WO2013056679A1

WO2013056679A1 - Novel heteroaryl-amino derivatives

Info

Publication number: WO2013056679A1
Application number: PCT/CN2012/083248
Authority: WO
Inventors: Bo Zhang; Jun Yang; Jinming Liu; Hai Huang; Yong Wu; Ran TAO; Jiangcheng XU; Ning SHEN; Sunghwan Moon; Maengsup KIM
Original assignee: Beijing Hanmi Pharmaceutical Co Ltd
Current assignee: Beijing Hanmi Pharmaceutical Co Ltd
Priority date: 2011-10-21
Filing date: 2012-10-19
Publication date: 2013-04-25
Anticipated expiration: 2014-04-21
Also published as: CN103059014B; CN103059014A

Abstract

Disclosed is a compound of formula (I), wherein R₁, R₂, L, R_mand R_nare as defined herein. The compound of formula (I) may be used in preventing and/or treating acyl CoA-diacylglycerol acyltransferase 1(DGAT-1) related diseases, such as obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke, hepatitis C, and the like.

Description

Novel Heteroaryl-amino Derivatives

Technical Field

The present invention relates to Novel Heteroaryl-amino Derivatives having activities as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors and the pharmaceutical compositions and use thereof.

Background

Triglycerides are the main form for storing energy in eukaryotes. In mammals, these compounds are synthesized mainly in three tissues: small intestine, liver and fat cells. Triglycerides have three main functions: absorbing fats in the diet, packaging newly synthesized fatty acids, and storing them in fat tissues (Subauste A, Burant CR, Curr Drug Targets Immune Endocr Metabol Disord., 4(3), 263-270, 2003).

Diacylglycerol acyltransferase (DGAT) is an enzyme catalyzing the formation of triglycerides in the last step of the biosynthesis of triglyceride, and mainly found in the endoplasmic reticulum of cells. DGAT is found in the microsomes of cells sap, and catalyzes the last step of the synthesis of triglycerides in the triglyceride phosphate route. DGAT is considered to be an important factor in the synthesis of triglyceride in cells, and may promote the linkage between diglyceride and fatty acid acyl co-enzyme A which finally leads to the synthesis of triglycerides. Although the rate of DGAT in catalyzing the synthesis of triglycerides is still unclear, it is well-accepted that DGAT catalyzes the synthesis of triglycerides in the last step (Richard Lehner and A. Kuksis, Progress in Lipid Research, 35(2), 169-201 , 1996).

Researchers have identified and cloned two DGAT genes, DGAT-1 and DGAT-2. Although the two kinds of proteins coded do not have sequence homology, they catalyze the same reaction. As they are similar to fatty acyl Co A cholesterol acyltransferase (AC AT) genes, DGAT-1 gene is identified and determined by searching the sequence database (Sylvaine Cases, et al, Proceedings of the National Academy of Sciences, 95(22), 13018-13023, 1998). DGAT-1 activity has been found in many mammal tissues (including fat cells, e.g. rat fat cells, differentiated 3T3-L1 fat cells, intestinal cells of small intestine and mammal glands). In addition, triglyceride is used for oxidation metabolism as a fat reserve in skeletal muscle and myocardium which also exhibit DGAT activities.

It has been found that DGAT-1 is significantly up-regulated during the differentiation of fat cells. DGAT-l-knocked-out mouse (Dgatl-/-) can survive and can synthesize triglyceride. Comparing with wild mouse, Dgatl-/- mouse exhibits lesser baseline fat tissue, and can resist obesity induced by diet. Under both normal diet and high- fat diet conditions, the metabolic rates in Dgatl-/- mouse are about 20% higher than those of wild mouse (Steven J. Smith, et al, Nature Genetics, 25(1), 87-90, 2000). The increase in the energy output in Dgatl-/- mouse is due to the increase in its physical activity. Dgatl-/- mouse also exhibits increased insulin sensitivity and glucose metabolic rate. The amount of fat in Dgatl-/- mouse decreases by about 50%; in line with this, the leptin level in Dgatl-/- mouse also decreases by 50%>.

Mouse obtained by hybridizing Dgatl-/- mouse with ob/ob exhibits ob/ob phenotype (Hubert C. Chen, et al, The Journal of Clinical Investigation, 109(8), 1049-1055, 2002). When Dgatl-/- mouse is hybridized with Agouti mouse, it exhibits decreases in body weight and normal glucose level. Comparing with wild Agouti or ob/ob mouse, hybridized mouse exhibits 79% decrease in insulin level. Transplanting fat tissue obtained from Dgatl-/- mouse to wild-type mouse may impart resistance to obesity induced by diet to the mouse, and improve its glucose metabolism (Hubert C. Chen, et al, The Journal of Clinical Investigation, 111(11), 1715-1722, 2003).

Excessive accumulation of triglycerides in fat tissue may lead to obesity and further shorten the life span of humans, and may cause a series of diseases, such as coronary heart disease, atherosclerosis, hyperlipidemia, type-II diabetes, stroke, hypertension, and even some cancers (C Ronald Kahn, Nature Genetics, 25(1), 6-7, 2000; S.Z. Yanovski and J. A. Yanovski, New England Journal of Medicine, 346(8), 591-602, 2002; Gary F. Lewis, et al, Endocrine Reviews, 23(2), 201-229, 2002; Melanie Brazil, Nature Reviews Drug Discovery, 1(6), 408, 2002; M J Malloy, J P Kane, Advances in Internal Medicine, 47, 111-136, 2001 ; Steven R. Smith, Current Drug Targets CNS Neurol. Disorder, 3(5), 431-439, 2004; Scott M. Grundy, Endrocrine, 13(2), 155-165, 2000). Accordingly, by inhibiting the synthesis of triglycerides and controlling the accumulation of triglycerides, various diseases caused by triglycerides may be prevented and/or treated and the adverse factors to the human health may be inhibited.

In addition, it has been found that DGAT-1 needs to be involved in the production of infective hepatitis C virus particles and catalyzes the synthesis of lipid droplets used for assembly instead of utilizing the lipid droplets randomly occurred around the virus; furthermore, DGAT- 1 binds to core protein of virus and concentrates the lipid droplets synthesized under the catalysis of DGAT-1 around the core protein of the virus, thereby transferring the RNA replication complex of the virus to an appropriate cite for virus assembly to conduct the assembly of the virus particles (Eva Herker, Nature Medicine, 16(11), 1295- 1298, 2010; Patrice Andre, Future Virology, 6(2), 179-182, 2011).

In summary, new drugs developed using DGAT-1 as a target and aiming at its signal transduction route may effectively inhibit the synthesis of triglycerides, and may be used in treating diseases such as obesity, hyperlipidemia, atherosclerosis, type-II diabetes, hepatitis C, and the like.

International application WO 2004/047755 relates to fused bicyclic nitrogen-containing heterocyclic compounds having DGAT inhibiting activities. International application WO 2006/004200 relates to urea and amino derivatives having DGAT-1 inhibiting activities. International application WO 2007/138304 discloses a group of 1 ,3,4-oxadiazole derivatives having DGAT- 1 inhibiting activities. Recently, Novartis AG (WO 2010/007046) has also disclosed a group of heterocyclic derivatives having DGAT-1 inhibiting activities.

In order to meet the requirements of clinical treatment, new compounds showing DGAT-1 inhibiting activities need to be developed.

Summary of the Invention

An objective of the present invention is to provide a compound as a DGAT-1 inhibitor, thereby clinically providing a new drug for treating DGAT-1 related diseases.

According to one aspect of the present invention, it relates to a compound of formula

I:

Formula I

wherein:

A independently represents C3-C₁₀ heteroaryl, wherein the heteroaryl is selected from:

B each independently represents phenyl or C5-C₆ heteroaryl;

Qi and Q₂ each independently represent -CH- or N;

Q₃ each independently represents NR₃, O or S;

Ri and R₂ each independently represent hydrogen, halogen, cyano (-CN), optionally substituted Ci-C₆ alkyl, optionally substituted Ci-C₆ alkoxy, optionally substituted mono- or di-cyclic aryl or heteroaryl, wherein the substituent is selected from one or more of halogen, hydroxy and amino, and the numbers of Ri and R₂ are independently one or two;

R₃ each independently represents hydrogen or C₁-C₄ alkyl;

R_m and R_n each independently represent hydrogen, halogen or Ci-C₆ alkyl; and the numbers of R_m and R_n are one or two;

R_x independently represents hydrogen or C₁-C₄ alkyl;

L is selected from the following formula:

wherein R₄ and R₅ each independently represent hydrogen or Ci-C₆ alkyl; or, R₄ and R₅ together form C3-C₆ eye lo alkyl,

or a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

According to one embodiment of the present invention, ring B in the above formula I independently represents phenyl or pyridinyl.

According to one embodiment of the present invention, A in the above formula I independently represents one of the following structures:

According to one embodiment of the present invention, A in the above formula I represents one of the following structures:

According to one embodiment of the present invention, in the above formula I, Ri and R₂ each independently represent hydrogen, fluoro, chloro, methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy, phenyl; R₃ independently represents hydrogen, methyl, ethyl; R_m and R_n each independently represent hydrogen, fluoro, chloro, methyl; R_x independently represents hydrogen, methyl, ethyl; L is selected from one of the following structures,

wherein R₄ and R₅ each independently represent methyl or ethyl; or R₄ and R₅ together form C₃-C₆ cycloalkyl.

According to one embodiment of the present invention, in the above formula I, L is selected from one of the following structures:

According to one embodiment of the present invention, the methylene in any of the above structures 1-6 for L is attached to O in the formula I.

According to one embodiment of the present invention, in the above formula I, the compound is selected from:

According to one embodiment of the present invention, the pharmaceutically acceptable salt of the compound of the present invention is selected from base addition salt and acid addition salt. Preferably, the base addition salt is selected from any of the group consisting of sodium, potassium, calcium, lithium, magnesium, zinc, ammonium, tetramethyl ammonium, tetraethyl ammonium, dimethyl ammonium, triethyl ammonium, trimethyl ammonium, ethyl ammonium and diethanol ammonium salts, arginine and lysine salts; and the acid addition salt is selected from any of the group consisting of hydrochloride, hydrobromide, phosphate, sulfate, mesylate and p-toluene sulfonate. More preferably, the pharmaceutically acceptable salt is selected from sodium, potassium and calcium salts.

According to another aspect of the present invention, it relates to a pharmaceutical composition, which comprises the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, and a pharmaceutically acceptable excipient.

According to another aspect of the present invention, it relates to a drug combination, which comprises the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, in combination with another drug, said another drug is selected from at least one of the following: anti-obesity drug, hypoglycemic drug, hypolipidemic drug, antihypertensive drug, coagulation regulating drug, non-steroidal anti-inflammatory drug, steroidal anti-inflammatory drug and anti hepatitis C virus drug. In the drug combination, the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, and said another drug may be formulated to a single pharmaceutical composition (a single dosage form), or may be formulated to separate pharmaceutical compositions (multiple separate dosage forms).

The anti-obesity drug includes, but is not limited to, gastrointestinal pancreatic lipase inhibitors (orlistat), central nerve inhibitors affecting the intake of food (sibutramine), and other drugs affecting nutrition absorption or energy consumption. The hypoglycemic drug includes, but is not limited to, sulfonylureas promoting insulin secretion, postprandial glucose regulators, DPP-IV (dipeptidyl peptidase-4) inhibitors, GLP-1 (glucagon- like peptide-1) agonists, insulin sensitizers including PPAR-Y (peroxisome proliferator activated receptor- Y) agonists, PPAR-a (peroxisome proliferator activated receptor-a) and PPAR-Y (peroxisome proliferator activated receptor- Y) combined agonists, biguanides deferring the uptake of glucose through the gastrointestinal tract and increasing the utilization of peripheral glucose by promoting insulin sensitivity, fructose 1 ,6-diphosphatase inhibitors, glycogen phosphorylase kinase inhibitors, glycogen synthetase inhibitors, glucorinase activators, glycoside hydrolase inhibitors, drugs hindering glucose re-absorption route in kidney such as SGLT (sodium glucose transporter) inhibitors, drugs for treating chronic complications of hyperglycemia such as aldose reductase inhibitors, and insulin drugs. The hypolipidemic drug includes, but is not limited to, HMG-CoA (P-hydroxy-P-methylglutaryl coenzyme A) reductase inhibitor (statins), PPAR-a (peroxisome proliferator activated receptor-a) agonists (fibrates), fish oils, nicotinic acid and analogues thereof, cholic acid absorption inhibitors, cholic acid multi-valent chelators, cholesterol absorption inhibitors (plant stanols or synthesized inhibitors), and the like. The antihypertensive drug includes, but is not limited to, β receptor blockers, ACE (angiotensin I converting enzyme) inhibitors, calcium-channel blockers, angiotensin II receptor antagonists, urinary system drugs, and the like. The coagulation regulating drug includes, but is not limited to, plasminogen activators, thrombin receptor antagonists, blood coagulation factor Xa inhibitors, blood coagulation factor Vila inhibitors, platelet aggregation inhibitors, anticoagulant drugs, and the like. The non-steroidal anti-inflammatory drug, the steroidal anti-inflammatory drug, and the anti hepatitis C virus drug. Preferably, said another drug is selected from hypolipidemic drugs, such as statins, fibrates, nicotinic acids, and fish oils.

