were
synthesized as in Example 418. The structural formulae and physical properties are shown in Table 26, respectively. The separation conditions in the notes 5 to the table are as follows:
Separation Condition A: CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase : hexane-ethanol system)

[0815] [Table 26-1]


(Table Remove)


[0817]
The compounds shown in Table 27 were
synthesized as in Example 418. The structural formulae
and physical properties are shown in Table 27, 5 respectively. The separation conditions in the notes
to the table are as follows:
Separation Condition A: CHIRALPAK™ AD-H available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase : hexane-ethanol system) 10 Separation Condition B: CHIRALCEL™ OJ-H available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase : hexane-ethanol system)
Separation Condition C: CHIRALCEL™ OD-H available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase : hexane-ethanol system)

[0818] [Table 27-1]
(Table Remove)

Example 927 and Example 928
Synthesis of (E)-l-{ (R)-(4-fluorophenyl)-[ (S)-tetrahydrofuran-2-yl]methyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one and (E)-l-5 {(S)-(4-fluorophenyl)-[(R)-tetrahydrofuran-2-
YJJjmethyl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one


[0825] [Formula 259]
(Figure Remove)




Synthesis of erythro-(4-fluorophenyl)-(tetrahydrofuran-2-yl)methyl azide
Diethyl azodicarboxylate (120 mg), threo-(4-fluorophenyl)-(tetrahydrofuran-2-yl)methanol (90 mg) 5 synthesized in accordance with a method described in Chem. Comm., 1999, p. 1745, and diphenylphosphoryl azide (0.099 mL) were sequentially added to a solution of triphenylphosphine (180 mg) in THF (5 mL) at 0°C, and the reaction solution was stirred for 1 hour.
Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane -> heptane:ethyl acetate = 4:1) to obtain 28 mg of the title compound. The physical properties of the compound are as follows. ^-NMR (CDC13) § (ppm) : 1.79-1.94 (m, 4H) , 3.76-3.82 (m,
1H), 3.85-3.93 (m, 1H) , 4.08-4.14 (m, 1H), 4.63 (d, J=4.8 Hz, 1H), 7.01-7.08 (m, 2H), 7.26-7.33 (m, 2H). [0826]

Synthesis of erythro-(4-fluorophenyl)-(tetrahydrofuran-2-yl)methylamine
10% palladium-carbon (water content: 50%, 5 mg) was added to a solution of erythro- (4-5 fluorophenyl)-(tetrahydrofuran-2-yl)methylazide (28 mg) in ethanol, and the reaction solution was stirred in a hydrogen stream at room temperature for 10 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure to
obtain 25 mg of the title compound. The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 1.55-1.99 (m, 4H), 3.66-3.83 (m, 2H), 4.25-4.40 (m, 2H), 6.97-7.06 (m, 2H), 7.44-7.55 (m, 2H), 8.78-9.02 (brs, 2H).
[0827]
Synthesis of (E)-l-{(R)-(4-fluorophenyl)-[ (S)-tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one and (E)-l-{(S)-(4-fluorophenyl)-[(R)-tetrahydrofuran-2-
yl]methyl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
41 mg of a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (63 mg)
and erythro-(4-fluorophenyl)-(tetrahydrofuran-2-
yl)methylamine (25 mg) in the same manner as in Example 418.
The racemate (41 mg) was fractionated using

CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol =3:7) to obtain the title optically active substance with a retention time of 43 minutes 5 (13.5 mg; >99% ee) and the title optically active
substance with a retention time of 64 minutes (10.5 mg; >99% ee) .
The physical properties of the optically active substance with a retention time of 43 minutes
(Example 927) are as follows.
XH-NMR (CDC13) 8 (ppm): 1.61-1.72 (m, 1H), 1.77-2.12 (m, 5H), 2.30 (s, 3H), 2.74-2.80 (m, 2H), 3.06-3.14 (m, 1H), 3.27-3.35 (m, 1H), 3.82-3.96 (m, 5H), 4.52-4.59 (m, 1H), 5.92 (d,J=8.8 Hz, 1H), 6.93 (brs, 1H), 6.99-
7.05 (m, 4H), 7.24 (d, J=8.0 Hz, 1H), 7.46-7.50 (m, 2H), 7.72 (d, J=1.2 Hz, 1H), 7.87 (brs, 1H).
The physical properties of the optically active substance with a retention time of 64 minutes (Example 928) are as follows.
XH-NMR (CDC13) 8 (ppm): 1.61-1.72 (m, 1H) , 1.77-2.12 (m, 5H), 2.30 (s, 3H), 2.74-2.80 (m, 2H), 3.06-3.14 (m, 1H), 3.27-3.35 (m, 1H), 3.82-3.96 (m, 5H), 4.52-4.59 (m, 1H), 5.92 (d, J=8.8 Hz, 1H), 6.93 (brs, 1H), 6.99-7.05 (m, 4H), 7.24 (d, J=8.0 Hz, 1H), 7.46-7.50 (m,
2H), 7.72 (d, J=1.2 Hz, 1H) , 7.87 (brs, 1H) . [0828]
Example 929 and Example 930 Synthesis of (E)-l-{(R)-(4-fluorophenyl)-[(R)-




tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one and (E)-l-{(S)-(4-fluorophenyl)-[(S)-tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-5 yl)benzylidene]piperidin-2-one [0829] [Formula 260]

(Figure Remove)
Synthesis of erythro-(4-fluorophenyl)-(tetrahydrofuran-2-yl)methanol
Diethyl azodicarboxylate (491 mg), threo-(4-fluorophenyl)-(tetrahydrofuran-2-yl)methanol (368 mg),
and benzole acid (251 mg) were sequentially added to a solution of triphenylphosphine (736 mg) in THF (20 mL) at 0°C. The reaction solution was stirred at 0°C for 1 hour, and was further stirred at room temperature for 12 hours. Saturated sodium bicarbonate water and ethyl
acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution
solvent: heptane -> heptane:ethyl acetate =3:1) to obtain 187 mg of (4-fluorophenyl)-(tetrahydrofuran-2-yl)methyl benzoate. A 1 N aqueous solution of sodium


hydroxide (3 mL) was added to a solution of the resulting (4-fluorophenyl)-(tetrahydrofuran-2-yl)methyl benzoate (187 mg) in methanol (5 mL) , and the reaction solution was stirred at room temperature for 4 hours. 5 Brine and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 120 mg of the title compound.
The physical properties of the compound are
as follows.
XH-NMR (CDC13) 6 (ppm): 1.54-1.90 (m, 4H) , 3.77-3.85 (m, 1H), 3.89-3.96 (m, 1H), 4.02-4.08 (m, 1H), 4.90 (d, J=4.0 Hz, 1H), 6.99-7.05 (m, 2H) , 7.31-7.36 (m, 2H) .
[0830]
Synthesis of threo-(4-fluorophenyl)-(tetrahydrofuran-2-yljmethylamine
81 mg of threo-(4-fluorophenyl)-(tetrahydrofuran-2-yl)methylamine was obtained from
erythro-(4-fluorophenyl)-(tetrahydrofuran-2-yl)methanol (120 mg) in the same manner as in Example 927.
The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 1.49-1.69 (m, 2H), 1.80-1.90 (m,
2H), 3.79-3.92 (m, 4H), 6.97-7.03 (m, 2H), 7.30-7.36 (m, 2H). [0831] Synthesis of (E)-l-{(R)-(4-fluorophenyl)-[ (R) -


tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one and (E)-l-{(S)-(4-fluorophenyl)-[(S)-tetrahydrofuran-2-yl]methyl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-5 yl)benzylidene]piperidin-2-one
A racemate obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetate (205 mg) and threo-(4-fluorophenyl)-(tetrahydrofuran-2-
yl)methylamine (81 mg) in the same manner as in Example 418 was fractionated using CHIRALCEL™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol =1:1) to obtain the title optically active substance with a retention time of 18
minutes (653 mg; >99% ee) and the title optically
active substance with a retention time of 27 minutes (59 mg; >99% ee).
The physical properties of the optically active substance with a retention time of 18 minutes
(Example 929) are as follows.
^-NMR (CDC13) 8 (ppm): 1.56-1.73 (m, 2H), 1.82-2.12 (m, 4H), 2.31 (s, 3H), 2.74-2.82 (m, 2H), 3.10-3.18 (m, 1H), 3.50-3.58 (m, 1H) , 3.81-3.98 (m, 5H), 4.58 (q, J=7.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H) , 6.92 (s, 1H),
6.99-7.06 (m, 4H), 7.23 (d, J=8.8 Hz, 1H), 7.40-7.46 (m, 2H), 7.73 (s, 1H), 7.86 (brs, 1H).
The physical properties of the optically active substance with a retention time of 27 minutes


(Example 930) are as follows.
^-NMR (CDC13) 8 (ppm): 1.56-1.73 (m, 2H) , 1.82-2.12 (m, 4H), 2.31 (s, 3H), 2.74-2.82 (m, 2H), 3.10-3.18 (m, 1H), 3.50-3.58 (m, 1H), 3.81-3.98 (m, 5H), 4.58 (q, 5 J=7.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H), 6.92 (s, 1H), 6.99-7.06 (m, 4H), 7.23 (d, J=8.8 Hz, 1H), 7.40-7.46 (m, 2H), 7.73 (s, 1H), 7.86 (brs, 1H). [0832]
Example 931
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-1-[phenyl(tetrahydrofuran-2-yl)methyl]piperidin-2-one [0833] [Formula 261]
(Figure Remove)
125 mg of the title compound was obtained in the same manner as in Example 418 from (E)-5-chloro-2-
(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetate (232 mg) and phenyl(tetrahydrofuran-2-yl)methylamine (92 mg) obtained in the same manner as in Example 927. The physical properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 1.58-2.14 (m, 6H), 2.30 (s, 3H), 2.73-2.80 (m, 2H), 3.07-3.21 (m, 1H), 3.27-3.35 (m, 0.3H), 3.50-3.58 (m, 0.7H), 3.82-3.97 (m, 5H), 4.58-


4.67 (m, 1H), 5.97 (d, J=8.8 Hz, 0.3H), 6.00 (d, J=8.0 Hz, 0.7H), 6.92 (s, 1H), 7.01-7.05 (m, 2H), 7.22-7.53 (m, 6H), 7.71 (s, 1H), 7.87 (brs, 1H). [0834] 5 Example 932
Synthesis of (E)-1-[(1R)-1-(4-fluorophenyl)-2-methoxyethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0835]
[Formula 262]
(Figure Remove)

Sodium hydride (containing mineral oil at 10 40%, 24 mg) was added to a solution of (E)-l-(l-(4-
fluorophenyl)-2-hydroxyethyl)-3-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)piperidin-2-one synthesized by the method described in Example 629 (216 mg) in THF (5 mL), and the reaction solution was 15 stirred at room temperature for 50 minutes. Then, methyl iodide (85 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for 14 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction 20 solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The


residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate = 1:1 -> ethyl acetate) to obtain 185 mg of the title compound. The physical 5 properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 1.64-1.76 (m, 1H), 1.81-1.92 (m, 1H) , 2,31 (s, 3H), 2.73-2.85 (m, 2H), 3.07-3.15 (m, 1H), 3.34-3.42 (m, 1H), 3.45 (s, 3H), 3.85 (s, 3H) , 3.86-4.01 (m, 2H), 6.17 (brt, J=6.4 Hz, 1H) , 6.94 (brs,
1H), 7.00-7.09 (m, 4H), 7.25 (d, J=8.0 Hz, 1H), 7.31-7.39 (m, 2H), 7.73 (brs, 1H), 7.88 (brs, 1H). [0836]
Example 933 Synthesis of (E)-1-{(I/3]dioxolan-2-yl-(4-
f1uorophenyl)methyl}-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0837] [Formula 263]
(Figure Remove)
A solution of dimethyl sulfoxide (0.19 mL) in methylene chloride (1 mL) was added dropwise to a solution of oxalyl chloride (167 mg) in methylene 20 chloride (2 mL) at -78°C. The reaction solution was stirred at -78°C for 5 minutes, and then a solution of (E)-1-(1-(4-fluorophenyl)-2-hydroxyethyl)-3-(3-methoxy-


4-(4-methyl-lH-imidazol-l-yl)benzylidene)piperidin-2-one synthesized by the method described in Example 629 (260 mg) in methylene chloride (3 mL) was added dropwise to the reaction solution. The reaction 5 solution was stirred at -78°C for 1 hour, and then triethylamine (0.42 mL) was added to the reaction solution. The reaction solution was stirred at -78°C for 15 minutes, and further stirred at room temperature for 45 minutes. Saturated sodium bicarbonate water and
ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 250 mg of crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-
IH-imidazol-l-yl)benzylidene)-2-oxopiperidin-l-
yl)acetaldehyde. p-Toluenesulfonic acid (107 mg) and ethylene glycol (0.29 mL) were added to a solution of the resulting crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-lH)benzylidene)-2-oxopiperidin-l-
yl)acetaldehyde (225 mg) in toluene (5 mL), and the reaction solution was heated to reflux for 1 hour and 20 minutes. After allowing the reaction solution to be cooled to room temperature, saturated sodium bicarbonate water and ethyl acetate were added to the
reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel


column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate = 1:1 -> ethyl acetate) to obtain 7 mg of the title compound. The physical properties of the compound are as follows. 5 ESI-MS; m/z478 [M++H]. XH-NMR (CDC13) 5 (ppm): 1.63-1.75 (m, 1H), 1.82-1.93 (m, 1H), 2,33 (s, 3H), 2.77-2.84 (m, 2H), 3.16-3.24 (m, 1H) , 3.47-3.55 (m, 1H), 3.86 (s, 3H), 3.92-4.10 (m, 4H), 5.52 (d, J=5.6 Hz, 1H), 6.07 (d, J=5.6 Hz, 1H), 6.94 (brs, 1H), 7.01-7.07 (m, 4H),
7.24 (d, J=8.0 Hz, 1H), 7.44-7.49 (m, 2H), 7.79 (brs, 1H), 7.89 (brs, 1H). [0838]
Example 934 Synthesis of (E)-2-(4-fluorophenyl)-2-{3-[3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)benzylidene]-2-oxopiperidin-1-yl}-N-methylacetamide [0839] [Formula 264]
(Figure Remove)
A 1 N aqueous solution of sodium hydroxide (0.8 mL) was added to a solution of a solution of methyl (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-20 IH-imidazol-l-yl)benzylidene)-2-oxopiperidin-l-yl)acetate synthesized by the method described in Example 924 (74 mg) in methanol (3 mL), and the

v

reaction solution was stirred at room temperature for 13 hours. 2 N hydrochloric acid (0.4 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure to obtain 72 mg of 5 crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)-2-oxopiperidin-l-yl)acetic acid. HOBT (16 mg) and EDC (23 mg) were added to a solution of the resulting crude (E)-(4-fluorophenyl) -(3-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)-2-oxopiperidin-l-yl)acetic acid (36 mg) and methylamine (2M THF solution, 0.4 mL) in DMF (3 mL), and the reaction solution was stirred at room temperature for 5 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction
solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution
solvent: ethyl acetate -> ethyl acetate:methanol = 9:1) to obtain 32 mg of the title compound. The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 1.72-1.96 (m, 2H), 2,31 (s, 3H), 2.68-2.78 (m,lH), 2.82-2.93 (m, 4H), 3.03-3.11 (m, 1H),
3.57-3.66 (m, 1H), 3.85 (s, 3H), 5.99 (brd, J=4.8 Hz, 1H), 6.35 (s, 1H), 6.93 (s, 1H), 6.99-7.09 (m, 4H), 7.25 (d, J=8.0 Hz, 1H), 7.37-7.45 (m, 2H), 7.74 (s, 1H), 7.83 (brs, 1H).

[0840]
Example 935
Synthesis of (E)-2-(4-fluorophenyl)-2-{3-[3-methoxy-4-(4-methyl-lH-irnidazol-l-yl) benzylidene] -2-oxopiperidin-5 1-yl}-N,N-dimethylacetamide [0841] [Formula 265]
(Figure Remove)
17 mg of the title compound was obtained from crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)-2-oxopiperidin-l-yl)acetic acid (36 mg) and dimethylamine (2M THF
solution, 0.4 mL) in the same manner as in Example 934. The physical properties of the compound are as follows. ^•H-NMR (CDC13) 8 (ppm) : 1.66-1.76 (m, 1H) , 1.89-1.99 (m, 1H), 2,31 (s, 3H), 2.67-2.75 (m, 1H), 2.81-2.91 (m, 2H), 2.95 (s, 3H), 3.04 (s, 3H), 3.63-3.70 (m, 1H),
3.85 (s, 3H), 6.79(s, 1H), 6.92(brs, 1H), 7.00-7.12 (m, 4H), 7.26 (d, J=8.0 Hz,lH), 7.28-7.32 (m, 2H), 7.72 (s, 1H), 7.82 (brs, 1H). [0842] Example 936 and Example 937
Synthesis of (E)-1-[5-fluoro-(2R)-hydroxyindan-(IS)-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one and (E)-1-[5-fluoro-


(2S)-hydroxyindan-(1R)-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0843] [Formula 266]
(Figure Remove)
Synthesis of 2-bromo-5-fluoroindan-l-one
Bromine (1.98 mL) was added to a solution of 5 5-fluoroindanone (5.53 g) in acetic acid (100 mL), and the reaction solution was stirred at 60°C for 10 minutes. After allowing the reaction solution to be cooled to room temperature, the solvent was evaporated under reduced pressure. Ethyl acetate and a saturated
aqueous solution of sodium bicarbonate were added to
the residue and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel
chromatography (elution solvent: heptane-ethyl acetate system) to obtain 8.43 g of the title compound. The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm) : 3.41 (dd, J=18.6, 2.8 Hz, 1H) , 3.83 (dd, J=18.6, 7.6 Hz, 1H), 4.66 (dd, J=7.6, 2.8 Hz,
1H), 7.10-7.16 (m, 2H), 7.85 (dd, J=8.4, 5.2 Hz, 1H). [0844] Synthesis of cis-2-bromo-5-fluoroindan-1-ol


Sodium borohydride (2.09 g) was added to a solution of 2-bromo-5-fluoroindan-1-one (8.43 g) in a mixture of tetrahydrofuran (120 mL) with methanol (30 mL) while cooling with ice, and the reaction solution 5 was stirred for 20 minutes. Water and ethyl acetate were added to the reaction solution while cooling with ice and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced
pressure. The resulting solid was washed with heptane to obtain 7.54 g of the title compound. The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 2.42 (d, J=9.2 Hz,lH), 3.32-3.44 (m, 2H), 4.88-4.95 (m, 2H), 6.93-7.00 (m, 2H), 7.38
(dd, J=8.0, 5.2Hz, 1H). [0845]
Synthesis of 2-bromo-5-fluoroindan-1-yl trans-4-nitrobenzoate
Diisopropyl azodicarboxylate (13.3 mL) was
added dropwise to a solution of cis-2-bromo-5-
fluoroindan-1-ol (7.74 g), 4-nitrobenzoic acid (10.9 g) and triphenylphosphine (17.1 g) in THF (250 mL), and the reaction solution was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the
reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by


silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 7.19 g of the title compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 3.34 (dd, J=17.2, 3.6 Hz, 1H) , 3.82 (dd, J=17.2, 6.8 Hz, 1H), 4.67-4.70 (m, 1H), 6.51 (d, J=3.2 Hz, 1H), 6.70-7.03 (m, 2H) , 7.46 (dd, J=8.0, 4.8 Hz, 1H), 8.17 (d, J=9.2 Hz, 2H) , 8.26 (d, J=9.2 Hz, 2H) .
[0846]
Synthesis of 4-fluoro-6,6a-dihydro-laH-oxacycloprop[a]indene
Sodium methoxide (25 wt% methanol solution, 3.52 mL) was added to a solution of (2-bromo-5-fluoro-
indan-1-yl)trans-4-nitrobenzoate (4.18 g) in
dichloromethane (120 mL), and the reaction solution was stirred for 5 minutes while cooling with ice. Water and dichloromethane were added to the reaction solution and the organic layer was partitioned. The resulting
organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.07 g of a crude purified product containing
the title compound at Ca 30%. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm): 2.99 (dd, J=18.0 Hz, 2.4 Hz, 1H), 3.20 (d, J=18.0 Hz, 1H), 4.14 (dd, J=2.4, 2.4 Hz,


1H), 4.23 (d, J=2.4Hz, 1H), 6.83-6.93 (m, 2H), 7.42 (dd, J=8.0, 5.2Hz, 1H). [0847]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-5 imidazol-1-yl)-benzylidene]valeric acid (5-fluoro-2-hydroxyindan-1-yl)amide
Concentrated sulfuric acid (0.7 mL) was added to a solution of 4-fluoro-6,6a-dihydro-laH-oxa-cycloprop[a]indene (purity: about 30 wt%, 2.07 g) in
acetonitrile (30 mL), and the reaction solution was stirred at room temperature for 1 hour. Then, concentrated sulfuric acid (1 mL) and water (10 mL) were added to the reaction solution, and the reaction solution was heated to reflux for 4 hours. The
reaction solution was returned to room temperature,
made basic by the addition of 5 N sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 5-chloro-2-(3-
methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetate (1.86 g), IPEA (2 mL), EDC (2.38 g) and HOBT (1.68 g) were added to a solution of the resulting residue in DMF (20 mL), and the reaction solution was stirred at room
temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated


under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 916 mg of the title 5 compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 2.05 (m, 2H) , 2.28 (d, J=1.2 Hz, 3H), 2.76 (m, 2H), 3.01 (dd, J=16.8 Hz, 2.0 Hz, 1H) , 3.24 (dd, J=16.8 Hz, 5.2 Hz, 1H), 3.60 (t, J=6.0 Hz,
2H), 3.84 (s, 3H), 4.78 (td, J=5. 2 Hz, J=2.0 Hz,lH), 5.48 (m, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.92-6.98 (m, 4H), 7.17 (d, J=8.0 Hz, 1H) , 7.20 (s, 1H) , 7.27 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H) . [0848]
Synthesis of (E)-1-[5-fluoro-(2R)-hydroxyindan-(IS)-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one and (E)-1-[5-fluoro-(2S)-hydroxyindan-(1R)-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
Sodium hydride (containing mineral oil at
40%, 136 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-
yl)benzylidene)valeric acid (5-fluoro-2-hydroxyindan-l-yl)amide (915 mg) in DMF (10 mL), and the reaction
solution was stirred at room temperature for 20
minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried


over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl 5 acetate-methanol system) to obtain 535 mg of the title compound as a racemate. The compound (16 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol = 1:1) to obtain the title
optically active substance with a retention time of 40 minutes (5.0 mg; >99% ee) and the title optically active substance with a retention time of 48 minutes (4.1 mg; >99% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 8 (ppm) : 1.77-1.88 (m, 2H) , 2.31 (d, J=1.2 Hz, 3H), 2.75-2.88 (m, 2H), 2.91-2.97 (m, 1H) , 3.10-3.13 (m, 2H), 3.27 (dd, J=16.8, 7.6 Hz, 1H), 3.86 (s, 3H), 4.90 (dd, J=7.6, 7.3 Hz, 1H) , 5.91 (d, J=7.2 Hz, 1H), 6.92-6.98 (m, 3H), 7.03 (s, 1H) , 7.03-7.06 (m,
1H), 7.19 (dd, J=8.0, 5.2 Hz, 1H) , 7.24-7.26 (m, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.84 (s, 1H). [0849]
Example 938 and Example 939 Synthesis of (E)-1-[(1S) and (lR)-(2,3-
difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0850] [Formula 267]

(Figure Remove)
Synthesis of 1-(2,3-difluorophenyl)ethylamine
Triethylamine (2.66 mL) and hydroxylamine hydrochloride (712 mg) were added to a solution of 2,3-dif luoroacetophenone (1 g) in ethanol (35 mL), and the 5 reaction solution was heated to reflux for 3 hours.
The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Zinc (2.29 g) was added to a solution of the resulting residue in trifluoroacetic acid (30 mL), and the
reaction solution was stirred at room temperature for 2 hours. The reaction solution was made basic with a 5 N aqueous solution of sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was
evaporated under reduced pressure to obtain 1.4 g of a crude purified product containing the title compound (purity: 72 wt%). The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 1.40 (d, J=6.8 Hz, 3H) , 4.43 (q,
J=6.8 Hz, 1H), 7.01-7.07 (m, 2H), 7.15-7.19 (m, 1H). [0851]
Synthesis of (E)-1-[(1R) and (lS)-(2,3-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one


1-(2,3-difluorophenyl)ethylamine (purity: 72 wt%, 195 mg) , IPEA (1 inL) , EDC (257 mg) and HOBT (181 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid 5 trifluoroacetate (200 mg) in DMF (5 mL), and the
reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried
over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 5-
chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene) valeric acid (1-(2, 3-difluorophenyl) ethyl) amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene)valeric acid (l-(2,3-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier:


,TM
Chromatorex NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 95 mg of the title compound as a racemate. The compound (18 mg) was fractionated using CHIRALPAK™ AD-H 5 manufactured by Daicel Chemical Industries, Ltd. (2
cmx25 cm: mobile phase: hexane:ethanol =5:5) to obtain the title optically active substance with a retention time of 28 minutes (7.5 mg; >99% ee) and the title optically active substance with a retention time of 37
minutes (7.5 mg; >90% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 5 (ppm) : 1.61 (d, J=7.2 Hz, 3H) , 1.79-1.86 (m, 2H), 2.33 (s, 3H), 2.75-2.80 (m, 2H), 3.03-3.10 (m, 1H), 3.30-3.36 (m, 1H) , 3.85 (s, 3H), 6.19 (q,
J=7.2 Hz, 1H), 6.93 (t, J=1.2 Hz, 1H) , 7.01 (s, 1H), 7.01-7.04 (m, 1H), 7.07-7.15 (m, 3H), 7.24-7.25 (m, 1H), 7.82 (s, 1H), 7.85 (s, 1H). [0852] Example 940 and Example 941
Synthesis of (E)-1-[(1S) and (lR)-(3,5-
difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0853] [Formula 268]

Synthesis of 1-(3,5-difluorophenyl)ethylamine
A crude purified product containing the title compound (purity: 83 wt%, 738 mg) was obtained from 3,5-difluoroacetophenone (611 mg) in the same manner as 5 in Example 938. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 1.48 (d, J=6.8 Hz, 3H) , 4.19 (q, J=6.8 Hz, 1H) , 6.72 (tt, J=8.4, 2.4 Hz, 1H) , 6.90 (dd, J=8.4 Hz, 2.4 Hz, 2H).
[0854]
Synthesis of (E)-1-[(1S) and (lR)-(3,5-
difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one
1-(2,3-difluorophenyl)ethylamine (purity: 83
wt%, 253 mg), IPEA (1 mL), EDC (320 mg) and HOBT (226 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (250 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1
hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-


yl)benzylidene)valeric acid (l-(3,5-
difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-lH-5 imidazol-1-yl)benzylidene)valeric acid (l-(3,5-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate
system -> ethyl acetate-methanol system), and the resulting oil was solidified with diethyl ether to obtain 80 mg of the title compound as a racemate. The compound (20 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2
cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 23 minutes (8.7 mg; >99% ee) and the title optically active substance with a retention time of 25 minutes (7.0 mg; >90% ee). The physical properties of the
compounds are as follows.
XH-NMR (CDC13) 6 (ppm): 1.55 (d, J=7.2 Hz, 3H) 1.70-1.79 (m, 1H), 1.82-1.89 (m, 1H), 2.32 (d, J=1.2 Hz, 3H), 2.71-2.79 (m, 1H), 2.84-2.90 (m, 1H), 2.95-3.00 (m,


1H), 3.25-3.31 (m, 1H), 3.86 (s, 3H), 6.18 (q, J=7.2 Hz, 1H), 6.72 (tt, J=8.8, 2.0 Hz, 1H) , 6.83-6.89 (m, 2H), 6.93 (t, J=1.2 Hz, 1H) , 7.03 (s, 1H), 7.03-7.06 (m, 1H) , 7.23-7.27 (m, 1H) , 7.77 (d, J=1.2 Hz, 1H) , 5 7.88 (s, 1H). [0855]
Example 942 and Example 943 Synthesis of (E)-1-[(1S) and (lR)-(2,5-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-

imidazol-1-yl)benzylidene]piperidin-2-one [0856] [Formula 269] (Figure Remove)



Synthesis of 1-(2,5-difluorophenyl)ethylamine
884 mg of the title compound was obtained
from 2,5-difluoroacetophenone (1 g) in the same manner
as in Example 938. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.42 (d, J=6.4 Hz, 3H), 4.40 (q,
J=6.4 Hz, 1H), 6.85-6.91 (m, 1H), 6.94-6.99 (m, 1H),
7.12-7.16 (m, 1H).
[0857] 20 Synthesis of (E)-1-[(1S) and (lR)-(2,5-
difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-

imidazol-l-yl)benzylidene]piperidin-2-one
IPEA (1 mL), EDC (320 mg) and HOBT (226 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid 5 trifluoroacetate (250 mg) and l-(2,5-
difluorophenyl)ethylamine (175 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate
system -> ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (l-(2,5-
difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of
the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (l-(2,5-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the
reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was


purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 140 mg of the title compound as a racemate. The compound 5 (15 mg) was fractionated using CHIRALPAK™ AD-H
manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol =3:7) to obtain the title optically active substance with a retention time of 25 minutes (6.2 mg; >99% ee) and the title
optically active substance with a retention time of 39 minutes (5.8 mg; >99% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 6 (ppm) : 1.57 (d, J=7.2 Hz, 3H) , 1.79-1.86 (m, 2H), 2.30 (d, J=1.2 Hz, 3H), 2.75-2.81 (m,
2H), 3.02-3.09 (m, 1H), 3.28-3.35 (m,1H), 3.85 (s, 3H), 6.15 (q, J=7.2Hz, 1H), 6.92-7.09 (m, 6H), 7.22-7.25 (m, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.85 (s, 1H) . [0858] Example 944 and Example 945
Synthesis of (E)-1-[(IS) and (lR)-(2,6-
difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0859] [formula 270]
(Figure Remove)




Synthesis of 1-(2,6-difluorophenyl)ethylamine
Triethylamine (2.37 mL) and hydroxylamine hydrochloride (634 mg) were added to a solution of 2,6-difluoroacetophenone (890 mg) in ethanol (30 mL), and 5 the reaction solution was heated to reflux for 4 hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Zinc (1.86 g) was added to a solution of the resulting residue in trifluoroacetic acid (10 mL), and the
reaction solution was stirred at room temperature overnight. The reaction solution was filtered on a celite, made basic with a 5 N aqueous solution of sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium
sulfate, and the solvent was evaporated under reduced pressure to obtain 210 mg of a crude purified product containing the title compound (purity: 50 wt%). The physical properties of the compound are as follows. '-H-NMR (CDC13) 6 (ppm) : 1.57 (d, J=6.8 Hz, 3H) , 4.57 (q,
J=6.8z, 1H), 6.72-6.77 (m, 1H), 7.07-7.31 (m, 2H) . [0860]
Synthesis of (E)-1-[(1S) and (lR)-(2,6-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
IPEA (1 mL), EDC (257 mg) and HOBT (181 mg)
were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (200 mg) and l-(2,6-


difluorophenyl)ethylamine (purity: 50 wt%, 210 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic 5 layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate
system -> ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (l-(2,6-
difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of
the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (l-(2,6-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the
reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier:
Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 105 mg of the title compound as a racemate. The compound (15 mg) was fractionated using CHIRALPAK™ AD-H


manufactured by Daicel Chemical Industries, Ltd. (2
cmx25 cm: mobile phase: hexane:ethanol =1:1) to obtain
the title optically active substance with a retention
time of 29 minutes (6.9 ing; >99% ee) and the title 5 optically active substance with a retention time of 34
minutes (6.2 mg; >93% ee). The physical properties of
the compounds are as follows.
^-NMR (CDC13) 5 (ppm) : 1.65 (dt, J=7.2, 1.6 Hz, 3H) ,
1.83-1.90 (m, 2H), 2.33 (s, 3H) , 2.72-2.82 (m, 2H) , 3.33-3.39 (m, 1H) , 3.51-3.57 (m, 1H), 3.84 (s, 3H) ,
6.24 (q, J=7.2Hz, 1H), 6.87-6.94 (m, 3H), 7.01 (s, 1H) ,
7.01-7.04 (m, 1H) , 7.19-7.27 (m, 2H) , 7.81 (s, 1H),
7.83 (s, 1H).
[0861] 15 Example 946 and Example 947
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
l-yl)benzylidene]-l-[(IS) and (IR)-o-
tolylethyl]piperidin-2-one
[0862]
[Formula 271]
(Figure Remove)




