Indian Patents
Title of Invention

2-AMINOPYRIDINE ANALOGS AS GLUCOKINASE ACTIVATORS
Abstract Provided are compounds of formula 1 that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes meilitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.
Full Text GLUCOKINASE ACTIVATORS
PRIORITY OF INVENTION
[0001] This application claims priority to United States Provisional Application Number
60/785,460 that was filed on 24 March 2006, which is hereby incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] Provided are compounds that are useful in the treatment and/or prevention of diseases
mediated by deficient levels of glucokinase activity, such as diabetes mellitus, and methods of
preparing such compounds. Also provided are methods of treating diseases and disorders
characterized by underactivation of glucokinase activity or which can be treated by activating
glucokinase, comprising administering an effective amount of a compound of this invention.
BACKGROUND OF THE INVENTION
[0003] Diabetes mellitus comprises a group of syndromes characterized by an inability of the
body to produce adequate insulin or to properly use insulin. Most diabetes patients can be classified
clinically as having either insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent
diabetes mellitus (NIDDM). Nearly all forms of diabetes mellitus result from either a decrease in the
secretion and blood concentration of insulin or a decrease in the response of tissues to insulin (insulin
resistance), often associated with an elevated level of hormones (e.g., glucagon) that act contrary to
insulin. Such abnormalities give rise to changes in carbohydrate, lipid and protein metabolism. The
syndrome's hallmark is hyperglycemia; other complications can include cardiovascular disease,
retinopathy, neuropathy, nephropathy, skin disorders and gastroparesis.
[0004] Diabetes mellitus affects millions of persons worldwide, including over 18 million in
the United States. It is estimated that IDDM (Type I diabetes), which results from the body's failure
to produce insulin, accounts for 5-10% of the cases of diabetes diagnosed in the United States. The
majority of diabetes patients in the United States are diagnosed with NIDDM (Type II diabetes),.
which results from insulin resistance combined with the inability of the pancreas to secrete sufficient
insulin to overcome such resistance. Type II diabetes occurs in at least 5% of the United States
population, and in 1996 alone NIDDM affected 16 million people (Roman, S. H.; Harris, M. I.,
Endocrinology and Metabolism Clinics of North America, 1997, 26.5, 443-474). Impaired glucose
tolerance (1GT), a syndrome characterized by impaired glucose processing that presents symptoms
similar to a mild form of Type II diabetes, is even more prevalent, affecting 35 to 40 million adults in
the United States.
[0005] Diabetes is most frequently diagnosed either by the presentation of a fasting plasma
glucose of greater than or equal to 126 mg/dL on two occasions, or by an oral glucose tolerance test
(OGTT) with a 2 hour post load value of greater than 200 mg/dL plus classic symptoms such as

polydipsia, polyphagia and/or polyuria (The Expert Committee on the Diagnosis and Classification of
Diabetes Mellitus, Diabetes Care, 1998, 21, S5-19). In the case of IGT, a fasting plasma glucose of
less than 126 mg/dL but a 2-hour post-oral glucose challenge lever greater than 140 mg/dL is
observed.
[0006] A primary goal in the treatment of each of these conditions is the reduction and
control of blood glucose levels. The reduction of hyperglycemia in insulin-dependent diabetes
(IDDM) can attenuate the development of many of the attendant complications of IDDM (Diabetes
Control and Complications Trial Research Group, New England J. Med., 1993, 329, 977-986). For
example, tight control of blood glucose levels through intensive insulin therapy can reduce the
development of retinopathy, nephropathy and neuropathy by >50% each in IDDM patients. These
findings, together with the similarity of the pathologies seen in IDDM and NTDDM, suggest that
control of blood glucose levels would produce similar benefits in NIDDM patients (American
Diabetes Association, Diabetes Care, 1998, 21, S88-90), as has been reported (Ohkubo, Y., et al.,
Diabetes Res. Clin. Pract. 1995, 28, 103-117).
[0007] Several methods to treat hyperglycemia have been attempted. Patients with Type I
diabetes receive insulin. In patients with Type II diabetes, the pancreas secretes insulin, but in
insufficient amounts to overcome the intrinsic insulin resistance of the disease. The administration of
agents such as metformin (De Fronzo, R. A.; Goodman, A. M. N. Engl. J. Med., 1995, 333, 541-549;
Bailey, C. J. Biguanides and NIDDM, Diabetes Care 1992, 15, 773-784) and glitazone (PPAR
agonist class of drugs; Willson, T. M., et al., J. Med Chem. 1996, 39, 665-668) can at least partially
ameliorate insulin resistance, but these agents do not promote insulin secretion. Treatment with
certain sulfonylureas has been shown to promote insulin secretion by affecting an ion channel;
however, the increase in insulin caused by this class of drugs is not glucose dependent or even
glucose sensitive, and such treatment can actually raise the risk of overt hypoglycemia. DPP-IV
inhibitors, such as Januvia, or GLP or a GLP mimetic (such as Exedin), promote cAMP secretion at
the P-cell through an incretin mechanism, and administration of these agents promotes insulin release
in a glucose dependent manner (Vahl, T. P., D'Alessio, D. A., Expert Opinion on Invest. Drugs 2004,
13, 177-188). However, even with these potential treatments, it is difficult to achieve tight control of
blood glucose levels in NIDMM patients in accordance with the guidelines recommended by the
American Diabetes Association. Accordingly, there is significant demand for novel therapeutic
approaches that allow sufficient glycemic control.
[0008] Possible approaches to glycemic control include enhancing clearance of glucose from
the blood and increasing the rate of glucose storage or utilization. Glucose enters most cells by a
specific transport protein, where it is phosphorylated to form glucose-6-phosphate in a reaction
catalyzed by a hexokinase. Inside the cell, glucose-6-phosphate has one of several fates: it can be

broken down by the glycolytic pathway, converted into glycogen or it can be oxidized by the pentose
phosphate pathway.
[0009] Glucokinase (GK) (ATP:D-hexose 6-phosphotransferase),- one of the four types of
mammalian hexokinases (hexokinase TV), plays an essential role in blood glucose homeostasis.
Expression of glucokinase is largely localized in the liver and pancreatic p-cells, where several types
of glucokinase are expressed: these types differ in the sequence of the 15 N-terminal amino acids due
to differences in splicing, but their enzymatic properties are virtually identical. Glucokinase is also
expressed in a population of neurons in the hypothalamus.
[0010] Unlike the enzymatic activities of the other three hexokinases (I, II, III), each of
which becomes saturated at a glucose concentration of below 1 mM, glucokinase has a Km for
glucose of 8 mM, which is close to the physiological glucose level (5 mM). Thus, at lower glucose
levels, glucose is more rapidly utilized in brain, muscle and other peripheral tissues - through
conversion by a hexokinase other than glucokinase - than in the liver. At elevated glucose levels,
such as after a meal or overnutrition (the postprandial glucose level can exceed 10-15 mM),
glucokinase-mediated glucose metabolism in the liver and pancreas is accelerated. Moreover,
hexokinases I, II and III are inhibited by high concentrations of glucose-6-phosphate, lowering
glucose utilization, whereas glucokinase continues to catalyze utilization of glucose even at high
levels of glucose-6-phosphate.
[0011] In tissues where glucokinase is expressed, it plays an important role in glucose uptake
and utilization: in the p-cell, the glucose-6-phosphate produced is a necessary signal for insulin
release; in the hypothalamus glucose-6-phosphate acts as a satiety signal and might contribute to the
secretion of enteroincretins; and in the liver, where glucose-6-phosphate production by the action of
glucokinase acts as a mechanism for disposal of excessive glucose through storage as glycogen
(Printz, R. L., et al., Annu. Rev. Nutr., 1993, 13, 463-496). Glucokinase-catalyzed glucose
phosphorylation is the rate-limiting reaction for glycolysis in hepatocytes and pancreatic P-cells. In
the liver, glucokinase determines the rates of both glucose uptake and glycogen synthesis, and it is
also thought to be essential for the regulation of various glucose-responsive genes (Girard, J., et al.,
Annu. Rev. Nutr., 1997, 17, 325-352). In both liver and pancreatic p-cells, glucokinase is rate
limiting for glucose utilization, and consequently is a major component of the regulation of insulin
secretion from the p-cell and glycogen storage in the liver. The control of insulin secretion and the
control of glycogen storage are deficient in diabetes (DeFronzo, R. A., Diabetes, 1988, 37, 667-687).
[0012] The theoretical importance of glucokinase in diabetes is supported by studies of
genetic populations and genetic manipulation of animal models of NIDDM. Mutation of glucokinase
to a less active form of the kinase is the cause of the Maturity Onset of Diabetes in the Young
(MODY-2) (Froguel, P., et al., New England J. Med., 1993, 328, 697-702; Bell, G. I., et al., Annual

Rev. of Physiol., 1996, 58, 171-186). Conversely, humans with a glucokinase activation mutation
are less prone to hyperglycemia and have increased insulin secretion in response to a glucose
challenge (Christesen, H. B., et al., Diabetes, 2002, 51, 1240-1246; Gloyn, A. L, et al., Diabetes, .
2003, 52, 2433-2440; Glaser, B., et al., New England J. Med., 1998, 338, 226-230). Also, NIDDM
patients have been reported to have inappropriately low glucokinase activity. Furthermore, over
expression of glucokinase in dietary or genetic animal models of diabetes either prevents,
ameliorates, or reverses the progress of pathological symptoms in the disease (Caro, J. F., et al.,
Hormone & Metabolic Res., 1995, 27, 19-22). For these reasons, compounds that activate
glucokinase have been sought by the pharmaceutical industry.
[0013] Substituted benzyl carbamoyl, substituted heterobenzyl carbamoyl., substituted phenyl
carbamoyl, and substituted heteroaryl carbamoyl compounds have been disclosed as glucokinase
activators. See, for example, WO 03/000267, WO 03/015774, WO 04/045614, WO 04/046139, WO
05/04480, WO 05/054200, WO 05/054233, WO 05/044801, WO 05/056530, WO 03/080585, WO
04/076420, WO 04/081001,.WO 04/063194, WO 04/050645, WO 03/055482, WO 04/002481, WO
05/066145, WO 04/072031, WO 04/072066, US 6,610,846, WO 00/058293, WO 03/095438, WO
01/44216, WO 01/083465, WO 01/083478, WO 01/085706, WO 01/085707, WO 02/008209, WO
02/014312, WO 02/046173, WO 02/048106, WO 03/095438, WO 04/031179, and WO 04/052869.
These compounds either lower the Km for glucose and/or increase the Vmax of glucokinase.
SUMMARY OF THE INVENTION
[0014] The present invention relates to novel compounds that are activators of glucokinase
which are useful in the treatment of diseases and disorders that would benefit from activation of
glucokinase.
[0015] More specifically, one aspect of this invention provides compounds of Formula I

[0016] and solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof,
wherein L, Y, Z, G, R1 and R2 are as defined below.
[0017] The invention also provides pharmaceutical compositions comprising a compound of
Formula I, or a solvate, metabolite, and solvate, metabolite, salt or pharmaceutically acceptable
prodrugs thereof, and a pharmaceutically acceptable carrier.

[0018] The inventive compounds may be used advantageously in combination with other
known therapeutic agents. Accordingly, this invention also provides pharmaceutical compositions
comprising a compound of Formula I or a solvate, metabolite, or pharmaceutically acceptable salt or
prodrug thereof, in combination with a second therapeutic agent.
[0019] This invention also provides methods of preventing or treating a disease or disorder
characterized by underactivation of glucokinase or which can be treated by activating glucokinase in
a mammal, comprising administrating to said mammal one or more compounds of Formula I, or a
metabolite, solvate, or pharmaceutically acceptable salt or prodrug thereof, in an amount effective to
treat said disease or disorder. The compounds of the present invention can be used, for example, as
prophylactics or therapeutic agents for treating diseases or disorders mediated by deficient levels of
glucokinase activity, including, but not limited to, diabetes mellitus (type I and type IT), impaired
glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glycemia), as well as
other diseases and disorders characterized by underactivation of glucokinase or which can be treated
by activation of glucokinase, such as those discussed below.
. [0020] This invention also provides compounds of Formula I for use in therapy.
[0021] An additional aspect of the invention is the use of a compound of Formula I for the
preparation of a medicament for use as a glucokinase activator.
[0022] This invention further provides kits for the treatment or prevention of a disease or
disorder characterized by underactivation of glucokinase, said kit comprising a compound of Formula
I, or a solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof; a container, and
optionally a package insert or label indicating a treatment. The kits may further comprise a second
compound or formulation comprising a second pharmaceutical agent useful for treating said disease
or disorder.
[0023] This invention further includes methods of preparing, methods of separating, and
methods of purifying of the compounds of this invention.
[0024] Additional advantages and novel features of this invention shall be set forth in part in
the description that follows, and in part will become apparent to those skilled in the art upon
examination of the following specification or may be learned by the practice of the invention. The
advantages of the invention may be realized and attained by means of the instrumentalities,
combinations, compositions, and methods particularly pointed out in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0025] Reference will now be made in detail to certain embodiments of the invention,
examples of which are illustrated in the accompanying structures and formulas. While the invention
will be described in conjunction with the enumerated embodiments, it will be understood that they

are not intended to limit the invention to those embodiments. On the contrary, the invention is
intended to cover all alternatives, modifications, and equivalents which may be included within the
scope of the present invention as defined by the claims. One skilled in the art will recognize many
methods and materials similar or equivalent to those described herein, which could be used in the
practice of the present invention. The present invention is in no way limited to the methods and •
materials described. In the event that one or more of the incorporated literature and similar materials
differs from or contradicts this application, including but not limited to defined terms, tern usage,
described techniques, or the like, this application controls.
DEFINITIONS
[0026] The term "alkyl" as used herein refers to a saturated linear or branched-chain
monovalent hydrocarbon radical of one to twelve carbon atoms, wherein the alkyl radical may be
optionally substituted independently with one or more substituents described below. Examples of
alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr,
n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -
CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -
CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, TC(CH3)3), 1-peniyl (n-pentyl, -
CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-
butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l -butyl (-
CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3),
2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3XCH2CH2CH3)), 2-methyl-2-pentyl (-
C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-
CH(CH3)CH2CH(CH3)2), 3-methyl-3-perityl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-
CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dirnethyI-2-butyl (-
CH(CH3)C(CH3)3, J-heptyl, 1-octyl, and the like.
[0027] In certain embodiments, the term "alkyl" refers to a saturated linear or branched-chain
monovalent hydrocarbon radical of one to six carbon atoms, wherein the alkyl radical may be
optionally substituted independently with one or more substituents described below.
[0028] The term "alkylene" as used herein refers to a linear or branched saturated divalent
hydrocarbon radical of one to twelve carbon atoms, wherein the alkylene radical may be optionally
substituted independently with one or more substituents described herein. Examples include, but are
not limited to, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
[0029] In certain embodiments, the term "alkylene" refers to a linear or branched saturated
divalent hydrocarbon radical of one to four carbon atoms, wherein the alkylene radical may be
optionally substituted independently with one or more substituents described herein.

[0030] The term "alkenyl" as used herein refers to a linear or branched-chain monovalent
hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a
carbon-carbon sp2 double bond, wherein the alkenyl radical may be optionally, substituted
independently with one or more substituents described herein, and includes radicals having "cis" and
'trans" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited
to, ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-buten-l-yl, l-buten-2-yl, and the like.
[0031] In certain embodiments, the term "alkenyl" as used herein refers to a linear or
branched-chain monovalent hydrocarbon radical of two to six carbon atoms with at least one site of
unsaturation, wherein the alkenyl radical may be optionally substituted independently with one or
more substituents described herein, and includes radicals having "cis" and "trans" orientations.
[0032] The term "alkenylene" as used herein refers to a linear or branched divalent
hydrocarbon radical of two to twelve carbons containing at least one double bond, wherein the
alkenylene radical may be optionally substituted independently with one or more substituents
described herein. Examples include, but are not limited to, ethenylene, propenylene, and the like.
[0033] The term "alkenylene" includes-linear or branched divalent hydrocarbon radical of
two to four carbons containing at least one double bond, wherein the alkenylene radical may be
optionally substituted independently with one or more substituents described herein.
[0034] The term "alkynyl" as used herein refers to a linear or branched monovalent
hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a
carbon-carbon .sp triple bond, wherein the alkynyl radical may be optionally substituted'
independently with one or more substituents described herein. Examples include, but are not limited
to, ethynyl (-C=CH), propyny] (propargyl, -CH2C=CH) and the like.
[0035] In certain embodiments, the term "alkynyl" refers to a linear or branched monovaient
hydrocarbon radical of two to six carbon atoms with at least one carbon-carbon sp triple bond.
[0036] The term "alkynylene" as used herein refers to a linear or branched divalent
hydrocarbon radical of two to twelve carbons containing at least one triple bond, wherein the
alkynylene radical may be optionally substituted independently with one or more substituents
described herein. Examples include, but are not limited to, ethynylene, propynylene, and the like.
[0037] In certain embodiments, the term "alkynylene" refers to a linear or branched divalent
hydrocarbon radical of two to four carbons containing at least one triple bond.
[0038] The terms "cycloalkyl," "carbocycle," "carbocyclyl" and "carbocyclic ring" are used
interchangeably and refer to a saturated or partially unsaturated cyclic hydrocarbon radical having
from three to twelve carbon atoms. The term "cycloalkyl" includes monocyclic and polycyclic (e.g.,
bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclic structures optionally include a

saturated or partially unsaturaled cycloalkyl fused to a saturated, partially unsaturated or aromatic
cycloalkyl or heterocyclic ring. Examples of cycloalkyl groups include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, and the like. Bicyclic carbocycles include those having 7 to 12 ring atoms arranged,
for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or as bridged systems such as
bicyclo[2.2.I]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The cycloalkyl may be
optionally substituted independently with one or more substituents described herein.
[0039] "Aryl" as used herein means a monovaJent aromatic. hydrocarbon radical of 6-20
carbon'atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent
aromatic ring system. Aryl includes bicyclic radicals comprising an aromatic ring fused to a
saturated, partially'unsaturated ring, or aromatic carbocyclic or heterocyclic ting. Exemplary aryl
groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene,
biphenyl, indene, indane, 1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthalene, and the like. Aryl
groups may be optionally substituted independently with one or more substituents described herein.
[0040] The terms "heterocycle", "hetercyclyl" and "heterocyclic ring" as used herein are used
interchangeably and refer to a saturated or partially unsaturated carbocyclic radical of 3 to 12 ring
atoms in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen
and sulfur, the remaining ring atoms being C, where one or more ring atoms may be optionally
substituted independently with one or more substituents described below. The radical may be a
carbon radical or heteroatom radical. The term "heterocycle" includes heterocycloalkoxy.
"Heterocyclyl" also includes radicals where heterocycle radicals are fused with a saturated, partially
unsaturated, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclicrings include, but
are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,
thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homapiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-
pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-
azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indoIyl quinolizinyl and N-pyridyl ureas.
Spiro moieties are also included within the scope of this definition. The heterocycle may be C-
attached. or N-attached where such is possible. For instance, a group derived from pyrrole may be
pyrrol-1 -yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be
imidazol-1-yl (N-attached) or imidazol-3-yl (C-attaehed). Examples of heterocyclic groups wherein
2 ring carbon atoms are substituted with oxo (=O) moieties are isoindoline-l,3-dionyl and 1,1-dioxo-

thiomorpholinyl. The heterocycle groups herein are unsubstituted or, as specified, substituted in one
or more substitutable positions with various groups described herein.
[0041] In certain embodiments, the term "heterocycle" includes bridged heterocycles.
[0042] The term "heteroaryl" as used herein refers to a monovalent aromatic radical of a 5-,
6-, or 7-membered ring, and includes fused ring systems (at least one of which is aromatic) of 5-12
atoms, containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur.
Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl,
irnidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,
thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,
benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and
furopyridinyl. Spiro moieties are also included within the scope of this definition. Heteroaryl groups
may be optionally substituted independently at one or more substitutable positions with one or more
substituents described herein. Particular examples of heteroaryl groups include thiazolyl,
thiadiazolyl, oxadiazolyl, oxazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-b]pyrazinyl, and
thiazolo[5,4-e][1,2,4]triazine.
[0043] By way of example and not limitation, carbon bonded heterocycles and heteroaryls
are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4,
5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,
tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,. position 2, 4, or 5 of an oxazole,
imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an
aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1,
3, 4, 5, 6, 7, or 8 of an isoquinoline. Further examples of carbon bonded heterocycles include 2-
pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-
pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-
pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
[0044] By way of example and not limitation, nitrogen "bonded heterocycles and heteroaryls
are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline,
imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-
pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of an isoindole, or
isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or -carboline. Still more
typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1 -pyrrolyl, 1-imidazolyl, 1-
pyrazolyl, and 1-piperidinyl.
[0045] The term "halogen" as used herein means fluoro, chloro, bromo or iodo.

[0046] The term "a" as used herein means one or more.
[0047] As used herein, the terms "compound of this invention," "compounds of the present
invention" and "compounds of Formula I" include compounds of Formula I and tautomers, resolved
enantiomers, resolved diastereomers, racemic mixtures, solvates, metabolites, salts and prodrugs
thereof, including pharmaceutically acceptable salts and prodrugs.
[0048] In general, the various moieties or functional groups of the compounds of this
invention may,be optionally substituted by one or more substituents. Examples of substituents
suitable for purposes of this invention include, but are not limited to, oxp, halogen, CN, nitro,
trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
azido, Vn-NR"SOaR1, Vn-SOaNR-R", Vn-C(=O)Rt, Vn-C(=O)OR(, Vn-OC(=O)R', Vn-NR"C(=O)OR',
Vn-NR"C(=O)R', Vn-C(=O)NR'R", Vn-NR"T, Vn-NR"'C(=O)N'R", Vn-OR', Vn-SR', Vn-S(O)R', Vn-
S(O)2R', alkyl, alkenyl, alkynyl, Vn-cycloalkyl; Vn-heterocyclyl, Vn-aryl, and Vn-heteroaryl, where R1,
R" and R"' are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
[0049] It is to be understood that in instances where two or more radicals are used in
succession to define a substituent attached to a structure, the first named radical is considered to be
terminal and the last named radical is considered to be attached to the structure in question. Thus, for
example, an arylalkyl radical is attached to the structure in question by the alkyl group.
GLUCOKINASE ACTIVATORS
[0050] The present invention provides compounds, and pharmaceutical formulations thereof,
that are useful in the treatment of diseases, conditions and/or disorders characterized by
underactivation of glucokinase or which can be treated by activation of glucokinase.
[0051] One aspect of the invention provides compounds of Formula I

and tautomers, resolved enantiomers, resolved diastereomers, racemic mixtures, solvates,
metabolites, salts and pharmaceutically acceptable prodrugs thereof, wherein:
[0052] L is O, S, C(=O) or CHR14;
[0053] Y is N or CR4;
[0054] Z is N or CR3, wherein at least one of G or Z is not N;
[0055] G is N or CR11;
[0056] R1 is a heteroaryl ring represented by the formula


[0057] D1 is S, O, or N;
[0058] D2 is N or CR12;
[0059] D3 is S,O or CR13;
[0060] R2 is aryl, hetcroaryl, saturated or partially unsaturated cycloalkyl, or saturated or
partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are
monocyclic or bicyclic and arc optionally substituted with one or more groups independently selected
from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6 cycloalkyl,
saturated and partially unsaturated C1-C6 heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF3, CN, NO2,
OR6, C(=O)R6, C(=O)0R6, OC(=O)R6, O(CH2)nC(=O)OR6, 0(CH2)nC(=0)NR6R7, C(-O)NR6R7,
NR6R7, NR6C(=O)R7, SR6, S(O)R6, and S(O)2R6, and wherein said alkyl, alkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups
independently selected from oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially
unsaturated C3-C6 Vn-cycloalkyl, saturated and partially unsaturated C1-C6 Vn-heterocyclyl, Vn-aryl,
Vn-hcteroaryl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)R8, Vn-C(=O)OR8, Vn-
OC(=O)R8, Vn-C(=O)NR8R9, Vn-NR8R9, V0-NR8C(=O)R9, Vn-SR8, Vn-S(O)R8, and Vn-S(O)2R8;
[0061] R3 is H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, saturated or partially
unsaturated C3-C12 cycloalkyl, saturated or partially unsaturated C1-C12 heterocyclyl, aryl, hetcroaryl,
F, Cl, Br, I, CN, OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7, OC(=O)NR6R7,
OC(=S)NR6R7, NR6R7, NR6C(=O)R7, SR6, S(O)R6, S(O)2R6 or S(O)2NR6R7, wherein said alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or
more groups independently selected from oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated
and partially unsaturated C3-C4 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-
aryl, Vn-heteroaryl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)R8, VB-(=0)OR;
Vn-OC(=O)R; Vn-C(=O)NR8R9, V0-NR8R9, Vn-NR8C(=O)R9, Vn-SR8, Vn-S(O)R8, Vn-S(O)2R8 and
Vn-S(O)2NR8R9;
[0062] R4 is H, methyl, ethyl, F, Cl, Br, I, CF3, CHF2 or CH2F;
[0063] R6 and R7 are independently H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, saturated
or partially unsaturated C3-C12 cycloalkyl, saturated or partially unsaturated C1-C12 heterocyclyl, Vo-
aryl or Vn-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl portions are optionally substituted with one or more groups independently selected from
CF3, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6

cycloalkyl,. saturated and partially unsaturated C1-C6 heterocyclyl optionally substituted with
C(O)O(1-6C alkyl), (l-6C)alkyl or (1-6C alkyl)OH], Vn-aryl, Vn-heteroaryl, Vn-F, Vn-Cl, Vn-Br, Vn-
I, Vn-CF3,.Vn-CN, Vn-OR8, Vn-C(=O)R83 Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-C(=O)NR8R9, Vn-NR8R9,
Vn-NR8C(=O)R9, Vn-SR8, Vn-S(O)R8, Vn-S(O)2R8, Vn-S(O>2NR8R9, and (C,-C6 alkyl)OH;
[0064] or R6 and R7 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or
more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic
ring is optionally substituted with one or more groups independently selected from oxo, Vn-F, Vn-Cl,
Vn-Br, Vn-I, Vn-OR8, Vn-C(=O)OR8, Vn-C(=O)NR8R9, Vn-NR8R9, Vn-NR8C(=O)R9, Vn-
NR8C(=O)NR9R10, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
[0065] R8, R9 and R10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
saturated and partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6
heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl
and heteroaryl are optionally substituted with one or more groups independently selected from oxo,
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6 cycloalkyl,
saturated and partially unsaturated C1-C6 heterocyclyl, Vn-aryl, Vn-heteroaryl, Vr-F, Vn-Cl, Vn-Br, Vn-
1, Vn-ORa, Vn-NRaRb, Vn-C(=O)ORa, Vn-C(=O)NRaRb, and Vn-NRaC(=O)Rb,
[0066] or R8 and R9 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or
more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic
ring is optionally substituted with one or more groups independently selected from oxo, C1-C6 alkyl,
C2-C6 alkenyl, C2-C6 alkynyl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-ORa, and Vn-CN,
[0067] or R9 and R10 together with the atoms to which they are attached form-a saturated or
partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or
more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic
ring is optionally substituted with one or more groups independently selected from oxo.Ci-Ce alkyl,
C2-C6 alkenyl, C2-C6 alkynyl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-ORa, and Vn-CN;
[0068] R1' is H, methyl, ethyl, F, Cl, Br, I, CF3, CHF2, CH2F, OH, O-(C1-C4 alkyl), or NH2;
[0069] R12 and R13 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated
and partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl,
CH2-heterocyclyl, aryl, heteroaryl, (1-3C alkyl)heteroaryl, (CH2)n(CRxRy)C(O)NR8R9, F, Cl, Br, I,
CF3, CN, OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6, S(O)R6,
S(O)2R6, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are
optionally substituted with one or more groups independently selected from oxo, Vn-F, Vn-Cl, Vn-Br,

Vn-I, Vn-CF3, Vn-CN, .Vn-OR8, Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-C(=O)NR8R9-; Vn-NR8R9, Vn-
NR8C(=O)R9, C(O)(C1-C6 alkyl), C(O)-heterocycle [optionally substituted with O-(C1-C6 alkyl], SRa,
SO2Rf, SO2NR°Re, C(O)(C,-C6 alkyl)NRcRdd, C(O)(C1-C6 alkyl)ORc, C(O)CH2C(O)(C1-C6 alkyl),
C(=O)CHR8NHC(=O)(C1-C6 alkyl), C(=0)CH2OC(=0)(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, saturated and partially unsaturated C3-C6 cycloalkyl, saturated and partially
unsaturated C1-C6 heterocyclyl, Vn-aryl, and Vn-heteroaryl, wherein said heterocyclyl is optionally
substituted with one or more oxo,
[0070] or R12 and R13 together with the atoms to which they are attached form a saturated,
partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein said carbocyclic and
heterocyclic rings are optionally substituted with one or more groups independently selected from C1-
C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6 cycloalkyl, saturated
and partially unsaturated C1-C6 heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br, I, CF3, CN, OR6,
C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6, S(O)R6, S(O)2R6 and
SO2NR6R7, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are
optionally substituted with one or more groups independently selected from oxo, Vn-F, Vn-Cl, Vn-Br,
Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-C(=O)NR8R9, Vn-NR8R9, Vn-
NR8C(=O)R9, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6
cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-aryl, and Vn-heteroaryl;
[0071] R14 is H, methyl, ethyl or OH;
[0072] Ra and Rb are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated
and partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-
aryl, or Vn-heteroaryl, wherein said alkyl, alkenyl, alkynyl, saturated or partially unsaturated Vn-
cycloalkyl, saturated or partially unsaturated Vn-heterocyclyl, Vn-aryl, and Vn-heteroaryl are
optionally substituted with one or more OH;
[0073] each Rc, Re and Rs is independently H or C1-C6 alkyl;
[0074] Rd is H,'C1-C6 alkyl or C(O)O(C1-C6 alkyl);
[0075] Rf is C1-C6 alkyl or (C1-C6 alkyl)NH2;
[0076] Rx is H or C1-C6 alkyl;
[0077] Ry is H, C1-C6 alkyl, or -O(C1-C6 alkyl);
[0078] V is alkylene having from 1 to 12 carbons, or alkenylene or alkynylene each having
from 2 to 12 carbons, wherein said alkylene, alkenylene, or alkynylene are optionally substituted with
one or more groups independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated
and partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl,

aryl, heteroaryl, F, Cl, Br, I, CF3, cyano, OR8, C(=O)OR8, OC(=O)R8, C(=O)NR8R9, NRSR9, (C1-C6
alkyl)NRcR, and NR8C(=O)R9; and
[0079] n is O or l.
[0080] In certain embodiments, R6 and R7 arc optionally substituted with one or more groups
independently selected from oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially
unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-aryl, Vn-
heteroafyl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)R8, Vn-C(=O)OR, Vn-
OC(=O)R8, Vn-C(=O)NR8R9, Vn-NR8R9, Vn-NR8C(=O)R9, VO-SR8, Vn-S(O)RS, Vn-S(O)2R8, and Vn-
S(O)2NTR8R9.
[0081] In certain embodiments, R12 and R1 J are independently H, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, saturated and partially unsaturated C3-C6 cycloalkyl, saturated and partially
unsaturated C1-C6 heterocyclyi, aryl, heteroaryl, F, Cl, Br, I, CF3, CN, OR6, C(=O)R6, C(=O)OR6,
OC(=O)R6, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6, S(O)R6 or S(O)2R6, wherein said alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or
more groups independently selected from oxo, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-OR8,
VB-C(=O)OR8, Vn-OC(=O)R8, Vn-C(=O)NR8R9, Vn-NR8R9, Vn-NR8C(=O)R9, C,-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6 cycloalkyl, saturated and partially
unsaturated C1-C4 hcterocyclyl, Vn-aryl, and Vn-heteroaryl, wherein said heterocyclyl is optionally
substituted with one or more oxo.
[0082] In certain embodiments of compounds of Formula I, G is R".
[0083] In certain embodiments of compounds of Formula I, RM is hydrogen.
[0084] In certain embodiments of compounds of Formula I, Y is N.
[0085] In other embodiments, Y is CR4. In certain embodiments, R4 is H.
[0086] In certain embodiments of compounds of Formula I, L is O.
[0087] In certain embodiments of compounds of Formula I, L is S.
[0088] In certain embodiments of compounds of Formula I, L is CUR14. In certain
embodiments, R14 is H.
[0089] The compounds of Formula I include compounds having the Formula la:


and tautomers, resolved enantiomers, resolved diastereomers, racemic mixtures, solvates,
metabolites, salts and pharmaceutically acceptable prodrugs thereof, wherein:
[0090] L is O,S,or CH2;
[0091] Y is N or CH;
[0092] D2 is N or CR12;
[0093] R2 is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, or saturated or
partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are
monocyclic or bicyclic and are optionally substituted with one or more groups independently selected
from C1-C6 alkyl, (C1-C6 alkyl)OH, C1-C6 heterocyclyl, F, Cl, Br, CF3, CN, NO2, OR6, C(=O)R6,
C(=O)OR6, C(=O)NR6R7, S(O)2R6, C(O)CH2NH2, and C(O)CH2NRaRb;
[0094] R3 is H, C1-C12 alkyl, aryl, heteroaryl, F, Cl, Br, OR6,or SR6S wherein said alkyl, aryl
and heteroaryl are optionally substituted with one or more groups independently selected from C1-C6
alkyl, C2-C6 alkenyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-OR8, Vn-C(=O)OR8,
and Vn-NR8R9;
[0095] R6 and R7 are independently H, C1-C12 alkyl, saturated or partially unsaturated C3-C12
cycloalkyl, saturated or partially unsaturated C1-C6 heterocyclyl, Vn-aryl, or Vn-heteroaryl, wherein
said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl portions are optionally substituted with one or
more groups independently selected from C1-C6 alkyl, saturated and partially unsaturated C1-C6
heterocyclyl [optionally substituted with C(O)O(C1-C6 alkyl) or (C1-C6 alkyl)OH], aryl, heteroaryl,
F, Cl, Br, I, CN, OR8, C(=O)R8, C(=O)OR8, C(=O)NR8R9, NR8R9, NR8C(=O)R9 or (C1-C6 alkyl)OH,
[0096] or R6 and R7 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or
more additional ring heteroatoms independently selected from N, O or S;
[0097] R8, R9 and R10 are independently H, C1-C6 alkyl, or saturated and partially
unsaturated C1-C6 heterocyclyl, wherein said alkyl and heterocyclyl are optionally substituted with
one or more groups independently selected from C1-C6 alkyl, saturated and partially unsaturated C1-
C6 heterocyclyl, ORa, NR, C(=O)ORa and C(=O)NRaRb,
[0098] or R8 and R9 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring;
[0099] or R9 and R10 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring;
[00100] R12 is H or C,-C6 alkyl;
[00101] R13 is H, C1-C6 alkyl, saturated and partially unsaturated C3-C6 cycloalkyl, saturated
and partially unsaturated C1-C6 heterocyclyl, CH2-heterocyclyl, aryl., heteroaryl, (1-3C

alkyl)heteroaryl, or (CH2)n(CRxRy)C(O)NR8R9, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, CH2-
heterocyclyl, heterocyclyl, aryl, heteroaryland (1-3C alkyl)heteroaryl are optionally substituted with
one or more groups independently selected from oxo, F, Cl, CF3, CN, OR8, C(=O)OR8, C(=O)NR8R9,
NR8R9, C(O)(Ci-C6 alkyl), C(0)-heterocycle [optionally substituted with O-(C1-C6 alkyl) or oxo),
SRa, SO2Rf, SO2NRcRe, C(O)(C1-C6 alkyl)NRcRdd, C(O)(C1-C6 alkyl)ORc, C(O)CH2C(O)(C1-C6
alkyl), C(=O)CHRgNHC(=O)(C1-C6 alkyl), C(=O)CH2OC(=O)(C1-C6 alkyl), C1-C6 alkyl, 5-6
membered heterocycle (optionally substituted with oxo) and aryi,
[00102] or R12 and R13 together with the atoms to which they are attached form an heteroaryl
ring;
[00103] Ra and Rb are independently H, C1-C6 alkyl, saturated or partially unsaturated C1-C6
heterocyclyl;
[00104] each Rc, Re and RE is independently H or C,-C6 alkyl;
[00105] Rd is Hs C1-C6 alkyl or C(O)O(C1-C6 alkyl);
[00106] Rf is C1-C6 alkyl or (C1-C6 alkyl)NH2;
[00107] V is alkylene having from 1 to 4 carbons, or alkenylene having from 2 to 4 carbons,
wherein said alkylene and alkenylene are optionally substituted with C1-C6 alkyl, O(C1-C6 alkyl), or
(C1-C6 alkyl)NRcRe; and
[00108] n is O or 1.
[00109] Exemplary embodiments of R1 include, but are not limited to, heteroaryl rings
selected from

[00110] wherein R20 is H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated
cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF3, CN,
OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6, S(O)R6, S(O)2R6
or SO2NR6R7, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are
optionally substituted with one or more groups independently selected from oxo, Vn-F, Vn-Cl, Vn-Br,
Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-C(=O)NR8R9, Vn-NR8R9, Vn-

Nk8C(=O)R9, alkyl, alkenyl, alkynyl, saturated and partially unsaturated Vn-cycloalkyl, saturated and
partially unsaturated Vn-heterocyclyl, Vn-aryl, and Vn-heteroaryl,
[00111] and each R20 is independent of the other.
[00112] In certain embodiments, R1 is

[00113] wherein R12 and R13 are as defined herein.
[00114] In particular embodiments, R20 is H.
[00115] In other embodiments, R1 is
[00116] In certain embodiments, R12 and R13 are independently selected from H, alkyl, or
cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted. For example, in certain
embodiments R12 and R13 are independently selected from H, methyl, ethyl, isopropyl, butyl,
isobutyl, cyclopropyl, CH2CH2COOMe, CH2COOH, and CH2CH2COOH.
[00117] In certain embodiments, R12 is H or C1-C6 alkyl.
[00118] In certain embodiments, R12 is H.
[00119] In other embodiments, R13 is selected from H, C1-C6 alkyl, cycloalkyl, heterocyclyl,
CHj-heterocyclyl, aryl, heteroaryl, (1-3C alkyl)heteroaryl, or (CH2)m(CRxRy)C(O)NR8R9, wherein
said alkyl, cycloalkyl, heterocyclyl, CH2-heterocyclyl, aryl, heteroaryl, and (1-3C a1kyl)heteroaryl
are optionally substituted with one or more groups independently selected from oxo, F, Cl, CF3, CN,
OR8, C(=O)OR8, C(O)NR8R9, NR8R9, C(O)(C1-C6 alkyl), C(O)-hetcrocycle [optionally substituted
with CK(C1-C6 alkyl], SRa, SO2, SO2NRcRe, C(O)(C1-C6 alkyl)NRcRdd, C(O)(C1-C6 alkyl)ORc,
C(O)CH2C(O)(C1-C6 alkyl), C(=O)CHReNHC(=O)(C1-C6 alkyl), C(=0)CH2OC(=O)(C1-C6 alkyl),
C1-C6 alkyl, C1-C6 heterocyclyl (optionally substituted with oxo), and aryl.
[00120] For example, in certain embodiments R13 is selected from H, C1-C6 alkyl, chloro(C1-
C6, alkyl), CF3, (3-6C)cycloalkyl, (C1-C6 alkyI)CN, (C1-C6 alkyl)CO2R8, (C1-C6 alkyl)SRa, (C1-C6
alkyl)SO2Rf, (C1-C6 alkyl)aryl, (C1-C6 alkyl)OR8, (C1-C6 alkyl)NR8R9, (CH2)n(CRxRy)C(O)NR8R9,
(CH2)n(CRxRy)C(O)NH-N=CHNR8R9, (C,-C6 aIkyl)C(O)-heterocyclyl, aryl, heteroaryl, (C1-C6
alkyl)hetAr', CH2(CRxRy)C(O)OR8, CH2(CRxRy)C(O)heterocyclyl [optionally substituted with one or
two groups selected from O-(C1-C6 alkyl) and oxo], CH2CH(CO2H)-CH2CH2NHR1, hetCyc1 and
CH2hetCyc2, wherein:

[00121] Rx and Ry are independently H, methyl or OMe,
[00122] n is 0 or 1,
[00123] hetCyc1 is a heterocyclic ring optionally substituted with one or more groups
independently selected from C1-C6 alkyl, C(O)(C1-C6 alkyl), (C1-C6 alkyl)OH, C(O)O(C1-C6 alkyl),
C(O)(C1-C6 alkyl)NRcRd, C(O)(C1-C6 alkyl)ORc, C(O)eH2C(O)(C1-C6 alkyl), C(O)NRaRb,
SO2NRcRe, SO2Rf, C(=O)CHRSNHC(=O)(C1-C6 alkyl), and C(=O)CH2OC(=O)(C1-C6 alkyl).
[00124] hetCyc2 is a heterocyclic ring optionally substituted with one or more groups
independently selected from C1-C6 alkyl, C(O)(C1-C6 alkyl), G(O)O(C1-C6 alkyl), and oxo, and
[00125] hetAr1 is a heteroaryl ring optionally substituted with C1-C6 alky, OH or CF3,
[00126] and RB, Rb, Rc, Rd, Re and Rf are as defined herein.
[00127] Examples of R13 when represented by C1-C6 alkyl include methyl, ethyl, isopropyl,
isobutyl, and butyl.
[00128] Examples R13 when represented by chloro(C1-C6 alkyl) include alkyl groups wherein
any one of the hydrogens is replaced with a chloro group. A particular example is CH2Cl.
[00129] Examples of R13 when represented by (3-6C)cycloalkyl include cycloalkyl and
cyclohexyl.
[00130] Examples of R13 when represented by (C1-C6 alkyl)CN include alkyl groups wherein
any one of the hydrogens is replaced with a nitrile group. A particular example is CH2CN.
[00131] Examples of R13 when represented by (C1-C6 alkyl)CO2R8 include alkyl groups
wherein any one of the hydrogens is replaced with a CO2R8 group. In certain embodiments, R8 is H
or C1-C6 alkyl. Particular values of R13 include CH2CH2CO2H, CH2CH2CO2Me, CH2CO2H,
C(CH3)2CO2H, CH2C(CH3)2CO2H, and C(CH3)2CH2CO2H.
[00132] Examples of R13 when represented by (C1-C6 alkyl)SRa include alkyl groups wherein
any one of the hydrogens is replaced with a SRa group. In certain embodiments, Ra is C1-C6 alkyl,
aryl or heteroaryl. Examples of heteroaryl groups include 5-membered rings having 1-3 atoms
independently selected from N and O (provide the ring does not contain an O-O bond). In certain
embodiments, the heteroaryl is substituted with C1-C6 alkyl. Particular values of R12 and R13 when
represented by (C1-C6 alkyl)SRa include CH2CH2SMe, CH2SPh and CH2-S-(2-methyl-l,3,4-
oxadiazol-5-yl).
[00133] Examples of R13 when represented by (C1-C6 alkyl)SO2Rf include alkyl groups
wherein any one of the hydrogens is replaced with a SO2Rf group. In certain embodiments, Rf is (C1-
C6 alkyl). Particular values of Rn and R13 include CH2CH2SO2Me.
[00134] Examples of R13 when represented by (C1-C6 alkyl)aryl include CH2Ph and
CH2CH2Ph.

[00135] Examples of R13 when represented by (C1-C6 alkyl)OR8 include alkyl groups wherein
any one of the hydrogens is replaced with a OR8 group. In certain embodiments, R8 is aryl or
heteroaryl: Examples of heteroaryl groups include 5-membered rings having 1-3 atoms
independently selected from N and O (provide the ring does not contain an O-O bond). In certain
embodiments, the heteroaryl ring is substituted with one or more groups independently selected from
C1-C6 alkyl and CF3. Particular values of R13 when represented by (C1-C6 alkyl)OR8 include CH2OPh
and CH2O-(l-methyl-3-(trifluoromemyl)-l.H-pyrazol-5-yl).
[00136] Examples of R13 when represented by (C1-C6 alkyl)NR8R9 include alkyl groups
wherein any one of the hydrogens is replaced with a NR8R9 group. In certain embodiments, R8 is H
or methyl and R9 is aryl or heteroaryl. Examples of heteroaryl groups include 5-membered rings
having 1-3 atoms independently selected from N and O (provide the ring does not contain an O-O
bond). In certain embodiments, the heteroaryl ring is substituted with C1-C6 alkyl. Particular values
of R12 and R13 when represented by (C1-C6 alkyl)NR8R9 include CH2NHPh and CH2NH(2-methyl-
1,3,4-oxadiazol-5-y 1).
[00137] In certain embodiments, R13 are an alkyl group that is substituted with two or three
groups independently selected from C1-C6 alkyl, O(C1-C6 alkyl) and NR8R9. In one embodiment, R12
and R13 can be represented by the formula (CH2)n(CRxRy)C(O)NR8R9 wherein Rx and Ry are
independently H, Me or OMe and n is 0 or 1.
[00138] Examples of R13 when represented by (CH2)n(CRxRy)C(O)NR8R9 include groups
wherein R8 and R9 are independently H or (C1-C6 alkyl), and Rx and Ry are H. Particular values
include CH2CH2C(O)NHMe, CH2CH2C(O)NMe2, CH2C(O)NHMe, and CH2C(O)NMe2.
[00139] Additional examples of R13 when represented by (CH2)n(CRxRy)C(O)NR8R9 include
groups wherein R8 is H or Me, R9 is (C1-C6 alkyl)OH or (C1-C6 alkyl)O(C1-C6 alkyl), Rx is H or Me,
and Ry is H, Me, or OMe. Particular values include CH2CH2C(O)NHCH2CH2OMe,
CH2CH2C(O)NHCH2CH2OH, CH2C(O)NHCH2CH2OMe, CH2C(O)NHCH2CH2OH,
CH2C(CH3)2C(O)NHCH2CH2OH, CH2C(CH3)(OMe)C(O)NHCH2CH2OH, and
CH2C(CH3)(OMe)C(O)NHCH2CH2OMe.
[00140] Additional examples of R13 when represented by (CH2)n(CRxRy)C(O)NR8R9 include
groups wherein Rx and Ry are H, R8 is H or Me, and R9 is (C1-C6 alkyl)NRaRb. In certain
embodiments, Ra and Rb are independently H or C1-C6 alkyl. Particular values include
CH2CH2C(O)NHCH2CH2NMe2 and CH2C(O)NHCH2CH2NMe2.
[00141] Examples of 13 when represented by (CH2)n(CRxRy)C(O)NH-N=CHNRaRb include
groups wherein Ra and Rb are independently H or C1-C6 alkyl. Particular values include
CH2C(CH3)(OMe)C(O)NH-N=CHNMe2.

[00142] Examples of R13 when represented by (C1-C6 alkyl)C(O)-heterocyclyl include alkyl
groups wherein any one of the hydrogens is replaced with a C(O)heterocyclyl moiety. In certain
embodiments, the heterocyclyl is a 5-6 membered ring having at least one nitrogen atom, for example
a pyrrolidinyl ring. Particular values include CH2CH2C(O)(pyrrolidin-l-yl) and CH2C(O)(pyrrolidin-
1-yl).
[00143] An example of R13 when represented by aryl is a phenyl group.
[00144] Examples of R13 when represented by heteroaryl include 5-6 membered heteroaryl
rings having one or two atoms independently selected from N and S. Particular values include
pyridyl and thienyl.
[00145] Examples of R13 when represented by. (C1-C6 alky)hetAr1 include alkyl groups
wherein any one of the hydrogens is replaced with a hetAr' group. In certain embodiments, hetAr1 is
a 5-6 membered heteroaryl ring having 2-4 atoms independently selected from N and O (provided the
ring does not have an O-O bond). Examples include oxazolyl, oxadiazolyl and tetrazolyl rings. In
certain embodiments, hetAr1 is substituted with C1-C6 alkyl or OH. Particular values of R13 when
represented by (C1-C6 alkyl)hetAr' include the structures:

[00146] Examples of R13 when represented by CH2(CRxRy)C(O)OR8 include groups wherein
R8 is H or C1-C6 alkyl. Particular values include CH2C(CH2)(OMe)CO2Me and
CH2C(CH2)(OMe)CO2H.
[00147] Examples of R13 when represented by CH2(CRxRy)C(0)heterocyclyl include groups
wherein the heterocyclyl is a 5-membered heterocyclyl having at least one nitrogen, for example
pyrrolidinyl. In certain embodiments the heterocyclyl is substituted with O-(C1-C6 alkyl). Particular
values include CH2C(CH2)(OMe)C(O)(pyrroIidin-l-yl) and CH2C(CH2)(OMe)C(O)-(3-
methoxypyrrolidin-1 -yl).
[00148] Examples of R13 when represented by CH2CH(CO2H)-CH3CH2NHRg include groups
wherein R8 is H or C1-C6 alkyl. Particular values include CH2CH(CO2H)-CH2CH2NH2 and
CH2CH(CO2H)-CH2CH2NHCO2-(t-butyl).

[00149] Examples of R13 when represented by hetCyc1 include groups wherein hetCyc1 is a 5-
6 membered ring having an atom selected from N and O.
[00150] An exemplary embodiment of hetCyc1 is tetrahydrofuranyl:
[00151] Further exemplary embodiments of hetCyc1 include piperidinyl and
pyrrolidinylrings.
[00152] In certain embodiments, hetCyc' is C-linked, that is, hetCyc1 is linked to'R1 through a
carbon atom of the hetCyc1 ring.
[00153] In-certain embodiments, hetCyc1 is a piperidinyl or pyrrolidinyl.ring substituted by
one or two groups independently selected from C1-C6 alkyl, C(O)(C1-C6 alkyl), (C1-C6 alkyl)OH,
C(O)O(C1-C6 alkyl), C(O)(C1-C6 alkyl)NRcRd, C(O)(C1-C6 alkyl)ORc, C(O)CH2C(O)(C1-C6 alkyl),
C(O)NRaRb, SO2NRcRe, and SO2Rf.
[00154] For example, in certain embodiments, hetCyc7 is a piperidinyl or pyrrolidinyLring
optionally substituted with one or two groups independently selected from methyl., C(O)(d-C6 alkyl),
(C1-C6 alkyl)OHs C(O)O(C1-C6 alkyl), C(O)(C1-C6 alkyl)NH(C1-C6 alkyl), C(O)(C1-C6 alkyl)NH(C1-
C6 alkyl), C(O)(C1-C6 alkyl)NHCO2(C1-C6 alkyl), C(O)(C1-C6 alkyl)OH, C(O)CH2C(O)(C1-C6 alkyl),
C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2, SO2NH2, SO2NMe2, SO2Me, SO2(C2-C6
alkyl)NH2, C(=O)CHR8NHC(=O)(C1-C6 alkyl), and C(=O)CH2OC(=O)(C1-C6 alkyl).
[00155] In certain embodiments, the substituent is on the N atom of hetCyc1.
[00156] . Particular Values for R13 when represented by hetCyc1 include the structures:



[00157] In particular embodiment of Formula I, hctCyc1 has the formula

[00158] wherein A is C(-O)(C1-C6 alkyl), C(=O)NH2, C(=O)NMe,, CC2Mc, or SO2NH2,
wherein any one of the carbons atoms of hetCyc1 is optionally substituted with methyl. Particular
values of hetCyc1 include the formulas:

[00159] Examples of R13 when represented by CH2 hetCyc2 include groups wherein hetCyc2 is
a 5-6 membered ring having one or two nitrogen atoms. Examples include piperidinyl, pyrrolidinyl
and piperazinyl groups. In certain embodiments, hetCyc2 is substituted with one or more groups
independently selected from C1-C6 alkyl, C(O)(C1-C6 alkyl), C(O)O(C1-C6 alkyl), and oxo. Particular
values for R13 when represented by CH2hctCyc2 include the structures:

[00160] In certain embodiments, R12 is H.
[00161] In certain embodiments of Formula I, R2 includes, but are not limited to, an aryl, or a
saturated or partially unsaturated cycloalkyl ring selected from phenyl, 1-naphthyl, 2-naphthyl,
1 -tctrahydronaphthalenyl, 2-tetrahydronaphthalenyl, 3-tetrahydronaphthalenyl,
4-tetrahydronaphthalenyl, 5-tetrahydronaphthalenyl, 6-tetrahydronaphthalenyl,

7-tetrahydronaphthalenyl, 8-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclohexenyl, and
substituted forms thereof.
[00162] In certain embodiments, R2 is selected from

[00163] wherein R2 is optionally substituted with one or more R20a groups, wherein R20a is
selected from alkyl, alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, saturated or
partially unsaturated heterocyclyl, aryl, heteroaryl, F, Cl, Br,1, CF3, CN, OR6, C(=O)R6, C(=O)OR6,
OC(=O)R6, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6, S(O)R6S S(O)2R6 and SO2NR6R7.
[00164] For example, in certain embodiments, R2 isphenyl optionally substituted with one or
more groups independently selected from F, Cl, Br, I, CN, alkyl, NO2, SO2R6, OR6, C(=O)OR6, and
NR6C(=O)R7, wherein said alkyl is optionally substituted with Vn-NR8R9, Vn-C(=O)ORS, or Vn-
OC(=O)R8.
[00165] In other embodiments, R2 is phenyl- optionally substituted with one or more groups
independently selected from F, Cl, Br, CN, CF3, C1-C6 alkyl, NO2, -SO2(C1-C6 alkyl), OH, -O(CC1-C6
alkyl), -CO2H, -CO2(C1-C6 alkyl), -C(O)hetercyclyl [optionally substituted with C1-C6 alkyl],
heterocyclyl and -C(O)NR8R9. In certain embodiments, R8 is H or C1-C6 alkyl and R9 is H or C1-C6
alkyl optionally substituted with NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl). Examples of the
heterocycle group for the C(O)hetercyclyl substituent of R2 include 5-6 membered heterocyclic rings
having one or two atoms selected from N and O (for example morpholinyl).
[00166] In particular embodiments of Formula I, R2 is phenyl optionally substituted with one
or two groups independently selected from F, Cl, Br, CN, CF3, NO2, SO2Me, OMe, OH, CO2H,
CO2Me, CO2Et, C(O)NHCH2CH2NMe2, C(O)NH:2, C(O)(4-methylpiperazinyl), and morpholinyl.
[00167] Exemplary embodiments of R2 include, but are not limited to, the structures:



[00169] Exemplary embodiments of R2 further include, but are not limited to, heteroaryl and
saturated or partially unsaturated heterocyclic rings selected from 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl,
2-quinoxalinyl, 3-quinoxalinyl, 5-quinoxalinyl, 6-quinoxaliriyl, 7-quinoxalinyl, 8-quinoxalinyI,
benzo[d]thiazo!-2-yl, 4-benzo[d]thiazolyl, 5-benzo[d]thiazolyl, 6-benzo[d]thiazolyU
7-benzo[d]thiazolyl, 2-l-Hr-benzo[d]imidazolyl, lif-benzofdjimidazole-4-yl, l//-benzo[d]imidazole-5-
yl, l/7-benzo[d]imidazole-6-yl, l/f-benzo[d]imidazole-7-yl, 2-thiophenyl, 3-thiophenyl,
5-tetrahydroquinolinyl, 6-tetrahydroquinolinyl, 7-tetrahydroquinolinyl, 8-tetrahydroquinolinyl,
5-tetrahydroisoquinolinyl, 6-tetrahydroisoquinolinyl, 7-tetrahydroisoquinolinyl, 8-tetrahydroiso-
quinolinyl, 1-pyrazolyl, 2-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyraz;olyl, 1-piperidinyl,

2-piperidinyi, 3-piperidinyl, 4-piperidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4-pyrrolinyl, 5-pyrrolinyl,
2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 5-piperidinyl, 6-piperidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
4-pyrrolidinyl, 5-pyrrolidinyl, and substituted forms thereof.
[00170] In other embodiments, R2 is a 5-6 membered heteroaryl ring having 1-2 nitrogen
atoms. Examples of heteroaryl rings include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2-
imidazolyl, and 4-imidazolyl. In certain embodiments, R2 is a heteroaryl ring optionally substituted
with one or two groups independently selected from C1-C6 alkyl, CO2(C1-C6 alkyl), C(O)NH(C1-C6
alkyl), C(O)NH(C1-C6 alkylN(di-C1-C6 alkyl), or (C1-C6 alkyl)OH.
[00171] In other embodiments, R2 is a 9-10 membered bicyclic heteroaryl ring having a
having 1 to 2 ring atoms independently selected from N and S.
[00172] In other embodiments, R2 is a 5 membered heterocyclic ring having at least one
nitrogen atom, for example a pyrrolidinyl ring. In certain embodiments, the heterocyclic ring is
substituted with CO2-(C1-C6 alkyl), C(O)NH(C1-C6 alkyl), C(O)CH2N(C1-C6 alkyl)2 C(O)(C1-C6
alkyl)CO2H, or SO2-(heteroaryl), wherein said heteroaryl of the SO2-heteraryol group is a 5-
membered ring having i-2 nitrogen atoms and optionally substituted with C1-C6 alkyl.
[00173] For example, in certain embodiments R2 is selected from the structures:

and substituted forms thereof.
. [00174] Further exemplary embodiments of R2 when represented by a heteroaryl ring include
the structures:



[00175] In certain embodiments of Formula I, Z. is N.
[00176] In other embodiments of Formula I, Z is CR3.
[00177] In certain embodiment, R3 is selected from halogen, C(=O)R6, SR6, OR6, heteroaryl,
alkyl, or alkenyl, wherein said heteroaryl, alkyl and alkenyl are optionally substituted.
[00178] In other embodiments, R3 is H, Br, Cl, SR6, OR6, aryl, heteroaryl, or C1-C6 alkyl,
wherein said aryl is optionally substituted with Cl and said alkyl is optionally substituted with
C(O)OR8, NR8R9, or OR8.
[00179] In certain embodiments, R3 includes Br, Cl and C(=O)H.
[00180] In certain embodiments, R3 is H.
[00181] In certain embodiments, R3 is Br.
[00182] In certain embodiments, R3 is SR6.
[00183] For example, in certain embodiments, R3 is SR6 wherein R6 is Vn-aryl, Vn-heteroaryl,
Vn-heterocyclyl, Vn-cycloalkyl or alkyl, wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl and
alkyl portions are optionally substituted. Exemplary embodiments include, but are not limited to, the
structures:



[00184] and substituted forms thereof.
[00185] In other embodiments, R3 is SR6 wherein R6 is Vn-aryl, n is 0, and aryl is phenyl
optionally substituted with one or two groups independently selected from Cl, OH, CN, CF3, CO2H,-
O(C1-C6 alkyl), -O(C1-C6 alkyl)CO2H, -O(C1-C6 alkyl)NRaRb, or -O(C1-C6 alkyl)heterocycle wherein
heterocycle is a 5-6 membered ring having a nitrogen atom. In certain embodiments, Ra and Rb are
independently H or C1-C6 alkyl.
[00186] Particular values of R3 when represented by S-(Vn-aryl) include -S-phenyl, -S-(2-
chlorophenyl), -S-(3-chlorophenyl), -S-(4-methoxyphenyl), -S-(3-hydroxyphenyl), -S-(4-
cyanophenyl), S-(4-carboxyphenyl), -S-(2-chloro-5-methoxyphenyl), -S-(3-methoxyphenyl), -S-(2,5.-
dimethoxyphenyl), -S-(2,5-dichlorophenyl), -S-(2,5-dimethylpyhenyl), -S-(2-hydroxyphenyl), -S-( 2-
trifluorornethyl-4-cyanophenyl), -S-(3-trifluoromethyl-4-cyanopheny'l), -S-(4-cyanophenyl),

[00187] In other embodiments, R3 is SR6 wherein R6 is Vn-aryl, n is 1, V is alkyl optionally
substituted with CH2CH2NRaRb, and aryl is phenyl optionally substituted with F, Cl, or O(C1-C6
alkyl). In certain embodiments Ra and Rb are independently H or alkyl.
[00188] Particular values of R3 when represented by S-(Vn-aryl) further include S-CH2-Ph, S-
CH2-(3-methoxyphenyl), S-CH2-(4-methyoxyphenyl), S-CH2-(3-chlorophenyl), S-CH2-(2-
fluorophenyl), and


[00189] In other embodiments, R3 is SR6 wherein R6 is Vn-heteroaryl, n is 1 and V is C1-C6
alkyl. In certain embodiments, V is substituted with C1-C6 alkyl. Examples of heteroaryl groups
include 5-6 membered rings having 1-2 atoms independently selected from N, S and O (provided the
ring does not contain an O-O bond). Particular examples of heteroaryl groups include pyridyl,
thiazolyl, thiadiazolyl, oxadiazolyl, and oxazolyl rings. In certain embodiments, the heteroaryl ring is
substituted with one or two groups independently selected from Cl, OH, -O(C1-C6 alkyl), C1-C6 alkyl,
(3-6C)cycloalkyl and -NHC(O)(C1-C6 alkyl). Particular values for R3 when represented by S-Vn-
heteroaryl include

[00190] In other embodiments, R3 is SR6 wherein R6 is Vn-heteroaryl, n is 1, V is C1-C6 alkyl,
and heteroaryl is a 10-membered bicyclic heteroaryl having at least one nitrogen, such as quinolinyl.
A particular value of R3 when represented by S-Vn-heteroaryl is:

[00191] In certain embodiments, R3 is -SR6 wherein R6 is Vn-heteroaryl, n is 0, and the
heteroaryl group is a 5-6 membered ring having 1-4 atoms independently selected from N and S.
Examples include pyridyl, pyrimidyl, thiazolyl, tetrazolyl, and triazolyl rings. In certain
embodiments, the heteroaryl ring is substituted with one or two groups independently selected from

Cl, CN, C1-C6 alkyl, -O(C1-C6 alkyl), -(C1-C6 alkyl)NRaRb, -(C1-C6 alkyl)CN, C(=O)O(C1-C6 alkyl),
and CF3. In certain embodiments, Ra and Rb are independently H or C1-C6 alkyl.
[00192] Particular values for R3 when represented by -S-heteroaryl include -S-(2-pyridyl), -S-
(3-pyridyl),-S-(4-pyridyl), -S-(2-pyrimidyl), -S-(6-methylpyrid-2-yl), -S-(2-chloropyrid-4-yl), -S-(2-
chloropyrimind-4-yl)," -S-(4,6-dimethylpyrimid-2-yl), -S-(4-methoxypyrimid-2-yl), -S-(2-
methoxymethylpyrimid-4-yl), -S-(4-methylthiazol-2-yl), -S-(l-(2-dimethylaminoethyl)-lH-tetrazol-
5-yl), -S-(4-methyl-4H-l,2,4-triazol-3-yl), -S-(5-cyanomethyl-4H-l,2,4-triazol-3-yl), -S-(5-
cyanopyrid-2-yl), -S-(2-cyano-3-methoxypyrid-5-yl), -S-(2-trifluoromethylpyrLd-5-yl), and -S-(2-
ethoxycarbonylpyrid-6-y 1).
[00193] In certain embodiments, R3 is represented by -S-CHR6aR6b. In certain embodiments,

[00194] wherein R& is optionally substituted with Ci-C6 alkyl, C(O)O(C1-C6 alkyl), or C1-C6
alkyl)OH. Particular values for R3 when represented by S-CHR6aR6b include:

R6b is pyridyl or pyrimidyl and R6a is piperidyl or a group having the formula,
[00195] In other embodiments, R3 is represented by S-CHR6aR b wherein R6a is a piperidyl
ring optionally substituted with C1-C6 alkyl, and R6b is C(O)O(C1-C6 alkyl), (C1-C6 alkyl)OH,
C(O)NH(C1-C6 alkyl) or C(O)NH-heterocycle. Examples of heterocycle groups include 5-6
membered rings having at least one nitrogen atom (e.g., pyrrolidinyl or piperidinyl), a 10-membered
partially unsaturated bicyclic ring having at least one nitrogen atom (e.g., tetrahydroquinolinyl), and a
. 7-membered bridged heterocyclic ring having at least one nitrogen atom (e.g., 7-
azabicyclo[2.2.1]heptyl). In certain embodiments, the heterocyclic ring is substituted with C1-C6
alkyl. Particular values for R3 when represented by S-CHR6aR6b further include:


[00196] In other embodiments, R3 is represented by S-CHR6aR6b wherein R6a is piperidyl
optionally substituted with (C1-C6 alkyl)OH, and R6b is heteroaryl. Examples of heteroaryl groups
include 5 membered rings having 1-3 atoms selected from N and O (provided the ring does not
contain an O-O bond), for example oxadiazolyl. In certain embodiments, the heteroaryl ring is
substituted with C1-C6 alkyl. A particular value of R3 when represented by S-CHR6aTR6b further
includes:

|00197] In other embodiments, R3 is represented by S-CHR6aR6b wherein R6a is piperidyl and
R66 is H or C1-C6 alkyl. Particular examples include:

[00198] In certain embodiments, R3 is SR6 wherein R6 is Vn-heteroaryl, n is 0, and the
heteroaryl group is a 9-10 membered bicyclic heteroaromatic ring having 2-3 atoms independently
selected from N, S and O (provided the ring does not contain O-O bonds). Examples include 5-6-
membered heteroaryl rings fused to 5-6 membered heteroaryl, heterocyclyl, or cycloalkyl rings.
Particular examples include thienopyridyl, thienopyrimidyl, isoxazolopyridyl, cyclopentapyridyl,
pyrazolopyrimidyl, furopyridyl, tetrahydropyridopyrimidyl, and triazolopyridyl rings. In certain
embodiments, the heteroaryl ring is substituted with one or two groups independently selected from I,
Br, C1-C6 alkyl and CO2H.