According to another aspect of the present invention, the present invention relates to use of the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof in preparing a medicament for inhibiting DGAT-1 activities. In an embodiment, the medicament is for treating and/or preventing a disease, disorder or condition selected from the group consisting of obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.

According to another aspect of the present invention, the present invention relates to use of the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof in preparing a medicament for treating and/or preventing DGAT-1 related diseases. The DGAT-1 related diseases include, but not limited to obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.

According to another aspect of the present invention, the present invention relates to a method for inhibiting DGAT-1 activities, the method comprising a step of contacting the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, with the DGAT-1. The method may be used in vivo, and also can be used in vitro.

Another aspect of the present invention relates to a method for inhibiting DGAT-1 activities in a mammal, especially in human, the method comprising administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or the pharmaceutical composition or the drug combination of the present invention, to the mammal in need thereof, especially human.

Another aspect of the present invention relates to a method for treating and/or preventing DGAT-1 related diseases in a mammal, especially human, the method comprising administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or the pharmaceutical composition or the drug combination of the present invention, to the mammal in need thereof, especially human. In a specific embodiment of the present invention, the DGAT-1 related diseases are selected from obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C. Detailed Description

Definitions

Certain chemical groups named herein may be preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example; Ci-C₆ alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms, and C3-C10 heteroaryl describes a heteroaryl group, as defined below, having a total of 3 to 10 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.

In addition to the foregoing, as used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:

In the present application, as a group or a part of other groups, the term "alkyl" refers to a straight or branched radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and which is attached to the rest of the molecule by a single bond. An alkyl may have for example from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6, further preferably from 1 to 4) carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.

In the present application, as a group or a part of other groups, the term "alkoxy" refers to the group "-OR_a", wherein R_a is alkyl as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, iso-propoxy, and the like.

In the present application, as a group or a part of other groups, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, for example, having from 3 to 15 carbon atoms (preferably from 3 to 10, from 3 to 8, more preferably from 3 to 6), and which is saturated or unsaturated and attached to the rest of the molecule by a single bond through any appropriate carbon atom. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, lH-indenyl, 2,3-dihydroindenyl, 1 ,2,3,4-tetrahydro-naphthyl, 5.6.7.8- tetrahydro-naphthyl, 8,9-dihydro-7H- benzocyclohepten-6-yl,

6.7.8.9- tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyc lo [3.2.1 ] o cteny 1, adamanty 1, o ctahydro -4 , 7-methy lene- 1 H-indeny 1, octahydro-2,5-methylene-benzocyclopentadienyl, and the like.

In the present application, as a group or a part of other groups, the term "aryl" refers to a ring system radical comprising from 6 to 18 (preferably from 6 to 10) carbon atoms and at least one aromatic ring. For purposes of this invention, aryl radical may be a monocyclic, bicyc lie, tricyclic or tetracyclic ring system etc., which may include fused or bridged ring systems. The aryl radical is attached to the rest of the molecule by a single bond through an aromatic ring atom. Examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2-benzoxazolinone, 2H-1 ,4- Benzoxazin-3(4H)-on-7-yl, and the like.

In the present application, as a group or a part of other groups, the term "heteroaryl" refers to a 5- to 16-membered ring radical which includes from 1 to 15 (preferably from 1 to 10, or from 3 to 10) carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; on condition that the attachment point is an aromatic ring atom. The nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; and the nitrogen atom may be optionally quaternized. For purposes of the present invention, the heteroaryl is preferably a stable 4- to 11-membered (or 4- to 10-membered, or 4- to 9-membered) aromatic mono- or bi-cyclic radical containing from 3 to 8 carbon atoms and from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or a stable 4- to 8-membered aromatic monocyclic radical containing from 3 to 6 carbon atoms and from 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl include, but are not limited to, thiophenyl, furanyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, triazinyl, pyrimidinyl, pyridazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, phenodiazinyl, naphthyridinyl, quinazolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, thiazolyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, cinnolinyl, quinazolinyl, thienyl, indolizinyl, phenanthrolinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, benzopyridinyl, and the like.

In the present application, the term "halogen" or "halo" refers to bromo, chloro, fluoro or iodo.

In the present application, "optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "alkyl optionally substituted by one or more halogens" means that the alkyl is not substituted or is substituted by one or more halogens, and that the description includes substituted alkyl and unsubstituted alkyl.

In the present application, the term "pharmaceutically acceptable salt" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness of the free bases, without any additional biologically undesirable effects, which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, formic acid, acetic acid, trifluoro acetic acid, propionic acid, octanoic acid, caproic acid, capric acid, undecylenic acid, glycolic acid, gluconic acid, lactic acid, oxalic acid, sebacic acid, adipic acid, glutaric acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, alginic acid, ascorbic acid, salicylic acid, 4-aminosalicylic acid, naphthalene disulfonic acid, and the like.

"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness of the free acids, without any additional biologically undesirable effects. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine,

2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.

Depending on the number of the charge-carrying functional groups and the valence of the cations and the anions, the compound of the present invention may comprise multiple cations and anions.

Crystallizations often produce a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. It either reacts in a solvent or precipitates or crystallizes from the solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. The solvate of the compound of the present invention is also within the scope of the invention.

In the present application, the term "prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood, prodrug The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism. For reviews of prodrugs, see: Kevin Beaumont, et al, Current Drug Metabolism, 4(6), 461-485, 2003; Peter Ettmayer, et al, Journal of Medicinal Chemistry, 47(10), 2393-2404, 2004; Stella V.J., Expert Opinion on Therapeutic Patents, 14(3), 277-280, 2004; Jarkko Rautio, et al, Nature Review Drug Discovery, 7(3), 255-270, 2008.

It is well-known in the art that an ester of a compound which contains carboxyl group (e.g. a compound of the present invention), such as a pharmaceutically acceptable ester, may be used as a prodrug of the compound of the present invention, and it may be decomposed to the parent acid in human or animal body. The pharmaceutically acceptable ester may include, but not limited to, Ci_₆ alkyl esters such as methyl ester, ethyl ester, propyl ester, or the like; Ci _₆ alkoxymethyl esters such as methoxymethyl ester; Ci _₆ acyloxymethyl esters such as acetyloxymethyl ester; alkyl substituted formamido alkyl esters such as Ν,Ν-dimethylformamidomethyl ester and N,N-diethylformamidomethyl ester, etc (see, for example, patent document US5073641).

In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present invention and a vehicle generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a vehicle includes a pharmaceutically acceptable excipient.

In the present application, "pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by a relevant government administration as being acceptable for use in humans or domestic animals.

In the present application, "therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment of a disease, disorder or condition in the mammal, preferably a human. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the specific disease to be treated, cause of the disease, target of the drug, severity of the disease, the manner of administration, and the age, weight and body condition of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

In the present application, "drug combination" may refer to that all the active ingredients constituting the drug combination together with a excipient form a pharmaceutical composition (i.e. a single dosage form), and may also refer to that all the active ingredients constituting the drug combination form individual pharmaceutical compositions with a excipient, respectively, in which case the drug combination comprises multiple individual dosage forms.

DGAT-1 related diseases, disorders or conditions related to abnormal lipid metabolism, include but not limited to hyperlipidemia, hyperglycemia, hypertension, obesity, fatty liver, coronary disease, stroke, atherosclerosis, hepatitis C, and the like.

Specific Embodiments

According to one aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof:

Formula I

The compounds of the invention may contain one or more chiral carbon atoms, and each asymmetric carbon atom may be R or S configuration, both configurations being within the scope of the present invention. Thus, the compound may be present as enantiomer, diastereomer or mixtures thereof. The above compounds may be prepared by choosing racemates, diastereomers or enantiomers as raw materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography. See, for example, Gerald Giibitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010.

Another aspect of the present invention relates to a pharmaceutical composition, which comprises a compound of the present invention and a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention may be formulated into preparations in solid, semi- so lid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.

The pharmaceutical compositions of the invention may be prepared by methodologies well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Actual methods of preparing a pharmaceutical composition are known in the art. See, for example, The Science and Practice of Pharmacy, 20^th Edition (Philadelphia College of Pharmacy and Science, 2000).

The routes of administering the pharmaceutical composition include, without limitation, oral, topical, transdermal, intramuscular, intravenous inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. For example, dosage forms suitable for oral administration include capsule, tablet, granule, syrup, and the like. The compound of the present invention contained in these dosage forms may be in a form of solid powders or granules; solution or suspension in an aqueous or non-aqueous liquid; water-in-oil or oil-in-water emulsion; etc. The above dosage forms may be prepared by common pharmaceutical methodologies from active compounds and one or more carriers or excipients. The above carriers shall be compatible with the active compound or other excipients. For solid dosage forms, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers used for liquid dosage forms include, but are not limited to, water, physiological saline, glucose aqueous solution, ethylene glycol, polyethylene glycol, and the like. The active compound may form a solution or a suspension with the above carriers. The specific administration route and dosage form may depend on the physical and chemical properties of the compound and the severity of the disease to be treated. A person skilled in the art can determine the specific administration route depending on the above factors in combination with his own knowledge. See, for example, Jun LI, Clinical Pharmacology, People's Medical Publishing House, June 2008; Yufeng DING, Discussion on Clinical Dosage Form Factors and Drug Rational Use in Hospital, Herald of Medicine, 26(5), 2007; Howard C. Ansel, Loyd V. Allen, Jr., Nicholas G. Popovich (Eds.), Zhiqiang JIANG (Translator), Pharmaceutical Dosage Forms and Drug Delivery Systems, China Medical Science Press, May 2003.

Another aspect of the present invention relates to use of the compound of the present invention or a pharmaceutical composition of the present invention in preparing a medicament for inhibiting DGAT-1 activities and treating and/or preventing DGAT-1 related diseases. In a specific embodiment of the present invention, the DGAT-1 related diseases are selected from obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.

Another aspect of the present invention relates to a method for inhibiting DGAT-1 activities in a mammal, especially human, the method comprising administering a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition or the drug combination of the present invention to the mammal in need thereof, especially human.

Another aspect of the present invention relates to a method for inhibiting DGAT-1 activities and treating and/or preventing DGAT- 1 related diseases in a mammal, especially human, the method comprising administering a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition or the drug combination of the present invention to the mammal in need thereof, especially human. In a specific embodiment of the present invention, the DGAT-1 related diseases are selected from obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.

In one aspect, the compound or the composition of the present invention is suitable for warm-blooded animals; in another aspect, the compound or the composition of the present invention is suitable for mammals, such as human.

The composition of the present invention is formulated, quantified and administered in a way which meets the regulations of medicinal practice. The "therapeutically effective amount" of the compound of the present invention mainly depends on the factors such as the specific disease to be treated, the subject to be treated, the cause of the disease, the target of the drug, and the manner of administration.

In some embodiments, the pharmaceutical composition is in a form suitable for administration including but not limited to oral administration, parenteral administration, topical administration and rectal administration. In further or additional embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution and suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. In further or additional embodiments, the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages. In further or additional embodiments the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.002 to about 6 g/day. In further or additional embodiments the amount of compound of formula I is about 0.005 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the pharmaceutical composition is for administration to a mammal. In further or additional embodiments, the mammal is human. In further or additional embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant. In further or additional embodiments, the pharmaceutical composition further comprises at least one therapeutic agent.

In some embodiments, the composition comprising a compound of formula I is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In further or additional embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulations, solution and suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. In further or additional embodiments, the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages. In some embodiments, the individual is a mammal. In further or additional embodiments, the individual is a human. In some embodiments, the composition comprising a compound of formula I may be used in combination with an additional therapy.