Synthesis of 1-o-tolyl-ethanol
Sodium borohydride (564 mg) was added to a
solution of 2-methylacetophenone (1 g) in a mixture of THF (8 mL) with methanol (32 mL) , and the reaction

solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried 5 over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 911 mg of the title compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 1.47 (d, J=6.4 Hz, 3H) , 1.68 (brs, 1H), 2.35 (s, 3H) , 5.14 (q, J=6.4 Hz, 1H) 7.14 (t, J=6.8 Hz, 1H), 7.18(t, J=6.8 Hz, 1H), 7.23 (d, J=6.8 Hz, 1H), 7.52 (d, J=6.8 Hz, 1H). [0863]
Synthesis of 1-(1-azidoethyl)-2-methylbenzene
Triethylamine (2.78 mL) and methanesulfonyl chloride (777 JJ.L) were added to a solution of l-o-tolylethanol (911 mg) in dichloromethane (30 mL), and the reaction solution was stirred at room temperature
for 5 hours. Water and dichloromethane were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Sodium azide (0.87 g) was
added to a solution of the residue in DMF (20 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution and the organic layer was


partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (heptane-ethyl acetate 5 system) to obtain 744 mg of the title compound. The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm): 1.52 (d, J=6.8 Hz, 3H) , 2.37 (s, 3H), 4.83 (q, J=6.8 Hz, 1H), 7.15-7.25 (m, 3H), 7.35-7.38 (m, 1H).
[0864]
Synthesis of 1-o-tolylethylamine
10% palladium-carbon (water content: 50%, 50 mg) was added to a solution of 1-(1-azidoethyl)-2-methylbenzene (744 mg) in methanol (5 mL), and the
reaction solution was stirred in a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure to obtain 482 mg of the title compound. The physical properties of the
compound are as follows.
^-NMR (CDC13) S (ppm): 1.35 (d, J=6.8 Hz, 3H) , 2.36 (s, 3H), 4.36 (q, J=6.8 Hz, 1H), 7.11-7.13 (m, 2H), 7.19-7.23 (m, 1H) , 7.45 (d, J=7.6 Hz, 1H) . [0865]
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-l-((IS) and (IR)-o-tolylethyl)piperidin-2-one
IPEA (0.5 mL), EDC (128 mg) and HOBT (90.4


mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (100 mg) and 1-o-tolylethylamine (60 mg) in DMF (5 mL), and the reaction solution was 5 stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid (1-o-tolylethyl)amide.
Sodium hydride (containing mineral oil at 40%, 50 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-1-yl)benzylidene)valeric acid (1-o-tolylethyl)amide in
DMF (4 mL), and the reaction solution was stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and
the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-


methanol system) to obtain 60 mg of the title compound as a racemate. The compound (10 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: 5 hexane:ethanol = 7:3) to obtain the title optically active substance with a retention time of 39 minutes (4.4 mg; >99% ee) and the title optically active substance with a retention time of 48 minutes (4.4 mg; >99% ee) . The physical properties of the compounds are
as follows.
1H-NMR (CDC13) 6 (ppm) : 1.57 (d, J=6.8 Hz, 3H) , 1.66-1.75 (m, 2H) , 2.78 (s, 3H) , 2.32 (s, 3H) , 2.61-2.71 (m, 2H), 2.79-2.86 (m, 1H) , 3.08-3.15 (m, 1H) , 3.85 (s, 3H) , 6.15 (q, J=6.8 Hz, 1H) , 6.93 (s, 1H) , 7.03 (s,
1H) , 7.03-7.04 (m, 1H) , 7.17-7.24 (m, 4H) , 7.35-7.38 (m, 1H), 7.76 (s, 1H) , 7.87 (s, 1H) . [0866]
Example 948 Synthesis of 1- [1- (2-f luorophenyl) -1-methylethyl] -3- [3-
methoxy-4- ( 4 -methyl -IH-imidazol-l-yl) benzylidene] piperidin-2-one [0867] [Formula 272]
(Figure Remove)


o

Synthesis of methyl (2-fluorophenyl)acetate

**
Trimethylsilyl chloride (4.12 mL) was added to a solution of 2-fluorophenylacetic acid (2 g) in methanol (40 mL) in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 2 5 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.978 g of the title compound. The physical properties of the
compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 3.68 (s, 2H) , 3.72 (s, 3H) ,
7.04-7.13 (m, 2H), 7.24-7.29 (m, 2H).
[0868]
Synthesis of methyl 2-(2-fluorophenyl)-2-
methylpropionate
A solution of methyl (2-fluorophenyl)acetate (1.98 g) in THF (30 mL) was added dropwise to a suspension of sodium hydride (containing mineral oil at 40%, 1.7 g) in THF (70 mL) in a nitrogen atmosphere.
Then, methyl iodide (1.76 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was
partitioned. The resulting organic layer was dried
over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane-


ethyl acetate system) to obtain 1.36 g of the title compound. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm) : 1.57 (s, 6H) , 3.67 (s, 3H) , 7.00 5 (ddd, J=11.6, 8.0, 1.2 Hz, 1H) , 7.12 (td, J=7.6, 1.2Hz, 1H), 7.21-7.26 (m, 1H), 7.31 (td, J=7.6, 1.6 Hz, 1H). [0869]
Synthesis of 2-(2-fluorophenyl)-2-methylpropionic acid A 5 N aqueous solution of sodium hydroxide
(10 mL) was added to a solution of methyl 2-(2-
fluorophenyl)-2-methylpropionate (1.357 g) in methanol (10 mL), and the reaction solution was stirred at 80°C for 3 hours. The reaction solution was returned to room temperature, made acidic with 5 N hydrochloric
acid, and then extracted with ethyl acetate. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.15 g of the title compound. The physical properties of the compound are as follows.
Hl-NMR (CDC13) 8 (ppm): 1.61 (s, 6H) , 7.03 (dd, J-11.2, 8.4 Hz, 1H) , 7.13 (t, J=7.6 Hz, 1H), 7.22-7.28 (m, 1H) , 7.33 (td, J=7.6, 1.6 Hz, 1H). [0870] Synthesis of 1-(2-fluorophenyl)-1-methylethylamine
t-Butyl alcohol (30 mL), diphenylphosphoryl
azide (1.63 mL) and triethylamine (1.05 mL) were added to a solution of 2-(2-fluorophenyl)-2-methylpropionic acid (1.15 g) in toluene (60 mL), and the reaction


solution was heated to reflux overnight. The reaction solution was returned to room temperature, and water and ethyl acetate were added thereto and the organic layer was partitioned. The resulting organic layer was 5 dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 10 mL of 5 N hydrochloric acid was added to a solution of the residue in THF (5 mL), and the reaction solution was heated to reflux for 3 hours. The reaction solution
was returned to room temperature, made basic with 5 N sodium hydroxide, and then extracted with ethyl acetate. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 735 mg of the title
compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.56 (s, 6H) . 6.99-7.07 (m, 1H) , 7.10 (dd, J=7.6, 1.2 Hz, 1H), 7.18-7.24 (m, 1H), 7.41-7.45 (m, 1H).
[0871]
Synthesis of 1-[1-(2-fluorophenyl)-1-methylethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
IPEA (0.5 mL), EDC (192 mg) and HOST (135 mg)
were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and 1-(2-fluorophenyl)-1-methylethylamine (102 mg) in DMF (5 mL), and the


reaction solution was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried 5 over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 5-
chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid (1-(2-fluorophenyl)-1-methylethyl)amide. Sodium hydride (containing mineral oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene)valeric acid (l-(2-
fluorophenyl)-1-methylethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate
system -> ethyl acetate-methanol system) to obtain 70 mg of the title compound. The physical properties of the compound are as follows. ESI-MS; m/z434 [M++H] . ^-NMR (CDC13) 6 (ppm) : 1.79 (s,


6H), 1.90-1.97 (m, 2H) , 2.29 (d, J=l.2 Hz, 3H), 2.73-2.77 (m, 2H), 3.64-3.67 (m, 2H), 3.80 (s, 3H), 6.89-6.99 (m, 4H), 7.10-7.21 (m, 3H), 7.40-7.45 (m, 1H), 7.58 (s, 1H), 7.69 (d, J=1.2 Hz, 1H). [0872]
Example 949
Synthesis of 1-[1-(3,4-difluorophenyl)-1-methylethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0873] [Formula 273]

(Figure Remove)
Synthesis of 1- (3,'4-difluorophenyl) -1-methylethylamine
928 mg of the title compound was obtained from 3,4-difluorophenylacetic acid (2 g) in the same manner as in Example 948. The physical properties of 5 the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 1.47 (s, 6H) , 7.04-7.11 (m, 1H) ,
7.17-7.21 (m, 1H), 7.30-7.35 (m, 1H).
[0874]
Synthesis of 1-[1-(3,4-difluorophenyl)-1-methylethyl]-
3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
IPEA (0.5 rtiL) , EDC (192 mg) and HOBT (135 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid
trifluoroacetate (150 mg) and 1-(3,4-difluorophenyl)-1-methylethylamine (114 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate


system -> ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (1-(3,4-difluorophenyl)-1-methylethyl)amide. Sodium hydride (containing mineral 5 oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (l-(3,4-fluorophenyl)-1-methylethyl)-amide in DMF (5 mL), and the reaction solution was stirred at room temperature
for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 85 mg of the title compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.71 (s, 6H) , 1.95-2.01 (m, 2H) , 2.30 (d, J=1.2 Hz, 3H), 2.78-2.82 (m, 2H), 3.62-3.65 (m, 2H), 3.82 (s, 3H), 6.92 (t, J=l.2 Hz, 1H), 6.97-7.13 (m, 5H), 7.22-7.24 (m, 1H) , 7.61 (s, 1H), 7.71 (d, J=1.2 Hz, 1H) .
[0875]
Example 950
Synthesis of 1-[1-(3, 5-difluorophenyl)-1-methylethyl]-
3-[3-methoxy-4-(4-methyl-lH-imidazol-l-


(Figure Remove) yl)benzylidene]piperidin-2-one [0876] [Formula 274]
Synthesis of 1-(3,5-difluorophenyl)-1-methylethylamine
780 mg of the title compound was obtained from 3,5-difluorophenylacetic acid (1.56 g) in the same 5 manner as in Example 948. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.47 (s, 6H) , 6.65 (tt, J=8.8, 2.4 Hz, 1H), 7.00-7.05 (m, 2H) . [0877]
Synthesis of 1-[1-(3,5-difluorophenyl)-1-methylethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
IPEA .(0.5 mL) , EDC (192 mg) and HOBT (135 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene)valeric acid
trifluoroacetate (150 mg) and 1- (3, 4-dif luorophenyl) -1-methylethylamine (114 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the
reaction solution and the organic layer was
partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was


purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-5 yl)benzylidene)valeric acid (1-(3,5-difluorophenyl)-1-methylethyl)amide. Sodium hydride (containing mineral oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (l-(3,5-
fluorophenyl)-1-methylethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried
over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 84
mg of the title compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 1.69 (s, 6H) , 1.96-2.04 (m, 2H) , 2.31 (d, J-1.2 Hz, 3H), 2.78-2.82 (m, 2H) , 3.63-3.65 (m, 2H), 3.82 (s, 3H), 6.61 (tt, J=8.8, 2.4 Hz, 1H),
6.78-6.83 (m, 2H), 6.92 (t, J=1.2 Hz, 1H), 6.96 (d, J=1.2 Hz, 1H) , 6.99 (dd, J=8.0,1.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H) , 7.60 (s, 1H) , 7.74 (d, J=1.2 Hz, 1H) . [0878]


Example 951
Synthesis of (E)-1-[ (IS)-(4-fluoro-3-methoxyphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0879] [Formula 275]
(Figure Remove)
Synthesis of 1-(4-fluoro-3-methoxyphenyl)ethanol
Methyl magnesium chloride (3 M
tetrahydrofuran solution, 7.8 mL) was added to a solution of 4-fluoro-3-methoxybenzaldehyde (3 g) in THF (200 mL) while cooling with ice, and the reaction
solution was stirred for 2 hours while cooling with
ice. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the
solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain 2.65 g of the title compound. The physical properties of the
compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.48 (d, J=6.4 Hz, 3H), 1.82 (brs, 1H), 3.90 (s, 3H), 4.86 (q, J=6.4 Hz, 1H), 6.83-


6.87 (m, 1H), 6.99-7.04 (m, 2H). [0880] Synthesis of 4-fluoro-3-methoxyacetophenone
A solution of dimethyl sulfoxide (1.33 mL) in 5 dichloromethane (5 mL) was added dropwise to a solution of oxalyl chloride (1.63 mL) in dichloromethane (80 mL) in a nitrogen atmosphere at -78°C. After stirring the reaction solution at -78°C for 3 minutes, a solution of 1-(4-fluoro-3-methoxyphenyl)ethanol (2.6 g) in
dichloromethane (15 mL) was added dropwises to the
reaction solution. Further, the reaction solution was stirred at -78°C for 20 minutes, and triethylamine (10.8 mL) was added dropwise to the reaction solution. Then, the reaction solution was stirred at -78°C for 10
minutes, and further stirred at room temperature for 30 minutes. Water and dichloromethane were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.54 g of the title compound. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 2.59 (s, 3H), 3.94 (s, 3H) , 7.13 (dd, J=10.8, 8.4 Hz, 1H), 7.49-7.53 (m, 1H) , 7.60 (dd, J=8.4, 2.0 Hz, 1H). [0881]

Synthesis of (IR)-(4-fluoro-3-methoxyphenyl)ethanol
A solution of 4-fluoro-3-methoxyacetophenone (1 g) in THF (10 mL) was added dropwise to a solution of (+)-DIPCl™ (2.29 g) in THF (30 mL) in a nitrogen 5 atmosphere at -20°C, and the reaction solution was
stirred at -20°C for 5 hours. The reaction solution was heated to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with an ether, diethanolamine (1.25 mL) was
added to the diluent, and the reaction solution was stirred at room temperature overnight. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain 918 mg of the title compound. The physical properties of the compound are as follows.
:H-NMR (CDC13) 8 (ppm): 1.48 (d, J=6.4 Hz, 3H), 1.82 (brs, 1H), 3.90 (s, 3H) , 4.86 (q, J=6.4 Hz, 1H) , 6.83-
6.87 (m, 1H), 6.99-7.04 (m, 2H). [0882]
Synthesis of 4-[(IS)-azidoethyl]-1-fluoro-2-methoxybenzene
1,8-diazabicyclo[5.4.0]undec-7-ene (1 mL) was
added dropwise to a solution of (IR)-(4-fluoro-3-
methoxyphenyl)ethanol (910 mg) and diphenylphosphoryl azide (1.44 mL) in toluene (12.5 mL) in a nitrogen atmosphere while cooling with ice. The reaction


solution was stirred at that temperature for 2 hours, and further stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The 5 resulting organic layer was dried over anhydrous
magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 789 mg of the title
compound.
^-NMR (CDC13) 5 (ppm) : 1.52 (d, J=6.8 Hz, 3H) , 3.92 (s, 3H), 4.59 (q, J=6.8 Hz, 1H), 6.82-6.86 (m, 1H), 6.93 (dd, J=8.0, 2.4 Hz, 1H), 7.60 (dd, J=11.2, S.OHz, 1H). [0883]
Synthesis of (IS)-(4-fluoro-3-methoxyphenyl)ethylamine 10% palladium-carbon (water content: 50%, 80 mg) was added to a solution of 4-((IS)-azido-ethyl)-1-fluoro-2-methoxybenzene (789 mg) in methanol (8 mL), and the reaction solution was stirred in a hydrogen
atmosphere at room temperature for 1 hour. The
reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure to obtain 352 mg of the title compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm): 1.37 (d, J=6.4 Hz, 3H) , 3.91 (s, 3H), 4.11 (q, J=6.4 Hz, 1H), 6.83-6.87 (m, 1H), 6.99-7.04 (m, 2H) . [0884]


Synthesis of 1-[(IS)-(4-fluoro-3-methoxyphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
IPEA (0.5 mL), EDC (192 mg) and HOBT (135 mg) 5 were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and (IS)-(4-fluoro-3-methoxy phenyl)ethylamine (114 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1
hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid ((IS)-(4-fluoro-3-
methoxyphenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2~(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid ((IS)-(4-fluoro-3-methoxyphenyl)ethyl)amide in DMF (5 mL), and the
reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried


over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate 5 system -> ethyl acetate-methanol system) to obtain 60 mg of the title compound. The physical properties of the compound are as follows.
^•H-NMR (CDC13) 8 (ppm) : 1.54 (d, J=6.8 Hz, 3H) , 1.60-1.73 (m, 1H), 1.80-1.86 (m, 1H), 2.32 (s, 3H), 2.75-
2.84 (m, 2H), 2.92-2.98 (m, 1H), 3.21-3.27 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H) , 6.20 (q, J=6.8 Hz, 1H), 6.85-6.89 (m, 1H), 6.19-6.95 (m, 2H), 7.01-7.06 (m, 3H), 7.24-7.27 (m, 1H), 7.78 (s, 1H), 7.88 (s, 1H). [0885]
Example 952
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-1-((IS)-p-tolylethyl)piperidin-2-one [0886] [Formula 276]
(Figure Remove)




80 mg of the title compound was obtained from (E)-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-20 yl)benzylidene)valeric acid trifluoroacetate (100 mg) and (IS)- (p-tolyl)ethylamine (60 mg) in the same manner as in Example 418. The physical properties of the


compound are as follows.
XH-NMR (CDC13) 5 (ppm): 1.55 (d, J=6.8 Hz, 3H), 1.66-1.73 (m, 1H) , 1.75-1.83 (m, 1H) , 2.30 (d, J=0.8 Hz, 3H), 2.34 (s, 3H), 2.71-2.83 (m, 2H), 2.92-2.97 (m, 5 1H), 3.19-3.25 (m, 1H), 3.85 (s, 3H), 6.21 (q, J=6.8 Hz, 1H), 6.93 (t, J=1.2 Hz, 1H), 7.03 (s, 1H), 7.04 (dd, J=6.4, 1.2 Hz, 1H) 7.14 (d, J=8.0 Hz, 2H), 7.21-7.7.2.4 (m, 3H), 7.73 (d, J=0.8 Hz, 1H) , 7.88 (s, 1H) . [0887] 10 Examples 953 and 954
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
l-yl)benzylidene]-l-[(IS) and (IR)-m-
tolylethyl]piperidin-2-one
[0888]
[Formula 277]
(Figure Remove)




67 mg of the title compound as a racemate was 15 obtained from (E)-chloro-2-(3-methoxy-4-(4-methyl-lH-iraidazol-1-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and 1-(m-tolyl)ethylamine (90.3 mg) in the same manner as in Example 418. The compound (16 mg) was fractionated using CHIRALPAK™ AD-H manufactured by 20 Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol =7:3) to obtain the title optically active substance with a retention time of 108


minutes (2.8 mg; >99% ee) and the title optically active substance with a retention time of 112 minutes (1.8 mg; >83% ee). The physical properties of the compounds are as follows.
XH-NMR (CDC13) 5 (ppm): 1.56 (d, J=6.8 Hz, 3H), 1.57-1.74 (m, 1H), 1.76-1.84 (m, 1H), 2.31 (s, 3H), 2.36 (s, 3H), 2.75-2.82 (m, 2H), 2.93-2.99(m,1H),3.21-3.27(m,1H),3.86(s,3H),6.22 (q, J=6.8 Hz, 1H), 6.94 (s, 1H), 7.05 (s, 1H), 7.05-7.10 (m, 2H), 7.14-7.16 (m,
2H), 7.22-7.27 (m, 2H) , 7.76 (s, 1H), 7.90 (s, 1H) . [0889]
Example 955
Synthesis of (E)-1-[(IS)-(3-fluoro-4-methoxyphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one [0890] [Formula 278]
(Figure Remove)
67 mg of the title compound was obtained from (E)-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (150 m) and (IS)-(3-fluoro-4-methoxyphenyl)ethylamine (114 mg) 20 in the same manner as in Example 418. The physical properties of the compound are as follows. XH-NMR (CDC13) 6 (ppm): 1.53 (d, J=7.2 Hz, 3H), 1.57-


1.84 (m, 2H), 2.31 (d, J=l.2 Hz, 3H), 2.71-2.85 (m, 2H), 2.92-2.98 (m, 1H), 3.19-3.26 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 6.17 (q, J=7.2 Hz, 1H), 6.91-6.94 (m, 2H), 7.03-7.08 (m, 3H), 7.23-7.27 (m, 2H), 7.74 (d, 5 J=1.2 Hz, 1H), 7.88 (s, 1H). [0891]
Example 956
Synthesis of (E)-1-[ (IS)-(2-fluoro-6-methoxyphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-10 imidazol-l-yl)benzylidene]piperidin-2-one [0892] [Formula 279]
(Figure Remove)




70 mg of the title compound was obtained from (E)-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and (IS)-(2-fluoro-6-methoxyphenyl)ethylamine (114 mg)
properties of the"compound are as follows. Hl-NMR (CDC13) 8 (ppm) : 1.60 (dd, J=7.2, 2.4 Hz, 3H) , 1.81-1.88 (m, 2H), 2.31 (d, J=0.8 Hz, 3H), 2.69-2.83 (m, 2H), 3.32-3.38 (m, 1H), 3.47-3.54 (m, 1H), 3.84 (s, 20 3H), 3.87 (s, 3H), 6.23 (q, J=7.2 Hz, 1H), 6.68 (t, J=8.0 Hz, 2H), 6.93 (t, J=1.2 Hz, 1H), 7.01-7.03 (m, 2H), 7.17-7.24 (m, 2H), 7.73 (d, J=0.8 Hz, 1H), 7.82( s, 1H).

w
[0893]
Example 957
(E)-2-fluoro-5-[(IS)-{3-[methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]-2-oxopiperidin-l-5 yl}ethyl)benzonitrile
[0894]
[Formula 280] (Figure Remove)

38 mg of the title compound was obtained from (E)-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (250 mg) and 5-((IS)-aminoethyl)-2-fluorobenzonitrile (220 mg)
in the same manner as in Example 418. The physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm) : 1.59 (d, J=6.8 Hz, 3H) , 1.60-1.88 (m, 2H) , 2.34 (s, 3H), 2.71-2.78 (m, 1H), 2.85-2.95 (m, 2H), 3.28-3.34 (m, 1H), 3.87 (s, 3H), 6.20 (q,
J=6.8 Hz, 1H), 6.94 (s, 1H), 7.04-7.06 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 7.25-7.27 (m, 1H), 7.58-7.62 (m, 2H) , 7.82 (s, 1H) , 7.88 (s, 1H) . [0895] Example 958 and Example 959
Synthesis of (E)-1-[(1S) and (1R)-(5-fluorothiophen-2-yl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-l-piperidin-2-one [0896]
(Figure Remove)






Synthesis of 2-(1-azidoethyl)-5-fluorothiophene
Methyl magnesium bromide (0.84 M, tetrahydrofuran solution, 20 mL) was added to a solution of 5-fluorothiophene-2-carboxyaldehyde (977 5 mg) in THF (10 mL) while cooling with ice, and the reaction solution was stirred for 30 minutes. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer
was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1,8-diazabicyclo[5.4.0]undec-7-ene (1.1 mL) was added to a solution of the resulting crude oil (952 mg) and diphenylphosphoryl azide (2.06 g) in toluene (5 mL)
while cooling with ice. The reaction solution was stirred for 2 hours, and further stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture and the organic layer was partitioned. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 518 mg


of the title compound. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 1.56 (d, J=6.8 Hz,3H), 4.63-4.69 (m, 1H), 6.34-6.35 (m, 1H), 6.62-6.64 (m, 1H). 5 [0897]
Synthesis of 1-(5-fluorothiophen-2-yl)ethylamine
Triphenylphosphine (873 mg) was added to a solution of 2-(1-azidoethyl)-5-fluorothiophene (518 mg) in THF (10 mL) , and the reaction solution was stirred
at room temperature for I hour. Water (2 mL) was added to the reaction mixture, and the mixture was heated to reflux for 3 hours. After allowing the reaction mixture to be cooled, a 5 N aqueous solution of hydrochloric acid and ethyl acetate were added thereto
to separate the aqueous layer. A 5 N aqueous solution of sodium hydroxide was added to the aqueous layer to make the layer basic, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure to obtain 324 mg of the title compound. The physical properties of the compound are as follows. Hl-NMR (CDC13) 8 (ppm): 1.44 (d, J=6.8 Hz, 3H) , 4.20-4.25 (m, 1H), 6.27 (dd, J=1.6, 4 Hz, 1H), 6.48 (t,
J=3.6 Hz, 1H). [0898]
Synthesis of (E)-1-[(IS)-(5-fluorothiophen-2-yl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-)benzylidene]-1-piperidin-


2-one and (E)-1-[(IR)-(5-fluorothiophen-2-yl)ethyl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]-1-piperidin-2-one
72 mg of a racemate was obtained from (E)-5-5 chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetate (112 mg) and 1-(5-fluorothiophen-2-yl)ethylamine (67 mg) in the same manner as in Example 418.
The racemate (58 mg) was fractionated using 10 CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol = 8:2; flow rate: 5 mL/min) to obtain the title optically active substance with a retention time of 43 minutes (19 mg; >99% ee) and the title 15 optically active substance with a retention time of 49 minutes (16 mg; >99% ee).
The physical properties of the optically active substance with a retention time of 43 minutes (Example 958) are as follows.
20 ^-NMR (CDC13) 5 :1.55 (d, J=7.2 Hz, 3H) , 1.73-1.91 (m, 2H), 2.30 (s, 3H), 2.69-2.77 (m, 1H), 2.83-2.90 (m, 1H), 3.16-3.22 (m, 1H), 3.26-3.32 (m, 1H), 3.86 (s, 3H), 6.16-6.23 (m, 1H), 6.30 (dd, J=1.6, 4.0 Hz, 1H), 6.57-6.59 (m, 1H), 6.93 (t, J=1.2 Hz, 1H), 7.03-7.05 25 (m, 2H), 7.25 (dd, J=1.6, 6.8 Hz, 1H) , 7.72 (d, J=1.2 Hz, 1H), 7.86 (s, 1H).
The physical properties of the optically active substance with a retention time of 49 minutes


(Example 959) are as follows.
XH-NMR (CDC13) 8 :1.55 (d, J=7.2 Hz, 3H), 1.73-1.91 (m, 2H) , 2.30 (s, 3H), 2.69-2.77 (m, 1H), 2.83-2.90 (m, 1H) , 3.16-3.22 (m, 1H), 3.26-3.32 (m, 1H), 3.86 (s, 5 3H), 6.16-6.23 (m, 1H), 6.30 (dd, J=1.6, 4.0 Hz, 1H), 6.57-6.59 (m, 1H), 6.93 (t, J=1.2 Hz, 1H), 7.03-7.05 (m, 2H), 7.25 (dd, J=1.6, 6.8 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H), 7.86 (s, 1H). [0899] 10 Example 960 and Example 961
Synthesis of (E)-1-[(1S) and (1R)-(5-chlorothiophen-2-yl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-y_l_)_benzylidene] -1-piperidin-2-one [0900] [Formula 282]
(Figure Remove)

65 mg of a racemate was obtained from (E}-5- chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetate (112 mg) and 1-(5-chlorothiophen-2-yl)ethylamine (48 mg) in the same manner as in Example 418.
The racemate (11 mg) was fractionated using 20 CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol = 8:2; flow rate: 5 mL/min) to obtain


the title optically active substance with a retention time of 54 minutes (4.0 mg; >99% ee) and the title optically active substance with a retention time of 60 minutes (4.6 mg; >99% ee).
The physical properties of the optically
active substance with a retention time of 54 minutes (Example 960) are as follows.
XH-NMR (CDC13) 6 :1.57 (d, J=7.6 Hz, 3H), 1.72-1.80 (m, 1H) , 1.84-1.92 (m, 1H), 2.30 (s, 3H) , 2.69-2.77 (m,
1H) , 2.84-2.91 (m, 1H), 3.16-3.22 (m, 1H), 3.27-3.33 (m, 1H), 3.86 (s, 3H), 6.25 (q, J=7.2 Hz, 1H), 6.75-6.78 (m, 2H), 6.94 (s, 1H), 7.04-7.06 (m, 2H), 7.26 (d, J=8.8 Hz, 1H), 7.72 (d, J=l.6 Hz, 1H), 7.88 (s, 1H). The physical properties of the optically
active substance with a retention time of 60 minutes (Example 961) are as follows.
^•H-NMR (CDC13) 5: 1.57 (d, J=7. 6 Hz, 3H) , 1.72-1.80 (m, 1H), 1.84-1.92 (m, 1H), 2.30 (s, 3H) , 2.69-2.77 (m, 1H), 2.84-2.91 (m, 1H), 3.16-3.22 (m, 1H), 3.27-3.33
(m, 1H), 3.86 (s, 3H), 6.25 (q, J=7.2 Hz, 1H), 6.75-
6.78 (m, 2H), 6.94 (s, 1H), 7.04-7.06 (m, 2H), 7.26 (d,
J=8.8 Hz, 1H), 7.72 (d, J=l.6 Hz, 1H), 7.88 (s, 1H) .
[0901]
Example 962 and Example 963
Synthesis of (E)-1-[(1S) and (1R)-(4-bromothiophen-2-yl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-l-piperidin-2-one [0902]

.Formula 283]
(Figure Remove)



85 mg of a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yljbenzylidene)valeric acid trifluoroacetate (112 mg) and 1-(4-bromothiophen-2-yl)ethylamine (62 mg) in the 5 same manner as in Example 418.
The racemate (10 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol; flow rate: 5 mL/min) to obtain the title optically
active substance with a retention time of 44 minutes (3.3 mg; >99% ee) and the title optically active substance with a retention time of 53 minutes (2.6 mg; >99% ee) .
The physical properties of the optically
active substance with a retention time of 44 minutes (Example 962) are as follows.
XH-NMR (CDC13) 8 :1.60 (d, J=7.2 Hz, 3H), 1.72-1.92 (m, 2H), 2.30 (s, 3H), 2.70-2.78 (m, 1H), 2.85-2.92 (m, 1H) , 3.14-3.20 (m, 1H), 3.28-3.35 (m, 1H) , 3.86 (s,
3H), 6.33 (q, J=7.2 Hz, 1H), 6.90 (d, J=1.2 Hz, 1H), 6.95 (s, 1H), 7.04-7.06 (m, 2H), 7.16 (d, J=1.2 Hz,

1H), 7.26 (d, J=8 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H), 7.89
(s, 1H).
The physical properties of the optically
active substance with a retention time of 53 minutes (Example 963) are as follows.
XH-NMR (CDC13) 5: 1.60 (d, J=7.2 Hz, 3H) , 1.72-1.92 (m,
2H), 2.30 (s, 3H), 2.70-2.78 (m, 1H) , 2.85-2.92 (m,
1H), 3.14-3.20 (m, 1H), 3.28-3.35 (m, 1H), 3.86 (s,
3H), 6.33 (q, J=7.2 Hz, 1H) , 6.90 (d, J=l. 2 Hz, 1H) , 6.95 (s, 1H), 7.04-7.06 (m, 2H), 7.16 (d, J=l.2 Hz,
1H), 7.26 (d, J=8 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H) , 7.89
(s, 1H).
[0903]
Example 964 and Example 965 15 Synthesis of (E)-1-[(1R) and (IS)-(lH-indol-3-
yl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
[0904]
[Formula 284]
(Figure Remove)




Synthesis of 1-(lH-indol-3-yl)ethanone oxime
Triethylamine (3.93 mL) was added to a
solution of 3-acetylindole (500 mg) and hydroxylamine hydrochloride (981 mg) in ethanol (20 mL), and the reaction solution was heated to reflux at 90°C for 14


hours. The reaction solution was allowed to be cooled to room temperature, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the resulting residue and the organic layer 5 was partitioned. The resulting organic layer was
washed with brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 0.53 g of
the title compound. The physical properties of the compound are as follows.
^-NMR (DMSO-de) 8 (ppm) : 2.17 (s, 3H) , 7.05 (dd, J=7.2, 14.4 Hz, 1H), 7.13 (dd, J=7.2, 14.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 8.13 (d, J=8.0 Hz, 1H),
10.49 (s, 1H) , 11.29 (s, 1H) . [0905] Synthesis of 1-(lH-indol-3-yl)ethylamine
10% palladium-carbon (water content: 50%, 12.2 mg) was added to a solution of 1-(lH-indol-3-
yl)ethanone oxime (0.20 g) obtained as above and acetic acid (0.7 mL) in ethanol (7 mL) at room temperature. The reaction mixture was stirred in a hydrogen stream at room temperature for 10 hours, and then filtered on a celite. The filtrate was concentrated under reduced
pressure. The residue was extracted with chloroform. The organic layer was washed sequentially with a 1 N aqueous solution of sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated


under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform-methanol system) to obtain 0.137 g of the title compound.
^-NMR (CDC13) 8 (ppm) : 1.55 (d, J=6.4 Hz, 3H) , 1.68 (s, 2H), 4.48 (q, J=6.4 Hz, 1H), 7.11-7.23 (m, 3H), 7.37 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 8.02 (s, 1H) . [0906]
Synthesis of (E)-1-[(1R) and (IS)-1-(lH-indol-3-yl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
EDC (384 mg), HOBT (271 mg) and IPEA (0.582 mL) were sequentially added to a solution of (E)-5-
chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 1-(lH-indol-3-yl)ethylamine (130 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 12 hours. After confirming that the
raw materials disappeared, ethyl acetate and water were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was sequentially washed with a saturated aqueous solution of ammonium chloride and brine, and then dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system) to obtain (E)-5-


chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (1-(lH-indol-3-yl)ethyl)amide (332 mg). Sodium hydride (containing mineral oil at 40%, 19.3 mg) was added to a solution of 5 the resulting (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (1-(lH-indol-3-yl)ethyl)amide (92 mg) in THF (3 mL) at 0°C, and the reaction solution was stirred at room temperature for 90 minutes. The reaction solution was cooled to 0°C,
water and ethyl acetate were added to the reaction
solution, and the organic layer was partitioned. The organic layer was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system) to obtain (E)-1-[1-(1H-indol-3-yl)ethyl]-3-(3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene)piperidin-2-one as a racemate (37.3 mg). The compound (37 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a
retention time of 10 minutes (15 mg; >99% ee) and the title optically active substance with a retention time of 14 minutes (14.2 mg; >99% ee).
The physical properties of the optically


active substance with a retention time of 10 minutes
(Example 964) are as follows.
XH-NMR (CDC13) 6 (ppm) : 1.58-1.64 (m, 1H) , 1.63 (d,
J=6.8 Hz, 3H), 1.69-1.74 (m, 1H), 2.31 (s, 3H), 2.71-5 2.78 (m, 2H}, 2.92-2.99 (m, 1H), 3.18-3.25 (m, 1H),
3.86 (s, 3H), 6.51 (q, J=6.8 Hz, 1H), 6.94 (s, 1H),
7.06-7.26 (m, 6H) , 7.38 (d, J=8.0 Hz, 1H), 7.63 (d,
J=8.0 Hz, 1H) , 7.74 (s, 1H) , 7.96 (s, 1H), 8.39 (s,
1H) .
The physical properties of the optically
active substance with a retention time of 14 minutes
(Example 965) are as follows.
1H-NMR (CDC13) 5 (ppm): 1.58-1.64 (m, 1H), 1.63 (d,
J=6.8 Hz, 3H), 1.69-1.74 (m, 1H) , 2.31 (s, 3H) , 2.71- 2.78 (m, 2H), 2.92-2.99 (m, 1H), 3.18-3.25 (m, 1H),
3.86 (s, 3H), 6.51 (q, J=6.8 Hz, 1H), 6.94 (s, 1H),
7.06-7.26 (m, 6H), 7.38 (d, J=8.0 Hz, 1H), 7.63 (d,
J=8.0 Hz, 1H) , 7.74 (s, 1H), 7.96 (s, 1H) , 8.37 (s,
1H) . 20 [0907]
Example 966
Synthesis of (E)-1-(2-chloroquinolin-4-ylmethyl)-3-[3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]piperidin-2-one



