Title of Invention

NOVEL CONDENSED IMIDAZOLE DERIVATIVES

Abstract A compound represented by the general formula (I) [wherein T1 means an optionally substituted, monocyclic or bicyclic, 4- to 12-membered, heterocyclic group containing one or two nitrogen atoms in the ring; X means optionally substituted C1-6 alkyl, etc.; Z1 and Z2 each independently means nitrogen or a group represented by the formula -CR2-; and R1 and R2 each independently means hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, etc.], a salt of the compound, or a hydrate of either. These are novel compounds having excellent DPPIV inhibitory activity.
Full Text DESCRIPTION
NOVEL CONDENSED IMIDAZOLE DERIVATIVES
Technical Field
The present invention relates to novel condensed imidazole derivatives useful as dipeptidyl peptidase-IV (DPPIV) inhibitors and uses thereof.
Background Art
Dipeptidyl peptidase IV (DPPIV) is a serine protease which specifically hydrolyzes dipeptide -X-Pro (X = arbitrary amino acid) from the free N terminus of a polypeptide chain.
Glucose-dependent, insulin secretion-stimulating hormones, known as incretins (GLP-1: Glucagon-Like Peptide-1 and GIP: Glucose-dependent Insulinotropic Polypeptide) secreted in the digestive tract following meals are rapidly hydrolyzed and inactivated by DPPIV. When the hydrolysis by DPPIV is suppressed, the action of incretin (GLP-1 and GIP) is enhanced, which in turn increases the glucose-stimulated secretion of insulin from the P cells of the pancreas. This has been shown to improve hyperglycemia in the oral glucose tolerance test (see Diabetologia 1999 Nov, 42(11), 1324-31). In addition, GLP-1 is known to be involved in the suppression of appetite and food intake. GLP-1 has also been reported to have the effect of protecting the P cells of the pancreas by enhancing P cell differentiation and proliferation. Thus, a DPPIV inhibitor can be a useful therapeutic or preventive agent for diseases with which GLP-1 and/or GIP are associated, such as obesity and diabetes mellitus.
Furthermore, there are many reports suggesting a relationship between dipeptidyl peptidase IV and various diseases as described below. Thus , a DPPIV inhibitor can be a therapeutic agent for diseases such as:
(1) preventive and therapeutic agents for AIDS (see Science 1993 ,
262, 2045-2050),
(2) preventive and therapeutic agents for osteoporosis (see

Clinical chemistry 1988, 34, 2499-2501),
(3) preventive and therapeutic agents for intestinal disorders
(see Endocrinology 2000, 141, 4013-4020),
(4) preventive and therapeutic agents for diabetes mellitus, obesity, and hyperlipidemia (see Diabetes 1998, 47, 1663-1670; and Life Sci 2000, 66(2), 91-103),
(5) preventive and therapeutic agents for angiogenesis (see Agents and Actions 1991, 32, 125-127),
(6) preventive and therapeutic agents for infertility (see International Publication WO 00/56296) ,

(7) preventive and therapeutic agents for inflammatory diseases , autoimmune diseases, and chronic rheumatoid arthritis (see The Journal of Immunology 2001, 166, 2041-2048), and
(8) preventive and therapeutic agents for cancer (see Br J Cancer 1999 Mar, 79 (7-8) , 1042-8; and J Androl 2000 Mar-Apr, 21 (2) , 220-6) .
Some DPPIV inhibitors are disclosed in the Publication of US patent No. 2002/0161001; International Publication WO 03/004496; and Publication of US patent No. 2002/0198205. However, there is no known DPPIV inhibitor having a hypoxanthine or imidazopyridazinone structure backbone.
A compound having DPPIV-inhibiting activity that can be used as a pharmaceutical agent is being anxiously sought as described above. However, a compound with excellent DPPIV-inhibiting activity, which is also highly useful as a clinically effective pharmaceutical is yet to be discovered. Specifically, an objective of the present invention is to provide compounds having DPPIV-inhibiting activity, which can be used as preventive, therapeutic, or alleviating agents for diabetes mellitus or such diseases.
Disclosure of the Invention
The present inventors conducted extensive studies in view of the above background. As a result, they succeeded in synthesizing novel condensed imidazole derivatives, including hypoxanthine and imidazopyridazinone derivatives. To complete the present invention they also found that these compounds had excellent DPPIV-inhibiting activity. Specifically, the present invention comprises:

[1] a compound represented by the following formula, or a salt or hydrate thereof,

wherein,
T1 represents a monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, that may have one or more substituents;
X represents a C1-6 alkyl group which may have one or more substituents, a C2-6 alkenyl group which may have one or more substituents, a C2-6 alkynyl group which may have one or more substituents, a C6-10 aryl group which may have one or more substituents, a 5 to 10-membered heteroaryl group which may have one or more substituents, a C6-10 aryl C1-6 alkyl group which may have one or more substituents, or a 5 to 10-membered heteroaryl C1-6 alkyl group which may have one or more substituents;
Z2 and Z2 each independently represent a nitrogen atom or a group represented by the formula -CR2=;
R and R2 each independently represent a group according to the
formula -A°-A2-A2
(wherein A° represents a single bond or a C1-6 alkylene group, which may have 1 to 3 substituents selected from group B consisting of the substituents described below; A2 represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula -0-CO-, a group represented by the formula -CO-0-, a group represented by

the formula -NR2-, a group represented by the formula -CO-NR*-, a group represented by the formula -NR*-CO-, a group represented by the formula -SO2-NR*-, or a group represented by the formula -NR2-SOa-;
A and R2 each independently represent a hydrogen atom, a halogen atom, a cyano group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a 5 to 10-membered heteroaryl C1-6 alkyl group, a C6-10 aryl C1-6 alkyl group, or a C2-7 alkylcarbonyl group;
however, A2 and R* each independently may have 1 to 3 substituents selected from the substituent group B described below:
when Z2 is a group represented by the formula -CR2=, R", and R2 may in combination form a 5 to 7-membered ring;
except in cases where: [1] R is a hydrogen atom; Z2 is a nitrogen atom; and Z2 is -CH=; and [2] Z2 is a nitrogen atom; and Z2 is -C(OH)=;
Oubstituent group B>
Substituent group B represents the group consisting of: a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C1-6 alkyl group which may have one or more substituents, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a C1-6 alkoxy group, a C1-6 alkylthio group, a group represented by the formula -S02-NR2-R2, a group represented by the formula -NR2-CO-R2, a group represented by the formula -NR2-R2 (where R° and R2 each independently represent a hydrogen atom or a C1-6 alkyl group) , a group represented by the formula -CO-R2 (where R2 represents a 4 to 8-membered heterocyclic group) ,

a group represented by the formula -CO-R2-R2 and a group represented by the formula -CH2-C0-R2*-R° (where R2 represents a single bond, an oxygen atom, or a group represented by the formula -NR2-; R2 and R2 each independently represent a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic C1-6 alkyl group, a C6-10 aryl C1-6 alkyl group, or a 5 to 10-membered heteroaryl C1-6 alkyl group)), and
[2] the compound according to [1], or a salt or hydrate thereof, wherein T1 is, a group represented by the following formula:

(wherein, n and m each independently represent 0 or 1) which may
have one or more substituents; an azetidin-1-yl group which may have one or more substituents; a pyrrolidin-1-yl group which may have one or more substituents; a piperidin-1-yl group which may have one or more substituents; or an azepan-1-yl group which may have one or more substituents;
[3] the compound according to [1], or a salt or hydrate thereof, wherein T1 is, a group represented by the following formula :


(where n and m each independently represent 0 or 1); an azetidin-1-yl group which may have an amino group; a pyrrolidin-1-yl group which may have an amino group; a piperidin-1-yl group which may have an amino group; or an azepan-1-yl group which may have an amino group;
[4] the compound according to [1], or a salt or hydrate thereof, wherein T1 is a piperazin-1-yl group or a 3-aminopiperidin-l-yl group;
[5] the compound according to [1], or a salt or hydrate thereof, wherein T" is a piperazin-1-yl group;
i [6] the compound according to any one of [1] to [5], or a salt or hydrate thereof, wherein X is a group represented by the formula -X-X (where X represents a single bond or a methylene group which may have one or more substituents; X represents a C2-6 alkenyl group which may have one or more substituents, a C2-6 alkynyl group may have one or more substituents, or a phenyl group which may have one or more substituents);
[7] the compound according to any one of [1] to [5], or a salt or hydrate thereof, wherein X is a group represented by the formula -X-X (where X represents a single bond or a methylene group; X represents a C2-6 alkenyl group, a C2-6 alkynyl group, or a phenyl group .which may have one or more substituents);
[8] the compound according to [6] or [7] , or a salt or hydrate thereof, wherein the phenyl group that may have one or more substituents is a phenyl group which may have at the 2-position a substituent selected from the group consisting of a hydroxyl group, a fluorine atom, a

chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a vinyl group, a methoxy group, an ethoxy group, an acetyl group, a cyano group, a formyl group, and a C2-7 alkoxycarbonyl group;
[9] the compound according to any one of [1] to [5], or a salt or hydrate thereof, wherein X is a 3-methyl-2-buten-l-yl group, a 2-butyn-l-yl group, a benzyl group, or a 2-chlorophenyl group;
[10] the compound according to any one of [1] to [5], or a salt or hydrate thereof, wherein X is a 2-butyn-l-yl group;
[11] the compound according to any one of [1] to [10] , or a salt or hydrate thereof, wherein either the Z2 or Z2 is a nitrogen atom;
[12] the compound according to any one of [1] to [10] , or a salt or hydrate thereof, wherein, Z2 is a nitrogen atom; and
T} is a group represented by the formula -CR2= (where R2 is as defined above in [1]);
[13] the compound according to any one of [1] to [10] , or a salt or a hydrate thereof, wherein, Z2 is a nitrogen atom; and
Z2 is a group represented by the formula -CR2= (where R2 is as defined above in [1]);
[14] the compound according to any one of [1] to [13] , or a salt or hydrate thereof,
wherein R2 represents a hydrogen atom, or a group represented by the formula -A"-A2-A2
(where A2° represents a C1-6 alkylene group which may have 1 to
3 substituents selected from the substituent group C described
below;
A2 represents a single bond, an oxygen atom, a sulfur atom or
a carbonyl group;
A2 represents a hydrogen atom, a C6-10 aryl group which may have

1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl group which may have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, or a C6-10 aryl C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below:

Substituent group C represents the group consisting of: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula -NR-R2 (where each of R* and R2 independently represent a hydrogen atom or C1-6 alkyl group), a group represented by the formula -CO-R2-R2 and a group represented by the formula -CH2-C0-R2"-R2 (where R2 represents a single bond, an oxygen atom, or a group represented by the formula -NR*-; R and R2 each independently represent a hydrogen atom or a C1-6 alkyl group));
[15] the compound according to any one of [1] to [13] , or a salt or hydrate thereof,
wherein R2 is a hydrogen atom, a C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, or a C6-10 aryl C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below:
Substituent group C represents the group consisting of: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula -NR2-R (where each of R2 and R independently represents a

hydrogen atom or a C1-g alkyl group) , a group represented by the formula -CO-R"-R2 and a group represented by the formula -CH2-C0-R-R2 (where R2 represents a single bond, an oxygen atom, or a group represented by the formula -UR"-; R2 and R2 each independently represent a hydrogen atom or a C1-6 alkyl group) ;
[16] the compound according to [14] or [15], or a salt or hydrate thereof, wherein the substituent group C is a group consisting of a cyano group, a C1-g alkoxy group, a C2-7 alkoxycarbonyl group, and a halogen atom;
[17] the compound according to any one of [1] to [13], or a salt or hydrate thereof, wherein R is a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyethyl group, or a 4-methoxycarbonylpyridin-2-yl group;
[18] the compound according to any one of [1] to [13], or a salt or hydrate thereof, wherein R2 is a methyl group or a 2-cyanobenzyl group;
[19] the compound according to any one of [1] to [18], or a salt or hydrate thereof,
wherein R2 is a hydrogen atom, a cyano group, or a group represented by the formula -A2-A"
(where A2 represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula -0-CO-, a group represented by the formula -CO-0-, a group represented by the formula -NR-, a group represented by the formula -CO-NR2-, or a group represented by the formula -NR2-CO-;
A2 and R* each independently represent a hydrogen atom, a cyano group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5-to 10-membered heteroaryl C1-6 alkyl group, or a C6-10 aryl C1-6 alkyl group;

however, A2 and R* each may independently have 1 to 3 substituents selected from the substituent group D described below:
Substituent group D represents the group consisting of: a hydroxyl group, a cyano group, a nitro group, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula -NR2-R" (where R° and R° each independently represent a hydrogen atom or a C1-6 alkyl group), a group represented by the formula -CO-R° (where R2 represents a 4 to 8-membered heterocyclic group), and a group represented by the formula -CO-R°-R° (where R° represents a single bond, an oxygen atom, or a group represented by the formula -NR°-; R° and R° each independently represent a hydrogen atom, a C3-8 cycloalkyl group, or a C1-6 alkyl group));
[20] the compound according to any one of [1] to [18] , or a salt or hydrate thereof,
wherein R2 represents a hydrogen atom, a cyano group, a carboxy group, a C2-7 alkoxycarbonyl group, a C1-6 alkyl group, a group represented by the formula -CONR°R° (where R° and R°® each independently represent

a hydrogen atom or a C1-6 alkyl group) , or a group represented by the
formula -A"-A2
4
(where A2 represents an oxygen atom, a sulfur atom or a group represented by the formula -NR2-;
A2 and R" each independently represent a hydrogen atom, a C1-6 alkyl group which may have a substituent selected from the substituent group Dl described below, a C3-8 cycloalkyl group which may have a substituent selected from the substituent group Dl described below, a C2-6 alkenyl group which may have a substituent selected from the substituent group Dl described below, a C2-6 alkynyl group which may have a substituent selected from the substituent group Dl described below, a phenyl group which may have a substituent selected from the substituent group Dl described below, or a 5 to 10-membered heteroaryl group which may have a substituent selected from the substituent group Dl

described below:

Substituent group Dl represents the group consisting of: a carboxy group, a C2-7 alkoxycarbonyl group, a C1-6 alkyl group, a group represented by the formula -CONR°R° (where R and R° each independently represent a hydrogen atom or C1-6 alkyl group) , a pyrrolidin-1-ylcarbonyl group, a C1-6 alkyl group, and a C1-6 alkoxy group) ;
[21] the compound according to any one of [1] to [18] , or a salt or hydrate thereof,
wherein R2 represents a hydrogen atom, a cyano group, a C1-6 alkoxy group, or a group represented by the formula -A2-A2
(where A2 represents an oxygen atom, a sulfur atom, or a group represented by the formula -NR*-;
A2 and R each independently represent a hydrogen atom, a C1-6 alkyl group having a substituent selected from the substituent group Dl described below, a C3-8 cycloalkyl group having a substituent selected from the substituent group Dl described below, or a phenyl group having a substituent selected from the substituent group Dl described below:
Substituent group Dl represents the group consisting of: a carboxy group, a C2-7 alkoxycarbonyl group, a C1-6 alkyl group, a group represented by the formula -CONR2R" (where R° and R° each independently represent a hydrogen atom or a C1-6 alkyl group) , pyrrolidin-1-ylcarbonyl group, a C1-6 alkyl group, and a C1-6 alkoxy group) ;
[22] the compound according to any one of [1] to [18] , or a salt or .hydrate thereof,
wherein R2 is a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, or a group represented by the following formula:



A2 and A2 each independently represent a hydrogen atom or a C1-
(where A2 represents an oxygen atom, a sulfur atom, or -NH-; A2 and A2 eac alkyl group);

[23] the compound according to any one of [1] to [18], or a salt or hydrate thereof, wherein R2 is a hydrogen atom, a cyano group, or a 2-carbamoylphenyloxy group;
[24] the compound according to [1], or a salt or hydrate thereof, wherein the compound of formula (I) indicated above is any one selected from the group consisting of:
7-(2-butynyl)-2-cyano-l-methyl-8-(piperazin-1-yl)-1,7-dihydropu
rin-6-one,
3-(2-butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,
5-d]pyridazin-4-one,
2-(3-aminopiperidin-l-yl)-3-(2-butynyl)-5-methyl-3,5-dihydroimi
dazo[4,5-d]pyridazin-4-one,
2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-
lH-purin-2-yloxy]benzamide,
7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-di
hydro-lH-purine-2-carbonitrile, and
2-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,
5-d]pyridazin-5-ylmethyl]benzonitrile;
[25] a pharmaceutical agent comprising a compound of any one of [1] to [24];

[26] a dipeptidyl peptidase IV inhibitor comprising a compound of any one of [1] to [24];
[27] a pharmaceutical composition comprising a compound of any one of [1] to [24] and an adjuvant useful for formulation;
[28] a preventive or a therapeutic agent for diabetes mellitus, which comprises a compound of any one of [1] to [24];
[29] a preventive or therapeutic agent, which comprises a compound of any one of [1] to [24], for diabetes mellitus, obesity, hyperlipidemia, AIDS, osteoporosis, a gastrointestinal disorder, angiogenesis, infertility, an inflammatory disease, an allergic disease, or cancer;
[30] an immunomodulator, a hormone modulator, or an anti-rheumatic drug, which comprises a compound of any one of [1] to [24];
[31] a therapeutic or preventive method for a disease in which the inhibition of dipeptidyl peptidase IV is effective , wherein the method comprises administering to a patient a compound of any one of [1] to [24] , or a salt or hydrate thereof, in a pharmaceutically effective amount;
[32] the use of a compound of any one of [1] to [24], or a salt or hydrate thereof, in producing a pharmaceutical agent;
[33] the use of a compound of any one of [1] to [24], or a salt or hydrate thereof, in producing a therapeutic or preventive agent for a disease in which the inhibition of dipeptidyl peptidase IV is effective;
[34] a compound represented by the following formula, or a salt or hydrate thereof


a group represented by T1 described above in [1] , a pyridyl group which may have one or more substituents , a pyridinium group which may have one or more substituents, a group represented by the following formula:

a group, which may have one or more substituents, represented by the following formula:

(where n and m each independently represent 0 or 1) , or a group, which may have one or more substituents, represented by the following formula:


(where n and m each independently represent 0 or 1);
x" represents a C3-8 cycloalkyl group which may have one or more substituents, a C1-6 alkyl group which may have one or more substituents, a C2-6 alkenyl group which may have one or more substituents, a C2-6 alkynyl group which may have one or more substituents, a C6-10 aryl group which may have one or more substituents, a 5 to 10-membered heteroaryl group which may have one or more substituents, a Cs-10 aryl C1-6 alkyl group which may have one or more substituents, or a 5 to 10-membered heteroaryl C1-6 alkyl group which may have one or more substituents; and
R2, Z2 and Z2 are, as defined above in [1];
[35] a compound represented by the following formula, or a salt or hydrate thereof,


wherein R\ R2 T\ Z2 and Z2 are, as defined above in [1] ;
[37] a compound represented by the following formula, or a salt or hydrate thereof,

R" is as defined above in [1] ;
R2 represents a t-butoxycarbonyloxy group, a trityl group or
a group represented by the formula -SO2NH2; and
T° represents a halogen atom or a hydrogen atom;
[38] a compound represented by the following formula, or a salt or hydrate thereof.


(where T" represents a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a formyl group));
[39] a compound represented by the following formula, or a salt or hydrate thereof,

[40] a compound represented by the following formula, or a salt or hydrate thereof,

X is as defined above in [1], except when X is a benzyl group; T21 and T22 each independently represent a halogen atom; and T1 represents a halogen atom or a group represented by the following formula:


(where T1 represents a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a formyl group));
[41] a compound represented by the following formula, or a salt or hydrate thereof

[42] a compound represented by the following formula, or a salt or hydrate thereof

the ring of T represents a monocyclic or bicyclic 6- to 12-membered heterocyclic group containing two nitrogen atoms in the ring, which may have one or more substituents; X represents a C1-6 alkyl group which may have one or more substituents, a C2-6 alkenyl group which may have one or more substituents, a C2-6 alkynyl group which may have one or more substituents, a C6-10 aryl group which may have one or more substituents, a 5 to 10-membered heteroaryl group which may have one or more substituents, a C6-10 aryl C1-6 alkyl group which may

have one or more substituents , or a 5 to 10-membered heteroaryl C1-6 alkyl group which may have one or more substituents; X may form a bond with an atom constituting the ring of T\-Z and Z each independently represent a nitrogen atom or a group represented by the formula -CR2=;
R" and R2 independently represent a hydrogen atom, a 4- to 8-membered heterocyclic group which may have one or more substituents, or a group represented by the formula -A°-A2-A2 (where A° represents a single bond or a C1-g alkylene group that may have 1 to 3 substituents selected from the substituent group B described below; Al represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula -0-C0-, a group represented by the formula -C0-0-, a group represented by the formula -NR2-, a group represented by the formula -CO-NR*-, a group represented by the formula -NR2-CO-, a group represented by the formula -SO2-NR*-, or a group represented by the formula -NR2-S02-;
A2 and R* each independently represent a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, or a 4 to 8-membered heterocyclic group. However, A2 and R* each may independently have 1 to 3 substituents selected from the substituent group B described below:
except in cases where: (i) both R2 and R2 are hydrogen atoms,
and (ii) R2 is a hydroxyl group.
Substituent group B represents the group consisting of: a hydroxyl group, a cyano group, a halogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group.

a C1-6 alkoxy group, a C1-6 alkylthio group, and a group represented by the formula -CO-R2-R2 (where R2 represents a single bond, an oxygen atom, or a group represented by the formula -NR2-; R2 and R" each independently represent a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, a C6-10 aryl C1-6 alkyl group, a 5 to 10-membered heteroaryl C1-6 alkyl group, a 1-pyrrolidinyl group, 1-morpholinyl group, a 1-piperazinyl group, or a 1-piperidyl group));
Best Mode for Carrying Out the Invention
The present invention is illustrated in detail below.
Herein, a structural formula of a compound sometimes represents a certain isomer for convenience of description. However, compounds of the present invention may include all possible isomers, such as structurally possible geometric isomers, optical isomers generated due to the presence of asymmetric carbons, stereoisomers, tautomers, and mixtures of isomers, and are not limited to formulae being used for the convenience of description, and may be either of two isomers or a mixture of both isomers . Thus , compounds of the present invention may be either optically active compounds having an asymmetric carbon atom in their molecules or their racemates, and are not restricted to either of them but include both. Furthermore, compounds of the present invention may exhibit crystalline polymorphism, but likewise are not restricted to any one of these but may be in any one of these crystal forms or exist as a mixture of two or more crystal forms. Compounds of the present invention also include both anhydrous and hydrated forms. Substances produced through in vivo metabolism of compounds of the invention are also within the scope of claims.
The terms and symbols used herein are defined and the present invention is described in detail below.
As used herein, the phrase "C1-6 alkyl group" refers to a linear or branched alkyl group containing 1 to 6 carbon atoms, which is a monovalent group obtained by removal of any one of the hydrogen atoms

from an aliphatic hydrocarbon containing 1 to 6 carbons, and specifically, includes, for example, a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 2-methyl-l-propyl group, a 2-methyl-2-propyl group, a 1-butyl group, a 2-butyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl-l-butyl group, a 3-methyl-l-butyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 2,2-dimethyl-l-propyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methyl-l-pentyl group, a 3-methyl-l-pentyl group, a 4-methyl-l-pentyl group, a 2-methyl-2-pentyl group, a 3-methyl-2-pentyl group, a 4-methyl-2-pentyl group, a 2-methyl-3-pentyl group, a 3-methyl-3-pentyl group, a 2,3-dimethyl-l-butyl group, a 3,3-dimethyl-l-butyl group, a 2,2-dimethyl-l-butyl group, a 2-6thyl-l-butyl group, a 3,3-dimethyl-2-butyl group, and a 2,3-dimethyl-2-butyl group.
As used herein, the phrase "C2-6 alkenyl group" refers to a linear or branched alkenyl group containing 2 to 6 carbons, and specifically includes, for example, a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a pentenyl group, and a hexenyl group.
As used herein, the phrase "C2-6 alkynyl group" refers to a linear or branched alkynyl group containing 2 to 6 carbons, and specifically includes, for example, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a butynyl group, a pentynyl group, and a hexynyl group.
As used herein, the phrase "C3-8 cycloalkyl group" refers to a cyclic aliphatic hydrocarbon group containing 3 to 8 carbon atoms, and specifically includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
As used herein, the phrase "C1-6 alkylene group" refers to a divalent group obtained by removal of another arbitrary hydrogen atom from a "C1-6 alkyl group" defined above, and specifically includes, for example, a methylene group, a 1,2-6thylene group, a 1,1-6thylene group, a 1,3-propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group.

As used herein, the phrase "C3-8 cycloalkylene group" refers to a divalent group obtained by removal of another arbitrary hydrogen atom from a "C3-8 cycloalkyl group" defined above.
As used herein, the phrase "C1-6 alkoxy group" refers to an oxy group linked to a "C1-6 alkyl group" defined above, and specifically includes, for example, a methoxy group, an ethoxy group, a 1-propyloxy group, a 2-propyloxy group, a 2-methyl-l-propyloxy group, a 2-methyl-2-propyloxy group, a 1-butyloxy group, a 2-butyloxy group, a 1-pentyloxy group, a 2-pentyloxy group, a 3-pentyloxy group, a 2-methyl-l-butyloxy group, a 3-methyl-l-butyloxy group, a 2-methyl-2-butyloxy group, a 3-methyl-2-butyloxy group, a 2,2-dimethyl-l-propyloxy group , a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-l-pentyloxy group, a 3-methyl-l-pentyloxy group, a 4-methyl-l-pentyloxy group, a 2-methyl-2-pentyloxy group, a 3-methyl-2-pentyloxy group, a 4-methyl-2-pentyloxy group, a 2-methyl-3-pentyloxy group, a 3-methyl-3-pentyloxy group, a 2,3-dimethyl-l-butyloxy group, a 3,3-dimethyl-l-butyloxy group, a 2,2-dimethyl-l-butyloxy group, a 2-6thyl-l-butyloxy group, a 3,3-dimethyl-2-butyloxy group, and a 2,3-dimethyl-2-butyloxy group.
As used herein, the phrase "C1-6 alkylthio group" refers to a thio group linked to a "Ci_6 alkyl group" defined above, and specifically includes, for example, a methylthio group, an ethylthio group, a 1-propylthio group, a 2-propylthio group, a butylthio group, and a pentylthio group.
As used herein, the phrase "C2-7 alkoxycarbonyl group" refers to a carbonyl group linked to a "C1-6 alkoxy group" defined above, and specifically includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a 1-propyloxycarbonyl group, and a 2-propyloxycarbonyl group.
. . As used herein, the phrase "C2-7 alkylcarbonyl group" refers to a carbonyl group linked to a "C1-6 alkyl group" defined above, and specifically includes, for example, a methylcarbonyl group, an ethylcarbonyl group, a 1-propylcarbonyl group, and a 2-propylcarbOnyl group.
As used herein, the term "halogen atom" refers to a fluorine

atom, a chlorine atom, a bromine atom, or an iodine atom.
As used herein, the phrase "Cg-10 aryl group" refers to an aromatic cyclic hydrocarbon group containing 6 to 10 carbon atoms, and specifically includes, for example, a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
As used herein, the term "heteroatom" refers to a sulfur atom, an oxygen atom, or a nitrogen atom.
As used herein, the phrase "5 to 10-membered heteroaryl ring" refers to an aromatic 5 to 10-raembered ring containing one or more heteroatoms, and specif ically includes , for example, a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a thiadiazole ring, an isothiazole ring, an imidazole ring, a triazole ring, a pyrazole ring, a furazan ring, a thiadiazole ring, an oxadiazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, indole ring, an isoindole ring, an indazole ring, a chromene ring, a guinoline ring, an isoquinoline ring, a cinnoline ring, a quinazoline ring, a quinoxaline ring, a naphthyridine ring, a phthalazine ring, a purine ring, a pteridine ring, a thienofuran ring, an imidazothiazole ring, a benzofuran ring, a benzothiophene ring, a benzoxazole ring, a benzothiazole ring, a benzothiadiazole ring, a benzimidazole ring, an imidazopyridine ring, a pyrrolopyridine ring, a pyrrolopyrimidine ring, and a pyridopyrimidine ring. Preferable "5 to 10-membered heteroaryl rings" include a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a 1,2,4-triazole ring, a thiazole ring, a thiadiazole ring, a pyrazole ring, a furazan ring, a thiadiazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, an isoquinoline ring, a benzoxazole ring, a benzothiazole ring, and a benzimidazole ring. The most preferable example is a pyridine ring.
As used herein, the phrase "5 to 10-membered heteroaryl group" refers to a monovalent or divalent group obtained by removal of any one or two hydrogen atoms from a "5 to 10-membered heteroaryl ring" described above.
As used herein, the phrase "4 to 8-membered heterocyclic ring" refers to a non-aromatic ring in which:

(i) the number of atoms constituting the ring is 4 to 8; (ii) the atoms constituting the ring include 1 to 2 heteroatoms;
(iii) the ring may contain 1 to 2 double bonds;
(iv) the ring may contain 1 to 3 carbonyl groups; and
(v) the ring is monocyclic.
Specifically, the 4 to 8-membered heterocyclic ring includes, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepan ring, an azocane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a thiazolidine ring, a dioxane ring, an imidazoline ring, a thiazoline ring, and a ring represented by one of the formulae:

(where s represents an integer from 1 to 3; T" represents a methylene group, an oxygen atom or a group represented by the formula -NT"-, wherein T1 represents a hydrogen atom or C1-6 alkyl group. Preferably the "4- to 8-membered heterocyclic rings " include a pyrrolidine ring, a piperidine ring, an azepan ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a dihydrofuran-2-one ring, and a thiazolidine ring.
As used herein, the phrase "4 to 8-membered heterocyclic group" refers to a monovalent or divalent group obtained by removal of any one or two hydrogen atoms from a "4 to 8-membered heterocycle" described above. Preferably, the "4 to 8-membered heterocyclic groups" include a piperidin-1-yl group, a pyrrolidin-1-yl group , and a morpholin-4-yl group.
As used herein, the phrase "Cg-10 aryl C1-6 alkyl group" refers to a group obtained by substitution of a "C6-10 aryl group" defined above for an arbitrary hydrogen atom in a "C1-6 alkyl group" defined above, and specifically includes, for example, a benzyl group, a

phenethyl group, and a 3-phenyl-l-propyl group.
As used herein, the phrase "5 to 10-membered heteroaryl C1-6 alkyl group" refers to a group obtained by substitution of a "5 to 10-membered heteroaryl group" defined above for an arbitrary hydrogen atom in a "C1-g alkyl group" defined above, and specifically, includes for example, a 2-pyridylmethyl and a 2-thienylmethyl group.
As used herein, the phrase "4 to 8-membered heterocyclic C1-6 alkyl group" refers to a group obtained by substitution of a "4 to 8-membered heterocyclic group" defined above for an arbitrary hydrogen atom in a "C1-6 alkyl group" defined above.
As used herein, the phrase "monocyclic or bicyclic 4 to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, that may have one or more substituents" refers to a non-aromatic cyclic group which may have one or more substituents. In the non-aromatic cyclic groups:
(i) the number of atoms constituting the ring of the cyclic group is 4 to 12;
(ii) the atoms constituting the ring of the cyclic group include one or two nitrogen atoms; and
(iii) the group is a monocyclic or bicyclic structure.
Specifically, the group is represented by the formula:

independently represent a hydrogen atom or a substituent selected ,from substituents referred to in the phrase "which may have one or more substituents" (the substituent group S defined below); any two of R to R* may in combination form a C1-6 alkylene group) . As used herein, the phrase "which may have one or more substituents" means that a group may have one or more substituents in any combination at replaceable positions. Specifically, such

substituents include, for example, a substituent selected from the substituent group S defined below. This group consists of:
(1) a halogen atom,
(2) a hydroxy1 group,
(3) a mercapto group,
(4) a nitro group,
(5) a cyano group,
(6) a formyl group,
(7) a carboxyl group,
(8) a trifluoromethyl group,
(9) a trifluoromethoxy group,

(10) an amino group,
(11) an oxo group,
(12) an imino group, and
(13) a group represented by the formula -T1-T1 (where T1" is a single bond, a C1-6 alkylene group, an oxygen atom, a group represented by the formula -CO-, a group represented by the formula -S-, a group represented by the formula -S(0)-, a group represented by the formula -S(0)2-, a group represented by the formula -0-CO-, a group represented by the formula -CO-0-, a group represented by the formula -NR-, a group represented by the formula -CO-NR-, a group represented by the formula -NR-CO- , a group represented by the formula -S02-NR-, a group represented by the formula -NR-S02-, a group represented by the formula -NH-CO-NR- or a group represented by the formula -NH-CS-NR-;
T1" represents a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 5 to 10-membered heteroaryl .gxoup or a 4 to 8-membered heterocyclic group;
R represents a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group; provided that T1 and R2 each may independently have 1 to 3 substituents selected from the substituent group T defined below) .

This group consists of: hydroxyl, cyano, a halogen atom, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, 1-naphthyl, 2-naphthyl, 5 to 10-membered heteroaryl, 4 to 8-membered heterocyclic ring, C1-6 alkoxy, C1-6 alkylthio, C2-7 alkoxycarbonyl group, etc. The preferably consists of:
(1) a halogen atom,
(2) a hydroxyl group,
(3) a cyano group,
(4) a carboxyl group,
(5) a trifluoromethyl group,
(6) a trifluoromethoxy group,
(7) an amino group,
(8) a C1-6 alkyl group,
(9) a C3-8 cycloalkyl group,

(10) a C2-6 alkenyl group,
(11) a C2-6 alkynyl group,
(12) a phenyl group, and
(13) a C1-6 alkoxy group.
As used herein, the term "group represented by the formula:

(where n and m each independently represent 0 or 1) , which may have one or more substituents" refers to a group represented by the formula :


(where R to R independently represent a hydrogen atom or a group selected from substituents referred to in the phrase "which may have one or more substituents" defined above (the substituent group S defined above); n and m each independently represent 0 or 1). The case where m=n=0 is preferred. More preferably, the term refers to a group represented by one of the formulae:

atom or a group selected from substituent groups referred to in the phrase "which may have one or more substituents" (the substituent group S defined above)); provided that, at least three of R2\ R-, R2, R, and R are hydrogen atoms Still more preferably, the term refers to a group represented by one of the formulae:

As used herein, the term "group represented by the formula:


As used herein, the term "piperidin-l-yl group which may have one or more substituents" refers to a "piperidin-1-yl group" which may have one or more substituents selected from the groups referred to in the phrase "which may have one or more substituents" (the substituent group S defined above) at replaceable positions. Preferably, the "piperidin-1-yl group which may have one or more substituents" refers to a group represented by the formula:

atom or a group selected from the substituents referred to in the phrase "which may have one or more substituents" (the substituent group S defined above)) ; provided that, at least three of R2\ R, R", R, and R2 are hydrogen atoms. Preferably, the term refers to a group represented by one of the formulae:


More preferably, the term refers to a group represented by one of the formulae:

As used herein, the phrase "azetidin-1-yl group may have one or more substituents" refers to an "azetidin-l-yl group" which may have one or more groups selected from the substituents referred to in the phrase "which may have one or more substituents" at replaceable

positions.
As used herein, the phrase "pyrrolidin-1-yl group may have one or more substituents" refers to a "pyrrolidin-1-yl group" which may have one or more groups selected from the substituents referred to in the phrase "which may have one or more substituents" at replaceable positions.
As used herein, the phrase "piperidin-1-yl group may have one or more substituents" refers to a "piperidin-1-yl group" which may have one or more groups selected from the substituents referred to in the phrase "which may have one or more substituents" at replaceable positions.
As used herein, the phrase "azepan-1-yl group may have one or more substituents" refers to an "azepan-1-yl group" which may have one or more groups selected from the substituents referred to in the phrase "which may have one or more substituents" at replaceable positions.
As used herein, the phrase "piperidin-1-yl group which may have an amino group" refers to a "piperidin-1-yl group" which may have an amino group at a replaceable position. Specifically, the "piperidin-1-yl group which may have an amino group", for example, refers to the group represented by one of the formulae:



As used herein, the phrase "azetidin-1-yl group which may have an amino group" refers to an "azetidin-1-yl group" which may have an amino group at a replaceable position.
As used herein, the phrase "pyrrolidin-1-yl group which may have an amino group" refers to a "pyrrolidin-1-yl group" which may have an amino group at a replaceable position.
As used herein, the phrase "piperidin-1-yl group which may have an amino group" refers to a "piperidin-1-yl group" which may have an amino group at a replaceable position.
As used herein, the phrase "azepan-1-yl group which may have an amino group" refers to an "azepan-1-yl group" which may have an amino group at a replaceable position.
As used herein, the phrase "C1-6 alkyl group which may have one or more substituents" in the substituent group B defined above refers to a "C1-6 alkyl group" which may have one or more groups selected from the substituents referred to in the phrase "which may have one or more substituents" at replaceable positions . Preferably, the "C1-g alkyl group which may have one or more substituents" refers to a C1-6 alkyl group which may have one or two substituents selected from the group consisting of a cyano group, a carboxyl group, a C2-7 alkoxycarbonyl group, a group represented by the formula -NR COR , a group represented by the formula -CONR2R (where R2 and R2 each independently represent a hydrogen atom or a C1-6 alkyl group), and a C1-6 alkoxy group.
In a compound represented by formula (I) indicated above, R2 and R2 each independently represent a group of the formula -A°-A-A2 (where A°, A2, and A2 are as defined above) ; when both A° and A2 are single bonds, "-A°-A-" represents a single bond.

In formula (I) indicated above, the phrase "when Z2 represents a group of the formula -CR2=, R1, and R2 may in combination form a 5 to 7-membered ring" means that compounds represented by formula (I) indicated above includes compounds (II) represented by the formula:

atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a methylene group which may have one or more substituents, or a nitrogen atom which may have one or more substituents; A represents a C2-6 alkylene group which may have one or more substituents). In formula (II) shown above , A preferably represents an oxygen atom, and A2 preferably represents a C2-4 alkylene group.
As used herein, the phrase "cyanobenzyl group" refers to a benzyl group having one cyano group, and specifically, includes, for example, a 2-cyanobenzyl group, a 3-cyanobenzyl group, and a 4-cyanobenzyl group.
As used herein, the phrase "fluorocyanobenzyl group" refers to a benzyl group having one fluorine atom and one cyano group, and specifically, includes, for example, a 2-cyano-4-fluorobenzyl group and a 2-cyano-6-fluorobenzyl group.
As used herein, the phrase "carbamoylphenoxy group" refers to a phenoxy group having a group represented by the formula -CONH2, and specifically, includes, for example, a 2-carbamoylphenoxy group, a .3-carbamoylphenoxy group, and a 4-carbamoylphenoxy group.
Herein, there is no limitation on the type of "salts" as long as salts are pharmaceutically acceptable and derived from any compound of the present invention. Such salts include, for example, inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, and acidic or basic amino acid salts.

Examples of preferred inorganic salts include hydrochloride, hydrobromide, sulfate, nitrate, and phosphate. Examples of preferred organic salts include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, and p-toluene sulfonate.
Examples of preferred inorganic base salts include: alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and ammonium salts. Examples of preferred organic base salts include diethylamine salts, diethanolamine salts, meglumine salts, and N,N-dibenzylethylenediamine salts.
Examples of preferred acidic amino acid salts include aspartate and glutamate. Examples of preferred basic amino acid salts include arginine salts, lysine salts, and ornithine salts.
The present invention provides compounds represented by the following formula (I), or salts or hydrates thereof:

T1 represents a monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, and may have one or more substituents; X represents a C1-6 alkyl group which may have one or more substituents, a C2-6 alkenyl group which may have one or more substituents, a C2-6 alkynyl group which may have one or more substituents, a C6-10 aryl group which may have one or more substituents, a 5- to 10-membered heteroaryl group which may have one or more substituents, a C6-10 aryl C1-6 alkyl group which may have one or more substituents, or a 5- to 10-membered heteroaryl C1-6 alkyl group which may have one or more substituents;

Z1 and Z3 each independently represent a nitrogen atom or a group
represented by the formula -CR2=;
R and R2 each independently represent a group of the formula
(where A° represents a single bond or a C1-6 alkylene group which may have 1 to 3 substituents selected from the substituent group B described below;
A2 represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula -0-CO-, a group represented by the formula -CO-0- , a group represented by the formula -NR*- , a group represented by the formula -CO-NR*-, a group represented by the formula -NR2-CO-, a group represented by the formula -SOa-NR2-, or a group represented by the formula -NR-SOZ-;
A2 and R* each independently represent a hydrogen atom, a halogen atom, a cyano group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a 5 to 10-membered heteroaryl C1-6 alkyl group, a C6-10 aryl C1-6 alkyl group, or a C2-7 alkylcarbonyl group, provided that, A2 and R* each may independently have 1 to 3 substituents selected from the substituent group B defined below);
when Z2 represents a group of the formula -CR2=, R2 and R2 may
in combination form a 5 to 7-membered ring.
However the cases where: [1] R2 is a hydrogen atom; Z2 is a nitrogen
atom; and Z2 is -CH=; and [2] Z2 is a nitrogen atom; and Z2 is
-C(OH)= are excluded.

The substituent group B represents the group consisting of: a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C1-6 alkyl group which may have one or more substituents, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a C1-6 alkoxy

Among the compounds listed above, Nos. 1, 2, 4, 6, 7, 8, 10, 13, 16, 41, 42, 44, 50, 53, 81, 85, 86, 87, 111, 141 and 183 are preferable, and compound Nos. 2, 4, 8, 10, 81, 87 and 111 are more preferable.
[Typical synthesis methods]

Representative methods for producing compounds of the present invention, represented by formula (I) above are described below.
Each symbol in the production methods is defined below. R2 to R2, n, m, R1 R2, X, A°, A1 A , R, and T1 are the same as defined above.
U and U each independently represent a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group.
R2 R, and R2 each independently represent an -NH-protecting group such as a pivalyloxymethyl group and a trimethylsilylethoxymethyl group.
R2 represents a hydroxyl group-protecting group such as a t-butyldimethylsilyl group and a t-butyldiphenylsilyl group.
R2 represents an NH-protecting group such as N,N-dimethylsulfamoyl, trityl, benzyl, and t-butoxycarbonyl.
U and U each independently represent a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group- a p-toluenesulfonyloxy group, a group represented by the formula -B(0H)2, a 4,4,5,5-tetramethyl-l,3,2-dioxaboran-2-yl group, or a group represented by the formula -Sn(R2)3 (where R2 represents a C1-e alkyl group).
R" is a group represented by the formula -0-A, a group represented by the formula -S-A, a group represented by the formula -N(R)A, or a 4- to 8-membered heterocyclic group which may have one or more substituents (for example, 1-pyrrolidinyl, 1-morpholinyl, 1-piperazinyl, or 1-piperidyl), etc.
R" represents a group of the formula -A°-A-A, such as a cyano group, a C1-6 alkyl group which .may have one or more substituents, a C3-8 cycloalkyl group which may have one or more substituents, a C2-6 alkenyl group which may have one or more substituents, a C2-6 alkynyl group which may have one or more substituents, and a C6-10 aryl group which may have one or more substituents.
2cooR represents a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C1-e alkyl group, or a C6-10 aryl C1-6

alkyl group, each of which contains an ester group.
2cooH represents a C1-e alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, Ce-10 aryl group, a 5- to lO-mfembered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to lO-membered heteroaryl C1-e alkyl group, or a Ce-10 aryl C1-e alkyl group, each of which contains a carboxylic acid.
A" represents a C1-e alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Ce-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C1-e alkyl group, or a Cs-10 aryl C1-e alkyl group, each of which contains a nitro group.
2NH2 represents a C1-e alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Ce-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C1-e alkyl group, or a Ce-10 aryl C1-e alkyl group, each of which contains- an amino group.
A represents a C1-e alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a Ce-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C1-e alkyl group, or a Ce-10 aryl C1-e alkyl group, each of which contains a nitrile group.
coNH2 represents a C1-e alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, Ce-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C1-e alkyl group, or a Ce-10 aryl C1-e alkyl group, each of which contains a carboxylic amide group.
M represents -MgCl, -MgBr, -Sn(R2)3 (where R2 is as defined above), etc.
The term "room temperature" refers to a temperature of about 20 to about 30°C.
T1 is defined as the group represented by T\ or represents a group of the formula:


schemes, unless otherwise specified, quantities of reagents, catalysts, and others, to be used (equivalent, weight%, and weight ratio) are represented as ratios to a main compound in each reaction scheme. A main compound refers to a compound represented by a chemical formula in the reaction scheme and having the backbone of compounds of the present invention. Production method A


In this step, an -NH-protecting reagent is reacted with compound (la) [CAS No. 56160-64-6] to give compound (2a). The reaction conditions are selected depending on the type of -NK-protecting reagent to be used. The reaction may be performed under conditions that are generally used to introduce a protecting group using the reagent.

An -NH-protecting reagent can be a reagent that is generally used to introduce an -NH-protecting group. Specifically, such -NH-protecting reagents include, fo.r example, chloromethyl pivalate. It is preferable to use 1 to 2 equivalents of a protecting reagent. Solvents for rhe reaction include acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane. N,N-dimethylformamide is preferably used.
The reaction can be achieved in the presence of a base . Examples of bases to be used in the reaction include cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, and sodium hydride . Sodium hydride is preferably used. In this case, a base is preferably used in an amount of 1 to 5 equivalents . The reaction can be conducted at a temperature ranging from 0°C to 150°C. A preferred reaction temperature is room temperature. [Step A2]
In this step, compound (2a) is reacted wi-th compound {2a-2) to give compound {3a) .
Compound (2a-2)-can be any compound that is an electrophilic reagent such as an alkyl halide. Specific examples include alkyl halides such as iodomethane, iodoethane, iodopropane, and benzyl bromide; alkenyl halides such as allyl bromide and . l-bromo-3-methyl-2-butene; and alkynyl halides such as propargyl bromide and l-bromo-2-butyne. One to two equivalents of an electrophilic reagent are preferably used.
Solvents for the reaction include, for example, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, and toluene.
The reaction can be achieved in the presence or absence of a base. Examples of bases to be used in the reaction include lithium hydroxide, sodium hydroxide , potassium hydroxide, lithium carbonate , sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodiumhydride, potassium hydride, butyllithium, methyllithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. In this case, one to two equivalents of a base are preferably used.

The reaction can be conducted at a temperature ranging from 0°C to
150°C.
[Step A3]
In this step, the benzyl group at the 7-position" is removed from compound (3a) to give compound (4a).
Specifically, compound (4a) can be prepared from compound (3a), for example, by catalytic reduction under a hydrogen atmosphere in the presence of a metal catalyst, but the reaction conditions are not limited thereto.
Specific solvents for the reaction include, for example, methanol, ethanol, propanol, acetic acid, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, and toluene. Examples of metal catalysts include palladium carbon, platinum oxide, and Raney nickel. A metal catalyst is preferably used at 0 . 5 to 50 weight% . A preferred hydrogen pressure is 1 to 5 atm. The reaction can be conducted at a temperature ranging from O-C to 150"C. [Step A4]
In this step, compound (4a) is reacted with compound (4a-2) to give compound (5a).
Specific examples of compound (4a-2) are: alkyl halides such as iodomethane, iodoethane, iodopropane, and benzyl bromide; alkenyl halides such as allyl bromide and l-bromo-3-methyl-2-butene; or alkynyl halides such as propargyl bromide and l-bromo-2-butyne. These halides are preferably used in an amount of one to two equivalents.
Solvents for the reaction include dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, and toluene.
The reaction can be carried out in the presence or absence of a base. Examples of bases to be used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyllithium, methyllithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.

In this case, 1 to 4 equivalents of a base are preferably used. The reaction can be conducted at a temperature ranging from CC to ISO-C.
Compound (5a) can be obtained by reacting compound (4a) with compound (4a-2) in the presence of a copper catalyst and a base. In this case, it is preferable to use 0.1 to 2 equivalents of a copper catalyst and 1 to 10 equivalents of a base.
In this reaction, compound (4a-2) may be arylboronic acid, heteroarylboronic acid, or such, in which X is a Ce-10 aryl group which may have one or more substituents or a 5- to 10-membered heteroaryl group which may have one or more substituents, and U is -B(0H)2 or such. One to three equivalents of compound (4a-2) are preferably used.
In this case, reaction solvents include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, pyridine, N,N-dimethylformamide, and N-methylpyrrolidone.
Bases include triethylamine, diisopropyl ethyl amine, pyridine, and N,N-dimethylaminopyridine. Copper catalysts include copper (II) acetate, copper (II) trifluoroacetate, copper (II) chloride, and copper (II) iodide. The reaction can be conducted at a temperature ranging from O-C to 150°C. [Step A5]
In this step, compound _{Sa) is reacted with a halogenating agent to give compound (6a).
Specific examples of halogenating agents include, for example, N-chlorosuccinimide, N-bromosuccinimide , and N-10dosuccinimide. A halogenating agent is preferably used in an amount of 1 to 4 equivalents.
Solvents for the reaction include acetonitrile, N,N-dimethyIformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane. The reaction can be conducted at a temperature ranging from 0°C to 150°C. [Step A6]
In this step, compound (6a) is reacted with compound (7a) to give compound (8a) . In this case, 1 to 4 equivalents of compound (7a) are preferably used.
The reaction can be carried out, for example, in a solvent such

as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, 1,4-dioxane, toluene, and xylene, or in the absence of a solvent. The reaction can be conducted at a temperature rangini from 0°C to 200°C in the presence or absence of a base. Examples of a base include triethylamine, potassium carbonate, and 1,8-diazabicyclo[5,4,0]undecene. In this case, 1 to 4 equivalents of a base are preferably used. [Step A7]
In this step, the -NH-protecting group at the 3-position of compound (8a) is removed to give compound (9a) . The reaction conditions are selected depending on the type of -NH-protecting group to be removed. The deprotection reaction may be preformed under conditions that are generally used for the protecting group.
For example, when R2 is a pivalyloxymethyl group, the reaction can be carried out in methanol, or a mixed solution of methanol and tetrahydrofuran , using a base such as sodium methoxide , sodium hydride, or 1,8-diazabicyclo[5,4,0]-7-undecene at a temperature of 0 to 150 °C. In this case, 0.1 to 2 equivalents of a base are preferably used.
Alternatively, when R2 is a trimethylsilylethoxymethyl group, the reaction can be carried out in a solvent such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane, using a fluoride reagent such as tetrabutyl ammonium fluoride or cesium fluoride at a temperature of 0 to 150 °C. In this case, 1 to 5 equivalents of a fluoride reagent are preferably used. [Step A8]
In this step, compound (9a) is chlorinated to give compound (10a) .
There are no particular limitations on the reaction conditions, and the The reaction can be conducted under standard conditions for chlorination. For example, the reaction can be carried out at a temperature ranging from 0 to 150°C in a solvent such as phosphorus oxychloride. In this case, it is preferable to use a 10 to 200 times amount of halogenating agent by weight.
When R2" is a t-butoxycarbonyl group or such, which is removed under the above-described conditions using phosphorus oxychloride

or such, the protecting group should be reintroduced.
There are no particular limitations on the reaction conditions for the protection. In the case of the t-butoxycarbonyl group, the reaction can be carried out using an -NH- protection reagent such as di-t-butyl dicarbonate, in a solvent such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, or triethylamine at 0 to 150°C. [Step A9]
In this step, compound (10a) is reacted with compound (lla-2) to give compound (11a).
Compound (lla-2) includes alcohol compounds or phenol compounds represented by A-OH, amine compounds represented by A (R)NH or such, and thiol compounds represented by A-SH. In this case, compound (lla-2) is preferably used in an amount of 1 to 10 equivalents or 5 to 100 times by weight.
Solvents for the reaction include acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, and ethanol.
The reaction can be carried out in the presence or absence of a base. Bases to be used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, po-assium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyllithium, methyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and triethylamine. In this case, 1 to 10 equivalents of a base is preferably used. The reaction can ■be conducted at a temperature ranging from OC to 150°C. [Step AlO]
In this step, compound (10a) is reacted with compound (13a) in the presence of a metal catalyst to give compound (12a) . In this case, 1 to 50 equivalents of compound (13a) are preferably used.
Solvents for the reaction include acetonitrile.

N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, and ethanol.
Metal catalysts include palladium catalyst and copper catalyst. Palladium catalysts include tetrakis triphenylphosphine palladium, palladium acetate, and dibenzylideneacetone palladium. Copper catalyst include copper iodide. It is preferable to use 0.01 to 2 equivalents of a metal catalyst.
The reaction can be conducted in the presence of an organophosphorous ligand. When the reaction is carried out in the presence of an organophosphorous ligand, examples of the ligands include o-tolyl phosphine and diphenylphosphinoferrocene. In this case, it is preferable to use 1 to 5 equivalents of an organophosphorous ligand to the metal catalyst.
The reaccion can be carried out in the presence or absence of a base. Bases to be used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, potassium phosphate, lithium bis trimethylsilyl amide, sodium bis trimethylsilyl amide, potassium bis trimethylsilyl amide, and triethylamine. The reaction can be conducted at a temperature ranging from 0°C to ISOC. [Step All]
In this step, compound (10a) is reacted with a cyanidation reagent to give compound (14a).
SpeC1-fically, cyanidation reagents include, for example, sodium cyanide and potassium cyanide. It is preferably used in an amount of 1 to 20 equivalents.
Solvents for the reaction include, for example, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, and ethanol. The reaction can be conducted at a temperature ranging from. 0°C to 150 °C. [Step A12]
In this step, the cyano group of compound (14a) is hydrolyzed to give compound (15a) . There are no particular limitations on the reaction conditions, and the reaction can be carried out under conditions generally used for the conversion of a cyano group to a

carbamoyl group by hydrolysis.
Solvents for the reaction include N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, ethanol, and a mixed "solvent of tetrahydrofuran and methanol.
The reaction can be carried out in the presence or absence of a base. When a base is used, the reaction can be carried out using an aqueous solution of a base such as potassium hydroxide, sodium hydroxide, lithium hydroxide, or ammonia. The reaction can be achieved after adding an aqueous solution of hydrogen peroxide (preferably an aqueous solution of 30% hydrogen peroxide).
The reaction can be conducted at a temperature ranging from CC to 150°C. [Step A13]
In this step, R2 of compound {16a) is removed to give compound (17a) . Compounds (11a) , (12a) , (14a) , (15a) , and others can be us-ed as compound (16a) . __
The deprotection reaction for R2 can be carried out under standard reaction conditions for removing an -NH-protecting group.
For example, when R2 is a t-butoxycarbonyl group, the reaction can be carried out in the presence of an acid such as an anhydrous methanol solution of hydrogen chloride, an anhydrous ethanol solution of hydrogen chloride, an anhydrous dioxane solution of hydrogen chloride, trifluoroacetic acid, or formic acid.
An alternative method for producing compound (-10a) is described


(19a) . There are no particular limitations on the reaction conditions, and the reaction can be conducted under standard conditions for chlorination. For example, the reaction can be carried out in a solvent such as phosphorus oxychloride at a temperature ranging from 0 to 150°C. Preferably 10 to 200 times by weight of chlorination reagent is used.
When R2" is a t-butoxycarbonyl group or such, which is removed under the above-described condition using phosphorus oxychloride or such, the protecting group should be reintroduced.
There are no particular limitations on the reaction conditions for the protection, and when R2 is a t-butoxycarbonyl group, the reaction can be carried out using an -NH- protection reagent such as di-t-butyl dicarbonate, in a solvent such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, or triethylamine at a . temperature ranging from 0 to 150°C. [Step A15]
In this step, compound (19a) is partially hydrolyzed to give compound (20a) . The reaction is carried out in the presence of a base such as sodium acetate, potassium carbonate, or sodium hydroxide. One to ten equivalents of a base are preferably used. Solvents for the reaction include dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, water, and mixtures thereof. The reaction can be conducted at a temperature ranging from 0°C to lOOC. [Step A16]
In this step, compound (20a) is reacted with compound (21a) to give compound (22a) . The reaction can be conducted under the same conditions as used in [Step A2] of production method A.
An alternative method for producing compound {19a) is described below.