The ranges of effective doses provided herein are not intended to be limiting and represent some preferred dose ranges. However, the most preferred dosage will be tailored to the individual subject, as is understood and determinable by one skilled in the relevant arts (see, e.g., Berkowet al, eds., The Merck Manual, 16^th edition, Merck and Co., Rahway, N.J., 1992). The compounds of the invention or the pharmaceutically acceptable salts, sovaltes or prodrugs thereof may be usefully combined with one or more other compounds of the invention or one or more other therapeutic agents or as any combinations thereof. The said other therapeutic agents, include, but not limited to:

1) anti-obesity drugs decreasing body weight by affecting the food intake, nutrient absorption, or energy consumption, such as orlistat and analogues;

2) anti-diabetic drugs, such as sulfonylurea drugs promoting the excretion of insulin (libenclamide, glipzide), post-prandial glucose regulators (repaglinide, nateglinide), drugs promoting the functions of incretin (DPP-IV inhibitors, GLP-1 agonist), insulin sensitizers (PPAR- γ agonists, PPAR-a and PPAR- γ dual agonists), drugs regulating liver glucose balance (metformin, fructose 1 ,6-diphosphatase inhibitors, glycogen phosphorylase kinase inhibitors, glycogen synthetase inhibitors, glucorinase activators), drugs decreasing glucose absorption in small intestine (acarbose), drugs blocking glucose re-absorption route in kidney (SGLT inhibitors) and drugs for treating chronic hyperglycemia complications (aldose reductase inhibitors);hypolipidemia drugs, such as HMG-CoA (P-hydroxy-P-methylglutaryl coenzyme A) reductase inhibitor (statins), PPAR-a (peroxisome proliferator activated receptor-a) agonist (fibrates, gemfibrozil), cholic acid multi-valent chelators (colestyramine), cholesterol absorption inhibitors (plant stanols or synthesized inhibitors), cholic acid absorption inhibitors and nicotinic acid and analogues thereof (nicotinic acid and sustained release formulations thereof);

3) antihypertensive drugs, such as β receptor blockers (atenolol, proparnolol), ACE (angiotensin I converting enzyme) inhibitors (lisinopril), calcium-channel blockers (amlodipine), angiotensin II receptor antagonists (telmisartan), urinary system drugs (furosemide, benzthiazide);

4) Anti-virus drugs, such as anti hepatitis C virus drugs (pegasys).

Preparation of the Compounds of the Present Invention

The following Reaction Schemes illustrate methods to make compounds of this invention. A person skilled in the art would understand that in the following description, combinations of substituents are permissible only if such combinations result in stable compounds.

It will also be appreciated by those skilled in the art that in the process described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein.

The use of protecting groups is described in detail in Greene, T.W. and R G. M. Wuts, Greene 's Protective Groups in Organic Synthesis (2006), 4th Ed., Wiley. The protecting group may also be a polymer resin.

The compounds of formula I of the present invention wherein R_x is H can be synthesized following the illustrative reaction schemes I and V, and a person skilled in the art can synthesize the compounds of formula I wherein R_x is C 1 -C4 alkyl by referring to these schemes.

Reaction Scheme I

P

The reaction scheme I includes the following steps:

Step 1 : a compound of formula 1 is subjected to a substitution reaction with bis(pinacolato)diboron to prepare a borate compound of formula 2.

In this step, a palladium catalyst is used, which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh₃)₂Cl₂), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh₃)₄), palladium acetate (Pd(OAc)₂), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl₂) and palladium(II) dichloride (PdCl₂). The reaction temperature may be 80°C to 160°C. The solvent which can be used in this reaction may be selected from 1 ,4-dioxane, tetrahydrofuran, toluene, and the like. The reaction is preferably conducted in the presence of a base, which may be selected from potassium acetate, sodium carbonate, potassium carbonate, and the like.

Step 2: the borate compound of formula 2 is subjected to a Suzuki coupling reaction with a compound of formula 3 to prepare a compound of formula 4.

A general description of Suzuki coupling reaction can be found in Kotha, S., et al, Tetrahedron, 58(48), 9633-9695, 2002. The reaction may be conducted in the presence of a palladium catalyst which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh₃)₂Cl₂), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh₃)₄), palladium acetate (Pd(OAc)₂), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl₂), Pd/C and palladium(II) dichloride (PdCl₂). The reaction temperature may be 80 °C to 160 °C. The solvent which can be used in this reaction may be selected from 1 ,4-dioxane, toluene, ethanol and water. The reaction is preferably conducted in the presence of a base, which is preferably an inorganic base, such as sodium carbonate, potassium carbonate, and the like.

Step 3 : the compound of formula 4 is hydro lyzed under a basic condition to give a corresponding compound of formula I(P).

The base which can be used may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like. The solvent which can be used in this reaction may be selected from methanol, ethanol, THF, water, and the like.

Reaction Scheme II

P The reaction scheme II includes the following steps:

Step 4: a compound of formula 3 is subjected to a substitution reaction with bis(pinacolato)diboron to prepare a borate compound of formula 7.

In this step, a palladium catalyst is used, which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh₃)₂Cl₂), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh₃)₄), palladium acetate (Pd(OAc)₂), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl₂) and palladium(II) dichloride (PdCl₂). The reaction temperature may be 80 °C to 160 °C. The solvent which can be used in this reaction may be selected from 1 ,4-dioxane, tetrahydrofuran, toluene, and the like. The reaction is preferably conducted in the presence of a base, which may be selected from potassium acetate, sodium carbonate, potassium carbonate, and the like.

Step 5 : the borate compound of formula 7 is subjected to a Suzuki coupling reaction with a compound of formula 1 to prepare a compound of formula 4.

The base which can be used may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like. The solvent which can be used in this reaction may be selected from methanol, ethanol, THF, water, and the like. Reaction Scheme III

reaction scheme III includes the following steps:

Step 6: the borate compound of formula 8 is subjected to a Suzuki coupling reaction with a compound of formula 3 to prepare a compound of formula 9.

A general description of Suzuki coupling reaction can be found in Kotha, S., et al, Tetrahedron, 58(48), 9633-9695, 2002. The reaction may be conducted in the presence of a palladium catalyst which may be selected from bis(triphenylphosphine) palladium(II) dichloride (Pd(PPh₃)₂Cl₂), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh₃)₄), palladium acetate (Pd(OAc)₂), [l , l'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl₂), Pd/C and palladium(II) dichloride (PdCl₂). The reaction temperature may be 80°C to 160°C. The solvent which can be used in this reaction may be selected from 1 ,4-dioxane, toluene, ethanol and water. The reaction is preferably conducted in the presence of a base, which is preferably an inorganic base, such as sodium carbonate, potassium carbonate, and the like.

Step 7: the compound of formula 10 to is subjected to a substitution reaction with a compound of formula 9 to prepare a compound of formula 4.

In this step, X is mainly selected from CI, Br, I and the reaction is generally catalyzed by base such as Na₂C0₃, K₂C0₃, Cs₂C0₃, NaOH, NaH, KOH or may not need any catalyst. The temperature of this reaction may be room temperature to 160 °C generally. The solvent which can be used in this reaction may be selected from DMF, 1 ,4-dioxane, i-propanol, ethanol, butanol, i-butanol, Ν,Ν-Dimethylacetamide, N-Methyl pyrrolidone, ethylene glycol dimethyl ether, etc. Step 3 : the compound of formula 4 is hydro lyzed under a basic condition to give a corresponding compound of formula I(P).

Examples

The experiments, synthesis methods and the related intermediates described below are illustrations of the present invention, without limiting the scope of the present invention.

The starting materials used in the experiments of the present invention were either purchased from vendors or prepared from known raw materials by standard methods. Unless otherwise indicated, the following conditions were employed in the Examples:

The unit of the temperature is degree Celsius (°C); and the room temperature is defined as 18-25°C;

The organic solvents were dried over anhydrous magnesium sulfate or anhydrous sodium sulfate; and were evaporated with rotary evaporator under reduced pressure and elevated temperature (e.g. 15 mmHg, 30 °C);

Column chromatographic isolation employed silica gel as the carrier, and TLC refers to silica gel thin layer chromatography;

Normally, the progresses of the reactions were monitored by TLC or LC-MS;

The characterizations of the final products were conducted with NMR (Bruker AVANCE 300, 300 MHz) and LC-MS (Bruker esquine 6000, Agilent 1200 series).

Example 1 :

Preparation of 3-(5-(4-(benzothiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)-2,2

-dimethylpropanoic acid

1 D Example 1

Preparation of intermediate 1A:

N-(4-bromophenyl)benzothiazol-2-ylamine

2-chlorobenzothiazole (1.24 mL, 10 mmol), 4-bromoaniline (1.72g, 10 mmol) were dissolved in ethanol, to which was added a solution of 4 N hydrochloric acid in 1 ,4-dioxane (1 mL, 4 mmol). Under microwave irradiation, the reaction proceeded at 120°C for 1 h. The mixture was cooled to room temperature and filtered. The precipitate was washed with a small amount of ethanol and dried to give 2.13 g of 1A. Yield: 70.0%. MS (ESI, m/z): [M+H]⁺: 304.9; 1H-NMR (300 MHz, OMSO-d₆): 10.62 (s, 1 H), 7.78-7.83 (m, 3H), 7.63 (d, 1H, J = 8.1 Hz), 7.51 -7.56 (m, 2H), 7.3 1 -7.36 (m, 1H), 7.15-7.20 (m, 1H).

Preparation of intermediate IB:

N-(4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl) benzothiazol-2-ylamine

Compound 1A ( 1.49 g, 4.89 mmol), bis(pinacolato)diboron (2.48 g, 9.78 mmol), palladium acetate (0.11 g, 0.49 mmol), tricyclohexylphosphine (0.27 g, 0.98 mmol) and potassium acetate (0.96 g, 9.78 mmol) were placed in a flask, to which was added 50 mL of 1 ,4-dioxane. The mixture was heated to 140 °C and reacted overnight under nitrogen protection. The mixture was cooled to room temperature and filtered to remove the solid. The filtrate was concentrated and purified with a silica gel column to give 1.53 g of compound I B. Yield: 88.9%.

MS (ESI, m/z): [M+H]⁺: 353.1 ; 1H-NMR (300 MHz, OMSO-d₆): 10.63 (s, 1 H), 7.77-7.84 (m, 3H), 7.63-7.68 (m, 3H), 7.32-7.37 (m, 1H), 7.15-7.20 (m, 1 H), 1.29 (s, 12H).

Preparation of intermediate 1 C:

3-(5-bromopyrimidin-2-yloxy)-2,2-dimethylpropanoic acid methyl ester

5-bromo-2-hydroxypyrimidine (3.5 g, 0.02 mol) and triphenylphosphine (7.86 g, 0.03 mol) were dissolved in THF. Under nitrogen protection, DIAD (4.95 mL, 0.025 mol) was added and the reaction mixture was stirred at room temperature for 1 h. Methyl hydro xypivalate (3.3 g, 0.025 mol) was dissolved in THF, and the resulting solution was added into the above reaction solution under nitrogen protection to react overnight at room temperature. The mixture was concentrated, and purified with a silica gel column to give 3.1 g of compound 1 C. Yield: 53.8%.

MS (ESI, m/z): [M+H]⁺: 290.9; 1H-NMR (300 MHz, OMSO-d₆): 8.75(s, 2H), 4.3 l (s, 2H), 3.61 (s, 3H), 1.23(s, 6H).

Preparation of Intermediate I D:

3-(5-(4-(benzothiazol-2-ylamino)phenyl)pyrimidin-2-yloxy) -2,2-dimethylpropanoic acid methyl ester

Compound I B (0.75 g, 2.1 mmol), compound 1 C (0.61 g, 2.1 mmol), palladium acetate (47 mg, 0.21 mmol), tricyclohexylphosphine ( 118 mg, 0.42 mmol) and potassium carbonate (0.57 g, 4.2 mmol) were placed in a flask, to which were added 5 mL of 1 ,4-dioxane and 1 mL of water. The reaction was carried out in a microwave reactor at 120°C for 1 h. The mixture was cooled to room temperature and then filtered to remove the solid. The filtrate was concentrated and purified with a silica gel column to give 0.24 g of compound ID. Yield: 26.2%>.

MS (ESI, m z): [M+H]⁺: 435.1 ; 1H-NMR (300 MHz, OMSO-d₆): 10.67 (s, 1 H), 8.93 (s, 2H), 7.91(d, 2H, J = 8.7 Hz), 7.82 (d, 1H, J = 7.5 Hz), 7.73 (d, 2H, J = 8.7 Hz), 7.62 (d, 1H, J = 7.8 Hz), 7.32-7.37 (m, 1H), 7.15-7.20 (m, 1H), 4.38 (s, 2H), 3.63 (s, 3H), 1.27 (s, 6H).