(Figure Remove)
28 mg of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (263 mg) and (2-chloroquinolin-4-yl)methylamine (200 mg) in the 5 same manner as in Example 418. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.90-2.00 (m, 2H) , 2.30 (s, 3H) , 2.85-2.94 (m, 2H), 3.38-3.45 (m, 2H), 3.87 (s, 3H), 5.20 (s, 2H), 6.92-6.95 (m, 1H) , 7.03-7.08 (m, 2H),
7.21-7.29 (m, 2H), 7.58-7.65 (m, 1H), 7.70-7.79 (m, 2H), 7.91 (s, 1H), 8.04-8.09 (m, 2H) . [0909]
Example 967 Synthesis of (E)-1-(2-morpholin-4-yl-quinolin-4-
ylmethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0910] [Formula 286]
(Figure Remove)


100 mq of the title compound was obtained from ethyl (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valerate (230 mg) and (2-morpholin-4-yl-quinolin-4-yl)methylamine (230 mg) in 5 the same manner as in Example 418. The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 1.82-1.90 (m, 2H), 2.34 (s, 3H), 2.81-2.88 (m, 2H), 3.30-3.38 (m, 2H), 3.67-3.75 (m, 4H), 3.80-3.90 (m, 4H), 3.88 (s, 3H), 5.14 (s, 2H),
6.88 (s, 1H), 6.96 (s, 1H), 7.02-7.10 (m, 2H), 7.24-7.34 (m, 2H), 7.56-7.62 (m, 1H), 7.74-7.84 (m, 1H), 7.83 (s, 1H), 7.86-7.92 (m, 1H), 7.93 (s, 1H). [0911] Example 968
Synthesis of (E)-1-(6-morpholin-4-yl-quinolin-2-ylmethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0912] [Formula 287]
(Figure Remove)
14 mg of the title compound was obtained from ethyl (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-20 imidazol-1-yl)benzylidene)valerate (300 mg) and (6-morpholin-4-yl-quinolin-2-yl)methylamine (200 mg) in


the same manner as in Example 418. The physical properties of the compound are as follows. ^-NMR (CDC13) 6 (ppm) : 1.83-1.93 (m, 2H) , 2.36 (s, 3H) , 2.80-2.90 (m, 2H) , 3.25-3.33 (m, 4H), 3.50-3.57 (m, 5 2H), 3.87 (s, 3H), 3.85-3.97 (m, 4H), 5.00 (s, 2H), 6.96 (s, 1H), 7.02-7.10 (m, 3H), 7.24-7.30 (m, 1H), 7.43-7.52 (m, 2H) , 7.84-7.92 (m, 2H), 7.92-8.04 (m, 2H) . [0913] 10 Example 969
Synthesis of (E)-1-(6-morpholin-4-yl-naphthalen-2-ylmethyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0914] [Formula 288]
(Figure Remove)
173 mg of the title compound was obtained 15 from ethyl (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valerate (350 mg) and (6-morpholin-4~yl-naphthalen-2-yl)methylamine (259 mg) in the same manner as in Example 418. The physical properties of the compound are as follows.
^-H-NMR (CDC13) 5 (ppm): 1.78-1.88 (m, 2H) , 2.32 (s, 3H) , 2.78-2.85 (m, 2H) , 3.22-3.30 (m, 4H) , 3.35-3.42 (m, 2H), 3.86 (s, 3H), 3.87-3.95 (m, 4H), 4.85 (s, 2H),


6.93 (s, 1H), 7.02-7.07 (m, 2H) , 7.10 (d, J=2.0 Hz, 1H), 7.22-7.28 (m, 2H), 7.39 (dd, J=2.0, 8.4 Hz, 1H), 7.62 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.76 (s, 1H), 7.90 (s, 1H). 5 [0915]
Example 970
Synthesis of (E)-1-[(IS)-(2-fluorophenyl)ethyl]-3- [3-
methoxy-4-(4-methyl-IH-imidazol-1-
yl)benzylidene]piperidin-2-one
(Figure Remove)
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid ((lS)-(2-fluorophenyl)ethyl)amide
IPEA (300 jiL) , EDC (165 mg) and HOBT (116 mg) were sequentially added to a solution of (E)-5-chloro-
2-(3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetate (193 mg) and (S)-1-(2-fluorophenyl)ethylamine (60.0 mg) in DMF (3.0 mL) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. After
confirming that the raw materials disappeared, water and ethyl acetate were added to the residue and the organic layer was partitioned. The organic layer was


washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl 5 acetate system -> ethyl acetate-methanol system) to obtain 258 mg of the title compound. The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 1.60 (d, J=7.2 Hz, 3H) , 1.95-2.02 (m, 2H), 2.32 (s, 3H) , 2.69-2.73 (m, 2H), 3.57 (t,
J=6.4 Hz, 2H), 3.86 (s, 3H) , 5.35 (quint, J=7.2Hz, 1H), 6.43 (d, J=7.2 Hz, 1H), 6.93-6.97 (m, 3H), 7.05-7.16 (m, 2H), 7.16 (s, 1H), 7.23-7.28 (m, 2H), 7.34 (t, J=7.2 Hz, 1H), 7.78 (s, 1H). [0917]
Synthesis of (E)-1-[(IS)-(2-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
Sodium hydride (containing mineral oil at 40%, 34.5 mg) was added to a solution of (E)-5-chloro-
2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid ((IS)-(2-fluorophenyl)ethyl)amide (258 mg) in DMF (3.0 mL) at 0°C, and the reaction solution was stirred at room temperature for 20 minutes. After confirming that the
raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate


and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 180 mg of the title 5 compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.60 (d, J=7.2 Hz, 3H) , 1.77-1.82 (m, 2H), 2.26 (s, 3H), 2.68-2.86 (m, 2H) , 2.96-3.02 (m, 1H), 3.29 (td, J=5.6, 12 Hz, 1H), 3.84 (s,
3H), 6.23 (q, J=7.2 Hz, 1H), 6.92 (t, J=1.2 Hz, 1H), 7.01-7.07 (m, 3H), 7.14 (dt, J=1.2, 7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.24-7.31 (m, 1H), 7.38 (dt, J=1.2, 7.6 Hz, 1H), 7.72 (d, J=l.2 Hz, 1H), 7.86 (brs, 1H). [0918]
Example 971 and Example 972
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-1-[(1R) and (IS)-7-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-l-yl]piperidin-2-one [0919] [Formula 290]
(Figure Remove)




Synthesis of 7-morpholin-4-yl-3,4-dihydro-2H- naphthalen-1-one

A solution of 7-bromo-3,4-dihydro-2H-naphthalen-1-one (600 mg), morpholine (1.16 g), tripotassium phosphate (850 mg),
tris(dibenzylideneacetone)dipalladium (0) (24.4 mg) and 5 2-(di-tert-butylphosphino)biphenyl (15.9 mg) in toluene (5.0 mL) was stirred in a nitrogen atmosphere at 100°C overnight. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine,
and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 360 mg of the title compound. The physical
properties of the compound are as follows.
^-H-NMR (CDC13) 8 (ppm) : 2.11 (quint, J=6.0 Hz, 2H) , 2.63 (t, J=6.0 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 3.16-3.18 (m, 4H), 3.85-3.87 (m, 4H), 7.07 (dd, J=2.8, 8.4 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.53 (d, J=2.8 Hz, 1H).
[0920]
Synthesis of 7-morpholin-4-yl-3,4-dihydro-2H-naphthalen-1-one oxime
A solution of 7-morpholin-4-yl-3,4-dihydro-2H-naphthalen-l-one (360 mg), hydroxylammonium chloride
(163 mg) and sodium acetate (384 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour and 50 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The

resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 384 mg of the title compound as a crude product. The physical properties 5 of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 1.80-1.89 (m, 2H), 2.69 (t, J=6.8 Hz, 2H), 2.78 (t, J=6.8 Hz, 2H) , 3.14-3.16 (m, 4H), 3.85-3.87 (m, 4H), 6.90 (dd, J=2.0,8.4 Hz,1H), 7.06 (d, J=8.4 Hz, 1H) , 7.43 (s, 1H) .
[0921]
Synthesis of 7-morpholin-4-yl-l,2,3,4-tetrahydro-naphthalen-1-ylamine
A solution of crude 7-morpholin-4-yl-3,4-dihydro-2H-naphthalen-l-one oxime (384 mg) and 10%
palladium-carbon (water content: 48%, 350 mg) in
ethanol (10 mL) was stirred in a hydrogen atmosphere (0.4 Mpa) at room temperature for 8 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The
resulting residue was purified by silica gel
chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 110 mg of the title compound. The physical properties of the compound are
as follows.
^-NMR (CDC13) 8 (ppm): 1.62-1.79 (m, 2H) , 1.86-1.95 (m, 1H), 1.98-2.04 (m, 1H), 2.62-2.77 (m, 2H), 3.12-3.14 (m, 4H), 3.84-3.86 (m, 4H) , 3.93 (t, J=5.6 Hz, 1H),

6.75 (dd, J=2.8, 8.4 Hz, 1H), 6.98-7.00 (m, 2H) . [0922]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)-benzylidene]valeric acid (7-morpholin-4-5 yl-1,2,3,4-tetrahydronaphthalen-l-yl)amide
IPEA (330 nL), EDC (181 mg) and HOBT (128 mg) were sequentially added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (276 mg)
and 7-morpholin-4-yl-l,2,3,4-tetrahydronaphthalen-l-ylamine (110 mg) in DMF (3.0 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. After confirming that the raw materials disappeared, water and ethyl acetate were
added to the residue and the organic layer was
partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography
(elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 213 mg of the title compound. The physical properties of the compound are as follows. XH-NMR (CDC13) 6 (ppm): 1.80-1.96 (m, 3H), 2.00-2.11 (m,
3H), 2.30 (s, 3H), 2.68-2.80 (m, 4H), 3.10-3.12 (m, 4H), 3.57 (t, J=6.4 Hz, 2H), 3.83-3.86 (m, 4H), 3.86 (s, 3H), 5.24-5.29 (m, 1H), 6.19 (d, J=8.8 Hz, 1H), 6.81-6.84 (m, 2H), 6.92-6.95 (m, 3H), 7.04 (d, J=8.4


Hz, 1H), 7.11 (s, 1H), 7.24 (d, J=8.8Hz, 1H), 7.72 (s, 1H) . [0923J
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-5 1-yl)benzylidene]-1-[(1R) and (IS)-7-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-l-yl]piperidin-2-one
Sodium hydride (containing mineral oil at 40%, 37.8 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)-
benzylidene) valeric acid (7-morpholin-4-yl-l, 2, 3, 4-tetrahydronaphthalen-l-yl) amide (213 mg) in DMF (5.0 mL) at 0°C, and the reaction solution was stirred for 30 minutes. After confirming that the raw materials disappeared, water and ethyl acetate were added to the
reaction solution and the organic layer was
partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:
heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 195 mg of (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)-1-(7-morpholin-4-yl-1, 2, 3, 4-t.etrahydronaphthalen-l-yl) piperidin-2-one as a racemate.
Next, the compound (8.00 mg) was fractionated
using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a


retention time of 1.6 minutes (Example 971, 3.60 mg; >99% ee) and the title optically active substance with a retention time of 12 minutes (Example 972, 1.40 mg; >99% ee). Properties data of the optically active 5 substances are as follows.
XH-NMR (CDC13) 8 (ppm): 1.68-1.90 (m, 3H), 1.90-2.24 (m, 2H) , 2.07-2.14 (m, 1H), 2.31 (s, 3H), 2.68-2.74 (m, 2H), 2.74-2.85 (m, 1H), 2.85-2.98 (m, 1H) , 3.04-3.08 (m, 4H), 3.05-3.12 (m, 1H), 3.17-3.25 (m, 1H), 3.81-
3.84 (m, 4H), 3.87 (s, 3H) , 6.07-6.11 (m, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.77 (dd, J=2.4, 8.4 Hz, 1H), 6.94 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.08-7.10 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.74 (brs, 1H), 7.91 (brs, 1H). [0924]
Example 973 and Example 974
Synthesis of 5,6-difluoro-1-indanone
Synthesis of (E)-1-[(1R) and (IS)-6-fluoro-5-morpholin-4-ylindan-l-yl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one [0925] [Formula 291]
(Figure Remove)


Oxalyl chloride (1.12 mL) and DMF (78.2 mg) were added to a solution of 3, 4-difluorohydrocinnamic acid (2.00 g) in dichloromethane (3.0 mL) at 0°C, and the reaction solution was stirred at room temperature 5 overnight. After confirming that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. Next, a solution of the resulting residue in dichloromethane (10 mL) was added to a solution of aluminum chloride (2.13 g) in
dichloromethane (20 mL) at -30°C. The reaction solution was stirred at room temperature for 1.5 hours. After confirming that the raw materials disappeared, the reaction solution was poured into ice water. The solution was extracted with ethyl acetate. The organic
layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 535 mg of the title
compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 2.72-2.75 (m, 2H) , 3.11-3.14 (m, 2H), 7.27 (t, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H). [0926]
Synthesis of 6-fluoro-5-morpholin-4-ylindan-l-one
A solution of 5,6-difluoro-1-indanone (535 mg) and morpholine (554 mg) in l-methyl-2-pyrrolidinone (6.0 mL) was stirred at 100°C for 7 hours. After


confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over 5 anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 635 mg of the title compound. The physical properties of the compound are
as follows.
XH-NMR (CDC13) 8 (ppm): 2.67-2.69 (m, 2H), 3.03-3.06 (m, 2H), 3.20-3.22 (m, 4H), 3.87-3.89 (m, 4H), 6.89 (d, J=7.2 Hz, 1H) , 7.35 (d, J=12 Hz, 1H). [0927]
Synthesis of 6-fluoro-5-morpholin-4-ylindan-l-ylamine
A solution of 6-fluoro-5-morpholin-4-ylindan-1-one (200 mg), hydroxylammonium chloride (102 mg) and sodium acetate (241 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour. After confirming that the raw
materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure
to obtain 218 mg of 6-fluoro-5-morpholin-4-ylindan-l-one oxime. Next, 10% palladium-carbon (water content: 48%, 200 mg) was added to a solution of the resulting 6-fluoro-5-morpholin-4-ylindan-l-one oxime (218 mg) in


ethanol (5.0 mL), and the reaction solution was stirred in a hydrogen atmosphere (0.4 MPa) at room temperature for 9 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced 5 pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-methanol system) to obtain 56.0 mg of the title compound. The physical properties of the compound are
as follows.
XH-NMR (CDC13) 8 (ppm): 1.60-1.72 (m, 1H), 2.50 (dtd, J=3.6, 7.2, 16 Hz, 1H), 2.74 (td, J=7.2, 16 Hz, 1H), 2.89 (ddd, J=3.6, 8.8,16 Hz, 1H), 3.03-3.05 (m, 4H), 3.85-3.88 (m, 4H) , 4.30 (t, J=7.2 Hz, 1H) , 6.79 (d,
J=7.6 Hz, 1H), 6.98 (d, J=12 Hz, 1H). [0928]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid (6-fluoro-5-morpholin-4-ylindan-l-yl)amide
IPEA (165 fiL) , EDC (90.9 mg) and HOBT (64.0
mg) were sequentially added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (138 mg) and 6-fluoro-5-morpholin-4-ylindan-l-ylamine (56.0 mg)
in DMF (3.0 mL), and the reaction solution was stirred at room temperature for 1 hour. After confirming that the raw materials disappeared, the solvent was concentrated under reduced pressure, and water and


ethyl acetate were added to the residue and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The 5 resulting residue was purified by silica gel
chromatography (elution solvent: heptane-ethyl acetate system, ethyl acetate-methanol system) to obtain 123 mg of the title compound. The physical properties of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 1.88-1.98 (m, 1H) , 2.00-2.08 (m, 2H), 2.30 (s, 3H), 2.62-2.78 (m, 3H), 2.82-3.20 (m, 2H), 3.05-3.08 (m, 4H), 3.61 (t, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.87-3.89 (m, 4H), 5.55 (q, J=7.6 Hz, 1H), 6.16-6.22 (m, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.94-6.99
(m, 3H) , 7.03 (d, J=12 Hz, 1H) , 7.19 (s, 1H), 7.25-7.27 (m, 1H) , 7.74 (s, 1H) . [0929]
Synthesis of (E)-1-[(1R) and (IS)-6-fluoro-5-morpholin-4-ylindan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
Sodium hydride (containing mineral oil at 40%, 19.0 mg} was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (6-fluoro-5-morpholin-4-
ylindan-1-yl)amide (123 mg) in DMF (3.0 mL) at 0°C, and the reaction solution was stirred for 15 minutes. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction


solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified 5 by silica gel chromatography (elution solvent: heptane-ethyl acetate system, ethyl acetate-methanol system) to obtain 85 mg of (E)-1-(6-fluoro-5-morpholin-4-ylindan-1-yl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)piperidin-2-one as a racemate. Next,
the compound (12.0 mg) was fractionated using CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol = 70:30) to obtain the title optically active substance with a retention time of 13 minutes
(Example 973, 4.60 mg; >99% ee) and the title optically active substance with a retention time of 15 minutes (Example 974, 4.70 mg; >99% ee). The physical properties of the optically active substances are as follows.
^-NMR (CDC13) 6 (ppm) : 1.76-2.04 (m, 3H) , 2.31 (s, 3H) , 2.46-2.58 (m, 1H), 2.74-3.00 (m, 5H), 3.04-3.10 (m, 4H), 3.08-3.18 (m, 1H), 3.87 (s, 3H), 3.87-3.89 (m, 4H), 6.43 (t, J=7.6 Hz, 1H), 6.82-6.88 (m, 2H), 6.95 (s, 1H), 7.06 (d, J=0.8 Hz, 1H), 7.26-7.27 (m, 2H),
7.74 (s, 1H), 7.89 (s, 1H). [0930]
Example 975 and Example 976 Synthesis of (£)-!-[(IS) and (1R)-1-(4-fluorophenyl)-2-


methylpropyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0931] [Formula 292]
(Figure Remove)





Synthesis of 1-(4-fluorophenyl)-2-methylpropan-l-one oxime
1.06 g of the title compound was obtained
from 1-(4-fluorophenyl)-2-methylpropan-l-one (1.00 g) in the same manner as in Example 971. The physical properties of the compound are as follows. XH-NMR (CDC13) 5 (ppm) : 1.11 (d, J=6.8 Hz, 3H) , 1.19 (d,
J=7.2 Hz, 3H), 2.78-2.85 (m, 1/2H), 3.55-3.62 (m,
1/2H), 7.02 (t, J=8.8 Hz, 1H), 7.09 (t, J=8.8 Hz, 1H), 7.28 (dd, J=5.6, 8.8 Hz, 1H), 7.34 (dd, J=5.6, 8.8 Hz, 1H) . [0932]
Synthesis of 1-(4-fluorophenyl)-2-methylpropylamine 364 mg of the title compound was obtained from 1-(4-fluorophenyl)-2-methylpropan-l-one oxime (500 mg) in the same manner as in Example 971. The physical properties of the compound are as follows.
'•H-NMR (CDC13) 8 (ppm): 0.75 (d, J=6.8 Hz, 3H) , 0.96 (d, J=6.4 Hz, 3H), 1.75-1.85 (m, 1H), 3.60 (d, J=7.6 Hz, 1H), 6.99 (t, J=8.8 Hz, 2H) , 7.24 (dd, J=5.6, 8.8 Hz,

2.H) . [0933]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]valeric acid (l-(4-5 fluorophenyl)-2-methylpropyl)amide
219 mg of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 1-(4-fluorophenyl)-2-methylpropylamine (168 mg) in
the same manner as in Example 418. The physical properties of the compound are as follows. ^•H-NMR (CDC13) 8 (ppm) : 0.94 (d, J=6.4 Hz, 3H) , 1.04 (d, J=6,0 Hz, 3H), 1.91-2.01 (m, 2H), 2.01-2.19 (m, 1H), 2.30 (s, 3H), 2.70-2.75 (m, 2H), 3.58 (s, 2H), 3.85 (s,
3H) , 4.81 (t, J=8.4 Hz, 1H) , 6.24 (d, J=8.4 Hz, 1H) , 6.92-6.96 (m, 3H), 7.03 (t, J=8.4 Hz, 2H), 7.18 (s, 1H), 7.23-7.28 (m, 3H), 7.71 (s, 1H). [0934] Synthesis of (E)-1-[(1R) and (IS)-1-(4-fluorophenyl)-2-
methylpropyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one
177 mg of (E)-1-(1-(4-fluorophenyl)-2-methylpropyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)piperidin-2-one as a racemate was
obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (l-(4-fluorophenyl)-2-methylpropyl)amide (219 mg) in the same manner as in Example 418. Next, the compound (10.0 mg)


was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 5.0 minutes (Example 5 975, 2.4 mg; >99% ee) and the title optically active substance with a retention time of 5.9 minutes (Example 976, 2.2 mg; >98% ee). The physical properties of the optically active substances are as follows. ^-NMR (CDC13) 8 (ppm) : 0.93 (d, J=6.4 Hz, 3H) , 1.05 (d,
J=6.0 Hz, 3H), 1.60-1.72 (m, 1H), 1.76-1.86 (m, 1H), 2.29 (s, 3H), 2.36-2.46 (m, 1H), 2.62-2.72 (m, 1H), 2.72-2.82 (m, 1H) , 3.00-3.08 (m, 1H), 3.24-3.32 (m, 1H), 3.84 (s, 3H), 5.68 (d, J=12 Hz, 1H), 6.91 (s, 1H), 7.00-7.04 (m, 4H), 7.21-7.28 (m, 1H), 7.37 (t, J=6.4
Hz, 2H), 7.69 (s, 1H), 7.84 (s, 1H). [0935]
Example 977 and Example 978
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl) benzylidene] -1- [ (IS) and (IR)-2-methyl-l-(4-
morpholin-4-ylphenyl)propyl]piperidin-2-one [0936] [Formula 293]
(Figure Remove)





Synthesis of 2-methyl-l-(4-morpholin-4-ylphenyl)propan
1-one
491 rng of the title compound was obtained from 1-(4-fluorophenyl)-2-methylpropan-l-one (500 mg) in the same manner as in Example 973. The physical 5 properties of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 1.20 (d, J=6.8 Hz, 6H) , 3.31 (t, J=4.8 Hz, 4H), 3.46-3.56 (m, 1H) , 3.86 (t, J=4.8 Hz, 4H), 6.88 (d, J=9.2 Hz, 2H), 7.92 (d, J=9.2 Hz, 2H). [0937]
Synthesis of 2-methyl-l-(4-morpholin-4-ylphenyl)propan-1-one oxime
424 mg of the title compound was obtained from 1-(4-fluorophenyl)-2-methylpropan-l-one (491 mg) in the same manner as in Example 971. The physical 15 properties of the compound are as follows.
^•H-NMR (CDC13) 5 (ppm): 1.12 (d, J=6.8 Hz, 3H) , 1.22 (d, J=6.8 Hz, 3H) , 2.80-2.87 (m, 1/2H), 3.17-3.22 (m, 4H) , 3.53-3.60 (m, 1/2H), 3.86 (t, J=4.8 Hz, 4H), 6.86 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.8 20 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H). [0938]
Synthesis of 2-methyl-l-(4-morpholin-4-ylpheriyl) propylamine
300 mg of the title compound was obtained 25 from 2-methyl-l-(4-morpholin-4-ylphenyl)propan-1-one oxime (424 mg) in the same manner as in Example 971. The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 0.75 (d, J-6.4 Hz, 3H), 0.97 (d,


J=6.8 Hz, 3H), 1.64 (brs, 2H), 1.77-1.86 (m, 1H), 3.14 (t, J=4.8 Hz, 4H), 3.53 (d, J=7.2 Hz, 1H), 3.85 (t, J=4.8 Hz, 4H), 6.86 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H). 5 [0939]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid (2-methyl-l-(4-morpholin-4-ylphenyl)propyl)amide
290 mg of the title compound was obtained
from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 2-methyl-l-(4-morpholin-4-ylphenyl)propylamine (235 mg) in the same manner as in Example 418. The physical properties of the compound are as follows.
XH-NMR (CDC13) 5 (ppm): 0.88 (d, J=6.4 Hz, 3H), 1.04 (d, J==6.8 Hz, 3H), 1.94-2.01 (m, 2H) , 2.06-2.14 (m, 1H) , 2.30 (s, 3H), 2.69-2.73 (m, 2H), 3.15 (t, J=4.8 Hz, 4H), 3.57 (dt, J=2.4, 6.0 Hz, 2H) , 3.85 (t, J=4.8 Hz, 4H), 3.85 (s, 3H), 4.78 (t, J-8.4 Hz ,1H), 6.26 (d, 20 J=8.4 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 6.92-6.95 (m,
3H), 7.14 (s, 1H), 7.19 (d, J=8.8 Hz, 2H), 7.23 (d, ' J=8.4 Hz, 1H), 7.70 (s, 1H). [0940]
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-25 l-yl)benzylidene]-l-[(IR) and (IS)-2-methyl-l-(4-morpholin-4-ylphenyl)propyl]piperidin-2-one
210 mg of (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)-1-(2-methyl-l-(4-morpholin-


4-ylphenyl)propyl)piperidin-2-one as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (2-methyl-l-(4-morpholin-4-ylpheriyl) propyl) amide (290 mg) in the same 5 manner as in Example 418. Next, the compound (100 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 11 minutes (Example
977, 50.0 mg; >99% ee) and the title optically active substance with a retention time of 26 minutes (Example 978, 46.0 mg; >99% ee). The physical properties of the optically active substances are as follows. ^-NMR (CDC13) 5 (ppm) : 0.93 (d, J=6.4 Hz, 3H) , 1.04 (d,
J=6.8 Hz, 3H), 1.56-1.72 (m, 1H), 1.74-1.84 (m, 1H) , 2.29 (s, 3H), 2.36-2.45 (m, 1H), 2.60-2.70 (m, 1H) , 2.72-2.80 (m, 1H), 3.06 (ddd, J=3.6, 7.6, 12 Hz, 1H), 3.15-3.18 (m, 4H), 3.25 (ddd, J=2.0, 7.2, 12 Hz, 1H) , 3.83 (s, 3H), 3.84-3.87 (m, 4H) , 5.65 (d, J=12 Hz, 1H) ,
6.86 (d, J=8.8 Hz ,2H), 6.91 (s, 1H) , 6.99-7.00 (m, 2H), 7.21 (d, J-8.4 Hz, 1H) , 7.29 (d, J=8.8 Hz, 2H) , 7.69 (s, 1H), 7.84 (s, 1H). [0941] Examples 979 and 980
Synthesis of (E)-1-[(S) and (R)-cyclopropyl- (4-
morpholin-4-ylphenyl)methyl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one

;0942J Formula 294 (Figure Remove)


Synthesis of cyclopropyl-(4-morpholin-4-
ylphenyl)methanone
680 mg of the title compound was obtained
from cyclopropyl 4-fluorophenyl ketone (750 mg) in the same manner as in Example 973. The physical properties
of the compound are as follows.
^-NMR (CDC13) 5 (ppm) : 0.95-0.99 (m, 2H) , 1.17-1.21 (m,
2H), 2.59-2.65 (m, 1H) , 3.30 (t, J=4.8 Hz, 4H), 3.85
(t, J=4.8 Hz, 4H), 6.88 (d, J=9.2 Hz, 2H), 7.96 (d, J=9.2 Hz, 2H).
[0943]
Synthesis of cyclopropyl-(4-morpholin-4-
ylphenyl)methanone oxime
267 mg of the title compound was obtained 15 from cyclopropyl-(4-morpholin-4-ylphenyl)methanone (680
mg) in the same manner as in Example 971. The physical
properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 0.64-0.68 (m, 2H), 0.92-0.97 (m,
2H), 2.18-2.25 (m, 1H), 3.18 (t, J=4.8 Hz, 4H), 3.86 20 (t, J=4.8 Hz, 4H), 6.85 (d, J=8.8 Hz, 2H), 7.33 (d,
J=8.4 Hz, 2H).

[0944]
Synthesis of cyclopropyl-(4-morpholin-4-ylphenyl)methylamine
131 mg of the title compound was obtained 5 from cyclopropyl-(4-morpholin-4-ylphenyl)methanone oxime (267 mg) in the same manner as in Example 971. The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm) : 0.22-0.33 (m, 2H) , 0.43-0.50 (m, 1H), 0.56-0.62 (m, 1H), 1.04-1.13 (m, 1H), 3.14-3.17
(m, 5H), 3.85-3.88 (m, 4H), 6.90 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H). [0945]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid (cyclopropyl-(4-
morpholin-4-ylphenyl)methyl)amide
The title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and cyclopropyl-(4-morpholin-4-ylphenyl)methylamine
(131 mg) in the same manner as in Example 418. The physical properties of the compound are as follows. ^-NMR (CDC13) 8 (ppm): 0.37-0.43 (m, 1H) , 0.49-0.54 (m, 1H), 0.60-0.66 (m, 2H), 1.20-1.28 (m, 1H), 1.97-2.02 (m, 2H), 2.04 (s, 3H), 2.66-2.76 (m, 2H), 3.14-3.17 (m,
4H), 3.54-3.66 (m, 2H), 3.82-3.88 (m, 4H), 3.84 (s,
3H) , 4.50 (t, J=8.4 Hz, 1H) , 6.39 (brd, J=8.4 Hz, 1H), 6.89-6.96 (m, 5H), 7.16 (s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.79 (d, J=1.2 Hz, 1H).

