Title of Invention

A SUBSTITUTED THIAZOLOPYRIDINONE COMPOUND USEFUL S MELANIN CONCENTRATING HERMONE (MCH) ANTAGONISTS AND PHARMACEUTICAL COMPOSITION THEREOF

Abstract The present invention relates to a substituted thiazolopyridinone compound of formula I wherein w, R1, q, p, R2, t, Ar1, L1, R3 and R4 are as defined, or a pharmaceutically acceptable salt, solvate, or enantiomer thereof useful in the treatment, prevention or amelioration of symptoms associated with obesity and related diseases.
Full Text Field of the Invention
The present invention relates to substituted thiazolopyridinone compounds as melanin
concentrating hormone (MCH) antagonists useful in the prevention and treatment or
obesity and related disease and to pharmaceutical compositions comprising the these
compounds.

Background of the Invention
The affluence of the 1990's along with tbe exponential increase in food production
particularly in Western and Asian economies has resulted in feeding patterns that lead to
obesity. Obesity is defined as being excessively overweight Excessive weight is
generally characterized by excessive body fat, because unused energy is stored in the
adipose tissues as fiat.
Obesity has associated with it, economic and social costs. Obese people, an
jncreasing proportion of developed and developing societies, are regarded as having out
of control feeding habits often associated with low self-esteem. Moreover, obese persons
are more likely to have medical problems associated with or exacerbated by the excess
body weight Examples of medical conditions caused, exacerbated or triggered by
excessive weight include bone fractures, pains in the knee joints, arthritis, increased risk
of hypertension, atherosclerosis, stroke, diabetes, etc
Melanin concentrating hormone (MCH) is a 19 amino acid neuropeptide produced
in the lateral hypothalamic area and'zona incerta. Although MCH-expressing neurons
project to numerous regions of the brain. MCH is processed from a larger pre-prohormono
that also includes a second peptide, NEI, and possibly a third, KGB (Nahon, Crit Rav in
Neurobiology, 8:221-262,1994). MCH mediates its effects through at least two G
protein-coupled receptors, MCHR1 and MCHR2 (Saito et al. Nature 400:265-269.1999;
Hill et al., J Biol Chem. 276:2012S-20129,2001). Both receptors are expressed in
regions of tbe brain consistent with MCH neuronal projection and known MCH
physiologic function (Hervieu et al., Enr J Neuroscience 12: 1194-1216,2000; Hill et al.

J Biol Chem. 276: 20125-20129,2001; Sailer et al., Proc Nat Acad Sci. 98: 7564-7569,
^001).
Extensive evidence exists to support the orexigenic activity of MCH. MCH
mRNA is elevated in rodent models of obesity and in the fasted state (Qu et al., Nature
380: 243-247,1996). Intra-cerebroventricularly administered MCH increases feeding and
blocks the anorexic effect of α-melanocyte stimulating hormone (Ludwig et al., Am J
Physiol 274: E627-E633,1998). MCH knockout mice (MCH-/- mice) are lean, hypophagic
and hypometabolic (Shimada et al., Nature 396: 670-674,1998), while MCH over-
expressing transgenic mice are obese and insulin resistant (Ludwig et al., J Clin Invest
107: 379-386,2001). MCHRl-/- mice have recently been reported to be lean and
hypermetabolic, indicating that the R1 isoform mediates at least some of the metabolic
effects of MCH (Marsh et al., Proc Nat Acad Sci 99: 3240-3245, 2002).
In addition to its effects on feeding, MCH has been implicated in regulation of the
hypothalamic-pituitary-adrenal axis through modulation of CRF and ACTH release
(Bluet-Pajot et al., J Neuroendocrinol 7: 297-303, 1995). MCH may also play a role in the
modulation of reproductive function (Murray et al., J Neuroendocrinol 12: 217-223,2000)
and memory (Monzon et al., Peptides 20: 1517-1519,1999).
The current preferred treatment for obesity as well as Type II non-insulin
dependent diabetes is diet and exercise with a view toward weight reduction and
improved insulin sensitivity for diabetics. Patient compliance, however, is usually poor.
The problem is compounded by the fact that there are currently only two medications
approved for the treatment of obesity (sibutramine, or Meridia and orlistat, or
Xenical™.
PCT application number WO 01/21577 (JP00/06375) filed September 19,2000,
discloses compounds reportedly useful as antagonists of the MCH receptor. In particular
the WO 01/21577 application claims a compound of formula A

wherein:

Ar1 is a cyclic group that may have substituents;
X is a spacer having a main chain of 1 to 6 atoms;
Y is a bond or a spacer having a main chain of 1 to 6 atoms;
Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8 membered non-
aromatic ring, and may have further substituents;
R1 and R2 are independently hydrogen atom or a hydrocarbon group which may have
substituents;
R1 and R2 together with the adjacent nitrogen atom may form a nitrogen-containing hetero
ring which may have substituent; R2 may form a spiro ring together with Ar; or R2,
together with the adjacent nitrogen atom and Y, may form a nitrogen-containing hetero
ring which may have substituents; or salts thereof.
PCT application number WO 01/82925, filed April 26, 2001, also discloses
compounds reportedly useful as antagonists of the MCH receptor. In particular the WO
01/82925 application claims a compound of formula B

wherein:
Ar1 is an optionally substituted cyclic group;
X and Y are independently a spacer having a C1-6 main chain;
Ar is an optionally substituted fused polycyclic aromatic ring;
R1 and R2 are independently hydrogen atom or an optionally substituted hydrocarbon
group; or alternatively R1 and R2 together with the nitrogen atom adjacent thereto may
form a nitrogenous heterocycle, or R2 together with the nitrogen atom adjacent thereto and
Y may form an optionally substituted nitrogenous heterocycle, or R2 together with the
nitrogen atom adjacent thereto, Y, and Ar may form a fused ring.
PCT application number WO 01/87834, filed May 15, 2001, also discloses
compounds reportedly useful as antagonists of the MCH receptor. In particular the WO
01/87834 application claims a compound of formula C.


wherein;
R represents hydrogen, halogen, or an optionally substituted cyclic group; X represents a
bond or a spacer in which the main chain has one to ten atoms; Y represents a spacer in
which the main chain has one to six atoms; ring A represents a benzene ring which may
have other substituents; ring B represents a five- to nine-membered nitrogen containing
nonaromatic heterocycle which may have other substituents; and R1 and R2 are the same
or different and each represents hydrogen, an optionally substituted hydrocarbon group, or
an optionally substituted heterocyclic group, or R1 and R2 may form an optionally
substituted nitrogenous heterocycle in cooperation with the adjacent nitrogen atom and R2
may form an optionally substituted nitrogenous heterocycle in cooperation with the
adjacent nitrogen atom and Y.
DE2502588 describes a compound of the formula:

Wherein the variables are as defined therein.
PCT International publication WO 03/033476 A1 discloses a compound of the
formula (Ia):

comprising a pharmaceutically acceptable salt, solvate, or physiologically functional
derivative thereof, wherein the variables are as described therein.

Current treatments targeted at obesity have side effects. Examples of such
treatments include various over-the-counter appetite suppressants. These agents have not
been proven effective for all patients and for sustainable periods of time. Similarly, the
approved treatments, sibutramine (Meridia™) and orlistat (Xenical™) have been
associated with side effects which may compromise compliance and may preclude long
term use for sustained weight loss for certain patient populations.
Therefore, there is a need for new and/or improved therapeutically effective agents
useful as antagonists of melanin concentrating hormone to better control the dietary
habits, minimize the preponderance of obesity and treat, prevent and/or ameliorate the
effects of obesity, including for example diabetes.
Summary of Invention
The present invention relates to a compound of formula I:

wherein:
" " is optionally a bond to form a double bond
q is 0,1, 2, or 3; wherein other positions on the phenyl ring have hydrogen atoms;
t is 1 or 2;
w is 1 or 2 depending on substitution pattern and/or the presence of a double bond;
R1 is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8
alkenyl, C2-C8 alkynyl, halo, hydroxy, C1-C8 haloalkyl, C1-C8 alkoxy, -C1-C8 alkyl
alcohol, C1-C8 haloalkoxy, aryl, -O-aryl, -O-heteroaryl, -OC1-C8 alkylaryl, -C1-C8
alkylaryl, -C1-C8 alkylheteroaryl, heterocyclic, -C1-C8 alkylheterocyclic, cycloalkyl, -C1-
C8 alkylcycloalkyl, amino, and C1-C8 alkylNR6R6', C0-C8 alkylCOOR6, C0-C8
alky]CONR6R6';
R2 is independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C1-
C4 haloalkyl, C2-C4 alkenyl, phenyl, and C1-C4 alkylaryl;

Ar1 is a cyclic group optionally substituted with one to three groups independently
selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, hydroxy,
-OC1-C8 alkyl, C1-C8 alkylaryl, C1-C8 alkylheteroaryl, phenyl, -O-aryl, -O-heteroaryl,
heterocyclic, C1-C4 alkylheterocyclic, cycloalkyl, C1-C8 alkylcycloalkyl, cyano, -C1-C8
alkylNR6R6', C1-C8 haloalkyl, C1-C8 alkyl alcohol, C1-C8 haloalkoxy, halo, (CH2)nCOR6,
-0(CH2)aCHR6R6', NR6SO2R6', (CH2)n NR6SO2R6', and -(CH2)nC(O)NR6R6';
L1 is a bond or a divalent linker selected from the group consisting of C1-C5 alkyl, C2-C5
alkynyl, C2-C5 alkenyl, C0-C5 alkyl-S-C0-C5 alkyl, C0-C5 alkyl-S- C1-C5 alkylhalide, Co-
C5 alkyl-NR6-C0-C5 alkyl, C0-C5 alkyl-NR6- C1-C5 alkyl-S- C0-C5 alkyl wherein each L1
group has a maximum of 6 carbon atoms in the main chain and wherein each alkyl is
optionally substituted with 1 to 3 groups independently selected from halo, cyano, and
hydroxy;
R3 and R4 are independently selected from the group consisting of hydrogen, C1-C8 alkyl,
C2-C8 alkenyl, C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclic, C1-C8 alkylaryl, C1-C8
alkylcycloalkyl, C1-C8 alkylheteroaryl, C1-C4 alkylheterocyclic; wherein each of the alkyl,
alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group or subgroup is optionally
substituted with one to three groups independently selected from C1-C8 alkyl, C2-C8
alkenyl, phenyl, alkylaryl, (CH2)nNSO2C1-C8 alkyl, (CH2)nNSO2phenyl, (CH2)nNSO2aryl,
-C(O)C1-C8 alkyl, COOH, -C(O)OC1-C8 alkyl and C0-C4 alkylNR6R6'; and wherein R3
and R4 optionally combine together with the nitrogen atom to which they are attached to
form an optionally substituted nitrogen containing 5 to7-member heterocyclic, or one or
both of R3 and R4 combine with L1 at a position α, β, γ, or, δ (e.g. 1, 2, 3, or 4 positions
adjacent) to the nitrogen of NR3R4 to form a nitrogen containing 5 to7-member
heterocyclic group with L1 said heterocyclic groups optionally having one to three
substituents independently selected from oxo, hydroxy, cyano, C1-C8 alkyl, C2-C8 alkenyl,
C3-C8 cycloalkyl, C1-C8 alkylaryl, C1-C8 alkylcycloalkyl, C1-C4 alkylheterocyclic, C1-C4
alkylheteroaryl, halo, (CH2)nNSO2C1-C8 alkyl, (CH2)nNSO2phenyl, (CH2)nNSO2aryl, -
C(O)C1-C8 alkyl, -C(O)OC1-C8 alkyl and C0-C4 alkylNR6R6';
R6 and R6' are independently selected from the group consisting of hydrogen, C1-C8 alkyl,
phenyl, aryl, C1-C8 alkylaryl, C3-C8 cycloalkyl, or C1-C6 alkylcycloalkyl; and wherein R6
and R6 may combine to form a 5-7 member nitrogen-containing heterocycle optionally
having one to three substituents independently selected from oxo, hydroxy, cyano, C1-C8

alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C1-C8 alkylaryl, C1-C8 alkylcycloalkyl, C1-C4
alkylheterocyclic, halo, (CH2)nNSO2C1-C8 alkyl, (CH2)nNSO2phenyl, (CH2)nNSO2aryl, -
C(O)C1-C8 alkyl, COOH, or -C(O)OC1-C8 alkyl and C0-C4 alkylNR7R8;
R7 and R8 are each independently selected from hydrogen, and C1-C4 alkyl; n is an integer
from 0 to 4 wherever it ocurrs; or a pharmaceutically acceptable salt, solvate, enantiomer,
diastereomer or mixture of or diastereomer thereof.
The present invention also relates to pharmaceutical compositions comprising a
compound of formula 1.
In another embodiment, the pharmaceutical composition of the present invention
may be adapted for use in treating obesity and related diseases.
The present invention also relates to a method for treating and/or preventing
-obesity in a patient in need thereof, wherein such treatment comprises administering to
said patient a therapeutically effective amount of a compound of formula I in association
with a pharmaceutically acceptable carrier, diluent or excipient.
The present invention also relates to a method for antagonizing the binding of
MCH to MCH receptors for the treatment of diseases caused, or exacerbated by melanin
concentrating hormone.
The present invention provides the use of a compound of formula I as an appetite
suppressant and/or as a weight loss agent.
The present invention is related to the use of a compound of formula I for the
manufacture of a medicament for treating obesity and related diseases.
Statement of the Invention
The present invention relates to a substituted thiazolopyridinone compound of formula I

wherein:
" " is optionally a bond to form a double bond
q is 0, 1,2, or 3; wherein other positions on the phenyl ring have hydrogen atoms;
tis 0;
w is 1 or 2 depending on substitution pattern and/or the presence of a double bond;
R1 is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
halo, hydroxy, C1-C8 haloalkyl, C1-C8 alkoxy, -C1-C8 alkyl alcohol, C1-C8 haloalkoxy,
aryl, -O-aryl, -O-heteroaryl, -OC1-C8 alkylaryl, -C1-C8 alkylaryl, -C1-C8 alkylheteroaryl,
heterocyclic, -C1-C8 alkylheterocyclic, -C1-C8 alkylcycloalkyl, amino, and C1-C8
alkylNR6R6', C1-C8 alkylCOOR6, C0-C8 alkylCONR6R6';
R2 is independently selected from the group consisting of hydrogen;

Ar1 is a cyclic group optionally substituted with one to three groups independently
selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, hydroxy,
-OC1-C8 alkyl, C1-C8 alkylaryl, C1-C8 alkylheteroaryl, phenyl, -O-aryl, -O-heteroaryl,
heterocyclic, C1-C4 alkylheterocyclic, cycloalkyl, C1-C8 alkylcycloalkyl, cyano, -C1-C8
alkylNR6R6', C1-C8 haloalkyl, C1-C8 alkyl alcohol, C1-C8 haloalkoxy, halo, (CH2)nCOR6,
-O(CH2)nCHR6R6', NR6SO2R6', (CH2)n NR6SO2R6', and -(CH2)nC(O)NR6R6';
L1 is a bond or a divalent linker selected from the group consisting of C1-C5 alkyl, C2-C5
alkynyl, C2-C5 alkenyl, C0-C5 alkyl-S-C0-C5 alkyl, C0-C5 alkyl-S- C1-C5 alkylhalide, C0-
C5 alkyl-NR6-C0-C5 alkyl, C0-C5 alkyl-NR6- C1-C5 alkyl-S-C0-C5 alkyl wherein each L1
group has a maximum of 6 carbon atoms in the main chain and wherein each alkyl is
optionally substituted with 1 to 3 groups independently selected from halo, cyano, and
hydroxy;
R3 and R4 are independently selected from the group consisting of hydrogen, C1-C8 alkyl,
C2-C8 alkenyl, C3-C8 cycloalkyl, aryl, heteroaryl heterocyclic, C1-C8 alkylaryl, C1-C8
alkylcycloalkyl, C1-C8 alkylheteroaryl, C1-C4 alkylheterocyclic; wherein each of the
alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group or subgroup is
optionally substituted with one to three groups independently selected from C1-C8 alkyl,
C2-C8 alkenyl, phenyl, alkylaryl, (CH2)nNSO2C1-C8 alkyl, (CH2)nNSO2phenyl,
(CH2)nNSO2aryl, -C(O)C1-C8 alkyl, COOH, -C(O)OC1-C8 alkyl and C0-C4 alkylNR6R6';
and wherein R3 and R4 optionally combine together with the nitrogen atom to which they
are attached, or one or both of R3 and R4 combine with L1 at a position □, □, □□r □ to
the nitrogen of NR3R4 to form a nitrogen containing 5 to7-member heterocyclic group
with L1 said heterocyclic group optionally having one to three substituents independently
selected from oxo, hydroxy, cyano, C1-C8 alkyl, C2-C8 alkenyl,'C3-C8 cycloalkyl, C1-C8
alkylaryl, C1-C8 alkylcycloalkyl, C1-C4 alkylheterocyclic, C1-C4 alkylheteroaryl, halo,
(CH2)nNSO2C1-C8 alkyl, (CH2)nNSO2phenyl, (CH2)nNSO2aryl, -C(O)C1-C8 alkyl, -
C(O)OC1-C8 alkyl and C0-C4 alkylNR6R6';
R6 and R6 are independently hydrogen, C1-C8 alkyl, phenyl, aryl, C1-C8 alkylaryl, C3-C8
cycloalkyl, or C1-C6 alkylcycloalkyl; and wherein R6 and R6 may combine to form a
substituted 5-7 member nitrogen-containing heterocycle, optionally having one to three
substituents independently selected from oxo, hydroxy, cyano, C1-C8 alkyl, C2-C8

alkenyl, C3-C8 cycloalkyl, C1-C8 alkylaryl, C1-C8 alkylcycloalkyl, C1-C4
alkylheterocyclic, halo, (CH2)nNSO2C1-C8 alkyl, (CH2)nNSO2phenyl, (CH2)nNSO2aryl, -
C(O)C1-C8 alkyl, COOH, or -C(O)OC1-C8 alkyl and C0-C4 alkylNR7R8;
R7 and R8 are each independently selected from hydrogen, and C1-C4 alkyl; n is an
integer from 0 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer or
mixture of or diastereomer thereof.
The present invention also relates a pharmaceutical composition comprising as an active
ingredient a compound such as herein described in combination with a pharmaceutically
acceptable carrier, diluent or excipient.
Detailed Description
For the purposes of the present invention, as disclosed and/or claimed herein, the
following terms are defined below.
The term "main chain" as used herein describes the number of atoms in the
shortest distance between two ends of a variable or radical or linker and includes the
distance in number of atoms when traversing a straight chain, branched chain or atoms in
a mono or bicyclic ring from one end of the variable or radical to the other. As used
herein the radical or group -CH2CH2OCH2CH(CH2CH2CH3)CH2- has a chain length of 6.
General chemical terms used in the description of compounds herein described
bear their usual meanings. For example, the term "C1-8 alkyl," or "(C1-C8)alkyl" or "C1-

C8 alkyl" or as indicated refers to a straight or branched aliphatic chain of 1 to 8 carbon
atoms including but not limited to methyl, ethyl, propyl, iso-propyl, n-butyl, pentyl, and
and the like as indicated. Unless otherwise stated, the term "alkyl" means C1-C8 alkyl.
Similarly, the term "C0-C8 alkyl" implies an alkyl group as indicated wherein when the
term Co applies, the alkyl group is not present, and the remaining groups attach directly to
the substrate. For example, the group -C0-C8 alkylCONRl0R11 implies that when C0
applies, the group -C0-C8 alkylCONR10R11 becomes to -CONR10R11.
The invention also contemplates that the term C1-C6 alkyl or C2-C6 alkenyl or
similar terms encompass the specified alkyl or alkenyl or similar group, which may be
crural, regio or steroisomeric. Such chiral or regio or stereoisomeric groups are also
objects of the present invention.
The term "C3-C8 cycloalkyl" as used herein refers to a cyclic hydrocarbon radical
or group having from 3 to 8 carbon atoms and having no double bonds. Examples of C3-
C8 cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl.
The term "C3-C8 cycloalkenyl" as used herein refers to a cyclic hydrocarbon
radical or group having from 3 to 8 carbon atoms and having from 1 to 3 double bonds.
Specific examples of C3-C8 cycloalkenyl include cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
The term "halo" means halogens including iodo, chloro, bromo and fluoro.
The term "C1-C4 haloalkyl" refers to a C1-C4 alkyl (or as indicated) group
substituted with one, two three or more halogen atoms as possible and chemically
appropriate. Examples of C1-C4 haloalkyl include but are not limited to trifluoromethyl,
chloroethyl, and 2-chloropropyl. Similarly, a "C1-C8 haloalkyl" group is a C1-C8 alkyl
moiety substituted with up to six halo atoms, preferably one to three halo atoms.
A "C1-C8 alkoxy" group is a C1-C8 alkyl moiety connected through an oxy
linkage. Examples of alkoxy groups include but are not limited to methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy.
The term "haloalkoxy", "C1-C8 haloalkyloxy", -OC1-C8 haloalkyl" or
"halogenated C1-C8 alkoxy" means an alkoxy group having halogen substituents at one or
more carbon atoms of the group. The term encompasses groups including for example,
difluoromethoxy, trifluoromethoxy, 2-haloethoxy, 2,2,2-trifluoroethoxy, 4,4,4-

trifluorobutoxy, up to and including the like groups having the indicated number of
carbon atoms.
The term "cyclic" as used herein refers to substituted or unsubstituted aromatic
(including heteroaromatic) and non-aromatic, carbocyclic or heterocyclic ring structures.
Cyclic groups may also be monocyclic or bicyclic unless otherwise specified. Aromatic
groups include, for example, benzene, thiophene, furan, pyrrole, imidazole, pyrazole,
thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrimidine, pyrazine, pyrimidine,
pyridazine, napthyl, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4,-thiadiazole, 1,3,4-
thiadiazole, pyrrolidine, imidazoline, imidazolidine, pyrazolone, pyrazolidine,
tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole,
piperidine, tetrahydropyridine, dihydropyridine, piperazine, morpholine, thiomorpholine,
tetrahydropyrimidine, tetrahydropyridazine, and hexamethyleneimine. Examples of
bicyclic groups within the ambit of cyclic groups as used herein include benzofuran,
benzimidazole, benzoxazole, benzothiophene, benzothiazole, benzisothiazole,
naphtho[2,3-b]thiophene, naphthyl, isoquinoline, quinoline, indole, indazole, quinoxaline,
phenanthridine, phenothiazine, phenoxathlin, phenoxazine, naphthylidene, quinazoline,
carbazole, β-carboline, acridine, phenazine, phthalimide, and thioxanthene each of which
may be optionally substituted. Cyclic groups as defined by Ar1 are optionally substituted
with one to five groups independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8
alkynyl, hydroxy, C1-C8 alkoxy, C1-C8 alkylaryl, phenyl, -O-aryl, heteroaryl, cycloalkyl,
C1-C8 alkylcycloalkyl, cyano, -(CH2)nNR6R6', C1-C8 haloalkyl, -OC1-C8 haloalkyl, halo,
(CH2)nCOR6, (CH2)n NR6SO2R6, -(CH2)nC(O)NR6R6, heterocyclic, and C1-C8
alkylheterocyclic; wherein the cycloalkyl, phenyl, aryl, and heterocyclic substituents are
each optionally substituted with one to three groups independently selected from hydroxy,
C1-C8 alkoxyalkyl, C1-C8 haloalkoxy, C1-C8 alkyl, halo, C1-C8 haloalkyl, nitro, cyano,
amino, carboxamido, phenyl, aryl, alkylheterocyclic, heterocyclic, and oxo.
The term "alkylcycloalkyl" as used herein refers to an alkyl group on which a
cycloalkyl group is substituted. Exemplary of alkylcycloalkyl groups are
methylcyclopropyl, methylcyclobexyl, methylcycloheptyl, ethylcyclopropyl, etc. The
alkylcycloalkyl group may optionally be substituted with one to five groups independently
selected from C1-C8 alkyl, phenyl, aryl, halo, amino, alkylsulfonyl, alkyl sulfonamide,
haloalkyl, carboxyalkyl, carboxamide, alkoxy, and perfluoroalkoxy.

The term "optionally substituted" as used herein and unless otherwise specified,
means an optional substitution of one to five (or as specified), preferably 1 or 2 groups
independently selected from halo, hydroxy, oxo, cyano, amino, alkylamino, nitro, phenyl,
benzyl, aryl, -O-aryl, triazolyl, tetrazolyl, 4,5-dihydrothiazolyl, C1-C6 alkyl, C1-C4
haloalkyl, -(CH2)nNR6R6', C1-C8 haloalkyl, C1-C8 haloalkoxy, (CH2)nCOR6, (CH2)n
NR6SO2R6', -(CH2)nC(O)NR6R6', heterocyclic, and C1-C8 alkylheterocyclic on the subject
group, subgroup, or substituent and wherein R6 , R6' and n are as defined herein.
The term "heterocycle" or "heterocyclic" represents a stable, saturated, partially
unsaturated, fully unsaturated, or aromatic 4, 5, or 6 or 7 membered ring or as otherwise
specified. Such heterocyclic ring has from one to three heteroatoms that are
independently selected from the group consisting of sulfur, oxygen, and nitrogen. The
heterocycle may be attached at any point which affords a stable structure. Representative
heterocycles include 1,3-dioxolane, 4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, furan,
imidazole, imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole,
oxazolidinedione, oxazolidone, piperazine, piperidine, pyrazine, pyrazole, pyrazoline,
pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazole, thiadiazole, thiazole,
thiophene and triazole.
The heterocyclic group or heterocyle according to the present invention unless
otherwise indicated is optionally substituted with one to three, preferably one or two
groups independently selected from oxo, hydroxy, cyano, C1-C8 alkyl, C2-C8 alkenyl, C3-
C8 cycloalkyl, C1-C8 alkylaryl, C1-C8 alkylcycloalkyl, C1-C4 alkylheterocyclic, C1-C4
alkylheteroaryl, halo, (CH2)nNHSO2C1-C8 alkyl, (CH2)nNHSO2phenyl, (CH2)nNHSO2aryl,
-C(O)C1-C8 alkyl, -C(O)OC1-C8 alkyl and C0-C4 alkylNR6R6' wherein R6 , R6' and n are
as defined herein.
The term "alkylheterocyclic" as used herein refers to an alkyl group further
substituted with a heterocyclic group. Examples of alkylheterocyclic include but are not
limited to 2-methylimidazoline, N-methylmorpholinyl, N-methylpyrrolyl and 2-
methylindolyl.
The term "nitrogen containing heterocyclic" means a heterocyclic ring having at
least one nitrogen and include heterocyclic groups optionally having in addition to a
nitrogen atom one or more of oxygen and sulfur atoms.

The term "oxo" as used herein implies an oxygen atom attached to a carbon atom
which is part of a ring or a chain to form a carbonyl group.
The term "basic group" refers to an organic radical which is a proton acceptor.
The term "basic group" also refers to an organic group containing one or more basic
radicals. Illustrative basic radicals are amidino, guanidino, amino, piperidyl, pyridyl, etc,
and exclude amides.
The term "suitable solvent" refers to any solvent, or mixture of solvents, inert to
the ongoing reaction, that sufficiently solubilizes the reactants to afford a medium within
which to effect the desired reaction.
As used herein, the term "patient" includes human and non-human animals such
as companion animals (dogs and cats and the like) and livestock animals. Livestock
animals are animals raised for food production. Ruminants or "cud-chewing" animals
such as cows, bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are
examples of livestock. Other examples of livestock include pigs and avians (poultry)
such as chickens, ducks, turkeys and geese. Also included are exotic animals used in food
production such as alligators, water buffalo and ratites (e.g., emu, rheas or ostriches). The
preferred patient of treatment is a human.
The terms "treating" and "treat", as used herein, include their generally accepted
meanings, e.g., preventing, prohibiting, restraining, alleviating, ameliorating, slowing,
stopping, or reversing the progression or severity of a pathological condition, or sequela
thereof.
The terms "preventing", "prevention of", "prophylaxis", "prophylactic" and .
"prevent" are used herein interchangeably and refer to reducing the likelihood that the
recipient of a compound of formula I will incur or develop any of the pathological
conditions, or sequela thereof, described herein.
As used herein, the term "effective amount" means an amount of a compound of
formula I that is sufficient for treating or preventing a condition, or detrimental effects
thereof herein described; or an amount of a compound of formula I that is sufficient for
antagonizing the MCHR1 receptor to achieve the objectives of the invention.
The term "pharmaceutically acceptable" is used herein as an adjective and means
substantially non-deleterious to the recipient patient.

The term "formulation", as in pharmaceutical formulation, is intended to
encompass a product comprising the active ingredient(s) (compound(s) of formula I), and
the inert ingredien(s) that make up the carrier, as well as any product which results,
directly or indirectly, from combination, complexation or aggregation of any two or more
of the ingredients, or from dissociation of one or more of the ingredients, or from other
types of reactions or interactions of one or more of the ingredients. Accordingly, the
pharmaceutical formulations of the present invention encompass any composition made
by admixing a compound of the present invention and a pharmaceutical carrier, or a
compound of formula I and a pharmaceutically acceptable co-antagonist of MCHR1
useful for the treatment and/or prevention of obesity or a related disease where
antagonism of a MCH receptor may be beneficial.
The terms "diseases related to obesity" or "related diseases" as used herein refer to
such symptoms, diseases or conditions caused by, exacerbated by, induced by, or adjunct
to the condition of being obese. Such diseases, conditions and/or symptoms include but
are not limited to eating disorders (bulimia, anorexia nervosa, etc.), diabetes, diabetic
complications, diabetic retinopathy, sexual/reproductive disorders, depression, anxiety,
epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleeping
disorders, atherosclerosis, rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycernia,
hyperglycemia, and hyperlipoproteinenamia, stress related disorders including post
traumatic stress disorder, substance abuse, including alcohol and drug abuse, and
nonpharamcologic disorders such as gambling, sex and internet related addictions.
The term "unit dosage form" refers to physically discrete units suitable as unitary
(i.e. individual, separate or separate able) dosages for human subjects and other non-
human animals (as described above), each unit containing a predetermined quantity of
active material/ingredient (compound of formula I) calculated to produce the desired
therapeutic effect, in association with a suitable pharmaceutical carrier.
Certain compounds of the invention may contain an acidic moiety (e.g., carboxylic
acid). Therefore, certain compounds of formula I may exist as a pharmaceutical base
addition salts or ionic salts.. Such salts include those derived from inorganic bases such
as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates,
and the like, as well as acid addition salts derived from basic organic amines such as
aliphatic and aromatic amines, aliphatic diamines, hydroxy alkylamines, and the like.