Preparation of Example 1 :

3-(5-(4-(benzothiazol-2-ylamino)phenyl)pyrimidin-2-yloxy) -2,2-dimethylpropanoic acid

Compound ID (239 mg, 0.55 mmol) was dissolved in methanol, to which was added 0.55 mL of 2 N sodium hydroxide solution. The mixture was heated to 50 °C and reacted for 3 h. Methanol was removed under reduced pressure. The aqueous phase was adjusted to pH = 3 with 2 N hydrochloric acid, and the resulting precipitate was filtered out. The precipitate was washed with water and dried to give 213 mg example 1. Yield: 92.2%. MS (ESI, m/z): [M+H]⁺: 421.2; 1H-NMR (300 MHz, OMSO-d₆): 10.67 (s, 1H), 8.93 (s, 2H), 7.91(d, 2H, J = 8.7 Hz), 7.82 (d, 1H, J = 7.5 Hz), 7.73 (d, 2H, J = 8.7 Hz), 7.62 (d, 1H, J = 7.8 Hz), 7.32-7.37 (m, 1H), 7.15-7.20 (m, 1H), 4.34 (s, 2H), 1.24 (s, 6H).

Example 2

Preparation of 2,2-dimethyl-3-(5-(4-(thiazolo[4,5-c]pyridin-2-ylamino)phi

pyrimidin-2-yloxy)propionic acid

Example 2

Example 2 Preparation of intermediate 2A:

thiazolo[4,5-c]pyridine-2(3H)-thione

4-Chloro-pyridin-3-ylamine (500 mg, 3.9 mmol) and ethylxanthic acid potassium salt (950 mg, 5.9 mmol) were dissolve in 6 mL of dry N-methylpyrrolidone, and heated in microwave to 150 °C and reacted under stirring for 1 h. The mixture was cooled to room temperature, to which were added 1 mL of acetic acid and 100 mL of water. The mixture was filtered, and the solid was washed with ethanol-water (1 :2) and dried to give 530 mg of black solid 2A. Yield: 80.9%.

MS (ESI, m/z): [M+H]⁺: 169.1; 1H-NMR (300 MHz, DMSC ¾): 8.52 (s, 1H ), 8.39 (d, 1H, J = 5.4 Hz), 7.81 (d, 1H, J= 5.1Hz).

Preparation of intermediate 2B:

2-chlorothiazolo[4,5-c]pyridine

Thiazolo[4,5-c]pyridine-2(3H)-thione 2A (200 mg, 1.2 mmol) and sulfonyl chloride (5 mL) were mixed and then reacted overnight at room temperature under stirring. Water was added slowly under an ice bath to remove excessive sulfonyl chloride. The solution was adjusted to pH = 7 with aq. NaOH. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated with a rotary evaporator to give 127 mg of black solid 2B. Yield: 62%.

MS (ESI, m/z): [M+H]⁺: 171.1; Ή-NMR (300 MHz, DMSC ¾): 9.24 (s, 1H), 8.59 (s, 1H), 8.20 (d, 1H, J= 5.1 Hz).

Preparation of intermediate 2C:

N-(4-bromophenyl)thiazolo[4,5-c]pyridin-2-ylamine

2-Chlorothiazolo[4,5-c]pyridine 2B (100 mg, 0.58 mmol), 4-bromoaniline (100 mg, 0.58 mmol) were mixed homogeneously, to which were added 5 mL ethanol and 0.1 mL hydrochloric acid in dixoane (4 N). The solution was heated with microwave to 120 °C and stirred for 1 h. To the reaction solution was added 5 mL of saturated sodium carbonate solution. The mixture was extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography (eluent: n-hexane/ethyl acetate = 1 : 1) to give 115 mg of yellowish solid 2C. Yield: 64.8%.

MS (ESI, m/z): [M+H]⁺: 307.9; 1H-NMR (300 MHz, DMSO-<¾): 10.87 (s, 1H), 8.83 (s, 1H), 8.29 (d, 1H, J = 5.1 Hz), 7.91 (dd, 1H, J= 0.6 Hz, J= 5.1 Hz), 7.78 (d, 2H, J = 9 Hz), 7.57 (d, 2H, J= 8.7 Hz).

Preparation of intermediate 2D:

2,2-dimethyl-3-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)oxy)propanoic acid methyl ester

Bis(pinacolato)diboron (17.6 g, 69.4 mmol),

3-(5-bromopyrimidin-2-yloxy)-2,2-dimethylpropanoic acid methyl ester 1A (10 g, 34.7 mmol), potassium acetate (10.2 g, 104.1 mmol), [Ι,Γ- bis(diphenylphosphino)ferrocene] palladium(II) dichloride dichloromethane complex (2.9 g, 3.5 mmol) were added into 120 mL of 1,4-dioxane under nitrogen protection. The reaction solution was heated to reflux overnight and then concentrated. The residue was dissolved in water, extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a silica gel column (eluent: n-hexane/ethyl acetate = 1 :4) to give 8.3 g of white solid 2D. Yield: 71.2%.

MS (ESI, m/z): [M+H]⁺: 337.1; 1H-NMR (300 MHz, CDC1₃): 8.82 (s, 2H), 4.46 (s, 2H), 3.69 (s, 3H), 1.35 (s, 12H).

Preparation of intermediate 2E:

2,2-dimethyl-3-(5-(4-(thiazolo[4,5-c]pyridin-2-ylamino)phenyl)

pyrimidin-2-yloxy) propionic acid methyl ester

N-(4-bromophenyl)-thiazolo[4,5-c]pyridin-2-yl-amine 2C (91 mg, 0.3 mmol), 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)-pyrimidin-2-yloxy)-propionic acid methyl ester 2D (100 mg, 0.3 mmol), anhydrous sodium carbonate (64 mg, 0.6 mmol), bis(triphenylphosphine) palladium(II) dichloride (5 mg, 0.007 mmol) were mixed in 5 mL of dioxane-water (8: 1), and heated with microwave to 120 °C and reacted for 1 h. The mixture was purified by column chromatography (eluent: n-hexane/ethyl acetate = 1 : 1) to give 80 mg of white solid 2E. Yield: 61.3%.

MS (ESI, m/z): [M+H]⁺: 436.3; 1H-NMR (300 MHz, DMSO-<¾): 10.90 (s, 1H), 8.92 (s, 1H), 8.85 (s, 1H), 8.29 (d, 1H, J = 5.1 Hz), 7.92 (m, 3H), 7.79 (s, 1H), 7.76 (s, 1H), 4.38 (s, 2H), 3.63 (s, 3H), 1.27 (s, 6H).

Preparation of Example 2:

2,2-dimethyl-3-(5-(4-(thiazolo[4,5-c]pyridin-2-ylamino)phenyl)

pyrimidin-2-yloxy)propionic acid

2,2-dimethyl-3-(5-(4-(thiazolo[4,5-c]pyridin-2-ylamino)phenyl) primidin-2-yloxy) propionic acid methyl ester 2E (80 mg, 0.18 mmol) was dissolved in 10 mL of ethanol, to which was added IN aqueous NaOH (2 mL). The mixture was stirred overnight at room temperature. Hydrochloric acid was added dropwise to adjust the mixture to weak acidic pH. The mixture was concentrated and filtered to give 75 mg of white solid example 2. Yield: 98%. MS (ESI, m/z): [M+H]⁺: 422.1 ; 1H-NMR (300 MHz, DMSC ¾): 12.37 (br, 1H), 11.28 (s, 1H), 8.83 (s, 2H), 8.57 (s, 1H), 8.05 (s, 1H), 7.60-7.74 (m, 5H), 4.28 (s, 2H), 1.08 (s, 6H).

Example 3

Preparation of sodium 3-((5-(4-((4-fluorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 3

Example 3

Preparation of intermediate 3A:

N-(4-bromophenyl)-4-fluorobenzothiazol-2-ylamine

2-Bromo-6-fluoroaniline (500 mg, 2.63 mmol) and potassium carbonate (5726 mg, 5.26 mmol) were placed in a flask, to which was added 10 mL of DMSO. l-Bromo-4-thiocyanato-benzene (845 mg, 3.95 mmol) was added under nitrogen protection and resulting mixture was stirred at room temperature for 30 min. Cuprous iodide (50 mg, 0.263 mmol) was added and then heated to 120 °C under nitrogen protection, and reacted overnight. The mixture was cooled to room temperature, poured into water to give a precipitate, which was filtered to give 383 mg of compound 3 A, which was used directly in the next step without further purification. Yield: 45.2%.

MS (ESI, m/z): [M+H]⁺: 324.0

Preparation of intermediate 3B:

3-((5-(4-((4-fluorobenzothiazol-2-yl)amino)phenyl)pyrimidin-2- yl)oxy)-2,2-dimethylpropionic acid methyl ester

N-(4-Bromophenyl)-4-fluorobenzothiazol-2-ylamine 3A (100 mg, 0.31 mmol), 2,2-dimethyl-3-((5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl) pyrimidin-2-yl)oxy) propionic acid methyl ester 2D (156 mg, 0.465 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene] palladium(II) dichloride (25 mg, 0.031 mmol) and sodium carbonate (66 mg, 0.62 mmol) were placed into a microwave tube, to which were added 5 mL of 1,4-dioxane and 1 mL of water. The reaction proceeded in a microwave reactor at 120 °C for 1 h. The reaction was cooled to room temperature and filtered to remove the solid. The filtrate was concentrated and isolated with a silica gel column to give 74 mg of compound 3B. Yield: 52.9%.

MS (ESI, m/z): [M+H]⁺: 453.2 Preparation of example 3C:

3-((5-(4-((4-fluorobenzothiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylprop ionic acid

3-((5-(4-((4-Fluorobenzothiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethy lpropionic acid methyl ester 3B (74 mg, 0.16 mmol) was dissolved in methanol, to which was added 0.16 mL of 2 N sodium hydroxide solution. The reaction proceeded at room temperature for 3 h. Methanol was removed under reduced pressure. The aqueous phase was adjusted to pH = 3 with 2 N hydrochloric acid, and the resulting precipitate was filtered. The precipitate was washed with water and dried to give 44 mg of compound 3C. Yield: 62.9%.

MS (ESI, m/z): [M+H]⁺: 439.3; 1H-NMR (300 MHz, DMSO- g) δ: 12.44 (s, 1H), 10.83 (s, 1H), 8.93 (s, 2H), 7.92 (d, 2H, J = 8.7 Hz), 7.78 (d, 2H, J = 9.0 Hz), 7.66-7.69 (m, 1H), 7.19-7.23 (m, 2H), 4.35 (s, 2H), 1.21 (s, 6H).

Preparation of example 3 :

sodium 3-((5-(4-((4-fluorobenzo[d]thiazol-2-yl)amino)phenyl)

pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

3-((5-(4-((4-Fluorobenzothiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)- 2,2-dimethylpropionic acid intermediate 3C (43 mg, 0.1 mmol) was dissolved in tetrahydroiuran, to which was added 0.1 mL of 1 N aqueous solution of sodium hydroxide. The reaction proceeded at room temperature for 3 h. To the reaction solution was added ethyl acetate to form a precipitate, which was then filtered. The cake was washed with 0.1 mL of water to give 45 mg of exmaple 3. Yield: 97.8%.

MS (ESI, m/z): [M+H]⁺: 439.3;

1H-NMR (300 MHz, DMSO- g) δ: 11.32 (s, 1H), 8.86 (s, 2H), 7.90 (d, 2H, J= 7.2 Hz), 7.70 (d, 2H, J= 8.7 Hz), 7.60 (d, 1H, J= 7.2 Hz), 7.10-7.20 (m, 2H), 4.30 (s, 2H), 1.10 (s, 6H).

Example 4

Preparation of 3-(5-[4-(benzoxazol-2-ylamino)phenyl]pyrimidin

-2-yloxy)-2,2-dimethylpropionic acid

Example 4

4B Example 4

paration of intermediate 4A:

3-((5-(4-aminophenyl)pyrimidin-2-yl)oxy)-2,2-dimethyl propionic acid methyl ester

4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (761 mg, 3.47 mmol), 3-(5-bromopyrimidin-2-yloxy)-2,2-dimethyl propionic acid methyl ester 1C (1 g, 3.47 mmol), tetrakis(triphenylphosphine) palladium (200 mg, 0.1735 mmol) and sodium carbonate (552 mg, 5.21 mmol) were placed in a flask and reacted at 120 °C for 8 h. The reaction was cooled to room temperature and filtered to remove the solid. The filtrate was washed with water. The organic layer was dried, concentrated, and recrystallized from methanol/water to give 760 mg of compound 4A. Yield: 72.76%.