[0946]
Synthesis of (E)-1-[(R) and (S)-cyclopropyl-(4-
morpholin-4-ylphenyl)methyl]-3-[3-methoxy-4-(4-methyl-
IH-imidazol-l-yl)benzylidene] piperidin-2-one
270 mg of (E)-1-(cyclopropyl-(4-morpholin-4-
ylphenyl)methyl)-3-(3-methoxy-4-(4-methyl-iH-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (cyclopropyl-(4-
morpholin-4-ylphenyl)methyl)amide in the same manner as in Example 418. Next, the compound (20 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active
substance with a retention time of 13 minutes (Example
979, 7.9 mg; >99% ee) and the title optically active
substance with a retention time of 17 minutes (Example
980, 4.6 mg; >99% ee). The physical properties of the
optically active substances are as follows.
XH-NMR (CDC13) 8 (ppm): 0.48-0.64 (m, 3H), 0.82-0.90 (m, 1H), 1.28-1.39 (m, 1H), 1.66-1.76 (m, 1H), 1.84-1.92 (m, 1H), 2.30 (s, 3H), 2.72-2.82 (m, 1H) , 2.82-2.94 (m, 1H), 3.10-3.20 (m, 1H), 3.15-3.17 (m, 4H) , 3.44-3.50 (m, 1H) , 3.85-3.87 (m, 4H), 3.86 (s, 3H), 5.20 (d, J=10
Hz, 1H), 6.88 (d, J=8.4 Hz, 2H) , 6.93 (s, 1H), 7.04 (s, 1H) , 7.04 (d, J=7.2 Hz, 1H) , 7.24 (d, J=7.2 Hz, 1H) , 7.36 (d, J=8.4 Hz, 2H) , 7.71 (s, 1H), 7.87 (s, 1H) . [0947]


Example 981 and Example 982
Synthesis of __(E) - [ (IS) and (1R) - (2-f luoro-4-morpholin-4-ylphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0948] [Formula 295]
(Figure Remove)
1-(2-fluoro-4-morpholin-4-yl-phenyl)ethanone
350 mg of the title compound was obtained
from 2, 4-difluoroacetophenone (1.0 g) in the same
manner as in Example 793. The physical properties of
the compound are as follows. 10 1H-NMR (CDC13) 8 (ppm) : 2.56 (d, J=5.6 Hz, 3H) , 3.30 (t,
J=4.8 Hz, 4H), 3.84 (t, J=4.8 Hz, 4H) , 6.46 (dd, J=2.8,
15 Hz, 1H), 6.64 (dd, J=2.8, 9.2 Hz, 1H), 7.83 (t,
J=8.8 Hz, 1H).
[0949] 15 Synthesis of 1-(2-fluoro-4-morpholin-4-yl-
phenyl)ethanone oxime
364 mg of the title compound was obtained
from 1-(2-fluoro-4-morpholin-4-yl-phenyl)ethanone (350
mg) in the same manner as in Example 971. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 2.27 (d, J=2.4 Hz, 3H), 3.18-


3.20 (m, 4H), 3.83-3.86 (m, 4H), 6.56 (dd, J=2.4, 12 Hz, 1H), 6.65 (dd, J=2.4, 8.8 Hz, 1H) , 7.37 (t, J=8.8 Hz, 1H). [0950]
Synthesis of 1-(2-fluoro-4-morpholin-4-yl-phenyl)ethylamine
140 mg of the title compound was obtained from 1-(2-fluoro-4-morpholin-4-ylphenyl)ethanone oxime (364 mg) in the same manner as in Example 971. The
physical properties of the compound are as follows. ^-NMR (CDC13) 5 (ppm) : 1.38 (d, J=6.4 Hz, 3H) , 3.11-3.14 (m, 4H) , 3.83-3.85 (m, 4H), 4.24 (q, J=6.4 Hz, 1H), 6.54 (dd, J=2.4, 14 Hz, 1H) , 6.64 (dd, J=2.4, 8.4 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H).
[0951]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]valeric acid [1-(2-fluoro-4-morpholin-4-ylphenyl)ethyl]amide
406 mg of the title compound was obtained
from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 1-(2-fluoro-4-morpholin-4-yl-phenyl)ethylamine (140 mg) in the same manner as in Example 418. The physical properties of the compound are as follows.
^-NMR (CDC13) 6 (ppm): 1.56 (d, J=6.8 Hz, 3H) , 1.94-2.04 (m, 2H), 2.31 (s, 3H), 2.70 (t, J=l.2 Hz, 2H), 3.13-3.15 (m, 4H), 3.56 (t, J=6.0 Hz, 2H), 3.83-3.85 (m, 4H), 3.85 (s, 3H), 5.22-5.30 (m, 1H), 6.36 (brd,


J=6.8 Hz, 1H), 6.58 (d, J=15 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.93-6.99 (m, 3H), 7.14 (s, 1H), 7.16-7.23 (m, 2H), 7.76 (s, 1H). [0952] 5 Synthesis of (E)-1-[(1R) and (IS)-(2-fluoro-4-
morpholin-4-ylphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one
267 mg of (E)-1-(1-(2-fluoro-4-morpholin-4-ylphenyl)ethyl)-3-(3-methoxy-4-(4-methylimidazol-l-
yl)benzylidene)piperidin-2-one as a racemate was
obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (1-(2-fluoro-4-morpholin-4-ylphenyl)ethyl)amide (406 mg) in the same manner as in Example 418. Next, the compound (160 mg)
was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 12 minutes (Example
981, 61 mg; >99% ee) and the title optically active
substance with a retention time of 14 minutes (Example
982, 31 mg; >92% ee). The physical properties of the
optically active substances are as follows.
^-NMR (CDC13) 8 (ppm) : 1.55 (d, J=7.2 Hz, 3H) , 1.72-1.80 (m,2H), 2.31 (s, 3H), 2.66-2.84 (m, 2H) , 2.97-3.03 25 (m, 1H), 3.15-3.18 (m, 4H), 3.24-3.29 (m, 1H), 3.80-
3.88 (m, 4H), 3.85 (s,3H), 6.18 (q, J=7.2 Hz, 1H), 6.58 (dd, J=2.0, 9.6 Hz, 1H), 6.65 (dd, J=2.0, 8.4 Hz, 1H), 6.93 (s, 1H), 7.02-7.04 (m, 2H) , 7.23-7.28 (m, 2H),


7.74 (s, 1H), 7.87 (s, 1H). [0953]
Example 983 and Example 984
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-5 l-yl)benzylidene]-l-[(2R) and (2S)-5-morpholin-4-ylindan-2-yl]piperidin-2-one [0954] [Formula 296]
(Figure Remove)
Synthesis of 5-morpholin-4-ylindan-l, 2-dinone 2-oxime 1.30 g of the title compound was obtained
from 5-morpholin-4-ylindan-l-one (1.50 g) synthesized in accordance with the method described in The Journal
of Medicinal Chemistry, 1991, vol.34, no.5, p.1662.
Properties data of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 2.64-2.66 (m, 4H) , 2.91 (s, 2H) ,
3.00-3.03 (m, 4H) , 6.18 (d, J=2.0 Hz, 1H) , 6.21 (dd, 15 J=2.0, 8.8 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H).
[0955]
Synthesis of 5-morpholin-4-ylindan-2-ylamine
258 mg of the title compound was obtained
from 5-morpholin-4-ylindan-l,2-dinone 2-oxime (300 mg) synthesized in accordance with the method described in
The Journal of Medicinal Chemistry, 1982, vol.25,

735
no.12, p.1442. Properties data of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 2.78-2.88 (m, 2H) , 3.09-3.12 (m, 4H), 3.16-3.25 (m, 2H), 3.78-3.98 (m, 1H), 3.84-3.87 5 (m, 4H), 4.90-5.44 (brs, 2H) , 6.75 (dd, J=2.4, 8.4Hz, 1H), 6.80 (s, 1H), 7.11 (d, J=8.4 Hz, 1H) . [0956]
Synthesis of (E) -5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)-benzylidene]valeric acid (5-morpholin-4-
ylindan-2-yl)amide
258 mg of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (288 mg) and 5-morpholin-4-ylindan-2-ylamine (100 mg) in the
same manner as in Example 418. Properties data of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 1.95-2.02 (m, 2H), 2.30 (s, 3H) , 2.67-2.95 (m, 4H), 3.12-3.14 (m, 4H), 3.33 (dd, J=6.8, 13 Hz, 1H), 3.37 (dd, J=6.8, 13 Hz, 1H) , 3.57 (t, J=6.4
Hz, 2H), 3.85 (s, 3H), 3.86-3.88 (m, 4H), 4.80-4.88 (m, 1H), 6.25 (brd, J=6.0 Hz, 1H), 6.74-6.80 (m, 1H), 6.84 (s, 1H), 6.92-6.94 (m, 3H), 7.10 (s, 1H), 7.15 (d, J=8.0, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.77 (s, 1H) . [0957]
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-1-[(2R) and (2S)-5-morpholin-4-ylindan-2-yl]piperidin-2-one
149 mg of (E)-3-(3-methoxy-4-(4-


methylimidazol-1-yl)benzylidene)-I-(5-morpholin-4-ylindan-2-yl)piperidin-2-one as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (5-morpholin-4-ylindan-2-5 yl)amide in the same manner as in Example 418. Next, the compound (149 mg) was fractionated using CHIRALCEL™ OJ manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 14
minutes (Example 983, 30.0 mg; >99% ee) and the title optically active substance with a retention time of 26 minutes (Example 984, 31.0 mg; >99% ee). The physical properties of the optically active substances are as follows.
XH-NMR (CDC13) 5 (ppm): 1.81-1.87 (m, 2H), 2.30 (s, 3H), 2.78-2.81 (m, 2H), 2.90-2.98 (m, 2H), 3.10-3.14 (m, 4H), 3.17-3.27 (m, 4H), 3.84-3.88 (m, 4H), 3.85 (s, 3H), 5.73-5.81 (m, 1H), 6.76 (dd, J=2.4, 8.4 Hz, 1H) , 6.81 (s, 1H), 6.92 (s, 1H), 7.02 (s, 1H), 7.03 (d,
J=8.0 Hz, 1H) , 7.12 (d, J=8.4 Hz, 1H) , 7.24 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.83 (s, 1H). [0958]
Example 985 and Example 986 Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
l-yl)benzylidene]-l-[(1R) and (IS)-(6-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-l-yl)]piperidin-2-one


[0959] [Formula 297]
(Figure Remove)
Synthesis of 5-oxo-5, 6, , 8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate
Trifluoromethanesulfonic anhydride (2.51 mL) was added to a solution of 6-hydroxy-3,4-dihydro-2H-5 naphthalen-1-one (2.00 g) and triethylamine (4.11 mL) in dichloromethane (20 mL) at -20°C, and the reaction solution was stirred at that temperature for 20 minutes. After confirming that the raw materials disappeared, the reaction solution was concentrated
under reduced pressure, and water and chloroform were added to the residue and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 3.30 g of the title compound. Properties data of the compound are as follows. XH-NMR (CDC13) 8 (ppm) : 2.15-2.21 (m, 2H) , 2.69 (t,
J=6.0 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 7.17-7.21 (m, 2H) , 8.12 (d, J=8.4 Hz, 1H) . [0960]


Synthesis of 6-morpholin-4-yl-3,4-dihydro-2H-naphthalen-1-one
A solution of 5-oxo-5,6,7,8-
tetrahydronaphthalen-2-yl trifluoromethanesulfonate 5 (3.40 g), morpholine (5.18 g), tripotassium phosphate (3.79 g), tris(dibenzylideneacetone) dipalladium (0) (109 mg) and 2-(di-tert-butylphosphino)biphenyl (71 mg) in 1,2-dimethoxyethane (24 mL) was stirred in a nitrogen atmosphere at 80°C for one and a half hours. 10 The reaction solution was returned to room temperature, and water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under 15 reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.56 g of the title compound. Properties data of the compound are as follows. 20 ^-NMR (CDC13) 6 (ppm) : 2.07-2.13 (m, 2H) , 2.59 (t,
J=6.4 Hz, 2H), 2.89 (t, J=6.4 Hz, 2H) , 3.31 (t, J=4.8 Hz, 4H), 3.85 (t, J=4.8 Hz, 4H), 6.61 (d, J=2.4 Hz, 1H), 6.79 (dd, J=2.4, 9.2 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H) . 25 [0961]
Synthesis of 6-morpholin-4-yl-3,4-dihydro-2H-naphthalen-1-one oxime
630 mg of the title compound was obtained

from 6-morpholin-4-yl-3,4-dihydro-2H-naphthalen-l-one (700 mg) in the same manner as in Example 971. Properties data of the compound are as follows. XH-NMR (CDC13) 5 (ppm): 1.82-1.89 (m, 2H), 2.71 (t, 5 J=6.4 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 3.20 (t, J=4.8 Hz, 4H), 3.85 (t, J=4.8 Hz, 4H) , 6.62 (d, J=2.4, 8.8 Hz, 1H) , 6.77 (dd, J=2.4, 8.8 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H). [0962]
Synthesis of 6-morpholin-4-yl-l, 2, 3,4-tetrahydro-naphthalen-1-ylamine
429 mg of the title compound was obtained from 6-morpholin-4-yl-3, 4-dihydro-2H-naphthalen-l-orie oxime (547 mg) in the same manner as in Example 971.
Properties data of the compound are as follows.
XH-NMR (CDC13) 6 (ppm): 1.52-1.68 (m, 1H), 1.70-1.78 (m, 1H), 1.86-2.04 (m, 2H), 2.65-2.81 (m, 2H), 3.12 (t, J=4.8 Hz, 4H), 3.84 (t, J=4.8 Hz, 4H) , 3.92 (t, J=5.6 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H) , 6.77 (dd, J=2.4, 8.4
Hz, 1H), 7.29 (d, J=8.4 Hz, 1H) . [0963]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)-benzylidene]valeric acid (6-morpholin-4-yl-lf2,3,4-tetrahydronaphthalen-l-yl)amide
300 mg of the title compound was obtained
from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (377 mg) and 6-morpholin-4-yl-l,2,3,4-tetrahydronaphthalen-l-


ylamine (150 mg) in the same manner as in Example 418. Properties data of the compound are as follows. XH-NMR (CDC13) 6 (ppm): 1.82-1.95 (m, 3H), 2.00-2.11 (m, 3H), 2.30 (s, 3H), 2.72-2.81 (m, 4H), 3.13-3.16 (m, 5 4H), 3.58 (t, J=6.4 Hz, 2H) , 3.84-3.86 (m, 4H), 3.85 (s, 3H), 5.20-5.25 (m, 1H), 6.11 (d, J=8.4 Hz, 1H), 6.63 (d, J=2.4, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H) , 6.92-6.95 (m, 2H). 6.93 (s, 1H) , 7.09 (s, 1H) , 7.20-7.24 (m, 2H), 7.71 (s, 1H).
[0964]
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-l-[(1R) and (IS)-(6-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-l-yl]piperidin-2-one
259 mg of (E)-3-(3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene)-1-(6-morpholin-4-yl-l,2,3,4-tetrahydronaphthalen-1-yl)piperidin-2-one as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (6-morpholin-4-yl-l,2,3,4-tetrahydronaphthalen-l-yl)amide
(300 mg) in the same manner as in Example 418. Next, the compound (70.0 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol = 30:70) to obtain the title optically
active substance with a retention time of 10 minutes
(Example 985, 27.0 mg; >98% ee) and the title optically active substance with a retention time of 14 minutes (Example 986, 28.0 mg; >97% ee). The physical


properties of the optically active substances are as follows.
^-NMR (CDC13) 5 (ppm): 1.71-1.88 (m, 4H) , 1.95-2.02 (m, 1H), 2.06-2.12 (m, 1H), 2.30 (s, 3H), 2.72-2.82 (m, 5 4H), 3.03-3.12 (m, 1H), 3.12-3.16 (m, 4H), 3.14-3.22 (m, 1H), 3.83-3.86 (m, 4H) , 3.86 (s, 3H), 6.60 (dd, J=6.4, lOHz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.73 (dd, J=2.4, 8.4 Hz, 1H), 6.93 (s, 1H) , 7.01 (d, J=8.8 Hz, 1H), 7.06 (s, 1H), 7.07 (d, J=8.8 Hz, 1H) , 7.25 (d,
J=8.4 Hz, 1H), 7.72 (s, 1H), 7.90 (s, 1H) . [0965]
Example 987 and Example 988
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-l-[(1R) and [(IS)-4-morpholin-4-

ylindan-1-yl]piperidin-2-one [0966] [Formula 298]
(Figure Remove)
Synthesis of l-oxo-indan-4-yl trifluoromethanesulfonate
1.30 g of the title compound was obtained from 4-hydroxyindanone (2.00 g) in the same manner as in Example 985. Properties data of the compound are as 20 follows.
XH-NMR (CDC13) 6 (ppm): 2.77-2.80 (m, 2H), 3.24-3.27 (m,


2H), 7.47-7.52 (m, 2H), 7.79 (dd, J=2.0, 6.0 Hz, 1H). [0967] Synthesis of 4-morpholin-4-ylindan-l-one
627 mg of the title compound was obtained
from l-oxo-indan-4-yl trifluoromethansulfonate (3.28 g) in the same manner as in Example 985. Properties data of the compound are as follows.
^-NMR (CDC13) 8 (ppm) : 2.69-2.72 (m, 2H) , 3.06-3.10 (m, 6H), 3.87-3.89 (m, 4H), 7.14 (d, J=8.0 Hz, 1H), 7.35 10 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H) . [0968] Synthesis of 4-morpholin-4-ylindan-l-one oxime
1.78 mg of the title compound was obtained from 4-morpholin-4-ylindan-l-one (250 mg) in the same 15 manner as in Example 971. Properties data of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 2.80-3.01 (m, 4H), 3.01-3.04 (m, 4H), 3.85-3.87 (m, 4H), 6.77 (dd, J=0.8, 8.0 Hz, 1/3H), 6.93 (dd, J=0.8, 8.0 Hz, 2/3H), 7.14 (t, J=8.0, 1/3H), 20 7.22-7.26 (m, 1H), 7.35 (dd, J=0.8, 8.0 Hz, 2/3H). [0969] Synthesis of 4-morpholin-4-ylindan-l-ylamine
140 mg of the title compound was obtained from 4-morpholin-4-ylindan-l-one oxime (178 mg) in the 25 same manner as in Example 971. Properties data of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.71-1.79 (m, 1H), 2.45-2.53 (m, 1H), 2.71 (td, J=8.0, 16 Hz, 1H) , 2.92-3.01 (m, 3H),


3.03-3.09 (m, 2H), 3.80-3.88 (m, 4H), 4.39 (t, J=7.6
Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 7.04 (d, J=7.6 Hz,
1H), 7.21 (t, J=7.6 Hz, 1H).
[0970] 5 Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)-benzylidene]valeric acid (4-morpholin-4-
ylindan-1-yl)amide
203 mg of the title compound was obtained
from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol- 1-yl)benzylidene)valeric acid trifluoroacetate (432 mg)
and 4-morpholin-4-ylindan-l-ylamine (140 mg) in the
same manner as in Example 418. Properties data of the
compound are as follows.
1H-NMR (CDC13) 8 (ppm): 1.82-1.94 (m, 2H), 2.02-2.09 (m, 1H), 2.29 (s, 3H), 2.65-2.73 (m, 1H), 2.72-2.79 (m,
2H), 2.79-2.88 (m, 1H), 2.93-2.99 (m, 2H) , 2.97-3.05
(m, 1H), 3.07-3.12 (m, 2H), 3.60 (t, J=6.0 Hz, 2H),
3.84-3.87 (m, 4H), 3.86 (s, 3H), 5.59 (q, J=8.0 Hz,
1H) , 6.21 (d, J=8.0 Hz, 1H) , 6.84 (d, J=8.0 Hz, 1H) , 6.92 (t, J=0.8 Hz, 1H), 6.95-6.97 (m, 2H), 7.00 (d,
J=8.0 Hz, 1H), 7.18 (s, 1H), 7.21-7.26 (m, 2H), 7.70
(s, 1H) .
[0971]
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol- 1-yl)benzylidene]-1-[(1R) and (IS)-4-morpholin-4-
ylindan-1-yl]piperidin-2-one
11.8 mg of (E)-3-(3-methoxy-4- (4-methyl-lH-
imidazol-1-yl)benzylidene)-1-(4-morpholin-4-ylindan-l-


yl)piperidin-2-one as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (4-morpholin-4-ylindan-l-yl)amide (203 mg) in the same manner as in Example 418. 5 Next, the compound (5.00 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol = 70:30) to obtain the title optically active substance with a retention time of 45 minutes
(Example 987, 0.80 mg; >99% ee) and the title optically active substance with a retention time of 47 minutes (Example 988, 0.90 mg; >87% ee). The physical properties of the optically active substances are as follows.
1H-NMR (CDC13) 5 (ppm): 1.74-1.90 (m, 2H) , 1.92-2.04 (m, 1H), 2.30 (s, 3H), 2.44-2.53 (m, 1H), 2.74-3.04 (m, 6H), 3.06-3.18 (m, 4H), 3.81-3.90 (m, 4H), 3.86 (s, 3H), 6.50 (t, J=8.0 Hz, 1H) , 6.81 (d, J=7.6 Hz, 1H) , 6.83 (d, J=7.6 Hz, 1H), 6.93 (s, 1H) , 7.05 (s, 1H),
7.06 (d, J=7.6 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.72 (s, 1H), 7.90 (s, 1H). [0972]
Example 989 and Example 990 Synthesis of (E)-1-[(1R) and (IS)-(2-fluoro-4-
[1,2,4]triazol-1-ylphenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [0973] [Formula 299]



(Figure Remove)


Synthesis of 1-(2-fluoro-4-[1,2,4]triazol-1-ylphenyl)ethanone
A solution of 2,4-difluoroacetophenone (2.43 mL), 1,2,4-triazole (1.59 g) and potassium carbonate 5 (5.32 g) in toluene (10 mL) was stirred at 100°C
overnight. The reaction solution was returned to room temperature, and then water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with
brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 187 mg of the title compound. Properties data
of the compound are as follows.
XH-NMR (CDC13) 6 (ppm) : 2.68 (d, J=4.8 Hz, 3H) , 7.56 (dd, J=2.5, 8.0 Hz, 1H), 7.60 (dd, J=2.5, 12 Hz, 1H), 8.05 (t, J=8.4 Hz, 1H), 8.13 (s, 1H), 8.65 (s, 1H). [0974]
Synthesis of 1-(2-fluoro-4-[1,2,4]triazol-1-ylphenyl)ethylamine
80 mg of the title compound was obtained from l-(2-fluoro-4-[1,2,4]triazol-1-yl-phenyl)ethanone (187 mg) via a crude oxime in the same manner as in Example


971. Properties data of the compound are as follows. XH-NMR (CDC13) § (ppm): 1.44 (d, J=6.8 Hz, 3H) , 4.45 (q, J=6.8 Hz, 1H), 7.41-7.47 (m, 2H) , 7.58-7.63 (m, 1H), 8.10 (s, 1H), 8.55 (s, 1H). 5 [0975]
Synthesis of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)-benzylidene]valeric acid [1-(2-fluoro-4-[1,2,4]-triazol-1-ylphenyl)ethyl]amide
171 mg of the title compound was obtained
from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (226 mg} and l-(2-fluoro-4-[l,2,4]triazol-1-ylphenyl)ethylamine (80 mg) in the same manner as in Example 418. Properties data of the compound are as follows.
^-NMR (CDC13) 8 (ppm): 1.64 (d, J=7.2 Hz, 3H) , 1.95-2.03 (m, 2H), 2.30 (s, 3H), 2.70-2.74 (m, 2H), 3.57-3.60 (m, 2H), 3.86 (s, 3H), 5.36 (quint, 7.2 Hz, 1H), 6.44-6.50 (brs, 1H), 6.93-6.97 (m, 3H), 7.21 (s, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.45 (dd, J=2.0, 8.4 Hz, 1H)
7.48-7.51 (m, 2H) , 7.72 (s, 1H), 8.09 (s, 1H), 8.54 (s, 1H) . [0976]
Synthesis of (E)-1-[(1R) and (IS)-(2-fluoro-4-[1,2,4]triazol-1-ylphenyl)ethyl]-3-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
121 mg of (E)-l-(l-(2-fluoro-4-
[1,2, 4]triazol-1-ylphenyl)ethyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)piperidin-2-one as


a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (1-(2-fluoro-4-[1,2,4]-triazol-1-ylphenyl)ethyl)amide (171 mg) in the same manner as in Example 418. Next, 5 the compound (10.0 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 13 minutes (Example 989, 2.6 mg; >99%
ee) and the title optically active substance with a
retention time of 15 minutes (Example 990, 3.9 mg; >94% ee). Properties data of the compounds are as follows. XH-NMR (CDC13) 8 (ppm): 1.65 (d, J=7.2 Hz, 3H), 1.80-1.88 (m, 2H), 2.30 (s, 3H), 2.75-2.84 (m, 2H), 3.09-
3.15 (m, 1H), 3.35-3.41 (m, 1H) , 3.85 (s, 3H), 6.17 (q, J=7.2 Hz, 1H), 6.93 (s, 1H), 7.02-7.04 (m, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.47-7.57 (m, 3H), 7.72 (s, 1H), 7.86 (s, 1H), 8.11 (s, 1H), 8.57 (s, 1H). [0977]
Example 991 and Example 992
Synthesis of (E)-1-[(2S) and (2R)-5-fluoroindan-2-yl]-
3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
[0978]
[Formula 300]
(Figure Remove)











IPEA (0.58 mL) , EDC (0.38 g) and HOBT (0.27 g) were added to a suspension of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-1-
yl)benzylidene)valeric acid trifluoroacetate (300 mg) 5 and 5-fluoroindan-2-ylamine (CAS #2340-06-9, 151 mg) in DMF (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate and ethyl, acetate were added to the reaction solution and
the organic layer was partitioned. The organic layer was washed sequentially with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: ethyl acetate-methanol system) to obtain (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (5-fluoroindan-
2-yl)amide (318 mg). Sodium hydride (containing
mineral oil at 40%, 60 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid (5-fluoroindan-2-yl)amide (318 mg) in DMF (6 mL) at room temperature, and the
reaction solution was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution and the organic layer was


partitioned. The organic layer was washed sequentially with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous 5 magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain (E)-l-(5-fluoroindan-2-yl)-3-(3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene)piperidin-2-one as a racemate (170 mg). The compound (10 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a
retention time of 9.1 minutes (Example 991, 4 mg; >95% ee) and the title optically active substance with a retention time of 9.8 minutes (Example 992, 4 mg; >94% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 8 (ppm) : 1.82-1.90 (m, 2H) , 2.29 (s, 3H) , 2.77-2.84 (m, 2H), 2.91-3.04 (m, 2H), 3.18-3.30 (m, 4H), 3.85 (s, 3H), 5.72-5.81 (m, 1H), 6.83-6.94 (m, 3H), 7.00-7.05 (m, 2H) , 7.15 (dd, J=5.2 Hz, 8.0 Hz, 1H), 7.22-7.26 (m, 1H), 7.70 (d, J=l.6 Hz, 1H), 7.82-
7.85 (m, 1H). [0979]
Example 993 and Example 994 Synthesis of (E)-1-[(1R and IS)-6-fluoroindan-1-yl]-3-


[3 -methoxy-4- ( 4 -methyl- IH-imidazol-l yl) benzyliden] )piperidin-2-one [0980] [Formula 301]
(Figure Remove)




IPEA (0.58 mL) , EDC (0.38 g) and HOBT (0.27 g) were added to a suspension of (E) -5-chloro-2- (3-5 methoxy-4- (4-methyl-lH-imidazol-l-
yl) benzylidene) valeric acid trif luoroacetate (300 mg) and 6-fluoroindan-l-ylamine (CAS #168902-77-0, 151 mg) in DMF (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours.
A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed sequentially with a saturated aqueous solution of ammonium chloride, water and a saturated
aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-
ethyl acetate system) to obtain (E) -5-chloro-2- (3-methoxy-4- ( 4 -methyl- lH-imidazol-1 -yl) benzylidene) valeric acid ( 6-f luoroindan-1-yl) amide

1
(270 mg). Sodium hydride (containing mineral oil at 40%, 60 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid (6-fluoroindan-l-yl)amide 5 (270 mg) in DMF (5 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution and the organic layer was
partitioned. The organic layer was washed sequentially with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain (E)-l-(6-fluoroindan-l-yl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate
(200 mg). The compound (200 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 7.4 minutes (Example 994, 72 mg; >99%
ee) and the title optically active substance with a
retention time of 8.4 minutes (Example 993, 68 mg; >96% ee). The physical properties of the compounds are as follows.



(CDC13) 8 (ppm): 1.75-1.92 (m, 2H), 1.97-2.10 (m, 1H), 2.30 (s, 3H), 2.48-2.57 (m, 1H), 2.74-3.22 (m, 6H), 3.87 (s, 3H), 6.44-6.50 (m, 1H), 6.83-6.88 (m, 1H), 6.90-6.96 (m, 2H), 7.03-7.08 (m, 2H) , 7.16-7.21 5 (m, 1H) , 7.23-7.28 (m, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.87-7.91 (m, 1H). [0981]
Example 995

Synthesis of (E)-1-[1-(4-fluorophenyl)-1-methylethyl] -10 3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0982] [Formula 302]


(Figure Remove)
43 mg of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (100 mg)
and 1-(4-fluorophenyl)-1-methylethylamine (CAS #17797-10-3, 51 mg) in the same manner as in Example 418. The physical properties of the compound are as follows. XH-NMR (CDC13) 8 (ppm): 1.75 (s, 6H), 1.90-2.00 (m, 2H), 2.32 (s, 3H), 2.76-2.85 (m, 2H) , 3.57-3.64 (m, 2H),
3.83 (s, 3H), 6.91-7.05 (m, 5H) , 7.20-7.33 (m, 3H), 7.63 (brs, 1H), 7.79 (brs, 1H). [0983]


Example 996
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-1-[(IS)-1,2, 3,4-tetrahydronaphthalen-1-yl]piperidin-2-one [0984] [Formula 303]
(Figure Remove)
72 mg of the title compound was obtained from
(E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and (IS) -1, 2, 3, 4-tetrahydroriaphthalen-l-ylamine (74 mg) in the same manner as in Example 418. The physical
properties of the compound are as follows.
XH-NMR (CDCl-j) 8 (ppm) : 1.70-1.96 (m, 4H) , 1.98-2.16 (m, 2H), 2.30 (s, 3H), 2.73-2.98 (m, 4H), 3.03-3.10 (m, 1H), 3.17-3.26 (m, 1H), 3.87 (s, 3H) , 6.10-6.17 (m, 1H), 6.93 (s, 1H), 7.04-7.18 (m, 6H), 7.22-7.28 (m,
1H), 7.71 (d, 3=1.2 Hz, 1H), 7.91 (brs, 1H) . [0985]
Example 997
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-1-(2-methylindan-2-yl)piperidin-2-one



[0986] [Formula 304]

(Figure Remove)
80 mg of the title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and 2-methylindan-2-ylamine (CAS #312753-94-9, 98 mg) 5 in the same manner as in Example 418. The physical properties of the compound are as follows. Hi-NMR (CDC13) S (ppm): 1.42 (s, 3H), 1.88-1.96 (m, 2H), 2.30 (s, 3H), 2.76-2.83 (m, 2H), 3.39 (s, 4H) , 3.53-3.59 (m, 2H), 3.85 (s, 3H), 6.91-6.93 (m, 1H), 7.00-
7.05 (m,2H), 7.13-7.25 (m, 5H) , 7.70 (d, J=1.6 Hz, 1H), 7.76-7.78 (m, 1H). [0987]
Example 998 and Example 999 Synthesis of (E)-1-[(2R and 2S)-5-methoxyindan-2-yl]-3-

[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0988] [Formula 305] (Figure Remove)

f




135 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 5-methoxyindan-2-ylamine 5 (CAS #73305-09-6, 164 mg) in the same manner as in Example 418. The compound (8 mg) was fractionated using CHIRALCEL™ OJ manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a
retention time of 8.8 minutes (Example 999, 1.3 mg,
>99% ee) and the title optically active substance with a retention time of 11.7 minutes (Example 998, 1.9 mg, >99% ee). The physical properties of the compounds are as follows.
XH-NMR (CDC13) 8 (ppm) : 1.81-1.89 (m, 2H), 2.37 (s, 3H) , 2.75-2.82 (m, 2H), 2.88-3.00 (m, 2H), 3.18-3.30 (m, 4H), 3.79 (s, 3H), 3.87 (s, 3H), 5.73-5.82 (m, 1H) , 6.72-6.80 (m, 2H), 6.97 (s, 1H), 7.02-7.14 (m, 3H) , 7.24-7.28 (m, 1H), 7.83 (s, 1H), 8.08 (s, 1H) .
[0989]
Example 1000 and Example 1001
Synthesis of (E)-1-[(2R and 2S)-4-methoxyindan-2-yl]-3-
[3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]piperidin-2-one
[0990] (Figure Remove)

[Formula 306]


205 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 4-methoxyindan-2-ylamine 5 (CAS #76413-92-8, 164 mg) in the same manner as in Example 418. The compound (3 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a
retention time of 10.3 minutes (Example 1000, 1.1 mg, >99% ee) and the title optically active substance with a retention time of 10.9 minutes (Example 1001, 1.2 mg, >93% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 6 (ppm) : 1.80-1.88 (m, 2H) , 2.30 (s, 3H) , 2.77-2.82 (m, 2H) , 2.87-3.00 (m, 2H), 3.20-3.35 (m, 4H), 3.83 (s, 3H), 3.87 (s, 3H), 5.77-5.86 (m, 1H) , 6.69 (d, J=8.0 Hz, 1H) , 6.84 (d, J=7.6 Hz, 1H) 6.91-6.93 (m, 1H), 7.00-7.05 (m, 2H), 7.16 (dd, J=7.6 Hz,
8.0 Hz, 1H) , 7.22-7.26 (m, 1H) , 7.70 (d, J=1.2 Hz, 1H), 7.82-7.85 (m, 1H). [0991]
Example 1002 and Example 1003 Synthesis of (E)-1-[(2R and 2S)-4-fluoroindan-2-yl]-3-
[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one

[0992] [Formula 307]
(Figure Remove)








97 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (500 mg) and 4-fluoroindan-2-ylamine (CAS #162752-09-2, 5 230 mg) in the same manner as in Example 418. The compound (8 mg) was fractionated using CHIRALCEL™ OJ manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol-hexane system) to obtain the title optically active substance with a
retention time of 18.2 minutes (Example 1003, 1.2 mg, >99% ee) and the title optically active substance with a retention time of 22.8 minutes (Example 1002, 1.0 mg, >99% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 8 (ppm) : 1.82-1.90 (m, 2H) , 2.30 (s, 3H) , 2.78-2.83 (m, 2H), 2.97-3.06 (m, 2H), 3.25-3.36 (m, 4H), 3.85 (s, 3H), 5.76-5.84 (m, 1H), 6.84-6.94 (m, 2H), 6.98-7.05 (m, 3H), 7.12-7.18 (m, 1H), 7.22-7.26 (m, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.84 (brs, 1H) .
[0993]
Example 1004 and Example 1005
Synthesis of (E)-1-[(1R and IS)-5-fluoroindan-1-yl]-3-
[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0994] [Formula 308]
(Figure Remove)