In this step, a substitution reaction is carried out using compound (23a) [CAS No. 1076-22-8] and compound (4a-2) to give compound (24a).
The reaction can be conducted under the same conditions as used in [Step A4] of production method -A. [Step A18]
In this step, compound (24a) is reacted with a halogenating agent to give compound (25a).
The reaction can be conducted under the same conditions as used in [Step A5] of production method A. [Step A19]
In this step, compound (25a) is chlorinated to give compound (26a) .
There are no particular limitations on the reaction conditions, and compound (25a) can be reacted with phosphorus oxychloride, phosphorus pentachloride, or a mixture thereof in a solvent or in the absence of a solvent at a temperature of 0 to 150°C. Solvents include, for example, toluene, acetonitrile, and dichloroethane. [Step A2 0]
In this step, compound (26a) is reacted with compound (7a) to give compound (19a).
The reaction can be conducted under the same conditions as used in [Step A6] of production method A. Production method B


In this step, compound (lb) is ber.zylated and the sugar chain is cleaved to give compound (2b).
There are no particular limi-tations on the reaction conditions . Compound (2b) can be obtained by reacting compound (lb) with benzyl bromide in a solvent such as acetonitrile, N,N-difnethylf ormamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, or ethanol, at a temperature of 0 to 150°C, adding 3 to 10 equivalents of hydrochloric acid, and incubating the mixture at a temperature of 0 to 150°C to cleave the sugar moiety. It is preferable to use 1 to 3 equivalents of benzyl bromide. [Step B2]
In this step, compound (2b) is reached with a halogenating agent to give compound (3b) . The halogenation reaction can be conducted under the same conditions as used in [Step A5] of production method A. - [-Step B3]
In this step, compound (3b) is reacted with compound (4b) to give compound (5b) . The reaction can be conducted under the same conditions as used in [Step A6] of production method A. [Step B4]
In this step, compound (5b) is reacted with compound (5b-2) to

give compound (6b) . The reaction can be conducted under the same condition as used in [Step A2] of production method A. [Step B5]
In this step, R2 of compound {6b) is removed to give compound (7b) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A. Production method B-2

can be obtained by using compound (8b) represented by H-T1, instead of compound (7a) in [Step A6] of production method A described above under the same reaction conditions as used in [Step A6], and then appropriately applying [Step A7] to [Step A13] described above.

can be obtained by using compound (8b) represented by H-T1, instead of compound (3b) in [Step B3] of production method B described above under the same reaction conditions as used in [Step B3] and then appropriately applying [Step B4] to [Step B6] described above. Preferable exa.mples of compound (8b) include piperidin-3-yl carbamic acid t-butyl ester. Production method C






In this step, compound (Ic) is reacted with compound (lc-2) to give compound (2c) . The reaction can be conducted under the same conditions as used in [Step A4] of production method A. [Step C2]
In this step, compound (Ic) is reacted with ethanol to give compound (3c) .
Compound (3c) can be obtained, for example, by heating an ethanol solution of compound (2c) under reflux in the presence of an acid such as sulfuric acid or hydrochloric acid. However, the reaction conditions are not limited thereto. In this reaction, it is preferable to use one to two equivalents of an acid. [.Step C3]
In this step, compound {2c) is reacted with ethanol to give compounds (4c) and (5c) . The reaction can be conducted under the same conditions as used in [Step C2] of production method C. [Step CA]
In this step, compound (3c) is reacted with compound (3c-2) to

give compounds (4c) and (5c) . The reaction can be conducted under the same conditions as used in [Step A4] of production method A. [Step C5]
In this step, compound (4c) is reacted with compound (6c) to give compound (7c) . The reaction can be conducted under the same conditions as used in [Step A6] of production method A. [Step C6]
-In this step, compound (7c) is thioamidated to give compound (8c). Solvents for the reaction include methanol, ethanol, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane. Thioamidation reagents include ammonium sulfide, sodium sulfide, and hydrogen sulfide. It is preferable to use 2 to 10 equivalents of a thioamidation reagent. When hydrogen sulfide is used as the thioamidation reagent, the reaction is carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine. The reaction can be con-ducted at a temperature ranging from CC to 150"C. [Step C7]
In this step, compound (8c) is reacted with a methylating reagent to give compound (9c). Methylating reagents include trimethyl oxonium tetrafluoroborate, methyl sulfate, methyl iodide, and trimethyl phosphite. It is preferable to use 1. 0 to 1. 5 equivalent of the methylating reagent.
When trimethyl oxonium tetrafluoroborate is used as the methylating reagent, compound (9c) can b-e obtained by carrying out the reaction in a halogenated solvent such as dichloromethane at a remperature ranging from 0°C to 50°C.
When methyl sulfate, methyl iodide, or trimethyl phosphite is used as the methylating reagent, compound (9c)" can be obtained by carrying out the reaction in the presence of a base such as potassium carbonate, triethylamine, or N,N-diisopropylethylamine. In this case, it is preferable to use 1.0 to 1.5 equivalent of a base. Solvents for the reaction include acetone, N,N-diraethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane. The reaction can be performed at a temperature ranging from O-C to lOOC.

[Step C8]
In this step, compound (9c) is hydrolyzed to give compound (10c) .
There are no particular limitations on the reaction conditions for the hydrolysis . The reaction can be carried out in a mixed solvent of ethanol and water in the presence of an acid such as sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid, at a temperature ranging from 0°C to 80°C. In this case, it is preferable to use 5 to 50 equivalents of the acid.
When R2 is a group, such as a t-butoxycarbonyl group, which is removed under the above-described condition, the protecting group should be reintroduced. There are no particular limitations on the reaction conditions for the introduction of this protecting group. When R2 is a t-butoxycarbonyl group, the reaction can be carried out using a reagent such as t-butyl dicarbonate in a solvent such as dichloromethane, chloroform, N,N-dimerhylformamide, or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, and N,N-diisopropylethylamine, at a temperature ranging from 0 to 80°C. In this case, it is preferable to use 2 to 3 equivalents of a base. [Step C9]
In this step, compound (10c) is reacted with a reducing agent to give compound (lie).
There are no particular limitations on the reaction conditions for the reduction. The reaction can be achieved by reaching compound (10c) wirh hydrogen in the presence of Raney nickel in a solvent such as benzene, ethanol, 2-propanol, or acetone, at a temperature ranging from 0°C to 50°C, or alternatively reacting compound (10c) with a reducing agen- such as sodium borohydride, in a solvent such as methanol,, ethanol, or 2-methyl-2-propanol, or in a mixed solvent of .water and tetrahydrofuran at a temperature ranging from 0°C to 50 °C, or alternatively reacting compound (10c) with a reducing agent such as sodium borohydride, in the presence of 1 to 5 equivalents of a mercury salt such as mercuric acetate in a solvent such as methanol, ethanol, or 2-methyl-2-propanol at a temperature ranging from OC to 50°C. It is preferable to use two to three equivalents of a reducing

tay en L .
[Step CIO]
In this step, compound (lie) is subjected to an oxidation reaction to give compound (12c).
When an oxidant such as manganese dioxide, pyridinium chlorochromate, or pyridinium dichromate is used in the oxidation reaction, compound (12c) can be obtained by carrying out the reaction in a solvent such as dichloromethane or chloroform, at a temperature ranging from 20°C to SCC. Alternatively, compound (12c) can also be obtained by carrying out the reaction under standard conditions for the oxidation of a primary alcohol to aldehyde, such as Swern oxidation. It is preferable to use 5 to 20 equivalents of an oxidant. [Step Cll]
In this step, compound (12c) is reacted with compound (13c) to give compound (17c) . In this case, it is preferable to use 2 to 10 equivalents of compound (13c) .
Compound (17c) can be obtained, for example, by combining compounds (12c) and (13c) in a solvent such as methanol, ethanol, l-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane, or in the absence of solvent, and reacting the mixture at a remperature of 20 to 150°C. However, the reaction conditions are not limited thereto. [Step C12]
In this step, compound (12c) is reacted with hydrazine to give compound (15c). The reaction can be conducted under the same conditions as used in [Step Cll] of production method C. It is preferable to use 2 to 10 equivalents of hydrazine. [Step C13]
In this step, a substitution reaction is carried out using compound (15c) and compound (16c) to give compound (17c). The reaction can be conducted under the same conditions as used in [Step A2] of production method A. It is preferable to use 1 to 3 equivalents of compound (16c). [Step C14]
In this step, R2 of compound (17c) is removed to give compound (14c). The reaction can be conducted under the same conditions as

used in [Step A13] of production method A. [Step C15]
In this step, compound (5c) is reacted with compound (6c) to give compound (18c) . The reactiofi can be conducted under the same conditions as used in [Step A6] of production method A. [Step C16]
In this step, compound (18c) is hydrolyzed to give compound {19c) .
There are no particular limitations on the reaction conditions for the hydrolysis. For example, compound (19c) can be obtained by incubating compound (18c) in the presence of a base at a temperature ranging from OC to 100°C.
Solvents for the reaction include methanol, ethanol, tetrahydrofuran, water, or mixtures thereof. Bases include lithium hydroxide, sodium hydroxide, and potassium hydroxide. It is preferable to use 1 to 2 equivalents of a base. [Step C17]
In this step, compound (19c) is reacted with a reducing agent to give compound (20c) . The reduction can be achieved under a standard condition for the reduction of carboxylic acid to merhyl alcohol.
Reducing agents include borane derivatives such as borane-tetrahydrofuran complex and borane-methyl sulfide complex, and sodium borohydride. It is preferable to use 5 to 30 equivalents of a reducing agent.
When a borane derivative is used as a reducing agent, compound (20c) can be obtained by carrying out the reaction using a solvent such as 1,4-dioxane, tetrahydrofuran, or dimethoxyethane at a temperature ranging from -78°C to 35°C.
Alternatively, when sodium borohydride is used as a reducing agent, first, compound (19c) is reacted with an activator such as .isobutyl chloroformate, at a temperature ranging from -78°C to 20°C, then reacted with a reducing agent such as sodium borohydride at a temperature ranging from -78°C to 35°C, to obtain compound (20c). Solvents for the reaction include 1,4-dioxane, tetrahydrofuran, and dimethoxyethane. [Step C18]

In this step, compound (20c) is thioamidated to give compound (21c). The reaction can be conducted under the same conditions as used in [Step C6] of production method C. [Step C19]
In this step, compound (21c) is reacted with a silylating agent in the presence of a base to give compound (22c) .
Solvents for the reaction include dichloromethane, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane. Bases include imidazole, pyridine, 4-dimethylaminopyridine, triethylamine, and N,N-diisopropylethylamine. Silylating agents include t-butyldimethylchlorosilane, and t-butylchlorodiphenylsilane. It is preferable to use 1.0 to 1.5 equivalent of a base and 1.0 to 1.5 equivalent of a silylating agent. The reaction can be conducted at a temperature ranging from 0°C to 80°C. [Step C20]
In this step, compound (22c) is methylated to give compound (23c) .
The reaction can be conducted under the same condition as used in [Step C7] of production method C. [Step C21]
In this step, compound (23c) is hydrolyzed to give compound (24c) .
There are no particular limitations on the reaction conditions for the hydrolysis. Compound (24c) can be obtained by carrying out the reaction in a mixed solvent of ethanol and water in the presence of an acid such as sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid, at a temperature ranging from 50°C to 100°C.
When such a reaction results in removal of -R2", -NH- is re-protected through a protection reaction. Specifically, for example,, when R2 is a t-butoxycarbonyl group, the reaction can be carried out using a reagent such as t-butyl dicarbonate, in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropyl ethylamine, at a temperature ranging from 0 to 80"C. However, the reaction is not


Specifically, compound (ld-2) includes, for example, alkyl halides such as iodomethane, iodoethane, iodopropane, benzyl bromide, 2-bromoacetophenone, chlorome-:hyl benzyl ether, and bromoacetonitrile; alkenyl halides such as allyl bromide and L-bromo-3-methyl-2-butene; and alkynyl halides such as propargyl bromide and l-bromo-2-butyne. It is preferable to use 1 to 1.5 equivalent of compound (.ld-2) .
Solvents for the reaction include N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and dichloromethane. The reaction can be carried out

in the presence or absence of a base. Bases to be used in the reaction include 1,8-diazabicyclo[5,4,0]undecene, triethylamine, N,N-diisopropylethylamine, and sodium hydride. In this case, it is preferable to use 1 to 1.5 equivalent of the base. The reaction can be conducted at a temperature ranging from 0°C to 150"C. [Step D2]
In this step, compound (2d) is reacted with a nitrite salt to give compound (3d).
Solvents for the reaction include a mixed solvent of water and a solvent from N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane. Nitrite salts include sodium nitrite and potassium nitrite. It is preferable to use 3 to 5 equivalents of a nitrite. The reaction can be conducted at a temperature ranging from 20°C to 120°C. [Step D3]
In this step, compound (3d) is reacted with ammonia to give compound (4d) . It is preferable to use 10 to 20 equivalents of-ammonia.
The reaction can be carried out in a solvent such as methanol, ethanol, or 1,4-dioxane at a temperature ranging from 20 "C to 200°C. [Step D4]
In thisstep, compound (4d) is subjected to catalytic reduction under hydrogen atmosphere or in the presence of 2 to 3 equivalents of hydrazine using a metal catalyst to give compound (5d) .
Solvents for the reaction include methanol, ethanol, N,N-dimethyIformamide, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, or a mixed solvent thereof. Metal catalysts include palladium carbon, platinum oxide, and Raney nickel. It is preferable to use a metal catalyst in the amount of 0.5 to 10% by weight. The reaction can be conducted at a temperature ranging from . O-C to 150 °C. [Step D5]
In this step, compound (5d) is reacted with an orthoformate ester to give compound (6d).
The reaction is carried out in the presence of a carboxylic anhydride such as acetic anhydride. Orthoformate esters include

methyl orthoformate, and ethyl orthoformate. It is preferable to use 1 to 20 times as much orthoformate ester by weight and 3 to 10 equivalents of carboxylic ©njiydride. The reaction can be conducted at a temperature ranging from 20°C to 200C. [Step D6]
In this step, the NH group at the 1-position of compound (6d) is protected to give compound (7d).
Protecting reagents include N,N-dimethylsulfamoyl chloride, trityl chloride, di-t-butyl dicarbonate, and benzyl bromide. It is preferable to use 1 to 1.5 equivalent of a protecting reagent. Solvents for the reaction include dichloromethane, chloroform, carbon tetrachloride, toluene, N,N-di.methylformamide, and tetrahydrofuran. Bases include pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5,4,0]undecene, triethylamine, and N,N-diisopropylethylamine. In typical cases , it is preferable to use 1.2 equivalents of a base. However, When the protecting reagent is di-t-butyl dicarbonate, 0.005 to 0.1 -equivalent of 4-dimethylaminopyridine is used preferably. The reaction can be conducted at a temperature ranging from 20C to 200"C. [Step D7]
In this step, compound (7d) is chlorinated to give compound
(8d) . . .
There are no particular limitations on the reaction conditions . For example, the reaction is carried out as follows. Compound (7d) is reacted with a base a-t a temperature ranging from -100°C to 20°C, and then a chlorinating reagen- is reacted thereto. This reaction produces compound (8d) . Compound (8d) can also be obtained by reacting compound (7d) with a base in the presence of a chlorination reagent. Solvents for the reaction include, for example, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane. Bases include n-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis(-rimethylsilyl)amide, and magnesium diisopropylamide. It is preferable to use 1 to 1.5 equivalent of a base. Chlorinating reagents include hexachloroethane, and N-chloro succinimide. It is preferable to use 1 to 3 equivalents of a chlorination reagent.

[Step D8]
In this step, compound (8d) is reacted with compound (9d) to give compound (lOd) . The reaction can be conducted under the same-conditions as used in [Step A6] of production method A. [Step D9]
In this step, a substitution reaction is carried out using compound (lOd) and compound (lOd-2) to give compound (lid). The reaction can be conducted under the same conditions as used in [Step A4] of production method A. [Step DIO]
In this step, R of compound (lid) is removed to give compound (12d) . The reaction can be conducted under the same condition as used in [Step A13] of production method A. [Step Dll]
In this step, the group at the 5-position of compound (lid) is obtained by dealkylation to give compound (13d). There are no particular limitations on the reaction conditions for the dealkylation. For example, such a reaction can be achieved as follows:
When R is a benzyloxymethyl group, compound (lid) is reacted with 3 to 10 equivalents of boron tribromide, boron trichloride, or such in a solution such as dichloromethane at a temperature ranging from -100°C to 20°C. This reaction produces compound (13d).
When such a reaction results in removal of R2, -NH- is re-protected through a protection reaction. Specifically, far example, when R2 is a t-butoxycarbonyl group, the reaction can be carried out using a reagent such as di-t-butyl dicarbonate, in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropylethylamine, at a temperature ranging from 0 to 80°C. However, the reaction is not limited thereto. [Step D12]
In this step, compound (13d) is reacted with compound (13d-2) to give compound (14d) . The reaction can be conducted under the same conditions as used in [Step Dl] of production method D.

[Step D13]
In this step, R2 of compound (14d) is removed to give compound (12d). The reaction can be conducted under the same conditions as used in [Step A13] of production method A.

The deprotection can be achieved under standard reaction conditions depending on the type of protecting group. For example, in the case of a t-butoxycarbonyl group, the deprotection can be achieved by carrying out the reaction using a base such as sodium hydroxide, potassium carbonate, and ammonia, in tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, water, or a mixed solvent thereof at a temperature ranging from 0°C to 100 °C. When a solvent and a base are added after chlorination in the previous step, the deprotection can be achieved without isolating compound (8d) . [Step D15]
In this step, X is introduced into compound (15d) to give compound (16d). The reaction can be conducted using X-U under the .same conditions as used in [Step A4] of production method A.
An alcohol (X-OH) can be introduced using Mitsunobus reaction. Specifically, compound (16d) can be obtained by reacting an alcohol (X-OH) with an azodicarboxylic acid dialkyl ester and triphenylphosphine in a solvent such as tetrahydrofuran, at a temperature-ranging from -70°C to 50°C.

[Step D16]
In this step, compound (16d) is reacted with compound (9d) to give compound (lid).
The reaction can be conducted under the same conditions as used in [Step A6] of production method A. Production method E

can be obtained by using compound (8b) represented by H-T, instead of compound (6c), in [Step C5] or [Step C15] of production method C described above under the same reaction conditions as used in [Step C5] , and then appropriately applying [Step C6] to {Step C21] described

can be obtained by using compound (8b) represented by H-T1, instead of compound (9d) in [Step D8] of production method D described above under the same reaction conditions as used in [Step D8], and then appropriately applying [Step D9] to [Step D13] described above. Production method F


In this step, the ester group of compound (If) is hydrolyzed to give compound (2f) . The reaction can be conducted under the same conditions as used in [Step C16] of production method C. [Step F2]
In this step, R2 of compound (2f) is removed to give compound (3f) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A.


In this step, the nitro group of compound (Ig) is reduced to give compound {2g).
So,lvents for the reaction include methanol, ethanol, tetrahydrofuran, water, or mixtures thereof. Reducing agents includes, iron, tin, and zinc. Catalysts include hydrochloric acid and ammonium salts such as ammonium chloride. The reaction can be conducted at a temperature ranging from 20°C to 120"C. [Step G2]
In this step, R2 of compound (2g) is removed to give compound (3g) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A. Production method H

There are no particular limitations on the reaction conditions. For example, the reaction is carried out as follows. Compound (2h) can be obtained by reacting compound (Ih) with hydrogen peroxide in the presence of a base at a temperature ranging from -20"C to 50°C.
Solvents include methanol, ethanol, tetrahydrofuran, water, or a
i
solvent mixture thereof. Bases include ammonia and alkyl amines such as triethylamine..

[Step H2]
In this step, R2 of compound (2h) is removed to give compound (3h) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A.

There are no particular limitations on the reaction conditions . For example, the reaction is carried out as follows. Compound (li) may be reacted.with an agent such as alkyllithium, aryllithium, alkyl Grignard reagent, or aryl Grignard reagent, in a solvent such as diethyl ether or tetrahydrofuran, at a temperature ranging from -lOCC to 100"C. Alternatively, the compound may be reacted with alkylzinc

or arylzinc in a solvent such as N,N-dimethylformamide or l-methyl-2-pyrrolidone, at a temperature ranging from CC to 50 "C. [Step 12]
In this step, compound (2i) is oxidized to give compound (3i) . A typical reagent that is generally used in the oxidation of an alcohol can be used as the oxidant. Specifically, for example, manganese dioxide can be used as the oxidant in a solvent such as dichloromethane or chloroform, at a temperature within the range of 20 to 100°C. Alternatively, sulfur trioxide pyridine can be used as the oxidant in a solvent such as dimethyl sulfoxide, at a temperature within the range of 20 to 100°C. Alternatively, Dess-Martin periodinane may be used in a solvent such as dichloromethane or chloroform, at a temperature wirhin the range of -50 to 50°C. [Step 13]
In this step, compound (3i) is reacted with hydrazine to give compound (41). The reaction can be conducted under the same conditions as used in [Step C12] of production method C. [Step 14]
In this step, a substitution reaction is carried out using compound (4i) and compound (5i) to give compound (6i) . The reaction can be conducted under the same conditions as used in [Step A2] of oroduction meuhod A. [Step 15]
In this step, R2 of compound (6i) is removed to give compound (7i) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A. [Step 16]
In this step, R2 of compound (4i) is removed to give compound (7i) when R2 of compound (71) is H. The reaction can be conducted under the same conditions as used in [Step A13] of production method A. Production method J


In this step, compound (Ij) is reacted with a cyanidation agent in the presence of a catalyst to give compound (2j).
Cyanidation agents include sodium cyanide, and potassium

cyanide. Catalysts include acetic acid. Solvents include, for example, acetonitrile. The reaction can be conducted at a temperature ranging from 0°C to lOCC. [Step J2]
In this step, the nitrile group of compound (2j) is hydrolyzed to give compound (3j) . The reaction can be conducted under the same conditions as used in [Step HI] of production method H. [Step J3]
In this step, the hydroxyl group of compound (3j) is oxidized to give compound (4j) . The reaction can be conducted under the same conditions as used in [Step 12] of production method I. [Step J4]
In this step, compound {4j) is reacted with compound (5j) to give compound (6j) . The reaction can be conducted under the same conditions as used in [Step Cll] of production method C. [Step J5]
In this step, R" of compound (6j) is removed to give compound (7j ) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A. [Step J5]
In this srep, the carbamoyl group of compound (6j) is dehydrated in the presence of a base to give compound {8j) .
Dehydrating agents include, for example, phosphorus oxychloride. Bases include alkyl amines such as triethylamine. Solvenrs include dichloromethane, and chloroform. Alternatively, rhe reaction can be carried out in the absence of solvent. The reaction can be conducted at a temperature ranging from 0 ° C to 100 °C. [Step J7]
In this s-ep, R2 of compound (8j) is removed to give compound (9j ) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A. Production method K


In this step, a substitution reaction using compound (Ik) and compound (2k) is carried out to give compound (3k) . The reaction can

be conducted under the same conditions as used in [Step A2] of production method A. [Step K2]
In this step, a substitution reaction using compound (3k) and compound (4k) is carried out to give compound (5k)
Compound (5k) can be obtained, for example, by reacting a mixture of compounds (3k) and (4k) in a solvent such as methanol, ethanol, l-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane, or in the absence of solvent at a temperature ranging from 20°C to 200°C. However, the reaction conditions are not limited thereto. [Step K3]
In this step, compound (5k) is chlorinated to give compound (6k) . The reaction can be conducted under the same conditions as used in [Step D7] of production method D. [Step K4]
In this step, compound (6k) is-reacted with compound (7k) to give compound (8k) . The reaction can be conducted under the same conditions as used in [Step A6] of production method A. [Step K5]
In this step, R2 of compound (8k) is removed to give compound
(9k) . . .
The deprotection reaction for R2 can be carried out under standard reaction conditions for removing an -NH-protecting group.
For example, when R2 is a benzyl group, the reaction can be achieved using a metal such as lithium or sodium in liquid ammonia at a temperature within the range of -78°C to -30°C. [Step K6]
In this srep, a substitution reaction using compound (9k) and compound (10k) is carried out to give co.mpound (Ilk) . The reaction can be conducted under the same conditions as used in [Step A4] of production method A. [Step K7]
In this step, R2 of compound (Ilk) is removed to give compound (12k). The reaction can be conducted under the same conditions as used in [Step A13] of production method A.


In this step, compound (11) is reacted with compound (21) in -he presence of an oxidant to give compound (31) .
Oxidants include salts such as iron (III) chloride. Solvents include methanol, ethanol, and water. The reaction can be conducted a- a temperature ranging from 20°C to 100°C.
When such a reaction results in removal of -R2", -NH- is re-protected through a protection reaction. Specifically, for example, when ?ro3 is a t-butoxycarbonyl group, the reaction can be carried out using a reagent such as di-t-butyl dicarbonate, in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropylethylamine, at a temperature ranging from 0 to 80°C. However, the reaction is not limited thereto. [Step L2]
In this step, compound (31) is reacted with compound (41) to give compound (51) . The reaction can be conducted under the same conditions as used in [Step A4] of production method A.

[Step L3]
In this step, R2 of compound (51) is removed to give compound (61) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A.

give compound (3m) . The reaction can be conducted under the same conditions as used in [Step A6] of production method A. [Step M2]
In this s-ep, compound (3m) is reacted with compound (4m) to give compound (5m) . The reaction can be conducted under the same •conditions as used in [Step A4] of production method A. [Step M3]
In this srep, R2" of compound (5m) is removed to give compound (6m) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A. Production method N .


In this step, compound (In) is reacted with allylamine to give compound {2n).

The reaction can be conducted at a temperature ranging from 20°C to 150°C. Solvents for the reaction include methanol, ethanol, water, and a mixed solvent thereof. [Step N2]
In this step, compound (2n) is reduced while being chlorinated to give compound (3n).
Reducing agents include tin salts such as tin chloride. Solvents include concentrated hydrochloric acid. The reaction can be conducted at a temperature ranging from 20C to 150°C. [Step N3]
In this step, compound (3n) is reacted with N,N-disuccinimidyl carbonate to give compound (4n).
The reaction can be achieved using a solvent such as acetonitrile or tetrahydrofuran. The reaction can be conducted at a temperature ranging from 20°C to lOOC. [Step N4]-
In this step, compound (4n) is reacted with compound (5n) to give compound {6n). The reaction can be conducted under the same conditions as used in [Step A4] of production method A. [Step N5]
In this srep, the allyl group is removed from compound (6n) to give compound (7n).
Compound (7n) can be obtained, for example, by reacting compound (6n) with osmic acid and sodium periodate in a solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or water at a temperature ranging from 20°C to 100°C. However, the reaction conditions are not limited to this example. [Step N6]
In this step, compound (Vn) is chlorinated to give compound (8n) .
There are no particular limitations on the reaction conditions . The reaction can be conducted under standard reaction conditions to be used for chlorination . Compound (8n) can be obtained, for example, by using a reagent such as phosphorus pentachloride in a solvent such as phosphorus oxychloride, at a temperature of 0 to 150°C. [Step N7]

In this step, compound {8n) is reacted with compound (9n) to give compound (lOn) . The reaction can be conducted under the same conditigns as used in [Step A6] of production method A. [Step N8]
In this step, R2 of compound (lOn) is removed to give compound (lln). The reaction can be conducted under the same conditions as used in [Step A13] of production method A.


In this step, the hydroxyl group of compound (lo) is oxidized to give compound (2o) . The reaction can be conducted under the same conditions as used in [Step 12] of production method I. [Step 02]
In this step, compound (2o) is reacted with ethyl diethylphosphonoacetate in the presence of a base to give compound {3o) .
Bases include sodium hydride and lithium diisopropylamide. Solvents include, for example, tetrahydrofuran and N ,N-diformamide. The reaction can be conducted at a temperature ranging from 0°C to lOOC. [Step 03]
In this step, the ester of compound (3o) is hydrolyzed to give compound {4o) . The reaction can be conducted under the same condition as used in [Step C16] of production method C. [Step 04]
In this step, compound (4o) is reacted with diphenylphosphoryl azide in the presence of a base to give compound (5o) .
Solvents for the reaction -include toluene, t-butanol, tetrahydrofuran, and dichloromethane . Bases include tertiary amines such as triethylamine and diisopropylethylamine. The reaction can be conducted at a temperature ranging from -50°C to 50°C. [Step 05]
In this step, compound (5o) is rearranged to give compound (So) .
The reaction can be achieved in t-butanol at a temperature ranging from 50°C to 100°C. [Srep 06]
In this step, the nitrile group of compound (6o) is hydrolyzed to give compound (7o) . The reaction can be conducted under the same conditions as used in [Step HI] of production method H. [Step 07]
In this _step, compound (7o) is reacted with an acid to give compound (8o) .
Acids include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. Solvents include methanol, ethanol,


In this step, compound (Ip) is protected to give compound (2p) .
A typical NH group-protecting reagent that is generally used in protecting NH groups can be used as an NK group-protecting reagent. For example, when R2 is a t-butoxycarbonyl group, the reaction can be achieved at a temperature ranging from 0 to 80 °C using a reagent such as di-t-buryl dicarbonate, in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, and tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, and N,N-diisopropylethylamine. [Step P2]
In this szep, compound (2p) is reacted with compound (3p) to give compound (4p) . The reaction can be conducted under the same :onditions as used in [Step A2] of production method A. [Step P3]
In this step, R2 of compound (4p) is removed to give compound (5p) . The reaction can be conducted under the same conditions as used

in [Step A13] of production method A. Production method Q



[Step Ql]
In this step, compound (Iq) is hydrolyzed to give compound (2q) .
Reaction solvents include tetrahydrofuran, methanol, and ethanol. Acids include inorganic acids such as hydrochloric acid and sulfuric acid. The reaction can be conducted at a temperature ranging from 0°C to 100°C. [Step Q2]
In this s-ep, the hydroxyl group of compound (2q) is oxidized ro give compound {3q) . The reaction can be conducted under the same conditions as used in [Step 12] of production method I. [Step Q3]
In this step, compound (3q) is reacted with methyl benzyloxycarbonylamino(dimethoxyphosphoryl) acetate in the presence of a base to give compound (4q).
Bases include sodium hydride, potassium t-butoxide, and 8-diazabicyclo[5.4.0]-7-undecene. Solvents include dichloromethane, tetrahydrofuran, and N,N-dimethylformamide. The reaction can be conducted at a temperature ranging from OC to 100°C. [Step Q4]
In this s-ep, compound (4q) is reacted with sodium methoxide -0 give compound (5q).
Methanol can be used as solvent. The reaction can be conducted a- a temperature ranging from 0°C to 80°C. [Step Q5]
In this s-ep, compound (5q) is reacted with compound (6q) to give compound (7q) . The reaction can be conducted under the same conditions as used in [Step A2] of production method A. [Step Q6]
In this s-ep, compound (7q) is reacted with an acid to give compound (8q). The reaction can be conducted under the same .conditions as used in [Step 07] of production method 0. [Step Q7]
In this s-ep,.R2 of compound (8q) is removed to give compound (9q) . The reaction can be conducted under -he same conditions as used in [Step A13] of production method A. [Step Q8]

In this step, compound (7q) is reacted with ammonia to give compound (lOq).
Reaction solvents include methanol, ethanol, and water. The reaction can be conducted at a temperature ranging from 20°C to 150°C. [Step Q9}
In this step, R2 of compound (lOq) is removed to give compound (llq) . The reaction can be conducted under the same conditions as used in [Step A13] of production method A.
The compounds indicated below, salts thereof, or hydrates thereof, are exceedingly useful as intermediates in the synthesis of compound (I) of the present invention.
Compounds, or salts thereof, or hydrates thereof, represented by the formula:


T1 represents a t-butoxycarbonyl group, a benzyloxycarbonyl group, or a formyl group];
Compounds, or salts thereof, or hydrates thereof, represented

Compounds, or salts thereof, or hydrates thereof, represented


T22 represents a halogen atom;
T13 represents a t-butoxycarbonyl group, a benzyloxycarbonyl group, -or a formyl group].
The methods indicated above are representative methods for producing compound (I) of the present invention. The starting compounds and various reagents to be used in the methods for producing compounds of the present invention may be salts or hydrates, or solvates depending on the type of starting materials, solvents to be used, or such, and are not limited as long as they do not inhibit the reactions. The type of solvents to be used depends on the types of starting compounds, reagents to be used, or such, and is not limited as long as it does not inhibit the reactions and dissolves starting materials to some extent. When compound (I) of the present invention is obtained in a free form, such a compound can be converted to a salt or a hydrate, which is a possible form of compound (I) described above, according to a conventional method.
When compound (I) of the present invention is obtained as a salt or a hydrate, such a product can be converted to a free form of compound (I) described above according to a conventional method.
In addition, various isomers of compound (I) of the present invention (for example geometric isomers, enantiomers on the basis of asymmetric carbon, rotamers, stereoisomers, and tautomers) can be purified and isolated by typical isolation means, for example, including recrystallization, diastereomer salt method, enzyme-based separation, and various chromatographic methods (for example, thin layer chromatography, column chromatography, and gas chromatography).
Compounds of the present invention, salts thereof, or hydrates thereof, can be formulated into tablets, powders, particles, granules, . coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, epithem, lotions, etc. by conventional methods. Such formulation can be achieved by using typical diluting agents , binders , lubricants, colorants, flavoring agents , and if required, stabilizers, emulsifiers, absorbefacients, surfactants, pH modulators.

preservatives, antioxidants, etc., and materials commonly used as ingredients of pharmaceutical preparations according to conventional methods. For example, an oral preparation can be produced by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with a diluting agent, and if required, a binder, a disintegrating agent, a lubricant, a colorant, a flavoring agent, or such, and formulating the mixture into powders, particles, granules, tablets, coated tablets, capsules, or the like according to conventional methods. Examples of the materials include, for example, animal and vegetable oils such as soya bean oil, beef tallow, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicon resins; silicone oils; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene block co-polymer; water-soluble polymers such as hydroxyethyl cellulose, poly-acrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propylene glycol, dipropylene glycol, and sorbitol; sugars such as glucose and sucrose; inorganic powder such as anhydrous silicic acid, magnesium aluminum silicate, and aluminum silicate; and pure water. Diluting agents include, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystal cellulose, and silicon dioxide. Binders include, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arable, tragacanth, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block co-polymer, and meglumine. Disintegrating agents include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and calcium carboxymethyl cellulose. Lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica, and

hydrogenated vegetable oil. Colorants include those pharmaceutically acceptable. Flavoring agents include cocoa powder, peppermint camphor, aromatic powder peppermint oil, Borneo camphor, and cinnamon powder. Tablets and granules may be coated with sugar, or if required, other appropriate coatings can be made. Solution, such as syrups or injectable preparations, to be administered can be formulated by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with a pH modulator, a solubilizing agent, an isotonizing agent, or such, and if required, with an auxiliary solubilizing agent, a stabilizer, or the like, according to conventional methods . Methods for producing an external preparation are not limited and such preparations can be produced by conventional methods. Specifically, various materials typically used for producing pharmaceuticals , quasi drugs, cosmetics, and such can be used as base materials for the external formulation. Specifically, base materials to be used include, for example, animal and vegetable oils, mineral oils, ester oil, wax, higher alcohols, fatty acids, silicone oil, surfactants, phospholipids, alcohols, polyhydric alcohols , water-soluble-polymers , clay minerals , and pure water. Furthermore, external preparations of the present invention can contain, as required, pH modulators, antioxidants, chelating agents, antibacterial/ antifungal agents, coloring matters, odoriferous substances, etc. But this does not limit the type of base materials that are to be used in an external preparation of the present invention. If required, the preparation may contain differentiation inducers, blood flow improving agents , antimicrobial agents, antiphlogistics, cell activators, vitamins, amino acids, humectants, keratolytic agents, etc. The amount of base materials listed above is adjusted within a concentration range used for producing typical external preparations.
When a compound of the present invention, or a salt thereof, or a hydrate thereof is administered, the forms of a compound are not limited and a compound can be given orally or parenterally by a conventional method. For example, a compound can be administered as a dosage form such as tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye

ointments, eye drops, nasal drops, ear drops, epithems, and lotions. The dose of a pharmaceutical of the present invention can be selected appropriately based on symptom severity; age, sex, weight, forms of compounds, type of salts, specific type of diseases, etc.
The dose varies depending on the patient"s disease, symptom severity, age and sex, drug susceptibility, etc. A pharmaceutical agent of this invention is administered once or several times at a dose of approx. 0.03 to approx. 1000 mg/adult/day, preferably 0.1 to 500 mg/adult/day, more preferably 0.1 to 100 mg/adult/day. An injection can be given at a dose of approx. 1 to approx. 3000 |J.g/k.g, preferably approx. 3 to approx. 1000 Hg/kg.
Compounds of the present invention can be produced, for example, by the methods described in Examples below. However, the compounds of the present invention are under no circumstances to be construed as being limited to specific examples described below.
[Production Example]
Production Example 1
t-Butyl
4- [1- (2-butynyl) -6-methyl-7-oxo-6 , 7-dihydro-lH-imidazo.[ 4 , 5-d] pyr
idazin-2-yl]piperazin-l-carboxylate
(a) t-Butyl ■ *
5-methyl-4-oxo-4,S-dihydroimidazo[4,5-d]pyridazine-l-carboxylate
A mixture consisting of 1.0 g of 5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one, 16 mg of 4-dimethylaminopyridine, 1.6 g of di-t-butyl dicarbonate, and 5 ml of tetrahydrofuran was stirred at room temperature overnight. Then, a 0.5-ml tetrahydrofuran solution containing 300 mg of di-t-butyl dicarbonate was added to the solution, and the resulting mixture was stirred at room temperature for three hours. 5 ml of t-butyl methyl ether was added to the reaction .mixture, and the mixture was cooled with ice. The resulting crystals were collected by filtration to give 1.63 g-of the title compound.
1H-NMR(CDCl3)
5 1.72 (s, 9H) 3.93 (s, 3H) 8.38 (s, IH) 8.54 (s, IH)
(b) 2-Chloro-5-methyl-l,5-dihydroimidazo[4,5-d]pyridazin-4-one

8.4 ml of lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution) was added dropwise over one hour -o a 300-ml tetrahydrofuran solution containing 1.68 g of t-butyl
5-methyl-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-carboxylate and 4.15 g of hexachloroethane under a nitrogen atmosphere at 0°C. The resulting mixture was stirred for 30 minutes. 2N ammonia water was added to the solution, and the mixture was stirred for three hours. Then, the reaction solution was concentrated to 50 ml, and washed with 20 ml of t-butyl methyl ether. The solution was acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, and washed successively with 10 ml of water and 10 ml of t-butyl methyl ether. Thus, 1.03 g of the title compound was obtained.
1H-NMR(DMS0-d6)
51.45 (s, 9H) 3.72 (s, 3H) 8.33 (s, IH) (c)
3- (2-Butynyl) -2-chloro-5-methyl-3 , 5-dihydroim"idazo [4 , 5-d] pyridaz in-4-one
-7.72 g of 2-chloro-5 methyl-1,5-dihydroimidazo[4,5-d]-pyridazin-4-one was suspended in 400 ml of tetrahydrofuran under a nitrogen atmosphere, and 14.22 g of triphenylphosphine and 3.85 g of 2-butyn-l-ol were added thereto. The resulting mixture was cooled to CC. A 100-ml tetrahydrofuran solution containing 12.55 g of azodicarboxylic acid di-t-butyl esrer was added dropwise, and the reaction mixture was stirred for three hours. The reaction mixture was concentrated under reduced pressure. 50 ml of dichloromethane and 50 ml of trifluoroacetic acid were added to the residue, and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in 400 ml of ethyl acetate, and washed with a 200 ml of a 5N aqueous sodium hydroxide solution. The aqueous layer was extracted with 100 ml of ethyl acetate. The organic layers were combined together, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. Thus, 8.7 8 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (4:1).

1H-NMR(CDCl3)
6 1.82 (t, J= 2.3Hz, 3H) 3.87 (s, 3H) 5.32 (q, J=2.3Hz, 2H) 8.19 (s, IH) - -(d) t-Butyl
4-[l-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-1-carboxylate
5 ml of l-methyl-2-pyrrolidone was added to a mixture consisting of 1.183 g of 3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo [4,5-d]pyridazin-4-one, 0.829 g of potassium carbonate, and 1.395 g of t-butyl piperazine-1-carboxylate under a nitrogen atmosphere. The resulting mixture was heated at 130"C for 6 hours. The reaction mixture was cooled, and 50 ml of water was added thereto. Then, the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed twice with 50 ml of wa-cer and then with 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried over magnesium sulfate , and concentrated under reduced pressure . The resulting residue was purified by silica gel column chromatography. Thus, 1.916 g of the title compound was obtained from the fraction elured with hexane-ethyl acetate (1:4).
1H-NMR(CDCl3)
5 1.52 (s, 9H) 1.83 (t, J=2.3Hz, 3H) 3.38-3.42 (m, 4H) 3.61-3.64 (m, 4H) 3.85 (s, 3H) 5.09 (q, J-=3.3Hz, 2H) 8.13 (s, IH)
Production Examole 2
-
t-3utyl
4- [7- (2-butynyl) -2 , 6-dichloro-7:-:-purin-8-yl] piperazine-1-carboxy
lare
(a) 7-(2-Butynyl)-3-methyl-3,7-dihydropurine-2,6-dione
55.3 ml of l-bromo-2-butyne and 84.9 g of anhydrous potassium carbonate were added to a mixture of 100 g of 3-methyl xanthine [CAS No. 1076-22-8] and 1000 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 18 hours. 1000 ml of water was added to the reaction solution, and "he mixture was stirred at room temperature for 1 hour. The resulting white precipitate was collected by filtration. The white solid was washed with water and then t-butyl merhyl ether. Thus, 112 g of the title compound was

obtained.
1H-NMR(DMS0-d6)
5 1.82 (t, J=2.2H2,3H), 3.34 (s, 3H) 5.06 {q,*J=2.2Hz, 2H) 8.12 (s, IH) 11.16 (br.s, IH)
(b) 7-(2-Butynyl)-8-chloro-3-methyl-3,7-dihvdropurine-2,6-dione
112 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione was dissolved in 2200 ml of N,N-dimethylformamide, and 75.3 g of N-chlorosuccinimide was added thereto. The resulting mixture was stirred at room temperature for five hours . 2200 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hour. The white precipitate was collected by filtration, and the white solid was washed with water and, with t-butyl methyl ether. Thus, 117 g of the title compound was obtained.
1H-NMR(DMS0-d6)
6l.7B (t, J=2.0H2,3H) 3.30 (s, 3H) 5.06 (q, J=2.0H2, 2H) 11.34 (br.s, IH)
(c) 7- (2-Butynyl)--2 , 6 , 8-trichloro-7H-purine
A mixture of 2.5-2 g of 7- (2-butynyl) -8-chloro-3-methyl-3 ", 7-dihydropurine-2 , 6-dione and 100 ml of phosphorus oxychloride was stirred at 120°C for 14 hours. After the reac-ion mixture had been cooled, 4.15 g of phosphorus pentachloride was added to the solution. The resulting mixture was stirred at 120°C for 24 hours. After the reaction solution had been cooled to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in cetrahydrofuran. The solution was poured into a saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water, then saturated brine, and was then concentrated under reduced pressure. The residue was purified by silica gel colu.mn chromatography (ethyl acetate: hexane = 1:3) to give 2.40 g of the title compound.
1H-NMR(CDCl3)
51.82 (t, J=2.4Hz,3H) 5.21 (q, J=2.4Hz, 2H)
(d) t-Butyl
4-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]pipera2ine-l-carboxy late

A mixture of 2.4 g of 7-(2-butynyl)-2,6,8-trichloro-7H-purine, 1.45 g of sodium bicarbonate, 2.43 g of t-butyl
piperazine-1-carboxylate, and 45 ml of acetonitrile was stirred, aj: room temperature for 2 hours and 20 minutes. Then, 0.73 g of sodium bicarbonate and 1. 21 g of t-butyl piperazine-1-carboxylate were added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with IN hydrochloric acid, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was triturated with diethyl ether. The crystals were collected by filtration, and washed with diethyl ether. Thus, 3.0 g of the title compound was obtained as a white solid.
1H-NMR(DMS0-d6)
5 1.42 (s, 9H) 1.83 (t, J=2Hz, 3H) 3.48-3.55 (m, 4H) 3.57-3.63
(m, 4H) 4.89 (q, J=2Hz, 2H)
[Example]
Example 1
£-hyl
[7-(2-chlorophenyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydr
o-lH-purin-2-yloxy]acetate trifluoroacetate
(a.) >[7-Benzyl-2 , 6-dioxo-l ,2,6, 7-tetrahydropurin-3-yl] methyl
2,2-dime-chylpropionate
8.66 g of 7-benzylxanthine was dissolved in 300 ml of N,N-dimeT:hylformamide, and 1.57 g of sodium hydride and 7.7 ml of chlorome"hyl pivalate were added thereto. The resulting mixture was srirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and washed with water and IN hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure. .The residue was purified by silica gel column chromatography. Thus, 2.66 g of the title compound was obtained from the fraction eluted wirh hexane-ethyl acetate (1:1).
1H-NMR(CDCl3)
6 1.18 (s, 9H) 5.45 (s, 2H) 6.06 (s, 2H) 7.34-7.39 Cm, 5H) 7.58
(s, IH) 8.18 (s, IH) .

ib)
[7-Benzyl-l-methyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropioRate
2.66 g of [7-benzyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate was dissolved in 30 ml of
N,N-dimethylformamide, and 1.6 g of potassium carbonate and 1 ml of methyl iodide were added thereto. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and IN hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure. The residue was triturated with toluene. Thus, 2.16 g of the title compound was obtained.
-H-NMR(CDCl3)
5 1.18 (s, 9H) 3.41 (s, 3H) 5.49 (s, 2H) 6.11 (s, 2H) 7.26-7.39
(m, 5H) 7.57 (s, IH) .
(c) [l-Me~hyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3-yl]methyl 2 ,2-dimethylpropionate
2.349 g of [7-benzyl-l-meuhy1-2,6-dioxo-l,2,6,7-te-rahydropurin-3-yl]methyl 2,2-dimeT:hylpropionate was dissolved in -IG-O ml of acetic acid, and 1 g of 10% palladium carbon was added thereto. The mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered and concentrated to give 1.871 g of the title compound.
-H-NMR(CDCl3)
6 1.19 (s, 9H) 3.48 (s, 3H) 6.17 (s, 2H) 7.83 (s, IH).
(d)
[7-(2-Chlorophenyl)-l-methyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3 --yl]methyl 2,2-dimethylopropionate 1.60 g of [l-methyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate, 1.83 g of 2-chlorophenylboronic acid, and 1.5 g of copper (II) acetate were suspended in 30 ml of. N,N-dimethylformamide, and 3 ml of pyridine was added thereto. The

mixture was stirred at room temperature for 3 days. The reaction mixture was filtered through a short column filled with silica gel, and the filtrate was diluted with ethyl acetate. The orgarric layer was washed with IN hydrochloric acid, water, and saturated saline, and dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. The residue was suspended in ether, and the suspension was filtered. The filtrate was purified by silica gel column chromatography. Thus, 724 mg of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2) .
(e) t-Butyl
4-[7-(2-chlorophenyl)-3- (2,2-dimethylpropionyloxymethyl)-1-methy 1-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl]piperazine-l-carbox ylate
724 mg of
[7-{2-chlorophenyl)-l-methyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3 -yl]methyl 2,2-dimethylpropionate was suspended in 15 ml of N,N-dimethylformamide, and" 7 60 mg of N-chlorosuccinimide was added thereto. The reaction solutior. was stirred overnight, and then diluted with ethyl acetate. The solution was washed with water and IN hydrochloric acid, and dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. Thus, 764 mg of
[8-chloro-7-(2-chlorophenyl)-l-methyl-2,6-dioxo-l,2,6,7-tetrahyd ropurin-3-yl]me~hyl 2,2-dimethylpropionate was obtained. This co.mpound was mixed with 4 g of t-butyl piperazine-1-carboxylate. The mixture was heared at 150°C, and stirred for three hours. Ethyl acetate and water were added to "he reaction mixture, and the mixture was separated. The organic layer was washed with IN hydrochloric acid, and dried over anhydrous magnesium sulfate, then filtered.. The filtrate was concentrated. The residue was purified by silica gel column chromatography. Thus, "24 mg of the title compound was .obtained from the fraction eluted with hexane-ethyl acetate (3:2) .
(f) t-Butyl
4-[7-(2-chlorophenyl)-l-methyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-p urin-8-yl]piperazine-l-.carboxylate
t-Butyl 4-[7-(2-chlorophenyl)-3-(2,2-dimethylpropionyloxy methyl)-l-methyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl]pipe

razine-1-carboxylate was dissolved in a mixture of 10 ml of methanol and 20 ml of tetrahydrofuran, and 200 mg of sodium hydride was added thereto. The resulting mixture was stirred at room temperature overnight. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. The residue was suspended in ether and the mixture was filtered. Thus, 450 mg of the title compound was obtained.
1H-NMR(DMSO-d)
5 1.35 (s, 9H) 3.04 (s, 3H) 3.06-3.12 (m, 4H) 3.17-3.22 (m, 4H) 7.48 (dt, J=1.6, 7.6Hz, IH) 7.53 (dt, J=2.0, 7.6Hz, IH) 7.63 (dd, J=2.0, 8.0Hz, IH) 7.65 (dd, J=l.6, 8.0Hz, IH). (g) t-Butyl
4-[2-chloro-7-(2-chlorophenyl)-l-methyl-6-oxo-6,7-dihydro-lH-pur i"h-8-yl]piperazine-l-carboxylate (g-1) , and t-butyl 4- [2 , 6-dichloro-7- (2-chlorophenyl) -7H-purin-8-yl] piperazine-1-ca "" rboxylate (g-2)
78 mg of t-butyl 4- [7- (2_-chlorophenyl) -l-methyl-2 , 6-dioxo-2 ,3,6, 7-tetrahydro-lH-p urin-8-yl]piperazine-1-carboxylate was dissolved in 3 ml of phosphorus oxyGhloride, and the mixture was stirred at 120 "C overnight. The reaction solution was concentrated, and the residue was dissolved in 1 ml of -etrahydrofuran. This solution was poured into a suspension consisting of 50 mg of di-t-butyl dicarbonaze, 1 ml of tetrahydrofuran, and 0.5 ml of water containing 100 mg of sodium bicarbonate. The resulting mixture was stirred at room temperature for rhree hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated, and the residue was .purified by silica gel column chromatography. Thus, 16 mg of t-butyl 4-[2,6-dichloro-7-(2-chlorophenyl)-7H-purin-8-yl]piperazine-1-ca rboxylate was obtained from the fraction eluted with hexane-ethyl acetate (3:2), and
10 mg of t-butyl 4-[2-chloro-7-(2-chlorophenyl)-l-methyl-5-oxo-6,7-dihydro-lH-pur

in-8-yl] piperazine-1-carboxylate was obtained from the fraction
eluted with hexane-ethyl acetate (1:9).
(h) Ethyl • -
[7- (2-chlorophenyl) -l-inethyl-6-oxo-8- (piperazin-1-yl) -6 , 7-dihydr
o-lH-purin-2-yloxy]acetate trifluoroacetate
10 mg of t-butyl 4-[2-chloro-7-(2-chlorophenyl)-l-methyl-6-oxo-6,7-dihydro-lH-pur in-8-yl]piperazine-l-carboxylate and 10 mg of ethyl glycolate were dissolved in 0 . 2 ml of N-methylpyrrolidone, and 10 mg of sodium hydride was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was dissolved in ethyl acetate, and the mixture was washed with IN hydrochloric acid. Thus, 24 mg of t-butyl
4-[7-(2-chlorophenyl)-2-ethoxycarbonylmethoxy-l-methyl-6-oxo-6,7 -dihydro-lH-purin-8-yl]piperazine-l-carboxylate was obtained. 8 mg of this compound was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trif luoroacetic acid)) to give 2-. 11 mg of the title compound.
MS m/e (ESI) 447 (MH-CFsCOOH)
Example 2
[7-(2-chlorophenyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydr
o-lH-purin-2-yloxy]acetic acid trifluoroacetate
16 mg of t-butyl 4-[7-(2-chlorophenyl)-2-ethoxycarbonylmethoxy-l-methyl-6-oxo-6 , 7 -dihydro-lH-purin-8-yl]piperazine-1-carboxylate was combined with 0 . 4 m], of methanol and 0 .1 ml of a 5N aqueous sodium hydroxide solution, and the mixture was allowed to stand a- room temperature for two hours . -IN hydrochloric acid was added to the reaction solution. The acidified solution was extracted wich ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1%

trifluoroacetic acid)) to give 2.45 mg of the title compound. MS mie (ESI) 419 (MH-CFsCOOH)
Example 3
7-(2-Chlorophenyl)-2-cyclobutyloxy-8-(piperazin-l-yl) -1,7-dihydr
opurin-6-one
(a)
[7-Benzyl-3-(2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-t
etrahydropurin-1-yl]methyl 2,2-dimethylpropionate
9.54 g of 7-benzylxanthine was dissolved in 250 ml of N,N-dimethylf ormamide, and 17 g of potassium carbonate and 14.2 ml of chloromethyl pivalate were added thereto. The mixture was stirred at 50°C overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and IN hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromafography. Thus, 12.8 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2) . (b)
[3-(2,2-Dimethylpropionyloxymethyl)-2,6-dioxo-2 ,3,6, 7-tetrahydro purin-1-yl]methyl 2,2-dimethylpropionate
The citle compound was obtained by -reating"* [7-benzyl-3-(2,2-dimethyl propionyloxy methyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-l-yl]methyl 2 ,2-dimethylpropionate by the same method as used in Example (Ic) . (c)
[7- (2-Chlorophenyl) -3- (2 , 2-dimei:hylpropionyloxymethyl) -2 , 6-dioxo -2,3,6,7--etrahydropurin-l-yl] methyl 2,2-dimethylpropionate
The itle compound was obtained by -reating [3-(2-2-dimethyl propionyloxymethyl)-2-6-dioxo-2,3,6,7-tecrahydropurin-l-yl]methy 1 2,2-dime"::hylpropionate by the same method as used in Example (Id) .
1H-NKiR(CDCl3)
6 1.16 (s, 9H) 1.22 (s, 9H) 5.99 (s, 2H) 6.19 (s, 2H) 7.42-7.52 (m, 3H) 7.58-7.61 (m, IH) 7.73 (s, IH) (d) t-Butvl