Methods of preparing and isolating salts are known to one of skill in the art.
Pharmaceutically acceptable salts and common methodology for preparing them are well
known to one of skill in the art. See, e.g. P. Stahl, et al. Handbook of Pharmaceutical
Salts: Properties, Selections and Use (VCHA/Wiley-VCH, 200); S. M. Berge, et al,
"Pharmaceutical Salts" Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.
Preferred Compounds of the Invention
Certain compounds of the invention are particularly interesting and preferred. The
following listing sets out several groups of preferred compounds. It will be understood
that each of the listings may be combined with other listings or groupings described
herein to create additional groups of preferred compounds.
Preferred R1 Groups
Preferred R1 groups are independently selected from the group consisting of
hydrogen, halo, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-
C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, heterocyclic, C1-C6
alkylheterocyclic, phenyl, benzyl, cyano, and C1-C4 alkylNR6R6', and wherein each
phenyl, aryl, cycloalkyl or heterocyclic group or subgroup is optionally substituted with 1
to 2 groups independently selected from halo, C1-C4 alkyl, amino, cyano, nitro, C1-C6
haloalkyl, or C1-C6 alkoxy haloalkyl.
Preferred R2 Groups
Preferred R2 groups are independently selected from the group consisting of
hydrogen, or C1-C6 alkyl.
Preferred Ar1
Preferred Ar1 groups are selected from optionally substituted C3-C8 cycloalkyl,
pyridinyl, indolyl, benzthiazolyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl,
pyrazolidinyl, phenyl, piperidinyl, benzothiophenyl, benzofuranyl, naphthyl,
benzimidazolyl, indolinyl, indazolyl, benztriazolyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzo[1,3]dioxolyl, dihydro-
benzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[1,4]-oxazinyl, each optionally substituted with

1-3 groups independently selected from C1-C6 alkyl, C1-C6 alkylcycloalkyl, C1-C6
haloalkyl, hydroxy, alkoxyalkyl, cyano, halo, aryl, COOR6, and CONR6R6'. Particularly
preferred Ar1 groups include phenyl, indolyl, benzthiazolyl, benzimidazolyl,
benzotriazolyl, imidazolyl, indazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, benzo[1,3]dioxolyl, dihydro-benzo[1,4]dioxinyl, and 3,4-
dihydro-2H-benzo[1,4]-oxazinyl optionally substituted with 1-3 groups independently
selected from halogen, -OC1-C4 alkyl, C1-C4 haloalkyl, and -C0-C4 alkylamine.
Preferred L1 Groups
A preferred L1 group is selected from the group consisting of -CH2-, -C(O)-
,CH2CH2-, -CH2CH2CH2-, -CH2CH2Oalkyl, -SCH2CH2-, -OCH2CH2-, -OCH2CH2CH2-,
-O(CH2)3CH2-, -OCH(Et)CH2CH2CH2-, -OCH(iPr)CH2CH2CH2-, -acetylene-CH2-,
-OCH(CH3)CH2CH2SCH2-, -O(CH2)3SCH(CH3)-, -O(CH2)2SCH(CF3)-,
-OCH(CN)CH2CH2-, -NR6CH2CH2-, -NR6CH2CH2CH2-, -NR6(CH2)3CH2-,
-NR6CH(Et)CH2CH2CH2-, -NR6CH(iPr)CH2CH2CH2, -NR6CH(CH3)CH2CH2SCH2-, -
NR6(CH2)2SCH(CF3)-, -OCH(CH3)CH(CH3)-, -OC(CH3)2CH2-, -OCH2C(CH3)2-, -
C(CH3)2CH2CH2-, and - CH2CH2C(CH3)2-, and -NR6CH(CN)CH2CH2-.
Preferred R3 and R4 Groups
Preferred R3 and R4 groups are independently selected from the group consisting
of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C8 alkylcycloalkyl, phenyl,
aryl, C1-C6 alkylaryl, heterocyclic, C1-C6 alkylheterocyclic, COR6, SO2R6 and
(CH2)nSO2R6.
Also preferred are R3 and R4 groups which combine with each other and the
nitrogen atom to which they are attached to form an optionally substituted 5-7 member
heterocyclic ring; or where one or both of R3 and R4 combine with L1 at a position α, β, or
γ to the nitrogen of NR3R4 to form an optionally substituted heterocyclic group selected
from the group consisting of optionally substituted morpholino, thiomorpholino, pyrrole,
2H-pyrrole, 2-pyrroline, pyrrolidine, oxazole, oxadiazolyl, thiazole, imidazoline,
imidazolidine, pyrazole, pyrazoline, piperazinyl, piperidinyl, pyrazinyl, pyrimidine,
azepine, diazepine, pyridinyl, indolyl, N-methylpyrrolidinyl, benzthiazolyl,
benzimidazolyl, and benzthiopheneyl.

Most preferred are R3 and R4 groups which singly or in combination with each
other and the nitrogen atom to which they are attached form or are respesented by groups
independently selected from methyl, ethyl, propyl, isopropyl, isobutyl, cyclopentyl,
cyclohexyl, N-morpholinyl, benzyl, pyridinyl, pyrrolidinyl, piperidinyl, N-
methylpiperidinyl, and N-methylpiperazinyl, 2-methylthiazolyl, N-methylimidazolyl, and
4-piperidinylpiperidine.
Preferred R6 groups
A preferred R6 or R6' is independently selected from hydrogen, C1-C8 alkyl,
phenyl, aryl, alkylaryl, and C3-C8 cycloalkyl.
A more preferred compound of the invention is a compound of formula I wherein
R1 is methyl, chloro, methoxy, fluoro, trifluoromethyl, dichloro, N,N-dimethyI, or
methylsulfonate;
W is 1 and p is 0 or 1;
R2 is hydrogen; t is 0;
Ar1 is selected from a group consisting of phenyl, benzimidazolyl, 1H-insazolyl, 2-
methylindolyl, 3-methoxyphenyl, 2,3-dimethylindolyl, 1-methylindoluyl, benzo-1,4-
oxazin, 4-methylquinolinyl-6yl, 2,3-dihydroindolyl, oxazolyl, 3-chlorophenyl,
L1 is selected from the group consisting of a bond, -C(O)-, -CH2-, -CH2CH2-, -
CH2CH2CH2, -NHCH2CH2, -N(CH3)CH2CH2, -OCH2, -OCH2CH2, -OCH2CH2CH2, and -
acetyleneCH2;
Preferably, R3 and R4 are independently selected from the group consisting of methyl,
ethyl, isopropyl, cyclohexyl; or R3 and R4 combine with each other or with a carbon atom
one to four atoms removed (α, β, or γ position) from the nitrogen of NR3R4 to form a
cyclic ring selected from pyrrole, morpholino, piperidinyl, 4-bipiperidinyl, piperazinyl,
pyridinyl, -morpholinyi-2yl, N-methylmorpholinyl-2yl, 3-hydroxypyrrloidin-1-yl, 3-
methyl,-3H-imidazole, 1H-1-methylimidazolyl, pyridine-4-one, 4-hydroxy-piperidin-1-yl,
pyridinyl, optionally containing 1 or 2 heteroatoms selected from O, N, or S.
An example of a preferred compound of the present invention is a compound
selected from the group consisting of:

2-(4-Chloro-phenyl)-5- {4- [2-(isopropyl-methyl-amino)-ethoxy] -3-methoxy-phenyl} -6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[1-((S)-pyrrolidine-3-carbonyl)-2,3-dihydro-1H-indol-5-yl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one, triflate salt,
2-(4-Chloro-phenyl)-5-[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
5-[3-Methoxy-4-(3-methyl-3H-imidazol-4-ylmethoxy)-phenyl]-2-(4-trifluoromethoxy-
phenyl)-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-{2-[methyl-(1-methyl-piperidin-4-yl)-amino]-benzooxazol-5-yl}-
6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt
5-[3-Methoxy-4-(3-methyl-3H-imidazol-4-ylniethoxy)-phenyl]-2-(4-methoxy-phenyl)-
5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Methoxy-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5- [3-methoxy-4-[2-(3-oxo-morpholin-4-yl)-ethoxy]-phenyl} -5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(2-pyrrolidin-1-yl-cthyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-
yl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(2,4-Dichloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5- {2-[(2-dimethyIamino-ethyl)-methyl-amino]-benzooxazoI-5-yl}-
6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-ChIoro-phenyl)-5- {4-[2-(cyclohexyl-methyl-amino)-ethoxy]-3-methoxy-phenyl} -6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(3-dimethylamino-propoxy)-3-methoxy-phenyl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-methyl-2-(2-morpholin-4-yl-ethylamino)-quinolin-6-yl]-6,7-
dihydro-5H-thiazolo [5,4-c]pyridin-4-one,

2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(2-dimethylamino-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo [5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one, 2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-5H-thiazolo[5,4-c]pyridin-4-one citrate salt,
2-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one, hydrochloride salt,
2-(4-Methoxy-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-
thiazolo[5,4-c]pyridin-4-one, hydrochloride salt
2-(4-Chloro-phenyl)-5-[1-methyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indol-6-yl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
5-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-trifluoromethoxy-phenyl)-5H-
thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(2-dimethylamino-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-metl.yl-3H-imidazol-4-ylmethoxy)-phenyl]-5H-
thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[ 1 -(2-pyrrolidin-1 -yl-ethyl)- 1H-indol-5-yl]-6,7-dihydro-5H-
thiazolo [5,4-c]pyridin-4-one,

2-(4-Chloro-phenyl)-5-{4-[2-(2,2-dimethyl-morpholin-4-yl)-ethoxy]-3-methoxy-phenyl}-
5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
5-[4-(2-Dimethylamino-ethoxy)-3-methoxy-phenyl]-2-(4-methoxy-phenyl)-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[1-methyl-3-(2-pyrrolidin-1-yl-ethyl)-lH-indol-6-yl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[2-methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indol-5-yl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenyl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
5-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-trifluoromethyl-phenyl)-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-{3-methoxy-4-[2-(2,2,6,6-tetramethyl-morpholin-4-yl)-ethoxy]-
phenyl }-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[ 1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-benzoimidazol-5-yl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-((R)-1-morpholin-2-ylrnethoxy)-phenyl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt,
2-(4-Chloro-phenyl)-5-[2,3-dimethyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
5-[4-(2-[ 1,4']Bipiperidinyl-1'-yl-ethoxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[ 1 -(2-morpholin-4-yl-ethyl)-1 H-indol-5-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one, hydrochloride salt, or a pharmaceutically acceptable salt,
solvate, enantiomer, or mixture of enantiomers thereof.

Preparing Compounds of the Invention
Scheme 1 shows a synthetic route for preparing a common intermediate VI
generally utilized in the preparation of compounds of the invention.


Preparation of the intermediate VI starts with the condensation of thioamide I and
β-keto ester II as shown in step 1. This can be achieved in polar solvent (such as MeOH,
EtOH or DMF) from about 2 to 24 hours (h) at a temperature range from about room
temperature to 80 °C to give a thiazole of formula III.
In step 2, reduction of the ester HI to the alcohol IV can be achieved using one of
several methods well known in the literature. For example, ester III can be reduced with
DIBAL (or other suitable reducing agent like LiAlH4, NaBH4, and LiBH4) in THF (or
other aprotic solvent such as ether or toluene) from about 1 to 8h at a temperature range
from about -78°C to 60 °C. Compound IV is isolated by aqueous work-up and purified
by means known in the art.
As shown in step 3, carboxylic acid V can be prepared from alcohol IV by
dissolving in THF (or ether) at about -78 °C, slowly treating with a solution of n-BuLi (or
other suitable base such as LDA or HMDA) over about 2 to 4 hours, then treating with a
solution of CO2 (g) in THF (or ether). Compound V is isolated by precipitation from a
dilute aqueous solution and purified by means known in the art.
The use of a Dean-Stark trap accelerates the reaction by removing H2O as it is produced.
Step 4 involves lactone formation to give VI using anhydrous conditions. For
example, a solution of alcohol V in anhydrous toluene (or THF, benzene, etc.) is treated
with an acid catalyst (ex. para-toluenesulfonic acid) and heated to reflux for 4 to 24 hours

to cyclize to VI. The use of a Dean-Stark trap accelerates the reaction by removing H2O
as it is produced.

Scheme 2. Synthesis of lactam compounds of formula XIII (Route 1).
Lactone VI can be elaborated to provide compounds of formula XIII as shown in
Scheme 2. In step 5, a nitro compound of formula VII that contains a free OH or NH
group is protected with an appropriate group, to give compound of formula VIII that can
be removed later in the synthetic sequence. For example, 2-methoxy-4-nitro-phenoI is
protected as a silyl ether by dissolving the phenol in a polar solvent such as DMF or THF,
treating with a base such as sodium hydride, and then adding triisopropylsilyl triflate (or
similar silyl reagent like TBSC1, TIPSC1, or TBSOTf). The reactions is stirred within a
temperature range of about RT to 50°C for 1 to 24 hours then isolated via aqueous work-
up and purified by means known in the art. Other protecting groups for an OH or NH
group can be employed and are familiar to those skilled in the art (see Philip J. Kocienski,
"Protecting Groups," Thieme: New York 1994 or Theodora W. Green, "Protective
Groups in Organic Synthesis," John Wiley and Sons: New York, 1981 for additional
examples).
In step 6, a compound of formula VIII is prepared by reduction of the nitro group
to give an amine of formula IX by treatment with 5-10% Pd/C under H2 atmosphere
(1atm) in a suitable solvent (like THF, EtOAc, EtOH or MeOH) from about 2 to 24 hours
at room temperature. Several other nitro reduction techniques known in the art can be
employed.
Amide formation, as shown in step 7, is accomplished using a typical Weinreb
protocol (see Basha, Anwer; Lipton, M.; Weinreb, Steven M. Tetrahedron Letters, 1977,

48, 4171-4174). For example, amine IX is dissolved in an aprotic solvent (such as
CH2Cl2 or toluene) and treated with a 2-2.5M solution of Me3Al in hexanes. The
resulting solution is stirred at a temperature from about 0 °C to room temperature for
about 5 to 60 minutes, and then treated with lactone VI. The resulting solution is stirred
at a range of between about room temperature and 110 °C for about 3 to 24 hours to give
amide X which is isolated by aqueous work-up and purified by trituration with ether or by
flash chromatography.
In step 8, lactam XI is prepared under Mitsunobu conditions (Maligres, P. E.;
Waters, M. S.; Weissman, S, A.; McWilliams, J. C; Lewis, S.; Cowen, J.; Reamer, R. A.;
Volante, R. P.; Reider, P. J.; Askin, D. J. Het. Chem. 2003, 40(2), 229-241). For
example, amide X is dissolved in a suitable anhydrous solvent (ex. THF, CH2Cl2, toluene,
etc.) and treated with a trialkyl- or triarylphosphine (ex. Me3P, Bu3P, or Ph3P) and
dialkylazo-dicarboxylate (ex. DEAD or DIAD) at a suitable temperature (about 0 °C to
RT) for about 4 to 24 hours. Compound XI is isolated by aqueous workup and
chromatographic purification.
In step 9, the protecting group that was installed in Step 5 is removed using
conditions that are appropriate for the type of protecting group used to give compound of
formula XII. For example, removal of a silyl ether, such as a triisopropylsilyl group, is
achieved by dissolving the silyl ether in a polar solvent like THF or CH2Cl2 and treating
with a fluoride source such as nBu4NF or HF.pyridine. The reaction is stirred from about
15 minutes to 4 hours at a temperature within a range of about 0 to 50°C and is isolated
by aqueous work-up and purified by means known in the art.
Compounds of formula XIII can be prepared by the alkylation of an NH or OH
group (see step 10) by dissolving in a polar solvent (like THF, DMF, DMSO, and NMP)
and treating with a base such as NaH or K2CO3 and an electrophile (e.g. alkyl halide, alkyl
mesylate, or alkyl tosylate). The reaction is stirred within a range of about room
temperature to about 100 °C from 4-24 hours and then isolated by aqueous work-up and
purified by means known in the art.


Scheme 3. Synthesis of lactam compounds of formula XIII (Route 2).
Scheme 3 shows an alternative route to compounds of formula XIII. In this
approach, the alkylation of an NH or OH group occurs early in the synthetic sequence.
For example, alkylation of VII as shown in Step 11 occurs under conditions similar to
step 8 above to give compounds of formula XIV.
In step 13, the nitro group is reduced to an amine as described in step 5. Also, step
13 and 14 proceed under similar conditions as described in steps 7 and 8, respectively, to
ultimately provide compounds of formula XIII.

Scheme 4. Synthesis of pyridone compounds of formula XIX (Route 1).
Schemes 4 and 5 show synthetic routes for preparing thiazole-pyridone
compounds of the invention and/or precursors thereof.

In step 13 of scheme 4, pyridone XVII is prepared in one step by the oxidation of
Intermediate alcohol X. For example compound X is dissolved in a suitable polar solvent
(e.g. CH2C12, THF) and treated with an oxidizing reagent (e.g. Dess-Martin periodinane,
pyridine.SO3, PDC, or under Swern-oxidation conditions). Oxidation conditions are
abundantly known to those skilled in the art and can be found in Comprehensive Organic
Transformations, by R.C. Larock, VCH Publishers, 1989, p. 604-614. Dess-Martin
periodinane is the reagent of choice for this transformation and the oxidation is performed
at about 0 °C to room temperature from about 1 hour to 3 days. Pyridone XVII is isolated
by aqueous workup and chromatographic purification.
In step 14, analogous to step 9 above, removal of the protecting group to reveal an
NH or OH group is achieved under similar conditions and the compound of formula
XVIII is isolated by aqueous work-up and purified by means known in the art.
Alkylation of the OH or NH group of XVIII (step 15) can occur under basic
conditions with an alkylating reagent, as described in step 10 above, or under Mitsunobu
conditions to provide compounds of formula XIX.
Alternatively, and as shown in step 16 of Scheme 5, intermediate XVI can be
oxidized with the sidechain already installed using similar conditions as described in step
13 above to afford thiazole-pyridone compounds of formula XIX.

Scheme 5. Synthesis of pyridone compounds of formula XIX (Route 2).

Scheme 6 shows a synthetic route for preparing compounds of the invention from
intermediate acetal wherein L1 is an alkylene of varying carbon chain lengths.

If groups A, B and D (Compound XIII) together define an acetal group (such as
A= CH and B=D=OMe or OEt), then hydrolysis to an aldehyde group is performed
according to conditions recognized by persons skilled in the art (Scheme 6). For example,
in step 17 acetal XX is dissolved in a suitable solvent (e.g. THF, acetone, MeOH) and
treated with water and an acid catalyst (e.g. p-toluenesulfonic acid) at reflux for about 4 to
24 hours to give aldehyde XXI. Reductive animation (step 18) is performed by dissolving
the aldehyde XXI in dichloroethane or another suitable solvent such as for example,
CH2Cl2 or THF and treated with an 1° or 2° amine and a reducing reagent such as for
example NaCNBH3, or NaBH(OAc)3. The mixture is stirred at about RT to 80 °C from
about 30 min to 8 hours. Amines of formula XXII are isolated by aqueous workup and
purified by means known in the art.
Scheme 7 shows an alternative synthetic route for preparing compounds of the
invention and/or precursors thereof. In step 19, lactone VI is treated with a protected
amine using conditions previously described in step 7 to give amide XXIII. In step 19,
Lactam XXIV is prepared using conditions previously described in step 8. The lactam
nitrogen is deprotected, as shown in step 21, using conditions consistent with the type of
protecting group that is used. For example, a 3,4-dimethoxy benzyl group is removed

under acidic conditions (e.g. p-toluene sulfonic acid or TFA) in a solvent such as toluene
at a temperature range of RT to reflux for 0.5 to 4h. Lactam XXIV is isolated by
precipitation from water and purified by means known in the art.
In step 22, the lactam is coupled to an aryl bromide using catalytic cross-coupling
conditions such as Buchwald arylation of an amide (see Yin, J.; Buchwald, S.J. J. Am.
Chem. Soc. 2002,124 (21), 6043-6048). For example, lactam of formula XXIV is
coupled to bromide XXV (where P2 is a protecting group for an OH or NH group) using a
base such as for example, CS2CO3), a palladium reagent such as. Pd2dba3, and a
phosphine ligand such as Xantphos™ in a non-protic solvent (ex. dioxane, toluene,
benzene etc.). The reaction is performed at a temperature range of about RT to reflux
from about 3 to 24h and is then isolated by aqueous work-up and purified by means
known in the art.
As shown in step 23, the protecting group of XXVII is removed using conditions
consistent with the type of protecting group that is used. For example, a silyl ether is
removed using a Bu4NF. In addition, a p-toluene sulfonate ester is removed under basic
conditions using for example, LiOH in 2:1 dioxane water, to afford a compound of
formula XII.
In step 24, alkylation of the free NH or OH group of XII is achieved using
conditions previously described in step 8 to afford a compound of formula XIII.

Scheme 7. Synthesis of lactam compounds of formula XIII (Route 3).
Scheme 8 shows the preferred synthesis of substituted morpholines that are used
as reagents in the synmesis of compounds of the invention.


In step 25, the amino group of methallyl amine (XXVIII) is protected with a
benzyl group via a reductive amination. Amine XXVUI is dissolved in a polar aprotic
solvent like and treated with benzaldehyde. The imine intermediate is then reduced with a
reducing reagent like NaBH4 for 10-24 hours at a temperature range of room temperature
to 50°C to give an amine of formula XXIX that is isolated by aqueous work-up and
purified by means known in the art.
In step 26, an amine of formula XXIX is alkylated by treating with an epoxide (for
example, isobutylene oxide) and Lewis acid such as LiBr at a temperature range from
room temperature to 60°C for 1 to 8 hours to give alcohol of formula XXX. The product
is isolated by aqueous work-up and purified by means known in the art.
In step 27, the preferred method for forming the substituted morpholine is via
halo-etherification methodology. In this approach, an alcohol of formula XXX is treated
with iodine. The reaction is performed in a biphasic mixture of a nonpolar aprotic
solvent, such as MTBE, and an aqueous basic solution (for example, 1M NaHCO3) for 12
to 24h. The iodide of formula XXXI is men isolated by aquoues work-up and purified by
means known in the art.
In step 28, the iodide is removed under reducing conditions to give the benzyl
morpholine of formula XXXII. Typical conditions to remove an alkyl iodide group are to
dissolve the iodide XXXI in a polar solvent such as DMSO and treat with a reducing

reagent like NaBH4 for 2 to 6 hours. Morpholine of formula XXXII is isolated by
aqueous work-up and purified by means known in the art.
In step 29, the benzyl protecting group is removed under typical reductive
conditions that are recognized by persons skilled in the art. For example, compound of
formula XXXII is dissolved in suitable solvent (example THF, ETOH), treated with 3%
palladium on activated carbon under hydrogen atmosphere that is pressurized up to 60psi
at 40°C for up to 24h. Morpholine of formula XXXIII is purified by means known in the
art and can be isolated as the hydrochloride salt by treating with an HC1 source (ex. 1 .OM
HC1 in ether).
Demonstration of Function
In order to demonstrate that compounds of the present invention have the capacity
to bind to and inhibit the function of MCHR1, binding and functional assays were
established. All ligands, radioligands, solvents and reagents employed in these assays are
readily available from commercial sources or can be readily prepared by those skilled in
the art.
The full-length cDNA for human MCHR1 was cloned from a human adult brain
cDNA library (Edge Biosystems, Cat. 38356) by standard polymerase chain reaction
(PCR) methodology employing the following primers: sense, 5'-GCCACCATGGACCT
GGAAGCCTCGCTGC-3'; anti-sense, 5'-TGGTGCCCTGACTTGGAGGTGTGC-3'.
The PCR reaction was performed in a final volume of 50 µl containing 5 µl of a 10x stock
solution of PCR buffer, 1 µl of 10 mM dNTP mixture (200 µM final), 2 µl of 50 mM
Mg(S04) (2 mM final), 0.5 µl of 20 µM solutions of each primer (0.2 µM final), 5 µl of
template cDNA containing 0.5 ng DNA, 0.5 µl of Platinum Taq High Fidelity DNA
polymerase (Gibco Life Technologies) and 36 µl of H2O. PCR amplification was
performed on a Perkin Elmer 9600 thermocycler. After denaturation for 90 sec at 94 °C,
the amplification sequence consisting of 94 oC for 25 sec, 55 °C for 25 sec and 72 °C for 2
min was repeated 30 times, followed by a final elongation step at 72 °C for 10 min. The
desired PCR product (1.1 Kb) was confirmed by agarose gel electrophoresis and the band
was extracted from the gel by Geneclean (Bio101) following the manufacturer's
instructions. Following extraction, the cDNA fragment was cloned into pCR2.1-TOPO
plasmid (Invitrogen Corp) to confirm the identity and sequence.

In order to generate cell lines stably expressing MCHR1, the insert was then
subcloned into the Xba I and Not I sites of pcDNA(+)-3.1-neomycin (Invitrogen). After
purification by Qiagen Maxi-prep kit (QIAGEN, Inc.), the plasmid was transfected by
Fugene 6 (Roche Applied Science) into AV12 cells that had been previously transfected
with the promiscuous G protein Gα15. The transfected cells were selected by G418 (800
µg/ml) for 10-14 days and single colonies were isolated from culture plates. The G418-
resistant colonies were further selected for MCHR1 expression by measuring MCH-
stimulated Ca2+ transients with a fluorometric imaging plate reader (FLIPR, Molecular
Devices).
Typically, individual clones are plated out in 96-well plates at 60,000 cells per
well in 100 µl of growth medium (Dulbecco's modified Eagle's medium (DMEM), 5%
fetal bovine serum, 2 mM L-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 0.5
mg/ml Zeocin, and 0.5 mg/ml Geneticin). After 24 hrs at 37°C, medium is removed and
replaced with 50 µl of dye loading buffer (Hank's balanced salt solution (HBSS)
containing 25 mM HEPES, 0.04% Pluronate 127 and 8 µM F1uo3 Both from Molecular
Probes)). After a 60 min loading period at room temperature, dye loading buffer is
aspirated and replaced with 100 µl of HEPES/HBBS. Plate is placed in FLIPR and basal
readings are taken for 10 sec, at which point 100 µl of buffer containing 2 181M MCH (1
µM final) is added and measurements are taken over 105 sec. To correct for variations
between clones in numbers of cells per well, the MCH response is normalized to the
response induced by epinephrine.
Both the 125I-MCH binding and functional GTPγ35S binding assays employed
membranes isolated from a clone designated as clone 43. Typically, cells from 20
confluent T225 flasks were processed by washing the monolayers in cold phosphate-
buffered saline (PBS), scraping the cells into same and re-suspending the cell pellet in 35
ml of 250 mM Sucrose, 50 mM HEPES, pH 7.5, 1 mM MgCl2,24 µg/ml DNase I, and
protease inhibitors (1 Complete® tablet, per 53 ml of buffer prepared, Roche
Diagnostics). Alternatively, greater levels of cells could be generated by adapting cell
growth to suspension culture in 20 L stirred vessel bioreactors. After incubation on ice
for 5 min, cells were disrupted with 20-25 strokes of a Teflon/Glass homogenizer attached
to an overhead motorized stirrer, and the homogenate was centrifuged at 40,000 rpm in

Beckman Type 70.1 Ti rotor. The pellets were re-suspended in 250 mM Sucrose, 50 mM
HEPES, pH 7.5,1.5 mM CaCl2, 1 mM MgSO4 and protease inhibitors by Teflon/Glass
homogenization to achieve a protein concentration of ~3-5 mg/ml (Pierce BCA assay with
Bovine serum albumin as standard). Aliquots were stored at -70°C.
Binding of compounds to MCHR1 was assessed in a competitive binding assay
employing 125I-MCH, compound and clone 43 membranes. Briefly, assays are carried out
in 96-well Costar 3632 white opaque plates in a total volume of 200 µl containing 25 mM
HEPES, pH 7.0,10 mM CaCl2, 2 mg/ml bovine serum albumin, 0.5% dimethyl sulfoxide
(DMSO), 5 µg of clone 43 membranes, 200 pM 125I-MCH (NEN), 0.625 mg/ml of wheat
germ agglutinin scintillation proximity assay beads (WGA-SPA beads, Amersham Inc.,
now GE Healthcare) and a graded dose of test compound. Non-specific binding is
assessed in the presence of 0.1 µM unlabeled MCH. Bound l25I-MCH is determined by
placing sealed plates in a Microbeta Trilux (Perkin Elmer Life and Analytical Sciences
Inc.) and counting after a 12 hr delay.
IC50 values (defined as the concentration of test compound required to reduce
specific binding of 125I-MCH by 50%) are determined by fitting the concentration-
response data to a 4-parameter model (max response, min response, Hill coefficient, IC50)
using Excel® (Microsoft Corp.). Ki values are calculated from IC50 values using the
Cheng-Prusoff approximation as described by Cheng et al ( Relationship between the
inhibition constant (Ki) and the concentration of inhibitor which causes 50% inhibition
(IC50) of an enzymatic reaction, Biochem. Pharmacol., 22: 3099-3108 (1973)). The Kd
for 125I-MCH is determined independently from a saturation binding isotherm.
Exemplified compounds showed a Ki of Specifically, a sample of observed Ki values is provided in Table 1 (below) for
demonstration purposes only.



Functional antagonism of MCH activity is assessed by measuring the ability of test
compound to inhibit MCH-stimulated binding of GTPγ35S to clone 43 membranes.
Briefly, assays are carried out in Costar 3632 white opaque plates in a total volume of 200
µl containing 50 mM Hepes, pH 7.4, 5 mM MgCl2, 10 µg/ml saponin, 1.0 mg/ml bovine
serum albumin, 100 mM NaCl, 3 µM GDP, 0.3 nM GTPγ35S, 10 nM MCH
(approximately equal to EC90), 20 µg of clone 43 membranes, 5.0 mg/ml of wheat germ
agglutinin scintillation proximity assay beads (WGA-SPA beads, Amersham Inc., now
GE Healthcare) and a graded dose of test compound. The plates are sealed and left for
16-18 hrs at 4°C. After a 1 hr delay to allow plates to equilibrate to ambient temperature,
bound GTPγ35S is determined by counting in a Microbeta Trilux (Perkin Elmer Life and
Analytical Sciences Inc).
IC50 values (defined as the concentration of test compound required to reduce
MCH-stimulated GTPγ35S binding by 50%) are determined by fitting the concentration-
response data to a 4-parameter model (max response, min response, Hill coefficient, IC50)
using Excel (Microsoft). After verifying competitive antagonism by Schild analysis, Kb
values are calculated from the IC50 values for each antagonist and the EC50 for MCH
(determined independently) using a modification of the Cheng-Prusoff approximation as
described by Leff and Dougal (Trends Pharmacol. Sci. (1993) 14: 110-112).
Exemplified compounds showed IC50 values of conditions disclosed herein.
In order to demonstrate in vivo efficacy, compounds of the invention were
administered by oral gavage to diet-induced obese male Long-Evans rats (Harlan, IN)
weighing 500-550g. Vehicle consisted of 1% CMC and 0.25% PS-80 in water.
Animals were individually housed in a temperature regulated room (24°C) with a
reverse 12 hour light/dark cycle (dark 10:00/22:00). Water and food (Teklad 95217,
Harlan, WI) were available ad libitum. Compounds were dosed orally once a day before
onset of dark for 3 days. Daily food intake and body weight change were measured for
the 3 day period. Exemplified compounds tested at 10 mg/kg showed reduction of 3 day
cumulative body weight gain when compared with vehicle-treated controls. Specifically,

a sample of observed 3 day cumulative body weight reduction, relative to control, is
provided in Table 2 (below) for demonstration purposes only.