26 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-5 imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (80 mg) and 5-fluoroindan-1-ylamine (CAS #148960-33-2, 54 mg) in the same manner as in Example 418. The compound (20 mg) was fractionated using CHIRALCEL™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2
cmx25 cm: mobile phase: ethanol) to obtain the title
optically active substance with a retention time of 8.0 minutes (Example 1005, 6.9 mg, >99% ee) and the title optically active substance with a retention time of 8.8 minutes (Example 1004, 5.3 mg, >95% ee). The physical
properties of the compounds are as follows.
^-NMR (CDC13) 6 (ppm) : 1.72-2.08 (m, 3H) , 2.30 (s, 3H) , 2.49-2.58 (m, 1H), 2.75-3.20 (m, 6H), 3.86 (s, 3H), 6.42-6.48 (m, 1H), 6.86-6.97 (m, 3H), 7.04-7.14 (m, 3H), 7.24-7.28 (m,lH), 7.71 (s, 1H), 7.89 (brs, 1H).
[0995]
Example 1006 and Example 1007


Synthesis of (E)-1-[(1R and IS)-5-methoxyindan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [0996]
[Formula 309]


27 mg of the title compound as a racemate was 5 obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (80 mg) and 5-methoxyindan-l-ylamine (CAS #52372-95-9, 58 mg) in the same manner as in Example 418. The compound (27 mg) was fractionated using CHIRALPAK™ AD-H
manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane-ethanol system) to obtain the title optically active substance with a retention time of 16.0 minutes (Example 1007, 3.5 mg, >99% ee) and the title optically active substance with
a retention time of 17.2 minutes (Example 1006, 2.1 mg, >95% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 5 (ppm) : 1.75-2.05 (m, 3H) , 2.37 (s, 3H) , 2.47-2.58 (m, 1H), 2.76-3.18 (m, 6H), 3.80 (s, 3H),
3.88 (s, 3H), 6.39-6.45 (m, 1H), 6.74-6.81 (m, 2H), 6.97 (s, 1H), 7.04-7.10 (m, 3H), 7.24-7.29 (m, 1H),


7.88 (s, 1H), 8.07 (brs, 1H). [0997]
Example 1008 and Example 1009 Synthesis of (E)-1-[(1R and IS)-4-fluoroindan-1-yl]

-3-

[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one [0998]
[Formula 310]
(Figure Remove)

178 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid
trifluoroacetate (300 mg) and 4-fluoroindan-1-ylamine (CAS #148960-34-3, 151 mg) in the same manner as in Example 418. The compound (178 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to
obtain the title optically active substance with a retention time of 7.2 minutes (Example 1009, 71 mg, >99% ee) and the title optically active substance with a retention time of 9.5 minutes (Example 1008, 72 mg, >99% ee). The physical properties of the compounds are
as follows.
^-NMR (CDC13) 8 (ppm) : 1.72-1.90 (m, 2H) , 1.98-2.08 (m, 1H), 2.30 (s, 3H), 2.50-2.60 (m, 1H), 2.75-2.98 (m,

3H), 3.02-3.21 (m, 3H), 3.86 (s, 3H), 6.49-6.55 (m, 1H), 6.90-7.00 (m, 3H), 7.02-7.08 (m, 2H), 7.16-7.28 (m, 2H), 7.71 (s, 1H), 7.89 (brs, 1H). [0999] 5 Example 1010 and Example 1011
Synthesis of (B)-1-[(1R and IS)-5,6-dimethoxyindan-l-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [1000] 10 [Formula 311]
(Figure Remove)
[1001]
178 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4- (4-methyl-lH-imidazol-1-yl)benzylldene)valeric acid trifluoroacetate (300 mg) and 5,6-dimethoxyindan-l-
ylamine (CAS #91247-06-2, 151 mg) in the same manner as in Example 418. The compound (178 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a
retention time of 9.3 minutes (Example 1011, 71 mg,
>99% ee) and the title optically active substance with a retention time of 10.9 minutes (Example 1010, 72 mg,


>93% ee). The physical properties of the compounds are as follows.
XH-NMR (CDC13) 6 (ppm): 1.70-1.89 (m, 2H), 1.93-2.03 (m, 1H), 2.30 (s, 3H), 2.49-2.59 (m, 1H), 2.75-3.07 (m, 5 5H), 3.11-3.20 (m, 1H) , 3.84 (s, 3H) , 3.87 (s, 3H) ,
3.88 (s, 3H), 6.47 (dd, J=6.4 Hz, 8.4 Hz, 1H), 6.69 (s, 1H), 6.78 (s, 1H), 6.94 (brs, 1H), 7.04-7.10 (m, 2H), 7.24-7.30 (m, 1H), 7.72 (brs, 1H), 7.91 (brs, 1H). [1002] 10 Example 1012 and Example 1013
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
l-yl)benzylidene]-l-[(1R and IS)-5-
trifluoromethoxyindan-1-yl]piperidin-2-one
[1003]
[Formula 312]
(Figure Remove)
6.8 mg of the title compound asa racemate 15 was obtained from 5-trifluoromethoxyindanone (CAS #173252-76-1, 1 g) in the same manner as in Example 973. The compound (6.8 mg) was fractionated using CHIRALCEL™ OJ manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane-20 ethanol system) to obtain the title optically active substance with a retention time of 10.2 minutes (Example 1012, 1.9 mg, >99% ee) and the title optically


active substance with a retention time of 17.3 minutes (Example 1013, 1.9 mg, >99% ee). The physical properties of the compounds are as follows. ^-NMR (CDC13) § (ppm) : 1.72-2.10 (m, 3H) , 2.30 (s, 3H) , 5 2.50-2.60 (m, 1H), 2.75-3.22 (m, 6H), 3.86 (s, 3H), 6.48 (dd, J=8.0 Hz, 8.4 Hz, 1H), 6.92-6.94 (m, 1H), 7.02-7.08 (m, 3.H) , 7.10 (brs, 1H) , 7.17 (d, J=8.4 Hz, 1H), 7.24-7.28 (m, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.89 (brs, 1H). 10 [1004]
Example 1014 and Example 1015
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
l-yl)benzylidene]-l-[(2R and 2S)-1,2,3,4-
tetrahydronaphthalen-2-yl]piperidin-2-one
[1005]
[Formula 313]
(Figure Remove)
IPEA (0.58 mL), EDC (0.38 g) and HOBT (0.27
g) were added to a suspension of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 1,2,3,4-tetrahydronaphthalen-2-ylamine (148 mg) in
DMF (10 mL) at room temperature, and the reaction
solution was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and


ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed sequentially with a saturated aqueous solution of ammonium chloride, water and a saturated 5 aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-
ethyl acetate system) to obtain (E)-5-chloro-2-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene)valeric acid (1,2,3,4-tetrahydronaphthalen-2-yl)amide (255 mg). Sodium hydride (containing mineral oil at 40%, 50 mg) was
added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid (1,2,3,4-tetrahydronaphthalen-2-yl)amide (255 mg) in DMF (6 mL) at room temperature, and the reaction solution was stirred at room temperature for 30
minutes. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed sequentially with a saturated aqueous solution of ammonium chloride,
water and a saturated aqueous solution of sodium
chloride. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica


gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain (E)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-2-one as a 5 racemate (210 mg). The compound (12 mg) was
fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 9.5 minutes (Example
1014, 6.0 mg; >99% ee) and the title optically active substance with a retention time of 13.0 minutes (Example 1015, 5.9 mg; >99% ee). The physical properties of the compounds are as follows. ^-NMR (CDC13) 5 (ppm) : 1.80-2.05 (m, 4H) , 2.31 (s, 3H) ,
2.76-3.10 (m, 6H), 3.41 (t, J=5.6 Hz, 2H) , 3.86 (s, 3H), 5.03-5.13 (m, 1H), 6.94 (s, 1H), 7.02-7.15 (m, 6H), 7.22-7.28 (m, 1H), 7.74 (s, 1H), 7.85 (brs, 1H). [1006] Example 1016 and Example 1017
Synthesis of (E)-1-[(4R and 4S)-7-methoxychroman-4-yl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one [1007] [Formula 314]
(Figure Remove)





285 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 7-methoxychroman-4-5 ylamine (CAS #802037-18-9, 180 mg) in the same manner as in Example 418. The compound (10 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active
substance with a retention time of 12.9 minutes
(Example 1016, 2.3 mg, >99% ee) and the title optically active substance with a retention time of 20.5 minutes (Example 1017, 2.8 mg, >99% ee). The physical properties of the compounds are as follows.
XH-NMR (CDC13) 5 (ppm) : 1.71-1.91 (m, 2H) , 2.08-2.22 (m, 2H) , 2.30 (s, 3H), 2.74-2.84 (m, 1H), 2.87-2.96 (m, 1H), 3.07-3.23 (m, 2H), 3.77 (s, 3H), 3.87 (s, 3H) , 4.18-4.27 (m, 1H), 4.30-4.37 (m, 1H), 6.12-6.18 (m, 1H), 6.40 (d, J=2.4 Hz, 1H) , 6.50 (dd, J=2.4 Hz, 8.8
Hz, 1H), 6.92-6.97 (m, 2H), 7.05-7.10 (m, 2H), 7.23-7.29 (m, 1H) , 7.73 (d, J=1.6 Hz, 1H), 7.91 (brs, 1H). [1008]
Example 1018 and Example 1019 Synthesis of (E)-1-[(4R and 4S)-6-methoxychroman-4-yl]-
3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one


;i009J
; Formula 315]
(Figure Remove)


MeO


215 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4- (4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 6-methoxychroman-4-5 ylamine (CAS #81816-60-6, 180 mg) in the same manner as in Example 418. The compound (12 mg) was fractionated using CHIRALCEL™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a
retention time of 10.7 minutes (Example 1018, 5.8 mg, >99% ee) and the title optically active substance with a retention time of 15.3 minutes (Example 1019, 5.5 mg, >99% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 5 (ppm) : 1.70-1.93 (m, 2H) , 2.10-2.24 (m, 2H), 2.31 (s, 3H), 2.75-2.85 (m, 1H), 2.89-2.98 (m, 1H), 3.08-3.27 (m, 2H), 3.73 (s, 3H) , 3.88 (s, 3H), 4.15-4.22 (m, 1H), 4.28-4.35 (m, 1H), 6.18-6.25 (m, 1H), 6.59 (d, J=3.2 Hz, 1H), 6.73-6.82 (m, 2H), 6.95
(s, 1H), 7.05-7.11 (m, 2H), 7.25-7.29 (m, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.91 (brs, 1H). [1010]


Example 1020 and Example 1021
Synthesis of (E)-1-[(4R and 4S)-6-fluorochroman-4-yl] 3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [1011] [Formula 316]
(Figure Remove)




207 mg of the title compound as a racemate
was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 6-fluorochroman-4-ylamine (CAS #238764-22-2, 220 mg} in the same manner as in
Example 418. The compound (11 mg) was fractionated using CHIRALCEL™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 9.4 minutes (Example 1020, 4.0 mg,
>99% ee) and the title optically active substance with a retention time of 12.8 minutes (Example 1021, 3.9 mg, >99% ee). The physical properties of the compounds are as follows. ^-NMR (CDC13) 6 (ppm) : 1.75-1.94 (m, 2H) , 2.07-2.26 (m,
2H), 2.31 (s, 3H), 2.74-2.84 (m, 1H), 2.91-3.01 (m, 1H), 3.07-3.15 (m, 1H), 3.19-3.28 (m, 1H), 3.88 (s,


3H), 4.17-4.26 (m, 1H), 4.32-4.40 (m, 1H), 6.19-6.25 (m, 1H), 6.75-6.82 (m, 2H), 6.84-6.90 (m, 1H), 6.95 (s, 1H), 7.05-7.11 (m, 2H), 7.25-7.30 (m, 1H), 7.74 (d, J=1.2 Hz, 1H), 7.92 (brs, 1H). 5 [1012]
Example 1022 and Example 1023
Synthesisof (E)-1-[(4R and 4S)-2,2-dimethylchroman-4-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one [1013] [Formula 317]
(Figure Remove)




217 mg of the title compound as a racemate
was obtained from (E)-5-chloro-2-(3-methoxy-4- (4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 2,2-dimethylchroman-4-ylamine (CAS #220634-41-3, 145 mg) in the same manner
as in Example 418. The compound (20 mg) was
fractionated using CHIRALCEL™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 8.2 minutes (Example
1022, 8.1 mg, >99% ee) and the title optically active substance with a retention time of 9.6 minutes (Example



1023, 8.0 mg, >99% ee). The physical properties of the compounds are as follows.
:H-NMR (CDC13) 8 (ppm) : 1.37 (s, 3H), 1.48 (s, 3H) , 1.73-2.04 (m, 4H), 2.31 (s, 3H), 2.74-2.83 (m, 1H) , 5 2.89-2.98 (m, 1H), 3.04-3.22 (m, 2H), 3.88 (s, 3H) , 6.23-6.33 (m, 1H), 6.83 (dd, J=l.2 Hz, 8.4 Hz, 1H), 6.86-6.91 (m, 1H), 6.95 (s, 1H), 7.05-7.12 (m, 3H), 7.14-7.19 (m, 1H), 7.24-7.30 (m, 1H), 7.73 (s, 1H) , 7.92 (brs, 1H). 10 [1014]
Example 1024 and Example 1025
Synthesis of (E)-1-[(4R) and (4S)-7-fluorochroman-4-
yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
[1015]
[Formula 318] (Figure Remove)


217 mg of the title compound as a racemate
was obtained from (E)-5-chloro-2-(3-methoxy-4- (4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 7-fluorochroman-4-ylamine (CAS #774163-31-4, 168 mg) in the same manner as in
Example 418. The compound (20 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical


Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 9.6 minutes (Example 1024, 8.1 ing, >99% ee) and the title optically active substance with 5 a retention time of 14.0 minutes (Example 1025, 8.0 mg, >99% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 6 (ppm) : 1.72-1.93 (m, 2H) , 2.10-2.25 (m, 2H), 2.30 (s, 3H), 2.74-2.83 (m, 1H), 2.89-2.97 (m,
1H), 3.04-3.11 (m, 1H) , 3.17-3.25 (m, 1H), 3.87 (s, 3H), 4.21-4.28 (m, 1H), 4.33-4.40 (m, 1H), 6.15-6.21 (m, 1H), 6.57 (dd, J=2.4 Hz, 9.6 Hz, 1H), 6.62 (ddd, J=2.4 Hz, 8.4 Hz, 8.4 Hz, 1H) , 6.93-7.04 (m, 2H), 7.05-7.10 (m, 2H), 7.25-7.30 (m, 1H) , 7.74 (brs, 1H), 7.91
(brs, 1H). [1016]
Example 1026 and Example 1027
Synthesis of (E)-1-[(3R and 3S)-chroman-3-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one [1017] [Formula 319]


171 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (250 mg) and chroman-3-ylamine (CAS 5 #60575-19-1, 75 mg) in the same manner as in Example 418. The compound (10 mg) was fractionated using CHIRALCEL™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a
retention time of 11.6 minutes (Example 1026, 4.3 mg, >99% ee) and the title optically active substance with a retention time of 13.9 minutes (Example 1027, 4.3 mg, >99% ee). The physical properties of the compounds are as follows.
XH-NMR (CDC13) 5 (ppm): 1.75-1.94 (m, 2H), 2.31 (s, 3H), 2.78-2.84 (m, 2H), 3.04 (dd, J=6.8 Hz, 17.2 Hz, 1H), 3.15 (dd, J=6.4 Hz, 17.2 Hz, 1H) , 3.40 (t, J=6.0 Hz, 2H), 3.86 (s, 3H), 4.21-4.32 (m, 2H), 5.09-5.16 (m, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.89-6.95 (m, 2H), 7.01-
7.16 (m, 1H), 7.24-7.28 (m, 1H), 7.74 (s, 1H), 7.84 (brs, 1H). [1018]
Example 1028 and Example 1029 Synthesis of (E)-1-[(1R,2R and IS,2S)-l-hydroxyindan-2-
yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]piperidin-2-one

[1019] [Formula 320] (Figure Remove)








125 mg of the title compound as a racemate was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (800 mg) and trans-2-aminoindan-l-ol 5 (CAS #13575-72-9, 446 mg) in the same manner as in Example 418. The compound (13 mg) was fractionated using CHIRALCEL™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol-hexane system) to obtain the title optically active
substance with a retention time of 11.1 minutes
(Example 1028, 5.7 mg, >99% ee) and the title optically active substance with a retention time of 13.7 minutes (Example 1029, 5.4 mg, >99% ee). The physical properties of the compounds are as follows.
^-NMR (CDC13) 8 (ppm) : 1.90-2.03 (m, 2H) , 2.32 (s, 3H) , 2.76-2.95 (m, 2H), 3.06-3.22 (m, 2H), 3.46-3.57 (m, 2H), 3.87 (s, 3H), 5.14-5.22 (m, 1H), 5.34 (d, J=7.6 Hz, 1H) , 6.95 (s, 1H), 7.02-7.07 (m, 2H), 7.22-7.33 (m, 4H), 7.43-7.48 (m, 1H), 7.76 (s, 1H) , 7.86 (s, 1H).
[1020]
Example 1030 and Example 1031


Synthesis of (E)-1-[(3R,4S and 3S,4R)-3-hydroxychroman-4-yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl) benzylidene],piperidin-2-one [1021] [Formula 321]
(Figure Remove)


MeO


198 mg of the title compound as a racemate 5 was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (600 mg) and cis-4-aminochroman-3-ol (CAS #58810-67-6, 332 mg) in the same manner as in Example 418. The compound (12 mg) was fractionated
using CHIRALCEL™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol-hexane system) to obtain the title optically active substance with a retention time of 9.6 minutes (Example 1030, 5.4 mg, >99% ee) and the title optically active
substance with a retention time of 12.6 minutes (Example 1031, 5.3 mg, >97% ee). The physical properties of the compounds are as follows. ^-NMR (CDC13) 6 (ppm) : 1.70-1.95 (m, 2H) , 2.31 (s, 3H) , 2.78-2.92 (m, 2H), 3.15-3.23 (m, 1H), 3.30-3.39 (m,
1H), 3.85-3.97 (m, 1H), 3.87 (s, 3H), 4.02 (dd, J=8.0 Hz, 11.2 Hz, 1H), 4.26-4.32 (m, 1H), 4.43-4.48 (m, 1H),


6.00 (d, J=4.4 Hz, 1H), 6.91-7.01 (m, 3H), 7.05-7.13 (m, 3H), 7.22-7.29 (m, 2H), 7.75 (d, J=1.2 Hz, 1H), 7.89 (brs, 1H). [1022] 5 Example 1032 and Example 1033
Synthesis of (E)-1-[(IS,2R and 1R,23)-l-hydroxyindan-2-
yl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
[1023]
[Formula 322]
(Figure Remove)


MeO


198 mg of the title compound as a racemate 10 was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (400 mg) and cis-2-aminoindan-l-ol (CAS #23337-80-6, 188 mg) in the same manner as in Example 418. The compound (12 mg) was fractionated 15 using CHIRALCEL™ OJ manufactured by Daicel Chemical
Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 5.4 minutes (Example 1032, 3.5 mg, >99% ee) and the title optically active substance with 20 a retention time of 7.9 minutes (Example 1033, 2.8 mg, >97% ee). The physical properties of the compound are


as follows.
^-NMR (CDC13) 8 (ppm) : 1.83-1.91 (m, 2H) , 2.34 (s, 3H) , 2.72-2.89 (m, 2H), 3.18 (dd, J=8.4 Hz, 16.4 Hz, 1H) , 3.30-3.45 (m, 3H), 3.87 (s, 3H), 5.17-5.24 (m, 1H), 5 5.39 (d, J=5.2 Hz, 1H), 6.95 (s, 1H) , 7.02-7.07 (m, 2H), 7.24-7.34 (m, 4H), 7.44-7.48 (m, 1H), 7.80-7.85 (m, 2H). [1024]
Example 1034 and Example 1035
Synthesis of (E)-(3S)-(4-fluorophenyl)-6-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-(9R)-hexahydroindolizin-5-one and (E)-(3R)-(4-fluorophenyl)-6-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(9S)-hexahydroindolizin-5-one [1025]
[Formula 323]
(Figure Remove)
Synthesis of 6-chloro-(33*)-(4-fluorophenyl)-(9S*)-hexahydroindolizin-5-one
Sec-butyl lithium (1 M cyclohexane solution, 0.65 mL) was added to a solution of (3S*)-(4-fluorophenyl)-(9R*)-hexahydroindolizin-5-one (130 mg)
synthesized in accordance with the method described in The Journal of Organic Chemistry, 2001, vol.66, p.886 in THF (5 mL) at -40°C, and the reaction solution was


stirred at -40°C for 1 hour. The reaction solution was added dropwise to a solution of p-toluenesulfonic acid chloride (117 mg) in THF (2 mL) at -40°C. The reaction solution was stirred at -40°C for 30 minutes, and 5 further stirred at room temperature for 1 hour. Then, a saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate = 1:1 -> ethyl acetate) to obtain 84 mg of the title compound. Properties data of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.44-1.63 (m, 2H), 1.75-1.85 (m, 1H), 2.12-2.30 (m, 3H), 2.40-2.56 (m, 2H), 3.87-3.96 (m, 1H), 4.36 (dd, J=9.6, 6.8 Hz, 1H), 5.12 (t, J=8.0 Hz, 1H), 6.96-7.02 (m, 2H), 7.15-7.20 (m, 2H) . [1026]
Synthesis of diethyl [(33*)-(4-fluorophenyl)-5-oxo-(9S*)-octahydroindolizin-6-yl3 phosphonate
A mixture of 6-chloro-(33*)-(4-fluorophenyl)-(9S*)-hexahydroindolizin-5-one (84 mg) with triethyl phosphite (1 mL) was stirred at 170°C for 10 hours.
After allowing the reaction solution to be cooled to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution


solvent: ethyl acetate -> ethyl acetate:methanol = 9:1) to obtain 86 mg of the title compound. Properties data of the compound are as follows.
^-NMR (CDC13) 6 (ppm) : 1.22-1.38 (m, 6H) , 1.49-1.79 (m, 5 2H), 2.07-2.29 (m, 4H), 2.36-2.54 (m, 1H), 3.70-3.88 (m, 1H), 4.02-4.25 (m, 5H), 5.13 (t, J=8.0 Hz, 1H), 6.93-6.99 (m, 2H), 7.15-7.27 (m, 2H). [1027] Synthesis of (E)-(3S*)-(4-fluorophenyl)-6-[3-methoxy-4-
(4-methyl-lH-imidazol-l-yl)benzylidene]-(9R*)-hexahydroindolizin-5-one
Lithium hydroxide monohydrate (29 mg) was added to a solution of diethyl ((3S*)-(4-fluorophenyl)-5-oxo-(9S*)-octahydroindolizin-6-yl)phosphonate (86 mg)
and 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (51 mg) obtained in Example 1 in THF (2 mL) and ethanol (0.4 mL), and the reaction solution was stirred at room temperature for 19 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction
solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution
solvent: heptane:ethyl acetate = 1:1 -> ethyl acetate) to obtain 74 mg of the title compound. Properties data of the compound are as follows.
(CDC13) 8 (ppm): 1.43-1.55 (m, 1H) , 1.56-1.67 (m,


1H), 1.78-1.89 (m, 1H) , 2.21-2.33 (m, 5H), 2.44-2.53 (m, 1H), 2.69 (tt, J=16.0, 3.6 Hz, 1H), 3.10 (dt, J=16.0, 2.8 Hz, 1H), 3.84 (S, 3H), 3.92-4.02 (m, 1H), 5.20 (t, J=8.4 Hz, 1H), 6.93 (brs, 1H), 6.98-7.06 (m, 5 4H), 7.23-7.28 (m, 3H) , 7.72 (brs, 1H), 7.73 (d, J=2.4 Hz, 1H). [1028]
Synthesis of (E)-(3S)-(4-fluorophenyl)-6-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(9R)-10 hexahydroindolizin-5-one and (E)-(3R)-(4-fluorophenyl)-6- [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(9S)-hexahydroindolizin-5-one
(E)-(3S*)-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)-(9R*)-15 hexahydroindolizin-5-one as a racemate (50 rag) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol =3:7) to obtain the title optically active substance with a retention time of 16 20 minutes (22.7 mg; >99% ee) and the title optically active substance with a retention time of 33 minutes (17.2 mg; >99% ee).
The physical properties of the optically active substance with a retention time of 16 minutes 25 (Example 1034) are as follows.
^-NMR (CDC13) 5 (ppm) : 1.43-1.55 (m, 1H) , 1.56-1.67 (m, 1H), 1.78-1.89 (m, 1H), 2.21-2.33 (m, 5H), 2.44-2.53 (m, 1H), 2.69 (tt, J=16.0, 3.6 Hz, 1H) , 3.10 (dt,


J=16.0, 2.8 Hz, 1H), 3.84 (S, 3H) , 3.92-4.02 (m, 1H), 5.20 (t, J=8.4 Hz, 1H), 6.93 (brs, 1H), 6.98-7.06 (m, 4H), 7.23-7.28 (m, 3H), 7.72 (brs, 1H) , 7.73 (d, J=2.4 Hz, 1H).
The physical properties of the optically
active substance with a retention time of 33 minutes (Example 1035) are as follows.
XH-NMR (CDC13) 5 (ppm): 1.43-1.55 (m, 1H), 1.56-1.67 (m, 1H), 1.78-1.89 (m, 1H), 2.21-2.33 (m, 5H) , 2.44-2.53
(m, 1H), 2.69 (tt, J=16.0, 3.6 Hz, 1H), 3.10 (dt,
J=16.0, 2.8 Hz, 1H), 3.84 (S, 3H) , 3.92-4.02 (m, 1H), 5.20 (t, J=8.4 Hz, 1H), 6.93 (brs, 1H), 6.98-7.06 (m, 4H), 7.23-7.28 (m, 3H), 7.72 (brs, 1H), 7.73 (d, J=2.4 Hz, 1H).
[1029]
Example 1036 and Example 1037
Synthesis of (E)-(3S)-(4-fluorophenyl)-6-[3-methoxy-4-(4-methyl-lH-inu.dazol-l-yl) benzylidene] - (9S) -hexahydroindolizin-5-one and (E)-(3R)-(4-fluorophenyl)-
6-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]-(9R)-hexahydroindolizin-5-one [1030] [Formula 324]
(Figure Remove)


Synthesis of (E)- (3S*)-(4-fluorophenyl)-6-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(9S*)-hexahydroindolizin-5-one
43 mg of the title compound as a racemate was obtained from (3S*)-(4-fluorophenyl)-(9S*)-
hexahydroindolizin-5-one (115 mg) in the same manner as in Example 1034. Properties data of the compound are as follows. XH-NMR (CDC13) 6 (ppm): 1.72-1.88 (m, 3H) , 2.05-2.11 (m,
1H), 2.27-2.37 (m, 5H) , 2.70-2.81 (m, 1H), 3.15 (dt, J=16.8, 2.4 Hz, 1H), 3.76-3.84 (m, 1H), 3.85 (s, 3H) , 5.21 (d, J=8.8 Hz, 1H), 6.94 (brs, 1H), 7.00 (t, J=8.8 Hz, 2H), 7.05 (d, J=1.2 Hz, 1H) , 7.09 (dd, J=8.4, 1.2 Hz, 1H), 7.16 (dd, J=8.8, 5.2 Hz, 2H), 7.25 (d, J=8.4
Hz, 1H), 7.74 (s, 1H), 7.76 (d, J=2.0 Hz, 1H). [1031]
Synthesis of (E)-(3S)-(4-fluorophenyl)-6-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(9S)-hexahydroindolizin-5-one and (E)-(3R)-(4-fluorophenyl)-
6-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(9R)-hexahydroindolizin-5-one
(E)-(3S*)-(4-fluorophenyl)-6-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-(9S*)-hexahydroindolizin-5-one as a racemate (30 mg) was
fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol = 1:1) to obtain the title optically active substance with a retention time of 19


minutes (12.5 mg; >99% ee) and the title optically active substance with a retention time of 26 minutes (11.3 mg; >99% ee).
The physical properties of the optically 5 active substance with a retention time of 19 minutes (Example 1036) are as follows.
^-NMR (CDC13) 6 (ppm): 1.72-1.88 (m, 3H), 2.05-2.11 (m, 1H), 2.27-2.37 (m, 5H), 2.70-2.81 (m, 1H), 3.15 (dt, J=16.8, 2.4 Hz, 1H) , 3.76-3.84 (m, 1H), 3.85 (s, 3H), 10 5.21 (d, J=8.8 Hz, 1H), 6.94 (brs, 1H), 7.00 (t, J=8.8 Hz, 2H), 7.05 (d, J=1.2 Hz, 1H), 7.09 (dd, J=8.4, 1.2 Hz, 1H), 7.16 (dd, J=8.8, 5.2 Hz, 2H), 7.25 (d, J=8 . 4 Hz, 1H), 7.74 (s, 1H), 7.76 (d, J=2.0 Hz, 1H).
The physical properties of the optically 15 active substance with a retention time of 26 minutes (Example 1037) are as follows.
^-NMR (CDC13) 8 (ppm): 1.72-1.88 (m, 3H) , 2.05-2.11 (m, 1H), 2.27-2.37 (m, 5H), 2.70-2.81 (m, 1H), 3.15 (dt, J=16.8, 2.4Hz, 1H), 3.76-3.84 (m, 1H), 3.85 (s, 3H), 20 5.21 (d, J=8.8 Hz, 1H), 6.94 (brs, 1H), 7.00 (t, J=8.8 Hz, 2H), 7.05 (d, J=1.2 Hz, 1H), 7.09 (dd, J=8.4, 1.2 Hz, 1H), 7.16 (dd, J=8.8, 5.2 Hz, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.76 (d, J=2.0 Hz, 1H). [1032] 25 Example 1038
Synthesis of (E)-3-[2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene] -1-((IS)- (4-fluorophenyl)ethyl)piperidin-2-one


[1033] [Formula 325]
(Figure Remove)

Synthesis of 2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzonitrile
Zinc cyanide (4.05 g),
tris(dibenzylideneacetone)dipalladium (527 mg) and 5 1,1'-bis(diphenylphosphino)ferrocene (638 mg) were added to a solution of 1-(4-bromo-5-fluoro-2-methoxyphenyl)-4-methyl-lH-imidazole (16.7 g) obtained in Example 18 in DMF (100 mL) at room temperature, and the reaction solution was stirred with heat in a
nitrogen atmosphere at 120°C for 7 hours. Further, zinc cyanide (4.05 g), tris(dibenzylideneacetone)dipalladium (527 mg) and 1,1'-bis(diphenylphosphino)ferrocene (638 mg) were added to the reaction solution, and the reaction solution was stirred with heat for 7 hours.
After allowing the reaction solution to be cooled, concentrated aqueous ammonia and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, and then dried over anhydrous
magnesium sulfate and concentrated under reduced
pressure. The residue was recrystallized from ethyl acetate to obtain 9.5 g of the title compound.