4-[7-(2-chlorophenyl)-1,3-bis- (2,2-dimethylpropionyloxymethyl)-2 ,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl]piperazine-l-carboxyla -te
The title compound was obtained by treating [7-(2-chlorophenyl)-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo -2,3,6,7-tetrahydropurin-l-yl]methyl 2,2-dimethylpropionate by the same method as used in Example (le).
1H-NMR(CDCl3)
5 1.16 (s, 9H) 1.23 (s, 9H) 1.44 (s, 9H) 3.20-3.35 (m, 4H) 3.32-3.37 (m, 4H) 5.92 (s , 2H) 6.09 (s, 2H) 7.41-7.49 (m, 2H) 7.52-7.57 (m, 2H) (e) t-Butyl
4-[7-(2-chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-2 , 6-dio xo-2,3,6,7-tetrahydro-lH-purin-8-yl]piperazine-l-carboxylate
2.227 g of t-butyl 4-[7-(2-chrorophenyl)-1,3-bis- (2,2-dimethylpropionyloxymethyl)-2 , 5-dioxo-2 ,"3,6, 7-tetrahydro-lH-purin-8-yl] piperazine-1-carboxyla te was dissolved in a mixture of 10 ml of tetrahydrofuran and 20 ml of methanol, and 0.518 ml of 1,8-dia2abicyclo[5,4,0]undec-7-ene was added thereto. The mixture was stirred at room temperature overnight. IN hydrochloric acid was added to the mixture, and the precipitated solid was collected by filtration. The solid was dried to give 1.025 g of the title compound.
1H-NMR(CDCl3)
5 1,16 (s, 9H) 1.44 (s, 9H) 3.22-3.24 (m, 4H) 3.33-3.35 (m, 4H) 5.90 (s, 2H) 7.43-7.47 (m, 2H) 7.51-7.57 (m, 2H) 8.71 (br, IH)
(f)
7-(2-Chlorophenyl)-2-cyclobutyloxy-8-(piperazin-1-yl)-1,7-dihydr
opurin-6-one
8 mg of t-butyl 4-[7-(2-chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dio xo-2,3,6,7-tetrahydro-lH- purin-8-yl]piperazine-1-carboxylate was dissolved in 0.3 ml of N,N-dimethylformamide, and 0.05 ml of bromocyclobutane and 20 mg of potassium carbonate were added thereto. The mixture was stirred at 50 °C overnight.- Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The

organic layer was concentrated. The residue was dissolved in methanol, and 5 mg of sodium hydride was added to the solution. The mixture was stirred at room temperature f-or three hours . The reaction mixture was neutralized with IN hydrochloric acid, and extracted with ethyl acetate. The solvent was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.89 mg of the title compound. MS mie (ESI) 375 (MH"-CFsCOOH)
Example 4
Methyl
2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-l
K-purin-2-yloxy]phenylacetate trifluoroacetate
(a)
[7-(2-Bu"ynyl)-1-methyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3-yl]m e~hyl 2,2-dimethylpropionate
1.871 g of [l-methyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3-yl]methyl. 2,2-dimezhylpropionate was dissolved in 30 ml of
N,N-dimethylformamide, and 1.5 g of potassium carbonate and 0; 7-ml of 2-butynyl bromide were added thereto. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl ace-ate, and washed with water and IN hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. Thus ,2.12 g of the -itle compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2) .
. (b) 7-(2-3utynyl)-l-methyl-3,7-dihydropurine-2,6-dione The title compound was obtained by treating [7-(2-butynyl)-l-methyl-2,6-dioxo-l,2,6,7-tetrahydropurin-3-yl]m ethyl 2,2-dimethylpropionate by the same method as used in Example (If).
1H-NMR(CDCl3)

6 1.91 (t, J=2.4Hz, 3H) 3.39 (s, 3H) 5.10 (s, 2H) 7.93 (s, IH) 10.62 (s, IH) .
(c) t-Butyl
4-[7-(2-butynyl)-l-methyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl]piperazine-l-carboxylate
The title compound was obtained by treating 7-(2-butynyl)-l-methyl-3,7-dihydropurine-2,6-dione by the same method as used in Example (le).
1H-NMR(CDCl3)
5 1.48 (s, 9H) 1.83 (t, J=2.4Hz, 3H) 3.37 (s, 3H) 3.37-3.39 (m, 4H) 3.58-3.60 (m, 4H) 4.87 (s, 2H) 9.68 (s, IH) .
(d) Methyl
2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydro-l H-purin-2-yloxy]phenylacetate trifluoroacetate
8 mg of t-butyl 4-[7-(2-butynyl)-l-methyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl]piperazine-l-carboxylate and 10 mg of methyl 2-bromophenylacetate were dissolved in 0.2 ml of
N,N-dimethylformamide, and 10 mg of potassium carbonate was added thereto. The mixture was stirred at 50°C overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and IN hydrochloric acid. The organic layer was concentrated. The residue was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.07 mg of the title compound.
MS m/e (ESI) 451 (MH-CFsCOOH)
Example 5
,7-(2-Butynyl)-2-cyclohexyloxy-l-methyl-8-(piperazin-1-yl)-1,7-di hydropurin-6-one trifluoroacetate
Using iodocyclohexane instead of methyl 2-broraophenylacetate in Example (4d), the title compound was obtained by the same method as used in Example 4.
MS m/e (ESI) 385 (ME"-CFSCOOH)

Example 6
7- (2-Butyny.l)-2- (2-butoxy) -l-methyl-S-(piperazin-1-yl) -1,7-dihyd
ropurin-6-one trifluoroacetate
Using 2-bromobutane instead of methyl 2-bromophenylacetate in Example (4d) , the title compound was obtained by the same method as used in Example 4.
MS m/e (ESI) 359 (MH-CFaCOOH)
Example 7
7-(2-Butynyl)-2-cyclopentyloxy-l-methyl-8-(piperazin-1-yl)-1,7-d
ihydropurin-6-one trifluoroacetate
Using bromocyclopentane instead of methyl 2-bromophenylacetate in Example (4d) , the title compound was obtained by the same method as used in Example 4.
MS m/e (ESI) 371 (MH"-CFSCOOH)
Example 8
E-hyl
2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-l
H-purin-2-yloxy]butanoate trifluoroaceta~e
Using 2-bromobutanoic acid -ethyl esrer instead of methyl 2-bromophenylacetate in Example (4d) , the title compound was obtained by the same method as used in Example 4.
MB :n/e (ESI) . 417 (MH-CFaCOOK)
Example 9
Erhyl
2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6 , 7-dihydro-l
H-purin-2-yloxy]propionate
Using ethyl 2-bromopropionate instead of methyl 2-bromophenylacetate in Example (4d) , trifluoroacetate of the title compound was obtained by the same method as used in Example 4. The compound was purified by chromatography using NH-silica gel (silica gel whose surface had been modified with amino groups: Fuji Silysia Chemical Ltd. NH-DM 2035) . Thus, -he title compound was obtained from

rhe fraction eluted with ethyl acetate-methanol (20:1). MS mte (ESI) 404 (MH"")
Example 10
2-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydro-l
H-purin-2-yloxy]propionic acid trifluoroacetate
8 mg of t-butyl 4-[7-(2-butynyl)-l-methyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl] piperazine-1-carboxylate and 10 mg of ethyl 2-bromopropionate were dissolved in 0.2 ml of N,N-dimethylformamide, and 10 mg of potassium carbonate was added thereto. The mixture was stirred at 50°C overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and IN hydrochloric acid. The organic layer was concentrated to give t-butyl
4-[7-(2-butynyi)-2- (1-carboxyethoxy)-1-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate. This compound was dissolved in 0.4 ml of ethanol, and 0.1 ml of a 5N aqueous sodium hydroxide solution was added thereto. The mixture was stirred at room temperature for 3 hours. IN-hydrochloric acid was added Uo the solution, and the mixture was extracted with ethyl acetate. The . organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.37 mg of the title compound.
MS mle (ESI) 375 (MH-CFsCOOK)
Example 11
7-(2-Butynyl)-2-methoxy-l-methyl-8-(piperazin-l-yl) -1,7-dihydrop urin-6-one trifluoroacetate Ca) t-Butyl
4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate(a-1), and t-butyl
4-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl] piperazine-1-carboxy late (a-2)
5. 127 g of- t-butyl

4-[7-(2-butynyl)-l-methyl-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 75 ml of phosphorus oxychloride, and then the mixture was stirred at 120°C overnight. The reaction solution was concentrated, and the residue was dissolved in 50 ml of tetrahydrofuran. This solution was poured into a suspension consisting of 7 g of di-t-butyl dicarbonate, 50 ml of tetrahydrofuran, 100 g of sodium bicarbonate, and 200 ml of water, and the mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography. Thus, 1.348 g of t-butyl 4-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperazine-1-carboxy
la-e [1H-NMR(CDCl3) 6l.50 (s, 9H) 1.87 (t, J=2.4Hz, 3H) 3.64 (m, 8H)
4.31 (q, J=2.4Hz, 2H)] was obtained from the fraction eluted with
hexane-e~hyl acetate (1:1), and 1.238 g of t-butyl
4-[7-(2-butynyl)-2-chloro-l-methyl
-6-OXO-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate
[-:-:-NMR(CDCl3) §1.49 (s, 9H) 1.83 (t, J=2.4Hz, 3H) 3.42-3.44 (m, 4H) 3.59-3.62 (m, 4K) 3.73 (s, 3H) 4.93 (q, J=2.4Hz, 2H)] was obtained from. tJie fraction eluted with hexane-ethyl acetate (1:9).
7-(2-Butynyl)-2-methoxy-l-methyl-8-(piperazin-1-yl) -1,7-dihydrop urin-6-one trifluoroacetate
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of methanol, and IC mg of sodium hydride was added thereto. The mixture was stirred a- room temperarure for one hour. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trif luoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.72 .mg of the title compound.

MS m/e (ESI) 317 (MH-CFsCOOH)
Example 12
7-(2-Butynyl)-2-ethoxy-l-methyl-8-(piperazin-l-yl)-1,7-dihydropu
rin-6-one
Using ethanol instead of methanol in Example (lib), the trifluoroacetate of the title compound was obtained by the same method as used in Example 11. This compound was purified by chromatography using NH-silica gel. Thus, the title compound was obtained from the fraction eluted with ethyl acetate-methanol (20:1).
1H-NMR(CDCl3)
5 1.42 (t, J=7.2Hz, 3H) 1.82 (t, J=2.4Hz, 3H) 3.02-3.06 (m, 4H) 3.40-3.42 (m, 4H) 3.46 (s, 3H) 4.51 (q, J=7.2Hz, 2H) 4.90 (q, J=2. 4Hz, 2K) .
MS m/e (ESI) 331 (MH)
Example 13
£-hyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-lH-
purin-2-yloxy]acetate
Exa.mple 14
[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-lH-
purin-2-yloxy]acetic acid
Ethyl [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-lH-purin-2-yloxy]acetate trifluoroacetate and
[7- (2-buT:ynyl) -l-methyl-6-oxo-8- (piperazin-l-yl) -6 , 7-dihydro-lH-purin-2-yloxy]acetic acid trifluoroacetate [MS w/e (ESI) 361 (MH"-CFsCOOH) ] were obtained by treating t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate using ethyl 2-hydroxyacetate, instead of ethanol, by zhe same method as used in Example 11. Ethyl [7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-lH-purin-2-yloxy] acetate trifluoroacetate was purified by chromatography using NH-silica gel. Thus, ethyl

[7-(2-butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-lH-purin-2-yloxy]acetate [1H-NMR(CDCI3) 5 1.29 (t, J=7.2Hz, 3H) 1.83 (t, J=2.4Hz, 3H) 3.02-3.06 (m, 4H) 3.38-3.41 (m, 4H) 3.55 (s, yRf 4.22 (q, J=7.2Hz, 2H) 4.90 (q, J=2.4Hz, 2H) 5.03 (s, 2H) IMS mle (ESI) 339 (MH"") ] was obtained from the fraction eluted with ethyl acetate-methanol (20:1)
Example 15
7-(2-Butynyl) -2-(2-methoxyethoxy)-l-methyl-8-(piperazin-1-yl)-1,
7-dihydropurin-6-one trifluoroacetate
Using 2-methoxy ethanol instead of ethyl 2-hydroxyacetate in Example 13, the title compound was obtained by the same method as used in Example 13.
MS mie (ESI) 361 (MH-CFsCOOH)
Example 16
E-hyl
1-[7-(2-butynyl)-1-methyl-6-0x0-8-(piperazin-1-yl) -6 , 7-dihydro-l
H-purin-2-yloxy]eyelopropanecarboxylate
Using ethyl 1-hydroxycyclopropanecarboxylate instead of ethyl 2-hydroxyacetate in Example 13, the trifluoroacetate of the title compound was obtained by the same method as used in Example 13. The compound was purified by chromatography using NH-silica gel. Thus, the title compound was obtained from the fraction eluted with ethyl acetate-.methanol (20:1) .
1H-NMR(CDC13)
5 1.19 (t, J=7.2Hz, 3H) 1.39-1.42 (m, 2H) 1.67-1.71 (m, 2H) 1.83 (-, J=2.4Hz, 3H) 3.02-3.05 (m, 4H) 3.37-3.40 (m, 4H) 3.49 (s,,3H) 4.14 (q, J=7.2Hz, 2H) 4.90 (q, J=2.4Kz, 2H)
MS m/e (ESI) 415 (MH*)
Example 17
1-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6 , 7-dihydro-l
H-purin-2-yloxy]cyclopropanecarboxylic acid trifluoroacetate
20 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin~8-

yi]piperazine-1-carboxylate and 20 mg of ethyl 1-hydroxycyclopropanecarboxylate were dissolved in 0.2 ml of N-raethylpyrrolidone, and 10 mg of sodium hydride was added thereto. The mixture was stirred at room temperature overnight. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 63 mg of t-butyl
4-[7-(2-butynyl)-2-(1-ethoxycarbonylcyclopropyloxy)-l-methyl-6-o xc-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate. This compound was dissolved in a solution consisting of 0 . 4 ml of ethanol and 0.1 ml of a 5N aqueous sodium hydroxide solution, and the mixture was stirred at 50°C overnight. IN hydrochloric acid solution was added to -he reaction solution, and the mixture was extracted with erhyl acerate. The organic layer was concentrated to give 22 mg of t-butyl
4- i"7- (2-butynyl) -2- (1-carboxycyclopropyloxy) -l-methyl-6-oxo-6 , 7-dihydro-lK-purin-8-yl]piperazine-1-carboxylate. 11 mg of this compound was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue-was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.64 mg of the title compound.
MS m/e (ESI) 387 (MH-CFaCOOH)
Example 18
1-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6 , 7-dihydro-l
H-purin-2-yloxy]cyclopropanecarboxylic amide trifluoroacetate
11 mg of t-butyl 4-[7-(2-butynyl)-2-(1-carboxycyclopropyloxy)-l-methyl-6-oxo-6 , 7-dihydro-lK-purin-8-yl]piperazine-l-carboxylate was dissolved in 1 ml of tetrahydrofuran, and 0.05 ml of triethylamine and 0.05 ml of ethyl chlorocarbonate were added thereto. The mixture was stirred at room temperature for 15 minutes. 0.1 ml of 20% ammonia water was added to the solution, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was

concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase {containing 0.1% trifluoroacetic acid)) to give 1.18 mg of the title compound. MS m/e (ESI) 386 (MH-CFBCOOH)
Example 19
7-(2-Butynyl)-l-methyl-2-(2-oxotetrahydrofuran-3-yloxy)-8-(piper
azin-1-yl)-1,7-dihydropurin-6-one trifluoroacetate
Using 3-hydroxydihydrofuran-2-one instead of ethyl 2-hydroxyacetate in Example 13, the title compound was obtained by the same method as used in Example 13.
MS m/e (ESI) 387 (MH-CFsCOOH)
Example 2 0
-7- (2-Bu"cynyl) -l-methyl-2-phenoxy-8- (piperazin-l-yl) -1, 7-dihydrop
urin--6-one trif luoroacetate
Using phenol "instead of ethyl 2-hydroxyacetate in Example 13-, the title compound was obtained by the same method, as used in Example 13.
MS m/e (ESI) 379 (MH-CFaCOOH)
Example 21 Ethyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-l-yl) -6, 7-dihydro-lH-purin-2-yl]acetare trifluoroacetate
Using ethyl 2-(t-butoxycarbonyl)acetate instead of ethyl 2-hydroxyacetate in Example 13, the title compound was obtained by the same method as used in Example 1.3.
MS m/e (ESI) 373 (MH-CFaCOOH)
Example 22
1-(2-Butynyl)-1,2-dimethyl-8-(piperazin-l-yl)-1,7-dihydropurin-6 -one trifluoroacetate 8 mg of t-butyl

4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate and 2 mg of
tetrakis(triphenylphosphine)palladium were dissolved in 0.2 ml of dioxane, and 0.2 ml of methylzinc chloride (1.5 M tetrahydrofuran solution) was added thereto. The mixture was stirred at 50°C for 0.5 hour. The reaction solution was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.56 .mg of the title compound. MS m/e (ESI) 301 (MH-CFsCOOH)
Example 23
7-(2-Butynyl)-l-methyl-2-butyl-8-(piperazin-1-yl) -1, 7-dihydropur
ir.-6-one trifluoroacetate
8 mg of t-butyl 4- [7- (2-butynyl) -2-chloro-l-methyl-6-oX"o-6 , 7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate and 2 mg of
te-rakis(triphenylphosphine)palladium were dissolved in 0.2 ml of dioxane, and 0.3 ml of a mixed solution consisting of 0.5 ml of buylmagnesium chloride (2.0 M diethyl ether solution) and 2 ml of zinc chloride (0.5 M tetrahydrofuran solution) was added thereto. The resulting mixture was stirred at 50 °C for five hours . The reaction solution was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.33 mg of the title compound.
MS mle (ESI) 343 (MH-CFsCOOH)
Example 2 4
7- (2-Butynyl) -l-.methyl-2-benzyl-8- (piperazin-1-yl) -1, 7-dihydropu
rin-6-one trifluoroacetate
The title compound was obtained using a mixed solution consisting of 0.5 ml of benzylmagnesium chloride (2.0 M diethyl ether solution) and 2 ml of zinc chloride (0.5 M tetrahydrofuran solution) by the

same method as used in Example 23. MS m/e (ESI) 377 (MH-CFsCOOH)
Example 25
7-(2-Butynyl)-l-methyl-2-(2-phenylethyl)-8-(piperazin-1-yl)-1,7-
dihydropurin-6-one trifluoroacetate
The title compound was obtained using a mixed solution consisting of 0.5 ml of phenethylmagnesium chloride (2.0 M diethyl ether solution) and 2 ml of zinc chloride (0.5 M tetrahydrofuran solution) by the same method as used in Example 23.
MS m/e (ESI) 391 (MH-CFaCOOH)
Example 2 6
7-(2-Butynyl)-l-methyl-2-phenyl-8-(piperazin-1-yl) -1,7-dihydropu
rin-6-one trifluoroacetate
10 mg of""t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl -6-0X0-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate and 2 mg of tetra)<.is palladium and mg of phenyltributyltin were dissolved in ml dioxane the mixture was srirred at hours. reaction solution concentrated residue trifluoroacetic acid. purified by reverse-phase high performance liquid chromatography an acetonitrile-water mobile phase acid to give title compound.> MS m/e (ESI) 363 (MH-CFsCOOH)
Example 27
7-(2-Butynyl)-l-methyl-2-amino-8-(piperazin-1-yl) -1,7-dihydropur
in-6-one trifluoroacetate
8 mg of t-butyl 4- [7- (2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.2 ml of 20% aqueous ammonia solution, and the mixture was stirred at 80°C for 5 hours. The reaction solution was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the

residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic _acid) ) to give 3.82 -mg of the title compound. MS m/e (ESI) 302 (MH-CFsCOOH)
Example 2 8
7-(2-Butynyl)-l-methyl-2-methylamino-(8-piperazin-l-yl)-1,7-dihy
dropurin-6-one trifluoroacetate
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl -6-OXO-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.2 ml of an aqueous solution of 40% methyl amine, and the mixture was stirred at 80°C for 5 hours. The reaction solution was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 6.95 mg of the title compound.
MS m/e (ESI) 316 (MH-CFaCOOH)
Example 29
7-(2-Butynyl) -l-methyl-2-dimethylamino-8-(piperazin-1-yl)-1,7-di
hydropurin-6-one trifluoroacetate ■ *
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.2-ml of an aqueous solution of 40% dimethylamine, and the mixture was stirred at 80°C for 5 hours. The reaction solution was concentrated, and the residue was dissolved in trif luoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing . 0-.l% trif luoroacetic acid)) to give 6.95 mg of the title compound.
1H-NMR(CDCl3)
5 1.82 (t, J=2.4Hz, 3H) 2.83 (s, 6H) 3.02-3.05 (m, 4H) 3.39-3.42 (m, 4H) 3.56 (s, 3H) 4.90 (d, J-2.4Hz, 2H)
MS m/e (ESI) 330 (MH-CFsCOOK)

Example 30
Ethyl
[7- (2-butynyl) -l-methyl-6-oxo-8- (piperazin-l-yl) -6, 7-dihy.dro-lH-
purin-2-ylamino]acetate trifluoroacetate
10 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 15 mg of glycine ethyl ester
hydrochloride and 50 |J.l of triethylamine were added thereto. The mixture was stirred at 80 °C for 12 hours . Then, the reaction solution was concentrated by flushing with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the solution was concentrated by flushing with nitrogen gas . The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 7.60 mg of the title compound. MS m/e (ESI) 388 (MH-CFjCOOH)
Example 31 ■
[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6 , 7-dihydro-lH-
purin-2-ylamino]acetic acid trifluoroacetate
6 mg of t-butyl 4-[7-(2-burynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 15 mg of glycine t-butyl ester hydrochloride and 50 M-l of triethyla.Tiine were added thereto, .nfter the mixture had been stirred at 80 °C for 12 hours, the reaction solution was concentrated by flushing with nitrogen gas. The resulting residue was dissolved in 0.40 ml of trif luoroacetic acid, and the solution was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chro.matography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.36 mg of the title compound.
MS m/e (ESI) 360(MH-CFaCOOH)
Example 32

Ethyl
[N-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-
lH-purin-2-y-lImethylamino] acetic acid trifluoroacetate
Using N-methyl glycine ethyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 2.06 mg of the title compound was obtained by the same method as used in Example 30.
MS mie (ESI) 402 (MH-CFaCOOH) Example 33 Methyl
(S)-l-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihyd ro-lH-purin-2-yl]pyrrolidine-2-carboxylate trifluoroacetate
Using L-proline methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 1.35 mg of the title compound was obtained by the same method as used in Example 30.
MS n]/e (ESI) 414 (MH"-CFSCOOH)
Example 34
[N-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-
lH-purin-?-yl]merhylamino]acetic acid trifluoroacetate
Using N-methyl glycine t-butyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 3.16 mg of the title co.-npound was obtained by the same method as used in Example 30.
MS m/e (ESI) 374 (MH-CFaCOOH)
Example 35 Methyl
(R)-1-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihyd ro-lH-purin-2-yl]pyrrolidine-2-carboxylate trifluoroacetate
Using D-proline methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30 , 0 .74 mg of the title compound was obtained by the same method as used in Example 30.
MS m/e (ESI) 414 (MH-CFsCOOK)
Example 36
Methyl
2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-l

H-purin-2-ylamino]propionate trifluoroacetate
Using DL-alanine methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30 , 1. 20 mg of the-title compound was obtained by the same method as used in Example 30.
MS m/e (ESI) 388 (MH-CFsCOOH)
Example 37
Methyl
2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-l
H-purin-2-ylamino]-2-methylpropionate trifluoroacetate
Using methyl 2-aminoisobutylate hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 1.18 mg of the title co.mpound was obtained by the same method as used in Example 30.
MS m/e (ESI) 402 (MH-CFsCOOH)
Example 38
(S)-2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihyd ro-lH-purin-2-ylamino]propionate trifluoroacetate
Using L-alanine ethyl ester hydrochloride instead of glycine erhyl ester hydrochloride in Example 30 , 2 . 38 mg of the title compound was obtained by the same method as used in Example 30.
MS m/e (ESI) 402 (MH-CFsCOOH)
Example 3 9
(S)-2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihyd ro-lH-purin-2-ylamino]propionic acid trifluoroacetate
Using L-alanine t-butyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30 , 0 . 76 mg of the title compound was obtained by the same method as used in Example 30.
MS m/e (ESI) 374 (MH-CFaCOOH)
Example 40
Ethyl
3-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-l
H-purin-2-ylamino]propionate trifluoroacetate

Using -alanine ethyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 0 .85 mg of the title compound was obtained by the same method as used in Example 30.
MS m/e (ESI) 402 (MH-CFsCOOK)
Example 41
7-(2-Butynyl)-2-(2-ethoxyethylamino)-l-methyl-8-(piperazin-1-yl)
-1,7-dihydro-purin-6-one trifluoroacetate
10 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-5-oxo-6,7-dihydro-lH-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 20 \xl of 2-ethoxyethylamine was added thereto. After the mixture had been stirred at 80"C for 12 hours, the reaction solution was concentrated by flushing with nitrogen. The resulting residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trif luoroacetic acid)) to give 6.95 .mg of the title compound.
MS m/e (ESI) 374 (MH-CFsCOOH)
Example. 42
7-(2-Butynyl)-l-methyl-2-(morpholin-4-yl)-8-(piperazin-1-yl)-1,7
-dihydropurin-6-one trifluoroace~ate
Using morpholine instead of 2-ethoxyethylamine in Example 41, 7.31 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 372 (MH-CFsCOOH)
Example 43
2-Benzylamino-7-(2-butynyl)-l-me-hyl-8-(piperazin-1-yl)-1,7-dihy
dropurin-6-one trifluoroacate
Using benzylamine instead of 2-ethoxyethylamine in Example 41, 8.40 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 392 (MH-CFsCODK)

Example 44
Ethyl
1-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydro-l
H-purin-2-yl]piperidine-4-carboxylate trifluoroacetate
Using ethyl isonipecotate instead of 2-ethoxyethylamine in Example 41, 7.43 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 442 (MH-CFsCOOH)
Example 45
2-(N-benzylmethylamino)-7-(2-butynyl)-l-methyl-8-(piperazin-1-yl
)-1,7-dihydropurin-6-one trifluoroacetate
Using N-methylbenzylamine instead of 2-ethoxyethylamine in Example 41, 2.38 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 406 (MH-CFaCOOH) "
Example 46"
7- (2-Butynyl) -2- (4-chlorobenzylamino) -l-rnethyl-8- (piperazin-1-yl
)-1,7-dihydropurin-6-one trifluoroacetate
Using 4-chlorobenzylamine instead of 2-eth®xyethylamine in Example 41, 2.84 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 42"6 (MH-CFaCOOH)
Example 47
7- (2-Butynyl) -2- (4-methoxyjoenzylamino) -l-methyl-8- (piperazin-1-y
1)-1,7-dihydropurin-6-one trifluoroacetate
Using 4-methoxybenzylamine, 3.77 mg of the title compound was .obtained by the same method as used in Example 41.
MS m/e (ESI) 422 (MH-CFaCOOH)
Example 48
7-(2-Butynyl)-l-methyl-2-(2-phenylethylamino)-8-(piperazin-1-yl)
-1,7-dihydropurin-6-one trifluoroacetate

Using phenethylamine instead of 2-ethoxyethylamine in Example 41, 2.7 0 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 406 (MH-CFaCOOH)
Example 49
7-(2-Butynyl) -l-methyl-2-[N-(2-phenylethyl)methylamino]-8-(piper
azin-l-yl) -1,7-dihydropurin-6-one trifluoroacetate
Using N-methylphenethylamine instead of 2-ethoxyethylamine in Example 41, 2.17 mg of the title compound was obtained by the same me-hod as used in Example 41.
MS mle (ESI) 420 (MH-CFaCOOH)
Exa.-nple 50
Ethvl
1-I 7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-l
H-purin-2-yl ] piperidine-3-carboylate trifluoroacetate
Using ethyl nipecotate instead of 2-ethoxyethylamine in Example 41, 2.93 mg of rhe title compound was obtained by the same method as used in Example 41.
MS iVi/e (ESI) 442 (MH-CF3CO0K)
Example 51
7-(2-Butynyl)-l-methyl-8- (piperazin-l-yl)-2-(pyridin-2-ylmethyla
mino)-1,7-dihydropurin-6-one trifluoroacetate
Using 2-aminomethylpyridine instead of 2-ethoxyethylamine in Example 41, 1.62 mg of the title compound was obtained by the same method as used in Example 41.
MS rale (ESI) 393 (MH-CFaCOOK)
Exa.mple 52
Ethyl
1-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-l
H-purin-2-yl]piperidine-2-carboxylate trifluoroacetate
Using ethyl pipecolate instead of 2-ethoxyethylamine in Example 41, 0.97 mg of the title compound was obtained by the same method

as used in Example 41.
MS 77?/e (ESI) 442 (MH-CF3C00H)
Example 53
(S)-1-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihyd
ro-lH-purin-2-yl]pyrrolidine-2-carboxylic acid trifluoroacetate
Using L-proline t-butyl ester instead of 2-ethoxyethylamine in Example 41, 4.07 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 400 (MH-CFsCOOH)
Example 54
7-(2-Butynyl)-2-diethylamino-l-methyl-8-(piperazin-1-yl)-1,7-dih
ydropurin-6-one trifluoroacetate
Using diethylamine instead of 2-ethoxyethylamine in Example 41, 2.24 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 358 (MH-CFaCOOH)
Example 55
7-(2-Butynyl) -2-(N-ethylmethylamino)-l-methyl-8-(piperazin-l-yl)
-1, 7-dihydropurin-6.-one trif luoroacetate
Using N-ethylmethylamine instead of 2-ethoxyethylamine in Example 41, 3.27 mg of the title compound was obtained by the same method as used in Example 41.
MS mle (ESI) 344 (MH-CFsCOOH)
Example 5 6 Ethyl
(R)-1-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihyd . ro-lH-purin-2-yl]piperidine-3-carboxylate trifluoroacetate
Using ethyl (R)-nipecotate instead of 2-ethoxyethylamine in Example 41, 0.87 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 442 (MH-CFsCOOH)

Example 57
Ethyl
(S) -1- [7- (2-butynyl) -l-methyl-6-ox-o-8- (piperazin-1-yl) -6 , 7-dihyd
ro-lH-purin-2-yl]piperidine-3-carboxylate trifluoroacetate
Using ethyl (L)-nipecotate instead of 2-ethoxyethylamine in Example 41, 2.94 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 442 (MH-CFsCOOH)
Exa.mple 58
[N-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-
lK-purin-2-yl]methylamino]acetonitrile trifluoroacetate
Using methylaminoacetonitrile instead of 2-ethoxyethylamine in Example 41, 1.00 mg of the title compound was obtained by the same method as used in Example 41.
MS m/e (ESI) 355 (MH-CFjCOOH)
Exa.mple- 5 9
7- (2-Butynyl) -2-isop"ropylamino-l-methyl-B- (piperazin-1-yl) -1, 7-d
ihydropurin-6-one trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lHpurin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 50 M-l of isopropylamine was added thereto. The mixture was stirred at 60°C"for five hours, and then concentrated by flushing with nitrogen gas. The residue was dissolved in 0.40 ml of rrifluoroacetic acid, and the mixture was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.28 .mg of the title compound.
MS m/e (ESI) 344 (MH-CFaCOOH)
Example 60
7-(2-Butynyl) -l-methyl-8-(piperazin-1-yl)-2-(pyridin-2-ylamino)-
1,7-dihydropurin-6-one trifluoroacetate

6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,V-dihydro-lH-purin-S-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 50 Hi of 2-aminopyridine was added thereto. The mixture was stirred at 110°C for 12 hours, and then the reaction solution was concentrated by flushing with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.10 mg of the title compound.
MS mfe (ESI) 379 (MH-CFaCOOH)
Example 61
7-(2-Butynyl)-l-methyl-2-phenylamino-8-(piperazin-1-yl)-1,7-dihy
dropurin-6-one -rifluoroacetate
6 mg of t-butyl 4-[7-(2-bu-ynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylatc was dissolved in 0.15 ml of
l-methyl-2-pyrrolidone, and 100 |il of aniline was added thereto. The mixture was stirred at 110°C for 12 hours, and then concentrated by flushing with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.23 mg of the title compound.
MS rvje (ESI) 378 (MH-CFsCOOH)
Example 62
1-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-l
H-purin-2-yl]piperidine-3-carboxylic acid trifluoroacetate
6 mg of t-butyl 4-[7- (2-butynyl)_-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 20 M.1 of ethyl nipecotate was added

thereto. The mixture was stirred at 80 "C for 12 hours, and then concentrated by flushing with nitrogen gas. The residue was diss-oived in a solution consisting of 0.20 ml of ethanol and 0.20 ml of a 5N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for five hours, and then concentrated by flushing with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.92 mg of the title compound.
MS m/e (ESI) 414 (MH"-CFsCOOH)
Example 63
(R)-1-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihyd
ro-lH-purin-2-yl]pyrrolidine-2-carboxylic acid trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 15 mg of D-proline methyl ester hydrochloride and 50 M-l of triethylamine were added thereto. After the resulting mixture had been stirred at 80°C for 12 hours, the reaction solution was concentrated by flushing with nitrogen gas. The residue was dissolved in a solution consisting of 0.20 ml of ethanol and 0.20 ml of a 5N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for five hours, and then concentrated by flushing with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by flushing with nitrogen gas . The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.42 mg of the title compound.
MS m/e (ESI) 400 (MH-CFaCOOH)
Example 64.
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-l

H-purin-2-ylamino]propionic acid trifluoroacetate
Using DL-alanine methyl ester hydrochloride instead of D-proline methyl ester hydrochloride in Example 63 , 1.1-2 mg of the title compound was obtained by the same method as used in Example 63.
MS m/e (ESI) 374 (MH-CFaCOOH)
Example 65
7-(2-Butynyl)-l-methyl-8-(piperazin-l-yl)-2-(pyridin-2-yl-methyl
oxy)-1,7-dihydropurin-6-one trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml of
l-methyl-2-pyrrolidone, and 25 |J.l of pyridin-2-ylmethanol and 5 mg of sodium hydride were added thereto. The mixture was stirred at room temperarure for five hours, and then concentrated by flushing with nitrogen gas . The residue was dissolved in 0 . 40 ml of trif luoroacetic acid, and the"mixture was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chro.matography (using an acetoriitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.58 mg of the title compound. MS m/e (ESI) 394 (MH-CFaCOOH)
Example 66
7-(2-Butynyl)-2-isopropoxy-l-methyl-8-(piperazin-l-yl)-1,7-dihyd
ropurin-6-one trifluoroacetate
6 mg of t-butyl 4- [7- (2-bu-cynyl) -2-chloro-l-methyl-6-oxo-6 , 7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in ,0.15 ml of l-methyl-2-pyrrolidone, and 0.10 ml of isopropanol and 5 mg of sodium hydride were added thereto. After the mixture was stirred at room temperature for five hours, an aqueous solution saturated with ammonium chloride was added to the reaction solution. The resulting mixture was- extracted with ethyl acetate. The organic layer was concentrated. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high

performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.68 mg of the title compound.
MS m/e (ESI) 345 (MH"-CFsCOOH)
Example 67
7-(2-Butynyl) -2-(2-butynyloxy)-l-methyl-8-(piperazin-l-yl)-1,7-d
ihydropurin-6-one trifluoroacetate
Using 2-butyn-l-ol instead of isopropanol in Example 66, 3.40 mg of the title compound was obtained by the same method as used in Example 66.
MS m/e (ESI) 355 (MH-CFsCOOH)
Example 68 Methyl
[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-lH-purin-2-ylsulfanyl]acetate trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 20 |J.l of methyl mercaptoacetate and 6 .mg of potassium carbonate were added thereto . The mixture was stirred at room temperauure for five hours. An aqueous solution saturated with ammonium chloride was added to "he reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The solution was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.83 mg of the title compound.
MS m/e (ESI) 391 (MH-CFsCOOH)
Example 69
Ethyl
2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-l

K-purin-2-yIsulfany1]propionate trifluoroacetate
Using ethyl 2-mercaptopropionate instead of methyl mercaptoacetats in Example 68, 4.30 mg of the title compound was obtained by the same method as used in Example 68. MS m/e (ESI) 419 (MH-CFaCOOH)
Example 70
Ethyl
3-[7-(2-bu-ynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-l
H-purin-2-yIsulfany1]propionate trifluoroacetate
Using ethyl 3-mercaptopropionate instead of methyl mercaptoacetate in Example 68, 3.75 mg of the title compound was ob-ained by the same method as used in Example 68.
MS mle (ESI) 419 (MH-CFsCOOH)
Example 71
7-(2-Butynyl)-2-ethylsurfanyl-l-methyl-8-(piperazin-l-yl)-1,7-di
hydropurin-6-one trifluoroacetate
Using ethanethiol instead of methyl mercaptoacetate in Example 68, 4.70 mg of the title compound was obtained by the same method as used in Example 68.
MS m/e (ESI) 347 (MH-CFaCOOH)
Example 7 2
7- (2-Butyhyl) -2- (2-hy.droxyethylsulfanyl) -l-methyl-8- (piperazin-1
-yl)-1,7-dihydropurin-6-one trifluoroacetate
Using 2-mercaptoethanol instead of methyl mercaptoacetate in Example 68, 3.57_mg of the title compound was obtained by the same method as used in Example 68.
MS mle (ESI) 363 (MH-CFaCOOH)
Example 7 3
7-(2-Butynyl)-l-methyl-8-(piperazin-l-yl)-2-(pyridin-2-ylsulfany
1)-1,7-dihydropurin-6-one trifluoroacetate
Using 2-mercaptopyridine instead of methyl mercaptoacetate in Example 68, 4.66 mg of the title compound was obtained by the same

method as used in Example 68.
MS m/e (ESI) 396 (MH-CFaCOOH)
Example 7 4
7-(2-Butynyl) -l-methyl-2-methylsulfanyl-8-(piperazin-l-yl)-1,7-d
ihydropurin-6-one trifluoroacetate
Using methyl mercaptan (30%; methanol solution) instead of methyl mercaptoacetate in Example 68, 4.08 mg of the title compound was obtained by the same method as used in Example 68.
MS m/e (ESI) 333 (MH-CFsCOOH)
Example 75
7-(2-Butynyl) -2-cyclohexylsulfanyl-l-methyl-8-(piperazin-1-yl)-1
,7-dihydropurin-6-one trifluoroacetane
Using cyclohexanethiol instead of methyl mercaptoacetate in Example 68, 4.13 mg of the title compound was obtained by the same merhod as used in Example 68.
MS m/e (ESI) 401 (MH-GFjCOOH)
Example 7 6
7-(2-Butynyl)-2-isopropylsulfanyl-l-methyl-8-(piperazin-l-yl)-1,
7-dihydropurin-6-one trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 15 mg of the sodium salt of propane-2-thiol was added thereto. The mixture was stirred at room temperature for five hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted wi-h ethyl acetace. The organic layer was concentrated, and the residue was dissolved in 0.40 ml of -rifluoroacetic acid. The solution was concentrated by flushing with nitrogen gas . The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.56 mg of the title compound. MS m/e (ESI) 361 (MH-CFsCOOH)

Example 77
2--Butylsulfanyl-7-(2-butynyl)-l-methyl-8-(piperazin-1-yl)-1,7-
dihydropurin-6-one trifluoroacetate
Using the sodium salt of 2-methyl-2-propanethiol instead of the sodium salt of propane-2-thiol in Example 76, 2.58 mg of the title compound was obtained by the same method as used in Example 76.
MS m/e (ESI) 37 5 (MH-CFBCOOH)
Exa.mple 7 8
7-(2-Butynyl) -2-mercapto-l-methyl-8-(piperazin-l-yl) -1,7-dihydro
purin-6-one trifluoroacetate
Example 79
[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-lH-purin-2-ylsulfanyl]acetic acid trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8--yl]piperazine-1-carboxylate was dissolved in 0.15 ml of N-.-nethylpyrrolidone, and 20 |il of methyl mercaptoacetate and 6 mg of potassium carbonate were added there-o. After the mixture had been stirred-ax room temperature for five hours, an aqueous solution sat-urated with ammonium chloride was added to the reaction solution. The mixture was ex-racted with ethyl acetate. The organic layer was concentrated. The resulting residue was dissolved in a solution consisting of 0.20 ml of ethanol and 0.20 ml of a 5N aqueous sodium hydroxide solution. The mixture was stirred at room temperature overnight, and then concentrated by flushing with nitrogen gas. The residue was dissolved in 0.40 ml of rrifluoroacetic acid, and the solution was concentrated by flushing with nitrogen gas . The residue was purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 0.96 mg of
7-(2-butynyl) -2-mercapto-l-methyi-8-(piperazin-l-yl) -1,7-dihydro
purin-6-one trif luoroacetate [MS m/e (ESI) 319 (MH-CFaCOOH) ] and 0.61
mg of

[7-(2-butynyl) -l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydro-lH-purin-2-ylsulfanyl]acetic acid trifluoroacetate [MS m/e (ESIj 377 (MH-CFaCOOH) ]
Example 80
7- (2-Butynyl) -2-ethanesulf inyl-l-methyl-8- (piperazin-1-yl) -1, 7-d
ihydropurin-6-one trifluoroacetate
6 mg of t-butyl 4- [7- (2-butynyl) -2-chloro-l-methyl-6-oxo-6 , 7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 20 |il of ethanethiol and 6 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for 5 hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated. The residue was dissolved in 0.30 ml of dichloromethane, and the mixture was cooled to -78°C. 5 mg of m-chloroperbenzoic acid was added to the solution, and the mixture was stirred at -78°C for 15 minutes. An aqueous solurion saturated with sodium sulfite was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the solution w-as concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase, (containing 0.1% trifluoroacetic acid)) to give 3.21 mg of the title compound.
MS m/e (ESI) 363 (MH"-CFSCOOK)
Example 81
7-(2-Butynyl) -2-ethanesulfonyl-l-methyl-8-(piperazin-1-yl)-1,7-d
ihydropurin-6-one trifluoroacetate
6 mg of t-butyl 4- [7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and 20 Hi of ethanethiol and 6 mg of potassium carbonate were added thereto. The mixture was stirred at room

temperature for 5 hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated. The residue v/as dissolved in 0.3 ml of dichloromethane, and the solution was cooled to-VS"C. lOmgof m-chloroperbenzoic acid was added to the solution. The mixture was stirred at -78°C for 15 minutes and then at CC for 15 minutes. An aqueous solution saturated with sodium sulfite was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated. The residue was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.19 mg of the title compound.
MS ;n/e (ESI) 379 (MH-CFsCOOH)
Example 82
7-(2-Butynyl)-2-cyano-l-methyl-8- (piperazin-1-yl)-1,7-dihydropur
ln-6-one trifluoroacetate
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of N-methylpyrrolidone, and 10 mg of sodium cyanide was added thereto. The mixture was stirred at 50°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 14 mg of t-butyl 4-[7-(2-butynyl)-2-cyano-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-y l]piperazine-l-carboxylate. 5 mg of this compound was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.12 mg of the title compound.
MS m/e (ESI) 312 (MH-CFaCOOH)
Example 83
7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-lH-p

urine-2-carboxamide (a) t-Butyl
4-[7-(2-butynyl)-2-carbamoyl-l-methyl-6-oxo-6,7-dihydro-lH-purin -8-yl]piperazine-l-carboxylate
176 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 2 ml of N-methylpyrrolidone, and 100 mg of sodium cyanide was added thereto. The mixture was stirred at 50"C for 0.5 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 170 mg of t-butyl 4-[7-(2-butynyl)-2-cyano-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-y llpiperazine-l-carboxylate. 98 mg of this compound was dissolved in a mixture of 3 ml of tetrahydrofuran and 2 ml of methanol, and 0.5 ml of an aqueous solution of 20% ammonia and 0.5 ml of an aqueous solution of 30% hydrogen peroxide were added thereto. The mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The_solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 77 mg of the title compoynd was obtained from the fraction eluted with ethyl acetate-methanol.
1H-NMR(CDCl3)
-5 1.49 (s, 9H) 1.83 (t, J=1.2Hz, 3H) 3.42-3.49 (m, 4H) 3.58-3.65 (m, 4H) 3.95 (s, 3H) 5.01 (d, J=2.4Hz,- 2H) 5.54 (br, IH) 7.61 (br, IH) . (b)
7-(2-Butynyl)-l-methyl-6-oxo-B- (piperazin-1-yl)-6,7-dihydro-lH-p urine-2-carboxamide
77 mg of t-butyl 4- [7- (2-butynyl) -2-carbamoyl-l-me-chyl-6-oxo-6 , 7-dihydro-lH-purin -8-yl]piperazine-1-carboxylate was dissolved in 1 ml of trifluoroacetic acid, and the solution was concentrated. The residue was purified by chromatography using NH-silica gel. Thus, 49 mg of the title compound was obtained fro.m the fraction eluted with ethyl

acetate-methanol (5:1).
1H-NMR(CDCl3)
5 1.83 (t, J=2.4Hz, 3H) 3.05-3.07 Km, 4H) 3.45-3.48 (m, 4H) 3.94 (s, 3H) 4.98 (s, 2H) 5.57 (br, IH) 7.65 (br, IH)
Example 84
7-(2-Butynyl) -2-carboxy-l-methyl-8- (piperazin-l-yl)-1,7-dihydrop
urin-6-one trifluoroacetate
Example 85
7- (2-Butyr.yl) -l-methyl-8- (piperazin-l-yl) -1, 7-dihydropurin-6-one
trifluoroacetate
12.5 mg of t-butyl 4-[7-(2-butynyl)-2-carbamoyl-l-methyl-6-oxo-6,7-dihydro-lH-purin -8-yl]piperazine-l-carboxylate was dissolved in 0.3 ml of tetrahydrofuran and 0.2 ml of methanol, and 0.05 ml of 2N sodium hydrox-ide was added thereto. The mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.44 mg of
7-(2-butynyl)-2-carboxy-l-methyl-8-(piperazin-l-yl) -1,7-dihydrop urin-6-one trif luoroacetate [MS ml e (ESI) 331 (MH-CFsCOOH) ] and 6.4 mg of
7-(2-butynyl)-l-methyl-8-(piperazin-l-yl)-1,7-dihydropurin-6-one trifluoroacetate [1H-NMR (CDCI3) 5 1.81 (t, J=2.4Hz, 3H) 3.54 (br, 4H) 3.63 (s, 3H) 3.83 (br, 4H) 5.02 (s, 2H)8.20 (s, IH) ; MS /n/e (ESI) 287 (MH-CF.COOH) ] .
Example 8 6
7-(2-Butynyl) -2-methoxy-l-(2-phenylethyl)-8-(piperazin-l-yl)-1,7 -dihydropurin-6-one hydrochloride
(a)[7-Benzyl-2,6-dioxo-l-(2-phenylethyl)-1,2,6,7-tetrahydropurin -3-yl]methyl 2,2-dimethylpropionate
A mixture consisting of 500 mg of

[7-benzyl-2 , 6-dioxo-l ,2,6, 7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate, 0.38 ml of"2-bromoethyl benzene, 390 mg of anhydrous potassium carbonate, and 5 ml of N,N-dimethylformamide was stirred in an oil bath at 50 °C for two hours. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated saline. The organic liquid was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized with ethyl acetate-hexane to give 540 mg of the title compound.
1H-NMR(CDCl3)
5 1.19 (s, 9H) 2.92-2.98 (m, 2H) 4.19-4.25 (m, 2H) 5.48 (s, 2H) 6.11 (s, 2H) 7.17-7.40 (m, lOH) 7.54 (s, IH)
(b)[7-(2-Butynyl)-8-chloro-2,6-dioxo-l-(2-phenylethyl)-1,2,6,7-t etrahydropurin-3-yl]methyl 2,2-dimethyl propionate
A mixture consisting of 540 mg of [7-benzyl-2,6-dioxo-l-(2-phenylethyl)-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate, 50 mg of 10%-palladium carbon, and 8 ml of acetic acid was stirred under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered and then concentrated under reduced pressure to give 410 mg of residue.
The entire residue was combined with 0 .15 ml of l-bromo-2-butyne, 300 mg of anhydrous potassium carbonate, and 5 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was washed with water and then with saturated brine. The organic liquid was dried, over anhydrous magnesium sulfate and concentrated under reduced pressure to give 470 mg of residue.
The entire residue was combined with 180 mg of N-chlorosuccinimide and 5 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 2 hours . After 0 . 5 ml of an aqueous solution of IM sodium thiosulfate had been added to the reaction solution, the mixture was extracted with ethyl acetate and water. The organic layer was washed with water and then with saturated brine. The organic liquid was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. 380 mg of the title

compound was obtained by crystallization using ethyl acetate-hexane.
1H-NMR(CDCl3)
5 l.-2i (s, 9H) 1.83 (t, J=2Hz, 3H) 2.92-2.98 (m, 2H) 4.19-4.25 (m, 2H) 5.11 (q, J=2Hz, 2H) 6.05 (s, 2H) 7.18-7.32 (m, 5H)
(c) t-Butyl
4-[7-(2-butynyl)-2,6-dioxo-l-(2-phenylethyl)-2 , 3 , 6, 7-tetrahydro-lH-purin-8-yl]piperazine-1-carboxylate
A mixture consisting of 380 mg of[7-(2-butynyl)-8-chloro-2,6-dioxo-l-(2-phenylethyl)-1,2,6,7-te trahydropurin-3-yl ] methyl 2 , 2-dimethyl propionate , 4 60 mg of t-buty 1 piperazine-1-carboxylate, and 0.5 ml of N-methylpyrrolidone was stirred in an oil bath at 150 °C for 15 minutes. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate/hexane (1/1) . The solution was filtered through a small amount of silica gel, and then washed with ethyl acetate/hexane (1/1) . The filtrate was combined with the washing-solution. The mixed solution was concentrated under reduced pressure to give 570 mg of residue.
The entire residue was combined with 5 ml of tetrahydrofuran and 2.5 ml of methanol. 33 mg of sodium hydride was added to the mixture, and the resulting mixture was stirred at room temperature for 30 minuses . 1 ml of 1 N hydrochloric acid was added to the reaction solution, and then the mixture was extracted with ethyl acetate and water, then was washed with water and then with saturated brine. The organic liquid was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 350 mg of the title compound.
1H-NMR(CDCl3)
5 1.50 (s, 9H) 1.85 (t, J=2Hz, 3H) 2.91-2.98 (m, 2H) 3.37 (br.s, 4H) 3.56-3.62 (m, 4H) 4.15-4.22 (m, 2H) 4.87 (q, J=2Hz, 2H) 7.18-7.35 (m, 5H)
(d) t-Butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-l-(2-phenylethyl)-6,7-dihydro-lH

-purin-8-yl]piperazine-1-carboxylate
A mixture consisting of 290 mg of t-butyl 4- [7- (2-butynyl) -2 , 6-dioxo-l- (2-phenylethyl) -2; 3*, 6 , 7-tetrahydro-lH-purin-8-yl]piperazine-l-carboxylate and 4 ml of phosphorus oxychloride was heated and stirred in an oil bath at 120 "C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5 ml of tetrahydrofuran. This solution was added dropwise to a mixture consisting of 250 mg of di-t-butyl dicarbonate, 10 ml of a saturated sodium bicarbonate solution, and 10 ml of tetrahydrofuran while the mixture was being stirred and cooled with ice. The mixture was incubated at room temperature for 4 hours, and then extracted with ethyl acetate. The organic layer was washed with water then with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduce pressure. The residue was purified by silica gel column chromatography using 30 to 50% ethyl acetate/hexane. Then, the material was further purified by reverse-phase-column chromatography using 50 to 100% methanol/water to give 50 mg of the title compound.
1H-NMR(CDCl3)
5 1.49 (s, 9H) 1.84 (t, J=2Hz, 3H) 3.10-3.16 (m, 2H) 3.40-3.46 (m, 2H) 3.57-3.63 (m, 4H) 4.42-4.49 (m, 4H) 4.94 (q, J=2Hz, 2H) 7.21-7.34 (m, 5H) (e)
7-(2-Butynyl)-2-methoxy-l-(2-phenylethyl)-8-(piperazin-1-yl)-1,7 -dihydropurin-6-one hydrochloride
10 mg of sodium hydride (50%; oily) was added to a mixture consisting of 7 mg of t-butyl
4- [7- (2-butynyl) -2-chloro-5-oxo-l- (2-phenylethyl) -,6 , 7-dihydro-lH -purin-8-yl]piperazine-l-carboxylate and 0.5 ml of methanol. The mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine,-and concentrated. 0.5 ml of trifluoroacetic acid was added to the residue. The mixture was stirred at room temperature for 30 minutes, and then concentrated. The residue was.purified by reverse-phase column chromatography using 20 to 80% methanol/water

(containing 0.1% concentrated hydrochloric acid) to give 4.3 mg of the title compound.
1H-NMR(DMS0-d6)
5 1.80 (br.s, 3H) 2.85 (t, J=7Hz, 2H) 3.28 (br.s, 4H) 3.48-3.54 (m, 4H) 3.83 (s, 3H) 4.15 (t, J=7Hz, 2H) 4.97 (br.s, 2H) 7.16-7.24 (m, 3H) 7.29 (t, J=8Hz, 2H) 9.08 (br.s, 2H)
Example 87
7-(2-Butynyl)-2-ethoxy-l-(2-phenylethyl)-8-(piperazin-1-yl)-1,7-
dihydropurin-6-one hydrochloride
Using ethanol instead of methanol in Example 86(e), the title compound was synthesized by the same method as used in Example 86 (e) .
1H-NMR(DMS0-d6)
51.28 (t, J=7Hz, 3H) 1.80 (s, 3H) 2.86 (t, J=7Hz, 2H) 3.27 (br.s, 4K) 3.46-3.53 (m, 4H) 4.15 (t, J=7Hz, 2H) 4.25 (q, J=7Hz, 2H) 4.97 (s, 2H) 7.17 (d, J=7Hz, 2H) 7.22 (t, J=7Hz, IH) 7.29 (t, J=7Hz, 2H) 9.04 (br.s, 2H)
Example 8 8 Methyl
[7- (2-butynyl) -6-oxo-l- (2-phenyle-t:hyl) -8- (piperazin-1-yl) -6 , 7-di hydro-lH-purin-2-ylsulfanyl]acetate hydrochloride
Using methyl thioglycolate instead of methanol and using potassium carbonate as a base in Example 86(e), the title compound was synthesized by the same method as used in Example 86.
1H-NMR(DMS0-d6)
5 1.80 (s, 3H) 2.96 (t, J=8Hz, 2H) 3.29 (br.s, 4H) 3.50-3.56 (m, 4H) 3.68 (s, 3H) 4.16 (s, 2H) 4.23 (t, J=8Hz, 2H) 4.99 (s, 2H) 7.24-7.38 (m, 5H) 8.96 (br.s, 2H)
Example 89 Ethyl
[7-(2-butynyl)-6-oxo-l-(2-phenylethyl)-8-(piperazin-1-yl)-6,7-di hydro-lH-purin-2-ylamino]acetate hydrochloride
Using glycine ethyl ester hydrochloride instead of methanol and using potassium carbonate as a base in Example 86(e), the title

compound was synthesized by the same method as used in Example 86. 1H-NMR(DMS0-d6)
5 1.22 (t, J=7Hz-, 3H) 1.78 (s, 3H) 2.87 (t, J=8H2, 2H) 3.26 (br.s, 4H) 3.47 (br.s, 4H) 4.05 (d, J=6H2, 2H) 4.12 (q, J=7Hz, 2H) 4.21 (t, J=8H2, 2H) 4.89 (br.s, 2H) 7.17-7.35 (m, 5H) 7.51 (t, J=6Hz, IH) 8.93 (br.s, 2H)
Example 90
2-[7- (2-Butynyl) -6-oxo-l-- (2-phenylethyl)-8- (piperazin-1-yl)-6 , 7d
ihydro-lH-purin-2-ylamino]acetamide hydrochloride
Using glycine amide hydrochloride instead of methanol and using potassium carbonate as a base in Example 86(e), the title compound was synthesized by the same method as used in Example 86.
-H-NKR(DMS0-d6)
5 1.79 (s, 3H) 2.87 (t, J=8Hz, 2H) 3.26 (br.s, 4H) 3.52 (br.s,4H) 3.84 (d, J=5Hz, 2H) 4.19 (t, J=8Hz, 2H) 4.91 (s, 2H) 7.02 (s, IH) 7.16-7.40 (m, 7H) 9.08 (br.s," 2H)
Example 91
Ethyl
N-[7-(2-butynyl)-6-oxo-l-(2-phenylethyl)-8-(piperazin-1-yl)-6,7-
dihydro-lH-purin-2-yl]-N-methylaminoacetate hydrochloride
Using N-methylglycine ethyl ester hydrochloride instead of methanol and using potassium carbonate as a base in Example 86(e), the title compound was synthesized by the same method as used in Example 86.
1H-NMR(DMS0-d6)
5 1.17 (t, J=7Hz,.3H) 1.80 (s, 3H) 2.76 (s, 3H) 2.96 (t, J=8Hz, 2H) 3.28 (br.s, 4H) 3.46-3.52 (m, 4H) 3.88 (s, 2H) 4.09 (q, J=7Hz, 2K) 4.27 (z, J=8Hz, 2H) 4.98 (s, 2H) 7.15-7.30 (m, 5H) 8.95 (br.s, .2H)
Example 92
Methyl
[7-(2-butynyl) -6-oxo-l-(2-phenylethyl)-8-(piperazin-l-yl)-6,7-di
hydro-lH-purin-2-yloxy]acetate hydrochloride