[00199] Particular values of R3 when represented by S-heteroaryl include:
[00200] In certain embodiments, R3 is SR6 wherein R6 is cycloalkyl. A particular value of
R3 is S-cyclohexyl.
[00201] In certain embodiments, R3 is SR6 wherein R6 is heterocycle. Examples of
heterocycles include 6 membered rings having at least one nitrogen atom (e.g., piperidinyl). In
certain embodiments, the heterocycle is substituted with oxo. A particular value of R3 is
[00202] In certain embodiments, R3 is SR6 wherein R6 is (C1-C6 alkyl)C(O)OR8. Examples
include alkyl groups wherein any one of the hydrogens is replaced with a C(O)OR8 moiety. In
certain embodiments, R8 is C1-C6 alkyl. A particular value of R3 is S-CH2CH2C(O)OCH3.
[00203] In certain embodiments, R3 is SR6 wherein R6 is CH2C(O)-heterocycle, CH2C(O)-
NR8(C1-C6 alkyl)NRaRb, CH2C(O)-NRs(C1-C6 alkyl)heterocycle, or (C1-C6 alkyl)NRBR9. In certain
embodiments, each R8, R9, Ra and Rb is independently selected from H and (C1-C6 alkyl). Examples
of heterocycle groups include 5-6 membered rings having 1-2 nitrogen atoms, wherein the ring is
optionally substituted with (C1-C6 alkyl). Particular values for R3 include


[00204] In certain embodiments, R3 is OR6 wherein R6 is H, alkyl, Vn-aryl, or Vn-heteroaryl,
wherein said alkyl, Vn-aryl, and Vn-heteroaryl are optionally substituted.
[00205] In other embodiments, R3 is OR6 wherein R6 is H, C1-C6 alkyl, (C1-C6 alkyl)aryl, (C1-
C6 alkyl)heterocycle, (C1-C6 alkyl)NR8R9, or phenyl optionally substituted with Br. In certain
embodiments, R8 and R9 are independently H or (C1-C6 alkyl). Examples of heterocycles include 5-6
membered rings having at least one nitrogen atom, for example piperidyl.
[00206] Exemplary embodiments of OR6 include, but are not limited to, OH3 OMe,

[00207] Further exemplary embodiments of R3 when represented by OR6 include phenoxy and
3-bromophenoxy.
[00208] In certain embodiments R3 is optionally substituted aryl or heteroaryl.
[00209] Examples of R3 when represented by an aryl group include phenyl optionally
substituted with a halogen, for example chloro. A particular example is 2-chlorophenyl.
[00210] Examples of R3 when represented by a heteroaryl group include 6 membered rings
having at least one nitrogen atom.
[00211] Exemplary embodiments include, but are not limited to, the structures:

[00212] and substituted forms thereof.
[00213] In certain embodiments R3 is optionally substituted alkyl or alkenyl.
[00214] In certain embodiments, R3 is C1-C6 alkyl, (C1-C6 alkyl)heterocycle, (C1-C1
alkyl)heteroaryl, ,(C1-C1 alkyl)OH, (C1-C1 alkyl)CO2R8, (C1-C1 alkyl)CO2(C1-C1 alkyl), (C1-C1
alkyl)NR8R9, or (C2-C6 alkenyL)CO2R8, wherein R8 and R9 are independently H or C1-C6 alkyl.
Examples of heterocyclic rings include 5-6 membered rings having one or two atoms independently

selected from N and O. Examples of heteroaryl rings include 5-6 membered rings having at least one
nitrogen atom.
[002151 Exemplary embodiments of R3 include, but are not limited to, the structures:



[00216] and substituted forms thereof.
[002171 Additional examples of R3 include CH2OH, CH2-(tetrahydro-2H-pyran-4-yl), 4-
dimethylaminobuten-1-yl, and 4-dimethylaminobutyl.
[00218] The compounds of Formula I include compounds having the Formula Ib



[00219] and salts thereof, wherein:


[00220] R13 is

[00221] A is C(=O)(C1-C6 alkyl), C(=O)NH2, C(=O)NMe2, SO2Me, or SO2NH2;
[00222] L is O or S;
[00223] Y is CH;
[00224] D2 is N or CR12;
[00225] R2 is aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted
with one or more groups independently selected from C1-C6 alkyl, F, Cl, Br, CF3, CN, OR6, C(=O)R6,
C(=O)OR6, C(=O)NR6R7, S(O)2R6, and C(O)CH2NH2,;
[00226] R3 is SR6 or OR6;
[00227] R6 is Vn-aryl or Vn-heteroaryl, wherein said aryl and heteroaryl portions are optionally
substituted with one or more groups independently selected from C1-C6 alkyl, saturated and partially
unsaturated C1-C6 heterocyclyl [optionally substituted with C(O)O(C1-C6 alkyl) or (C1-C6 alkyl)OH],

aryl, heteroaryl, F, CI, Br, I, CN, OR8, C(=O)R8, C(=0)OR8, C(=O)NR8R9, NRSR9, NR8C(=O)R9 or
(C,-C6alkyl)OH;
[00228] R7 is H or C1-C12 alkyl;
[00229] R11 is H;
[00230] R12 is H or C1-C6 alkyl;
[00231] V is alkylene having from 1 to 4 carbons, wherein said alkylene is optionally
substituted with C1-C6 alkyl, O(C1-C6 alkyl), or (C1-C6 alkyl)NRcRe;
[00232] each Rc and Re is independently H or C1-C6 alkyl; and
[00233] n is O or l.
[00234] The compounds of Formula I include compounds having the Formula Ic

[00235] and salts thereof, wherein:
[00236] R13 is
[00237] A is C(=O)(C1-C6 alkyl), C(=O)NH2, C(C=O)NH(C1-C6 alkyl), C(=O)N(C1-C6
alkyl)2, C(=O)CH(C1-C6 alkyL)N(C1-C6 alkyl)2, SO2(C1-C6 alkyl), SO2NH2, SO2NH(C1-C6
alkyl), S(C1-C6 alkyl)2 or C(O)CH(CH3)OH;
[00238] L is O;
[00239] D2 is N or CH;
[00240] R2 is aryl optionally substituted with one or more groups independently selected
from C1-C6 alkyl, F, Br, and CF3;
[00241] R3 is SR6;
[00242] R6 is aryl, hetAr8 or hetArb, wherein R6 is optionally substituted with one or more
groups independently selected from C1-C6 alkyl, Br, Cl, CF3, CN, OR8, and C(=O)OR8;
[00243] R8is C1-C6 alkyl;
[00244] hetAra is a 5-6 membered heteroaryl ring having 1-4 nitrogen atoms; and
[00245] hetArb is a 9-10 membered bicyclic heteroaromatic ring having 2-6 atoms
independently selected from N, S and O (provided the ring does not contain an O-O bond).

[00246] In one embodiment, A is selected from C(=O)(C1-C6 alkyl), C(=O)NH2,
C(=O)NMe2, C(=O)CH2NMe2, SO2Me, SO2NH2, and C(O)CH(CH3)OH.
[00247] In certain embodiments of Formula Ic, A is C(=O)(C1-C6 alkyl).
[00248] In certain embodiments of Formula Ic, A is C(=O)NH2.
[00249] In certain embodiments of Formula Ic, A is C(=O)NMe2.
[00250] In certain embodiments of Formula Ic, A is C(=O)CH2NMe2.
[00251] In certain embodiments of Formula Ic, A is SO2Me.
[00252] In certain embodiments of Formula Ic, A is SO2NH2.
[00253] In certain embodiments of Formulaic, A is C(O)CH(CH3)OH.
[00254] In certain embodiments, R2 is aryl optionally substituted with one or more groups
independently selected from C1-C6 alkyl, Br, C1, CF3, CN, OR8, and C(=O)OR8. In certain
embodiments, R2 is phenyl. Particular values for R2 include phenyl optionally substituted with
one or two groups independently selected from F, Br and CF3.
[00255] Exemplary embodiments of R2 for Formula Ic include, but are not limited to, the
structures:

[00256] In certain embodiments of Formula Ic, R3 is SR6 wherein R6 is aryl. In particular
[00257] In certain embodiments of Formula Ic, R3 is SR6 wherein R6 is hetAr1, and hetAra
embodiment, the aryl group is phenyl. In certain embodiments, the aryl group is substituted with
one or two groups independently selected from CN, CF3, and -O(C1-C6 alkyl). Particular values
of R3 when represented by S-aryl include the structures:


is a 5-6 membered heteroaryl ring having 1-4 nitrogen atoms. In particular examples, hetAr8 is a
5-6 membered ring having 1-2 nitrogen atoms. Examples include pyridyl and pyrimidyl rings.
In certain embodiments, hetAea is substitutedwith one or two groups independently selected from
Cl, CN, -O(C1-C6 alkyl), C(=O)O(C1-C6 alkyl), and CF3. Particular values for R3 for Formula Ic
when represented by S-hetAr8 include the structure:

[00258] In certain embodiments of Formula I, R3 is SR6 wherein R6 is hetArb and hetArb is
a 9-10 membered bicyclic heteroaromatic ring having 2-6 heteroatoms independently selected
from N, S and O (provided the ring does not contain an O-O bond). In particular embodiments,
hetArb is a 9-10 membered bicyclic heteroaromatic ring having 2-3 heteroatoms independently
selected from N, S and O. Examples include 5-6-membered heteroaryl rings fused to 5-6
membered heteroaryl rings. Particular examples include thienopyridyl, thienopyrimidyl,
isoxazolopyridyl, pyrazolopyrimidyl and rings. In certain embodiments, hetArb is substituted
with one or two groups independently selected from Br, Cl and C1-C6 alkyl.
[00259] Particular values of R3 for Formula Ic when represented by S- hetArb include the
[00260] The compound of Formula I also include compound of Formula Id:
structures:




[00261] and salts thereof, wherein:

[00262] R13 is
[00263] A is C(=O)(C1-C6 alkyl), C(=O)NH2, C(=O)NMe2, C(=O)CH2NMe2, SO2Me, or
SO2NH2;
[00264] D2 is N or CH;
[00265] R2 isvphenyl optionally substituted with F; and



[00266] R3 is selected from

and

[00267] Exemplary embodiments of compounds of Formula I "include, but are not limited to,
compounds of the general formulas

[00268] and substituted forms thereof, wherein L, R1, R2, R3, R4 and R11 are as defined herein.
[00269] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas


[00270] and substituted forms thereof, wherein L, R2, R3, R4, R11, R12 and R13 are as defined
herein.
[00271] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas



[00272] and substituted forms thereof, wherein L, R1, R3, R4, and R11 are as defined herein.
[00273] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas

[00274] and substituted forms thereof, wherein R1, R3, R4, and R11 are as defined herein.
[00275] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas

[00276] and substituted forms thereof, wherein R1, R3, R4, R11, R12 and R13 are as defined
herein. In certain embodiments, the phenyl ring is optionally substituted with one or more R2Oa
groups independently selected from F, Cl, Br, I, CN, C1-C12 alkyl, NO2, SO2R6, OR6, C(=O)OR6, and

NR6C(=O)R7, wherein said alkyl is optionally substituted. In certain embodiments, the phenyl group
is optionally substituted with one or more groups independently selected from Cl, OMe, CN, NO2,
C(=O)OMe, C(=O)OEt, SO2Me, and OCH2CH2NMe2. In certain embodiments, R12 is H and R13 is
selected from C1-C6 alkyl, C3-C6 cycloalkyl. and (CH2)1-2CO2R6. In certain embodiments, R13 is
methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, CH2CH2COOMe, CH2COOEt,
CH2COOH, or CH2CH2COOH.
[00277] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas

[00278] wherein R4, R6, R11, R12, R13, and R20a are as defined herein.
[00279] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas



[00280] and substituted forms thereof, wherein L, R1, R4, and R11 are as defined herein.
[00281] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas


[00282] and substituted forms thereof, wherein L, R1, R3, and R4 are as defined herein.
[00283] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas

[00284] and substituted forms thereof, wherein L, R1, R3, and R11 are as defined herein.
[00285] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas



[00286] and substituted forms thereof wherein L, R3, R4, Rn, R12 and R13 are as defined
herein.
[00287] Additional exemplary embodiment of compounds of Formula I include, but are not
limited to, compounds of the general formulas



[00288] and substituted forms thereof, wherein L, R3, R4, R11 and R20 are as defined herein,
and each R20 is independent of the other.
[00289] The compounds of this invention may possess one or more asymmetric centers; such
compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a particular compound in the specification
and claims is intended to include both individual enantiomers and diastereomers, and mixtures,
racemic or otherwise, thereof. Accordingly, this invention also includes all such isomers, including
diastereomeric mixtures, pure diastereomers and pure enantiomers of the compounds of this
invention. The term "enantiomer" refers to two stereoisomers of a compound which are non-
superimposable mirror images of one another. The term "diastereomer" refers to a pair of optical
isomers which are not mirror images of one another. Diastereomers have different physical
properties, e.g. melting points, boiling points, spectral properties, and reactivities.

[00290] The compounds of the present invention may also exist in different tautomeric forms,
and all such forms are embraced within the scope of the invention. The term "tautomer" or
"tautomeric form" refers to structural isomers of different energies which are interconvertible by a
low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include
interconversions by migration of a proton, such as keto-enol and imine-enamine isomerizations.
Valence tautomers include interconversions by reorganization of some of the bonding electrons.
[00291] In the structures shown herein, where the stereochemistry of any particular chiral
atom is not specified, then all stereoisomers are contemplated and included as the compounds of the
invention. Where stereochemistry is specified by a solid wedge or dashed line representing a
particular configuration, then that stereoisomer is so specified and defined.
[00292] In addition to compounds of Formula I, the ' invention also includes solvates,
pharmaceutically acceptable prodrugs, and salts of such compounds.
[00293] A "solvate" refers to an association or complex of one or more solvent molecules and
a compound of the invention. Examples of solvents that form solvates include, but are not limited to,
water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolarnine. The term
"hydrate" can also be used to refer to a complex wherein the solvent molecule is water.
[00294] A "prodrug" is a compound that may be converted under physiological conditions or
by solvolysis to the specified compound or to a salt of such compound. Prodrugs include compounds
wherein an amino acid residue, or a polypeptide chain of two or more amino acid residues, is
covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group
of a compound of the present invention. The amino acid residues include but are; not limited to the 20
naturally occurring amino acids commonly designated by three letter symbols and also includes
phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine,
isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine,
l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine. 3-methylhistidine,
norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, methyl-
alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone
and tert-butylglycine.
[00295] Additional types of prodrugs are also encompassed. For instance, a free carboxyl
group of a compound of Formula I can be derivatized as an amide or alkyl ester. As another
example, compounds of this invention comprising free hydroxy groups may be derivatized as
prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester,
hemisuccinate, dimethylaminoacetate, or phosphoryldxymethyloxycarbonyl group, as outlined in
Advanced Drug Delivery Reviews, 1996,19, 115. Carbamate prodrugs of hydroxy and amino groups

are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl
group may be an alkyl ester optionally substituted with groups including, but not limited to, ether,
amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described
above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., 1996, 39, 10.
More specific examples include replacement of the hydrogen atom of the alcohol group with a group
such as (C,-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, l-methyl-l-((C1-
C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl,
succinoyl, (C1-C6)alkanoyl, a-amino(C1-C4)alkanoyl, arylacyl and -aminoacyl, or a-aminoacyl-a-
aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-
amino acids, P(O)(0H)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of
a hydroxyl group of the hemiacetal form of a carbohydrate).
[00296] Free amines . of compounds of Formula I can also be derivatized as amides,
sulfonamides or phosphonamides. All of these moieties may incorporate groups including, but not
limited to, ether, amine and carboxylic acid functionalities. For example, a prod rug can be formed by
the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-
carbonyl, NRR'-carbonyl, wherein R and R' are each independently (C1-C10)alkyl, (C3-C7)cycloalkyl,
or benzyl, or R-carbonyl is a natural -aminoacyl or natural -aminoacyl-natural -aminoacyl, -
C(OH)C(O)OY wherein Y is H, (C1-C6)alkyl or benzyl, -C(OY0)Y1 wherein Yo is (C1-C4) alkyl and
Y1 is (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N- or di-N,N-(C1-
C6)alkylaminoalkyl, or -C(Y2)Y3 wherein Y2 is H or methyl and Y3 is mono-N- or di-N,N-(C1-
C6)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.
[00297] For additional examples of prodrug derivatives, see, for example, a) Design of
Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-
396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and
Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of
Prodrugs" by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews,
8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e)
N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated
herein by reference.
[00298] A compound of the invention may possess a sufficiently acidic group, a sufficiently
basic group, or both functional groups, and accordingly react with any of a number of inorganic or
organic bases or acids to form a salt Examples of salts include those salts prepared by reaction of the
compounds of the present invention with a mineral or organic acid or an inorganic base, such salts

including, but not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites; phosphates,
monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,
bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates,,
caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates,
maleates, butyn-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates,
glycollates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene-2-
sulfonates, and mandelates. Since a single compound of the present invention may include more than
one acidic or basic moiety, the compounds of the present invention may include mono, di or tri-salts
in a single compound.
[00299] If the inventive compound is a base, the desired salt may be prepared by any suitable
method available in the art, for example, by treatment of the free base with an acidic compound, for
example an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid,
mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a
pyranosidyl acid such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as citric
acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as
benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid,
or the like.
[00300] If the inventive compound is an acid, the desired salt may be prepared by any suitable
method, for example, by treatment of the free acid with an inorganic or organic base. Examples of
suitable inorganic salts include those formed with alkali and alkaline earth metals such as lithium,
sodium, potassium, barium and calcium. Examples of suitable organic base salts include, for
example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-
hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzylethylenediamine, and the like salts.
Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and
N-methylglucosamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine,
phenylglycine, lysine and arginine.
[00301] In certain embodiments, the salt of a compound of Formula I is a pharmaceutically
acceptable salt. The phrase "pharmaceutically acceptable" indicates that the substance or
composition is compatible chemically and/or toxicologically with the other ingredients comprising a
formulation, and/or the mammal being treated therewith. A "pharmaceutically acceptable- salt,"
unless otherwise indicated, includes salts that retain the biological effectiveness of the corresponding
free acid or base of the specified compound and are not biologically or otherwise undesirable.

[00302] The present invention also embraces isotopically-labeled compounds of the present
invention which are identical to those recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different from the atomic mass or mass
number usually found in nature..
METABOLITES OF COMPOUNDS OF FORMULA I
[00303] Also falling within the scope of this invention are the in vivo metabolic products of
compounds of Formula I described herein. A "metabolite" is a pharmacologically active product
produced through metabolism in the body of a specified compound or salt thereof. Such products
may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation,
esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
Accordingly, the invention includes metabolites of compounds of Formula I, including compounds
produced by a process comprising contacting a compound of this invention with a mammal for a
period of time sufficient to yield a metabolic product thereof.
SYNTHESIS OF GLUOCOKINASE ACTIVATORS
[00304] Compounds of this invention may be synthesized by synthetic routes that include
processes analogous to those well known in the chemical arts, particularly in light of the description
contained herein. The starting materials are generally available from commercial sources such as
Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those
skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser,
Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), or Beilsteins Handbuch der
organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements).
[00305] Compounds of Formula I may be prepared singly or as compound libraries
comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of
compounds of Formula I may be prepared by a combinatorial 'split and mix' approach or by multiple
parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those
skilled in the art. Thus according to a further aspect of the invention there is provided a compound
library comprising at least 2 compounds of Formula t or salts thereof.
[00306] For illustrative purposes, Schemes A-U show general methods for preparing the
compounds of the present invention as well as key intermediates. For a more detailed description of
the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate
that other synthetic routes may be used to synthesize the inventive compounds. Although specific
starting materials and reagents are depicted in the Schemes and discussed below, other starting
materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction
conditions. In addition, many of the compounds prepared by the methods described below can be

further modified in light of this disclosure using conventional chemistry well known to those skilled
in the art.

[00307] Scheme A shows a method of preparing compounds (3A) of Formula I wherein R1 is
thiazolyl and L = O or S. To prepare compound (3A), a 2-aminoheterocycle (1) is reacted with
benzoylisothiocyanate to afford a benzoylthiourea intermediate, which is hydrolyzed to the thiourea
(2)- with a base such as, but not limited to, potassium carbonate in a suitable solvent such as, but not
limited to, ethanol. Alternatively, the aminoheterocycle (1) can be treated with an inorganic or
ammonium isothiocyanate, e.g., Meckler's procedure, in the presence of an acid to afford the thiourea
(2) in one step. Treatment of the thiourea (2) with an a-haloketone R13COCHR12X, wherein X =
OTs, Cl, Br, I, or NR3 (wherein R = C1-C6 alkyl), in a suitable base such as triethylamine, Hunig's
base, DBU, alkali carbonate, sodium hydroxide, etc. and a suitable solvent such as ethanol affords the
thiazole (3A). If the desired -halo ketone R13COCHRI2X is not commercially available, it can be
prepared by various methods known to those skilled in the art. Examples include, but are not limited
to, bromination of commercially or readily synthesized methyl ketones (Tetrahedron (1970) 5611-
5615; Organic Synthesis (1946) 13-15; Tetrahedron (1990) 2943-2964), diazomethane treatment of
carbonyl chlorides, oxidation of l-chloro-2-alkanols, bromination of silyl enol ethers, or halogenation
of -keto esters followed by decarboxylation.


[00308] Scheme B shows an alternative method of preparing a compound of Formula I.
According to Scheme B, hydroxylated heteroaryl halide (5) (if not commercially available) can be
prepared from heteroaryl halide (4) by: 1) ortho metalation with LDA or another suitable base; 2)
conversion of the anion to the boronate by reaction with B(OR)3; and 3) oxidation of the boronate
with a suitable oxidant such as N-methylmorpholine oxide or hydrogen peroxide. The ortho metalated
species can also be quenched with (TMSO)2 to obtain the hydroxylated material (5) directly upon
acidic workup. The hydroxylated heteroaromatic compound (5) can be alkylated with R2X in the
presence of a base such as, but not limited to, cesium carbonate or sodium hydride and in a suitable
solvent such as, but not limited to, DMF to afford compound (6) wherein L is O. Examples of R2X
that may be utilized include substituted 2- and 4-nitrohalobenzenes, substituted 2- and 4-
cyanohalobenzenes, 2-chloro-l-fluorobenzene, halogenated pyridines, halogenated pyrimidines, and
other halogenated heterocycles. Compound (6) can be converted to compound (7) by the method of
Hartwig et al. (for an example of this transformation by analogy see: Organic Letters (2001) 2729-
2732), or by treatment with a Pd catalyst and benzophenone imine, or by heating in the presence of
ammonia (or NH2PG where PG is a protecting group).
[00309] Compounds of the formulas (6) and (7) wherein L is S can be prepared according to
methods described in Schemes I, J, K, M, N, O, and P. Compounds of the formulas (6) and (7)
wherein L is CH2 can be prepared according to methods described below in Schemes I, K, M, N, O,
and P. Compounds of formulas (6) and (7) subsequently can be used in Schemes A-H.
[00310] Compound (7) can be converted to compound (3) of Formula I upon reaction with an
aryl or heteroaryl halide R1X in the presence of a base catalyst or metal (e.g., copper or palladium)

catalyst. Alternatively, compound (6) can be converted directly to a compound (3) of Formula I upon
treatment with R1NH2 by base catalysis or by copper or palladium catalysis; i.e., the Buchwald
reaction.

(00311] Scheme C shows a method of preparing 2-aminothiazole and 2-bromothiazole
intermediates (8) and (9), respectively, which are suitable for use in preparing compounds of Formula
I as shown in Scheme B. According to Scheme C, -haloketone R13COCHR12X can be treated with
thiourea in the presence of a suitable base such as potassium carbonate or triethylamine in an
appropriate solvent such as DMF or ethanol to afford aminothiazole (8). The aminothiazole (8) can
be converted to a diazonium salt intermediate by numerous methods including, but not limited to,
treatment with sodium nitrite in acid or isobutylnitrite. Treatment of the in situ diazonium salt with
Cu(X1)2 (X1 =Cl or Br) or HBr affords the corresponding 2-halothiazole (9). Alternatively, using the
Hantzsch synthetic method, the -haloketone RI3COCHRI2X can be treated first with KSCN, then
with HX wherein X is Cl or Br, to provide the 2-halothiazole (9). The 2-halothtazole compounds (8)
and (9) can be converted into compound (3A) by th.e methods shown in Scheme B.


[00312] Scheme D shows a method of preparing 3-aminothiadiazole and 3-bromothiadiazole
intermediates (11) and (12), respectively, which are suitable for use in preparing compounds of
Formula I as shown in Scheme B. According to Scheme D, acylguanidine (10) (Can. J. Chem.,
(1961) 39, 1017-29) can be treated with Lawesson's reagent or similar reagent in an appropriate
solvent such as toluene to afford the corresponding thioamide (EP 0307142). Oxidation of the
thioamide to form 3-amino-1,2,4 thiadiazole (11) can be accomplished with bromine, iodine,
hydrogen peroxide or nitric acid. Cyclization of compound (10) may also be achieved by treatment
with hydroxylamine-O-sulphonic acid in an alcohol solvent such as methanol or ethanol in the.
presence of pyridine (EP 0307142). Formation of the diazonium salt of compound (11), followed by
treatment of the in situ diazonium salt with CuBr2, affords the corresponding 3-bromo-l,2,4-
thiadiazole (12) (EP 0307142). The chloro derivative of compound (12) could also be synthesized
through the use of CuCl2. Alternatively, palladium-mediated coupling of the commercially available
3-bromo-5-chloro-l,2,4-thiadiazole (13) with a zinc reagent affords 3-bromo-l,2,4-thiadiazole (12)
(WO 2003/037894). Intermediate thiadiazoles (11) and (12) can be converted into compound (3B) of
Formula I by the methods shown in Scheme B.


[00313] Scheme E shows a method of preparing 5-amino-l,2,4-thiadiazole and 5-chloro-l ,2,4-
thiadiazole intermediates (15) and (16), respectively, which are suitable for use in preparing
compounds of Formula I as shown in Scheme B. According to Scheme E, primary amide (14) can be
converted into 5-amino-l,2,4 thiadiazole (15) by heating with KSCN in an appropriate solvent such
as methanol or ethanol (Adv. Heterocycl. Chem., (1982) 32, 285). Formation of the diazonium salt of
compound (15), followed by treatment of the in situ diazonium salt with CuCl2 affords the
corresponding 5-chloro-l,2,4-thiadiazole (16). The corresponding bromo derivative can also be
synthesized through the use of CuBr2. Alternatively, reaction of amidine (17) with perchloromethyl
mercaptan affords 5-chloro-l,2,4-thiadiazole (16) (Bioorg. Med. Chem., (2003) 11, 5529r5537).
Intermediates (15) and (16) can be converted into compound (3C) of Formula I by the methods
shown in Scheme B.

[00314] Scheme F shows a method of preparing 3-amino-l ,2,4-oxadiazole and 3-bromo-l,2,4-
oxadiazole intermediates (19) and (20), respectively, which are suitable for use in preparing
compounds of Formula I as shown in Scheme B. According to Scheme F, cyanamide can be reacted
with an appropriate acylchloride (18) or the corresponding anhydride, and subsequently reacted with
hydroxylamine to afford 3-amino-l,2,4-oxadiazole (19) (Heterocycles, (2002) 57, 811-823).
Formation of the diazonium salt of (19), followed by treatment of the in situ diazonium salt with
CuBr2 affords the corresponding 3-bromo-l,2,4-oxadiazole (20). The chloro derivative could also be
synthesized through the use of CuCl2. Alternatively, alkyl nitrite (21) can be reacted with
dibromoformaldoxime (neat) in the presence of an appropriate base such as sodium bicarbonate to
afford 3-bromo-l ,2,4-oxadiazole (20) (J. Heterocyclic Chem., (1989) 26, 23-24). The oxadiazole


intermediates (19) and (20) can be converted into compound (3D) of Formula I by the methods
shown in Scheme B.
[00315] Scheme G shows a method of preparing 5-amino-l,2,4-oxadiazole and 5-chloro-
1,2,4-oxadiazole intermediates (23) and (24), respectively, which are suitable for use in preparing
compounds of Formula I as shown in Scheme B. According to Scheme G, imidate hydrochloride salt
(22) (made by the Pinner reaction) can be reacted with cyanamide in a suitable solvent such as
methanol or ethanol to afford an intermediate N-cyanoimidate. Cyclization can be achieved by
reacting the N-cyanoimidate with hydroxylamine hydrochloride in an appropriate solvent such as
methanol or ethanol in the presence of an appropriate base such as triethylamine, Hunig's base,
pyridine or sodium acetate to afford 5-amino-l,2,4-oxadiazole (23) (J. Org. Chem., (1963) 28, 1861-
21). Formation of the diazonium salt of compound (23), followed by treatment of the in situ
diazonium salt with CuCl2 affords the corresponding 5-chloro-l,2,4-oxadiazole (24). The bromo
derivative could also be synthesized through the use of CuBr2. Alternatively, alkyl nitrile (21) can be
converted into 5-chloro-l,2,4-oxadiazole (24) (WO 95/005368) by reaction with hydroxylamine
hydrochloride in an appropriate solvent such as methanol or ethanol, in the presence of an appropriate
base such as triethylamine, Hunig's base, pyridine or sodium acetate, followed by cyclization to a
1,2,4-oxadiazolone with a bisacylating agent such as ethyl chloroformate, carbonyldiimidazole or
phosgene. In certain embodiments, the cyclization requires the use of a base such as NaOH, NaH or
triethylamine to allow for the formation of the 1,2,4-oxadiazolone. Reaction of the 1,2,4-
oxadiazolone with a dehydrating agent such as POCl3, POBr3 or PCl5 affords the 5-halo-1,2,4-
oxadiazole (24). The oxadiazole intermediates (23) and (24) can be converted into a compound (3E)
of Formula I by the methods shown in Scheme B.


[00316] Scheme H shows a method of preparing 2-aminooxazole and 2-halo-oxazole
intermediates (26) and (27), respectively, which are suitable for use in preparing compounds of
Formula I as shown in Scheme B. According to Scheme H, a-hydroxyketone (25) is reacted with
cyanamide to afford 2-aminooxazole (26) (Aust. J. Chem. (1985), 38, 447-458). Formation of the
diazonium salt of compound (26), followed by treatment of the in situ diazonium salt with CuX2
(where X = Cl or Br) affords the corresponding 5-halo-l,2,4-thiadiazole (27). Intermediates (26) and
(27) can be converted into compound (3F) of Formula I by the method of Scheme B.

[00317] Scheme 1 shows a method of preparing compound (3G) of Formula I wherein Z is
CR3. According to Scheme I, the halo-substituted heterocycle (28) (prepared by the method of
Scheme A or B) wherein X1 = Cl, Br or I, is first treated with an appropriate amount of methyl
lithium solution to remove exchangeable proton(s), and then transmetalated with an alkyl lithium
reagent such as n-BuLi, sec-butyl or tert-butyl lithium, or a Grignard reagent such as, i-PrMg-halide.
The resulting anion is then quenched with an electrophile to provide compound (3G). Suitable
electrophiles include, but are not limited to: 1) aldehydes, 2) nitriles, 3) N-methoxy-N-methylamides
(Weinreb amides), 4) dialkylsulphides, 5) hexachloroethane, 6) trialkyl boronates, 7) sulphonyl
chlorides, 8) sulfamyl chlorides, 9) isocyanates, 10) carbon dioxide, (11) alkyl halides, (12)

trifluoroiodomethane (13) Mander's reagent, and (14) chloroformates. Exemplary compounds of the
present invention which can be prepared according to the method of Scheme I include compounds
(3G) wherein R3 is alkyl, phenylalkyl, cycloalkyl, hydroxylalkyl (from R3Si(CH2)nI), CI, SH, SR',
SOR1, SO2R1, OR1, I, SCH2R', OCH2R', CO2H, CH(OH)-R' and C(=O)R', wherein R' is alkyl,
alkenyl, alkynyl, cycloalkyl, or aryl.
[00318] Alternatively, the halo-substituted heterocycle (28) can be converted to compound
(3G) wherein R3 is alkyl, aryl, heteroaryl, alkenyl or alkynyl, by a metal (e.g., Cu or Pd) mediated
coupling reaction such as, but not limited to, the Negishi reaction, the Suzuki reaction, the
Sonogashira reaction, or the Stille reaction.

[00319] Scheme J shows a method of preparing compounds (3H) of Formula I, wherein Z =
C-SR3 or C-OR3, and Q = O or S, from a halo substituted heterocycle (28). According to Scheme J,
the halo-substituted heterocycle (28), prepared by the method of Scheme A or B, can be converted to
a thiol or alcohol (29) by one of several procedures. According to one method, the halo-substituted
heterocycle (28) is first treated with an appropriate amount of methyl lithium solution to remove
exchangeable proton(s), and then transmetalated with an alkyl lithium reagent such as n-BuLi, sec-
butyl or /erf-butyl lithium, or a Grignard reagent such as, 7-PrMg-halide. The resulting anion is then
quenched with either elemental sulfur or bis(trimethylsilyl) peroxide to form the corresponding
mercapto- or hydroxyl-substituted compound (29). Alternatively, the anion can be quenched with
trimethyl borate and oxidized with either hydrogen peroxide (J. Med. Chem. (2004) 3089-3104) or N-
methyl morpholine oxide (Syn. Lett. (1995) 931-932) to afford the phenol (29). As a third synthetic
route, the halide (28) can be converted under Pd-mediated conditions to thiol or phenol (29) utilizing
potassium triisopropylsilanethiolate (Tetrahedron Letters (1994) 3225-3226) or sodium tert-
butyldimethylsiloxide (J. Org. Chem., (2002) 5553-5566). The thiol or phenol (29) can be alkylated
with a variety of electrophiles using standard reaction conditions to provide the corresponding ether
(3H) of Formula I. Suitable electrophiles include, but are not limited to, alkyl halides, benzylic
halides, heteraroyl-CH2X, cycloalkyl halides, Michael acceptors, and activated heteroaryl halides
such as, but not limited to, 2-fluorocyanobenzene, 4-fluorocyanobenzene, 2-fluoronitrobenzene, 4-

fluoronitrobenzene, 2-chloro-4-nitropyridine, 2-halopyridine, 2-halopyrimidine, 4-halopyrimidine,
aryl halides and heteroaryl halides.
[00320] Alternatively, halide (28) can be converted to an alkyl sulfide using Pd-mediated
conditions with appropriately functionalized sulfides. Examples of such sulfides include, but are not
limited to, esters of 3-mercaptopropanoic acid, 3-mercaptopropanenitrile or 2-
(trimethylsilyl)ethanethiol. Sulfides of this type can be deprotected to the thiol and alkylated with a
variety of electrophiles under standard conditions (Chemical & Pharmaceutical Bulletin (1990),
38(10), 2667-75).

[00321] Scheme K shows a method of adding a linker L, wherein L is O or S, to a core
heterocycle to provide a compound (31) of Formula I wherein G = CR11, Z == C-Br, and Y = N .
According to Scheme K, 2-amino-3,5-dibromopyrazine (30) is reacted with R2LH, wherein L is O or
S, in the presence of a suitable base such as K2CO3 or NaH in a suitable, solvent such as DMF or
ethanol to afford compound (31) regioselectively. Compound (31) can be converted to compound
(31) of Formula I by the method of Scheme A or B. Compound (31) can be converted into additional
5-substituted compounds of Formula I by the methods shown in Scheme I or J.

[00322] Scheme L shows an alternate method of adding the linker OR2 to a core heterocycle
to provide a compound (3) of Formula I wherein L is O. According to Scheme L, a benzyl ether (32),
prepared by the method of Scheme A or B, can be converted to the hydroxyl substituted heterocycle
(33), for example by hydrolysis with a strong acid (e.g., 6N HC1) or by hydrogenation (e.g., H2 or
ammonium formate in the presence of a metal catalyst). Alkylation of the hydroxylated heterocycle
(33) with R2X, wherein X = F, Cl, Br, I, or NR3, in the presence of a base such as, but not limited to,

cesium carbonate, in a suitable solvent such as, but not limited to, DMF, or by copper or palladium
catalysis (i.e., the Ullman reaction) affords compound (3) of Formula I.

[00323] Scheme M shows a method of preparing a compound (3J) of Formula I wherein G =
N, Z = CR3, Y = CH, and L = O or S. According to Scheme M, 6-chloropyridazin-3-amine (34) is
regioselectively brominated with a suitable brominating agent such as bromine, NBS, etc., to provide
compound (35). Reaction of compound (35) with R2LH (wherein L is O or S) in the presence of a
suitable base such cesium carbonate or sodium hydride either with or without a metal catalyst (e.g.,
Cul) in DMSO or DMF regioselectively affords compound (36). Compound (36) can be converted to
the chlorinated compound (37) of Formula I by the method of Scheme A or B. Compound (37) can
be converted into a 5-substituted compound (3J) of Formula I by the method of Scheme I or J.


[00324] Scheme N shows a method of preparing a compound (3L) of Formula I wherein G =
CR11, Z = CR3, Y = CR4, and L is O or S. According to Scheme N, the 2-aminopyridine (38) is
regioselectively brominated with a suitable brominating agent such as NBS or bromine to provide
compound (39). The brominated compound can be converted to compound (40) upon reaction with
R2LH (wherein L is O or S ) in the presence of a suitable base such as cesium carbonate, sodium
hydride or triethylamine in the presence of a metal catalyst (i.e.; CuI or Pd2dba3) in a suitable solvent
such as DMSO or DMF. The chlorinated product (40) can be converted to compound (41) by the
method of Scheme A or B. Compound (41) can be converted to a 5-substituted compound (3L) of
Formula I by the method of Scheme I or J. Alternatively, the chlorinated 2-aminopyridine (40) can
be converted to a 5-substituted compound (42) by the method of Scheme I or J, and then the
heterocyclyl group R1 can be added to compound (42) by the method of Scheme A or B to provide
compound (3L).

[00325] Scheme O shows a method of preparing a compound (3L) of Formula I wherein G =
CR11, Z = CR3, Y = CR4, and L is O or S. According to Scheme O, reaction of compound (43) with
R2LH (wherein L is O or S) in the presence of a suitable base such cesium carbonate or sodium
hydride either with or without a metal catalyst (i.e.; Pd2dba3 or CuI) in DMSO or DMF affords
compound (44) wherein L is O or S. Alternatively, reaction of compound (43) with R2CH2Zn under
similar conditions affords compound (44) wherein L is CH2. To prepare compound (44) wherein L is

C=O, compound (43) can be treated to lithiation conditions as described in Scheme 1, followed by
treatment with R2CO(NMeOMe).
[00326] The 2-aminopyridine (44) is then regioselectively brominated with a suitable
brominating agent such as NBS or bromine to provide compound (45). The brominated product (45)
can be converted to compound (46) by the method of Scheme A or B. Compound (46) can be
converted to 5-substituted compounds (3L) of Formula I by the method of Scheme I or J.
Alternatively, the brominated 2-aminopyridine (45) can be converted to a 5-substituted compound
(47) by the method of Scheme I or J, and then the heterocyclyl group R1 can be added to compound
(47) by the method of Scheme A or B to provide compound (3L).

[00327] Scheme P shows an alternative method of preparing a compound (3L) of Formula I
wherein G = CR11, Z - CR3, Y = CR4, and L is O, S or CH2. According to Scheme P, reaction of
compound (48) (which if not commercially available can be made from commercial aminopyridines
by regioselective bromination) in the presence of a suitable base such cesium carbonate or sodium
hydride and with or without a metal catalyst (e.g., Pd2dbaa or CuI) in DMSO or DMF affords
compound (49) by a method such as: ipso replacement (with R6OH or R6SH to provide compound
(49) wherein R3 is OR6 or SR6, respectively); Buchwald ether or thioether formation (with R6OH or
R6SH to provide compound (49) wherein R3 is OR6 or SR6, respectively); a Negishi reaction (with
R3Zn); an aryl or alkyl Suzuki reaction (with R3B(OH)2); a Heck reaction, etc., according to
procedures well known in the literature and further exemplified in the Examples below. The 2-
aminopyridine (49) is then regioselectively brominated with a suitable brominating agent such as

NBS or bromine to provide compound (50). The bromininated product (50) can be converted to
compound (51) by the method of Scheme A or B. Compound (51) can be converted to 5-substituted
compounds (3L) of Formula I by Buchwald ether or thioether formation (with R2OH when L = O or
R2SH when L = S), Negishi reactions (with R2CH2Zn when L = CH2), or by lithiation chemistry as
described in Scheme I (when L is C=O) to provide compound (3L). Alternatively, the brominated 2-
aminopyridine (50) can first be converted to compound (52) by the Buchwald, Negishi, or lithiation
chemistry, and compound (52) can be converted to compound (3L) by the method of Scheme A or B.

[00328] Scheme Q shows a method of preparing a compound (3L) of Formula I wherein G =
CR11, Z = CR3, Y = CR4 and L is O. Treatment of compound (53) with R2X in the presence of a
suitable base such as cesium carbonate or sodium hydride, with or without a metal catalyst, affords
compound 54. Examples of R2X that can be utilized include substituted 2- and 4-nitrohalobenzenes,
substituted 2- and 4-cyanohalobenzenes, 2-chloro-l -fluorobenzene, halogenated pyridines,
halogenated pyrimidines, and other halogenated heterocycles. When R2X contains two halogens, the
halogen ortho or para to an electron withdrawing group is selectively displaced in preference to the
meta substituted halogen, and the leaving group potential using sodium hydride as a base is F > C1 >
Br > I. In this way, a bromine-containing compound suitable for further functionalization can be
made. For example using a brominated version of 2-chloro-l-fluorobenzene with 3-hydroxy-2-amino
pyridine affords a brominated version of compound (54). The bromine can be converted to a variety
of functional groups at this stage to form other analogs of compound (54) using palladium mediated
or anion chemistry. Subsequently, compound (54) can be fegioselectively brominated to afford
compound (55). This compound can be converted to compound (56) by the methods described in

Schemes I or J. Compound (56) is then converted to compound (3L) by the procedures found in
Schemes A or B. Alternatively, compound (55) can be converted to compound (57) by the
procedures found in Schemes A or B, and then converted to compound (3L) by the procedures found
in Schemes I or J.

[00329] Scheme R shows a method of preparing compounds of Formula I wherein R1 is a
substituted thiazolyl. According to Scheme R, phthalimide-containing compound (58) wherein V is
alkylene optionally substituted by one or more alkyl groups (which can be prepared by the method of
Scheme A or B), can be converted to amine (59) by treatment with hydrazine. Amine (59) can be
elaborated to the amide, carbamate, urea, thiourea, monoalkylamine, dialkylamine, amidine, or
guanidine (60) by routine methods in the literature.

[00330] Scheme S shows an alternative method of preparing compounds of Formula I wherein
R1 is a substituted thiazolyl. According to Scheme S, the ester-containing compound (61), wherein V
is alkylene optionally substituted by one or more alkyl groups (which can be prepared by the method
of Scheme A or B), can be converted to carboxylic acid (62) by reduction or hydrolysis with a
hydride or hydroxide, respectively. Compound (62) can be converted to alcohol (64) upon treatment

with a lithium reagent R'Li. Alternatively, the carboxylic acid (62) can be converted to a primary,
secondary or tertiary amide (63) using a variety of amide coupling methods known to those skilled in
the art. Compound (62) can also be converted to compound (65), wherein R9 is a heterocyclyl group
such as, but not limited to, tetrazolyl, imidazolyl, triazolyl, or thiazoyl, by coupling methods known
to those skilled in the art.

[00331] Scheme T describes the preparation of intermediates (68), (72) and (75) and
substituted forms thereof suitable for use in preparing compounds of Formula (3A) wherein R12 and
R13 form a fused heterocyclic ring. To prepare intermediate (68), 2-halo-3-aminopyridine (66) is
reacted with a thiocyanate (for example, sodium or potassium thiocyanate) in acidic media (for
example, acetic acid) to provide thiazolopyridine (67). Compound (67) is converted to the
corresponding 2-halo compound (68) by standard methods (for example, by diazotization of the
amine with NaNO2 and HX3, followed by reaction with Cu(X3)2).

[00332] To prepare intermediate (72), the 2-amino-3-haiopyridazine (69) is reacted with a
protected isothiocyanate to provide protected 2-aminothiazolopyridazine (70), which is deprotected
under standard hydrolytic conditions to provide 2-aminothiazolopyridazine (71) (Koren, B., et al.,
Heterocycles 1987, 26(3), 689-697). The aminohetcrocyclic compound (71) is converted to the
corresponding 2-halo compound (72), for example, as described above.
[00333] To prepare intermediate (75), compound (73) is converted to the 2-
aminothiazolotriazine (74), for example, using the method of Jacobsen, et al., (Aust. J. Chem. 1987,
40(3), 491-499). The aminoheterocyclic compound (74) is then converted to the corresponding 2-
halo compound (75), for example, as described above.
[00334] It will be appreciated that the aminoheterocycles (68), (72) and (75) can be further
functionalized if desired, for example by halogenation of the 6-membered ring (for example with
NBS or bromine). Such halogenated derivatives may be further modified using well known methods.

[00335] Scheme U shows an alternative method of preparing compounds of Formula (3A)
wherein R12 and R13 form a fused heterocyclic ring. Substituted 2-halo-aminoheterocycles (76),
wherein at least one X = N, but no more than two consecutive X are N, is reacted with thiophosgene
to provide the isothiocyanate (77). Refluxing the isothiocyanate (77) with the 5-brominated
aminopyridine (45) in a suitable solvent such as ethanol or THF affords the heterocycle (78), which
can be converted to compounds of Formula (3A) by the methods described in Scheme P.
Alternatively, the aminopyridine (47), prepared as in Scheme P, is refluxed with the isocyanate (77)
to afford compounds of structure (3A).


[00336] Scheme V shows an alternative method for producing compounds of the formula 3C
wherein D2 is N. Formation of oxime (80) -from aldehyde (79) allows for the chlorination with N-
chlorosuccinimide in a suitable solvent, such as DMF, to produce compound (81). Compound (81) is
sulfonylated with a sulfonyl chloride having the formula R'SO2C1 wherein R1 is, Ci-Cg alkyl (for
example, methyl) or aryl optionally substituted with Ci-C$ alkyl (for example, tolyl) in the presence
of a base, such as but not limited to triethylamine, to afford compound (82) (See, for example,
Gibbons, L. US Patent No. 3,983,246). Reaction of compound (82) with a thiocyanate salt, such as
NaNCS, in a suitable solvent, such as acetonitrile, and in the presence of a base, such as but not
limited to pyridine, affords the activated intermediate (83) (see, for example, Takeuchi, K., JP
2001081084). Intermediate (83) can be reacted in situ with an appropriate amino heterocycle (7) to
afford compounds of the structure (3C) of Formula I.