Utility
As antagonists of the MCHRlbinding, a compound of the present invention is
useful in treating conditions in human and non-human (especially companion) animals in
which the MCHR1 receptor has been demonstrated to play a role. The diseases, disorders
or conditions for which compounds of the present invention are useful in treating or
preventing include, but are not limited to, diabetes mellitus, hyperglycemia, obesity,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, atherosclerosis of coronary,
cerebrovascular and peripheral arteries, gastrointestinal disorders including peptic ulcer,
esophagitis, gastritis and duodenitis, (including that induced by H. pylori), intestinal
ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and
proctitis) and gastrointestinal ulcerations, neurogenic inflammation of airways, including
cough, asthma, depression, prostate diseases such as benign prostate hyperplasia, irritable
bowel syndrome and other disorders needing decreased gut motility, diabetic retinopathy,
neuropathic bladder dysfunction, elevated intraocular pressure and glaucoma and non-
specific diarrhea dumping syndrome. The diseases, disorders or conditions for which
compounds of the present invention are useful in treating or preventing also include.stress
related disorders including post traumatic stress disorder, substance abuse, including
alcohol and drug abuse, and nonpharamcologic disorders such as gambling, sex and
internet related addictions. By inhibiting MCH activity the compounds of the present
invention provide anorexic effects. That is, the compounds of the invention are useful as
appetite suppressants and/or weight loss agents. The compounds of the invention may
also be used in combination with other approved therapeutic agents for the treatment,

prevention and/or amelioration of obesity and related diseases. In this format, the
compounds of the present invention enhance the positive effects of such approved
combination treatments while minimizing the side effects due to the potential requirement
of lower doses of such combination compounds. Such combination therapies may be
delivered individually or in a combined formulation. Examples of compounds useful in
combination with a compound of formula I include weight loss agents (Meridia™,
Xenical™), cholesterol lowering agents (such as for example lovastatin, simvastatin
pravastatin, fluvastatin, and atorvastatin), glucose level control or modulating agents,
nerve growth factor agonists (such as for example, axokine), cannabinoid CB-1 antagonist
compounds (such as for example rimonanbant) and the like.
In treating non-human, non-companion animals, the compounds of the present
invention are useful for reducing weight gain and/or improving the feed utilization
efficiency and/or increasing lean body mass.
Formulation
The compound of formula I is preferably formulated in a unit dosage form prior to
administration. Therefore, yet another embodiment of the present invention is a
pharmaceutical formulation comprising a compound of formula I and a pharmaceutical
carrier.
The present pharmaceutical formulations are prepared by known procedures using
well-known and readily available ingredients. In making the formulations of the present
invention, the active ingredient (formula I compound) will usually be mixed with a
carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a
liquid, tablet, capsule, sachet, paper or other container. When the carrier serves as a
diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or
medium for the active ingredient. Thus, the compositions can be in the form of tablets,
pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,
syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules,
suppositories, sterile injectable solutions and sterile packaged powders.
One of skill in the art is aware of methods, reagents and conditions for preparing various
standard formulations or can assess such information without undue experimentation.
The compositions of the invention may be formulated so as to provide quick, sustained or
delayed release of the active ingredient after administration to the patient.

Dose
The specific dose administered is determined by the particular circumstances
surrounding each situation. These circumstances include, the route of administration, the
prior medical history of the patient, the pathological condition or symptom being treated,
the severity of the condition/symptom being treated, and the age and sex of the recipient.
However, it will be understood that the therapeutic dosage administered will be
determined by the physician in me light of the relevant circumstances, or by the
veterinarian for non-human recipients.
Generally, an effective minimum daily dose of a compound of formula I is about
20 to 200 mg. Typically, an effective maximum dose is about 200 to 1000 mg. The exact
dose may be determined, in accordance with the standard practice in the medical arts of
"dose titrating" the recipient; that is, initially administering a low dose of the compound,
and gradually increasing the dose until the desired therapeutic effect is observed.
Route of Administration
The compounds may be administered by a variety of routes including the oral,
rectal, transdermal, subcutaneous, topical, intravenous, intramuscular or intranasal routes.
Ap referred route of administration is oral.

Combination Therapy
A compound of formula I may be used in combination with other drugs or
therapies that have been approved for the treatment/prevention/suppression or
amelioration of the diseases or conditions for which compounds of formula I are useful.
Such other drug(s) may be administered, by a route and in an amount commonly used
therefor, contemporaneously or sequentially with a compound of formula L When a
compound of formula I is used contemporaneously with one or more other drugs, a
pharmaceutical unit dosage form containing such other drugs in addition to the compound
of formula I is preferred. Accordingly, the pharmaceutical compositions of the present
invention include those that also contain one or more other active ingredients, in addition
to a compound of formula I. Examples of other active ingredients that may be combined
(upon approval) with a compound of formula I, and either administered separately or in
the same pharmaceutical composition, include, but are not limited to:
(a) insulin sensitizers including (i) PPARγ agonists such as the glitazones (e.g.
troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like), and
compounds disclosed in WO97/27857,97/28115, 97/28137 and 97/27847; (ii)
biguanides such as metformin;
(b) insulin or insulin mimetics;
(c) sulfonylureas such as tolbutamide and glipizide;
(d) alpha-glucosidase inhibitors (such as acarbose);
(e) cholesterol lowering agents such as
i. HMG-CoA reductase inhibitors (lovastatin, simvastatin pravastatin,
fluvastatin, atorvastatin, and other statins),
ii. sequestrants (cholestyramine, colestipol and a dialkylaminoalkyl
derivatives of a cross-linked dextran),
iii. nicotinyl alcohol nicotinic acid or a salt thereof,
iv. proliferator-activator receptor a agonists such as fenofibric acid derivatives
(gemfibrozil, clofibrat, fenofibrate and benzafibrate),
v. inhibitors of cholesterol absorption for example β-sitosterol and (acyl
CoAxholesterol acyltransferase) inhibitors for example melinamide,
vi. probucol,

vii. vitamin E, and
viii. thyromimetics;
(f) PPARδ agonists such as those disclosed in W097/28149;
(g) Anti obesity compounds such as fenfluramine, dexfenfluramine, phentermine,
sibutramine, orlistat, axokine, rimonanbant, etc;
(h) feeding behavior modifying agents such as neuropeptide Y antagonists (e.g.
neuropeptide Y5) such as those disclosed in WO 97/19682, WO 97/20820, WO
97/20821, WO 97/20822 and WO 97/20823;
(i) PPARoα agonists such as described in WO 97/36579 by Glaxo;
(j) PPARγ antagonists as described in W097/10813; and
(k) serotonin reuptake inhibitors such as fluoxetine and sertraline
(1) antipsychotic agents such as for example olanzapine.
Examples
The following examples are only illustrative of the preparation protocols and
Applicants' ability to prepare compounds of the present invention based on the schemes
presented or modifications thereof. The examples are not intended to be exclusive or
exhaustive of compounds made or obtainable.
Materials and Method
Solvents and reagents were used as purchased from chemical suppliers and
reactions were conducted at ambient atmosphere unless otherwise stated. Mass spectrum
data was obtained on a Micromass Platform LCZ spectrometer using electrospray (ES)
ionization. NMR data was obtained on a Varian 400 MHz spectrometer and is reported in
ppm. A CEM Discover microwave reactor was used where indicated. Common
abbreviations used throughout the experimentals are: methanol (MeOH), ethanol (EtOH),
ethyl acetate (EtOAc), dichloromethane (CH2Cl2), dimethylformamide (DMF),
tetrahydrofuran (THF), and room temperature (RT).

Preparation 1
Triisopropyl-(2-methoxy-4-nitro-phenoxy)-silane

Dissolve 4-nitroguiacol (50.0 g, 295.6 mmol) in DMF (anhydrous, 1000 mL) and
cool the solution to 0-5 °C then slowly treat with NaH (60% in mineral oil, 13.4 g, 335.0
mmol) keeping the temp. temp, for ca. 30 min. then cool to 0-5°C. Treat the mixture with TIPS triflate (90.0 mL,
334.8 mmol), keeping the temp. mixture with 14% aqueous NH4Cl (1000 mL) then extract with EtOAc (3 x 1000 mL).
Combine the organic solutions, wash with brine (1000 mL), and concentrate in vacuo to
give a light yellow oil that was purified by flash chromatography, using 100% hexanes
then 10% EtOAc/hexanes, to give the title compound as a yellow oil (95.8 g, 99.6%
yield). MS (ES+)326.2 (M+1)+.
Preparation 2
3-Methoxy-4-triisopropylsilanyloxy-Phenylamine

Dissolve triisopropyl-(2-methoxy-4-nitro-phenoxy)-silane (95.7 g, 294.0 mmol) in
EtOH (1800 mL) and add 5% Pd/C (10.0 g). Hydrogenate the slurry at room temperature
under 50 psi hydrogen for 8 h. Filter the slurry through a pad of Celite® and rinse with
EtOH. Concentrate the filtrate in vacuo to give a brown oil. Purify by flash
chromatography, using a gradient from 100% hexanes to 20% EtOAc/hexanes, to give the
title compound as a brown solid (67.4 g, 77.6% yield). MS (ES+) 296.2 (M+1)+.

Preparation 3
[2-(4-chloro-phenyl)-thiazol-4-yl]-acetic acid ethyl ester

Dissolve 4-chlorothiobenzamide (74.0 g, 431.1 mmol) in absolute EtOH (470 ml,
absolute). Add ethyl-4-chloroacetoacetate (58.0 ml, 70.1 g, 426.0 mmol) to the solution,
stir mechanically at reflux for 2 h. Allow the reaction to cool to room temperature and
dilute with water (1000 ml). Extract the mixture with Et2O (2000 ml, then 2 x 500 ml).
Combine the organic layers and wash with brine (950 ml). Concentrate the organic layer
in vacuo to give an oil weighing 121.8 g. The oil solidifies on standing.
Suspend the solid in isopropyl alcohol (610 ml) and heat the slurry to 35 °C at
which temperature all the solids dissolve. Charge the solution with water (1830 mL) and
allow to cool to room temperature. At approximately 32 °C, precipitation occurs. Stir me
resulting slurry mechanically at room temperature for 4.5 h and filter. Dry the solid in a
vacuum oven at 35 °C for 2 days to give a solid weighing 107.3 g (89.4% yield). MS
(ES+) 282.1 (M)+.
Preparation 4
[2-(4-Methoxy-phenyl)-thiazol-4-yl]-acetic acid ethyl ester

Prepare the title compound by essentially following the procedure as described in
Preparation 7, using 4-methoxythiobenzamide. MS (ES+) 278.2(M+1)+. 1H NMR (400
MHz, CDC13): δ 7.82 (d, J = 8.8 Hz, 2H), 7.11 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 4.21 (q,
J = 7.0 Hz, 2H), 3.87 (s, 2H), 3.85 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H).

Preparation 5
2-[2-(4-chloro-phenyl)-thiazol-4-yl]-ethanol

Dissolve [2-(4-chloro-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (107.4 g, 381.2
mmol) in THF (800 mL) and cool to 0-5 °C. Add DIBAL (1.0 M in THF, 800 mL, 800
mmol) slowly over approximately 3.5 h (somewhat exothermic) keeping the temp. Allow the reaction to warm to room temperature with mechanical stirring overnight. Cool
the reaction to 0-5 °C and slowly add more DIBAL (150 mL) over approximately 15 min
keeping the temperature Cool to 0-5 °C and slowly add over 5 h aqueous saturated Rochelle's salt (2900 mL, very
exothermic at first, minor gas evolution) keeping the temperature solidifies after approximately 150 mL has been added. It becomes more fluid and then
solidifies again as the addition continues. Extract the mixture with EtOAc (2 x 3300 mL).
Combine the organic layers and concentrate in vacuo to give an oil weighing 112.9 g.
Take the oil up in toluene (600 mL), concentrate in vacuo and repeat. Dry the residue on
a vacuum pump for 6 h to give a residue weighing 107.4 g (110% yield). MS (ES+) 240.1
(M)+. 1H NMR (400 MHz, CDCl3): δ 7.84 (dt, J = 8.4, 2.2 Hz, 2H), 7.39 (dt, J = 8.4,2.2
Hz, 2H), 6.98 (s, 1H), 3.98 (m, 2H), 3.44 (bs, 1H), 3.02 (t, 7= 5.5 Hz, 2H).
Preparation 6
2-[2-(4-Methoxy-phenyl)-thiazol-4-yl]-ethanol

Prepare the title compound by essentially following the procedure as described in
Preparation 5, using [2-(4-methoxy-phenyl)-thiazol-4-yl]-acetic acid ethyl ester. MS
(ES+) 236.2(M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.88 (d, 7= 8.8 Hz, 2H), 6.95 (d, J =
8.8 Hz, 2H), 6.91 (s, 1H), 3.98 (t, J= 5.3 Hz, 2H), 3.85 (s, 3H), 3.03 (t, J = 5.3 Hz, 2H).

Preparation 7
2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid

Suspend 2-[2-(4-chloro-phenyl)-thiazol-4-yl]-ethanol (107 g gross, 91 g net, 380
mmol) in THF (1210 mL). Decant the solution from the undissolved solids. Cool the
THF solution to -75 oC. Evacuate under vacuum and purge with nitrogen three times.
Add n-butyl lithium (1.6 M in hexanes, 530 mL, 848 mmol) slowly over 4 h keeping the
temp. flask containing THF at -75 °C that has been saturated with CO2 gas (approximately 390
g) keeping the temp. slurry with additional CO2 gas (approximately 355 g). Allowed the reaction to come to
room temperature while stirring mechanically at room temperature overnight.
Add 1N HCl (2100 mL + 900 mL), cool the slurry to 16 °C and filter. Rinse the
resulting solid with hexane (1400 mL) and dry on the filter funnel with vacuum and a
stream of nitrogen to give a solid weighing 81.3 g (75.4% yield). MS (ES+) 284.0
(M+l)+. 1H NMR (400 MHz , DMSO-d6): δ 7.96 (dt, J = 8.8, 2.2 Hz, 2H), 7.55 (dt, J =
8.4, 2.2 Hz, 2H), 3.74 (t, J = 7.0 Hz, 2H), 3.35 (s, 1H), 3.26 (t, J = 7.0 Hz, 2H).
Preparation 8
4-(2-Hydroxy-ethyl)-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid

Prepare the titled compound by essential following the procedure as described in
Preparation 7, using 2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethanol. MS (ES+)
280.2(M+1)+. 1H NMR (400 MHz, CD3OD): δ 7.92 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8
Hz, 2H), 3.92 (t, J =7.0 Hz, 2H), 3.86 (s, 3H), 3.38 (t, J = 7.0 Hz, 2H).

Preparation 9
2-(4-Chloro-phenyl)-4-(2-methoxy-ethyl)-thiazole-5-carboxylic acid methyl ester

Add a 1.0 M solution of sufuryl chloride in dichloromethane (20.0 mL, 20.0
mmol) dropwise to a solution of 5-methoxy-3-oxo-pentanoic acid methyl ester (3.0 g,
18.8 mmol) in dichloromethane (20.0 mL) at 0 °C and stir under nitrogen at 0 °C for 2 h.
Concentrate the reaction mixture on a rotavap (rotary evaporator), keeping the bath
temperature at RT. Add 4-chlorothiobenz-amide (3.67 g, 21.5 mmol) to the residue,
followed by methanol (30.0 mL) and heat to 60 °C for 18 h. Quench the reaction with
water and extract with EtOAc (2x). Combine the organic portions, wash with brine, dry
over MgSO4, filter, and concentrate under vacuum. Purify by flash chromatography on
silica gel, using a gradient of EtOAc/Hexane (0-60%) to give the title compound (3.3 g,
57%). Exact mass = 311.0, MS (ES+) 312.0 (M+1). 1H NMR (CDCl3): δ 7.89 (d, 2H, J
= 8.8 Hz), 7.40 (d, 2H, J = 8.8 Hz), 3.88 (s, 3H), 3.82 (t, 2H, J = 6.8 Hz), 3.47 (t, 2H, J =
6.8 Hz), 3.38 (s, 3H).
Prepare the compounds below, Preparations 9b to 9f, by essentially following the
procedure as described in Preparation 13, using the appropriate thiobenzamide as starting
material.




Preparation 10
5-Acetoxy-3-oxo-peatanoic acid ethyl ester

In a 2 L round bottom flask with stir bar, dissolve acetic acid 3-buten-1-yl ester
(50 g, 438,1 mmol) in 1.5 L of dichloromethane and cool to -78 °C. Vigorously bubble
ozone through the reaction solution for about 2 h at which time the solution becomes very
deeply colored (blue/purple). Bubble ozone through for an additional 5 min. Discontinue
the ozone and bubble in oxygen until the color fades completely (about 15 min). To die
reaction, which is maintained at a temperature of -78 °C, add dimethyl sulfide (83.8 g,
99.0 mL, 1.35 mole). Allow to warm to ambient temperature overnight. Concentrate the
reaction in vacuo to provide ccetic acid 3-oxo-propyl ester. Use the material as is, with
no further purification or characterization.
Charge a round-bottom flask with tin(II) chloride (16.6 g, 0.088 mol), purge with
nitrogen, and add dichloroethane (300 mL) by cannula. Add ethyl diazoacetate (92 mL,
0.88 mol) by cannula and stir 10 min. Add a solution of acetic acid 3-oxo-propyl ester
(0.44 mol) in CH2Cl2 (600 mL) slowly by cannula over 1 h, then stir the reaction in a 50
°C oil bath for 3 h. Concentrate under vacuum, add saturated aqueous NaHCO3 and
remove the organic phase. Extract the aqueous portion with EtOAc (2x). Wash the
combined organic portions with brine, dry over MgSO4, filter through Celite®, and
concentrate under vacuum. Purify by flash chromatography on silica gel, eluting with a
gradient of EtOAc/hexane 8%-25% to give the tide compound (27.8 g, 31%), exact mass
202.08, mass spectrum (ES) 225.1 (M + Na). 1H NMR (CDCl3): δ 4.34 (t, J = 6.1 Hz,
2H), 4.20 (q, J = 7.1 Hz, 2H), 3.46 (s, 2H), 2.89 (t, J = 6.1 Hz, 2H), 2.03 (s, 3H), 1.28 (t, /
= 7.1 Hz,3H).

Preparation 11
5-Acetoxy-2-bromo-3-oxo-pentanoic acid ethyl ester

Purge a round-bottom flask containing 5-acetoxy-3-oxo-pentanoic acid ethyl ester
(11.3 g, 55.9 mmol) with nitrogen, add acetonitrile (250 mL) by cannula and chill in an
ice water bath. Add copper(II) bromide (13.1 g, 58.7 mmol) neat and stir 5 min under
nitrogen. Add [hydroxy(tosyloxy)iodo]benzene (23.0 g, 58.7 mmol) neat, stir 5 min and
quench with water. Extract with ether (3x), wash combined organics with brine, dry over
MgSO4, filter and concentrate under vacuum. Purify by flash chromatography on silica
gel, using a gradient of EtOAc/hexane (8%-30%) to give the title compound (6.56 g,
42%). 1H NMR (CDCl3): δ 4.78 (s, 1H), 4.35 (t, J = 6.2 Hz, 2H), 4.29 (q, J = 7.1 Hz,
2H), 3.12 (q, 7= 5.7 Hz, 2H), 2.04 (s, 3H), 1.32 (t, J = 7.1Hz, 3H).
Preparation 12
2-(4-Chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one

Method 1: Purge a round-bottom flask containing 4-chloro-thiobenzarnide (5.23 g, 18.6
mmol), with nitrogen, and add acetonitrile (50 mL) by syringe. Add a solution of 5-
acetoxy-2-bromo-3-oxo-pentanoic acid ethyl ester (3.83 g, 22.3 mmol) in acetonitrile (15
mL) by syringe and stir at RT under nitrogen for 1 h. Concentrate under vacuum to a
solid, dilute with toluene (100 mL), water (5 drops) and add p-toluenesulfonic acid
monohydrate (7.08 g, 37.2 mmol) neat. Attach a fractional distillation apparatus with
collection flask and set in 120 °C oil bath. After first distillate is collected at
approximately 80 °C (monitored at head of distillation column) increase oil bath
temperature in 5 degree increments to 140 °C until reaction has been concentrated to one-
half volume. Remove from heat, neutralize with saturated aqueous NaHCO3, extract with
EtOAc (3x), dry over MgSO4, filter and concentrate under vacuum. Purify by flash
chromatography on silica gel, using a gradient of EtOAc in CH2Cl2 (0%-10%) to give the

title compound (2.48 g, 48%). Exact mass = 265.0, MS (ES+) 266.0 (M+l)+. 1H NMR
(CDCl3): δ 7.93 (dt, J = 8.4, 2.1 Hz, 2H), 7.46 (dt, J= 8.4,2.2 Hz, 2H), 4.67 (t, J= 6.4
Hz, 2H), 3.23 (t, J= 6.4 Hz, 2H).
Method 2: Add 1.0 M solution of boron tribromide in dichloromethane (21.0 mL, 21.0
mmol) dropwise to a solution of 2-(4-chloro-phenyl)-4-(2-methoxy-ethyl)-thiazole-5-
carboxylic acid methyl ester (6.0 g, 19.3 mmol) in dichloromethane (60.0 mL) at -78 °C
and stir under nitrogen at 0 °C for 3 h. Quench reaction mixture with ether (50.0 mL) and
water (50.0 mL), stir for additional 30 min and concentrate. Dilute residue with water and
extract EtOAc (2x). Combine EtOAc, wash with brine, dry over MgSO4, filter, and
concentrate under vacuum. Add p-TsOH (7.0 g, 36.8 mmol) and toluene (100.0 mL) to
the residue, reflux at 110 °C for 18 h, and concentrate the reaction mixture. Add saturated
NaHCO3 solution and extract with EtOAc (2x). Combine EtOAc, wash with brine, dry
over MgSO4, filter, and concentrate under vacuum. Purify by flash chromatography on
silica gel, using a gradient of MeOH/dichloromethane (0-5%) to give the title compound
(1.5 g, 29%).
Method 3: Combine 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid
(81.2 g, 286.2 mmol) with p-TsOH monohydrate (32.0 g, 168.2 mmol) in toluene (1200
mL). Heat the resulting slurry to reflux, eventually reaching a temperature of
approximately 112 °C. Stir the resulting tan solution mechanically at reflux for 2 h while
using a Dean-Stark trap to collect water. Allow the reaction to cool to room temperature
and add saturated aqueous NaHCO3 (1700 mL) and EtOAc (1700 mL). Separate the
layers and extract the aqueous layer with EtOAc (2 x 1700 mL). Combine the organic
layers, wash with brine (1700 mL) and concentrate in vacuo. Take up the resulting solid
in CH2CI2 (500 mL) and concentrate in vacuo, repeating with CH2CI2 twice more to
obtain 60.1 g (79.2% yield).
Prepare the compounds below, Preparations 12b to 12f, by essentially following the
procedure as described in Preparation 12, Method 2, using the appropriate (2-methoxy-
ethyl)-thiazole-5-carboxyIic acid methyl ester as starting material.


12g:2-(4-Memoxy-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one

Prepare the title compound by essentially following the procedure of Example 12,
Method 3, using 4-(2-hydroxy-ethyl)-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid.
MS (ES+) 262.2 (M+l)+. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J= 9.2 Hz, 2H), 6.98
(d, J = 9.2 Hz, 2H), 4.66 (t, J = 6.2 Hz, 2H), 3.88 (s, 3H), 3.21 (t, J= 6.2 Hz, 2H).
—— — — - ■ ■ *

Preparation 13
rm-Butyl-(2-methoxy-4-nitro-phenoxy)-dimethyl-silane

Add tert-butyl-dimethylsilylchloride (14 g, 90 mmol) to a solution of 4-
nitroguaiacol (5 g, 30 mmol) in DMF (250 mL) and then add imidazole (6.13 g, 90
mmol). Stir the mixture at room temperature for 16 h. Quench the reaction mixture with
water (150 mL). Extract with diethyl ether (3 x 200 mL). Wash the combined organic
portions with water, brine, and dry over MgSO4 Filter and concentrate to a residue.
Purify the residue by silica gel flash chromatography, eluting with 15%
ethylacetate:hexanes to give the title compound (8.053 g, 95%) as a pale yellow oil. MS
(ES+) 284.1 (M+1)+. 1H NMR(CDCl3): δ 7.79 (dd, J = 7.8 Hz, 2.7 Hz, 1H), 7.26 (d, J =
2.7 Hz, 1H), 6.69 (d, J = 7.8 Hz 1H), 3.85 (s, 3H), 0.96 (s, 9H), 0.18 (s, 6H).
Preparation 14
l-(2,2-Dimethoxy-ethoxy)-4-nitro-benzene

Dissolve glycolaldehyde dimethylacetal (5 g, 47.12 mmol) in dry DMF (100 mL)
and cool to 0 °C. Add portion-wise NaH (60% dispersion, 1.88 g, 47.12 mmol). Heat the
reaction mixture to 100 °C overnight. Add water (200 mL) and extract with EtOAc (3 x
50 mL). Dry the organic layer with Na2SO4, filter, and concentrate. Purify by silica gel
chromatography, eluting with 0-50% EtOAc in hexanes to give the title compound as a
wet yellow solid (7.96 g, 74%). 1H NMR(CDCl3): δ 8.23 (d, J = 8.8 Hz, 2H), 7.02 (d, J =
8.8 Hz, 2H), 4.77 (t, J = 4.8 Hz, 1H), 4.12 (d, J = 5.3 Hz, 2H), 3.50 (s, 6H).
Preparation 15
2,2-Dimethyl-propionic acid 2-methoxy-4-nitro-phenyl ester


Dissolve trimethylacetyl chloride (3.64 mL, 29.56 mmol) in dry pyridine (100
mL). Add 4-nitroguaiacol (5.0 g, 29.56 mmol) followed by addition of DMAP (100 mg)
and stir overnight. Remove the pyridine via reduced pressure and then add IN HCl
solution to give a white solid precipitate which is collected by vacuum filtration and
washed with water to give the title compound as a white solid (7.4 g, 99%).
1H NMR(CDCl3): δ 7.87 (dd, J = 8.8, 2.6 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.15 (d, J =
8.8 Hz, 1H), 3.91 (s, 3H), 1.37 (s, 9H).
Preparation 16
l-(2,2-Dimethoxy-ethoxy)-2-methoxy-4-nitro-benzene

To an oven-dried round bottom flask, add 2-methoxy-4-nitro-phenol (2.45 g, 14.5
mmol) and purge with nitrogen. Add DMF (25 mL) by syringe, followed by K2CO3 (3.0
g, 21.7 mmol) and KI (catalytic) neat. Stir 30 min at room temperature and add 2-bromo-
1,1-dimethoxy-ethane (1.9 mL, 15.9 mmol) by syringe. Attach a reflux condenser and stir
overnight in a 120 °C oil bath. Quench with water, extract with ether (3x), dry over
MgSO4, filter and concentrate under vacuum. Add xylenes and concentrate again under
vacuum. Purify by flash chromatography on silica gel using a gradient of EtOAc/hexane
(20% to 60%) to give the title compound as a white residue (2.55 g, 68%). Exact mass =
257.1, MS (ES+) 258.2 (M+l)+. 1H NMR (CDCl3): δ 7.88 (dd, J = 9.1, 2.8 Hz, 1H), 7.74
(d, J = 2.8 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 4.77 (t, J = 5.2 Hz, 1H), 4.13 (d, J = 4.9 Hz,
2H), 3.93 (s, 3H), 3.48 (s, 6H).

Preparation 17
4-(2-Methoxy-4-nitro-phenyl)-morpholine

Mix morpholine (1.50 mL, 17.20 mmol) and l-chloro-2-methoxy-4-nitro-benzene
(1.06 g, 5.65 mmol) and heat to 100 °C for 4 h while stirring. Cool the solution to room
temperature, then partition between EtOAc (40mL) and 1N HCl (20mL). Wash the
organic solution with water (20 mL) and brine (20 mL), dry, filter, and concentrate.
Purify the crude material by flash chromatography, using a linear gradient of 100%
hexanes to 50% EtOAc/hexanes, to give the title compound as a yellow solid (250 mg,
18%). MS (ES+) 239.0 (M+l)+. lH NMR (400 MHz, CDCl3) 5: 7.86 (dd, 1H, 7=8.8,2.6
Hz), 7.71 (d, 1H, 7=2.2 Hz), 6.87 (d, 1H, 7=9.2 Hz), 3.94 (s, 3H), 3.87 (m, 4H), 3.21 (m,
4H).
Preparation 18
l-(2-Methoxy-4-nitro-phenyl)-piperidin-4-ol

Prepare the title compound by essentially following the procedure as described for
Preparation 17, using 4-hydroxypiperidine. MS (ES+) 253.0 (M+1)+. 1H NMR (400
MHz, CDCl3) δ 7.83 (dd, 1H, 7=8.8,2.6 Hz), 7.69 (d, 1H, 7=2.6 Hz), 6.88 (d, 1H, 7=9.2
Hz), 3.99 (s, 1H), 3.94 (s, 3H), 3.90 (m, 1H), 3.56-3.50 (m, 2H), 2.99-2.91 (m, 2H), 2.07-
2.00 (m, 2H), 1.79-1.69 (m, 2H).
Preparation 19
1 -Prop-2-ynyl-pyrrolidine

Add propargyl bromide (18.0 g, 120.0 mmol) dropwise at 0 °C to a solution of
pyrrolidine (23.0 g, 323.0 mmol) in ether (50 mL). Stir for 18 h at room temperature and
filter the reaction to remove the solids. Dilute the filtrate with water and extract with

ether. Dry the ether with brine, then Na2SO4. and concentrate on a rotary evaporator at
low temperature to give the title compound (10.0 g, 77%). MS (ES+) 110 (M+l)+. 1H
NMR (400 MHz, DMSO-d6): δ 3.33 (d, 2H, 7=2.2 Hz), 2.53 (m, 4H), 2.12 (t, 1H, 7=2.4
Hz), 1.72 (m, 4H).
Preparation 20
1-[3-(2-Methoxy-4-nitro-phenyl)-prop-2-ynyl]-pyrrolidine

Dissolve l-iodo-2-methoxy-4-nitro-benzene (618 mg, 2.21 mmol) in acetonitrile
(10 mL) and treat sequentially with l-prop-2-ynyl-pyrrolidine (352 mg, 3.22 mmol), Et3N
(2 mL), Cul (77 mg, 0.404 mmol) and Pd(PPh3)4 (360 mg, 0.311 mmol). Stir the mixture
at room temperature for 3 h, then dilute with EtOAc (50 mL) and wash with saturated
NaHCO3 (30 mL). Dry, filter and concentrate the organic solution. Purify the crude
material by flash chromatography, using a linear gradient of 50% EtOAc/hexanes to 100%
EtOAc, to give the title compound as an orange oil (292 mg, 51%). MS (ES+) 261.1
(M+l)+. lH NMR (400 MHz, CDCl3) δ: 7.77 (dd, 1H, 7=8.3, 2.2 Hz), 7.70 (d, 1H, 7=2.2
Hz), 7.50 (d, 1H, 7=8.3 Hz), 3.95 (s, 3H), 3.72 (s, 2H), 2.75-2.70 (m, 4H), 1.87-1.83 (m,
4H).
Preparation 21
1 -(3,3-Diethoxy-prop- l-ynyl)-2-methoxy-4-nitro-benzene

Prepare the title compound by essentially following the procedure as described for
Preparation 20, using propargylaldehyde diethylacetal. 1H NMR (400 MHz, CDCl3) δ:
7.78 (dd, 1H, 7=8.6, 2.0 Hz), 7.70 (d, 1H, J = 2.0 Hz), 7.55 (d, 1H, 7=8.8 Hz), 5.52 (s,
1H), 3.95 (s, 3H), 3.87-3.78 (m, 2H), 3.71-3.63 (m, 2H), 1.27 (t, 6H, 7=7.0 Hz).