Using methyl glycolate instead of methanol in Example 86(e), the title compound was synthesized by the same method as used in Example 86.
H-NMR(DMS0-d6)
5 1.80 (s, 3H) 2.93 (t, J=8Hz, 2H) 3.28 (br.s, 4H) 3.49 (br.s, 4H) 3.72 (s, 3H) 4.20 (t, J=8Hz, 2H) 4.96 (s, 2H) 5.02 (s, 2H) 7.20-7.34 (m, 5H) 8.87 (br.s, 2H)
Example 93
7-(2-Butynyl)-2-(2-hydroxyethoxy)-1- (2-phenylethyl) -8-(piperazin
-1-yl)-1,7-dihydropurin-6-one hydrochloride
Using ethylene glycol instead of methanol in Example 86 (e), the title compound was synthesized by the same method as used in Example 86.
H-NMR(DMS0-d6)
5 1.80 (s, 3H) 2.88 (t, J=8Hz, 2H) 3.29 (br.s, 4H) 3.49 (br.s, 4H) 3.71 (t, J=6Hz, 2H) 4.18 (t, J=8Hz, 2H) 4.28 (t, J=6Hz, 2H) 4.97 (s, 2H) 7.16-7.32 (m, 5H) 8.90 -(br.s, 2H)
Example 94
7-(2-Butynyl)-2-dimethylamino-l-(2-phenylethyl) -8-(piperazin-1-y
1)-1,7-dihydropurin-6-one hydrochloride
Using an aqueous solution of 50% dimethylamine instead of methanol in Example 86(e) , the title compound was synthesized by the same method as used in Example 86.
H-NMR(DMS0-d6)
5 1.80 (s, 3H) 2.60 (s, 6H) 2.89 (t, J=8Hz, 2H) 3.28 (br.s, 4H) 3.49 (br.s, 4H) 4.26 (t, J=8Hz, 2H) 4.98 (s, 2H) 7.06-7.27 (m, 5H) 8.93 (br.s, 2H)
Example 95
7-(2-Butynyl)-2-chloro-8-(piperazin-1-yl)-1,7-dihydropurin-6-one trifluoroacetate (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]pipera zine-1-carboxylate

A mixture consisting of 1.0 g of t-butyl 4-[7-(2-butynyl) -2,6-dichloro-7H-purin-8-yl]piperazine-l-carboxylate, 580 mg of sodium acetate, and 10 ml of dimethyl sulfoxide was stirred in an oil bath at 80°C for 24 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was washed with water and then with saturated brine, then was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50 to 70% ethyl acetate/hexane and crystallized with ethyl acetate-hexane to give 800 mg of the title compound.
H-NMR(CDCl3)
5 1.49 (s, 9H) 1.83 (t, J=2Hz, 3H) 3.44 (br.s, 4H) 3.56-3.63 (m, 4H) 4.94 (q, J=2Hz, 2H) (b)
7-(2-Butynyl) -2-chloro-8-(piperazin-1-yl)-1,7-dihydropurin-6-one "crif luoroacetate
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]pipera zine-1-carboxylate was dissolved in trifluoroacetic acid, and the solution was concentrated . The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase • (-containing 0.1% trifluoroacetic acid)) to give 3.45 mg of the title compound.
MS m/e (ESI) 307 (MH-CFsCOOH)
Example 96
2-[7-(2-Butynyl)-2-dimethylamino-6-oxo-8-(piperazin-1-yl)-6,7-di hydropurin-l-ylmethyl]benzonitrile hydrochloride (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-l- (2-cyanobenzyl)-6-oxo-6,7-dihydro-lH ,-purin-8-yl]piperazine-l-carboxylate
A mixture consisting of 100 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]pipera zine-1-carboxylate , 60 mg of 2-cyanobenzyl bromide , 68 mg of anhydrous potassium carbonate, and 1 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours . Ethyl acetate/hexane (1/1) and water

were added to the reaction solution. The insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30 to 50% ethyl acetate/hexane to give 50 mg of the title compound.
H-NMR(CDCl3)
5 1.49 (s, 9H) 1.83 (t, J=2Hz, 3H) 3.43-3.49 (m, 4H) 3.58-3.64 (m, 4H) 4.95 (q, J=2Hz, 2H) 5.72 (s, 2H) 7.06 (d, J=8Hz, IH) 7.39 (-, J=8Hz, IH) 7.51 (t, J=8Hz, IH) 7.71 (d, J=8Hz, IH) (b) t-Butyl
4-[7-(2-butynyl)-1-(2-cyanobenzyl)-2-dimethylamino-6-oxo-6,7-dih ydro-lH-purin-8-yl]piperazine-l-carboxylate
A mixture consisting of 8 mg of t-butyl 4-[7-{2-butynyl)-2-chloro-l-(2-cyano
benzyl)-6-oxo-6,7-dihydro-lH-purin-8-yl] piperazine-1-carboxylate, 20-JXI of an aqueous solution of 50% dimethylamine, and 0.2 ml of N,N-dimethylforTnamide was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was washed with water and with saturated brine, and concentrated. The residue was separated by silica gel thin-layer chromatography using 70% ethyl acetate/hexane to give 6.5 mg of the title compound.
-H-NMR(CDCl3)
5 1.50 (s, 9H) 1.81 (t, J=2Hz, 3H) 2.73 (s, 6H) 3.38-3.45 (m, 4K) 3.56-3.64 (m, 4H) 4.91, (q, J=2Hz , 2H> 5.55 (s, 2H) 7.07 (d, J=8Hz, IH) 7.32 (t, J=8H2, IH) 7.46, .(t, J=8Hz, IH) 7.65 (d, J=8Hz, IH) (c)
2-[7-(2-Butynyl)-2-dimethylamino-6-oxo-8-(piperazin-1-yl)-6,7-di hydropurin-l-ylmethyljbenzonitrile hydrochloride
6.5 mg of t-butyl 4-[7-(2-butynyl)-1-(2-cyanobenzyl)-2-dimethylamino-6-oxo-6,7-dih ydro-lH-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.5 ml of trif luoroacetic acid, and the mixture was allowed to stand at ■room temperature for 20 minutes. The reaction solution was

concentrated, and the residue was purified by reverse-phase column chromatography using 20 to 80% methanol/water (containing 0.1% concentrated hydrochloric acid) to give 6.4 mg of the title compound. H-NMR(DMS0-d6)
5 1.76 (s, 3H) 2.69 (s, 6H) 3.28 (br.s, 4H) 3.51 (br.s, 4H) 4.91 (s, 2H) 5.40 (s, 2H) 7.04 (d, J=8Hz, IH) 7.43 (t, J=8Hz, IH) 7.60 (t, J=8Hz, IH) 7.83 (d, J=8Hz, IH) 8.90 (br.s, 2H)
Example 97 Methyl
[7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-di hydro-lH-purin-2-ylsulfanyl]acetate hydrochloride
Using methyl thioglycolate instead of dimethylamine and using anhydrous potassium carbonate as a base in Example 96 (b) , the title compound was synthesized by the same method as used in Example 96.
H-NMR(DMS0-d6)
5l.79(s, 3H) 3.29 (br.s, 4H) 3.56 (br.s, 4H) 3.65 (s, 3H) 4.12 (s, 2H) 4.99 (s, 2H) 5.48 (s, 2H) 7.10 (d, -J=8Hz, IH) 7.50 (t, J=8Hz, IH) 7.65 (-, J=8Hz, IH) 7.92 (d, J-8Hz, IH) 8.95 (br.s, 2H)
Example 9 8
2-[7-(2-Butynyl)-2-methoxy-6-oxo-8-(piperazin-1-yl) -6,7-dihydrop
urin-1-ylmethyl]benzonitrile hydrochloride
Using methanol instead of dimethylamine and using anhydrous potassium carbonate as a base in Example 96(b), the title compound was synthesized by the same method as used in Example 96.
H-NMR(DMS0-d6)
5 1.79 (s, 3H) 3.28 (br.s, 4H) 3.48-3.56 (m, 4H) 3.91 (s, 3H) 4.97 (s, 2H) 5.32 (s, 2H) 7.19 (d, J-8Hz, IH) 7.48 (t, J=8Hz, IH) 7.63 (t, J=8Hz, IH) 7.87 (d, J=8Hz, IH), 9.05 (br.s, 2H)
Example 99 Methyl
[7-(2-butynyl)-l-cyanomethyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydr o-lH-purin-2-ylsulfanyl]acetate hydrochloride
(a) t-Butyl

4-[7-(2-butynyl)-2-chloro-l-cyanomethyl-6-oxo-6,7-dihydro-lH-pur in-8-yl]piperazine-l-carboxylate
Using bromoacetonitrile instead of dimethylamine in Example 96 (b) , the title compound was synthesized by the same method as used in Example 96(a).
H-NMR(CDCl3)
5 1.49 (s, 9H) 1.84 (t, J=2Hz, 3H) 3.43-3.49 (m, 4H) 3.58-3.63 (m, 4H) 4.91 (q, J=2Hz, 2H) 5.18 (s, 2H) (b) Methyl
[7-(2-butynyl)-l-cyanomethyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydr o-lH-purin-2-ylsulfanyl]acetate hydrochloride
Using the compound obtained in Example 99 (a) described above instead of the compound obtained in Example 96(a) in Example 97, the title compound was synthesized by the same method as used in Example 97.
H-NMR"(DMS0-d6)
5 1.80" (s, 3H) 3.29 (br.s, 4H) 3.55 (br.s, 4H) 3.68 (s, 3H) 4.22 (s, 2H) 4.98 (s, 2H) 5.21 (s, 2H) 8.93 (br.s, 2H)
Example 100 Methyl
[1, 7-bis (2-butynyl) -6-ox-o-8- (piperazin-1-yl) -6 , 7-dihydro-lH-puri n-2-ylsulfanyl]acetate hydrochloride
(a) t-Butyl
4-[1,7-bis(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]p iperazine-1-carboxylate
Using l-bromo-2-butyne instead of 2-cyanobenzyl bromide in Example 96(a), the title compound was synthesized by the same method as used in Example 96 (a) .
H-NMR(CDCl3)
5 1.49 (s, 9H) 1.80 (t, J=2Hz, 3H) 1.83 (t, J=2Hz, 3H) 3.40-3.45 (m, 4H) 3.57-3.62 (m, 4H) 4.93 (q, J=2Hz, 2H) 4.98 (q, J=2Hz, 2H)
(b) Methyl
[1,7-bis(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-lH-puri n-2-ylsulfanyl]acetate hydrochloride
Using the compound obtained in Example 100(a) described above

instead of the compound obtained in Example 96(a) in Example 97, the title compound was synthesized by the same method as used in Example 97.
H-NMR{DMS0-d6)
5 1.79 (s, 6H) 3.28 (br.s, 4H) 3.53 (br.s, 4H) 3.67 (s, 3H) 4.15 (s, 2H) 4.83 (s, 2H) 4.98 (s, 2H) 9.02 (br.s, 2H)
Example 101
1,7-Bis(2-butynyl)-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-lH-purin
e-2-carbonitrile hydrochloride
Using sodium cyanide instead of methyl thioglycolate in Example 100, the title compound was synthesized by the same method as used in Example 100.
H-NMR(DMS0-d6)
5 1.81 (s, 3H) 1.82 (s, 3H) 3.28 (br.s, 4H) 3.56-3.63 (m, 4H) 4.95 (q, J=2Hz, 2H) 5.07 (q, J=2Kz, 2H) 9.04 (br.s, 2H)
Example 102 -
1,7-Bis(2-butynyl)-2-methoxy-8- (piperazin-1-yl) -1, 7-dihydropurin
-6-one hydrochloride
Using methanol instead of methyl thioglycolate and using sodium hydride as the base in Example 100, the title compound was synthe"srzed by the same method as used in Example 100.
H-NMR(DMS0-d6)
5 1.75 (s, 3H) 1.80 (s, 3H) 3.28 (br.s, 4H) 3.47-3.55 (m, 4H) 3.98 (s, 3H) 4.66 (s, 2H) 4.96 (s, 2H) 9.01 (br.s, 2H)
Example 103 Methyl
[l-allyl-7-(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-lH-p urin-2-ylsulfanyl]acetate hydrochloride
(a) t-Butyl
4-[l-allyl-7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-y
1]piperazine-1-carboxylate
Using allyl bromide instead of 2-cyanobenzyl bromide in Example 96(a) , the title conpound was synthesized by the same method as used

in Example 96 (a) .
H-NMR(CDCl3)
5 1.49 (s, 9H) 1.83 (t, J=2Hz, 3H) 3.38-3.45 (m, 4H.) .3.55-3.63 (m, 4H) 4.90 (d, J=5Hz, 2H) 4.93 (q, J=2Hz, 2H) 5.19-5.29 (m, 2H) 5.93 (ddt, J=10, 17, 5Hz, IH) (b) Methyl
[l-allyl-7-(2-butynyl)-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-lH-p urin-2-ylsulfanyl]acetate hydrochloride
Using the compound obtained in Example 103 (a) described above instead of the compound obtained in Example 96 (a) in Example 97, the title compound was synthesized by the same method as used in Example 97.
H-NMR(DMS0-d6)
5 1.79 (s, 3H) 3.27 (br.s, 4H) 3.48-3.56 (m, 4H) 3.66 (s, 3H) 4.12 (s, 2H) 4.70 (d, J=5Hz, 2H) 4.98 (br.s, 2H) 5.07 (d, J=17Hz, IH) 5.21 (d, J=10Hz, IH) 5.89 (ddt, J=10, 17, 5Hz, IH) 9.07 (br.s, 2H)
Example 104
1-Ally1-7-(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-lH-pu
rine-2-carbonitrile hydrochloride
The title compound was synthesized by using sodium cyanide, instead of allyl bromide by the same method as used in Example 103.
H-NMR(DMS0-d6)
5 1.81 (t, J=2Hz, 3H) 3.29 (br.s, 4H) 3.57-3.64 (m, 4H) 4.81 (d,
J=5Hz, 2H) 5.04-5.10 (m, 3H) 5.26 (d, J=10Hz, IH) 6.00 (ddt, J=10,
17, 5Hz, IH) 9.12 (br.s, 2H)
Example 105
l-Allyl-7-(2-butynyl)-2-methoxy-8-(piperazin-1-yl)-1,7-dihydropu . r.in-6-one hydrochloride
Using methanol instead of methyl thioglycolate and using sodium hydride as a base in Example 103, the title compound was synthesized by the same method as used in Example 103.
H-NMR(DMS0-d6)
6 1,79 (t, J=2Hz, 3H) 3.27 (br.s, 4H) 3.48-3.56 (m, 4H) 3.93 (s.

3H) 4.55 (d, J=5Hz, 2H) 4.94-5.02 (m, 3H) 5.12 (d, J=10H2, IH) 5.87 (ddt, J=10, 17, 5H2, IH) 9.04 (br.s, 2H)
Example 106 Methyl
[7-(2-butynyl)-1-(2-methoxyethyl)-6-oxo-8-(piperazin-1-yl)-6,7-d ihydro-lH-purine-2-ylsulfanyl]acetate hydrochloride
(a) t-Butyl
4-[7-(2-butynyl) -1-(2-methoxyethyl)-2-chloro-6-oxo-6,7-dihydro-l K-purin-8-yl]piperazine-l-carboxylate
Using 2-bromoethyl methyl ether instead of 2-cyanobenzyl bromide in Example 96(a) , the title compound was synthesized by the same method as used in Example 96 (a) .
H-NKR(CDCl3)
5 1.49 (s, 9H) 1.83 (t, J=2Hz, 3H) 3.36 (s, 3H) 3.39-3.45 (m, .E) 3.56-3.61 (m, 4H) 3.69 (t, J=6Hz, 2H) 4.50 (t, J=6H2, 2H) 4.92 (q, J=2Hz, 2H)
(b) Methyl
[7-(2-butynyl)-1-(2-methoxyethyl)-6-oxo-8- (piperazin-l-yl)-6,7-d ihydro-lK-purine-2-ylsulfanyl]acetate hydrochloride
Using the compound obtained in Example 106 (a) described above instead of the compound obtained-isi Example 96(a) in Example 97, the ti-le compound was synthesized by the same method as used in Example 97.
-■H-NMR(DMS0-d6)
51.80 (s, 3H) 3.25-3.32 (m, 7H) 3.50-3.55 (m, 4H) 3.61 (t, J=6Hz, 2K) 3.67 (s, 3H) 4.14 (s, 2H) 4.25 (t, J=6Hz, 2H) 4.98 (s, 2H) 9.00 (br.s, 2H)
Example 107
7-(2-Butynyl) -1-(2-methoxyethyl)-6-oxo-8-(piperazin-l-yl)-6,7-di
hydro-lH-purine-2-carbonitrile hydrochloride
Using sodium cyanide instead of methyl thioglycolate in Example 106, the title compound was synthesized by the same method as used in Example 106.
H-NMR(DMS0-d6)

5 1.81 (s, 3H) 3.25 (s, 3H) 3.29 (br.s, 4H) 3.55-3.64 (m, 6H) 4.34 (t, J=5Hz, 2H) 5.08 (s, 2H) 9.05 (br.s, 2H)
Example 108
7-(2-Butynyl) -1-(2-methoxyethyl)-2-methoxy-8-(piperazin-1-yl)-1,
7-dihydropurin-6-one hydrochloride
Using methanol instead of methyl thioglycolate and using anhydrous potassium carbonate as the base in Example 106, the title compound was synthesized by the same method as used in Example 106.
H-NMR(DMS0-d6)
5 1.79 (s, 3H) 3.23 (s, 3H) 3.27 (br.s, 4H) 3.46-3.55 (m, 6H) 3.94 (s, 3H) 4.13 (t, J=6Hz, 2H), 4.96 (s, 2H), 9.03 (br.s, 2H)
Example 109
7-Benzyl-l-methyl-8-(piperazin-l-yl)-1,7-dihydropurin-6-one
trifluoroacetate
(a) 7-Benzyl-l,7-dihydropurin-6-one
18.23 g of inosine was dissolved in 90 ml of dimethyl sulfoxide, and 16 ml of benzyl bromide was added thereto . The mixture was stirred at room temperature overnight. The reaction solution was poured into 3 L of ethyl acetate. The resulting supernatant was removed and the precipitated oil was dissolved in 10% hydrochloric acid (135 ml). The solution was heated at 70"C with stirring for 4 hours. The solution was cooled to room temperature, and then neutralized to pH 7 using a 5N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, and dried to give 12.748 g of the title compound.
(b) t-Butyl
4- (7-benzyl-6-oxo-6,7-dihydro-lH-purin-8-yl)piperazine-1-carboxy late
12.748 g of 7-benzyl-l,7-dihydropurin-6-one was dissolved in 150 ml of N,N-dimethylformamide, and 7.9 g of N-chlorosuccinimide was added thereto. The reaction solution was stirred overnight, and then diluted with ethyl acetate. The solution was washed with water and IN hydrochloric acid, and dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated to give

6.103 g of 7-benzyl-8-chloro-l,7-dihydropurin-6-one. This compound was combined with 20 g of t-butyl piperazine-1-carboxylate, and the mixture was heated at 150"C. After being stirred for one hour, the reaction mixture was combined with ethyl acetate and water, and partitioned. The organic layer was washed with IN hydrochloric acid, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography. Thus, 1.539 g of the title compound was obtained from the fraction eluted with ethyl acetate-methanol (10:1) .
H-NMR(CDCl3)
6 1.39 (s, 9H) 3.07-3.10 (m, 4H) 3.35-3.39 (m, 4H) 5.44 (s, 2H) 7.16-7.18 (m, 2H) 7.22-7.32 (m, 3H) 7.91 (s, IH) 12.18 {s, IH) (c) 7-Benzyl-l-methyl-8- (piperazin-1-yl)-1,7-dihydropurin-6-one trifluoroacetate
15 mg of t-butyl 4-(7-benzyl-6-oxo-6,7-dihydro-lH-purin-8-yl)piperazine-1-carboxy late was dissolved in 1 ml of N,N-dimethylformamide, and 10 mg of sodium hydride and 10 fxl of methyl iodide were added thereto. The mixture was stixred at room temperature for 3 days, then ethyl acetate and water were added and the layers separated. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.31 mg of the title compound.
MS m/e (ESI) 325 (MH-CFjCOOH)
Example 110
7-Ben2yl-l-ethyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
The title compound was obtained by using iodoethane, instead of methyl iodide, by the same method as used in Example 109.
MS rale (ESI) 339 (MH"-CFsCOOH)
Example 111 Ethyl

[7-ben2yl-6-oxo-8-(piperazin-1-yl)-6,7-dihydropurin-l-yl]acetate trifluoroacetate
The title compeund was obtained by using ethyl bromoacetate, instead of methyl iodide, by the same method as used in Example 109.
MS /n/e (ESI) 397 (MH-CFaCOOH)
Example 112
7-Benzyl-l- (2-methoxyethyl) -8- (piperazir.-1-yl) -1, 7-dihydropurin-
6-one trifluoroacetate
The title compound was obtained by using 2-methoxyethyl bromide, instead of methyl iodide, by the same method as used in Example 109.
MS m/e (ESI) 369 (MH"-CFaCOOH)
Example 113
7-Benzyl-l-(2-propynyl)-8-(piperazin-1-yl)-1,7-dihydropurin-6-on
e trifluoroacetate
The ritle compound was obtained by using propargyl bromide, instead of methyl iodide, by the same method as used in Example 109.
MS m/e (ESI) 349 (MH-CFsCOOH)
Example 114
7-Benzyl-l-cyanomethyl-8- (piperazin-1-yl)-—1, 7-dihydropurin-6-one
trifluoroacetate
The -citle compound was obtained by using bromoacetonitrile, instead of methyl iodide, by the same method as used in Example 109.
MS m/e (ESI) 350 (MH-CFaCOOH)
Example 115
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo [4,5 -d]pyridazin-4-one trifluoroacetate
. (a) Ethyl 2-bromo-3- (2-butynyl)-5-cyano-3K-imidazole-4-carboxylate 4 .56 ml of sulfuric acid was added to 170 ml of ethanol containing 16.80 g of 2-bromo-lH-imidazole-4,5-dicarbonitrile [CAS No. 50847-09-1], and the mixture was heated under reflux for 48 hours. The solution was cooled, and then 500 ml of ethyl acetate and 200 ml of water were added thereto. The organic layer was dried over

anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformaraide, and 14.1 g of potassium carbonate and 8.6 ml of 2-butynyl bromide were added thereto. The mixture was stirred at room temperature for 18 hours. 500 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 300 ml of water, and then with 300 ml of a saturated sodium chloride solution. Then, the solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 4.09 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (9:1) .
H-NMR(CDCl3)
5 1.43 (t, J=7.2Hz, 3H) 1.81 (s, 3H) 4.47 (q, J=7.2Hz, 2H) 5.16 (s, 2H)
(b) t-Butyl
4-[1-(2-butynyl)-4-cyano-5-ethoxycarboxyl-lH-imidazol-2-yl]piper azine-1-carboxylate
4.09 g of ethyl 2-bromo-3-(2-butynyl)-5-cyano-3H-imidazole-4-carboxylate was combined with 7.70 g of t-butyl piperazine-1-carboxylate, and the mixture was heated to 150°Cwith stirring for 50 minutes . The reaction mixture was dissolved in toluene. The mixture was purified by silica gel column chromatography. Thus, 4.47 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (2:1)-.
H-NMR(CDCl3)
5 1.43 (t, J=7.2Hz, 3H) 1.47 (s, 9H) 1.82 (t, J=2.3Hz, 3H) 3.08-3.13 (m, 4H) 3.57-3.61 (m, 4H) 4.44 (q, J=7.2Hz, 2H) 4.89 (q, J=2.3Hz, 2H)
(c) t-Butyl
4-[1-(2-butynyl)~5-ethoxycarbonyl-4-thiocarbamoyl-lH-imida2ol-2-yl]piperazine-l-carboxylate
5 ml of an aqueous solution of 50% ammonium sulfide was added to a 20-ml ethanol solution containing 0.80 g of t-butyl 4-[1-(2-butynyl)-4-cyano-5-ethoxycarbonyl-lH-imidazol-2-yl] piperazine-1-carboxylate, and the mixture was heated at 60 "C for 14

hours. 100 ml of ethyl acetate and 50 ml of water were added to the mixture, and the organic layer was washed successively with 50 ml of water and 50 ml of a saturated sodium chloride solution. The reaction solution was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.58 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
H-NMR(CDCl3)
5 1.43 (t, J=7.2Hz, 3H) 1.48 (s, 9H) 1.82 (t, J=2.3Hz, 3H) 3.12-3.16 (m, 4H) 3.54-3.59 (m, 4H) 4.44 (q, J=7.2H2, 2H) 4.89 (q, J=2.3H2, 2H) 7.41 (br.s, IH) 8.88 (br.s, IH)
(d) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-methylsulfanylcarbonimidoyl-lH-imidazol-2-yl]piperazine-1-carboxylate
0 . 235 of trimethyl oxonium tetraf luoroborate was added to a 20-ral dichloromethane solution of 0.58 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-thiocarbamoyl-lH-imidazol-2-yl]piperazine-1-carboxylatG, and the mixture was stirred at room temperature for 18 hours. 50 ml of dichloromethane was added to the solution, and the mixture was washed with 20 ml of a saturated sodium bicarbonate solution . The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.55 g of the title compound.
H-NMR(CDCl3)
5 1.41 (t, J=7.2Hz, 3H) 1.47 (s, 9H) 1.81 (t, J=2.3Hz, 3H) 2.39 (s, 3H) 3.12-3.16 (m, 4H) 3.56-3.59 (m, 4H) 4.42 (q, J=7.2Hz, 2H) 4.80 (q, J=2.3Hz, 2H)
(e) t-Butyl
4-[1-(2-butynyl) -5-ethoxycarbonyl-4-methylsulfanylcarbonyl-lH-im - idazol-2-yl]piperazine-1-carboxylate
5 ml of a 2N aqueous solution of hydrochloric acid was added to a 30-ml ethanol solution of 0.55 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-methyl
sulfanylcarbonimidoyl-lH-imidazol-2-yl] piperazine-1-carboxylate, and the mixture was heated at 60 °C for 5 hours. After the reaction

solution had been concentrated under reduced pressure, 25 ml of ethyl acetate and IN sodium hydroxide solution were added thereto. The aqueous layer was extracted-with 25 ml of ethyl acetate, and the organic layers were combined together. The mixture was washed with 10 ml of a saturated sodium chloride solution containing 1 ml of IN sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 0.10 ml of triethylamine and 0.256 g of di-t-butyl dicarbonate were added thereto. The mixture was stirred at room temperature for 15 hours, and then 25 ml of ethyl acetate was added thereto. The mixture was washed successively with 10 ml of 0 . IN hydrochloric acid, 10 ml of a saturated sodium bicarbonate solution, and 10 ml of a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.15 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (4:1) .
H-NMR(CDCl3)
5 1.43 (t, J=7.1Hz, 3H) 1.48 (s, 9H) 1.81 .(t, J=2.3Hz, 3H) 2.40
(s, 3H) 3.16-3.20 (m, 4H) 3.55-3.59 (m, 4H) 4.35 (q, J=7.IHz, 2H)
4.80 (q, J=2.3Hz, 2H) ■ -
(f) t-Butyl
4- [ 1- (2-butynyl) -5-ethoxycarbonyl-4-hydroxymethyl-lH-imidazol-2-yl]piperazine-1-carboxylate
0.187 g of mercury (II) acetate and 0.090 of sodium borohydride were added to 8 ml of an ethanol solution containing 0.265 g of t-butyl 4- [ 1- (2-butynyl) -5-ethoxycarboriyl-4-methylsulfanyl carbonyl-lH-imidazol-2-yl]piperazine-l-carboxylate at 0°C, and the mixture was stirred at room temperature for 4 hours. After 0.187 g of mercury (II) acetate and 0 . 090 of sodium borohydride had been added to the solution, the mixture was stirred at room temperature for 15 hours. 100 ml of ethyl acetate and 50 ml of 0 . 5N hydrochloric acid were added to the solution, and the organic layer was washed successively with 50 ml of water and 50 ml of a saturated sodium chloride solution. The mixture was dried over anhydrous magnesium

sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 0 .172 g of the starting material was collected from the fraction eluted with hexane-ethyl" acetate (4:1) . Then, 0.061 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:4).
H-NMR(CDCl3)
5 1.42 (t, J=7.1Hz, 3H) 1.48 (s, 9H) 1.81 (t, J=2.3Hz, 3H) 3.17-3.21 (m, 4H) 3.41 (t, J=4.8H2, IH) 3.56-3.60 (m, 4H) 4.36 (q, J=7.1Hz, 2H) 4.75 (d, J=4.8Hz, 2H) 4.81 (q, J=2.3Hz, 2H) (g) t-Butyl
4-[1-(2-butynyl) -5-ethoxycarbonyl-4-formyl-lH-imidazol-2-yl]pipe razine~l-carboxylate
0 .120 g of manganese dioxide was added to a 2-ml dichloromethane solution of 0.061 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-hydroxymethyl-lH-imidazol-2-yl]piperazine-l-carboxylate, and the mixture was stirred at room temperature for 15 hours. The reactio"h solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.055 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (7:3).
H-NMR(CDCl3)
5 1.42 (t, J=7.1Hz, 3H) 1.48 (s, 9H) 1.82 (t, J=2.3Hz, 3H) 3.23-3.26 (m, 4H) 3.55-3.59 (m, 4H) 4.45 (q, J=7.1Hz, 2H) 4.89 (q, J=2.3Hz, 2H) 10.36 (s, IH) (h) t-Butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]pipera2ine-l-carboxylate
0 , 05 ml of methylhydrazine was added to a 2 . 5-ml ethanol solution of 0.055 g of t-butyl
,4-[1-(2-butynyl) -5-ethoxycarbonyl-4-formyl-lH-imidazol-2-yl] piperazine-1-carboxylate. The mixture was stirred at 80"C for 15 hours, and then heated at 130°C for 14 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography. Thus, 0.035 g of the title compound was obtained from the fraction eluted with hexane-ethyl

acetate (1:1) .
H-NMR(CDCl3)
5 1.52 (s, 9H) 1.83 (t, J=2.3Hz, 3H) 3.38-3.42 (m, 4H) 3.61-3.64 (m, 4H) 3.85 (s, 3H) 5.09 (q, J=2.3Hz, 2H) 8.13 (s, IH)
MS m/e (ESI) 387.4 (MH) (i)
3-(2-Butynyl) -5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5 -d]pyrida2in-4-one trifluoroacetate
0.4 ml of trifluoroacetic acid was added to a 0.4-ml dichloromethane solution of 0.0351 g of t-butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-l-carboxylate, and the mixture was stirred at room temperature for one hour. The solvent was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0295 g of the title compound.
H-NMR(CD30D)
5 1.83 (t, J=2.3Hz, 3H) 3.45-3.49 (m, 4H) 3.65-3.69 (m, 4H) 3.83 (s, 3H) 5.15 (q, J=2.3Hz, 2H) 8.2-0 (s, IK)
MS m/e (ESI.) 287.09 (MH-CFaCOOH)
Example 116
5-Benzyloxymethyl-3- (2-butynyl)-2-(piperazin-1-yl)-3,5-dihydro-i midazo[4,5-d]pyridazin-4-one trifluoroacetate (a) .
5-Benzyloxymethyl-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-su Ifonic acid dimethylamide
2.08 g of triethylamine, 2.80 g of N,N-dimethyl sulfamoyl chloride, and 0.22 g of 4-dimethylaminopyridine were added to 50 ml of a dichloromethane solution of 3.04 g of 5-benzyloxy methylimmidazo[4,5-d]pyridazin-4-one [CAS NO. 82137-50-6] (R. Paul Gagnier, Michael J. Halat, and Brian A. Otter Journal of Heterocyclic Chemistry, 21, p481, 1984) , and the mixture was heated under reflux for 4 hours. 250 ml of eLhyl acetate was added to the solution, and the mixture was washed successively with 50 ml of an aqueous solution of IN hydrochloric acid, 50 ml of a saturated sodium bicarbonate

solution, and 50 ml of a saturated sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was"purified by silica gel column chromatography. Thus, 2.86 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (2:3).
H-NMR(CDCl3)
5 2.98 (s, 6H) 4.77 (s, 2H) 5.74 (s, 2H) 7.30-7.39 (m, 5H) 8.21 (s, IH) 8.46 (s, IH) (b)
5-Benzyloxymethyl-2-chloro-4-oxo-4,5-dihydroimidazo[4,5-d]pyrida zine-l-sulfonic acid dimethylamide
5.3 ml of n-butyl lithium (2.0 M cyclohexane solution) was added to a 150-ml tetrahydrofuran solution of 3.34 g of 5-benzyloxymethyl-4-oxo-4,5-dihydroimidazo[4,5-dlpyridazine-l-su Ifonic acid dimethylamide under a nitrogen atmosphere at -7 8°C, and the mixture was stirred at -78°C for one hour. Then, 20 ml of a tetrahydrofuran solution of 3.26 g of hexachloroethane was added to this solution. The mixture was allowed to warm to room temperature. 25 ml of a 5% aqueous solution of ammonium chloride was added to the solution, and the mixture was extracted with 50 ml of ethyl acetate. The organic layer was washed successively with 25 ml of water and 25 ml of a saturated sodium chloride solution, and then drie"d*over anhydrous magnesium sulfate. The organic liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.31 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (2:3).
H-NMR(CDCl3)
5 3.12 (s, 6H) 4.77 (s, 2H) 5.70 (s,.2H) 7.30-7.39 (m, 5H) 8.48 (s, IH) (c) t-Butyl . 4- (6-benzyloxymethyl-7-oxo-6,7-dihydro-lH-imida20[4,5-d]pyridazi n-2-yl)piperazine-1-carboxylate
A mixture consisting of 2.31 g of 5-benzyloxymethyl-2-chloro -4-OXO-4,5-dihydroimidazo[4,5-d]pyridazine-l-sulfonic acid dimethylamide and 4.49 g of t-butyl piperazine-1-carboxylate was heated at 150"C under nitrogen atmosphere for 2.5 hours. The residue

was purified by silica gel column chromatography. Thus, 1.94 g of the title compound was obtained from the fraction eluted with ethyl acetate.
H-NMR{CDCl3)
5 3.54-3.58 (m, 4H) 3.71-3.75 (m, 4H) 4.68 (s, 2H) 5.65 (s, 2H) 7.25-7.35 (m, 5H) 8.21 (s, IH) 12.58 (br.s, IH) (d) t-Butyl
4-[6-benzyloxymethyl-l- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-imidazo [ 4,5-d] pyrida2in-2-yl]piperazine-l-carboxylate
0.74 g of potassium carbonate and 0.078 g of 2-butynyl bromide were added to a 20-ml N,N-dimethylformamide solution of 0.216 g of t-butyl 4- (6-benzyloxymethyl-7-oxo-6,7-dihydro-lH-imidazo [4,5-d]pyridazin-2-yl)pipera2ine-l-carboxylate, and the mixture was stirred at room temperature for 16 hours. Then, 50 ml of ethyl acetate was added to the solution. The organic layer was washed three times with 20 ml of water, and then with 10 ml of a saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The" residue was purified by silica gel column chromatography. Thus, 0.139 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
H-NMR(CDCl3)
5 1.50 (s, 9H) 1.86 (t, J=2.3Hz, 3H) 3.38-3.44 (m, 4H) 3.61-3.66 (m, 4H) 4.72 (s, 2H) 5.10 (q, J=2.3Hz, 2H) 5.65 (s, 2H) 7.25-7.38 (m, 5H) 8.18 (s, IH) (e)
5-Benzyloxymethyl-3-(2-butynyl)-2-(piperazin-1-yl) -3,5-dihydroim idazo[4,5-d]pyridazin-4-one trifluoroacetate
0.0043 g of the title compound was obtained by treating 0.0073 g of t-butyl
4- [6-benzyloxymethyl-l- (2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[ 4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and purifying the product by the same method as used in Example 115 (i) .
"H-NMR(CD30D)
5 1.83 (t, J=2.3Hz, 2H) 3.45-3.49 (m, 4H) 3.65-3.69 (m, 4H) 4.69 (s, 2H) 5.15 (q, J=2.3Hz, 2H) 5.64 (s, 2H) . 7.17-7.32 (m, 5H) 8.20

{s, IH)
MS m/e (ESI) 393 . 28 (MH-CFsCOOH)
Example 117
3-(2-Butynyl) -2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyrida
zin-4-one trifluoroacetate
8 ml of a dichloromethane solution of 0.123 g of t-butyl 4- [6-benzyloxymethyl-l- (2-butynyl) -7-oxo-6, 7-dihydro-lH-imidazo [ 4,5-d]pyridazin-2-yl]piperazine-l-carboxylate was cooled to -78°C under a nitrogen atmosphere, and 1.9 ml of boron trichloride (1.0 M dichloromethane solution) was added thereto. The mixture was stirred at -78°C for five hours, and 10 ml of a 1:1 mixed solvent of dichloromethane-methanol was added thereto. The mixture was stirred at -7 8°C for two hours, and then allowed to warm to room temperature. The solvent was concentrated under reduced pressure, and 10 ml of methanol was added thereto. Then, the solution was again concentrated under reduced pressure. The residue was dissolved in 3 ml of pyridine, and the mixture was heated under reflux for two hours. 0.3 ml of this solution was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.005 g of the title compound.
H-NMR(CD30D)
5 1.83 (t, J=2.3Hz, 3H) 3.45-3.49 (m, 4H) 3.65-3.69 (m, 4H) 5.16 (q, J=2.3Hz, 2H) 8.21 (s, IH)
MS m/e (ESI) 273.16 (MH-CFaCOOH)
Example 118
2-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydro-l . H-purin-2-yloxy]benzamide hydrochloride (a) t-Butyl
4-[7-(2-butynyl) -2-(2-carbamoylphenoxy)-l-methyl-6-oxo-6,7-dihyd ro-lH-purin-8-yljpiperazine-l-carboxylate
200 mg of t-butyl 4- [7- (2-butynyl) -2-chloro-l-methyl-6-oxo-6 , 7-dihydro-lH-purin-8-

yl]piperazine-l-carboxylate was dissolved in 2.0 ml of l-methyl-2-pyrrolidone, and 85 mg of salicylamide and 129 mg of potassium carbonate were added thereto. The mixture was stirred at 100"C for 2 hours . After the reaction mixture had been cooled to room temperature, 5.0 ml of water was added thereto. After the mixture had been stirred at room temperature for 1 hour, the white precipitate was collected by filtration. The resulting white solid was washed with water and ether to give of 221 mg of the title compound (89%) . H-NMR(DMS0-d6)
5 1.43 (s, 9H) 1.79 (t, J=2.5Hz, 3H) 3.23-3.27 (m, 4H) 3.36 (s,
3H) 3.48-3.52 (m, 4H) 4.95 (q, 2.5Hz, 2H) 6.59 (td, J=8.0, 1.OHz,
IH) 6.63 (dd, J=8.0, l.OHz, IH) 7.14 (ddd, J=8.0, 7.5, 2.0Hz, IH)
7.80 (dd, J=7.5, 2.0Hz, IH)
MS mle (ESI) 522 (MH*) (b)
2-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-l H-purin-2-yloxy]benzamide hydrochloride
210 mg of t-butyl 4-[7-(2-butynyl)-2-(2-carbamoylphenoxy)-l-methyl-6-oxo-6,7-dihyd ro-lH-purin-8-yl]piperazine-1-carboxylate was combined with 3 . 5 ml of methanol and 2 .1 ml of 4N hydrochloric acid-ethyl acetate solution. After the mixture had been stirred at room temperature for 4 hours, the reaction solution was concentrated by flushing with nitrogen gas. The resulting residue was washed with ethanol and ethyl acetate to give 177 mg of the title compound (96%).
H-NMR(DMS0-d6)
6 1.82 (t, J=2.3Hz, 3H) 3.28-3.32 (m, 4H) 3.48 (s, 3H) 3.54-3.58
(m, 4H) 5.04 (q, 2.3Hz, 2H) 6.96 (br.t, J=7.0Hz, IH) 6.99 (br.d,
J=8.0Hz, IH) 7.46 (ddd, J=8.0, 7.0, 1.5Hz, IH) 7.93 (br.d, J=8.0Hz,
IH)
. . MS m/e (ESI) 422 (MH"-HCI)
Example 119
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,S-dihydroimidazo[4,5
-d]pyridazin-4-one
(a) 5-Methyl-l-trityl-l,5-dihydroimidazo[4,5-d]pyridazin-4-one

78.8 g of 5-methyl-l,5-dihydroimidazo [4,5-d] pyridazin-4-one [CAS No. 76756-58-6] (Shih-Fong Chen and Raymond P. Panzica, Journal of Organic Chemistry 46, p2467, 1981) was suspended in 2.5 L of dichloromethane at room temperature, and 78.8 of triethylamine was added thereto. 176 g of trityl chloride was added to the mixture, which was then stirred for three hours. 7.5 L of ethyl acetate was added to the mixture. After being washed successively with 3 L of water and 3 L of a saturated sodium chloride solution, the mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography . Thus , 136 . 5 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (20:80 to 0:100).
H-NMR(CDCl3)
5 3.79 (s, 3H) 5.92 (s, IH) 7.07-7.13 (m, 6H) 7.32-7.40 (m, 9H) 7.87 (s, IH) (b)
2-Chloro-5-methyl-l-trityl-l,5-dihydroimidazo[4,5-d]pyridazin-4-one
220 ml of lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution) was added.to a 4-L tetrahydrofuran solution of 68.3 g of 5-methyl-l-trityl-l,5-dihydroimidazo[4,5-d]pyridazin-4-one at -75 °C under a nitrogen atirrosphere, and the mixture was stirred at -75°C for 1 hour. Then, 200 ml of a tetrahydrofuran solution of 82.3 g of hexachloroethane was added to the solution. The mixture was allowed tO- warm to -20 °C. 5 L of 5% aqueous ammonium chloride was added, and the mixture was extracted with 4 L of ethyl acetate. The organic layer was washed successively with 5 L of water and 5 L of a saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure . The residue was suspended in 150 ml of t-butyl methyl ether, and then collected by filtration. The solid was washed twice with 100 ml of t-butyl methyl ether to give 59.7 g of the title compound.
H-NMR(CDCl3)
5 3.78 (s, 3H) 5.81 (s, IH) 7.25-7.27 (m, 6H) 7.28-7.38 (m, 9H) (c) t-Butyl 4-(6-methyl-7-oxo-5,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl)pi

perazine-1-carboxylate
69.7 g of 2-chloro-5-methyl-l-trityl-l,5-dihydroimidazo [4,5-d] pyridazin-4-9ne was combined wi-cri*153.4 g of t-butyl piperazine-l-carboxylate, and the mixture was stirred and heated to 100°C under nitrogen atmosphere. When the reaction mixture became easily stirrable, the temperature was raised to 150°C. The mixture was kept at this temperature for one hour. The reaction solution allowed to cool and then suspended in 2 50 ml of t-butyl methyl ether. The suspended material was collected by filtration. The solid was washed twice with 200 ml of t-butyl methyl ether and three times with 200 ml of water. The solid was again washed twice with 200 ml of t-butyl methyl ether, and dried to give 50.3 g of the title compound.
H-NMR{CDCl3)
5 1.50 (s, 9H) 3.56-3.62 (m, 4K) 3.73-3.80 (m, 4H) 3.87 (s, 3H) 8.16 (s, IH) 12.65 (br.s, IH) (d) t-Butyl
4-[1-(2-burynyl) -6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-l-carboxylate
43.9 g of potassium carbonate and 27.8 ml of 2-butynyl bromide were successively added to a 5.5-L N,N-dimethylformamide solution of 88.4 g of t-butyl
4-(6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]
pyridazin-2-yl)piperazine-l-carboxylate at 15"C under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 22 hours, and then poured into 10 L of water.- The mixture was extracted with 5 L of ethyl acetare. The organic layer was successively washed twice with 5 L of water, and with 5 L of a saturated sodium chloride solution. The aqueous layer was extracted twice with 3 L of ethyl acetate. The organic layers were combined together, and then dried over anhydrous magnesium sulfate. The organic layer was -concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 54.3 gof the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2 to 3:7) .
H-NMR(CDCl3)
5 1.52 (s, 9H) 1.83 (t, J=2.3.Hz, 3H) 3.38-3.42 (m, 4H) 3.61-3.64

(rn, 4H) 3.85 (s, 3H) 5.09 (q, J=2.3Hz, 2K) 8.13 (s, IH) (e)
3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3 , 5-dihydroimida7.o [4,5 -d]pyrida2in-4-one
200 ml of trifluoroacetic acid was addegi to 200 ml of a dichloromethane solution containing 54.3 g of t-butyl 4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-l-carboxylate, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the residue was dissolved in 500 ml of ethyl acetate. 1 L of 10% aqueous sodium bicarbonate solution was gradually added. Then, 1 L of ethyl acetate and 500 ml of a 5N aqueous sodium hydroxide solution were added to the solution. The organic layer was separated. Then, the aqueous layer was extracted five times with 1 L of dichloromethane. The organic layers were combined together, washed with 500 ml of an aqueous solution of 2N sodium hydroxide, dried over anhydrous magnesium sulfate , and concentrated under reduced pressure . The residue was recrystallized from ethyl acetate to give 30.5g of the crystalline title compound.
H-NMR{CDCl3)
5 1.84 (t, J=2.3Hz, 3H) 3.05-3.09 (m, 4H) 3.38-3.44 (m, 4H) 3.85 (s, 3H) 5.06 (q, J=2.3Hz, 2H) 8.13 (s, 3H)
Example 119-2
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo [4,5
-d]pyridazin-4-one toluene-4-sulfonate
98.7 mg of 3-(2-butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo [4 , 5-d] pyridazin-4-one was dissolved in 1 ml of ethanol, and then 1 ml of an ethanol solution of 101 mg of p-toluenesulfonic acid monohydrate was added thereto while the solution was being stirred. The mixture was cooled with ice for two hours while being stirred. The precipitate was collected by filtration, and then dried under reduced pressure at 50°C for one hour to give 153.2 mg of the title compound.
H-NMR (DMS0-d6)
5l.7 9(t, J=2Hz, 3H) 2.27 (s, 3H) 3.2 5-3.35 (m, 4H) 3.. 50-3.54 (m,

4H) 3.70 (s, 3H) 5.13 (d, J= 2 Hz, 2H) 7.10 (d, J= 8 Hz, 2H) 7.47 (d, J= 8 Hz, 2H) 8.25 (s, IH) 8.79 (br.s, 2H)
Furthermore, 107.95 mg of the title compound was recrystallized from acetone, yielding 84.9 mg of crystalline product.
Example 120
2- (3-Aminopiperidin-l-yl)-3- (2-butynyl)-5-methyl-3 , 5-dihydroimid
azo[4,5-d]pyridazin-4-one trifluoroacetate
(a) 9H-fluoren-9-ylmethyl
3-t-butoxycarbonylaminopiperidine-l-carboxylate
1.84 g of diisopropylethylamine and 4.71 g of diphenylphosphorylazide were added to 10 ml of a t-butanol solution of 5.01 g of 9H-fluoren-9-ylmethyl
3-carboxypiperidine-l-carboxylate, and the mixture was heated at 60 ° C under a nitrogen atmosphere for 18 hours. The reaction solution was cooled, and 150 ml of ethyl acetate was added thereto. The organic layer was washed successively with 100 ml of 5% aqueous sulfuric acid, 100 ml of 5% aqueous sodium bicarbonate solution, 100 ml of water, and 100 ml of a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.88 g of the"title compound was obtained from the fraction eluted with hexane-ethyl acetate (4:1).
-H-NMR(CDCl3)
5 1.45 (s, 9H) 1-.45-1.72 (m, 3H) 1.82-1.87 (br.s, IH) 3.09-3.30 (br.s, 2H) 3.58 (br.s, 2H) 3.82-3.98 (br.s, IH) 4.24 (t, J=7.2 Hz, IH) 4.27-4.48 (br.s, 2H) 4.52-4.59 (br.s, IH) 7.32 (dd, J=10.3, 10.0 Hz, 2H) 7.3 9 (t,,J=10.0 Hz, 2H) 7.59 (d, J=10.0 Hz, 2H) 7.7 5 (d, J=10.3 Kz, 2H)
(b) t-Butyl piperidin-3-ylcarbamae
25 ml of diethylamine was added to 250 ml of an ethanol solution of 1.88 g of 9H-fluoren-9-ylmethyl
3-t-butoxycarbonylaminopiperidine-l-carboxylate, and the mixture was stirred at room temperature for 18 hours. After the solution had been concentrated under reduced pressure, the residue was dissolved in a mixture consisting of 150 ml of toluene and 100 ml of 10% aqueous

citric acid solution. The aqueous layer was made alkaline with a 5N aqueous sodium hydroxide solution, and then extracted twice with 100 ml of dichloromethane. The organic layers were combined together, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.79 g of the title compound. H-NMR(CDCl3)
61.45 (s, 9H) 1.41-1.53 (m, 2H) 1.65-1.72 (m, IH) 1.79-1.86 (m, IH) 2.48-2.56 (m, IH) 2.64-2.70 (m, IH) 2.78-2.86 (m, IH) 3.06 (dd, J=12.0,4.0 Hz, IH) 3.48-3.62 (br.s, IH) 4.71-4.88 (br.s, IH) (c)
2-(3-Aminopiperidin-l-yl)-3-(2-butynyl)-5-methyl-3,5-dihydroimid azo[4,5-d]pyridazin-4-one trifluoroacetate
0.020 g of 2-chloro-5-methyl-l-trityl-l,5-dihydroimidazo [4,5-d]pyridazine-4-one and 0.040 g of t-butyl
piperidin-3-ylcarbamate were combined together, and the mixture was heated under a nitrogen atmosphere at 150""C for 1 hour. The reaction mixture was purified"by silica gel column chromatography. Thus, 0.016 g of t-butyl
[1-(6-methyl-7-0x0-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl)p iperidin-3-yl]carbamate was obtained from the fraction eluted with ethyl acetate. 0.0080 g of this compound was dissolved in 0.6 ml of N,N-dimethylformamide, and then 0.0038 g of potassium carbonate and 0.003 ml of 2-butynyl bromide were added thereto. The mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between 1 ml of ethyl acetate and 1 ml of water,-and the organic layer was concentrated. The residue was dissolved in 0 . 5 ml of dichloromethane, and then 0.5 ml of trif luoroacetic acid was added thereto. After 1 hour, the reaction solution was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0046 g of the title compound.
H-NMR(CDCl3)
6 1.74-1.80 (br.s, IH) 1.82 (br.s, 3H) 1.96-2.19 (br.m, 3H) 3.43-3.79 (br.m, 5H) 3.86 (s, 3H) 5.05 (br.d, J=16.0 Hz, IH) 5.23 (br.d, J=16.0 Hz, IH) 8.15 (s, IH) .