[00337] Scheme W shows an alternative method for the construction of compounds of
Formula I where G and Y are CH, Z is C-SR6 or C-OR6, and L is O or S. Starting from the
commercially available 2-cyanopyridine (84), selective nucleophilic displacement can be achieved
with compounds of the formula R2Q1H, where Q1 is O or S, and an appropriate base, such as sodium
hydride, in a suitable solvent, such as DMF to provide compound (85). Addition of a second
nucleophile having the formula R6Q2H, wherein Q2 is O or S, under similar conditions, affords the
functionalized 2-cyanopyridine (86). Hydrolysis of the nitrite can occur under many conditions, with
NaOH in aqueous ethanol being preferred, to afford the picolinate (87). Curtius rearrangement in the
presence of an appropriate alcohol affords the carbamate (88). The carbamate can be removed using
various conditions, depending on the alcohol used in the previous step, to provide the 2-
aminopyridine (89). Using procedures outlined in Schemes A, B or T, compounds (90) of the
Formula I can be synthesized from compound (89).
[00338] Accordingly, another embodiment of the invention provides a method for preparing a
compound of Formula I or a salt thereof, comprising:
[00339] (a) reacting a corresponding compound of the formula

[00340] with a compound of the formula RlNH2 in the presence of a base catalyst or metal
catalyst; or
[00341] (b) reacting a corresponding compound of the formula

[00342] with a compound of the formula R1-X, wherein X is Cl or Br, in the presence of a
base catalyst or metal catalyst; or

[00344] reacting a corresponding compound of the formula
[00343] (c) for a compound of Formula I wherein R1 is


[00345] with a compound of the formula R13COCHR12X, wherein X is a leaving group such as

[00347] ■ reacting a corresponding compound of the formula

[00348] with a compound having the formula

OTs, Cl, Br, I, or NR3 and R is C1-C6 alkyl, in the presence of a base; or
[00346] (d) for a compound of Formula I wherein R1 is
[00349] where R' is C1-C6 alkyl or aryl optionally substituted with C1-C6 alkyl, in the presence
of a base;or
[00350] (e) for a compound of Formula I wherein Z is SR6, reacting a corresponding
compound, having the formula

[00351] with a compound having the formula R SSR in the presence of a suitable base, for
example, an alkyl lithium such as methyl lithium, butyl lithium, or a mixture thereof; or
[00352] (e) for a compound of Formula I wherein Z is SR6, reacting a corresponding
compound having the formula


[00353] with a compound having the formula R6X wherein X is a leaving group or atom such

[00355] reacting a corresponding compound having the formula

[00356] with a compound having the formula

as a halogen (e.g., F, Cl or Br) or a sulfonate (e.g., OMs or OTs) in the presence of a suitable base, for
example an alkali metal alkoxide such as potassium t-butoxide; or
[00354] (f) for a compound of Formula I wherein R1 is
[00357] in a suitable solvent, for example DMF, at elevated temperatures, for example 80-110
°C; or
[00358] g) for a compound of Formula I wherein Z is CR3, reacting a corresponding
compound having the formula

[00359] wherein X6 is a leaving group or atom (e.g., a halogen such as Br, Cl or I,) with a
compound having the formula R3-Xb wherein Xb is a leaving group or atom, in the presence of a
suitable base (e.g., an alkyl lithium such as methyl lithium, butyl lithium, or a combination thereof);
or
[00360] h) for a compound of Formula I wherein Z is C-SR6 and R6 is alkyl, CH2-aryl,
heteroaryl, or aryl and wherein said R6 groups are optionally substituted, reacting a corresponding
compound having the formula


[00361] with a compound having the formula R6-Xc wherein Xc is a leaving group or atom
(e.g., a halogen such as Cl or Br) in the presence of a suitable base; or
[00362] i) for a compound of Formula I wherein L is O, reacting a corresponding compound
having the formula

[00363] with a compound having the formula R2-Xd, wherein Xd is a leaving group or atom
(e.g., a halogen such as Cl or Br; or a triflate or tosylate group), in the presence of a base (e.g., an
alkali metal carbonate such as CsCCb) or in the presence of a copper or palladium catalyst; or
[00364] j) for a compound of Formula I wherein L is O or S, reacting a corresponding
compound having the formula

[00365] wherein Xe is a leaving group or atom (e.g., Br, I or OTf) with a compound having the
formula R2LH wherein L is O or S, respectively; in the presence of a palladium catalyst (e.g.,
Pd(OAc)2 and a ligand) and a suitable base (e.g., K2CO3, NaH, NaOt-Bu) and a suitable solvent (e.g.,
toluene) at temperatures ranging from ambient temperature to 100°C; or
[00366] k) for a compound of Formula I wherein L is CH2, reacting a corresponding
compound having the formula

[00367] wherein Xf is a leaving group or atom (e.g., Cl, Br, 1, OTf or acetyloxy) in the
presence of an organozinc compound having the formula R2-Zn-XE wherein Xs is a halide (e.g., Cl,
Br, or I) and a nickel or palladium catalyst; and
[00368] removing any protecting group or groups and, if desired, forming a salt.
[00369] In preparing compounds of Formula I, protection of remote functionalities (e.g.,
primary or secondary amines, etc.) of intermediates may be necessary. The need for such protection

will vary depending on the nature of the remote functionality and the conditions of the preparation
methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl
(BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such
protection is readily determined by one skilled in the art. For a general description of protecting
groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,
New York, 1991.
METHODS OF SEPARATION
[00370] In any of the synthetic methods for preparing compounds of Formula I, it may be
advantageous to separate reaction products from one another and/or from stalling materials. The
desired products of each step or series of steps is separated and/or purified to the desired degree of
homogeneity by the techniques common in the art.
METHODS OF TREATMENT WITH COMPOUNDS OF FORMULA I
[00371] The compounds of the present invention can be used as prophylactics or therapeutic
agents for treating diseases or disorders mediated by deficient levels of glucokinase activity or which
can be treated by activating glucokinase including, but not limited to, diabetes mellitus, impaired
glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glycemia), as well as
other diseases and disorders such as those discussed below. Furthermore, the compounds of the
present invention can be also used to prevent the progression of the borderline type, impaired glucose
tolerance, IFG (impaired fasting glucose) or IFG (impaired fasting glycemia) to diabetes mellitus.
[00372] Accordingly, another aspect of the invention provides methods of treating or
preventing diseases or conditions described herein by administering to a mammal, such as a human, a
therapeutically effective amount of a compound of Formula I.
[00373] The phrase "therapeutically effective amount" means an amount of a compound of the
present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii)
attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or
disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease,
condition, or disorder described herein. The amount of a compound of Formula I that will
correspond to such an amount will vary depending upon factors such as the particular compound,
disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but
can nevertheless be routinely determined by one skilled in the art.
[00374] The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic
or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired
physiological change or disorder. For purposes of this invention, beneficial or desired clinical results
include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized
(i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or

palliation of the disease state, and remission (whether partial or total), whether detectable or
undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not
receiving treatment Those in need of treatment include those already with the condition or disorder
as well as those prone to have the condition or disorder or those in which the condition or disorder is
to be prevented.
[00375] As used herein, the term "mammal" refers to a warm-blooded animal that has or is at
risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs,
cats, rats, mice, hamsters, and primates, including humans.
[00376] In certain embodiments, the methods of this invention are useful for treating diabetes
mellitus. Diabetes meliitus is a condition where the fasting plasma glucose level (glucose
concentration in venous plasma) is greater than or equal to 126 mg/dL (tested on two occasions) and
the 2-hour plasma glucose level of a 75 g oral glucose tolerance test (OGTT) is greater than or equal
to 200 mg/dL. Additional classic symptoms include polydipsia, polyphagia and polyuria.
[00377] In certain embodiments, the methods of this invention are useful for treating the
syndrome of impaired glucose tolerance (IGT). IGT is diagnosed by the presentation of a fasting
plasma glucose level of less than 126 mg/dL and a 2-hour post-oral glucose challenge lever greater
than 140 mg/dL.
[00378] The compounds of the present invention can be also used as prophylactics or
therapeutic agents of diabetic complications such as, but not limited to, neuropathy, nephropathy,
retinopathy, cataract, macroangiopathy, osteopenia, diabetic hyperosmolar coma), infectious diseases
(e.g., respiratory infection, urinary tract infection, gastrointestinal tract infection, dermal soft tissue
infection, lower limb infection etc.), diabetic gangrene, xerostomia, decreased sense of hearing,
cerebrovascular disease, peripheral circulatory disturbance, etc.
[00379] The compounds of the present invention can be, also used as prophylactics or
therapeutic agents in the treatment of diseases and disorders such as, but not limited to, obesity,
metabolic syndrome (syndrome X), hyperinsulinemia, hyperinsulinemia-induced sensory disorder,
dyslipoproteinemia (abnormal lipoproteins in the blood) including diabetic dyslipidemia,
hyperlipidemia, hyperlipoproteinemia (excess of lipoproteins in the blood) including type I, II-a
(hypercholesterolemia), II-b, III, IV (hypertriglyceridemia) and V (hypertriglyceridemia), low HDL
levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, neurodegenerative
disease, depression, CNS disorders, liver steatosis, osteoporosis, hypertension, renal diseases (e.g.,
diabetic nephropathy, glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive
nephrosclerosis, terminal renal disorder etc.), myocardiac infarction, angina pectoris, and
cerebrovascular disease (e.g., cerebral infarction, cerebral apoplexy).

[00380] The compounds of the present invention can be also used as prophylactics or
therapeutic agents in the treatment of diseases and disorders such as, but not limited to, osteoporosis,
fatty liver, hypertension, insulin resistant syndrome, inflammatory diseases (e.g., chronic rheumatoid
arthritis, spondylitis deformans, osteoarthritis, lumbago, gout, postoperative or traumatic
inflammation, remission of swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including non-
alcoholic steatohepatitis), pneumonia, inflammatory colitis, ulcerative colitis), pancreatitis, visceral
obesity syndrome, cachexia (e.g., carcinomatous cachexia, tuberculous cachexia, diabetic cachexia,
hemopathic cachexia, endocrinopathic cachexia, infectious cachexia, cachexia induced by acquired
immunodeficiency syndrome), polycystic ovary syndrome, muscular dystrophy, tumor (e.g.,
leukemia, breast cancer, prostate cancer, skin cancer etc.), irritable bowel syndrome, acute or chronic
diarrhea, spondylitis deformans, osteoarthritis, remission of swelling, neuralgia, pharyngolaryngitis,
cystitis, SIDS, and the like.
[00381] This invention also provides the use of a compound of Formula I in the treatment of
diseases or disorders mediated by deficient levels of glucokinase activity or which can be treated by
activating glucokinase.
[00382] An additional aspect of the invention is the use of a compound of Formula I in the
preparation of a medicament for the treatment or prevention of diseases or disorders mediated by
deficient levels of glucokinase activity or which can be treated by activating glucokinase.
[00383] COMBINATION THERAPY
[00384] The compounds of the present invention can be used in combination with one or more
additional drugs such as described below. The dose of the second drug can be appropriately selected
based on a clinically employed dose. The proportion of the compound of the present invention and
the second drug can be appropriately determined according to the administration subject, the
administration route, the target disease, the clinical condition, the combination, and other factors. In
cases where the administration subject is a human, for instance, the second drug may be used in an
amount of 0.01 to 100 parts by weight per part by weight of the compound of the present invention.
[00385] The second compound of the pharmaceutical combination formulation or dosing
regimen preferably has complementary activities to the compound of this invention such that they do
not adversely affect each other. Such drugs are suitably present in combination in amounts that are
effective for the purpose intended. Accordingly, another aspect of the present invention provides a
composition comprising a compound of this invention in combination with a second drug, such as
described herein.
[00386] A compound of this invention and the additional pharmaceutically active agent(s)
may be administered together in a unitary pharmaceutical composition or separately and, when

administered separately this may occur simultaneously or sequentially in any order. Such sequential
administration may be close in time or remote in time. The amounts of the compound of this
invention and the second agent(s) and the relative timings of administration will be selected in order
to achieve the desired combined therapeutic effect.
[00387] The combination therapy may provide "synergy" and prove "synergistic", i.e., the
effect achieved when the active ingredients used together is greater than the sum of the effects that
results from using the compounds separately. A synergistic effect may be attained when the active
ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit
dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by
some other regimen. When delivered in alternation therapy, a synergistic effect may be attained
when the compounds are administered or delivered sequentially, e.g., by different injections in
separate syringes. In general, during alternation therapy, an effective dosage of each active
ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective
dosages of two or more active ingredients are administered together.
[00388] The compounds of the present invention can be used, for example, in combination
with additional drug(s) such as a therapeutic agent for diabetes mellitus, and/or a therapeutic agent for
diabetic complications, as defined above. Examples of known therapeutic agents for diabetes
mellitus which can be used in combination with a compound of this invention include insulin
preparations (e.g., animal insulin preparations extracted from the bovine or swine pancreas; human
insulin preparations synthesized by a genetic engineering technique using Escherichia coli or a
yeast), a fragment of insulin or derivatives thereof (e.g., INS-1), agents for improving insulin
resistance (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazohe or its maleate, GI-262570,
JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614), alpha-glucosidase inhibitors (e.g.,
voglibose, acarbose, miglitol, emiglitate), biguanides (e.g., phenformin, metformin, buformin),
insulin secretagogues [sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide,
tolazamide, acetohexamide, glyclopyramide, glimepiride, giipizide, glybuzole), repaglinide,
nateglinide, mitiglinide or its calcium salt hydrate, GLP-1], dipeptidylpeptidase IV inhibitors (e.g.,
NVP-DPP-278, PT-100), beta-3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552,
AJ-9677, BMS-196085, AZ-40140, etc.), amylin agonists (e.g., pramlintide), phosphoryrosine
phosphatase inhibitors (e.g., vanadic acid), gluconeogenesis inhibitors (e.g., glycogen phosphorylase
inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists), SGLT (sodium-glucose
cotransporter) inhibitors (e.g., T-l 095 ), and the like.
[00389] Examples of known therapeutic agents for diabetic complications include aldose
reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (SNK-
860), CT-112), neurotrophic factors (e.g., NGF, NT-3, BDNF), neurotrophic factor production

secretion promoters, PKC inhibitors (e.g., LY-333531), AGE inhibitors (e.g., ALT946, pimagedine,
pyratoxathine, N-phenacylthiazolium bromide (ALT766), EXO-226), active oxygen scavengers (e.g.,
thioctic acid), and cerebral vasodilators (e.g., tiapuride, mexiletine).
[00390] The compounds of the present invention can also be used, for example in combination
with antihyperlipidemic agents. Epidemiological evidence has firmly established hyperlipidemia as a
primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years,
emphasis has been placed on lowering plasma cholesterol levels, and low density lipoprotein
cholesterol in particular, as an essential step in prevention of CVD. Cardiovascular disease is
especially prevalent among diabetic subjects, at least in part because of the existence of multiple
independent risk factors in this population. Successful treatment of hyperlipidemia in the general
population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
Examples of antihyperlipidemic agents include, but are not limited to, statin compounds which are
cholesterol synthesis inhibitors (e.g., cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin,
fluvastatin, itavastatin or their salts, etc.), squalene synthase inhibitors or fibrate compounds (e.g.,
bezafibrate, clofibrate, simfibrate, clinofibrate) having a triglyceride lowering action and the like.
[00391] The compounds of the present invention can also be .used, for example, in
combination with hypotensive agents. Hypertension has been associated with elevated blood insulin
levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are
to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also
acts to promote vascular cell growth and increase renal sodium retention, among other things. These
latter functions can be accomplished without affecting glucose levels and are known causes of
hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral
capillaries, while sodium retention increases blood volume. Thus, the lowering of insulin levels in
hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high
insulin levels and thereby alleviates hypertension. Examples of hypotensive agents include, but are
not limited to, angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril),
angiotensin II antagonists (e.g., candesartan cilexetil, losartan, eprosartan, valsantan, termisartan,
irbesartan, tasosartan), calcium antagonists (e.g., manidipine, nifedipine, nicardipine, amlodipine,
efonidipine), and clonidine.
[00392] The compounds of the present invention can be used in combination with antiobesity
agents. The term "obesity" implies an excess of adipose tissue. Obesity is a well-known risk factor
for the development of many very common diseases such as diabetes, atherosclerosis, and
hypertension. To some extent appetite is controlled by discrete areas in the hypothalamus: a feeding
centre in the ventrolateral nucleus of the hypothalamus (VLH) and a satiety centre in the
ventromedial hypothalamus (VMH). The cerebral cortex receives positive signals from the feeding

center that stimulate eating, and the satiety center modulates this process by sending inhibitory
impulses to the feeding center. Several regulatory processes may influence these hypothalamic
centers. The satiety center may be activated by the increases in plasma glucose and/or insulin that
follow a meal. Examples of antiobesity agents include, but are not limited to, antiobesity drugs
acting on the central nervous system (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine,
anfepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex), pancreatic lipase
inhibitors (e.g. orlistat), beta-3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552,
AJ-9677, BMS-196085, AZ-40140), anorectic peptides (e.g.; leptin, CNTF (Ciliary Neurotrophic
Factor) and cholecystokinin agonists (e.g. lintitript, FPL-15849).
ROUTES OF ADMINISTRATION
[00393] The compounds of the invention may be administered by any route appropriate to the
condition to be treated. Suitable routes include oral, parenteral (including subcutaneous,
intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal,
nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and
intranasal. It will be appreciated that the preferred route may vary with, for example, the condition of
the recipient. Where the compound is administered orally, it may be formulated as a pill, capsule,
tablet, etc. with a pharmaceutically acceptable carrier or excipient. Where the compound is
administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle
and in a unit dosage injectable form, as detailed below.
PHARMACEUTICAL FORMULATIONS
[00394] In order to use a compound of this invention for the therapeutic treatment (including
prophylactic treatment) of mammals including humans, it is normally formulated in accordance with
standard pharmaceutical practice as a pharmaceutical composition. According to this aspect of the
invention there is provided a pharmaceutical composition that comprises a compound of this
invention in association with a pharmaceutically acceptable diluent or carrier.
[00395] In another embodiment of the invention, an article of manufacture, or "kit",
containing materials useful for the treatment of the disorders described above is provided. In one
embodiment, the kit comprises a container comprising a compound of this invention. Suitable
containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be
formed from a variety of materials such as glass or plastic. The container may hold a compound of
this invention or a formulation thereof which is effective for treating the condition and may have a
sterile access port (for example, the container may be an intravenous solution bag or a vial having a
stopper pierceable by a hypodermic injection needle).

EXAMPLES
[00396] In order to illustrate the invention, the following examples are included. However, it
is to be understood that these examples do not limit the invention and are onty meant to suggest a
method of practicing the invention. Persons skilled in the art will recognize that the chemical
reactions described may be readily adapted to prepare a number of other glucokinase activators of the
invention, and alternative methods for preparing the compounds of this invention are deemed to be
within the scope of this invention. For example, the synthesis of non-exemplified compounds
according to the invention may be successfully performed by modifications apparent to those skilled
in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents
known in the art other than those described, and/or by making routine modifications of reaction
conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as
having applicability for preparing other compounds of the invention.
[00397] The compounds of this invention also include the compounds of Examples 1 -478
described below, with the exception of the examples labeled as "reference examples". Compounds
labeled "Reference Examples" were found to be weakly active in the in vitro assays described below,
and are provided to illustrate representative methodology in preparing compounds of Formula I.
[00398] In the examples described below, unless otherwise indicated all temperatures are set
forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich
Chemical Company, Lancaster, TCI or Maybridge, and were used without further purification unless
otherwise indicated.
[00399] The reactions set forth below were done generally under a positive pressure of
nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the
reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents
by syringe. Glassware was oven dried and/or heat dried.
[00400] Column chromatography was done on a Biotage system (Manufacturer: Dyax
Corporation) having a silica gel column or on a silica SepPak cartridge (Waters). *H NMR spectra
were recorded on a Varian instrument operating at 400 MHz. *H NMR spectra were obtained as
CDC13 or d6-DMSO solutions (reported in ppm), using (7.25 ppm) or tetramethylsilane (0.00 ppm) as
the reference standard (7.25 ppm). When peak multiplicities are reported, the following
abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet
of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).


[00401] Step A: 2-f2-chloropvridin-3-vIoxyl)benzonitrile: A 50 mLround bottom flask was
charged with 2-chloropyridin-3-ol (2.5 g, 19 mmol), 2-fluorobenzonitrile (2.6 g, 21 mmol) and
potassium carbonate (6.7 g, 48 mmol) in DMF (10 mL) and heated at 90 °C for 1.5 days. Water was
added water, and the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate,
filtered and concentrated. The residue was purified by silica gel column chromatography using 10-
20% ethyl acetate in hexanes as eluent to afford the title compound as an off white solid (2.1 g, 47%
yield).
[00402] Step B: 2-(2-(4-methvlthiazol-2-vlamino'>pvridin-3-vloxv')benzonitrile: A 50
mLround bottom flask was charged with 2-(2-chloropyridin-3-yloxy)benzonitrile (0.667 g, 2.89
mmol), 4-rnethylthiazol-2-amine (0.300 g, 2.63 mmol), potassium phosphate (0.614 g, 2.89 mmol)
and toluene (7 mL). The reaction mixture was degassed with nitrogen. Tris(dibenzylideneacetone)-
dipalladium (0) (0.0602 g, 0.0657 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene
(0.0418 g, 0.0723 mmol) were added, and the reaction mixture was degassed with nitrogen. The
reaction mixture was warmed to 90 °C and degassed water (2 mL) was added. The reaction mixture
was stirred at 90 °C overnight. Water was added and the reaction mixture was extracted with ethyl
acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated . The residue
was purified by silica gel column chromatography using 10-40% ethyl acetate in hexanes as eluent to
afford the title compound as a yellow solid (0.385 g, 46.6% yield). H NMR (CDC13) 8 8.19 (dd,
1H), 7.68 (dd, 1H), 7.49 (m, 1H), 7.19 (dd, 1H), 7.15 (dd, 1H), 6.85 (m, 2H), 6.39 (m, 1H), 2.29 (d,
3H); Mass spectrum (esi) m/z = 309 (100).

[00403] Prepared according to the method of Example 1, starting with 4-(2-chloropyridin-3-
yloxy)benzonitrile. 'H NMR (CDCI3) 5 8.19 (dd, 1H)," 7.62 (m, 1H), 7.59 (m, 1H), 7.21 (dd,. 1H),

7.02 (m, 1H), 7.00 (m, 1H), 6.87 (dd, 1H), 6.39 (m, 1H), 2.28 (d, 3H); Mass spectrum (esi) m/z = 309
(100).

[00404] Prepared according to the method of Example 1, Step B, starting with 2-(2-
chloropyridin-3-yloxy)benzonitrile. 'H NMR (CDC13) 5 9.14 (bs, 1H), 8.28 (dd, 1H), 7.73 (dd, 1H),
7.56 (m, 1H), 7.24-7.29 (m, 2H), 7.00 (dd, 1H), 6.94 (d, 1H) 2.52 (s, 3H); Mass spectrum (esi) m/z =
310(100).

[00405] Prepared according to the method of Example -1, Step B, starting with 4-
methylthiazol-2-amine. ]H NMR (CDC13) 8 10.12 (bs, 1H), 8.13 (m, 1H), 7.84 (dd, 1H), 7.71 (dt,
1H), 7.59 (m, 2H), 7.41 (dd, 1H), 7.11 (dd, 1H), 6.23 (m, 1H), 2.28 (d, 3H); Mass spectrum (esi) m/z
= 329(100).

[00406] Prepared according to the method of Example 1, Step B, starting with 4-
methylthiazol-2-amine. 'HNMR (CDC13) 8 9.30 (bs, 1H), 8.24 (m, 1H), 8.22 (m, 1H), 8.00 (dd, 1H),
7.44 (dd, 1H), 7.33 (m, 1H), 7.30 (m, 1H), 7.21 (dd, 1H), 6.53 (m, 1H), 2.36 (d, 3H); Mass spectrum
(esi) m/z = 329 (100).


[00407] Prepared according to the method of Example 1, starting with 2-chloro-3-(4-
(methylsulfonyl)phenoxy)pyridine. lH NMR (CDC13) 8 8.28 (dd, 1H), 7.94 (m, 1H), 7.92 (m, 1H),
7.63 (dd, 1H), 7.23 (m, 1H), 7.21 (m, 1H), 7.13 (dd, 1H), 6.74 (bs, 1H), 3.20 (s, 3H), 2.26 (d, 3H);
Mass spectrum (esi) m/z = 362 (100).

[00408] Step A: 3-bromo-5-chloropyridin-2-amine: A 250 mLround-bottomed flask was
charged with 5-chloropyridin-2-amine (80 g, 622.3 mmol) and CHCI3 (100 mL). Added bromine
(31.98 mL, 622.3 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was
poured into saturated bicarbonate and NaHSC>3 and extracted with CH2C12. The organic layer was
dried with sodium sulfate, filtered and concentrated to afford the title compound (113.8 g, 88.1%
yield) as a tan solid. 'HNMR (dVDMSO) 8 7.97 (d, 1H), 7.90 (d, 1H), 6.44 (bs:, 2H).
[00409] Step B: 5-chloro-3-phenoxvpyridin-2-amine: 3-Bromo-5-chloropyridin-2-amine
(50.0 g, 241 mmol), phenol (45.4 g, 482 mmol), copper(I)oxide (1.72 g, 12.1 mmol), (E)-2-
hydroxybenzaldehyde oxime (6.61 g, 48.2 mmol), CS2CO3 (157 g, 482 mmol), and 3A powdered
molecular (72.3 g) sieves were placed in DMF (300 mL) and heated at 110 °C for 3 days. Reaction
was cooled, then filtered through celite. Reaction was then partitioned between water and ether. An
emulsion was formed and was filtered through a plug of celite. Water was extracted with ether men
dried, filtered, and concentrated. Crude material was purified on a first silica gel chromatography (5-
10% EtOAc in hexanes), and then on a second column to provide the title compound (8.00 g, 15.0%
yield). JH NMR (CDC13) 5 7.80 (d, 1H), 7.39 (t, 2H), 7.19 (t, 1H), 7.03 (d5 2H), 6.94 (d, 1H), 4.76
(bs, 2H); Mass spectrum (apci) m/z = 221 (100).
[00410] Step C: 1 -beirzovl-3-(5-chloro-3-phenoxvpvridin-2-vDthiourea: 5-chloro-3-
phenoxypyridin-2-amine (8.493 g, 38.490 mmol) and benzoyl isothiocyanate (6.9096 g, 42339

mmol) were placed in THF (200 mL) and stirred at room temperature for 2 hours. THF was
removed. A suspension was made by adding Hexanes:EtOAc (9:1). The suspension was filtered and
the solid was washed with hexanes then dried to afford the title compound (13.752 g, 93.1% yield) as
a yellow solid. *H NMR (d6-DMSO) 5 12.35 (s, 1H), 11.84 (s, 1H), 8.34 (d, 1H), 7.95 (d, 2H), 7.66
(t, 1H), 7.53 (t, 2H), 7.44 (m, 3H), 7.24 (t, 1H), 7.18 (m, 2H); Mass spectrum (apci) m/z = 383.1
(M+H).
[00411] Step D: l-(5-chloro-3-phenoxvpvridin-2-vl)thiourea: A 250 mLround-bottomed flask
was charged with l-benzoyl-3-(5-chloro-3-phenoxypyridin-2-yl)thiourea (13.752 g, 35.826 mmol)
and THF (100 mL). 3M NaOH (119.42 mL, 358.26 mmol) was added and the reaction mixture was
heated to 90 °C for 18 hours. The reaction mixture was cooled to room temperature and concentrated
The resulting solids were filtered, washed with water, and dried to provide the title compound (9.49
g, 94.689% yield) as a yellow solid. 'HNMR (d6-DMSO) 5 9.97 (s, 1H), 9.25 (s, 1H), 8.87 (s, 1H),
8.11 (d, 1H), 7.49 (t, 2H), 7.31 (d, 1H), 7.28 (m, 2H), 7.23 (d, 2H); Mass spectrum (apci) m/z = 279.9
(M+H).
[00412] Step E: 5-chloro-N-f4-methvlthiazol-2-vn-3-phenoxvpvridin-2-amine: A mixture of
l-chloropropan-2-one (3.827 g, 41.36 mmol), l-(5-chloro-3-phenoxypyridin-2-yl)thiourea (8.265 g,
29.54 mmol), triethylamine (7.001 mL, 50.23 mmol), and ethanol (30 mL) was refluxed for 3 hours.
The ethanol was removed to about one third original volume, and then the reaction mixture was
cooled in an ice bath and filtered. The solids were washed with cold ethanol and dried to afford the
title compound (8.35 g, 88.96% yield) as a light yellow powder. JH NMR (d^DMSO) 5 10.94 (bs,
1H), 8.15 (d, 1H), 7.43 (t, 2H), 7.32 (d, 1H), 7.20 (t, 1H), 7.19 (d, 2H), 6.60 (s, 1H), 2.23 (s, 3H);
Mass spectrum (apci) m/z = 318.2 (M+H).

[00413] 5-Chloro-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (0.150 g, 0.472 mmol)
was placed in THF (30 mL) and cooled to -78 °C. MeLi (0.369 mL, 0.590 mmol) was slowly added
and the reaction mixture was stirred for 10 minutes. Butyllithium (0.236 mL, 0.590 mmol) was
added and the reaction mixture was stirred for 30 minutes. 1,2-Diphenyldisulfane (0.103 g, 0.472
mmol) was added and the reaction mixture was warmed to .room temperature, then stirred for 15
minutes. The reaction mixture was quenched with ammonium .chloride and extracted with CH2CI2.

The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel
chromatography (10-20% EtOAc in hexanes), and then by reverse phase chromatography to give the
title compound (0.0572 g, 28.3% yield) after salt formation. *H NMR (de-DMSO) 8 10.94 (bs, 1H).
8.15 (d, 1H), 7.43 (t, 2H), 7.32 (d, 1H), 7.20 (t, 1H), 7.19 (d, 2H), 6.60 (s, 1H), 2:23 (s, 3H); Mass
spectrum (apci) m/z = 392.2 (M+H-HC1).

[00414] 5-Chloro-N-(4-methylthiazol-2-yl)-3-phenoxvpyridin-2-amine (0.150 g, 0.472 mmol),
phenylboronic acid (0.0691 g, 0.566 mmol), Pd(PPh3)4 (0.0545 g, 0.0472 mmol), in DME (10 mL),
and 2M Na2CO3 (5 mL) were placed in a round bottom flask, heated to 80 °C and stirred overnight.
An extra equivalent of Pd(PPh3)4 (0.0545 g, 0.0472 mmol), and phenylboronic acid (0.0691 g, 0.566
mmol) were added and the reaction mixture was heated for 2 weeks. The reaction mixture was
cooled to room temperature and partitioned between CH2CI2 and water. The organic layer was dried,
filtered, and concentrated. The residue was purified by silica gel chromatography and then by reverse
phase chromatography to give the title compound (0.0134 g, 7.17% yield) after salt formation. *H
NMR (d6-DMSO) 5 8.53 (d, 1H), 7.65 (m, 3H), 7.45 (m, 4H), 7.37 (m, 1H), 7.21 (t, 1H), 7.16 (d,
2H), 6.78 (s, 1H), 2.29 (s, 3H); Mass spectrum (apci) m/z = 360.3 (M+H-HC1).

[00415] Step A: 3-phenoxvpyridin-2-amine: Prepared according to the method of Example 7
Step A, starting with bromopyridin-2-amine, phenol, and (E)-2-hydroxybenzaldehyde oxime (20.61
g, 150.3 mmol).
[00416] Step B: 5-bromo-3-phenoxvpvridin-2-amme: 3-Phenoxypyridin-2-amine (20.50 g,
110.1 mmol) was placed in acetic acid (50 mL) and cooled to 0 °C. Bromine (d 3.12) (7.049 mL,
137.6 mmol) was slowly added and the reaction mixture was stirred for 1 hour. The reaction mixture

was poured onto saturated sodium bisulfite and ice and allowed to sit overnight. Solids were
removed by filtration and washed with water to give pure 5-bromo-3-phenoxypyridin-2-amine. The
filtrate was then extracted with CH2CI2 several times, combined, and washed with water. Organic
layer was dried, filtered, and concentrated. The residue was purified by silica gel (5-20% EtOAc in
hexanes) to give additional 5-bromo-3-phenoxypyridin~2-amine (total yield: 22.69 g, 77.74% yield).
[00417] Step C: l-benzovl-3-f5-bromo-3-phenoxvpvridin-2-ynthiourea: Prepared according to
the method of Example 7 Step C.
[00418] Step D: l-(5-bromo-3-phenoxvpvridin-2-vl*)thiourea: Prepared according to the
method of Example 7 Step D.
[00419] Step E 5-bromo-N-(4-methvlthiazol-2-vl'>-3-phenoxvpvridin-2-amine: Prepared
according to the method of Example 7 Step E, using l-chloropropan-2-one. !H NMR (d6-DMSO) 8
10.90 (bs, 1H), 8.21 (d, 1H), 7.43 (t, 2H), 7.39 (d, 1H), 7.20 (t, IH), 7.09 (d, 2H), 6.61 (s, 1H), 2.23
(s, 3H); Mass spectrum (apci) m/z = 364.1 (M+H).

[00420] 5-Bromo-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine (0.070 g, 0.1932
mmol), pyridin-3-ylboronic acid (0.02850 g, 0.2319 rnmol), Pd(PPh3)4 (0.02233 g, 0.01932 mmol),
DME (10 mL), and 2M sodium bicarbonate (2 mL) were combined, heated to 80 °C and stirred
overnight. The reaction mixture was cooled and partitioned between CH2CI2 and water. The organic
layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography
(30-40% EtOAc in hexane) to give N-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-
amine. N-(4-methylthiazol-2-yI)-3-phenoxy-5-(pyridin-3-yl)pyridin-2-amine was dissolved in
CH2CI2 and 2M HC1 in ether was added to give N-(4-methylthiazol-2-yl)-3-phenoxy-5-(pyridin-3-
yl)pyridin-2-amine dihydrochloride (0.050 g, 59.71% yield). lH NMR (ds-DMSO) 8 9.19 (d, IH),
8.78 (dd, IH), 8.70 (m, 2H), 7.93 (m, 2H), 7.42 (t, 2H), 7.18 (t, IH), 7.12 (d, 2H), 6.74 (s, IH), 2.28
(s, 3H); Mass spectrum (apci) m/z = 361.2 (M+H-2HCI).


[00421] Prepared according to the method of Example 11, using 5-bromo-N-(4-methylthiazol-
2-yl)-3-phenpxypyridin-2-amine and pyridin-4-ylboronic acid. 'H NMR (d6-DMSO) 5 8.96 (d, 1H),
8.86 (d, 2H), 8.05 (d, 1H), 7.42 (t, 2H), 7.17 (t, 1H), 7.17 (t, 1H), 7.10 (d, 2H), 6.73 (s, 1H), 2.26 (s,
3H); Mass spectrum (apci) m/z = 361.3 (M+H-2HC1).

[00422] A 25 mL round-bottomed flask was charged with 5-bromo-N-(4-methylthiazol-2-yl)-
3-phenoxypyridin-2-amine (350 mg, 0.966 mmol), Pd2dba3 (22.1 mg, 0.024 mmol), 4,5-
bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9 mg, 0.048 mmol), N-ethyl-N-
isopropylpropan-2-amine (0.33 mL, 1.9 mmol), methyl 3-mercaptopropanoate (0.12 mL, 1.1 mmol),
and dioxane (10 mL). The reaction mixture was heated to 100 °C under nitrogen for 2 hours. The
reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified
by silica gel chromatography (40% EtOAc in hexanes) to afford the title compound (328 mg, 84.5%
yield) as a pale yellow solid. HCI salt made for characterization. 'H NMR (de-DMSO) 8 8.18 (d, 1H),
7.45 (m, 2H), 7.36 (d, 1H), 7.22 (t, 1H), 7.13 (d, 2H), 6.79 (s, 1H), 3.55 (s, 3H), 3.07 (t, 2H), 2.57 (t,
2H), 2.2? (s, 3H); Mass spectrum (esi) m/z = 402.2 (100)(M+H-HCl).
Example 14
N-fS-fcvclohexvlthioVS-phenoxvpvridin^-vn^-methvlthiazol^-aminehvdrochloride
CrsT^Nx>
a
n H
HCI

[00423] Prepared according to the method of Example 13, using 5-bromo-N-(4-methylthiazol-
2-yl)-3-phenoxypyridin-2-amine and cyclohexanethiol. 'H NMR (de-DMSO) 5 8.17 (d, 1H), 7.45 (m,
2H), 7.30 (d, 1H), 7.22 (t, 1H), 7.13 (m, 2H), 6.80 (s, 1H), 3.08 (m, 1H), 2.29 (s, 3H), 1.82 (m, 2H),
1.66 (m, 2H), 1.52 (m, 1H), 1.23 (m, 5H); Mass spectrum (esi) m/z = 398.2 (100)(M+H-HCl).

[00424] Prepared according to the method of Example 13, using 5-bromo-N-(4-inethylthiazol-
2-yI)-3-phenoxypyridin-2-amine and phenylmethanethiol. *H NMR (d6-DMSO) 5 8.08 (d, 1H), 7.42
(m, 2H), 7.28-7.15 (m, 7H), 6.98 (m, 2H), 6.74 (s, 1H), 4.12 (s, 2H), 2.27 (s, 3H); Mass spectrum
(esi) m/z = 406.2 (100) (M+H-HC1).

[00425] A 20 mL vial was charged with methyl 3-(6-(4-methylthiazol-2-ylamino)-5-
phenoxypyridin-3-ylthio)propanoate (135.8 mg, 0.338 mmol) and THF (0.5 mL). 1M KOtBu in THF
(1.184 mL, 1.184 mmol) was added and the reaction mixture was stirred at room temperature for 30
seconds. 2-(Bromomethyl)pyridine hydrobromide (85.55 mg, 0.3382 mmol) was added and the
reaction mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium
chloride was added and the reaction mixture was extracted with EtOAc. The concentrated residue
was purified on silica gel to afford N-(4-methylthiazol-2-yI)-3-phenoxy-5-(pyridin-2-
ylmethyltb.io)pyridin-2-amine dihydrochloride (98.2 mg, 60.5% yield) as a pale yellow solid after
HC1 salt formation. 'H NMR (d6-DMSO) 8 8.66 (dd, 1H), 8.22 (td, 1H), 8.12 (d, 1H), 7.70 (t, 1H),
7.62 (d, 1H), 7.45 (m, 2H), 7.23 (t, 1H), 7.16 (d, 1H), 7.06 (m, 2H), 6.82 (m, 1H), 4.42 (s, 2H), 2^9
(s, 3H); Mass spectrum (esi) m/z = 407.2 (100) (M+H-2HC1).


[00426] Prepared according to the method of Example 16, using methyl 3- methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate. 'H NMR (d6-DMSO) 8 8.83 (m,
1H), 8.52 (m, 1H), 8.18 (dd, 1H), 7.43 (m, 2H), 7.36 (dd, 1HX 7.20 (td, 1H), 7.10 (m, 2H), 6.72 (s,
1H), 3.57 (d, 1H), 3J21 (m, 2H), 2.86 (m, 2H), 2.79 (m, 2H), 226 (s, 3H), 1.87 (m, 2H), 1.67 (m, 1H),
1.35 (m, 2H); Mass spectrum (esi) m/z= 413.1 (100)(M+H-2HC1).

[00427] Prepared according to the method of Example 7, using 1-bromobutan-2-one. Mass
spectrum (esi) m/z = 332 (100), 334 (38).

[00428] Prepared according to the method of Example 7, using 3-chlorobutan-2-one. 'H
NMR (dfi-DMSO) 8 10.78 (bs, 1H), 8.11 (s, 1H), 7.42 (t, 2H), 7.29 (s, 1H), 7.19 (t, 1H), 7.09 (d, 2H),
222 (s, 3H), 2.12 (s, 3H); Mass spectrum (esi) m/z = 332 (100), 334 (38).


[00429] Prepared according to the method of Example 7, using l-chloro-4-methylpentan-2-
one. ^NMRCds-DMSO) 8 10.89 (bs, 1H), 8.15 (s, 1H), 7.43 (t, 2H), 7.31 (s, 1H), 7.20 (t, 1H), 7.11
(d, 2H), 6.61 (s, 1H), 2.42 (d, 2H), 1.98 (m, 1H), 0.88 (d, 6H); Mass spectrum (esi) m/z = 360 (100),
362 (37).

[00430] Prepared according to the method of Example 7, using l-chlorohexan-2-one. 'H NMR
(d6-DMSO) 8 10.89 (bs, 1H), 8.15 (s, 1H), 7.42 (t, 2H), 7.32 (s, 1H), 7.21 (t, 1H), 7.10 (d,2H), 6.61
(s, 1H), 2.56 (t, 2H), 1.59 (m, 2H), 1.31 (m, 2H), 0.87 (t, 3H); Mass spectrum (esi) m/z = 360 (100),
362 (37).

[00431] Prepared according to the method of Example 7, using 2-bromo-l-
cyclopropylethanone. !H NMR (d6-DMSO) 8 10.82 (bs, 1H), 8.15 (s, 1H), 7.43 (t, 2H), 7.31 (s, 1H),
7.21 (t, 1H), 7.10 (d, 2H), 6.64 (s, 1H), 1.94 (m, 1H), 0.72-0.85 (m, 4H); Mass spectrum (esi) m/z -
344 (100), 346 (37).


[00432] Prepared according to the method of Example 16 with l-(chloromethyl)-2-
methoxybenzene. *H NMR (de-DMSO) 8 8.05 (d, 1H), 7.43 (t, 2H), 7.21 (q, 2H), 7.11 (d, 1H), 7.01
(m, 3H), 6.93 (d, 1H), 6.80 (t, 1H), 6.69 (s, 1H), 4.01 (s, 2H), 3.68 (s, 3H), 2.26 (s, 3H); Mass
spectrum (apci) m/z = 436.2 (M+H-HC1).

[00433] • Prepared according to the method of Example 16 with l-(chloromethyl)-4-
methoxybenzene. 'H NMR (de-DMSO) 8 8.09 (d, 1H), 7.42 (t, 2H), 7.21 (t, 1H), 7.14 (d, 1H), 7.10
(d, 2H), 7.00 (d, 2H), 6.81 (d, 2H), 6.75 (s, 1H), 4.06 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H); Mass
spectrum (apci) m/z = 436.2 (M+H-HC1).

[00434] F Prepared according to the method of Example 16, with l~(bromomethyl)-2-
chlorobenzene (0.0512 g, 0^49 mmol) were reacted to provide 5-(2-chlorobenzylthio)-N-(4-
methylthiazol-2-yl)-3-phenoxypyridin-2-amine hydrochloride (0.073 g, 61.5%) after HC1 salt
formation. ]H NMR (d6-DMSO) 8 8.09 (d, 1H), 7.42 (m, 3H), 7.27 (dt, 1H), 7.18 (m, 3H), 7.08 (d5

1H), 7.00 (d, 2H), 6.71 (s, 1H), 4.15 (s, 2H), 2.26 (s, 3H); Mass spectram (apci) m/z = 440.1 (M+H-
HC1).

[00435] Prepared according to the method of Example 16 with l-(l-bromoethyl)benzene
(0.0461 g, 0.249 mmol) were reacted to provide N-(4-methylthiazol-2-yl)-3-phenoxy-5-(l-
phenylethylthio)pyridin-2-amine hydrochloride (0.058 g, 51.1%). 'HNMR (d6-DMSO) 5 8.05 (d,
1H), 7.42 (t, 2H), 7,22 (m, 6H), 7.03 (d5 1H), 6.94 (d, 2H), 6.73 (s, 1H), 4.43 (q, 1H), 2.26 (s, 3H),
1.51 (d, 3H); Mass spectrum (apci) m/z = 420.1 (M+H-HC1).

[00436] Prepared according to the method of Example 13 with 3-bromo-N-(4-methylthiazol-
2-yl)pyridin-2-amine and benzenethiol. 'H NMR (d6-DMSO) 5 8.42 (m, 1H), 7.90 (m, 1H), 7.41-7.25
(m, 5H), 7.12 (m, 1H), 6.74 (m, 1H), 2.25 (s, 3H); Mass spectrum (esi) m/z = 300.2 (100)(M+H-
HC1).

[00437] Prepared according to the method of Example 13, with 3-bromo-N-(4-methylthiazol-
2-yl)pyridin-2-amine and 2-chlorobenzenethiol. *H NMR (de-DMSO) 8 8.45 (m, 1H), 7.80 (bs, 1H),
7.57 (m, 1H), 7.27 (m, 2H), 7.07 (m, 1H), 6.84 (m, 1H)5 6.62 (m, 1H), 2.21 (s, 3H); Mass spectrum
(esi) m/z = 334.2 (100)(M+H-HCl).


[00438] Prepared according to the method of Example 13, with 3-bromo-N-(4-methylthiazol-
2-yl)pyridin-2-amine and 3-methoxybenzenethiol. *H NMR (ds-DMSO) S 8.43 (d, 1H), 7.92 (bs,
1H), 7.27 (m, 1H), 7.12 (m, 1H), 6.86 (m, 2H), 6.80 (d, 1H), 6.72 (s, 1H), 3.72 (s, 3H), 2.25 (s, 3H).

[00439] Prepared according to the method of Example 13, with 3-bromo-N-(4-methylthiazoI-
2-yl)pyridin-2-amine and methyl 2-mercaptobenzoate. 'H NMR (d6-DMSO) 5 8.54 (d, 1H), 8.07 (s,
1H), 8.01 (dd, 1H), 7.41 (m, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 6.73 (m, 1H), 6.61 (d, 1H), 3.92 (s,
3H), 2^1 (s, 3H).

[00440] Prepared according to the method of Example 13, with 3-bromo-N-(4-methylthiazol-
2-yl)pyridin-2-amine and cyclopentanethiol. jH NMR (d6-DMSO) 6 8.39 (d, 1H), 8.05 (d, 1H), 7.18
(dd, 1H), 6.89 (s, 1H), 3.64 (m, 1H), 2.33 (s, 3H), 1.95 (m, 2H), 1.75 (m, 2H), 1.53 (m, 4H); Mass
spectrum (esi) m/z = 292.1 (100)(M+H-HCl).


[00441] Prepared according to the method of Example 8, using 5-bromo-N-(4-methylthiazol-
2-yl)-3-phenoxypyridin-2-amine. *H NMR (d6-DMSO) 8 8.20 (d, 1H), 7.46 (t, 2H), 7.39 (d, 1H),
7.24 (t, 1H), 7.15 (m, 3H), 6.89 (s, 1H), 2.33 (s, 3H); Mass spectrum (apci) m/z == 284.2 (M+H-HC1).

[00442] Step A: Preparation of 2-f 1-bromoethyHpyridine: 2-Ethylpyridine (20.0 g, 186.65
mmol) was placed in carbon tetrachloride (830 mL) and benzoyl peroxide (4.5211 g, 18.665 mmol)
and l-bromopyrrolidine-2,5-dione (33.221 g, 186.65 mmol) were added. The reaction mixture was
heated to reflux for 18 hours, then cooled to room temperature and filtered. The filtrate was
concentrated and the residue was purified over a plug of silica to give 2-(l -bromoethyl)pyridine
(17.312 g, 49.9%). 'H NMR (CDCi3) 8 8.58 (d, 1H), 7.69 (td, 1H), 7.76 (d, 1H), 7.20 (dd, 1H), 5.24
(q,lH),2.08(d,3H)
[00443] Step B: Preparation of N-r4-methvlthiazol-2-vlV3-phenoxy-5-n-fpvridin-2-
vnethvlthiotevridin^-amine dihvdrochloride: Following the procedure in Example 16, methyl 3-(6-
(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (0.325 g, 0.809 mmol), 1M
potassium 2-methylpropan-2-olate (2.83 ml^ 2.83 mmol), and 2-(l-bromoethyl)pyridine (0.151 g,
0.809 mmol) were reacted to provide N-(4-methylthiazol-2-yl)-3-phenoxy-5-(l-(pyridin-2-
yl)ethylthio)pyridin-2-amine hydrochloride (0.114 g, 30.8%) after reverse phase purification and HC1
salt formation. !H NMR (d6-DMSO) 5 8.58 (d, 1H), 8.09 (m, 1H), 8.04 (d, 1H), 7.58 (d, 2H), 7.45 (t,
2H), 7^3 (t, 1H), 7.02 (d, 2H), 6.95.(d, 1H), 6.79 (s, 1H), 4.67 (q, 1H), 228 (s, 3H), 1.62 (d, 3H);
Mass spectrum (esi) m/z = 421.1 (M+H-2HC1).


[00444] Prepared according to the method of " Example 16, using methyl 3-(6-(4-
methylthiazol-2-ylamino)-5-phenoxypyridin-3-yIthio)propanoate and . l-(chloromethyl)-3-
methoxybenzene. JH NMR (d6-DMSO) 8 8.09 (d, 1H), 7.42 (t, 2H), 7.18 (m, 3H), 6.98 (d, 2H), 6176
(m, 4H), 4.09 (s, 2H), 3.68 (s, 3H), 2.26 (s5 3H); Mass spectrum (esi) tn/z = 436.2 (M+H-1HC1).

[00445] 2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (0.250 g, 1.21 mmol) and Cs2CO3 (1.18
g, 3.62 mmol) were added to DMF (3 mL). 3-Bromocyclohex-l-ene (0.216 g, 1.21 mmol) was added,
and the reaction mixture was stirred for 3 hours. Water was added and the reaction mixture was
extracted with ether. The organic layer was dried, filtered, and concentrated. The residue was
purified by silica gel chromatography provide 3-(cyclohex-2-enyloxy>N-(4-methylthiazol-2-
yl)pyridin-2^amine (0.130 g; 37.5%). ]H NMR (d6-DMSO) 5 9.53 (s, 1H), 7.85 (dd, 1H), 7.41 (d,
1H), 6.90 (dd, 1H), 6-58 (s, 1H), 6.00 (m, 1H), 6.88 (m, 1H), 6.88 (m, 1H), 4.99 (m, 1H), 2.24 (s,
3H), 2.05 (m, 2H), 1.87 (m, 3H), 1.62 (m, 1H); Mass spectrum (apci) m/z = 288.0 (M+H).

[00446] 3-(Cyclohex-2-enyloxy)-N-(4-methylthiazoI-2-yl)pyridin-2-amine (0.115 g, 0.400
mmol) and 4-methylbenzenesulfonohydrazide (1.12 g, 6.00 mmol) were placed in dimethoxyethane
(5 mL). NaOAc (0.492 g, 6.00 mmol) was dissolved in water (2 mL) and added to the above solution
and refluxed. Additional 4-methylbenzenesulfonohydrazide (1.12 g, 6.00 mmol) was added and the

reaction mixture was refluxed overnight. An aqueous work up was done and the crude material was
purified by silica gel chromatography to provide 3-(cyclohexyloxy)-N-(4-methylthiazol-2-yl)pyridin-
2-amine (0.064 g, 553%) after HC1 salt formation. 'H NMR (tU-DMSO) 8 7.79 (d, 1H), 7.57 (d,
1H), 7.09 (m, 1H), 6.83 (s, 1H), 4.54 (m, 1H), 2.32 (s, 3H), 1.97 (m, 2H), 1.79, (m, 2H), 1.57 (m,
3H), 1.36 (m, 3H); Mass spectrum (apci) m/z = 291.1 (M+H-HC1).

[00447] Prepared according to the method of Example 35 with iodocyclopentane. 'H NMR
(tU-DMSO) 8 7.92 (d, 1H), 7.46 (d, 1H), 7.08 (dd, 1H), 6.80 (s, 1H), 5.49 (m, 1H), 2.32 (s, 3H), 1.88
(m, 6H), 1.60 (m, 2H); Mass spectrum (apci) m/z = 276.1 (M+H-HC1).

[00448J Prepared according to Example 16 from methyl 3-(6-(4-mcthylthiazol-2-ylamino)-5-
phenoxypyridin-3-ylthio)propanoate and potassium 2-methylpropan-2-olate, with the exception that
the reaction mixture was heated to 50 °C for 30 minutes. *H NMR (d«-DMSO) 8 9.90 (s, 1H), 8.21
(d, 1H), 7.43 (t, 2H), 739 (d, 1H), 7.18 (t, 1H), 7.08 (d, 2H), 6.67 (s, 1H), 3.10 (m, 2H), 2.92 (t, 2H),
2.72 (d, 6H). 2.24 (s, 3H), 1.85 (m. 2H); Mass spectrum (apci) m/z = 4012. (M+H-2HC1).


[00449] Step A: Preparation of 3-(5-bromo-2-chlorophenoxv)pvridin-2-amine: 4-2-
aminopyridin-3-ol (7.56 g, 68.6 mrnol) was added to a mixture of sodium hydride (1.72 g, 71.9
mmol) in DMF (20 mL) and stirred for 10 minutes. 4-Bromo-l -chloro-2-fluorobenzene (13.69 g,
65.4 mmol) was added and the reaction mixture was stirred at 100 °C for 38 hours. The reaction
mixture was cooled to room temperature and partition between IN NaOH and ether. The organic
layer was dried over sodium sulfate, filtered, and concentrated . The residue was triturated with
hexanes to give 3-(5-bromo-2-chlorophenoxy)pyridin-2-amine (11.30 g, 57.7%) as a yellow solid.
[00450] Step B: Preparation of ethvl 3-(2-aminopvridin-3-vloxv>4-chIorobenzoate: 3-(5-
Bromo-2-chlorophenoxy)pyridin-2-amine (11.30 g, 37.72 mmol), triethylamine (3.817 g, 37.72
mmol), Pd(OAc)2 (0.8469 g, 3.772 mmol), and triphenylphosphine (0.9894 g, 3.772 mmol) were
added to ethanol (100 mL) in a bomb. The bomb was pressurized with 100 psi CO and heated to 100
°C for 4 hours. The reaction mixture was cooled to room temperature and filtered. Dichloromethane
was added and solids were filtered off. The filtrate was washed with water. The organic layer was
dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel
chromatography to give ethyl 3-(2-aminopyridin-3-yloxy)-4-chlorobenzoate (7.555 g, 68.42%).
[00451] Step C: Preparation of ethyl 3-f2-amino-5-bromopvridin-3-vloxv')-4-chlorobenzoate:
Prepared according to the method of Example 10, Step B.
[00452] Step D: Preparation of ethvl 3-(2-(3-benzoylthioureidoV5-bromopvridin-3-vloxv')-4-
chlorobenzoate: Ethyl 3-(2-amino-5-bromopyridin-3-yloxy)-4-chlorobenzoate (9.645 g, 25.95 mmol)
and benzoyl isothiocyanate (4.659 g, 28.55 mmol) were placed in THF (250 mL) and the reaction
mixture was stirred at room temperature for 18 hours, then heated at 55 °C for two days. THF was
removed and the residue was purified by silica gel chromatography (5-25% EtOAc in hexane) to
provide ethyl 3-(2-(3-benzoylthioureido)-5-bromopyridin-3-yloxy)-4-chlorobenzoate (7.08 g, 51.0%)
as a yellow solid.
[00453] Step E: Preparation of ethvl 3-(5-bromo-2-thioureidopyridm-3-yloxy')-4-
chlorobenzoate: Ethyl 3-(2-(3-benzoylthioureido)-5-bromopyridin-3-yloxy)-4-chlorobenzoate (8.05
g, 15.1 mmol) and K2CO3 (10.4 g, 75.3 mmol) were placed in ethanol (150 mL) and heated to reflux
for 2 days and then cooled. The reaction mixture was filtered and the filtrate was concentrated,
triturated with water, and dried. The remaining solid was dissolved in CH2CI2 and purified by silica
gel chromatography to give ethyl 3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate (1.70
g, 26.2% yield).
[00454] Step F: Ethvl 3-(5-bromo-2-(4-methylftiazol-2-vlamino')pvridin-3-vloxv)-4-
chlorobenzoate: l-chloropropan-2-one (0.469 g, 5.07 mmol), ethyl 3-(5-bromo-2-thioureidopyridin-
3-yloxy)-4-chlorobenzoate (1.680 g, 3.39 mmol), triethylamine (0.671 g, 6.63 mmol), and ethanol (70

mL) were reacted according to the method of Example 10, Step E, to provide the title compound
(1.40 g, 77% yield). *H NMR (d6-DMSO) 8 8.26 (d, 1H), 7.78 (m, 2H), 7.50 (s, 1H), 7.46 (d, 1H),
6.59 (s, 1H), 4.29 (q, 2H), 2.23 (s, 3H), 1.28 (t, 3H); Mass spectrum (apci) m/z = 470.1 (M+H).

[00455] Step A: Preparation of 3-(phenvlthio)pyridin-2-amine: A mixture of 3-
bromopyridin-2-amine (167 mg, 0.966 mmol), Pd2dba3 (22.1 mg, 0.024 mmol), 4,5-
bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9 mg, 0.048 mmol), N-ethyl-N-
isopropylpropan-2-amine (0.33 mL, 1.9 mmol), thiophenol (121 mg, 1.1 mmol), and dioxane (10 mL)
was heated at 100 °C under nitrogen for 2 hours. The reaction mixture was cooled to room
temperature, filtered and concentrated. The reaction mixture was purified by MPLC to afford 3-
(phenylthio)pyridin-2-amine.
[00456] Step B: Preparation of 5-bromo-3-fphenvlthio*)pvridin-2-amine: Prepared according
to the method of Example 10, Step B.
[00457] Steps C-E: N-fS-bromo-S-fphenvlthio^pyridin^-vn^-methvlthiazol^-amine:
Prepared according to the method of Example 7 Steps C-E. 'H NMR (CDC13) 8 9.01 (s, 1H), 8.42
(m, 1H), 7.92 (m, 1H), 7.32-7.15 (m, 5H), 6.44 (m, 1H0,2.32 (m, 3H). Mass spectrum (apci) m/z
= 379.8 (M+H).

[00458] N-(5-Bromo-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine (2.66 mmol) is
dissolved in THF (30 mL) and cooled to -78 °C. MeLi (2.07 mL, 3.32 mmol) is slowly added and
the reaction mixture is stirred for 10 minutes. n-Butyllithium (1.33 mL, 3.32 mmol) is added and the
reaction mixture-is stirred for 15 minutes. Triisopropylborate (0.613 mL, 2.66 mmol) is added and
the reaction mixture is stirred for 30 minutes. The reaction mixture is wanned to 0 °C, and methanol
(5 mL), ]0% aqueous NaOH (5.1 mL, 12.8 mmol), and 30% aqueous H2O2 (1.27 mL, 13.3 mmol) are

added. The reaction mixture is stirred at 0 °C for 1 hour, then purified by silica gel chromatography
(10-20% EtOAc in hexanes) to afford 6-(4-methylthiazoI-2-ylamino)-5-phenoxypyridin-3-ol.

[00459] A degassed mixture of N-(S-bromo-3-(2-chlorophenylthio)pyridin-2-yl)~4-
methylthiazol-2-amine (1.10 g, 2.66 mmol), 4,4,4',4',5,5,5',5'-octaniethyl-2,2l-bi(l,352-dioxaborolane)
(1.35 g, 5.32 mmol), Pd(OAc)2 (60 mg, 0.27 mmol), tricyclopehtylphosphine (93 mg. 0.40 mmol)
and cesium fluoride (3.64 g, 23.9 mmol) in acetonitrile is heated at 90 °C for 5 hours. The reaction
mixture is cooled and partitioned between ether and water. The crude product is dissolved in THF.
N-morpholine N-oxide (1.40 g, 12.0 mmol) is added and the reaction mixture is heated at reflux for
12 hours. The reaction mixture is cooled and partitioned.between ether and waterl The organic layer
is washed with water and brine, dried and concentrated. The residue is purified by silica gel
chromatography, eluting with 10-20% EtOAc in hexanes to afford the title compound.

[00460] Iodomethane (0.0362 g, 0.255 mmol) is added to a mixture of 6-(4-methylthiazol-2-
ylamino)-5-phenoxypyridin-3-ol (0.255 mmol) and potassium carbonate (0.0794 g, 0.574 mmol) in
DMF (3 mL) and stirred overnight at room temperature. The reaction mixture is partitioned between
water and ether. The organic layer is washed with water, dried, and concentrated. The residue is
purified by silica gel chromatography, eluting with 15-20% EtOAc in hexanes, to afford the title
compound.


[00461] Step A: N-(5-bromo-3-phenoxypyridin-2-yl)-4-methylthiazol-2-amine (724 mg, 2.00
mfflol) was dissolved in THF (20 mL) and cooled to -78 °C. MeLi (1.30 mL, 2.20 mmol) is added
slowly, and stirred for 10 minutes. n-Butyllithium (0.88 mL, 2.20 mmol).was added and the reaction
mixture was stirred for 15 minutes. DMF (0.31.mL, 4.00 mmol) was added, and the reaction mixture
was stirred for 30 minutes. The reaction mixture was warmed to room temperature and AcOH (2
mL) is added. The reaction mixture was stirred at room temperature for 1 hour, poured into saturated
aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were
dried over sodium sulfate, filtered and concentrated . The residue was purified by silica gel (10-20%
EtOAc in hexanes) to afford 6-(4-methyltluazol-2-ylainino)-5-phenoxynicotirialdehyd.
[00462] . Step B: Step B: To a mixture of mL6-(4-methylthiazol-2-ylamino)-5-
phenoxynicotinaldehyde (311 mg, 1.00 mmol) and THF (10 mL) was added
methyl(triphenylphosphoranylidLene)acetate (500 mg, 1.5 mmol)and the reaction mixture was
stirred at room temperature. After 4 hours, additional methyl(triphenylphosphoranylidene)acetate
(500 mg, 1.5 mmol) was'added and the reaction mixture was stirred overnight. Filtered,
concentrated the filtrate, and purified by silica gel chromatography (1:1 EtOAc in hexanes) to
afford (E)-methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-yl)acrylate.
[00463] Step C: A mixture of mL (E)-methyl 3-(6-(4-methyltluazol-2-ylainino)-S-
phenoxypyridin-3-yl)acrylate (500 mg, 1.36 mmol), 4-methylbenzenesulfonohydrazide (1.27 g,
6.8 mmol), and toluene (15 mL) was heated at reflux for 12 hours, cooled to room temperature
and concentrated. The residue was purified by silica gel (20 to 30% EtOAc in hexanes) to afford
the title compound.