Properties data of the compound are as follows. XH-NMR (CDC13) § (ppm): 2.35 (s, 3H), 3.93 (s, 3H), 6.98 (s, 1H), 7.20 (d, J=8.8 Hz, IE), 7.23 (d, J=5.6 Hz, 1H), 7.80 (s, 1H) . 5 [1034]
Synthesis of 2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzaldehyde
Sodium bis(2-methoxyethoxy)aluminum hydride (65% solution in toluene, 11.4 mLj was added dropwise
to a suspension of 2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzonitrile (8.85 g) in THF (180 mL) in a nitrogen atmosphere at -15°C, and the reaction solution was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at
room temperature for 10 minutes. Then, a 5 N aqueous solution of sodium hydroxide and ethyl acetate were added to the mixture and the organic layer was partitioned. The resulting organic layer was made acidic with 5 N aqueous hydrochloric acid, and the
mixture was stirred. Then, the mixture was neutralized with 5 N aqueous sodium hydroxide and the organic layer was partitioned. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (elution solvent: ethyl acetate) to obtain 3.32 g of the title compound. Properties data of the compound are as follows.
(CDC13) 8 (ppm): 2.30 (s, 3H) , 3.94 (s, 3H) , 7.00


(t, J=1.2 Hz, 1H), 7.14 (d, J=10 Hz, 1H) , 7.49 (d, J=5.6 Hz, 1H), 7.88 (d, J=1.2 Hz, 1H), 10.35 (s, 1H). [1035]
Synthesis of (E)-5-chloro-2-[2-fluoro-5-methoxy-4-(4-5 methyl-lH-imidazol-1-yl)benzylidene]valeric acid trifluoroacetate
Sodium hydride (containing mineral oil at 40%, 0.68 g) was added to a solution of tert-butyl 5-chloro-2-(diethoxyphosphoryl)valerate (5.59 g) in THF
(50 mL) in a nitrogen atmosphere at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. A solution of 2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzaldehyde (3.19 g) in THF (10 mL) was added to the reaction mixture,
and the reaction solution was stirred at room
temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl (E)-5-chloro~2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-l-yl)benzylidene)valerate (5.93
g). A solution of tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-l-yl) benzylidene)valerate in trifluoroacetic acid (30 mL) was stirred while cooling with ice. After 2 hours, the



reaction solution was concentrated under reduced pressure. Tert-butyl methyl ether was added to the resulting residue, and the resulting deposited solid was filtered to obtain 3 g of the title compound. 5 Properties data of the compound are as follows.
^-NMR (CDC13) § (ppm) : 2.03-2.10 (m, 2H) , 2.52 (s, 3H) , 2.65-2.69 (m, 2H) , 3.60 (t, J=6.4 Hz, 2H), 3.94 (s, 3H), 7.08 (d, J=6.4 Hz, 1H), 7.10 (t, J=1.6 Hz, 1H) , 7.21 (d, J=8.8 Hz, 1H), 7.78 (s, 1H) , 7.88 (d, J=2 Hz,
1H).
[1036]
Synthesis of (E)-3-[2-fluoro-5-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]-l-[(lS)-(4-
fluorophenyl)ethyl]piperidin-2-one
0.57 g of the title compound was obtained
from (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (1.0 g) and (S)-1-(4-fluorophenyl)ethylamine (447 mg) in the same manner as in Example 418. Properties data
of the compound are as follows.
^-NMR (CDC13) 8: 1.56 (d, J=7.2 Hz, 3H) , 1.65-1.74 (m, 1H), 1.78-1.87 (m, 1H), 2.30 (s, 3H) , 2.62-2.66 (m, 2H), 2.91-2.96 (m, 1H), 3.22-3.28 (m, 1H), 3.83 (s, 3H), 6.23 (q, J=7.2 Hz, 1H), 6.92-6.93 (m, 2H), 7.01-
7.06 (m, 3H), 7.30-7.35 (m, 2H), 7.75 (s, 1H), 7.84 (s, 1H) . [1037] Example 1039


Synthesis of (E)-1-[(4S)-chroman-4-yl]-3-[2-fluoro-5-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one [1038] [Formula 326]
(Figure Remove)
14 mg of the title compound was obtained from 5 (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-lH-imidazol-1-yl)-benzylidene)valeric acid trifluoroacetate (20 mg) and (4S)chroman-4-ylamine (10 mg) in the same manner as in Example 418. Properties data of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.70-1.90 (m, 2H), 2.12-2.25 (m, 2H) , 2.30 (s, 3H), 2.64-2.80 (m, 2H), 3.07-3.13 (m, 1H), 3.05-3.14 (m, 1H), 3.85 (s, 3H), 4.22-4.28 (m, 1H), 4.35-4.39 (m, 1H) , 6.23 (dd, J=6.4, 9.6 Hz, 1H), 6.84-6.96 (m, 4H), 7.05 (s, 1H), 7.08 (s, 1H) , 7.15-
7.19 (m, 1H), 7.76 (d, J=l.2 Hz, 1H), 7.87 (s, 1H). [1039]
Example 1040
Synthesis of (E)-1-[2,3-dihydrobenzo[1,4]dioxin-5-ylmethyl]-3-[2-fluoro-5-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one [1040] [Formula 327]



(Figure Remove)


10 mg of the title compound was obtained from (E) -5-chloro-2- (2-f luoro-5-methoxy-4- (4-methyl-lH-imidazol-1-yl) benzylidene) valeric acid trif luoroacetate (20 mg) and 2, 3-dihydro-l, 4-benzodioxin-5-ylmethylamine 5 hydrochloride (14 mg) in the same manner as in Example 418. Properties data of the compound are as follows. XH-NMR (CDC13) 8 (ppm) : 1.85-1.91 (m, 2H) , 2.30 (s, 3H) , 2.68 (t, J=6.4 Hz, 2H), 3.43 (t, J=6.0 Hz, 1H) , 3.83 (s, 3H) , 4.26-4.32 (m, 4H) , 4.73 (s, 2H) , 6.78-6.86 (m,
3H), 6.92 (d, J=6.4 Hz, 1H) , 6.93 (s, 1H) , 7.05 (d, J=9.6 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H) , 7.89 (s, 1H) . [1041]
Example 1041 Synthesis of (E) -3- [2-f luoro-5-methoxy-4- (4-methyl-lH-
imidazol-1-yl) benzylidene] -1- ( ( IS) -phenylethyl ) piperidin-2-one [1042]
[Formula 328]
(Figure Remove)

8 mg of the title compound was obtained from (E) -5-chloro-2- (2-f luoro-5-methoxy-4- (4-methyl-lH-


imidazol-1-yl)-benzylidene)valeric acid
trifluoroacetate (20 mg) and (S)-1-phenylethylamine (10 mg) in the same manner as in Example 418. Properties data of the compound are as follows.
^-NMR (CDC13) 8: 1.58 (d, J=7.2 Hz, 3H) , 1.65-1.74 (m, 1H), 1.65-1.84 m, 3H), 2.32 (s, 3H) , 2.62-2.65 (m, 2H), 2.92-2.98 (m, 1H) , 3.22-3.28 (m, 1H) , 3.84 (s, 3H) , 6.25 (q, J=7.2 Hz, 1H), 6.93-6.95 (m, 2H), 6.25 (q, J=8.8 Hz, 1H), 7.26-7.36 (m, 5H), 7.84 (s, 1H) . 10 [1043]
Example 1042
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]-l-methyl-6-phenylpiperidin-2-one
[1044]
[Formula 329]
(Figure Remove)
Lithium bis(trimethylsilyl)amide (1.0 M 15 solution in THF, 1.59 mL) was added dropwise to a
solution of l-methyl-6-phenylpiperidin-2-one (200 mg) synthesized in accordance with a technique described in a document (see N.P. Baens et al., "Tetrahedron", 1993, vol.49, pp.3193-3202, for example) in THF (5 mL) at -20 78°C, and the reaction solution was stirred at room temperature for 30 minutes. This solution was added dropwise to a solution of 3-methoxy-4-(4-methyl-lH-


imidazol-1-yl)benzaldehyde (248 mg) and a boron trifluoride-dimethyl ether complex (134 f^L) in THF at -78°C, and the reaction solution was stirred overnight while heating to room temperature. A saturated aqueous 5 solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to collect the part in which an aldol derivative eluted. The elution part was concentrated under reduced pressure. Methanesulfonyl chloride (33.9 mg),
triethylamine (206 ^L) and methylene chloride (25 mL) were added to the residue, and the reaction solution was stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer
was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by LC-MS to obtain 4.54 mg of the title compound. Properties data of the compound are as follows.
XH-NMR (CDC13) 8: 1.94-2.01 (m, 1H), 2.24-2.33 (m, 1H), 2.29 (s, 3H), 2.53-2.62 (m, 1H), 2.73-2.79 (m, 1H), 3.02 (s, 3H), 3.84 (s, 3H), 4.67 (t, J=4.4 Hz, 1H), 6.92 (s, 1H), 6.93-7.02 (m, 2H), 7.21-7.23 (m, 2H),


7.29-7.36 (m, 2H), 7.38-7.44 (m, 2H), 7.71 (s, 1H), 7.90 (s, 1H). ESI-MS; m/z388 [M++H]. [1045] 5 Example 1043 and Example 1044
Synthesis of (E)-1-(4-fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-(6R and S)-methylpiperidin-2-one [1046]
(Figure Remove) [Formula 330] MeO,
28.7 mg of the title compound as a racemate
10 was obtained from 1-(4-fluorobenzyl)-6-methylpiperidin-2-one (198 mg) and 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (194 mg) in the same manner as in Example 1042. The racemate (28.7 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical 15 Industries, Ltd. (2 cmx25 cm: mobile phase:
hexane:ethanol = 60:40) to obtain the title optically active substance with a retention time of 29 minutes (Example 1043, 5.97 mg; >99% ee) and the title optically active substance with a retention time of 31 20 minutes (Example 1044, 6.76 mg; >95% ee). The physical properties of the optically active compounds are as follows.


ESI-MS; m/z420 [M++H] . ^-NMR (CDC13) 6: 1.31 (d, J=6.8 Hz, 3H), 1.74-1.80 (m, 1H), 1.86-1.95 (m, 1H), 2.31 (s, 3H), 2.87-2.96 (m, 2H), 3.58-3.62 (m, 1H), 3.88 (s, 3H), 4.11 (d, J=14.8 Hz, 1H), 5.33 (d, J=14.8 Hz, 1H) , 5 6.95 (s, 1H), 6.99-7.11 (m, 4H) , 7.24-7.31 (m, 3H), 7.74 (s, 1H), 7.88 (s, 1H) . [1047]
Example 1045, Example 1046, Example 1047 and Example 1048
Synthesis of (E)-1-(4-fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-(4R,6S)-dimethylpiperidin-2-one, (E)-1-(4-fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(4S,6R)-dimethylpiperidin-2-one, (E)-1- (4-
fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(4S,6S)-dimethylpiperidin-2-one and (E)-1-(4-fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-(4R,6R)-dimethylpiperidin-2-one [1048] [Formula 331]
(Figure Remove)
Synthesis of diethyl[1-(4-fluorobenzyl)-4,6-dimethyl-2-oxopiperidin-3-yl]phosphonate
A solution of tert-butyl 2-


diethoxyphosphoryl-3-methyl-5-oxohexanoate (500 mg) synthesized in accordance with a technique described in a document (see A.M. Pudovik et al., "Chemical Abstracts", 1956, vol.50, p.2429, for example) and 5 trifluoroacetic acid (5.0 mL) in chloroform (5.0 mL) was stirred at room temperature for 4 hours, and then concentrated under reduced pressure. 4-fluorobenzylamine (170 jaL) , acetic acid (512 |^L) , and sodium triacetoxyborohydride (947 mg) were added to a
solution of the residue in THF (10 mL). The reaction solution was stirred at room temperature overnight, and further stirred with heat at 50°C for 10 hours. Ethyl acetate and water were added to the reaction solution, and the solution was adjusted to about pH 8 with a 5 N
aqueous solution of sodium hydroxide and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: hexane-ethyl acetate system) to obtain 292.8 mg of the title compound as a low-polar diastereomer and 88.4 mg of the title compound as a high-polar diastereomer.
Properties data of the low-polar diastereomer
are as follows.
ESI-MS; m/z372 [M++H]. 1H-NMR (CDC13) 8: 1.17 (d, J=6.8 Hz, 3H), 1.20 (d, J=6.4 Hz, 3H), 1.33 (d, J=7.6 Hz, 3H), 1.37 (d, J=7.2 Hz, 3H) 1.95-2.01 (m, 1H), 2.32-

2.48 (m, 1H), 2.80 (dd, J=26.8, 8.0 Hz, 1H), 3.54-3.62
(m, 1H), 4.14-4.26 (m, 4H), 4.38 (d, J=19.2 Hz, 1H),
4.44 (d, J=19.2 Hz, 1H), 5.39 (d, J=15.6 Hz, 1H), 6.97-
7.04 (m, 2H), 7.23-7.31 (m, 2H).
Properties data of the high-polar
diastereomer are as follows.
ESI-MS; m/z372 [M++H] . ^-NMR (CDC13) 8: 1.13 (d, J=6.8 Hz, 3H) , 1.22 (d, J=6.4 Hz, 3H), 1.34 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.48-1.56 (m, 1H), 1.86-
1.93 (m, 1H), 2.55-2.68 (m, 1H), 2.78 (dd, J=27.6, 6.0 Hz, 1H), 3.42-3.51 (m, 1H), 4.16-4.26 (m, 5H), 5.04 (d, J=14.8 Hz, 1H), 5.04 (d, J=14.8 Hz, 1H), 6.96-7.01 (m, 2H), 7.23-7.27 (m, 2H). [1049]
Synthesis of (E)-1-(4-fluorobenzyl)-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-4,6-dimethylpiperidin-2-one
Lithium hydroxide (175 mg) was added to a solution of low-polar diethyl[1-(4-fluorophenyl)-4,6-
dimethyl-2-oxopiperidin-3-yl]phosphorate (292.8 mg) obtained as above and 3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzaldehyde (150 mg) in a mixture of THF (3.0 mL) with ethanol (1.0 mL), and the reaction solution was stirred at room temperature. After 1
hour, the reaction solution was diluted with water and ethyl acetate and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then


concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: hexane-ethyl acetate system) to obtain 309.5 mg of the title compound as a 5 single diastereomer. The diastereomer was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmxSO cm; mobile phase: ethanol) to obtain an optically active substance with a retention time of 52 minutes (Example 1045, 36.8 mg; >99% ee) and
an optically active substance with a retention time of 56 minutes (Example 1046, 15.3 mg; >85% ee). The physical properties of the optically active compounds are as follows. ESI-MS; m/z434 [M++H] . ^-NMR (CDC13) 5: 1.35 (d, J=7. 6
Hz, 3H), 1.41 (d, J=6.8 Hz, 3H), 1.64-1.70 (m, 1H), 2.11-2.18 (m, 1H), 2.32 (s, 3H), 3.34-3.41 (m, 1H), 3.57-3.66 (m, 1H), 3.86 (s, 3H), 4.33 (d, J=15.6 Hz, 1H), 5.26 (d, J=15.6 Hz, 1H), 6.95 (s, 1H) , 6.99-7.08 (m, 5H), 7.24-7.28 (m, 2H), 7.75 (s, 1H), 7.76 (s, 1H).
Lithium hydroxide (52.5 mg) was added to a
solution of high-polar diethyl[1-(4-fluorophenyl)-4,6-dimethyl-2-oxopiperidin-3-yl]phosphorate (88.4 mg) obtained as above and 3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzaldehyde (45 mg) in a mixture of THF
(1.0 mL) with ethanol (0.3 mL), and the reaction solution was stirred at room temperature. After 1 hour, the reaction solution was diluted with water and ethyl acetate and the organic layer was partitioned.


The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: 5 Chromatorex™ NH, elution solvent: hexane-ethyl acetate system) to obtain 102.8 mg of the title compound as a single diastereomer. The diastereomer was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmxSO cm; mobile phase: ethanol) to
obtain an optically active substance with a retention time of 47 minutes (Example 1047, 41.5 mg; >97% ee) and an optically active substance with a retention time of 55 minutes (Example 1048, 45.4 mg; >86% ee). The physical properties of the optically active compounds
are as follows.
ESI-MS; m/z434 [M++H] . XH-NMR (CDC13) 5: 1.19 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.4 Hz, 3H), 1.76-1.81 (m, 2H), 2.35 (s, 3H), 3.22-3.32 (m, 1H), 3.58-3.64 (m, 1H), 3.87 (s, 3H)r 4.32 (d, J=15.2 Hz, 1H) , 5.31 (d, J=15.2
Hz, 1H), 6.96 (s, 1H), 7.00-7.06 (m, 5H), 7.25-7.31 (m, 2H) , 7.68 (s, 1H), 7.86 (s, 1H) . [1050]
Example 1049 and Example 1050 Synthesis of (E)-1-[(IS)-(4-fluorophenyl)ethyl]-3-[3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(6R and S)-methylpiperidin-2-one

(Figure Remove)
[1051] [Formula 332]
Synthesis of tert-butyl (E)-2-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]-5-oxohexanoate
5 N aqueous hydrochloric acid (1.0 mL) was added to a solution of tert-butyl 2-diethoxyphosphoryl-5 4-(2-methyl-[l,3]dioxolan-2-yl)butyrate (500 mg)
synthesized in the same manner as in Example 425 in THF (5.0 mL), and the reaction solution was stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction solution and the organic layer
was partitioned. The organic layer was washed with
brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (278 mg) and lithium hydroxide (93 mg) were added to a solution of
the residue in a mixture of THF (6.0 mL) with ethanol
(2.0 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was
washed with brine, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column


chromatography (elution solvent: hexane-ethyl acetate system) to obtain 250 mg of the title compound. ESI-MS; m/z385 [M++H] . ^-NMR (CDC13) 8: 1.56 (s, 9H) , 2.17 (s, 3H), 2.31 (s, 3H), 2.68-2.72 (m, 2H), 2.76-5 2.81 (m, 2H), 3.87 (s, 3H) , 6.94 (s, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.02 (s, 1H) , 7.26 (d, J==8.0 Hz, 1H) , 7.58 (s, 1H), 7.74 (s, 1H). [1052] Synthesis of (E)-1-[(IS)-(4-fluorophenyl)ethyl]-3-[3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-(6S and R)-methylpiperidin-2-one
(IS)-(4-fluorophenyl)ethylamine (90.5 mg), acetic acid (223 jo,L) and sodium triacetoxyborohydride (413 mg) were added to a solution of tert-butyl (E)-2-
(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-5-oxohexanoate (250 mg) in THF (5.0 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the reaction solution was adjusted to
about pH 8 with a 5 N aqueous solution of sodium
hydroxide and the organic layer was partitioned. The organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (elution solvent: chloroform-methanol
system) to obtain 224 mg of an amino derivative.
Trifluoroacetic acid (2.0 mL) was added to a solution of the amino derivative in chloroform (1.0 mL), and the reaction solution was stirred at room temperature for 6


hours. I PEA (167 yL) , EDC (137 mg) and HOBT (132 mg) were sequentially added to a solution of the residue obtained by concentrating the reaction solution under reduced pressure in DMF (20 mL), and the reaction 5 solution was stirred at room temperature for 5.5 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by
silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: hexane-ethyl acetate system) to obtain 68.5 rng of the title compound as a racemate. The racemate (68.5 mg) was fractionated using
CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: hexane:ethanol = 50:50) to obtain the title optically active substance with a retention time of 28 minutes (Example 1049, 19.9 mg; >99% de) and the title
optically active substance with a retention time of 31 minutes (Example 1050, 23.44 mg; >91% de). Title optically active substance with a retention time of 28 minutes (Example 1049) ^-NMR (CDC13) 8: 0.74 (d, J=6.8 Hz, 3H) , 1.61 (d, J=7.2
Hz, 3H), 1.78-1.91 (m, 2H), 2.34 (s, 3H), 2.85-2.88 (m, 2H), 3.68-3.71 (m, 1H), 3.87 (s, 3H), 5.99 (q, J=7.2 Hz, 1H), 6.96 (s, 1H), 6.99-7.07 (m, 2H), 7.10 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.38-


7.42 (m, 2H) , 7.81 (s, 1H) , 7.84 (s, 1H) .
ESI-MS; m/z434 [M++H].
Title optically active substance with a retention time
of 31 minutes (Example 1050) 5 ESI-MS; m/z434 [M++H] . ^-NMR (CDC13) 5: 1.31 (d, J=6.8
Hz, 3H), 1.52-1.69 (m, 2H), 1.64 (d, J=7.6 Hz, 3H),
2.34 (s, 3H), 2.79-3.00 (m, 2H), 3.40-3.45 (m, 1H),
3.88 (s, 3H), 6.13 (q, J=7.6Hz, 1H), 6.96 (s, 1H),
7.00-7.07 (m, 2H) , 7.12 (s, 1H) , 7.15 (d, J=8.0 Hz, 10 1H), 7.27 (d, J=8.0 Hz, 1H), 7.33-7.37 (m, 2H), 7.81
(s, 1H), 7.83 (s, 1H) .
[1053]
Example 1051 and Example 1052
Synthesis of (Z)-[(R) and (S)-chroman-4-yl]-2-[3-15 methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]morpholin-3-one
[1054]
[Formula 333]
(Figure Remove)
8.49 mg of the title compound as a racemate was obtained from 4-chroman-4-yl-morpholin-3-one (200 mg) synthesized in accordance with a technique 20 described in a document (see T. Morie et al., "J.
Heterocycles", 1994, vol.38, p.1033, for example) and 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde


(185 mg) in the same manner as in Example 1042. The racemate (8.49 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase: ethanol) to obtain the title 5 optically active substance with a retention time of 23 minutes (Example 1051, 1.47 mg; >99% ee) and the title optically active substance with a retention time of 31 minutes (Example 1052, 1.72 mg; >99% ee). The physical properties of the optically active compounds are as
follows.
ESI-MS; m/z432 [M++H] . ^-NMR (CDC13) 8: 2.17-2.22 (m, 2H), 2.32 (s, 3H), 3.21-3.26 (m, 1H), 3.43-3.49 (m, 1H), 3.87 (s, 3H), 4.16-4.28 (m, 3H), 4.32-4.35 (m, 1H), 6.13 (t, J=8.4 Hz, 1H) , 6.87 (d, J=7. 6 Hz, 1H) ,
6.91-6.95 (m, 3H), 7.07 (d, J=7.6 Hz, 1H) , 7.19 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.39-7.44 (m, 2H), 7.77 (s, 1H) . [1055] Example 1053
Synthesis of (Z)-4-[(IS) -(4-fluorophenyl)ethyl]-2-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]morpholin-3-one [1056] [Formula 334]

(Figure Remove)


1.4 mg of the title compound was obtained
from 4-((IS)-(4-fluorophenyl)ethyl)morpholin-3-one (200
mg) synthesized in accordance with a technique
described in a document (see T. Morie et al., "J. 5 Heterocycles", 1994, vol.38, p.1033, for example) and
3-methoxy-4~(4-methyl-lH-imidazol-l-yl)benzaldehyde
(194 mg) in the same manner as in Example 1042.
Properties data of the compound are as follows.
ESI-MS; m/z422 [M++H] . XH-NMR (CDC13) 8: 1.58 (d, J=7.6 Hz, 3H), 2.30 (s, 3H), 3.05-3.11 (m, 1H), 3.44-3.50 (m,
1H), 3.86 (s, 3H), 4.04-4.09 (m, 1H) , 4.20-4.25 (m,
1H), 6.14 (q, J=7.6 Hz, 1H), 6.91 (s, 1H) , 6.93 (s,
1H), 7.04-7.08 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.32-
7.41 (m, 4H), 7.73 (s, 1H). 15 [1057]
(Z)-4-[(IS)-(4-fluorophenyl)ethyl]-2- [3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]morpholin-3-one can also be separately
synthesized by the following method. [1058]
Synthesis of (Z)-4-[(IS)-(4-fluorophenyl)ethyl]-2-[3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]morpholin-3-one
[1059]
[Formula 335]

(Figure Remove)



Synthesis of tert-butyl (Z)-2-(2-chloroethoxy)-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]acrylate Lithium hydroxide (52.1 mg) was added to a solution of tert-butyl 2-chloroethoxy-
(diethoxyphosphoryl)acetate (240 mg) synthesized by a technique described in a document (see C.J. Moody et al., "Tetrahedron", 1992, vol.48, p.3991, for example) and 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (173 mg) in a mixture of THF (5.0 mL) with ethanol (1.0
mL), and the reaction solution was stirred at room temperature for 2.5 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain 51 mg of the title compound.
ESI-MS; m/z393 [M++H] . 1H-NMR (CDC13) 8: 1.58 (s, 9H) , 2.30 (s, 3H), 3.79 (t, J=5.2 Hz, 2H) , 3.90 (s, 3H), 4.25 (t, J=5.2 Hz, 2H) 6.89 (s, 1H), 6.96 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.32 (dd, J=8.4, 2.0 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.76 (s, 1H).
[1060]
Synthesis of (Z)-4-[(IS)-(4-fluorophenyl)ethyl]-2-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]morpholin-3-one

44.3 mg of the title compound was obtained
from tert-butyl (Z)-2-(2-chloroethoxy)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)acrylate (51 mg)
obtained as above and (S)-1-(4-fluorophenyl)ethylamine (26.3 nD in the same manner as in Example 418.
Properties data of the compound are as follows.
ESI-MS; m/z422 [M++H]. 1H-NMR (CDC13) 8: 1.58 (d, J=7. 6
Hz, 3H), 2.30 (s, 3H), 3.05-3.11 (m, 1H), 3.44-3.50 (m,
1H), 3.86 (s, 3H), 4.04-4.09 (m, 1H), 4.20-4.25 (m, 1H), 6.14 (q, J=7.6 Hz, 1H), 6.91 (s, 1H), 6.93 (s,
1H), 7.04-7.08 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.32-
7.41 (m, 4H), 7.73 (s, 1H).
[1061]
Example 1054 15 Synthesis of (E)-1-[(IS)-(4-fluorophenyl)ethyl]-3-[3-
methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene]pyrrolidin-2-one
[1062]
(Figure Remove) [Formula 336]
(X
Synthesis of diethyl {1-[(IS)-(4-fluorophenyl)ethyl]-2
oxo-pyrrolidin-3-yl}phosphonate
A mixture of 3-bromo-l-((IS)-(4-
fluorophenyl)ethyl)pyrrolidin-2-one (117 mg) synthesized in accordance with the method described in


Journal of Medicinal Chemistry, 1987, vol.30, p.1995 with triethyl phosphite (0.71 mL) was stirred at 150°C for 2 hours. The reaction solution was allowed to be cooled to room temperature, and concentrated under 5 reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate:methanol = 9:1) to obtain 60 mg of the title compound. Properties data of the compound are as follows.
ESI-MS; m/z344 [M++H]. [1063]
Synthesis of (E) -1-[(IS)-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-IH-imidazol-1-yl)benzylidene]pyrrolidin-2-one
Lithium hydroxide monohydrate (12.5 mg) was
added to a solution of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (21 mg) obtained in Example 1 and diethyl (1-((IS)-(4-fluorophenyl)ethyl)-2-oxopyrrolidin-3-yl)phosphonate (34 mg) in a mixture of
THF (2 mL) and ethanol (0.4 mL), and the reaction
solution was stirred at room temperature for 14 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was
dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate = 1:1 -> ethyl


acetate) to obtain 26 mg of the title compound. Properties data of the compound are as follows. ^-NMR (CDC13) 6 (ppm) : 1.60 (d, J=7.2 Hz, 3H) , 2,30 (s, 3H), 2.92-3.15 (m, 3H) , 3.44-3.51 (m, 1H), 3.87 (s, 5 3H), 5.68 (q, J=7.2 Hz, 1H) , 6.93 (brs, 1H), 7.00-7.05 (m, 2H), 7.09 (d, J=1.6 Hz, 1H) , 7.12 (dd, J=8.0, 1.6 Hz, 1H), 2.78 (d, J=8.0Hz, 1H), 7.30-7.34 (m, 2H), 7.37 (t, J=2.8 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H). [1064] 10 Example 1055 and Example 1056
Synthesis of (E) and (Z)-3-fluoro-N-(indan-1-yl)-3- [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-2-methylacrylamide [1065] [Formula 337]
(Figure Remove)




Synthesis of methyl 3-fluoro-3-[3-methoxy-4-(4-methyl- IH-imidazol-l-yl)phenyl]-2-methylacrylate
Diethyl (fluoro-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl)methyl)phosphonate (1.1 g) was obtained from 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (1 g) in accordance with the method 20 described in Tetrahedron Letters, 1996, vol.37, no. 5, p.629. Lithium diisopropylamide (1.5 M solution in


THF, 0.25 mL) was added to a solution of the resulting diethyl (fluoro-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)methyl)phosphonate (110 mg) in THF at -78°C, and the reaction solution was stirred at -78°C for 2 5 hours. Methyl pyruvate (32 mg) was added to the
reaction solution at -78°C. The reaction solution was stirred at -78°C for 15 minutes, and then further stirred at room temperature for 45 minutes. Saturated sodium bicarbonate water and ethyl acetate were added
to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl
acetate = 1:1 -> ethyl acetate) to obtain 39 mg of
methyl 3-fluoro-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl)-2-methylacrylate as a mixture of isomers (E) and (Z). Properties data of the compounds are as follows.
ESI-MS; m/z305 [M++H] . 1H-NMR (CDC13) 5 (ppm) : 2.02 (d, J=3.2 Hz, 1.5H), 2.07 (d, J=4.0 Hz, 1.5H), 2.31 (s, 3H), 3.66 (s, 1.5H), 3.86 (s, 1.5H), 3.87 (s, 1.5H), 3.89 (s, 1.5H), 6.96 (s, 1H), 7.09 (brd, J=8.8 Hz, 0.5H), 7.13 (brs, 1H), 7.16 (brd, J=8.8 Hz, 0.5H), 1.18
(brs, 1H), 7.26 (d, J=8.8 Hz, 0.5H), 7.31 (d, J=8.8 Hz, 0.5H), 7.77 (brs, 1H). [1066] Synthesis of (E) and (Z)-3-fluoro-N-indan-l-yl-3-[3-


methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]-2-methylacrylamide
A 1 N aqueous solution of sodium hydroxide (1.3 mL) was added to a solution of methyl 3-fluoro-3-5 (3-methoxy-4-(4-methyl-lH-imidazol-1-yl)phenyl)-2-methylacrylate (39 mg) in methanol (3 mL), and the reaction solution was stirred at room temperature for 18 hours. 5 N hydrochloric acid (0.26 mL) was added to the reaction solution, and the solution was
concentrated under reduced pressure. IPEA (0.09 mL)
was added to a solution of the resulting residue in DMF (5 mL). Further, 1-aminoindan (0.032 mL), HOBT (34.5 mg) and EDC (49 mg) were sequentially added thereto. The reaction solution was stirred at room temperature
for 3 hours, and saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate = 1:1 -> ethyl acetate) to obtain 16.8 mg of an isomer (E) of the title compound and 21.9 mg of an isomer (Z) of the title compound. Properties data of the
compounds are as follows.
(E)-3-fluoro-N-(indan-1-yl)-3-(3-methoxy-4-(4-methyl-IH-imidazol-l-yl)phenyl)-2-methylacrylamide (Example 1055)

(CDC13) 8 (ppm) : 1.52-1.63 (m, 1H) , 2.11 (d,
J=3.2 Hz, 3H), 2.33 (s, 3H) , 2.45-2.54 (m, 1H), 2.80 (t, J=6.8 Hz, 2H), 3.86 (s, 3H) , 5.40 (q, J=3.2 Hz,
1H) , 5.55 (d, J=8.4 Hz, 1H) , 6.87 (d, J=7 .2 Hz, 1H) , 5 6.93 (brs, 1H), 7.06-7.29 (m, 7H).
(Z)-3-fluoro-N-(indan-1-yl)-3-(3-methoxy-4-(4-methyl-
IH-imidazol-l-yl)phenyl)-2-methylacrylamide (Example
1056)
XH-NMR (CDC13) 8 (ppm): 1.87-1.97 (m, 1H), 2.08 (d, 10 J=2.8 Hz, 3H), 2.30 (s, 3H) , 2.65-2.74 (m, 1H), 2.88-
2.97 (m, 1H), 2.99-3.08 (m, 1H), 3.87 (s, 3H), 5.64 (q,
J=2.8 Hz, 1H), 6.59 (t, J=8. 4 Hz, 1H), 6.94 (brs, 1H),
7.11-7.40 (m, 7H), 7.74 (brs, 1H).
[1067]
The compounds shown in Table 28 were
synthesized as in Example 418. The structural formulae
and physical properties are shown in Table 28,
respectively. The separation conditions in the notes
to the table are as follows: 20 Separation Condition A: CHIRALPAK™ AD-H available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase: hexane-ethanol system)
Separation Condition B: CHIRALCEL™ OJ-H available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile 25 phase: hexane-ethanol)
Separation Condition C: CHIRALCEL™ OD-H available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase; hexane-ethanol)


Separation Condition D: CHIRALCEL™ IA available from Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase; hexane-ethanol)
Separation Condition E: CHIRALCEL™ OD available from 5 Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase; hexane-ethanol) [1068] [Table 28-1]
(Table Remove)
[1077]
Example 1119
Synthesis of (E)-1-[1-(4-fluorophenyl)-(1R,2R)-2-
hydroxy propyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-5 yl)ben2ylidene]piperidin-2-one [1078] [Formula 338]
HO,,,,
(Figure Remove)

By the same method as in Example 418, 8 mg of
the title compound was obtained from (E)-5-chloro-2-(3-
methoxy-4-(4-methyl-IH-imidazol-l-
yDbenzylidene)valeric acid trifluoroacetic acid salt 5 (17 mg) and (1R,2R)-1-amino-l-(4-fluorophenyl)propan-2-
ol 1 trifluoroacetic-acid salt (8.4 mg) synthesized
according to the method described in Tetrahedoron:
Asymmetry, 2000, vol. 11, p. 3079.
The physical properties of the compound are 10 as follows.
ESI-MS; m/z450 [M++H] . ^-NMR (CDC13) 6 (ppm) : 1.29 (d,
J=6.4 Hz, 3H), 1.72-1.93 (m, 2H), 2.31 (s, 3H), 2.69-
2.88 (m, 2H), 3.15-3.23 (m, 1H), 3.44-3.53 (m, 1H),
3.86 (s, 3H), 4.51 (dq, J-8.4, 6.4 Hz,lH), 5.44 (d, J=8.4 Hz, 1H), 6.94 (s, 1H), 7.02-7.09 (m, 4H), 7.25
(d, J=8.0 Hz, 1H), 7.34-7.40 (m, 2H) , 7.77 (d, J=0.8
Hz, 1H), 7.86 (brs, 1H).
[1079]
Example 1120 20 Synthesis of (E)-1-[1-(4-fluorophenyl)-(1R,2R)-2-
methoxypropyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
[1080]
[Formula 339]
(Figure Remove)


To a THF (1 mL) solution of (E)-l-(l-(4-fluorophenyl)-(IR,2R)-2-hydroxy propyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)piperidin-2-one(4 mg) obtained in Example 1119, sodium hydride (40% 5 mineral oil content, 0.5 mg) was added, and the
reaction solution was agitated at room temperature for 30 minutes. Methyl iodide (2 mg) was added to the reaction solution, and the reaction solution was agitated at room temperature for 2 hours. Saturated
sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate and concentrated under reduced pressure. By purifying the residue with silica gel
chromatography (Carrier: Chromatorex™ NH, elution
solvent: ethyl acetate -> ethyl acetate: methanol 9:1), 3 mg of the title compound was obtained. The physical properties of the compound are as follows. ESI-MS; m/z464 [M++H].
[1081]
Example 1121
Synthesis of (E)-1-[1-(4-fluorophenyl)-(IR,2S)-2-
hydroxy propyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
[1082]
[Formula 340;