Example 121
2-(3-Aminopiperidin-l-yl)-5-methyl-3-(3-methyl-2-butenyl)-3,5-di
hydroimidazo[4,5-d]pyrida2in-4-one trifluoroacetate
0.0034 g of the title compound was obtained using 0.0080 g of t-butyl
[1-(6-methyl-7-oxo-6,7-dihydro-lH-imida20[4,5-d]pyridazin-2-yl)p iperidin-3-yl]-carbamate and 0.004 ml of 4-bromo-2-methyl-2-butene by the same method as used in Example 120.
""H-NMR(CDCl3)
61.66-1.74 (br.s, IH) 1.76 (s, 3H) 1.80 (s, 3H) 1.96-2.20 (br.m, 3H) 3.20-3.79 (br.m, 5H) 3.85 (s, 3H) 4.90-5.05 (m, 2H) 5.37-5.42 (m, IH) 8.15 (s, IH)
Example 122
2-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-l
K-purin-2-yloxy]benzamide
53.0 g of t-butyl 4-[7-(2-butynyl)-2- (2-carbamoylphenoxy)-l-methyl-6-oxo-6,7-dihyd ro-lK-purin-8-yl]piperazine"l-carboxylate was dissolved in 160 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for one hour. 1250 ml of a 2 M aqueous sodium hydroxide soluti-OH was added drop wise to the reaction solution, and the mixture was stirred at room temperature for one hour and 50 minutes. The resulting white precipitate was collected by filtration. The white solid was washed with water and then with ethanol, and dried at 60 °C overnight to give 42.8 g of the tirle compound.
H-NMR(DMS0-d6)
5 1.78 (t, J=2.4 Hz, 3H) 2.82-2.86 (m, 4H) 3.18-3.22 (m, 4H) 3.36 (s, 3H) 4.91 (q, 2.4 Hz, 2H) 6.58 ("d, J=8.4, 1.2 Hz, IH) 6.63 (dd, J=8.0, 0.8 Hz, IH) 7.14 (ddd, J=8.0, 7.2, 2.0 Hz, IH) 7.80 (dd, J=7.6, .2.0 Hz, IH)
MS mie (ESI) 422 (MH*)
Example 123
7-(2-Butynyl) -2-(3-hydroxypropylsulfanyl)-l-methyl-8-(piperazin-l-yl) -1,7-dihydropurin-6-one trifluoroacetate

7 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro -IH-purin-S-yllpiperaziTie-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and then 20 |il of 3-mercapto-l-propanol and 6 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for five hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and 0.5 ml of 5N aqueous hydrochloric acid was added to the residue. The mixture was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.15 mg of the title compound.
MS mie (ESI) 377 (MH"-CFaCOOH)
Example 124
7-(2-Butynyl)-2-(2-hydroxypropylsulfanyl)-l-methyl-8-(piperazin-
1-yl)-1,7-dihydropurin-6-one trifluoroacetate
1.70 fng of the title compound was obtained by using " l-mercapto-2-propanol, instead of 3-mercapto-l-propanol, by the same method as used in Example 123.
MS mIe (ESI) 377 (MH-CFaCOOH) " "
Example 125
7-(2-Butynyl) -2-(2,3-dihydroxypropylsulfanyl)-l-methyl-8- (pipera
zin-l-yl)-1,7-dihydropurin-6-one trifluoroacetate
2.63 mg of the title compound was obtained by using 3-mercapto-l,2-propanediQl, instead of 3-mercapto-l-propanol, by the same method as used in Example 123.
MS ra/e (ESI) 393 (MH-CFaCOOH)
Example 12 6
3-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-l
H-purin-2-ylsulfanyl]propionic acid trifluoroacetate
7 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-

yl]pipera2ine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and then 20 Jil of 3-mercaptopropionic acid and 6 mg of potassium carbonate were adde thereto. The mixture was stirred at room temperature for five hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The solution was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.60 mg of the title compound. MS mie (ESI) 391 (MH"-CFaCOOH)
Example 127
2-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydro-l
H-purin-2-ylsulfanyl]propionic acid trifluoroacetate
6.10 mg of the title compo"und was obtained by using 2-mercaptopropionic acid, instead "Of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS mIe (ESI) 391 (MH-CFsCOOH)
Example 128
2-s-Butylsulfanyl-7-(2-butynyl)-l-methyl-8-(piperazin-1-yl)-1,7-
dihydropurin-6-one trifluoroacetate
4 . 68 mg of the tirle compound was obtained by using butane-2-thiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 12 6.
MS rale (ESI) 375 (MH-CFsCOOH)
Example 129
7-(2-Butynyl) -l-methyl-8-(piperazin-1-yl)-2-propylsulfanyl-l,7-d
ihydr6purin-6-one trifluoroacetate
4 . 61 mg of the title compound was obtained by using propane-1-thiol, instead of S-mercapropropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 361(MH""-CF3COOH)

Example 130
7- (2-Butynyl)-l-methyl-2-cyclopentylsulfanyl-8-(piperazin-1-yl)-
1,7-dihydropurin-6-one trifluoroacetate
5.15 mg of the title compound was obtained by using cyclopentanethiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 387 (MH-CFsCOOH)
Example 131
7-(2-Butynyl) -2-dodecylsulfanyl-l-methyl-8-(piperazin-1-yl)-1,7-
dihydropurin-6-one trifluoroacetate
4.96 mg of the title compound was obtained by using dodecane-1-thiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126. "MS m/e (ESI) 487 (MH"-CFsCOOH)
Example 132
2- (2-Aminoethylsulf anyl) ■-7 (2-butynyl) -l-methyl-8- (piperazin-1-y
1)-1,7-dihydropurin-6-one trifluoroaceta~e
3.98 mg of the title compound was obtained by using 2-aminoethaneth-i0l, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 362 (MH-CFaCOOH)
Example 133
7-(2-Butynyl) -l-methyl-8-(piperazin-1-yl)-2-(thiophen-2-ylsulfan
yl)-1,7-dihydropurin-6-one trifluoroacetate
5.11 mg of the title compound was ob-ained by using thiophene-2-thiol, instead of 3-mercaptopropionic acid, by the same .method as used in Example 126.
MS m/e (ESI) 401 (MH-CFaCOOH)
Example 134
7-(2-Butynyl) -l-methyl-8-(piperazin-l-yl)-2-(IH-[1,2,4]triazol-3
-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

2.54 mg of the title compound was ob-ained by using 1H-[1,2,4] triazole-3-thiol, instead of 3-.-nercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 386 (MH""-CF3C00H)
Example 135
7-(2-Butynyl) -l-methyl-8-(piperazin-1-yl)-2-(pyridin-4-ylsulfany
1)-1,7-dihydropurin-6-one trifluoroaceta.e
0.77 mg of the title compound was obtained by using pyridine-4-thiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 396 (MH"-CFaCOOH)
Example 13 6
7-(2-Butynyl) -l-methyl-2-phenylsulfanyl-8-(piperazin-l-yl)-1,7-d
ihydropurin-6-one trifluoroacetate
1. 44 mg of the title compound was obtained by using benzene thiol, instead of 3-mercaptopropionic acid, by the same method as used in E."".ample 126. "
MS m/e (ESI) 395 (MH-CFsCOOH)
Example 137
(R)-2-Amino-3-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6 ,7-dihydro-lH-purin-2-ylsulfanyl]propionic acid trifluoroacetate 4.38 mg of the title compound was obtained by using L-cystine, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 406 (MH-CFaCOOH) .
Example 138
7-(2-Butynyl) -2-(2-methylpropylsulfanyl)-l-methyl-8-(piperazin-1
-yl)-1,7-dihydropurin-6-one trifluoroacetate
4.52 mg of the title compound was obtained by using 2-methylpropane-l-thiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 375 (MH-CFjCOOH)

Example 139
7-(2-Butynyl)-2-(1,2-dimethyl
propylsulfanyl) -l-methyl-8-(piperazin-l-yl)-1,7-dihydropurin-6-o
ne trifluoroacetate
3.03 mg of the title compound was obtained by using 3-methylbutane-2-thiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 389 (MH-CFsCOOH)
Example 14 0
7-(2-Butynyl) -l-methyl-8-(piperazin-l-yl)-2-(pyrimidin-2-ylsulfa
nyl)-1,7-dihydropurin-6-one trifluoroacetate
3.60 mg of the title compound was obtained by using pyrimidine-2-thiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 397 (MH-CFsCOOH)
Example 141
7-(2-Butynyl) -2-(lH-imidazol-2-ylsulfanyl)-l-methyl-8-(piperazin
-1-yl)-1,7-dihydropurin-6-one trifluoroacetate
5.75 mg of the title compound was obtained by using lK-imidazole-2-thiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 385 (MH-CFaCOOH)
Example 142
7-(2-Butynyl) -l-methyl-8- (piperazin-l-yl)-2-(thiazol-2-ylsulfany
1)-1,7-dihydropurin-6-one trifluoroacetate
3.86 mg of the title compound was obtained by using thiazole-2-thiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 402 (MII-CFsCOOH)
Example 143
7-(2-Butynyl) -2-(furan-2-ylmethylsulfanyl)-l-methyl-8-(piperazin

-1-yl)-1,7-dihydropurin-6-one trifluoroecetate
4.84 mg of the title compound was ob-ained by using (f-u3?an-2-yl) methanethiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126. MS mfe (ESI) 399 (MH-CFsCOOH)
Example 144
2-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-l
H-purin-2-ylsulfanyl]acetamide trifluoroacetate
1.86 mg of the title compound was obtained by using 2-mercaptoacetamide, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS m/e (ESI) 376 (MH*-CF3C00H)
Example 145
7-(2-Butynyl) -l-methyl-8-(piperazin-1-yl)-2-(thiophen-2-ylmethyl
sulfanyl)-1,7-dihydropurin-6-one trifluoroacetate
3.35 mg of the title compound was ob~ained by using (thiophen-2-yl)methanethiol, instead- of 3-mercaptopropionic acid, by the same method as used in Example 126. MS rale (ESI) 415 (MH-CFaCOOH)
Example 146
7-(2-Butynyl) -l-methyl-8-(piperazin-1-yl)-2-[1-(thiophen-2-yl)et
hylsulfanyl]-1,7-dihydropurin-6-one -rifluoroacetate
0.51 mg of the title compound was obtained by using 1-(thiophen-2-yl) ethanethiol, instead of 3-mercaptopropionic acid, by the same method as used in Example 126.
MS /n/e (ESI) 429 (MH-CFsCOOH)
■Example 147
7-(2-Butynyl)-l-methyl-2-(l-methyl-lK-imidazol-2-ylsulfanyl)-8- ( piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate
5 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and then 10 mg of

l-methyl-lH-imidazole-2-thiol and 8 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for five hours. A saturated a_mmoniura chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The solution was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.75 mg of the title compound. MS m/e (ESI) 399 (MH-CFsCOOH)
Example 14 8
7-(2-Butynyl) -l-methyl-2-(4-methylpyrimidin-2-ylsulfanyl)-8- (pip
erazin-1-yl)-1,7-dihydropurin-6-one trifluoroacetate
4.00 mg of the title compound was obtained by using 4-methylpyrimidine-2-thiol, instead of
l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS m/e (ESI) 411 (MH-CFaCOOH)
Example 149 " *
7-(2-Butynyl) -l-methyl-8-(piperazin-1-yl)-2-(pyrazin-2-ylsulfany 1)-1,7-dihydropurin-6-one trifluoroacetate
4.00 mg of the title compound was obtained by using pyrazine-2-thiol, instead of l-methyl-lH-imida2ole-2-thiol, by the same method as used in Example 147.
MS m/e (ESI) 411 (MH-CFaCOOH)
Example 150
.2-(Benzothiazol-2-ylsulfanyl)-7-(2-butynyl)-l-methyl-8-(piperazi n-l-yl)-1,7-dihydropurin-6-one trifluoroacetate
0.07 mg of the title compound was obtained by using benzothiazole-2-thiol, instead of l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MG m/e (ESI) 452 (MH-CFsCOOH)

Example 151
2-(lH-benzimidazol-2-ylsulfanyl)-7- (2-butynyl)-l-methyl-8-{piper
azin-l-yl) -1, 7-dihydropurin-6-one trifluoroacetate
3.18 mg of the title compound was obtained by using lH-benzimidazole-2-thiol, instead of l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS mie (ESI) 435 (MH-CFsCOOH)
Example 152
2-(5-Amino-[1,3,4]thiadiazol-2-ylsulfanyl)-7-(2-butynyl)-1-methy
1-8-(piperazin-1-yl)-1,7-dihydropurin-6-one trifluoroacetate
3.62 mg of the title compound was obtained by using 5-amino-[1,3,4] thiadiazole-2-thiol, instead of
l-."nethyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS mIe (ESI) 418 (MH-CFaCOOH)
Example 153
6-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-l
H-purin-2-ylsulfanyl]nicotinic acid trifluoroacetate
1.01 mg of the title compound was obtained by using 6-.mercaptonicotinic acid, instead of l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS mIe (ESI) 440 (MH-CFsCOOH)
Example 15 4
7-(2-Butynyl) -2-(4-methoxyphenylsulfanyl)-l-methyl-8-(piperazin-
1-yl)-1,7-dihydropurin-6-one trifluoroacetate
4.14 mg of the title compound was obtained by using 4-methoxybenzenethiol, instead of l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS mIe (ESI) 425 (MH-CFsCOOH)
Example 15 5
7-(2-Butynyl)-l-methyl-2-(4-nitrophenylsulfanyl) -8-(piperazin-1-

yl)-1,7-dihydropurin-6-one trifluoroacetate
1.52 mg of the title compound was obtained by using
4-nitroben2eTiethiol, instead of l-methyl-lH-imidazole-2-thiol, by
the same method as used in Example 147. MS m/e (ESI) 440 (MH-CFaCOOH)
Example 156
N-[2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydr
o-lH-purin-2-ylsulfanyl]ethyl]acetamide trifluoroacetate
2.39 mg of the title compound was obtained by using N-(2-mercaptoethyl)acetamide, instead of
l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS m/e (ESI) 404 (ME"-CFaCOOH)
Example 157
7-(2-Butynyl)-l-methyl-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfany
1)-8-(piperazin-l-yl)-1,7-dihydropurin-6-one trifluoroacetate
1.24 mg of the title compound was obtained-by using 5-methyl-[1,3 ,4] thiadiazole-2.-thiol, instead of
l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS m/e (ESI) 417 (MH-CFaCOOH)
Example 15 8
7-(2-ButyRyl) -2-(4,6-dimethylpyrimidin-2-ylsulfanyl) -l-methyl-8-
(piperazin-l-yl) -1,7-dihydropurin-6-one trifluoroacetate
3.11 mg of the title compound was obtained by using 4,6-dimethylpyrimidine-2-thiol, instead of
L-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS m/e (ESI) 425 (MH-CFsCOOH)
"example 159
"-(2-Butynyl)-l-methyl-2-(4-methylthiazol-2-ylsulfanyl)-8-(piper azin-l-yl)-1,7-dihydropurin-6-one trifluoroacetate

4.01 mg of the title compound was obtained by using 4-methylthiazo.l-2-thiol, instead of l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS m/e.,.(ESI) 416 (MH*-CF3C00H)
Example dj
2- (Benzoxazol-,2-ylsuifanyl) -7- (2-butynyl)-l-methy.1-8- (piperazin-
1-yl) -1, 7--dihydropurin-6-one trifluoroacetate
0.84 mg, of the title compound was obtained by using benzoxazole-2-thiol, instead of l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS m/e (ESI) 436 (MH-CFsCOOH)
Example 161
7-(2-Butynyl)-l-methyl-8-(piperazin-1-yl)-2-([1,3,4]thiadiazol-2
-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate
1.95 mg of the title compound was obtained by using [1, 3,4]thiadiazole-2-thiol, instead of
l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS m/e (ESI) 403 (MH-CFsCOOH)
Example 162
2-Allylsulfanyl-7-(2-butynyl)-l-methyl-8-(piperazin-1-yl)-1,7-di
hydropurin-6-one trifluoroacetate
2 . 85 mg of the title compound was obtained by using allyl mercaptan, instead of l-methyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS m/e (ESI) 359 (MH-CFaCOOH)
ELxample 163
7-(2-Butynyl) -l-methyl-2-(3-methylsulfanylphenylamino)-8-(pipera
zin-l-yl)-1,7-dihydropurin-6-one trifluoroacetate
1.32 mg of the ritle compound was obtained by using 3-methylsulfanylphenylamine, instead of l-mcthyl-lH-imidazole--thiol, by the same method as used in Example

147.
MS mie (ESI) 424 (MH-CFaCOOH)
Example 164
7-(2-Butynyl) -l-methyl-8-(piperazin-1-yl)-2-(thiomorpholin-4-yl)
-1,7-dihydropurin-6-one trifluoroacetate
5 . 33 mg of the title compound was obtained by using thiomorpholine ,
instead of l-methyl-lH-imidazole-2-thiol, by the same method as used
in Example 147.
MS mIe (ESI) 388 (MR"-CFaCOOH)
Example 165
2-[7-(2-Butynyl) -l-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-l
H-purin-2-ylsulfanyl]-2-methylpropionic acid trifluoroacetate
1.63 mg of the title compound was obtained by using 2-mercapto-2-methylpropionic acid, instead of
l-.-nethyl-lH-imidazole-2-thiol, by the same method as used in Example 147.
MS rale (ESI) 405 (MH-CFgCOOH)
Example 166
7-(2-Butynyl)-2-(N-isopropylmethylamino)-l-methyl-8-(piperazin-1
-yl)-1,7-dihydropurin-6-one trifluoroacetate
6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml of
l-methyl-2-pyrrolidone, and then 30 |il of N-isopropylmethylamine was added thereto. After the mixture was stirred at 80°C for 12 hours, the reaction solution was concentrated by flushing with nitrogen gas . The resulting residue was dissolved in 0.60 ml of trifluoroacetic acid. The solution was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trif luoroacetic acid)) to give 1.66 mg of the title compound. MS m/e (ESI) 358 (MH-CFaCOOH)

Example 167
3-[7-(2-Butynyl) -l-methyl-6-oxo-8- (piperazin-1-yl) -6 , 7-dihydro-l
H-purin-2-yloxy] benzoYittrile trifluoroacetate
5 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl] piperazine-1-carboxylate was dissolved in 0 . 2 ml of l-methyl-2-pyrrolidone, and then 5 mg of 3-cyanophenol and 8 mg of sodium hydride were added thereto. The mixture was stirred at 90 °C for three hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.02 mg of the title compound. KS m/e (ESI) 404 (MH-CFaCOOH)
Example 168
4-[7-(2-butynyl) -l-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-l
H-purin-2-yloxy]benzonitrile trifluoroacetate
2 . 76 mg of the title compound was obtained by using 4-cyanophenol,
instead of 3-cyanophenol, by the same method as used in Example 167.
MS m/e (ESI) 404 (MH-CFaCOOH)
Example 169
7-(2-Butynyl) -1-methyl-B- (piperazin-1-yl)-2-(3-tolyloxy)-1,7-dih
yQropurin-6-one trifluoroacetate
3 .14 mg of the title compound was obtained by using 3-methylphenol,
instead of 3-cyanophenol,. by the same method as used in Example 167.
MS m/e (ESI) 393 (MH-CFsCOOH)
Example 170
7-(2-Butynyl)-l-methyl-2- (2-methylsulfanylphenoxy)-8-(piperazin-
1-yl) -1, 7-dihydropurin-6-one trif luoroacetate
3.50 mg of the title compound was obtained by using 2-methylsulf anylplienol, instead of 3-cyanophenol, by the same method as used in Example 167.

MS m/e (ESI) 425 (MH-CFaCOOH)
Example 171
3- [7- (2-Butynyl) -l-n\ethyl-6-oxo-8- (piperazin-1-yl) -6 , 7-dihydro-l
H-purin-2-yloxy]benzoic acid trifluoroacetate
5 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate and 10 mg of ethyl 3-hydroxybenzoate were dissolved in 0.2 ml of N-methylpyrrolidone, and then 8 mg of sodium hydride was added rhereto. The mixture was stirred at 90°C for 3 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in a mixture consisting of 0 .4 ml of ethanoi and 0 .1 ml of a 5N aqueous sodium hydroxide solution. The mixture was stirred at 50°C overnight IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.09 mg of the title compound.
MS m/e (ESI) 423 (MM"-CFsCOOH)
Example 172
4-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-l
H-purin-2-yloxy]benzoic acid trifluoroacetate
1.55 mg of the title compound was obtained by using ethyl 4-hydroxybenzoate, instead of 3-hydroxybenzoic acid, by the same merhod as used in Example 171.
MS m/e (ESI) 423 (MH-CFsCOOH)
Example 17 3
7-(2-Butynyl)-l-methyl-8- (piperazin-1-yl)-2-(2-tolyloxy) -1,7-dih ydropurin-6-one trifluoroacetate 7 mg of t-butyl

4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxc-5,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.2 ml of l-methyl-2-pyrrolidone, and then 5 mg of 2-methylphenol and 8 mg of potassium carbonate were added thereto. The mixture was stirred at 90 "C for five hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.40 mg of the title compound. MS mie (ESI) 393 (MH-CFsCOOH)
Example 174
7-(2-Butynyl)-l-methyl-8- (piperazin-1-yl)-2-(4-tolyloxy)-1,7-dih
ydropurin-6-one trifluoroacetate
3\ 95 mg of the title compound was obtained by using 4-methylphenol, instead of 2-methylphenol, by the same me~hod as used in Example 173.
MS m/e (ESI) 393 (MH-CFsGOOH)
Example 175
7- (2-Butynyl) -2--(2—methoxyphenoxy) -l-me~hyl-8- (piperazin-1-yl) -1
, 7-dihydropurin-6-one trifluoroacetate
5 . 24 mg of the title compound was obtained by using 2-methoxyphenol, instead of 2-methylphenol, by the same method as used in Example 173.
MS m/e (ESI) 409 (MH-CFaCOOH)
Example 17 6
7-(2-Butynyl)-2-(3-methoxyphenoxy)-l-me-hyl-8-(piperazin-1-yl)-1 ,7-dihydropurin-6-one trifluoroacetate ■ - 2 . 84 mg of the title compound was obtained by using 3-methoxyphenol, instead of 2-methylphenol, by the same method as used in Example 173. MS mie (ESI) 409 (MH-CFaCOOH)
Example 17 7
7-(2-Butynyl) -2-(4-methoxyphenoxy)-l-merhyl-B-(piperazin-1-yl)-1

,7-dihydropurin-6-one trifluoroacetate
5 . 61 mg of the title compound was obtained by using 4-methoxyphenol, instead of 2-methylphenol, by the s*ame method as used in Example 173.
MS mie (ESI) 409 (MH-CFaCOOH)
Example 17 8
4-[7-(2-Butynyl) -l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydro-l
H-purin-2-yloxy]benzenesulfonamide trifluoroacetate
4.21 mg of the title compound was obtained by using 4-hydroxybenzenesulfonamide, instead of 2-methylphenol, by the same method as used in Example 173.
MS m/e (ESI) 458 (MH-CFaCOOH)
Example 179
4-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-l H-purin-2-yloxy]-3-methoxyben2onitrile trifluoroacetate " 4.24 mg of the title compound was obtained by using 4-hydroxy-3-methoxybenzonitrile, instead of 2-methylphenol, by the same method as used" in Example 173. MS mIe (ESI) 434 (MH"-CFBCOOH)
Example 180
2-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-l
H-purin-2-yloxy]benzonitrile trifluoroacetate
5 .26 mg of the title compound was obtained by using 2-cyanophenol, instead of 2-methylphenol, by the same method as used in Example 173.
MS xnle (ESI) 404 (MH-CFsCOOH)
Example 181
4-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-l
H-purin-2-yloxy]benzamide trifluoroacetate
4.80 mg of the title compound was obtained by using 4-hydroxybenzamide, instead of 2-methylphenol, by the same method as used in Example 173.
MS m/e (ESI) 422 (MH-CFsCOOH)

Example 182
Ethyl
2-[7-(2-butynyl) -l-methyl-6-oxo-8- (piperazin-l-yl)-6 , 7-dihydro-l
H-purin-2-yloxy]benzoate trifluoroacetate
4.38 mg of the title compound was obtained by using ethyl 2-hydroxybenzoate, instead of 2-methylphenol, by the same method as used in Example 173.
MS mie (ESI) 451 (MH-CFsCOOH)
Example 183
7- (2-Butynyl) -l-methyl-8- (piperazin-l-yl) -2- (pyrimidin-2-yloxy) -
1,7-dihydropurin-6-one trifluoroacetate
1.12 mg of the title compound was obtained by using pyrimidin-2-ol, instead of 2-methylphenol, by the same method as used in Example 173.
MS /n/e (ESI) 381 (MH-CFsCOOH)
Example 184
7- (2-Butynyl) -2- (4 , 6-dimethylpyrimidin-2-yloxy) -l-methyl-8- (pipe -razin-1-yl)-1, 7-dihydropurin-6-one trifluoroacetate
0.66 mg of the title compound was obtained by using 4,6-dimethylpyrimidin-2-ol, instead of 2-methylphenol, by the same merhod as used in Example 173.
MS mIe (ESI) 409 (MH"-CFsCOOH)
Example 185
3-[7-(2-Butynyl) -l-methyl-6-oxo-8- (piperazin-l-yl) -6 , 7-dihydro-l
H-purin-2-yloxy]benzamide trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate and 10 mg of ethyl 3-hydroxybenzoate were dissolved in 0.2 ml of N-methylpyrrolidone, and then 10 mg of potassium carbonate was added thereto. The mixture was stirred at 90 °C for 3 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in 1.0 ml of ammonia (7N methanol solution) . The mixture was stirred at 50"C overnight. The reaction solution was

concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.91 mg of the title compound. MS m/e (ESI) 422 (MH-CFaCOOH)
Example 186
4- [7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-l-yl) -6,7-dihydro-l
H-purin-2-yloxy]-3,5-dimethylbenzoic acid trifluoroacetate
7 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo -6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.2 ml of l-methyl-2-pyrrolidone, and then 8 mg of 4-hydroxy-3 ,5-dimethylbenzoic acid and 8 .mg of potassium carbonate were added thereto. The mixture was stirred at 100°C for 2 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonirrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.71 mg of -the title compound.
MS m/e (ESI) 451 (MH-CFaCOOH)
Example 187 .
4-[7-(2-Butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl) -6,7-dihydro-l
H-purin-2-yloxy]-3-fluorobenzoic acid trifluoroacetate
3.49 mg of the title compound was obtained by using 3-fluoro-4-hydroxybenzoic acid, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in Example 186.
MS m/e (ESI) 441 (MH-CFsCOOH)
Example 188
[4-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-l-yl)-6,7-dihydro-
lH-purin-2-yloxy]phenyl]acetic acid trifluoroacetate

3.45 mg of the title compound was obtained by using (4-hydroxyphenyl)acetic acid, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in Example 186.
MS m/e (ESI) 437 (MH-CFsCOOH)
Example 189
[2-[7-(2-Butynyl) -l-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-
lH-purin-2-yloxy]phenyl]acetic acid trifluoroacetate
1.34 mg of the title compound was obtained by using (2-hydroxyphenyl)acetic acid, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in Example 186.
MS m/e (ESI) 437 (MH-CFsCOOH)
Example 190
2-(2-Acetylphenoxy)-7-(2-butynyl)-l-methyl-8-(piperazin-1-yl)-1,
7-dihydropurin-6"one trifluoroacetate
1.99 mg of the title compound was obtained by using 1-(2-hydroxyphenyl)ethanone, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in Example 18 6.
MS m/e (ESI) 421 (MH-CFaCOOH)
Example 191
7-(2-Butynyl)-2-(2,6-difluorophenoxy)-l-methyl-8-(piperazin-1-yl
)-1,7-dihydropurin-6-one trifluoroacetate
5.2 6 mg of the title compound was obtained by using 2,6-difluorophenol, instead of 4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in Example 186.
MS m/e (ESI) 415 (MH"-CFsCOOH)
Example 192
7-(2-Butynyl)-l-methyl-2-pentafluorophenoxy-8-(piperazin-1-yl)-1
,7-dihydropurin-6-one trifluoroacetate
5.61 mg of the title compound was obtained by using

2 , 3 , 4 , 5,6-pentafluorophenol, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in
Example 186.
MS ;n/e (ESI) 469 (MH-CFsCOOH)
Example 193
7-(2-Butynyl)-l-methyl-8- (piperazin-1-yl)-2-[4-(pyrrolidine-1-ca
rbonyl)phenoxy]-1,7-dihydropurin-6-one trifluoroacetate
30 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl -6-OXO-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 1 ml of l-methyl-2-pyrrolidone, and then 15 mg of 1- (4-hydroxybenzoyl) pyrrolidine and 11 mg of potassium carbonate were added thereto. The mixture was stirred at 100°C for 2 . 5 hours . Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 23.7 mg of the title compound.
MS m/e (ESI) 476 (MH-CFaCOOH)
Example 194
2-[7-(2-Butynyl) -l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-l
H-purin-2-yloxy]-N-[2-(piperidin-1-yl)ethyl]benzamide
trifluoroacetate
3.05 mg of the title compound was obtained by using 2-hydroxy-N-[2-(piperidin-1-yl)ethyl]benzamide by the same method a.s used in Example 193.
MS m/e (ESI) 533 (MH-CFaCOOH)
Example 195
5-Acetyl-2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-
dihydro-lH-purin-2-yloxy]benzamide rrifluoroacetate
0.82 mg of the title compound was obtained by using 5-acetyl salicylamide, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by the

sa.T.e method as used in Example 193. MS mie (ESI) 464 (MH-CFsCOOH)
Example 196
2-[7-(2-Butynyl) -l-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-l
H-purin-2-ylsulfanyl]benzoic acid trifluoroacetate
0.70 mg of the title compound was obtained by using thiosalicylic acid, instead of 1-(4-hydroxybenzoyl) pyrrolidine, by the same method as used in Example 193.
MS mIe (ESI) 439 (MH-CFsCOOH)
Example 197
6-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-l
H-purin-2-ylamino]nicotinamide trifluoroacetate
1.43 mg of the title compound was obtained by using
6-amino-nicotinamide, instead of 1-(4-hydroxybenzoyl)pyrrolidine ,
by the same method as used in Example 193.
MS m/e (ESI) 422 (MH-CFaCOOH)
Example 198
3-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-l
H-purin-2-yloxy]pyridine-2-carboxylic mide trifluoroacetate
1.44 mg of the title compound was obtained by using 3-hydroxy
picolinamide, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by the
same method as used in Example 193.
MS m/e (ESI) 423 (MH"-CFsCOOH)
Example 199
N-t-butyl-2-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6,7
-dihydro-lH-purin-2-ylamino]benzamide trifluoroacetate
0.87 mg of the title compound was obtained by using 2-amino-N-t-butylbenzamide, instead of
1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in Example 193.
MS m/e (ESI) 477 (MH-CFgCOOH)

Examples 200 and 201
2-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-l-yl)-6,7-dihydro-l
H-purin-2-ylamino]benzamide trifluoroace~ate - *
1.36 mg of the polar compound of the title compound and 0.39 mg of the non-polar compound of the title compound were obtained by using 2-aminobenzamide, instead of 1-(4-hydroxybenzoyl) pyrrolidine, by the same method as used in Example 193.
MS m/e (ESI) 477 (MH-CFaCOOH)
Example 202
N-[3-[7-(2-butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydr
o-lH-purin-2-yloxy]phenyl]acetamide trifluoroacetate
10.79 mg of the title compound was ofc-ained by using 3-acetamidophenol, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in Example 193.
MS ra/e (ESI) 436 (MH-CFsCOOH)
Example 203
N-[4-[7-(2-butynyl)-l-methyl-6-oxo-8-(pjperazin-l-yl) -6,7-dihydr
o-lH-purin-2-yloxy]phenyl]acetamide trifluoroacetate
11.38 mg of the title compound was ob-ained by using 4-acetamidophenol, instead of 1-(4-hydroxybenzoyl) pyrrolidine, by the same method as used in Example 193.
MS ni/e (ESI) 436(MH-CF3COOH)
Example 204
2-[N-[7-(2-butynyl)-l-methyl-6-oxo-8- (piperazin-l-yl) -6,7-dihydr
o-lH-purin-2-yl]methylamino]benzoic acid trifluoroacetate
3.48 mg of the title compound was obtained by using N-methylanthranilic acid, instead of
.1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in Example 193.
MS m/e (ESI) 436 (MH-CFsCOOH)
Example 205
2-[7-(2-butynyl) -l-methyl-6-oxo-8- (piperazin-l-yl) -6,7-dihydro-l

H-purin-2-yloxy]benzoic acid trifluoroacetate
25.75 mg of the title compound was obtained by using salicylic acid, instead of 1-(4-hydroxybenzoyl) pyrrolidine, by the same method as used in Example 193.
MS m/e (ESI) 423 (MH"-CFaCOOH)
Example 20 6
2-[7-(2-butynyl)-1-methyl-6-oxo-8- (piperazin-1-yl) -6, 7-dihydro-l
H-purin-2-ylamino]benzenesulfonamide trifluoroacetate
0.91 mg of the title compound was obtained by using 2-aminobenzenesulfonamide, instead of
1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in Example 193.
MS m/e (ESI) 457 (MH-CFaCOOH)
Example 2 07
2-[7-(2-Butynyl)-l-methyl-6-oxo-8- (piperazin-l-yl) -6,7-dihydro-l
H-purin-2-yl sulfanyl]benzoic acid ethyl ester trifluoroacetate
0.66 mg of the title compound was obtained by using ethyl thiosalicylate, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in Example 193.
MS m/e. (ESI) 467 (MH-CFsCOOH)
Examole 208
3-[7-(2-Butynyl) -l-methyl-6-oxo-8- (piperazin-l-yl) -6,7-dihydro-l
H-purin-2-yloxy]pyridine-2-carboxylic acid trifluoroacetate
4.36 mg of the title compound was obtained by using 3-hydroxypicolinic acid, instead of 1-(4-hydroxybenzoyl) pyrrolidine , by the same method as used in Example 193.
MS m/e (ESI) 424 (MH-CFsCOOH)
Example 209
TS!-[2- [7- (2-butynyl) -l-methyl-6-oxo-8- (piperazin-l-yl) -6 , 7-dihydr
o-lH-purin-2-yloxy]phenyl]acetamide trifluoroacetate
0.126 mg of the title compound was obtained by using 2-acetamidophenol, instead of 1-(4-hydroxybenzoyl)pyrrolidine , by

the same method as used in Example 193. MS m/e (ESI) 436 (MH-CFsCOOH)
Example 210
2-[7-(2-butynyl)-l-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-l
H-purin-2-yloxy]-N,N-dimethylbenzamide trifluoroacetate
100 mg of salicylic acid and 0.76 ml of a 2 M tetrahydrofuran solution of dimethylamine were dissolved in 1 ml of N,N-dimethylformamide, and then 109 |il of diethyl cyanophosphonate and 250 |J.l of triethylamine were added thereto. The mixture was stirred at room temperature for 5.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and 20 mg of 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-
dihydro-lH-purin-8-yl]piperazine-l-carboxylic acid t-butyl ester, potassium carbonate and 1 ml of l-methyl-2-pyrrolidone were added to a one-third aliquot of the residue. The mixture was stirred at 150°C for 1.5 hours. Water was added to -he reaction solution, and the mixture was extracted with ethyl acetaiie. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.06 mg of the title compound.
MS m/e (ESI) 450 (MH-CFsCOOH)
Example 211
7-(2-Butynyl)-l-methyl-8-(piperazin-1-yl)-2-[2-(thiazolidine-3-c
arbonyl)phenoxy]-1,7-dihydropurin-6-one trifluoroacetate
2.10 mg of the title compound was obtained by using thiazolidine, instead of dimethylamine, by the same method as used in Example 210.
MS m/e (ESI) 494 (MH-CFaCOOH)
Eample 212
7-(2-Butynyl)-l-methyl-8-(piperazin-l-yl)-2-[2-(pyrrolidine-l-ca
rbonyl)phenoxy]-1,7-dihydropurin-6-one trifluoroacetate

6.86 mg of the title compound was obtained by using pyrrolidine, instead of dimethylamine, by the same method as used in Example 210. MS m/e (ESI) 47 6 (MH-CFaCOOH)
Example 213
7-(2-Butynyl)-l-methyl-2-[2- (morpholine-4-carbonyl)phenoxy]-8- (p
iperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate
3.63 mg of the title compound was obtained by using morpholine, instead of dimethylamine, by the same method as used in Example 210.
MS mIe (ESI) 492 (MH-CFsCOOH)
Example 214
[7-(2-butynyl) -l-methyl-6-oxo-8- (piperazin-1-yl)-6,7-dihydro-lH-purin-2-yl]acetonitrile trifluoroacetate
Example 215
[7-(2-butynyl)-2-cyanomethyl-l-methyl-6-oxo-8-(piperazin-l-yl)-2
,3,6,7-tetrahydro-lH-purin-2-yl]acetonitrile trifluoroacetate
8 mg of 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylic acid t-butyl ester was dissolved in 0 . 8 ml of acetonitrile, and then 8 mg of sodium hydride was added thereto. The mixture was stirred at 60°C for three hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic" acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.85 mg and 2.20 mg of rhe title compounds (Examples 214 and 215), respectively.
(Example 214) MS mlB (ESI) 326(MK-CFaCOOH)
(Example 215) MS mle (ESI) 367 (MK-CFsCOOH)
Example 216
7-(2-butynyl)-l-methyl-2-(2-oxopropyl)-8-(piperazin-l-yl) -1,7-di
hydropurin-6-one trifluoroacetate

8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.8 ml of acetone, and then 8 mg of sodium hydride was added thereto. The mixture was stirred at 60 ° C for three hours . IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.17 mg of the title compound.
MS m/e (ESI) 343 (MH-CFaCOOH)
Example 217
7-(2-Butynyl)-2-ethynyl-l-methyl-8-(piperazin-1-yl) -1,7-dihydrop
urin-6-ohe trifluoroacetate
50 |il of trimethylsilylacetylene was dissolved in 1.0 ml of tetrahydrofuran, and then 0.27 ml of n-butyl lithium (1.56 M hexane solution) was added thereto at -78 °C. The mixture was stirred at 0°C for 15 minutes, and then 1.0 ml of a tetrahydrofuran solution of 10 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl -6-OXO-6,7-dihydro-lE-purin-8-yl]piperazine-1-carboxylate was added to the reaction solution. After the mixture had been stirred at room temperature for 30 minutes, a saturated ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in 1. 0 ml of methanol. 10 mg of potassium carbonate was added to the solution. After the mixture had been stirred at room temperature for 1 hour, a saturated ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.06 mg of the title compound.

MS m/e (ESI) 311 (MH-CFsCOOH)
Example 218
7- (2-Butynyl) -l-methyl-8- (piperazin-1-yl) -2- ("propane-2-sulf inyl)
-1, 7-dihydropurin-6-one trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and then 20 \il of 2-propanethiol and 6 mg of potassium carbonate were added -hereto. The mixture was stirred at room temperature for five hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in 0.30 ml of dichloromethane. The mixrure was cooled to -78 °C . 5 mg of m-chlorcperbenzoic acid was added to -he mixture, and the resulting mixture was stirred at -78°C for 15 minutes. A saturated sodium sulfite solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated, and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The solution was-concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chro.matography (using an acezonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.89 mg of the title compound.
MS m/e (ESI) 377 (MH-CFBCOOH)
Example 219
N-acetyl-N-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl)-6 ,7-
dihydro-lH-purin-2-yl]acetamide trifluoroacetate
8 mg of t-butyl 4-[7-(2-butynyl)-2-chioro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of a 20% aqueous ammonia, and the mixture was stirred at 80 °C for 5 hours. The reaction solution was concentrated, and the residue was dissolved in 0. 4 ml of pyridine. 0 . 05 ml of acetic anhydride was added to the mixture . The resulting mixture was stirred at room temperature for 48 hours . The reaction solution was concentrated, and the residue was dissolved in trif luoroacetic acid. The solution was concentrated.

and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-warer mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.49 mg of the title compound. MS m/e (ESI) 386 (MH"-CFaCOOH)
Example 220
N- [7- (2-butynyl) -l-methyl-6-oxo-8- (piperazin-l-yl) -6 , 7-dihydro-l
H-purin-2-yl]acetamide trifluoroacetate
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0 . 2 ml of 20% aqueous ammonia, and the mixture was stirred at QO"C for 5 hours . The reaction solution was concentrated, and the residue was dissolved in 0 . 4 ml of pyridine. 0 . 05 ml of acetic anhydride was added to 1He solution. The mixture was stirred at room temperature for 48 hours. The reaction solution was concen-rated, and the residue was dissolved,.in methanol. 10 mg of potassium carbonate was added to the solution. The mixture was stirred ar room temperature for 6 hours. The reaction solution was concentrated, and the residue was dissolved in zrifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.36 mg of the title compound.
MS m/e (ESI) 344 (MH-CFaCOOH)
Example 221
[7- (2-Butynyl)-l-methyl-6-oxo-8- (piperazin-l-yl) -6,7-dihydro-lH-purin-2-yloxy]acetonitrile trifluoroace-a-e
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-di-hydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in
0.15 ml of l-methyl-2-pyrrolidone, and then 50 fil of hydroxy acetonitrile and 5 mg of sodium hydride were added thereto. The mixture was stirred at room temperature for one hour. IN hydrochloric acid was added to the reaction solution, and rhe mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high

performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.12 mg of the title compound.
MS m/e (ESI) *342 (MH-CFsCOOH)
Example 222
N-[7-(2-butynyl)-l-methyl-6-oxo-8-(piperazin-1-yl) -6,7-dihydro-l
H-purin-2-yl]guanidine trifluoroacetate
7 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and then 10 mg of guanidine was added thereto. The mixture was stirred at 90°C for 12 hours. The reaction solution was concentrated, and the residue was dissolved in 1.0 ml of trifluoroacetic acid. The solution was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonirrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.20 mg of the title compound.
MS m/e (ESI) 344 (MH-CFsCOOH)
Example 223
7-(2-Butynyl)-2-methylsulfanyl-8-(piperazin-l-yl) -1,7-dihydropur
in-6-one trifluoroacetate
(a) t-Butyl
4- [7- (2-butynyl) -2-chloro-6-oxo-l-- (2-trimethylsilanylethoxymethy
1)-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate
50 mg of r-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 1. 2
ml of N,N-dimethylformamide, and then 44 il of (2-chloromethoxyethyl)trimethylsilane and 34 mg of potassium .carbonate were added thereto. The mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel chromatography to give 5 5 mg of the title compound.

-H-NMR(CDC13)
5 0.07 (s, 9H) 0.97 (t, J=8.4Hz, 2H) 1.49 (s, 9H) 1.82 (t, J=2.4
Hz, 3H) 3.40-3.44 (m, 4H) 3.58-3.62 (m, 4H) 3.71 (t, J=8.4 Hz, 2H)
4.92 (q, J= 2.4 Hz, 2H) 5.67 (s, 2H)
(b) 7-(2-Butynyl)-2-methylsulfanyl-8-(piperazin-l-yl) -1, 7-dihydro purin-6-one trifluoroacetate
6 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-l-(2-trimethyl
silanylethoxymethyl) -6 , 7-dihydro-lH-purin-8-yl] piperazine-1-carb
oxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and then
50 pil of methyl mercaptan (30%; methanol solution) and 10 mg of
potassium carbonate were added thereto. The mixture was stirred at
room temperature for five hours. A saturated aqueous ammonium
chloride solution was added to the reaction solution, and the mixture
was extracted with ethyl acetate. The organic layer was concentrated,
and -he residue was dissolved in 0.60 ml of trifluoroacetic acid.
The resulting mixture was stirred at room temperature for 5 hours.
Then, the solution was concentrated by flushing with nitrogen gas.
The residue was purified by reverse-phase high performance liquid
chro.matography (using an acetonitrile-water .mobile phase (containing
0.1% trif luoroacetic acid)) to give 3.99 mg of the title compound.
MS m/e (ESI) 319 (MH-CFsCOOH)
Example 224
7- (2-Butynyl) -2-isopropylsulfanyl-8- (piperazin-l-yl) -1, 7-dihydro
purin-6-one trifluoroacetate
2 . 97 mg of the title compound was obtained by using propane-2-thiol sodium salt, instead of methyl mercaptan, according to the method described in Example 223.
MS m/e (ESI) 347 (MH-CFaCOOH)
Example 225
2-t-Butylsulfanyl-7-(2-butynyl)-8-(piperazin-l-yl) -1, 7-dihydropu rin-6-one trifluoroacetate
2.99 mg of the title compound was obtained by using 2-methyl-2-propanethiol sodium salt, instead of methyl mercaptan, according to the method described in Example 223.

MS m/e (ESI) 361 (MH-CFBCOOH)
Example 226
7-(2-Butynyl)-6-OXO-8-(piperazin-1-yl)-6,7-dihydro-lH-purine-2-c
arbonitrile trifluoroacetate
6 mg Of t-butyl 4-[7-{2-butynyl)-2-chloro-6-oxo-l-(2-trimethyl silanylethoxymethyl)-6,7-dihydro-lH-purin-8-yl]piperazine-1-carb oxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and then 8 mg of sodium cyanide and 10 mg of potassium carbonate were added thereto. The mixture was stirred at 50 °C for five hours . A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in 0.60 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 5 hours. Then, the solution was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.46 mg of the title compound.
MS m/e (ESI) 298 (MH-CFsCOOH)
Example 227
2-[7-(2-Butynyl)-6-oxo-B-(piperazin-1-yl)-6,7-dihydro-lH-purin-2
-yloxyjbenzamide trifluoroacetate
6. mg of t-butyl 4-[7- (2-butynyl)-2-chloro-6-oxo-l- (2-trimethylsilanylethoxymethy 1)-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.15 ml of l-methyl-2-pyrrolidone, and then 8 mg of salicylamide and 8 mg of potassium carbonate were added thereto. The mixture was stirred at 100°C for three hours. A saturated ammonium .ch.loride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in 0.80 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 5 hours . The solution was concentrated by flushing with nitrogen gas. The residue was purified by reverse-phase high performance liquid chromatography

(using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.45 mg of the title compound. MS m/e (ESI) 408 (MH-CFaCOOH)
Example 228
4-[7-(2-Butynyl) -6-oxo-8-(piperazin-1-yl)-6,7-dihydro-lH-purin-2
-yloxy]benzoic acid trifluoroacetate
1.55 mg of the title compound was obtained by using 4-hydroxybenzoic acid, instead of salicylamide, according to the me-hod described in Example 227.
MS m/e (ESI) 409 (MH-CFaCOOH)
Exa.-nple 229
7-(2-Butynyl) -1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dih ydro-lH-purine-2-carbonitrile hydrochloride (a) t-Butyl
4-[7-(2-butynyl) -2-cyano-l- (2-cyanobenzyl)-6-oxo-6 , 7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate
.2 mixture- consisting of 8 mg of t-bu.yl 4-[7-(2-butynyl) -2-chloro-l- (2-cyanobenzyl)-6-oxo-6,7-dihydro-lH -purin-8-yl]piperazine-1-carboxylate obtained in Example 96(a) , 10 mg of sodium cyanide and 0.3 ml of N, N-dimethylf ormamide was stirred at room temperature for 4 hours . The reaction mixture was extracted wi-h ethyl acetate-water, and the organic layer was washed with water and then with saturated brine. The organic layer was concentrated. The residue was purified by thin layer chromatography (50% ethyl acetate/hexane) to give 6.1 mg of the ti-le compound.
-H-NMR(CDCl3)
5 1.50 (s, 9H) 1.83 (s, 3H) 3.50 (s, 4H) 3.58-3.64 (m, 4H) 4.99 (s, 2H) 5.74 (s, 2H) 7.02 (d, J=8 Hz, IH) 7.44 (t, J=8 Hz, IH) 7.55 . (t, J=8 Hz, IH) 7.74 (d, J=8 Hz, IH) (b)
7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dih ydro-lH-purine-2-carbonitrile hydrochloride
A mixture consisting of 6.1 mg of t-butyl 4-[7-(2-butynyl) -2-cyano-l- (2-cyanobenzyl)~6-oxo-6,7-dihydro-lH-

purin-8-yl]piperazine-l-carboxylate and 0.2 ml of trifluoroacetic acid was stirred at room temperature for 20 minutes. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography using a 20% to 60% methanol/water (0.1% concentrated hydrochloric acid) solvent to give 5.0 mg of the title compound.
1H-NMR(DMS0-d6)
5 1.80 (s, 3H) 3.30 (s, 4H) 3.60-3.70 (m, 4H)- 5.09 (s, 2H) 5.60 (s, 2H) 7.27 (d, J=8 Hz, IH) 7.54 (t, J=8 Hz, IH) 7.68 (t, J=8 Hz, IH) 7.94 (d, J=8 Hz, IH) 9.36 (br.s, 2H)
Example 23 0
3-[7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-l-yl)-6,7-
dihydro-lH-purin-2-yloxy]pyridine-2-carboxylic amide
trifluoroacetate
7 mg of t-butyl 4- [7- (2-butynyl) -2-chloro-l- (2-cyanobenzyl) -6-oxo-6 , 7 ... -dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of l-methyl-2-pyrrolidone, and then 8 mg of 3-hydroxypyridine-2-carboxylic amide and 8 mg of potassium carbonate were added thereto. The mixture was stirred at 100°C for 2 hours. IN hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The orga.-.ic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.93 mg of the title compound.
MS m/e (ESI) 524 (MH-CFsCOOH)
■Example 231
4-[7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-lH-purin-2-yloxy]benzenesulfonamide trifluoroacetate
1.90 mg of the title compound was obtained by using 4-hydroxybenzenesulfonamide, instead of 3-hydroxypyridine-2-carboxylic amide, according to the method

described in Example 230.
MS m/e (ESI) 559(MH-CFsCOOH)
Example 232
2-[7-(2-Butynyl) -1-(2-cyanoben2yl) -6-oxo-8-(piperazin-1-yl)-6,7-
dihydro-lH-purin-2-yloxy]benzonitrile trifluoroacetate
2 .15 mg of the title compound was obtained by using 2-cyanophenol, insxead of 3-hydroxypyridine-2-carboxylic amide, according to the method described in Example 230.
MS m/e (ESI) 505 (MH-CFsCOOH)
Example 233
4-[7-(2-Butynyl) -1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-
dihydro-lK-purin-2-yloxy]benzoic acid trifluoroacetate
3.74 mg of the title compound was obtained by using 4-hydroxybenzoic acid, instead of 3-hydroxypyridine-2-carboxylic amide, according to the method described in Example 230.
MS m/e (ESI) 524 (MH-CFsCOOH)
Example 234
2-[7-(2-Butynyl) -1-(2-cyanobenzyl)-6-OXG-8-(piperazin-1-yl)-6,7-
dihydro-lK-purin-2-yloxy]benzamide trifluoroacetate
3.74 .mg of the title compound was obtained by using salicylamide, instead of 3-hydroxypyridine-2-carboxylic amide, according to the mexhod described in Example 230.
MS m/e (ESI) 523 (MH-CFaCOOH)
Example 23 5
2-[7-(2-Butynyl) -1-(4-cyanobenzyl)-6-oxo-S-(piperazin-1-yl)-6,7-dihydro-lK-purin-2-yloxy]benzamide trifluoroacetate ■ (.a) t-Buxyl
4-[7-(2-Butynyl)-2-chloro-l- (4-cyanoben2yl)-6-oxo-6,7-dihydro-lH -purin-8-yl]piperazine-l-carboxylate
100 mg of t-butyl 4-[7-(2-butynyl) -2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 1.2 ml of

N,N-dimethylformamide, and then 97 mg of 4-cyanobenzyl bromide and 68 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for 4 hours . A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel chromatography to give 71 mg of the title compound.
1H-NMR(CDC13)
5 1.49 (s, 9H) 1.84 (t, J=2.5Hz, 3H) 3.43-3.47 (m, 4H) 3.59-3.63 (m, 4H) 4.94 (q, 2.5 Hz, 2H) 5.53 (s, 2H) 7.42 (d, J=8.0 Hz, 2H) 7.62 (d, J=8.0 Hz, 2H) (b)
2-[7-(2-Butynyl)-1-(4-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-lH-purin-2-yloxy]benzamide trifluoroacetate
12 mg of t-butyl 4-[7-(2-butynyl) -2-chloro-l-(4-cyanobenzyl)-6-oxo-6,7 -dihydro-lH-purin-8-yl]pip.erazine-l-carboxylate was dissolved in 0 . 3 ml of l-methyl-2-pyrrolidone, and then 10 mg of salicylamide and 10 mg of potassium carbonate were added the-reto. The mixture was stirred at 100 °C for 12 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and rhe residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trif luoroacetic acid)) to give 6.69 mg of the title compound.
MS ;7!/e (ESI) 523 (MH-CFaCOOH)
Example 236
7-(2-Butynyl)-1-(4-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dih
ydro-lH-purine-2-carbonitrile trifluoroacetate
12 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l- (4-cyanobenzyl)-6-oxo
-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.3 ml of l-methyl-2-pyrrolidone, and then 10 mg of sodium cyanide rfas added thereto. The mixture was stirred at 50°C for 2 hours. IN

hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.87 mg of the title compound.
MS m/e (ESI) 413 (MH"-CFaCOOH)
Example 237
4-[7-(2-Butynyl) -2-methylsulfanyl-6-oxo-8-(piperazin-1-yl)-6,7-d
ihydropurin-l-ylmethyl]benzonitrile trifluoroacetate
12 mg of t-butyl 4-[7-(2-butynyl) -2-chloro-l-(4-cyanobenzyl) -6-oxo
-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate was dissolved in 0 . 3 ml of l-methyl-2-pyrrolidone , and then 20 M-l of methyl mercaptan (.30%; methanol solution) and 10 mg of potassium carbonate were added thereto. The mixture was stirred at 50 °C for 2 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 6.69 -mg of the title compound.
MS /n/e (ESI) 434 (MR"-CFsCOOH)
Example 238
2-[7-(2-Butynyl) -1-(3-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-lH-purin-2-yloxy]benzamide trifluoroacetate - (3) t-Butyl
4-[7-(2-butynyl) -2-chloro-l- (3-cyanobenzyl)-6-oxo-6,7-dihydro-lH -purin-8-yl]piperazine-l-carboxylate
100 mg of t-butyl 4-[7-(2-butynyl) -2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 1.2 ml of

N,N-dimethylformamide, and then 97 mg of 3-cyanobenzyl bromide and 58 ing of potassium carbonate were added thereto. The mixture was stirred at room temperature for 12 hours. Then, a saturated ammonium chloride"solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel chromatography to give 71 mg of the title compound.
-H-NMR(CDC13)
5 1.49 (s, 9H) 1.84 (t, J=2.5Hz, 3H) 3.43-3.47 (m, 4H) 3.59-3.63 (m, 4H) 4.94 (q, 2.5 Hz, 2H) 5.53 (s, 2H) 7.42 (d, J=8 .0 Hz, 2H) 7.62 (d, J=8.0 Hz, 2H) (b)
2-[7-(2-Butynyl)-1-(3-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-lH-purin-2-yloxy]benzamide trifluoroacetate
12 mg of t-butyl 4- [7- (2-butynyl) -2-chloro-l- (3-cyanobeTizyl) -6-oxo-6 , 7-dihydro-lH-purin-B-yl] piperazinel-carboxylate was dissolved in 0.3 ml of l-methyl-2-pyrrolidone, and then 10 mg of salicylamide and 10 mg of potassium carbonate were added thereto. The mixture was stirred at 100°C for five hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and thg residue was dissolved in trifluoroacetic acid. The solution was concentrated, and rhe residue was purified by reverse-phase high performance liquid chromatography (using an a-cetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 8.76 mg of the title compound.
FiS m/e (ESI) 523 (MH-CFsCOOH)
Example 239
7-(2-Butynyl)-1-(3-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dih .ydro-lH-purine-2-carbonitrile trifluoroacetate
12 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-l- (3-cyanobenzyl)-6-oxo-6,7 -dihydro-lH-purin-8-yl]piperazine-l-carboxylate was dissolved in 0.3 ml of l-methyl-2-pyrrolidone, and then 10 mg of sodium cyanide was added thereto. The mixture was stirred at 50"C for 1 hour. IN

hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution, was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.96 mg of the title compound.
MS m/e (ESI) 413 (MH"-CFaCOOH)
Example 24 0
1-(2-Butynyl) -2-(piperazin-1-yl)-7 , 8-dihydro-lH,6H-5-oxa-l,3,4,8
a-tetraazacyclopenta[b]naphthalen-9-one hydrochloride
(a) t-Butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-l- [3- (tetrahydropyran-2-yloxy)pr opyl]-6,7-dihydro-lH-purin-8-yl]pipera2ine-l-carboxylate
- A mixture consisting of 20 mg of t-buyl 4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]piperazine-1-carboxylate obtained in Example 95 (a) , 20 fil of 2- (3-bromopropoxy) tetrahydropyran, 20 mg of anhydrous potassium carbonate and 0.2 ml of -N,N-dimethylformamide was stirred at roo.m temperature overnight. The reaction solution was extracted with ezhyl acetate-water, and the organic layer was washed with water and -hen with saturated brine. The organic layer was then concentrated, and the residue was purified by thin layer chromatography (70% ethyl acerate /hexane) to give 8 mg of the title compound.
1H-NMR(CDCl3)
6 1.49 (s, 9H) 1.50-1.81 (m, 6H) 1.83(t, J=2 Hz, 3H) 2.06 (quint, J=7 Hz, 2H) 3.38-3.62 (m, lOH) 3.80-3.90 (m, 2H) 4.34-4.47 (m, 2H) 4.59 (t, J=3 Hz, IH) 4.92 (q, J=2 Hz, 2H)
(b) t-Butyl
.4-[1-(2-butynyl)-9-oxo-l,7,8,9-tetraazacyclopenta[b] naphthalen-2 -yl]piperazine-l-carboxylate
A. mixture consisting of 8 mg of. t-butyl 4-[7-(2-butynyl) -2-chloro-6-oxo-l-[3-(tetrahydropyran-2-yloxy)pr opyl]-6,7-dihydro-lH-purin-8-yl]piperazine-l-carboxylate, 0 . 2 ml of ethanol and a catalytic amount of para-toluenesulfonic acid

monohydrate was stirred at room -cemperature for 4 hours, and then 40 mg of anhydrous potassium carbonate was added thereto. The mixture was further stirred overnight. The reaction solution was extracted with ethyl acetate-water, and the organic layer was washed with water and then with saturated brine. The organic layer was then concentrated, and the residue was purified by thin layer chromatography (20% methanol/ethyl acetate) to give 3 mg of the title compound.
-H-NMR(CDCl3)
5 1.48 (s, 9H) 1.82 (t, J=2 Hz 3H) 2.13-2.26 (m, 2H) 3.37-3.43 (m, 4H) 3.56-3.62 (m, 4H) 4.07 (t, J=6 Hz, 2H) 4.43 (t, J=5 Hz, 2H) 4.88 (q, J=2 Hz, 2H) (c)
1- (2-Butynyl)-2-(piperazin-1-yl)-7,8-dihydro-lH,6H-5-oxa-l,3,4,8 a-tetraazacyclopenta[b]naphthalen-9-one hydrochloride
A mixture consisting of 3 mg of t-butyl 4-[1-(2-butynyl)-9-oxo-l,7,8,9-tetraazacyclopenta[b]naphthalen-2 -yl] piperazine-1-carboxylate and 0.5 ml of trif luoroacetic acid was stirred ar room temperature for 20 minutes. Then, the solution was concentrated, and the residue was purified by reverse-phase column chro.matography using 20% to 50% methanol/water (0.1% concentrated hydrochloric acid) solvent to give 2.1 mg of the title compound.
1H-NMR(DMS0-d6)
61.79 (s, 3H) 2.08-2.16 (m, 2H) 3.27 (br.s, 4H) 3.44-3.54 (m, 4H) 3.90 (t, J=6 Hz, 2H) 4.38 (t, J=5 Hz, 2H) 4.94 (s, 2H) 9.02 (br. s, 2K)
Example 241
1- (2-Butynyl)-2-(piperazin-1-yl)-6,7-dihydro-lH-5-oxa-l,3,4,7a-t
etraaza-s-indacen-8-one hydrochloride
In Example 240, the title compound was obtained by using 2-(2-bromoethoxy)tetrahydropyran, instead of 2-(3-bromopropoxy)tetrahydropyran, according to the method described in Example 240.
1H-NMR(DMS0-d6)
5 1.80 (s, 3H) 3.27 (br.s, 4H) 4.19 (t, J=8 Hz, 2H) 4.70 (t, J=8