Preparation 22
l-(2-Methoxy-4-nitxo-phenyl)-4-triisopropylsilanyloxy-piperidine

Dissolve l-(2-methoxy-4-nitro-phenyl)-piperidin-4-oI (1.19 g, 4.72 mmol) in
DMF (25 mL), followed by addition of triisopropylsilyl-trifluoromethanesulfonate (1.50
mL, 5.56 mmol) and Et3N (0.80 mL, 5.87 mmol). Stir the solution at room temperature
for 2 h, then add water (50 mL) and extract with EtOAc (2 x 50 mL). Combine the
organic solutions and wash with water (2 x 30 mL) and brine (30 mL), then dry, filter, and
concentrate. Purify the crude material by flash chromatography, using a linear gradient of
100% hexanes to 20% EtOAc/hexanes, to give the title compound as a yellow solid (1.55
g, 80%). MS (ES+) 409.3 (M+l)+. 1H NMR (400 MHz, CDCl3) δ: 7.84 (dd, 1H, 7=8.8,
2.6 Hz), 7.68 (d, 1H, 7=2.6 Hz), 6.89 (d, 1H, 7=8.8 Hz), 4.07-4.01 (m, 1H), 3.93 (s, 3H),
3.45-3.38 (m, 2H), 3.13-3.06 (m, 2H), 1.99-1.91 (m, 2H), 1.81-1.73 (m, 2H), 1.07-1.06
(m, 21H).
Preparation 23
3-Methoxy-4-(3-pyrrolidin-1 -yl-propyl)phenylamine

Dissolve l-[3-(2-methoxy4-nitro-phenyl)-prop-2-ynylJ-pyrrolidine (292 mg, 1.12
mmol) in EtOH (5 mL) and treat with 5% Pd/C. Purge the black mixture with hydrogen,
then stir overnight at room temperature under a hydrogen atmosphere (1 atm). Filter the
black mixture through a pad of Celite® and wash the solids with additional EtOH (20
mL). Concentrate the filtrate to give the title compound as an oil (240 mg, 91%). MS
(ES+) 235.2 (M+l)+. 1H NMR (400 MHz, CDCl3) δ: 6.88 (d, 1H, 7=8.3 Hz), 6.22-6.18
(m, 2H), 3.73 (s, 3H), 3.55 (s, 2H), 2.53-2.41 (m, 8H), 1.79-1.72 (m, 6H).

Preparation 24

4-(3,3-Diethoxy-propyl)-3 -methoxy-phenylamine
Prepare the title compound using procedures as essentially described for
Preparation 23. 1H NMR (400 MHz, CDCl3) δ: 6.89 (d, 1H, J=8.3 Hz), 6.23-6.20 (m,
2H), 4.48 (t, 1H, J=5.9 Hz), 3.75 (s, 3H), 3.68-3.60 (m, 2H), 3.64 (br s, 2H), 3.52-3.44
(m, 2H), 2.57-2.52 (m, 2H), 1.80-1.89 (m, 2H), 1.20 (t, 6H, J=7.0 Hz).
Preparation 25
7 -Nitro-4H-benzo [ 1,4] oxazin-3-one

Mix 2-amino-5-nitro-phenol (10.0 g, 64.9 mmol) and NaHCO3 (13.1 g, 155.7
mmol) in 4-methy]-pentan-2-one (40 mL) and water (40 mL). Cool the mixture to 0 °C
and slowly add chloroacetyl chloride (6.0 mL, 75.3mmol) with stirring. After the addition
is complete, reflux the mixture for 5h. Cool the mixture to room temperature and let
stand for 2.5 days. Collect the light yellow solid, wash with water and dry in a vacuum
oven at 80 °C for 3 h. MS (ES-) 193.1 (M-1). 1H NMR (400 MHz, DMSO-d6): δ 11.31
(s, 1H), 7.90 (dd, 1H, J=8.8,2.2 Hz), 7.76 (d, 1H, J=2.6 Hz), 7.06 (d, 1H, J=8.8 Hz), 4.72
(s,2H),
Preparation 26
7-Nitro-3,4-dihydro-2H-benzo[ 1,4]oxazine

Mix 7-nitro-4H-benzo[1,4]oxazin-3-one (2.00 g, 10.3 mmol) in THF (10 mL) and
treat with BH3.THF (1.0M in THF, 35 mL). Heat the solution to reflux for 30 min, then

cool to 0 °C and quench with 1N HCl (20 mL). Stir the solution for 30 min, then
concentrate to ½ volume. Collect the orange solid, wash with water, and dry under
vacuum to give the title compound (1.66 g, 89%). MS (ES+) 181.1 (M+1)+, MS (ES-)
179.2 (M-1)-. 1H NMR (400 MHz, DMSO-d6): δ 7.68 (dd, 1H, J=8.8,2.6 Hz), 7.53 (s,
1H), 7.47 (d, 1H, J=2.6 Hz), 6.63 (d, 1H, J=9 2 Hz), 4.15 (t, 2H, J=4.4 Hz), 3.44-3.40 (m,
2H),
Preparation 27
5-nitro-1 -(2-pyrrolidin-1- yl-eth yl)-1H-indole

Dissolve l-(2-chloro-ethyl)-pyrrolidine hydrochloride (2.36 g, 13.9 mmol) and 5-
nitro-1H-indole (1.50 g, 9.23 rnmol) in DMF (25 mL) and carefully treat with sodium
hydride (60% dispersion, 1.50 g, 37.5 mmol). Stir the mixture at room temperature
overnight, then dilute with cold water (100 mL) and extract with EtOAc (3 x 50 mL).
Was the combined organic portions with water (2 x 50 mL) and brine (50 mL). Dry, filter
and concentrate under vacuum. Purify the crude material by flash chromatography, using
100% acetone as eluant, to give the title compound as a yellow oil (2.08 g, 87%). MS
(ES+) 260.1 (M+l)+. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, 1H, J= 2.2 Hz), 8.10 (dd,
1H, J = 9.2, 2.2 Hz), 7.37 (d, 1H, J = 9.2 Hz), 7.30 (d, 1H, J=3.1 Hz), 6.67 (d, 1H, J =
3.1 Hz), 4.29 (t, 2H, J = 7.3 Hz), 2.89 (t, 2H, J = 7.0 Hz), 2.54 (m, 4H), 1.78 (m, 4H).
Prepare the compounds below, Preparations 28 to 36, by essentially following the
procedure as described in Preparation 27, using the appropriate nitroaryl or
nitroheterocycle.




Preparation 37
(R)-1-(2-Methoxy-4-nitro-phenyl)-3-triisopropylsilanyloxy-pyrrolidine

Combine l-chloro-2-methoxy-4-nitro-benzene (10 g, 53.3 mmol) and (3R)-3-
pyrrolidinol (9.3 g, 106.6 mmol). Heat the mixture to 100 °C overnight. Cool the
mixture and dissolve in CH2Cl2 (200 mL) and wash with 1N NaOH (100 mL). Wash the
extract with brine (3 x 50 mL). Dry the organic layer with Na2SO4, filter, and concentrate
to give the intermediate pyrrolidinol as a crude dark reddish wet solid (12.17 g, 95%).
MS (ES+) 239.1 (M+1)+.
Dissolve the crude (R)-1-(2-methoxy-4-nitro-phenyl)-pyrrolidin-3-ol (10.9 g, 45.5
mmol) in dry pyridine (50 mL) and chill to 0 °C. Add chloro-triisopropyl-silane (19.8
mL, 91 mmol) dropwise and then heat to 80 °C overnight. Remove the pyridine via
reduced pressure and then wash the crude material with NaHSO3 solution and extract
with EtOAc (3 x 100 mL). Combine the organic solutions, then dry and concentrate to
give the crude product. Purify over a silica plug with hexanes (300 mL) and flush with
10% EtOAc in hexanes (800 mL) to give the title compound as a reddish oil (17.85 g,
99%). MS (ES+) 395.2 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.81 (dd, J = 8.8, 2.2
Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 6.45 (d, J = 88 Hz, 1H), 4.57-4.52 (m, 1H), 3.84 (s,

3H), 3.84-3.78 (m, 1H), 3.72-3.64 (m, 1H), 3.61-6.53 (m, 1H), 3.45 (dd, J = 11.0,2.2 Hz,
1H), 2.06-1.92 (m, 2H), 1.04-1.01 (m, 21H).
Preparation 38
1 -(6-Nitro- 1H-indol-3-yl)-2-pyrrolidin-1 -yl-ethane-1,2-dione

Add oxalyl chloride (11.6 g, 90.6 mmol) dropwise to a solution of 6-nitroindole
(10.6 g, 65.4 mmol) in ether (100 mL). Stir at room temperature for 18 h, filter the
precipitate formed, and dry. Dissolve the precipitate in CH2Cl2 (100 mL), cool to -20 °C,
and add pyrrolidine (16.0 mL, 191.5 mmol) dropwise. Warm to room temperature and
stir for 2 h. Filter the solid from the reaction, wash several times with ether, and dry to
give the title compound (8.5 g, 45%). MS (ES+) 288 (M+l)+-
Preparation 39
l-(l-Methyl-6-nitro-lH-indol-3-yl)-2-pyrrolidin-1-yl-ethane-l,2-dione

Add NaH (0.83 g, 20.8 mmol) to a solution of l-(6-nitro-lH-indol-3-yl)-2-
pyrrolidin-1-yl-ethane-l,2-dione (5.0 g, 17.42 mmol) in THF (60 mL). Stir at room
temperature for 10 min, add iodomethane (1.18 mL, 19.2 mmol), and continue stirring for
18 h. Dilute with water and extract with EtOAc (2x). Filter the solid that formed
between the layers during the extraction. Dry organic portion, concentrate, and combine
the solids. Triturate the solid with ether, filter, and dry to obtain the title compound (5.20
g, 99%). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (m, 2H), 8.30 (d, 1H, J =8.8 Hz), 8.17

(dd, 1H, J=8.8,2.2 Hz), 4.01 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.41 (t, 2H, J=6.4 Hz), 1.85
(m,4H).
Preparation 40
l-Methyl-6-nitro-3-(2-pyrrolidin- 1-yl-ethyl)- 1H-indole

Treat a solution of 1-(1-methyl-6-nitro-1H-indol-3-yl)-2-pyrrolidin-1-yl-ethane-
1,2-dione (5.0 g, 17.4 mmol) in THF (20 mL) with BH3.THF (70 mL of 1N in THF, 70
mmol) and stir at room temperature for 18 h. Concentrate the reaction mixture and add
EtOH (100 mL) followed by 5N HCl (20 mL) and reflux for 6 h. Concentrate and dilute
with 1N NaOH (100 mL). Extract with CH2Cl2 (2x), then extract with EtOAc (2x).
Combine the organics, dry, and concentrate. Purify by flash chromatography using 0 -
10% 2N NH3/MeOH in CH2Cl2, to give the title compound (2.5 g, 53%). 1H NMR (400
MHz, DMSO-d6): δ 8.26 (d, 1H, J=2.2 Hz), 7.98 (dd, 1H, J=8.8, 1.8 Hz), 7.61 (d, 1H,
J=8.8 Hz), 7.19 (s, 1H), 3.84 (s, 3H), 2.97 (t, 2H, J=8.1 Hz), 2.76 (t, 2H, J=8.1 Hz), 2.61
(m, 4H), 1.83 (m, 4H).
Preparation 41
1-(2-Methoxy-4-nitro-benzyl)-4-methyl-piperazine

To a round bottom flask or vial containing 2-methoxy-4-nitro-benzaldehyde (1.0
g, 5.5 mmol), add dichloroethane (40 mL), 1-methylpiperazine (1.0 ml, 8.3 mmol), and
sodium triacetoxyborohydride (3.5 g, 16.5 mmol). Stir at room temperature overnight.

Quench with saturated aqueous NaHCO3 and extract with CH2Cl2 (1x) and EtOAc (2x).
Combine the organic portions, dry over MgSO4, filter, and concentrate under vacuum.
Purify the residue by flash chromatography on silica gel using a gradient of
MeOH(0.005% NH4OH)/CH2Cl2 (5% to 10%) to give the title compound. MS (ES+)
266.0 (M+1)+. 1H NMR(CDCl3): δ 7.80 (dd, J = 8 Hz, 2 Hz, 1H), 7.66 (d, J = 2 Hz, 1H),
7.56 (J = 8 Hz, 1H). 3.89 (s, 3H), 3.58(8, 2H) 2.52 (br. 4H), 2.45 (br, 2H), 2.28 (s, 3H).
Preparation 42
l-(2-Pyrrolidin-1-yl-ethyl)-lH-indol-5-ylamine

Dissolve 5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indole (375 mg, 1.45 mmol) in
ethanol (15 mL) and add 5% Pd/C (149 mg). Purge the black mixture with hydrogen (1
atm) and stir overnight under a hydrogen atmosphere. Filter the black mixture through
Celite® and wash the solids with additional ethanol (~10mL). Concentrate the filtrate to
give the title compound as a yellow solid. MS (ES+) 230.2 (M+l)+. 1H NMR (400MHz
CDCl3): δ: 7.17 (d, 1H, J=8.8 Hz), 7.05 (d, 1H, J=3.1 Hz), 6.92 (d, 1H, J=2.2 Hz), 6 67
(dd, 1H, J=8.3, 2.2 Hz), 6.29 (d, 1H, J=3.1 Hz), 4.21 (t, 2H, J=7.5 Hz), 3.37 (s, 2H), 2 86
(t, 2H, J=7.5 Hz), 2.55 (m, 4H), 1.79 (m, 4H).
Prepare the compounds below, Preparations 43 to 59, essentially following the
procedure as described in Preparation 42 using the appropriate nitro compound which is
previously prepared or commercially available.







Preparation 60
5-Nitro-1 -triisopropylsilanyl-1H-indole

Dissolve 5-nitro-1H-indole (5.00 g, 30.8 mmol) in DMF (100 mL) and treat with
NaH (1.62 g, 40.5 mmol). Stir the mixture at room temperature for 1 h and then add
triisopropyl-silyl-trifluoromethanesulfonate (9.15 mL, 33.9 mmol). Stir the mixture for
an additional 2 h then dilute with water (100 mL) and 1N HCl (40 mL), then extract with
EtOAc (3X100mL). Combine the organic solutions and wash with water (2X50mL) and
brine (50mL). Dry, filter and concentrate the organic solution and purify the crude
material by flash chromatography, using a linear gradient of 100% hexanes to 20%
EtOAc/hexanes as eluant, to give the title compound as a clear yellow oil (6.30g, 64%).
1H NMR (400 MHz, CDCl3) δ:8.56 (d, 1H, J=2.6 Hz), 8.05 (dd, 1H, J=9.0,2.4 Hz), 7.51
(d, 1H, J=9.2 Hz), 7.38 (d, 1H, J=3.1 Hz), 6.78 (d, 1H, J=3.5 Hz), 1.74-1.66 (m, 3H),
1.14 (d, 18H, J=7.9 Hz).
Preparation 61
5-Nitro-1-triisopropylsilanyl-2,3-dihydro-1H-indole

Prepare the title compound by essentially following procedures as described for
Preparation 60, using 5-nitroindoline. MS (ES+) 320.1 (M)+. 1H NMR (400 MHz,
CDCl3): δ 7.95 (dd, 1H, J=8.8, 2.6 Hz), 7.92-7.90 (m, 1H), 6.56 (d, 1H, J=9.2 Hz), 3.86
(t, 2H, J=8.8 Hz), 3.08 (t, 2H, J=8.8 Hz), 1.46 (m, 3H), 1.14 (d, 18H, J=7.5 Hz).
Prepare the compounds below, Preparations 62-65, by essentially following the procedure
as described in Preparation 42.

Preparation 62
l-Triisopropylsilanyl-2,3-dihydro-1H-indol-5-ylamine

MS (ES+) 290.2 (M)+. 1H NMR (400 MHz, CDCl3): δ 6.62-6.27 (m, 3H), 3.66 (s, 2H),
2.89 (s, 2H), 1.45-1.33 (m, 3H), 1.10 (d, 18H, J=7.5 Hz).
Preparation 63
1-Triisopropylsilanyl-1H-indol-5-yl amine

1H NMR (400 MHz, CDCl3): δ 7.29 (d, 1H, J=8.8 Hz), 7.16 (d, 1H, J=3.1 Hz), 6.92 (d,
1H, J=2.6 Hz), 6.59 (dd, 1H, J=8.8,2.2 Hz), 6.43 (d, 1H, J=3.1 Hz), 1.69-1.61 (m, 3H),
1.12 (d, 18H, J=7.5 Hz).
Preparation 64
2,2-Dimethyl-propionic acid 4-amino-2-methoxy-phenyl ester

lH NMR (400 MHz, CDCl3): δ 6.76 (d, J=8.8 Hz, 1H), 6.31 (d, J=2.6 Hz, 1H), 6.25 (dd,
J= 8.8, 2.2 Hz, 1H), 3.74 (s, 3H), 1.34 (s, 9H).

Preparation 65
(R)-3-Methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenylamine

Dissolve (R)-1-(2-Methoxy-4-nitro-phenyl)-3-triisopropylsilanyloxy-pyrrolidine
(12 g, 30.4 mmol) in EtOH (200 mL) and add 5% Pd/C (1.26 g). Purge the black mixture
with hydrogen (1 atm) and stir overnight under a hydrogen atmosphere at ambient
temperature at 60 psi. Filter the black mixture through Celite® and wash the solids with
additional EtOH (100mL). Concentrate the filtrate to give the title compound as a dark
brown oil. 1H NMR (400 MHz, CDCl3): δ 6.76 (d, 1H, J=8.8 Hz), 6.31 (d, 1H, J=2.6
Hz), 6.25 (dd, 1H, J = 8.8,2.6 Hz), 3.74 (s, 3H), 1.34 (s, 9H). Note: title compound
decomposed rapidly. Store compound in freezer immediately after use. MS (ES+) 365.2
(M+l)+.
Preparation 66
3-Chloro-4-(2-pyrrolidin-1 -yl-ethoxy)-phenylamine

Add sodium borohydride (0.58 g, 15.26 mmol) to a solution of l-[2-(2-chloro-4-
nitro-phenoxy)-ethyl]-pyrrolidine (0.83 g, 3.07 mmol) and NiCl2.6H2O (1.45 g, 6.12
mmol) in MeOH (20 mL). Stir at room temperature for 2 h and add 10% NH4OH
solution. Extract with CH2Cl2 and then EtOAc, combine the organics, dry, and
concentrate. Purify by flash chromatography using 0 -10% 2N NH3/MeOH in CH2Cl2, to
give the title compound (0.5 g, 69%). MS (ES+) 241.2 (M+1)+. 1H NMR (400 MHz,
CDCl3): δ 6.78 (d, 1H, J=8.4 Hz), 6.72 (d, 1H, J=3.1 Hz), 6.51 (dd, 1H, J=8.4, 3.1 Hz),
4.07 (t, 2H, J=6.2 Hz), 3.47 (s, 2H), 2.90 (t, 2H, J=6.2 Hz), 2.64 (m, 4H), 1.79 (m, 4H).

Preparation 67
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-earboxylic acid [3-methoxy-4-(4-
triisopropylsilanyloxy-piperidin-1 -yl)-phenyl]-amide

Dissolve 1-(2-Methoxy-4-nitro-phenyl)-4-triisopropylsilanyloxy-piperidine(1.53g,
3.74 mmol) in THF (30 mL) and add 5% Pd/C then stir the slurry at room temperature
under a hydrogen atmosphere for 3 h. Filter the black mixture through a pad of Celite®
and concentrate the filtrate in vacuo to give 3-methoxy-4-(4-triisopropyIsilanyloxy-
piperidin-1-yl)-phenylamine (1.42 g, 100%) that was used immediately.
Dissolve the above 3-methoxy-4-(4-triisopropylsilanyIoxy-piperidin-1-yl)-
phenylamine (1.41 g, 3.72 mmol) in CH2Cl2 and add a trimethylaluminum solution (2.0M
in hexanes, 2.25 mL, 4.50 mmol). Stir the solution at room temperature for 1 h, then add
solid 2-(4-chloro-phenyl)-6,7-dmydro-pyrano[4,3-d]thiazol-4-one (1.01 g, 3.80 mmol)
and continue stirring at room temperature overnight. Carefully quench reaction with
saturated Rochelle's salt solution (15 mL) and stir at room temperature for 1 h. Extract
the mixture with CH2Cl2 (3 x 20mL). Combine all organic solutions, dry, filter, and
concentrate in vacuo. Purify the crude material by flash chromatography using 2N
NH3/MeOH in CH2Cl2 as eluent to give the title compound as a sold (1.00 g, 42%). MS
(ES+) 644.0 (M+l)+, (ES-) 642.3 (M-l)-. lH NMR (400 MHz, CDCl3): δ 10.76 (s, 1H),
8.00 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=8.8 Hz), 7.35 (d, 1H, J=2.2 Hz), 7.13 (dd, 1H,
J=8.8,2.2 Hz), 6.88 (d, 1H, J=8.8 Hz), 5.78 (t, 1H, J=4.4 Hz), 3.94-3.86 (m, 3H), 3.78 (s,
3H), 3.21-3.13 (m, 4H), 2.78-2.70 (m, 2H), 1.93-1.85 (m, 2H), 1.67-1.57 (m, 2H), 1.06-
1.04(m,21H).

Preparation 68
(R)-2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [3-methoxy-4-(3-
triisopropylsilanyloxy-pyrrolidin-1 -yl)-phenyl]-amide

Charge an oven-dried round bottom flask with (R)-3-methoxy-4-(3-
triisopropylsilanyloxy-pyrrolidin-1-yl)-phenylaraine (750 mg, 2.05 mmol), purge with
nitrogen, and dilute with CH2Cl2 (11 mL). Add tximethylaluminum (2M in hexanes, 1.03
mL, 2.05 mmol) dropwise by syringe and stir 20 rain at room temperature. Add solid 2-
(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (364 mg, 1.37 mmol) to the
reaction mixture and stir overnight at ambient temperature. Absorb the reaction mixture
on silica gel and purify by silica gel flash chromatography, using a gradient of
EtOAc/hexane (0-100%) to give the title compound (1.02 g, 73%). MS (ES+) 630.1
(M+l)+. 1H NMR (CDCl3): δ 9.88 (bs, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.48 (bs, 1H), 7.37
(d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 6.69 (bs, 1H), 4.60-4.52 (m, 1H), 4.19-4.11
(m, 2H), 3.81 (s, 3H), 3.69-3.58 (m, 1H), 3.39 3.29 (m, 1H), 3.26 (t, J = 5.3 Hz, 2H),
3.20-3.02 (m, 2H), 2.21-2.08 (m, 1H), 1.93-1.83 (m, 1H), 1.59 (bs, 1H), 1.12-0.95 (m,
21H).

Preparation 69
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [1-(2-pyrrolidin-1-yl-
ethyl)-1H-indol-5-yl]-amide

Dissolve l-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-ylaminc (247 mg, 1.08 mmol)in
CH2Cl2 (5 mL), cool to 0 °C, and treat with a solution of trimethylaluminum (2.0 M in
hexanes, 0.7 mL, 1.40 mmol). Stir the solution at 0 °C for 15 min and then at room
temperature for 30 min. Add 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]fhiazol-4-one
(272 mg, 1.02 mmol) neat and stir the reaction at room temperature overnight. Carefully
quench the mixture with saturated Rochelles salt solution (5 mL) and stir at room
temperature for 1 h. Dilute with additional saturated Rochelles salt solution (10 mL) and
extract with CH2Cl2 (3 x 20 mL). Combine the organic portions, dry, filter, and
concentrate under vacuum. Triturate the crude solid with diethyl ether to give the title
compound as a white powder (400 mg, 75%). MS (ES+) 495.1 (M+1)+ MS (ES-) 493.2
(M-1)-. 1H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.01 (d, 2H, J = 8.3 Hz), 7.92
(s, 1H), 7.60 (d, 2H, J = 8.8 Hz), 7.46 (d, 1H, J = 8.8 Hz), 7.40 (d, 1H, J = 3.1 Hz), 7.34
(dd, 1H, J = 8.8, 1.8 Hz), 6.41 (d, 1H, J = 3.1 Hz), 5.S4 (m, 1H), 4.26 (t, 2H, J = 6.6 Hz),
3.91 (q, 2H, J = 5.3 Hz), 3.21 (t, 2H, J = 5.9 Hz), 2.78 (t, 2H, J = 6.8 Hz), 2.46 (s, 4H),
1.65 (m,4H).
Prepare the compounds below, Preparations 70 to 88, by essentially following the
procedure as described in Preparation 69. Preparation 82 was made using
4-methyl-N2-(2-morpholin-4-yl-emyl)quinoline-2,6-diamine (Krahler, S. E.; Burger, A. 7.
Am. Chem. Soc, 1941, 55 2367-71).

Preparation 70
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [1-(2-pyrrolidin-1-yl-
ethyl)-1H-benzoimidazol-5-yl]-amide

MS (ES+) 496.0 (M+1)+, (ES-) 494.2 (M-1)-.
Preparation 71
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [1- (2-pyrrolidin-1-
yl-ethy])-1H-indazol-5-yl]-amide

MS (ES+) 496.0 (M+1)+, (ES-) 494.2 (M-1)-.
Preparation 72
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [2-(2-pyrrolidin-1-yl-
ethyl)-2H-indazol-5-yl] -amide

MS (ES+) 496.0 (M+1)+, (ES-) 494.2 (M-1)-.

Preparation 73
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazo]e-5-carboxylic acid [2-methyl-1 -(2-
pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-amide

MS (ES+) 509.0 (M+1)+, (ES-) 507.0 (M-1)-.
Preparation 74
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [2,3-dimethyl-1-(2-
pyrrolidin-1 -yl-ethyl)-1 H-indol-5-yl]-amide

MS (ES+) 523.1 (M+1)+.
Preparation 75
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [1-methyl-3-(2-
pyrrolidin-1 -yl-ethyl)-1H-indol-6-yl] -amide

MS (ES+) 509.1 (M+1)+.

Preparation 76
2 (4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [ 1 -(2-pyrrolidin-1 -yl-
ethyl)-2-trifluoromethyl-1H-benzoimidazol-5-yl]-amide

MS (ES+) 564.1 (M+1)+.
Preparation 77
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid(3-methoxy-4-
triisopropylsilanyloxy-phenyl)-amide

MS (ES+) 561.1 (M+1)+.
Preparation 78
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [6-(4-methyl-
piperazin-1-yl)-pyridin-3-yl]-amide

MS (ES+) 458.0 (M+1)+.
Preparation 79
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [3-chloro-4-(2-
pyrrolidin-1-yl-ethoxy)-phenyl] -amide

MS (ES+) 506.0 (M+1)+.

Preparation 80
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [4-(2-pyrrolidin-1-yl-
ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-amide

MS (ES+) 513.0 (M+1)+, (ES-) 511.2 (M-1)-.
Preparation 81
2-(4-ChIoro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [3-methoxy-4-(3-
pyrrolidin-1-yl-propyl)-phenyl]-amide

MS (ES+) 500.4 (M+1)+.
Preparation 82
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5 -carboxylic acid [4-methyl-2-(2-
morpholin-4-yl-ethylamino)-quinolin-6-yl]-amide

MS (ES+) 552.1 (M+1)+.
Preparation 83
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [4-(3,3-diethoxy-
propyl)-3-methoxy-phenyl]-amide


1H NMR (400 MHz, CDCl3): δ 9.99 (s, 1H), 7.85 (d, 2H, J=8.8 Hz), 7.54 (d, 1H, J=1.8
Hz), 7.41 (d, 2H, J=8.3 Hz), 7.04 (d, 1H, J=7.9 Hz), 6.87 (dd, 1H, J=8.1, 2.0 Hz), 4.50 (t,
1H, J= 5.9 Hz), 4.19 (t, 2H, J=5.3 Hz), 3.82 (s, 3H), 3.69-3.60 (m, 2H), 3.53-3.45 (m,
2H), 3.29 (t, 2H, J=5.3 Hz), 2.62 (t, 2H, J=7.9 Hz), 1.91-1.81 (m, 2H), 1.23-1.17 (m, 6H).
Preparation 84
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [4-(2-pyrrolidin-1 -yl-
ethoxy)-phenyl]-amide

MS (ES+) 472.0 (M+1)+, 470.0 (M-1)-.
Preparation 85
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid(3-methoxy-4-
morpholin-4-yl-phenyl)-amide

MS (ES+) 474.0 (M+1)+, (ES-) 472.3 (M-1)-.
Preparation 86
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid (1 -triisopropylsilanyl-
1H-indol-5-yl)-amide

MS (ES+) 554.1 (M+1)+, 552.3 (M-1)-.

Preparation 87
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid (1-
triisopropylsilanyl-2,3-dihydro-1H-indol-5-yl)-amide

MS (ES+) 556.0 (M+1)+.
Preparation 88
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid 3,4-dimethoxy-
benzylamide

MS (ES+) 433.0 (M+1)+, MS (ES-) 431.0 (M-1)-. 1H NMR(CDCl3): δ 9.13 (t, 1H, J=5.7
Hz), 7.96 (d, 2H, J=8.8 Hz), 7.58 (d, 2H, J=8.8 Hz), 6.94 (d, 1H, J=1.8 Hz), 6.91 (d, 1H,
J=7.9 Hz), 6.85 (dd, 1H, J=8.4,1.8 Hz), 5.29 (t, 1H, J=4.6 Hz), 4.40 (d, 2H, J=5.7 Hz),
3.82-3.76 (m, 2H), 3.71 (s, 3H), 3.70 (s, 3H), 3.15 (t, 2H, J=6.2 Hz).
Preparation 89
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [4-(2,2-dimethoxy-
ethoxy)-3-methoxy-phenyl]-amide

Method 1: Charge an oven-dried round bottom flask with 4-(2,2-dimethoxy-ethoxy)-3-
methoxy-phenylamine (0.65 g, 2.88 mmol), purge with nitrogen, and dilute with toluene
(5 mL). Add trimethylaluminum (2 M in hexanes, 1.44 mL, 2.88 mmol) dropwise by
syringe and stir 5 min at room temperature. Add 2-(4-chloro-phenyl)-6,7-dihydro-
pyrano[4,3-d]thiazol-4-one (0.5 lg, 1.91 mmol) in toluene (20 mL), attach a reflux
condenser and stir overnight in an 80 °C oil bath. Allow to cool to ambient temperature

and add IN HCl, extracting with EtOAc (3x). Dry the combined organic portions over
MgSO4, filter, and concentrate under vacuum. Purify by flash chromatography on silica
gel, using a gradient of EtOAc/hexane (20%-70%) to give the title compound (0.78 g,
83%). Exact mass = 492.1, MS (ES+) 493.4 (M+1)+. 1H NMR (CDCl3): δ 9.91 (s, 1H),
7.88 (dt, J = 8.5,2.2 Hz, 2H), 7.57 (ap d, 1H), 7.42 (dt, J = 8.5,2.2 Hz, 2H), 6.94 (dd, J =
8.8,2.4 Hz, 1H), 6.87 (d, J= 8.8 Hz, 1H), 4.75 (t, J = 5.2 Hz, 1H), 4.22 (t, J = 5.2 Hz,
2H), 4.03 (d, J = 5.2 Hz, 2H), 3.87 (s, 3H), 3.46 (s, 6H), 3.31 (t, J = 5.2 Hz, 2H).
Prepare the compounds Preparations 90 and 91, by essentially following the procedures
as described in Preparation 89, Method 1.
Preparation 90
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid[4-(tert-butyl-
dimethyl-silanyloxy)-3-methoxy-phenyl]-amide

Exact mass 518, mass spectrum (ES) 519.3 (M+1)+.
Preparation 91
2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid[3-methoxy-4-(4-
methyl-piperazin-1 -ylmethyl)-phenyl]-amide

Exact mass: 500.0, MS(ES+): δ01.3 (M+1)+.