[00464] A mixture of mLmethyl 3-(6-(4-memyl1hiazol-2-ylamino)-5-phenoxypyridin-3-
yl)propanoate (1.50 mmol) and ethanol (30 mL) and 1M NaOH (10 mL) was stirred and heated at
60 °C for 3 hours. Concentrated and water and 6N HC1 (2 mL) were added. Filtered and dried to
yield the title compound.


[00465] A mixture of mL3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-aminc (70 mg, 0.26
mmol), Cs2CO3 (250 mg, 0.78 mmol), PdCl2(dppf) (21.2 mg, 0.026 mmol), and DMF (2 mL) and
water (0.5 mL) was purged with nitrogen and 9-benzyl-9-bora-bicyclo[3.3.1]nonane (1.5 mL,
0.78 mmol) was added and heated to 60 °C overnight. Additional 9-benzyl-9-bora-
bicyclo[3.3.1]nonanc (1.5 mL, 0.78 mmol) was added and heated again overnight. Poured into
water and extracted with ether. The organic layer was dried with sodium sulfate, filtered and
concentrated. The residue was purified on silica gel (10% EtOAc in hexanes) to afford the title
compound (41.7 mg, 50.6% yield) as a white solid after HC1 salt formation. ]H NMR (de-DMSO)
8 8.30 (d, 1H), 7.62 (d, 1H), 7.35-7.10 (m, 6H), 6.82 (s, 1H), 4.21 (s, 2H), 2.32 (s, 3H); Mass
spectrum (esi) m/z = 282.2 (100)(M+H-HCl).

[00466] Prepared according to the method of Example 40. 'H NMR (CDClj) 8 8.95 (bs, 1H),
8.49 (d, lh), 7.95 (d, Ih), 7.41 (dd, 1H), 7.19-7.08 (m, 2H), 6.69 (dd, 1H), 6.45 (s, 1H), 2.32 (s, 3H);
Mass spectrum (esi) m/z = 414.1 (M+H).

[00467] Prepared according to the method of Example 13 from N-(5-brorao-3-(2-
chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (prepared according to Example 47) and

benzenethiol. 'H NMR (d6-DMSO) 5 8.36 (bs, 1H), 7.57 (dd, 1H), 7.40-7.15 (m, 10H), 6.54 (s, 1H),
2.20 (s, 3H); Mass spectrum (esi) m/z = 442.2 (M+H-HC1).

[00468] Prepared according to the method of Example 13 from N-(5-bromo-3-(2-
chlorophenyhhio)pyridin-2-yl)-4-methylthiazol-2-amine (prepared according to Example 47) and
methyl 3-mercaptopropanoate. *H NMR (CDCU) 8 9.01 (bs, IH), 8.52 (d, 1H), 7,95 (d, 1H), 7.40 (dd,
1H), 7.16-7.06 (m, 2H), 6.66 (dd, 1H), 6.46 (s, 1H), 3.68 (s, 3H), 3.07 (t, 2H), 2.61 (t, 2H), 2.32 (s,
3H).; Mass spectrum (esi) m/z = 452.1 (M+H).

[00469] Prepared according to the method of Example 16 from methyl 3-(5-(2-
chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to
Example 49), and 2-(l-bromoethyl)pyridine. *H NMR (dfi-DMSO) 6 8.54 (d, 1H), 8.19 (bs, 1H), 7.97
(m, 1H), 7.61 (dd, 1H), 7.50 (m, 2H), 7.37 (m, 2H), 7.04 (bs, 2H), 6.52 (s, 1H), 4.56 (q, 1H), 2.18 (s,
3H), 1.59 (d, 3H); Mass spectrum (esi) m/z = 471.2 (M+H-2HC1).


[00470] Prepared according to the method of Example 16 using methyl 3-(5-(2-
chlorophenylthio)-6-(4-methylthiazol-2-ylaniino)pyridin-3-ylthio)propanoate and tert-butyl 4-
(bromomethyl)piperidine-l-carboxylate. 'H NMR (d6-DMSO) 5 12.15 (bs, 1H), 10.05 (bs, 1H), 8.64
(m, 1H), 8.32 (m, 2H), 7.63 (m, 1H), 7.36 (m, 2H), 6.52 (s, 1H), 3.22 (m, 2H), 2.79 (m, 4H), 2.17 (s,
3H), 1.86 (m, 2H), 1.61 (m, 1H), 1.36 (m, 2H); Mass spectrum (esi) m/z = 463.0 (M+H-2HC1).

[00471] Prepared according to the method of Example 16 using methyl 3-(5-(2-
chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate and 3-chloro-N,N-
dimethylpropan-1-amine hydrochloride. 'H NMR (de-DMSO) 8 10.12 (bs, 1H), 8.41 (s, 1H), 7.61 (d,
1H), 7.33 (m, 2H), 7.07 (m, 1H), 6.52 (s, 1H), 3.09 (m, 2H), 2.90 (m, 2H), 2.70 (d, 6H), 2.18 (s, 3H),
1.84 (m, 2H); Mass spectrum (esi) m/z * 451.0 (M+H-2HC1).


[00472] Prepared according to the method of Example 13, using 5-bromo-N-(4-methylthiazoI-
2-yl)-3-phenoxypyridin-2-amine and 2-chlorobenzenethiol. *H NMR (d6-DMSO) 8 8.26 (d, 1H),
7.49 (dd, 1H), 7.42 (t, 2H), 7.29 (d, 1H), 7.27-7.12 (m, 4H), 6.96 (dd, 1H), 6.80 (s, 1H), 2.30 (s, 3H);
Mass spectrum (esi) m/z = 426.4 (M+H-HCI).

[00473] Prepared according to the method of Example 13, using 3-chlorobenzenethiol. 'H
NMR (oV-DMSO) 8 8.27 (d, 1H), 7.42 (t, 2h), 7.35-7.10 (m, 8H), 6.81 (s, 1H), 2.30 (s, 3H); Mass
spectrum (esi) m/z = 426.3 (M+H-HCI).

[00474] Prepared according to the method of Example 13j, using 2-methoxybenzenethiol. JH
NMR (de-DMSO) 8 8.14 (d, 1H), 7.42 (t, 2H), 7.27-7.18 (m, 2H), 7.13 (m, 2H), 7.02 (d, 1H), 6.98 (d,
1H), 6.89 (t, 1H), 6.80 (s, 1H), 3.77 (s, 3H), 2.30 (s, 3H); Mass spectrum (esi) m/z = 422.2 (M+H-
HC1).

[00475] Prepared according to the method of Example 13, using 3-methoxybenzenethiol. JH
NMR (de-DMSO) 8 8.22 (s, 1H), 7.42 (m, 2H), 7.27-7.18 (m, 3h), 7.14 (m, 2H), 6.86-6.77 (m, 4H),
3.71 (s, 3H), 2.31 (s, 3H); Mass spectrum (esi) m/z = 422.2 (M+H-HCI).


[00476] A mixture of N-(5-(3-methoxyphenylthio)-3-phenoxypyridin-2-yl)-4-
methylthiazol-2-amine (prepared according to Example 56; 1.1 g, 2.6 mmol) and CH2CI2 (20 mL)
was cooled to 0 °C and tribromoborane (1M in CH^Cfe, 7.83 mL, 7.83 mmol) was added and
stirred at 0 CC for 1 hour. The reaction was slowly poured into saturated aqueous sodium
bicarbonate and extracted with 10% methanol in CH2CI2. The organic layer was dried with
sodium sulfate, filtered and concentrated. The residue was purified on silica gel (50 to 80%
EtOAc in hexanes) to afford 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyiidin-3-ylthio)phenol
(692 mg, 65.1% yield) as a white solid. JH NMR (d^-DMSO) 8 8.18 (dd, 1H), 7.37 (m, 2H), 7.31
(d, 1H), 7.19 (m, 1H), 7.16 (dd, 1H), 7.11-7.02 (m, 3H)5 6.69-6.61 (m, 3H), 6,45 (m, 1H), 2.33 (s,
3H); Mass spectrum (esi) m/z = 408.2 (M+H).

[00477] A mixture of 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol
(prepared according to Example 57; 200 mg, 0.491 mg), potassium carbonate (203 mg, 1.47 mmol),
tert-butyl 2-bromoacetate (0.0725 mL, 0.491 mmol), and DMF (4 mL) was stirred at room
temperature for.30 minutes. Water (15 mL) was added and the reaction mixture was extracted with
ether. The organic layer was dried with sodium sulfate, filtered and concentrated . The residue was
purified on silica gel (10 to 15% EtOAc in hexanes) to afford the tert-butyl ester of the desired
material. The material was dissolved in CH2C12 (3 mL) and 4N HC1 in dioxane added (4 mL) and
stirred at room temperature overnight and concentrated. The residue was dissolved in a small amount
of CH2CI2 and added to vigorously stirred ether. The resultant precipitate was filtered to afford 2-(3-
(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenoxy)acetic acid hydrochloride (21.1
mg, 8.56% yield) as a white solid. 'H NMR (dg-DMSO) 6 9.70 (bs, 1H), 8.17 (d, 1H), 7.36 (t, 2H),

7.19 (d, 1H), 7.15 (m, 2H), 6.99 (ds 2H), 6.71 (m, 2H), 6.65 (m, 3H), 4.86 (s, 2H), 2.15 (s, 3H); Mass
spectrum (esi) m/z = 466.1 (M+H-HCl).

[00478] A mixture of 3-(6-(4-methylthiazol-2-yIamino)-5-phenoxypyridin-3-ylthio)phenol
(prepared according to Example 57; 70.0 mg, 0.172 mmol), potassium carbonate (712. mg, 0.515
mmol), l-(2-chloroethyl)piperidine hydrochloride (31.6 mg, 0.172 mmol), and DMF (2 mL) was
stirred at room temperature for 30 minutes and heated to 50 °C overnight. The reaction was cooled to
room temperature and water (15 mL) was added and extracted with ether. A white precipitate formed
in the ether layer and was filtered to afford N-(4-methy]thiazoI-2-yl)-3-phenoxy-5-(3-(2-(piperidin-l-
yl)ethoxy)phenyIthio)pyridin-2-amine (34.2 mg, 38.4% yield) as a white solid. *H NMR (d6-DMSO)
6 9.56 (s, 1H), 8.29 (dd, 1H), 7.50 (dd^ 1H), 7.28 {m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.82 (ra, 2H),
6.65 (m, 1H)3 6.58 (m, 1H), 6.54 (m3 1H), 6.35 (m, 1H), 3.79 (t, 2H), 2.23 (s, 3H), 2.17 (m, 4H), 2.12
(t,2H), 1.38 (m,4H), 1.31 (m, 2H); Mass spectrum (esi) m/z = 519.1 (M+H).

[00479] Prepared according to the method of Example 60 using 3-(6-(4-methylthiazol-2-
ylamino)-5-phenoxypyridin-3-yIthio)phenol and 3-chloro-N,N-dimethylpropan-1 -amine
, hydrochloride. 'H1STMR (dt-DMSO) 8 9.55 (s, 1H)S 8.28 (dd, 1H), 7.49 (dd, 1H), 7.29 (m, 2H), 7.11
(t, 1H), 7.00 (t, 1H), 6.85 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.38 (m, 1H), 3.70 (m,
2H), 2.21 (s, 3H), 2.04 (s, 6H) 1.96 (t, 2H), 1.44 (m, 2H); Mass spectrum (esi) m/z = 493.1 (M+H).


[00480] A mixture of 5-bromo-2-{4-mcthylthiazol-2-ylamino)pyridin-3-ol hydrochlbride (1.0
g, 3.10 mmoIX tert-butyl 3-bromopyrrolidine-l-carboxylate (WO 2003/062224) (1.01 g, 4.03 mmol),
K2CO3 (1.29 g, 930 mmol), and DMF (20 mL) were reacted at 50 °C over the weekend. The reaction
was cooled to room temperature, poured into water (250 mL) and extracted with EtOAc:ether (1:1).
The organic layer was dried with sodium sulfate, filtered and concentrated . The residue was purified
on silica gel (40% EtOAc in hexanes) to afford tert-butyl 3-(5-bromo-2-(4-methylthiazol-2-
ylamino)pyridin-3-yloxy)pyrrolidine-l-carboxylate (584 mg, 41.4% yield) as a tan solid. 'H NMR
(CDCI3) 8 8.42 (bs, 1H), 8.02 (s, lh), 7.10 (d, 1H), 6.42 (s, 1H), 4.95 (m, 1H), 3.75-3.44 (m, 4H),
2.35 (d, 3H), 2.21 (m, 2H), 1.50 (s, 9H); Mass spectrum (apci) m/z ° 456.9 (M+H).

[00481] A mixture of tert-butyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-
yloxy)pyiTolidine-l-carboxylate (prepared according to Example 61; 550 mg, 1.21 mmol) and
CH2C12 (10 mL) and MeOH (2 mL) was stirred at room temperature. 4N HC1 in dioxanc (5 mL) was
added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was
concentrated and dissolved in small amount of CHjCh/methanol and added to vigorously stirred ether
and filtered to afford N-(5-bromo-3- dihydrochloride (478 mg, 92.4% yield) as a white solid. 'H NMR (d6-DMSO) 5 11.18 (bs, 1H), 9.80
(bs, 1H), 9.27 (bs, 1H), 8.09 (d, 1H), 7.83 (d, 1H), 6.80 (s, 1H), 5.42 (m, 1H), 3.62-3.30 (m, 4H), 2.31
(s, 3H), 2.22 (m, 2H); Mass spectrum (apci) m/z - 357.0 (M+H-2HCI).


[00482] A mixture of N-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methy]thiazol-2-
amine dihydrochloride (prepared according to Example 62; 70 mg, 0.16 mmol), triethylamine (0.11
mL, 0.82 mmol), and THF (2 mL) was stirred at room temperature. Acctyl chloride (0.009 mL, 0.16
mmol) was added and stirred at room temperature for 30 minutes. Water (15 mL) was added and
extracted with EtOAc. The organic layer was dried with sodium sulfatc, filtered and concentrated .
The residue was purified on silica gel (10% methanol in EtOAc) to afford l-(3-(5-bromo-2-{4-
methylthiazol-2-yIamino)pyridin-3-yloxy)pyrroIidin-l-yl)cthanone hydrochloride (16 mg, 22.56%
yield) as a white solid after HC1 salt formation. *H NMR (dVDMSO) 6 11.60 (bs, 1H), 8.11 (m, 1H),
7.82 (m, 1H), 6.90 (m, 1H), 5.28 (m, 1H), 3.81 (m, 1H), 3.59 (m, 3H), 2.33 (s, 3H), 2.25 (m, 2H),
1.97 (m, 311); Mass spectrum (apci) m/z - 399.1 (M+H-HC1).

[00483] Prepared according to the method of Example 63, using 2-(dimethylamino)acetyl
chloride hydrochloride. 'H NMR (d«-DMSO) 8 11.13 (bs, 1H), 9.75 (bs, 1H), 8.07 (d, 1H), 7.75 (m,
1H), 6.78 (s, 1H), 5.33 (m, 1H), 4.25 (m, 2H), 4.10 (m, 1H), 3.71 (m, 4H), 2.83 (m, 6H), 2.29 (m,
5H); Mass spectrum (apci) m/z =- 440.1 (M+H-2HCI).


[00484] Prepared according to the method of Example 63 using 2-isocyanatopropane. "H
NMR (d6-DMSO) 6 10.49 (bs, 1H), 7.97 (ra, 1H), 7.52 (m, 1H), 6.61 (m, 1H), 5.82 (d, 1H), 5.17 (m,
1H), 3.75 (m, 1H), 3.56 (m, 2H), 3.45 (m, 2H), 2.28-2.20 (m, 4H), 2.12 (m, 1H), 1.05 (m, 6H); Mass
spectrum (apci) m/z = 440.1 (M+H).

[00485] Prepared according to the method of Example 63 using l-methyl-lH-imidazole-4-
sulfonyl chloride. 'H NMR (d6-DMSO) 5 10:05 (bs, 1H), 7.96 (d, 1H), 7.79 (s, 1H), 7.49 (ms 2H),
6.65 (s, 1H), 5.07 (m, 1H), 3.63 (m, 2H), 3.55-3.40 (m, 5H), 2.28 (s, 3H), 2.19 (m, 1H), 2.02 (m, 1H);
Mass spectrum (apci) m/z = 501.1 (M+H).

[00486] Prepared according to the method of Example 16 using l-(chloromethyl)-2-
fluorobenzene. !H NMR (d6-DMSO) 5 8.06 (d, 1H), 7.42 (t, 2H), 7.28 (m, 1H), 7.15 (m, 4H), 7.09
(m, 1H), 6.97 (d, 2H), 6.69 (s, 1H), 4.09 (s, 2H), 2.25 (s, 3H); Mass spectrum (esi) m/z = 424.2 (100)
(M+H-HC1).


[00487] Step A: Preparation of 2-C1 -bromopropyDpyridine: Prepared according to the method
of Example 33, Step A from 2-propylpyridine.
[00488] Step B: Preparation of N-f4-methylthiazo1-2-yn-3-phenoxy-5-fl-(pvridin-2-
vnpropvIthio^pvridin-2-amine dihvdrochloride: Prepared according to the method of Example 16.
'H NMR (de-DMSO) 8 8.47 (s, 1H), 7.98 (d, 1H), 7.80 (m, 1H), 7.43 (t, 2H), 7.33 (m, 2H), 7.20 (t,
1H), 6.95 (d, 2H), 6.92 (d, 1H), 6.65 (s, 1H), 4^6 (t, 1H), 2.24 (s, 3H), i.95 (m, 2H), 0.85 (t, 3H).
Mass spectrum (esi) m/z = 435.1 (100) (M+H-2HC1).

[00489] Prepared according to the method of Example 16 with 2-(bromomethyl)pyridin-3-ol
hydrobromide. *H NMR (d6-DMSO) 5 8.16 (d, 1H), 8.11 (d, 1H), 7.82 (m, 1H), 7.64 (m, 1H), 7.45
(t5 2H), 7.22 (t, 1H), 7.08 (m, 3H), 6.76 (s, 1H), 4.26 (s, 2H), 2.28 (s, 3H); Mass spectrum (esi) m/z =
423.1 (100)(M+H-2HCl).


[00490] Step A: Preparation of methvl 5-bromo-4-oxopentanoate: A solution of bromine
(27.71 g, 173.4 mmol) in methanol (40 mL) was added dropwise to a solution of ethyl 4-
oxopentanoate (25.0 g, 173.4 mmol) in methanol (200 mL) at room temperature over a period of 30
minute, and the reaction mixture was stirred overnight. The reaction mixture was concentrated, and
the residue was partitioned between 3:1 ethertethyl acetate and water, washed with saturated sodium
bicarbonate, water, brine, dried, and concentrated to afford 17 g of a crude clear oil. The oil was
purified by MPLC (Biotage) eluting with 8:1 hexane ethyl acetate to afford methyl 5-bromo-4-
oxopentanoate (10.65 g, 29.38% yield) as a clear oil. *H NMR (CDCI3) 8 3.96 (s, 2H), 3.69 (s, 3H),
2.96 (t, 2H), 2.66 (t, 2H).
[00491] Step B: Preparation of methyl 3-(2-(5-bromo-3%phenoxvpvridin-2-vlarnino*)thiazol-4-
vDpropanoate: Prepared according to the method of Example 7, Step E, using l-(5-bromo-3-
phenoxypyridin-2-yl)thiourea. 'H NMR (de-DMSO) 8 10.95 (s, 1H), 8.22 (d, 1H), 7.43 (t, 2H), 7.39
(s, 1H), 7.21 (t, 1H), 7.10 (d, 2H), 6.68 (s, 1H), 3.59 (s, 3H), 2.84 (t, 2H), 2.68 (t, 2H); Mass spectrum
(esi) m/z = 435.1 (100) (M+H).
[00492] Step C: Preparation of methvl S-Q-fS-G-methoxv-S-oxopropvlthioy-S-
phenoxypvridin-2-vlamino*)thiazoI-4-vOpropanoate: Prepared according to the method of Example
13. 'H NMR (de-DMSO) 8 10.87 (s, 1H), 8.13 (d, 1H), 7.42 (t, 2H), 7.32 (d, 1H), 7.17 (t, 1H), 7.08
(d, 2H), 6.67 (s, 1H), 3.59 (s, 3H), 3.55 (s, 3H), 3.03 (t, 2H), 2.84 (t, 2H), 2.68 (t, 2H), 2.56 (t, 2H);
Mass spectrum (esi) m/z = 474.1 (100) (M+H).
[00493] Step D: Preparation of 3-f2-f3-phenoxv-5-(l -fpvridin-2-vnethvlthio^pvridin*2-
vlamino)thiazol-4-vDpropanoic acid dihvdrochloride: Prepared according to Example 16. The
product was further purified by reverse phase to give 106 mg of the t-Butyl ester. This was
dissolved in CH2CI2, and 4M HC1 in dioxane was added and the mixture was stirred at room
temperature for 5 hours. The mixture was concentrated to give impure product. The product was
dissolved in IN NaOH and extracted with ether. The aqueous layer was acidified with 1M HC1 and
concentrated. The residue was dissolved in 10% MeOH in CH2CI2, filtered, and concentrated. The
residue was dissolved in IN NaOH and extract with 10% EtOAc in Ether. The aqueous layer was
acidified with 1M HC1 and concentrated. The residue was dissolved in 10% MeOH in CH2CI2,
filtered and concentrated without the aid of heat to give 3-(2-(3-phenoxy-5-(l-(pyridin-2-
yl)ethylthio)pyridin-2-ylamino)thiazol-4-yl)propanoic acid dihydrochloride (0.027 g, 5.80% yield).
'H NMR (de-DMSO) 8 8.41 (s, 1H), 7.99 (s, 1H), 7.65 (t, 1H), 7.40 (t, 2H), 7.20 (m, 3H), 6.92 (in,
3H), 6.50 (s3 1H), 4.42 (m, 1H), 2.70 (m, 2H), 229 (m, 2H), 1.54 (d, 3H) ; Mass spectrum (esi) m/z =
479.1 (100) (M+H-2HC1).


[00494] Step A: Preparation of ethyl 4-chloro-3-(2-f4-methvlthiazol-2~vlamino>5-
(phenylthio^pvridin-S-vloxvMaenzoate: Prepared according to the method of Example 13, using Ethyl
3-(5-bromo-2-(4-methylthiazol-2-yIamino)pyridin-3-yIoxy)-4-chIorobenzoate and benzenethiol.
[00495] Step B: Preparation of 4-chloro-3-f2-f4-methvlthiazol-2-vlaminoV5-
(phenvlthio>pvridin-3-vloxV)benzoic acid hvdrochloride: Prepared according to the method of
Example 45. 'H NMR (d6-DMSO) 5 8.26 (d, 1H), 7.71 (s, 2H), 7.41 (m, 1H), 730 (m, 3H), 7.19 (m,
3H), 6.62 (s, 1H), 2.23 (s, 3H) ; Mass spectrum (esi) m/z = 470.2 (100) (M+H-HC1).

[00496] 4-Chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yloxy)benzoic
acid (prepared according to Example 71; 0.131 g, 0.279 mmol) and TEA (0.117 mL, 0.836 mmol)
were placed in a flask and cooled to 0 °C. Ethyl carbonochloridate (0.0303 g, 0.279 mmol) was
added, and the reaction mixture was stirred at 0 °C for 30 minutes. Nl.Nl-dimethylethane-1,2-
diamine (0.0306 mL, 0.279 mmol) was added, and the reaction mixture was stirred at room
temperature for 1 hour. Water was added and the reaction mixture was extracted with CH2CI2. The
organic layer was concentrated and the residue was purified first by silica gel chromatography and
then by reverse phase chromatography to provide the desired product as the free base. The free base
was dissolved in CH2C12 and HC1 in ether was added to give 4-chloro-N-(2-(dirnethylamino)ethyl)-3-
(2-(4-methylthiazol-2-ylamino)-5-(phenylthio)pvridin-3-yloxy)ben2amide dihydrochloride (0.069 g,
40.4% yield). >H NMR (d«-DMSO) 5 9.83 (bs, 1H), 8.90 (m, 1H), 8.24 (m, 1H), 7.75 (m, 2H), 7.58

(s, 1H), 7.30 (m, 2H), 7.19 (m, 4H), 6.67 (s, 1H), 3.59 (m, 2H), 3.23 (m, 2H), 2.80 (d, 6H), 2.25 (s,
3H); Mass spectrum (csi) m/z = 540.1 (100) (M+H-2HC1).

[004971 Step A: Preparation of ethvl 4-chloro-3-^5-(3-methoxv-3-oxopropvlthioV2-(4-
methvlthiazol^-vlamuio^pvridin-S-vloxvibenzoate: Prepared according to the method of Example
13 from ethyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)-4-chlorobenzoate. 'H
NMR (de-DMSO) 5 11.12 (bs, 1H), 8.18 (d, 1H), 7.77 (s, 2H), 7.44 (s, 1H), 735 (d, 1H), 6.61 (s,
1H), 4.47 (q, 2H), 3.54 (s, 3H), 3.04 (t, 2H), 2.54 (t, 2H), 2.23 (s, 3H), 1.26 (t, 3H); Mass spectrum
(esi) m/z = 508.2 (100) (M+H).
[00498] Step B: Preparation of 4-chloro-3-f2-f4-mcthvhhiazol-2-vlaminoV5-fWpvridin-2-
yl1ethvlthio')pvridin-3-vloxY')benzoic acid sodium salt: Prepared according to the method of Example
16 using 2- 7.78 (m, 2H), 7.40 (m, 3H), 6.98 (d, 1H), 6.68 (s, 1H), 4.60 (m, 1H), 2.25 (s, 3H), 1.58 (d, 3H); Mass
spectrum (esi) m/z = 499.1 (100) (M+H-Na).

[00499J 4-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-{l-(pyridin-2-yl)ethylthio)pyridin-3-
yloxy)benzoic acid (prepared according to Example 73; 0.131 g, 0.263 mmol), TEA (d. 6.726)

(0.0732 mL, 0.525 mmol), ethyl- oarbonochloridate (0.057 g, 0.525 mmol), and N1,N1-
dimethylethane-l,2-diamine (0.0231 g, 0.263 mmol) were reacted according the method of Example
72. IN NaOH was added and the reaction mixture was stirred for 3 hours. The reaction mixture was
extracted with CH2CI2. The combined extracts were concentrated and purified by silica gel
chromatography (4% MeOH in CH2C12, using 2% 7N ammonia in MeOH) and then purified by
reverse phase chromatography to give the compound as the free base. The free base was dissolved in
CH2CI2 and HC1 in ether was added. The mixture was concentrated to give 4-chloro-N-(2-
(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)-5-(l-(pyridin-2-yl)ethylthio)pyridin-3-
yloxy)benzamide triihydrochloride (0.025 g, 14.8% yield). JH NMR (ds-DMSO) 8 9.73 (s, 1H), 8.91
(m, 1H), 8.42 (m, 1H), 8.01 (d, 1H)S 7.78 (m, 3H), 7.51 (s, 1H), 7.29 (m, 2H), 6.83 (s, 1H), 6.66 (m,
1H), 4^48 (q, 1H), 3.60 (m, 2H)S 3.24 (m, 2H), 2.81 (d, 6H), 2.24 (s, 3H), 1.54 (d, 3H); Mass
spectrum (esi) m/z = 569.2 (100) (M+H-3HC1).
[00500] Following the procedure of Example 13, the following compounds were also
prepared.







[00501] Following the procedure of Example 16, the following compounds were also
prepared:




[00502] Prepared according to the method of Example 57. lH NMR (CDClj) 8 8.18 (dd,
1H), 7.38 (m, 2H), 7.31 (d, 1H), 7.19 (tq, 1H), 7.16 (dd, 1H), 7.10-7.03 (m, 3H), 6.69-6.61 (m,
3H), 6.45 (t, 1H), 2.33 (s, 3H). Mass Spectrum (apci): 408.2 (M+H).


[00503] Prepared according to the method of Example 59. JH NMR (dg-DMSO) 5 9.56 (s,
1H), 8.29 (dd, 1H), 7.50 (dd, 1H), 7.28 (m, 2H), 7.12 (t5 1H), 7.00 (t, 1H), 6.83 (m, 2H), 6.65 (m,
1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.35 (s, 1H), 3.79 (t, 2H), 2.24 (s, 3H), 2.18 (m, 4H), 2.12 (t,
2H), 1.38 (m, 4H), 1.31 (m, 2H). MS (apci): 519.1 (M+H).



[00504] Prepared according to the method of Example 58. 1H NMR (de-DMSO) 8 9.70
(bs, 1H), 8.17 (d, 1H), 7.36 (t, 2H), 7.19 (d, 1H), 7.15 (m, 2H), 6.99 (d, 2H), 6.71 (d, 1H), 6.66
(d, 1H), 6.63 (d, 2H), 4.86 (s, 2H), 2.15 (s, 3H). Mass Spectrum (apci): 466.1 (M+H-HC1).



[00505] Prepared according to the method of Example 60. *H NMR (dfr-DMSO) 6 9.55 (s,
1H), 8.28 (d, 1H), 7.49 (d, 1H), 7.29 (t, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.85 (d, 2H), 6.65 (d, 1H),
6.58 (dd, 1H), 6.54 (m, 1H), 6.38 (s, 1H), 3.70 (m, 2H), 2.21 (s, 3H), 2.04 (s,.6K), 1.96 (t, 2H),
1.44 (m, 2H). Mass Spectrum (apci): 493.1 .(M+H).

[00506] Prepared according to the method of Example 63. JH NMR (dfi-:DMSO) 8 11.55 (bs,
1H), 8.11 (d, 1H), 7.81 (d, 1H), 6.90 (d, 1H), 5^8 (m, 1H), 4.00-3.52 (m, 4H), 2.33 (s, 3H), 2.31-2.09
(m3 2H), 1.98 (d , 3H). Mass spectrum (apci) m/z = 399.1 (M+H-HC1).

(00507) Following the procedure of Example 105, Step H, the following compounds were also
prepared.

Example 110
N-(S-bromo-3-C2-chlorophenvlthio)pvridin-2-vlV4-methvlthiazol-2-amine
^■^ ci ■

[005081 Prepared according to the method of Example 40. *H NMR (CDC13) 8 8.96 (bs,
1H), 8.49 (d, 1H), 7.95 (d, 1H), 7.41 (dd, 1H), 7.13 (m, 2H), 6.69 (dd, lh), 6.46 (s, 1H), 2.32 (s,
3H). Mass spectrum (apci) m/z = 414.1 (M+H).
[00509] The following compounds were prepared according to the method of Example 7.





[00510] To a mixture ofrnL 6-(4-mcthylthiazol-2-ylamino)-5-phenoxynicotinaldehyde
(Example 44, Step A; 150 mg, 0.48 mmol) and EtOH (5 raL) was added sodium borohydride
(27.3 mg, 0.72 mmol) and stirred at ambient temperature for 30 minutes. Poured into saturated
aqueous NH4CI and extracted with CH2CI2. The organic layer was dried with sodium sulfate,
filtered and concentrated. The residue was purified on silica gel (1:1 EtOAc-.hexanes) to afford
the title compound (132 mg, 87.4% yield) as a white solid.lH NMR (CDClj) 6 8.66 (bs, 1H),
8.06 (d, 1H), 7.38 (m, 2H), 7.19 (m, 1H), 7.12 (d, 1H), 7.03 (m, 2H), 6.42 (q, 1H), 4.58 (s, 2H),
2.33 (d,3H), 1.77 (bs, 1H).

[00511] A mixture of mL [3-(dimethylamino)propyl]-triphenylphosphonium bromide (413
mg, 0.964 mmol) and THF (5 mL) was cooled to 0 °C. Butyllithium (0.385mL mL, 0.964 mmol)
was added and stirred at 0 °C for 20 minutes. 6-(4-Methyltaiazol-2-ylamino)-5-
phenoxynicotihaldehyde (100 mg, 0.321 mmol) was added and stirred at ambient temperature for
20 minutes. The reaction was poured into aqueous NH4CI and extracted with EtOAc. The organic
layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica
gel (0 to 20% methanol in EtOAc) to afford both isomers of desired material as white solids after
HC1 salt formation. Cis-isomer: 'H NMR (CDClj) 5 12.82 (bs, 1H), 12.55 (bs, 1H), 8.06 (s, 1H),
7.42 (m, 2H), 7.21 (m, 3H), 7.04 (m, 1H), 6.47 (s, 1H), 6.39 (d, 1H), 5.67 (m, 1H), 3.05 (m, 2H),
2.84 (m, 2H), 2.74 (d, 6H), 2.46 (s, 3H). Mass spectrum (apci) m/z = 381.2 (M+H-2HC1). Trans-
isomer: 'H NMR (CDCI3) 6 12.73 (bs, 1H), 12.50 (bs, 1H), 8.04 (d, 1H), 7.41 (m, 2H), 7.21 (m,


4H), 6.43 (m, 2H), 6.02 (m, 1H), 3.09 (m, 2H), 2.81 (m, 8H), 2.45 (s, 3H). Mass spectrum (apci)
m/z - 381.2 (M+H-2HC1).
[00512] Prep»ared according to the method of Example 44, Step C from 5-(4-
(dimethylammo)but-l^nyl>N^4-methylthia2ol-2-yl)-3-phenoxypyridin-2-amine. !H NMR
(CDC13) 6 12.59 (bs, 1H), 12.25 (bs, 1H), 7.94 (s, 1H), 7.40 (m, 2H), 7.21 (t, 1H), 7.15 (m, 2H),
7.03 (s, 1H), 6.42 (s, 1H), 2.96 (m, 2H), 2.76 (d, 6H), 2.61 (t, 2H), 2.44 (s, 3H), 1.90 (m, 2H),
1.63 (m, 2H). Mass spectrum (apci) m/z = 383.2 (M+H-2HC1).
Example 127
5-f2-chloropvridin-4-vlthioVN-(4-methvlthiazol-2-vl>-3-phenoxvpvridin-2-aininedihvdrochloride
ci /wo H
HO ll HCI
|00513] A mixture of methyl 3^65-phenoxypyridin-3-
ylthio)propanoate (72 mg, 0.18 mmol), 2-chloro-4-nitropyridine (85.3 mg, 0.54 mmol) and
DMSO (2.0 mL) and purged with nitrogen for 5 minutes. Potassium 2-mcthylpropan-2-olate
(60.4 mg, 0.54 mmol) was added and stirred for 30 minutes. The reaction was poured into
aqueous NH4CI and extracted with EtOAc (1 x 20 mL). The organic phase was washed with
water, dried with sodium sulfate, filtered and concentrated . The residue was purified on silica gel
(25% EtOAc in hexanes) to afford the title compound (37.1 mg, 41.4% yield) as a white solid
after HCI salt formation. *H NMR (CDCI3) 8 12.89 (bs, 1H), 8.24 (m, 2H), 8.17 (d, 1H), 7.43 (t,
2H), 7.31 (d, 1H), 7.28-7.18 (m, 3H), 6.88 (s, 1H), 6.84 (m, 1H), 6.53 (s, 1H), 3.93 (s, 1H), 2.50
(s, 3H). Mass spectrum (apci) m/z = 427.2 (M+H-2HC1).

[00514] The following compounds were prepared according to the method of Example
127.












[00515] Step A: Preparation of 4-Q-(wridln^-vlViisuifanvlVyridine: A mixture of 5-
bromo-3-phenoxypyridin-2-amine (2.1 g, 7.9 xnmol) THF (80 raL) was purged with nitrogen and
cooled to -78 °C. Methyllithium (5.9 mL, 9.5 mmol) was added and stirred for 5 minutes.
Butyllithium (3.8 mL, 9.5 mmol) was added and stirred for 10 minutes at -78 °C. 4-(2-(Pyridin-4-
yl)disulfanyl)pyridine (4.4 g, 20 mmol) was added and warmed to ambient temperature. The
reaction was poured into saturated aqueous NH4CI and extracted with EtOAc. The organic layer
was dried, filtered and concentrated. The. resiauewas dissolved in methanol andNaBH* (excess)
added. The reaction was poured into saturated aqueous NH4CI and extracted with EtOAc (2 x 75
mL). The organic layer was dried with sodium sulfete, filtered and concentrated . The residue
was purified on silica gel (50% EtOAc in hexanes to 5% methanol in EtOAc) to afford the title
compound (4.4 g, 20 mmol).
[00516] Steps B-D: Preparation of N-f4-cyclopropvlthiazol-2-vlV3-phenoxv-5-(pvridin-4-
vltHo'tovridin-2-amine dihvdrochloride: Prepared according to the method of Example 7, Steps
C-E. *H NMR (de-DMSO) 5 8.52 (m, 2H), 8.34 (d, 1H), 7.52 (m, 2H), 7.42 (m, 3H), 7.17 (m,
3H), 6.72 (s, 1H), 1.97 (m, 1H), 0.84 (m, 2H), 0.78 (m, 2H). Mass spectrum (apci) m/z = 419.3
(M+H-2HC1).
[00S17] The following compounds were prepared according to the method of Example 7,
StepE.






[00518] Step A: Following the procedure in Example 7, step E using l-(5-bromo-3-
phenoxypyridin-2-yl)thiourea and tert-butyl 4-(2-bromoacetyl)piperidine-l-carboxylate
providedtert-butyl 4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-l-
carboxylate.
[00519] Step B: tert-Butyl 4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)tbiazol-4-
yl)piperidine-l-carboxylate was dissolved in 1:1 CHbCbimethanol and 4N HC1 in dioxane was
added and stirred at room temperature for 1 hour. The solvents were removed to afford the title
compound. !H NMR (ds-DMSO) 5 10.98 (bs, 1H), 8.90 (bs, 1H), 8.70 (bs, 1H), 8.23 (d, 1H),
7.45 (m, 2H), 7.40 (d, 1H), 7.22 (m, 1H), 7.12 (m, 2H), 6.76 (s, 1H), 3.31 (m, 2H), 2.98 (ms 2H),
2.89 (m, 1H), 2.10 (m, 2H), 1.79 (m, 2H). Mass spectrum (apci) m/z = 431.2, 433.2 (M+H-
2HC1).

[00520] To a mixture of 5-bromo-3-phenoxy-N-(4-(piperidin-4-yl)tbiazol-2-yl)pyridin-2-
amine dihydrochloride (80 mg, 0.16 mmol), paraformaldehyde (7.15 mg, 0.24 mmol), and
C1CH2CH2C1 (2 mL) was added NaBH(OAc)3 (134 mg, 0.64 mmol) and the reaction was stirred
at ambient temperature for 2 days. Poured into saturated aqueous NaHCCb and extracted with

EtOAc. The organic layer was dried with sodium sulfatc, filtered and concentrated. The residue
was purified on silica gel (10% methanol in EtOAc with 0.2% NHj) to afford the title compound
(51.2 mg, 623% yield) as a white solid after HC1 salt formation. !H NMR (OVDMSO) 6 11.00
(bs, 1HX 10.22 (bs, III), 8.23 (s, 1H), 7.48-7.38 (m, 3H), 7.22 (t, III), 7.12 (m, 2H), 6.77 (s, 1H),
3.46 (m, 2H), 3.05 (m, 2H), 2.82 (m, 1H), 2.74 (d, 3H), 2.14 (m, 2H), 1.88 (m, 2H). Mass
spectrum (apci) m/z = 445.3 (M+H-2HC1).

[00521] Prepared according to the method of Example 175. 'H NMR (dg-DMSO) 8 11.00
(bs, 1H), 9.94 (bs, III), 8.23 (d, 1H), 7.48-7.38 (m, 3H), 7.23 (m, 1H), 7.12 (m, 2H), 6.76 (s. 1H),
3.79 (m, 211), 3.74 (m, 1H), 3.58 (m, 2H), 3.23-3.02 (m, 4H), 2.85 (m, 1H), 2.16 (m, 2H), 1.93
(m, 2H). Mass spectrum (apci) m/z =- 475.3 (M+H-2HC1).

[00522] To mL5-bromo-3-phcnoxy-N-(4-(piperidin-4-yl)thia2ol-2-yl)pyridin-2-amine
dihydrochloride (80 mg, 0.159 mmol), triethylaminc (O.O88mL mL, 0.64 mtnol) and THF (2 mL)
was added acetic anhydride (0.015ml. ml, 0.16 mmol)and stirred at ambient temperature for 30
minutes. Poured into saturated aqueo:is NaHCC>3 and extract with EtOAc (2 x 20 mL). The
organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified
on silica gel (5% methanol in EtOAc) to afford the title compound (47.6 mg, 58.8% yield) as a
white solid after HC1 salt formation. *H NMR (d«-DMSO) 5 11.00 (bs, 1H), 8.23 (d, 1HX 7.44
(m, 2H), 7.40 (d, III), 7.21 (t, 1H), 7.11 (d, 2H), 6.70 (s, III), 4.41 (d, 1H), 3.12 (m, HI), 2.83 (tt,
1H), 2.62 (td, 1H), 2.50 (m, 1H), 2.00 (s, 3H), 1.93 (m, 2H), 1.55 (qd, 1H), 1.42 (qd, 1H). Mass
spectrum (apci) m/z = 475.2 (M+H-HC1).


(00523] Prepared according to the method of Example 7 Step E from l-(5-bromo-3-
phenoxypyridin-2-yl)thiourca and l-bromo-4-phcnylbutan-2-one. 'H NMR (d«-DMSO) 8 826
(m, 1H), 7.45 (m, 3H), 7.31-7.11 (m, 8H), 6.74 (s, 1H), 2.92 (m, 411). Mass spectrum (apci) m/z
= 452.3 (M+H).

[00524) Step A: 5-bromo-3-(4-fluorophencixv*)Dicolinonirrile: To a solution of 4-
fluoropheool (0 49g, 4.4 ramoJ) in DMF (JO mL) cooled to 0°C was added 60% sodium hydride
(0.19 g, 4 8 mmol) was added and the reaction was warmed to ambient temperature. 5-Bromo-3-
nitropicolinonitnle (l.Og, 4.4 mmol, solution in 5 mL DMF) and stirred for 3 hours. Poured into
water, filtered, washed with water, and dried to yield the title compound (1.0 g, 78%).
[00525] Step B: 5-bromo-3-(4-fluoroptienoxv>picolinamidc To 5-bromo-3-(4-
fluorophcnoxy)picolinonitrilc (48.5 g, 165 mmol) was added concentrated ml.) and stirred overnight at ambient temperature, then added portionwisc to water (1000 mL)
cooled in an ice bath at a rate such that the solution temperature did not exceed above 35°C. The
aqueous layer was extracted with ethyl acetate. The combined organics were washed with water,
briac, dried, and concentrated to 200 mL, filtered and dried to yield the title compound (49 g,
95%).
(00526) Step C: 5-bromo-3-(4-fluorophenoxv)pvridin-2-apjine: To a solution of 2M
sodium hydroxide (300 mL) at 0°C was added bromine (6.94 mL, 135 ramol). The reaction was
stirred at 0°C for 15 minutes, followed by addition of 5-bromo-3-(4-fluoropheooxy)picoUnamide
(35g, 113 mmol) in dioxancs (600 mL). Stirred at room temperature for 1 hour, then heated at 80
CC for 2 hours. The reaction was acidified with IN HC1 (800 mL) until no off gas was produced.

The aqueous layer was basified using IN NaOH. The aqueous layer was extracted with ethyl
acetate. The organic layer was washed with water, brine, dried and concentrated. The residue was
purified by chromatography using 15% ethyl acetate/CtkCfe as eluent to yield the title compound
(27.3 g, 86%).
[00527] Step D: Following the procedure in Example 7, Step C, 5-bromo-3-(4-
fluorophenoxy)pyridin-2-amine (800 mg, 2.83 mmol) and benzoyl isothiocyanatc (0.457 mL,
3.39 mmol) afforded l-benzoyl-3-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (1150 mg,
91.2% yield).
[00528] Step E: Following the procedure in Example 7, Step D, l-benzoyl-3-(5-bromo-3-
(4-fluorophenoxy)pyridin-2-yl)thiourea (1150 mg, 2.58 mmol) and 3M sodium hydroxide (1.7
mL, 5.1 mmol) provided l-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (743 mg, 84.3%
yield) as a white solid.
[00529] Step F: Following the procedure in Example 7 Step E, l-(5-bromo-3-(4-
fluorophenoxy)pyridin-2-yl)tbiourca (740 mg, 2.163 mmol), l-bromo-4-phenylbutan-2-one
(687.6 mg, 3.028 mmol) and triethylamine (0.5014 mL, 3.676 mmol) afforded 5-bromo-3-(4-
fluorophenoxy)-N-(4-phenethylthiazol-2-yl)pyridin-2-amine (1040 mg, 102.2% yield) as a white
solid after drying. *H NMR (CDC13) 5 8.71 (bs, 1H), 8.13 (d, 1H), 7.28 (m, 2H), 7.20 (m, 3H),
7.13 (m, 2H), 7.06 (m, 3H), 6.43 (s, 1H), 3.05-2.92 (m, 4H)t Mass spectrum (apci) m/z -= 470.2,
472.2 (M+H).

[00530] Step A: Preparation of 2-nitro-3- (30.6 g, 193 mmol) was dissolved in DMSO (200 mL). Benzenethiol (20.7 mL, 203 mmol) was
added followed by cesium carbonate (69.3 g, 212 mmol) and stirred at ambient temperature for
1.5 hours. The solution was diluted with water (750 mL) and the solids filtered. The crude
material was recrystallized from EtOAc (400 mL) and with adding hexanes (1L) to give an A-
crop of 23.5 g. The filtrate was concentrated and recrystallized from EtOAc/hexanes to give 7.87
g. The solids were dried on high vacuum to provide the title compound (31.38 g, 69.8% yield)..

[00531] Step B: Preparation of 5-bromo-3-(phenvlthio')pvridin-2-amine: mL2-Nitro-3-
(phenylthio)pyridine (16.3 g, 70.2 namol) and AcOH (250 mL) were cooled in a water bath. Zinc
(22.9 g, 351 mmol) was slowly added and stirred for 5 minutes. Filtered through celite and the
cake washed with CH2CI2. The CH2CI2 was removed and to the solution was added bromine (3.6
ml., 70.2 mmol). After 10 minutes, the HO Ac was removed and partitioned between EtOAc and
saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfatc, filtered
and concentrated. The residue was purified on silica gel (1.5 L S1O2 and 30% EtOAc in hexanes)
to afford the title compound (18.2 g, 92.21% yield).
[00532] Step C: Preparation of l-benzovl-3- mL5-Bromo-3-(phenylthio)pyridin-2-amine (17 g, 60.5 mmol), benzoyl isothiocyanate (9.79 mL,
72.6 mmol), and THF (300 mL) was stirred at 40 °C overnight Concentrated to half of the
original volume and 9:1 hexanesJitOAc (500 mL) was added. Filtered to afford the title
compound (25.7 g, 95.7% yield).
[00533] Step D: Preparation of M5-bromo-3-(phenylthio')pvridin-2-vl')thiourea: To 1-
Benzoyl-3-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea (25.7 g, 57.8 mmol) and MeOH (250
mL) was added sodium hydroxide (38.6 mL, 116 mmol) and stirred at ambient temperature for 8
hours. Diluted with water (250 mL) and filtered and washed with water. The precipitate was
dried in vacuum oven to afford the title compound (19.0 g, 96.5% yield).
[00534] Step E: Preparation of 5-bromo-N-f4-methvlthiazol-2-yl>-3-(phenvlthio)pvridin-2-

[00535] mL5-Bromo-3-(phenylthio)pyridin-2-amine (1.0 g, 3.6 mmol), 2-chloro-3-
isothiocyanatopyridine (0.61 g, 3.6 mmol), DMF (2 mL) were heated to 90 °C for 8 hours.
amine: mLl-(5-Bromo-3-(phenylthio)pyridin-2-yl)thiourea (5.0 g, 14.69 mmol), triethylamine
(6.0 mL, 44 mmol), l-chloropropan-2-one (2.3 mL, 29.4 mmol), and EtOH (100 mL)were heated
to 70 °C for 6 hours. The ethanol was reduced to -1/2 volume and water (150 mL) added and the
precipitate was filtered to afford the title compound (5.6 g, 100% yield) as a tan solid after
drying. 'HNMR (CDC13) 8 9.01 (s, 1H), 8.42 (m, 1H), 7.92 (m, 1H), 7.32-7.15 (m, 5H), 6.44 (m,
1H0, 2.32 (m, 3H). Mass spectrum (apci) m/z = 379.8 (M+H).

Cooled to ambient temperature and the solids were diluted with mLCPfeCh (2 mL) and filtered
and washed with small amount of CH2C12 to afford the thle compound (0.98 g, 61% yield). *H
NMR (de-DMSO) 5 8.50 (d, 1H), 8.39 (dd, 1H), 7.98 (s, 1H), 7.92 (dd, lh), 7.38-7.25 (m, 6H).
Mass spectrum (apci) m/z ^414.8 (M+H).

[00536] Step A: Preparation of methvl N'-S-bromo-3-Cphenvlthio'>pvridin-2-vl-N-('l-
fdimethvlamino'tethvlideneVcarbamimidothioate: 1 -(5-Bromo-3-(pheaylthk>)pyridin-2-yl)thiourea
(100 mg, 0.29 mmol) and l,l-dimethoxy-N,N-dimcthylethanaminc (0.096 mL, 0.59 mmol) wcTe
heated to 70 °C for 1 hour. The reaction was cooled to ambient temperature to afford 120 mg of
the title compound as a crude mixture.
|00537] Step B: Preparation of 5-bromo-N-('3-incthvl-1.2.4-oxadiazol-5-vl')-3-
(phcnvlthio'tovridin-2-amine: To N1-5-Bromo-3-(phenylthio)pyridin-2-yl-N-(l-

[00538] Step A: Preparation of tetrahvdrofuran-2-carbaldeuvde oxime: Tetrahydrofuran-2-
carbaldehyde (100 g, 500 mmol, 50 wt% in water) was dissolved in methanol:water (1:1, 1500
(dimethylamino)ethylidene)carbamimidothioate (120 mg, 0.283 mmol), sodium acetate (69.8 mg,
0.850 mmol), and THF (2 mL) was added hydroxylamine hydrochloride (59.1 mg, 0.850 mmol)
followed by 0.1 mL water. Stirred at 50 °C for 3 hours and poured into saturated aqueous
NaHCOj and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered
and concentrated. The residue was purified on silica gel (1:1 EtOAc in hexanes) to afford the title
compound (89 mg, 86.5% yield). 'H NMR (CDC13) 5 8.54 (m, 1H), 8.49 (bs, 1H), 7.96 (m, 1H),
7.64-7.49 (m, 1H), 7.31 (m, 3H), 7.21 (m, 2H), 2.35 (s, 3H). Mass spectrum (apci) m/z - 362.4,
364.2 (M+H).

mL) and cooled in an ice bath. Sodium carbonate (26.5 g, 250 mmol) and hydroxylamine
hydrochloride (41.6 g, 600 mmol) were added and the reaction was stirred overnight at ambient
temperature. The reaction was concentrated to half volume and extracted with EtOAc (2 x 800
mL) The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the
title compound (44.3 g, 80%).
(005391 Step B: Preparation of tetrahvdrofuran-2-carboDvI chloride oxime: A 250 mL
roUDd-bottomod flask was charged with tetrahydroturan-2-carbaldehyde oxime (2.0 g, 17 mmol)
and DMF (100 mL). l-chloropyrrolidinc-2,5-dione (2.3 g, 17 mmol) was added and stirred at
ambient temperature overnight. The reaction was poured into 1:1 bruje.watei (800 mL) and
extracted with EtOAc (500 mL). The organic layer was washed twice with water, dried over
sodium sulfate, filtered and concentrated to afford the title compound (2.6 g, 100%).
[00540] Step C: Preparation of N-^methy1^u]fcin^oxyrtotrabvarofuran-2^aThimidovl
chjonde: A 500 mL round-bottomed flask was charged with retrahydrofuran-2-carbooy] chloride
oxime (2.6 g, 17.4 mmol), methanesulfonyl chloride (1.4 mL, 17.4 mmol), and Et2O (200 mL).
Triethylamine (2.4 mL, 17.4 mmol) was added dropwise over 1 minute and stirred at ambient
temperature for 10 minutes. The solids were filiered and the filtrate- was concentrated. The
residue was purified on silica gel (100% CH2CI2) to afford the title compound (2.1 g, 53.07%
yield).
[00541] Step D Preparation of 5-bromo-3-phcnoxv-N-(3-(tetrahvdroruran-2-vlV1^.4-
thiadiazoi-S-yOpyridin-2-amine: A 20 mL vial was charged with N-
(methylsulfonyloxy)tetmhydrofuran-2-carbiinidoyl chloride (129 mg, 0.57 mmol), pyridinc
(0.137 mL, 1.7 roniol), NaSCN (45.9 mg. 0.57 nunoJ) and CH,CN (4 mL). The reaction was
heated to 40 °C for 40 minutes. 5-bTomo-3-phenoxypyridin-2-amine (100 mg, 0.38 mmol) was
added and the reaction was heated to 50 °C overnight The reaction was poured into saturated
aqueous NallCOj and extracted with EtOAc. The organic layer was dried with sodium sulfate,
filtered and concentrated. The residue was purified on silica gel (30% EtOAc in hexanes) to
afford the tide compound (121 mg. 76.5% yield) as a tan solid. *H NMR (6VDMSO) 8 12.22 (s,
1H), 8.32 (d, IH), 7.47 (d, HI), 7.39 (m, 2H), 7.17 (m, 1H), 7.07 (m, 211), 3.98 (t, 1H), 3.83-3.68
(m, 3H), 3.53 (m, JH), 2.19 (q, 2H). Mass spectrum (apci) m/z - 419.1 (M+H).
100542] By the procedures in Example 183, the following compounds were also prepared.






[00543J Step A: Preparation of (6-(4-mefeylthiazol-2-vlaminoy5-fphenylthio)pyridin-3-
vl)ftetrahydro-2H-pvran-4-vr)methanol hvdrocbloride: A 10 mL round-bottomed flask was
charged with 5-bromo-N^4-methyltiiiazol-2-yl)-3-(phenyltMo)pyridin-2-ainine (250 mg, 0.661
■mmol), THF (6 mL) and cooled to -78 °C and methyllithium (0.496 mL, 0.793 mmol) was added.
The reaction was stirred for 5 minutes and butyUithium (0.317 mL, 0.793 mmol) was added. The
reaction was stirred for 10 minutes and tetrahydro-2H-pyran-4-carbaldehyde (151 mg, 1.32
mmol) was added. The reaction was warmed to ambient temperature and poured into saturated
aqueous NH4CI and extracted with EtOAc (2 x 20 mL). The organic layer was dried with sodium
sulfate, filtered and concentrated. The residue was purified on silica gel (50% EtOAc in hexanes)
to afford the titie compound (217 mg, 73.0% yield) after HC1 salt formation.
[00544] Step B: Preparation of N-(4-methvlthiazol-2-vlV3-(phenvlthioV5-
((tetrahvdropvran-^vlidene'imethvlVpvridin^-amine hvdrochloride: A 10 mL round-bottomed
flask was charged with (6-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yl)(tetrahydro-
2H-pyran-4-yl)methanol hydrochloride (125 mg, 0.278 mmol), 4-methylbenzenesulfonic acid
hydrate (5.28 mg, 0.0278 mmol), Toluene (5 mL) and heated to reflux in dean stark trap for 24 7
hours. The reaction was cooled to ambient temperature and partitioned between saturated
aqueous sodium bicarbonate and CH2Cl2- The organic layer was dried with sodium sulfate,
filtered and concentrated. The residue was purified on silica gel (25% EtOAc in hexanes) to

afford the title compound (42 mg, 35.0% yield) as after HCI salt formation. 'H NMR (CDC13) 8
12.24 (bs, 1H), 8.18 (m, 1H), 7.71 (m, 1H), 7.54 (m, 2H), 7.30 (m, 3H), 6.40 (s, 1H), 6.20 (s,
1H), 3.78 (t, 2H), 3.65 (t, 2H), 2.45 (s, 3H), 2.42 (ms 4H). Mass spectrum (apci) m/z = 396.2
(M+H-HC1).
100545] Step C: Preparation of N-f4-methvlthiazol-2-vlV3-fphenvl1hioV5-frtetrahvdro-2H-
pvran-4-vDmetfavDpvridin^-amine hvdrochloride: Prepared according to the method of Example
44, Step C. lH NMR (dg-DMSO) 8 8.26 (s, 1H), 7.85 (s, 1H), 7.35-7.19 (m, 5H), 6.82 (s, 1H),
3.74 (m, 2H), 3.15 (t, 2H)5 2.49 (d, 2H), 2.24 (s, 3H), 1.67 (m, 1H), 1.38 (m, 2H), 1.12.(m, 2H).
Mass spectrum (apci) m/z = 398.3 (M+H-HC1).