Hz, 2H) 4.94 (s, 2H) 9.06 (br.s, 2H)
Example 242
8-(3-amino
piperidin-1-yl) -7-(2-butynyl)-1- (2-cyanob6nzyl)-6-oxo-6,7-dihydr
o-lH-purine-2-carbonitrile hydrochloride
(a) Benzyl 3-t-butoxycarbonylaminopiperidine-l-carboxylate
88 g of benzyl chloroformate (30% toluene solution) was added dropwise to a mixture consisting of 24.3 g of ethyl piperidine-3-carboxylate, 26 ml of triethylamine and 300 ml of ethyl acexate over 30 minutes while the mixture was being cooled with ice. The reaction mixture was filtered to remove insoluble material. The filxrate was again filtered through a small amount of silica gel. The filtrate was concentrated.
200 ml of ethanol and 40 ml of a 5 M aqueous sodium hydroxide solution were added to the residue. The mixture was stirred at room temperature overnight. The reaction solution was concentrated, and 200 ml of water was added to the residue. The mixture was extracted with"t-butyl .methyl ether.- 5 M aqueous hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, .and then concentrated to give an oily residue (30.9 g).
A mixture consisting of 30 g of this residue, 24.5 ml of diphenyl phosphoryl azide, 15.9 ml of triethylamine and 250 ml of t-butanol was stirred at room temperature for 1. 5 hours . The mixture was further stirred in an oil bath at 100 °C for 20 hours. The reaction solution was concentrated, and the residue was extracted with ethyl acetate-water. The organic layer was washed with dilute aqueous sodium bicarbonate solution and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography using 10% to 20% ethyl acetate/hexane, followed by recrystallization from ethyl acetate-hexane to give 21.4 g of the title compound.
1H-NMR(CDCl3)

5 1.43 (s, 9H) 1.48-1.92 (m, 4H) 3.20-3.80 (m, 5H) 4.58 (br.s,
IH) 5.13 (s, 2H) 7.26-7.40(m, 5H)
(b) t-Butyl piperidin-3-ylcarbamate
A mixture consisting of 10 g of benzyl 3-t-butoxycarbonylaminopiperidine-l-carboxylate, 500 mg of 10% palladium carbon and 100 ml of ethanol was stirred at room temperature under a hydrogen atmosphere overnight. The catalyst was removed by filtration. The filtrate was concentrated and dried to give 6.0 g of the title compound.
1H-NMR{CDCl3)
51.44 (s, 9H) 1.47-1.80 (m, 4H) 2.45-2.60 (m, IH) 2.60-2.75 (m, IH) 2.75-2.90 (m, IH) 3.05 (dd, J=3 Hz, 12 Hz, IH) 3.57 (br.s, IH) 4.83 (br.s, IH)
(c) t-Butyl
[1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin-3-yl]carb amate
A mixture consisting of 1.25 gof 7-(2-butynyl)-2,6,8-trichloro-7H-purine, 1.0 g of t-butyl piperidin-3-ylcarbamate and 10 ml of acetonitrile was stirred at room temperature for 10 minutes. 0.63 ml of triethylamine was added dropwise over 10 minutes, and then the mixture was continuously stirred at room temperature for 30 minutes. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated. The residue was crystallized with t-butyl methyl ether-hexane to give 1.79 g of the title compound.
1H-NMR(CDCl3)
6 1.43 (s, 9H) 1.60-2.02 (m, 4H) 1.83 (t, J=2 Hz, 3H) 3.32-3.41
(m, IH) 3.42-3.52 (m, IH) 3.67-3.76 (m, IH) 3.80-3.91 (m, IH) 4.76-4.90
(jn, 3H)
(d) t-Butyl
[1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]piper idin-3-yl]carbamate
A mixture consisting of 1.79 g of t-butyl [1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin-3-yl]carb

amate, 1.0 g of sodium acetate and 18 ml of dimethyl sulfoxide was stirred in an oil bath at 120""C for three hours. The mixture was removed from the oil bath, and 18 ml of water was added to the reaction solution. The mixture was cooled to room temperature. The crystals were collected by filtration, and washed with water and then with t-butyl methyl ether. The crystals were "hen dried to give 1.59 g of the title compound.
1H-NMR(DMS0-d6)
6 1.39 (s, 9H) 1.34-1.88 (m, 4H) 1.78 (s, 3H) 2.81 (t, J=ll Hz, IH) 2.95 (t, J=ll Hz, IH) 3.48-3.60 (m, 2H) 3.64 (d, J=6 Hz, IH) 4.90 (s, 2H) 6.94 (d, J=8 Hz, IH)
(e) t-Butyl
[1-[7-(2-butynyl) -2-chloro-l-(2-cyanoben2yl)-6-oxo-6,7-dihydro-l H-purin-8-yl]piperidin-3-yl]carbamate
A mixture consisting of 100 mg of t-butyl [1-[7-(2-butynyl) -2—ehloro-6-oxo-6,7-dihydro-lH-purin-8-yl]piper idin-3-yl]carbamate,.66 mg of anhydrous potassium carbonate, 70 mg of 2-cyanobenzyl bromide and 1 ml of N ,N-dimethylf ormamide was stirred a" room temperature for five hours. The reaction solution was partitioned between ethyl acetate and warer, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography using 50% ethyl acetate/hexane to give 44.7 mg of the title compound.
1H--NMR(CDCl3)
5 1.44 (s, 9H) 1.59-1.81 (m, 2H) 1.83 (t, J=2 Hz, 3H) 1.86-1.94 (m, 2H) 3.20-3.50-(m, 3H) 3.66 (d, J=7Hz, IH) 3.86 (br.s, IH) 4.88-5.06 (--n, 3H) 5.72 (s, 2H) 7.06 (d, J=8 Hz, IH) 7.38 (t, J=8 Hz, IH) 7.51 (-, J=8 Hz, IH) 7.70 (d, J=8 Hz, IH)
(f) t-Butyl
■ [1-[7-(2-butynyl) -2-cyano-l-(2-cyanobenzyl)-6-oxo-6 , 7-dihydro-l-purin-8-yl]piperidin-3-yl]carbamate
A mixture consisting of 15 mg of t-butyl [l-[7-(2-butynyl)-2-chloro
-1-(2-cyanobenzyl) -6-oxo-6,7-dihydro-lH-purin-8-yl]piperidin-3-y 1]carbamate, 20 mg of sodium cyanide and 0.2 ml of

N,N-dimethylformamide was stirred at room temperature for three hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and theij with saturated brine. Then, the organic layer was concentrated, and the residue was purified by thin layer chromatography using 50% ethyl acetate/hexane solvent (developed three times) to give 10.3 mg of the title compound.
1H-NMR(CDCl3)
5 1.44 (s, 9H) 1.52-1.98 (m, 4H) 1.81 (t, J=2 Hz 3H) 3.24 (dd, J=7 Hz, 12 Hz, IH) 3.30-3.40 (m, IH) 3.46-3.56 (m, IH) , 3.72 (d, J=12 Hz, IH) 3.86 (br.s, IH) 4.86-5.10 (m, 3H) 5.73 (s, 2H) 7.00 (d, J=8 Hz, IH) 7.42 (t, J=8 Hz, IH) 7.54 (dt, J=2 Hz, 8 Hz, IH) 7.73 (dd, J=2 Hz, 8 Hz, IH)
i2)_
8-(3-Aminopiperidin-l-yl)-7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-
6,7-dihydro-lH-purine-2-carbonitrile hydrochloride
A mixture consisting of 10.3 mg of t-butyl [1- [7- (2-butynyl) -2.-cyano-l- (2-cyanobenzyl) -6-oxo-6 , 7-dihydro-lH -purin-8-yl] piperidin-3-yl]carbamate and 0.2 ml of trifluoroacetic acid was stirred for 20 minutes. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography using 20% to 80% methanol/water (0.1% concentrated hydrochloric acid) solvent to give 8.0 mg of the title compound.
1H-NMR(DMS0-d6)
61.60-1.74 (m, 2H) 1.79 (t, J=2 Hz , 3H) 1.88-2.03 (m, 2H) 3.14-3.28 (m, 2H) 3.42 (br.s, IH) 3.52-3.82 (m, 2H) 4.98-5.12 (m, 2H) 5.58 (s, 2H) 7.26 (d, J=8 Hz, IH) 7.53 (t, J=8 Hz, IH) 7.66 (t, J=8 Hz, IH) 7.93 (d, J=8 Hz, IH) 8.16 (br.s, 3H)
Example 243 2-[8-(3-Amino
■piperidin-l-yl)-7-(2-butynyl)-2-methoxy-6-oxo-6,7-dihydropurin-l -ylmethyl]benzonitrile hydrochloride
A mixture consisting of 15 mg of t-butyl [1-[7-(2-butynyl) -2-chloro-l-(2~cyanobenzyl)-6-oxo-6,7-dihydro-lH-purin-8-yl]pipe ridin-3-yl] carbamate, 20 mg of anhydrous potassium carbonate and 0.2 ml of methanol was stirred for three hours. Subsequent steps were

carried out according to the same procedure as used in Examples 242 (f) and (g) . Thus, the title compound was synthesized.
-H-NMR(DMS0-d6)
51.58-1.72 (m, 2H) 1.84-1.94 (m, IH) 1.56-2.04 (m, IH) 3.08-3.20 (m, 2H) 3.36-3.70 (m, 3H) 3.90 (s, 3H) 4.S0-5.02 (m, 2H) 5.32 (s, 2H) 7.20 (d, J=8 Hz, IH) 7.47 (t, J=8 Hz, IH) 7.63 (t, J=8 Hz, IH) 7.87 (d, J=8 Hz, IH) 8.12 (br.s, 3H)
Example 244 8- (3-Amino
piperidin-1-yl) -7-(2-butynyl)-6-oxo-l-(2-phenylethyl)-6,7-dihydr o-lH-purine-2-carbonitrile hydrochloride (a) t-Butyl
[l-[7-(2-butynyl)-2-chloro-6-oxo-l- (2-phenylethyl)-6,7-dihydro-l H-purin-8-yl]piperidin-3-yl] carbamate
The title compound was obtained using 2-bromoethyl benzene, instead of 2-cyanobenzyl bromide, according to the method described in Example 242 (e) .
1H-NMR(CDCl3)
5 1.44 (s, 9H) 1.58-1.80 (m, 2H) 1.83 (., J=2 Hz, 3H) 1.86-1.94 (m, 2H) 3.00-3.06 (m, 2H) 3.20-3.50 (m, 3H) 3.60 (d, J=12 Hz, IH) 3.85 (b.s, IH) 4.42-4.48 (m, 2H) 4.88-5.04 (.-n, 3H) 7.02-7.34 (m, 5H) (b)
8- (3-Aminopiperidin-l-yl) -7- (2-butynyl) -6-oxo-l- (2-phenylethyl) -6,7-dihydro-lH-purine-2-carbonitrile hydrochloride
The title compound was synthesized by using t-butyl [l-[7-(2-butynyl) -2-chloro-6-oxo-l- (2-phenylethyl)-6,7-dihydro-lH-purin-8-yl]piperidin-3-yl]carbamate according to the method described in Example 242 (f) and (g).
1H-NMR(DMS0-d6) . - 5 1.60-1.72 (m, 2H) 1.83 (s, 3H) 1.88-2.06 (m, 3H) 3.04 (t, J=7 Hz, 2H) 3.35-3.60 (m, 2H) 3.75 (d, J=12 Hz, IH) 4.35 (t, J=7 Hz, 2H) 5.09 (s, 2H) 7.18 (d, J=7 Hz, 2H) 7.22-7.34 (m, 3H) 8.16 (br.s, 3H)
Example 245
8- (3-Aminopiperidin-l-yl) -7- (2-butynyl) -2-methoxy-l- (2-phenyleth

yl)-1,7-dihydropurin-6-one hydrochloride
The title compound was synthesized by using t-butyl
[1-[7-(2-butynyl)-2-phloro-6-oxo-l-(2-phenylethyl)-6,7-dihydro-l
H-purin-8-yl]piperidin-3-yl]carbamate, according to the method
described in Example 243. 1H-NMR(DMS0-d6) 5 1.56-1.72 (m, 2H) 1.80 (t, J=2 Hz, 3H) 1.84-2.04 (m, 2H) 2.85
(t, J=7 Hz, 2H) 3.08-3.18 (m, 2H) 3.34-3.54 (m, 2H) 3.64 (d, J=12
HZ, IH) 3.83 (s, 3H) 4.15 (t, J=7 Hz, 2H) 4.88-5.02 (m, 2H) 7.16-7.24
(m, 3H) 7.29 (t, J=7 Hz, 2H) 8.09 (br.s, 3H)
Example 246
8-(3-Aminopiperidin-l-yl)-7-(2-butynyl)-1-(4-cyanobenzyl)-6-oxo-
6,7-dihydro-lH-purine-2-carbonitrile hydrochloride
(a) t-Butyl
[1-[7-(2-butynyl)-2-chloro-l-(4—cyanobenzyl)-6-oxo-6,7-dihydro-l
H-purin-8-yl]piperidin-3-yl]carbamate
The title compound was obtained by using 4-cyanobenzyl bromide, instead-Of 2-cyanobenzyl bromide, according to the method described in Example 242 (e) .
1H-NMR(CDCl3)
5 1.44 (s, 9H) 1.58-1.80 (m, 2H) 1.82 (t,. J=2 Hz, 3H) , 1.85-1.95 (m, 2H) 3.18-3.26 (m, IH) 3.29-3.37 (m, IH) 3.40-3.48 (m, IH) 3.65 (d, J=12 Hz, IH) 3.86 (br.s, IH) 4.86-5.04 (m, 3H) 5.22 (s, 2H) 7.41 (d, J=8 Hz, 2H) 7.62 (d, J=8 Hz, 2H) (b)
8-(3-Aminopiperidin-l-yl)-7-(2-butynyl)-1-(4-cyanobenzyl)-6-oxo-6,7-dihydro-lH-purine-2-carbonitrile hydrochloride
The title compound was synthesized by using t-butyl [1-[7-(2-butynyl)-2-chloro-l-(4-cyanobenzyl)-6-oxo-6,7-dihydro-l H-purin-8-yl]piperidin-3-yl]carbamate according to the method described in Examples 242 (f) and (g) .
1H-NMR(DMS0-d6) ~ 5 1.62-1.72 (m, 2H) 1.80 (s, 3H) 1.88-1.96 (m, IH) 1.98-2.06 (m, IH) 3.16-3.26 (m, 2H) 3.41 (br.s, IH) 3.50-3.80 (m, 2H) 5.07 (s, 2H) 5.49 (s, 2H) 7.49 (d, J=8 Hz, 2H) 7.85 (d, J=8 Hz, 2H) 8.16 (br.s.

Example 247
4-[8- (3-Aminopiperidin-l-yl) -7- (2-butynyl)-2-methoxy-6-oxo-6 , 7-d
ihydropurin-1-ylmethyl ] benzonitrile hydrochloride
The title compound was synthesized by using t-butyl [l-[7- {2-butynyl) -2-chloro-l- {4-cyanobenzyl) -6-oxo-6,7-dihydro-l H-purin-8-yl]piperidin-3-yl]carbamate according to the method described in Example 243.
1H-NMR(DMS0-d6)
5 1.58-1.70 (m, 2H) 1.79 (s, 3H) 1.84-2.04 (m, 2H) 3.08-3.20 (m, 2H) 3.36-3.70 (m, 3H) 3.89 (s, 3H) 4.88-5.02 (m, 2H) 5.22 (s, 2H) 7.39 (d, J=8 Hz, 2H) 7.79 (d, J=8 Hz, 2H) 8.14 (br.s, 3H)
Example 248
2- [8- (3-Aminopiperidin-l-yl) -7- (2-butynyl) -l-methyl-6-oxo-6 , 7-di
hydro-lH-purin-2-yloxy]benzamide trifluoroacetic acid salt
(a) t-Butyl
[l-[7-(2-butynyl) -2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8 -yl]piperidin-3-y1]carbamate 700 mg of t-butyl
[1-[7-(2-butynyl) -2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]piper idin-3-yl]carbamate was dissolved in 7.0 ml of dimethyl sulfoxide, and then 114 Hi of methyl iodide and 299 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for 30 minutes, and 40 ml of water was added to the reaction solution. The mixture was stirred at room temperature for 30 minutes, and the white precipitate was collected by filtration. The resulting white solid was washed with water and then with hexane to give 540 mg of the title compound. . . 1H-NMR(CDC13)
5 1.44 (s, 9H) 1.72-1.94 (m, 4H) 1.81 (t, j=2.4 Hz, 3H) 3.16-3.92
(m, 5H) 3.72 (s, 3H) 4.91 (dd, J= 17.6, 2.4 Hz, IH) 5.01 (d, J=17.6 Hz, IH)
(b)
2-[8- (3-Aminopiperidin-l-yl) -7- (2-butynyl) -1-methyl-6-oxo-6 , 7-di

hydro-lH-purin-2-yloxy] benzamide trif luoroacetate
10 mg of t-butyl [1- [7- {2-butynyl) -2-chloro,-l-methyl-6-oxo-6 , 7-dihydro-lH-purin-8 -yl]piperidin-3-yl] carbamate was dissolved in 0.3 ml of l-methyl-2-pyrrolidone, and then 10 mg of salicylamide and 10 mg of potassium carbonate were added thereto. The mixture was stirred at 100°C for 2 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 5.54 rag of the title compound.
MS /n/e (ESI) 436 (MH-CFsCOOH)
Example 24 9
8- (3-Aminopiperidin-l-yl) -7- (2-butynyl) -l-methyl-6-oxo-6 , 7-dihyd
ro-lH-purine-2-carbonitrile trifluoroacetate
10 mg of. t-butyl [1- [7- (2-butynyl) -2-chloro-l-methyl-6-oxo-6 , 7-dihydro-lH-purin-8 -yl]piperidin-3-yl] carbamate dissolved in 0.3 ml of l-methyl-2-pyrrolidone, and then 10 mg of sodiunj cyanide was added thereto. The mixture was stirred at 60°C for 2 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.67 mg of the title compound.
MS mie (ESI) 326 (MH"-CFSCOOH)
Example 250
8- (3-Aminopiperidin-l-yl) -2-t-butylsulfanyl-7- (2-butynyl) -1-meth yl-1,7-dihydropurin-6-one trifluoroacetate 10 mg of t-butyl

[l-[7-(2-butynyl)-2-chloro-l-methyl-6-0x0-6,7-dihydro-lH-purin-8 -yl]piperidin-3-yl]carbamate was dissolved in 0.3 ml of l-methyl-2-pyrrolidone, and then 10 mg of the sodium salt of 2-methyl-2-propanethiol was added thereto. The mixture was stirred at room temperature for 2 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 5.00 mg of the title compound. MS mie (ESI) 38 9 (MH""-CF3C00H)
Example 251
8-(3-Aminopiperidin-l-yl)-7- (2-butynyl)-2-methoxy-l-methyl-l,7-d
ihydropurin-6-one trifluoroacetate
10 mg of t-butyl [l-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin-8-yl ] piperidin-3-yl ] carbamate was dissolved in 0 . 6 ml of methanol, and then 8 mg of sodium hydride was added thereto. The mixture was stirred at room temperature for one hour. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-wa"ter mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.14 mg of the title compound.
MS mIe (ESI) 331 (MH-CFaCOOH)
Example 252
.8-(3-Aminopiperidin-l-yl)-7- (2-butynyl)-2-diethylamino-l-methyl-1, 7-dihydropurin-6-one trifluoroacetate
10 mg of t-butyl [1- [7- (2-butynyl) -2-chloro-l-methyl-6-oxo-6 , 7-dihydro-lH-purin-8 -yl]piperidin-3-yl]carbamate was dissolved in 0.3 ml of l-methyl-2-pyrrolidone, and then 50 jil of diethylamine was added

thereto. The mixture was stirred at 60°C for 4 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the resulting residue was dissolved in trifluoroacetic acid. The solution was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.17 mg of the title compound. MS mle (ESI) 372 (MH-CFaCOOH)
Example 253
8-(3-Aminopiperidin-l-yl)-7-(2-butynyl)-l-methyl-2-(pyrrolidin-1
-yl)-1,7-dihydropurin-6-one trifluoroaceare
1.94 mg of the title compound was obtained by using pyrrolidine, instead of diethylamine, according to the me-chod described in Example 252. -
MS .m/e (ESI) 370 (MR"-CFsCOOH)
Example 254
8-(3-Methylaminopiperidin-l-yl)-7- (2-butynyl)-l-methyl-6-oxo-6,7
-dihydro-lH-purine-2-carbonitrile hydrochloride
(a) t-Butyl N-methyl-N-(piperidin-3-yl)carbamate
0.4 g of sodium hydride (60%; in oil) was added to a mixture consisting of 3.3 g of benzyl 3-t-butoxycarbonylarainopiperidine-l-carboxylate, 0.75 ml of methyl iodide and 20 ml of N,N-dimethylformamide in a water bath at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography using 10% to 20% ethyl acetare/hexane to give an oily material (3.04 g). This whole ammount was combined with 20 ml of ethanol and 10% palladium carbon. This mixture was stirred at room temperature under a hydrogen atmosphere for five hours. After the catalyst was removed by filtration, the filtrate was concentrated

to give 1.82 g of the title compound.
1H-NMR(CDCl3)
5 1.46 (s, 9H) 1.48-1.64 (m, 2H} 1.72-1.84 (m, 2H) 2.43 (dt, J=3 Hz, 12 Hz, IH) "2.60 (t, J=12 Hz, IH) 2.75 (s, 3H) 2.74-3.02 (m, 2H) 3.86 (br.s, IH)
(b) t-Butyl
N-[1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin-3-yl]-N -methylcarbamate
The title compound was synthesized by using 7-(2-butynyl)-2,6,8-trichloro-7H-purine and t-butyl piperidin-3-ylcarbamate according to the me"Lhod described in Example 242 (c).
1H-NMR (CDCI3)
5 1.48 (s, 9H) 1.70-2.02 (m, 7H) 2.83 (s, 3H) 3.00 (t, J=12 Hz, IK) 3.14 (t, J=12 Hz, IH) 3.96-4.25 (m, 3H) 4.80 (s, 2H)
(c) t-Butyl
N-[l7[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-&,7-dihydro-lH-purin -8-yl]piperidin-3-yl]-N-methylcarbamate
A mixture consisting of 580 mg of t-butyl N-[1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin-3-yl]-N -methylcarbamate, 315 mg of sodium acetate and 6 ml of dimethyl sulfoxide was stirred in an oil bath at 120 °C for 7 hours . The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered through a small amount of silica gel. The filtrate was concentrated, and the residue was crystallized with ethyl acetate-hexane to give 420 mg of t-butyl
N-[l-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-lH-purin-8-yl]pip eridin-3-yl]-N-methylcarbamate. A mixture consisting of an 100 mg .aliquot of the compound obtained above, 0.17 ml of methyl iodide, 48 mg of anhydrous potassium carbonate and 0.5 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. Then, the organic layer was concentrated, and the residue was

purified by silica gel column chromatography using 50% ethyl acetate/hexane to give 104 mg of the title compound.
1H-NMR(CDCl3)
5 1.47 (s, 9H) 1.62-1.74 (m, IH) 1.81 (t, J=2 Hz,"3H) 1.82-1.96 (m, 3H) 2.82 (s, 3H) 2.86 (t, J=12 Hz, IH) 3.02 (t, J=12 Hz, IH) 3.68-3.82 (m, 2H) 3.72 (s, 3H) 4.20 (br. s, IH) 4.90 (s, 2H) (d)
7- (2-Butynyl) -l-methyl-8- (3-methylaminopiperidin-l-yl) -6-oxo-6 , 7
-dihydro-lH-purine-2-carbonitrile hydrochloride
The title compound was synthesized by using t-butyl N-[1-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin -8-yl]piperidin-3-yl]-N-methylcarbamate according to the method described in Example 242 (f) and (g).
1H-NMR{DMS0-d6)
5 1.60-1.77 (m, 2H) 1.81 (s, 3H) 1.84-2.00 (m, IH) 2.02-2.12 (m, IH) 2.60 (t, J=5 Hz, 3H) 3.17-3.40 (m, 3H) 3.46-3.56 (m, IH) 3.79 (d, J=12 Hz, IH) 5.00-5.15 (m, 2H) 9.01 (br..s, 2H)
Example 255
2-[7-(2-Butynyl)-l-methyl-8- (3-methylaminopiperidin-l-yl)-6-oxo-
6,7-dihydro-lH-purin-2-yloxy]benzamide hydrochloride
A mixture consisting of 20 mg of t-butyl N-[l-[7-(2-butynyl)-2-chloro-l-methyl-6-oxo-6,7-dihydro-lH-purin -8-yl]piperidin-3-yl]-N-methylcarbamate, 20 mg of
2-hydroxybenzamide, 20 mg of anhydrous potassium carbonate, and 0.3 ml of N-methyl-2-pyrrolidone was stirred in an oil bath at 80 °C for 4 hours. Subsequent synthesis steps were carried out according to the same procedure as used in Examples 242(f) and (g) to give the title compound.
1H-NMR(DMS0-d6) - .- 5 1.69 (br.s, 2H) 1.82 (s, 3H) 1.92 (br.s, IH) 2.07 (br.s, IH) 2..62 (s, 3H) 3.10-3.40 (m, 4H) 3.48 (s, 3H) 3.76 (br.s, IH) 5.02 (br.s, 2H) 6.96 (br.s, 2H) 7.44 (br.s, IH) 7.91 (br.s, IH) 8.81 (br.s, 2H)
Example 256
8- (3-Aminopyrrolidin-l-yl) -7- (2-butynyl) -l-methyl-6-oxo-6 , 7-dihy

dro-lH-purine-2-carbonitrile hydrochloride
In Example 254 , the title compound was synthesized by using t-butyl pyrrolidin-3-ylcarbamate, instead of t-butyl
N-methyl-N-(piperidin-3-yl)carbamate, according to the method described in Examples 254(b), (c), and (d).
1H-NMR(DMS0-d6)
5 1.81 (s, 3H) 2.13 (br.s, IH) 2.32 (br.s, IH) 3.64 (s, 3H) 3.74-3.86 (m, 2H) 3.93 (br.s, 3H) 5.19 (d, J=18Hz, IH) 5.28 (d, J=18Hz, IH) 8.32 (br.s, 3H)
Example 257
2-[8-(3-Aminopyrrolidin-l-yl)-7- (2-butynyl)-l-methyl-6-oxo-6,7-d
ihydro-lH-purin-2-yloxy]benzamide hydrochloride
The title compound was synthesized by using 2-hydroxybenzamide according to the method described in Examples 255 and 256.
1H-NMR(DMS0-d6)
5 1.82 (s, 3H) 2.11 (br.s, IH) 2.32 (br.s, IH) 3.46 (s, 3H) 3.72-4.00 (m, 5H) 5.15 (d, J=19Hz, IH) 5.23 (d, J=19Hz, IH) 6.90-7.02 (m, 2H) 7.42-7.50 (m, IH)- 7.90-7.99 (m, IH) 8.22 (br.s, 3H)
Example 258
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(2-propynyl)-3,5-dihydroimida
zo[4,5-d3pyridazin-4-one trifluoroacetate
(a) t-Butyl
4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-
yl]piperazine-1-carboxylate
0.299 g of triethylamine, 0.023 g of 4-dimethylaminopyridine and 0.645 g of di-t-butyl dicarbonate were added to 20 ml of an N,N-dimethylformamide solution of 0.448 g of
3-(2-butynyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyrida -z-in-4-one trif luoroacetate at room temperature, and the mixture was stirred for five hours. Then, 2 ml of a 5N aqueous sodium hydroxide solution was added to this solution, and the mixture was stirred for one hour. The reaction solution was poured into a mixture of 200 ml of ethyl acetate and 100 ml of a saturated aqueous ammonium chloride solution. The organic layer was washed twice with 100 ml of water

and then with 100 ml of a saturated sodium chloride solution. The organic liquid was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0 . 29 8 g of the title compound was obtained from the fraction eluted with ethyl acetate. -H-NMR(CDCl3)
5 1.50 (s, 9H) 1.84 (t, J=2.3Hz, 3H) 3.41 (m, 4H) 3.63 (m, 4H) 5.06 (q, J=2.3Hz, 2H) 8.17 (s, IH) 9.92 (br.s, IH) (b)
3- (2-Butynyl)-2-(piperazin-1-yl)-5-(2-propynyl)-3,5-dihydroimida zo[4,5-d]pyridazin-4-one trifluoroacetate
0.005 g of potassium carbonate and 0.003 ml of 3-bromo-l-propyne were added to 0.5 ml of an N,N-dimethylformamide solution of 0.010 g of t-butyl
4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl] piperazine-1-carboxylate , and the mixture was stirred at room temperature for 10 hours. 1 ml of ethyl acetate and 1 ml of water were added to the reaction solution, and the layers were separated. The organic layer was concentrated, and rhe resulting residue was dissolved in a mixture consisting of 0.5 .ml of dichloromethane and 0.5 ml of trifluoroacetic acid. The mixture was stirred for 1 hour, and then concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.011 g-of the title compound.
MS mie (ESI) 311 . 29 (MH-CFsCOOH)
Example 259
[3- (2-Bu"tynyl) -4-oxo-2- (piperazin-l-yl)-3 , 4-dihydroimidazo [4 , 5-d ]pyridazin-5-yl]acetonitrile trifluoroacetate - . The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and bromoacetonitrile according to the method described in Exampje 258(b). MS m/e (ESI) 312.28 (MH*-CF3C00H)

Example 260
3-(2-Butynyl)-5-(2-hydroxyethyl)-2-(piperazin-1-yl) -3,5-dihydroi
midazo [4 , 5-d] pyridazin-4-one trif luoroaceta.tfe
The title compound was obtained by using t-butyl 4-[1-{2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 2-bromoethanol according to the method described in Example 258(b).
MS m/e (ESI) 317 . 30 (MH-CFsCOOH)
Example 261
3-(2-Butynyl)-5-(2-methoxyethyl)-2-(piperazin-1-yl)-3,5-dihydroi
midazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl ] piperazine-1-carboxylate and bromoethyl methyl ether according to the method described in Example 258(b).
K.S m/e (ES.I) 331 . 32 (MH-CFsCOOH)
Example 262
Ethyl
[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d ]pyridazin-5-yl]acetate trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lK-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and ethyl bromoacetate according to the method described in Example 258(b).
MS m/e (ESI) 359 . 13 (MH-CFBCOOH)
Example 263
3- (2-Butynyl) -5- (2-phenylethyl) -2- (piperazin--l-yl) -3 , 5-dihydroim
idazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6 , 7-dihydro-lK-imidazo[4,5-d]pyridazin-2-yl] piperazine-1-carboxylate and (2-bromoethyl)benzene according to the method described in Example 258(b).
MS m/e (ESI) 377 . 34 (MH-CFaGOOH)

Example 264
3-(2-Butynyl)-5-(2-phenoxyethyl)-2- (piperazin-l-yl)-3,5-dihydroi
midazo[4,5-d]pyrida2in-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyrida2in-2-yl]piperazine-l-carboxylate and 2-bromoethyl phenyl ether according to the method described in Example 258(b).
MS /n/e (ESI) 393 . 32 (MH-CFsCOOH)
Example 2 65
3-(2-Butynyl)-5-(2-oxo-2-phenylethyl)-2-(piperazin-l-yl)-3,5-dih
ydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imida20[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 2-bromoacetophenone according to the method described in Example 258 (b) .
MS m/e (ESI) 391 . 32 (MH-CFa"COOH)
Example 266
3-(2-Butynyl) -5-[2-(3-methoxyphenyl)-2-oxoethyl]-2-(piperazin-l-yl) -3,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl] piperazine-1-carboxylate and 2-bromo-3"-methoxy acetophenone according to the method described in Example 258 (b) .
MS /n/e (ESI) 421 . 33 (MH-CFaCOOH)
Example 267
2- [3- (2-Butynyl) -4-oxo-2-"(piperazin-l-yl) -3 , 4-dihydroimidazo [4 , ."j .--d]pyridazin-5-ylmethyl]benzonitrile trif luoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyrida2in-2-yl]piperazine-l-carboxylate and 2-bromomethylbenzonitrile according to the method described in Example 258(b).
1H-NMR(CD30D)

6 1.81 (t, J=2.5Hz, 3H) 3.45-3.49 (m, 4H) 3.66-3.70 (m, 4H) 5.15 (q, J=2.5Hz, 2H) 5.62 (s, 2H) 7.34 (dd, J=7.6,1.5H2, IH) 7.45 (td, J=7.6,1.5Hz, 1H).7.59 (td, J=7.6,1.7Hz, IH) 7.75 (dd, J=7.6,1.7Hz, IH) 8.25 (s, IH)
MS mie (ESI) 388 . 32 (MH-CFBCOOH)
Example 268
3- (2-Butynyl)-2-(piperazin-1-yl)-5- (2-trifluoromethylbenzyl)-3 , 5
-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-{2-butynyl) -7-oxo-6,7-dihydro-lH-imida2o[4,5-d]pyridazin-2-yllpiperazine-1-carboxylate and 2-(trifluoromethyl)benzyl bromide according to the method described in Example 258 (b) .
MS /n/e (ESI) 431 . 21 (MH-CFaCOOH)
Example 269
3- (2-Butynyl)-2-(piperazin-1-yl)-5- (3-trifluoromethylbenzyl)-3 , 5
-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
. The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lK-imidazo[4,5-d] pyridazin-2-yl]piperazine-l-carboxylate and 3-(trifluoromethyl)benzyl bromide according to the method described in Example 258 (b) . MS m/e (ESI) 431 . 23 (MH-CFsCOOH)
Example 27 0■
3-(2-Butynyl)-5-(2-nitrobenzyl)-2-(piperazin-1-yl) -3,5-dihydroim
idazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 2-nitrobenzyl bromide according to the method described in Example 258 (b) .
MS m/e (ESI) 408 . 25 (MH-CFsCOOH)
Example 271
3-[3-(2-Butynyl)-4-oxo-2- (piperazin-1-yl)-3,4-dihydroimidazo[4,5
-d]pyridazin-5-ylmethyl]benzonitrile trifluoroacetate

The title compound was obtained by using t-butyl
4-[l-(2-butynyl)-7-0x0-6,7-dihydro-lH-imida2o[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 3-bromomethylbenzonitrile according to the method described in Example 258(b). MS ;n/e (ESI) 388 . 27 (MH-CFsCOOH)
Example 272
4-[3-(2-Butynyl)-4-0x0-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5
-d]pyrida2in-5-ylmethyl]ben2onitrile trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 4-bromomethylbenzonitrile according to the method described in Example 258(b).
MS /n/e (ESI) 388 . 29 (MH-CFaCOOH)
Example 27 3
Methyl
3-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5
-d] pyridazin-5-ylmethyl ] benzoate trif luo-roacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and methyl 3-(bromomethyl)benzoate according to the method described in Example 258(b).
MS /n/e (ESI) 421 . 29 (MH"-CFaCOOH)
Example 274
Methyl
4-[3-(2-butynyl) -4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo [4,5
-d]pyridazin-5-ylmethyl]benzoate trifluoroacetate
The title compound was obtained by using t-butyl .4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d] pyridazin-2-yl]piperazine-l-carboxylate and methyl 4-(bromomethyl)benzoate according to the method described in Example 258(b).
MS m/e (ESI) 421 . 31 (MH-CFaCOOH)
Example 27 5

Ethyl
5- [3-(2-butynyl)-4-oxo-2- (piperazin-1-yl)-3,4-dihydroimidazo[4,5
-d]pyridazin-5-ylmethyl]furan-2-carboxylate trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and ethyl
5-(bromomethyl) furan-2-carboxylate according to the method described in Example 258 (b) .
MS rale (ESI) 425 . 30 (MH-CFaCOOH)
Example 276
3- (2-Butynyl) -5-[2-(2-nitrophenyl)-2-oxoethyl] -2-(piperazin-1-yl
)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl] piperazine-1-carboxylate- and 2-bromo-2"-nitroacetophenone according to the method described in Example 258(b).
MS m/e (ESI) 436 . 28 (MH-CFsCOOH)
Example 277
4-[2-[3-(2-Butynyl)-4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo[
4,5-d]pyridazin-5-yl]acetyl]benzonitrile trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl ] piperazine-1-carboxylate and 2-bromo-4"-cyanoacetophenone according to the method described in Example 258(b).
MS jn/e (ESI) 416 . 31 (MH-CFsCOOH)
Example 27 8
3-(2-Butynyl) -5-[2-(4-methoxyphenyl)-2-oxoethyl]-2-(piperazin-1-.yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lK-imidazo[4,5-d]pyridazin-2-yllpiperazine-1-carboxylate and 2-bromo-4"-methoxyacetophenone according to the method described in Example 258(b).
MS m/e (ESI) 421 . 32 (MH-CFsCOOH)

Example 279
3-(2-Butynyl)-5-[2-(2-methoxyphenyl)-2-oxoethyl]-2-(piperazin-1-
yl)"-3, 5-dihydroimidazo [4 , 5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4- [1- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-iinidazo [ 4 , 5-d]pyrida2in-2-yl]piperazine-l-carboxylate and 2-bromo-2"-methoxyacetophenone according to the method described in Example 258(b).
MS m/e (ESI) 421. 33 (MH-CFsCOOH)
Example 2 80
4-[2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[
4,5-d]pyridazin-S-yl]ethyljbenzoic acid trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and t-butyl 4-(2-bromoethyl)benzoate according to the method described in Example 258(b).
MS m/e (ESI) 421. 33 (MH"-CFaCOOH)
Example 281
*
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(pyridin-2-ylmethyl)-3,5-dihy droimidazo[4,5-d]pyridazin-4-one bis trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxyate and 2-(chloromethyl)pyridine hydrochloride according to the method described in Example 258(b).
MS ;T?/e (ESI) 364 . 24 (MH-2CF3COOH)
Example 2 82
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(pyridin-3-ylmethyl)-3,5-dihy
droimidazo[4,5-d]pyridazin-4-one bis trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pipera2ine-l-carboxylate and 3-(chloromethyl)pyridine hydrochloride according to the method described in Example 258 (b) .
MS /n/e (ESI) 364 . 30 (MH-2CF3COOH)

Example 283
3- (2-Butynyl)-2-(piperazin-1-yl)-5-(pyridin-4-ylmethvl) -3,5-dihy.
droimidazo[4,5-d]pyridazin-4-one bis trifjuoroacetate
The title compound was obtained by using t-butyl 4-[l-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 4-(chloromethyl)pyridine hydrochloride according to the method described in Example 258(b).
MS m/e (ESI) 364 . 26 (MH*-2CF3COOH)
Example 284
3-(2-Butynyl) -5-[2-oxo-2-(pyridin-2-yl)ethyl]-2-(piperazin-1-yl)
-3,5-dihydroimidazo[4,5-d]pyridazin-4-one bis trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 2-(2-bromoacetyl)pyridine hydrobromide according to the met.hod described in Example 258 (b) .
MS m/e (ESI) 392 . 27 (MH-2CF3COOH)
Example 28 5
3-(2-Butynyl)-5-[2-oxo-2-(pyridin-3-yl)ethyl] -2-(piperazin-1-yl)
-3,5-dihydroimidazo[4,5-d]pyridazin-4-one bis trifjuoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 3-(2-bromoacetyl)pyridine hydrobromide according to the method described in Example 258(b).
MS /n/e (ESI) 392 . 27 (MH-2CF3COOH)
Example 28 6
3-(2-Butynyl) -5-[2-OXO-2-(pyridin-4-yl)ethyl]-2-oxoethyl]]-2-(pi perazin-1-yl) -3,5-dihydroimidazo[4,5-d]pyridazin-4-one bis trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 4-(2-bromoacetyl)pyridine hydrobromide according to the method described in Example 258(b)

MS We (ESI) 392.28 {MH*-2CF3COOH)
Example 287
3- (2-Butynyl) -5-(2-methoxypyridin-3-ylmethyl)-2-(piperazin-1-yl)
-3 ,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl
4- [1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d)pyridazin-2-
yl]piperazine-l-carboxylate and 3-(chloromethyl)-2-methoxypyridine
according to the method described in Example 258 (b) .
MS m/e (ESI) 394 . 30 (MH-CFaCOOH)
Example 288
Merhyl
6-[3-(2-butynyl) -4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5
-d]pyridazin-5-ylmethyl]nicotinate bis trifluoroacetate
The-title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl] piperazine-1-carboxylate and methyl 6-(chloromethyl)nicotinate according to the method described in Example 258(b).
MS We (ESI) 422.31 (MH"-CFgCOOH)
Exa.mple 289
5- (6-Aminopyridin-3-ylmethyl)-3-(2-butynyl)-2-(piperazin-1-yl)-3
,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and
2- (t-butoxycarbonylamino) -5- (bromomethyl) pyridine according to the method described in Example 258(b).
MS m/e (ESI) 379.31 (MH"-CFaCOOH)
Example 290
4-[3-(2-Butynyl) -4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo [4,5 -d]pyridazin-5-ylmethyl]-3-cyano-5-ethoxy-N-methylbenzamide trifluoroacetate"
The title compound was obtained by using t-butyl

4-[l- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-imida2o [4 , 5-d]pyriclazin-2-yl]piperazine-l-carboxylate and
4-bromomethyl-3-cyano-5-ethoxy-N-methylbenzamide according to the method describe"d in Example 258(b).
MS m/e (ESI) 489 . 35 (MH-CFBCOOH)
Example 291
4-[3-(2-Butynyl) -4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5
-d]pyridazin-5-ylmethyl]-3,5-dicyano-N-methylbenzamide
trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and
4-bromomethyl-3 , 5-dicyano-N-methylbenzamide according to the method described in Example 258(b).
MS m/e (ESI) 470.33 (MH-CF3C00H)
Example 292
4- [3- (2-Butynyl) -4-oxo.-2- (piperazin-1-yl) -3, 4-dihydroimidazo [4,5
-d]pyridazin-5-ylmethyl]-3-cyano-5-fluoro-N-methylbenzamide
trifluoroacetate
The title compound was obtained by using t-butyl . . 4-[1-(2-burynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl] piperazine-1-carboxylate and
4-bromomethyl-3-cyano-5-fluoro-N-methylbenzamide according to the method described in Example 258(b).
MS m/e (ESI) 463.33 (MH-CFaCOOH)
Example 293
4-[3-(2-Butynyl)-4-oxo-2- (piperazin-1-yl)-3,4-dihydroimidazo[4,5 .-d]pyridazin-5-ylmethyl]-5-cyano-2-ethoxy-N-methylbenzamide trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-OXO-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 4-bromomethyl-5-cyano-2-ethoxy-N-methylbenzamide according to the

method described in Example 258(b). MS m/e (ESI) 489 . 35 (MH-CFaCOOH)
Example 294
5-[3-(2-Butynyl) -4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5
-d]pyridazin-5-ylmethyl]-2-fluorobenzonitrile trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 5-bromomethyl-2-fluorobenzonitrile according to the method described in Example 258(b).
MS m/e (ESI) 406 .15 (MH-CFsCOOH)
Examole 295
-
2-[3-(2-Butynyl) -4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5 -d]pyridazin-5-ylmethyl]-5-fluorobenzonitrile trifluoroacetate
The title compound was obtained by using t-buryl 4- [1- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-imida.zo [4 , 5-d] pyridazin-2-yl ]piperazine-l-carboxylate and 2-bromomethyl-5-fluorobenzonitrile according to the method described in Example 258(b).
MS m/e (ESI) 406 .16 (MH-CFjCOOH)
Example 296
4-[3-(2-Butynyl) -4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo [4,5
-d]pyridazin-5-ylmethyl]-3-fluorobenzonitrile trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 4-bromomethyl-3-fluorobenzonitrile according to the method described in Example 258(b).
MS m/e (ESI) 406 . 23 (MH"-CFaCOOH)
.Example 29 7
2-[3-(2-Butynyl) -4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5 -d]pyridazin-5-ylmethyl]-3-fluorobenzonitrile trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 2-broraomethy1-3-fluorobenzonitrile

according to the method described in Example 258(b). MS ra/e (ESI) 406 . 25 (MH-CFsCOOH)
Example 298
3-(2-Butynyl) -5-(isoquinolin-1-ylmethyl)-2-(piperazin-1-yl)-3,5-
dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imida20[4,5-d]pyridazin-2-yljpiperazine-l-carboxylate and 1-bromomethylisoquinoline according to the method described in Example 258(b).
1H-NMR(CDCl3)
61.80 (t, J=2.4Hz, 3H) 3.46 (m, 4H) 3.68 (m, 4H) 5.17 (q, J=2.4H2, 2H) 6.22 (s, 2H) 7.94 (dd, J= 8.2,8.GHz, IH) 8.08 (t, J=8.2Hz, IH) 8.21 (d, J=8.0Hz, IH) 8.24 (d, J=6.4Hz, 1) 8.27 (s, IH) 8.46 (d, J=6.4Hz, IH) 8.68 (d, J=8.2Hz, IH)
MS m/e (ESI) -414 . 32 (MH-CFsCOOH)
Example 299
3-(2-Butynyl) -5-(2-fluoropyridin-3-ylmethyl) -2-(piperazin-1-yl)-
3,5-dihydroimidazo[4,5-d]pyrida2in-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-{2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4, 5-d]pyridazin-2-yl] piperazine-1-carboxylate and 3- (bromomethyl) -2-fluoropyridine hydrochloride according to the method described in Example 258 (b) . -MS m/e (ESI) 384.22 (MH-CFaCOOH)
Example 300
3-(2-Butynyl)-5-(2-fluoropyridin-4-ylmethyl)-2-(piperazin-1-yl)-
3,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl . 4-[1-(2-butynyl)-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 4-(bromomethyl)-2-fluoropyridine hydrochloride according to the method described in Example 258(b) . MS m/e (ESI) 384.20 (MH-CFsCOOH)
Example 301

3-(2-Butynyl) -5-(6-fluoropyridin-2-ylmethyl)-2-(piperazin-l-yl)-3,5-dihydroimida20[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using, --butyl 4- [1- (2-butynyl) -7-oxo-6", 7-dihydro-lH-imida20 [4 , 5-d]pyridazin-2-yl]piperazine-l-carboxylate and 2- (bromomethyl)-6-fluoropyridine hydrochloride according to the method described in Example 258(b).
MS m/e (ESI) 384.22 (MH-CFaCOOH)
Example 3 02
2-[3-(2-Butynyl)-4-oxo-2-(piperazin-l-yl)-3,4-dihydroimidazo[4,5 -d]pyridazin-S-ylmethyl]benzamide trifluoroacetate 0.005 g of potassium carbonate and 0.007 g of 2-bromomethylbenzonitrile were added to a 0.5 ml N,N-dimethylformamide solution containing 0.010 g of t-butyl 4-[1-{2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate, and the mixture was stirred at room temperature for 20 hours. 1 ml of ethyl acetate and 1 ml of water were added to the reaction solution, and the layers were separated. The organic layer was concentra.ted, and the residue was dissolved in 1.0 ml of methanol. 0.2 ml of aqueous ammonia solution and 0.2 ml of 31% aqueous hydrogen peroxide were added to the solution, and the mixture was stirred at 5°C for 20 hours. 1 ml of ethyl acetate and 1 ml of water were added to the reaction solution, and the layers were separated. The organic layer was concentrated, and the resulting residue was dissolved in a mixture consisting of 0.5 .ml of dichloromethane and 0.5 ml of trifluoroacetic acid. The mixture was stirred for 1 hour, and then concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.009 g the title compound. MS tn/e (ESI) 406 . 28 (MH-CFaCOOH)
Example 303
3-[3-(2-Butynyl)-4-oxo-2-(piperazin-l-yl)-3,4-dihydroimidazo[4,5 -d]pyridazin-5-ylmethyl]benzamide trifluoroacetate The title compound was obtained by using t-butyl

4- [ 1- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-imidazo [ 4 , 5-d] pyridazin-2-yl]piperazine-l-carboxylate and S-bromomethylbenzonitrile according to the method described in Example 302. MS /n/e (ESI) 406 . 30 (MH-CFgCOOH)
Example 304
4-[3-(2-Butynyl)-4-oxo-2- (piperazin-l-yl)-3 , 4-dihydroimidazo [4 , 5
-d]pyridazin-S-ylmethyl]benzamide trifluoroacetate
The title compound was obtained by using t-butyl 4- [1- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-imidazo [4, 5-d] pyridazin-2-yl ]piperazine-l-carboxylate and 4-bromomethylbenzonitrile according to the method described in Example 302.
MS mle (ESI) 406 . 31 (MH-CFBCOOH)
Example 305
3- [3- (2-Butynyl) -4-oxo-2- (piperazin-l-yl) -3 , 4-dihydroimidazo [4,5
-d]pyridazin-5-ylmethyl]benzoic acid trifluoroacetate
0.005 g of potassium carbonate and 0.008 g of methyl
3- (bromomethyl) benzoate were added to a 0 . 5 ml N,N-dimethylformamide solution of 0.010 g of t-butyl
4- [1- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-imidazo [4 , 5-d] pyridazin-2-yl] piperazine-1-carboxylate, and the mixture was stirred at room temperature for 20 hours. 1 ml of ethyl acetate and 1 ml of water were added to the reaction mixture, and the layers were separated. The organic layer was concentrated, and the residue was dissolved in 1. 0 ml of methanol. 0 .1 ml of a 5N aqueous sodium hydroxide solution was added to this solution, and the mixture was stirred at room temperature for 20 hours. 1 ml of ethyl acetate and 1 ml of water were added to the reaction solution. The solution was acidified using concentrated hydrochloric acid, and the layers were separated. The
.organic layer was concentrated, and the residue was dissolved in a mixture consisting of 0.5 ml of dichloromethane and 0.5 ml of trif luoroacetic acid. The mixture was s-irred for one hour and then concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.008

g of the title compound.
MS m/e (ESI) 407.29(MH-CFaCOOH)
Example 306
4-[3-(2-Butynyl) -4-oxo-2-(piperazin-l-yl)-3,4-dihydroimidazo[4,5
-d]pyridazin-5-ylmethyl]benzoic acid trifluoroacetate
The title compound was obtained by using t-butyl 4- [1- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-imidazo [4 , 5-dlpyridazin-2-yl]piperazine-l-carboxylate and methyl 4-(bromomethyl)benzoate according to the method described in Example 305.
MS m/e (ESI) 407.30(MH-CFaCOOH)
Example 307
5-[3-(2-Butynyl) -4-oxo-2-(piperazin-l-yl)-3,4-dihydroimidazo [4,5
-d]pyridazin-5-ylmethyl]furan-2-carboxylic acid trifluoroacetate
The title compound was-obtained by using t-butyl 4- [1- (2-butynyl) -7-oxo-6 , 7-dihydro-lH-imidazo [4 , 5-d] pyridazin-2-yl]piperazine-l-carboxylate and ethyl
5-(bromomethyl)furan-2-carboxylate according to the method described in Example 305.
MS m/e (ESI) 397 . 28 (MH"-CFaCOOH)
Example 308
3-Benzyl-2-(piperazin-l-yl)-3,5-dihydroimidazo[4,5-d]pyrida2in-4 -one trifluoroacetate (a) t-Butyl
4- (l-benzyl-6-benzyloxymethyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d ]pyridazin-2-yl)piperazine-l-carboxylate
The title compound was obtained by using t-butyl 4- (6-benzyloxymethyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazi .n-2-yl)piperazine-l-carboxylate and benzyl bromide according to the method described in Example 116(d).
1H-NMR(CDCl3)
5 1.48 (s, 9H) 3.13-3.18 (m, 4H) 3.50-3.54 (m, 4H) 4.72 (s, 2H) 5.61 (s, 2H) 5.65 (s, 2H) 7.20-7.35(m, lOH) 8.22 (s, IH) (b)

3-Benzyl-2- (piperazin-l-yl)-3,5-dihydroimidazo[4,5-d] pyridazin-4 -one trifluoroacetate
The title compound was obtained by treating t-butyl. 4- (l-benzyl-6-ben2yloxymethyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d ]pyridazin-2-yl)pipera2ine-l-carboxylate according to the method described in Example 117.
1H-NMR(CD30D)
5 3.31-3.37 (m, 4H) 3.40-3.46 (m, 4H) 5.68 (s, 2H) 7.22-7.36(m, 5K) 8.25 (s, IH)
MS m/e (ESI) 311. 24 (MH-CFsCOOH)
Example 309
3-3enzyl-5-methyl-2- (piperazin-l-yl) -3 , 5-dihydroimidazo [4 , 5-d]py
ridazin-4-one trifluoroacetate
(a) t-Butvl
4- (l-benzyl-7-oxo-6 , 7-dihydro-lH-imidazo [4 , 5-d] pyridazin-2-yl) pj" perazine-l-carboxylate ..
The ti-le compound vfas obtained by using 3-benzyl-2- (piperaziTi-1-yl) -3 , 5-dihydroimidazo [4 , 5-d] pyridazin-4-one trifluoroacetate according to the method described in Example 258 (a) .
1H-NMR(CDCl3)
6 1.47 (s, 9H) 3.12-3.16 (m, 4H) 3.47-3.52 (m, 4H) 5.58 (s, 2H) 7.20-7.34(m, 5H) 8.20 (s, IH) 10.04 (br.s, IH) (b)
3-3enzyl-5-methyl-2- (piperazin-l-yl) -3 , 5-dihydroimidazo [4 , 5-d]py ridazin-4-one trifluoroacetate
The tile compound was obtained by using t-butyl 4- (l-benzyl-7-oxo-6 , 7-dihydro-lH-imidazo [4 , 5-d] pyridazin-2-yl) pi perazine-l-carboxylate and methyl iodide according to the method .described in Example 258(b).
1H-NMR(CD30D)
5 3.29-3.35 (m, 4H) 3.36-3.41 (m, 4K) 3.83 (s, 3H) 5.68 (s, 2H) 7.21-7.34{m, 5H) 8.20 (s, IH)
MS m/e (ESI) 325 . 01 (MH"-CFaCOOH)

Example 310
3-Benzyl-5-(2-oxo-2-phenylethyl)-2- (piperazin-1-yl)-3,5-dihydroi
midazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and 2-bromoacetophenone according to the method described in Example 258(b).
1H-NMR(CD30D)
5 3.31-3.36 (m, 4H) 3.44-3.49 (m, 4H) 5.69 (s, 2H) 5.77 (s, 2H) 7.22-7.52(m, 8H) 8.06 (d, J=9.3Hz, 2H) 8.32 (s, IH) MS mie (ESI) 429 . 39 (MH-CFaCOOH)
Example 311
3-Benzyl-5-(2-phenylethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo
[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4- [l-benzyl-7-oxo-6 , 7-dihydro-lH-imidazo [4 , 5-d] pyridazin-2-yl3-piperazine-l-carboxylate and (2-bromoethyl)benzene according to the method described in Example 258(b).
1H-NMR(CDCl3)
8 3.11 (t, J=8.1Hz,2H) 3.24-3.29 (m, 4H) 3.37-3.42 (m, 4H) 4.46 (t, J=8.1Hz,2H) 5.58 (s, 2H) 7.09-7.34 (m, lOH) 8.20 (s, IH)
MS ra/e (ESI) 415.54 (MH-CFaCOOH)
Example 312
3-Benzyl-5-(2-phenoxyethyl)-2- (piperazin-1-yl)-3,5-dihydroimidaz
o [4 , 5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and 2-bromoethyl phenyl ether according to .the method described in Example 258(b).
1H-NMR{CDCl3)
5 3.21-3.24 (m, 4H) 3.37-3.42 (m, 4H) 4.37 (t, J=5.8Hz,2H) -4.64 (t, J=5.8Hz,2H) 5.58 (s, 2H) 6.86-6.94 (m, 3H) 7.07-7.34 (m, 7H) 8.21 (s, IH)
MS m/e (ESI) 431. 57 (MH-C.FsCOOH)

Example 313
3-benzyl-2-(piperazin-1-yl)-5-(2-propynyl)-3,5-dihydroimidazo[4,
5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and 3-bromo-l-propyne according to the method described in Example 258(b).
KS m/e (ESI) 349 . 31 (MH"-CFaCOOH)
Example 314
[3-Benzyl-4-oxo-2-(piperazin-l-yl)-3,4-dihydroimidazo[4,5-d]pyri dazin-5-yl]acetonitrile trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and bromoacetonitrile according to the method described in Example 258(b).
MS mle (ESI) 350 . 30 (MH"-CFaCOOH)
Example 315
3-Ben2yl-5-(2-hydroxyethyl)-2- (piperazin-l-yl)-3,5-dihydroimidaz
o[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and 2-bromoethanol according to the method described in Example 258(b).
MS m/e (ESI) 355.32 (MH-CFaCOOH)
Example 316
3-Benzyl-5-(2-methoxyethyl)-2-(piperazin-l-yl)-3,5-dihydroimidaz . o. [4 , 5-d]pyridazin-4-one trif luoroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and bromoethyl methyl ether according to the method described in Example 258(b).
MS mie (ESI) 369 .35 (MH-CFaCOOH) .