MS (ESI, m/z): [M+H]⁺: 302.1; 1H-NMR (300 MHz, CDC1₃) δ: 8.64 (s, 2H), 7.33 (d, 2H, J = 8.4 Hz), 6.83 (d, 2H, J= 8.4 Hz), 4.42 (s, 2H), 3.71 (s, 3H), 1.36 (s, 6H).

Preparation of ntermediate 4B:

3-(5-(4-(benzoxazol-2-ylamino)phenyl)pyrimidin-2-yloxy)- 2,2-dimethylpropionic acid methyl ester

2- Chlorobenzoxazole (224 mg, 1.46 mmol) and 3-((5-(4-aminophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropionic acid methyl ester 4A (200 mg, 0.66 mmol) were dissovled in DMF and reacted at 110 °C for 3 h. The reaction mixture was cooled to room temperature, washed with water, and extracted with ethyl acetate. The organic layer was dried, concentrated, and purified with a silica gel column to give 240 mg of compound 4B. Yield: 87.0%.

MS (ESI, m/z): [M+H]⁺: 419.2.

Preparation of example 4:

3-(5-[4-(benzoxazol-2-ylamino)phenyl]pyrimidin-2-yloxy)- 2,2-dimethylpropionic acid

3- (5-(4-(Benzoxazol-2-ylamino)phenyl)pyrimidin-2-yloxy)-2,2-dimethyl propionic acid methyl ester 4B (240 mg, 0.57 mmol) was dissolved in methanol, to which was added 0.57 mL of 2 N aqueous sodium hydroxide solution. The reaction proceeded at room temperature for 3 h. Methanol was removed under reduced pressure. The aqueous solution was adjusted to pH = 3 with 2 N hydrochloric acid and the resulting precipitate was filtered. The precipitate was washed with water and dried to give 142 mg of example 4. Yield: 61.7%.

MS (ESI, m z): [M+H]⁺: 405.1; 1H-NMR (300 MHz,

δ: 12.51 (s, 1H), 10.82 (s, 1H), 8.91 (s, 2H), 7.89 (d, 2H, J = 8.7 Hz), 7.76 (d, 2H, J = 8.7 Hz), 7.50 (t, 2H, J = 7.5 Hz), 7.22-7.27 (m, 1H), 7.12-7.18 (m, 1H), 4.35 (s, 2H), 1.23 (s, 6H).

Example 5

Preparation of l-(((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyrimidin

-2-yl)oxy)methyl)cyclopropanecarboxylic acid

Example 5

Preparation of intermediate 5A:

1 -(hydro xymethyl)cyclopropanecarboxylic acid ethyl ester

Cyclopropane- 1,1-dicarboxylic acid diethyl ester (0.88 mL, 5 mmol) was dissolved in 10 mL of THE Under nitrogen protection and at room temperature, THF solution of LiAl(0-t-Bu)3H (1.1 M, 10 mL, 11 mmol) was added dropwise. The reaction solution was heated to reflux for 2 hours and it was terminated by adding saturated aqueous solution of ammonium chloride. A great amount of precipitate was produced which was filtered. The organic phase was collected, dried, evaporated, and the resulting residue purified with a silica gel column (n-hexane: ethyl acetate = 10: 1) to give 400 mg of colorless liquid 5A. Yield: 55.5%. MS (ESI, m/z): [M+H]⁺: 167.1; 1H-NMR(300MHz, CDC1₃) δ: 4.14 (q, 2H, J = 7.2 Hz), 3.54 (s, 2H), 1.38 (t, 3H, J= 7.2 Hz), 1.01-1.23 (m, 4H).

Reference: Tetrahedron Letters, 1999, 40(30), 5467-5470.

Preparation of intermediate 5B:

l-(((5-bromopyrimidin-2-yl)oxy)methyl)cyclopropane carboxylic acid ethyl ester

5-Bromo-2-hydroxypyrimidine (850 mg, 4.86 mmol) and triphenylphosphine (1.91 g, 7.3 mmol) were dissolved in THF, to which was added diisopropyl azodicarboxylate DIAL⁾ (1.19 mL, 6 mmol). The reaction solution was stirred at room temperature for 1 h, after which was added l-(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester 5A (700 mg, 4.86 mmol). The reaction proceeded overnight at room temperature under stirring. The solvents were evaporated and the residue was purified with a silica gel column (n-hexane: ethyl acetate = 20: 1) to give 580 mg of white solid 5B. Yield: 39.7%.

MS (ESI, m/z): [M+H]⁺: 300.9; 1H-NMR (300 MHz, CDC1₃): 8.55 (s, 2H), 4.53 (s, 2H), 4.16 (q, 2H, J= 7.2 Hz), 1.41(dd, 2H, J = 4.2 Hz, J = 3.0 Hz), 1.23 (t, 3H, J= 7.2 Hz), 1.06 (dd, 2H, J = 4.2 Hz, J= 3.0 Hz).

Preparation of intermediate 5C:

Ethyl- 1 -(((5 -(4-(benzo [d]thiazo l-2-ylamino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropa necarboxylate

Ethyl l-(((5-bromopyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylate 5B (68 mg, 0.22 mmol), N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2

-yl)phenyl)benzo[d]thiazol-2-amine (78 mg, 0.22 mmol), palladium acetate (4.9 mg, 0.022 mmol), tricyclohexylphosphine (12.3 mg, 0.044 mmol) and potassium carbonate (43.2 mg,0.44 mmol) were placed in a flask, to which were added 5 mL of 1,4-dioxane and 2.5 mL of water. The reaction mixture was stirred overnight at 140^°C under N₂ atmosphere. The mixture was cooled to room temperature and filtered to remove the solid. The filtrate was concentrated and purified with a silica gel column to obtain the compound 38 mg .Yield: 38.8%.

MS(ESI, m/z): [M+H]⁺ 447.2.

Preparation of compound example 5 :

l-(((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropanecar boxy lie acid

Ethyl 1 -(((5 -(4-(benzo [d]thiazo l-2-ylamino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropanecar boxylate(38 mg, 0.085 mmol) , LiOH (42 mg ,1 mmol) was added to a mixture of solvents (5 mL, THF/MeOH/H₂0 = 2:2: 1). The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was acidified to pH = 4 with 2N HC1 solution. The resulting precipitate was collected by filtration and dried to obtain 4 mg of the product. Yield: 10.2%.

MS(ESI, m/z): [M+H]⁺ 419.1; 1H-NMR (300 MHz, DMSO-<¾) δ: 12.41 (br, 1H), 8.94 (s, 2H), 7.92 (d, 2H, J= 8.7 Hz ), 7.83 (d, 1H, J= 7.5 Hz), 7.74 (d, 2H, J= 8.7 Hz ), 7.63 (d, 1H, J= 7.8 Hz), 7.31-7.38 (m, 1H), 7.15-7.20 (m, 1H), 4.44 (s, 2H), 1.35 (s, 4H).

Example 6

Preparation of l-(((5-(4-(benzothiazol-2-ylamino)phenyl)pyrimidin

-2-yl)oxy) methyl)cyclopentanecarboxylic acid

Example 6

6D Example 6

tion of intermediate 6A:

l-((benzyloxy)methyl)cyclopentanecarboxylic acid methyl ester

Cyclopentanecarboxylic acid methyl ester (1.28 g, 10 mmol) was dissolved in 20 mL of tetrahydrofuran, to which was added dropwise a tetrahydrofuran solution of KHMDS (3.0 g, 15 mmol) at -78 °C under nitrogen protection. After the addition was completed, the reaction proceeded at -78 °C for further 30 min, after which benzyl chloromethyl ether (2.03 g, 13 mmol) was added. The reaction solution was allowed to warm up to room temperature and reacted overnight. Water was added and the reaction solution was extracted with ethyl acetate. The organic phase was combined, dried, filtered, and rotary evaporated to give 1.69 g of colorless liquid 6A. Yield: 68.1%. The crude product was used directly in the next step without further purification.

MS (ESI, m/z): [M+H]⁺: 249.1.

Preparation of intermediate 6B:

1 -(hydro xymethyl)cyclopentanecarboxylic acid methyl ester

To an ethanol solution of the compound l-((benzyloxy)methyl)

cyclopentanecarboxylic acid methyl ester 6A (1.69 g, 6.81 mmol) were added Pd/C (0.17 g, 10% w/w) and 1 mL of hydrochloric acid. The catalyzed hydrogenation proceeded for 1 day. The reaction solution was filtered and the crude product isolated by column chromatography to give 663 mg colorless liquid 6B. Yield: 61.4%.

MS (ESI, m/z): [M+H]⁺: 180.9; 1H-NMR (300 MHz, CDC1₃) δ: 3.71 (s, 3H), 3.57 (s, 2H), 2.42 (s, 1H), 1.92-2.00 (m, 2H), 1.64-1.78 (m, 6H).

Reference: Bioorganic & Medicinal Chemistry Letters, 2010, 20(8), 2617-2621. Preparation of intermediate 6C:

l-(((5-bromopyrimidin-2-yl)oxy)methyl)cyclopentanecarboxylic acid methyl ester

5-bromopyrimidin-2-ol (354 mg, 2.24 mmol) and

1 -(hydro xymethyl)cyclopentanecarboxylic acid methyl ester 6B (395 mg, 2.04 mmol) were placed in a flask, to which were added 10 mL of tetrahydrofuran and sodium hydroxide (163 mg, 4.08 mmol). The reaction proceeded at 80 °C for 3 h. After cooling to room temperature, the solid was removed by filtration. The filtrate was concentrated, and the residue was purified with a silica gel column to give 468 mg of compound 6C. Yield: 73.0%>.

MS (ESI, m/z): [M+H]⁺: 315.0.

Preparation of intermediate 6D:

l-(((5-(4-(benzothiazol-2-ylamino)phenyl)pyrimidin-2-yl) oxy)methyl) cyclopentanecarboxylic acid methyl ester

N-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-phenyl)-benzothiazol-2-ylamine IB (100 mg, 0.28 mmol), l-(((5-bromopyrimidin-2-yl)oxy)methyl) cyclopentanecarboxylic acid methyl ester 6C (74 mg, 0.24 mmol), palladium acetate (5 mg, 0.024 mmol), tricyclohexylphosphine (13 mg, 0.048 mmol) and potassium acetate (47 mg, 0.48 mmol) were placed in a flask, to which were added 5 mL of 1,4-dioxane and 1 mL of water. The reaction proceeded in a microwave reactor at 120 °C for 1 h. After cooling to room temperature, the solid was removed by filtration. The filtrate is concentrated and isolated with a silica gel column to give 30 mg of compound 6D. Yield: 27.3%.

MS (ESI, m/z): [M+H]⁺: 461.2.

Preparation of example 6:

l-(((5-(4-(benzothiazol-2-ylamino)phenyl)pyrimidin-2-yl)oxy)

methyl)cyclopentanecarboxylic acid

l-(((5-(4-(Bbenzothiazol-2-ylamino)phenyl)pyrimidin-2-yl)oxy)methyl)

cyclopentanecarboxylic acid methyl ester 6D (30 mg, 0.065 mmol) was dissolved in methanol, to which was added 0.16 mL of 2 N sodium hydroxide solution. The reaction proceeded at room temperature for 3 h. Methanol was removed under reduced pressure. The aqueous layer was adjusted to pH = 3 with 2 N hydrochloric acid and the resulting precipitate was filtered. The precipitate was washed with water and dried to give 18 mg of example 6. Yield: 60.0%.

MS (ESI, m/z): [M+H]⁺: 447.2; 1H-NMR (300 MHz, DMSO- g) δ: 12.39 (s, 1H), 10.83 (s, 1H), 8.92 (s, 2H), 7.95 (d, 2H, J = 8.7 Hz), 7.83 (d, 1H, J = 7.5 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.34 (t, 1H, J = 7.2 Hz), 7.18 (t, 1H, J = 7.8 Hz), 4.41 (s, 2H), 1.99-2.08 (m, 2H), 1.67-1.71 (m, 6H).

Example 7

Preparation of 3-(5-(4-(4-chlorobenzo[d]thiazol-2-ylamino)phenyl)

pyrimidin-2-yloxy)-2,2-dimethylpropanoic acid

xamp e

The title compound was synthesized from intermediate 7C (methyl

3 -(5 -(4-(4-chlorobenzo [d]thiazo l-2-ylamino)phenyl)pyrimidin-2-yloxy)

-2,2-dimethylpropanoate) using a hydrolysis procedure similar to that described for

Example 1. The intermediate 7C was synthesized from intermediate 7B

(4-chloro-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-

2-yl)phenyl)benzo[d]thiazol-2-amine) and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 7C (ESI, m/z): [M+H]⁺: 469.1). The intermediate 7B was synthesized from 7A

(N-(4-bromophenyl)-4-chlorobenzo[d]thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The MS data for 7B (ESI, m/z): [M+H]⁺: 387.1). The intermediate 7A was synthesized from 2,4-dichlorobenzo[d]thiazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 7A (ESI, m z): [M+H]⁺: 338.9).