[00546] Step A: Preparation of l.,2-bis(2-chloro-5-methoxvphenvi')disulfane: To a solution
of 2-bromo-l-chloro-4-memoxybenzene (4.42 g, 19.9 mmol) in THF stirring at -10 °C under
nitrogen was added isopropylmagnesium chloride (9.9 mL, 19.9 mmol, 2M in THF). The reaction -
was allowed to wann to ambient temperature stirred for 4 hours. The reaction was cooled to -40
°C and zinc(II) chloride (19.9 mL, 19.9 mmol, 1M in ether) was added and the solution stirred for
30 minutes. The reaction was cooled to -78 °C and sulfiirothioyl dichloride (0.80 mL, 9.9 mmol)
was added. After stirring for 15 minutes at -78 °C, saturated NH4CI was added and the mixture
was wanned to ambient temperature and extracted multiple times with EtOAc. The combined
organic layers were dried with sodium sulfate, filtered, and concentrated to give a residue which
was purified by silica chromatography (10 % EtOAc in hexanes) to afford the title compound
(1.52 g, 21.9% yield).
[00547] Step B: Preparation of 5-(2-chloro-5-methoxyphenvlthioVN-f4-methvlthia2ol-2-
vlV3-phenoxypvridin-2-amine hvdrochloride: Prepared according to the method of Example 8,
using l,2-bis(2-chloro-5-methoxyphenyl)disulfane to afford the title compound (0.960 g, 56.5%
yield) after HCI salt formation. 'H NMR (dg-DMSO) 6 8.26 (m, 1H), 7.40 (m, 3H), 7.32 (m, H),

7.18 (t, 1H), 7.11 (d, 2H), 6.81 (dd, 1H), 6.73 (s, 1H), 6.41 (d, 1H), 3.64 (s, 3H), 2.27. (s, 3H).
Mass spectrum (apci) m/z = 456.3 (M+H-HC1).

[00548] Step A: Preparation of (2RVethvl 2-methvI-5-(proT)an-2-
ylidene'tevclopentanecarboxvlate: To a 3 L round bottom flask was added (r)-Pulegone (300 g,
1.97 mol), anhydrous NaHCO3 (82 g, 0.99 mol) and Ether (1.5 L). The mixture was cooled to -5
°C ice-salt bath under N2. Then bromine (101 mL, 1.97 mol) was added dropwise over 45
minutes. The mixture was filtered and carefully added dropwise (addition is exothermic in
nature) to NaOEt (20 wt%, 4.3 mol) cooled at 6 °C. The reaction was allowed to stir with
warming to ambient temperature overnight. Then 1L of 5% HC1 and 300 mL of ether was added.
The aqueous phase was extracted with ether and the combined organic layers washed with brine,
dried with MgSO/and concentrated. The resulting brown oil diluted with EtOH was added to a
warm solution of semicarbazide HC1 (150 g, 1.3 mol), NaOAc (150 g, 1.8 mol) and H2O (2 L) to
give a brownish solution. The mixture was then refluxed for 3 hours and stirred at ambient
temperature overnight. The mixture was treated with 1 L of water and 500 mL of ether. The
aqueous phase was extracted with ether. The combined organic layers were dried with MgSO4
and concentrated to- give a brown oil. The oil was subject to vacuum distillation, and the title
compound (247 g, 64% yield) was collected at 73-76 °C.
[00549] Step B: Preparation of (2RVethvl 2-methvl-5-oxocvclopentanecarboxvlate: The
(2R)-ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (139 g, 662 mmol) in EtOAc
(900 mL) was cooled to -78 °C using a dry ice-isopropanol bath. This mixture was subjected to
ozonolysis until the reaction turn purple in color. Ozone generation ceased and the reaction
removed from the dry-ice bath. Oxygen was bubbled through the reaction until the reaction
turned yellow. The reaction was concentrated and the resulting residue dissolved in 60 mL of
glacial acetic acid. The solution was cooled to 0 °C and Zn dust was added portionwise over 30
minutes. The reaction was then allowed to stir for 1 hour, then filtered through celite to remove

the zinc. The acetic acid was neutralized to pH 7 with aqueous NaOH and NaHCC>3 and extracted
with ether. The organics were dried with brine, MgSCU and concentrated to give the desired
material as a brownish liquid. The material was passed through a silica plug (eluting 8:1,
hex/EtOAc) to remove polar impurities to afford the title compound (82 g, 73% yield).
[00550] Step C: Preparation of (RVethvl 2-amino-5-methvlcvclopent-l-enecarboxvlate: To
a solution of (R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (106 gs 622 mmol) in 1.2L
MeOH was added ammonium acetate (240 g, 3.1 mol). The reaction was stirred for 20 hours and
concentrated to remove MeOH. The resulting residue was dissolved in CH2CI2, washed with
H2O, brine, dried (Na2SO4>, filtered and concentrated to give the title compound (102 g, 97%
yield) as an orange oil.
[00551] Step D: Preparation of (RV5-methvl-6,7-dihvdro-5H-cvclopentafd1pvrimidin-4-ol:
A 2L 3-neck round bottom flask equipped with a condenser, internal temperature probe, was
charged with (R)-ethyl 2-amino-5-methylcyclopent-l-enecarboxylate (185 g, 1093 mmol) and
ammonium formate (103.4 g, 1640 mmol) in formamide (400 mL) and toluene (200 mL). The
reaction was heated to an internal temperature of 150 °C and stirred for 36 hours. The reaction
was cooled and transferred to a 2L single next flask and excess formamide was removed by high
vacuum distillation. The resulting oil was dissolved in CH2CI2 and washed with brine. The
combined aqueous layers were extracted with CH2CI2. The combined organic layers were dried
over sodium sulfate, filtered and concentrated to give the crude product as a brown semi solid
which was taken into the next step without any further purification.
[00552] Step E: Preparation of (R)-4-chloro-5-methvl-6.7-dihvdro-5H-
cvclopentafdipyrimidine: The solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-
4-ol (2.08g, 13.9mmol) in POCI3 (10ml) was refluxed for 2 hours. After cooling, the excess
POCI3 was evaporated and the residue was dissolved in CH2CI2 (50ml) and was neutralized with
saturated NaHCC>3. The aqueous phase was extracted with CH2CI2. The organic phase was dried
and concentrated. The residue purified on silica gel (20% EtOAc in hexanes) to afford the title
compound (1.0 g, 44% yield).
[00553] Step F: Preparation of (R)-5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-
ylthio)-N-(4-methylthiazol-2-yl)-3-phenoxypyridin-2-amine dihydrochloride: Prepared according
to the method of Example 127 using (R)-4-chloro-5-methyl-6,7-dihydro-5H-
cyclopenta[d]pyrimidine to afford the title compound (51.6 mg, 49.8% yield) after HCI salt
formation. *H NMR (de-DMSO) 5 8.63 (m, 1H), 8.26 (m, 1H), 7.42 (m, 3H), 7.16 (m, 3H), 6.75

(s, 1H), 3.29 (m, 1H), 3.03 (m, 1H), 2.80 (m, 1H), 2.28 (m, 4H), 1.72 (m, 1H), 1.27 (d, 3H). Mass
spectrum (apci) m/z = 448.3 (M+H-2HC1).

[00554] Prepared according to the method of Example 45 from Methyl 3-(2-(3-phenoxy-5-
(pyridm^-yl1hio)pyridin-2-ylamino)thiazol-4-yl)propanoate. ]H NMR (d6-DMSO) 8 8.58 (m,
2H), 8.38 (m, 1H), 7.64 (m, 2H), 7.48 (m, 1H), 7.43 (m, 2H), 7.18 (m, 3H), 6.78 (m, 1H), 2.86
(m, 2H), 2.71 (m, 1H), 2.62 (m, 1H). Mass spectrum (apci) m/z = 451.2 (M+H-2HC1).

[00555] Step A: Preparation of 3.5-dimethylisoxazolor4.5-b1pvridine 4-oxide: 3,5-
dimethyl-4-nitroisoxazole (2.50 g, 17.6 mmol) in 25 mL EtOH was dissolved. Piperidine (0.174
mL, 1.76 mmol) was added followed by propionaldehyde (1.52 mL, 21.1 mmol). The solution
was heated at 90 °C overnight. The solution was concentrated and chromatographed using EtOAc
to obtain the title compound (0.650 g, 22.5% yield).
[00556] Step B: Preparation of 7-chioro-3,5-diTnethvlisoxazolor4.5-b1pvridine: 3,5-
dimethylisoxazolo[4,5-b]pyridine 4-oxide (0.650 g, 3.96 mmol) in chloroform (5 mL), was added
POC13 (1-45 mL, 15.8 mmol) and the mixture was heated at 80 °C for 2 hours. The solution was
cooled and poured onto ice water. The solution was neutralized with saturated NaHCCb and the
solution was then extracted with EtOAc, dried, and concentrated. The solid was triturated with
ether and filtered twice to obtain two crops of the title compound (0.417 g, 57.7% yield).
[00557] Step C: Preparation of 5-(3,5-dimethylisoxazolo[4,5-b]pyridm-7-yltbio)-N-(4-
methyIthiazol-2-yl)-3-phenoxypyridin-r2-amine dihydrochloride: Prepared according to the

method of Example 127. 2H NMR (de-DMSO) 5 8.39 (dd, 1H), 7.48 (dd, 1H), 7.39 (m, 3H), 7.15
(m, 3H), 7.06 (d, 1H), 6.74 (s, 1H), 2.54 (m, 3H), 2.52 (m, 3H), 2.28 (s, 3H). Mass spectrum
(apci) m/z = 461.9 (M+H-2HC1).

{005583 Step A: A 100 mL round-bottomed flask was charged with tert-butyl 4-(2-(5-
bromo-3-phenoxypyridia-2-ylamino)thia2ol-4-yl)piperidine-l-carboxylate (1.6 g, 3.0 mmol), N-
ethyl-N-isopropylpropan-2-amine (1.0 mL, 6-.0 mmol), Xantphos (0.087 g, 0.15 mmol), and
Dioxane (25 mL). Nitrogen was bubbled through the solution for 10 minutes. Methyl 3-
mercaptopropanoate (0.40 mL, 3.6 mmol) and Pd2dba3 (0.068 g, 0.075 mmol) were added and the
reaction was plunged into a 95 °C oil bath for 6 hours. The reaction was cooled to room
temperature and the solids filtered through celite and concentrated. The residue was purified on
silica (30% EtOAc in hexanes) to afford tert-butyl 4-(2-(S-(3-methoxy-3-oxopropylthio)-3-
phenoxypyridin-2-ylamino)thiazol-4-yi)piperidine-l-carboxylate (1.4 g, 81.48% yield) as a white
foam.
[00559] Step B: A 25 mL round-bottomed flask was charged with tert-butyl 4-(2-(5-(3-
methoxy-3-oxopropyltMo)-3-phenoxypyridm-2-ylamino)thiazol-4-yl)piperidine-l-carboxylate
(500 mg, 0.876 mmol), 7-chlorothieno[3:2-b]pyridine (178 mg, 1.05 mmol), and DMSO (8 mL).
Nitrogen was bubbled through liie solution for 10 minutes. Potassium 2-methylpropan-2-olate
(295 mg, 2.63 mmol) was added and stirred at room temperature for 30 minutes. The reaction
was poured into saturated aqueous NKUCl and extracted with EtOAc (2 x 20 mL). The organic
layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica
(50% EtOAc in hexanes) to afford tert-butyl 4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-
ylthio)pyridin-2-ylamino)tbjazol-4-yl)piperidine-l-carboxylate.
[00560] Step C: tert-Butyl 4-(2-(3-phenoxy-5-(thieno[3^-b]pyridin-7-yltbio)pyridin-2-
ylamino)thiazol-4-yl)piperidine-l-carboxylate was dissolved in 1:1 GHbCfomethanol and 4N
HC1 in dioxane added and stirred for 1 hour at room temperature. The reaction was concentrated

and the residue was partitioned between CH2CI2 and saturated aqueous sodium bicarbonate. The
organic layer was dried over sodium sulfate,-filtered and concentrated to afford 3-phenoxy-N-(4-
(piperidm-4-yl)tMazol-2-yl)-5-(iMeno[3,2-b]pyridm-7-ylthio)pyridin-2-aniine (238 mg, 52.5%
yield over 2 steps) as a white solid
[00561] Step D: A 20 mL vial was charged with 3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-
yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine (80 mg, 0.15 mmol), triethylamine (0.043
mL, 0.31 mmol), and THF (2 mL). Acetyl chloride (0.011 mL, 0.15 mmol) was added and stirred
at ambient temperature for 10 minutes. The reaction was poured into saturated aqueous NaHC(>j
and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and
concentrated. The residue was purified on silica gel (5 to 10% methanol in EtOAc) to afford the
title compound (35.1 mg, 35.9% yield) as a yellow solid after HC1 salt formation. }H NMR (dg-
DMSO) 5 8.65 (d, 1H), 8.48 (d, 1H), 8.46 (d, 1H), 7.77 (d, 1H), 7.54 (d, 1H), 7.41 (m, 2H), 7.18
(m,4H), 6.82 (s, 1H), 4.43 (m, 1H), 3.88 (m, 1H), 3.14 (ra, 1H), 2.89 (m, 1H), 2.64 (m, 1H), 2.01
(s, 3H), 1.96 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z = 560.4 (M+H-
2HC1).
[00562] The following compounds were also prepared according to the procedure of
Example 198, Step D.







[00563] Step A: Preparation of tert-butyl 4-(2-(5-(3-methoxy-3-oxopropylthio)-3-
(phenyliMo)pyridin.-2-ylamino)thiazol-4-yl)piperidine-l-carboxylate: Prepared according to the
method of Example 13 from tert-butyl 4-(2-(5-bromo-3-(phenyltWo)pyridin-2-ylamino)thiazol-4-
yl)piperidine-1 -carboxylate.
[00564] Step B: Preparation of tert-butyl 4-(5-(3-(plienylthio)-5-(thieno[3,2-b]pyridin-7-
ylthio)pyridin-2-ylamino)-l,2,4-thiadiazol-3-yl)piperidine-l-carboxylate Prepared according to
the method of Example 127.
[00565] Step C: Preparation of 3-(phenylthio)-N-(3-(piperidin-4-yl)-l ,2,4-thiadiazol-5-yl)-
5-(thieno[3^-b]pyridin-7-ylthio)pyridin-2-amine dihydrochloride: Tert-butyl 4-(5-(3-
(phenyltruo)-5-(thieno[3,2-b]pyridin-7-yltbio)pyridin-2-ylammo)-l,2,4-tbiadiazol-3-
yl)piperidine-l-caiboxylate was dissolved in 1:1 CHbCtzimethanol (4 mL) and 4N HC1 in dioxane
added (2 mL) and stirred at ambient temperature for 1 hour. The solvent was removed and placed
on high vacuum to afford the title compound (100 mg, 89.6% yield) as a yellow solid. *H NMR
(de-DMSO) 8 8.70 (m, 2H), 8.20 (m, 3H), 7.95 (m, 1H), 7.40 (m, 5H), 3.80-3.05 (m, 9H). Mass
spectrum (apci>m/z = 535.2 (M+H-3HC1).
[00566] Using the procedure in Example 211, steps A and B or steps A-C, the following
compounds were prepared.



[00567] Step A: Preparation of methyl 4-f6-f4-methvlthiazol-2-vlaminoV-5-
phenoxypvridin-3-vlthio')benzoate: Prepared according to the method of Example 127 from
methyl 3^6-(4-methyltMazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate.
[00568] Step B: Preparation of 4-f6-(4-meifavltibdazol-2--ylamino^-5-phenoxvpvridin-3-
vlthio^benzoic acid: Prepared according to the method of Example 45 to afford the title
compound (10.3 mg, 38.0% yield) as a white solid. *H NMR (dg-DMSO) 5 8.26 (m, 1H), 7.82
(m, 2H), 7.39 (m, 2H), 7.28 (m, 1H), 7.18 (m, 3H), 7.10 (m, 2H), 6.65 (s, 1H), 2^5 (s, 3H). Mass
spectrum (apci) m/z = 436.3 (M+H-Na).



[00570] Step A: Preparation of ethyl 5H-pvnrolor3v4-b1pyridme-6(7H>K;arboxvlate N-
oxide: mCPBA (7.3 g, 30 mmol) was added into a solution of ethyl 5H-pyrrolo[3,4-b]pyridine-
6(7H)-carboxylate (5 g, 26 mmol) in CH2CI2 (200 mL) and stirred for 2 hours. The reaction was
poured into water and extracted with CH2CI2. The organic layer was washed with aqueous
sodium bisulfate, NaHCOs and brine, dried with Na2SC>4, filtered and concentrated to afford the
title compound (4 g, 74% yield) as a white solid.
[00571] Step B: Preparation of ethvl 4-chloro-5H-pvrrolor3.4-b1pvridine-6Y7ir)-
carboxvlate: POCI3 (20 mL, 218 mmol) was added into ethyl 5H-pyirolo[3,4-b]pyridine-6(7H)-
carboxylate N-oxide (1 g, 4.80 mmol) and heated to 35 °C for 12 hours and 50 °C for another 5
hours. The solvent was evaporated and poured into water. The material was extracted with
CH2C125 washed with NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The
residue was purified on silica gel to afford the title compound (0.5 g, 45.9% yield).
[00572] Step C: Preparation of 5-f6.7-dihvdro-5H-Pvrrolor3.4-blpvridin-4-vlthioVN-(4-
methvlthiazol-2-vlV3-phenoxvpvridin-2-amine trihvdrochloride: A 10 mL round-bottomed flask
was charged with methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-
ylthio)propanoate (65 mg, 0.16 mmol), ethyl 4-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-
carboxylate (55 mg, 0.24 mmol), and DMSO (2 mL). The reaction was bubbled through with
nitrogen and potassium 2-methylpropan-2-olate (54 mg, 0.49 mmol) was added and stirred at
ambient temperature for 30 minutes. The reaction was poured into saturated aqueous NH4CI and
extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated

The residue was purified on silica gel (50% EtOAc in hexanes) to afford a residue that was
dissolved in methanol, KOH (xs) and water (0.5 mL) added and heated to 60 °C over the
weekend. The reaction was poured into saturated aqueous NH4CI and extracted with EtOAc. The
organic layer was dried with sodium sulfate, filtered and concentrated . The residue was purified
on silica gel (100% EtOAc to 20% methanol in CH2C12 with 0.2% ammonia) to afford the title
compound (29 mg, 33% yield) as a yellow solid after HC1 salt formation. lH NMR (d6-DMSO) 5
10.12 (bs, 2H), 8.34 (d, 1H), 8.31 (d, 1H), 7.42 (m, 2H), 7.36 (d, 1H), 7.17 (m, 3H), 6.84 (d, 1H),
6.76 (s, 1H), 4.47 (m, 4H), 2.28 (s, 3H). Mass spectrum (apci) m/z = 434.2 (M+H-3HC1).

[00573] Step A: Preparation of tert-butyl 4-chloro-7,8-dihvdropvridor4.3-d]pvrimidine-
6(5HVcarboxvlate: A mixture of PPI13 (81.4 g, 310 mmol) and N-chlorosuccinimide (41.4 g, 310
mmol) in dioxane (850 mL) was stirred at ambient temperature for 30 minutes. To this
suspension was added tert-butyl 4-hydroxy-7,8-dmydropyrido[4,3-d]pyrimidine-6(5H)-
carboxylate and the mixture stirred at 50 °C for 18 hours. The mixture was subsequently treated
with triethylamine (25 mL, 183 mmol) and the resulting brown solution concentrated. The black
oil was dry packed onto silica gel and purified by chromatography eluting with 15-20%
EtOAc/Hexanes to give the title compound as a yellow gum.
[005741 Step B: Preparation of afford N-(4-methylthiazol-2-yl)-3-phenoxy-5-(5,6,7,8-
tettahydropyrido[4,3-d]pyriniidin-4-ylthio)pyridin-2-amine trihydrochloride: Prepared according
to the method of Example 218, Step B. lH NMR (de-DMSO) 8 9.56 (bs, 2H), 8.75 (s, 1H), 8.24
(d, 1H), 7.43 (m, 2H), 7.34 (m, 1H), 7.15 (m, 3H), 6.70 (s, 1H), 4.21 (m, 2H), 3.04 (m, 2H), 2.26
(s, 3H). Mass spectrum (apci) m/z = 449.2 (M+H-3HC1).


[00575] Step A: Preparation of tert-butyl 4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-
b]pyridin-7-ylthio)pyridin-2-ylarcrino)-l,2,4-tM
Prepared according to the method of Example 127.
[00576] Step B: Preparation of 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-lJ234-
1hiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride: Prepared
according to the method of Example 196, step C.
[00577] Step C: Preparation of l-(4-^5-(3-(4-fluorophenoxvyS-fthienor3.2-b1pyrid
vlihio^pvradin-2-vlaniinoyi.2.4-thiadiazol-3-yl)meifo dihydrochloridc:
Prepared according to the method of Example 198. JH NMR (dg-DMSO) 8 12.47 (bs, 1H), 8.57
(d, 1H), 8.51 (d, 1H), 8.33 (d, 1H), 7.68 (d, 1H), 7.57 (a, 1H), 7.23 (m, 4H), 7.08 (d, lh), 4.34
(m, 1H), 3.78 (m, 1H), 2.98 (t, 1H), 2.72 (d, 2H), 2.09 (m, 1H), 1.97 (s, 3H), 1.65 (m, 2H), 1.18
(m, 1H), 1.05 (m, 1H). Mass spectrum (apci) m/z = 593.2 ^vI+H-2HCl).
[00578] The following compounds were prepared according to the method of Example
220.



[00579] Step A: Preparation of tert-butyl 4-("5-f5-bromo-3rphenoxvpvridin-2-vlaminoV
1.2v4-thiadiazol-3-yl)piperidine-l-carboxvlate: Prepared according to the method of Example 183
stepD.
(005801 Step B: Preparation of tert-butvl 4-(5-(5-(3-methoxv-3-oxopropvlthioV3-
phenoxvpvridin^-vlaminoVl^^-thiadiazol-S-vl^piperidine-l-carboxvlate: Prepared according
to the method of Example 13.
[00581] Step C: Preparation of tert-butvl 4-r5-f3-phenoxv-5-(thienor3^-b1pvridin-7-
vlthio^Pvridin^-vlamtDLoVl^.^tbiadiazol-S-vnpiperidine-l-carboxvlate: Prepared according to
the method of Example 127. !H NMR (CDC13) 5 9.18 (s, 1H), 8.48 (d, 1H), 8.37 (d, 1H), 7.79 (d,
1H), 7.55 (d, 1H), 7.40 (m, 2H), 7.24 (m5 2H), 7.06 (m, 2H), 6.77 (d, 1H), 4.16 (m, 2H), 3.00 (m,
1H), 2.91 (m, 2H), 2.05 (m, 2H), 1.83 (m, 2H), 1.47 (s, 9H). Mass spectrum (esi) m/z =519.2
(M+H-Boc).



[00582] Placed 2 pyridine-3-ol (prepared ia Example 69) (0.180 gs 0.426 mmol) in DMF (5 mL) and cooled to 0
°C. Sodium hydride (0.0307 g, 1.28 mmol) was added and stirred for 10 minutes then Mel
(0.0605 g, 0.426 mmol) was added stirred at ambient temperature for 30 minutes. Added water
and extracted with CH2CI2. The organic layer was concentrated and purified by silica gel. The
product was still impure. Mixture was purified by medium pressure reverse phase followed by
two high pressure reverse phase purifications. Combined all clean fractions then dissolved in
CH2CI2 and added HC1 in ether, then concentrated to give the title compound (0.0085 g, 4.22%
yield). !H NMR (ds-DMSO) S 8.14 (m, 1H), 8.10 (d, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.34-7.27
(m, 3H), 7.03 (m, 1H), 6.85 (d, 2H), 6.36 (s, 1H), 4.24 (s, 2H), 3.17 (s, 3H), 2.18 (s, 3H).

[00583] Step A: Preparation of give tert-butvl 4-(hvdroxy(pyridin-2-vl)methvl)piperidine-
1-carboxvlate: Placed 2-bromopyridine (0.833 g, 5.27 mmol) in THF (25 mL) and cooled to -78
°C. Butyllithium (2.11 mL, 5.27 mmol) was slowly added and stirred for 5 minutes. Dissolved
tert-butyl 4-formylpiperidine-l-carboxylate (0.500 g, 2.34 mmol) in THF (3 mL) and added
slowly to the above solution then stirred at -78 °C for 30 minutes. Added ammonium chloride
and extracted with CH2CI2. Concentrated and purified by silica gel to give the title compound
(0.229 g, 33.4% yield)
(00584] Step B: Preparation of tert-butvl 4-(fmethvlsulfonvloxvVpvridin-2-
yDmethytynperidine-l-carboxvlate: Placed 2-bromopyridine (0.833 g, 5.27 mmol) in THF (25
mL) and cooled to -78 °C. Slowly added butyl lithium (2.11 mL, 5.27 mmol) and stirred for 5
min. Dissolved tert-butyl 4-formylpiperidine-l-carboxylate (0.500 g, 2.34 mmoL) in THF (3 mL)
and added slowly to the above solution and stirred at -78 °C for 30 min. Added ammonium
chloride and extracted with CH2CI2. Concentrated and purified by silica gel to give the title
compound (0.229 g, 33.4% yield)

[00585] Step C: Preparation of gave tert-butyl 4-f(6-(r4-methvlthia2ol-2-vlamino')-5-
phenoxvpvrLdin-3-vlthio¥pvridin-2-vnmethvl)piperidine-l-carboxvlate: Prepared according to
the method of Example 16.
[00586] Step D: Preparation of 4-methvI-N-(3-phenoxv-5-(piperidin-4-vlCpvridin-2-
vl)methvlthio')pvridin-2-vI>thiazol-2-aniine tris(2.2,2-trifluoroacetate): Placed Me2S (0.0072 g,
0.12 mmol) in Trifhioroacetic acid (10 mL) followed by tert-butyl 4-((6-(4-methylthiazol-2-
ylamino)-5-phenoxypyridin-3-yltUo)(pyridin-2-yl)methyl)piperidine-l-carboxylate (0.068 g,
0.12 mmol) stirred at ambient temperature for 30 minutes, then concentrated to give the title
compound (0.086 g, 90% yield). !H NMR (de-DMSO) 8 8.52 (bs, 1H), 8.42 (m, 1H), 8.17 (bs,
1H), 8.00 (d, 1H), 7.70 (dt, 1H), 7.41 (t, 2H), 7.25-7.16 (m, 3H), 6.92 (d, 2H), 6.90 (s, 1H), 6.63
(s, 1H), 4.22 (d, 1H), 3.32 (d, 1H), 3.17 (d, 1H), 2.9872.74 (m, 2H), 2.30 (m, 2H), 2.23 (s, 3H),
1.45 (m, 2H), 1.30 (m, 1H).
[00587] The following compounds were also made according to the procedure of Example


225.


[00588] Step A: Preparation of ethyl 3-f2-aminopvridin-3-vloxv)benzoate hydrochloride:
Placed ethyl 3-(2-aminopyridin-3-yloxy)-4-chlorobenzoate (prepared according to Example 39,
Step B; 8.96 g, 30.6 mmol) and PdCOFTfc/C (0.86 g, 6.2 mmol) in EtOH (200 mL) and placed
under balloon hydrogen pressure for 18 hours. The reaction mixture was transferred to a Parr
bottle and the pressure was increased to 30 psi for several hours, and then the hydrogen pressure
was increased to 50 psi for 2 more days. The reaction mixture was filtered though a plug of celite
and concentrated to give the title compound e (8.3 g, 92.04% yield).
[00589] Step B: Preparation of ethyl 3-(2-amino-5-bromopvridin-3-yloxv)benzoate:
Prepared according to the method of Example 10, Step B,.
[00590] Step C: Preparation of ethvl 3-f5-bromo-2-f3-(4-chlorobenzoyl')mioureido')
pyridine-3-vloxv)benzoate: Prepared according to the method of Example 39, Step D.
[00591] Step D: Preparation of ethyl 3-(r5-bromo-2-thioureidopvridin-3-vloxv')benzoate:
Prepared according to the method of Example 39, Step E.
[00592] Step E: Preparation of S-fS-bromo^-^-isobutvlthiazol^-vlamino^pvridine-S-
yloxvybenzoate: Prepared according to the method of Example 39, Step F.

[00593] Step F: Preparation of ethyl 3-(2-f4-isobutvItfaia3:ol-2-v}amino)-5-(3-methoxv-3-
oxopropyltMo')pvridine-3-yIoxv)benzoate: Prepared according to the method of Example 13.
[00594] Step G: Preparation of .ethyl S-Cl^-isobutvlthiazol-l-vlaminoVS-Cpvrimidin^-
ylthio^pyridine-3-vIoxy')benzoate: Prepared according to the method of Example 127.
[00595] Step H: Preparation of 3-(2-f4-isobutylmiazol-2-ylaminoV5-(pvrimidin--2-
yItmo")pvridine-3-yloxv)benzoic acid: Prepared according to the method of Example 70, Step B.
[00596] Step I: Preparation of N-q-fdimethvlamino^emvD-S-Q-r^isobutvlthiazol^-
ylairunoVS^pvrimidm^-yltMoVpvridiae-S-vloxy^benzarnide dihydrochloride: Prepared
according to the method of Example 7.

[00597] Prepared according to the method of Example 175 from N-(4-methylthiazol-2-yl)-
3-phenoxy-5-(piperidin^-yl(pyridin-2-yl)memyltiuo)pyridin-2-amine and 2-
hydroxyacetaldehyde. ltt NMR (de-DMSO) S 9.95 (bs, 1H), 8.50 (d, 1H), 8.04 (s, 1H), 7.88 (m,
1H), 7.48-7.36 (m, 4H), 7.22 (t, 1H), 6.97 (m, 3H), 6.76 (s, 1H), 4.32 (d, 1H), 3.73 (m, 2H), 3.57
(d, 1H), 3.40 (d, 1H), 3.07 (m, 2H), 3.01-2.80 (m, 2H), 2.40-2.21 (m, 6H), 1.71 (m, 1H), 1.57 (m,
lH),1.42(d,lH).
[00598] The following compounds were made according to the method of Example 175.



[00599] Step A: Preparation of l-fchloromethvl)pyrroIidin-2-one: Placed pyrrolidin-2-one
(2.00 g, 23.5 mmol), and paraformaldehyde (1.06 g, 35.3 mmol) in chlorotrimethylsilane (60 mL)
and heated to reflux for 2 hours and then concentrated to give the title compound (2.97 g, 94.6%
yield).
[00600] Step B: Preparation of l-Cfe-^-meihvlthiazol^-vlamino^-S-phenoxvTjvridin-S-
vlthiotoethvDpyrrolidiTi-2-one: Prepared according to the method of Example 16. 'H NMR (d6-
DMSO) 8 10.83 (bs, 1H), 8.16 (d, 1H), 7.41 (t, 2H), 7.34 (d, 1H), 7.17 (t, 1H), 7.07 (d, 2H), 6.62
(s, 1H), 4.59 (s, 2H), 3.40 (t, 2H), 2.23 (s, 3H), 2.08 (t, 2H), 1.84 (m, 2H).



[00601] Step A: Preparation of tert-butvl 4-f2.2.2-trichloro-l-hvdroxvethvl'>Diperidine-l-
carboxvlate: Placed 2,2,2-trichloroacetic acid (5.746 g, 35.17 mmol) in DMF.(5 mL) and added
slowly sodium 2,2,2-trichloroacetate (6.519 g, 35.17 mmol). The reaction was stirred for 10
minutes and tert-butyl 4-formylpiperidine-l-carboxylate (5.00 g, 23.44 mmol) was added. The
reaction was stirred for 40 minutes then quenched with saturated sodium bicarbonate and filtered.
The solids were washed with water and dried. The product was triturated with water and filtered
to give the title compound (5.734 g, 73.53% yield).
[00602] Step B: Preparation of tert-butvl 4-(2-ethoxv-l-(6-(4-methvlthiazol-2-vlaminoV5-
phenoxvpyridm-3-yltMo)-2-oxoethvDpiperidine-1 -carboxvlate: Placed methyl 3-(6-(4-
methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (2.20 g, 5.48 mmol), tert-butyl
4-(2,2,2-trichloro-l-hydroxyethyl)piperidine-l-carboxyIate (1.86 g, 5.59 mmol), and sodium
ethanolate (3.55 g, 10.9 mmol) in ethanol (75 mL) and stirred at ambient temperature for 4 hours.
The reaction was' quenched with sat NH4CI and extracted with CH2CI2. The organic phase was
concentrated and purified by silica gel (10-25% EtOAc in hex) to give the title compound (2.63
g, 75.5% yield).
[00603] Step C: Preparation of ethyl 2-(6-f4-methvlthiazol-2-vlamino>-5-phenoxvpvridip-
3-vlthioV2-(piperidin-4-vl)acetate: Prepared according to the method of Example 225, Step D.
[00604] Step D: Preparation of ethyl 2-(l-methvlpiperidin-4-ylV2-(6- ylaminoV5 -phenoxvpvridin-3-vlthio')acetate dihvdrochloride: Prepared according to the method
of Example 230. ]H NMR (de-DMSO) 5 9.84 (bs, 1H), 8.18 (d, 1H), 7.44 (t, 2H), 7.30 (d, 1H),
7.21 (t, 1H), 7.09 (d, 2H), 6.63 (s, 1H), 3.98 (q, 2H), 3.81 (m, 1H), 3.62 (d, 1H), 3.37 (m, 2H),
2.90 (m, 2H), 2.69 (d, 3H), 2.25 (s, 3H), 1.85-1.70 (m, 2H), 1.56 (m, 2H), 1.05 (t, 3H).

[00605] Placed ethyl 2-(l-methylpiperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-
phenoxypyridin-3-ylthio)acetate (prepared in Example 235; 0.405 g, 0-812 mmol) in THF (8 mL)
and cooled to 0 °C added LLAJH4 (2.44 mL, 2.44 mmol) and warmed to ambient temperature for
30 minutes. Saturated NH4CI was slowly added and extracted with CH2C12. The organic layer

was dried, filtered, and concentrated to give the title compound (0.315 g, 84.9% yield). 'HNMR
(de-DMSO) 6 10.92 (bs, 1H), 8.16 (d, 1H), 7.41 (t, 2H), 7.33 (d,.lH), 7.17 (t,, 1H), 7.05 (d, 2H),
• t
6.60 (s, 1H), 4.82 (t, 1H), 3.49 (m, 2H), 2.87 (m, 1H), 2.80 (m, 2H), 2.23 (s, 3H), 2.15 (s, 3H),
1.86-1.53 (m, 6H), 1.29 (m, 1H).

[00606] Step A: Preparation of 2-fl-ftert-butoxycarbonvl')piperidin-4-vlV2-(6-(4-
methvlthiazol^-ylaminoVS-phenoxvpyridin-S-vlthio^acetic acid: Prepared according to the
method of Example Example 70, Step B, using tert-butyl 4-(2-ethoxy-l-(6-(4-methylthiazol-2-
ylammo)-5-phenoxypyridin-3-ylthio)-2-oxoethyl)piperidine-l-carboxylate (1.51 g, 2.59 mmol)
and 4NNaOH (15 mL); (1.42 g, 98.6% yield).
[00607] Step B: Preparation of tert-butvl 4-f2-(ethvlamino')-l-f6-(4-methvlthiazol-2-
vlamino)-5-phenoxvpvridin-3-vlihio)-2-oxoethvnpiperidine-l-carboxvlate: Prepared according
to the method of Example 71, using ethyl carbonochloridate (0.0292 g, 0.269 mmol), and
ethanamine; (0.034 g, 21.6% yield).
[00608] Step C: Preparation of N^myl-2-f6^4-methvlthiazol-2-ylaiiuiioV5-
phenoxvpvridin-3-vlthio)-2-(piperidin-4-vl)acetamide bisf2.2.2-trifluoroacetate): Prepared
according to the method of Example 225, Step D, to provide the title compound (0.040 g, 96%
yield). *H NMR (de-DMSO) 8 8.53 (m, 1H), 8.20 (m, 1H), 8.17 (d, 1H), 8.02 (t, 1H), 7.42 (t,
2H), 7.29 (d, 1H), 7.17 (t, 1H), 7.07 (d, 1H), 6.65 (s, 1H), 3.33 (d, 1H), 3.25 (t, 2H), 2.97 (m,
2H), 2.84 (m, 2H), 2.24 (s, 3H), 2.15 (d, 1H), 1.90 (m, 1H), 1.69 (d, 1H), 1.36 (m, 2H), 0.88 (t,
3H).
[00609] The following compounds were prepared according to the method of Example
237, Steps B and C.




[00610] Step A: Preparation of tert-butyl ^(fS-f^phenethvlthiazol^-vlaminoVS-
phenoxvpyridin-3-vlthio")(pyridin-2-vl)metfavl)piperidine-l-carboxylate: Prepared according to
the method of Example 16 from methyl 3-(6-(4-phenethyl1hiazol-2-ylamino)-5-phenoxypyridin-
3-ylthio)propanoate, potassium 2-methylpropan-2-olate, and tert-butyl 4-
((methylsulfonyloxy)(pyridin-2-yl)methyl)piperidine-1 -carboxylate.
[00611] Step B: Preparation of N-(4-phenethylthiazol-2-vlV3-phenoxv-5-fpiperidin-4-
vl(pvridin-2-vl')methvlthio'>pvridin-2-amine: Prepared according to the method of Example 225,
Step C.
[00612] Step C: Preparation of 2-(4-((6-(4-phenethvlthiazol-2-ylamino')-5-phenoxvpvridin-
3-vllluo)(pvridin-2-vl')taethvl>)piperidin-l-vl')ethanol: Prepared according to the method of
Example 230. JH NMR (dg-DMSO) 6 10.95 (bs, IH), 9.61 (bs, 1H), 8.41 (d, 1H), 8.79 (d, 1H),
7.67 (dt, 1H), 7.42 (t, 2H), 7.30-7.14 (m, 8H)V6.92 (m, 3H), 6.64 (s, 1H), 5.25 (s, IH), 4.15 (s,.
IH), 3.71 (m, 2H), 3.51 (m, 2H), 3.10-2.80 (m, 8H), 2.29 (m, 2H), 1.66 (m, IH), 1.46 (m, IH).

[00613] Step A: Preparation of tert-butvl 4-((3-methvl-1.2.4-oxadiazol-5-vl'>f6-f4-
methvlthin7.nl-2-vlaminoV5-phenoxvpvridin-3-ylthio'>methvnpiperidine-l-carboxvlate: Placed 2-
(l-(tert-butoxycarbonyl)piperidin-4-yl)-2-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-

ylthio)acetic acid (.250 g, 0.449 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0638 g, 0.494
mmol) in DMF (10 mL) and added N-((dimethylamino)fluoromethylene)-N-
methylmethanaminium hexafluorophosphate(V) (0.119 g, 0.449 mmol) and stirred for 30
minutes. Added N-hydroxyacetamidine (0.0366 g, 0.494 mmol) and heated to 110 °C for 4 days.
The reaction was diluted with EtOAc and washed with water, dried, filtered and concentrated.
The residue was purified by reverse phase chromatography to provide the title compound (0.122
g, 35.6%) Product was contaminated with —15% acid. Crude material was used in Step B.
[00614] Step B: Preparation of 5-ff3-methvl-1.2.4-oxadia2ol-5-vl¥piperidin-4-
vnmethvlthio*)-N-f4-methvlthiazol-2-vlV3-phenoxvpvridin-2-amine: Prepared according to the
method of Example Example 225, Step D.
[00615] Step C: Preparation of provide 2-(4-f(3-methvl-1.2.4-oxadiazol-5-vl¥6-(4-
methvltMazol-2-vlammo)-5-phenoxvp^din-3-vlthio)methvl)piperidin-l-vl')ethanol
dihvdrochloride: Prepared according to the method of Example 230. *H NMR (CDC13) 5 11.96
(bs, 1H), 8.02 (s, 1H), 7.44 (t, 2H), 7.25 (t, 1H), 7109 (d, 2H), 6.98 (s, 1H), 6.48 (s, 1H), 4.64 (s,
1H), 4.03 (m, 3H), 3.82 (d, 1H), 3.62 (d, 1H), 3.13 (s, 2H), 2.75 (m, 2H), 2.60 (d, 1H), 2.40 (s,
3H), 2.29 (s, 3H), 2.21 (m, 2H), 1.67 (m, 2H).

[00616] 4-Memyl-N-(3-phenoxy-5 hydrochloride prepared in Example 33 was purified by chiral chromatography to give two
enantiomers. Enantiomer 1, XHNMR (CDCI3) 6 8.58 (d, 1H), 8.09 (m5 1H), 8.04 (4 1H), 7.58 (d,
2H), 7.45 (t, 2H), 7.23 (t, 1H), 7.02 (d, 2H), 6.95 (d, 1H), 6.97 (s, 1H), 4.67 (q, 1H), 2.28 (s, 3H),
1.62 (d, 1H). Enantiomer 2, JHNMR (CDCI3) 8 8.58 (d, 1H), 8.09 (m, 1H), 8.04 (d, 1H), 7.58 (d,
2H), 7.45 (t, 2H), 7.23 (t, 1H), 7.02 (d, 2H), 6.95 (d, 1H), 6.97 (s, 1H), 4.67 (q, 1H), 2.28 (s, 3H),
1.62 (d, 1H).
[00617] Following the method of Example 16 the following compounds were made:






[00618] Following the procedure in Example 16 and using methyl 3-(6-(4-methylthiazol-
2-ylamino)-5-(phenylthio)pyridin-3-ylthio)pTopanoate hydrochloride (Example 90) the following
compounds were made:







[00619] Step A: Preparation of 2-chloro-l-fpyrrolidin-l-vI')ethanope: A solution of mL2-
chloroacetyl chloride (1.409mL mL, 17.71 mmol) and THF (50 mL)was cooled to 0 °C and
pyrrolidine (1.259 g, 17.71 mmol) was slowly added and stirred at ambient temperature for 3

hours. Partitioned between CH2CI2 and water, and the organic layer was separated, dried, filtered,
and concentrated to give the title compound (1.73 g, 66.19% yield) as a clear oil.
[00620] Step B: Preparation of 2-(6-(4-methvlthiazol-2-ylamino)-5-phenoxvpvridin-3-
vlmioVl-fpyrrolidin-l-yDethanone hvdrochloride: Prepared according to the method of Example
16. 'H NMR (dc-DMSO) 8 8.21 (d, 1H), 7.45 (t, 2H), 7.39 (d, 1H), 7.23 (t, 1H), 7.13 (d, 2H),
6.83 (s, 1H), 3.83 (s, 2H), 3.41 (t, 2H), 2.30 (s, 3H), 1.82 (m, 2H), 1.73 (m, 2H).
[00621] Following the method of Example 32, Step A, and Example 16, the following


compounds were made:


[00622] Step A: Preparation of pvridm-2-vlfte1rahvdro-2H-miopvran-4-yl)methanol:
Prepared according to the method of Example 225, Step A, from 2-bromopyridineand tetrahydro-
2H-thiopyran-4-carbaldehyde.
[00623] Step B: Preparation of n.l-Dioxo-hexahydro-lft, -thiopvran-4-vl>-pvridin-2-vl-
methanol: Placed pyridin-2-yl(tetrahydro-2H-thiopyran-4-yl)methanol (1.560 g, 7.453 mmol) in
glacial acetic acid (2 mL). Sodium perborate tetrahydrate (2.293 g, 14.91 mmol) was added and
stirred for 18 hours. The reaction was partitioned between saturated sodium bisulfite and CH2CI2.
The solids were filtered off, washed with water and dried to afford the title compound (1.233 g,
68.56% yield)
[00624] Step C: Preparation of methanesulfonic acid (1,1-dioxo-hexafavdro-lA.-thiopvran-
4-vlVpvridin-2-vl-methvl ester: Prepared according to the method of Example 225, Step B.
[00625] Step D: Preparation of ■r5-r(l.l-Dioxo-hexahvdro-lX6-thiopyran-4-vlV-pyridin-2-
vl-methvlsulfanvl]|-3-phenoxv-pvridin-2-vll-('4-methvl-thiazol-2-vlVamine dihvdrochldride:
Prepared according to the method of Example 16 using methyl 3-(6-(4-methylthiazol-2-ylamino)-
5-phenoxypyridin-3-ylthio)propanoate. JH NMR (de-DMSO) 8 8.47 (d, Iff), 8.02 (d, 1H), 7.76
(t, 1H), 7.43 (t, 2H), 7.29 (t, 2H), 7.20 (t, 1H), 7.01 (d, 1H), 6.95 (d, 2H), 6.70 (s, 1H), 4.45 (d,
1H), 3.21-2.95 (m, 5H), 2.36 (m, 1H), 2.25 (s, 3H), 1.85 (m, 1H), 1.74 (m, 1H), 1.61 (m, 1H).

[00626] Step A: Preparation of l-chloro-4-(methvltirio'rt)Utan-2-one: LDA prepared from
diisopropylamine (12.44 g, 123.0 mmol) and butyl lithium (44.71 mL, 111.8 mmol) combined in

THF (100 mL) at -78 °C was added dropwise to a solution containing methyl 3-
(methylthio)propanoate (3.00 g, 22.36 mmol), and chloroiodomethane (15.77 g, 89.42 mmol) in
THF (100 mL) at -78 °C over 30 minutes. The reaction was stirred for an additional 10 minutes
then added a solution of acetic acid 30 mL in THF (200 mL) keeping the temp below -65 °C. The
solution was stirred for 10 minutes and partitioned between EtOAc and brine. The organic layer
was washed with saturated bicarbonate, concentrated and purified by silica gel to give the title
compound (1.021 g, 29.92% yield).
[00627] Step B: Preparation of 5-bromo-N-r4-(2-fmethvlthio phenoxvpvridin-2-aTnme: Prepared according to the method of Example 7, Step E. *H NMR (dg-
DMSO) 8 10.96 (bs, 1H), 8.22 (d, 1H), 7.43 (t, 2H), 7.40 (d, 1H), 7.21 (t, 1H), 7.10 (d, 2H), 6.74
(s, 1H), 2.83 (m, 2H), 2.77 (m, 2H), 2.06 (s, 3H).

[00628] 5-Bromo-N (1.132 g, 2.680 mmol) was dissolved in CH2C12 (25 mL) and cooled to 0 °C. MCPBA (1.98 g,
8.04 mmol) was added and stirred at ambient temperature overnight. The reaction was quenched
with sodium bisulfite and extracted with CH2C12. The organic layer was washed with saturated
sodium bicarbonate, dried, filtered, and concentrated. The residue was purified by silica gel (15-
40% EtOAc in hexanes) to provide the title compound (0.503 g, 41.31% yield). !H NMR (de-
DMSO) 5 11.05 (bs, 1H), 8.20 (d, 1H), 7.43 (t, 2H), 7.38 (m, 1H), 7.20 (t, 1H), 7.09 (d, 2H), 6.79
(s, 1H), 3.43 (m, 2H), 3.00 (m, 2H), 2.97 (s, 3H).


[00629] Step A: Preparation of tert-butyl 4-n-hvdroxvethvr)piperidine-l-carboxylate:
Placed tert-butyl 4-formylpiperidine-l-carboxylate (2.00 g, 9.38 mmol) in THF (40 mL) and
cooled to -78 °C. Slowly added methylmagnesium. bromide (3.44 mL, 10.3 mmol) stirred for 1
hour. Slowly added saturated ammonium chloride and extracted with CH2CI2. Concentrated and
redisolved in 5% MeOH in CH2CI2. Added ether and filtered off solids. Concentrate filtrate to
give the title compound (1.94 g, 90.2% yield)
[00630] Step B: Preparation of tert-butyl 4-fl-fmethvlsulfonvloxv>ethvl)piperidine-l-
carboxylate: Prepared according to the method of Example 225, Step B.
[00631] Step C: -Preparation of 4-methvl-N-f3-phenoxv-5-d-(piperidin-4-
vDetiivltiuo^pvridm-2-vl)ifaiazol-2-amine bis(2.2.2-trifluoroacetate'): A nitrogen purged vial was
charged with methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate
(.150 g, 0.374 mmol) and THF (5 mL). Potassium 2-methylpropan-2-olate (0.934 mL, 0.934
mmol) was added and stirred at ambient temperature for 30 seconds. Tert-butyl 4-(l-
(methylsulfonyloxy)ethyl)piperidine-l-carboxylate (0.144 g, 0.467 mmol) was added and stirred
at ambient temperature under nitrogen for 20 hours. Saturated NH4CI was added and extracted
with CH2CI2. The organic layer was dried, filtered, and concentrated. The residue was dissolved
in CH2C12 (5 mL) and TFA (2 mL) was added and stirred for 1 hour. The reaction was
concentrated and purified by reverse phase chromatography (with 0.1% TFA) to provide the title
compound (0.0363 g, 14.8% yield). *H NMR (dVDMSO) 8 8.57 (bs, 1H), 8.23 (bs, 1H), 8.18 (d,
1H), 7.42 (t, 2H), 7.34 (d, 1H), 7.19 (t, 1H), 7.07 (d, 2H), 6.64 (s, 1H), 3.26 (d, 2H), 3.13 (m,
1H), 2.80 (m, 2H), 2.24 (s, 3H), 1.87 (m, 2H), 1.67 (m, 1H), 1.47 (m, 2H), 1.15 (d, 3H).

[00632] Step A: Preparation of 5-fbenzvloxvV2-chloropvridine: 6-Chloropyridin-3-ol
(30.00 g, 231.6 mmol), l-(bromomethyl)benzene (43.57 g, 254.7 mmol), and potassium
carbonate (80.01 g, 579.0 mmol) were added to DMF (500 mL) and stirred at ambient
temperature overnight. Water was added and extracted with ether. The organic phase was

washed with 1M NaOH, dried, filtered, and concentrated to provide the title compound (50.8 g,
99.86% yield).
[00633] Step B: Preparation of 5-(benzyloxvtpvridin-2-amine hvdrochloride: To a nitrogen
purged solution of mL Pd2(dba)3 (10.19 g, 11.12 mmol), 5-(beiizyloxy)-2-chloropyridine (48.87
g, 222.5 mmol), (2-diphenyl)dicyclohexyl-phosphine (7.797 g, 22.25 mmol) and THF (700 mL)
was added lithium hexamethyl disilazide (267.0mL mL, 267.0 mmol). The reaction was heated at
65 °C overnight and cooled to ambient temperature. 1M HC1 (250 mL) was added and stirred for
30 minutes. Saturated sodium bicarbonate was added slowly. The mixture was extracted several
times with CH2CI2, dried, filtered, and concentrated to give the title compound (52.1 g, 98.94%
yield)..
[00634] Step C: Preparation of 5-(benzvloxvV3-bromopvridm-2-amine: 5-
(Benzyloxy)pyridin-2-amine hydrochloride (52.3 g, 221 mmol) and sodium acetate (45.3 g, 552
mmol) were dissolved in acetic acid (300 mL). Bromine (11.3 mL, 221 mmol) was added slowly
and stirred at ambient temperature for 18 hours. After an aqueous workup, the material was
purified over silica gel to give the title compound (10.5 g, 17.0% yield).
[00635] Steps D-F: Preparation of 5-(benzvloxv')-3-bromo-N-(f4-methvlthiazol-2-
vl)pvridm-2-amine: Prepared according to the method of Example 7, Steps C- E.
[00636] Step F: Preparation of 5-(benzvloxv')-N-(4-methvlthiazol-2-vn-3-
fphenvlthio')pvridin-2-amine: Prepared according to the method of Example 8 to give the title
compound (2.80 g, 60.5% yield). !H NMR (d6-DMSO) 8 8.22 (s, 1H), 7.57 (bs, 1H), 7.49-7.30
(m, 11H), 6.68 (s, 1H), 5.18 (s, 2H), 2.25 (s, 3H).

[00637] Prepared according to the method of Example 193, Steps A-C, using 5-bromo-N-
(4-memylthiazol-2-yl)-3-(phenylthio)thiazole-2-amine and Tert-butyl 4-(2-oxoethyl)piperidine-
1-carboxylate as the starting materials. 'H NMR (de-DMSO) 8 8.53 (bs, 1H), 8.27 (s, 1H), 8.22

(bs, 1H), 7.76 (bs, 1H), 7.36 (t, 2H), 7.28 (t, 1H), 7.23 (d, 2H), 6.60 (s, 1H), 3.25 (d, 2H), 2.82 (q,
2H), 2.53 (t, 2H), 2.21 (s, 3H), 1.82 (m, 2H), 1.51 (m, 3H), 1.27 (m, 2H).

[00638] Step A: Preparation of methyl 3-r2-(5-bromo-3-phenoxvpyridiii-2-
vlamino^thiazol-4-yl')-2.2-dimethvlpropanoate: Prepared according to the method of Example 7,
Step E.
[00639] Step B: Preparation of methvl 3-(2-C5-f3-methoxv-3-oxopropvlthioV3-
phenoxypvridin-2-vlarflino)thiazol-4-vn-2.2-dimetfavlpropanoate: Prepared according to the
method of Example 13.
[00640] Step C: Preparation of methvl 2.2-diTnethv1-3-f2-(3-phenoxv-5-(thienof3.2-
b1pyridin-7-vlthio')pvridin-2-vlamino')miazol-4-vl>propanoate: Prepared according to the method
of Example 127.
[00641] Step D: Preparation of 2.2-diTnethv1-3-(2-(3-phenoxv-5-rthienor3.2-b"|pvridin-7-
vlthio')pvridin-2-vlamino')thiazol-4-vl*)propanoic acid: Prepared according to the method of
Example 45 to provide the title compound (0.024 g, 88% yield). !H NMR (CDC13) 8 8.44 (d,
1H), 8.29 (d, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 7.31-7.24 (m, 3H), 7.09 (t, 1H), 7.01 (d, 2H), 6.71
(d, 1H), 6.45 (s, 1H), 2.93 (s, 2H), 1.05 (s, 6H).


[00642] Step A: Preparation of 2-f2-fpvridin-3-vlMisulfanvl>>vridine: Prepared according
to the method of Example 162, Step A from 5-bromo-3-phenoxypyridin-2-amine.
[00643] Step B: Preparation of tert-butyl 4-(5-(3-phenoxy-5-(pvridin-2-ylthio^pyridin-2-


vlaminoVl .2,4-thiadiazol-3-vDpiperidine-l-cafboxvlate: A solution of pyridine (0.493 mL, 6.09
mmol), (Z)-tert-butyl 4-(cMoro(methylsulfonyloxyimino)methyl)piperidine-l-carboxylate (0.165
g, 2.03 mmol), and CH3CN (4 mL). The reaction was heated to 40 °C for 40 minutes. 3-phenoxy-
5-(pyridin-2-ylthio)pyridin-2-amine (0.400 g, 1.35 mmol) was added and stirred at 50 °C over the
weekend. The reaction was cooled to ambient temperature and poured into saturated aqueous
NaHCC>3 and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered,
and concentrated . The residue was purified on silica gel (20-25% EtOAc in hexanes) to provide
the title compound (0.598 g, 78.5% yield). JH NMR (ds-DMSO) 8 12.33 (s, 1H), 8.39 (m, 1H),
8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 3.96 (d, 2H), 2.98 (m3
3H), 1.97 (m, 2H), 1.64 (m, 2H), L40 (s, 9H).
[00644] Following the method of Example 267 the following compounds were made:


[00645] Tert-butyl 4^5-(3-phenoxy-5^pyridin-2-ylthio)pyridin-2-ylainino)-l,2,4-
thiadiazol-3-yl)piperidine-l-carboxylate (0.587 g, 1.04 mmol) was dissolved in 1:1
CHaCb/methanol and 4N HC1 in dioxane added. The reaction was stirred at ambient temperature
for 1 hour. The reaction was concentrated and dried in a vacuum oven to provide the title
compound (0.473 g, 98.0% yield). JH NMR (de-DMSO) 8 12.39 (s, 1H), 8.95 (bs, 1H), 8.80 (bs,
1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H)S 7.47 (d, 1H), 7.43 (t, 2H), 7.22-7.12 (m, 5H), 3.30
(d, 2H), 3.16-2.99 (m, 3H), 2.17 (d, 2H), 1.98 (m, 2H).

[00646] 3-Phenoxy-N-(3-(piperidm-4-yl)-lA4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)
pyridin-2-amine (0.075 g, 0.16 mmol), TEA (0.090 mL, 0.65 mmol), and acetic anhydride (0.017
g, 0.16 mmol) were added to THF and stirred for 3hr. Water was added and extracted with
CH2CI2. The organic layer was dried, filtered, and concentrated. The residue was purified by
silica gel (5% MeOH in CH2C12) to provide the title compound (0.044 g, 54% yield).1!* NMR
(de-DMSO) 8 12.34 (s, 1H), 8.38 (m, 2H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m,
5H), 4.32 (d, 1H), 3.84 (d, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.76 (t,lH), 2.01 (m, 5H), 1.74 (m,
1H), 1.59 (m,lH).
[00647] The following compounds were made according to the method of Example 272.





[00648] To a solution of 3-phenoxy-N-(3-(piperidine-4-yl)-l^,4-thiadiazol-5-yl)-5-
(piperidi-2-ylthio)piperidi-2-amine (.055 g, 0.119 mmol) in CH2C12 (4 mL) was added pyridine
(0.0940 g, 1.19 mmol), acetic acid (0.0714 g, 1.19 mmol), TEA (0.033 mL, 0.238 mmol), and
potassium cyanate (0.0193 g, 0.238 mmol). The reaction was stirred for 18 hours. Water was
added and extracted with CH2Cl2- The organic layer was dried, filtered, and concentrated. The
residue was purified by silica gel (1-4% MeOH in CH2C12) to give the title compound (0.0333 g,
48.4% yield) after HC1 salt formation. *H NMR (dg-DMSO) S 12.33 (s, 1H), 8.39 (d, 1H), 8.37
(m, 1H), 7.67 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 3.94 (d, 2H), 2.97 (m, 1H),
2.83 (t, 2H), 1.19 (m, 2H), 1.64 (m, 2H).