Example 317
Ethyl
[3-benzyl-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyri
da2in-5-yl]acetate trifludroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and ethyl bromoacetate according to the method described in Example 258(b).
MS m/e (ESI) 397.33 (MH-CFaCOOH)
Example 318
3-Benzyl-5-[2-(3-methoxyphenyl)-2-oxoethyl]-2-(piperazin-1-yl)-3
,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and 2-brorao-3"-methoxyacetophenone according to the method described in Example 258 (b) .
MS m/e (ESI) 459.34 (MH-CFsCOOH)
Example 319
2-[3-3enzyl-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d] py
ridazin-5-ylmethyl]benzonitrile trifluoroacetate
The title compound was obtained by using t-butyl 4-[l-benzyl-7-oxo-6,7-dihydro-lH-iraida20[4,5-d]pyridazin-2-yl]pi perazine-1-carboxylate and 2-bromomethylbenzonitrile according to the method described in Example 258 (b) .
MS /n/e (ESI) 326 . 33 (MH-CFsCOOH)
Example 320
.5-Methyl-2-(piperazin-1-yl)-3- (2-propynyl)-3,5-dihydroimidazo[4, 5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-(6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl)pi perazine-1-carboxylate and 3-bromo-l- propyne according to the method described in Example 258(b).

1H-NMR(CD30D)
5 2.99 (t, J=3.3Hz, IH) 3.45-3.49 (m, 4H) 3.65-3.69 (m, 4H) 3.83 (s, 3H) 5.75 (d, J=3.3Hz, 2H) 8.20 (s, IH) MS ;n/e (ESI) 273 .1 (MH-CFsCOOH)
Example 321
3- (2-Butenyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5
-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl
4- (6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl)pi
perazine-1-carboxylate and l-bromo-2-butene according to the method
described in Example 258(b).
1H-NMR(CD30D)
51.69 and 1.84 (dd, J=6.3,1.3Hz anddd, J=6.3,1.3Hz, 3H) 3.4 3-3.4 8 (m, 4H) 3.54-3.58 (m, 4H) 3.82 and 3.84 (s, 3H) 4.94 and 5.07 (d, J=6.5Hzand d, J=6.5Hz, 2H) 5.63-5.80 and 6.11-6.20 (m, 2H) 8.19 and 8.22 (s,- IH)
MS m/e (ESI) 289.2 (MH-CFsCOOH)
Example 322
5-.Methyl-3- (2-pentenyl) -2- (piperazin-1-yl) -3 , 5-dihydroimidazo [4 ,
5-dlpyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4- (6-methyl-7-oxo-6 , 7-dihydro-lH-imidazo [4 , 5-d] pyridazin-2-yl) pi perazine-1-carboxylate and l-bromo-2-pentene according to the method described in Example 258(b).
1H-NMR(CD30D)
5 0.97 and 1.08 (t, J=7.7Hz and t, J=7.7Hz, 3H) 2.04-2.27 (m, 2H) 3.42-3.46 (m, 4H) 3.54-3.58 (m, 4H) 3.81 and 3.84 (s, 3H) 4.91-4.96 (m, 2H) 5.59-5.81 and 6.14-6.22 (m, 2H) 8.19 and 8.22 (s, IH) ,
MS m/e (ESI) 303.25 (MH"-CFaCOOH)
Example 323
5-Methyl-3- (3-methyl-2-butenyl) -2- (piperazin-1-yl) -3 , 5-dihydroim
idazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl

4-(6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl)pi perazine-1-carboxylate and l-bromo-3-methyl-2-butene according to the method described in Example 258(b). 1H-NMR(CD36Df
6 1.75 (s, 3H) 1.83 (s, 3H) 3.43-3.47 (m, 4H) 3.52-3.57 (m, 4H) 3.84 (s, 3H) 5.00 (d, J=6.8Hz, 2H) 5.40-5.45 {m, IH) 8.17 (s, IH) MS mie (ESI) 303 . 27 (MH"-CFaCOOH)
Example 3 24
3-Cyclopropylmethyl-5-methyl-2-(piperazin-1-yl) -3 , 5-dihydroimida
zo [4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-(6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl)pi perazine-1-carboxyate and cyclopropylmethyl bromide according to the method described in Example 258(b).
1H-NMRCCDaOD)
5g.44-0.55 (m, 4H) 0.81-0.85 (m, IH) 3.42-3.46 (m, 4H) 3.54-3.58 (m, 4H) 3.83 (s, 3H) 4.39 (d, J=6.6Hz, 2H) 8.21 (s, IH) MS mIe (ESI) 289 . 25 (MH"-CFsCOOH)
Example 325
5-[2-(2-Aminophenyl)-2-oxoethyl]-3- (2-butynyl)-2-(piperazin-1-yl
)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one bistrifluoroacetate
(a) t-Butyl
4-[l-(2-butynyl) -6-[2-(2-nitrophenyl)-2-oxoethyl]-7-oxo-6,7-dihy
dro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
The ti"cle compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate and 2-bromo-2"-nitroacetophenone according to the method described in Exa.mple 258 (b) . . _ -H-NMR(CDCl3)
5 1.49 (s, 9H) 1.83 (t, J=2.3Hz, 3H) 3.37-3.44 (m, 4H) 3.50-3.55
(m, 4H) 5.04 (q, J=2.3Hz, 2H) 5.44 (s, 2H) 7.62 (m, IH) 7.71-7.74
(m, 2H) 8.13 (d, J=7.9Hz, IH) 8.21 (s, IH)
(b)
5-[2-(2-Aminophenyl)-2-oxoethyl]-3- (2-butynyl)-2-(piperazin-1-yl

)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one bistrifluoroacetate
2 ml of water, 0.070 g of iron and 0.007 g of ammonium chloride were added to a 5 ml ethanol solution of 0.058 g of t-butyl 4-[1-(2-butynyl) -6-[2-(2-nitrophenyl)-2-oxoethyl]-7-oxo-6,7-dihy dro-lH-imidazo[4,5-d]pyridazin-2-yl]piperazine-l-carboxylate, and the mixture was heated under reflux for three hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 4 ml of dichloromethane, and 4 ml of trifluoroacetic acid was added thereto. After the mixture had been stirred for two hours, the solvent was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.051 g of the title compound.
*H-NMR(CD30D)
5 1.82-(t, J=2.3Hz, 3H) 3.45-3.50 (m, 4H) 3.68-3.72 (m, 4H) 5.16 (q, J=2.3Hz, 2H) 5.68 (s, 2H) 6.56 (t, J=7.2Hz, IH) 6.67 (d, J=7.2Kz,lH) 7.30 (t, J=7.2Hz, IH) 7.85 (d, J=7.2Hz, IH) 8.25 (s, IH)
MS m/e (ESI) 406 . 22 (MH-2CF3COOH)
Example 326
3-(2-Butynyl)-5,7-dimethyl-2-(piperazin-l-yl)-3,5-dihydroimidazo
[4 , 5-d]pyridazin-4-one trifluoroacetate
(a) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4- (1-hydroxyethyl)-IH-imidazol
-2-yl]piperazine-l-carboxylate
0.5 ml of a 0.3 M tetrahydrofuran solution of methyl magnesium bromide was added to a 3 ml tetrahydrofuran solution of 0.050 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-lH-imidazol-2-yl]pipe , r.azine-1-carboxylate at -70 °C under a nitrogen atmosphere, and the mixture was allowed to warm to room temperature. 10 ml of a 5% aqueous ammonium chloride solution was added to this solution, and the mixture was extracted with 30 ml of ethyl acetate. The organic layer was washed successively with 10 ml of water and 10 ml of a saturated sodium chloride solution, and then dried over magnesium sulfate. The

organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.049 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1).
1H-NMR{CDCl3)
5 1.37 (t, J=7.1Hz, 3H) 1.47 (d, J=6.9H2, 3H) 1.48 (s, 9H) 1.81 (t, J=2.3Hz, 3H) 3.17-3.22 (m, 4H) 3.55-3.59 (m, 4H) 3.84 (d, J=6.9Hz, IH) 4.38 (q, J=7.1Hz, 2H) 4.78 (q, J=2 . SHz, 2H) 5.12 (quint, J=6.9Hz, IH)
(b) t-Butyl
4-[4-acetyl-l-(2-butynyl)-5-ethoxycarbonyl-lH-imidazol-2-yl]pipe razine-1-carboxylate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4- (1-hydroxyethyl) -IH-imidazol -2-yl] piperazine-1-carboxylate according to the method described in Example 115 (g)v
-H-NMR(CDCl3) " .
5 1.38 (t, J=7.1Hz, 3H) 1.48 (s, 9H) 1.79 (t, J=2.3Hz, 3H) 2.53 (s, 3H) 3.14-3.18 (m, 4H) 3.56-3.60 (m, 4H) 4.38 (q, J=7.IHz, 2H) 4.77 (q, J=2.3Hz, 2H) (c)
3-(2-Butynyl) -5 , 7-dimethyl-2-(piperazin-1-yl)-3,5-dihydroimidazo [4,5-d]pyridazin-4-one trifluoroacetate
0.15 ml of methylhydrazine was added to a 3 ml ethanol solution of -0.019 g of t-butyl
4-[4-acetyl-l-{2-butynyl)-5-ethoxycarbonyl-lH-imidazol-2-yl]pipe razine-1-carboxylate, and the mixture was heated at 110""C for 25 hours. The solvent was concentrated under reduced pressure. The residue was dissolved in 0.5 ml of dichloromethane, and 0.5 ml of trifluoroacetic acid was added thereto. The solvent was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.017 g of the title compound.
MS mie (ESI). 301.33 (MH-CFaCOOH)

Example 327
3- (2-Butynyl) -7-phenyl-2- (piperazin-1-yl) -3 , S-dihydroimidazo [4,5
-d] pyridazin-4-one trifluoroacetate
(a) t-Butyl 4-[l- (2-butynyl)-5-ethoxycarbonyl-4- (1-hydroxyphenylmethyl) -iH-i midazol-2-yl]piperazine-l-carboxylate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -5-ethoxycarbonyl-4-formyl-lH-imidazol-2-yl]pipe razine-1-carboxylate and phenylmagnesium bromide according to the method described in Example 326(a).
1H-NMR(CDCl3)
51.33 (t, J=7.3Hz, 3H) 1.48 (s, 9H) 1.81 (t, J=2.2Hz, 3H) 3.16-3.27 (m, 4H) 3.55-3.59 (m, 4H) 4.24-4.34 (m, 2H) 4.39 (d, J=8.3Hz, IH) 4.78 (q, J=2.2Hz, 2H) 6.09 (d, J=8.3Hz, IH) 7.22 (t, J=8.0Hz, IH) 7.30 (-, J=8.0Hz, 2H) 7.41 (d, J=8.0Hz,2H)
(b) t-Butyl
4-[4-benzoyl-l-,(2-butynyl)-5-ethoxycarbonyl-lH-imidazol-2-yl]pip erazine-1-carboxylate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -5-ethoxycarbonyl-4- (1-hydroxyphenylmethyl)-IH-i midazol-2-yl]piperazine-1-carboxylate according to the method described in Example 115(g).
1H-NMR(CDCl3)
50.92 (t, J=7.1Hz, 3H) 1.48 (s, 9H) 1.83 (t, J=2.3Hz, 3H) 3.22-3.28 (m, 4K) 3.57-3.62 (m, 4H) 4.03 (q, J=7.1Hz, 2H) 4.88 (q, J=2.3Hz, 2H) 7.43 (t, J=8.1Hz, 2K) 7.55 (t, J=8.1Hz, IH) 7.92 (d, J=8.1Hz, 2H)
(c) t-Butyl
4-[1-(2-butynyl) -7-oxo-4-phenyl-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl] piperazine-1-carboxylate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -5-ethoxycarbonyl-4- (1-hydroxyphenylmethyl)-iH-i midazol-2-yl]piperazine-1-carboxylate and hydrazine according to the method described in Example 115(h).
1H-NMR(CDCl3)
5 1.50 (s, 9H) 1.83 (t, J=2.3Hz, 3H) 3.44-3.48 (m, 4H) 3.63-3.67

(m, 4H) 5.15 (q, J=2.3Hz, 2H) 7.40-7.50 (m, 3H) 8.34 (d, J=8.1Hz, 2H) 10.70 (s, IH)
(d)
3-(2-Butynyl) -7-phenyl-2-(piperazin-1-yl)-3,S-dihydroimidazo[4,5
-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-4-phenyl-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-l-carboxylate according to the method described in Example 115 (i).
MS m/e (ESI) 349 . 30 (MH-CFaCOOH)
Example 328
3-(2-Butynyl)-5-methyl-7-phenyl-2- (piperazin-1-yl) -3,5-dihydroim
idazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-4-phenyl-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-l-carboxylate and methyl iodide according to the method described in Example 258(b).
-H-NMR(CD30D)
5 1.83 (t, J=2.4Hz, 3H) 3.47-3.51 (m, 4H) 3.71-3.75 (m, 4H) 3.92 (s, 3H) 5.22 (q, J=2.4Hz, 2H) 7.43-7.48 (m, 3H) 8.35 (d, J=8.1Hz, 2H)
MS m/e (ESI) 363.31 (MH-CFsCOOH)
Example 329
[3-(2-Butynyl)-4-oxo-7-phenyl-2- (piperazin-1-yl)-3,4-dihydroimid
azo[4,5-d]pyridazin-5-yl]acetic acid trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-4-phenyl-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-l-carboxylate and t-butyl bromoacetate a,ccording to the method described in Example 258 (b) .
MS mie (ESI) 407 . 29 (MH"-CFaCOOH)
Example 33 0
2-[3-(2-Butynyl)-4-oxo-7-phenyl-2- (piperazin-1-yl) -3,4-dihydroim
idazo[4,5-d]pyridazin-5-ylmethyl]benzonitrile trifluoroacetate

The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-7-oxo-4-phenyl-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-l-carboxylate and 2-bromomethylbenzonitrile according to the method described in Example 258 (b) .
MS m/e (ESI) 464 . 33 (MH-CFsCOOH)
Example 331
3-(2-Butynyl) -5-methyl-2-(piperazin-1-yl)-7-trifluoromethyl-3,5-
dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
(a) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-(2,2,2-trifluoro-1-hydroxyet
hyl)-lH-imida2ol-2-yl]piperazine-1-carboxylate
0.065 g of zinc and a 2 ml N,N-dimethylformamide solution of 0.200 g of trifluoromethyl iodide were added to a 3 ml N,N-dimethylformamide solution of 0.155 g of t-butyl
4-[1-(2-butynyl) -5-ethoxycar±)onyl-4-formyl-lH-imidazol-2-yl]pipe razine-1-carboxylate under a nitrogen atmosphere, and the mixture was stirred under sonication for 30 minutes. 30 ml of ethyl acetate and 3.0 ml of a 5% ammmonium chloride solution were added to the mixture. The organic layer was washed twice with 20 ml of water and then with 20 ml of a saturated sodium chloride solution, and dried over magnesium sulfate . The organic liquid was concentrated under reduced pressure . The residue was purified by silica gel column chromatography. Thus, 0.013 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:9).
-H-NMR(CDCl3)
51.39 (t, J=6.9Hz, 3H) 1.48 (s, 9H) 1.83 (t, J=2.4Hz, 3H) 3.15-3.26 (m, 4H) 3.55-3.60 (m, 4H) 4.34 (qq, J=10.2,6.9Hz, 2H) 4.53-4.64 (br.s, IH) 4.83 (qq, J=17 . 6*, 2 . 4Hz, 2H) 5.39-5.47 (br.s, IH) (b) .3-(2-Butynyl)-5-methyl-2- (piperazin-1-yl)-7-trifluoromethyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
0.060 g of Dess-Martin reagent was added to a 4 ml dichloromethane solution of 0.013 g of t-butyl
4-[1-(2-butynyl) -5-ethoxycarbonyl-4-(2,2,2-trifluoro-1-hydroxyet hyl)-lH-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was

stirred at room temperature for 15 hours. 5 ml of dichloromethane, 10 ml of a saturated aqueous sodium bicarbonate solution and 0.100 g of sodium hydrogen sulfite were added to the solution. The organic layer was dried over magnesium sulfate", and concentrated under reduced pressure. The residue was dissolved in 4 ml of ethanol, and 0 .2 ml of methylhydrazine was added to the solution. The mixture was heated at 110"C for 20 hours. The solvent was concentrated under reduced pressure. The residue was dissolved in 0.5 ml of dichloromethane, and 0.5 ml of trifluoroacetic acid was added thereto. The solvent was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.008 g of the title compound. 1H-NMR(CD30D)
5 1.83 (t, J=2.3Hz, 3H) 3.45-3.49 (m, 4H) 3.71-3.75 (m, 4H) 3.87 (s, 3H) 5.18 (q, J=2.3Hz, 2H)
MS m/e (ESI) 355 .16 (MH"-CFaCOOH)
Example 332
1-(2-Butynyl) -6-methyl-7-oxo-2-(piperazin-1-yl)-6,7-dihydroimida
20 [4,5-d] pyridazine-4-carboxamide trifluoroacetate
(a) t-Butyl
4-[1-(2-butynyl) -4-(cyano-hydroxymethyl)-5-methoxycarbonyl-lH-im
idazol-2-yl]piperazine-l-carboxylate
0.200 g of sodium cyanide and 0.010 ml of acetic acid were added to a 15 ml acetonitrile solution of t-butyl
4-[1-(2-butynyl)-5-methoxycarbonyl-4-formyl-lH-imidazol-2-yl]pip erazine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 100 ml of ethyl acetate was added to the solution, and the mixture was washed twice with 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0 .274 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3) .
1H-NMR(CDCl3)

6 1.49 (s, 9H) 1.83 (t, J=2.5Hz, 3H) 3.19-3.23 (m, 4H) 3.56-3.60 (m, 4H) 3.95 (s, 3H) 4.68 (d, J=9.0Hz, IH) 4.82 (q, J=2.5Hz, 2H) 5.72 (d, J=9.0Hz, IH)
(b) t-Butyl
4-[l- (2-butynyl) -4- (carbamoyl-hydroxymethyl)-5-methoxycarb&ivyl-l H-imidazol-2-yl]piperazine-l-carboxylate
3.2 ml of 30% aqueous hydrogen peroxide and 3.2 ml of 28% aqueous ammonia solution were added to an 8 ml methanol solution of 0.274 g of t-butyl
4-[1-(2-butynyl) -4-(cyano-hydroxymethyl)-5-methoxycarbonyl-lH-im idazol-2-yl]piperazine-l-carboxylate at 5°C, and the mixture was stirred for 15 hours. 100 ml of a saturated sodium hydrogen sulfite solution was added to the solution, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined together. The conbined organic layers were dried over magnesium -sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.039 g of th.e title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:9).
"H-NMR(CDCl3)
6 1.48 (s, 9H) 1.83 (t, J=2.5Hz, 3H) 3.13-3.25 (m, 4H) 3.54-3.57 (m, 4H) 3.91 (s, 3H) 4.33-4.37 (br.s, IH) 4.77 (q, J=2.5Hz, 2H) 5.54 (s, IK) 5.63 (s, IH) 6.82 (s, IH)
(c) t-Butyl
4-[4-aminooxalyl-l-(2-butynyl)-5-methoxycarbonyl-lH-imidazol-2-y l]piperazine-l-carboxylate
0.051 ml of triethylamine and a 1 ml dimethyl sulfoxide solution of 0.058 g of sulfur trioxide pyridine were added to a 2 ml dichloromethane solution of 0.038 g of t-butyl
4-[1-(2-butynyl)-4-(carbamoyl-hydroxymethyl)-5-methoxycarbonyl-l .K-imidazol-2-yl]piperazine-l-carboxylate at 0°C, and the mixture was stirred at room temperature for 15 hours. Then, 0.102 ml of triethylamine and a 1 ml dimethyl sulfoxide solution of 0.116 g of sulfur trioxide pyridine were added, and the mixture was stirred at room temperature for 8 hours. 50 ml of ethyl acetate was added to the solution, and the organic layer was washed successively with 20

ml of an aqueous solution of 1% sulfuric acid, 20 ml of a saturated sodium bicarbonate solution, and 20 ml of a saturated sodium chloride solution. The organic layerwas dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0 . 021 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:1) . 1H-NMR(CDCl3)
5 1.48 (s, 9H) 1.82 (t, J=2.5H2, 3H) 3.19-3.23 (m, 4H) 3.56-3.59 (m, 4H) 3.84 (s, 3H) 4.84 (q, J=2. 5Hz, 2H) 5.62 (br.s, IH) 7.02 (br.s, IH)
(d) t-Butyl
4-[1-(2-butynyl)-4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-lH-dihyd roimidazo[4,5-dl pyrida2in-2-yl]piperazine-l-carboxylate
The title compound was obtained by using t-butyl 4-[4-aminooxalyl-l-{2-butynyl)-5-methoxycarbonyl-lH-imidazol-2-y 1]piperazine-l-carboxylate according to the method described in Example 115 (h) . -H-NMR(CDCl3)
5 1.50 (s, 9H) 1.84 (t, J=2.3Hz, 3H) 3.46-3.50 (m, 4H) 3.63-3.66 (m, 4H) 3.99 (s, 3H) 5.12 (q, J=2.3Hz, 2H) 6.16 (s, IH) 8.85 (s, IH) (e)
1-(2-Butynyl) -6-methyl-7-oxo-2-(piperazin-1-yl)-6,7-dihydroimida zo[4,5-d]pyrida2ine-4-carboxamide trifluoroaceate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-lH-dihyd roimidazo[4,5-d] pyrida2in-2-yl]piperazine-l-carboxylate according to the method described in Example 115 (i). MS mie (ESI) 330 .18 (MH-CFaCOOH)
Example 333
.1-(2-Butynyl) -6-methyl-7-oxo-2- (piperazin-1-yl)-6,7-dihydroimida zo[4,5-d]pyridazine-4-carbonitrile trifluoroacetate
0.030 ml of triethylamine and 0.015 ml of phosphorus oxychloride were added to a 1 ml dichloromethane solution of 0.015 g of t-butyl 4-[1-(2-butynyl)-4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-lH-dihyd roimidazo [4 , 5-d]pyrida7.in-2-yl]piperazine-l-carboxylate, and the

mixture was stirred at room temperature for 15 hours. 1 ml of dichloromethane and 1 ml of trifluoroacetic acid were added to the solution. After one hour, the solvent was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.001 g of the title compound.
1H-NMR(CD30D)
5 1.83 (t, J=2.3Hz, 3H) 3.45-3.49 (m, 4H) 3.74-3.78 (m, 4H) 3.88
(s, 3H) 5.18 (q, J=2.3Hz, 2H)
MS m/e (ESI) 312 . 25 (MH-CFsCOOH)
Example 334
3- (2-Butynyl) -7-dimethylamino-5-methyl-2- (piperazin-l-yl) -3 , 5-di hydroimidazo [ 4 , 5-d] pyridazin-4-one trif luoroacetate (a)-
l-Benzyl-7-chloro-5-methyl-l, 5-dihydrpimidazo [4 , 5-d] pyridazin-4-one
0.604 g of potassium carbonate and 0.297 ml of methyl iodide were added to a 30 ml N,N-dimethylformamide solution of 1.035 g of l-benzyl-7-chloro-l,5-dihydroimidazo [4,5-d]pyridazin-4-one (J. A. Carbon Journal of the American Chemical Society, 80, pp. 6083, 1958) , and the mixture was stirred at room temperature for 15 hours. 300 ml of ethyl acetate and 100 ml of water were added to the solution, and the organic layer was washed twice with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0 . 280 g of the title compound was obtained from the fraction eluted with ethyl acetate. . . 1H-NMR(CDCl3)
6 3.86 (s, 3H) 5.64 (s, 2H) 7.11-7.16 (m, 2H) 7.35-7.43 (m, 3H)
7.90 (s, IH)
(b)
l-Benzyl-7-dimethylamino-5-methyl-l, 5-dihydroimidazo [ 4 , 5-d] pyrid
azin-4-one

A 2 ml aqueous solution of 50% dimethylamine was added to a 2 ml ethanol solution of 0.138 g of
l-benzyl-7-chloro-5-methyl-l,_5-dihydroimidazo[4,5-d]pyridazin-4-one, aiid"the mixture was heated at 130°C for 72 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus , 0 .139 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:19).
K-NMR(CDCl3)
52.73 (s, 6H) 3.79 (s, 3H) 5.59 (s, 2H) 7.12-7.16 (m, 2H) 7.30-7.39 {m, 3H) 7.79 (s, IH) (c)
l-Benzyl-2-chloro-7-dimethylamino-5-methyl-l,5-dihydroimidazo[4, 5-d]pyridazin-4-one
1.15 ml of a 1 M tetrahydrofuran solution of dibutylmagnesium was added to a 2 ml tetrahydrofuran solution of 0.320 ml of diisopropylamine at room temperature under a nitrogen atmosphere, and the mixture was stirred for 8 hours. This solution was added to a 4 ml retrahydrofuran solution of 0.162 g of
l-benzyl-7-dimethylamino-5-methyl-l,5-dihydroimidazo[4,5-d]pyrid azin-4-one at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 hours.. Then, a 5 ml tetrahydrofuran solution of 0.540 g of hexachloroethane was added dropwise to the solution. After the mixture had been stirred for 4 hours, 30 ml of a 5% aqueous ammonium chloride solution was added therero. The mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 30 ml of water and 30 ml of a saturated sodium chloride solution, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, .0.094 g of the title compound was obtained from the fraction eluted with exhyl acetate-hexane (2:1).
1H-NMR(CDCl3)
52.68 (s, 6H) 3.78 (s, 3H) 5.60 (s, 2H) 7.05-7.08 (m, 2H) 7.29-7.37 (m, 3H) (d) t-Butyl

4-[l-benzyl-7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-lH-imidaz o [4,5-d]pyridazin-2-yl]piperazine-l-carboxylate
The title compound was obtained by using l-benzyl-2-chloro-7-dimethylamino-5-iT\ethyl-l", 5"-dihydroiraidazo[4 , 5-d]pyridazin-4-one according to the method described in Example 116(c).
"H-NMR(CDCl3)
5 1.47 (s, 9H) 2.68 (s, 6H) 3.19-3.22 (m, 4H) 3.41-3.46 (m, 4H) 3.76 (s, 3H) 5.40 (s, 2H) 6.88 (m, 2H) 7.20-7.25 (m, 3H) (e) t-Butyl
4-[7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-lH-imidazo[4,5-d]p yrida2in-2-yl]piperazine-1-carboxylate
A 5 ml tetrahydrofuran solution of 0.117 g of t-butyl 4-[l-benzyl-7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-lH-imidaz o[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate was added to 15 ml of liquid ammonia, and 0.009 g of lithium was added to the mixture under reflux. 1 ml of a 5% aqueous ammonium chloride solution was added to the solution , and the solvent was evaporated off . The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.007 g of the title compound.
1H-NMR(CD30D)
5 1.48 (s, 9H) 3.11 (s, 6H) 3.55-3.58 (m, 8H) 3.69 (s, 3H) (f)
3-(2-Butynyl)-7-dimethylamino-5-methyl-2-(piperazin-1-yl) -3,5-di hydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-lH-imidazo[4,5-d]p yridazin-2-yl]piperazine-l-carboxylate and l-bromo-2-butyne according to the method described in Example 258 (b) .
-H-NMR(CD30D)
5 1.80 (t, J=2.3Hz, 3H) 2.75 (s, 6H) 3.44-3.48 (m, 4H) 3.62-3.65 (m, 4H) 3.68 (s, 3H) 5.16 (q, J=2.3Hz, 2H)
MS m/e (ESI) 330.16 (MR"-CFBCOOH) Example 335 3-(2-Butynyl)-5-methyl-2-(piperidin-4-yl)-3,5-dihydroimid

azo[4,5-d]pyridazin-4-one trifluoroacetate
(a)
5-Methyl-2-(piperidin-4-yl)-3,S-dihydroimidazo[4,5-dlpyridazin-4
-one trifluoroacetate
2.71 g of iron (III) chloride was added to a 16 ml ethanol solution-of 0.292 g of 4,5-diamino-2-methyl-2H-pyridazin-3-one [CAS No. 4725-76-2] (Martine Beljean-Leymarie, Michel Pays and Jean-Claude Richer, Canadian Journal of Chemistry 61, pp. 2563, 1983) and 0.426 g of t-butyl 4-formylpiperidine-l-carboxylate, and the mixture was heated under reflux for 6 hours. The reaction solution was cooled to room temperature. The solution was filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.061 g of the title compound.
""H-NMR-(CD30D)
6 2.06-2.17 (m, 2H) 2.28-2.35 (m, 2H) 3.15-3.24 (m, 2H) 3.29-3.35 (m, IH) 3.50-3.56 (m, 2H) 3.85 (s,.3H) 8.28 (s, IH)
(b) t-Butyl
4-(6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl)pi peridine-1-carboxylate
The title compound was obtained by using 5-methyl-2- (piperidin-4-yl) -3 , 5-dihydroi.midazo [4 , 5-d] pyridazin-4-one trifluoroacetate according to the method described in Example 258 (a) .
1H-NMR(CDCl3)
5 1.50 (s, 9H) 2.00-2.16 (m, 4H) 2.85-2.99 (br.s, 2H) 3.23 (tt, J=11.9,4.0Hz, IH) 3.95 (s, 3H) 4.11-4.40 (br.s, 2H) 8.39 (s, IH) 13.90 (s, IH)
(c) t-Butyl
.4-[1-(2-butynyl)-6-methyl-7-oxo-6 , 7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-y1]piperidine-1-carboxylate
The title compound was obtained by using t-butyl 4-(6-methy1-7-0X0-6,7-dihydro-lH-imidazo[4,5-d]pyridazin-2-yl)pi peridine-1-carboxylate according to the method described in Example 119(d) .

1H-NMR(CDCl3)
5 1.48 (s, 9H) 1.81 (t, J=2.3Hz, 3H) 1.93-2.00 (m, 4H) 2.85-2.96
(br.s, 2H) 3.14 (quint, J=7.9Hz, 1H),3..85 (s, 3H) 4.16-4.37 (br.s,
2H) 5.39 (q, J=2 .*3Hz, 2H) 8.24 (s, IH)
(d)
3-(2-Butynyl)-5-methyl-2-(piperidin-4-yl)-3,5-dihydroimid
azo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-6-methyl-7-oxo-6 , 7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperidine-l-carboxylate according to the method described in Example 115 (i) .
1H-NMR(CD30D)
6 1.80 (t, J=2.3Hz, 3H) 2.10-2.11 (m, 2H) 2.25-2.32 (m, 2H)
3.18-3.41 (m, 3H) 3.56-3.61 (m, 2H) 3.83 (s, 3H) 5.47 (t, J=2.3Hz,
2H) 8.27 (s, IH)
MS mle (ESI) 286 . 27 (MH"-CFaCOOH)
Example 336
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5
-c]pyridin-4-one trifluoroacetate
(a) 3-(2-Butynyl)-4-chloro-3H-imidazo[4,5-c]pyridine
2.0 g of 4-chloro-lH-imidazo[4,5-c]pyridine, 1.37 ml of. l-bromo-2-butyne, and 1.98 g of potassium carbonate were suspended in 15 ml of N,N-dimethylformamide, and the suspension was stirred at room temperature for 18 hours. -The reaction solution was diluted with ethyl acetate , and washed with water . The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.79 g of a 1:1 mixture consisting of the title compound and the compound alkylated at the . 1-position was obtained from the fraction eluted with hexane-ethyl acetate (1:2) .
(b) 3-(2-Butynyl)-2,4-dichloro-3H-imidazo[4,5-c3pyridine
2 .22 ml of a tetrahydrof uran solution of lithium diisopropylamide was added dropwise to a 5 ml tetrahydrofuran solution of 490 rag of 3-(2-butynyl)-4-chloro-3H-imidazo [4,5-c] pyridine in a dry

ice-methanol bath, and the mixture was stirred below -66°C for 20 minutes. The resulting reaction mixture was added dropwise to a 2 ml tetrahydrofuran solution of 1.13 g of hexachloroethane while the temperature of the mixture was controlled to be -63°C or lower. The mixture was stirred for one hour and 40 minutes in the same bath, and then a saturated aqueous ammonium chloride solution was added thereto. The resulting mixture was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography. Thus, 120 mg of brown oily material was obtained from the fraction eluted with hexane-ethyl acetate (2:1) .
1H-NMR{d6-DMS0)
6 : 1.78 (s, 3H) 5.29 (s, 2H) 7.70 (d, J=5.6Hz, IH) 8.21 (d, J=5.6Hz, IH)
(c) t-Butyl
4- [3- (2-butynyl) -4-chloro-3H-imida20 [4 , 5-c]pyj:idin-2-yl ] piperazi ne-1-carboxylate
211 mg of t-butyl 3-(2-butynyl)-2 , 4-dichloro-3H-imidazo[4,5-c]pyridine, 197 mg of piperazine-1-carboxylate, and 222 mg of sodium bicarbonate were dissolved in ethanol, and the mixture was stirred at 80°C for 30 minutes and then at room temperature for three hours and 20 minutes. The reaction solution was diluted with ethyl acetate, and the solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 244 mg of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:1).
-H-NMR(CDCl3)
5 : 1.52 (s, 9H) 1.87 (s, 3H) 3.47-3.49 (m, 4H) 3.65-3.68 (m, 4H) 4.94 (s, 2H) 7.41 (d, J=5.2Hz, IH) 8.15 (d, J=5.2Hz, IH) (d)
3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3 , 5-dihydroimidazo [4,5 -c]pyridin-4-one trifluoroacetate
98 mg of sodium acetate was dissolved in 2 ml of dimethyl sulfoxide

containing 0.3 mmol of t-butyl
4-[3-(2-butynyl)-4-chloro-3H-imidazo[4,5-c]pyridin-2-yl]piperazi ne-1-carboxylate, and the mixture was stirred at 120""C for 4 hours. Then, 100 mg of potassium carbonate and 1 ml of methyl iodide were added to the reaction solution. The mixture was stirred at room temperature. The reaction solution was diluted with ethyl acetate, and the solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 5 mg of the product obtained from the fraction eluted with methanol-ethyl acetate (1:10) was dissolved in 0 .5 ml of trif luoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trif luoroacetic acid)) to give 0.55 mg of the title compound. MS m/e (ESI) 286(MH-CFsCOOH)
Example 337
3-Benzyl-2-(piperazin-1-yl)-3,S-dihydroimidazo[4,5-c]pyridin-4-o
ne trifluoroacetate
(a) Allyl-(3-nitropyridin-4-yl)amine
40 ml of allylamine was added to a 400 ml ethanol solution of 18.0 g of 4-ethoxy-3-nitropyridine hydrochloride, and the mixture was heated under reflux for 8 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 13.6 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1) .
1H-NMR(CDCl3)
64.00 (m, 2H) 5.29-5.35 (m, 2H) 5.87-5.98 (m, IH) 6.63 (d, J=6.5Hz, IH) 8.30 (d, J=6.5Hz, IH) 8.31 (br.s, IH) 9.23 (s, IH)
(b) N*4*-allyl-2-chloropyridine-3,4-diamine
55 ml of 35% hydrochloric acid was added to 3.02 g of allyl- (3-nitropyridin-4-yl) amine, and the mixture was heated to 90""C . 19.1 g of tin chloride was added to the solution, and the mixture was kept at 90°C for 30 minutes. The reaction solution was cooled in an ice-water bath, and then 250 ml ice/water was added thereto.

The reaction solution was concentrated under reduced pressure, and then 250 ml of ammonia-saturated methanol was added thereto. The mixture was stirred for 20 hours. 750 ml of ethy.l .acetate was added to the solution, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.88 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1).
-H-NMR(CDCl3)
5 3.29-3.58 (br.s, 2H) 3.84 (d, J=6.3H2, 2H) 4.26-4.37 (br.s, IH) 5.24 (d, J=11.0Hz, IH) 5.29 (d, J=16.0Hz,lH) 5.85-5.98 (ddt, J=16.0,11.0,6.5Hz, IH) 6.43 (d, J=6.5H2, IH) 7.66 (d, J=6.5Hz, IH) (c) l-Allyl-4-chloro-l,3-dihydroimidazo[4,5-c]pyridin-2-one
A 400 ml acetonitrile solution of 4.46 g of N,N"-disuccinimidyl carbonate was added to an acetonitrile solution containing 2.88 g of N*4*-allyl-2-chloropyridine-3,4-diamine, and the mixture was heated under reflux for 7 0 hours. The solvent was concentrated under reduced pressure, and the residue was dissolved in a mixture consisring of 500 ml of ethyl acetate and 300 ml of water. The organic layer was washed twice with 100 ml of IN hydrochloric acid and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.30 g of the title compound was obtained from the fraction eluted with ethyl acetate-dichloromethane (1:1) .
1H-NMR(CDCl3)
5 4.51 (d, J=5.7Hz, IH) 5.25 (d, J=16.0Hz, IH) 5.30 (d, J=10.9Hz,lH) 5.85-5.95 (ddt, J=16.0,10.9,5.7Hz , IH) 6.91 (d, J=6.9Hz, IH) 8.10 (d, J=6.9Hz, IH) 8.99 (br.s, IH) (d) l-Allyl-3-benzyl-4-chloro-l,3-dihydroimidazo[4 , 5-c]pyridin-2-one
0.76 g of potassium carbonate and 0.94 g of benzyl bromide were added to a 50 ml N,N-dimethylformamide solution of 1.05 g of l-allyl-4-chloro-l,3-dihydroimidazo[4,5-c]pyridin-2-one, and the mixture was stirred at room temperature for 14 hours. 300 ml of water and 300 ml of ethyl acetate were added to the solution, and the organic

layer was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give 1.57 g of the title compound.
1H-NMR(CDCl3)
5 4.56 (d, J-5.7HZ, IH) 5.23 (d, J=16.0Hz, IH) 5.30 (d, J=10.9Hz,lH) 5.44 (s, 2H) 5.85-5.95 (ddt, J=16.0,10.9,5.7Hz, IH) 6.91 (d, J=6.9Hz, IH) 7.25-7.34 (m, 5H) 8.08 (d, J=6.9Hz, IH) 8.99 (br.s, IH)
(e) 3-Benzyl-4-chloro-l,3-dihydroimidazo[4,5-c]pyridin-2-one
1.5 ml of water, 1.06 g of 4-methyl morpholine N-oxide, 3 ml of an aqueous solution of 2% osmic acid, and a 6 ml aqueous solution of 1. 94 g of sodium periodate were added to a 15 ml 1, 4-dioxane solution of 0.75 g of
l-allyl-3-benzyl-4-chloro-l,3-dihydroimidazo[4,5-c] pyridin-2-one, and the mixture was heated at 60°C for 18 hours. 200 ml of water was added to the solution, and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed twice with 50 ml of water and then washed with 50 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.38 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1).
-H-NMR(CDCl3)
5 5.44 (s, 2H) 7.01 (d, J=6.5Hz, IH) 7.30-7.38 (m, 5H) 8.08 (d, J=6.5Hz, IH) 9.18 (s, IH)
(f) 3-Benzyl-2, 4-dichloro-l,3-dihydroimidazo[4,5-c]pyridine
5 ml of phosphorus oxychloride and 0.338 g of phosphorus
pentachloride were added to 0.383 g of
3-benzyl-4-chloro-l,3-dihydroimidazo[4,5-c]pyridin-2-one, and the mixture was heated under reflux for 24 hours. The solvent was concentrated under reduced pressure, and the residue was poured into 50 g of ice/water. The mixture was extracted with 100 \ml of ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.13 gof the title compound

was obrained from the fraction eluted with ethyl acetate-hexane (2:1) . -K-NMR(CDCl3)
5 5.43 (s, 2H) 7-12 (d, J=6.5Hz, IH) 7.30-7.38 (m, 5H) 8.18 (d, J=6.5Kz, IH) (g) t-Butyl
4-(3-benzyl-4-chloro-3H-imida2o[4,5-c]pyridin-2-yl)piperazine-l-carboxylate
0.094 g of t-butyl piperazine-1-carboxylare was added to a 1 ml N,N-dimethylformamide solution of 0.127 g of 3-benzyl-2, 4-dichloro-l,3-dihydroimidazo[4,5-c]pyridine, and the mixture was heated at 150°C for two hours. 25 ml of ethyl acetate was added to the mixture, and the organic layer was washed three times with 10 ml of water and then with 10 ml of an aqueous solution saturated with sodium chloride . The organic liquid was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.029 g of the title compound was obtained from the fraction eluted with ethyl acerate-hexane (3:2).
-H-NMR(CDCl3)
5 1.44 (s, 9H) 3.21-3.25 (m, 4H) 3.49-3.53 (m, 4H) 5.53 (s, 2H)
7.08 (d, J=6.5Hz, IH) 7.30-7.38 (m, 5H) 8.14 (d, J=6.5Hz, IH)
(h) . .
3-Ben2yl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-c]pyridin-4-o ne trifluoroacetate
1 ml of water and 1 ml of 35% hydrochloric acid were added to a 2 ml N,N-dimethylformamide solution of 0.029 g of t-butyl 4- (3-benzyl-4-chloro-3H-imidazo[4,5-c]pyridin-2-yl) piperazine-1-carboxylate, and the mixture was heated under reflux for 36 hours. The solvent was concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.006 g of the title compound.
.MS m/e (ESI) 310 . 29 (MH-CFsCOOH)
Example 338
3- (2-Butynyl) -2- (piperazin-1-yl) -3 , 5-dihydroi.midazo [4 , 5-c]pyridi

n-4-one trifluoroacetate
(a) 2-bromo-l-(2-butynyl)-lH-imidazole-4,S-dicarbonitrile
69.8 g of potassium carbonate and 50 ml N,N-dimethylf.ormamide solution of 74 ml of l-bromo-2-butyne were added to a 520 ml N,N-dimethylformamide solution of 90.5 g of
2-bromo-lH-imidazole-4,5-dicarbonitrile [CAS No 50847-09-1], and the mixture was heated at 50°C for 8 hours. 1 L of ethyl acetate and 500 ml of water were added to the solution, and the organic layer was washed twice with 500 ml of water and then with 500 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 48.0 g of the title compound was obtained from the fraction eluted with ethyl acetare-hexane (1:4).
1H-NMR(CDCl3)
5 1.87 (t, J=2.3Hz, 3H) 4.85 (q, J=2.3Hz, 2H)
(b) Ethyl 2-bromo-l- (2-butynyl) -5-cyano-lH-imidazole-4-carboxylate
25 ml of concentrated sulfuric acid was added to a 500 ml ethanol
solution of 48.0 g of
2-bromo-l-(2-butynyl)-lH-imidazole-4,5-dicarbonitrile, and the mixture was heated under reflux for 110 hours. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in a mixture consisting of 500 ml of ethyl acetate and 500 ml of water, and the pH of the solution was adjusted to 8 using potassium hydroxide. The aqueous layer was extracted with 500 ml of ethyl acetate, and the organic layers were combined together. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 21.7 g of the title compound was obtained from the frac-ion eluted with ethyl acetate-hexane (1:3) .
1H-NMR(CDCl3)
5 1.43 (t, J=7.0Hz, 3H). 1.87 (t, J=2.3Hz, 3H) 4.46 (q, J=7 . OHz, 2H) 4.85 (q, J=2.3Hz, 2H)
(c) t-Butyl
4-[1-(2-butynyl) -5-cyano-4-ethoxycarbonyl-lH-imidazol-2-yl]

piperazine-l-carboxylate
25.1 g of the title compound was obtained by using 21.7 g of ethyl 2-bromo-l- (2-butynyl) -5-cyano-lH-imidazole-4-carboxylate according to the method described in Example 115(b).
1H-NMR(CDCl3)
51.43 (t, J=7.0Hz, 3H) 1.49 (s, 9H) 1.87 (t, J=2.3Hz, 3H) 3.22-3.26 (m, 4H) 3.56-3.61 (m, 4H) 4.44 (q, J=7.0Hz, 2H) 4.68 (q, J=2.3Hz, 2H)
(d) t-Butyl 4- [1- (2-butynyl) -4-carboxy-5-cyano-lH-imidazol-2-yl]
piperazine-l-carboxylate
16 ml of a 5N aqueous sodium hydroxide solution was added to a 500 ml ethanol solution of 25.1 g of t-butyl
4-[1-(2-butynyl) -5-cyano-4-ethoxycarbonyl-lK-imidazol-2-yl]piper azine-1-carboxylate, and the mixture was stirred at room temperature for two hours. Then, the solvent was concentrated under reduced pressure. The residue was dissolved in a mixture consisting of IL of ethyl acetate and 500 ml of water. 50 ml of 2N hydrochloric acid-was added to the solution. The organic layer was washed with 200 ml of a saturated sodium chloride solution, and dried over magnesium sulfate. The organic liquid was concentrated under reduced pressure to give 23.2 g of the title compound.
1H-NMR(CDCl3)
5 1.49 (s, 9H) 1.87 (t, J=2.3Hz, 3H) 3.22-3.26 (m, 4H) 3.56-3.61 (m, 4K) 4.68 (q, J=2.3H2, 2H)
(e) t-3utyl
4-[1-(2-butynyl)-5-cyano-4-hydroxymethyl-lH-imida2ol-2-yl] piperazine-l-carboxylate
6.9 g of triethylamine and then 100 ml tetrahydrofuran solution of 10.19 g of isobutyl chloroformate were added dropwise to 600 ml of tetrahydrofuran containing 22.9 g of t-butyl . 4,- [1- (2-butynyl) -4-carboxy-5-cyano-lK-imidazol-2-yl] piperazine-l-carboxylate at -10°C. After the precipitate had been removed by filtration, the solution was again cooled to -10°C. A IQO ml aqueous solution of 9.45 g of sodium borohydride was added dropwise to the solution. After one hour, 500 ml of ethyl acetate and 500 ml of water were added to the solution. The pH of the solution was

adjusted to 5 using 1 N hydrochloric acid, and then adjusted to 10 using a saturated sodium bicarbonate solution. The organic layer was washed successively with 500 ml of water and 500 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 19.1 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (4:1).
1H-NMR(CDCl3)
5 1.48 (s, 9H) 1.84 (t, J=2.3Hz, 3H) 2.26 {t, J=6 . 3Hz , IH) 3.13-3.17 (m, 4H) 3.53-3.57 (m, 4H) 4.58 (q, J=2.3Hz, 2H) 4.64 (d, J=6.3Hz, 2H)
(f) t-Butyl
4-[1-(2-butynyl) -5-cyano-4-formyl-lH-imidazol-2-yl]piperazine-1-carboxylate
3.28 g of manganese dioxide was added to a 5 ml dichloromethane solution of 1.35 g of t-butyl
4-[1-(2-butynyl)-5-cyano-4-hydroxymethyl-lH-imidazol-2-yl]pipera zine-1-carboxylate. The reaction solution was stirred at room_ temperature for 15 hours, then stirred and heated under reflux for five hours. The solution was filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.11 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
"H-NMR(CDCl3)
5 1.50 (s, 9H) 1.88 (t, J=2.3Hz, 3H) 3.24-3.28 (m, 4H) 3.59-3.63 (m, 4H) 4.70 (q, J=2.3Hz, 2H) 9.87 (s, IH)
(g) t-Butyl
4-[1-(2-butynyl)-5-cyano-4-(2-ethoxycarbonylvinyl)-lH-imidazol-2 -yl]piperazine-1-carboxylate
0.038 g of sodium hydride was added to a 5 ml tetrahydrofuran solution of 0.243 g of ethyl diethylphosphonoacetate at 5"C under a nitrogen atmosphere. 0.310 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-formyl-lH-imidazol-2-yl] piperazine-1-carboxylate dissolved in 5 ml of tetrahydrofuran was added, and the mixture was stirred for 30 minutes. 50 ml of ethyl

acetate and 2 5 ml of 0 . IN sodium hydroxide were added to the solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column, chromatography. Thus, 0 . 380 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane(3:7) .
1H-NMR(CDCl3)
61.33 (t, J=7.4Hz, 3H) 1.50 (s, 9H) 1.86 (t, J=2.3Hz, 3H) 3.19-3.23 (m, 4H) 3.55-3.59 (m, 4H) 4.25 (q, J=7.4Hz, 2H) 4.59 (q, J=2.3Hz, 2H) 6.70 (d, J=15.8Hz, IH) 7.50 (d, J=15.8Hz, IH) (h) t-3utyl
4-[1-(2-butynyl) -5-cyano-4-(2-carboxyvinyl)-lH-imidazol-2-yl]pip erazine-l-carboxylate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -5-cyano-4-(2-ethoxycarbonylvinyl) -lH-imidazol-2 -yl]piperazine-l-carboxylate according to the method described in Example 338(d).
-K-NMR(CDCl3)
5 1.50 (s, 9H) 1.86 (t, J=2.3Hz, 3H) 3.19-3.23 (m, 4H) 3.55-3.59 (m, 4K) 4.59 (q, J=2.3Hz, 2H) 6.70 (d, J=15.8Hz, IH) 7.50 (d, J=15.8Hz, IK)
(i) t-5utyl
4-[1-(2-butynyl)-5-cyano-4-(2-azidecarbonylvinyl)-lH-imidazol-2-yl] piperazine-1-carboxylate
A .mixture consisting of 0.200 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-(2-carboxyvinyl)-lH-imidazol-2-yl]pip erazine-l-carboxylate, 0 . 073 ml of triethylamine, and a 2 ml t-butanol solution of 0.108 ml of diphenylphosphoryl azide was heated at 50 "C under a nitrogen atmosphere for 4 hours. 50 ml of ethyl acetate was added uo the solution, and the mixture was washed with 20 ml of water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chroma uography. Thus , 0.178 g of the title compound was obtained from the fraction eluted with ethyl aceta-e-hexane (2:3).
1H-NMR(CDCl3)
5 1.48 (s, 9H) 1.86 (t, J=2.2Hz, 3H) 3.19-3.23 (m, 4H) 3.55-3.59 (m, 4H) 4.59 (q, J=2.2Hz, 2H) 6.67 (d, J=15.4Hz, IH) 7 56 (d, J=15.4Hz,

IH)
(j) --Butyl
5- [4-(2-t-butoxycarbonylaminovinyl)-1-(2-butynyl)-5-cyano-lH-imi dazol-2-yl] piperazine-1-carboxylate
A 10 ml t-butanol solution of 0.178 g of t-butyl 4-[1-{2-butynyl)-5-cyano-4-(2-azide
carbonylvinyl)-lH-imidazol-2-yl] piperazine-1-carboxylate was heated under reflux under a nitrogen atmosphere for 15 hours. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.169 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (9:11).
-K-NMR(CDCl3)
5 1.48 (s, 9H) 1.84 (t, J=2.2Hz, 3H) 3.16-3.19 (m, 4H) 3.54-3.58 (m, 4H) 4.51 (q, J=2.2Hz, 2H) 5.83 (d, J=15.0Kz, IH) 6.43-6.53 (m, IK) 7.55-7-. 66 (m, IH) (k) -Butyl
4-[4- (2-t-butoxycarbonylaminovinyl)-1-(2-butynyl)-5-carbamoyl-lH -imidazol-2-yl] piperazine-1-carboxylate
The title compound was obtained by using t-butyl 4- [4-(2-t-butoxycarbonylaminovinyl)-1-(2-butynyl)-5-cyano-lH-imi dazol-2-yl] piperazine-1-carboxylate according to the method described in Example 332(b).
-K-NMR(CDCl3)
5 1.48 (s, 9H) 1.84 (t, J=2.2Hz, 3H) 3.21-3.25 (m, 4H) 3.54-3.58 (m, 4H) 4.68 (q, J=2.2Hz, 2H) 5.90 (br.s, IH) 6.36 (br.d, J=14.8Hz, IH) 6.92 (br.d, J= 8.4Hz, IH) 7.45 (br.s, IH) 7.52 (m, IH)
(1)
3- (2-Butynyl)-2-(piperazin-l-yl)-3,5-dihydroimidazo[4,5-c]pyridi
n-4-one trifluoroacetate
0.1 ml of 5N hydrochloric acid was added to a 0.3 ml ethanol solution of 0.0075 g of t-butyl
4-[4- (2-t-butoxycarbonylaminovinyl)-1- (2-butynyl)-5-carbamoyl-lH -imidazol-2-yl]piperazine-l-carboxylate, and the mixture was stirred at room temperature for 15 hours. The solvent was concentrated under reduced pressure. The residue was purified by

reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0043 g of the title, Qompound. 1H-NMR(CD30D")
5 1.81 (t, J=2.4Hz, 3H) 3.45-3.48 (m, 4K) 3.62-3.65 (m, 4H) 5.15 (q, J=2.4Hz, 2H) 6.60 (d, J=7.1Hz, IH) 7.18 (d, J=7.1Hz, IH)
MS m/e (ESI) 272 . 32 (MH-CFaCOOH) Example 339:
3-(2-Butynyl)-5-(2-phenylethyl)-2- (piperazin-l-yl) -3,5-dihydroim idazo[4,5-c]pyridin-4-one trifluoroacetate
(a) t-Butyl
4-[3-(2-butynyl) -4-oxo-4,5-dihydro-3H-imidazo[4,5-c] pyridin-2-yl ]piperazine-1-carboxylate
The title compound was obtained by using 3- (2-bu-ynyl)-2-(piperazin-l-yl)-3,5-dihydroimidazo[4,5-c]pyridi n-4-one trif luoroacetate according to the method described in Example 258(a) ,.
1H-NMR(CDCl3) "5 1.49 (s, 9H) 1.83 (t, J=2.3Hz, 3H) 3.35-3.39 (m, 4H) 3.60-3.64 (m, 4H) 5.07 (q, J=2. 3Hz, 2H) 6.55 (d, J=7.1Kz, IH) 6.97 (d, J=7.1Hz, IH)
(b) . .
3-(2-Buynyl)-5-(2-phenylethyl)-2- (piperazin-l-yl) -3,5-dihydroim idazo[4,5-c]pyridin-4-one trifluoroacetate
The -itle compound was obtained by using t-butyl 4-[3-(2-butynyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c] pyridin-2-yl ]piperazine-l-carboxylate and (2-bromoethyl)benzene according to the method described in Example 258(b).
1H-NMR(CD30D)
5 1.83 (t, J=2.4Hz, 3H) 3.05 (t, J=7.3Hz, 2H) 3.45-3.48 (m, 4H) .3..62-3.65 (m, 4H) 4.26 (t, J=7.3Hz, 2H) 5.18 (q, J=2.4Hz, 2H) 6.46 (d, J=7.3Hz, IH) 7.15 (d, J=7.3Hz, IK) 7.16-7.30 (m, 5H)
MS mie (ESI) 376 . 36 (MH-CFsCOOH) Example 340:
3-(2-Butynyl)-5-(2-phenoxyethyl)-2-(piperazin-l-yl) -3,5-dihydroi midazo[4,5-c]pyridin-4-one trifluoroacetate