The MS and 1H-NMR data for Example 7:

MS (ESI, m/z): [M+H]⁺: 455.2; 1H-NMR (300 MHz, DMSO- g) δ: 12.41 (s, 1H), 10.88 (s, 1H), 8.93 (s, 2H), 7.96 (d, 2H, J= 8.7 Hz), 7.77-7.83 (m, 3H), 7.42-7.45 (dd, 1H, J= 8.1 Hz, J = 0.9 Hz), 7.17 (t, 1H, J= 8.1 Hz), 4.34 (s, 2H), 1.24 (s, 6H).

Example 8

Preparation of 2,2-dimethyl-3-((5-(4-((6-methylbenzo[d]thiazol-2-yl)

amino)phenyl)pyrimidin-2-yl)oxy)propanoic acid

The title compound was synthesized from intermediate 8C (methyl 2,2-dimethyl-3-((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)phenyl)

pyrimidin-2-yl)oxy)propanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 8C was synthesized from intermediate 8B

(6-methyl-N-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)benzo[d]thiazol-2-a mine) and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 8C (ESI, m/z): [M+H]⁺: 449.2). The intermediate 8B was synthesized from 8A

(N-(4-bromophenyl)-6-methylbenzo[d]thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The MS data for 8B (ESI, m/z): [M+H]⁺: 367.2). The intermediate 8Awas synthesized from 2-chloro-6-methylbenzo[d]thiazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 8 A MS (ESI, m z): [M+H]⁺: 319.2).

The MS and 1H-NMR data for Example 8:

MS (ESI, m/z): [M+H]⁺: 435.1; 1H-NMR (300 MHz, CD₃OD) δ: 8.83 (s, 2H), 7.87 (d, 2H, J = 8.7 Hz), 7.66 (d, 2H, J= 8.7 Hz), 7.51 (d, 1H, J= 8.4 Hz), 7.18 (d, 1H, J= 8.7 Hz), 4.48 (s, 2H), 1.34 (s, 6H).

Example 9

Preparation of 3-((5-(4-((5-fluorobenzo[d]thiazol-2-yl)amino)phenyl)

pyrimidin-2-yl)oxy)-2,2-dimeth lpropanoic acid

Example 9

The title compound was synthesized from intermediate 9B (methyl 3-((5-(4-((5-fluorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropan oate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 9B was synthesized from intermediate 9A

(N-(4-bromophenyl)-5-fluorobenzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 2E in Example 2 (the MS and 1H-NMR data for 9B: MS (ESI, m/z): [M+H]⁺: 453.2; 1H-NMR (300 MHz, DMSO-d₆) δ: 10.76 (s, 1H), 8.92 (s, 2H), 7.90 (d, 2H, J = 9.0 Hz), 7.82-7.87 (m, 1H), 7.76 (d, 2H, J = 9.0 Hz ), 7.45-7.49 (m, 1H), 7.01-7.08 (m, 1H), 4.38 (s, 2H), 3.63 (s, 3H), 1.27 (s, 6H).).

The intermediate 9A was synthesized from 5-fluoro-2-iodoaniline and

l-bromo-4-thiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3A in Example 3 (the MS data for 9A: MS (ESI, m/z): [M+H]⁺: 323.1).

The MS and 1H-NMR data for Example 9:

MS (ESI, m z): [M+H]⁺: 439.1 ; 1H-NMR (300 MHz,

δ: 12.44 (s, 1H), 10.77 (s, 1H), 8.92 (s, 2H), 7.90 (d, 2H, J= 9.0 Hz), 7.82-7.87 (m, 1H), 7.76 (d, 2H, J= 8.7Hz ), 7.45-7.49 (m, 1H), 7.01-7.08 (m, 1H), 4.35 (s, 2H), 1.24 (s, 6H).

Example 10

Preparation of l-(((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyrimidin

-2-yl)oxy)methyl)cyclohexanecarboxylic acid

Example 10

The title compound was synthesized from intermediate 10B (ethyl

l-(((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexanecarboxyla te) using a hydrolysis procedure similar to that described for Example 1. The intermediate 10B was synthesized from intermediate 1 OA (ethyl l-(((5-bromopyrimidin-2-yl)oxy)methyl) cyclohexanecarboxylate) and IB following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 10B (ESI, m/z): [M+H]⁺: 489.2) The intermediate 1 OA was synthesized from 5-bromopyrimidin-2-ol and ethyl

cyclohexanecarboxylate using a similar synthetic procedure that was described for intermediate

6C in Example 6 (The MS and 1H-NMR data for 10A (ESI, m/z): [M+H]⁺: 343.1; 1H-NMR (300 MHz, CDCls) δ: 8.50 (s, 2H),4.38 (s,2H),4.19 (m, 2H),1.22-1.59 (m, 13H)). The MS and 1H-NMR data for Example 10:

MS (ESI, m/z): [M+H]⁺: 461.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 12.40 (s, 7H), 10.66 (s, 7H), 8.91 (s, 2H), 7.93 (d, 2H, J= 8.7 Hz), 7.84 (d, 1H, J= 7.5 Hz), 7.76 (d, 2H, J= 8.7 Hz), 7.65 (d, 1H, J= 7.8 Hz), 7.34 (t, 1H, J= 7.2 Hz), 7.18 (t, 1H, J= 7.8 Hz), 4.38 (s, 2H), 1.56 (m, 10H).

Example 11

Preparation of 3-(5-(2-fluoro-4-(l-methyl-lH-benzo[d]imidazol-2- ylamino)phenyl)pyrimidin-2- loxy)-2,2-dimethylpropanoic acid

Example 11

The title compound was synthesized from intermediate 11B (methyl

3-(5-(2-fluoro-4-(l -methyl- lH-benzo[d]imidazol-2-ylamino)phenyl)pyrimidin-2-yloxy)-2,2-di methylpropanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 11B was synthesized from intermediate 11A

(N-(4-bromo-3-fluorophenyl)- 1 - methyl-lH-benzo[d]imidazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 11B MS (ESI, m/z): [M+H] : 450.2). The intermediate 11A was synthesized from

2-bromo-l-methyl-lH-benzo[d]imidazole and 4-bromo-3-fluoroaniline using a similar synthetic procedure that was described for intermediate 4B in Example 4 (The MS data for 11A (ESI, m/z): [M+H] : 321.9).

The MS and 1H-NMR data for Example 11 :

MS (ESI, m z): [M+H]⁺: 436.2; 1H-NMR (300 MHz, DMSO-<¾) δ: 12.42 (s, 1H), 9.81 (s, 1H), 8.80 (s, 2H), 8.00 (d, 1H, J= 13.8 Hz), 7.65 (d, 2H, J= 5.4 Hz), 7.41-7.46 (m, 2H), 7.15-7.18 (m, 2H), 4.36 (s, 2H), 3.77 (s, 3H), 1.24 (s, 6H). Example 12

Preparation of methyl 2,2-dimethyl-3-((5-(4-(quinazolin-2-ylamino)

yl)pyrimidin-2-yl)oxy)propanoic acid

Example 12

The title compound was synthesized from intermediate 12B (methyl

2,2-dimethyl-3-((5-(4-(quinazolin-2-ylamino)phenyl)pyrimidin-2-yl)oxy)propanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 12B was synthesized from intermediate 12A and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 2E in Example 2 (The MS data for 12B: MS (ESI, m/z): [M+H]⁺: 430.2).

The intermediate 12A was synthesized from 2-chloroquinazoline and 4-bro mo aniline similar to that described for intermediate 1 A in Example 1.

The MS and 1H-NMR data for Example 12:

MS (ESI, m/z): [M+H]⁺: 416.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 12.45 (s, 1H), 10.08 (s, 1H), 9.35 (s, 1H), 8.92 (s, 2H), 8.14 (d, 2H, J=4.8 Hz), 7.95 (d, lH, J=8.7Hz), 7.81-7.86 (m ,1H), 7.68-7.74 (m, 3H,), 7.39-7.44 (m, 1H), 4.34 (s, 2H), 1.24 (s, 6H).

Example 13

Preparation of (l s,4s)-4-((5-(4-(benzo[d]thiazol-2-ylamino)ph<

pyrimidin-2-yl)oxy)cyclohexanecarboxylic acid

Example 13

The title compound was synthesized from intermediate 13B ((ls,4s)-ethyl

4-((5 -(4-(benzo [d]thiazo l-2-ylamino)phenyl)pyrimidin -2-yl)oxy)cyclohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 13B was synthesized from intermediate 13A ((ls,4s)-ethyl 4-((5 -bromopyrimidin

-2-yl)oxy)cyclohexanecarboxylate) and intermediate IB following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 13B (ESI, m/z): [M+H] : 475.1). The intermediate 13A was synthesized from (lr, 4r)-ethyl

4-hydroxycyclohexanecarboxylate and 5-bromopyrimidin-2-ol using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 13 A: (ESI, m/z): [M+H]⁺: 239.3;

¹ H-NMR (300 MHz, CDC1₃) δ: 8.50 (s,2H), 5.12-5.16 (m,lH), 4.17 (m, 2H), 2.23-2.45 (m,lH), 2.01-2.09 (m,4H),1.76-1.81(m,4H), 1.28 (m, 3H)).

The MS and ¹ H-NMR data for Example 13:

MS (ESI, m z): [M+H]⁺: 447.2; ¹ H-NMR (300 MHz, DMSO- g) δ: 8.90 (s, 2H), 7.93 (d, 2H, J= 8.7 Hz), 7.84 (d, 1H, J= 7.8 Hz), 7.75 (d, 2H, J= 8.7Hz), 7.65 (d, 1H, J= 7.8 Hz), 7.37 (t, 1H, J= 7.2 Hz, J= 7.2 Hz), 7.20 (t, 1H, J= 7.8 Hz), 3.36 (m, 1H), 2.40 (m, 1H), 1.8 (m, 8H). Example 14

Preparation of sodium 2,2-dimethyl-3-((5-(4-(thiazol-2-ylamino)

phenyl)pyrimidin-2-yl)oxy ropanoate

Example 14

The title compound was synthesized from intermediate 14C (methyl

2,2-dimethyl-3-((5-(4-(thiazol-2-ylamino)phenyl)pyrimidin-2-yl)oxy)propanoate) using a procedure similar to that described for Example 3. The intermediate 14C was synthesized from intermediate 14B

(N-(4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-amine) and intermediate 1C following a Suzuki coupling procedure similar to that described for

intermediate ID in Example 1 (The MS data for 14C (ESI, m z): [M+H]⁺: 385.1). The intermediate 14B was synthesized from 14A (N-(4-bromophenyl)thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The MS data for 14B (ESI, m/z): [M+H]⁺: 303.2). The intermediate 14Awas synthesized from 2-chlorothiazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 14A (ESI, m/z): [M+H]⁺: 257.0).

The MS and 1H-NMR data for Example 14:

MS (ESI, m/z): [M+H]⁺: 371.1 ; 1H-NMR (300 MHz, DMSO-d₆) δ: 10.51 (s, 1H), 8.83 (s, 2H), 7.76 (d, 2H, J= 8.7 Hz), 7.55 (d, 2H, J= 8.7 Hz), 7.28 (d, 1H, J= 3.9 Hz), 6.93 (d, 1H, J= 3.6 Hz), 4.28 (s, 2H), 1.09 (s, 6H).

Example 15

Preparation of 3-((5-(4-((4,6-difluorobenzo[d]thiazol-2-yl)

phenyl)pyrimidin-2-yl)ox -2,2-dimethylpropanoic acid

Example 15

The title compound was synthesized from intermediate 15B (methyl

3-((5-(4-((4,6-difluorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpro panoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 15B was synthesized from intermediate 15 A

(N-(4-bromophenyl)-4,6-difluorobenzo[d]

thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 2E in Example 2 (The MS data for 15B: MS (ESI, m z): [M+H]⁺:

471.1).

The intermediate 15Awas synthesized from 2,4-difluoro-6-iodoaniline and

l-bromo-4-thiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3A in Example 3 (The MS data for 15A: MS (ESI, m/z): [M+H]⁺: 341.0).