[00649] 2-Oxo-2-(4-(5-(3-phenoxy-5-(piperidi-2-ylthio)piperidi-2-ylamino)-ls2,4-
thiadiazol-3-yl)piperidine-l-yl)ethyl acetate (0.089 g, 0.158 mmol) and potassium carbonate

(0.109 g, 0.791 ramol) were refluxed in ethanol (25 mL) for 2 hours. The reaction was cooled to
ambient temperature, filtered and concentrated. The residue was purified by silica gel (1-2%
MeOH in EtOAc) to give the title compound (0.030 g, 36.4% yield). *H NMR (de-DMSO) 5
12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m,
5H), 4.49 (t, 1H), 4.31 (d, 1H), 4.10 (t, 2H), 3.71 (d, 1H), 3.10 (m, 2H), 2.86 (t, 1H), 2.02 (m,
2H),1.79-1.60(m,2H).

[00650] 3-Phenoxy-N-(3-(piperidin-4-yl)-lA4-thiadiazol-5-yl)-5-(pyridin-2-
ylthio)pyridin-2-amine (0.100 g, 0.2162 nrmol), 2-(tert-butoxycarbonyl)acetic acid (0.04544 g,
0.2594 mmol), Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride
(0.06216 g, 0.3243 mmol), and NJSf-dimethylpyridin-4-amine (0.002641 g, 0.02162 mmol) were
dissolved in CH2C12 (5 mL). Triethylamine (0.04375 g, 0.4323 mmol) was added and the solution
was stirred at ambient temperature for 3 hours. Water was added and the solution was extracted
with CH2C12, dried, filtered, and concentrated. The residue was purified by silica gel (1-2%
MeOH in CH2C12) to give the title compound (0.1116 g, 83.30% yield). lH NMR (de-DMSO) 8
12.35 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m,
5H), 6.73 (t, 1H), 4.29 (t, 1H), 3.81 (m, 3H), 3.20-3.02 (m, 2H), 2.81 (t, 1H), 2.01 (m, 2H), 1.76-
1.53 (m,2H)3 1.38 (s,9H).


[00651] 3-Phenoxy-N-(3-(piperidin-4-yl)-l,2,4-thiadiazol-5-yl>5-(pyridin-2-


ylthio)pyridin-2-atnine (Example 39, step C, 0.075 g, 0.16 mmol), (S)-2-hydroxypropanoic acid
(0.018 g, 0.19 mmol), Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine
hydrochloride (0.047 g, 0.24 mmol), and N,N-dimethylpyridin-4-amine (0.002 g, 0.016 mmol)
were dissolved in CH2C12 (5 mL). Triethylamine (0.033 g, 0.32 mmol) was added and the
solution was stirred at room temperature for 3 hours. Water was added and extracted with
CH2C12, dried, filtered, and concentrated. The residue was purified by silica gel (1-2% MeOH in
CH2C12) to give (R)-2-hydroxy-l-(4-(5^3-phenoxy-5^yridin-2-ylthio)pyridin-2-ylamino)-l,2,4-
thiadiazol-3-yl)piperidin-l-yl)propan-l-one (0.023 g, 27% yield). lH NMR (de-DMSO) 5 12.34
(s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H),
4.82 (t, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 4.01 (m, 1H), 3.25-3.04 (m, 2H), 2.84 (m, 1H), 2.02 (d,
2H), 1.81-1.55 (m, 2H), 1.18 (d, 3H).
[00652] The following compound was made according to the method of Example 282:

[00653] tert-Butyl 2-oxo-2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-
l^,4-thiadiazol-3-yl)piperidin-l-yl)ethylcarbamate (.098 g, 0.16 mmol) was dissolved in

CH2Cl2:MeOH (1:1, 20 mL) and added 5 mL of 4M HC1 in dioxane and stirred for 2 hours. The
reaction was concentrated and dried in high vacuum oven to provide 2-amino-l-(4-(5-(3-
phenoxy-5-(pyridm-2-yliMo)pyridm-2-ylain^
• dihydrochloride (0.081 g, 78% yield). !H NMR (dg-DMSO) 8 12.34 (s, 1H), 8.39 (d, 1H), 8.37
(m, 1H), 8.13 (m, 3H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.43 (t, 2H), 7.21-7.11 (m, 5H), 4.32 (d, 1H),
3.90 (m, 2H), 3.70 (m, 2H), 3.48 (m, 1H), 3.26-3.02 (m, 2H), 2.94 (t, 1H), 2.06 (d, 2H), 1.76-
1.53 (m, 2H).

[00654] Prepared according to the method of Example 230 from 3-phenoxy-N-(3-
(piperidm-4-yl)-l,2,4-tWadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine. *H NMR (dfi-DMSO)
5 12.37 (s, 1H), 9.26 (bs, 1H), 8.39 (d, 1H), 8.37 (d, 1H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.43 (t,
2H), 7.22-7.12 (m, 5H), 3.96 (s, 1H), 3.77 (t, 2H), 3.61 (d, 2H), 3.20-3.06 (m, 5H), 2.26 (d, 2H),
2.00 (m, 2H).

[00655] N-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-l,2s4-
thiadiazol-5-amine (Example 34, step C, 7.2 g, 14.01 mmol) and sulfamide (1.414 g, 14.71
mmol) were dissolved in dioxane (15 mL) and heated to reflux overnight. The reaction was
cooled and water was added and extracted with DCM. The organic layer was dried over sodium
sulfate, filtered and concentrated. The residue was purified by silica gel (l:lEtOAc in DCM).
The purified material was dissolved in DCM and 2M HC1 in ether was added. The solution was
concentrated and dried in a vacuum oven to afford 4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-

2-ylamino)-l32,4-thiadiazol-3-yl)piperidiae-l-sulfonamide hydrochloride (3.145 g, 38.8% yield).
'H NMR (de-DMSO) 8 12.35 (s, 1H)3 8.39 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H), 7.48 (d, 1H),
7.42 (t, 2H), 7.21-7.11 (m, 5H), 6.73 (bs, 2H)3 3.47 (d, 2H), 2.87 (m, 1H), 2.71 (t, 2H), 2.11 (d,
2H), 1.85 (m32H).

[00656] Step A: Preparation of 2-r2-f4-(5-f3-phenoxv-5-fpvridin-2-ylthio')pvridin-2-
ylainino>l,2,4-thiadiazol-3-vnpiperidin-l-vIsulfonvl')ethvl')isoindoline-l,3-dione: Prepared
according to the method of Example 272 from 3-phenoxy-N-(3-(piperidin-4-yl)-l3234-thiadiazol-
5-yl)-5-(pyridin-2-yltnio)pyridin-2-amine.
[00657] Step B: Preparation of N-f3-d-f2-aminoethvlstdfonvnpiperidin-4-vl'>-U2.4-
thiadiazol-5-vlV3-phenoxv-5-fpvridin-2-vlthio^pyridin-2-araine: 2-(2-(4-(5-(3-phenoxy-5-
ylsulfonyl)ethyl)isoindoline-l,3-dione (0.110 g, 0.157 mmol) and hydrazine monohydrate
(0.0236 g, 0.472 mmol) were dissolved in EtOH (25 mL) and heated to reflux for 8 hours. The
reaction was cooled to ambient temperature and the solids filtered arid triturated with EtOH to
afford the title compound (0.013 g, 14.5% yield). !H NMR (d^DMSO) S 8.38 (d, 1H), 8.36 (m,
1H), 7.66 (dt, 1H), 7.45 (d31H), 7.41 (t, 2H)3 7.20-7.10 (m, 5H)3 3.61 (d, 2H)3 3.12 (t, 2H), 3.01-
2.89 (m, 5H), 2.09 (d, 2H), 1.79 (m3 2H).


[00658] Step A: Preparation of tert-butvl 4-(methoxv(methvncarbamovlV3-
methvlpiperidine-1 -carboxvlate: To a solution of l-(tert-butoxycarbonyl)-3-methylpiperidine-4-
carboxylic acid (3.00 g, 12.3 mmol) in CH2C12 (200 mL) was added di(lH-imidazol-l-
yl)methanone (2.19 g, 13.6 mmol) portionwise. After the bubbling ceased (~60. minutes), N-
methoxymethanamine hydrochloride (1.32 g, 13.6 mmol) was added in one portion. The mixture
was allowed to stir overnight at ambient temperature, then was washed with water, IN HCL, and
saturated sodium bicarbonate. The organic layer was dried, filtered, and concentrated to give the
desired product (2.29 g, 64.8% yield) as a colorless oil.
[00659] Step B: Preparation of tert-butvl 4-acetvl-3-methvlpiperidine-l-carboxvlate: 3.0 M
methylmagnesium chloride in THF (4.50 mL, 13.5 mmol) was added dropwise to a solution of
tert-butyl 4-(methoxy(methyl)carbamoyl)-3-methylpiperidine-l-carboxylate (3.10 g, 10.8 mmol)
in THF (50 mL) at 0 °C. The reaction was warmed to ambient temperature and stirred for 90
minutes. The reaction was partitioned between ether and 2N HC1, washed the organic layer twice
with water, brine, dried, and concentrated to afford the title compound (2.32 g, 84.3% yield) as
clear oil.
[00660] Step C: Preparation of tert-butvl 4-(2-bromoacetvlV3-methvipiperidine-l-
carboxvlate: To a cooled (-78 °C) solution of LDA (5.69 mL, 11.4 mmol) in THF (100 mL) was
added dropwise over 40 minutes a solution of tert-butyl 4-acetyl-3-methylpiperidine-l-
carboxylate (2.29 g, 9.48 mmol) in THF (40 mL). After an additional 25 minutes,
chlorotrimethylsilane (2.41 mL, 18.9 mmol) was added dropwise over 20 minutes. After stirring
for 1 hour the reaction was poured into 600 mL saturated sodium bicarbonate and extracted with
ether (2 x 400 mL). The combined ether layers were washed with brine, dried, filtered, and
concentrated to afford crude TMS-enol ether, which was then redissolved in 500 mL THF and
cooled to 0 °C and treated with sodium bicarbonate (1.20 g, 14.2 mmol), followed by NBS (1.69
g, 9.48 mmol). The reaction was allowed to warm to ambient temperature while stirring for 90
minutes at which point it was poured into 400 mL of saturated sodium bicarbonate solution and
extracted with EtaO and the combined organic layers were washed with saturated NaHCC>3,
brine, dried, and concentrated to give the title compound (3.35 g, 110% yield) as an orange oil.
[00661] Step D: Preparation of tert-butvl 3-methvl-4-(2-f3-phenoxv-5-(pyridin-2-
vlthio)pvridin-2-vlamino)thia20l-4-vl')piperidme-1 -carboxvlate: Prepared according to fee
method of Example 7, Step E; (0.302 g, 68.6% yield). !H NMR (de-DMSO) 8 11.06 (s, 1H), 8.37
(m, 1H), 8.26 (d, 1H), 7.65 (dt, 1H), 7.41 (t, 2H), 7.32 (d, 1H), 7.20-7.11 (m, 4H), 7.06 (d, 1H),



[00662] Step A: Preparation of N-^-O-methvlpiperidin^-vnthiazol-^-vlVS-phenoxv-S-
Cpvridin-2-vlthio^pvridin-2-ainine: Prepared according to the method of Example 271 from tert-
butyl 3-methyM-(2-(3-phenoxy-5-(pyridin-2-ylthio)pyridln-2-ylamino)ihiazol-4-yl)piperidine-l-
carboxylate.
[00663] Step B: Preparation of l-r3-methvl-4-f2-G-phenoxv-5-fpvridin-2-vlthio')pvridin-
2-ylamino')thiazol-4-vlYpiperidin-l -vDethanone dihvdrochloride: Prepared according to the
method of Example 272 to provide the title compound (0.0553 g, 51.4% yield) as a 1:1 mixture
of diastereomers. !H NMR (de-DMSO) 5 8.37 (d, 1H), 8.29 (s, 1H), 7.67 (dt, 1H), 7.43 (t, 2H),
7.37 (d, 1H), 7.17 ( m, 4H), 7.10 (d, 1H), 6.73 (d, 1H), 4.50 (d, 0.5H), 4.27 (d, 0.5H), 3.94 (d,
0.5H), 3.74 (d, 0.5H), 3.33 (d, 0.5H), 3.15 (t, 0.5), 3.04 (m, 1H), 2.87 (d, 0,5), 2.67 (m, 0.5H),
2.32 (m, 1H), 2.05 (ss 1.5H), 1.98 (s, 1.5H), 1.89-1.69 (m, 2H), 0.64 (d, 1.5H), 0.56 (d, 1.5H).

[00664] Step A: Preparation of l-benzovl-S-fS-phenoxv-S-Cpvridin^-vlthiolpviidin^-
vDthiourea: Prepared according to the method of Example 7, Step C, from 3-phenoxy-5-(pyridin-
2-ylthio)pyridin-2-amine.
[00665] Step B: Preparation of l-G-phenoxv-S-Cpvridin^-vlthioVvridin^-vDthiovirea:
Prepared according to the method of Example 39, Step D.

[00666] Step C: Preparation of l-(4-f2-f3-phenoxv-5-(pvridm-2-vlthio)pvridin-2-
vlammo)tbia2ol-4-vr>piperidin-1 -vDethanone dihvdrochloride: Prepared according to the method
of Example 7, Step E in 6.2% yield after HC1 salt formation. *H NMR (dg-DMSO) 5 8.38 (m,
1H), 8.29 (d, 1H), 7,67 (dt, 1H)5 7.45-7.37 (m, 3H), 7.21-7.08 (m, 5H), 6.78 (s, 1H), 4.32 (d, 1H),
3.87 (d, 1H), 3.13 (t, 1H), 2.87 (m, 1H), 2.64 (t, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.63-1.39 (m,
2H).

[00667] Heated a mixture of 2-chloro-3-isotmocyanatopyridine (0.257 g, 1.51 mmol) and
5-bromo-3-phenoxypyridin-2-arnme (0.400 g, 1.51 mmol) in DMF (4 mL) at 80 °C for 3 hours.
Heated at 120 °C overnight. Cooled, partitioned between 2N NaOH and ethylacetate. Washed
the organic layer twice with water, brine, dried, and concentrated. Subjected the residue to
Biotage, eluting with 3:1 hexane:ethyl acetate to afford the title compound (0.465 g, 77.2% yield)
as a white powder. !H NMR (ds-DMSO) 5 7.15 (d, 2H), 7.23 (t, 1H), 7.40-7.50 (m, 4H), 7.92 (s,
1H), 8.34 (s, 1H), 8.37 (d, 1H), 11.63 (bs, 1H).

[0066S] Prepared according to the method of Example 13 from N-(5-bromo-3-
phenoxypyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine, methyl 3-mercaptopropanoate and N-ethyl-
N-isopropylpropan-2-amine in 75% yield. !H NMR (de-DMSO) 8 2.59 (t, 2H), 3.09 (t, 2H), 3.56
(s, 3H), 7.12 (d, 2H), 7.20 (t, 1H), 7.38-7.46 (m, 4H), 7.91 (bs, 1H), 8.24 (s, 1H), 8.36 (d, 1H),
11.53 (bs, 1H).


[00669] Prepared according to the method of Example 292 from 2-chloro-3-
isothiocyanatopyridine (0.116 g, 0.677 mmol) and 3-phenoxy-5-(pyridm-4-ylthio)pyridin-2-
amine. 'HNMR (de-DMSO) 8 7.10 (d, 2H), 7.17-7.23 (m, 3H), 7.40-7.47 (m, 4H), 7.97 (bs, 1H),
8.36-8.41 (m, 4H), 11.88 (bs, 1H).

[00670] Step A: Preparation of N-(3-bromopvridin-2-vlMiiazolor5,4-b1pvridin-2-amine:
Heated a mixture of 2-chloro-3-isothiocyanatopyridine (0.986 g, 5.78 mmol) and 3-
bromopyridin-2-amine (1.00 g, 5.78 mmol) in DMF (4 mL) at 80°C for 3 hours. Heated at 120
°C overnight Cooled, partitioned between ethyl acetate and water, washed with 2N NaOH,
water, brine, dried, and concentrated. Crystallized from dichloromethane:hexanes (1:10, 110
mL) and filtered. The filtered material was further purified by dissolving in dichloromethane (10
mL), and subjecting to MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate. The higher Rf
component was concentrated to afford the title compound (0.654 g, 36.8% yield) as a white
powder.
[00671] Step B: Preparation of methyl 3-(2-fthiazolof 5.4-b]pvridm-2-ylamino)pvridin-3-
vlthio")propanoate: A mixture of N-(3-bromopyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine (0.55
g, 1.79 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.052 g, 0.090 mmol),
Pd2dba3 (0.041 g, 0.045 mmol), methyl 3-mercaptopropanoate (0.21 mL, 1.88 mmol), N-ethyl-N-
isopropylpropan-2-amine (0.62 mL, 3.60 mmol), and dioxane (40 mL) was heated to 95 °C under
nitrogen. Cooled to ambient temperature and filtered the solids. Concentrated and purified- by

MPLC (Biotage) eluting with 1:1 hexane:ethyl acetate to afford the title compound (0.541 g, 87%
yield) as a dark yellow oil.
[00672] Step C: Preparation of 4-f2-dfaiazolof5.4-b1pvridin-2-vlamino'>pvridin-3-
ylthio)benzonitrile: Added potassium 2-methylpropan-2-olate (0.097 g, 0.87 mmol) to a solution
of methyl 3-(2-(thiazoIo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)propanoate (100 mg, 0.289
mmol) in DMSO (1 mL). Stirred 15 minutes, added 4-fluorobenzonitrile (0.105 g, 0.866 mmol)
and stirred overnight. Partitioned between ethyl acetate and water. Washed the organic layer
with water, brine, dried, and concentrated. Purified by MPLC eluting with 3:2 hexane:etbyl
acetate to afford the title compound (0.034 g3 33% yield) as a white powder: ]H NMR (CDC13) §
7.10-7.15 (m, 3H), 7.32 (dd, 1H), 7.52 (d, 2H), 7.87 (d, 1H), 7.96 (d, 1H),.8.42 (d, 1H), 8.58 (d,
1H), 9.10 (bs, 1H).

[00673] Prepared according to the method of Example 295, step C. !H NMR (CDC13)
8 6.91 (d, JH), 7.11 (dd, 1H), 7.27-7.34 (m, 2H), 7.42 (t, 1H), 7.69 (d, 1H), 7.90 (d, 1H), 7.99 (d,
1H), 8.43 (d, 1H), 8.57 (d, 1H), 9.13 (bs, 1H).

[00674] Prepared according to the method of Example 295, step C. JH NMR (CDC13)
S 7.07-7.16 (m, 4H), 7.25 (m, 1H), 7.35 (dd, 1H), 7.41-7.46 (m, 2H), 7.49 (d, 2H), 7.93 (d, 1H),
8.30 (s, 1H), 8.44 (d, 1H), 9.00 (bs, 1H).


[00675] Prepared according to the method of Example 295, step C. *H NMR
(CDCI3) 8 7.00 (t, 1H), 7.13 (d, 2H), 7.23 (t, 1H), 7.31-7.43 (m, 4H), 7.91 (d, 1H), 8.35 (s, 1H),
8.42 (d, 1H), 8.47 (d, 2H), 9.02 (bs, 1H).

[00676] Prepared according to the method of Example 295, step C. 'H NMR
(CDCI3) 8 6.79 (d, 1H), 7.06 (d, 2H), 7.24 (m, 2H), 7.33-7.42 (m, 3H), 7.55 (d, 1H), 7.74 (d, 1H),
7.93 (d, 1H), 8.38 (s, 1H), 8.44 (d, 1H), 8.49 (d51H), 9.07 (bs, 1H).

[00677] Prepared according to the method of Example 295, step C. 'H NMR
(CDC13)8 6.64 (d, 1H), 7.13 (dd, 1H), 7.31 (dd, 1H), 7.59 (d, 1H), 7.80 (d, 1H), 7.85 (d, 1H),
8.01 (d, 1H), 8.42 (d, 1H), 8.47 (d, 1H), 8.61 (d, 1H), 9.16 (bs, 1H).


[00678] Step A: Preparation of 5-bromo-3-phenoxvpvrazin-2-amine: Added sodium
hydride (0.348 g, 8.70 mmol) to a solution of phenol (0.819 g, 8.70 mmol) in THF (50 mL) at 0
°C and stirred 30 minutes. Added 3,5-dibromopyrazin-2-amine (2.00 g, 7.91 mmol) in THF (10
mL). Removed the ice bath and refluxed overnight. Partitioned between ethyl, acetate and water,
washed with brine, dried, and concentrated. Purified by MPLC (Biotage) eluting with 5:1
hexane:ethyl acetate to afford the title compound (1.36 g, 64.6% yield) as a light yellow solid.
[00679] Step B: Preparation of N-(5-bromo-3-phenoxvpvrazin-2-vDthiazolor5.4-b"|pvridin-
2-amine: 5-Bromo-3-phenoxypyrazin-2-amine (0.100 g, 0.376 mmol) and 2-chloro-3-
isothiocyanatopyridine (0.0641 g, 0.376 mmol) afforded the title compound (0.078 g, 51.9%
yield) as light yellow crystals: 'H NMR (de-DMSO) 5 7.28-7.33 (m, 3H), 7.43-7.51 (m, 3H),
7.94 (d, 1H), 8.27 (s, 1H), 8.39 (d, 1H), 12.30 (bs, 1H).

[00680] Prepared according to the method of Example 301, step B. H NMR
(CDC13) 6 7.08-7.18 (m, 5H), 7.34 (dd, 1H), 7.91 (d, 1H), 8.21 (s, 1H), 8.43 (d, 1H), 8.83 (bs,
1H).


[00681] Step A: Preparation of 4-C2-aminopyridin-3-yloxy)benzordtrile: Heated a mixture
of potassium carbonate (31.38 g, 227.0 tnmol), 2-aminopyridin-3-ol (10.00 g, 90.82 mmol), 4-
fluorobenzonitrile (11.00 g, 90.82 mmol), and DMF (80 mL) at 90 °C for 3 hours. Cooled,
partitioned between ethyl acetate and water, washed the organic layer twice with water, once
with 2N NaOH, brine, dried, and concentrated. Dissolved the residue in dichloromethane (20
mL), added hexanes (150 mL), concentrated to 130 mL, filtered, and dried to afford the title
compound (13.95 g, 72.72% yield) as a tan powder.
[00682] Step B: Preparation of 4-(2-amino-5-bromopvridin-3-vloxv')benzonitrile: Placed
4-(2-aminopyridin-3-yloxy)benzonitrile (13.95 g, 66.05 mmol) in acetic acid (50 mL) and cooled
to 0°C. Slowly added bromine (4.229 mL, 82.56 mmol) and stirred for an hour. The reaction
mixture was poured onto saturated sodium bisulfite and ice. Extracted with dichloromethane
three times, washed with 2N NaOH, water, brine, dried, and concentrated. Purified by MPLC
ehrting with 3:2 hexanetethyl acetate to afford the title compound (12.7 g» 66.28% yield) as a
light yellow solid.
[00683] Step C: Preparation of 4-(5-bromo-2-(thia2olof5.4-b1pyridin-2-vlamino')pvridin-3-
vloxv)benzonitrile: Prepared according to the method of Example 301, Step B. *H NMR (de-
DMSO) 8 7.21 (d, 2H), 7.41 (dd, 1H), 7.85-7.88 (m, 3H), 7.94 (s, 1H), 8.36 (d, 1H), 8.47 (s, 1H),
U.91 (bs, 1H).


[00684] Step A: Preparation of l-benzovl-3-f5-bromo-3-f4-cvanophenoxv)pvridin-2-
vnthiourea: Prepared according to the method of Example 1, step C from benzoyl
isothiocyanate and 4-(2-amino-5-bromopyridin-3-yloxy)benzoxiitrile.
[00685] Step B: Preparation of l-(5-bromo-3-(4^yanophenoxv)pyridm-2-vnthiourea:
Added 3 M aqueous sodium hydroxide (4.41 mL, 13.2 mmol) to a mixture of l-benzoyl-3-(5-
bromo-3-(4-cyanophenoxy)pyridin-2-yl)thiourea (3.00 g, 6.62 mmol) and MeOH (50 mL) and
heated to 50°C for 2 hours. Cooled, partitioned between ethyl acetate and water, washed twice
with water, brine, dried, and concentrated. Added ethyl acetate (6 mL), heated to try to afford a
solution. Added hexanes (8 mL) slowly, and cooled and triturated for 15 minutes. Filtered, to
afford the title compound a (1.70 g, 73.6% yield) as a white solid.
[00686] Step C: Preparation of 4-(5-bromo-2-(4-methvlthiazol-2-vlamino')pvridin-3-
vloxv)benzonitri1e: Prepared according to the method of Example 7, step E. *H NMR (de-
DMSO) 8 2.20 (s, 3H), 6.57 (s, 1H), 7.13 (d, 2H), 7.82 (s, 1H), 7.84 (d, 2H), 8.34 (s, 1H), 11.20
(bs, 1H).

[00687] Step A: Preparation of methyl 4-f2-iu1ropvridin-3-vlthioYbenzoate: Stirred a
mixture of methyl 4-mercaptobenzoate (4.46 g, 26.5 mmol), 3-chloro-2-nitropyridine (4.00 g,
25.2 mmol) and cesium carbonate (9.04 g, 27.8 mmol) in DMSO (60 mL) at ambient temperature
for 90 minutes. The solution was diluted with water, extracted with EtOAc, dried, and
concentrated. The crude solid was suspended in MeOH (80 mL) and triturated for 0.5 hours.
The solid was filtered and dried to provide the title compound (6.16 g, 84-1% yield)..
[00688] Step B: Preparation of methyl 4-(2-aminopvridin-3-vltbio'>benzoate: Added zinc
powder (13.88 g, 212.2 mmol) slowly to a solution of methyl 4-(2-nitropyridin-3-ylthio)benzoate
(6.16 g, 21.22 mmol) in acetic acid (75 mL) at ambient temperature in an ambient water bath.
Stirred for an hour, diluted with dichloromethane, and filtered through celite. Washed the celite
pad several times with dichloromethane. Concentrated the filtrate, and partitioned the residue

between 2N NaOH and ethyl acetate. The organic layer was washed with water, brine, dried and
concentrated to afford the title compound (5.5 g, 99.57% yield).
[00689] Step C: Preparation of methyl 4-(2-amino-5-bromopvridin-3-vlthio^benzoate:
Placed methyl 4-(2-ammopyridin-3-ylthio)benzoate (5.50 g, 21.1 mmol) in acetic acid (25 mL)
and cooled to 0°C. Slowly added bromine (1.35 mL, 26.4 mmol) and stirred for an hour. Poured
reaction mixture onto saturated sodium bisulfite and ice. Extracted with dichloromethane three
times, washed with 2N NaOH, water, brine, dried, and concentrated. Subjected to MPLC
(Biotage) eluting with 3:2 hexane:ethyl acetate to afford the title compound (4.87 g, 68.0%
yield).
[00690] Step D: Preparation of methyl 4-(5-bromo-2-rthiazolor5.4-b1t>vridin-2-
ylamino^pyridin-3 -vlthio^benzoate hvdrochloride: Added methyl 4-(2-amino-5-bromopyridin-3-
yltbio)benzoate (1.00 g, 2.95 mmol) to a mixture of 2-chloro-3-isothiocyanatopyridine (0.503 g,
2.95 mmol) in DMF (4 mL). Stirred at 80 °C for an hour, then at 110 °C for 2 hours. Cooled,
diluted with dichloromethane (8 mL), filtered, washed with dichloromethane, and dried to afford
the title compound (0.625 g, 41.6% yield). *H NMR (da-DMSO ) 5 3.84 (s, 3H), 7.40 (dd, 1H),
7.45 (d, 2H), 7.72 (d, 1H), 7.79 (bs, 1H), 7.96 (d, 2H), 8.34 (d, 1H), 8.56 (s, 1H).

[00691] Prepared according to the method of Example 303 using 4-fiuoro-2-
(trifluoromethyl)benzonitrile . 'H NMR (de-DMSO) 8 7.39-7.45 (m, 2H), 7.74 (s, 1H), 7.89 (d,
1H), 8.11 (s, 1H), 8.14 (d, 1H), 8.38 (d, 1H), 8.52 (s, 1H)..


[00692] Heated a mixture of methyl 4-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-
ylamino)pyridin-3-ylthio)benzoate hydrochloride (0.570 g, 1.12 mmol), IN aqueous sodium
hydroxide (2.80 mL, 2.80 mmol), and methanol (6 mL) at 65°C for an hour. Cooled, and
partitioned between saturated NH4CI (30 mL), IN HC1 (3 mL), water (10 mL) and chloroform.
The mixture was filtered, washed with water, and dried to afford the title compound (0.360 g,
70.1% yield). ]HNMR (ds-DMSO) 8 7.35 (dd, 1H), 7.43 (d, 2H), 7.50 (s, 1H), 7.67 (d, 1H), 7.94
(d, 2H), 8.44 (s, 1H).

[00693] Prepared according to the method of Example 305 from ethyl 5-fiuoro-2-
mercaptobenzoate and 3-chloro-2-nitropyridine. !H NMR (CDCI3) 5 1.48 (s, 3H), 4.50 (q, 2H),
6.66 (dd, 1H), 7.07 (m, 1H), 7.32 (dd51H), 7.81 (d, 1H), 7.86 (d, 1H), 8.07 (s, 1H), 8.42 (d, 1H)3
8.61 (s, 1H), 9.19 (bs, 1H).



[00694] Prepared according to the method of Example 303 using 4-fhioro-3-
methylbenzonitrile . VH NMR (ds-DMSO) 8 2.47 (s, 3H), 7.02 (d, 1H), 7.16 (s, 1H), 7.43 (dd,
1H), 7.78 (d, 1H), 7.89 (s, 1H), 7.90 (d, 1H), 8.38 (d, 1H), 8.46 (s, 1H).

[00695] Prepared according to the method of Example 303 using 4-chloro-3-
fluorobenzonitrile JH NMR (ds-DMSO) 5 7.20 (t, 1H), 7.44 (dd, 1H), 7.66 (d, 1H), 7.91 (d, 1H),
7.99 (s, 1H), 8.07 (d, 1H), 8.39 (d, 1H), 8.48 (s, 1H).

[00696] Prepared according to the method of Example 303 using 3-chloro-4-
fluorobenzonitrile . 'H NMR (de-DMSO) 5 7.14 (d, 1H), 7.41 (dd, 1H), 7.78 (d, 1H), 7.83 (bs,
1H), 7.93 (d, 1H), 8.23 (s, 1H), 8.36 (d, 1H), 8.48 (s, 1H), 11.97 (bs, 1H).


[00697] 3-(2-aminopyridin-3-yloxy)-4-chlorobenzonitrile was isolated as a byproduct from
step A of Example 311 and carried through the reactions in Example 303 to afford the title
compound. lH NMR (dg-DMSO) 5 7.44 (dd, 1H), 7.71 (d, 1H), 7.74-7.77 (m, 2H), 7.84 (d, 1H),
7.92 (m, 1H), 8.39 (d, 1H), 8.43 (s, 1H).

[00698] Step A: Preparation of methyl 3-f5-amino-6-phenoxvpvrazin-2-
vlthio>propanoate: Prepared according to the method of Example from 5-Bromo-3-
phenoxypyrazin-2-amiQe and methyl 3-mercaptopropanoate.
[00699] Step B: Preparation of S-O-methvlisoxazolofS^-blpvridin^-vlthioVS-
phenoxvpvrazin-2-amine: Prepared according to the method of Example 127 using methyl 3-(5-
amino-6-phenoxypyrazin-2-yltiiio)propanoate.
[00700] Step C: Preparation of 3-methvl-N-(5-f3-methvlisoxazolor5.4-b1pyridin-4-
ylthioV3 -phenoxvpvrazin-2-vlV 1.2.4-thiadiazol-5-amine: Prepared according to the method of
Example 183, Step D to provide the title compound (3.9 mg, 12.7% yield). 'H NMR (CDC13) 5
2.59 (s, 3H), 2.64 (s, 3H), 6.88 (d, J = 5 Hz, 1H), 7.06, (m, 2H), 7.26 (m, 2H), 7.34 (m, 2H), 8.29
(m, 2H). Mass spectrum m/e 450.2/451.2/453.2 (M+H)+.
Example 314
N-f5-bromo-3-f4-fluorophenoxv>>pvrazin-2-vn-3-methvl-l,2,4-thiadiazo1-5-amine


[00701] Step A: Preparation of 5-bromo-3-(4-fluorophenoxy)pyrazin-2-amine: Prepared
according to the method of Example 301, Step A, from 3,5-dibromo-2-arninopyrazine.
[00702] Step B: Preparation of N-(5-bromo-3-(4-fluorophenoxvtpvrazin-2-vlV3-methvl-
1,2,4-thiadiazol-5-amine: Prepared according to the method of Example 183, Step D. 1H NMR.
(CDC13) 8 2.57 (s, 3H), 7.12-7.23 (m, 4H), 8.15 (s, 1H), 9.14 (br s, 1H). Mass spectrum (ESI+)
m/z 382.384 fM+HY1".

[00703] Step A: Preparation of methyl 3-(2-(5-brorno-3-phenoxypyridin-2-
vlamino)thiazol-4-yl)propanoate: A mixture of methyl 5-bromo-4-oxopentanoate (2.51 g, 12.0
mmol), l-(5-bromo-3-phenoxypyridin-2-yl)thiourea (3.00 g, 9.25 mmol), triethylamine (2.19 mL,
15.7 mmol), and ethanol (60 mL) was refluxed for 3 hours and then stirred at ambient
temperature overnight. The solvent was removed to about one third original volume and
partitioned between CH2CI2 and water. The organics were concentrated and purified on silica gel
eluting with 40% EtOAc/Hexanes to give the title compound (3.22 g, 80.1% yield).
[00704] Step B: Preparation of 3-(2-(5-bromo-3-phenoxvpyridin-2-ylamino)thiazol-4-
yl)propanoic acid: To a mixture of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-
yl)propanoate (0.100 g, 0.230 mmol) in 10 mL THF, and 5 mL water was added sodium
hydroxide (0.0368 g, 0.921 mmol) and the reaction was stirred overnight. The mixture was
concentrated to dryness. Water was added and washed with Et2O and EtOAc. The aqueous was
acidified with a saturated NH4CI solution, extracted with 3:1 CH2C12-THF. The organics were
dried over Na2SO4 and concentrated to a residue. The crude solids were recrystallized from
EtOAc/Hexanes to give the title compound (0.050 g, 51.7% yield). 1H NMR (d6 DMSO) 8 2.58
(t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 6.66 (s, 1H), 7.10 (d, J = 7.8 Hz, 2H), 7.21 (t, J - 7.4
Hz, 1H), 7.39 (d, J = 2.0 Hz,lH), 7.44 (t, J = 8.0 Hz, 2H), 8.21 (d, J - 2.0 Hz, 1H).

[00705] The following compounds were prepared from l-(5-bromo-3-phenoxypyridin-2-
yl)thiourea and the corresponding 1 -chloroketone or 1-bromoketone, following the methods of
Example 315.

[00706] The following compounds were prepared from l-(5-bromo-3-phenoxypyridin-2-
yl)thiourea and the corresponding 1-chloroketone or 1-bromoketone, following similar methods to
Example 315, Step A.




[00707] A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic
acid (0.100 g, 0.238 mmol) (Example 315) HOBT-H2O (0.0547 g, 0.357 mmol), DEEA (d 0.742)
(0.0870 mL, 0.500 mmol), EDCI (0.0684 g, 0.357 mmol), and methanamine (0.238 mL, 0.476
mmol) in 10 mL acetonitrile was stirred at ambient temperature for 5 hours and then heated at 50
°C overnight. The mixture was concentrated to a residue, dissolved in THF and precipitated with
the addition of water. The solids were filtered, washed with water and dried on high vacuum
overnight to give the title compound (0.072 g, 69.8% yield) as white solids. !H NMR (d« DMSO)
8 2.41 (t, J = 7.8 Hz, 2H), 2.56 (d, J = 4.7 Hz, 3H), 2.79 (t, J = 7,7 Hz, 2H), 6.62 (s, 1H), 7-10 (d,
J = 8.0 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 7.77
(d, J = 4.3 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 10.94 (br s, 1H).

[00708] The following compounds were prepared from the corresponding acids (Example
322) and amines following the method of Example 323.






[00709] Step A: Preparation of N>-acetvl-3-f2-f5-bromo-3-phenoxvpvridin-2-
vlamino*)thia2ol-4-yl')propanehvdrazide: A mixture 3-(2-(5-bromo-3-phenoxypyridin-2-
ylamino)thiazol-4-yl)propanoic acid (0.300 g, 0.714 mmol), HOBT-H2O (0.164 g, 1.07 mmol),
DIEA (0.261 mL, 1.50 mmol), EDCI (0.205 g, 1.07 mmol), and acetohydrazide (0.106 g, 1.43
mmol) in 10 mL acetonitrile and 2 mL THF was stirred at 50 °C for 3 hours and then overnight at
ambient temperature. The mixture was concentrated and diluted with CH2CI2, washed with
saturated aqueous NaHCC>3, dried over Na2SC>4, and concentrated to provide the title compound
(0.431 g, 127% yield) that was carried directly on to the next step.
[00710] Step B: Preparation of 5-bromo-N-(4-f2-f5-methvl-l,3.4-oxadiazol-2-
yl)ethvl)thiazol-2-vlV3-phenoxvpvridin-2-amine: To a mixture of N'-acetyl-3-(2-(5-bromo-3-
phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide (0.100 g, 0.210 mmol) in 5 mL
acetonitrile was added POC13 (0.0769 mL, 0.840 mmol) and the reaction was heated at 50 °C for
72 hours. The mixture was concentrated to dryness, diluted with water and extracted with
CH2C12. The organic layer was dried over Na2SO4 and purified by preparative HPLC to give the
title compound (0.029 g, 30.1% yield). *H NMR (deDMSO) 5 2.50 (2, 3H), 3.00 (t, J = 7.4 Hz,
2H), 3.17 (t, J = 7.5 Hz, 2H), 6.76 (s, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.40
(d, J = 2.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 8.22 (d, J = 2.2 Hz, 1H), 10.99 (a, 1H).
[00711] The following compounds were prepared from the corresponding acid (Example 315)
and corresponding acylhydrazine following the method of Example 336.


[00712] To a mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-
yl)propanoic acid (0.100 g, 0.238 mmol), DIEA (0.0456 mL, 0.262 mmol) in 5 mL DMF at
ambient temperature was added N-((dimethylamino)fluoromethylene)-N-methylmethanaminium
hexafluorophosphate(V) (0.0628 g, 0.238 mmol). The mixture was stirred for 30 minutes at
ambient temperature and then N-hydroxyacetamidine (0.0194 g, 0.262 mmol) was added in one
portion and the reaction was heated at 110 °C overnight. The reaction was then cooled to ambient
temperature and EtOAc was added and the organic layer washed with water (2 X 10 mL), dried
over Na2SO4 and concentrated to a residue that was purified on silica gel eluting with 25 %
EtOAc/Hexanes to give 5 the title compound (0.067 g, 61.4% yield). *H NMR (dg DMSO) 5
2.29 (s, 3H), 3.04 (t, 7.6 Hz, 2H), 3.26 (t, J = 7.6 Hz, 2H), 6.74 (s, 1H), 7.11 (d, J - 7.8 Hz, 2H),

7.21 (t, J = 7.3 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 8.22 (d, J = 2.0 Hz,
1H), 11.00 (s,lH).

[007131 Prepared from the corresponding acid (Example 314) following the method of
Example 340. 'H NMR (deDMSO) 5 2.29 (s, 3H), 4.29 (s, 2H), 7.00 (s, 1H), 7.08 (s, 1H), 7.10 (s,
1H), 7.20 (t, J = 7.3 Hz, 1H), 7.41-7.45 (m, 3H), 8.23 (d, J = 2.0 Hz, 1H), 11.13 (s, 1H).

[00714] Step A: Preparation of 3-f2-f5-bromo-3-phenoxvpvridin-2-vlamino')thiazol-4-vlV
N-(2-oxopropvl)propanamide: A mixture of 3-(2-(5-hromo-3-phenoxypyridirj-2-ylamiiio)thiazol-
4-yl)propanoic acid (0.800 g, 1.90 mmol), HOBT-H2O (0.437 g, 2.86 mmol), DIEA (1.36 mL,
7.80 mmol), EDCI (0.547 g, 2.86 mmol), and l-aminopropan-2-one hydrochloride (0.834 g, 7.61
mmol) in 50 mL THF was stirred at 50 °C for 2 days. The mixture was concentrated and diluted
with CH2CI2 and washed with water, dried over sodium sulfate and concentrated to a residue that
was carried on to the next step without further purification.
[00715] Step B: Preparation of 5-bromo-N-(4-(2-(5-methvloxazol-2-vl)ethvl)thiazol-2-vl')-
3-phenoxvpvridin-2-amine hvdrochloride: Prepared according to the method of Example 336,
Step B (0.043 g, 12.2% yield). lH NMR (d6DMSO) 6 2.25 (s, 3H), 3.00-3.08 (m, 4H), 6.72 (s,
1H), 6.81 (s, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.43-7.47 (m, 3H), 8.25 (d, J
= 2.0Hz,lH).


[007161 The following compound was prepared from the corresponding acid (Example
315) following the method of Example 342. 1H NMR (d6 DMSO) 8 2.22 (d, J = 1.6 Hz, 3H),
4.05 (s, 2H), 6.71 (d, J = 1.2 Hz, 1H), 6.86 (s, 1H), 7.09 (d, J = 7.8 Hz, 2H), 720 (t, J = 7.4 Hz,
1H), 7.40-7.45 (m, 3H), 8.22 (d, J = 2.2 Hz, 1H), 11.09 (s, 1H).

[00717] To a nitrogen purged vial was added TBAF (0.249 mL, 0.249 mmol), 3-(2-(5-
bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanenitrile (0.200 g, 0.498 mmol) (Example
320), and TMSN3 (0.0992 mL, 0.748 mmol) were added, and the reaction was stirred at 120 °C
for 24 Hr. The crude reaction mixture was dissolved in CH2CI2 and washed with aqueous sodium
bicarbonate solution. The organic layer was concentrated to a residue that was purified on silica
gel by-eluting with 7% MeOH/CH2CI2 and further purified by triturating in refluxing EtOAc to
give the title compound (0.128 g, 57.8% yield). 1H NMR (d6 DMSO) 8 3.03 (t, J = 7.5 Hz, 2H),
3.25 (t, J = 7.6 Hz, 2H), 6.70 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.38 (d, J
= 2.0 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 8.22 (d, J = 2.2 Hz, 1H), 11.01 (s, 1H).

[00718] Phenol (0.0356 g, 0.378 mmol) was dissolved in 3 mL THF at ambient
temperature. NaH (0.00907 g, 0.378 mmol) was added and the mixture stirred for 30 minutes at

ambient temperature. Solid N-(5-Bromo-3-phenoxypyridin-2-yl)-4-(chloiomethyl)thiazol-2-
amine (0.030 g, 0.0756 mmol) (Example 322) was then added to the reaction and the mixture
was stirred at ambient temperature overnight. The reaction was concentrated to dryness,
dissolved in CH2CI2, washed with water, dried over Na2SO4, and concentrated to dryness. The
residue was purified by preparative HPLC to give the title compound (0.007 g, 20.4% yield) as
the least polar of the two major products. 1H NMR (CDC13)  5.07 (s, 2H), 6.88 (s, 1H), 6.96 (t, J,
= 7.3 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.14 ( d, J == 2.0 Hz, 1H), 7.23-
7.31 (m, 3H), 7.43 (t, J = 8.0 Hz, 2H), 8.14 (d, J = 2.0 Hz, 1H), 8.76 (br s, 1H).
[00719] The following compounds were prepared from the corresponding phenols and


thiophenols and N-(5-Brorno-3-phenoxypyridin-2-yl)-4-(chloromethyl)thiazol-2-amine (Example
322) following the method of Example 345.
(00720] Aniline (0.0352 g, 0.378 mmol) was dissolved in 2 mL NMP at ambient
temperature. Cs2CO3 (0.0246 g, 0.0756 mmol) and solid 5-bromo-N-(4-(chloromethyl)thiazol-2-
yl)-3-phenoxypyridin-2-amine (0.030 g, 0.0756 mmol) were added to the reaction and the

mixture was stirred at ambient temperature overnight. The reaction was concentrated to dryness,
dissolved in CH2Cl2, washed with water, dried over Na2SO4, and concentrated to dryness. The
residue was purified by preparative HPLC to give the title compound (0.010 g, 29.2% yield) as
tan solids. 1H NMR (CDC13)  4.34 (br s, 3H), 6.67-6.74 (m, 4H), 7.07 (d, J = 8.0 Hz, 2H), 7,13
(d, J = 1.8 Hz, 1H), 7.18 (t, J = 7.7 Hz, 2H), 7.24-7.27 (m, 1H), 7.43 (t, J = 7.9 Hz, 2H), 8.13 (d, J
= 1.6 Hz, 1H), 8.74 (br s, 1H).
[00721] The following compounds were prepared from the corresponding amines and N-


(5-Bromo-3-phenoxypyridin-2-yl)-4-(chloromethyl)thiazol-2-amine (Example 322) following the
method of Example 348.
[00722] Prepared according to the method of Example 345 using 5-bromo-N-(4-
(chloromethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine and benzenethiol. 1H NMR (CDCI3) 
4.13 (s, 2H), 6.48 (s, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.26-7.32 (m, 5H), 7.38 (d, J = 7.0 Hz, 2H),
7.44 (t, J = 7.6 Hz, 2H), 8.12 (d, J = 1.6 Hz, 1H), 12.71 (s, 1H).


[00723] Step A: Preparation of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-
yl)propanehydrazide: To a mixture of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-
ylamino)thiazol-4-yl)propanoate (1.00 g, 2.303 mmol) (Example 315) in 15 mL EtOH was added
hydrazine monohydrate (8.835 mL, 11.51 mmol) and the mixture heated at 75 °C for 4 hours.
The reaction was cooled to ambient temperature and quenched with water and the solids were
filtered to give the title compound (0.831 g, 83.10% yield) as off white solids there were used
without further purification.
[00724] Step B: Preparation of 5-(2-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-
yl)ethyl)-1,3,4-oxadiazol-2-ol: To a mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-
ylamino)thiazol-4-yl)propanehydrazide (0.150 g, 0.345 mmol) in THF (5 mL) was added TEA
(0.04814 mL, 0.3454 mmol) and cooled in an ice bath. To this mixture was added. CDI (0.0672 g,
0.414 mmol) in one portion. The mixture was allowed to warm to ambient temperature and was
then heated at 50 °C overnight. The reaction was concentrated to dryness, dissolved in CH2C12
and washed with water, dried over Na2SO4, concentrated to a residue that was purified by
preparative HPLC to give the title compound (0.045 g, 28.31% yield) was white solids. 1H NMR
(d6 DMSO)  2.91 (s, 4H), 6.75 (s, 1H), 7.10 (d, J - 7.8 Hz, 2H), 7.21 (t, J == 7.4 Hz, 1H), 7.40
(d, J = 2.1 Hz, 1H), 7.44 (t, J - 7.9 Hz, 2H), 8.22 (d, J - 2.1 Hz, 1H), 11.03 (br s, 1H), 12.04 (br
s, 1H).


[00725] Step A: Preparation of (Z)-3-(2-(5-bromo-3-phenoxypvridin-2-ylamino)thiazol-4-
yl)-N'-hydroxypropanamidine: To a mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-
ylamino)thiazol-4-yl)propanenitrile (1.00 g, 2.49 mmol) (Example 320) in 150 mL EtOH was
added a mixture of hydroxylamine hydrochloride (0.866 g, 12.5 mmol) and NaOH (12.5 mL,
12.5 mmol) and the combined mixture was heated at reflux overnight. To the reaction was then
added hydroxylamine hydrochloride (0.866 g, 12.5 mmol) and IN NaOH (12.5 mL, 12.5 mmol)
and the reaction reluxed overnight. The mixture was cooled, concentrated to a residue, diluted
with CH2CI2 and IN HC1, the aqueous layer was made basic with NH4OH and extracted with
CH2CI2. The basic organic extracts were dried on Na2SO4, filtered and concentrated to give the
title compound (1.02 g, 94.2% yield).
[00726] Step B: Preparation of (Z)-N'-acetoxy-3-(2-(5-bromo-3-phenoxypyridin-2-
ylamino)thiazol-4-yl)propanimidamide: To a suspension of (Z)-3-(2-(5-bromo-3-
phenoxypyridin-2-ylamino)thiazol-4-yl)-N'-hydroxypropanamidine (0.200 g, 0.460 mmol) and
K2CO3 (0.070 g, 0.506 mmol) in acetone (5 mL), cooled in an ice bath, was added a solution of
acetyl chloride (0.032 mL, 0.460 mmol) in 3 mL acetone and the mixture was allowed to slowly
warm to ambient temperature. The reaction was concentrated to dryness, dissolved in CH2CI2
and washed with water, dried over Na2SO4, and concentrated to give the title compound (0.205
g, 93.4% yield) that was used without further purification.
[00727] Step C: Preparation of 5-bromo-N-(4-(2-(5-methvl-1,2.4-oxadiazol-3-
yl)ethyl)thiazol-2-ylV3-phenoxypyridin-2-amine: The (Z)-N'-acetoxy-3-(2-(5-bromo-3-
phenoxypyridm-2-ylamino)thiazol-4-yl)propanimidamide (0.050 g, 0.10 mmol) was heated
(neat) at 150 °C under high vacuum for 3 hrs. The crude reaction residue was then purified by
preparativeHPLC to give the title compound (0.015 g, 31% yield) as a white solid.1H NMR (d6
DMSO)  2.55 (s, 3H), 2.97-3.05 (m, 4H), 6.72 (s, 1H), 7.11 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4
Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 8.22 ( d, J = 2.0 Hz, 1H), 11.00 (s
1H).


[00728] Step A: Preparation of methyl 3-(2-(5-bromo-3-(phenylthio)pyridin-2-
ylamino)thiazol-4-yl)propanoate: A mixture of methyl 5-bromo-4-oxopentanoate (1.20 g, 5.73
mmol), l-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea (1.50 g, 4.41 mmol) (Example 179),
triethylamine (1.04 mL, 7.49 mmol), and MeOH (25 mL) was refluxed overnight. The reaction
was concentrated to a residue and partitioned between CH2CI2 and water. The organics were
concentrated to a residue and triturated in refluxing EtOAc and the solids filtered (solids are
acid). The flitrate was concentrated and purified on silica gel eluting with 30% EtOAc/Hexanes
to the title compound (1.43 g, 72.0% yield).
[00729] Step B: Preparation of 3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-
yl)propanoic acid: To a mixture of methyl 3-(2-(5-bromo-3-(phenylthio)pyridin-2-
ylammo)thiazol-4-yl)propanoate (1.40 g, 3.11 mmol) in 50 mL THF was added 25 mL water
followed by sodium hydroxide (0.249 g, 6.22 mmol) and the mixture was stirred overnight The
mixture was concentrated to dryness, water added and acidified with NH4Cl. The mixture was
then extracted with THF. The organics were dried over Na2SO4 and concentrated to give the title
compound (1.38 g, 102% yield) that was used as the crude material.
[00730] Step C: Preparation of N'-acetyl-3-(2-(5-bromo-3-(phenylthio)pyridin-2-
ylamino)thiazol-4-yl)propanehydrazide: Prepared according to the method of Example 336, Step
A.
[00731] Step D: Preparation of 5-bromo-N-(4-(2-(5-methyl-l,3.4-oxadiazol-2-

[00732] Step A: Preparation of 3-f2-bromo-4-(trifluoromethyl)phenoxy)pyridin-2-amine:
A mixture of 2-aminopyridin-3-ol (1.00 g, 9.08 mmol) and DMF (20 mL) was cooled in a 0 °C
yl)ethylzol-2-yl)-3-(phenylthio)pyridin-2-amine: Prepared according to the method of
Example 336, Step B. 1H NMR (CDC13)  2.48 (s, 3H), 3.09-3.22 (m, 4H), 6.53 (s, 1H), 7.19-
7.26 (m, 3H), 7.29-7.32 (m, 2H), 7.92 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.98 (br s,
1H).

bath and sodium hydride (0.240 g, 9.49 mmol) was slowly added in portions with vigorous
stirring (significant gas evolution). After the addition was completed, the mixture was stirred at
ambient temperature for 30 minutes to ensure all the NaH was consumed (reaction becomes very
viscous). The 2-bromo-l-fluoro-4-(trifluoromethyl)benzene (1.17 mL, 8.26 mmol) was added
and the mixture heated to 110 °C under nitrogen overnight. The reaction was cooled to ambient
temperature and the DMF removed under reduced pressure. The resulting black sludge was
quenched with 0.5 N NaOH (100 mL) and extracted with Et2O). The organic layer was washed
with 1N NaOH and brine, dried over sodium sulfate, filtered and concentrated to afford a brown
solid. The solids were purified on silica gel eluting with 40% EtOAc/Hexanes to afford 3-(2-
bromo-4-(trifluoromethyl)phenoxy)pyridin-2-amine the title compound.
[00733] Step B: Preparation of 3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine: Step B:
Preparation of 3-(4-ftrifluoromethyl)phenoxy)pyridin-2-amine: A 500mL mL parr shaker was
charged with 3-(2-bromo-4-(trifluoromethyl)phenoxy)pyridin-2-amine (1.85 g, 5.55 mmol),
NaOAc (0.911 g, 11.1 mmol) and EtOH (100mL mL), purged with nitrogen and Pd(OH)2/C
(0.200 g, 1.42 mmol) was added and a pressure of 30 psi Hydrogen was maintained. After 2
hours, the mixture was filtered through GFF paper and the filtrate concentrated to a residue. The
residue was dissolved in EtOAc, washed with a sodium bicarbonate solution, dried over Na2SO4,
filtered, concentrated to a residue and purified on silica gel by eluting with 50% EtOAc/Hexanes
to give the title compound (1.24 g, 87.8% yield) as a white solid.
[00734] Step C: Preparation of 5-bromo-3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine:
A 250 mL round-bottomed flask was charged with 3-(4-(trifluoromethyl)phenoxy)pyridin-2-
amine (1.24 g, 4.88 mmol) and CHC13 (150 mL), cooled to 0 °C and bromine (0.275 mL, 5.37
mmol) was added dropwise. The reaction was stirred for 60 minutes. The reaction was quenched
into a saturated aqueous NaHCO3 solution and extracted with CH2CI2 (2 X 150 mL). The
combined organics were dried over sodium sulfate, filtered and concentrated . The residue was
purified on silica gel eluting with 20% EtOAc/hexanes. The combined fractions of product were
treated with charcoal, filtered through GFF paper and concentrated to afford the title compound
(0.850 g, 52.3% yield) as a tan solid.
[00735] Step D: Preparation of 5-bromo-N-(3-(tetrahydrofuran-2-yl)-l,2.4-thiadiazol-5-
vl)-3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine: Prepared according to the method of
Example 183, Step D. 1H NMR (d6 DMSO)  2.21-2.27 (m, 2H), 3.54-3.61 (m, 1H), 3.74-3.86
(m, 3H), 4.03 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.94 (d, J =
2.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 12.37 (s, 1H).


[00736] Prepared from 5-bromo-N-(3-(tetrahydrofuran-2-yl)-l,2,4-thiadiazol-5-yl)-3-(4-
(trifluoromethyl)phenoxy)pyridin-2-amine according to the method of Example 162, Step A. 1H
MMR (d6 DMSO) 8 2.23-2.28 (m, 2H), 3.56-3.63 (m, 1H), 3.75-3.80 (m, 1H), 3.82-3.88 (m, 2H),
4.04 (t, J = 8.0 Hz, 1H), 7.15-7.19 (m, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.66-7.70 (m, 1H), 7.76 (d, J
= 8.6 Hz, 2H), 7.85 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 4.7 Hz, 1H), 8.50 (d, J = 1.8 Hz, 1H), 12.50
(s, 1H).

[00737] Prepared according to the method of Example 211, Steps A and B, using 5-bromo-
N-(4-(2-(5-methyloxazol-2-yl)ethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine as the starting
material. 1H NMR (d6-DMSO) 5 8.63 (d, 1H), 8.44 (m, 2H), 7.75 (d, 1H), 7.52 (d, 1H), 7.40 (m,
2H), 7.17 (m, 4H), 6.83 (s, 1H), 6.72 (m, 1H), 3.11-2.99 (m, 4H), 2.25 (d, 3H). Mass spectrum
(apci) m/z = 543.5 (M+H-2HC1).


[00738] Prepared according to the method of Example 34. 1H NMR (d6-DMSO)  11.40
(bs, 1H), 8.95 (m, 1H), 8.65 (m, 1H), 8.18 (m, 1H), 7.44 (t, 2H), 7.36 (s,.lH)a 7.21 (t, 1H), 7.12
(d, 2h), 6.83 (s, 1H), 6.72 (s, 1H), 3.20 (m, 2H), 3.04 (m, 4H), 2.87 (d, 2H), 2.78 (m, 2H), 2.24 (s,
3H), 1.87 (m, 2H), 1.67 (m, 1H), 1.36 (m, 2H). Mass spectrum (apci) m/z = 507.5 (M+H-2HC1).

[00739] Step A: Preparation of 3-(4-fluorophenylthio)-2-nitropyridine: Prepared
according to the method of Example 180, Step A using 3-chloro-2-nitropyridine and 4-
fluorobenzenethiol.
[00740] Steps B and C: Preparation of N-(5-bromo-3-(4-fluorophenvlthio)pyridin-2-
yl)thiazolo[5.4-b]pyridin-2-amine hydrochloride: Prepared according to the method of Example 181,
Steps B and C. 1H NMR (CDC13) 5 7.05 (t, 2H), 7.27 - 7.32 (m, 2H), 7.32 - 7.36 (m, 1H), 7.90 -
7.94 (m, 2H), 8.43 (dd, 1H), 8.49 (d, 1H).