Preparation 92
2,2-Dimethyl-propionic acid 4-{[4-(2-hydroxy-ethyl)-2-(4-methoxy-phenyl)-thiazole-5-
carbonyl]-amino} -2-methoxy-phenyl ester

Method 2: Prepare the title compound by essentially following procedures as described in
Preparation 89, Method 1, except the reaction mixture is run overnight at ambient
temperature. Quench the reaction mixture with 1N HCl (20 mL) and extract with CH2Cl2
(3 x10 rnL). Dry the combined organic portions with Na2SO4, filter, and concentrate.
Purify by flash chromatography on silica gel, using a gradient of EtOAc/hexane (20%-
70%) to give the title compound. MS (ES+) 485.2 (M+1)+. 1H NMR (CDCl3): δ 10.01
(s, 1H), 7.90 (d, J = 9.2 Hz, 2H), 7.70 (d, J = 1.8 Hz, 1H), 6.95 (dd, J = 8.4,2.2 Hz, 2H),
6.92 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.18 (t, J = 5.3 Hz, 2H), 3.85 (s, 3H),
3.79 (s, 3H), 3.29 (t, J= 5.3 Hz, 2H), 1.36 (s, 9H).
Preparation 93
4-(2-Hydroxy-ethyl)-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid [4-(2,2-dimefhoxy-
ethoxy)-3-methoxy-phenyl]-amide

Method 3: Prepare the titled compound by essentially following procedures as described
in Preparation 89, Method 1, except run the reaction overnight at ambient temperature.
Cool the reaction mixture and add 1N NaOH (25 mL), extract with EtOAc (3 x 10 mL).
Filter the solid precipitate from the partitioned aqueous/organic layer to give the title
compound as a fine yellow powder. MS (ES+) 489.2 (M+1)+. 1H NMR (d4MeOH): δ
7.92 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 2.2 Hz, 1H), 7.11 (dd, J = 8.8,2.2 Hz, 1H), 7.03 (d,
J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 1H), 4.70 (t, J = 5.3 Hz, 1H), 4.05 (t, J = 5.3 Hz,

2H), 3.99 (d, J= 5.3 Hz, 2H), 3.86 (d, J = 4.4 Hz, 6H), 3.44 (s, 6H), 3.25 (t, J= 5.7 Hz,
2H).
Preparation 94
4-(2-Hydroxy-ethyl)-2-pheny]-thiazoIe-5-carboxylic acid [4-(2,2-dimethoxy-ethoxy)-
phenyl]-amide

Method 4: Prepare the title compound by essentially following the procedures as
described in Preparation 89, Method 1, using 4-(2,2-dimethoxy-ethoxy)-phenylamine (385
mg, 1.95 rnmol) and 2-phenyl-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (300 mg, 1.30
mmol). Heat the reaction mixture for 1 h at 70 °C (no reflux condenser is needed). Cool
the reaction mixture and add water (20 mL), then extract with EtOAc (3 x 10 mL). Dry
the organic layer with Na2SO4, filter, and concentrate. Purify on silica gel
chromatography with 0-100% EtOAc in hexanes to give the title compound as a light
brown solid. MS (ES+) 429.2 (M+1)+, (ES-) 427.2 (M-1)-.
Preparation 95
2-(3-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid[4-(2,2-dimethoxy-
ethoxy)-3-methoxy-phenyl]-amide

Method 5: Prepare the title compound by essentially following procedures as described
in Preparation 89, Method 1, using the following alternate work-up. Dilute with 1N
NaOH, and extract with EtOAc (3 x 10 mL). Dry with Na2SO4, filter, and concentrate.
Add minimal amounts of CH2Cl2 to extract color and then add hexanes to give a solid
precipitate. Collect the solid via vacuum filtration. Wash the solid with hexanes to give
the title compound. MS (ES+) 493.2 (M+1)+.

Prepare the following compounds, Preparations 96 to 98, by essentially following the
procedures as described in Preparation 95, Method 5.


Example 1
2-(4-Chloro-phenyl)-5-[ 1 -(2-pyrrolidin-1 -yl-ethyl)-1H-indol-5-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

Method 1: Dissolve 2-(4-chloro-phenyl)-4-(4-hydroxy-ethyl)-thiazole-5-carboxylic acid
[1 -(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-amide (390 mg, 0.79 mmol) in THF (8.0 mL)
and cool to 0 °C. Treat the solution with tributylphosphine (0.255 mL, 1.03 mmol) and
diisopropylazodicarboxylate (0.205 mL, 1.04 mmol). Warm the solution to room
temperature and stir overnight. Dilute the solution with EtOAc (50 mL) and wash with
water (25 mL) and brine (25 mL). Dry the organic portion, filter and concentrate under
vacuum. Purify the crude material by flash chromatography, using 8% 2N NH3/MeOH in
CHCl3, to give a foam. Triturate the foam with ether to give the title compound as a
yellow solid (289 mg, 77%). MS (ES+) 477.4 (M+1)+. lH NMR (400MHz, DMSO-d6):
δ 8.06 (d, 2H, J = 8.8 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.49-7.53 (m, 2H), 7.44 (d, 1H, J =
3.1 Hz), 7.13 (dd, 1H, J = 8.8, 2.2 Hz), 6.43 (d, 1H, J = 3.1 Hz), 4.29 (t, 2H, J = 6.6 Hz),
4.11 (t, 2H, J = 6.8 Hz), 3.29 (t, 2H, J = 6.8 Hz), 2.80 (t, 2H, J = 6.8 Hz), 2.49 (m, 4H),
1.66 (m,4H).
Prepare Example 2 to 13 and Preparations 99 to 106 by essentially following the
procedures as described in Example 1, Method 1, using the appropriate intermediate 4-
hydroxy-ethyl-thiazole.

Example 2
2-(4-Chloro-phenyl)-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-benzoimidazol-5-yl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one

MS (ES+) 478.4 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 7.93 (d, 2H, J =
8.8 Hz), 7.72 (d, 1H, J = 1.8 Hz), 7.43-7.46 (m, 3H), 7.34-7.38 (m, 1H), 4.37 (s, 2H), 4.18
(t, 2H, J = 7.0 Hz), 3.32 (t, 2H, J = 7.0 Hz), 2.99 (s, 2H), 2.61 (s, 4H), 1.82 (s, 4H).
Example 3
2-(4-Chloro-phenyl)-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

MS (ES+) 478.4 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.93 (d, 2H, J =
8.8 Hz), 7.65 (d, 1H, J = 1.3 Hz), 7.48 (d, 1H, J = 8.8 Hz), 7.44 (d, 2H, J = 8.8 Hz), 7.39
(dd, 1H, J = 9.0, 2.0 Hz), 4.55 (t, 2H, J = 7.5 Hz), 4.16 (t, 2H, J = 7.0 Hz), 3.32 (t, 2H, J =
7.0 Hz), 3.01 (t, 2H, J = 7.3 Hz), 2.58 (s, 4H), 1.78 (m, 4H).
Example 4
2-(4-Chloro-phenyl)-5-[2-(2-pyrrolidin-1 -yl-ethyl)-2H-indazol-5-yl]-6,7-dihydro-5H-'
thiazolo[5,4-c]pyridin-4-one

MS (ES+) 478.4 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.42 (d, 1H, J = 0.9 Hz),
8.06 (d, 2H, J = 8.8 Hz), 7.67-7.69 (m, 1H), 7.60-7.64 (m, 3H), 7.25 (dd, 1H, J= 9.0,2.0

Hz), 4.54 (t, 2H, J= 6.4 Hz), 4.14 (t, 2H, J= 6.8 Hz), 3.28 (t, 2H, J= 7.0 Hz), 2.97 (t, 2H,
V- 6.4 Hz), 2.47 (s, 4H), 1.65 (m, 4H).
Example 5
2-(4-Chloro-phenyl)-5-[2-methyl-1-(2-pyrrolidin-1-y]-ethyl)-1H-indo]-5-y]]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one

MS (ES+) 491.1 (M+1)+. 1H NMR (400MHz,DMSO-d6):δ 8.05(d,2H,.J =7.9 Hz),
7.62 (d, 2H, J = 8.3 Hz), 7.37-7.42 (m, 2H), 7.06 (d, 1H, J = 8.3 Hz), 6.22 (s, 1H), 4.23 (s,
2H), 4.09 (t, 2H, J = 6.6 Hz), 3.27 (s, 2H), 2.69 (s, 2H), 2.43 (s, 3H), 1.69 (s, 4H), 1.69 (s,
4H).
Example 6
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phe
nyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one

MS (ES+) 483.3 (M+1)+. 1HNMR(CDCl3): δ 7.92 (d, J = 7.4 Hz, 2H), 7.44 (d, J = 7.4
Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 1.8Hz, 1H), 6.86 (dd, J = 8.0Hz, 1.8Hz,
1H), 4.11 (t, J = 5.2.Hz, 2H), 3.82 (s, 3H), 3.55 (s, 2H), 3.28 (t, J = 5.2 Hz, 2H), 2.62-2.44
(m, 8H), 2.29 (s, 3H).
Example 7
2-(4-Chloro-phenyl)-5-[2,3-dimethyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one


MS (ES+) 505 (M+1)+. 1H NMR (400 MHz, CDCl3: 5 7.94 (d, 2H, J=8.3 Hz), 7.44 (m,
3H), 7.27 (d, 1H, J=10.1 Hz), 7.10 (dd, 1H, J=8.6, 2.0 Hz), 4.24 (brs, 2H), 4.15 (t, 2H,
J=6.8 Hz), 3.31 (t, 2H, J=7.0 Hz), 2.77 (brs, 2H), 2.63 (brs, 4H), 2.37 (s, 3H), 2.22 (s,
3H), 1.85 (brs, 4H).
Example 8
2-(4-Chloro-phenyl)-5-[1-methyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indol-6-yl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one

MS (ES+) 491.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H, J=8.3 Hz), 7.63 (d,
1H, J=8.3 Hz), 7.45 (d, 2H, J=8.3 Hz), 7.29 (s, 1H), 7.04 (d, 1H, J=8.3 Hz), 6.92 (s, 1H),
4.17 (t, 2H, J=7.0 Hz), 3.72 (s, 3H), 3.32 (t, 2H, J=6.8 Hz), 2.99 (t, 2H, J=8.1 Hz), 2.78
(t, 2H, J=8.1 Hz), 2.63 (m, 4H), 1.84 (m 4H).
Example 9
2-(4-Chloro-phenyl)-5-[4-(2-pyrrolidin-1-yl-ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-
yl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one

MS (ES+) 495.0 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.03 (d, 2H, J=8.4 Hz),
7.61 (d, 2H, J=8.4 Hz), 6.78 (dd, 1H, J=8.6, 2.4 Hz), 6.73-6.67 (m, 2H), 4.16 (t, 2H,
J=4.0 Hz), 3.99 (t, 2H, J=7.0 Hz), 3.42-3.37 un, 4H), 3.22 (t, 2H, J=7.0 Hz), 2.61 (t, 2H,
J=6.8 Hz), 2.52-2.47 (m, 4H), 1.68 (s, 4H).

Example 10
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-6,7-dihydro-5H-
thiazolo [5,4-c]pyridin-4-one

MS (ES+) 482.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H, J=8.3 Hz), 7.45 (d,
2H, J=7.9 Hz), 7.16 (d, 1H, J=7.9 Hz), 6.89 (d, 1H, J=1.8 Hz), 6.82 (dd, 1H, J=7.9,2.2
Hz), 4.12 (t, 2H, J=6.8 Hz), 3.82 (s, 3H), 3.29 (t, 2H, J=7.0 Hz), 2.65 (t, 2H, J=7.7 Hz),
2.54 (s, 6H), 1.87-1.77 (m, 6H).
Example 11
2-(4-Chloro-phenyl)-5-[4-methyl-2-(2-morpholin-4-yl-ethylamino)-quinolin-6-yl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one

MS (ES+) 534.0 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (d, 2H, J=8.3 Hz),
7.71 (s, 1H), 7.63 (d, 2H, J=8.3 Hz), 7.49 (s, 2H), 6.84 (m, 1H), 6.67 (s, 1H), 4.18 (t, 2H,
J=6.8 Hz), 3.59 (t, 4H, J=4.4 Hz), 3.54-3.48 (m, 2H), 3.35-3.28 (m, 2H), 2.51 (m, 2H),
2.44 (m, 7H).
Example 12
2-(4-Chloro-phenyl)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo [5,4-c]pyridin-4-one

MS (ES+) 454.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H, J=8.8 Hz), 7.45 (d,
2H, J=8.8 Hz), 7.25 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 4.15 (t, 2H, J=5.7 Hz),
4.08 (t, 2H, J=7.0 Hz), 3.28 (t, 2H, J=6.8 Hz), 2.94 (s, 2H), 2.67 (s, 4H), 1.83 (s, 4H).

Example 13
2-(4-Ch]oro-phenyl)-5-(3-methoxy-4-morpholin-4-yl-phenyl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one, hydrochloride salt

Prepare the hydrochloride salt of the free base by mixing 2-(4-chloro-phenyl)-5-(3-
methoxy-4-morpholin-4-yl-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (273
mg, 0.599 mmol) in MeOH (4 mL) and adding a 1.0M HCl/ether (0.7 mL, 0.70 mmol)
solution. After all solids dissolve, cool the solution to -20 °C for 4 days. Collect the
white precipitate by filtration, wash with ether, and dry under vacuum to give the title
compound as a white solid (275 mg, 57%). MS (ES+) 456.0 (M+1)+. 1H NMR(400
MHz, DMSO-d6): δ 8.05 (d, 2H, J=8.4 Hz), 7.62 (d, 2H, J=8.4 Hz), 7.18 (s, 1H), 7.12 (s,
1H), 7.00-6.96 (m, 1H), 5.69 (s, 1H), 4.10 (t, 2H, J=7.0 Hz), 3.86-3.80 (m, 7H), 3.27 (t,
2H, J=7.0 Hz), 3.20-3.12 (m, 4H).
Preparation 99
2-(4-Chloro-phenyl)-5-[4-(2,2-dimethoxy-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-clpyridin-4-one

Exact mass = 474.1, MS (ES+) 475.2 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.5 Hz,
2H), 7.45 (d, J = 8.5 Hz, 2H), 6.97-6.93 (m, 2H), 6.83 (dd, J = 8.5, 2.5 Hz, 1H), 4.76 (t, J = 5.2 Hz, 1H), 4.09 (t, J = 7.0 Hz, 2H), 4.06 (d, J = 5.2 Hz, 2H), 3.86 (s, 3H), 3.46 (s,
6H), 3.29 (t,J = 7.0 Hz, 2H).

Preparation 100
5-[4-(2,2-Dimethoxy-ethoxy)-3-methoxy-phenyl]-2-(4-methoxy-phenyl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

MS (ES+) 471.3 (M+1)+. 1H NMR (CDCl3): δ 8.01 (d, J = 8.8 Hz, 2H), 7.00 (d, J= 9.2
Hz, 2H), 6.96-6.99 (m, 2H), 6.81-6.87 (m, 1H), 4.76 (t, J = 5.3 Hz, 1H), 4.09 (t, J = 7.0
Hz, 2H), 4.06 (d, J = 5.3 Hz, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.46 (s, 6H), 3.34 (t, J = 7.0
Hz, 2H).
Preparation 101
5-[4-(2,2-Dimethoxy-ethoxy)-phenyl]-2-phenyl-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-
one

MS (ES+) 411.2 (M+1)+. 1H NMR (CDCl3): δ 8.02 (d, J = 7.9 Hz, 2H), 7.52-7.49 (m,
3H), 7.31 (d, J = 9.2 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.77 (t, J= 5.3 Hz, 1H), 4.12 (t, J
= 6.6 Hz, 2H), 4.06 (d, J = 5.3 Hz, 2H), 3.50 (s, 6H), 3.33 (t, J = 7.0 Hz, 2H).
Preparation 102
5-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one

Exact mass = 500.1, MS (ES+) 501.3 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.6 Hz,
2H), 7.44 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (dd,
J= 8.4, 2.5 Hz, 1H), 4.09 (t, J = 7.0 Hz, 2H), 3.81 (s,3H), 3.28 (t, J = 7.0 Hz, 2H), 1.00 (s,
9H), 0.17 (s, 6H).

Preparation 103
2-(4-Chloro-phenyl)-5-(3-methoxy-4-triisopropylsilanyloxy-phenyl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

MS (ES+) 543.4 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, 2H, J=8.4 Hz), 7.43 (d,
2H, J=8.8 Hz), 6.86 (m, 2H), 6.72 (dd, 1H, J=8.4, 2.6 Hz), 4.07 (t, 2H, J=6.8 Hz), 3.78
(s, 3H), 3.26 (t, 2H, J=6.8 Hz), 1.23 (m, 3H), 1.08 (d, 18H, J=7.5 Hz).
Preparation 104
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(4-triisopropylsilanyloxy-piperidin-1-yl)-phenyl]-
6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one

MS (ES+) 626.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, 2H, J=8.8 Hz), 7.44 (d,
2H, J=8.4 Hz), 6.96 (d, 1H, J=8.4 Hz), 6.88 (d, 1H, J=2.2 Hz), 6.84 (dd, 1H, J=8.4,2.6
Hz), 4.09 (t, 2H, J=7.0 Hz), 4.00-3.94 (m, 1H), 3.86 (s, 3H), 3.27 (t, 4H, J=7.0 Hz), 2.90-
2.83 (m, 2H), 2.01-1.93 (m, 2H), 1.84-1.75 (m, 2H), 1.08-1.06 (m, 21H).
Preparation 105
2-(4-Chloro-phenyl)-5-(l-triisopropylsilany]-2,3-dihydro-1H-indol-5-yl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

MS (ES+) 538.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.91 (d, 2H, J=8.3 Hz), 7.43
(d, 2H, J=8.3 Hz), 7.05-7.03 (m, 1H), 6.86 (dd, 1H, J=8.3,2.2 Hz), 6.61 (d, 1H, J=8.8

Hz), 4.04 (t, 2H, J=6.8 Hz), 3.74 (t, 2H, J=8.6 Hz), 3.23 (t, 2H, J=6.8 Hz), 3.00 (t, 2H,
J=8.8 Hz), 1.47-1.38 (m, 3H), 1.13 (d, 18H, J=7.5 Hz).
Preparation 106
2-(4-Chloro-phenyl)-5-(3,4-dimethoxy-benzyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-
one

MS (ES+) 415.0 (M+1)+. 1H NMR(CDCl3): δ 7.88 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.8
Hz), 6.88-6.85 (m, 2H), 6.81 (d, 1H, J=8.8 Hz), 4.66 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H),
3.58 (t, 2H, J=7.0 Hz), 3.07 (t, 2H, J=7.0 Hz).
Preparation 107
2-(3-Chloro-phenyl)-5-[4-(2,2-dimethoxy-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

Method 2: Prepare the title compound by essentially following procedures as described
for Example 1, Method 1, with the following exceptions. When the reaction is complete
remove the solvent via reduced pressure. Dissolve the residue in minimal amounts of
CH2Cl2, then add hexanes until a solid precipitates. Collect the solid via vacuum
filtration. Wash the solid with hexanes several times to give the title compound. MS
(ES+) 475.2 (M+1)+. 1HNMR(CDCl3): δ 8.02 (s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.49-7.39
(m, 2H), 6.97-6.93 (m, 2H), 6.87-6.82 (m,1H), 4.77 (t, J = 5.4 Hz, 1H), 4.10 (t, J = 7.0
Hz, 2H), 4.07 (d, J = 4.8 Hz, 2H), 3.86 (s, 3H), 3.46 (s, 6H), 3.30 (t, J = 7.0 Hz, 2H).
Prepare the compounds below, Preparation 108 to 110, by essentially following the
procedure as described in Preparation 107, Method 2, using the appropriate 4-hydroxy-
ethyl-thiazole intermediate.

Preparation 108
5-f4-(2,2-Dimethoxy-ethoxy)-3-methoxy-phenyJ]-2-(4-trifluoromethyl-phenyl)-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one

MS (ES+) 509.2 (M+1)+.
Preparation 109
2-(2,4-Dichloro-phenyl)-5-[4-(2,2-dimethoxy-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-onc

MS (ES+) 509.0 (M+1)+.
Preparation 110
5-[4-(2,2-Dimethoxy-ethoxy)-3-methoxy-phenyl]-2-(4-fluoro-phenyl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

MS (ES+) 459.2 (M+1)+.
Preparation 111
(4-[2-(4-Chloro-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-
phenoxy) -acetaldehyde

Method 1: Combine 2-(4-chloro-phenyl)-5-[4-(2,2-dimethoxy-ethoxy)-3-tnethoxy-
phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (0.695 g, 1.46 rnmol), p-
toluenesulfonic acid (0.224 g, 1.16 mmol), acetone (10 mL) and water (2 mL). Attach a
reflux condenser and stir at 70 °C overnight. Concentrate under vacuum, neutralize with

saturated aqueous NaHCO3, and extract with EtOAc (3x). Wash the combined organic
portions with brine, dry over MgSO4, and concentrate under vacuum to give the title
compound. 1H NMR (CDCl3): δ 9.90 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.45 (d, J= 8.6
Hz, 2H), 7.01-6.84 (m, 3H), 4.62 (d, J= 1.2 Hz, 2H), 4.13-4.05 (m, 2H), 3.86 (s, 3H),
3.30 (t, J=6.1 Hz, 2H).
Preparation 112
{2-Methoxy-4-[2-(4-methoxy-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
y l]-phenoxy} -acetaldehyde

Method 2: Dissolve 5-[4-(2,2-Dimethoxy-ethoxy)-3-methoxy-phenyl]-2-(4-methoxy-
phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (145 mg, 0.309 mmol) in THF (2
ml) and 1N HCl solution (360 µl). Heat to 50-60 °C overnight (no reflux condenser
used). Cool reaction mixture, filter solid via vacuum filtration and wash solid with H2O
to give the title compound. MS (ES+) 425.4 (M+1)+.
Prepare the compounds in the table below, Preparations 113 to 117, by essentially
following the procedure as described in Preparation 112, Method 2 using the appropriate
starting acetal.




General Procedure 1

To a round bottom flask or vial containing {4-[2-(4-chloro-phenyl)-4-oxo-6,7-
dihydro-4H-miazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenoxy}-acetaldehyde (0.064 g,
0.15 mmol) add dichloroethane (1.5 mL), a secondary amine (1.2 molar equivalent), and
sodium triacetoxyborohydride (1.1 molar equivalent). Stir at room temperature overnight.
Quench with saturated aqueous NaHCO3, extract with CH2Cl2 (1x), EtOAc (2x), dry over
MgSO4, filter and concentrate under vacuum. Purify by flash chromatography on silica
gel, using a gradient of MeOH (2 N NH3)/EtOAc (5%-15%) to give the title compound.
Prepare Examples 14 to 29 by essentially following the general procedure as described
above, using the appropriate amine reagent. For Examples 28 and 29 prepare the citrate
salt by dissolving the free base in acetone and treating with a stoichiometric amount of
citric acid.
Example 14
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

Exact mass = 483.1, MS (ES+) 484.2 (M+1)+. 1H NMR (CDCl3): δ 7.93 (dt, J = 8.5, 2.1
Hz, 2H), 7.45 (dt, J = 8.5,2.1 Hz, 2H), 6.93 (m, 2H), 6.84 (dd, J = 8.6, 2.4 Hz, 1H), 4.18
(t, J = 6.6 Hz, 2H), 4.09 (t, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.28 (t, J =1.0 Hz, 2H), 2.96 (t,
J = 6.6 Hz, 2H), 2.64 (br s, 4H), 1.81 (m, 4H).
Example 15
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one


Exact mass = 497.1, MS (ES+) 498.3 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.7 Hz,
2H), 7.44 (d, J= 8.7 Hz, 2H), 6.92 (m, 2H), 6.84 (m, 1H), 4.20 (t, J = 5.5 Hz, 2H), 4.09 (t,
J= 6.9 Hz, 2H), 3.86 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H), 2.87 (br s, 2H), 2.58 (br s, 4H),
1.65 (br s, 4H), 1.47 (br s, 2H).
Example 16
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo [5,4-c]pyridin-4-one

Exact mass = 499.1, MS (ES+) 500.3 (M+1)+. 1H NMR (CDCl3): δ 7.92 (d, J = 8.4 Hz,
2H), 7.44 (d, J = 8.4 Hz, 2H), 6.94-6.91 (m, 2H), 6.84 (dd, J = 8.6,2.6 Hz, 1H), 4.18 (t, J
= 5.8 Hz, 2H), 4.09 (t, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.75 (m, 4H), 3.28 (t, J = 7.0 Hz,
2H), 2.87 (ap t, 2H), 2.62 (br s, 4H).
Example 17
2-(4-ChIoro-phenyl)-5-[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

Exact mass = 485.1, MS (ES+) 486.3 (M+1)+. :H NMR (CDCl3): δ 7.93 (d, J = 8.6 Hz,
2H), 7.45 (d, J = 8.6 Hz, 2H), 6.94-6.91 (m, 2H), 6.84 (dd, J = 8.6, 2.4 Hz, 1H), 4.15-4.07
(m, 4H), 3.86 (s, 3H), 3.27 (t, J = 6.9 Hz, 2H), 2.95 (ap d, 2H), 2.67 (ap t, 4H), 1.09 (t, J =
7.1 Hz, 6H).
Example 18
2-(4-Chloro-phenyl)-5-{4-[2-(cyc]ohexyl-methyl-amino)-ethoxy]-3-methoxy-phenyl}-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one


Exact mass = 525.2, MS (ES+) 526.3 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.6 Hz,
2H), 7.45 (d, J= 8.6 Hz, 2H), 6.93-6.90 (m, 2H), 6.84 (dd, J = 8.6, 2.4 Hz, 1H), 4.14-4.07
(m, 4H), 3.86 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H), 2.95 (ap t, 2H), 2.45 (br s, 1H), 2.40 (s,
3H), 1.90-1.77 (m, 4H), 1.64 (br s, 2H), 1.29-1.20 (m, 4H).
Example 19
2-(4-Chloro-phenyl)-5-{3-methoxy-4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one

Exact mass = 512.2, MS (ES+) 513.3 (M+1)+. 1H NMR (CDCl3): δ 7.92 (d, J = 8.7 Hz,
2H), 7.44 (d, J = 8.7 Hz, 2H), 6.93-6.89 (m, 2H), 6.83 (dd, J = 8.6, 2.3 Hz, 1H), 4.16 (t, J = 6.2 Hz, 2H), 4.09 (t, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H), 2.86 (t, J =
6.2 Hz, 2H), 2.64 (br s, 4H), 2.50 (br s, 4H), 2.30 (s, 3H).
Example 20
2-(4-Chloro-phenyl)-5-{4-[2-(isopropyl-methyl-amino)-ethoxy]-3-methoxy-phenyl}-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one

Exact mass = 485.2, MS (ES+) 486.3 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.5 Hz,
2H), 7.45 (d, J = 8.5 Hz, 2H), 6.94-6.91 (m, 2H), 6.84 (dd, J = 8.4, 2.5 Hz, 1H), 4.15-4.07
(m, 4H), 3.86 (s, 3H), 3.28 (t, J = 7.0 2H), 2.94-2.85 (m, 3H), 2.35 (br s, 3H), 1.05 (d, J =
6.5 Hz, 6H).

Example 21
5-t4-(2-[1,4']Bipiperidinyl-1'-yl-ethoxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one

Exact mass = 580.2, MS (ES+) 581.4 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.6 Hz,
2H), 7.45 (d, J = 8.6 Hz, 2H), 6.94-6.91 (m, 2H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 4.15 (t, J
= 6.4 Hz, 2H), 4.09 (t, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H), 3.06 (d, J =
5.7 Hz, 2H), 2.83 (t, J = 6.4 Hz, 2H), 2.52 (br s, 4H), 2.12 (t, J = 11.7 Hz, 2H), 1.80 (ap d,
2H), 1.70-1.52 (m, 7H), 1.43 (br s, 2H).