The title compound was obtained by using t-butyl 4-[3-(2-butynyl)-4-oxo-4,5-dihydro-3H-imida20[4,5-c]pyridin-2-yl ]piperazine-l-carboxylate and 2-bromoethyl phenyl ether according to the method described in Example 258(b).
1H-NMR(CD30D)
5.1.80 (t, J=2.4Hz, 3H) 3.45-3.48 (m, 4H) 3.62-3.65 (m, 4H) 4.30 (t, J=5.5Hz, 2H) 4.44 (t, J=5.5Hz, 2H) 5.16 (q, J=2.4Hz, 2H) 6.59 (d, J=6.1Hz, IH) 6.87-6.91 (m, 3H) 7.20-7.24 (m, 2H) 7.50 (d, J=6.1Hz, IH)
MS .7i/e (ESI) 392.34 (MH-CFaCOOH) Example 341:
3-(2-Bu-ynyl)-5-(2-oxo-2-phenylethyl)-2-(piperazin-1-yl) -3,5-dih ydroimidazo[4,5-c]pyridin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4-[3-(2-butynyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl ]pipera2ine-l-carboxylate and 2-bromoacetophenone according to the method described in Example 258(b).
1H-NMR(CD30D)
6 1.79 (t, J=2.3Hz, 3H) 3.46-3.50 (m, 4H) 3.64-3.68 (m, 4H) 5.16 (q, J=2.3Hz, 2H) 5.61 (s, 2H) 6.65 (d, J=7.3Hz, IH) 7.37 (d, J=7.3Hz, IH) 7.57 (t, J=8.0Hz, 2H) 7.69 (t, J=8.0Hz, IH) 8.10 (d, J=8.0Hz, 2H)
MS in/e (ESI) 392 . 34 (MH-CFjCOOH) Example 342:
2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5 -c]pyridin-5-ylmethyl]benzonitrile trifluoroacetate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl) -7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyridin-2-yl ]piperazine-l-carboxylate and 2-bromomethylbenzonitrile according to the method described in Example 258(b).
-H-NMR(CD30D)
5 1.78 (t, J=2.3Hz, 3H) 3.45-3.49 (m, 4H) 3.64-3.67 (m, 4H) 5.14 (q, J=2.3Hz, 2H) 5.47 (s, 2H) 6.67 (d, J=7.0Kz, IH) 7.20 (dd, J=7.2,1.0Hz, IH) 7.46 (td, J=7.2,1.0Hz, IH) 7.50 (d, J=7.OHz, IH) 7.60 (td, J=7.2,1.0Hz, IH) 7.80 (dd, J=7.2,1.OHz,IH)
MS m/e (ESI) 387.34 (MH-CFsCOOH)

Example 343
Methyl
3-(2-bu-ynyl) -4-oxo-2-(piperazin-1-yl)-4,5-dihydroimidazo[4,5-c]
pyridine-6-carboxylate trifluoroacetate
(a) t-Butyl
4-[1-(2-butynyl) -4-hydroxymethyl-5-thiocarbamoyl-lH-imidazol-2-y 1]piperazine-1-carboxylate
10 ml of a 50%. aqueous solution of ammonium sulfide was added to a 50 ml ethanol solution of 3.596 g of t-butyl
4-[1-(2-butynyl) -5-cyano-4-hydroxymethyl-lH-imidazol-2-yl]pipera zine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 400 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magn-esium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 3 . 221 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane(4:1).
-K-NMR(CDCl3)
5 1.49 (s, 9H) 1.84 (t, J=2.4Hz, 3H) 3.17-3.21 (m, 4H) 3.54-3.60 (m, 4H) 3.62 (t, J=5.8Hz, IH) 4..68 (d, J=5.8Hz, 2H) 5.05 (q, J=2.4Hz, 2H) 7.35 (br.s, IH) 8.46 (br.s, IH)
(b) t-Butyl
4-[4(t-butyldiphenylsilanyloxymethyl)-1-(2-butynyl)-5-thiocarba moyl-lH-imidazol-2-yl]piperazine-1-carboxylate
0.668 g of imidazole and 2.70 g of t-butylchlorodiphenylsilane were added to a 25 ml N,N-dimethylformamide solution of 3.221 g of t-buryl
4-[1-(2-butynyl)-4-hydroxymethyl-5-thiocarbamoyl-lH-imidazol-2-y , l]piperazine-l-carboxylate, and the mixture was stirred at room temperature for 16 hours. 300 ml of ethyl acetate was added to the solution, and the organic layer was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure . The residue was purified by silica gel column

chromatography . Thus , 4 . 357 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
1H-NMR(CDCl3) " . .
6 1.05 (s, 9H) 1.49 (s, 9H) 1.84 (t, J=2.4Hz, 3H) 3.06-3.11 (m, 4H) 3.53-3.57 (m, 4H) 4.74 (s, 2H) 5.19 (q, J=2.4Hz, 2H) 7.31 (br.d, J=4.1Hz, IH) 7.37 (t, J=7.2Hz, 4H) 7.44 (d, J=7.2Hz, 2H) 7.63 (d, J=7.2Hz, 4H) 9.28 (br.d, J=4.1Hz, IH)
(c) t-Butyl
4-[4-(t-butyldiphenylsilanyloxymethyl)-1-(2-butynyl)-5-methylsul fanylcarbonimidoyl-lH-imidazol-2-yl]piperazine-1-carboxylate
1.23 g of trimethyloxonium tetrafluoroborate was added to a 100 ml dichloromethane solution of 4.351 g of t-butyl 4-[4-(t-butyldiphenylsilanyloxymethyl)-1- (2-butynyl)-5-thiocarba moyl-lH-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was srirred at room temperature for 15 hours. 300 ml of ethyl acetate was added to the solution, and the" organic layer was washed successively witJn 100 ml of a saturated sodium bicarbonate solution and 100 ml a saturated ammonium chloride solution. The organic layer was dried over magnesium sulfate,- and concentrated under reduced pressure to give 4.439 g of the title compound.
1H-NMR(CDCl3)
5 1.05 (s, 9H) 1.49 (s, 9H) 1.84 (br.s, 3H) 2.36 (br.s, 3H) 3.11-3.15 (m, 4H) 3.54-3.58 (m, 4H) 4.63 (br.s, 2H) 4.66 (br.s, 2H) 7.37 (t, J=7.2Hz, 4H) 7.44 (d, J=7.2Hz, 2K) 7.63 (d, J=7.2Hz, 4H)
(d) t-Butyl
4-[1-(2-butynyl)-4-hydroxymethyl-5-methylsulfanylcarbonyl-lH-imi dazol-2-yl]piperazine-1-carboxylate
30 ml of 5N hydrochloric acid was added to a 100 ml tetrahydrofuran solution of 5.05 g of t-butyl 4-[4-(t-butyl
diphenylsilanyloxymethyl) -1- (2-butynyl) -5-.methylsulfanylcarbonim .idoyl-lK-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 22 hours. The solvent was concentrated under reduced pressure. The residue was dissolved in 100 ml of dichloromethane, and 2.05 g of di-t-butyl dicarbonate was added thereto. The solution was made alkaline with 5N sodium hydroxide, and stirred for 2 hours. The organic layer was dried over

magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus ,2.24 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3) .
1H-NMR(CDCl3)
5 1.49 (s, 9H) 1.84 (t, J=2.3Hz, 3H) 2.47 (s, 3H) 3.21-3.25 (m, 4H) 3.27 (t, J=5.6Hz, IH) 3.56-3.60 (m, 4H) 4.81 (q, J=2.4Hz, 2H) 4.89 (d, J=5.6Hz, 2H) (e) t-Butyl
4- [1-(2-butynyl)-4-formyl-5-methylsulfanylcarbonyl-lH-imidazol-2 -yl]piperazine-l-carboxylate
The title compound was obtained by using t-butyl 4-[1-(2-butynyl)-4-hydroxymethyl-5-methylsulfanylcarbonyl-lH-imi dazol-2-yl]piperazine-l-carboxylate according to the method described in Example 115(g) .
1H-NMR(CDCl3)
5 1.48 (s, 9H) 1.84 (t, J=2.3Hz, 3H) 2.58 (s, 3H) 3.-22-3.26 (m, 4H) 3.56-3.60 (m, 4H) 4.80 (q, J=2.4Hz, 2H) 9.88 (s, IH)
(f)
2- (4-t-Butoxycarbonylpiperazin-l-yl)-3-(2-butynyl) -4-oxo-3,4-dih ydroimidazo[4,5-c]pyridine-5,6-dicarboxylic acid 5-benzyl ester 6-methyl ester
0.079 g of 1, 8-diazabicyclo[5.4.0]-7-undecene and then 5 ml of dichloromethane containing 0.194 g of t-butyl
4-[1-(2-butynyl)-4-formyl-5-methylsulfanylcarbonyl-lH-imidazol-2 -yl]piperazine-1-carboxylate were added to a 2 ml dichloromethane solution of 0.174 g of methyl
benzyloxycarbonylamino-(dimethoxyphosphoryl)-acetate, and the mixture was stirred at room .temperature for 16 hours. The solvent was concentrated under reduced pressure. The residue was purified .by silica gel column chromatography. Thus, 0.147 g of the title compound was obtained from the fraction eluted with ethyl ace-ate-hexane(3:2). -H-NMR(CDCl3)
5 1.49 (s, 9H) 1.83 (t, J=2.3Hz, 3H) 3.37-3.41 (m, 4H) 3.59-3.64 (m, 4H) 3.83 (s, 3H) 5.04 (q, J=2.3Hz, 2H) 5.46 (s, 2H) 7.33-7.38

(m, 3H) 7.41 (s, IH) 7.45-7.48 (m, 2H) (g) t-Butyl 4-[3-(2-butynyl)-4-oxo-6-trimethoxv
me thy 1-4 , 5-dihydro-_3H-imidazo [4 , 5-c] pyridin-2-yl] piperazine-l-ca rboxylate
0.023 g of sodium was added to 2 ml of methanol under a nitrogen atmosphere. After hydrogen generation stopped, a 2 ml methanol solution of 0.147 g of
2-(4-t-butoxycarbonypiperazin-l-yl)-3- (2-butynyl)-4-oxo-3,4-dihy droimidazo[4,5-c]pyridine-5,6-dicarboxylic acid 5-benzyl ester 6-methyl ester was added to the solution. The mixture was stirred at room temperature for 16 hours. Then, 40 ml of ethyl acetate, 20 ml of 5% agueous ammonium chloride solution, and 1 ml of 1 N hydrochloric acid were added to the solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel colu-mn chromatography. Thus, 0.108 g of the title compound-was obtained from the fraction eluted with ethyl acetate.
-K-NMR(CDCl3)
5-1.50 (s, 9H) 1.83 (t, J=2.3Hz, 3H) 3.20 (s, 9H).3.37-3.41 (m, 4H) 3.59-3.64 (m, 4H) 5.07 (g, J=2.3Hz, 2H) 6.82 (s, IH) 8.60 (br.s, IH)
(h) Methyl
3- (2-butynyl)-4-oxo-2-(piperazin-1-yl)-4,5-dihydroimidazo [4,5-c]pyridine-6-carboxylate trifluoroacetate
The title compound was obtained by using t-butyl 4-[3-{2-butynyl)-4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo [4 , 5-c]pyridin-2-yl] pipera2in-l-carboxyla~e according to the method described in Example 338(1).
-K-NMR(CD30D)
5 1.81 (t, J=2.3Hz, 3H) 3.45-3.49 (m, 4r:) 3.64-3.67 (m, 4H) 3.95 As, 3H) 5.17 (q, J=2.3Hz, 2H) 7.35 (s, IH)
KS m/e (ESI) 330.16(MH-CFaCOOH)
Example 344
Methyl
3- (2-butynyl)-5-methyl-4-oxo-2-(piperazin-1-yl) -4,5-dihydroimida

zo [4 , 5-c]pyridine-6-carboxylate trifluoroacetate
0.024 g of potassium carbonate and 0.027 ml of methyl iodide were added to a 2 ml N,N-dimethylformamide solution of 0.030 g of, t-butyl 4- [3- {2-butynyl) -4-oxo-6-trimethoxymethyl-4 , 5-dihydro-3H-imidazo [4,5-c]pyridin-2-yl]piperazine-l-carboxylate, and the mixture was heated at 50°C for 48 hours. 2 ml of ethyl acetate and 2 ml of water were added to the solution. The aqueous layer was extracted with 1 ml of ethyl acetate. The organic layers were combined together, and then divided into equal halves. One of the halves was concentrated by flushing with nitrogen gas, and the residue was dissolved in 0 .5 ml of methanol. The solution was combined with 0.1 ml of 5N hydrochloric acid, and the mixture was left for 1 hour. The solvent was removed, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.007 g of the title compound.
-H-NMR(CD30D)
5 1.81 (t, J=2.4Hz, 3H) 3.45-3.48 (m, 4H) 3.62-3.65 (m, 4H) 3.74 (s, 3H) 3.94 (s, 3H) 5.17 (q, J=2.4Hz, 2H) -7.25 (s, IH)
MS m/e (ESI) 344 . 30 (MH-CFjCOOH)
Example 345
3-(2-Butynyl) -5-methyl-4-oxo-2-(piperazin-1-yl) -4,5-dihydroimida
zo[4,5-c]pyridine-6-carboxylic amide trifluoroacetate
The other half of the solution prepared in Example 344 was concentrated by flushing with nitrogen gas. The residue was treated with 1 ml of 28% ammonia water. The solution was heated under reflux in a sealed tube for 48 hours. The solvent was concentrated under reduced pressure. Subsequent synthetic steps were carried out according to the same procedure as used in Example 115 (i) . Thus , 0.010 .g of the title compound was synthesized. MS m/e (ESI) 329.32(MH-CF3COOH)
Example 34 6
Methyl
3- (2-butynyl)-4-oxo-5-(2-oxo-2-phenylethyl)-2-(piperazin-1-yl)-4

,S-dihydroimidazo[4,5-c]pyridine-6-carboxylate trifluoroacetate The title compound was obtained by using t-butyl
4-[3-(2-butynyl)-4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo
[4,5-c]pyridin-2-yl]piperazine-l-carboxylate and
2-bromoacetophenone according to the method described in Example 344 . MS ;n/e (ESI) 448 . 31 (MH-CFaCOOH)
Example 347
Methyl
3-(2-butynyl)-5-(2-cyanobenzyl)-4-oxo-2-(piperazin-1-yl)-4,5-dih
ydroimidazo[4,5-c]pyridine-6-carboxylate trifluoroacetate
The title compound was obtained by using t-butyl 4- [3-(2-butynyl)-4-oxo-6-trimethoxy
methyl-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]piperazine-1-ca rboxylare and 2-bromomethylbenzonitrile according to the method •described in Example 344.
MS mie (ESI) 445 . 32 (MH-CFaCOOH)
Example 34 8
3- (2-Bui:ynyl) -5- (2-cyanobenzyl) -4-oxo-2- (piperazin-1-yl) -4 , 5-dih
ydroimidazo[4,5-c]pyridine-6-carboxylic amide trifluoroacetate
The title compound was obtained by using t-butyl 4-[3-(2-butynyl)-4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo [4,5-c]pyridin-2-yl]piperazine-l-carboxylate and 2-bromomethylbenzonitrile according to the method described in Example 345.
MS mIe (ESI) 43 0.34 (MH-CFsCOOH)
Example 349
1-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-1,5-dihydroimidazo[4,5 ,-d]pyridazin-4-one trifluoroacetate (a)-l
3- (2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridaz in-4-one and (a)-2

1-(2-butynyl)-2-chloro-5-methyl-l,S-dihydroimidazo[4,5-d]pyridaz in-4-or.e
0.166 g of potassium carbDnate and 0.106 Hi of 2-butynyl bromide were added to a 10 ml N,N-dimethylformamide solution of 0.184 g of 2-chloro-5-methyl-l,5-dihydroimidazo[4,5-d]pyridazin-4-one, and the mixture was stirred at room temperature for 18 hours. 50 ml of ethyl acetate was added to the solution, and the mixture was washed three -imes with 20 ml of water and then with 20 ml of a saturated sodium chloride solution. The organic liquid was dried over magnesium sulfate, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography. Thus, 0.175 g of
3-(2-bu-ynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridaz in-4-one was obtained from the fraction eluted with hexane-ethyl acetate (4:1), and 0.033 g of
1- {2-bu-ynyl)-2-chloro-5-methyl-l,5-dlhydroimidazo[4,5-d]pyridaz in-4-or.e was obtained from the fraction eluted with hexane-ethyl acetate (2:3) .
3- (2-butynyl) -2-chloro-5-methyl-3 , 5-dihydroimidazo [4 , 5-d].pyri dazin-4-one
1H-NMR(CDCl3)
5 1.82 (t, J= 2.3Hz, 3H) 3.87 (s, 3H) 5.32 (q, J=2.3Hz, 2H) 8.19 (s, IH)
1-(2-butynyl)-2-chloro-5-methyl-l,5-dihydroimidazo [4,5-d] pyridazin-4-one
1H-NMR(CDCl3)
5 1.87 (t, J=2.3Hz, 3H) 3.91 (s, 3H) 4.90 (q, J=2.3Hz, 2H) 8.20 (s, IH) (b) t-Butyl
4-[1-(2-butynyl)-5-methyl-4-oxo-4,5-dihydro-lH-imidazo[4,5-d]pyr .. idazin-2-yl] piperazine-1-carboxylate
The title compound was obtained by using 1-(2-butynyl)-2-chloro-5-methyl-l,5-dihydroimidazo[4,5-d]pyridaz in-4-one and t-butyl piperazine-1-carboxylate according to the method described in Example 119(c).
1H-NMR(CDCl3)

5 1.50 (s, 9H) 1.87 (t, J=2.3Hz, 3H) 3.30-3.34 (m, 4H) 3.59-3.63 (m, 4H) 3.90 (s, 3H) 4.70 (q, J=2.3Hz, 2H) 8.11 (s, IH) (c)
1- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -l", S-dihydroiinidazo [4 , 5 -d]pyridazin-4-one trifluoroacetate
The title compound was obtained by using t-butyl 4- [5-me-hyl-l-(2-butynyl)-4-oxo-4,5-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]piperazine-l-carboxylate according to the method described in Example 115 (i) .
-H-NMR(CD30D)
5 1.84 (t, J=2.4Hz, 3H) 3.44-3.48 (m, 4H) 3.58-3.62 (m, 4H) 3.86
(s, 3H) 4.96 (q, J=2.4Hz, 2H) 8.39 (s, IH)
MS m/e (ESI) 287 . 17 (MH"-CFsCOOH)
Example 350
2-[ (1R*,2R*)2-aminocyclohexylamino]-3- (2-butynyl)-5-methyl-3,5-d
ihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by reacting 3- (2-buzynyl) -2-chloro-5-methyl-3 , S-dihydroi.Tiidazo [4-, 5-d] pyridaz in-4-one and trans-1,2-cyclohexanediamine by the method as used in Example 119(c) and purifying the product by reverse-phase high performance liquid chromatography.
-H-NMR(CD30D)
6 1.39-1.49 (m, 2H) 1.50-1.61 (m, 2H) 1.80 (t, J=2.3Hz, 3H)
1.85-1.92 (m, 2H) 2.11-2.18 (m, 2H) 3.19 (td, J=ll . 0 ,4 . IHz , IH) 3.80
(s, 3H) 3.93 (td, J=11.0,4.2Hz, IH) 4.91 (dq, J=18.0,2 . 3Hz , IH) 5.44
(dq, J=18.0,2.3Hz, IH) 8.07 (s, IH)
MS m/e (ESI) 315 . 19 (MH-CFsCOOH)
Example 351
2-[(IR*,2S*)2-aminocyclohexylamino]-3- (2-butynyl)-5-methyl-3,5-d
ihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
The title compound was obtained by reacting 3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridaz in-4-one and cis-1,2-cyclohexanediamine by the method as used in Example 119(c) and purifying the product by reverse-phase high

performance liquid chromatography.
""H-NKR(CD30D)
5 1.54-1.68 (m, 3H) 1.71-1.81 (m, 2H) 1.83 (t, J=2.4Hz, 3H) 1.85-1.91 (m, 2H) 1.91-2.01 (m, IH) 3.69 (m, IH) 3.80 (s, 3H) 4.37 (m, IH) 5.04 (dq, J=18 . 3 , 2 . 4Hz , IH) 5.55 (dq, J=18 . 3 , 2 . 4Hz , IH) 8.09 (s, IH)
MS m/e (ESI) 315.27 (MH-CFaCOOH)
ExamDle 352
3- (2-Buvynyl) -5-inethyl-2- (1, 2,3, 6-tetrahydropyridin-4-yl) -3 , 5-di
hydroimidazo[4 , 5-d] pyridazin-4-one trifluoroacetate
(a)
5-Me-chyl-2- (pyridin-4-yl) -1, 5-dihydroimidazo [4 , 5-d] pyridazin-4-o
ne
0.560 g of 4,5-diamino-2-methyl-2H-pyridazin-3-one and 0.535 g of
4-pyridinecarbaldehyde were added to 10 ml of nitrobenzene, and the
mixture was heated at 190°C under a nitrogen atmosphere for three
hours. The reaction solution was cooled down, and the precipitate
was collected by filtration to give 0.381 g of the title compound.
-H-NKR(d6DMS0)
63.78 (s, 3H) 8.14 (d, J=6.0Hz, 2H) 8.48 (s, IH) 8.76 (d, J=6.0Hz, 2H)
MS m/e (ESI) 228.1 (MH) (b)
3- (2-Bu-ynyl)-5-methyl-2-(pyridin-4-yl)-3,5-dihydroimidazo[4,5-d
]pyrida2in-4-one
The -itle compound was obtained by using 5-methyl-2-(pyridin-4-yl)-1,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 2-butynyl bromide according to the method described in Example 119(d). . . -H-NKR(CDCl3)
5 1.84 (t, J=2.3Hz, 3H) 3.91 (s, 3H) 5.37 (q, J=2.3Hz, 2H) 7.89 (d, J=6.1Hz, 2H) 8.32 (s, IH) 8.85 (d ,J=2.3Hz, 2H) (c)
4- [1-(2-Butynyl)-6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyr
idazin-2-yl]-1-(4-methoxybenzyl)pyridinium chloride

0.045 g of 3-(2-butynyl)-5-raethyl-2-{pyridin-4-yl)-3,S-dihydroimidazo[4,5-d ]pyridazin-4-one and 0.060 1 of p-methoxybenzyl chloride were added to 0.100 ml of N,N-dimethylforTnamide, and the mixture was stirred at 65 ° C under a nitrogen atmosphere for 4 hours . The reaction solution was cooled down, and 1 ml of acetone and 1 ml of diethyl ether were added thereto. The precipitate was collected by filtration to give 0.060 g of the title compound.
1H-NMR(CD30D)
51.75 (t, J=2.3Hz, 3H) 3.74 (s, 3H) 3.77 (s, 3H) 5.64 (q, J=2.3Hz, 2H) 5.86 (s, 2H) 7.05 (d, J=8.3Hz, 2H) 7.54 (d, J=8.3Hz, 2H) 8.43 {s, IH) 8.70 (d, J=6.3Hz, 2H) 9.24 (d, J=6.3Hz, 2H) (d)
3- (2-Bu-ynyl)-2-[1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4 -yl] -5-.methyl-3 , 5-dihydroimidazo [ 4 , 5-d] pyridazin-4-one
0 . 020 g of sodium borohydride was added to a 5 .ml"methanol solution of 0.06.0 g of
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-lH-imidazo[4,5-d]pyr idazin-2-yl]-1-{4-methoxybenzyl)pyridinium chloride, and the mixture was stirred for one hour. 15 ml of water and 0.1 ml of 5N hydrochloric acid were added to the solution to quench the reducing agent. Then, the solution was made alkaline with 1 ml of 5N sadium hydroxide, and extracted with 30 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0 . 033 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:19).
1H-NMR(CDCl3)
5 1.80 (t, J=2.4Hz, 3H) 2.71-2.78 (m, 4H) 3.25-3.28 (m, 2H) 3.62 (s, 2H) 3.82 (s, 3H) 3.87 (s, 3H) 5.30 (q, J=2.4Kz, 2H) 6.61 (m, IH) &.89 (d, J=9.1Hz, 2H) 7.30 (d, J=9.1Hz, 2H) 8.22 (s, IH) (e)
3- (2-Butynyl)-5-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)-3,5-di hydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
0.10 ml of 1-chloroethyl.chloroformate was added to a 2 ml 1,2-dichloroethane solution of 0.033 g of "

3- (2-buynyl)-2-[i-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4 -yl]-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one, and the mixture was heated under reflux "for 90 minutes. 5 ml of methanol was added to the solution, and the mixture was further heated under reflux for 4 hours . The solvent was then concentrated under reduced pressure, The residue was purified by reverse-phase high performance liquid chromatography to give 0.010 g of the title compound.
*H-NMR(CD30D)
5 1.31 (t, J=2.4Hz, 3H) 2.89-2.94 (m, 2H) 3.52 (t, J=6.2Hz, 2H) 3.84 (s, 3H) 4.01 (q, J=2.8Hz, 2H) 5.27 (q, J=2.4Hz, 2H) 6.67 (m, IH) 8.30 (s, IH)
MS .•::/e (ESI) 284 . 22 (MH-CFsCOOH)
[Assay Example 1] DPPIV-ir.hibiting activity assay
Porcine kidney-derived DPP-IV was dissolved in a reaction buffer
(50mM Tris-HCl (pH 7.4)70.1% BSA) at a concentration of 10 mH/ml. After 110 Hi of this solution had been combined with 15 |il of an agent, the mix-ure was incubated at room temperature for 20 minutes. 25 )il of 2 mK Gly-Pro-p-nitroanilide was added (to a final concentration of 0.33 .mM) to the solution to initiate the enzyme reaction. The reaction time was 20 minutes. 25 P-l of IN phosphoric acid solution was added to the reaction solution to quench the reaction. Absorbance of this solution at 405 nm was determined, and then the inhibition rate for the enzyme reaction was calculated to determine the IC50.




Effect on the glucose tolerance of normal mice {in vivo test)
Animal: male C57BL/6N mice (purchased from Charles River Japan, Inc.)
Method:
[Preparation and administration of test compounds]
Each test compound was suspended in a 0.5% methyl cellulose (MC) solution at the concentration indicated below in Table. The suspension of a test compound, and of NVP DPP728 (US patent No. 6011155), or a 0.5% MC solution that was used as a medium control group was given orally at a dose of 10 mL/kg. After 30 minutes, a glucose solution was given orally at a dose of 10 mL/kg. The dose of glucose given orally was 2 g/kg. [Blood collection and determination of blood glucose levels]
Immediately before administering the test compound and NVP DPP728, immediately before administering the glucose solution, and 30, 60, and 120 minutes after the administration, without anesthetic the caudal vein was lightly cut with a razor blade to let bl"ood out.
10 |il of blood was collected and immediately combined with 140 \xl of 0.6 M perchloric acid. The sample was centrifuged at 1500 g at 4°C for 10 minutes in a refrigerated centrifuge GS-6KR (Beckman Corp.). The glucose concentration in the resulting supernatant was determined using Glucose CII TEST WAKO (Wako Pure Chemical Industries). Result:
The area under the blood glucose level time curve (AUCo-120; Area Under the Curve) obtained from the curve of time vs . blood glucose level between the start of glucose administration and 120 minutes after administration was determined for each of the 0.5% MC solution-treated group, NVP DPP72 8-treated group and test compound-treated group. The improvement factor for glucose tolerance of a test compound was determined by taking the AUC0-12Q of the 0.5% MC solution-treated group as 100% and the AUCo-120 of the NVP .DPP728 (10 mg/kg)-treated group as 0% according to the formula indicated below.
Improvement factor for glucose tolerance (%) = (AUCo-120 of the group treaxied with a test compound - AUCo-120 of the group treated with NVP DPP728 (10 mg/kg))/ AUCo-120 of the group treated with 0.5% MC solution - AUCo-120 of the group treated with NVP DPP728 (10 mg/kg))

X 100
The lower the % value, the grater the improvement in the glucose tolerance.
Some of the novel condensed imidazole derivatives of the present invention were found to have significant effects on the glucose tolerance of normal mice through the in vivo experiment described above which comprised oral administration of the compounds at doses of 0.1-10 (mg/kg).
[Assay Example 3] Acceptable timing of administration in in vivo test
A drug for treating postprandial hyperglycemia is ideally required to have comparable, effectiveness in treating postprandial hyperglycemia when it is given immediately before meals as well as 1 hour before meals. Thus, an excellent drug exhibiting higher efficacy can be achieved by widening the range of acceptable timing of administration Method:
The respective tests described below were carried out in combinarion with the in vivo test (administration before 0.5 hour) as described in Assay Example 2:
1. A test compound is administered simultaneously with glucose loading (2 g/kg) (the test compound is suspended in an aqueous solution of 0 . 5% methyl cellulose ; the solution is combined with an equal volume of a glucose solution; and the mixture is administered orally at a dose of 10 ml/kg);
2. A test compound is administered one hour before glucose loading (2 g/kg) (the test compound suspended in an aqueous solution of 0.5% methyl cellulose is administered orally one hour before the oral administration of the glucose solution; each is given orally
.at a dose of 10 ml/kg).
The improvement factor for glucose tolerance is estimated in each test. The range of acceptable timing of administration can be assessed by estimating whether comparable degrees of improvement are obtained by the two types of administrations, preferably when the dose difference is 3 times or lower, and most preferably estimating

whether comparable degrees of improvement are obtained by the two types of administrations when the doses are identical. Such representative compounds of the present invention (in particular, compounds selected from the group consisting of those shown in Examples 82, 119, 120, 122, 229, and 267) were shown to have sufficiently wide ranges of acceptable timing of administration as defined above.
[Assay Example 4]
Purpose: Effect of a test compound on the blood glucose level of fasted male Wistar rats (in vivo test.)
Animal: male Wistar rats (purchased from Charles River Japan, Inc.) Met-hod: [Preparation and administration of test compounds]
A rest compound was suspended in 0.5% methyl cellulose (MC) solution and administered orally at a dose of 5 mL/kg. The control group was treated with a 0.5% MC solution. The solution was administered orally at a dose of 5 mL/kg. [Blood collection and determination of blood glucose levels]
Inmediately before administering a test compound or 0.5% MC solution, and 0.5, 1, and 3 hours after the administration, without anesthetic the caudal vein was lightly cut with a razor blade to let the blood out. 10 fiL of blood was collected and combined with 140 HL of 0.6 M perchloric acid solution. The sample was centrifuged at 3000 g ar 4°C for 10 minutes and the resultant supernatant was assayed with the Glucose CXI TEST WAKO (Wako Pure Chemical Industries) . Result:
Some of the novel condensed imidazole derivatives of the present invention (in particular, compounds selected from the group consisting of those shown in Examples 82, 119, 120, 122, 229, and 267) showed no significant change in the blood glucose level in blood sa.mples collected at any sampling time, as compared with the control group treated with the medium alone in the in vivo experiment as described above, where each compound was administered orally at a dose of 10-30 (mg/kg).

[Assay Example 5]
Effect of a test compound on the glucose tolerance of male Zucker fa/fa rat (obesity type II diabetes mellitus model animal) (in vivo test)
Animal: male Zucker fa/fa rats (purchased from Charles River Japan, Inc.) Method: [Preparation and administration of test compounds]
The test compound was suspended in 0.5% methyl cellulose (MC) solution. The suspension of the test compound or a 0.5% MC solution that was used as a medium-control group was given orally at a dose of 5 mL/kg. After 0.5 hr, a glucose solution was given orally at a dose of 5 mL/kg. The dose of glucose given orally was 2 g/kg. [Blood collection method and determination of blood glucose, insulin, and GLP-1 levels]
Immediately before administering a test compound or 0.5% MC solution, immediately before the glucose loading, and 0.5, 1, 2, and 3 hours after the glucose loading, without anesthetic the caudal vein was slightly cut with a razor blade to let blood out. 250 |il of blood was collected using a heparin-coated capillary, and transferred into a centrifuge tube. The sample was centrifuged at 10000 g at 4°C for 2 minutes. The levels of insulin and GLP-1 in the resultant supernatant were determined with an insulin assay kit (Morinaga Biochemical Institute) and Active GLP-1 ELISA kit (Linco), respectively. At the same time, 10 fil of blood was collected and combined with 140 [il of 0 . 6 M perchloric acid solution. The sample was centrifuged at 3000 g at 4""C for 10 minutes, and the resultant supernatant was assayed with the Glucose CII TEST WAKO (Wako Pure Chemical Industries) . Only the blood glucose level was determined three hours after glucose loading. Result:
The area under the blood glucose level (AUCciuco-sh)) between the start of glucose administration and 3- hours after administration, the area under insulin level time curve (AUCins(o-2h)) , and the area under GLP-1 level time curve (AUCGLP-i{o-2h)) were determined for each

of the 0.5% MC solution-treated group and eath of the test compound-treated groups. The variation in glucose tolerance, variations in the insulin level, and G.LP-1 level due to the test compound were determined by taking the AUG of the 0.5% MC solution-treated group as 100% according to the following formula.
* The rate of change in glucose tolerance (%) = AUCo-an of the
group treated with a test compound/ (AUCo-3h of the group treated with
0.5% MC solution) X 100
* The rate of change in insulin and GLP-1 level (%) = AUCo-2h of
the group treated with a test compound / (AUCo-2h of the group treated
with 0.5% MC solution) X 100
Some of the novel condensed imidazole derivatives of the present invention (in particular, compounds selected from the group consisting of those shown in Examples 82, 119, 120, 122, 229, and 267) were shown to change the insulin and GLP-1 levels at rates higher than 100% and exhibit glucose tolerance at a rate of change lower than 100% in the in vivo experiment as described above, where each compound was administered orally at a dose of 0.1-10 (mg/kg).
[Assay Example 6]
The inhibitory activity IC50 was determined using an expression system for recombinant P450 and the fluorescent substrates (GENTEST Corp.) indicated in Tables 2 and 3 according to the Assay Procedure (WWW.gentest.com) prepared by GENTEST Corp. P450 molecular species assessed were the five molecular species, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The experimental conditions used are shown below. The fluorescence intensity was determined using a plate reader (CYTO FLUOR Multi-Well Plate Reader Series 4000; PerSeptive Biosystems Corp.) . The degree of inhibition was determined as a mean value from nine independent assays per second using as an index the intensity fluorescence emitted from the metabolite of the fluorescent substra.e.
The substrates, metabolites, inhibitors, excitation wavelengths, and fluorescence wavelengths used in the assay are shown in Table 2.































































Industrial Applicability
The present invention provides condensed imidazole derivatives having a DPPIV-inhibiting a.ctivity.
Accordingly, the condensed imidazole derivatives of the present invention are useful as therapeutic and preventive agents , for example, for diabetes mellitus, obesity, hyperlipidemia, AIDS, osteoporosis, gastrointestinal disorders, angiogenesis, infertility, as anti-inflammatory agents, anti-allergy agents, immunomodulators, hormone regulators, anti-rheumatic drugs, and anti-cancer agents.
Furthermore, using their glucose tolerance improving action as an index, these compounds were tested to assess their efficacy after oral administration. In result, it was confirmed-that these compounds were sufficiently effective, thereby demonstrating their usefulness as pharmaceuticals.



1. A compound represented by the following formula, or a salt or hydrate thereof,

T1 represents a monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, that may have one or more substituents;
X represents a C1-6 alkyl group which may have one or more substituents, a C2-6 alkenyl group which may have one or more substituents, a C2-6 alkynyl group which may have one or more substituents, a C6-10 aryl group which may have one or more substituents, a 5 to 10-membered heteroaryl group which may have one or more substituents, a C6-10 aryl C1-6 alkyl group which may have one or more substituents, or a 5 to 10-membered heteroaryl C1-6 alkyl group which may have one or more substituents;
Z and Z each independently represent a nitrogen atom or a group represented by the formula -CR2=;
R2 and R2 each independently represent a group according to the
formula -A°-A-A
(wherein A° represents a single bond or a C1-6 alkylene group which may have 1 to 3 substituents selected from group B consisting of the substituents described below; A represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a

group represented by the formula -0-C0-, a group represented by the formula -C0-0-, a group represented by the formula -NR"-, a group represented by the formula -CO-NR2-, a group represented by the formula -NR*-CO-, a group represented by the formula -S02-NR2-, or a group represented by the formula -NR*-S02-;
A and R" each independently represent a hydrogen atom, a halogen atom, a cyano group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a 5 to 10-membered heteroaryl C1-6 alkyl group, a C6-10 aryl C1-6 alkyl group, or a C2-7 alkylcarbonyl group;
however, A and R" each independently may have 1 to 3 substituents selected from the substituent group B described below:
when Z is a group represented by the formula -CR2=, R1 and R2 may in combination form a 5 to 7-membered ring;
except in cases where: [1] R1 is a hydrogen atom; Z is a nitrogen atom; and Z is -CH=; and [2] Z1 is a nitrogen atom; and Z is -C(OH) = ;

Substituent group B represents the group consisting of: a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C1-6 alkyl group which may have one or more substituents, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a C1-6 alkoxy group, a C1-6 alkylthio group, a group represented by the formula -S02-NR2-R2, a group represented by the formula -NR2-CO-R2, a group represented by the formula -NR2-R82 (where R2 and R2 each independently represent a hydrogen atom or a C1-6

alkyl group), a group represented by the formula -CO-R2 (where R2" represents a 4 to 8-membered heterocyclic group) , a group represented by the formula -CO-R2-R° and a group represented by the formula -CHa-CO-R2-R2 (where R2 represents a single bond, an oxygen atom, or a group represented by the formula -NR2-; R° and R2 each independently represent a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic C1-6 alkyl group, a C6-10 aryl C1-6 alkyl group, or a 5 to 10-membered heteroaryl C1-6 alkyl group)).
2. The compound according to claim 1, or a salt or hydrate thereof,
wherein T""" is,
a group represented by the following formula:

(wherein, n and m each independently represent 0 or 1) which may have one or more substituents; an azetidin-1-yl group which may have one or more substituents; a pyrrolidin-1-yl group which may have one or more substituents; a piperidin-1-yl group which may have one or more substituents; or an azepan-1-yl group which may have one or more substituents.
.3-. The compound according to claim 1, or a salt or hydrate thereof, wherein T""" is, a group represented by the following formula :


(where n and m each independently represent 0 or 1); an azetidin-1-yl group which may have an amino group; a pyrrolidin-1-yl group which may have an amino group; a piperidin-1-yl group which may have an amino group; or an azepan-1-yl group which may have an amino group.
4. The compound according to claim 1, or a salt or hydrate thereof, wherein T" is a piperazin-1-yl group or a 3-aminopiperidin-l-yl group.
5. The compound according to claim 1, or a salt or hydrate thereof, wherein T is a piperazin-1-yl group.
6. The compound according to any one of claims 1 to 5, or a salt or
hydrate thereof, wherein X is a group represented by the formula -X-X
(where X""" represents a single bond or a methylene group which may have
one or more substituents; X represents a C2-6 alkenyl group which may have one or more substituents, a C2-6 alkynyl group may have one or more substituents, or a phenyl group which may have one or more substituents).
7. The compound according to any one of claims 1 to 5, or a salt or
hydrate thereof, wherein X is a group represented by the formula
-X"""-X (where X""" represents a single bond or a methylene group; X
represents a C2-6 alkenyl group, a C2-6 alkynyl group, or a phenyl group
-w-hich may have one or more substituents) .
8 . The compound according to claim 6 or 7, or a salt or hydrate thereof, wherein the phenyl group that may have one or more substituents is a phenyl group which may have at the 2-position a substituent selected from the group consisting of a hydroxyl group, a fluorine atom, a

chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a vinyl group, a methoxy group, an ethoxy group, an acetyl group, a cyano group, a formyl group, and a C2-7 alkoxycarbonyl group.
9. The compound according to any one of claims 1 to 5, or a salt or
hydrate thereof, wherein X is a 3-methyl-2-buten-l-yl group, a
2-butyn-l-yl group, a benzyl group, or a 2-chlorophenyl group.
10. The compound according to any one of claims 1 to 5, or a salt or hydrate thereof, wherein X is a 2-butyn-l-yl group.
11. The compound according to any one of claims 1 to 10, or a salt or hydrate thereof, wherein either the T} or Z is a nitrogen atom.
12. The compound according to any one of claims 1 to 10, or a salt or hydrate thereof, wherein,
Z is a nitrogen atom; and
Z is a group represented by the formula -CR2= (where R2 is as defined above in claim 1).
13. The compound according to any one of claims 1 to 10, or a salt
or a hydrate thereof, wherein,
Z is a nitrogen atom; and
?} is a group represented by the formula -CR2= (where R2 is as defined above in claim 1).
14. The compound according to any one of claims 1 to 13, or a salt
or hydrate thereof,
wherein represents a hydrogen atom, or a group represented by the formula -A"-A"-A"
(where A° represents a C1-6 alkylene group which may have 1 to
3 substituents selected from the substituent group C described
below;
A"""""" represents a single bond, an oxygen atom, a sulfur atom or
a carbonyl group;
A represents a hydrogen atom, a C6-10 aryl group which may have

1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl group which may-have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, or a C6-10 aryl Ci_6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below:

Substituent group C represents the group consisting of: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C1-6 alkyl group, a C1-g alkoxy group, a C1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula -NR2-R* (where each of R2 and R" independently represent a hydrogen atom or C1-s alkyl group), a group represented by the formula -CO-R -R and a group represented by the formula -CH2-C0-R2-R" (where R2 represents a single bond, an oxygen atom, or a group represented by the formula -NR"-; R2"* and R2 each independently represent a hydrogen atom or a C1-6 alkyl group) .
15. The compound according to any one of claims 1 to 13, or a salt or hydrate thereof,
wherein R2 is a hydrogen atom, a C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, or a C6-10 aryl C1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below:
Substituent group C represents the group consisting of: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula -NR"-R2 (where each of R" and R2 independently represent a

hydrogen atom or a C1-6 alkyl group) , a group represented by the formula -CO-R"-R2 and a group represented by the formula -CH2-CO-R -R (where R represents a single bond, an oxygen atom, or a group represented by the formula -NR2-; R"* and R2 each independently represent a hydrogen atom or a C1-6 alkyl group);
16. The compound according to claim 14 or 15, or a salt or hydrate thereof, wherein the substituent group C is a group consisting of a cyano group, a C1-6 alkoxy group, a C2-7 alkoxycarbonyl group, and a halogen atom.
17. The compound according to any one of claims 1 to 13, or a salt or hydrate thereof, wherein R2 is a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyethyl group, or a 4-methoxycarbonylpyridin-2-yl group.
18. The compound according to any one of claims 1 to 13, or a salt or hydrate thereof, wherein R2 is a methyl group or a 2-cyanobenzyl group.
19. The compound according to any one of claims 1 to 18, or a salt or hydrate thereof,
wherein R2 is a hydrogen atom, a cyano group, or a group represented by the formula -A-A"
(where A represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula -0-CO-, a group represented by the formula -C0-0-, a group represented by the formula -NR"-, a group represented by the formula -CO-NR*-, or a group represented by the formula -NR*-CO-;
A and R" each independently represent a hydrogen atom, a cyano group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5-to 10-membered heteroaryl C1-6 alkyl group, or a C6-10 aryl C1-6

alkyl group;
however, A and R* each may independently have 1- to 3
substituents selected from the substituent group D described
below:

Substituent group D represents the group consisting of: a hydroxyl group, a cyano group, a nitro group, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-s alkylthio group, a trifluoromethyl group, a group represented by the formula -NR°-R° (where R° and R° each independently represent a hydrogen atom or a C1-6 alkyl group) , a group represented by the formula -CO-R°" (where R° represents a 4 to 8-membered heterocyclic group), and a group represented by the formula -CO-R°""-R° (where R2"* represents a single bond, an oxygen atom, or a group represented by the formula -NR°-; R° and R° each independently represent a hydrogen atom, a C3-8 cycloalkyl group, or a C1-6 alkyl group)) .
20. The compound according to any one of claims 1 to 18, or a salt or hydrate thereof,
wherein R2 represents a hydrogen atom, a cyano group, a carboxy group, a C2-7 alkoxycarbonyl group, a C1-6 alkyl group, a group represented by the formula -CONR°R°® (where R° and R°® each independently represent a hydrogen atom or a C1-6 alkyl group) , or a group represented by the formula -A"-A
(where A represents an oxygen atom, a sulfur atom or a group represented by the formula -NR*""-;
A and R2 each independently represent a hydrogen atom, a Ci_6 alkyl group which may have a substituent selected from the substituent group Dl described below, a C3-8 cycloalkyl group which may have a substituent selected from the substituent group Dl described below, a C2-6 alkenyl group which may have a substituent selected from the substituent group Dl described below, a C2-5 alkynyl group which may have a substituent selected from the substituent group Dl described below, a phenyl group which may have a substituent selected from the substituent group

Dl described below, or a 5 to 10-membered heteroaryl group which may have a substituent selected from the substituent group Dl described below:

Substituent group Dl represents the group consisting of: a carboxy group, a C2-7 alkoxycarbonyl group, a C1-6 alkyl group, a group represented by the formula -CONR°""R° (where R° and R°® each independently represent a hydrogen atom or C1-6 alkyl group) , a pyrrolidin-1-ylcarbonyl group, a C1-6 alkyl group, and a C1-6 alkoxy group) .
21. The compound according to any one of claims 1 to 18, or a salt
or hydrate thereof,
wherein R2 represents a hydrogen atom, a cyano group, a C1-6 alkoxy group, or a group represented by the formula -A-A
(where A represents an oxygen atom, a sulfur atom, or a group represented by the formula -NR*""-;
A and R2"" each independently represent a hydrogen atom, a C1-6 alkyl group having a substituent selected from the substituent group Dl described below, a C3-8 cycloalkyl group having a substituent selected from the substituent group Dl described below, or a phenyl group having a substituent selected from the substituent group Dl described below:
Substituent group Dl represents the group consisting of: a carboxy group, a C2-7 alkoxycarbonyl group, a C1-6 alkyl group, a group represented by the formula -CONR°R°® (where R° and R° each independently represent a hydrogen atom or a C1-6 alkyl group) , pyrrolidin-1-ylcarbonyl group, a C1-s alkyl group, and a C1-6 alkoxy group) .
22. The compound according to any one of claims 1 to 18, or a salt
or hydrate thereof,
wherein R2 is a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, or a group represented by the following formula:


(where A represents an oxygen atom, a sulfur atom, or -NH-;
and A each independently represent a hydrogen atom or a C1-s
alkyl group]
23. The compound according to any one of claims 1 to 18, or a salt or hydrate thereof, wherein R2 is a hydrogen atom, a cyano group, or a 2-carbamoylphenyloxy group.
24. The compound according to claim 1, or a salt or hydrate thereof, wherein the compound of formula (I) indicated above is any one selected from the group consisting of:
7-(2-butynyl)-2-cyan6-l-methyl-8-(piperazin-1-yl)-1,7-dihydropu
rin-6-one,
3-(2-butynyl)-5-methyl-2-(piperazin-1-yl) -3,5-dihydroimidazo[4,
5-d]pyridazin-4-one,
2-(3-aminopiperidin-l-yl)-3-(2-butynyl)-5-methyl-3,5-dihydroimi
dazo[4,5-d]pyridazin-4-one,
2-[7-{2-butynyl)-l-methyl-6-oxo-8-(piperazin-l-yl)-6,7-dihydro-
lH-purin-2-yloxy]benzamide,
7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-l-yl)-Sl-di
hydro-lH-purine-2-carbonitrile, and
2- [3- (2-butynyl) -4-oxo-2- (piperazin-l-xH -3 , 4-dihydr6imida20*[4,
5-d]pyridazin-5-ylmethyl]benzonitrile.

26 A dipeptidyl peptidase IV inhibitor comprising a compound of claim

27. A pharmaceutical composition comprising a compound of claim 1 and an adjuvant useful for formulation.
28. A preventive or a therapeutic agent for diabetes mellitus, which comprises a compound of claim 1.
29. A preventive or therapeutic agent, which comprises a compound of claim 1, for diabetes mellitus, obesity, hyperlipidemia, AIDS, osteoporosis, a gastrointestinal disorder, angiogenesis, infertility, an inflammatory disease, an allergic disease, or cancer.
30. An immunomodulator, a hormone modulator, or an anti-rheumatic drug, which comprises a compound of claim-1.
31. A therapeutic or preventive method for a disease in which the inhibition of dipep-tidyl peptidase IV is effective, wherein the method comprises administering to a patient a compound of claim 1, or a salt or hydrate thereof, in a pharmaceutically effective amount.
32. The use of a compound of claim 1, or a salt or hydrate thereof, in producing a pharmaceutical agent.
33. The use of a compound of claim 1, or a salt or hydrate thereof, in producing a therapeutic or preventive agent for a disease in which the inhibition of dipeptidyl peptidase IV is effective.


The compounds of the present invention were evaluated for their ability to inhibit metabolic reactions due to P450 in Assay Example 6. This experiment showed that representative compounds of the present invention (in particular, compounds selected from the group consisting of those shown in Examples 82, 119, 120, 122, 229, and 267) exhibited 10 uM or higher IC50 values with respect to five out of the P450 group of molecules, namely the molecular species, CYP1A2 , CYP2C9, CyP2C19, CYP2D6, and CYP3A4.
[Assay Example 7]


(1) Activity towards inhibiting the hERG channel current was evaluated according to the report Zhou, Z et al, Biophysical Journal, 74 (1) , 230-241 (1998) .
(2) This experiment was carried out using HEK-293 cells into which the hERG channel gene (subtype 1) had been introduced (the cell line was established by the inventors).
(3) One to several days before the experiment, cells were plated on a poly-lysine-coated glass plate. The cells were cultured until the day of the experiment. At the start of the experiment, the cell-seeded glass plate was transferred into a bath for current measurement. The hERG channel current was measured by the voltage clamp method using the patch clamp technique. The current was measured using a current amplifier (Axon Instruments). The current was recorded and analyzed using pCLAMP software (Axon Instruments).
(4) The hERG channel current was induced by applying to the cells a depolarizing pulse from a holding potential of -80 mV to +20 mV for 5 seconds and to -50 mV for 4 seconds, at 20 second intervals. After rhe current became stable in a control solution, the-cells were perfused with solutions containing various concentrations of test compounds.
(5) The amplitude of the hERG channel current was defined as
the peak value of the tail current observed upon restoring the
potential to -50 mV. The inhibiting effect of a test compound on the
hERG channel current (IC50) was estimated based on the change in th-e
peak value of tail current upon addition of the test compound at
various concentrations. The peak value of tail current recorded for
a nor.mal solution was taken as 100%.

Representative compounds of the present invention (in particular , compounds selected from the group consisting of those shown in Examples 82, 119,120, 122, 229, and 267) were evaluated for their ability to inhibit the hERG channel current in Assay Example 7 . The
IC50 values of the compounds were 30 |IM or higher.
The structural formulae for the compounds in Production examples and Examples described above are shown below.



















A pharmaceutical composition substantially as herein described and exemplified.
35. The use of a compound substantially as herein described and exemplified.

Documents:

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2990-chenp-2004 claims.pdf

2990-chenp-2004 correspondence others.pdf

2990-chenp-2004 correspondence po.pdf

2990-chenp-2004 description (complete) duplicate-1.pdf

2990-chenp-2004 description (complete) duplicate-2.pdf

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2990-chenp-2004 description (complete)-4.pdf

2990-chenp-2004 description (complete)-5.pdf

2990-chenp-2004 description (complete).pdf

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Patent Number 203533
Indian Patent Application Number 2990/CHENP/2004
PG Journal Number 05/2007
Publication Date 02-Feb-2007
Grant Date 29-Nov-2006
Date of Filing 31-Dec-2004
Name of Patentee M/S. EISAI CO., LTD.
Applicant Address 6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo 112-8088
Inventors:
# Inventor's Name Inventor's Address
1 YOSHIKAWA, Seiji 202, Gracias Merci, 3-4-30, Shitte-chuo, Kamisu-machi, Kashima-gun, Ibaraki 314-0112
2 EMORI, Eita 202, Dolce I, 1-8-19, Namiki, Tsuchiura-shi, Ibaraki 300-0061
3 MATSUURA, Fumiyoshi 3-25-2-205, Matsushiro, Tsukuba-shi, Ibaraki 305-0035
4 RICHARD, Clark 2-20-22, Ottominami, Tsuchiura-shi, Ibaraki 300-0845
5 IKUTA, Hironori 2-35-12, Sakae-cho, Ushiku-shi, Ibaraki 300-1233
6 KIRA, Kazunobu F-205, Life Square Teshirogi, 4-9-10, Matsushiro, Tsukuba-shi, Ibaraki 305-0035
7 YASUDA, Nobuyuki 820-1, Oaza Hitana, Tsuchiura-shi, Ibaraki 300-0065
8 NAGAKURA, Tadashi 3-406, Este Square, 39-1, Tagu 2-chome, Ushiku-shi, Ibaraki 300-1237
9 YAMAZAKI, Kazuto 3-304, Park Hill Azuma, 19-1, Azuma 3-chome, Tsukuba-shi, Ibaraki 305-0031
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/JP2003/007010
PCT International Filing date 2003-06-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2002-166069 2002-06-06 Japan
2 2002-209373 2002-07-18 Japan
3 2002-307750 2002-10-23 Japan