[00741] Prepared according to the method of Example 359. 1H NMR (CDC13) 8 3.91 (s,
3H), 7.31 - 7.39 (m, 3H), 7.88 - 7.92 (m, 3H), 8.0 (s, 1H), 8.43 (d, 1H), 8.54 (s, 1H), 9.14 (bs,
1H).



[00742] Step A: Preparation of 3-(l-methyl-1H-imidazol-2-ylthio)pyridin-2-amine: 3-(l-
methyl-lH-imidazol-2-ylthio)-2-nitropyridine (prepared according to the procedure of Example
359 (2.2 g, 9.3 mmol) was dissolved in acetic acid (30 mL) and cooled in a water bath. Zn dust ( 10 micron, 3.0 g, 47 mmol) was slowly added in portions and the reaction stirred at ambient
temperature for 30 minutes. The solution was filtered through celite (rinsing with
dichloromethane) and the filtrate was concentrated. The solution was neutralized with NH4OH
solution and extracted with EtOAc. The organic layer was dried and concentrated to provide the
title compound (1.8 g, 94% yield) as a dark brown solid.
[00743] Step B: Preparation of N-(3-(1-methyl- lH-imidazol-2-ylthio)pyridin-2-
yl)thiazolo [5.4-b] pyridin-2-amine: Prepared according to the method of Example 181 using 2-
chloro-3-isothiocyanatopyridine. 1H NMR (CDCl3) 6 3.77 (s, 3H), 6.92 - 6.96 (m, 1H), 7.00 (s,
1H), 7.20 (s, 1H), 7.32 (dd, 1H), 7.88 (d, 1H), 8.00 (d, 1H), 8.40 (d, 2H), 10.80 (bs, 1H).

[00744] Prepared according to the method of Example 7, Steps C, D and E, from 5-bromo-
3-(4-fluorophenylthio)pyridin-2-amine. 1H NMR (CDC13)  2.33 (s, 3H), 6.44 (s, 1H), 7.01 (t,
2H), 7.23 (dd, 2H), 7.87 (d, 1H), 8.40 (d, 1H).
[00745] The following compounds were also prepared following the procedure of Example
362.


[00746] Prepared according to the method of Example 45 from methyl 3-(5-bromo-2-
(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoate. 1H NMR (DMSO-d6) 5 7.37 - 7.42
(m, 1H), 7.61 (t, 1H), 7.72 (bs, 2H), 7.96 (bs, 3H), 8.32 (dd, 1H), 8.42 (bs, 1H).

[00747] 3-5 -bromo-2-(thiazolo [5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoic acid
(0.080 g, 0.17 mmol) and N1,N1-dimethylethane-l,2-diamine (0.020 g, 0.23mmol) were
dissolved in DMF. l-(3-dimethylaminopropyl)-3-ethylcarbodihnide hydrochloride (0.037 g, 0.19
mmol) and HOBT-H2O (0.029 g, 0.19 mmol) were then added. N, N-Diisopropylethylamine

(0.034 mL, 0.19 mmol) was added last The reaction was stirred at ambient temperature for 2
days. The material was diluted with water and the solid was filtered and recrystallized in
EtOAc/hexanes to afford the title compound (0.030 g, 33% yield) as a white solid. 1H NMR
(CDC13)  2.25 (s, 6H), 2.50 (t, 2H), 3.46 - 3.51 (m, 2H), 6.91 (bs, 1H), 7.28 - 7.37 (m, 3H),
7.62 (d, 1H), 7.68 (s, 1H), 7.86 (d, 1H), 7.97 (s, 1H), 8.41 (d, 1H), 8.48 (s, 1H).
[00748] The following compounds were also prepared following the procedure of Example

The following compounds were also prepared following the procedure of Example 366.

366.


[00749] Methyl 2-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)-l -methyl-lH-
imidazole-5-carboxylate (0.076 g, 0.17 mmol) dissolved in THF (5 mL) was cooled to 0 °C.
DIBAL-H (1M in hexanes, 0.52 raL, 0.52 mmol) was added. After 15 minutes, DIBAL-H (0.52
mL, 0.52 mmol) was added again. The solution was diluted with a saturated solution of
Rochelle's Salt (10 mL) and the solution stirred overnight. The material was extracted with
dichloromethane and the organic layer was dried, and concentrated. Reverse phase HPLC
purification gave the title compound (0.006 g, 9% yield) as a white solid. lH NMR (DMSO-d6) 
2.18 (s, 3H), 3.64 (s, 3H), 4.50 (d, 2H), 5.22 (t, 1H), 5.75 (s, 1H), 6.38 (bs, 1H), 7.11 (s, 1H),
8.22 (bs, 1H).

[00750] Prepared from 3-(5-bromo-2-thioureidopyridin-3-ylthio)benzoic acid according to
the method of Example 7, Steps C, D and E. 1H NMR (DMSO-d6)  2.17 (s, 3H), 6.44 (s, 1H),
7.40 (s, 1H), 7.56 - 7.66 (m, 3H), 7.90 - 7.95 (m, 2H), 8.32 (s, 1H), 12.40 (bs, 1H).



[00751] 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzoic acid (0.35 g,
0.83 mmol) was dissolved in DMF (5 mL). l-(3-dimethylaminopropyl)-3-ethylcarbodimide
hydrochloride (0.24 g, 1.2 mmol), NH4CI (0.133 g, 2.5 mmol) and HOBT-H2O (0.19 g, 1.2
mmol) were added Triethylamme(0.29mL, 2.1 mmol) was added last. The reaction stirred at
room temperature overnight. The material was diluted with water and the solid was filtered to
give the title compound (0.23 g, 67% yield). 1H NMR (DMSO-d6) 5 2.17 (s, 3H), 6.40 (bs, 1H),
7.48 (s, 1H), 7.53 - 7.56 (m, 2H), 7.90 - 7.96 (m, 2H), 8.08 (s, 1H), 8.27 (bs, 1H).

[00752] 3-(5-Bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzamide (0.20 g,
0.48 mmol) was suspended in acetonitrile (4 mL). POCl3 (0.11 mL, 1.2 mmol) was added and the
reaction stirred in a sealed tube at 70 °C for 4 hours. The solution was cooled and neutralized
with saturated NaHCO3 solution. The material was extracted with EtOAc, dried, and
concentrated. The crude material was triturated with ether/EtOAc and filtered. The solid was
dried to give the title compound (0.065 g, 34%). 1H NMR (DMSO-d6)  2.17 (s, 3H), 6.44 (bs,
1H), 7.58 - 7.68 (m, 3H), 7.83 (d, 1H), 7.92 (s, 1H), 8.36 (s, 1H).

[00753] Step A: Preparation of l,2-bis(2-(trifluoromethyl)phenyl)disulfane: A solution of
2-(trifluoromethyl)benzenethiol (0.185 mL, 1.40 mmol) in wet acetonitrile (1:5
water/acetonitrile) was added Iodine (0.178 g, 0.702 mmol) and allowed to stir over night at
room temperature. The reaction was concentrated, then diluted with EtOAc and quenched with
aqueous sodium thiosulfate, extracted and dried organic with brine, Na2SO4 filtered and
concentrated to afford the title compound (219mg, 44% yield) as a colorless oil.

[00754] Step B: Preparation of 4-methyl-N-G-(2-(trifluoromethyl)phenylthio)pyridin-2-
yl)thiazol-2-amme: A 25 mL round-bottomed flask was charged with 3-bromo-N-(4-
methylthiazol-2-yl)pyridin-2-amine (0.082 g, 0.304 mmol) and THF (3mL). The reaction was
cooled to -78 °C and methyllithium (0-228 mL, 0.364 mmol) as a 1.6M solution in ether was
added and stirred for 5 minutes. Butyllithium (0.146 mL, 0.364 mmol) as a 2.5M solution in
hexane was added and the reaction was stirred fox 5 minutes. 1,2-Bis(2-
(trifluoromethyl)phenyl)disulfane (0.215 g, 0.607 mmol) was added and the reaction was wanned
to room temperature and stirred for one hour. Saturated NH4C1 was added, and the reaction
mixture was extracted with EtOAc. The combined organic layers were dried, filtered, and
concentrated. The residue was purified on silica gel (1-10% EtOAc in hexanes) to afford the title
compound (59 mg, 52% yield) as a white solid. 1H NMR (CDC13) S 9.04 (s, 1H), 8.47 (dd, 1H),
7.87 (dd, 1H), 7.69 (m, 2H), 7.31 (m, 1H), 6.97 (q, 1H), 6.83 (d, 1H), 6.43 (m, 1H), 2.32 (d, 3H).
Mass spectrum (apci) m/z = 368.2 (M+H).
[00755] The following compounds were prepared according to the method of Example
375.



[00756] Step A: 4-(3-(2-Nitropyridin-3-yloxy)phenyl)morpholine. In a 125 mL round-
bottom flask, 3-morpholinophenol (0.91 g, 5.07 mmol) was dissolved in THF (40 mL). Solution
was cooled to 0 °C and NaHMDS (5.07 mL, 5.07 mmol) (1M in THF) was added slowly. The
mixture was agitated for 15 minutes and solution of 3-fluoro-2-nitropyridine (0.60 g, 4.22 mmol)
in THF (5 mL) was added slowly. After agitating for 2 hours the solvent was evaporated and the
residue dissolved in 100 mL of CH2C12 and washed with diluted sodium bicarbonate solution
twice, dried over magnesium sulfate, filtered and evaporated. Crude material was purified by
chromatography on silica gel, eluted with 25% ethyl acetate/Hexane to give the title compound
(0.93 g, 72%) was obtained as thick red oil.
[00757] Step B: 3-(3-Morpholinophenoxy)pyridin-2-amine. In a 125 mL round-bottom
flask, 4-(3-(2-nitropyridin-3-yloxy)phenyl)morpholine (0.92 g, 3.05 mmol) was dissolved in 30
mL of ethanol and 200 mg of 10% Pd/C (Degussa type, 50% wet) added. The resulting mixture
was agitated overnight under the atmospheric pressure of hydrogen. The mixture was filtered
and the solvent was evaporated to give the title compound (0.80 g, 97%) as thick oil.
[00758] Step C: 3-(2-bromo-5-morpholinophenoxy)pyridin-2-amine. In a 250 mL round-
bottom flask, 3-(3-morpholinophenoxy)pyridin-2-amine (0.720 g, 2.654 mmol) was dissolved in
25 mL of acetic acid and Bromine (2.654 mL, 2.654 mmol) (1M in AcOH) was added slowly.
After agitating for 1 hour the mixture was evaporated and the residue was distributed between
dichloromethane and sodium bicarbonate solution. The organic phase was separated and
evaporated. The residue was purified by column chromatography on silica gel, eluted with 1-3%
methanol/dicloromethane to give the title compound (0.72g, 77%) as white solid.
[00759] Steps D, E and F: N-(3-(2-bromo-5-morpholinophenoxy)pyridin-2-yl)-4-
methylthiazol-2-amine. Prepared according to the method of Example 7, Steps C, D and E;
(0.48g, 61% yield). 1H NMR (CDCl3)  2.35 (s, 3H), 3.10 (t, 4H), 3.82 (t, 4H), 6.42-6.89 (m,
5H), 7.48 (d, 1H), 8.07 (d, 1H), 8.71 (d, 1H).


[00760] Step A: Preparation of methyl 4-bromo-2-methoxy-2-methylpent-4-enoate. A 500
mL round-bottom flask was charged with diisopropylamine (12.89 mL, 92.00 mmol) and dry
THF (100 mL) and cooled to -78 °C. Butyllithium (2.5 M in hexanes) (36.80 mL, 92.00 mmol)
was added dropwise over 20 minutes and the mixture was agitated for additional 30 minutes.
Methyl 2-methoxypropanoate (10.35 g, 87.61 mmol) was added dropwise over 20 minutes and
the mixture was agitated for 30 minutes. 2,3-Dibromopropene (10.70 mL, 87.61 mmol) was
added dropwise over 20 minutes, the mixture was agitated for 30 minutes and then allowed to
warm up to ambient temperature and agitated for additional 2 hours. The reaction was quenched
with saturated ammonium chloride solution and extracted twice with ether. Extracts were
washed with sodium bicarbonate solution, brine, dried and evaporated to give the title compound
(22.7 g, 98.4% yield) as pale yellow oil.
[00761] Step B: Preparation of methyl 5-bromo-2-methoxv-2-methyl-4-oxopentanoate. To
a 125 mL round-bottom flask, methyl 4-bromo-2-methoxy-2-methylpent-4-enoate (0.525 g, 2.21
mmol) was added acetonitrile (8 mL), water (2 mL) and N-bromosuccinimide (0.493 g, 2.77
mmol). A catalytic amount of 1M HBr was added (0.066 mL, 0.066 mmol). The resulting
solution was agitated overnight, diluted with 50 mL of dichloromethane and washed twice with
saturated sodium bicarbonate, dried and evaporated. The residue was purified by
chromatography on silica gel, eluting with 10% ethyl acetate/hexane to provide the title
compound (0.52 g, 92.8% yield) as clear oil.
[00762] Step C: Preparation of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-
ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoate. In a 125 mL round-bottom flask, l-(5-
bromo-3-phenoxypyridin-2-yl)thiourea (0.50 g, 1.54 mmol) (prepared as described in Example
10, Steps A-D) and methyl 5-bromo-2-methoxy-2-methyl-4-oxopentanoate (0.586 g, 2.31 mmol)
were dissolved in dry THF (25 mL), heated to 50 °C and agitated overnight. The solvent was
evaporated and the residue was dissolved in chloroform and washed with diluted sodium
bicarbonate solution twice, dried over magnesium sulfate, filtered and evaporated. The resulting

solid was purified by chromatography on silica gel, eluted with 10-15% ethyl acetate/hexane to
give the title compound (0.485 g, 65.7% yield) as yellow solid. 1H NMR (CDCl3)  1.46 (s,
3H), 3.12 (s, 2H), 3.34 (s, 3H), 3.73 (s, 3H), 6.58 (s, 1H), 7.06-7.45 (m, 6H), 8.11 (s, 1H), 8.64
(bs, 1H).

[00763] Prepared according to the method of Example 45 from methyl 3-(2-(5-bromo-3-
phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoate. 1H NMR (DMSO-d6 5
1.32 (s, 3H), 3.00 (q, 2H), 3.21 (s, 3H), 6.71 (s, 1H), 7.11-7.23 (m, 3H), 7.36 (s, 1H), 7.44 (t,
2H), 8.12 (s, 1H).

[00764] In a 20 mL scintillation vial, 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-
4-yl)-2-methoxy-2-methylpropanoic acid (0.087 g, 0.187 mmol) was dissolved in CH2C12 (5 mL)
and DMF (2 mL) and N-methylmorpholine (0.031 mL, 0.281 mmol), followed by addition of 1-
hydroxybenzotriazole. The mixture was cooled to 0 °C and EDCI (0.0467 g, 0.244 mmol) was
added. The resulting mixture was agitated for 30 minutes and pyrrolidine (0.020 g, 0.28 mmol)
was added. The mixture was then agitated overnight, diluted with 50 mL of CH2C12 and washed
with citric acid solution and sodium bicarbonate solution, dried and evaporated to give crude
product which was purified by chromatography on silica gel, eluting with 50-70% ethyl
acetate/Hexane, to provide the title compound (0.079 g, 79% yield) as white solid. 1H NMR
(DMSO-d6  1.23 (s, 3H), 1.66-1.80 (m, 4H), 3.03-3.63 (m, 9H), 7.01 (m, 1H), 7.16-7.46 (m,
7H), 8.25 (s, 1H).


[007651 Prepared according to the method of Example 382 from 3-(2-(5-bromo-3-
phenoxypyridin-2-ylammo)thiazol-4-yl)-2-methoxy-2-methylpropanoic. 1H NMR (DMSO-d6 
1.40 (s, 3H), 3,14-3.48 (m, 9H), 7.03 (s, 1H), 7.21-7.53 (m, 7H), 8.23 (s, 1H).

[00766] Step A : Preparation of N'-acetvl-3-f2-(5-bromo-3-phenoxvpvridin-2-
ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanehydrazide: In a 20 mL scintillation vial, 3-(2-
(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoic acid (0.087
g, 0.187 mmol) was dissolved in CH2C12 (5 mL) and DMF (2 mL) and N-methylmorpholine
(0.0309 mL, 0.281 mmol), followed by addition of HOBT. The mixture was cooled to 0 °C and
EDCI (0.047 g, 0.244 mmol) was added. The resulting mixture was agitated for 30 minutes and
acetohydrazide (0.021 g, 0.28 mmol) was added. The mixture was then agitated overnight,
diluted with 50 mL of CH2CI2 and washed with citric acid solution, sodium bicarbonate solution
twice, dried and evaporated to give the title compound (0.0975 g, quantitative yield). Crude
product was used in the next step.
[00767] Step B : Preparation of N'-(3-(2-(5-bromo-3-phenoxypyridin)-2-ylamino)thiazol-4-
yl)-2-methoxy-2-methylpropanoyl)-N,N-dimethylformohydrazonamide: In a 125 mL round-
bottom flask, N'-acetyl-3-(2-(5-bromo-3 -phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-
methylpropanehydrazide (0.0975 g, 0.187 mmol) was dissolved in 5 mL of acetonitrile and
phosphorous oxychloride (0.052 mL, 0.56 mmol) was added. The resulting mixture was heated
to 50 °C and agitated for two hours. The solvent was evaporated and the residue was distributed

between CH2Cl2 and saturated sodium bicarbonate solution. The organic layer was washed with
sodium bicarbonate solution, dried and evaporated. The residue was purified by chromatography
on silica gel, eluting with 20% ethyl acetate/hexane to afford the title compound (30 mg, 29%) as
white solid. 1H NMR (CDCl3)  1.50 (s, 3H), 2.86 (s, 6H), 3.16 (dd, 2H), 3.73 (s, 3H), 6.62 (s,
1H), 7.06-7.45 (m, 6H), 7.71 (s, 1H), 8.11 (s, 1H), 8.58 (s, 1H), 8.71 (bs, 1H).

[00768] Step A: Preparation of methyl 3-(2-(5-bromo-3-(phenylthio)pyridin-2-
ylamino)thiazol-4-yl)2-methoxy-2-methylpropanoate. Prepared according to the method of
Example 380, Step C from l-(5-bromo-3-(phenyltbio)pyridin-2-yl)thiourea.
[00769] Step B: Preparation of 3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-
yl)-2-methoxy-2-methylpropanoic acid. Prepared according to the method of Example 381. 1H
NMR (DMSO-d6 5 1.32 (s, 3H), 3.00 (q, 2H), 3.21 (s, 3H), 6.71 (s, 1H), 7.11-7.23 (m, 3H), 7.36
(s, 1H), 7.44 (t, 2H), 8.12 (s, 1H). MS (APCI, pos) m/z 481 (M+l).

[00770] Prepared according to the method of Example 382 using 2-aminoethanol. 1H
NMR (DMSO-d6  1.40 (s, 3H), 3.14-3.48 (m, 9H), 7.03 (s, 1H), 7.21-7.53 (m, 7H), 8.23 (s, 1H).


[00771] Prepared according to the method of Example 382 using 2-methoxyethanamine.
1H NMR (DMSO-d6  1.30 (s, 3H), 3.01-3.38 (m, 12H), 7.03 (s, 1H), 7.21-7.53 (m, 7H), 8.23 (s,
1H).

[00772] Prepared according to the method of Example 382 using 2-(methylamino)ethanol.
1H NMR (DMSO-d6  1.41 (s, 3H), 2.58 (t, 2H), 3.13-3.28 (m, 8H), 4.20-4.35 (m, 2H), 7.03 (s,
1H), 7.21-7.53 (m, 7H), 8.23 (s, 1H).

[00773] Prepared according to the method of Example 382 with (R)-pyrrolidin-3-ol. 1H
NMR (DMSO-d6  1.29 (s, 3H), 1.70-1.87 (m, 2H), 3.03-3.48 (m, 7H), 4.25 (bd, 1H), 6.86 (bs,
1H), 7.36-7.50 (m, 5H), 7.79 (bs, 1H), 8.47 (s, 1H).


[00774] Step A: Preparation of l-(3-chloro-2-hydroxypropyl)pyrrolidin-2-one. 2-
Pyrrolidinone (4.47 g, 52.5 mmol) was mixed with THF (25 mL) and cooled to -78 °C.
Butyllithium (1.6 M in hexanes) (32.8 mL, 52.5 mmol) was added slowly then and the mixture
was agitated for 10 minutes. Boron trifluoride ethereate (6.59 mL, 52.5 mmol) was added
dropwise, followed by dropwise addition of epichlorohydrin (4.11 mL, 52.5 mmol). The
resulting mixture was allowed to warm up overnight, then cooled and quenched with saturated
sodium bicarbonate solution, and extracted 3 times with ethyl acetate. The extracts were washed
with brine, dried and evaporated to give ~4g of crude oil. The crude oil was purified by
chromatography on silica gel, eluting with 1-2% methanol/dichloromethane, to provide the title
compound (1.53 g, 16.4% yield) as clear oil.
[00775] Step B: Preparation of l-(3-chloro-2-oxopropyl)pyrrolidin-2-one: l-(3-Chloro-2-
hydroxypropyl)pyrrolidin-2-one (0.380 g, 2.14 mmol) was dissolved in dichloromethane (10 mL)
and cooled to 0 °C. Dess-Martin periodinane (0.907 g, 2.14 mmol) was added and the mixture
agitated at ambient temperature for 2 hours. The mixture was loaded on silica gel
chromatographic column and eluted with 1% methanol/dichloromethane to provide the title
compound.
[00776] Step C: Preparation of l-((2-(5-bromo-3-phenoxvpvridin-2-vlamino)thiazol-4-
yl)methyl)pyrrolidin-2-one: Prepared according to the method of Example 7, Step E. 1H NMR
(DMSO-d6 8 2.06-2.18 (m, 5H), 2.42 (t, 2H), 3.69 (t, 2H), 7.10 (d, 2H), 7.21 (t, 1H), 7.42-7.47
(m, 3H), 8.21 (s, 1H).


[00777] Step A: 3-(2-bromoallyl)-l-methylpyrrolidin-2-one. l-Methyl-2-pyrrolidinone
(3.87 mL, 40.3 mmol) was combined with 25 mL of THF and cooled to -78 °C. Lithium
diisopropylamide (26.9 mL, 40.3 mmol) (1.5M in THF) was added slowly and the mixture was
agitated for 30 minutes. 2,3-Dibromopropene (4.93 mL, 40.3 mmol) was added and the mixture
was agitated overnight and allowed to warm up to ambient temperature. The reaction was
quenched with sodium bicarbonate solution and extracted twice with ether. The extracts were
washed with brine and evaporated. The crude product was purified by chromatography on silica
gel, eluting with 30-50% ethyl acetate/hexane, to provide the title compound (5.01 g, 56.9%
yield) as clear oil.
[00778] Step B: 3-(3-bromo-2-oxopropyl)-l-methylpyrrolidin-2-one. 3-(2-Bromoallyl)-l-
methylpyrrolidin-2-one (1.40 g, 6.42 mmol) was dissolved in acetonitrile (20 mL) and water (5
mL) and N-bromosuccinimide (1.71 g, 9.63 mmol) was added. The resulting mixture was
agitated for 4 hours, diluted with 200 mL of ether, washed with sodium bicarbonate, sodium
thiosulfate, brine, dried and evaporated. The residue was purified by chromatography on silica
gel, eluted with 1-2% methanol/dichloromethane to provide the title compound.
[00779] Step C: 3-((2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)-1-
methylpvrrolidin-2-one. Prepared according to the method of Example 7, step E. 1H NMR
(DMSO-d6  1.60-1.72 (m, 1H), 2.08-2.14 (m, 1H), 2.51-2.58 (m, 1H), 2.68-2.78 (m, 5H), 3.00
(d, 1H), 3.21-3.29 (m, 2H), 6.72 (s, 1H), 7.38-7.48 (m, 6H), 8.41 (s, 1H).

[00780] Prepared according to the method of Example 391, Step C, from l-(5-bromo-3-
(phenoxypyridin-2-yl)thiourea and 3-(3-bromo-2-oxopropyl)-l-methylpyrrolidin-2-one. 1H
NMR (DMSO-d6  1.60-1.72 (m, 1H), 2.08-2.14 (m, 1H), 2.51-2.58 (m, 1H), 2.68-2.78 (m, 5H),
3.02 (d, 1H), 3.21-3.29 (m, 2H), 6.80 (s, 1H), 7.13-7.47 (m, 6H), 8.25 (s, 1H).
Example 393
3-((2-(5-bromo-3-phenoxypyridin-2-ylamnino)thiazol-4-yl)methynpyrrolidin-2-one


[00781] Step A: Preparation of tert-butyl 3-(2-bromoallyl)-2-oxopyrrolidine-l-carboxylate.
In a 250 mL round-bottom flask, tert-butyl 2-oxopyrrolidine-l-carboxylate (4.12 g, 22.2 mmol)
was combined with 25 mL of THF and cooled to -78 °C. Lithium diisopropylamide (1.5M in
THF) (14.8 mL, 22.2 mmol) was added slowly and the mixture was agitated for 30 minutes. 2,3-
Dibromopropene (2.72 mL, 22.2 mmol) was added and the mixture was agitated overnight and
allowed to warm to ambient temperature. The reaction was then quenched with sodium
bicarbonate solution and extracted twice with ether. The extracts were washed with brine and
evaporated. The crude product was purified by column chromatography, eluting with 20% ethyl
acetate/hexane, to provide the title compound (0.560 g, 8.3% yield).
[00782] Step B: Preparation of tert-butyl 3-(3-bromo-2-oxopropyl)-2-oxopyrrolidine-l-
carboxylate. In a 125 mL round-bottom flask, tert-butyl 3-(2-bromoallyl)-2-oxopyrrolidine-l-
carboxylate (0.560 g, 1.84 mmol) was dissolved in mixture of acetonitrile (8 mL) and water (2
mL). N-bromosuccinimide (0.41 g, 2.30 mmol) was added and the mixture was agitated
overnight. The reaction mixture was diluted with 100 mL of ether, washed with sodium
bicarbonate solution, brine, dried and evaporated to provide the title compound (0.25 g, 42.4%
yield).
[00783] Step C: Preparation of 3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-
yl)methyl)-l-methylpyrrolidin-2-one. Prepared according to the method of Example 7, step E.
[00784] Step D: Preparation of 3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-
yl)methyl)pyrrolidin-2-one, In a 20 mL scintillation vial, tert-butyl 3-((2-(5-bromo-3-
phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-2-oxopyrrolidine-l-carboxylate (35mg, 0.064
mmol) was dissolved in CH2C12 (1 mL) and HC1 (4.0M solution in dioxane) (2.00 mL, 8.00
mmol) was added. The resulting mixture was agitated overnight. The solvents and excess HC1
were evaporated, and product was obtained as yellow solid (25mg,.87.5% yield). 1H NMR
(DMSO-d6  1.70-1.80 (m, 1H), 2.12-2.20 (m, 1H), 2.60-2.74 (m, 1H), 3.02 (d, 1H), 3.16-3.22
(m, 2H), 3.44-3.76 (m, 5H), 6.97 (s, 1H), 7.19-7.50 (m, 6H), 7.83 (s, 1H), 8.30 (s, 1H).


[00785] Prepared according to the method of Examples 391 and 393. 1H NMR
((CD3)2SO)  1.70-1.80 (m, 1H), 2.12-2.20 (m, 1H), 2.60-2.74 (m, 1H), 3.02 (d, 1H), 3.16-3.22
(m, 2H), 3.44-3.76 (m, 5H), 6.77 (s, 1H), 7.38-7.50 (m, 6H), 7.76 (s, 1H), 8.43 (s, 1H).

[00786] tert-Butyl 3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-2-
oxopyrrolidine-1-carboxylate (0.070 g, 0.128 mmol) (Example 393, Steps A-C) was dissolved in
1 mL of THF and sodium hydroxide (0.963 mL, 1.93 mmol) 2M solution was added. The
resulting solution was heated to 55 °C and agitated for 3 hours. Reaction was quenched with 3
mL of 2M potassium hydrosulfate solution and extracted twice with ethyl acetate. The extracts
were washed with water, brine, dried and evaporated to produce the title compound. 1H NMR
(CDCl3)  1.40 (s, 9H), 1.60-1.74 (m, 2H), 2.64-3.08 (m, 5H), 4.65 (bs, 1H), 6.47 (s, 1H), 7.09-
7.43 (m,7H), 8.14 (s,1H).


[00787] Prepared according to the method of Example 395 from tert-butyl 3-((2-(5-
bromo-3-(phenylthio)pyridin-2-ylammo)thiazol-4-yl)methyl)-2-oxopyrrolidine-l-carboxylate.
1H NMR (CDCI3)  1.41 (s, 9H), 1.64-1.86 (m, 2H), 2.80-3.22 (m, 5H), 4.93 (bs, 1H), 6.55 (s,
1H), 7.22-7.32 (m, 6H), 7.85 (s, 1H), 8.38 (s, 1H).

[00788] Prepared according to the method of Example 393, Step D. 1H NMR (DMSO-d6 
1.65-1.79 (m, 2H), 2.74-3.10 (m, 5H), 6.55 (s, 1H), 7.12-7.45 (m, 7H), 8.26 (s, 1H).

[00789] Step A: Preparation of l-acetyl-N-methoxy-N-methylpiperidine-4-carboxamide.
To a solution of l-acetylpiperidine-4-carboxylic acid (58.50 g, 342 mmol) in dichloromethane
(700 mL) was added di(1H-imidazol-l-yl)methanone (58.18 g, 359 mmol). After the addition the
mixture was agitated for two hours and N-methoxymethanamine hydrochloride (35.00 g, 359

mmol) was added at once. The mixture was allowed to agitate overnight at ambient temperature
and 4M HC1 in dioxane (75 mL) was added slowly. The slurry was agitated for 30 minutes and
then filtered. Filtrate was washed twice with sodium bicarbonate solution, dried and concentrated
to give the title compound (59.10 g, 80.72% yield).
[00790] Step B: Preparation of 1 1'-piperidine-l,4-diyl)diethanone. 1-Acetyl-N-methoxy-
N-methylpiperidine-4-carboxamide (59.10 g, 276 mmol) was dissolved in THF (800 mL) and
cooled to 0°C. Methylmagnesium bromide (110.3 mL, 331 mmol) (3.0M in diethyl ether) was
added slowly and the resulting white slurry was agitated for 1 hour. The reaction was quenched
with 300 mL of 2M HC1 and the solvent was evaporated. The resulting aqueous slurry was
filtered and the solids were washed with water and small amount of ether to provide the title
compound (38.4 g, 82.2% yield).
[00791] Step C: Preparation of l-(l-acetylpiperidin-4-yl)-2-bromoethanone. 1,1'-
(Piperidine-1,4-diyl)diethanone (38.0 g, 225 mmol) was dissolved in methanol (700 mL) and
bromine (12.1 mL, 236 mmol) was added. After agitating for 3 hours the solvent was removed .
The resulting solid was washed with ethyl acetate, then distributed between ethyl acetate and
sodium carbonate. The organic phase was separated, washed with brine, dried and evaporated to
give the title compound.
[00792] Step D: Preparation of l-(4-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-
4-yl)piperidin-l -yl)ethanone. Prepared according to the method of Example 7, Step E lH NMR
(CDC13)  1.58-1.64 (m, 2H), 1.99-2.11 (m, 5H), 2.64-2.86 (m, 2H), 3.16 (t, 1H), 3.88 (d, 1H),
4.68 (d, 1H), 6.44 (s, 1H), 7.18-7.32 (m, 5H), 7.92 (s, 1H), 8.23 (s, 1H), 8.50 (s, 1H).
Example 399
2-(dimethylamino)-l-(4-(5-(3-(4-fluorophenoxy)-5-(thieno[3.2-b]pyridin-7-ylmio)pyridin-2-
ylamino)-l,2,4-thiadiazol-3-yl)piperidin-l -yl)ethanone trihydrochloride

[00793] Prepared according to the method of Example 198. 1H NMR (d6-DMSO)  12.49
(bs, 1H), 9.62 (bs, 1H), 8.58 (d, 1H), 8.52 (d, 1H), 8.33 (d, 1H), 7.69 (d, 1H), 7.59 (d, 1H), 7.23
(m, 4H), 7.08 (d, 1H), 4.41-4.22 (m, 3H), 3.66 (d, 1H), 3.28-3.11 (m, 2H), 3.01-2.89 (m, 2H),
2.82 (d, 6H), 2.09 (m, 2H), 1.82 (m, 1H), 1.65 (m, 1H). Mass spectrum (apci) m/z = 622.2
(M+-H-3HC1).


[00794] Step A: Preparation of tert-butyl 4-((5-(3-(4-fluorophenoxyl)-5-(thieno[3,2-
b]pyridin-7-ylthio)pyridin-2-ylamino)-l.2,4-thiadiazol-3-yl)methyl)piperidine-l-carboxylate:
Prepared according to the method of Example 127 from tert-butyl 4-((5-(3-(4-fluorophenoxy)-5-
(3-methoxy-3-oxopropylthio)pyridin-2-ylamino)-l,2,4-thiadiazol-3-yl)methyl)piperidine-1-
carboxylate (Example 96,230 mg, 0.381 mmol).
[00795] Step B: Preparation of 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-
thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride: A 10 mL
round-bottomed flask was charged with tert-butyl 4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-
b]pyridin-7-ylthio)pyridin-2-ylamino)-l,2,4-thiadiazol-3-yl)methyl)piperidine-l-carboxylate
(52.2 mg, 0.0802 mmol) and a 1:1 mix of methanol and CH2CI2 (4 mL). 4N HC1 in dioxane (2
mL) was added and the reaction stirred at room temperature for 10 minutes. The solvent was
removed to afford crude 3-(4-fluorophenoxy)-N-(3-(piperidin-4-y]methyl)-l,2,4-thiadiazol-5-
yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (52.9 mg, 100%).
[00796] Step C: Preparation of l-(4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-
ylthio)pyridin-2-ylamino)-l,2,4-thiadiazol-3-yl)methyl)piperidin-l -yl)ethanone dihydrochloride;
Prepared according to the method of Example 198. 1H NMR (d6-DMSO)  12.46 (bs, 1H), 8.58
(d, 1H), 8.52 (d, 1H), 8.33 (d, 1H), 7.68 (d, 1H), 7.57 (d, 1H), 7.23 (m, 4H)5 7.08 (d, 1H), 4.34 (d,
1H), 3.78 (d, 1H), 2.99 (t, 1H), 2.72 (d, 2H), 2.09 (m, 1H), 1.97 (s, 3H), 1.65 (m, 2H), 1.18 (m,
1H), 1.05 (m, 1H). Mass spectrum (apci) m/z = 593.2 (M+H-2HC1).


[00797] Prepared according to Example 400, using tert-butyl 4-(5-(3-(4-fluorophenoxy)-5-
(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)pyridin-2-ylamino)-l,2,4-thiadiazol-3-yl)piperidine-1 -
carboxylate in Step B.. 1H NMR (d6-DMSO)  12.48 (bs, 1H), 8.49 (d, 1H), 8.32 (d, 1H), 7.54
(m, 1H), 7.25 (m, 4H), 6.75 (d, 1H), 4.33 (d, 1H), 3.85 (d, 1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.77
(t, 1H), 2.69 (s, 3H), 2.02 (m, 5H), 1.74 (m, 1H), 1.60 (m, 1H). Mass spectrum (apci) m/z = 578.1
(M+H-HC1).

[00798] Prepared according to the method of Example 198 using 3-(4-fluorophenoxy)-5-
(3-methylisoxazolo[5,4-b]pyridin-4-ylthio)-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-
amine. 1H NMR (d6-DMSO)  12.44 (bs, 1H), 9.55 (bs, 1H), 8.49 (d, 1H), 8.32 (d, 1H), 7.55 (d,
1H), 7.25 (m, 4H), 6.74 (d, 1H), 4.32 (m, 3H), 3.65 (d, 1H), 3.28-3.10 (m, 2H), 2.97 (t, 1H), 2.82
(d, 6H), 2.70 (s, 3H), 2.10 (d, 2H), 1.82 (m, 1H), 1.66 (m, 1H). Mass spectrum (apci) m/z = 621.1
(M+H-2HC1).


[00799] Step A: Preparation of 5-bromo-3-(3-methoxyphenylthio)picolinonitrile: A 10 mL
round-bottomed flask was charged with 5-bromo-3-nitropicolinonitrile (300 mg, 1.31 mmol), 3-
methoxybenzenethiol (0.150 mL, 1.31 mmol), and DMF (12 mL). NaH (37.8 mg, 1.58 mmol)
was added and reaction stirred at room temperature for 10 minutes. The reaction was poured into
water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and
concentrated. The resulting residue was purified on silica gel (10% EtOAc in Hexanes) to afford
the title compound (345 mg, 81%).
[00800] Step B: Preparation of 5-f3-bromophenoxvV3-(3-methoxyphenylthio)
picolinonitrile: A 10 mL round-bottomed flask was charged with 5-bromo-3-(3-
methoxyphenylthio)picolinonitrile (214 mg, 0.666 mmol), 3-bromophenol (138 mg, 0.800
mmol), and DMF (6 mL). NaH (24.0 mg, 0.999 mmol) was added and reaction stirred at room
temperature for 24 hours. The reaction was poured into water and extracted with EtOAc. The
organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was
purified on silica gel (10% EtOAc in Hexanes) to afford the title compound (225 mg, 81.7%
yield).
[00801] Step C: Preparation of 5-f3-bromophenoxvV3-(3-methoxvphenvlthio)picolinic
acid: A 25 mL round-bottomed flask was charged with 5-(3-bromophenoxy)-3-(3-
methoxyphenylthio)picolinonitrile (225 mg, 0.544 mmol), potassium hydroxide (2.5 M, 1.09 mL,
2.72 mmol), and EtOH (5 mL). The reaction was heated to reflux overnight After cooling to
room temperature the reaction was poured into water and pH adjusted with IN HC1 to ~pH=3.
The cloudy solution was extracted with CH2Cl2. The organic layer was dried over sodium sulfate,
filtered and concentrated to afford the title compound (235 mg, 100%) which was taken forward
without further purification.
[00802] Step D: Preparation of 5-(3-bromophenoxy)-3-(3-methoxyphenylthio)pyridin-2-
amine: A 25 mL round-bottomed flask was charged with 2-methylpropan-2-ol (0.284 mL, 3.26
mmol), 5-(3-bromophenoxy)-3-(3-methoxyphenylthio)picolinic acid (235 mg, 0.544 mmol),

triethylamine (0.0985 mL, 0.707 mmol), and Toluene (5 mL). The reaction was heated to 100 °C
and DPPA (0.118 mL, 0.544 mmol) was added dropwise. The reaction was stirred at 100 °C for
30 minutes after complete addition and then cooled to room temperature and partitioned between
CH2Cl2 and water. The organic layer was dried over sodium sulfate, filtered and concentrated.
The residue was purified on silica gel (10% EtOAc in hexanes) to afford the Boc protected
material. This residue was dissolved in 1:1 CH2Cl2:methanol (4 mL) and 4N HC1 in dioxane (2
mL) was added and stirred at room temperature for 4 hours. The solvent was removed and
partitioned between aqueous sodium bicarbonate and CH2Cl2. The organic phase was dried,
filtered and concentrated to afford the title compound (128 mg, 58.4% yield).
[00803] Step E: Preparation of 5-C3-bromophenoxv)-3-(3-methoxyphenylthio)-N-(3-
(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine: Prepared according to the method
of Example 183 step D.
[00804] Step F: Preparation of 5-(3-bromophenoxy)-3-(3-methoxvphenvlthio)-N-(3-
(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine hydrochloride: A 10 mL round-
bottom flask was charged with 5-(3-bromophenoxy)-3-(3-methoxyphenyltbio)-N-(3-
(tetrahydrofuran-2-yl)-l,2,4-thiadiazol-5-yl)pyridin-2-amine (20 mg, 0.036 mmol) and dissolved
in CH2Cl2 (1 mL). 2M HC1 in ether (0.1 mL, 0.2 mmol) was added and the solvent removed to
afford the title compound (21 mg, 100%). 1H NMR (d6-DMSO)  11.51 (bs, 1H), 8.40 (d, 1H),
8.36 (bs, 1H), 7.68 (bs, 1H), 7.51-7.18 (m, 5H), 7.10-6.73 (m, 3H), 4.10-3.74 (m, 3H), 3.72 (s,
3H), 2.25 (m, 4H). Mass spectrum (apci) m/z = 559.1 (M+H-HC1).

[00805] A 10 mL round-bottomed flask was charged with 5-(3-bromophenoxy)-3-(3-
methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-l,2,4-miadiazol-5-yl)pyridin-2-amine (41 mg,
0.074 mmol) and THF (2 mL). The reaction was cooled to -78 °C and methyllithium (0.055 mL,
0.088 mmol) was added and stirred for 5 minutes. Butyllithium (0.035 mL, 0.088 mmol) was
added and stirred for 5 minutes. The reaction was then poured into saturated aqueous NH4Cl and
extract with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated .

The residue was purified on silica gel (35% ethyl acetate in hexanes) to afford the title compound
(36 mg, 95%) after HC1 salt formation. 1H NMR (d6-DMSO)  11.47 (bs, 1H), 8.30 (bs, 1h), 7.59
(bs, 1H), 7.37 (m, 2H), 7.28 (t, 1H), 7.14 (t, 1H), 7.03 (d, 2H), 6.88 (m, 3H), 4.04 (t, 1H), 3.90-
3.75 (m, 3H), 3.72 (s, 3H), 3.57 (m, 1H), 2.25 (m, 2H). Mass spectrum (apci) m/z = 479.2 (M+H-
HC1).

[00806] A 10 mL round-bottomed flask was charged with 5-(3-bromophenoxy)-3-(3-
methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-l,2,4-thiadiazol-5-yl)pyridin-2-amine (43.3 mg,
0.077 mmol) and THF (2 mL). The reaction was cooled to -78 °C and methyllithium (0.058 mL,
0.093 mmol) was added and stirred for 5 min. Butyllithium (0.037 mL, 0.093 mmol) was added
and the reaction was stirred for 5 min. Acetaldehyde (0.0086 mL, 0.16 mmol) was added and the
reaction wanned to room temperature and poured into saturated aqueous NH4Cl and extracted
with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated . The
residue was purified on silica gel (35 to 100% ethyl acetate in hexanes) to afford the title
compound (4.5 mg, 11.1% yield). 1H NMR (CDCl3)  9.26 (bs, 1H), 8.25 (d, 1H), 7.63 (d, 1H),
7.33 (t, 1H), 7.21 (t, 1H), 7.14 (d, 1H), 7.05 (m, 1H), 6.90 (dd, 1H), 6.76 (m, 2H), 6.70 (m, 1H),
4.89 (q, 1H), 4.15 (t, 1H), 4.03 (m, 2H), 3:90 (m, 1H), 3.77 (s, 3H), 3.64 (m, 1H), 2.34 (q, 2H),
1.47 (d, 3H). Mass spectrum (apci) m/z = 523.2 (M+H).


[00807] Steps A- E: Preparation of l-benzoyl-3-(3-(2-bromo-4-fluorophenoxy)-5-(3-
methoxyphenylthio)pyridin-2-vl)thiourea: Prepared according-to Example 403, Steps A-D.
[00808] Step F: A 250 mL round-bottomed flask was charged with 3-(2-bromo-4-
fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-amine (7.4 g, 17.6 mmol), benzoyl
isothiocyanate (3.08 mL, 22.8 mmol), and THF (125 mL). The reaction was stirred at room
temperature overnight. Hexanes (700 mL) was added and stirred at room temperature for 1 hour.
The solid material was decanted to afford 5.6 g of material as a yellow foam. The mother liquor
was concentrated and resuspended in 9:1 hexanes:EtOAc (200 mL) to afford another 4.7 g of
material. The combined crops affordedthe title compound (10.3g, 100%).
[00809] Step G: Preparation of l-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxvphenvlthio)
pyridin-2-yl)thiourea: A 250 mL round-bottomed flask was charged with l-benzoyl-3-(3-(2-
bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea (10.3 g, 17.6 mmol) and
EtOH (125 mL). 3M Sodium hydroxide (11.7 mL, 35.2 mmol) was added and heated to 50 °C
overnight. The reaction was cooled to room temperature and poured into 750 mL water and
stirred vigorously for 1 hour. The solids were filtered to afford the title compound (6.5 g, 76.8%
yield).
[00810] Step H: Preparation of tert-butyl 4-(2-(3-(2-bromo-4-fiuorophenoxy)-5-(3-
memoxyphenvlthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-l-carboxylate: A 50 mL round-
bottomed flask was charged with l-(3-(2-bromo-4-fluorophenoxy)-5-(3-
methoxyphenylthio)pyridin-2-yl)thiourea (1.5 g, 3.12 mmol), triethylamine (0.740 mL, 5.31
mmol), tert-butyl 4-(2-bromoacetyl)piperidine-l-carboxylate (1.15 g, 3.75 mmol), and EtOH (25
mL). The reaction was heated to 70 °C for 3 hours. The reaction was cooled to room temperature
and partitioned between EtOAc and water. The organic layer was dried over sodium sulfate,
filtered and concentrated. The residue was purified on silica gel (10% EtOAc in hexanes) to
afford (1.76 g, 82.0% yield).
[00811] Step I: Preparation of 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxvphenvlthio)-N-
(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine: A 20 mL vial was charged with tert-butyl 4-(2-
(3-(2-bromo-4-fluorophenoxy)-5-(3-memoxyphenylthio)pyridin-2-ylamino)thiazol-4-
yl)piperidine-l-carboxylate (100 mg, 0.145 mmol) and CH2C12 (2 mL). TFA (2 mL) was added
and stirred at room temperature for 5 minutes. The reaction was poured into water and diluted
with CH2C12. Solid Na2CO3 added slowly to neutralize the TFA. The aqueous layer was extracted
and dried to afford the title compound (88 mg, 103% yield). 1H NMR (d6-DMSO)  8.16 (d,
1H), 7.74 (m, 1H), 7.30 (m, 2H), 7.21 (t, 1H), 6.92 (d, 1H), 6.78 (m, 1H), 6.70 (m, 3H), 3.69 (s,

3H), 3.17 (m, 2H), 2.77 (m, 3H), 2.01 (m, 2H), 1.62 (m, 2H). Mass spectrum (apci) m/z = 587.2,
589.2 (M+H).

[00812] A 10 mL round-bottomed flask was charged with tert-butyl 4-(2-(3-(2-bromo-4-
fluorophenoxy)-5-(3-memoxyphenylthio)pyridm-2-ylammo)thiazol-4-yl)pipericline-l-
carboxylate (200 mg, 0.29 mmol) and THF (3 mL). The reaction was cooled to -78 °C and
methyllithium (0.22 mL, 0.35 mmol) was added and stirred for 5 min. Butyllithium (0.140 mL,
0.35 mmol) was added and the reaction was stirred for 5 min. Iodomethane (0.0273 mL, 0.436
mmol) was added and the reaction was stirred for 5 min and then poured into saturated aqueous
NH4C1 and extracted with EtOAc (1 x 20 mL). The organic layer was dried with sodium sulfate,
filtered and concentrated to afford a mixture of products. The residue was purified on reverse
phase column (35 to 100% acetonitrile in water with 0.1% TFA) to afford the title compound
(68.3 mg, 33% yield). 1H NMR (CDC13)  8.13 (d, 1H), 7.28 (d, 1H), 7.22 (m, 1H), 7.04 (m,
4H), 6.85 (m, 1H), 6.80 (m, 2H), 6.43 (s, 1H), 4.22 (m, 2H), 3.76 (s, 3h), 2.89 (m, 3H), 2.06 (m,
2H), 1.56 (m, 2H), 1.47 (s, 9H).

[00813] Step A: Preparation of tert-butyl 4-(2-(3-(4-fluoro-2-methylphenoxy)-5-(3-
methoxyphenvlthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-l-carboxvlate trifluoroacetate:
From the reaction mixture in Example 407, the title compound was isolated from the reverse
phase chromatography (70 mg, 33% yield).

[00814] Step B: Preparation of N-(3-(4-fluoro-2-methylphenoxy)-5-(3-
methoxyphenylthio)pyridin-2-vl)-4-(piperidin-4-yl)thiazol-2-amine ditrifluoroacetate: A 10 mL
round-bottomed flask was charged with tert-butyl 4-(2-(3-(4-fluoro-2-methylphenoxy)-5-(3-
methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-l -carboxylate trifluoroacetate (70
mg, 0.097 mmol) and CH2Cl2 (2 mL). TFA (2.mL) was added and stirred at room temperature for
30 minutes. The solvent was removed and dried on high vacuum overnight The crude material
was taken on to the next reaction without further purification.
[00815] Step C: Preparation of l-(4-(2-(3-(4-fluoro-2-methvlphenoxy)-5-(3-
methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-l-yl)ethanone hvdrochloride: A 20
mL vial was charged with 3-(4-fluoro-2-methylphenoxy)-5-(3-methoxyphenylthio)-N-(4-
(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine ditrifluoroacetate (70 mg, 0.098 mmol) and CH2Cl2
(2 mL). Triethylamine (0.109 mL, 0.78 mmol) was added followed by Ac2O (0.012 mL, 0.12
mmol) and the reaction was stirred for 5 minutes. The reaction was poured into saturated aqueous
NaHCO3 and extracted with CH2Cl2 (1 x 20 mL). The organic layer was dried with sodium
sulfate, filtered and concentrated . The residue was purified on silica gel (20 to 40% EtOAc in
hexanes) to afford the title compound (44.8 mg, 76.3% yield) after HC1 salt formation. 1H NMR
(d6-DMSO)  11.20 (bs, 1H), 8.14 (d, 1H), 7.22 (m, 2H), 7.04 (m, 2H), 6.88 (d, 1H), 6.77 (m,
2H), 6.71 (m, 2H), 4.43 (d, 1H), 3.88 (d, 1H), 3.69 (s, 3H), 3.14 (t, 1H), 2.87 (m, 1H), 2.65 (m,
1H), 2.19 (s, 3H), 2.01 (s, 3H), 1.95 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci)
m/z = 565.3 (M+H-HC1).

[00816] Step A: Preparation of 3-(4-fluorophenoxvV5-(3-methoxvphenvlthio)-N-(4-
(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine ditrifluoroacetate: A 10 mL round-bottomed flask
was charged with tert-butyl 4-(2-(3-(4-fluorophenoxy)-5-(3-methoxyphenyltbio)pyridin-2-
ylamino)thiazol-4-l)piperidine-l-carboxylate (68 mg, 0.11 mmol) and CH2Cl2 (2 mL). TFA
(2mL) was added and stirred at room temperature for 30 minutes. The reaction was concentrated
and taken on to next reaction without further purification.

[00817] Step B: Preparation of l-(4-(2-(3-(4-fluorophenoxy)-5-(3-
methoxyphenvlthio)pyridin-2-ylamino)thiazol-4-piperidin-1 -yl)ethanone hvdrochloride:
Prepared according to the method of Example 198. 1H NMR (d6-DMSO)  11.10 (bs, 1H), 8.19
(m, 1H), 7.22 (m, 4H), 7.15, (m, 2H), 6.79 (m, 1H), 6.74 (m, 3H), 4.42 (d, 1H), 3.87 (d, 1H), 3.70
(s, 3H), 3.13 (t, 1H), 2.85 (t, 1H), 2.63 (t, 1H), 2.01 (d, 3H), 1.94 (m, 2H), 1.57 (m, 1H), 1.44 (m,
1H). Mass spectrum (esi) m/z = 551.0 (M+H-HC1).

[00818] A 20 mL vial was charged with 3-(2-bromo-4-fluorophenoxy)-5-(3-
methoxyphenylthio)-N-(4-(piperidin^-yl)thiazol-2-yl)pyridin-2-amine (40 mg, 0.068 mmol),
triethylamine (0.0190 mL, 0.14 mmol), and CH2C12 (2 mL). Ac2O (0.008 mL, 0.082 mmol) was
added and the reaction was stirred at room temperature for 10 minutes. The reaction was
partitioned between CH2CI2 and saturated aqueous sodium bicarbonate. The organic layer was
dried with sodium sulfate, filtered and concentrated to afford the title compound (38.2 mg,
84.2% yield) as a white solid after HC1 salt formation. JH NMR (de-DMSO) 8 11.20 (bs, 1H),
8.17 (d, 1H), 7.74 (m, 1H), 7.31 (m, 2H), 7.21 (t, 1H), 6.93 (d, 1H), 6.78 (m, 1H), 6.74 (s, 1H),
6.71 (m, 2H)3 4.43 (d, 1H), 3.87 (d, 1H), 3.69 (s, 3H), 3.14 (m, 1H), 2.86 (m, 1H), 2.64 (m, 1H),
2.01 (s, 3H), 1.95 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z = 631.4 (M+H-
HC1).

[00819] A 20 mL vial was charged with 3-(2-bromo-4-fluorophenoxy)-5-(3-
methoxyphenylthio)-N-(4-(piperidin-yl)thiazol-2-yl)pyridin-2-amine (40 mg, 0.068 mmol),

triethylamine (0.028 mL, 0.20 mmol), and CH2C12 (2 mL). 2-(Dimethylamino)acetyl chloride
hydrochloride (12.9 mg, 0.0817 mmol) was added and stirred at room temperature for 10
minutes. The reaction was partitioned between CH2C12 and saturated aqueous sodium
bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated. The
residue was purified on silica gel (15% MeOH in EtOAc with 0.3% ammonia) to afford 1the title
compound (35.6 mg, 70.1% yield) after HC1 salt formation. 1H NMR (d6-DMSO)  11.15 (bs,
1H), 9.60 (bs, 1H), 8.17 (d, 1H), 7.75 (m, 1H), 7.32 (m, 2H), 7.21 (t, 1H), 6.94 (d, 1H), 6.79 (m,
1H), 6.75 (s, 1H), 6.71 (m, 2H), 4.42 (d, 1H), 4.31 (qd, 2H), 3.69 (s, 3H), 3.19 (t, 1H), 2.93 (m,
1H), 2.82 (m, 6H), 2.04 (d, 2H), 1.64 (m, 1H), 1.52 (m, 1H). Mass spectrum (apci) m/z = 674.3
(M+H-2HC1).








[00821] Prepared according to the method of Example 355, Example 13 and Example 127.
H1 NMR (d6 DMSO)  1.55-1.65 (m, 1H), 1.69-1.79 (m, 1H), 1.97-2.05 (m, 5H), 2.77 (t, J = 11.3
Hz, 1H), 3.05-3.10(m, 1H), 3.20 (t, J = 11.5 Hz, 1H), 3.85 (d, J = 13.5 Hz, 1H), 4.33 (d, J = 13.1 Hz,
1H), 6.91 (d, J - 5.1 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 1.8 Hz,
1H), 7.58 (d, J = 5.5 Hz, 1H), 7.65 (t, J - 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 5.5 Hz,
1H), 8.48 (d, J = 5.1 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 12.62 (s, 1H).


[00822] Step A: Preparation of tert-butyl 4-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-
ylamino)thiazol-4-yl)piperidine-l-carboxylate: 1 -(5-bromo-3-(4-fluorophenoxy)pyridin-2-
yl)tbiourea (3.00 g, 8.77 mmol; prepared according to Example 179, Step D), TEA (2.08 mL,
14.9 mmol) and tert-butyl 4-(2-bromoacetyl)piperidine-l-carboxylate (3.49 g, 11.4 mmol) were
refluxed in ethanol (75 mL) for 2 hours. The reaction was cooled to room temperature and
filtered to afford the title compound (3.6 g, 74.7% yield).
[00823] Step B: tert-butvl 4-(2-(3-(4-fluorophenoxy)-5-(3-methoxy-3-oxopropylthio)
pyridin-2-vlamino)thiazol-4-tl)piperidine-1-carboxylate: Prepared according to the method of
Example 13.
[00824] Step C: tert-butvl 4-(2-(3-(4-fluorophenoxyl)-5-(thieno[3,2-b]pyridin-7-ylthio)
pyridin-2-ylammo)thiazol-4-yl)piperidine-1 -carboxylate: Prepared according to the method of
Example 127. 1H NMR (d6-DMSO)  11.21 (bs, 1H), 8.49 (d, 1H), 8.36 (d, 1H), 8.16 (d, 1H),
7.59 (d, 1H), 7.39 (d, 1H), 7.25-7.15 (m, 4H), 6.90 (d, 1H), 6.74 (s, 1H), 4.03 (m, 2H), 2.81 (m,
3H), 1.93 (m, 2H), 1.50 (m, 2H), 1.41 (s, 9H).

[00825] Prepared according to the method of Example 271. 1H NMR (d6-DMSO)  11.26
(bs, 1H), 8.79 (m, 1H), 8.59 (m, 1H), 8.53 (d, 1H), 8.38 (d, 1H)S 8.23 (d, 1H), 7.62 (d, 1H), 7.43
(d, 1H), 7.26-7.16 (m, 4H), 6.97 (d, 1H), 6.82 (s, 1H), 3.33 (d, 2H), 3.06-2.86 (m, 3H), 2.13 (d,
2H),1.80(m,2H).

[00826] The following compounds also were made according to the method of Example
272.



[00827] The following compounds were also made according to the method of Example



282.
[00828] Step A: Preparation of 2-(2-(4-(2-(3-f4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-
ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidin-l-ylsulfonvl)ethyl)isoindoline-l,3-dione:
Prepared according to the method of Example 288, Step A.
[00829] Step B: Preparation of 4-(l-(2-aminoethvlsulfonyl)piperidin-4-vn-N-(3-(4-
fluorophenoxvV5-(thienor3.2-b1pvridin-7-vltfaio)pyridin-2-vnthiazol-2-amine dihvdrochloride:

Prepared according to the method of Example 288, Step B using hydrazine monohydrate. 1H
NMR (d6-DMSO)  8.58 (d, 1H), 8.41 (d, 1H), 8.34 (d, 1H), 8.15 (bs, 2H), 8.07 (bs, 1H), 7.89 (m,
1H), 7.69 (d, 1H), 7.47 (d, 1H), 7.27-7.17 (m, 4H), 7.07 (d, 1H), 6.81 (s, 1H), 3.70 (d, 1H), 3.43
(t, 2H), 3.17 (m, 2H), 3.00 (t, 2H), 2.80 (m,lH), 2.08 (d, 2H), 1.65 (m, 2H).