Preparation 118
2,2-Dimethyl-propionic acid 2-methoxy-4-[2-(4-methoxy-phenyl)-4-oxo-6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl]-phenyl ester

i
Dissolve 2,2-dimethyl-propionic acid 4-{ [4-(2-hydroxy-ethyl)-2-(4-methoxy-
phenyl)-thiazole-5-carbonyl]-amino} -2-methoxy-phenyl ester (480 mg, 0.98 mmol) and
NEt3 (177 mL, 1.27 mmol) in dry CH2Cl2 and cool to 0 °C. Add dropwise
methanesulfonyl chloride (98.1 mL, 1.27 mmol) and stir for 30 min. Quench the reaction
mixture with saturated NH4Cl solution and extract with CH2Cl2 (3 x 10 mL). Dry, filter,
and concentrate. Redissolve the crude material in dry DMF (6.5 mL) and chill to 0 °C.
Add portionwise NaH (60% dispersion, 51 mg, 1.27 mmol) then warm to ambient
temperature overnight. Add 1N HCl (20 mL) and extract with EtOAc (3 x 10 mL).
Collect insoluble solid from portioned layers via filtration. Wash the filtrate with water
(40 mL), dry, filter, and concentrate. Combine the resulting material with the collected
solid to give the title compound as a yellow solid (749 mg, 99%). MS (ES+) 467.3
(M+1)+. 1HNMR(400MHz,CD3OD):δ 7.96(d,2H,J =8.4Hz),7.14(d, 1H,J = 2.2
Hz), 7.05 (d, 2H, J = 8.4 Hz), 7.04 (dd, 1H, J= 8.8, 2.2 Hz), 6.96 (dd, 1H, J= 8.4,2.2
Hz), 4.15 (t, 2H, J = 7.0 Hz), 3.87 (s, 3H), 5.81 (s, 3H), 3.27 (t, 2H, J = 7.5 Hz), 1.35 (s,
9H).
Preparation 119
5-(4-Hydroxy-3-methoxy-phenyl)-2-(4-methoxy-phenyl)-6,7-dihydro-5H-thiazolo[5,4-
c]pyridin-4-one


Dissolve 2,2-dimethyl-propionic acid 2-methoxy-4-[2-(4-methoxy-phenyl)-4-oxo-
6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-phenyl ester (749 mg, 1.61 mmol) in absolute
ethanol (18 mL) and add NaOMe (183.1 mg, 6.44 mmol). Allow the reaction mixture to
stir for 4 h at ambient temperature. Quench the reaction mixture with IN HCl solution, to
pH = 7. Add a small amount of EtOAc (15 mL) and filter the solid precipitate via
vacuum filtration to give the title compound as a yellow solid (430 mg, 70%). MS (ES+)
383.3 (M+1)+. 1HNMR(CDCl3): δ 7.95 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.94
(d, J = 6.2 Hz, 1H), 6.93 (s,1H), 6.80 (dd, J = 8.8, 2.2 Hz, 1H), 4.07 (t, J = 7.0.Hz, 2H),
3.90 (s, 3H), 3.87 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H).
Preparation 120
2-(4-Chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one

Dissolve 2-(4-chloro-phenyl)-5-(3,4-dimethoxy-benzyl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one (376 mg, 0.91 mmol) in toluene (5.0 mL) and treat with para-
toluene sulfonic acid (176 mg, 0.92 mmol). Stir the solution at reflux for 2 d, then
concentrate and purify the crude material by flash chromatography, using 5% MeOH (2N
NH3)/CH2Cl2 as eluent, to give the title compound as a white solid (170 mg, 70%). MS
(ES+) 265.0 (M+1)+. 1H NMR(CDCl3): δ 8.02 (d, 2H, J=8.8 Hz), 7.94 (s, 1H), 7.60 (d,
2H, J=8.4 Hz), 3.52 (dt, 2H, J=7.1,2.5 Hz), 3.04 (t, 2H, J=7.3 Hz).
Preparation 121
ToIuene-4-suIfonic acid 4-[2-(4-chloro-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-
c]pyridin-5-yl]-2-methoxy-phenyl ester


Mix 2-(4-chloro-pbenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (128 mg,
0.48 mmol), toluene-4-sulfonic acid 4-bromo-2-methoxy-phenyl ester (218 mg, 0.61
mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17.2 mg, 0.030 mmol),
Cs2CO3 (0.123 mg, 0.377 mmol) in dioxane (13 mL). Purge the solution with nitrogen
for 30 min and then add tris(dibenzylideneacetone)dipalladium(O) (Pd2(dba)3) (6.7 mg,
0.0073 mmol). Stir the mixture at reflux overnight, then cool to room temperature.
Dilute the mixture with EtOAc (50 mL) and wash with water (2 x 30mL) and brine (30
mL). Dry, filter and concentrate the organic solution and purify the residue by flash
chromatography, using a linear gradient of 100% hexanes to 80% EtoAc/hexanes as
eluent, to give the title compound as a light brown solid (155 mg, 60%). MS (ES+) 541.0
(M+1)+. 1H NMR(CDCl3): δ 7.92 (d, 2H, J=8.4 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.44 (d, 2H,
J=8.8 Hz), 7.31 (d, 2H, J=8.4 Hz), 7.17 (d, 1H, J=8.8 Hz), 6.96 (d, 1H, J=2.6 Hz), 6.82
(dd, 1H, J=8.6, 2.4 Hz), 4.11 (t, 2H, J=6.8 Hz), 3.57 (s, 3H), 3.28 (t, 2H, J=6.8 Hz), 2.44
(s, 3H).
Preparation 122
2-(4-Chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-6,7-dihydro-5H-thiazolo[5,4-
c]pyridin-4-one

Method 1. Mix toluene-4-sulfonic acid 4-[2-(4-chloro-phenyl)-4-oxo-6,7-dihydro-
4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenyl ester (110 mg, 0.20mmol) in dioxane
(mL) and water (mL) and treat with LiOH.H2O (44 mg, 1.0 mmol). Stir the mixture at
reflux for 3 h, cool to room temperature, neutralize with 1N HCl (1.0 mL), and dilute with

additional water. Collect the solid by filtration and purify by flash chromatography, using
a 5% MeOH (2N NH3)/CH2Cl2 as eluent, to give the title compound as an off-white solid
(29 mg, 37%). MS (ES+) 387.0 (M+1)+, MS (ES-) 385.0 (M-1)-. 1H NMR(CDCl3): δ
7.92 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=8.4 Hz), 6.95-6.92 (m, 2H), 6.80 (dd, 1H, J=8.6,
2.4 Hz), 5.61 (s, 1H), 4.08 (t, 2H, J=7.0 Hz), 3.90 (s, 3H), 3.28 (t, 2H, J=7.0 Hz).
Method 2. Combine 5-[4-(tert-butyl-dimethyl-silanyloxy)~3-methoxy-phenyl]-2-
(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (0.92 g, 1.84 mmol), THF
(10 mL), and tetrabutylammonium flouride (1M in THF, 2.0 mL, 2.0 mmol and stir at
room temperature overnight. Neutralize with saturated aqueous NH4Cl, extract with
diethyl ether (1x), EtOAc (2x), dry over MgSO4, filter, and concentrate under vacuum.
Purify by flash chromatography on silica gel, eluting with a gradient of EtOAc/hexane
20%-45% to give the title compound as a yellow residue (0.28 g, 40%). Exact mass =
386.0, MS (ES+) 387.1 (M+1)+.
Preparation 123
(R)-2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-
phenyl]-6,7-dihydro-5H-thazolo[5,4-c]pyridin-4-one

Prepare the title compound by essentially following the procedures as described
for Preparation 118, with the following alternate workup. Quench the reaction mixture
with saturated NH4Cl solution (10 mL) and extract with EtOAc (3 x 20 mL). Wash the
organic layer with water (2 x 20 mL). Dry the organic layer with Na2SO4, filter, and
concentrate. Purify on silica gel chromatography using 0-25% EtOAc in hexanes to give
the title compound. MS (ES+) 612.1(M+1)+. 1HNMR(CDCl3): δ 7.90 (d, J = 8.4 Hz, 2H),
7.42 (d, J= 8.8 Hz, 2H), 6.85 (bs,1H), 6.80 (dd, J= 8.4, 2.2 Hz, 1H), 6.75-6.68 (m, 1H),
4.57 (bs, 1H), 4.06 (t, J = 7.0 Hz, 2H), 3.81 (s, 3H), 3.72-3.63 (m, 1H), 3.43-3.29 (m, 2H),
3.25 (t, J= 7.0 Hz, 2H), 3.17-3.09 (m, 1H), 2.20-2.06 (m, 1H), 1.96-1.86 (m, 1H), 1.12-
0.98 (m, 21H).

Preparation 124
5-Chloromethyl-1 -methyl-1H-imidazole

Add thionyl chloride (4.00 ml, 53.8 mmol) to a solution of (3-methyl-3H-
imidazol-4-yl)-methanol (4.0 g, 35.7 mmol) in dichloroethane (30 mL) and stir at room
temperature for 18 h. Concentrate the reaction mixture and add ether to the residue.
Sonicate for 5 min, filter, and dry to give the title compound (5.8 g, 98%). MS (ES+) 131
(M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 14.99 (s, 1H), 9.18 (s, 1H), 7.75 (s, 1H),
5.00 (s, 2H), 3.85 (s, 3H).
Preparation 125
4-chloromethyl-1H-imidazole

Prepare the title compound by essentially following the procedure as described for
Preparation 124, using (3H-irnidazol-4-yl)-methanol. MS (ES+) 117.1 (M+1)+. 1H NMR
(400 MHz, DMSO-d6): δ 15.03 (s, 1H), 9.12 (d, 1H, J =1.3 Hz), 7.71 (d, 1H, J=1.3 Hz),
4.85 (s, 2H)
General Procedure 2

To a vial containing 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one ( 0.050 g, 0.13 mmol) add DMF (1 mL), K2CO3
(3 molar equivalents), potassium iodide (catalytic), and an alkyl halide (1.2 molar
equivalents). Stir overnight at room temperature. If reaction is not complete, heat in a
microwave reactor at 100 °C for 10 min, or heat in a 100 °C oil bath until the phenol

starting material is consumed. Add water, extract with EtOAc (3x), dry by elution
through a Na2SO4 drying tube and concentrate under vacuum. Purify by flash
chromatography on silica gel to give the title compound.
Prepare Examples 30 to 36 as essentially described according to the general procedure,
above, using the appropriate alkyl halide reagent.
Example 30
2-(4-Chloro-phenyl)-5-[4-(3-dimethylamino-propoxy)-3-methoxy-phenyl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridine-4-one

Exact mass = 471.1, MS (ES+) 472.3 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.6 Hz,
2H), 7.45 (d, J = 8.6 Hz, 2H), 6.94-6.91 (m, 2H), 6.84 (dd, J = 8.5,2.4 Hz, 1H), 4.12-4.07
(m, 4H), 3.87 (s, 3H), 3.29 (t, J = 6.9 Hz, 2E), 2.57 (br s, 2H), 2.34 (br s, 6H), 2.07 (m,
2H).
Example 31
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-piperidin-1-yl-propoxy)-phenyl]-6,7-dihydro-5H-
thiazolo [5,4-c]pyridin-4-one
Exac mass = 511.2, MS (ES+) 512.3 (M+1)+. 1H
NMR (CDCl3): δ 7.93 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 6.94-6.91 (m, 2H),
6.84 (dd, J = 8.7, 2.3 Hz, 1H), 4.11-4.06 (m, 4H), 3.86 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H),
2.53 (br s, 2H), 2.45 (br s, 4H), 2.06 (m, 2H), 1.62 (br s, 4H), 1.45 (br s, 2H).
Example 32
2-(4-Chloro-phenyl)-5-[4-(3-diethylamino-propoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo [5,4-c]pyridin-4-one


Exact mass = 499.2, MS (ES+) 500.3 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.4 Hz,
2H), 7.44 (d, J = 8.4 Hz, 2H), 6.94-6.91 (m, 2H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 4.11-4.06
(m, 4H), 3.86 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.2 Hz,
4H), 2.02-1.94 (m, 2H), 1.02 (t, J = 7.2 Hz, 6H).
Example 33
2-(4-Chloro-phenyl)-5-[4-(2-dimethylamino-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

Exact mass = 457.1, MS (ES+) 458.2 (M+1)+. 1H NMR (CDCl3): δ 7.93 (d, J = 8.5 Hz,
2H), 7.45 (d, J = 8.5 Hz, 2H), 6.94-6.91 (m, 2H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 4.13 (t, J = 6.1 Hz, 2H), 4.09 (t, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H), 2.79 (t, J L
6.1Hz,2H),2.35(s,6H).
Example 34
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(Pyridin-4-ylmethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

Exactmass = 477.1,MS (ES+) 478.2 (M+1)+. 1H NMR (CDCl3): δ 8.64 (br s, 2H), 7.93
(d, J = 8.5 Hz, 2H), 7.49 (ap d, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 2.5 Hz, 1H),
6.86 (d, J = 8.5 Hz, 1H). 6.81 (dd, J = 8.5,2.2 Hz, 1H), 5.21 (s, 2H), 4.09 (t, J = 7.0 Hz
2H), 3.91 (s, 3H), 3.29 (t, J = 7.0 Hz, 2H).

Example 35
2-(4-Chloro-phenyl)-5-[3-rnethoxy-4-(1-methyl-1H-imidazol-2-ylmethoxy)-phenyl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one

Exact mass = 480.1, MS (ES+) 481.2 (M+1)+. 1H NMR (CDCl3): δ 7.92 (dt, J = 8.4,2.2
Hz, 2H), 7.44 (dt, J = 8.7, 2.2 Hz, 2H), 7.18 (d,J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.95 (d,J=
2.5 Hz, 1H), 6.89 (s, 1H), 6.81 (dd, J = 8.4,2.5 Hz, 1H), 5.26 (s, 2H), 4.08 (t, J = 7.0 Hz,
2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H).
Example 36
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-methyl-thiazol-5-ylmethoxy)-phenyl]-6,7-
dihydro-5H-thiazoIo[5,4-c]pyridin-4-one

Exact mass = 497.1, MS (ES+) 498.2 (M+1)+. 1H NMR (CDCl3): δ 7.93 (dt, J = 8.7,2.2
Hz, 2H), 7.45 (dt, J = 8.7,2.2 Hz, 2H), 7.19 (ap s, 1H), 6.99-6.95 (m, 2H), 6.81 (dd, J-
8.7, 2.2 Hz, 1H), 5.25 (ap d, 2H), 4.09 (t, J = 7.0 Hz, 2H), 3.89 (s, 3H), 3.28 (t, J = 7.0
Hz, 2H), 2.73 (s, 3H).
Example 37
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(morpholin-2-ylmethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one


Dissolve 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one (103 mg, 0.267 mmol), 2-hydroxymethyl-morpholine-4-
carboxylic acid tert-butyl ester (Pharmacore, CAS: 135065-69-9)(70 mg, 0.324 mmol),
and PBu3 (84 µl, 0.324 mmol) in dry toluene (1.2 mL). Cool to 0 °C then add 1,1'-
(azodicarbonyl)piperidine (84 µl, 0.324 mmol). Let stir for 10 min at 0 °C, then warm to
ambient temperature overnight. Reaction mixture thickens and turns gel like. Add
hexanes and collect solid via vacuum filtration. Wash the solid with hexanes several
times. Dissolve the crude material in dry CH2Cl2 (500 µl) and TFA (200 µl) and stir
overnight. Add 1N NaOH until the reaction is pH = 10 and extract with EtOAc (3 x 10
mL). Dry the combined organic portions with Na2SO4, filter, and concentrate to give the
title compound. MS (ES+) 486.0 (M+1)+.
Example 38
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(4-methyl-morpholin-2-ylmethoxy)-phenyl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt

Dissolve 2-(4-chloro-phenyl)-5-(3-methoxy-4-(morpholin-2-ylmethoxy)-phenyl]-
6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (460 mg, 0.928 mmol) in dry acetone (3 mL)
under nitrogen. Add K2CO3 (321 mg, 1.11 mmol) and Nal (14 mg, 0.092 mmol).
Evacuate under vacuum and charge the reaction mixture with nitrogen. Mix well and
then add Mel (70 mL, 1.11 mmol). Stir the reaction mixture overnight. Add saturated
NH4Cl solution (5 mL) and extract with EtOAc (3x10 mL). Wash the combined organic
layers with water (10 mL), dry with Na2SO4, filter, and concentrate. Purify the resulting
residue with silica gel chromatography, using 0-10% MeOH/CHCl3 to give the title
compound. Dissolve the compound in minimal CH2Cl2 and add HCl/Et2O to make the
HCl salt as a yellow-orange solid (74 mg, 15%). MS (ES+) 500.0 (M+1)+.

Example 39
(R)-2-(4-Chloro-phenyl)-5-[4-(3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one, hydrochloride salt

Dissolve (R)-2-(4-chloro-phenyl)-5-[3-methoxy-4-(3-triisopropylsilanyloxy-
pyrrolidin-1-yl)-phenyl]-6,7-dihydro-5H-miazolo[5,4-c]pyridin-4-one (370 mg, 0.610
mmol) in dry THF (2 mL). Add TBAF (1.0M in THF, 610 µl, 0.610 mmol) and stir 2 h.
Absorb the reaction mixture on silica gel and remove organic solvent via reduce pressure.
Purify by silica gel chromatography using 0-100% EtOAc in hexanes to give the title
compound. Dissolve the compound in a minimal amount of CH2Cl2 and add HCl/Et2O
solution to give precipitated product. Remove the organic solvent via reduced pressure
and triturate with MeOH to give the desired product as white solid HCl salt (144 mg,
48%). MS (ES+) 456.0 (M+1)+. 1H NMR (CD3OD): δ 8.01 (d, J = 8.8 Hz, 2H), 7.71 (br
d,J = 8.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.35 (br s, 1H), 7.16 (br d, J = 8.8 Hz, 1H),
4.73-4.67 (m, 1H), 4.19 (br t, J = 6.6 Hz, 2H), 4.02 (br s, 3H), 3.97-3.85 (m, 3H), 3.66 (br
d, J= 11.0 Hz, 1H), 3.31 (t, J= 7.0 Hz, 2H), 2.49-2.36 (m, 1H), 2.26-2.17 (m, 1H).
Preparation 126
2-(4-Chloro-phenyl)-5-(3-methoxy-4-triisopropylsilanyloxy-phenyl)-5H-thiazolo[5,4-
c]pyridin-4-one

Treat a solution 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic
acid (3-methoxy-4-triisopropylsilanyloxy-phenyl)-amide (1.0 g, 1.79 mmol) in CH2Cl2

(30 mL) with Dess- Martin periodinane (1.13 g, 2.67 mmol). Stir at room temperature for
dilute with IN NaOH, and extract with CH2Cl2 (2x). Dry, filter, and concentrate the
organic solution and purify the crude material by flash chromatography, using a gradient
of 0 - 10% MeOH in CH2Cl2 to give the title compound (0.47 g, 48%). MS (ES+) 541.0
(M+1)+. 1H NMR (400 MHz, CDCl3) δ: 8.01 (d, 2H, J=8.8 Hz), 7.46 (d, 2H, J=8.4 Hz),
7.41 (d, 1H, J=7.5 Hz), 6.93 (m, 3H), 6.81 (dd, 1H, J=8.4, 2.6 Hz), 3.80 (s, 3H), 1.25 (m,
3H), 1.09 (d, 18H, J=7.5 Hz).
Preparation 127
2-(4-Chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one

Treat a solution of 2-(4-chloro-phenyl)-5-(3-methoxy-4-triisopropylsilanyloxy-
phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.47 g, 0.87 mmol) in THF ( 5.0 mL) with
TBAF (1.3 mL of 1N in THF) and stir for 4 h. Acidify reaction mixture to pH 4 with 1N
HCl. Filter precipitate, wash several times with water, and dry to give title compound
(0.23 g, 69%). MS (ES+) 385 (M+1)+. lH NMR (400MHz, DMSO-d6) δ: 9.33 (s, 1H),
8.11 (d, 2H, J=8.4 Hz), 7.69 (d, 1H, J=7.0 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.02-6.97 (m,
2H), 6.86-6.81 (m, 2H), 3.74 (s, 3H).
Example 40
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one

Mix 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [3-
methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide (80 mg, 0.16 mmol) and Dess-
Martin periodinane (70 mg, 0.1 6mmol) in CH2Cl2 and stir at RT for 48 h. Dilute the
mixture with aqueous 1 N NaOH and extract with CH2Cl2. Dry, filter, and concentrate

the organic solution. Purify the crude material by flash chromatography, using a gradient
of 100% EtOAc to 12% 2 N NH3/MeOH in EtOAc, to give the title compound (12 mg,
16%). MS (ES+) 482.0 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, 2H, J = 8.8
Hz), 7.46 (d, 2H, J = 8.3 Hz), 7.40 (d, 1H, J= 7.0 Hz), 7.34 (s, 1H), 6.89-6.99 (m, 3H),
4.20 (t, 2H, J = 6.4 Hz), 3.86 (s, 3H), 2.96 (t, 2H, J= 6.4 Hz), 2.64 (s, 4H), 1.80 (m, 4H).
Example 41
2-(4-Chloro-phenyl)-5-[3-memoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-
thiazolo[5,4-c]pyridin-4-one hydrochloride

Add NaH (0.7 g, 17.5 mmol) to a solution of 2-(4-chloro-phenyl)-5-(4-hydroxy-3-
methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (1.6 g, 4.2 mmol) in DMF (15 mL) at
room temperature. Stir for 10-30 min, add l-(2-chloro-ethyl)-pyrrolidine hydrochloride
(2.1 g, 12.4 mmol), and warm to 90 °C for 1-2 days. Cool the reaction mixture, dilute
with water, and extract with CH2Cl2 (2x). Combine the organic portions, dry, and
concentrate. Purify by flash chromatography- using 0 -10% 2N NH3/MeOH in CH2Cl2,
to give the free amine. Dissolve the free amine in MeOH (10.0 mL) and add 1N HCl in
ether (10.0 mL), sonicate for 5 min, and concentrate. Triturate the solid with ether, filter
the solid, and dry to give the title compound (0.97 g, 45%). MS (ES+) 481.8 (M+1)+; free
amine)+. 1H NMR (400 MHz, DMSO-δ6): δ 10.76 (s, 1H, HCl), 8.11 (d, 2H, J=8.8 Hz),
7.72 (d, 1H, J=7.0 Hz), 7.63 (d, 2H, J=8.4 Hz), 7.17-7.14 (m, 2H), 7.03-6.99 (m, 2H),
4.37 (t, 2H, J=5.1 Hz), 3.77 (s, 3H), 3.61 (m, 4H), 3.10 (m, 2H), 1.99 (m, 2H), 1.86 (m,
2H).
Prepare Example 42 to 44 by essentially following the procedures as described for
Example 41, using the appropriate alkylating agent.
Example 42
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-methyl-3H-imidazol-4-ylmethoxy)-phenyl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one


MS (ES+) 479.0 (M+1)+. 1H NMR (400MHz, DMSO-d6): δ 14.56 (s, 1H), 9.18 (s, 1H),
8.16 (d, 2H, J=8.4 Hz), 7.86 (d, 1H, J=1.3 Hz), 7.76 (d, 1H, J=7.5 Hz), 7.67 (d, 2H,
J=8.4 Hz), 7.32 (d, 1H, J=8.8 Hz), 7.20 (d, 1H, J=2.6 Hz), 7.06 (ra, 2H), 5.32 (s, 2H),
3.93 (s, 3H), 3.79 (s, 3H).
Example 43
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one hydrochloride

MS (ES+) 498.0 (M+1)+. 1H NMR (400MHz, DMS0-d6): δ 11.03 (s, 1H), 8.11 (d, 2H,
J=8.8 Hz), 7.71 (d, 1H, J=7.3 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.16 (m, 2H), 7.02 (m, 2H),
4.44 (t, 2H, J=4.9 Hz), 3.96 (d, 2H, J=10.5 Hz), 3.77 (m, 5H), 3.56-3.52 (m, 4H), 3.21
(m, 2H).
Example 44
2-(4-Chloro-phenyl)-5-[4-(1H-imidazol-4-ylmethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one hydrochloride

1H NMR (400 MHz, CD3OD): δ 8.92 (d, 1H, J=1.3 Hz), 8.00 (d, 2H, J=8.8 Hz), 7.62 (s,
1H), 7.51 (d, 2H, J=8.8 Hz), 7.08 (m, 2H), 6.91 (dd, 1H, J=8.4,2.4 Hz), 5.19 (s, 2H),
4.11 (t, 2H, J=7.0 Hz), 3.83 (s, 3H), 3.28 (t, 2H, J=7.0 Hz).

Preparation 128
4-(2-Benzyloxy-ethyl)-morpholin-3-one

Add NaH (0.47 g, 11.8 mmol) to a solution of morpholin-3-one (Vieles, P.;
Seguin, J., Bulletin de la Societe Chimique de France, 1953, 287-9) (1.0 g, 9.9 mmol) in
DMF (10 ml) at room temperature. Stir for 30 min, add (2-bromo-ethoxymethyl)-benzene
(2.2 g, 10.2 mmol), and stir at room temperature for 18 h. Dilute with water and extract
with EtOAc (2x). Combine the organics, dry, and concentrate. Purify by flash
chromatography using 0-5% MeOH in CH2Cl2, to give the product as an oil.(1.7 g,
74%). 1H NMR (400 MHz, CDCl3): δ 7.28 (m, 5H), 4.48 (s, 2H), 4.13 (s, 2H), 3.80 (t,
2H, J=5.1 Hz), 3.65 (m, 2H), 3.59 (dd, 2H, J=7.5, 2.6 Hz), 3.48 (t, 2H, J=5.1 Hz).
Preparation 129
4-(2-Hydroxy-ethyl)-morpholin-3-one

Dissolve 4-(2-benzyloxy-ethyl)-morpholin-3-one (1.7 g, 7.23 mmol) in ethanol
(25 mL) and add 5% Pd/C (0.30 g). Hydrogenate at 60 psi overnight, filter the black
mixture through Celite®, and wash the Celite® with additional ethanol (approximately
10mL). Concentrate the filtrate to give the title compound as an oil (0.7 g, 70%). MS
(ES+) 146.3 (M+1)+. lH NMR (400 MHz, CDCl3): δ 4.11 (s, 2H), 3.83 (t, 2H, J=5.1 Hz),
3.73 (t, 2H, J=5.3 Hz), 3.49 (t, 2H, J=5.3 Hz), 3.43 (t, 2H, J=5.1 Hz), 3.12 (s, 1H).

Example 45
2-(4-Chloro-pheny])-5-{3-methoxy-4-[2-(3-oxo-morpholin-4-yl)-ethoxy]-phenyl}-5H-

thiazoIo[5,4-c]pyridin-4-one
Combine 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-
c]pyridin-4-one (0.70 g, 1.82 mmol), 4-(2-hydroxy-ethyl)-morpholin-3-one (0.50 g, 3.45
mmol) and triphenylphosphine (0.50 g, 1.90 mmol) in THF (10.0 mL), stir for 10 min and
add DIAD (0.77 g, 3.81 mmol). Heat to 80 °C for 2 days, cool the reaction mixture, and
dilute with water. Extract with CH2Cl2 (2x), combine the organics, dry, and concentrate
under vacuum. Purify the product by flash chromatography using 0 - 10% MeOH in
CH2Cl2 to give the tide compound (0.40 g, 43%). MS (ES+) 512.0 (M+1)+. 1H NMR
(400 MHz, CDCl3): δ 8.01 (d, 2H, J=8.6 Hz), 7.47 (d, 2H, J=8.6 Hz), 7.40 (d, 1H, J=7.5
Hz), 6.98-6.95 (m, 3H), 6.91 (dd, 1H, J=8.6,2.4 Hz), 4.27 (t, 2H, J=5.2 Hz), 4.17 (s, 2H),
3.89-3.81 (m, 7H), 3.68 (t, 2H, J=5.1 Hz).
Example 46
2-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,

Dissolve 3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.20 g, 0.83 mmol)
in CH2Cl2 (10.0 mL) and treat with trimethylaluminum (2.0M in hexanes, 0.6 mL, 1.20
mmol). Stir at room temperature for 15 min and add 2-(4-chloro-phenyl)-6,7-dihydro-
pyrano[4,3-d]thiazol-4-one (0.22 g, 0.83 mmol) neat and stir the reaction at room
temperature for 2 h. Carefully quench the mixture with saturated Rochelles salt solution
and stir at room temperature for 1 h. Dilute with water and extract with CH2Cl2 (2x).
Combine the organic portions and dry, filter and concentrate. Dissolve the residue in
CH2Cl2, and treat with triethylamine (0.50 mL, 3.56 mmol) followed by methanesulfonyl

chloride (0.05 mL, 0.65 mmol). Stir for 1 h at room temperature, dilute with water and
extract with CH2Cl2 (2x). Combine the organic portions and dry, filter, and concentrate.
Dissolve the residue in THF and treat with NaH (0.03 g, 0.75 mmol) and stir at room
temperature for 18 h. Dilute the reaction with water and extract with CH2Cl2 (2x).
Combine the organic portions, dry, filter, and concentrate. Purify the crude material by
flash chromatography, using a gradient of 0% to 10% 2N NH3/MeOH in CH2Cl2, to give
the title compound (80 mg, 37%). MS (ES+) 488.0 (M+1)+. 1H NMR (400 MHz,
CDCl3): δ 7.93 (d, 2H, J=8.3 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.39 (d, 1H, J=2.2 Hz), 7.22
(dd, 1H, J=8.8, 2.6 Hz), 6.97 (d, 1H, J=9.2 Hz), 4.22 (t, 2H, J=5.9 Hz), 4.07 (t, 2H,
J=7.0 Hz), 3.28 (t, 2H, J=7.0 Hz), 3.01 (t, 2H, J=5.9 Hz), 2.73 (m 4H), 1.84 (m 4H).
Example 47
2-(4-Chloro-phenyl)-5-tl-methyl-3-(2-pyrro)idin-1-yl-ethyl)-1H-indol-6-yl]-6,7-dihydro-
5H-thiazolo [5,4-c]pyridin-4-one hydrochloride

Dissolve 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [1-
methyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indol-6-yl]-amide (0.92 g, 1.81 mmol) in THF (20
mL) and treat the solution with tributylphosphine (1.0 mL, 3.47 mmol) and
diisopropylazodicarboxylate (0.73 mL, 3.61 mmol). Stir the reaction at room temperature
for 18 h. Concentrate and purify the crude material by flash chromatography, using 0-
10% 2N NH3/MeOH in CH2Cl2, to give the free amine. Dissolve the free amine in MeOH
(10.0 mL) and add 1N HCl in ether (5.0 mL), sonicate for 5 min, and concentrate.
Triturate the solid with ether, filter the solid, and dry to give the title compound (0.64 g,
69%). MS (ES+) 491.1 (M+1)+. lH NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 8.03
(d, 2H, J=8.6 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.59 (d, 2H,J=8.6 Hz), 7.44 (d, 1H, J=1.8
Hz), 7.26 (s, 1H), 7.06 (dd, 1H, J=8.5,1.6 Hz), 4.1 l(t, 2H, J=7.0 Hz), 3.72 (s, 3H), 3.54
(m, 2H), 3.33 (m, 2H), 3.27 (t, 2H, J=6.9 Hz), 2.97 (m, 4H), 1.98 (m, 2H), 1.85 (m, 2H).