(Figure Remove)
By the same method as in Example 418, 15 mg
of the title compound was obtained from (E)-5-chloro-2-
(3-methoxy-4-(4-methyl-IH-imidazol-l-
yl)benzylidene)valeric acid trifluoroacetic acid salt 5 (126 mg) and (IR,2S)-1-amino-l-(4-fluorophenyl)propan-
2-ol 1 trifluoroacetic-acid salt (63 mg) synthesized
according to the method described in Tetrahedoron:
Asymmetry, 2000, vol. 11, p. 3079.
The physical properties of the compound are as follows.
ESI-MS; m/z450 [M++H]. xH-NMR (CDC13) 8 (ppm): 1.36 (d,
J=6.0 Hz, 3H), 1.68-1.84 (m, 2H) , 2.30 (s, 3H), 2.67-
2.85 (m, 2H), 3.15-3.20 (m, 1H) , 3.25-3.35 (m, 1H),
3.84 (s, 3H), 4.55 (dq, J=7.6, 6.0 Hz,lH), 5.44 (d, 15 J=7.6 Hz, 1H), 6.92 (s, 1H), 7.02-7.09 (m, 4H), 7.24
(d, J=8.0 Hz, 1H), 7.45-7.50 (m, 2H) , 7.72 (d, J=0.8
Hz, 1H), 7.86 (brs, 1H).
[1083]
Examples 1122 and 1123 20 Synthesis of (E)-1-[(1R and IS)-1-(4-fluorophenyl)-2-
hydroxy-1-methylethyl]-3-[3-methoxy-4-(4-methyl-lH-
imidazol-1-yl)benzylidene]piperidin-2-one
[1084]
[Formula 341]
(Figure Remove)

[1085]
Synthesis of 2-(4-fluorophenyl)-3-methoxymethoxy-2-methylpropionic acid
To a methyl chloride (10 mL)-and-THF (5 mL) solution of 2-(4-fluorophenyl)-3-hydroxy-2-5 methylpropionic acid methyl ester (825 mg) synthesized according to the method described in Tetrahedron Letters, 1999, vol. 40, p. 5467, IPEA (2 mL) and chloromethyl methyl ether (0.74 mL) were added at 0°C. The reaction solution was agitated at 0°C for 1 hour,
and then at room temperature for 10 hours. IN
hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was washed with saturated sodium bicarbonate water, dried over
magnesium sulfate, and then concentrated under reduced pressure. To a methanol (5 mL) solution of the obtained residue, 5N sodium hydroxide aqueous solution (4 mL) was added, and the reaction solution was agitated at room temperature for 10 hours. 5N
hydrochloric acid (4 mL) and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate and concentrated under reduced pressure to obtain 850 mg of the title compound. The
physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm) : 1.60 (sr 3H) , 3.25 (s, 3H), 3.69 (d, J-9.2 Hz, 1H), 4.00 (d, J=9.2 Hz, 1H), 4,55 (d,


J-6.4 Hz,lH), 4.60 (d, J=6.4 Hz, 1H), 6.97 (t, J=8.4
Hz, 2H), 7.31 (dd, J=8.4, 4.8 Hz, 2H). [1086]
Synthesis of [1-(4-fluorophenyl)-2-hydroxy-l-5 methylethyl]carbamic acid tertiary butyl ester
252 mg of the title compound was obtained
from 2-(4-fluorophenyl)-3-methoxymethoxy-2-
methylpropionic acid (850 mg) obtained above according
to the method described in Tetrahedron Letters, 1998, vol. 39, p. 3749. The physical properties of the
compound are as follows.
ESI-MS; m/z270 [M++H].
[1087]
Synthesis of 2-amino-2-(4-fluorophenyl)propan-1-ol hydrochloric acid salt
To an ethyl acetate (1 mL) solution of (l-(4-
fluorophenyl)-2-hydroxy-l-methylethyl)carbamic acid
tertiary butyl ester (252 mg), 4 N hydrochloric acid
ethyl acetate solution (3 mL) was added, and the 20 reaction solution was agitated at room temperature for
3 hours. The reaction solution was concentrated under
reduced pressure to obtain 192 mg of the title
compound. The physical properties of the compound are
as follows. 25 ^-NMR (CDC13) 8 (ppm) : 1.69 (s, 3H) , 3.72 (d, J=11.6
Hz, 1H), 3.81 (d, J=11.6 Hz, 1H), 7.16-7.29 (m, 2H),
7.48-7.56 (m, 2H).
[1088]


Synthesis of (E)-1-[(1R and IS)-1-(4-fluorophenyl)-2-hydroxy-1-methylethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one
By the same method as in Example 418, 36 mg 5 of the racemic title compound was obtained from 2-amino-2-(4-fluorophenyl)propan-1-ol hydrochloric acid salt (192 mg) and (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (526 mg). The racemate
obtained (36 mg) was separated by CHIRALPAK™ AD-H
available from Daicel Chemical Industries, Ltd. (2 cm x 25 cm: mobile phase; IPA) to obtain the title optically-active substance with a retention time of 11 minutes (Example 1122, 15 mg; > 99% ee) the title
optically-active substance with a retention time of 12 minutes (Example 1123, 15 mg; > 99% ee).
The physical properties of the title
optically-active substance with a retention time of 11 minutes (Example 1122) are as follows.
ESI-MS; m/z450 [M++H]. xH-NMR (CDC13) 8 (ppm): 1.65-1.78 (m, 4H), 1.82-1.96 (m, 1H) , 2.31 (s, 3H), 2.76-2.82 (m, 2H),2.94-3.02 (m, 1H) , 3.13-3.21 (m, 1H), 3.51 (brd, J=11.2 Hz, 1H), 3.86 (s, 3H), 4.29 (d, J=11.2 Hz, 1H), 5.37 (brs, 1H),6.93 (d, J=1.2 Hz, 1H), 7.03-7.09 (m,
4H), 7.26 (d, J=7.6 Hz, 1H), 7.32 (dd, J=8.0, 5.2 Hz, 2H), 7.73 (s, 1H), 7.82 (brs, 1H).
The physical properties of the title optically-active substance with a retention time of 12


minutes (Example 1123) are as follows.
ESI-MS; m/z450 [M++H]. :H-NMR (CDC13) S (ppm): 1.65-1.78 (m, 4H), 1.82-1.96 (m, 1H) , 2.31 (s, 3H), 2.76-2.82 (m, 2H), 2.94-3.02 (m, 1H), 3.13-3.21 (m, 1H) , 3.51 (brd, 5 J-11.2 Hz, 1H), 3.86 (s, 3H) , 4.29 (d, J=11.2 Hz, 1H), 5.37 (brs, 1H), 6.93 (d, J=l.2 Hz, 1H), 7.03-7.09 (m, 4H), 7.26 (d, J=7.6 Hz, 1H), 7.32 (dd, J=8.0, 5.2 Hz, 2H), 7.73 (s, 1H), 7.82 (brs, 1H). [1089] 10 Examples 1124 and 1125
Synthesis of (E)-1-[(1R and IS)-1-(4-fluorophenyl)-2-methoxy-1-methylethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one [1090] [Formula 342]
-°(Figure Remove)
By the same method as in Examples 1122 and
15 1123, 10 mg of the racemic title compound was obtained from 1-(4-fluorophenyl)-2-methoxy-l-methylethylamine (11 mg) and (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (33 mg). The racemate obtained (5 mg) was 20 separated by CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase; hexanerlPA 8:1) to obtain the title optically-active

substance with a retention time of 41 minutes (Example
1124, 2.3 mg; > 99% ee) and the title optically-active
substance with a retention time of 50 minutes (Example
1125, 1.6 mg; > 99% ee).
The physical properties of the title
optically-active substance with a retention time of 41 minutes (Example 1124) are as follows.
ESI-MS; m/z464 [M++H]. ^-NMR (CDC13 ) 8 (ppm) : 1.78 (s, 3H), 1.90-1.98 (m, 2H), 2.31 (s, 3H), 2.76-2.83 (m,
2H), 3.36(s, 3H) , 3.63-3.67 (m, 2H) , 3.76 (brd, J=10.0 Hz, 1H), 3.83 (s, 3H), 4.07 (d, J=10.0 Hz, 1H), 6.93 (brs, 1H), 6.97-7.07 (m, 4H) , 7.22-7.28 (m, 3H), 7.62 (brs, 1H), 7.75 (s, 1H).
The physical properties of the title
optically-active substance with a retention time of 50 minutes (Example 1125) are as follows.
ESI-MS; m/z464 [M++H]. lH-NMR (CDC13) 5 (ppm): 1.78 (s, 3H), 1.90-1.98 (m, 2H) , 2.31 (s, 3H), 2.76-2.83 (m, 2H), 3.36 (s, 3H) , 3.63-3.67 (m, 2H), 3.76 (brd, J=10.0
Hz, 1H), 3.83 (s, 3H), 4.07 (d, J=10.0 Hz, 1H), 6.93 (brs, 1H), 6.97-7.07 (m, 4H), 7.22-7.28 (m, 3H), 7.62 (brs, 1H), 7.75 (s, 1H). [1091] Examples 1126 and 1127
Synthesis of (E)-1-[(IS)-2-hydroxy-l-(3, 4, 5-
trifluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one and (E)-l-[(1R)-2-hydroxy-l-(3,4,5-trifluorophenyl)ethyl]-3-[3-


methoxy-4-(4-methyl-lH-imidazol-l-yl) benzylidene]piperidin-2-one
[1092] [Formula 343]
(Figure Remove)
Synthesis of amino-(3,4,5-trifluorophenyl)acetonitrile
To a THF solution (20 mL) of 3,4,5-
trifluorobenzaldehyde (1.3 g) , trimethylsilylcyanide (1.35 mL) and zinc iodide (259 mg) were added, and the reaction solution was agitated at room temperature for 40 minutes. 2N ammonia solution in ethanol (15 mL) was added to the reaction solution, and the reaction
solution was agitated at 50°C for 4 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was
partitioned. The organic layer obtained was dried over magnesium sulfate, the solvent was removed under reduced pressure, and 780 mg of the title compound was obtained by purifying the residue with silica gel chromatography (Carrier: Chromatorex, elution solvent:
heptane-ethyl acetate system). The physical properties of the compound are as follows. XH-NMR (CD3OD) 8 (ppm) : 5.02 (s, 1H) , 7.32-7.37 (m,

2H) . [1093]
Synthesis of amino-(3,4,5-trifluorophenyl)acetic acid hydrochloric acid salt
To arnino- (3, 4, 5-trif luorophenyl) acetonitrile
(780 mg), 5N hydrochloric acid (10 mL) was added and the reaction solution was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature, washed with ether, and then the
aqueous layer was separated. The aqueous layer
obtained was concentrated under reduced pressure to obtain 933 mg of the title compound. The physical properties of the compound are as follows. XH-NMR (DMSO-d6) 8 (ppm): 7.18-7.46 (m, 2H), 7.54-7.58
(m, 1H) , 9.10 (brs, 1H) . [1094]
Synthesis of 2-amino-2-(3,4,5-trifluorophenyl)ethanol To a THF suspension (10 mL) of LAH (641 mg), THF suspension (15 mL) of amino-(3,4,5-
trifluorophenyl)acetic acid hydrochloric acid salt (933 mg) was added dropwise under cooling with ice. The reaction mixture was warmed to room temperature, and then agitated at room temperature for 7 hours. The reaction solution was once again cooled with ice, and
methanol (4 mL) and water (2 mL) were consecutively added to the reaction solution. The insoluble matter formed in the reaction solution was filtered off by celite, and the insoluble matter was further washed


with ether. The filtrate collected was dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain 587 mg of the title compound. The physical properties of the compound are 5 as follows.
1H-NMR (CDC13) 6 (ppm): 3.50 (dd, J-10.8, 8.0 Hz, 1H), 3.71 (dd, J=10.8, 4.0 Hz, 1H) , 4.03 (dd, J=8.0, 4.0 Hz, 1H), 6.97-7.02 (m, 2H). [1095]
Synthesis of (E)-1-[(IS)-2-hydroxy-l-(3,4,5-
trifluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]piperidin-2-one and (E)-l-[(1R)-2-hydroxy-l-(3,4,5-trifluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-lH-imidazol-l-
yl)benzylidene]piperidin-2-one
By the same method as in Example 418, 140 mg of the racemic title compound was obtained from (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetic acid salt
(400 mg) and 2-amino-2-(3,4,5-trifluorophenyl)ethanol (180 mg). The racemate obtained (15 mg) was separated by CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cm x 25 cm: [1096]
Examples 1128 and 1129
Synthesis of (E)-3-[3-methoxy-4-(4-methyl-lH-imidazol-
1-yl)benzylidene]-1-[(IS)-2-methoxy-l-(3,4,5-
trifluorophenyl)ethyl]piperidin-2-one and (E)-3-[3-


methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]-1-[(1R)-2-methoxy-l-(3,4,5-trifluorophenyl)ethyl]piperidin-2-one [1097] [Formula 344]
(Figure Remove)
To a THF (2 mL) solution of racemic (E)-l-(2-5 hydroxy-1-(3,4,5-trifluorophenyl)ethyl)-3-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl-benzylidene)piperidin-2-one (85 mg) obtained in Examples 1126 and 1127, sodium hydride (40% mineral oil content, 9.5 mg) was added under cooling with ice, and the reaction solution was
agitated for 30 minutes. Then, methyl iodide (12.3 ^L) was added to the reaction solution, and the reaction mixture was further agitated at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was
partitioned. The organic layer obtained was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex NH, elution solvent: heptane-ethyl acetate system -> ethyl acetate-
methanol system) to obtain 50 mg of the racemic title compound. The racemate obtained (50 mg) was separated by CHIRALPAK™ AD-H available from Daicel Chemical


Industries, Ltd. (2 cmx25 cm: mobile phase; ethanol), and the title optically-active substance with a retention time of 43 minutes (Example 1128, 10.5 mg; > 99% ee) and the title optically-active substance with a 5 retention time of 50 minutes (Example 1129, 6.9 mg; 95% ee) of the title compound were obtained. The physical properties of these title compounds are as follows. ESI-MS; m/z486 [M++H] . XH-NMR (CDC13) 8 (ppm): 1.71-1.92 (m, 2H), 2.30 (s, 3H), 2.74-2.90 (m, 2H), 3.10-3.17 (m,
1H), 3.36-3.43 (m, 1H) , 3.43 (s, 3H), 3.82-3.92 (m, 2H), 3.85 (s, 3H), 6.03 (t, J=6.0 Hz, 1H) , 6.93 (s, 1H), 6.98-7.05 (m, 4H) , 7.25 (d, J=8.0 Hz, 1H) , 7.74 (s, 1H), 7.86 (s, 1H). [1098]
Example 1130
Synthesis of (E)-2-(4-fluorobenzyl)-4-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]tetrahydropyrazine-
3-one
[1099]
[Formula 345]
(Figure Remove)
Synthesis of 4-bromo-2-(4-fluorobenzyl)-3-20 oxotetrahydropyrazine-1-carboxylic acid tertiary butyl ester
N'-(4-fluorobenzyl)hydrazine carboxylic acid


tertiary butyl ester (1.5 g) synthesized according to the method described in the literature (see, for example, H. L. Sham et al., J. Chem. Soc., Chem. Commun., 1993, vol. 13, p. 1052-1053) and 2,4-dibromo 5 dibromobutyrylchloride (908 uL) in a mixture of
dichloromethane (30 mL)-and-2N sodium hydroxide aqueous solution (5.0 mL) mixture of were vigorously agitated at room temperature. After 4.5 hours, the organic layer was separated. The organic layer obtained was
washed with aqueous saline solution, dried over
anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was diluted with acetonitrile (21 mL), potassium carbonate (1.55 g) was added, and the reaction mixture was agitated at room
temperature for 3.5 hours. Water and ethyl acetate were added to reaction solution and the organic layer was partitioned. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced
pressure. By purifying the residue with silica gel
chromatography (elution solvent: heptane-ethyl acetate system), 614 mg of the title compound was obtained. The physical properties of the compound are as follows. ESI-MS; m/z331 [M+-tert-butyl].
[1100]
Synthesis of (E)-2-(4-fluorobenzyl)-4-[3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene]-3-oxotetrahydropyrazine-1-carboxylic acid tertiary butyl

ester
A mixture of 4-bromo-2-(4-fluorobenzyl)-3-oxotetrahydropyrazine-1-carboxylic acid tertiary butyl ester (500 mg) and triethyl phosphite (3 mL) was 5 agitated under heating overnight at 120°C. The reaction solution was concentrated under reduced pressure, the residue was diluted with THF (20 mL) and ethanol (2 mL), lithium hydroxide (271 mg) and 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde (279 mg) were
added, and the reaction mixture was agitated at room temperature for 4 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with saturated saline solution, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate system) to obtain 614 mg of the title compound. The physical properties of the compound are as follows.
ESI-MS; m/z507 [M++H]. [1101]
Synthesis of (E)-2-(4-fluorobenzyl)-4-[3-methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]tetrahydropyrazine-3-one
A mixture of (E)-2-(4-fluorobenzyl)-4-(3-
methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)-3-oxotetrahydropyrazine-1-carboxylic acid tertiary butyl ester (582 mg) and trifluoroacetic acid (5 mL) was


agitated at. room temperature for 1 hour, and then concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate were added to the residue and the organic layer was partitioned. The 5 organic layer obtained was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate system), and 385 mg of
the title compound was obtained. The physical properties of the compound are as follows. ESI-MS; m/z407 [M++H] . ^-NMR (CDC13) 5 : 3.31 (s, 3H) , 2.91-2.95 (m, 2H), 3.15-3.21 (m, 2H), 3.87 (s, 3H), 4.08 (t, J=7.6 Hz, 1H), 4.78 (s, 2H), 6.94 (s, 1H),
7.00-7.05 (m, 2H), 7.07 (s, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.36-7.40 (m, 2H), 7.76 (s, 1H), 7.86 (s, 1H). [1102] Example 1131
Synthesis of (E)-l-acetyl-2-(4-fluorobenzyl)-4-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene]tetrahydropyrazine-3-one [1103] [Formula 346]
(Figure Remove)


(E)-2-(4-fluorobenzyl)-4-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)tetrahydropyrazine-3-one (31 mg) and a mixture of acetic anhydride (1 mL) and pyridine (1 mL) were agitated for 1 hour at room 5 temperature. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer obtained was washed with saturated saline solution,
dried over anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: chloroform-2-propanol system) to obtain 26.0 mg of the title compound. The physical properties of the
compound are as follows.
ESI-MS; m/z449 [M++H] . ^-NMR (CDC13) 8 : 2.13 (s, 3H) , 2.33 (s, 3H), 2.44-2.52 (m, 1H), 2.61-2.66 (m, 1H), 3.15-3.26 (m, 1H) , 3.87 (s, 3H) , 4.19 (d, J=14.4 Hz, 1H), 4.49-4.55 (m, 1H), 5.51 (d, J=14.4 Hz, 1H), 6.95
(s, 1H), 6.99-7.11 (m, 4H),7.27 (d, J=8.4 Hz, 1H), 7.38-7.42 (m, 2H), 7.67 (s, 1H), 7.84 (s, 1H). [1104]
Example 1132 Synthesis of (E)-2-(4-fluorobenzyl)-4-[3-methoxy-4-(4-
methyl-lH-imidazol-1-yl)benzylidene]-1-methyltetrahydropyrazine-3-one [1105] [Formula 347]

(Figure Remove)
(E)-2-(4-fluorobenzyl)-4-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)tetrahydropyrazine-3-one (50 mg) and a mixture of formic acid (2 mL) and formalin (2 mL) were heated under reflux for 2 hours. 5 Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated
under reduced pressure. The residue was purified by
silica gel chromatography (elution solvent: chloroform-2-propanol system) to obtain 36.7 mg of the title compound. The physical properties of the compound are as follows.
ESI-MS; m/z421 [M++H] . XH-NMR (CDC13) 8 : 2.31 (s, 3H) , 2.68 (s, 3H), 3.04-3.07 (m, 2H), 3.13-3.17 (m, 2H), 3.87 (s, 3H), 4.70 (s, 2H), 6.95 (s, 1H) , 6.98-7.03 (m, 2H), 7.11 (d, J=1.6 Hz, 1H) , 7.15 (dd, J=8.0, 1.6 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.37-7.41 (m, 2H), 7.75
(s, 1H), 7.80 (s, 1H). [1106]
Example 1133
Synthesis of (E)-l-ethyl-2-(4-fluorobenzyl)-4-(3-methoxy-4-[4-methyl-lH-imidazol-l-

yl)benzylidene]tetrahydropyrazine-3-one
(Figure Remove)
(E)-2-(4-fluorobenzyl)-4-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene}tetrahydropyrazine-3-one (50 ing) and a mixture of acetaldehyde (20.7 \iL) 5 and acetic acid (42.2 uL) and triacetoxy sodium
borohydride (78.2 mg) were agitated overnight at room temperature. Ethyl acetate and water were added to the reaction solution, the solution was adjusted to around pH 8 with 5N sodium hydroxide aqueous solution, and the
organic layer was separated. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: chloroform-
2-propanol system), and 38.8 mg of the title compound was obtained. The physical properties of the compound are as follows.
ESI-MS; m/z435 [M++H] . ^-NMR (CDC13) 8 : 1.13 (t, J=7.2 Hz, 3H), 2.34 (s, 3H), 2.93 (q, J=7.2 Hz, 2H) , 2.90-
2.98 (m, 2H), 3.11-3.15 (m, 2H), 3.88 (s, 3H), 4.70 (s, 2H), 6.96 (s, 1H), 6.98-7.03 (m, 2H), 7.11 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.39-


7.43 (m, 2H), 7.74 (s, 1H), 7.85 (s, 1H). [1108]
Example 925
Synthesis of (E)-1-[(1R)-1-(3-fluorophenyl)ethyl)-3-(3-5 methoxy-4-(4-methyl-IH-imidazol-l-yl)benzylidene]piperidin-2-one [1109] [Formula 349]
(Figure Remove)
To a DMF (3 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzylidene)valeric acid trifluoroacetic acid salt
(100 mg) obtained according to the method described in Example 418 and (S)-1-(3-fluorophenyl)ethylamine hydrochloric acid salt (31 mg), IPEA (0.2 mL) and HOBT (36 mg) and EDC (51 mg) were added, and the reaction solution was agitated at room temperature for 3 hours.
Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate and concentrated under reduced pressure. By purifying the residue with silica
gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate 1:1 -> ethyl acetate), 79 mg of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-1-yl)benzylidene)valeric acid ((lS)-l-(3-


fluorophenyl)ethyl)amide was obtained. Sodium hydride (40% mineral oil content, 8 mg) was added to the DMF (3 mL) solution of 5-chloro-2-(3-methoxy-4-(4-methyl-lH-imidazol-l~yl)benzylidene)valeric acid ((lS)-l-(3-5 fluorophenyl)ethyl)amide obtained, and the reaction solution was agitated at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over
anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate system 1:1 -> ethyl acetate) to obtain 48 mg of the
racemic title compound. The physical properties of the compound are as follows.
XH-NMR (CDC13) 8 (ppm): 1.56 (d, J=7.2 Hz, 3H), 1.60-1.80 (m, 2H), 2.32 (s, 3H), 2.72-2.90 (m, 2H), 2.94-3.00 (m, 1H) , 3.22-3.30 (m, 1H) , 3.86 (s, 3H) , 6.23 (d,
J=7.2, 1H), 6.92-7.00 (m, 2H), 7.02-7.07 (m, 3H), 7.12 (dd, J=7.2, 0.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.28-7.34 (m, 2H), 7.76 (d, J=1.2 Hz, 1H), 7.89 (s, 1H). [1110] Example 1134
Synthesis of (E)-N-[(IS)-indan-l-yl-3-[4-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyrimidin-2-yl]acrylamide [1111] [Formula 350]

(Figure Remove)
Synthesis of 4-methoxy-5-nitro-2-pyrimidine
To a solution of 2-chloro-3-methoxy-5-nitropyrimidine (CASNo. 282102-07-02, 670 ing), vinyl tri-n-butyltin (2.07 mL) and 2,6-di-t-butyl-4-5 methylphenol (30 mg) in DMF (15 mL) was added
bis(triphenylphosphine)palladium(II) dichloride (124 mg), and the reaction mixture was stirred at 35°C for 2 hrs. To the reaction mixture was added water and ethyl acetate, and the organic layer was separated. The
obtained organic layer was sequentially washed with water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent:
heptane/ethyl acetate) to give the title compound (261 mg). The physical data of the title compound was described as below.
ESI-MS; m/z!82 [M++H]. 1H-NMR(CDC13) 8.(ppm): 4.21 (s, 3H), 5.94 (dd, J=9.6, 2.8 Hz, 1H), 6.75-6.88
(m, 2H), 9.15 (s, 1H). [1112]
Synthesis of (E)-3-(4-methoxy-5-nitropyrimidin-2-yl)acrylic acid ethyl ester
A solution of 4-methoxy-5-nitro-2-


vinylpyrimidine (260 mg) in methylene chloride (15 mL) was stirred with an ozone stream of bubbling at -50°C for 1 hr. After the reaction mixture was warmed to -20°C, the ozone stream was stopped and dimethyl sulfide 5 (1.06 mL) was added to the reaction mixture. The reaction mixture was gradually warmed up to room temperature with stirring for 30 min. The reaction mixture was concentrated under reduced pressure to obtain the corresponding crude aldehyde. To a solution
of the crude aldehyde and triethyl phosphonoacetate (0.432 mL) in THF (5 mL) was added lithium hydroxide monohydrate (90.6 mg) at 0°C. After stirring for 1.5 hr at room temperature, water and ethyl acetate was added to the reaction mixture and an organic layer was
separated. The obtained organic layer was sequentially washed with water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent:
heptane/ethyl acetate) to give the title compound (100 mg). The physical data of the title compound was described as below.
^i-NMFUCDCls) 6.(ppm): 1.37 (t, J=6.8 Hz, 3H) , 4.23 (s, 3H), 4.32 (q, J=6.8 Hz, 2H), 7.25 (d, J=15.6 Hz, 1H),
7.60 (d, J=15.6 Hz, 1H), 9.18 (s, 1H). [1113]
Synthesis of (E)-3-[4-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyrimidin-2-yl]acrylic acid ethyl ester


According to the method described in Example 23, the title compound (27.8 mg) was obtained from (E)-3-(4-methoxy-5-nitropyrimidin-2-yl)acrylic acid ethyl ester (100 mg). The physical data of the title 5 compound was described as below.
1H-NMR(CDC13) 5(ppm): 1.37 (t, J=7.2 Hz, 3H), 2.31 (s, 3H), 4.14 (s, 3H) , 4.31 (q, J=7.2 Hz, 2H) , 6.99 (d, J=1.6 Hz, 1H), 7.15 (d, J=15.6 Hz, 1H), 7.61 (d, J=15.6 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 8.50 (s, 1H) .
[1114]
Synthesis of (E)-[(IS)-N-indan-1-yl]-3-[4-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyrimidin-2-yl]acrylamide To a solution of (E)-3-[4-methoxy-5-(4-methyl-lH-imidazol-1-yl)pyrimidin-2-yl]acrylic acid
ethyl ester (27.8 mg) in THF (1 mL) and ethanol (0.5
mL) was added IN sodium hydroxide aqueous solution (1.0 mL) at 0°C. After the reaction mixture was stirred at room temperature for 2hrs, saturated aqueous ammonium chloride was added to the reaction mixture, and the
reaction mixture was concentrated under reduced
pressure. The residue was diluted with MeOH, and the diluted solution was filtrated on florisil. The filtrate was concentrated under reduced pressure to give the corresponding crude carboxylic acid.
According to the method described in Example 23, the title compound (7.1 mg) was obtained from the crude carboxylic acid and (S)-1-aminoindan (61.8 jaL) . The physical data of the title compound was described as

below.
ESI-MS; m/z376 [M++H]. ^-NMR (CDC13) 6(ppm): 1.87-1.96 (m, 1H), 2.30 (s, 3H), 2.64-2.73 (m, 1H), 2.88-3.06 (m, 2H), 4.11 (s, 3H), 5.65 (dd, J=15.2, 7.6 Hz, 1H), 6.08 5 (d, J=7.6 Hz, 1H), 6.98 (s, 1H) , 7.18 (d, J=15.2 Hz, 1H), 7.20 -7.36 (m, 4H), 7.60 (d, J=15.2 Hz, 1H), 7.81 (s, 1H), 8.47 (s, 1H). [1115]
The compounds shown in Table 29 were
synthesized as in Example 121. The structural formulae 10 and physical properties are shown in Table 29, respectively.

[Table 29]
(Table Remove)
[1116]
The compounds shown in Table 30 were
synthesized as in Example 409. The structural formulae and physical properties are shown in Tables 30 and 31, respectively. [Table 30-1]
(Table Remove)
[1120]
The compounds shown in Table 31 were
synthesized as in Example 418. The structural formulae
and physical properties are shown in Table 31, respectively.
Separation Condition A: CHIRALPAK™AD-H available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase: hexane-ethanol system)
Separation Condition B: CHIRALCEL™ OJ-H available from Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase: hexane-ethanol)
Separation Condition C: CHIRALCEL™ OD-H available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase; hexane-ethanol) 15 Separation Condition D: CHIRALCEL™ IA available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase; hexane-ethanol)
Separation Condition E: CHIRALCEL™ OD available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile phase; hexane-ethanol)
Separation Condition F: CHIRALCEL™ OJ available from
Daicel Chemical Industries, Ltd. (2 cmx25 cm: mobile
phase; hexane-ethanol)
(Table Remove)

















Industrial Applicability [1129]
The compound of the general formula (I) of the present invention has an effect to reduce the production of AJHO and Ap42, hence is useful as a preventive or therapeutic agent for neurodegenerative 5 diseases caused by A0, such as in particular Alzheimer's disease and Down syndrome.