[00830] Prepared according to the method of Example 287 from 3-(4-fluorophenoxy)-N-
(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine. 1H NMR (d6-
DMSO)  11.22 (s, 1H), 8.49 (d, 1H), 8.37 (d,lH), 8.16 (d, 1H), 7.59 (d, 1H), 7.41 (d, 1H), 7.26-
7.14 (m, 4H), 6.90 (d, 1H), 6.78 (s, 1H), 6.73 (s, 2H), 3.53 (d, 2H), 2.65 (m, 3H), 2.05 (m, 2H),
1.69 (m, 2H).

[00831] Prepared according to the method of Example 280 from 3-(4-fluorophenoxy)-N-
(4-(piperidin-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridm-7-ylthio)pyridin-2-amine. 1H NMR (d6-
DMSO) 8 8.62 (d, 1H), 8.43 (m, 2H), 7.73 (d,lH), 7.50 (d, 1H), 7.27-7.18 (m, 4H)5 7.14 (d, 1H),
6.79 (s, 1H), 4.01 (d, 2H), 2.78 (m, 3H), 1.88 (d, 2H), 1.50 (m, 2H).


[00832] Prepared according to the method of Example 127 from tert-butyl 4-(2-(3-(4-
fluorophenoxy)-5-(3-methoxy-3-oxopropy lthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1 -
carboxylate. 1H NMR (d6-DMSO)  11.25 (bs, 1H), 8.35 (d, 1H), 8.32 (d, 1H), 7.40 (d, 1H),
7.27-7.21 (m, 4H), 6.76 (s, 1H), 6.71 (d, 1H), 4.02 (m, 2H), 2.83 (m,-3H), 2.69 (s, 3H), 1.94 (d,
2H), 1.50 (m, 2H), 1.41 (s, 9H).

[00833] Prepared according to the method of Example 271 from tert-butyl 4-(2-(3-(4-
fluorophenoxy)-5-(3-methylisoxazolo[5,4-b]pyridm-4-ylthio)pyridin-2-ylamino)tbiazol-4-
yl)piperidine-l-carboxylate. 1H NMR (d6-DMSO)  8.88 (m, 1H), 8.70 (m, 1H), 8.36 (d, 1H),
8.32 (d, 1H), 7.42 (d, 1H), 7.29-7.10 (m, 4H), 6.83 (s, 1H), 6.72 (d, 1H), 3.33 (d, 2H), 3.06-2.85
(m, 3H), 2.69 (s, 3H), 2.14 (d, 2H), 1.81 (m, 2H).
[00834] The following compounds were also made according to the procedure of Example
272.



[00835] Prepared according to the method of Example 272 from 3-phenoxy-N-(3-
(piperidin-4-yl)-l,2,4-thiadiazo]-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine. 1H NMR (d6-
DMSO)  12.33 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (d, 2H),
7.21-7.11 (m, 5H), 3.98 (m, 2H), 3.60 (s, 3H), 3.01(m, 3H), 1.99 (d, 2H), 1.65 (m, 2H).


[00836] Step A: 3-amino-4-methylthiophene-2-carboxylic acid: Methyl 3-amino-4-
methylthiophene-2-carboxylate (4.67 g, 27.3 mmol) and NaOH (2N in H2O, 68 mL, 136 mmol)
were stirred at 100 °C for 1 hour. The solution was cooled to 0 °C and acidified to pH = 5 with
addition of concentrated HC1 solution to form a precipitant. The solution was filtered and the
solid was dried under vacuum to give the title compound (2.8 g, 65%).
[00837] Step B: 4-methvlthiophen-3-amine: 3-amino-4-methylthiophene-2-carboxylic
acid (5.64 g, 36 mmol) in HC1 (6N in H2O, 30 mL, 179 mmol) was stirred at 50 °C overnight. It
was cooled to room temperature, and neutralized by the addition of solid NaHCO3. The solution
was extracted with dichloromethane (2 times), dried over Na2SO4, filtered and concentrated to
yield the title compound (3.8 g, 94% yield).
[00838] Step C: 2.2-dimethvl-5-((4-methvlthiophen-3-vlaminolmethvlene)-l,3-dioxane-
4.6-dione: A stirred solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (4.85 g, 34 mmol) in
trimethoxymethane (37 mL, 337 mmol) was heated to 90 °C under nitrogen. After 2 hours, a
solution was 4-methylthiophen-3-amine (3.81 g, 34 mmol) was added (as a solution in
trimethoxymethane (37 mL, 337 mmol). The reaction stirred at 90 °C for 6 hours and then was
allowed to cool to room temperature and concentrated. The material was placed in the
refrigerator where it solidified after two days to obtain the title compound (9 g, quantitative).
[00839] Step D: 3-methvlthieno[3.2-b]pyridin-7-ol: A solution of Dowtherm A (7 mL)
was heated in oil bath at 235 °C under nitrogen. 2,2-dimethyl-5-((4-methylthiophen-3-
ylamino)methylene)-l,3-dioxane-4,6-dione (5.0 g, 19 mmol) was added in portions over a 20
minutes period. After the last portion was added, the solution stirred at 235 °C for another 5
minutes. The solution was removed from the oil bath and allowed to cool to room temperature.
Upon cooling, the product precipitated out of solution. Diethyl ether was added and the solid
was filtered and dried to give the title compound (3.2 g) with residual amounts of Dowtherm A
remaining.

[00840] Step E: 7-chloro-3-methvlthieno[3.2-b]pyridine: Phosphorous oxychloride (2.2
mL, 24 mmol) in 1,2-dichloroethane (12 mL) was charged with 3-methylthieno[3,2-b]pyridin-7-
ol ( 2.0 g, 12 mmol). The reaction, stirred overnight at reflux under nitrogen. The mixture was
the cooled and. concentrated. Saturated NaHCO3 solution was carefully added to neutralize the
residue. The biphasic mixture was extracted with dichloromethane, dried, and concentrated.
Flash chromatography (15% EtOAc/hexanes ) gave the title compound (1.23 g, 55%).
[00841] Step F: l-(4-(2-(5-(3-methylthieno[3.2-b]pyriin-7-ylthio)-3-phenoxvpvridin-2-
ylamoni)thiazol-4-yl)piperidin-1 -yl)ethanone: 7-chloro-3-methylthieno[3,2-b]pyridine (0.072 g,
0.39 mmol) and methyl 3-(6-(4-(l-acetylpiperidin-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-
ylthio)propanoate (0.20 g, 0.39 mmol) were dissolved in DMSO (3 mL). The solution was
degassed for 15 minutes under nitrogen. KOtBu (0.13 g, 1.2 mmol) was added and the reaction
stirred at room temperature for two hours. The solution was quenched with water, extracted with
dichloromethane, dried, and concentrated. Flash chromatography gave the title compound (0.100
g, 44% yield). 1H NMR (400 MHz, CDC13) 8 1.60 - 1.72 (m, 2H), 2.03 - 2.09 (m, 2H), 2.11 (s,
3H), 2.51 (s, 3H), 2.66 - 2.73 (m, 1H), 2.83 - 2.90 (m, 1H), 3.15 - 3.22 (m, 1H), 3.88 - 3.94 (m,
1H), 4.70 - 4.73 (m, 1H), 6.51 (s, 1H), 6.75 (d, 1H), 7.05 (d, 2H), 7.17 - 7.25 (m, 2H), 7.36 -
7.40 (m, 3H), 8.30 (d, 1H), 8.48 (d, 1H), 8.84 (bs, 1H).

[00842] Steps A and B: Thiophen-3-amine: Prepared according to the method of Example
442, Steps A and B, using methyl 3-aminothiophene-2-carboxylate as the starting material.
[00843] Step C and D: l-(4-(2-(5-(5-chlorothieno[3.2-b]pyridin-7-ylthio)-3-
phenoxvpvridin-2-ylamino)thiazol-4-yl)piperidin-1 -yl)ethanone: Prepared according to the
method of Example 442, Steps E and F. 1H NMR (400 MHz, CDCl3) -1.73 (m, 2H), 2.05
- 2.10 (m, 2H), 2.12 (s, 3H), 2.66 (t, 1H), 2.85 - 2.91 (m, 1H), 3.17 (t, 1H), 3.91 (d, 1H), 4.71 (d,
1H), 6.53 (s, 1H), 6.67 (s, 1H), 7.08 (d, 2H), 7.17 (s, 1H), 7.22-7.26 (m, 1H), 7.41 (t, 2H), 7.47
(d, 1H), 7.76 (d, 1H), 8.32 (s, 1H), 8.96 (s, 1H).


[00844] Step A: Preparation of tert-Butyl 4-(3-chloro-2-hydroxvproptl)-3-oxopiperazine-
1-carboxylate. In a 50 0ml round bottom flask with magnetic stirrer 4-Boc-piperazinone (5.08 g,
25.4 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. Butyllithium (1.6M in
hexanes) (15.9 mL, 25.4 mmol) was added then and the mixture agitated for 30 minutes at -78
°C. Boron trifluoride ethereate (3.19 mL, 25.4 mmol) was added slowly and then
epichlorohydrin (1.99 mL, 25.4 mmol). The mixture was agitated for 1 hour at -78 °C and then
allowed to warm up and agitated overnight. Reaction was quenched with saturated ammonium
chloride, extracted three times with ethyl acetate, extracts washed with brine and evaporated.
Purified by column chromatography on silica gel, eluting with 3% MeOH/CH2Cl2 to give the title
compound (3.34 g, 45% yield).
[0084S] Step B: Preparation of tert-Butvl 4-(3-chloro-2-oxopropvlV3-oxopiperazine-l-
carboxvlate. In a 125ml round-bottom flask equipped with a magnetic stirrer tert-butyl 4-(3-
chloro-2-hydroxypropyl)-3-oxopiperazine-l-carboxylate (3.30 g, 11.3 mmol) was dissolved in
acetonitrile (10ml) and Dess-Martin periodinane (5.26 g, 12.4 mmol) was added. After agitating
for 3 hours the mixture was diluted with ethyl acetate (100ml) and washed with sodium
bicarbonate and brine, dried and evaporated. Purified by column chromatography and eluting
with 3% MeOH/CH2Cl2 to give the title compound (0.600 g, 18.31% yield).
[00846] Step C: Preparation of tert-Butvl 4-((2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-
ylamino)thiazol-4-yl)methyl)-3-oxopiperazine-1 -carboxvlate. In a 20 mL scintillation vial equipped
with magnetic stirrer l-(5-bromo-3-(4-fiuorophenoxy)pyridin-2-yl)thiourea (0.25 g, 0.73 mmol) was
suspended in ethanol (5ml) and tert-butyl 4-(3-chloro-2-oxopropyl)-3-oxopiperazine-l-carboxylate
(0.32 g, 1.10 mmol) was added followed by DIEA (0.22 mL, 1.28 mmol). Resulting mixture was
heated to 60 °C and agitated for 3 hours. Mixture was then diluted with ethyl acetate and washed
with sodium bicarbonate solution, brine, dried and evaporated.. Purified by column chromatography
on silica gel, eluting with 50-100% ethyl acetate/hexane to give the title compound (0.106 g, 25.1%

yield). 1H NMR (CDC13) 8 1.41 (s, 9H), 2.79-3.42 (m, 6H), 6.55 (s, 2H), 7.03-7.12 (m, 4H), 8.12 (s,
1H), 8.95 (bs, 1H).

[00847] In a 20 mL scintillation vial equipped with magnetic stirrer tert-butyl 4-((2-(5-
bromo-3-(4-fluorophenoxy)proidin-2-ylamino)thiazol-4-yl)methyl)-3-Oxopiperazine-l-
carboxylate (0.020 g, 0.035 mmol) was dissolved in lml of CH2C12 and 4M HC1 in dioxane (0.50
mL, 2.0 mmol) was added. The resulting mixture was agitated for 2 hours, diluted with 5 mL of
ether and the solvent was decanted off. The residue was dried to provide the title compound
(0.012 g, 73% yield). 1H NMR (d6-DMSO)  3.25-3.78 (m, 6H), 6.99 (s, 1H), 7.28-7.36 (m, 4H),
8.23 (s, 1H), 8.34 (s, 1H), 10.24 (s, 2H).

[00848] Step A: Thieno[2,3-dlpyrimidin-4(3H)-one: Methyl 2-aminothiophene-3-
carboxylate (10 g, 64 mmol) was charged with fonnamide (50 mL). The reaction was heated at
190 °C under nitrogen for 3 hours. The solution was cooled to room temperature. The slurry
was poured into 125 mL of water and extracted with chloroform:isopropyl alcohol mixture (2
times). The solution was concentrated and triturated to afford the title compound (2.25 g, 23%).
[00849] Step B: 4-Chlorothienor2.3-dlpvrimidine: Thieno[2,3-d]pyrimidin-4(3H)-one (1.2
g, 7.9 mmol) was diluted in 1,2-dichloroethane (10mL). Phosphorous oxychloride (1.4 mL, 15.7
mmol) was added. The reaction was stirred at 90°C for 16 hours. An additional equivalent of
phosphorous oxychloride (0.7 mL, 7.9 mmol) was added and the solution continued stirring for 4
hours. The solution was cooled,' concentrated, and neutralized with saturated NaHCO3 solution.

The material was extracted with a chloroform:isopropyl alcohol mixture and the organic layer
was separated and concentrated. Flash chromatography gave the title compound (0-39 g, 29%).
[00850] Step C: l-(4-(2-(3-phenoxy-5-(thienor2,3-d]pvrirnidin-4-ylthio)pvridin-2-
ylammo)tinazol-4-yl)piperidin-1-yl)ethanone: 4-chlorothieno[2,3-d]pyrimidine (0.050 g, 0.29
mmol) and methyl 3-(6-(4-(l-acetylpiperidin-4-yl)tbiazol-2-ylamino)-5-phenoxypyridin-3-
ylthio)propanoate (0.15 g, 0.29 mmol) were dissolved in DMSO (3 mL). The solution was
degassed for 15 minutes. KOtBu (0.098 g, 0.88 mmol) was added and the reaction stirred at
room temperature for two hours. The solution was quenched with water, extracted with
dichloromethane, dried, and concentrated. Flash chromatography gave the title compound
(0.075, 46%). 1H NMR (400 MHz, CDC13)  1.60 - 1.72 (m, 2H), 2.08 - 2.15 (m, 2H), 2.11 (m,
3H), 2.65 - 2.75 (m, 1H), 2.82 - 2.93 (m, 1H), 3.15 - 3.24 (m, 1H), 3.91 (d, 1H), 4.72 (d, 1H),
6.49 (s, 1H), 7.15 (d, 2H), 7.19 (t, 1H), 7.27 - 7.29 (m, 1H), 7.36 - 7.42 (m, 3H), 7.53 (d, 1H),
8.27 (d, IH), 8.68 (s, 1H), 8.81 (s, 1H).

[00851] Step A: Preparation of tert-butyl 4-(2-(methoxy(methyl)amino)-2-
oxoethvl)piperidipe-l-carboxvlate: N-methoxymethanamine hydrochloride (2.61 g, 26.7 mmol),
Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (5.91 g, 30.8
mmol), lH-benzo[d][l,2,3]triazol-l-ol hydrate (4.72 g, 30.8 mmol), and triethylamine (11.5 mL,
82.2 mmol) were added sequentially to a solution of 2-(l-(tert-butoxycarbonyl)piperidin-4-
yl)acetic acid (5.00 g, 20.6 mmol) in methylene chloride (150 mL) at 0 °C. Stirred at ambient
temperature for 4 hours, and partitioned between ethyl acetate and 2N HC1. Washed the organic
layer again with 2N HC1, twice with 2N NaOH, brine, dried, and concentrated to afford the title
compound (5.93 g, 101% yield) as a clear colorless viscous oil.
[00852] Step B: Preparation of tert-butvl 4-(2-oxopropyl)piperidine-l-carboxvlate:
Added dropwise 3.0 M methylmagnesium chloride in THF (8.63 mL, 25.9 mmol) to a solution of
tert-butyl 4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-l-carboxylate (5.93 g, 20.7
mmol) in THF (100 mL) at 0 °C. Warmed to ambient temperature and stirred for 90 minutes.

Partitioned between ether and 2N HC1, washed the organic layer twice with water, brine, dried,
and concentrated to afford the title compound (4.95 g, 99.1% yield) as a clear oil.
[00853] Step C: Preparation of tert-butyl 4-(2-(trimethylsilyloxy)allyl)piperidine-l-
carboxvlate: To a cooled (-78 °C) solution of LDA (12.3 mL, 24.6 mmol) in THF (50 mL) was
added dropwise over 40 minutes a solution of tert-butyl 4-(2-oxopropyl)piperidine-l-carboxylate
(4.95 g, 20.5 mmol) in THF (20 mL). After an additional 25 minutes, chlorotrimethylsilane (5.21
mL, 41.0 mmol) was added dropwise over 20 minutes. After stirring for an hour, the reaction was
poured into saturated NaHCO3 and extracted with ether (2 x 400 mL). The combined ether layers
were washed with brine, dried, filtered and concentrated to afford the title compound (6.95 g,
108% yield) which was used as is in the next step.
[00854] Step D: Preparation of tert-butvl 4-f3-bromo-2-oxopropyl)piperidine-l-
carboxylate: To a solution of tert-butyl 4-(2-(trimethylsilyloxy)allyl)piperidine-l-carboxylate
(6.43 g, 20.5 mmol) in THF (100 mL) at 0 °C was added sodium bicarbonate (2.58 g, 30.7 mmol)
followed by l-bromopyrrolidine-2,5-dione (3.65 g, 20.5 mmol). Warmed to ambient temperature
and stirred 90 minutes. Partitioned between ether (150 mL) and saturated sodium bicarbonate.
The aqueous layer was reextracted with ether (100 mL). The combined organic layers were
washed with saturated bicarbonate, brine, dried, and concentrated to afford the title compound
(7.2 g, 110% yield) as a yellow oil. Purity was 85% with the major impurity being succmimide.
The crude material was used in the next step.
[00855] Step E: Preparation of tert-butvl 4-((2-(5-bromo-3-phenoxvpvridin-2-
ylamino)thiazol-4-yl)methyl)piperidine-1 -carboxylate: Heated a mixture tert-butyl 4-(3-bromo-
2-oxopropyl)piperidine-l-carboxylate (1.38 g, 4.32 mmol), l-(5-bromo-3-phenoxypyridin-2-
yl)thiourea (1.0 g, 3.08 mmol), triethylamine (0.731 mL, 5.24 mmol), and ethanol (50 mL) at
reflux overnight. Cooled to ambient temperature and partitioned between into water and ethyl
acetate. Washed the organic layer with water, brine, dried and concentrated . Purified by MPLC
(Biotage) eluting with 3:1 hexane:ethyl acetate to afford the title compound (1.54 g, 92%) as a
white powder: 1H NMR (CDC13)  8.66 (s, 1H), 8.13 (s, 1H), 7.43 (t, 2H), 7.25 (t, 1H), 7.12 (s,
1H), 7.06 (d, 2H), 6.45 (s, 1H), 4.08 (m, 2H), 2.67 (m, 2H), 2.56 (d, 2H), 1.85 (m, 1H), 1.66 (m,
2H), 1.44 (s, 9H), 1.15 (m, 2H).
[00856] The following compounds were prepared from the appropriate carboxylic acid
according to the procedure of Example 447.



[00857] A 40 mL flask was charges withwith tert-butyl 3-(chloro(methylsulfonyl-
oxyimino)methyl)pyrrolidine-l-carboxylate (1.60 g, 4.90 mmol) and acetonitrile (25 mL). Added
pyridine (1.22 mL, 15-1 mmol) and isothiocyanatosodium (0.398 g, 4.90 mmol) and heated to 40
°C for 45 minutes. Added 5-bromo-3-phenoxypyridin-2-amine (1.00 g, 3.77 mmol) and heated at
60 °C overnight. The reaction was cooled to ambient temperature, poured into water and
extracted with EtOAc (100 mL). The organic layer were dried with sodium sulfete, filtered and
concentrated . The residue was purified by MPLC (Biotage) eluting with 3:1 hexane:ethyl acetate
to afford tert-butyl 3-(5-(5-bromo-3-phenoxypyridin-2-ylamino)-l,2,4-thiadiazol-3-
yl)pyrrolidine-l-carboxylate as a light yellow/off white solid: 1H NMR (d6-DMSO)  12.21 (s,

1H), 8.34 (s, 1H), 7.48 (s, 1H), 7.39 (t, 2H), 7.18 (t, 1H), 7.07 (d, 2H), 3.42-3.63 (m, 3H), 3.36
(m, 1H), 2.02-2.21 (m, 3H), 1.35 (s, 9H).



[00858] The atmosphere above a mixture of tert-butyl 4-((2-(5-bromo-3-phenoxypyridin-
2-ylamino)thiazol-4-yl)methyl)piperidine-l-carboxylate (1.52 g, 2.79 mmol), N-ethyl-N-
isopropylpropan-2-amine (0.971 mL, 5.57 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-
xanthene (0.161 g, 0.279 mmol), and dioxane (25 mL) was purged with nitrogen. Methyl 3-
mercaptopropanoate (0.332 mL, 3.07 mmol) and Pd2dba3 (0.128 g, 0.139 mmol) were added, and
the reaction was heated at 95 °C overnight. The reaction was cooled to ambient temperature and
filtered through celite. The filtrate was concentrated and purified by MPLC (Biotage) eluting
with 3:2 hexane: ethyl acetate to afford the title compound (1.54 g, 94.5% yield) as a tacky white
solid: 1H NMR (CDC13)  8.70 (s, 1H), 8.16 (s, 1H), 7.40 (t, 2H), 7.24 (t, 1H), 7.14 (s, 1H), 7.06
(d, 2H), 6.46 (s, 1H), 4.08 (m, 2H), 3.65 (s, 3H), 2.99 (t, 2H), 2.67 (m, 2H), 2.56 (d, 2H), 2.55 (t,
2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.45 (s, 9H), 1.16 (m, 2H).
[00859] The following compounds were prepared from the appropriate bromide according
to the procedure of Example 452.



[00860] Added potassium 2-methylpropan-2-olate (0.443 g, 3.95 mmol) to a solution of 7-
chlorothieno[3,2-b]pyridine (0.268 g, 1.58 mmol) and tert-butyl 4-((2-(5-(3-methoxy-3-
oxopropyltthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)rnethyl)piperidine-1-carboxylate (0.77
g, 1.32 mmol) in DMSO (8 mL). The reaction was stirred for two hours, then set aside to react at
ambient temperature for 60 hours. The reaction was partitioned between ethyl acetate and
saturated ammonium chloride. Washed the organic layer twice with water and brine, dried, and
concentrated. The residue was purified by MPLC (Biotage) eluting with 1:1 hexane:ethyl
acetate. The major UV active component with an Rf of 0.3 was collected and concentrated to
afford the title compound (0.810 g, 97.4% yield) as a white powder: 1H NMR (CDCl3) 8 8.88 (s,
1H), 8.46 (d, 1H), 8.32 (s, 1H), 7.72 (d, 1H), 7.54 (d, 1H), 7.38 (t, 2H), 7.20 (t, 1H), 7.18 (s, 1H),
7.04 (d, 2H), 6.73 (d, 1H), 6.51 (s, 1H), 4.09 (m, 2H), 2.68 (m, 2H), 2.59 (d, 2H), 1.87 (m, 1H),
1.66 (m, 2H), 1.45 (s, 9H), 1.16 (m, 2H).
[00861] Using the procedure in Example 457, the following compounds were prepared
from the appropriate thiopropionate and electrophile.





[00862] Added 4N HC1 in dioxane (3.0 mL, 12.0 mmol) to a solution of tert-butyl 4-((2-(3-
phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-
carboxylate (0.790 g, 1.25 mmol) in dichloromethane (4 mL) and methanol (4 mL). The reaction
was stirred at ambient temperature for 3 hours. Concentrated, triturated with hexanes, filtered to
afford the title compound (0.745 g, 98.5% yield) as a light yellow powder: 1H NMR (d6-DMSO)
 9.13 (m, 1H), 8.89 (m, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 7.80 (d, 1H), 7.57 (s, 1H),
7.42 (t, 2H), 7.16-7.23 (m, 4H), 6.91 (s, 1H), 3.21 (m, 2H), 2.80 (m, 2H), 2.60 (d, 2H), 1.95 (m,
1H), 1.76 (m, 2H), 1.45 (m, 2H).
[00863] Using the procedure in Example 464, the following compounds were prepared
from the appropriate Boc-protected cyclic amine.




[00864] Added 2,2,2-trifluoroacetic acid (4 mL, 51.9 mmol) to a solution of tert-butyl 4-
((2-(5-(4-cyanophenylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-l-
carboxylate (0.600 g, 1.00 mmol). Stirred at ambient temperature for 3 hours. Partitioned
between ethyl acetate and 2N NaOH. Washed the organic layer with water, brine, dried and
concentrated. The residue was dissolved in ether (5 mL) and 2N HC1 in ether was added.
Filtered, washed with hexanes, filtered to afford 4-(5-phenoxy-6-(4-(piperidin-4-
ylmethyl)thiazol-2-ylamino)pyridin-3-ylthio)benzonitrile dihydrochloride (0.454 g, 79.3% yield)
as a white powder: 1H NMR (d6 -DMSO)  8.94 (m, 1H), 8.67 (m, 1H), 8.31 (s, 1H), 7.72 (d,
2H), 7.42 (t, 2H), 7.35 (s, 1H), 7.10-7.26 (m, 5H), 7.83 (s, 1H), 3.23 (m, 2H), 2.80 (m, 2H), 2.58
(d, 2H), 1.92 (m, 1H),1.75 (m, 2H), 1.39 (m, 2H).
[00865] Using the procedure in Example 468, the following compounds were prepared
from the appropriate Boc-carbamate.


[00866] Added acetic anhydride (0.0169 g, 0.165 mmol) to a mixture of 3-phenoxy-N-(4-
(piperidin-4-ylmethyl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine
dihydrochloride (0.100 g, 0.165 mmol), triethylamine (0.0837 g, 0.827 mmol), and THF (5 mL)
at 0 °C. Warmed to ambient temperature and stirred for 4 hours. Partitioned between ethyl
acetate and 2N NaOH, washed with water, brine, dried, and concentrated. The residue was
dissolved in dichloromethane (2 mL) and IN HC1 in ether was added. Diluted in hexanes, and
concentrated, added hexanes again and concentrated to afford the title compound ((Mixture of
rotamers; 0.092 g, 91.2% yield) as a light yellow powder: 1H NMR (d6-DMSO)  8.65 (d, 1H);
8.47 (d, 1H), 8.46 (s, 1H), 7.77 (d, 1H), 7.41 (s, 1H), 7.41 (d, 2H), 7.15-7.20 (m, 4H), 6.84 (s,
1H), 0.95-4.36 (m, 11H), 1.97 (s, 3H).
[00867] Using the procedure in Example 471, the following compounds were prepared
from the appropriate amine.





[00868] Using the procedure in Example 16, the title compound was prepared: 1H NMR
(CDCl3) 5 8.24 (s, 1H), 8.13 (d, 1H), 7.42 (t, 2H), 7.24 (t, 1H), 7.07-7.12 (m, 2H), 6.82-6.86 (m,
2H), 6.52 (s, 1H), 4.72 (m, 1H), 3.91 (m, 1H), 3.19 (m, 1H), 2.88 (m, 1H), 2.70 (m, 1H), 2.12 (m,
1H), 2.03-2.11 (m,2H), 1.60-1.71 (m,2H).
Example A
In Vitro Glucokinase Assays
[00869] The in vitro efficacy of glucokinase activators of the present invention was assessed
in two separate assays: an EC50 assay to evaluate the potency of each compound at a fixed,
physiologically relevant concentration of glucose, and a glucose S0.5 assay at a fixed, near saturating
(if possible) concentration of compound to evaluate its effect on the Vm and S0.5 for glucose. For
each of these assays, glucokinase activity was estimated by monitoring the increase in absorbance at
340 nm in a coupled assay system containing NAD+ and glucose 6-phosphate dehydrogenase.
Assays were conducted at 30 °C using a thermostatically controlled absorbance plate reader
(Spectramax 340PC, Molecular Devices Corp.) and clear, 96-well, flat bottom, polystyrene plates
(Costar 3695, Corning). Each 50-L assay mixture contained 10 mM K+MOPS, pH 7.2, 2 mM
MgCl2, 50 mM KC1, 0.01% Triton X-100, 2% DMSO, 1 mM DTT, 1 mM ATP, 1 mM NAD+, 5
U/mL glucose 6-phosphate dehydrogenase, approximately 5 nM human glucokinase and (depending
on the assay) varying concentrations of glucose and test compound. The absorbance at 340 nm was
monitored kinetically over a period of 5 minutes (10 s/cycle), and rates were estimated from the
slopes of linear fits to the raw data.
Glucokinase EC50 Assay.
[00870] For this assay, the glucose concentration was fixed at 5 mM, while the control or test
compound was varied over a 10-point, 3-fold dilution series and typically ranged from a high dose of
50 M to a low dose of approximately 2.5 nM. A standard, four-parameter logistic model (Equation
1) was fit to the raw data (rate versus concentration of compound):



[00871] where x is the concentration of compound, y is the estimated rate, A and B are the
lower and upper asymptotes, respectively, C is the EC50 and D is the Hill slope. The EC50 is defined
as the midpoint or inflection point between the upper and lower asymptotes.
[00872] The compounds exemplified herein have been found to have an ECso in the range of 6
and 50,000 nM in the above described assay. Certain compounds exemplified herein have been
found to have an EC50 in the range of 3nM and 5000 nM.
Glucose S0.5 Assay:
[00873] For this assay, the concentration of control or test compound was fixed at or near a
saturating concentration, if possible, typically 50 M, while the glucose concentration was varied
over a 10-point, 2-fold dilution series ranging from 80 to approximately 0.16 mM. The same four-
parameter logistic model used for the ECso assay (Equation 1) was employed to estimate the relevant
kinetic parameters. In this assay, the definitions for the variables and parameters are similar except
that x represents the concentration of glucose, B is the rate at saturating glucose (Vm), C is the S0.5 for
glucose (the concentration of glucose at Vm/2) and D is the Hill Coefficient.
[00874] The compounds exemplified herein have been found to have an S0.5 of between 0.3
and 5 mM in the above described assay.
[00875] The foregoing description is considered as illustrative only of the principles of the
invention. Further, since numerous modifications and changes will be readily apparent to those
skilled in the art, it is not desired to limit the invention to the exact construction and process shown as
described above. Accordingly, all suitable modifications and equivalents may be resorted to falling
within the scope of the invention as defined by the claims that follow.
[00876] The words "comprise," "comprising," "include," "including," and "includes" when
used in this specification and in the following claims are intended to specify the presence of stated
features, integers, components, or steps, but they do not preclude the presence or addition of one or
more other features, integers, components, steps, or groups thereof.

What is claimed is:
1. A compound selected from the Formula

and salts thereof, wherein:
L is O, S, C(=O)or CHR14;
Y is N or CR4;
Z is N or CR3, wherein at least one of G or Z is not N;
G is N or CR11;
R1 is a heteroaryl ring represented by the formula

D1is S, O, or N;
D2 is N or CR12;
D3 is S, O or CR13;
R2 is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, or saturated or
partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are
monocyclic or bicyclic and are optionally substituted with one or more groups independently
selected from Ct-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-
C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, aryl, heteroaryl, F, Cl, Br, I,
CF3, CN, NO2, OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, O(CH2)nC(=O)OR6,
O(CH2)nC(=O)NR6R7, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6, S(O)R6, and S(O)2R6, and
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally
substituted with one or more groups independently selected from oxo, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, saturated and partially unsaturated C3-C6 Vn-cycloalkyl, saturated and partially
unsaturated C1-C6 Vn-heterocyclyl, Vn-aryl, Vn-heteroaryl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-
CN, Vn-OR8, Vn-C(=O)R8, Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-C(=O)NR8R9, Vn-NR8R9, Vn-
NR8C(=O)R9, Vn-SR8, Vn-S(O)R8, and Vn-S(O)2R8;

R3 is H, C1-C12 alkyl, C2-d12 alkenyl, C2-C12 alkynyl, saturated or partially unsaturated
C3-C12 cycloalkyl, saturated or partially unsaturated C1-C12 heterocyclyl, aryl, heteroaryl, F, Cl,
Br, 1, CN, OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7J OC(=O)NR6R7, OC(=S)NR6R7,
NR6R7, NR6C(=O)R7, SR6, S(O)R6, S(O)2R6 or S(O)2NR6R7, wherein said alkyl, alkenyl,
alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more
groups independently selected from oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and
partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-
aryl, Vn-heteroaryl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)R8, Vn-
C(=O)OR8, Vtt-0C(=O)R8, Vn-C(=O)NR8R9, Vn-NRSR9, Vn-NR8C(=O)R9, Vn-SR8, Vn-S(O)RS,
Vn-S(O)2R8 and Vn-S(O)2NR8R9;
R4 is H, methyl, ethyl, F, Cl, Br, I, CF3, CHF2 or CH2F;
R6 and R7 are independently H, C1-C12 alkyl, C2-C12 alkenyl, C1-C12 alkynyl, saturated or
partially unsaturated C3-C12 cycloalkyl, saturated or partially unsaturated C1-C12 heterocyclyl,
Vn-aryl, or Vn-heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl portions are optionally substituted with one or more groups independently selected
from oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6
cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl [optionally substituted with
C(O)O(J-6C alkyl), (l-6C)alkyl or (1-6C alkyl)OH], Vn-aryl, Vn-heteroaryl, Vn-F, Vn-CI, Vn-Br,
Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)R8, Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-C(=O)NR8R9,
Vn-NR8R9, Vn-NR8C(=O)R9, Vn-SR8, Vn-S(O)R8, Vn-S(O)2R8, VB-S(O)2NR8R9, and (C1-C6
alkyI)OH;
or R6 and R7 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one
or more additional ring heteroatoms independently selected from N, O or S, wherein said
heterocyclic ring is optionally substituted with one or more groups independently selected from
oxo, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-OR8, Vn-C(=O)OR8, Vn-C(=O)NR8R9, Vn-NR8R9, Va-
NR8C(=O)R9, Vn-NR8C(=O)NR9R10, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
R8, R9 and R10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated
and partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl,
aryl or heteroaryl, wherein said alkyl, alkenyl, alkyny], cycloalkyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one or more groups independently selected from oxo,
C1-C6 alky], C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6 cycloalkyl,

saturated and partially unsaturated C1-C6 heterocyclyl, Vn-aryl, Vn-heteroaryl, Vn-F, Vn-Cl, Vn-
Br, Vn-I, Vn-ORa, Vn-NRBRb, Vn-C(=O)ORa, Vn-C(=O)NRaRb, and Vn-NRaC(=O)Rb,
or R8 and R9 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one
or more additional ring heteroatoms independently selected from N, O or S, wherein said
heterocyclic ring is optionally substituted with one or more groups independently selected from
oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-ORa, and Vn-CN,
or R9 and R10 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one
or more additional ring heteroatoms independently selected from N, O or S, wherein said
heterocyclic ring is optionally substituted with one or more groups independently selected from
oxo.C1-C6 alkyl, C2-C6 alkenyl, C2-Cfi alkynyl, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-ORa, and Vn-CN;
R11 is H, methyl, ethyl, F, Cl, Br, I, CF3, CHF2, CH2F, OH, O-(d-C4 alkyl), or NH2;
R12 and R13 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and
partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl,
CH2-heterocyclyl, aryl, heteroaryl, (1-3C alkyl)heteroaryl, (CH2)n(CRxRy)C(O)NR8R9, F, Cl, Br,
I, CF3, CN, OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6,
S(O)R6, S(O)2R6, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one or more groups independently selected from oxo,
Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)OR8, Vn-OC(O)R8, Vn-
C(=O)NR8R9, Vn-NR8R9, Vn-NR8C(=O)R9, C(O)(C1-C6 alkyl), C(O)-heterocycle [optionally
substituted with O-(C1-C6, alkyl], SRa, SO2Rr, SO2NRcRe, C(O)(CrC6 alkyl)NRcRdd, C(O)(C1-C6
alkyl)ORc, C(O)CH2C(O)(C1-C6 alkyl), C(=O)CHRgNHC(=O)(C1-C6 alkyl),
C(=O)CH2OC(=O)(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and
partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-
aryl, and Vn-heteroaryl, wherein said heterocyclyl is optionally substituted with one or more oxo,
or R12 and R13 together with the atoms to which they are attached form a saturated,
partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein said carbocyclic and
heterocyclic rings are optionally substituted with one or more groups independently selected
from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6
cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br,
I, CF3, CN, OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6,
S(O)R6, S(O)2R6 and SO2NR6R7, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,

aryl and heteroaryl are optionally substituted with one or more groups independently selected
from oxo, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-0R8, Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-
C(=O)NR8R9, Vn-NR8R9, Vn-NR8C(=O)R9, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated
and partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl,
Vn-aryl, and Vn-heteroary];
R14 is H, methyl, ethyl or OH;
Ra and Rb are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and
partially unsaturated C1-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-
aryl, or Vn-heteroaryl, wherein said alkyl, alkenyl, alkynyl, saturated or partially unsaturated Vn-
cycloalkyl, saturated or partially unsaturated Vn-heterocyclyl, Vn-aryl, and Vn-heteroaryl are
optionally substituted with one or more OH;
each Rc, Re and Rg is independently H or C1-C6 alkyl;
Rd is H, C1-C6 alkyl or C(O)O(C1-C6 alkyl);
Rf is C1-C6 alkyl or (C1-C6 alkyl)NH2;
Rx Is H or C1-C6 alkyl;
Ry is H, C1-C6 alkyl, or -O(C1-C6 alkyl);
V is alkylene having from 1 to 12 carbons, or alkenylene or alkynylene each having from
2 to 12 carbons, wherein said alkylene, alkenylene, or alkynylene are optionally substituted with
one or more groups independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
saturated and partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6
heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, CF3, cyano, OR8, C(=O)OR8, OC(=O)R8,
C(=O)NR8R9, NR8R9, (C1-C6 alkyl)NRcRe, and NR8C(=O)R9; and
n is 0 or 1.
2. The compound of claim 1, wherein:
R6 and R7 are optionally substituted with one or more groups independently selected from
oxo, C1-C6 alkyl, C1-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6
cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-aryl, Vn-heteroaryl, Vn-F,
Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)R8, Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-
C(=O)NR8R93 Vn-NR8R9, Vn-NR8C(=O)R9, Vn-SR8, Vn-S(O)R8, Vn-S(O)2R8, and Vn-
S(O)2NR8R9, and
R12 and R13 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and
partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl,
aryl, heteroaryl, F, Cl, Br, I, CF3, CN, OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7,

NR6R7, NR6C(=O)R7, SR6, S(O)R6 or S(O)2R6, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups
independently selected from oxo, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Va-OR8, Vn-
C(=O)OR8, Vn-OC(=O)R8, Vn-C(=O)NR8R9, Vn-NR8R9, Vn-NR8C(O)R9, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6 cycloalkyl, saturated and
partially unsaturated C1-C6 heterocyclyl, Vn-aryl, and Vn-heteroaryl, wherein said heterocyclyl is
optionally substituted with one or more oxo,
or R12 and R13 together with the atoms to which they are attached form a saturated,
partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein said carbocyclic and
heterocyclic rings are optionally substituted with one or more groups independently selected
from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated and partially unsaturated C3-C6
cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl, aryl, heteroaryl, oxo, F, Cl, Br,
I, CF3, CN, OR6, C(=O)R6, C(=O)OR6, OC(=O)R6, C(=O)NR6R7, NR6R7, NR6C(=O)R7, SR6,
S(O)R6, S(O)2R6 and SO2NR6R7, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl and heteroaryl are optionally substituted with one or more groups independently selected
from oxo, Vn-F, Vn-Cl, Vn-Br, Vn-I, Vn-CF3, Vn-CN, Vn-OR8, Vn-C(=O)OR8, Vn-OC(=O)R8, Vn-
C(=O)NR8R9, Vn-NR8R9, Vn-NRSC(=O)R9, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated
and partially unsaturated C3-C6 cycloalkyl, saturated and partially unsaturated C1-C6 heterocyclyl,
Vn-aryl, and Vn-heteroaryl.
3. The compound according to claim 1 or 2, wherein R1 is selected from:

4. The compound of claim 3, wherein R20 is H.
5. The compound according to any of claims 1-4, wherein:
G is CH;
Y is CH or N; and
Z is CR3.
6. The compound of claim 1, having the Formula Ia


wherein:
L is O, S, or CH2;
Y is N or CH;
D2 is N or CR12;
R2 is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, or saturated or
partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, cycioalkyl and heterocyclyl are
monocyclic or bicyclic and are optionally substituted with one or more groups independently
selected from C1-C6 alkyl, (C1-C6 alkyl)OH, C1-C6 heterocyclyl, F, Cl, Br, CF3, CN, NO2, OR6,
C(=O)R6, C(=O)OR6, C(=O)NR6R7, S(O)2R6, C(O)CH2NH2, and C(O)CH2NRaRb;
R3 is H, C1-C12 alkyl, aryl, heteroaryl, F, Cl, Br, OR6,or SR6, wherein said alkyl, aryl and
heteroaryl are optionally substituted with one or more groups independently selected from C1-C6
alkyl, C2-C6 alkenyl, saturated and partially unsaturated C1-C6 heterocyclyl, Vn-OR8, Vn-
C(=O)OR8, and Vn-NR8R9;
R6 and R7 are independently H, C1-C12 alkyl, saturated or partially unsaturated C3-C12
cycloalkyl, saturated or partially unsaturated C1-C12 heterocyclyl, Vn-aryl, or Vn-heteroaryl,
wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl portions are optionally
substituted with one or more groups independently selected from C1-C6 alkyl, saturated and
partially unsaturated C1-C6 heterocyclyl [optionally substituted with C(O)O(C1-C6 alkyl) or (C1-
C6 alkyl)OH], aryl, heteroaryl, CF3, F, Cl, Br, I, CN, OR8, C(=O)R8, C(=O)OR8, C(=O)NR8R9,
NR8R9, NR8C(=O)R9 or (C1-C6 alkyl)OH,
or R6 and R7 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one
or more additional ring heteroatoms independently selected from N, O or S;
R8, R9 and R10 are independently H, C1-C6 alkyl, or saturated and partially unsaturated
C1-C6 heterocyclyl, wherein said alkyl and heterocyclyl are optionally substituted with one or
more groups independently selected from C1-C6 alkyl, saturated and partially unsaturated C1-C6
heterocyclyl, ORa, NRaRb, C(=O)ORB and C(=O)NRaRb,

or R8 and R9 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring;
or R9 and R10 together with the atoms to which they are attached form a saturated or
partially unsaturated heterocyclic ring;
RI2 is H or C1-C6 alkyl;
R13 is H, C1-C6 alkyl, saturated and partially unsaturated C3-C6 cycloalkyl, saturated and
partially unsaturated C1-C6 heterocyclyl, CH2-heterocyclyl, aryl, heteroaryl, (1-3C
alkyl)heteroaryl, or (CH2)n(CRxRy)C(O)NR8R9, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,
CH2-heterocyclyl, heterocyclyl, aryl, heteroaryl and (1-3C alkyl)heteroaryl are optionally
substituted with one or more groups independently selected from oxo, F, Cl, CF3, CN, OR8,
C(=O)OR8, C(=O)NR8R9, NR8R9, C(O)(C1-C6 alkyl), C(O)-heterocycle [optionally substituted
with O-(C1-C6 alkyl) or oxo], SRa, SO2Rf, SO2NRcRe, C(O)(C1-C6 alkyl)NRcRdd, C(O)(C1-C6
alkyl)ORc, C(O)CH2C(O)(C1-C6 alkyl), C1-C6 alkyl, C1-C6 heterocycle (optionally substituted
with oxo) and aryl,
or R12 and R13 together with the atoms to which they are attached form an heteroaryl ring;
Ra and Rb are independently H, C1-C6 alkyl, saturated or partially unsaturated C1-C6
heterocyclyl;
each Rc, Re and Rg is independently H or C1-C6 alkyl;
Rd is H, C1-C6 alkyl or C(O)O(C1-C6 alkyl);
Rf is C1-C6 alkyl or (C1-C6 alkyl)NH2;
V is alkylene having from 1 to 4 carbons, or alkenylene having from 2 to 4 carbons,
wherein said alkylene and alkenylene are optionally substituted with C1-C6 alkyl, O(C1-C6 alkyl),
or (C1-C6 alkyl)NRcRe; and
n is 0 or 1,
7. The compound according to any of claims 1-6, wherein R12 is H.
8. The compound according to any of claims 1-7, wherein R13 is selected from H,
C1-C6 alkyl, chloro(C1-C6 alkyl), CF3, (3-6C)cycloalkyl, (C1-C6 alkyl)CN, (C1-C6 alkyl)CO2R8,
(C1-C6 alkyl)SRa, (C1-C6 alkyl)SO2Rf, (C1-C6 alkyl)aryl, (C1-C6 alkyl)OR8, (C1-C6 alkyl)NR8R9,
(CH2)n(CRxRy)C(O)NR8R9, (CH2)n(CRxRy)C(O)NH-N=CHNR8R9, (C1-C6 alkyl)C(O)-
heterocyclyl, aryl, heteroaryl, (C1-C6 alkyl)hetAr', CH2(CRxRy)C(O)OR8,
CH2(CRxRy)C(O)heterocyclyl [optionally substituted with one or two groups selected from O-
(C1-C6 alkyl) and oxo], CH2CH(CO2H)-CH2CH2NHRa, hetCyc1 and CH2hetCyc2, wherein:
Rx and Ry are independently H, methyl or OMe,

n is 0 or 1,
hetCyc1 is a heterocyclic ring optionally substituted with one or more groups
independently selected from C1-C6 alkyl, C(O)(C1-C6 alkyl), (C1-C6 alky)OH, C(O)O(C1-C6
alkyl), C(O)(C1-C6 alkyl)NRcRd, C(O)(C1-C6 alkyl)ORc, C(O)CH2C(O)(C1-C6 alkyl),
C(O)NRaRb, SO2NRcRe, SO2Rf, C(=O)CHR8NHC(=O)(C1-C6 alkyl) and C(=O)CH2OC(=O)(C1-
C6 alkyl),
hetCyc2 is a heterocyclic ring optionally substituted with one or more groups
independently selected from C1-C6 alkyl, C(O)(C1-C6 alkyl), C(O)O(C1-C6 alkyl), and oxo, and
hetAr1 is a heteroaryl ring optionally substituted with C1-C6 alky, OH or CF3.
9. The compound according to any of claims 1-8, wherein R2 is:
(i) phenyl optionally substituted with one or more groups independently selected from F,
Cl, Br, CN, CF3, C1-C6 alkyl, NO2, SO2(C1-C6 alkyl), OH, O(C1-C6 alkyl), CO2H, CO2(C1-C6
alkyl), C(O)hetercyclyl [optionally substituted with C1-C6 alkyl], heterocyclyl and C(O)NR8R9;
(ii) a 5-6 membered heteroaryl ring having 1-2 nitrogen atoms;
(iii) a 9-10 membered bicyclic heteroaryl ring having a having 1 to 2 ring atoms
independently selected from N and S;
(iv) , a 5 membered heterocyclic ring having at least one nitrogen atom, wherein the
heterocyclic ring is unsubstituted or substituted with CO2-(C1-C6 alkyl), C(O)NH(C1-C6 alkyl),
C(O)CH2N(C1-C6 alkyl)2, C(O)(C1-C6 alkyl)CO2H, or SO2-(heteroaryl); or
(v) a 5-6 membered saturated or partially unsaturated cycloalkyl ring.
10. The compound according to any of claims 1-9, wherein R3 is H, Br, Cl, SR6, OR6,
ary], heteroaryl, or C1-C6 alkyl, wherein said aryl is optionally substituted with Cl and said alkyl
is optionally substituted with C(O)0R8, NR8R9, or OR8.
11. The compound of according to any of claims 1-10, wherein R3 is:
(i) S-Vn-aryl wherein n is 0, and aryl is phenyl optionally substituted with one or two
groups independently selected from Cl, OH, CN, CF3, CO2H, O(C1-C6 alkyl), O(C1-C6
alkyl)CO2H, O(C1-C6 alkyl)NRaRb, or O(C1-C6 alkyl)heterocycle;
(ii) S-Vn-aryl wherein n is 1, V is alkyl optionally substituted with CH2CH2NRaRb, and
aryl is phenyl optionally substituted with F, Cl, or O(C1-C6 alkyl);
(iii) S-Vn-heteroaryl wherein n is 1, V is C1-C6 alkyl optionally substituted with C1-C6
alkyl, and heteroaryl is a 5-6 membered ring having 1-2 atoms independently selected from N, S
and O;

(iv) S-Vn-heteroaryl wherein n is 1, V is C1-C6 alkyl, and heteroaryl is a 10-membered
bicyclic heteroaryl having at least one nitrogen;
(v) SR6 wherein R6 is Vn-heteroaryl,'n is 0, and the heteroaryl group is a 9-10 merabered
bicyciic heteroaromatic ring having 2-3 atoms independently selected from N, S and O, and
optionally substituted with one or two groups independently selected from I, Br, C1-C6 alkyl and
CO2H;
(vi) S-Vn-heteroaryl wherein n is 0, and heteroaryl is a 5-6 membered ring having 1-4
atoms independently selected from N and S and optionally substituted with one or two groups
independently selected from Cl, CN, C1-C6 alkyl, O-(C1-C6 alkyl), (C1-C6 aIkyl)NRaRb, (C1-C6
alkyl)CN, C(=O)O(C1-C6 alkyl), and CF3;
(vii) S-CHR6aR6b wherein R6a is piperidinyl (optionally substituted with C1-C6 alkyl, CO2-
(C1-C6 alkyl) or (C1-C6 alkyl)OH) or a structure having the formula

R6b is pyridyl, pyrimidyl, C(O)O(C1-C6 alkyl), (C1-C6 alkyl)OH, C(O)NH(C1-C6 alkyl),
C(O)NH-heterocycle, or (C1-C6 alkyl);
(viii) S-cycloalkyl,
(ix) S-heterocyclyl which is optionally substituted with oxo;
(x) S-(C1-C6 alkyl)C(O)OR8;
(xi) S-CH2C(O)-heterocycle, S-CH2C(O)-NR8(C1-C6 alkvl)NRaRb, S-CH2C(0)-NR8(C1-
C6 alky3)heterocycle, or S- (C1-C6 alkyl)NR8R9;
(xii) OH, O-(C1-C6 alkyl), O-(C1-C6 alkyl)aryl, O-(C1-C6 alkyl)heterocycle, O-(C1-C6
alkyI)NR8R9, or O-phenyl which is optionally substituted with Br;
(xiii) phenyl optionally substituted with Cl;
(xiv) a 6-membered heteroaryl having at least one nitrogen;
(xv) C1-C6 alkyl, (C1-C1 alkyl)heterocycle, (C1-C1 alkyl)heteroaryl, (C1-C1 alkyl)OH, (C1-
C1 alkyl)CO2R8, (C1-C1 aIkyl)CO2(C1-C1 alkyl), (C1-C1 alkyl)NR8R9, or (C2-C6i alkenyl)CO2R8;
or
(xvi) Br, Cl or H.

12- A composition comprising a compound according to any of claims 1-11 and a
pharmaceutically acceptable diluent or carrier.
13. A compound according to any of claims 1-11 for use in therapy.
14. The use of a compound according to any of claims 1-11 in the manufacture of a
medicaments for the treatment of a disease or condition resulting from underactivity of
glucokinase or which can be treated by activating glucokinase.
15. A method of treating disease or condition in a mammal resulting from
underactivity of glucokinase or which can be treated by activating glucokinase, comprising
administering to said mammal an effective amount of a compound according to any of claims 1-
12.
16. The method of claim 15, wherein said disease or condition is insulin-dependent
diabetes mellitus or non-insulin-dependent diabetes mellitus.
17. A method of preparing a compound of claim 1, said method comprising:
(a) reacting a compound of the formula

with a compound of the formula R1NH2 in the presence of a base catalyst or metal catalyst; or
(b) reacting a compound of the formula

with a compound of the formula R1-X, wherein X is Cl or Br, in the presence of a base catalyst or
metal catalyst; or
(c) for a compound of Formula I wherein R is
reacting a compound of the formula

with a compound of the formula R13COCHRI2X, wherein X is a leaving group, in the presence of
a base; or

(d) for a compound of Formula I wherein R1 is



reacting a compound of the formula

with a compound having the formula

where R1 is C1-C6 alkyl or aryl optionally substituted with C1-C6 alkyl, in the presence of a base;
(e) for a compound of Formula I wherein Z is SR , reacting a corresponding compound
having the formula

with a compound having the formula R X wherein X is a leaving group or atom in the presence
of abase;
(f) for a compound of Formula I wherein R1 is

reacting a corresponding compound having the formula

with a compound having the formula


at elevated temperatures; or
g) for a compound of Formula I wherein Z is CR3, reacting a corresponding compound
having the formula

wherein Xa is a leaving group or atom (e.g., a halogen such as Br, Cl or I,) with a compound
having the formula R3-Xb wherein Xb is a leaving group or atom, in the presence of a suitable
base; or
h) for a compound of Formula I wherein Z is C-SR6 and R6 is alkyl, CH2-aryl, heteroaryl,
or aryl and wherein said R groups are optionally substituted, reacting a corresponding compound
having the formula

with a compound having the formula R6-Xc wherein Xc is a leaving group or atom, in the
presence of a suitable base; or
i) for a compound of Formula I wherein L is O, reacting a corresponding compound
having the formula

with a compound having the formula R2-Xd, wherein Xd is a leaving group or atom, in the
presence of a base, or in the presence of a copper or palladium catalyst; or
j) for a compound of Formula I wherein L is O or S, reacting a corresponding compound
having the formula


wherein Xs is a leaving group or atom with a compound having the formula R2LH wherein L is O
or S, respectively; in the presence of a palladium catalyst and a suitable base; or
k) for a compound of Formula I wherein L is CH2, reacting a corresponding compound
having the formula

wherein Xf is a leaving group or atom (e.g., Cl, Br, I, OTf or acetyloxy) in the presence of an
organozinc compound having the formula R2-Zn-X8 wherein Xs is a halide, and a nickel or
palladium catalyst; and
removing any protecting group or groups and, if desired, forming a salt.

Provided are compounds of formula 1 that are useful in the treatment
and/or prevention of diseases mediated by deficient levels of glucokinase activity, such
as diabetes meilitus. Also provided are methods of treating or preventing diseases and
disorders characterized by underactivity of glucokinase or which can be treated by activating
glucokinase.

Documents:

4314-KOLNP-2008-(01-08-2014)-ABSTRACT.pdf

4314-KOLNP-2008-(01-08-2014)-ANNEXURE TO FORM 3.pdf

4314-KOLNP-2008-(01-08-2014)-CLAIMS.pdf

4314-KOLNP-2008-(01-08-2014)-CORRESPONDENCE.pdf

4314-KOLNP-2008-(01-08-2014)-FORM-2.pdf

4314-KOLNP-2008-(01-08-2014)-OTHERS.pdf

4314-KOLNP-2008-(01-08-2014)-PETITION UNDER RULE 137.pdf

4314-KOLNP-2008-(13-08-2014)CORRESPONDENCE.pdf

4314-KOLNP-2008-(13-08-2014)OTHERS.pdf

4314-kolnp-2008-abstract.pdf

4314-KOLNP-2008-ASSIGNMENT.pdf

4314-kolnp-2008-claims.pdf

4314-KOLNP-2008-CORRESPONDENCE-1.1.pdf

4314-kolnp-2008-correspondence.pdf

4314-kolnp-2008-description (complete).pdf

4314-kolnp-2008-form 1.pdf

4314-kolnp-2008-form 13.pdf

4314-KOLNP-2008-FORM 18.pdf

4314-KOLNP-2008-FORM 3-1.1.pdf

4314-kolnp-2008-form 3.pdf

4314-kolnp-2008-form 5.pdf

4314-kolnp-2008-gpa.pdf

4314-kolnp-2008-international publication.pdf

4314-kolnp-2008-international search report.pdf

4314-kolnp-2008-others.pdf

4314-kolnp-2008-pct request form.pdf

4314-kolnp-2008-specification.pdf

abstract-4314-kolnp-2008.jpg


« Previous Patent
Next Patent »
Patent Number 264070
Indian Patent Application Number 4314/KOLNP/2008
PG Journal Number 49/2014
Publication Date 05-Dec-2014
Grant Date 03-Dec-2014
Date of Filing 23-Oct-2008
Name of Patentee ARRAY BIOPHARMA INC.
Applicant Address 3200 WALNUT STREET, BOULDER, COLORADO 80301
Inventors:
# Inventor's Name Inventor's Address
1 BOYD, STEVEN, ARMEN 5665 ST, VRAIN ROAD, LONGMONT, COLORADO 80503-9061
2 CONDROSKI, KEVIN, RONALD 13892 FOX RIDGE DRIVE, BROOMFIELD, COLORADO 80020
3 HINKLIN, RONALD, JAY 3515 BLUESTEM A VENUE, LONGMONT, COLORADO 80503
4 SINGH, AJAY 2028 SOUTH EVANSTON COURT, AURORA, COLORADO 80014
5 AICHER, THOMAS, DANIEL 3070 N. TORRY'S PEAK DRIVE,SUPERIOR, COLORADO 80027
6 CHICARELLI, MARK, JOSEPH 1600 SOUTH EMERY STREET, LONGMONT, COLORADO 80501
PCT International Classification Number C07D 417/12
PCT International Application Number PCT/US2007/007444
PCT International Filing date 2007-03-23
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/785,460 2006-03-24 U.S.A.