Example 48
2-(4-Chloro-phenyl)-5-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one, dihydrochloride salt

Prepare the title compound by essentially following procedures as described for
Example 46 and isolating as the dihydrochloride salt. MS (ES+) 439.8 (M+1)+. 1H NMR
(400 MHz, DMSO-d6): δ 11.38 (s, 1H), 8.19 (d, 1H, J=2.6 Hz), 8.01 (d, 2H, J=8.6 Hz),
7.80 (dd, 1H, J=9.1,2.5 Hz), 7.58 (d, 2H, J=8.8 Hz), 7.14 (d, 1H, J=9.4 Hz), 4.42 (d, 2H,
J=13.8 Hz), 4.04 (t, 2H, J=6.9 Hz), 3.42 (m, 4H), 3.24 (t, 2H, J=6.9 Hz), 3.08 (m, 2H),
2.75 (d, 3H, J=4.2 Hz).
Example 49
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-methyl-3H-imidazol-4-ylmethoxy)-
phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one

Treat a solution of (3-rnethyl-3H-imidazol-4-yl)-methanol (60.0 mg, 0.54 mmol)
in CH2Cl2 with oxalyl chloride (0.15 g, 1.2 mmol) and 2 drops of DMF. Stir at room
temperature for 4 h, concentrate, and dissolve in DMF (5.0 mL). Add this solution to a
suspension of NaH (62.5 mg, 1.6 mmol) and 2-(4-chloro-phenyl)-5-(4-hydroxy-3-
methoxy-phenyO-5H-thiazolo[5,4-c]pyridin-4-one (200.0 mg, 0.5 mmol) in DMF (5 mL).
Stir at room temperature for 2 h, dilute with water, and extract with CH2Cl2 (2x).
Combine the organics, dry, and concentrate. Purify by flash chromatography, using 0 -
10% 2N NH3/MeOH in CH2Cl2, to give the title compound (100.0 mg, 40%). MS (ES+)
481.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, 2H, J=8.4 Hz), 7.44 (d, 2H,
J=4.0 Hz), 7.41 (s, 1H), 7.07 (s, 1H), 6.97 (d, 1H, J=8.8 Hz), 6.94 (d, 1H, J=2.2 Hz),

6.81 (dd, 1H, J=8.6,2.4 Hz), 5.04 (s, 2H), 4.07 (t, 2H, J=7.0 Hz), 3.83 (s, 3H), 3.72 (s,
3H), 3.27 (t, 2H, J=6.8 Hz).
Preparation 130
2-(4-Chloro-phenyl)-5-[4-(3,3-diethoxy-propyl)-3-methoxy-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one

Prepare the title compound by essentially following the procedures as described for
Preparation 132. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 2H, J=8.3 Hz), 7.48 (d, 2H,
J=8.3 Hz), 7.42 (d, 1H, J=7.0 Hz), 7.25 (d, 1H, J=7.9 Hz), 6.96 (d, 1H, J=7.5 Hz), 6.93-
6.87 (m, 2H), 4.54 (t, 1H, J=5.7 Hz), 3.83 (s, 3H), 3.72-3.63 (m, 2H), 3.56-3.47 (m, 2H),
2.74-2.68 (m, 2H), 1.97-1.90 (m, 2H), 1.22 (t, 6H, J=7.0 Hz).
Preparation 131
3-{4-[2-(4-Chloro-phenyl)-4-oxo-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenyl}-
propionaldehyde

Dissolve 2-(4-chloro-phenyl)-5-[4-(3,3-diethoxy-propyl)-3-methoxy-phenyl]-5H-
thiazolo[5,4-c]pyridin-4-one (180 mg, 0.36 mmol) in THF (2.0 mL) and water (1.0 mL)
then add glacial acetic acid (0.6 mL). Stir the solution at 45 °C overnight. Dilute the
solution with EtOAc (50 mL), wash with saturated NaHCO3 (20 mL), then dry, filter and
concentrate the solution. Purify the crude material by flash chromatography, using a
linear gradient of 100% hexanes to 80% EtOAc/hexanes, to give the title compound (94
mg, 61%). MS (ES+) 425.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 9.83 (s, 1H), 8.03
(d, 2H, J=8.3 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.41 (d, 1H, J=7.5 Hz), 7.26 (m, 1H), 6.99-
6.89 (m, 3H), 3.84 (s, 3H), 2.99 (t, 2H, J=7.3 Hz), 2.77 (t, 2H, J=7.3 Hz).

Example 50
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one

Dissolve 3-{4-[2-(4-chloro-phenyl)-4-oxo-4H-thiazolo[5,4-c]pyridin-5-yl]-2-
methoxy-phenyl]-propionaldehyde (94mg, 0.22mmol) in 1,2-dichloroethane (2.2 mL) and
add pyrrolidine (20 µL, 0.24 mmol), AcOH (19 µL, 0.33 mmol), and NaHB(OAc)3 (70
mg, 0.33 mmol). Stir the yellow solution at room temperature for 1 h, then add 1N NaOH
(5 mL), and extract the mixture with CH2Cl2 (2x10 mL). Combine the organic portions,
then dry, filter, and concentrate. Purify the crude material by flash chromatography, using
8% 2N NH3 in MeOH/CHCl3 as eluent, to give the title compound (75 mg, 71%). MS
(ES+) 480.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 2H, J=8.3 Hz), 7.48 (d, 2H,
J=8.8 Hz), 7.43 (d, 1H, J=7.5 Hz), 7.25 (t, 1H, J=3.7 Hz), 6.97 (d, 1H, J=7.5 Hz), 6.93-
6.88 (m, 2H), 3.83 (s, 3H), 2.70 (t, 2H, J=7.7 Hz), 2.60 (br s, 6H), 1.96-1.79 (m, 6H).
Example 51
2-(4-Chloro-phenyl)-5-[4-(4-hydroxy-piperidin-1-yl)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one, hydrochloride salt

Dissolve 2-(4-chloro-phenyl)-5-[3-methoxy-4-(4-triisopropylsilanyloxy-piperidin-
1-yl)-phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (681 mg, 1.09 mmol) in THF
(10 mL) then add tert-butylammonium fluoride (1.0 M solution in THF, 1.30 mL, 1.30
mmol). Stir the solution at room temperature for 2 h, then dilute with EtOAc (50 mL) and
wash with 2N NH4Cl (20 mL). Concentrate the organic solution and purify the crude
material by flash chromatography, using 8% MeOH (2N NH3)/CHCl3 as eluent, to give
semi-pure material. Triturate the solids with ether to give the title compound as the free

base (265 mg, 52%). Mix 2-(4-chloro-phenyl)-5-[4-(4-hydroxy-piperidin-1-yl)-3-
methoxy-phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (53 mg, 0.11 mmol) in
MeOH (1 mL) and add 1N HCl (2.0 mL, 2.0 mmol). Stir the mixture at room temperature
until all the solids dissolve and then cool to -20 °C overnight. Collect the precipitate by
filtration, wash with ether, and dry under vacuum to give the title compound (40 mg,
70%). MS (ES+) 470.0 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 11.69 (s, 1H), 8.06
(d, 2H, J=8.4 Hz), 7.70 (s, 1H), 7.63 (d, 2H, J=8.4 Hz), 7.34 (s, 1H), 7.14 (s, 1H), 4.65 (s,
4H), 4.16 (t, 2H, J=6.8 Hz), 3.95 (s, 3H), 3.64-3.32 (m, 2H), 3.29 (t, 2H, J=7.0 Hz), 2.11-
1.76 (m,4H),
Example 52
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one hydrochloride

Mix 2-(4-chloro-phenyl)-5-t3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5H-
thiazolo[5,4-c]pyridin-4-one (833 mg, 1.74 mmol) in MeOH (10 mL) and add 1N HCl
(2.0 mL, 2.0 mmol). Stir the mixture at room temperature until all the solids dissolve
then cool to -20 °C overnight. Collect the precipitate by filtration, wash with ether, and
dry under vacuum to give the title compound (725 mg, 81%). MS (ES+) 480.0 (M+1)+.
1H NMR (400 MHz, CDCl3): δ 10.14 (s, 1H), 8.16 (d, 2H, J=8.8 Hz), 7.77 (d, 1H, J=7.5
Hz), 7.67 (d, 2H, J=8.8 Hz), 7.34 (d, 1H, J=8.4 Hz), 7.15 (d, 1H, J=1.8 Hz), 7.09-7.02 (m,
2H), 3.83 (s, 3H), 3.58-3.50 (m, 2H), 3.20-3.13 (m, 2H), 3.02-2.94 (m, 2H), 2.68 (t, 2H,
J=7.7 Hz), 2.03-1.93 (m, 4H), 1.90-1.83 (m, 2H).

Example 53
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one
Prepare the titled compound by essentially following procedures as described for
Example 52. MS (ES+) 482.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 10.45 (s, 1H),
8.05 (d, 2H, J=8.4 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=7.9 Hz), 7.05 (d, 1H, J=1.8
Hz), 6.93 (dd, 1H, J=7.9, 1.8 Hz), 4.11 (t, 2H, J=7.0 Hz), 3.80 (s, 3H), 3.55-3.47 (m, 2H),
3.27 (t, 2H, J=6.8 Hz), 3.15-3.08 (m, 2H), 3.00-2.91 (m, 2H), 2.62 (t, 2H, J=7.5 Hz),
2.02-1.81 (m,6H).
Preparation 132
Methanesulfonic acid 2-[2-(4-chloro-phenyl)-5-(1-triisopropylsilanyl-1H-indol-5-
ylcarbamoyl)-thiazol-4-yl]-ethyl ester

Dissolve 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid (1-
triisopropylsilanyl-1H-indol-5-yl)-amide (1.54g, 2.77mmol) in CH2Cl2 (25 mL) and add
Et3N (0.33 mL, 2.36 mmol) and methanesulfonyl chloride (0.16 mmol, 2.13 mmol). Stir
the mixture at room temperature for 2 h, then add additional Et3N (0.33 mL, 2.36 mmol)
and methanesulfonyl chloride (0.16 mmol, 2.13 mmol). Stir the mixture for an additional
2 h, dilute with EtOAc (50 mL), then wash with water (20 mL) and brine (20 mL). Dry,
filter and concentrate the organic solution. Purify the crude material by flash
chromatography, using a linear gradient of 100% hexanes to 50% EtOAc/hexanes as
eluent, to give the tide compound (1.15 g, 100%). MS (ES+) 632.1 (M+1)+. 1H NMR

(400 MHz, CDCl3): δ 7.96-7.84 (m, 4H), 7.50-7.43 (m, 3H), 7.30-7.26 (m, 2H), 6.62 (d,
1H, J=3.1 Hz), 4.77 (t, 2H, J=6.2 Hz), 3.60 (t, 2H, J=6.4 Hz), 2.99 (s, 3H), 1.73-1.65 (ra,
3H), 1.14 (d, 18H, J=7.5 Hz).
Preparation 133
2-(4-Chloro-phenyl)-5-(l-triisopropylsilanyl-1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-
c]pyridin-4-one

Dissolve 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid (1-
triisopropylsilanyl-1H-indol-5-yl)-amide in CH2Cl2 (25 mL) and add Et3N (0.33 mL, 2.36
mmol) and methanesulfonyl chloride (0.16 mmol, 2.13 mmol). Stir the mixture at room
temperature for 2h, then add additional Et3N (0.33 mL, 2.36 mmol) and methanesulfonyl
chloride (0.16 mmol, 2.13 mmol). Stir the mixture for an additional 2 h, dilute with
EtOAc (50 mL), then wash with water (20 mL) and brine (20 mL). Dry, filter and
concentrate the organic solution then and purify the crude material by flash
chromatography, using a linear gradient of 100% hexanes to 50% EtOAc/hexanes as
eluent, to give the title compound (1.15 g, 100%). MS (ES+) 536.1 (M+1)+. 1HNMR
(400 MHz, CDCl3) δ: 7.93 (d, 2H, J=8.3 Hz), 7.56 (d, 1H, J=1.8 Hz), 7.50 (d, 1H, J=8.8
Hz), 7.44 (d, 2H, J=8.3 Hz), 7.27 (d, 1H, J=3.1 Hz), 7.14-7.10 (m, 1H), 6.61 (d, 1H,
J=2.6 Hz), 4.16 (t, 2H, J=6.8 Hz), 3.29 (t, 2H, J=7.0 Hz), 1.73-1.65 (m, 3H), 1.14 (d,
18H, J=7.5 Hz).
Preparation 134
2-(4-Chloro-phenyl)-5-(lH-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one


Mix 2-(4-chloro-phenyl)-5-(1-triisopropylsilanyl-1H-indol-5-yl)-6,7-dihydro-5H-
[5,4-c]pyridin-4-one (4.23 g, 7.89 mmol) in THF (50 mL) and add tetrabutyl-
ammonium fluoride (1.0M in THF, 10vmL, 10 mmol). Stir the red solution at room
temperature for 2 h, then quench with aqueous 2M NR,C1 (50 mL) and extract with
CH2Cl2 (3 x 50mL). Dry, filter, and concentrate the organic solution. Purify the crude
material by flash chromatography, using 8%MeOH (2N NH3)/CHCl3 as eluent, then
triturate the resulting yellow solid with ether to give the title compound (2.68 g, 89%).
MS (ES+) 380.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 11.20 (s, 1H), 8.05 (d, 2H,
J=8.4 Hz), 7.62 (d, 2H, .J=8.4 Hz), 7.53 (d, 1H, J=1.8 Hz), 7.43-7.38 (m, 2H), 7.09 (dd,
1H, J=8.6, 2.0 Hz), 6.45-6.43 (m, 1H), 4.11 (t, 2H, J=7.0 Hz), 3.28 (t, 2H, J=7.0 Hz).
Preparation 135
2-(4-Chloro-phenyl)-5-(2,3-dihydro-1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-
c]pyridin-4-one

Prepare the title compound by essentially following procedure as described in Preparation
134. MS (ES+) 381.9 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.91 (d, 2H, J=8.3 Hz),
7.43 (d, 2H, J=8.8 Hz), 7.13 (s, 1H), 6.99 (dd, 1H, J=8.1, 2.0 Hz), 6.76 (d, 1H, J=8.3 Hz),
4.04 (t, 2H, J=6.8 Hz), 3.64 (t, 2H, J=8.3 Hz), 3.26 (t, 2H, J=6.8 Hz), 3.08 (t, 2H, J=8.3
Hz).
Preparation 136
(±)-3-{5-[2-(4-Chloro-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2,3-
dihydro-indole-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester

Dissolve 2-(4-chloro-phenyl)-5-(2,3-dihydro-1H-indol-5-yl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one (163 mg, 0.43 mmol) in CH2Cl2 (4.0 mL) and add (±)-

pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (140 mg, 0.65 mmol), Et3N (0.09 mL,
(1.64 mmol), and [dimethylamino-([1,2,3]txiazolo[4,5-b]pyridin-3-yloxy)-methylene]-
dimethyl-ammonium hexafhioro phosphate (246 mg, 0.65 mmol). Stir the solution at
room temperature for 2 h. Concentrate and purify by flash chromatography, using a 8%
MeOH (2N NH3)/CHCl3 as eluent, to give the title compound (231 mg, 93%). 1H NMR
(400 MHz, DMSO-d6): δ 8.10 (d, 1H, J=8.8 Hz), 8.05 (d, 2H, J=8.8 Hz), 7.62 (d, 2H,
J=8.3 Hz), 7.29 (s, 1H), 7.19-7.15 (m, 1H), 4.22 (t, 2H, J=8.8 Hz), 4.07 (t, 2H, J=7.0 Hz),
3.54 (t, 1H, J=8.8 Hz), 3.47-3.36 (m, 3H), 3.29 (m, 1H), 3.26 (t, 2H, J = 6.2 Hz), 3.18 (t,
2H, J=8.3 Hz), 2.16 (m, 1H), 2.01 (m, 1H), 1.41 (s, 9H).
Example 54
(±)-2-(4-Chloro-phenyl)-5-[1-(pyrrolidine-3-carbonyl)-2,3-dihydro-1H-indol-5-yl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-onium trifluoroacetate

Dissolve (±)-3-{5-[2-(4-chloro-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-
c]pyridin-5-yl] -2,3-dihydro-indole-1 -carbonyl} -pyrrolidine-1 -carboxylic acid tert-butyl
ester (225 mg, 0.39 mmol) in TFA (2 mL) and stir at room temperature for 1 h.
Concentrate the solution and re-dissolve the crude material in MeOH. Remove the light
yellow solid by filtration and wash with ether. Dry under vacuum to give the title
compound (188 mg, 82%). MS (ES+) 479.0 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ
8.89 (s, 2H), 8.10 (d, 1H, J=8.8 Hz), 8.05 (d, 2H, J=8.8 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.31
(s, 1H), 7.22-7.18 (m, 1H), 4.22 (t, 2H, J=9.4 Hz), 4.07 (t, 2H, J=7.0 Hz), 3.56-3.47 (m,
2H), 3.42-3.35 (m, 1H), 3.29-3.20 (m, 6H), 2.35-2.27 (m, 1H), 2.13-2.03 (m, 1H).
Example 55
(±)-2-(4-Chloro-phenyl)-5-[ 1 -(1 -methyl-pyrroIidine-3-carbonyl)-2,3-dihydro-1H-indol-5-
yl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one


Dissolve (±)-2-(4-chloro-phenyl)-5-[ 1-(pyrrolidine-3-carbonyl)-2,3-dihydro- 1H-
indol-5-yl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-onium trifluoroacetate (167 mg, 0.28
mmol) in 1,2-dichloroethane (3.0 mL) and add paraformaldehyde (203 mg), acetic acid
(0.02 mL, 0.35 mmol), and sodium triacetoxyborohydride (78 mg, 0.37 mmol). Stir the
mixture at room temperature for 4 h, then dilute with CH2Cl2 (20 mL) and wash with 1N
NaOH (10 mL). Dry, filter and concentrate the organic solution then and purify the crude
material by flash chromatography, using a 8% MeOH (2N NH3)/CHCl3 as eluent, to give
the title compound as a yellow solid (86 mg, 62%). MS (ES+) 493.0 (M+1)+. 1H NMR
(400 MHz, DMSO-d6): δ 8.30 (d, 1H, J=8.8 Hz), 7.95 (d, 2H, J=8.3 Hz), 7.47 (d, 2H,
J=8.3 Hz), 7.28 (s, 1H), 7.15 (d, 1H, J=10.1 Hz), 4.17 (t, 2H, J=8.8 Hz), 4.12 (t, 2H,
J=6.8 Hz), 3.33-3.22 (m, 5H), 3.17-3.10 (m, 1H), 3.01-2.90 (m, 1H), 2.85-2.76 (m, 1H),
2.64-2.56 (m, 1H), 2.50 (s, 3H), 2.29-2.21 (m, 2H).
Example 56
2 (4-Chloro-phenyl)-5-(1-pyridin-2-ylmethyl-1H-indol-5-yl)-6,7-dihydro-5H-
thiazoIo[5,4-c]pyridin-4-one

Dissolve 2-(4-chloro-phenyl)-5-(1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-
c]pyridin-4-one (49 mg, 0.13 mmol) in DMF (1 mL) and add sodium hydride (17 mg,
0.42 mmol). Stir the mixture at room temperature for 30 min then add 2-bromomethyl-
pyridine hydrobromide (35 mg, 0.14 mmol). Stir the mixture at room temperature for 5 h,
then dilute with EtOAc (30 mL) and wash with saturated NaHCO3 (10 mL). Dry, filter
and concentrate the organic solution. Purify the crude material by flash chromatography,
using a linear gradient of 20% to80% EtOAc/hexanes as eluent, to give the title

compound (32 mg, 52%). MS (ES+) 471.0 (M+1)+. 1H NMR (400MHZ, CDCl3) δ: 8.55-
8:53 (m, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.73 (dt, 1H, J=7.7, 1.8 Hz), 7.62 (d, 2H, .J=8.8 Hz),
7.57-7.55 (m, 2H), 7.45 (d, 1H, .J=8.8 Hz), 7.30-7.26 (m, 1H), 7.10 (dd, 1H, J=8.6,2.0
Hz), 7.03 (d, 1H, J=7.9 Hz), 6.52 (d, 1H, J=3.5 Hz), 5.53 (s, 2H), 4.10 (t, 2H, J=7.0 Hz),
3.27 (t, 2H, J=7.0 Hz).
Prepare Examples 57 and 58 by essentially following the procedure as described for
Example 56, using the appropriate alkyl halids.
Example 57
2-(4-Chloro-phenyl)-5-(1-pyridin-4-ylmethyl-1H-indol-5-yl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

MS (ES+) 471.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.50 (d, 2H, J=5.7 Hz), 8.05 (d,
2H, J=8.8 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.58 (d, 2H, J=2.6 Hz), 7.42 (d, 1H, J=8.8 Hz),
7.14-7.09 (m, 3H), 6.56 (d, 1H, J=3.1 Hz), 5.53 (s, 2H), 4.11 (t, 2H, J=6.8 Hz), 3.28 (t,
2H, J=7.0 Hz).
Example 58
2-(4-Chloro-phenyl)-5-[1-(2-morpholin-4-yl-ethyl)-1H-indol-5-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one

MS (ES+) 493.0 (M+1)+. 1H NMR (400MHz, DMSO-d6): δ 8.06 (d, 2H, J=8.8 Hz), 7.68
(d, 1H, J=8.8 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.58 (d, 1H, J=2.2 Hz), 7.50 (d, 1H, J=3.1 Hz),
7.22 (dd, 1H, J=8.6,2.0 Hz), 6.53 (d, 1H, J=2.6 Hz), 4.71 (s, 2H), 4.12 (t, 2H, J=7.0 Hz),
4.02-3.94 (m, 2H), 3.84-3.75 (m, 2H), 3.56-3.42 (m, 4H), 3.29 (t, 2H, J=7.0 Hz), 3.20-
3.08 (m, 2H).

Preparation 137
5-nitro-3H-benzooxazole-2-thione

Combine 2-amino-4-nitrophenol (15.8 g, 102 mmol) and potassium ethyl xanthate
(18.3 g, 114 mmol) in pyridine (200 mL). Heat the reaction at reflux for 1 h. Allow the
reaction to cool to room temperature and pour into concentrated HCl (100 mL) and ice.
Filter and wash the solids with 1N HCl to remove excess pyridine. Dry the solids under
house vacuum at 50 °C for 2 days to obtain the title compound (15.85 g, 79%). 1H NMR
(400 MHz, DMSO-d6): δ 8.18 (dd, 1H, J = 8.8, 2.2 Hz), 7.93 (d, 1H, J = 2.2 Hz), 7.73 (d,
1H, J = 8.8 Hz).
Preparation 138
2-Ethylsulfany]-5-nitrobenzooxazole
Dissolve 5-Nitro-3H-benzooxazole-2-thione (10.58 g, 53.9 mmol) in anhydrous THF
(300mL). Cool the mixture to 0 °C in an ice bath. Add NaH (4.90 g, 60% dispersion in
mineral oil) slowly. Stir the resulting mixture at 0 °C for 10 min. Add iodoethane (20.0
mL, 0.250 mmol) to the stirring mixture. Allow the mixture to warm to room temperature
and stir overnight. Adsorb the reaction mixture onto silica gel and subject to flash column
chromatography in 2 batches (330 g, 120 g columns, eluting with 10-50% ethyl acetate/n-
hexane both times) to yield the desired product (4.93g, 41%). 1H NMR (400 MHz,
DMSO-d6): δ 8.47 (d, J=2.4 Hz, 1H), 8.23 (dd, J= 9.2,2.6Hz, 1H), 7.88 (d, J=8.8 Hz,
1H), 3.37 (q, J= 6.8 Hz, 2H), 1.45 (t, J=7.6 Hz, 3H).

Preparation 139
Methyl-(l-methyl-piperidin-4-yl)-(5-nitro-benzooxazol-2-yl)-amine

Dissolve 2-ethylsulfanyl-5-nitro-benzooxazole (1.17 g, 5.23 mmol) in anhydrous THF (10
mL) in a reaction tube and blow nitrogen into the vessel for 10 s. Add methyl-(l-methyl-
piperidin-4-yl)-amine (1.37 mL, 9.42 mmol) to the solution. Quickly seal the vessel and
immerse into a pre-heated oil bath (100 °C) and stir for 24 h. Concentrate the reaction
mixture in vacuo, wash with 1.0M NaOH(aq) (2 x 50mL), dry over Na2SO4, filter, and
concentrate in vacuo. Subject the residue by silica gel flash column chromatography,
eluting with 2N NH3 in MeOH/CH2Cl2, to yield the desired product (0.608 g, 40%).
MS(ES+) 291.0 (M+1)+.
Preparation 140
N2-Methyl-N2-(l-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine

Dissolve methyl-(1-methyl-piperidin-4-yl)-(5-nitro-benzooxazol-2-yl)-amine
(0.583 g, 2.01 mmol), in acetic acid (8 mL), and add iron (1.12 g, 20.1 mmol) to the
solution. Stir the mixture at 40 °C for 3 h. Filter the reaction mixture through Celite®
and wash with water/MeOH. Concentrate the reaction mixture in vacuo. Subject the
residue to silica gel flash column chromatography, eluting with 10% 2N NH3 in
MeOH/CH2Cl2, to yield the desired product (0.474 g, 91%). MS(ES+) 261.2 (M+1)+.

Preparation 141
N,N, N'-Trimethyl-N'-(5-nitro-benzooxazol-2-yl)-ethane-1,2-diamine

Prepare the title compound by essentially following the procedure as described in
Preparation 139, using 2-methylsulfanyl-5-nitro-benzooxazole (5.0 g, 23.8 mmol) and
N,N,N'-Trimethyl-ethane-1,2-diamine (15.4 mL, 118.9mmol) at 140 °C. The product is
purified by silica gel flash column chromatography (330 g column, eluting with 5% 2N
NH3 in MeOH/CH2Cl2) to yield the desired product (2.8 g, 44%). MS(ES+) 265.3
(M+1)+.
Preparation 142
N2-(2-Dimethylamino-ethyl)-N2-methyl-benzooxazole-2,5-diarnine

The title compound was prepared according to the procedure described in General
Method B using N,N,N'-Trimemyl-N'-(5-nitro-benzooxazol-2-yl)-emane-1,2-diamine
(4.131g, 15.63mmol), acetic acid (50 mL), and Fe (8.72 g, 78.15 mmol), stirring for 3h:
(3.57g, 98%): mass spectrum (m/e): 265.3 (M+1).
Example 59
2-(4-Chloro-phenyl)-5-{2[(2-dimethylamino-ethyl)-methyl-amino]-benzooxazol-5-yl}-
6,7-dihydro-5H-miazolo[5,4-c]pyridin-4-one hydrochloride

Dissolve N -(2-dimethylamino-ethyl)-N2 -methyl-benzooxazole-2,5-diamine (0.50
g, 2.14 mmol) in CH2Cl2 (10.0 mL) and treat with 2N aluminum trimethyl in hexanes (2.0

mL, 4.0 mmol). Stir at room temperature for 15 min and add 2-(4-chloro-phenyl)-6,7-
pyrano[4,3-d]thiazol-4-one (0.60 g, 2.26 mmol) neat and stir the reaction at room
temperature for 2 h. Carefully quench the mixture with saturated Rochelles salt solution
and stir at room temperature for 1 h. Dilute with water, filter the precipitate and dry.
Dissolve the solid (0.30 g, 0.60 mmol) and treat with tributylphophine (0.26 mL, 0.90
mmol) and diisopropylazodicarboxylate (0.18 mL, 0.09 mmol). Stir the reaction at room
temperature for 18 h and concentrate. Purify the crude material by flash chromatography,
using 0 -10% 2N NH3/MeOH in CH2Cl2 to give the free amine. Dissolve the free amine
in MeOH (2.0 mL) and add 1N HCl in ether (1.0 mL), sonicate for 5 min, and
concentrate. Triturate the solid with ether, filter, and dry to give the title compound (0.13
g). MS (ES+) 482 (M+1)+. 1H NMR (400 MHz, DMSO- d6): δ 10.59 (s, 1H), 8.01 (d,
2H, J=8.4 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.44 (d, 1H,J=8.4 Hz), 7.30 (d, 1H, J=2.2 Hz),
7.03 (dd, 1H, J=8.4,2.2 Hz), 4.07 (t, 2H, J=6.8 Hz), 3.92 (t, 2H, J=5.3 Hz), 3.39 (t, 2H,
J=5.3 Hz), 3.24 (t, 2H, J=6.8 Hz), 3.17 (s, 3H), 2.81 (d, 6H, J=4.8 Hz).
Example 60
2-(4-ChIoro-phenyl)-5- {2-[methyl-( 1 -methyl-piperidin-4-yl)-amino]-benzooxazol-5-yl} -

6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one
Prepare the title compound by essentially following the procedure as described in
Example 59, using N2-methyl-N2-(l-methyl-piperdin-4-yl)-benzooxazole-2,5-diamine.
MS (ES+) 508 (M+1, free amine)+. 1H NMR (400 MHz, DMSO-d6): δ 10.79 (brs, 1H),
8.04 (d, 2H, J=8.4 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.31 (d, 1H,
J=2.2 Hz), 7.04 (dd, 1H, J=8.6,2.2 Hz), 4.39 (m, 1H), 4.10 (t, 2H, J=7.0 Hz), 3.48 (d,
2H, J=11.4 Hz), 3.28 (t, 2H, J = 2.0 Hz), 3.17 (m, 2H), 3.04 (s, 3H), 2.73 (d, 3H, J=4.8
Hz), 2.27 (m, 2H), 1.94 (d, 2H, J=13.2 Hz).