The MS and 1H-NMR data for Example 15: MS (ESI, m/z): [M+H]⁺: 457.2; 1H-NMR (300 MHz, DMSO- g) δ: 12.42 (s, 1H), 10.81 (s, 1H), 8.92 (s, 2H), 7.89 (d, 2H, J= 8.7 Hz), 7.78 (d, 2H, J= 9.0 Hz ), 7.65-7.69 (m, 1H), 7.25-7.33 (m, 1H), 4.35 (s, 2H), 1.24 (s, 6H).

Example 16

Preparation of l-(((5-(4-((6-methoxybenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)meth l)cyclohexanecarboxylic acid

Example 16

The title compound was synthesized from intermediate 16C (ethyl

l-(((5-(4-((6-methoxybenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexa necarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 16C was synthesized from intermediate 16B

(6-methoxy-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]thiazol-2-amine) and intermediate 10A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 16C (ESI, m/z): [M+H]⁺: 519.2). The intermediate 16B was synthesized from 16A

(N-(4-bromophenyl)-6-methoxybenzo[d]thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The MS data for 16B (ESI, m z): [M+H]⁺: 383.2). The intermediate 16Awas synthesized from 2-chloro-6-methoxybenzo[d]thiazole and

4-bromoaniline using a similar synthetic procedure that was described for intermediate 1 A in

Example 1 (The MS data for 16A (ESI, m/z): [M+H] : 335.2).

The MS and 1H-NMR data for Example 16:

MS (ESI, m/z): [M+H]⁺: 491.3; 1H-NMR (300 MHz,

δ: 8.89 (s, 2H), 7.89 (d, 2H, J= 8.7 Hz), 7.74 (d, 2H, J =8.7 Hz), 7.56 (d, 1H, J= 8.7 Hz), 7.47 (d, 1H, J= 2.7 Hz), 6.96 (dd, 1H, J= 2.4 Hz, J= 8.7 Hz), 4.36 (s, 2H), 3.78 (s, 3H), 1.4 (m, 10H). Example 17

Preparation of (l s,4s)-4-((5-(4-((6-methoxybenzo[d]thiazol-2-yl)

amino)phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylic acid

Example 17

The title compound was synthesized from intermediate 17A ((ls,4s)-ethyl

4-((5-(4-((6-methoxybenzo[d]thiazol-2-yl)amino)phenyl)

pyrimidin-2-yl)oxy)cyclohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 17A was synthesized from intermediate 13 A and intermediate 16B following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 17 A MS (ESI, m/z): [M+H]⁺: 505.1).

The MS and 1H-NMR data for Example 17:

MS (ESI, m/z): [M+H]⁺: 477.2; 1H-NMR (300 MHz, DMSO-<¾) δ: 8.89 (s, 2H), 7.89 (d, 1H, J = 8.7 Hz), 7.73 (d, 1H, J= 8.7 Hz), 7.56 (d, 1H, J= 8.7 Hz), 7.47 (d, 1H, J= 2.7 Hz), 6.96 (dd, 1H, J= 2.7 Hz, J= 8.7 Hz), 3.82 (s, 3H), 3.72 (m, 1H), 2.40 (m, 1H), 1.81 (m, 8H).

Example 18

Preparation of l-(((5-(4-((6-cyanobenzo[d]thiazol-2-yl)amino

)phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexanecarboxylic acid

Example 18

The title compound was synthesized from intermediate 18C (ethyl

l-(((5-(4-((6-cyanobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexane carboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 18C was synthesized from intermediate 18B (2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)benzo[d]thiazole-6-carbonitr ile) and intermediate 10A following a Suzuki coupling procedure similar to that described for intermediate ID in Example l(The MS data forl8C: MS (ESI, m/z): [M+H]⁺: 514.3).

The intermediate 18B was synthesized from 18 A

(2-((4-bromophenyl)amino)benzo[d]thiazole-6-carbonitrile) using a similar procedure described for intermediate IB in Example 1 (The MS data forl8B: MS (ESI, m/z): [M+H]⁺:378.1). The intermediate 18Awas synthesized from 4-amino-3-iodobenzonitrile and

l-bromo-4-isothiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3A in Example 3 (The MS data for 18A: MS (ESI, m z): [M+H]⁺: 329.9).

The MS and 1H-NMR data for Example 18:

MS (ESI, m/z): [M+H]⁺: 486.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 12.42 (s, 1H), 11.06 (s, 1H), 8.92 (s, 2H), 8.38 (s, 1H), 7.92 (d, 2H, J = 8.7 Hz), 7.75-7.79 (m, 4H), 4.38 (s, 2H), 1.99-2.03 (m, 2H), 1.25-1.56 (m, 8H).

Example 19

Preparation of l-(((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexanecarboxylic acid

Example 19

The title compound was synthesized from intermediate 19A (ethyl

l-(((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexan ecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 19A was synthesized from intermediate 8B and intermediate 1 OA following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 19A: (ESI, m/z): [M+H] : 503.2).

The MS and 1H-NMR data for Example 19:

MS (ESI, m/z): [M+H]⁺: 475.2; 1H-NMR (300 MHz,

δ: 8.80 (s, 2H), 7.86 (d, 2H, J= 8.7 Hz), 7.64 (d, 2H, J= 8.4 Hz), 7.50 (d, 2H, J= 8.4 Hz), 7.17 (d, 1H, J= 9.0 Hz), 4.49 (s, 2H), 1.44 (m, 9H).

Example 20

Preparation of sodium 3-(5-(3-fluoro-4-(l-methyl- lH-benzo

[d]imidazol-2-ylamino)phenyl rimidin-2-yloxy)-2,2-dimethylpropanoate

Example 20

The title compound was synthesized from intermediate 20B (methyl

3-(5-(3-fluoro-4-(l -methyl- lH-benzo[d]imidazol-2-ylamino)phenyl)pyrimidin-2-yloxy)-2,2-di methylpropanoate) using a procedure similar to that described for Example 3. The intermediate 20B was synthesized from intermediate 20A

(N-(4-bromo-2-fluorophenyl)-l-methyl-lH-benzo[d]imidazol-2-amine) and 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 20B: (ESI, m/z): [M+H] : 450.2). The intermediate 20A was synthesized from 2-bromo-l-methyl-lH-benzo[d]imidazole and 4-bromo-2-fluoroaniline using a similar synthetic procedure that was described for intermediate IB in Example 1 (The MS data for 20A (ESI, m/z): [M+H] : 321.9).

The MS and 1H-NMR data for Example 20:

MS (ESI, m/z): [M+H]⁺: 436.2; 1H-NMR (300 MHz, DMSO-<¾) δ: 8.92 (s, 2H), 8.49 (s, 1H), 7.70 (d, 1H, J= 12.9 Hz), 7.56 (d, 1H, J= 8.4 Hz), 7.32 (s, 1H), 7.07 (d, 2H, J= 2.7 Hz), 4.32 (s, 2H), 3.71 (s, 3H), 1.11 (s, 6H)

Example 21

Preparation of l-(((5-(4-((6-cyanobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexanecarboxylic acid

Example 21

The title compound was synthesized from intermediate 21 A (methyl

l-(((5-(4-((6-cyanobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopentan ecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 21 A was synthesized from intermediate 18B and intermediate 6C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 21A: MS (ESI, m/z): [M+H]⁺: 486.2).

The MS and 1H-NMR data for Example 21 :

MS (ESI, m/z): [M+H]⁺: 472.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 12.39 (s, 1H), 11.04 (s, 1H), 8.92 (s, 2H), 8.38 (s, 1H), 7.92 (d, 2H, J= 8.7 Hz), 7.74-7.79 (m, 4H), 4.41 (s, 2H), 2.04-2.08 (m, 2H), 1.67-1.71 (m, 6H).

Example 22

Preparation of (l s,4s)-4-((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylic acid

The title compound was synthesized from intermediate 22 A ((ls,4s)-ethyl

4-((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)phenyl)

pyrimidin-2-yl)oxy)cyclohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 22 A was synthesized from intermediate 13 A and intermediate 8B following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 22A (ESI, m z): [M+H]⁺: 489.2).

The MS and 1H-NMR data for Example 22: MS (ESI, m/z): [M+H]⁺: 461.2; 1H-NMR (300 MHz, DMSO- g) δ: 12.21 (s, 1H), 11.46 (s, 1H), 8.94 (s, 2H), 8.42 (s, 1H), 7.94 (d, 2H, J= 8.7 Hz), 7.76 (m, 4H), 5.19 (s, 1H), 2.56 (s, 1H), 1.62-1.97 (m, 9H).

Example 23

Preparation of sodium sodium 3-((5-(4-(benzo[d]thiazol -2-ylamino)

-2,5-difluorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 23

The title compound was synthesized from intermediate 23 B (methyl

3- ((5-(4-(benzo[d]thiazol-2-ylamino)-2,5-difluorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethy lpropanoate) using a procedure similar to that described for Example 3. The intermediate 23B was synthesized from intermediate 23A (N-(4-bromo-2,5-difluorophenyl)

benzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 23B (ESI, m z): [M+H]⁺: 471.2). The intermediate 23Awas synthesized from 2-chlorobenzo[d]thiazole and

4- bromo-2,5-difluoroaniline using a similar synthetic procedure that was described for intermediate 1A in Example 1 (The MS data for 23A (ESI, m/z): [M+H]⁺: 339.3).

The MS and 1H-NMR data for Example 23:

MS (ESI, m/z): [M+H]⁺: 455.2; 1H-NMR (300 MHz, DMSO-<¾) δ: 8.76 (s, 2H), 8.63 (dd, 1H, J= 7.2 Hz, J= 13.8 Hz), 7.71 (m, 1H), 7.53 (m, 2H), 7.27 (t, 1H, J= 15.3 Hz), 7.08 (t, 1H, J = 6.9 Hz, J= 14.1 Hz), 4.30 (s, 2H), 1.10 (s, 6H).

Example 24

Preparation of l-(((5-(4-((6-cyanobenzo[d]thiazol-2-yl)amino

pyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylic acid

Example 24

The title compound was synthesized from intermediate 24A (ethyl

l-(((5-(4-((6-cyanobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropan ecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 24A was synthesized from intermediate 18B and intermediate 5B following a Suzuki coupling procedure similar to that described for intermediate ID in Example l(The MS data for 24A: MS (ESI, m/z): [M+H]⁺: 472.2).

The MS and 1H-NMR data for Example 24:

MS (ESI, m/z): [M+H]⁺: 444.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 12.48 (s, 1H), 11.06 (s, 1H), 8.93 (s, 2H), 8.38 (s, 1H), 7.92 (d, 2H, J= 8.7 Hz), 7.78 (d, 2H, J= 8.7 Hz), 7.75 (s, 2H), 4.45 (s, 2H), 1.22-1.24 (m, 2H), 1.06-1.07 (m, 2H).

Example 25

Preparation of l-(((5-(4-((6-methoxybenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylic acid

Example 25

The title compound was synthesized from intermediate 25 A (ethyl

l-(((5-(4-((6-methoxybenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cycloprop anecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 25 A was synthesized from intermediate 16B and intermediate 5B following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 25A(ESI, m z): [M+H]⁺: 477.1).

The MS and 1H-NMR data for Example 25: MS (ESI, m/z): [M+H]⁺: 449.2; 1H-NMR (300 MHz, DMSO- g) δ: 8.84 (s, 2H), 7.91 (d, 1H, J= 8.7 Hz), 7.68 (d, 1H, J= 8.7 Hz), 7.55 (d, 1H, J= 8.7 Hz), 7.36 (d, 1H, J= 2.7 Hz), 6.97 (dd, lH, J= 2.7 Hz, J= 8.7 Hz), 4.31 (s, 2H), 3.50 (s, 3H), 1.27 (s, 4H).

Example 26

Preparation of sodium 2,2-dimethyl-3-(5-(4-(4-phenylthiazol-2-yl

amino)phenyl)pyrimidin-2-yloxy)propanoate

Example 26

The title compound was synthesized from intermediate 26B (methyl

2,2-dimethyl-3-(5-(4-(4-phenylthiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)propanoate) using a procedure similar to that described for Example 3. The intermediate 26B was

synthesized from intermediate 26A (N-(4-bromophenyl)-4-phenylthiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 26B MS (ESI, m/z): [M+H]⁺: 461.2). The intermediate 26A was synthesized from 2-chloro-4-phenylthiazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 4B in Example 4 (The MS data for 26A MS (ESI, m/z): [M+H]⁺: 332.9).