WE CLAIM:
1. A biarylacrylamide compound represented by Formula (I):
[Formula 1]
(Formula Removed)
or a pharmacologically acceptable salt thereof,
wherein Ar1 represents an imidazolyl group which may be substituted with 1 to 3 substituents
selected from Substituent Group Al shown below; Ar2 represents a pyridinyl group, a pyrimidinyl
group or a phenyl group which may be substituted with 1 to 3 substituents selected from
Substituent Group A2 shown below;
X1 represents (1) -C=C- or (2) -CR3=CR4- (wherein R3 represents a substituent selected from
Substituent Group A3 shown below and R4 represents a substituent selected from Substituent
Group A3-1 shown below); and
(1) R1 and R2 represent groups selected from Substituent Group A4 shown below; or
R1 and R2, together with a nitrogen atom to which they are bonded, form:
(2-1) a 5- to 11-membered heterocyclic group which may be substituted with 1 to 4 substituents
selected from Substituent Group A4 and is represented by Formula (II):
[Formula 2]
(Formula Removed)
wherein Y1 represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5=CR6- (wherein R5 and R6 represent substituents selected from Substituent Group A4 shown below), (11) a single bond or (12) >C=CR13R14 (wherein R13 and R14 represent substituents selected from Substituent Group A4 shown below); and ma and mb represent an integer of 0 to 4;
(2-2) a 6- to 20-membered non-aromatic heterocyclic group which may be substituted with 1 to 4 substituents selected from Substituent Group A4 and is represented by Formula (III):
[Formula 3]
(Formula Removed)
wherein Y2 represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5a=CR6a- (wherein R5a and R6a represent substituents selected from Substituent Group A4 shown below or R5a and R6a, together with a carbon atom to which they are bonded, form a 6- to 14-membered aromatic hydrocarbon ring group or a 3- to 14-membered non-aromatic hydrocarbon ring group) or (11) a single bond; and ma, mb, mc and mb represent an integer of 0 to 4;
(2-3) a 9- to 16-membered non-aromatic heterocyclic group which may be substituted with 1 to 4 substituents selected from Substituent Group A4 and is represented by Formula (IV): [Formula 4]
(Formula Removed)
wherein Y3 represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -
CONH-, (9) -NHCO- or (10) a single bond; and
ma and mb are the same as defined above;
(2-4) a group which may be substituted with 1 to 4 substituents selected from Substituent Group A4
and is represented by the following formula:
[Formula 5]
(Formula Removed)
(2-5) a group which may be substituted with 1 to 4 substituents selected from Substituent Group A4 and is represented by the following formula:
[Formula 6]
(Formula Removed)
R1 and R2, together with -X1-CO-N, form:
(3-1) a cyclic group which may be substituted with 1 to 4 substituents selected from Substituent
Group A4 and is represented by Formula (V):
[Formula 7]
(Formula Removed)
wherein Z1 represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -
CONH-, (9) -NHCO- or (10) a single bond; Z2 represents (1) a methine group or (2) a nitrogen
atom; R7 represents a substituent selected from Substituent Group A3 shown below; and na, nb and
nc represent an integer of 0 to 4;
(3-2) a cyclic group represented by Formula (VI):
[Formula 8]
wherein Z3 represents (1) a single bond, (2) -CO-, (3) -(CH2)nd- (wherein nd represents an integer
of 1 to 3) or (4) -CR8R9- (wherein R8 and R9 represent substituents selected from Substituent
Group A4 shown below);
Z4 represents (1) a single bond, (2) -O-, (3) -NRCO-, (4) -CONR-, (5) -CSNR-, (6) -NRCS-
(wherein R represents a substituent selected from Substituent Group A4 shown below) or (7) -S-;
Z5 represents (1) a single bond, (2) an imino group which may be substituted with a substituent
selected from Substituent Group A4 shown below, (3) -(CH2)ne- (wherein ne represents an integer
of 1 to 3), (4) -CR8R9- (wherein R8 and R9 are the same as defined above) or (5) -O-; and
R1 and R7 are the same as defined above; or
(3-3) a cyclic group which may be substituted with 1 to 4 substituents selected from Substituent
Group A4 and is represented by the following formula:
[Formula 9]
(Formula Removed)
wherein Rl and R7 are the same as defined above.
Substituent Group Al: (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a nitro group, (5) a C3-8 cycloalkyl group, (6) a C2-6 alkenyl group, (7) a C2-6 alkynyl group, (8) a C1-6 alkoxy group, (9) a C3-8 cycloalkoxy group, (10) a formyl group, (ll)aCl-6 alkylcarbonyl group and (12) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C1-6 alkoxy group, a C3-8 cycloalkyl group and a C1-6 alkylcarbonyl group). Substituent Group A2: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkoxy group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-8 cycloalkyl group), (6) a C3-8 cycloalkoxy group, (7) a C2-6 alkenyloxy group and (8) a C2-6 alkynyloxy group.
Substituent Group A3: (1) a hydrogen atom, (2) a halogen atom, (3) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 3- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (5) a C1-6 alkoxy group.
Substituent Group A3-1: (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (5) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 3- to 14-membered non-aromatic
hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (6) a C1-6 alkoxy group. Substituent Group A4:
(1) a hydrogen atom,
(2) a halogen atom,
(3) a hydroxyl group,
(4) a cyano group,
(5) a nitro group,
(6) a C3-8 cycloalkyl group,
(7) a C2-6 alkenyl group,
(8) a C2-6 alkynyl group,
(9) a C3-8 cycloalkoxy group,

(10) a C3-8 cycloalkylthio group,
(11) a formyl group,
(12) a C1-6 alkylcarbonyl group,
(13) a C1-6 alkylthio group,
(14) a C1-6 alkylsulfinyl group,
(15) a C1-6 alkylsulfonyl group,
(16) a hydroxy imino group,
(17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:

(a) a halogen atom,
(b) a hydroxyl group,
(c) a cyano group,
(d) a C3-8 cycloalkyl group,
(e) a C1-6 alkylthio group,
(f) a C1 -6 alkylsulfinyl group,
(g) a C1-6 alkylsulfonyl group, (h) a C1-6 alkylcarbonyl group, (i) a hydroxyimino group,
(j) a C1-6 alkoxyimino group,
(k) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a hydroxyl group),
(1) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(m) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(n) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(o) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(p) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below) and
(q) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below)),
(19)aC1-6 alkoxy group,
(20) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group which may be substituted with a 6- to 14-membered aromatic hydrocarbon ring group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(21) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(22) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(23) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(24) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(25) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(26) a C2-6 alkenyloxy group,
(27) a C2-6 alkynyloxy group,
(28) a C3-8 cycloalkylsulfinyl group,
(29) a C3-8 cycloalkylsulfonyl group,
(30) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(31) -CO-A (wherein A is the same as defined above) and
(32) =CH-A (wherein A is the same as defined above). Substituent Group A4-1:

(1) a halogen atom,
(2) a hydroxyl group,
(3) a cyano group,
(4) a nitro group,
(5) a C1-6 alkylcarbonyl group,
(6) a C1-6 alkylthio group,
(7) a C1-6 alkylsulfinyl group,
(8) a C1-6 alkylsulfonyl group,

(9) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a halogen atom),
(10) a C2-6 alkenyloxy group,
(11) a C2-6 alkynyloxy group,
(12) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a C3-8 cycloalkyl group),
(iv) a C2-6 alkenyloxy group,
(v) a C2-6 alkynyloxy group,
(vi) a C1-6 alkylthio group,
(vii) a C1-6 alkylsulfinyl group,
(viii) a C1-6 alkylsulfonyl group,
(ix) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(x) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(xi) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a
halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group) and
(xii) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(13) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(14) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(15) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(16) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6 alkyl group which may be substituted with 1 to 3 hydroxyl groups, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(17) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a
C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(18) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms) and
(19) -CO-A (wherein A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms).

2. The compound or pharmacologically acceptable salt thereof as claimed in claim 1 wherein Arl is an imidazolyl group which may be substituted with 1 to 2 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8 cycloalkyl group, (4) a C2-6 alkenyl group, (5) a C2-6 alkynyl group and (6) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 halogen atoms).
3. The compound or pharmacologically acceptable salt thereof as claimed in claim 1 wherein Ar2 is a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxy 1 group, (4) a cyano group, (6) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-8 cycloalkyl group), (7) a C2-6 alkenyloxy group and (8) a C2-6 alkynyloxy group.
4. The compound or pharmacologically acceptable salt thereof as claimed in claim 2 wherein Ar1 is an imidazolyl group which may be substituted with 1 to 2 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8 cycloalkyl group and (4) a C1-6 alkyl group.
5. The compound or pharmacologically acceptable salt thereof as claimed in claim 3 wherein Ar2 is a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group and (4) a C1-6 alkoxy group.
6. The compound or pharmacologically acceptable salt thereof as claimed in claim 1 wherein X1 is -C=C-.
7. The compound or pharmacologically acceptable salt thereof as claimed in claim 1 wherein X1 represents -CR3=CR4- (wherein R3 represents a substituent selected from Substituent Group A3 shown below and R4 represents a substituent selected from Substituent Group A3-1 shown below).
Substituent Group A3: (1) a hydrogen atom, (2) a halogen atom, (3) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 3- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (5) a C1-6 alkoxy group.
Substituent Group A3-1: (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (5) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a
protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 3- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (6) a C1-6 alkoxy group. Substituent Group A4:
(1) a hydrogen atom,
(2) a halogen atom,
(3) a hydroxyl group,
(4) a cyano group,
(5) a nitro group,
(6) a C3-8 cycloalkyl group,
(7) a C2-6 alkenyl group,
(8) a C2-6 alkynyl group,
(9) a C3-8 cycloalkoxy group,

(10) a C3-8 cycloalkylthio group,
(11) a formyl group,
(12) a C1-6 alkylcarbonyl group,
(13) a C1-6 alkylthio group,
(14) a C1-6 alkylsulfinyl group,
(15) a C1-6 alkylsulfonyl group,
(16) a hydroxyimino group,
(17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:
(a) a halogen atom,
(b) a hydroxyl group,
(c) a cyano group,
(d) a C3-8 cycloalkyl group,
(e) a C1-6 alkylthio group,
(f) a C1-6 alkylsulfinyl group,
(g) a C1-6 alkylsulfonyl group, (h) a C1-6 alkylcarbonyl group, (i) a hydroxyimino group,
(j) a C1-6 alkoxyimino group,
(k) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a hydroxyl group),
(1) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(m) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(n) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(o) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(p) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below) and
(q) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below)),
(19) a C1-6 alkoxy group,
(20) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group which may be substituted with a 6- to 14-membered aromatic hydrocarbon ring group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(21) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(22) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(23) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(24) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(25) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(26) a C2-6 alkenyloxy group,
(27) a C2-6 alkynyloxy group,
(28) a C3-8 cycloalkylsulfmyl group,
(29) a C3-8 cycloalkylsulfonyl group,
(30) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(31) -CO-A (wherein A is the same as defined above) and
(32) =CH-A (wherein A is the same as defined above). Substituent Group A4-1:
(1) a halogen atom,
(2) a hydroxyl group,
(3) a cyano group,
(4) a nitro group,
(5) a C1-6 alkylcarbonyl group,
(6) a C1-6 alkylthio group,
(7) a C1-6 alkylsulfinyl group,
(8) a C1-6 alkylsulfonyl group,

(9) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a halogen atom),
(10) a C2-6 alkenyioxy group,
(11) a C2-6 alkynyloxy group,
(12) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:
(i) a halogen atom,
(ii) a hydroxyl group,
(Hi) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a C3-8 cycloalkyl group),
(iv) a C2-6 alkenyioxy group,
(v) a C2-6 alkynyloxy group,
(vi) a C1-6 alkylthio group,
(vii) a C1-6 alkylsulfinyl group,
(viii) a C1-6 alkylsulfonyl group,
(ix) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyioxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(x) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the
group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(xi) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group) and
(xii) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(13) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(14) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(15) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(16) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy 1 group, a C1-6 alkyl group which may be substituted with 1 to 3
hydroxyl groups, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(17) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(18) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms) and
(19) -CO-A (wherein A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms).
8. The compound or pharmacologically acceptable salt thereof as claimed in claim 7
wherein X1 is -CR31=CR41- (wherein R31 is a group selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a C1-6 alkyl group and (4) a C1-6 alkoxy group; and R41 represents a group selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A5, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5 and (5) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C1-6 alkyl group, a C1-6 alkoxy group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A5, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5 and -O-Al (wherein Al represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent
Group A5 or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A5))).
Substituent Group A5: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 5 halogen atoms), (8) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 5 halogen atoms) and (9) an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms).
9. The compound or pharmacologically acceptable salt thereof as claimed in claim 8 wherein X1 is -CR32=CR42- (wherein R32 represents a hydrogen atom or a halogen atom; and R42 represents a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with a C3-8 cycloalkyl group or a phenyl group) and a phenyl group).
10. The compound or pharmacologically acceptable salt thereof as claimed in claim 1 wherein R1 and R2 are groups selected from Substituent Group A4 shown below.
Substituent Group A4:
(1) a hydrogen atom,
(2) a halogen atom,
(3) a hydroxyl group,
(4) a cyano group,
(5) a nitro group,
(6) a C3-8 cycloalkyl group,
(7) a C2-6 alkenyl group,
(8) a C2-6 alkynyl group,
(9) a C3-8 cycloalkoxy group,

(10) a C3-8 cycloalkylthio group,
(11) a formyl group,
(12) a C1-6 alkylcarbonyl group,
(13) a C1-6 alkylthio group,
(14) a C1-6 alkylsulfinyl group,
(15) a C1-6 alkylsulfonyl group,
(16) a hydroxyimino group,
(17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:

(a) a halogen atom,
(b) a hydroxyl group,
(c) a cyano group,
(d) a C3-8 cycloalkyl group,
(e) a C1-6 alkylthio group,
(f) a C1-6 alkylsulfinyl group,
(g) a C1-6 alkylsulfonyl group, (h) a C1-6 alkylcarbonyl group, (i) a hydroxyimino group,
(j) a C1-6 alkoxyimino group,
(k) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a hydroxyl group),
(1) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(m) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(n) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(o) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(p) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below) and
(q) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below)),
(19) a C1-6 alkoxy group,
(20) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group which may be substituted with a 6- to 14-membered aromatic hydrocarbon ring group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(21) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(22) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(23) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(24) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(25) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(26) a C2-6 alkenyloxy group,
(27) a C2-6 alkynyloxy group,
(28) a C3-8 cycloalkylsulfinyl group,
(29) a C3-8 cycloalkylsulfonyl group,
(30) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(31) -CO-A (wherein A is the same as defined above) and
(32) =CH-A (wherein A is the same as defined above). Substituent Group A4-1:

(1) a halogen atom,
(2) a hydroxyl group,
(3) a cyano group,
(4) a nitro group,
(5) a C1-6 alkylcarbonyl group,
(6) a C1-6 alkylthio group,
(7) a C1-6 alkylsulfinyl group,
(8) a C1-6 alkylsulfonyl group,

(9) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a halogen atom),
(10) a C2-6 alkenyloxy group,
(11) a C2-6 alkynyloxy group,
(12) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a C3-8 cycloalkyl group),
(iv) a C2-6 alkenyloxy group,
(v) a C2-6 alkynyloxy group,
(vi) a C1-6 alkylthio group,
(vii) a C1-6 alkylsulfinyl group,
(viii) a C1-6 alkylsulfonyl group,
(ix) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group
consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(x) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(xi) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group) and
(xii) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(13) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(14) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(15) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(16) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy I group, a C1-6 alkyl group which may be substituted with 1 to 3 hydroxy 1 groups, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(17) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(18) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms) and
(19) -CO-A (wherein A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms).
11. A compound as claimed in claim 1, represented by Formula (I):
[Formula 10]
(Formula Removed)
or a pharmacologically acceptable salt thereof,
wherein Ar1 represents an imidazolyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A1 shown below; Ar2 represents a pyridinyl group, a pyrimidinyl group or a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A2 shown below;
X1 represents (1) -C=C- or (2) -CR3=CR4- (wherein R3 represents a substituent selected from Substituent Group A3 shown below and R4 represents a substituent selected from Substituent Group A3-1 shown below);
R1 is a group selected from Substituent Group A8 shown below; and R2 is a group selected from Substituent Group A6 shown below.
Substituent Group Al: (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a nitro group, (5) a C3-8 cycloalkyl group, (6) a C2-6 alkenyl group, (7) a C2-6 alkynyl group, (8) a C1-6 alkoxy group, (9) a C3-8 cycloalkoxy group, (10) a formyl group, (ll)aC1-6 alkylcarbonyl group and (12) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C1-6 alkoxy group, a C3-8 cycloalkyl group and a C1-6 alkylcarbonyl group). Substituent Group A2: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkoxy group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-8 cycloalkyl group), (6) a C3-8 cycloalkoxy group, (7) a C2-6 alkenyloxy group and (8) a C2-6 alkynyloxy group. Substituent Group A3: (1) a hydrogen atom, (2) a halogen atom, (3) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 3- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-
membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (5) a C1-6 alkoxy group.
Substituent Group A3-1: (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (5) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 3- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (6) a C1-6 alkoxy group. Substituent Group A4:
(1) a hydrogen atom,
(2) a halogen atom,
(3) a hydroxyl group,
(4) a cyano group,
(5) a nitro group,
(6) a C3-8 cycloalkyl group,
(7) a C2-6 alkenyl group,
(8) a C2-6 alkynyl group,
(9) a C3-8 cycloalkoxy group,
(10) a C3-8 cycloalkylthio group,
(11) a formyl group,
(12) a C1-6 alkylcarbonyl group,
(13) a C1-6 alkylthio group,
(14) a C1-6 alkylsulfinyl group,
(15) a C1-6 alkylsulfonyl group,
(16) a hydroxyimino group,
(17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:

(a) a halogen atom,
(b) a hydroxyl group,
(c) a cyano group,
(d) a C3-8 cycloalkyl group,
(e) a C1-6 alkylthio group,
(f) a C1-6 alkylsulfinyl group,
(g) a C1-6 alkylsulfonyl group, (h) a C1-6 alkylcarbonyl group, (i) a hydroxyimino group,
G) a C1-6 alkoxyimino group,
(k) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a hydroxyl group),
(1) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(m) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(n) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(o) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(p) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3-substituents selected from Substituent Group A4-1 shown below) and
(q) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below)),
(19) a C1-6 alkoxy group,
(20) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group which may be substituted with a 6- to 14-membered aromatic hydrocarbon ring group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(21) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(22) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(23) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(24) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(25) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(26) a C2-6 alkenyloxy group,
(27) a C2-6 alkynyloxy group,
(28) a C3-8 cycloalkylsulfinyl group,
(29) a C3-8 cycloalkylsulfonyl group,
(30) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(31) -CO-A (wherein A is the same as defined above) and
(32) =CH-A (wherein A is the same as defined above). Substituent Group A4-1:

(1) a halogen atom,
(2) a hydroxyl group,
(3) a cyano group,
(4) a nitro group,
(5) a C1-6 alkylcarbonyl group,
(6) a C1-6 alkylthio group,
(7) a C1-6 alkylsulfinyl group,
(8) a C1-6 alkylsulfonyl group,

(9) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a halogen atom),
(10) a C2-6 alkenyloxy group,
(11) a C2-6 alkynyloxy group,
(12) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:
(i) a halogen atom, (ii) a hydroxyl group,
(iii) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a C3-8 cycloalkyl group),
(iv) a C2-6 alkenyloxy group,
(v) a C2-6 alkynyloxy group,
(vi) a C1-6 alkylthio group,
(vii) a C1-6 alkylsulfinyl group,
(viii) a C1-6 alkylsulfonyl group,
(ix) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(x) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(xi) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group) and
(xii) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(13) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(14) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(15) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(16) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6 alkyl group which may be substituted with 1 to 3 hydroxyl groups, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(17) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(18) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms) and
(19) -CO-A (wherein A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms). Substituent Group A6: (1) a hydrogen atom, (2) a C3-8 cycloalkyl group, (3) a C3-8 cycloalkoxy group, (4) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a C1-6 alkylthio group, a hydroxyimino group, a C1-6 alkoxyimino group, a C1-6 alkoxy group, an amino group (wherein
the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below and -0-A2 (wherein A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below)) and (5) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a C1-6 alkylthio group, a hydroxyimino group, a C1-6 alkoxyimino group, a C1-6 alkoxy group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below and -0-A2 (wherein A2 is the same as defined above)). Substituent Group A7: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a C1-6 alkylcarbonyl group, (8) a C1-6 alkylthio group, (9) a C1-6 alkylsulfinyl group, (10) a C1-6 alkylsulfonyl group, (11) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a 6- to 14-membered aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group and -0-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group)), (12) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 5 halogen atoms or the adjacent C1-6 alkoxy groups, together with a carbon atom to which they are bonded, may form a cyclic group), (13) an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), (14) a 6- to
14-membered aromatic hydrocarbon ring group, (15) a 5- to 14-membered aromatic heterocyclic group, (16) a 5- to 14-membered non-aromatic heterocyclic group and (17) -CO-A3 (wherein A3 is the same as defined above).
Substituent Group A8: (1) a hydrogen atom, (2) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a formyl group, a C1-6 alkyl group (wherein the one or two C1-6 alkyl groups may substitute the same carbon atom in the C1-6 alkylene group and the two C1-6 alkyl groups, together with a carbon atom to which they are bonded, may form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a C1-6 alkoxy group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, a 5-to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 and -X-A2 (wherein X represents an imino group, -O- or -S- and A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7)), (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 and (5) -X-A2 (wherein X and A2 are the same as defined above).
12. The compound or pharmacologically acceptable salt thereof as claimed in claim 11
wherein R1 is a C1-6 alkyl group (wherein the C1-6 alkyl group is a hydrogen atom, a C3-8 cycloalkoxy group, a C1-6 alkyl group (wherein the one or two C1-6 alkyl groups may substitute the same carbon atom in the C1-6 alkylene group and the two C1-6 alkyl groups, together with a carbon atom to which they are bonded, may form a cyclic group (wherein a methylene group in the cyclic group which constitutes the ring may be substituted with one oxygen atom)), a C1-6 alkoxy
group, a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and -0-A4 (wherein A4 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9)); and R2 is (1) a hydrogen atom or (2) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkoxy group, a C1-6 alkylthio group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A9, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9 and a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A9).
Substituent Group A9: (1) a hydrogen atom, (2) a halogen atom, (3) a C3-8 cycloalkyl group, (4) a C3-8 cycloalkoxy group, (5) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom and a C1-6 alkyl group), (6) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 5 halogen atoms or the adjacent C1-6 alkoxy groups, together with a carbon atom to which they are bonded, may form a cyclic group), (7) an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), (8) a 5- to 14-membered non-aromatic heterocyclic group, (9) -CO-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group), (10) a 6- to 14-membered aromatic hydrocarbon ring group and (11) a 5- to 14-membered aromatic heterocyclic group.
13. The compound or pharmacologically acceptable salt thereof as claimed in claim 1
wherein R1 and R2, together with a nitrogen atom to which they are bonded, form a 5- to 11-membered heterocyclic group which may be substituted with 1 to 4 substituents selected from Substituent Group A4 shown below and is represented by Formula (II):
[Formula 11]
(Formula Removed)
wherein Yl represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5=CR6- (wherein R5 and R6 represent substituents selected from Substituent Group A4 shown below), (11) a single bond or (12) >C=CR13R14 (wherein R13 and R14 represent substituents selected from Substituent Group A4 shown below); and ma and mb represent an integer of 0 to 4. Substituent Group A4:
(1) a hydrogen atom,
(2) a halogen atom,
(3) a hydroxyl group,
(4) a cyano group,
(5) a nitro group,
(6) a C3-8 cycloalkyl group,
(7) a C2-6 alkenyl group,
(8) a C2-6 alkynyl group,
(9) a C3-8 cycloalkoxy group,

(10) a C3-8 cycloalkylthio group,
(11) a formyl group,
(12) a C1-6 alkylcarbonyl group,
(13) a C1-6 alkylthio group,
(14) a C1-6 alkylsulfinyl group,
(15) a C1-6 alkylsulfonyl group,
(16) a hydroxyimino group,
(17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:

(a) a halogen atom,
(b) a hydroxyl group,
(c) a cyano group,
(d) a C3-8 cycloalkyl group,
(e) a C1-6 alkylthio group,
(f) a C1-6 alkylsulfinyl group,
(g) a C1-6 alkylsulfonyl group, (h) a C1-6 alkylcarbonyl group, (i) a hydroxyimino group,
(j) a C1-6 alkoxyimino group,
(k) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a hydroxyl group),
(1) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(m) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(n) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(o) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(p) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below) and
(q) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below)), (19) a C1-6 alkoxy group,
(20) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group which may be substituted with a 6- to 14-membered aromatic hydrocarbon ring group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(21) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(22) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(23) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(24) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(25) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(26) a C2-6 alkenyloxy group,
(27) a C2-6 alkynyloxy group,
(28) a C3-8 cycloalkylsulfinyl group,
(29) a C3-8 cycloalkylsulfonyl group,
(30) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(31) -CO-A (wherein A is the same as defined above) and
(32) =CH-A (wherein A is the same as defined above). Substituent Group A4-1:

(1) a halogen atom,
(2) a hydroxyl group,
(3) a cyano group,
(4) a nitro group,
(5) a C1-6 alkylcarbonyl group,
(6) a C1-6 alkylthio group,
(7) a C1-6 alkylsulfinyl group,
(8) a C1-6 alkylsulfonyl group,

(9) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a halogen atom),
(10) a C2-6 alkenyloxy group,
(11) a C2-6 alkynyloxy group,
(12) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a C3-8 cycloalkyl group),
(iv) a C2-6 alkenyloxy group,
(v) a C2-6 alkynyloxy group,
(vi) a C1-6 alkylthio group,
(vii) a C1-6 alkylsulfinyl group,
(viii) a C1-6 alkylsulfonyl group,
(ix) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(x) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be
substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(xi) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group) and
(xii) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(13) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(14) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(15) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(16) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6 alkyl group which may be substituted with 1 to 3 hydroxyl groups, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be
substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(17) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(18) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms) and
(19) -CO-A (wherein A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms).
14. The compound or pharmacologically acceptable salt thereof as claimed in claim 13
wherein the 5- to 11-membered heterocyclic group is a piperidinyl group, a pyrrolidinyl group, an
azepinyl group, an azocanyl group, a piperazinyl group, a 1,4-diazepanyl group, a morpholinyl
group or a thiomorpholinyl group.
15. A compound as claimed in claim 1, represented by Formula (I):
[Formula 12]
or a pharmacologically acceptable salt thereof,
wherein Arl represents an imidazolyl group which may be substituted with 1 to 3 substituents
selected from Substituent Group Al shown below; Ar2 represents a pyridinyl group, a pyrimidinyl
group or a phenyl group which may be substituted with 1 to 3 substituents selected from
Substituent Group A2 shown below;
X1 represents (1) -C=C- or (2) -CR3=CR4- (wherein R3 represents a substituent selected from
Substituent Group A3 shown below and R4 represents a substituent selected from Substituent
Group A3-1 shown below); and
R1 and R2, together with a nitrogen atom to which are bonded, form a piperidinyl group, a pyrrolidinyl group, an azepinyl group, an azocanyl group, a piperazinyl group, a 1,4-diazepanyl group, a morpholinyl group or a thiomorpholinyl group which may be substituted with 1 to 3 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a formyl group, (5) a hydroxyimino group, (6) a C1-6 alkoxyimino group, (7) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 hydroxyl groups or 1 to 3 substituents selected from the group consisting of a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below and a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below), (8) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from substituents of A7 shown below, (9) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below, (10) -0-A2 (wherein A2 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A7 shown below), (11) -CO-A2 (wherein A2 is the same as defined above) and (12) =CH-A2 (wherein A2 is the same as defined above). Substituent Group Al: (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a nitro group, (5) a C3-8 cycloalkyl group, (6) a C2-6 alkenyl group, (7) a C2-6 alkynyl group, (8) a C1-6 alkoxy group, (9) a C3-8 cycloalkoxy group, (10) a formyl group, (ll)aC1-6 alkylcarbonyl group and (12) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C1-6 alkoxy group, a C3-8 cycloalkyl group and a C1-6 alkylcarbonyl group). Substituent Group A2: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a C1-6 alkoxy group, a C2-6 alkenyl group, a C2-6 alkynyl group and a C3-8 cycloalkyl group), (6) a C3-8 cycloalkoxy group, (7) a C2-6 alkenyloxy group and (8) a C2-6 alkynyloxy group. Substituent Group A3: (1) a hydrogen atom, (2) a halogen atom, (3) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent
Group A4, (4) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 3- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (5) a C1-6 alkoxy group.
Substituent Group A3-1: (1) a hydrogen atom, (2) a halogen atom, (3) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (4) a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, (5) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a formyl group, a halogen atom, a hydroxyl group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkylcarbonyl group, an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 3- to 14-membered non-aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A4, a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with 1
to 3 substituents selected from Substituent Group A4 and -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4)) and (6) a C1-6 alkoxy group. Substituent Group A4:
(1) a hydrogen atom,
(2) a halogen atom,
(3) a hydroxy 1 group,
(4) a cyano group,
(5) a nitro group,
(6) a C3-8 cycloalkyl group,
(7) a C2-6 alkenyl group,
(8) a C2-6 alkynyl group,
(9) a C3-8 cycloalkoxy group,

(10) a C3-8 cycloalkylthio group,
(11) a formyl group,
(12) a C1-6 alkylcarbonyl group, (13)aC1-6 alkylthio group,

(14) a C1-6 alkylsulfinyl group,
(15) a C1-6 alkylsulfonyl group,
(16) a hydroxy imino group,
(17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:

(a) a halogen atom,
(b) a hydroxyl group,
(c) a cyano group,
(d) a C3-8 cycloalkyl group,
(e) a C1-6 alkylthio group,
(f) a C1-6 alkylsulfinyl group,
(g) a C1-6 alkylsulfonyl group,
(h) a C1-6 alkylcarbonyl group,
(i) a hydroxyimino group,
(j) a C1-6 alkoxyimino group,
(k) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a hydroxyl group),
(1) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(m) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(n) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(o) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(p) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below) and
(q) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below)),
(19) a C1-6 alkoxy group,
(20) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group which may be substituted with a 6- to 14-membered aromatic hydrocarbon ring group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(21) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(22) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(23) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(24) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(25) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(26) a C2-6 alkenyloxy group,
(27) a C2-6 alkynyloxy group,
(28) a C3-8 cycloalkylsulfinyl group,
(29) a C3-8 cycloalkylsulfonyl group,
(30) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(31) -CO-A (wherein A is the same as defined above) and
(32) =CH-A (wherein A is the same as defined above). Substituent Group A4-1:

(1) a halogen atom,
(2) a hydroxyl group,
(3) a cyano group,
(4) a nitro group,
(5) a C1-6 alkylcarbonyl group,
(6) a C1-6 alkylthio group,
(7) a C1-6 alkylsulfinyl group,
(8) a C1-6 alkylsulfonyl group,
(9) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a halogen atom),
(10) a C2-6 alkenyloxy group,
(11) a C2-6 alkynyloxy group,
(12) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a C3-8 cycloalkyl group),
(iv) a C2-6 alkenyloxy group,
(v) a C2-6 alkynyloxy group,
(vi) a C1-6 alkylthio group,
(vii) a C1-6 alkylsulfinyl group,
(viii) a C1-6 alkylsulfonyl group,
(ix) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(x) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(xi) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3
halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group) and
(xii) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(13) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(14) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(15) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(16) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy 1 group, a C1-6 alkyl group which may be substituted with 1 to 3 hydroxyl groups, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(17) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group and a C1-6 alkylsulfonyl group),
(18) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms) and
(19) -CO-A (wherein A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms). Substituent Group A7: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl group, (6) a C3-8 cycloalkoxy group, (7) a C1-6 alkylcarbonyl group, (8) a C1-6 alkylthio group, (9) a C1-6 alkylsulfinyl group, (10) a C1-6 alkylsulfonyl group, (11) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 5 substituents selected from the group consisting of a halogen atom, a C1-6 alkyl group, a 6- to 14-membered aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group and -0-A3 (wherein A3 represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group)), (12) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with 1 to 5 halogen atoms or the adjacent C1-6 alkoxy groups, together with a carbon atom to which they are bonded, may form a cyclic group), (13) an amino group (wherein the amino group may be substituted with a C1-6 alkyl group optionally having 1 to 5 halogen atoms), (14) a 6- to 14-membered aromatic hydrocarbon ring group, (15) a 5- to 14-membered aromatic heterocyclic group, (16) a 5- to 14-membered non-aromatic heterocyclic group and (17) -CO-A3 (wherein A3 is the same as defined above).
16. The compound or pharmacologically acceptable salt thereof as claimed in claim 15
wherein R1 and R2, together with a nitrogen atom to which they are bonded, form a piperidinyl group, a pyrrolidinyl group, an azepinyl group, an azocanyl group, a piperazinyl group, a 1,4-diazepanyl group, a morpholinyl group or a thiomorpholinyl group which may be substituted with 1 to 4 substituents selected from the group consisting of (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 3 hydroxyl groups or 1 to 3 substituents selected from the group consisting of a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A10 shown below), (5) a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from substituents of A10 shown below, (6) a 5- to 14-membered aromatic heterocyclic group which may
be substituted with 1 to 3 substituents selected from Substituent Group A10 shown below, (7) -O-A6 (wherein A6 represents a 6- to 14-membered aromatic hydrocarbon ring group which may be substituted with 1 to 3 substituents selected from Substituent Group A10 shown below) and (8) =CH-A6 (wherein A6 is the same as defined above).
Substituent Group A10: (1) a hydrogen atom, (2) a halogen atom, (3) a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted with 1 to 5 halogen atoms), (4) a C1-6 alkoxy group and (5) a 6- to 14-membered aromatic hydrocarbon ring group.
17. The compound or pharmacologically acceptable salt thereof as claimed in claim 1
wherein R1 and R2, together with a nitrogen atom to which they are bonded, form a 6- to 20-membered non-aromatic heterocyclic group which may be substituted with 1 to 4 substituents selected from Substituent Group A4 shown below and is represented by Formula (111): [Formula 13]
wherein Y2 represents (1) -NH-, (2) -O-, (3) -S-, (4) -SO-, (5) -S02-, (6) -CH2-, (7) -CO-, (8) -CONH-, (9) -NHCO-, (10) -CR5= CR6- (wherein R5 and R6 represent substituents selected from Substituent Group A4 shown below or R5 and R6, together with a carbon atom to which they are bonded, form a 6- to 14-membered aromatic hydrocarbon ring group or a 3- to 14-membered non-aromatic hydrocarbon ring group) or (11) a single bond; and ma, mb, mc and md represent an integer of 0 to 4. Substituent Group A4:
(1) a hydrogen atom,
(2) a halogen atom,
(3) a hydroxyl group,
(4) a cyano group,
(5) a nitro group,
(6) a C3-8 cycloalkyl group,
(7) a C2-6 alkenyl group,
(8) a C2-6 alkynyl group,
(9) a C3-8 cycloalkoxy group,

(10) a C3-8 cycloalkylthio group,
(11) a formyl group,
(12) a C1-6 alkylcarbonyl group,
(13) a C1-6 alkylthio group,
(14) a C1-6 alkylsulfinyl group,
(15) a C1-6 alkylsulfonyl group,
(16) a hydroxyimino group,
(17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group (wherein the C1-6 alkyl group may have 1 to 3 substituents selected from the following substituent group:

(a) a halogen atom,
(b) a hydroxyl group,
(c) a cyano group,
(d) a C3-8 cycloalkyl group,
(e) a C1-6 alkylthio group,
(f) a C1-6 alkylsulfinyl group,
(g) a C1-6 alkylsulfonyl group, (h) a C1-6 alkylcarbonyl group, (i) a hydroxyimino group,
(j) a C1-6 alkoxyimino group,
(k) a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be substituted with a hydroxyl group),
(1) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(m) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(n) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(o) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(p) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below) and
(q) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below)),
(19) a C1-6 alkoxy group,
(20) an amino group (wherein the amino group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group which may be substituted with a 6- to 14-membered aromatic hydrocarbon ring group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(21) a carbamoyl group (wherein the carbamoyl group may be substituted with 1 to 2 substituents selected from the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group),
(22) a 6- to 14-membered aromatic hydrocarbon ring group (wherein the 6- to 14-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(23) a 5- to 14-membered aromatic heterocyclic group (wherein the 5- to 14-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(24) a 3- to 14-membered non-aromatic hydrocarbon ring group (wherein the 3- to 14-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(25) a 5- to 14-membered non-aromatic heterocyclic group (wherein the 5- to 14-membered non-aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(26) a C2-6 alkenyloxy group,
(27) a C2-6 alkynyloxy group,
(28) a C3-8 cycloalkylsulfinyl group,
(29) a C3-8 cycloalkylsulfonyl group,
(30) -X-A (wherein X represents an imino group, -O- or -S- and A represents a 6- to 14-membered aromatic hydrocarbon ring group or 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below),
(31) -CO-A (wherein A is the same as defined above) and
(32) =CH-A (wherein A is the same as defined above). Subst