Example 61
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-y]-prop-1-ynyl)-phenyl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one

Treat a suspension of 5-(4-bromo-3-methoxy-phenyl)-2-(4-chloro-phenyl)-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one (0.25 mg, 0.56 mmol), 1-prop-2-ynyl-
pyrrolidine (0.12 g, 1.10 mmol), dichlorobis(triphenylphosphine)palladium (II) (12.0 mg,
0.02 mmol), triethylamine (0.5 mL) in DMF with CuI (4.0 mg, 0.02 mmol). Stir at 80 °C
under nitrogen for 2 days. Dilute the reaction with water and extract with CH2Cl2 (2x).
Dry, filter, and concentrate the organic solution and purify the crude material by flash
chromatography, using a gradient of 0 - 10% MeOH in CH2Cl2 to give the title compound
(30.0 mg, 12%). MS (ES+) 478.0 (M+1)+. 1H NMR (400 MHz, CDCl3): 6 7.89 (d, 2H,
J =8.8 Hz), 7.40 (m, 3H), 6.95 (d, 1H, J=2.2 Hz), 6.82 (dd, 1H, J=8.1, 2.0 Hz), 4.10 (t,
2H, J=6.8 Hz), 3.84 (m, 5H), 3.26 (t, 2H, J=6.8 Hz), 2.88 (m, 4H), 1.89 (m, 4H).
Example 62
2-(4-Chloro-phenyl)-5-[4-(2-imidazoH-yl-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one hydrochloride

Treat a solution of 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one (0.20 g, 0.52 mmol), 2-imidazol-1-yl-ethanol
(0.09 g, 0.80 mmol), and triphenylphosphine (0.27 g, 1.03 mmol) with
diisopropylazodicarboxylate (0.27 g, 1.34 mmol). Warm the solution to 80 °C and stir for
18 h. Concentrate the reaction and purify the residue by flash chromatography, using 0 -
10% 2N NH3/MeOH in CH2Cl2, to give the free amine. Dissolve the free amine in MeOH
(2.0 mL) and add 1N PIC1 in ether (2.0 mL), sonicate for 5 min, and concentrate. Triturate
the solid with ether, filter, and dry to give the title compound (0.15 g, 58%). MS (ES+)

481 (M+1, free amine)+, 1H NMR (400 MHz, DMSO-d6): δ 14.84 (s, 1H), 9.17 (s, 1H),
800 (d, 2H, J=8.4 Hz), 7.79 (t, 1H, J=1.8 Hz), 7.67 (t, 1H, J=1.8 Hz), 7.57 (d, 2H, J=8.8
Hz), 7.00 (m, 2H), 6.86 (dd, 1H, J=8.6, 2.4 Hz), 4.58 (t, 2H, J=4.8 Hz), 4.35 (t, 2H,
J=4.8 Hz), 4.01 (t, 2H, J=7.0 Hz), 3.70 (s, 3H), 3.21 (t, 2H, J=7.0 Hz).
Example 63
2-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one hydrochloride

Treat a solution of 2-(4-chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (60.0 mg, 0.12 mmol) in MeOH
(2.0 mL) with 1N HCl in ether (1.0 mL). Sonicate at room temperature for 15 min,
concentrate, and dry to give the title compound (50 mg, 78%). MS (ES+) 488 (M+1; free
amine)+. 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.02 (d, 2H, J=8.6 Hz), 7.59
(m, 2H), 7.55 (d, 1H, J=2.4 Hz), 7.36 (dd, 1H, J=8.8,2.4 Hz), 7.25 (d, 1H, J=8.8 Hz),
4.43 (t, 2H, J=4.8 Hz), 4.05 (t, 2H, J=7.0 Hz), 3.62 (m, 4H), 3.24 (t, 2H, J=7.0 Hz), 3.14
(m, 2H), 2.01 (m, 2H), 1.86 (m, 2H).
Example 64
2-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-y]-ethoxy)-phenyl]-5H-
thiazolo[5,4-c]pyridin-4-one

Treat a solution of 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic
acid [3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide (0.15 g, 0.30 mmol) in CH2Cl2
(20 ml) with pyridinium dichromate (0.33 g, 0.88 mmol) and stir suspension at room
temperature for 3 days. Apply reaction mixture onto silica gel chromatography column
and purify using 0 -10% 2N NH3/MeOH in CH2Cl2, to give the free amine. Dissolve the
free amine in MeOH (1.0 mL) and add 1N HCl in ether (0.5 mL), sonicate for 5 min, and

concentrate. Triturate the solid with ether, filter, and dry to give the title compound (16
teg, 10%). MS (ES+) 486 (M+1, free amine)+. 'H NMR (400 MHz, DMSO-d6): δ 10.59
(s, 1H), 8.13 (d, 2H, J=8.8 Hz), 7.75 (d, 1H, .J=7.3 Hz), 7.70 (d, 1H,J=2.6 Hz), 7.64 (d,
2H, J=8.8 Hz), 7.48 (dd, 1H, J=8.8, 2.4 Hz), 7.34 (d, 1H, J=8.8 Hz), 7.04 (d, 1H, J=7.5
Hz), 4.49 (t, 2H, J=4.9 Hz), 3.62 (m, 4H), 3.15 (m, 2H), 2.02-1.87 (m, 4H).
Preparation 143
Benzyl-(2-methy]-allyl)-amine

Add benzaldehyde (14.5 mL, 143 mmol) to a mixture of methallylamine (9.73 g,
137 mmol) and MgSO4 (15.0 g, 125 mmol) in THF (180 mL). Stir for 22 h, filter the
mixture, and concentrate the filtrate. Dissolve the residue in EtOH (200 mL) and treat
with NaBH4 (5.00 g, 132 mmol) in 3 portions. After 19 h, remove the solvent by rotary
evaporation. Treat the residue with 1 M HCl (200 mL) then 5 M HCl (20 mL). Wash the
solution with tert-Mutyl methyl ether (250 mL) and then treat with 5 M NaOH (50 mL) to
make basic. Extract the mixture with CH2Cl2 (200 mL followed by 100 mL). Dry, filter
and concentrate the organic solution to give the title compound (20.3 g, 92%) as a
colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 4.84 (1H, s), 4.79
(1H, s), 3.63 (2H, s), 3.03 (2H, s), 1.69 (3H, s).
Preparation 144
1-[Benzyl-(2-methyl-allyl)-amino]-2-methyl-propan-2-ol

Add lithium bromide (955 mg, 11.0 mmol) to a mixture of isobutylene oxide
(6.20 mL, 68.8 mmol) and benzyl-(2-mefhyl-allyl)-amine (9.51 g, 59.0 mmol). Stir the

mixture for 3.5 h at room temperature then treat with additional epoxide (1.5 mL, 16.6
mmol) and heat at 60 °C for 1.7 h. Dilute the mixture with CH2Cl2 (200 mL) and wash
with water (200 mL). Dry, filter and concentrate the organic solution. Dry the residue at
80 °C under vacuum to give the title compound (13.5 g, 98%) as a colorless oil. 1H NMR
(400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 4.90 (1H, s), 4.83 (1H, s), 4.18 (1H, s), 3.59
(2H, s), 2.98 (2H, s), 2.27 (2H, s), 1.71 (3H, s), 1.05 (6H, s).
Preparation 145
4-Benzyl-2-iodomethyl-2,6,6-trimethyl-morpholine

Add solid I2 (21.1 g, 83.1 mmol) to a biphasic mixture of 1 -[benzyl-(2-methyl-
allyl)-amino]-2-methyl-propan-2-ol (17.6 g, 75.4 mmol) in tert-butyl methyl ether(250
mL) and 1 M NaHCO3 (100 mL). Stir for 18 h and then add 1 M Na2S2O3 (100mL).
Dilute the mixture with additional tert-butyl methyl ether (200 mL) and separate the
organic solution. Wash the organic solution with a mixture of 1 M Na2S2O3 (100 mL)
and 1M NaHCO3 (100 mL). Dry, filter, and concentrate the organic solution. Dry the
residue at 60 °C under vacuum to give the title compound (25.2 g, 93%) as a golden oil.
1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 3.49 (1H, d), 3.47 (2H, s), 3.41 (1H,
s), 2.49 (1H,d), 2.23 (1H,s), 2.20 (1H, s), 2.10 (1H,d), 1.24 (3H,s), 1.22 (3H,s), 1.15
(3H, s).
Preparation 146
4-Benzyl-2,2,6,6-tetramethyl-morpholine


Add solid NaBH4 (776 mg, 20.5 mmol) to a solution of 4-benzyl-2-iodomethyl-
2,6,6-trirnethyl-morpholine (6.22 g, 17.3 mmol) in DMSO (20 ml.) and then heat the
mixture at 100 °C. After 2 h, add additional DMSO (10 mL). After an additional 1.25 h,
add extra NaBH4 (120 mg, 3.17mmol). Remove the heat after an additional 1.25 h (total
reaction time = 4.5 h). Quench the excess NaBH4 with 5 M HCl (20 ml). After 15 min,
add 5 M NaOH (20 mL) and 1 M Na2S2O3 (20 mL) and then stir the mixture overnight.
Dilute the mixture with tert-butyl methyl ether (250 mL) and water (100 mL). Separate
the organic solution and wash with additional water (4 x 100 mL). Dry, filter and
concentrate the organic solution. Purify the residue by flash chromatography, using a
gradient from 50% to 100% CH2Cl2 in pentane as eluent. Dry the product so obtained
briefly at 60 °C under vacuum to give the title compound (2.43 g, 60%) as a colorless
liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 3.45 (2H, s), 2.12 (4H, s),
1.15(12H,s).
Preparation 147
2,2,6,6-Tetramethymorpholine

Dissolve 4-benzyl-2,2,6,6-tetramethylmorpholine (Bennett, G.B.; Houlihan, W.J.;
Mason, R.B.; Engstrom, R.G. J. Med. Chan. 1976,19, 709-714) (11.0 g, 47.1 mmol) in
EtOH (650 mL) and add 3% Pd/C (8.61 g). Shake the mixture under hydrogen (60 psi) at
40 °C for 24 h. Filter the mixture to remove Pd catalyst, and treat the filtrate with 2M
HCl in ether, then concentrate. Dry the residue at 80 °C under vacuum to give the title
compound (6.79 g) as a white solid. lH NMR (DMSO-d6,400 MHz) 8 9.8 (2H, br s),
2.88 (4H,s), 1.25 (12H,s).
Preparation 148
4-(2-Benzyloxy-ethyl)-2,2,6,6-tetramethyl-morpholine


Dissolve 500 mg (2.79 mmol) of 2,2,6,6-tetramethyl-morpholine (500 mg, 2.79
mmol) in dichloroethane (10 mL). Add benzyloxy-acetaldehyde (470 µl, 3.35 mmol) and
stir at room temperature for 20 min. Add sodium triacetoxyborohydride (770 mg, 3.63
mmol) and continue stirring at room temperature for 20 h. Pour the reaction mixture into
100 mL of 1N NaOH (100 mL) and extract with CH2Cl2 (2 x 100 mL). Wash the
combined organic layers with brine (100 mL). Purify using silica gel chromatography,
using a gradient of 0% to 10% (2N NH3 in MeOH)/CHCl3 as eluent, to give 490 mg
(63%) of the desired product. MS (ES+) 278.3 (M+1)+.
Preparation 149
2-(2,2,6,6-Tetramethyl-morpholin-4-yl)-ethanol

Dissolve 4-(2-benzyloxy-ethyl)-2,2,6,6-tetramethyl-morpholine (490 mg, 1.77 mmol)
MeOH (40 mL). Add to a pressure vessel containing a slurry of 10% Pd/C (100 mg) in
MeOH (20 mL). Pressurize with 45 psi hydrogen gas. Monitor the reaction by MS.
After 48 h, add another portion of 10% Pd/C (100 mg )and re-pressurize to 45 psi
hydrogen. Stir an additional 3 days. Filter the reaction mixture through Celite® eluting
with MeOH. Concentrate to give the desired product in quantitative yield. MS (ES+)
188.3 (M+1)+.
Example 65
2-(4-Chloro-phenyl)-5-{3-methoxy-4-[2-(2,2,6,6-tetramethyl-morpholin-4-yl)-ethoxy]-
phenyl}-5H-thiazolo[5,4-c]pyridine-4-one Hydrochloride

Dissolve 2-(2,2,6,6-tetramethyl-morpholin-4-yl)-ethanol (100 mg, 0.53 mmol) CH2Cl2 (5
mL). Add triethylamine (96 µL, 0.69 mmol) and then cool the reaction to 0 °C. Add
methanesulfonyl chloride (53 µL, 0.69 mmol) and stir for 2 h. Add more methanesulfonyl

chloride (53 µL, 0.69 mmol) and stir 1 h. Add more methanesulfonyl chloride (53 µL,
0.69 mmol) and triethyl amine (96 µL, 0.69 mmol). Store in freezer (-4 °C) overnight.
Pour the reaction mixture into 1N NaOH (100 mL) and extract with CH2Cl2 (2 x 100
mL). Wash the combined organics with brine (100 mL). Concentrate the organic portion
to give crude mesylate which is dissolved in l-methyl-2-pyrrolidinone (2 mL). Add this
solution to a room temperature slurry of 2-(4-chloro-pbenyl)-5-(4-hydroxy-3-rnethoxy-
phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (204 mg, 0.53 mmol) and NaH (21 mg, 0.53
mmol) in l-methyl-2-pyrrolidinone (6 mL). Stir at room temperature for 2 h and then
warm to 80 °C for 48 h. Cool to room temperature and pour into 1N NaOH (200 mL) and
extract with EtOAc (2 x 200 mL). Purify via silica gel chromatography, using a gradient
of 0% to 10% (2N NH3 in MeOH)/CHCl3 as eluent to give a mixture of product and
recovered phenol. Dissolve the mixture in CH2Cl2 (100 mL) and extract with 1N NaOH
(5 x 100 mL). Concentrate to give the pure product as the free amine. Dissolve in
CH2Cl2 (20 mL) and add 4M HCl in dioxane (200 µL). Concentrate to give the product
as the hydrochloride salt. MS (ES+) 554.3 (M+1)+, 1H NMR (400 MHz, DMSO-d6) δ
10.11 (bs, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.70 (d, J= 7.2 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H),
7.19-7.16 (m, 2H), 7.02 (d, J= 7.2 Hz, 2 H), 4.52 (bs, 2H), 3.77 (s, 3H), 3.59-3.54 (m,
4H), 2.95 (t, J = 10.0 Hz, 2H), 1.41 (s, 6H), 1.16 (s, 6H).
Preparation 150
2-[Benzyl-(2-methyl-allyl)-amino]-ethanol

Add methallyl chloride (68.8 g, 0.760 mol, Aldrich) to a mixture of N-
benzylethanolamine (100 g, 0.663 mol) and potassium carbonate (139 g, 1.00 mol) in
water (600 mL). Heat the mixture to 62 °C for 23 h and then transfer to a separatory
funnel. Extract the product with tert-butyl methyl ether (500 mL). Dry, filter, and
concentrate the organic solution to give the title compound (131g, 96%) as a colorless

liquid. 1H NMR (DMS0-d6,400 MHz) δ 7.20-7.33 (5H, m), 4.92 (1H, br s), 4.83 (1H, br
s), 4.35 (1H, t), 3.53 (2H, s), 3.44-3.50 (2H, m), 2.94 (1H, s), 2.42 (2H, t), 1.69 (1H, s).
Preparation 151
4-Benzyl-2,2-dimethyl-morpholine

Add 2-[benzyl-(2-methyl-allyl)-amino]-ethanol (13.0 g, 63.2 mmol) to a slurry of
mercury (II) acetate (20.7 g, 65.0 mmol) in water (45 mL) and THF (45 mL). After 3 h,
treat the mixture with NaOH (25 mL, 2.5 M aqueous, 125 mmol) followed by NaBH4
(2.72 g, 71.9 mmol). After 19 h, decant the mixture away from the metallic mercury and
add to a separatory funnel with tert-butyl methyl ether (250 mL). Separate the organic
solution, wash with water (250 mL), filter through a silica plug, and concentrate. Purify
the residue by flash chromatography using a gradient from 5% to 10% tert-butyl methyl
ether in CH2Cl2. Collect and concentrate the fractions containing product then dissolve
the residue in hexanes (100 mL). Filter the solution through Celite® to remove metallic
mercury and then concentrate the filtrate to give the title compound (7.01 g, 54%) as a
colorless liquid. 1H NMR (DMSO-d6,400 MHz) δ 7.20-7.40 (5H, m), 3.60 (2H, m), 3.42
(2H, s), 2.29 (2H. m), 2.10 (2H, s), 1.14 (6H, s).
Preparation 152
2,2-Dimethylmorpholine hydrochloride

Dissolve 4-benzyl-2,2-dimethyl-morpholine (5.67 g, 27.6 mmol) in CH2Cl2 (50
mL) and add 1-chloroethyl chloroformate (4.60 mL, 42.2 mmol) while stirring at room
temperature. After 4 h, concentrate the solution and treat the residue with MeOH (60
mL). Heat the mixture at 60 °C for 2 h, then concentrate again. Dissolve the residue in
water (125 mL) and wash with tert-butyl methyl ether (125 mL). Concentrate the aqueous

layer and dry the resulting residue at 80 °C under vacuum to give the title compound (3.91
g, 93%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (2H, br s), 3.75 (2H, m),
2.89-2.96 (4H, m), 1.25 (6H, s).
Preparation 153
2-(2,2-Dimethyl-rnorpholin-4-yl)-ethanol

Dissolve 2,2-dimethylmorpholine (151 mg, 1.0 mmol) in 1,2-dichloroethane (3 mL) and
add glycolaldehyde (60 mg, 1.0 mmol). Stir at room temperature for 30 min followed by
addition of NaBH(OAc)3 (233 mg, 1.1 mmol). Stir 3 h, then quench by adding 30 mL of
1N NaOH. Pour into a separatory funnel and extract with EtOAc (2 x 50 mL). Wash the
combined organic layers with brine (50 mL). The crude alcohol was used as is without
further purification. MS (ES+) 160.2 (M+1)+.
Example 66
2-(4-Chloro-phenyl)-5- {4-[2-(2,2-dimethyl-morpholin-4-yl)-ethoxy]-3-methoxy-phenyl} -
5H-thiazolo [5,4-c]pyridin-4-one

Dissolve 2-(2,2-dimethyl-morpholin-4-yl)-ethanol (88 mg, 0.55 mmol) in 4.5 mL THF
(4.5 mL). Add 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-
c]pyridin-4-one (211 mg, 0.55 mmol). This forms a slurry to which is added 217 mg
(0.83 mmol) of triphenylphosphine (217 mg, 0.83 mmol) followed by 161 pL (0.83
mmol) of diisopropyl azodicarboxylate (DIAD). The reaction then becomes a solution.
Heat the reaction to 80 °C for 16 h. Pour into 1N NaOH (200 mL) and extract with
CH2Cl2 (2 x 150 mL). Purify via silica gel chromatography, using a gradient of 0% to
10% (2N NH3 in MeOH)/CHCl3 as eluent, to obtain a mixture of product and starting
phenol. Dissolve the mixture in CH2Cl2 (300 mL) and extract with 5N NaOH (5 x 100
mL) until all the phenol is removed from the organic layer. Wash the organic layer with

brine (100 mL) and concentrate. Dissolve the residue in CH2Cl2 (30 mL) and treat with
4M HCl in dioxane (100 µL). Diethyl ether is added until the solution becomes cloudy.
Let sit at room temperature for 1.5 h then filter the resulting precipitate to give 18 mg
(6%) of the desired product. MS (ES+) 526.0 (M+1)+, 1H NMR (400 MHz, (CD3OD): δ
8.11 (d, J= 8.5 Hz, 2H), 7.66 (d, J= 7.3 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5
Hz, 1H), 7.17 (d, J= 2.0 Hz, 1 H), 7.09 (d, J = 7.3 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H),
4.51-4.43 (m, 2H), 4.07-4.00 (m, 2H), 3.93-3.90 (m, 1H), 3.89 (s, 3H), 3.70-3.56 (m, 4H),
3.26-3.19 (m, 1H), 3.07 (d, J = 12.2 Hz, 1H), 1.44 (s, 3H), 1.30 (s, 3H).

We Claim:
1. A substituted thiazolopyridinone compound of formula I

wherein:
is optionally a bond to form a double bond
q is 0, 1, 2, or 3; wherein other positions on the phenyl ring have hydrogen atoms;
t is 0;
w is 1 or 2 depending on substitution pattern and/or the presence of a double bond;
R1 is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halo,
hydroxy, C1-C8 haloalkyl, C1-C8 alkoxy, -C1-C8 alkyl alcohol, C1-C8 haloalkoxy, aryl, -O-aryl, -
O-heteroaryl, -OC1-C8 alkylaryl, -C1-C8 alkylaryl, -C1-C8 alkylheteroaryl, heterocyclic, -C1-C8
alkylheterocyclic, -C1-C8 alkylcycloalkyl, amino, and C1-C8 alkylNR6R6', C0-C8 alkylCOOR6,
C0-C8 alkylCONR6R6';
R2 is hydrogen;
Ar1 is a cyclic group optionally substituted with one to three groups independently selected from
the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, hydroxy, -OC1-C8 alkyl, C1-C8
alkylaryl, C1-C8 alkylheteroaryl, phenyl, -O-aryl, -O-heteroaryl, heterocyclic, C1-C4
alkylheterocyclic, cycloalkyl, C1-C8 alkylcycloalkyl, cyano, -C1-C8 alkylNR6R6', C1-C8
haloalkyl, C1-C8 alkyl alcohol, C1-C8 haloalkoxy, halo, (CH2)nC0R6, -O(CH2)nCHR6R6',
NR6SO2R6', (CH2)n NR6SO2R6', and -(CH2)nC(O)NR6R6';
L1 is a bond or a divalent linker selected from the group consisting of C1-C5 alkyl, C2-C5 alkynyl,
C2-C5 alkenyl, C0-C5 alkyl-S-C0-C5 alkyl, C0-C5 alkyl-S- C1-C5 alkylhalide, C0-C5 alkyl-NR6-C0-
C5 alkyl, C0-C5 alkyl-NR6- C1-C5 alkyl-S- C0-C5 alkyl wherein each L1 group has a maximum of
6 carbon atoms in the main chain and wherein each alkyl is optionally substituted with 1 to 3
groups independently selected from halo, cyano, and hydroxy;

and R4 are independently selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8
alkenyl, C3-C8 cycloalkyl, aryl, heteroaryl heterocyclic, C1-C8 alkylaryl, C1-C8 alkylcycloalkyl,
C1-C8 alkylheteroaryl, C1-C4 alkylheterocyclic; wherein each of the alkyl, alkenyl, cycloalkyl,
aryl, heteroaryl, or heterocyclic group or subgroup is optionally substituted with one to three
groups independently selected from C1-C8 alkyl, C2-C8 alkenyl, phenyl, alkylaryl,
(CH2)nNSO2C1-C8 alkyl, (CH2)nNSO2phenyl, (CH2)nNSO2aryl, -C(O)C1-C8 alkyl, COOH, -
C(O)OC1-C8 alkyl and C0-C4 alkylNR6R6'; and wherein R3 and R4 optionally combine together
with the nitrogen atom to which they are attached, or one or both of R3 and R4 combine with L1
at a position α, β, γ, or, 5 to the nitrogen of NR3R4 to form a nitrogen containing 5 to7-member
heterocyclic group with L1 said heterocyclic group optionally having one to three substituents
independently selected from oxo, hydroxy, cyano, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl,
C1-C8 alkylaryl, C1-C8 alkylcycloalkyl, C1-C4 alkylheterocyclic, C1-C4 alkylheteroaryl, halo,
(CH2)nNSO2C1-C8 alkyl, (CH2)nNSO2phenyl, (CH2)nNSO2aryl, -C(O)C1-C8 alkyl, -C(O)OC1-C8
alkyl and C0-C4 alkylNR6R6';
R6 and R6 are independently hydrogen, C1-C8 alkyl, phenyl, aryl, C1-C8 alkylaryl, C3-C8
cycloalkyl, or C1-C6 alkylcycloalkyl; and wherein R6 and R6' may combine to form a substituted
5-7 member nitrogen-containing heterocycle, optionally having one to three substituents
independently selected from oxo, hydroxy, cyano, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl,
C1-C8 alkylaryl, C1-C8 alkylcycloalkyl, C1-C4 alkylheterocyclic, halo, (CH2)nNSO2C1-C8 alkyl,
(CH2)nNSO2phenyl, (CH2)nNSO2aryl, -C(O)C1-C8 alkyl, COOH, or -C(O)OC1-C8 alkyl and C0-
C4 alkylNR7R8;
R7 and R8 are each independently selected from hydrogen, and C1-C4 alkyl; n is an integer from 0
to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture of or
diastereomer thereof.
2. A compound as claimed in Claim 1 wherein the R1 is halo, C1-C3 alkyl, C2-C4
alkenyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkyl alcohol, C1-C3 haloalkoxy, C1-C3
alkylcycloalkyl, amino, -N(C1-C3 alkyl)2, and (CH2)nC(O)NR6R6.
3. A compound as claimed in claim 1 wherein R1 is chloro, methoxy, amino, or -
N(CH3)2.

4. A compound as claimed in Claim 1 wherein the group L1 is a bond or a divalent
linker selected from the group consisting of:- -C(O)-, -CH2-, -CH2CH2-,
-CH2CH2CH2, -NHCH2CH2, -N(CH3)CH2CH2, -OCH2, -OCH2CH2, -OCH2CH2CH2, and -
acetyleneCH2-CH2-.
5. A compound as claimed in Claim 1 wherein Ar1 is selected from the group
consisting of phenyl, benzimidazolyl, 1H-indazolyl, 2-methylindolyl, 3-methoxyphenyl, 2,3-
dimethylindolyl, 1-methylindolyl, benzo-l,4-oxazin, 4-methylquinolinyl-6yl, 2,3-dihydroindolyl,
oxazolyl, and 3-chlorophenyl.
6. A compound as claimed in Claim 6 wherein said Ar1 group is substituted with 1
to 2 groups independently selected from C1-C3 alkyl, C1-C3 alkylamino, C1-C6 haloalkyl, halo,
C1-C3 alkoxy, and C1-C3 haloalkoxy.
7. A compound as claimed in Claim 1 wherein R3 and R4 combine with the nitrogen
atom to form an optionally substituted pyridinyl, piperidinyl, pyrrolidinyl, imidazolidinyl,
pyrazolinyl, piperazinyl, thiazolyl, piperidinyl, and morpholinyl.
8. A compound as claimed in Claim 8 wherein said optional substituent is selected
from the group consisting of C1-C3 alkyl, C1-C3 alkylamino, C1-C3 haloalkyl, halo, C1-C3 alkoxy,
and C1-C3 haloalkoxy.
9. A compound as claimed in Claim 1 wherein R3 and R4 are independently selected
from the group consisting of C1-C6 alkyl, C1-C6 alkylamine, C1-C6 alkylNR6R6', pyrrolidinyl,
methylpyrrolidinyl, phenyl, benzyl, cyclopentyl, cyclohexyl, methylcyclopropane and
methylcyclobutane or combine with one, two, or three adjacent carbon atoms on the L group to
form a piperidinyl, pyrrolidinyl, pyridinyl, piperazinyl, imidazolidinyl, and
methylimidazolidinyl.

10. A compound as claimed in Claim 1 selected from the group consisting of:
2-(4-Chloro-phenyl)-5-{4-[2-(isopropyl-methyl-amino)-ethoxy]-3-methoxy-phenyl}-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[1-((S)-pyrrolidine-3-carbonyl)-2,3-dihydro-1H-indol-5-yl]-6,7-dihydro-
5H-thiazolo [5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
5-[3-Methoxy-4-(3-methyl-3H-imidazol-4-ylmethoxy)-phenyl]-2-(4-trifluoromethoxy-phenyl)-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-{2-[methyl-(1-methyl-piperidin-4-yl)-amino]-benzooxazol-5-yl}-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
5-[3-Methoxy-4-(3-methyl-3H-imidazol-4-ylmethoxy)-phenyl]-2-(4-methoxy-phenyl)-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Methoxy-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo [5,4-c] pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-{3-methoxy-4-[2-(3-oxo-morpholin-4-yl)-ethoxy]-phenyl}-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(2-pyrrolidin-1-yl-ethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(2,4-Dichloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzooxazol-5-yl}-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-{4-[2-(cyclohexyl-methyl-amino)-ethoxy]-3-methoxy-phenyl}-6,7-
dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(3-dimethylamino-propoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,

2-(4-Chloro-phenyl)-5-[4-methyl-2-(2-morpholin-4-yl-ethylamino)-quinolin-6-yl]-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(2-dimethylamino-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-6,7-dihydro-5H-thiazolo[5,4-
c]pyridin-4-one, 2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-
thiazolo[5,4-c]pyridin-4-one
2-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Methoxy-phenyl)-5-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[1-methyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indol-6-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
5-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-trifluoromethoxy-phenyl)-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[4-(2-dimethylamino-ethoxy)-3-methoxy-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-methyl-3H-imidazol-4-ylmethoxy)-phenyl]-5H-
thiazolo[5,4-c]pyridin-4-one,

2-(4-Chloro-phenyl)-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-6,7-dihydro-5H-thiazolo[5,4-
c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-{4-[2-(2,2-dimethyl-morpholin-4-yl)-ethoxy]-3-methoxy-phenyl}-5H-
thiazolo[5,4-c]pyridin-4-one,
5-[4-(2-Dimethylamino-ethoxy)-3-methoxy-phenyl]-2-(4-methoxy-phenyl)-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[1-methyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indol-6-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-chloro-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[2-methyl-1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-5-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
5-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-trifluoromethyl-phenyl)-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-{3-methoxy-4-[2-(2,2,6,6-tetramethyl-morpholin-4-yl)-ethoxy]-phenyl}-
5H-thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-benzoimidazol-5-yl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one,
2-(4-Chloro-phenyl)-5-[3-methoxy-4-((R)-1-morpholin-2-ylmethoxy)-phenyl]-6,7-dihydro-5H-
thiazolo[5,4-c]pyridin-4-one, 2-(4-Chloro-phenyl)-5-[2,3-dimethyl-1-(2-pyrrolidin-1-yl-ethyl)-
1H-indol-5-yl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one,
5-[4-(2-[1,4']Bipiperidinyl-l'-yl-ethoxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-
5H-thiazolo[5,4-c]pyridin-4-one,

2-(4-Chloro-phenyl)-5-[1-(2-morpholin-4-yl-ethyl)-1H-indol-5-yl]-6,7-dihydro-5H-thiazolo[5,4-
c]pyridin-4-one, or a pharmaceutically acceptable salt, enantiomer, or mixture of enantiomers
thereof.
11. A pharmaceutical composition comprising a compound as claimed in Claim 1 and
a pharmaceutically acceptable carrier and/or diluent.
12. A substituted thiazolopyridinone compound and/or a pharmaceutical composition
substantially as herein described with reference to the foregoing examples.


The present invention relates to a substituted thiazolopyridinone compound of formula I

wherein w, R1, q, p, R2, t, Ar1, L1, R3 and R4 are as defined, or a pharmaceutically
acceptable salt, solvate, or enantiomer thereof useful in the treatment, prevention or
amelioration of symptoms associated with obesity and related diseases.

Documents:

02669-kolnp-2007-abstract.pdf

02669-kolnp-2007-assignment.pdf

02669-kolnp-2007-claims 1.0.pdf

02669-kolnp-2007-claims 1.1.pdf

02669-kolnp-2007-correspondence others.pdf

02669-kolnp-2007-description complete.pdf

02669-kolnp-2007-form 1.pdf

02669-kolnp-2007-form 13.pdf

02669-kolnp-2007-form 18.pdf

02669-kolnp-2007-form 2.pdf

02669-kolnp-2007-form 26.pdf

02669-kolnp-2007-form 3.pdf

02669-kolnp-2007-form 5.pdf

02669-kolnp-2007-international publication.pdf

02669-kolnp-2007-international search report.pdf

02669-kolnp-2007-others.pdf

02669-kolnp-2007-pct request form.pdf

02669-kolnp-2007-priority document.pdf

2669-KOLNP-2007-(07-10-2011)-CORRESPONDENCE.pdf

2669-KOLNP-2007-(11-01-2012)-FORM-27.pdf

2669-KOLNP-2007-(29-11-2011)-CORRESPONDENCE.pdf

2669-KOLNP-2007-(29-11-2011)-Other Document.pdf

2669-KOLNP-2007-CORRESPONDENCE-1.1.pdf

2669-kolnp-2007-correspondence.pdf

2669-kolnp-2007-examination report.pdf

2669-kolnp-2007-form 13.pdf

2669-kolnp-2007-form 18.pdf

2669-kolnp-2007-form 26.pdf

2669-kolnp-2007-form 3.pdf

2669-kolnp-2007-form 5.pdf

2669-kolnp-2007-granted-abstract.pdf

2669-kolnp-2007-granted-claims.pdf

2669-kolnp-2007-granted-description (complete).pdf

2669-kolnp-2007-granted-form 1.pdf

2669-kolnp-2007-granted-form 2.pdf

2669-kolnp-2007-granted-specification.pdf

2669-kolnp-2007-others.pdf

2669-kolnp-2007-reply to examination report.pdf

abstract-02669-kolnp-2007.jpg


Patent Number 248983
Indian Patent Application Number 2669/KOLNP/2007
PG Journal Number 38/2011
Publication Date 23-Sep-2011
Grant Date 19-Sep-2011
Date of Filing 18-Jul-2007
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, CITY OF INDIANAPOLIS, STATE OF INDIANA
Inventors:
# Inventor's Name Inventor's Address
1 BECK, JAMES, PETER 6839 WINDEMERE DRIVE ZIONSVILLE, INDIANA 46077
2 AMEGADZIE, ALBERT, KUDZOVI 10569 CAMILLE COURT INDIANAPOLIS, INDIANA 46236
3 GARDINIER, KEVIN, MATTHEW 11874 GRAY EAGLE DRIVE FISHERS, INDIANA 46037
4 HEMBRE, ERIK, JAMES 1332 NORTH NEW JERSEY STREET INDIANAPOLIS, INDIANA 46202
5 RUBLE, JAMES , CRAIG 3595 TALLWOOD LANE GREENWOOD, INDIANA 46143
6 SAVIN, KENNETH, ALLEN 4925 KATELYN DRIVE INDIANAPOLIS, INDIANA 46228
7 WAKEFIELD, BRIAN, DAVID 8226 CRAWFORD AVENUE SKOKIE, ILLINOIS 60076
PCT International Classification Number C07D 513/04
PCT International Application Number PCT/US2005/045866
PCT International Filing date 2005-12-16
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/637,143 2004-12-17 U.S.A.