The MS and 1H-NMR data for Example 26:

MS (ESI, m z): [M+H]+: 447.2; 1H-NMR (300 MHz, DMSO-<¾) δ: 10.70 (s, 1H), 8.86 (s, 2H), 7.95 (d, 2H, J= 7.2 Hz), 7.88 (d, 2H, J= 8.4Hz), 7.71 (d, 2H, J= 8.7 Hz), 7.45 (t, 2H, J= 7.5 Hz), 7.38 (s, 1H), 7.32 (t, 1H, J= 7.5 Hz), 4.30 (s, 2H), 1.10 (s, 6H).

Example 27

Preparation of l-(((5-(4-((4-chlorobenzo[d]thiazol-2-yl)amino)phenyl) pyrimidin-2-yl)oxy)methyl)cyclopentanecarboxylic acid

Example 27

The title compound was synthesized from intermediate 27A (methyl

l-(((5-(4-((4-chlorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopentan ecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 27A was synthesized from intermediate 7B and intermediate 6C following a Suzuki coupling procedure similar to that described for intermediate ID in Example l(The MS data for 27A: MS (ESI, m/z): [M+H]⁺:495.2).

The MS and 1H-NMR data for Example 27:

MS (ESI, m/z): [M+H]⁺: 481.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 12.38 (s, 1H), 10.90 (s, 1H), 8.93 (s, 2H), 7.96 (d, 2H, J= 9.0 Hz), 7.80 (m, 3H), 7.44 (d, 1H, J= 7.2 Hz), 7.17 (t, 1H, J = 8.1 Hz), 4.41 (s, 2H), 1.99-2.08 (m, 2H), 1.67-1.71 (m, 6H).

Example 28

Preparation of 3-((5-(5-(benzo[d]thiazol-2-ylamino)pyridin-2-yl)

pyrimidin-2-yl)oxy)-2,2-dimethylpropanoic acid

Example 28

The title compound was synthesized from intermediate 28B (methyl

3-((5-(5-(benzo[d]thiazol-2-ylamino)pyridin-2-yl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 28B was synthesized from intermediate 28A

(N-(6-bromopyridin-3-yl)benzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data and 1H-NMR for 28B (ESI, m/z): [M+H]⁺: 436.1 ; 1H-NMR (300 MHz, DMSO-d₆) δ: 9.21(s,2H),8.99 (m,lH),8.49 (m,lH), 8.09 (m,lH),7.88 (m,lH), 7.69(m,lH), 7.34-3.40 (m,lH), 7.12-7.18 (m,lH), 4.40 (s,2H), 3.63 (s,3H), 1.27 (s,6H).). The intermediate 28Awas synthesized from 6-bromopyridin-3 -amine and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 28A (ESI, m/z): [M+H]⁺: 306.1).

The MS and 1H-NMR data for Example 28:

MS (ESI, m/z): [M+H]⁺: 422.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 9.21 (s, 2H), 9.01 (d, 1H, J= 2.4 Hz), 8.51 (dd, 1H, J= 8.7 Hz, J= 2.7 Hz), 8.08 (d, 1H, J= 8.7 Hz), 7.87 (d, 1H, J= 7.8 Hz), 7.69 (d, 1H, J= 7.8 Hz), 7.37 (t, 1H, J= 7.5 Hz), 7.23 (t, 1H, J= 7.5 Hz), 4.37 (s, 2H), 1.24 (s, 6H).

Example 29

Preparation of sodium 2,2-dimethyl-3-(5-(4-(l-methyl-lH-benzo[d]

imidazol-2-ylamino)phenyl)pyrimidin-2-yloxy)propanoate

Example 29

The title compound was synthesized from intermediate 29B (methyl

2,2-dimethyl-3-(5-(4-(l -methyl- lH-benzo[d]imidazol-2-ylamino)phenyl)pyrimidin-2-yloxy)pro panoate) using a procedure similar to that described for Example 3. The intermediate 29B was synthesized from intermediate 29A

(N-(4-bromophenyl)-l -methyl- lH-benzo[d]imidazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 29B (ESI, m/z): [M+H]⁺: 432.3). The intermediate 29A was synthesized from 2-bromo-l-methyl-lH-benzo[d]imidazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 4B in Example 4 (The MS and NMR data for

29A (ESI, m z): [M+H] : 302.1

1H-NMR (300 MHz, OMSO-d₆) δ : 10.74 (s, 1H), 7.33 (d, 2H, J= 8.7 Hz), 7.63 (d, 1H, J= 7.5 Hz), 7.47 (d, 2H, J= 8.7 Hz), 7.31-7.40 (m, 3H), 3.78 (m, 3H).)

The MS and 1H-NMR data for Example 29:

MS (ESI, m/z): [M+H]⁺: 418.2; 1H-NMR (300 MHz, DMSO-<¾) δ: 9.44 (s, 1H), 8.86 (s, 2H), 8.03 (d, 2H, J= 8.4 Hz), 7.68 (d, 2H, J= 8.7 Hz), 7.29-7.42 (m, 2H), 7.05 (m, 3H), 4.29 (s, 2H), 3.75 (s, 3H), 1.09 (s, 6H).

Example 30

Preparation of l-(((5-(4-((4,6-dichlorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)methyl)cyclopentanecarboxylic acid

Example 30

The title compound was synthesized from intermediate 30C (methyl

l-(((5-(4-((4,6-dichlorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclope ntanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 30C was synthesized from intermediate 30B

(4,6-dichloro-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]thiazol-2-ami ne) and intermediate 6C following a Suzuki coupling procedure similar to that described for intermediate ID in Example l(The MS data for 30C MS (ESI, m/z): [M+H]⁺: 529.2).

The intermediate 30B was synthesized from 30A

(N-(4-bromophenyl)-4,6-dichlorobenzo[d]thiazol-2-amine) using a similar procedure described for intermediate IB in Example l(The MS data for 30B MS (ESI, m z): [M+H]⁺:421.1).

The intermediate 30Awas synthesized from 2, 4-dichloro-6-iodoaniline and

l-bromo-4-isothiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3A in Example 3 (The MS data for 30A MS (ESI, m/z): [M+H]⁺: 375.0).

The MS and 1H-NMR data for Example 30:

MS (ESI, m/z): [M+H]⁺: 515.0; 1H-NMR (300 MHz,

δ: 12.39 (s, 1H), 10.99 (s,

1H), 8.93 (s, 2H), 7.98 (d, 1H, J= 1.8 Hz), 7.94 (d, 2H, J= 9.0 Hz), 7.79 (d, 2H, J= 8.7 Hz), 7.57 (d, 1H, J= 1.8 Hz), 4.41 (s, 2H), 1.99-2.08 (m, 2H), 1.67-1.71 (m, 6H).

Exam le 31

Preparation of 3-((5-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophi

pyrimidin-2-yl)oxy)-2,2-dimethylpropanoic acid

Example 31

The title compound was synthesized from intermediate 3 IB (methyl

3- ((5-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropano ate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 3 IB was synthesized from intermediate 31 A

(N-(4-bromo-2-fluorophenyl)benzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 31B (ESI, m/z): [M+H] : 453.1). The intermediate 31A was synthesized from

4- bromo-2-fluoroaniline and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate lA in Example 1 (The MS data for 31A (ESI, m z): [M+H]⁺: 323.2).

The MS and 1H-NMR data for Example 31 :

MS (ESI, m/z): [M+H]⁺: 439.1 ; 1H-NMR (300 MHz,

δ: 8.99 (s, 2H), 8.73 (t, 1H, J = 8.7 Hz), 7.85 (d, 1H, J=7.5 Hz), 7.80 (dd, 1H, J= 12.9 Hz, J= 1.8 Hz), 7.67 (t, 2H, J= 7.5 Hz), 7.34 (t, 1H, J= 8.1 Hz), 7.19 (t, 1H, J= 7.8 Hz), 6.62 (s, 1H), 4.35 (s, 2H), 1.24 (s, 6H).

Example 32

Preparation of 3-((5-(4-((l -ethyl- lH-benzo[d]imidazol -2-yl)

amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoic acid k ^H Example 32

The title compound was synthesized from intermediate 32B (methyl

3-((5-(4-((l -ethyl- lH-benzo[d]imidazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimet hylpropanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 32B was synthesized from intermediate 32A

(N-(4-bromophenyl)- l -ethyl- lH-benzo[d]imidazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 32B (ESI, m/z): [M+H]⁺: 446.2). The intermediate 32A was synthesized from 2-bromo-l -ethyl- lH-benzo[d]imidazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 32A (ESI, m/z):

[M+H]⁺: 316.2).

The MS and 1H-NMR data for Example 32:

MS (ESI, m z): [M+H]⁺: 432.2; 1H-NMR (300 MHz, DMSO-<¾) δ: 8.99 (s, 2H), 7.92 (d, 2H, J= 8.7 Hz), 7.69 (t, 3H, J= 8.1 Hz, J= 6.0 Hz), 7.42 (m, 1H), 7.33 (m, 2H), 4.43 (m, 2H), 4.36 (s, 2H), 1.42 (t, 3H, J= 7.2 Hz, J= 6.9 Hz), 1.25 (s, 6H).

Example 33

Preparation of 2,2-dimethyl-3-((5-(4-((6-(trifluoromethyl)

benzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)prop

Example 33

The title compound was synthesized from intermediate 33 C (methyl

2,2-dimethyl-3-((5-(4-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)amino)phenyl)pyrimidin- 2-yl)oxy)propanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 33C was synthesized from intermediate 33B

(N-(4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)-6-(trifluoromethyl)benzo[d]th iazol-2-amine) and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 33 C MS (ESI, m/z): [M+H]⁺: 503.2). The intermediate 33B was synthesized from 33A (N-(4-bromophenyl)

-6-(trifluoromethyl)benzo[d]thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The MS data for 33 B MS (ESI, m/z): [M+H]⁺: 421.2). The intermediate 33 A was synthesized from 2-iodo-4-(trifluoromethyl)aniline and

l-bromo-4-isothiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3A in Example 3 (The MS data for 33 A MS (ESI, m z): [M+H]⁺: 374.9).

The MS and 1H-NMR data for Example 33:

MS (ESI, m/z): [M+H]⁺: 489.2; 1H-NMR (300 MHz, CD₃OD) δ: 8.81 (s, 2H), 8.04 (s, 1H), 7.89 (d, 2H, J= 8.7 Hz), 7.71 (d, 1H, J= 8.7 Hz), 7.64 (d, 2H, J= 8.7 Hz), 7.59 (dd, 1H, J= 1.2 Hz, J= 8.4 Hz), 4.45 (s, 2H), 1.34 (s, 6H).

Example 34

Preparation of 3-((5-(4-(benzo[d]thiazol-2-ylamino)-2-fluoroph<

pyrimidin-2-yl)oxy)-2,2-dimethylpropanoic acid

Example 34

The title compound was synthesized from intermediate 34B (methyl

3-((5-(4-(benzo[d]thiazol-2-ylamino)-2-fluorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropano ate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 34B was synthesized from intermediate 34A

(N-(4-bromo-3-fluorophenyl)benzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 34B (ESI, m/z): [M+H]⁺: 453.1). The intermediate 34Awas synthesized from 4-bromo-3-fluoroaniline and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate lA in Example 1 (The MS data for 34A (ESI, m/z): [M+H]⁺: 323.2).

The MS and 1H-NMR data for Example 34:

MS (ESI, m/z): [M+H]⁺: 439.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 8.80 (s, 2H), 8.07 (d, 1H, J= 13.5 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.70 (dd, 2H, J= 8.1 Hz, J= 8.7 Hz), 7.57 (d, 1H, J= 8.4 Hz), 7.39 (t, 1H, J= 7.5 Hz), 7.23 (t, 1H, J= 7.8 Hz), 6.62 (s, 1H), 4.35 (s, 2H), 1.24 (s, 6H).

Example 35

Preparation of 3-(5-(4-(6-chlorobenzo[d]thiazol-2-ylamino)phenyl)

pyrimidin-2-yloxy)-2,2-dimeth lpropanoic acid

Example 35

The title compound was synthesized from intermediate 35 C (methyl

3-(5-(4-(6-chlorobenzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)-2,2-dimethylpropanoat e) using a hydrolysis procedure similar to that described for Example 3. The intermediate 35C was synthesized from intermediate 35B

(6-chloro-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]thiazol-2-amine) and 1 C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS and NMR data for 35C (ESI, m/z): [M+H]⁺: 469.1, 1H-NMR (300MHz, DMSO-dg) δ : 10.74 (s, 1H), 8.91 (s, 2H), 7.92 (d, 1H, J= 2.4 Hz), 7.90 (d, 2H, J= 8.7 Hz), 7.75 (d, 2H, J= 9.0 Hz), 7.62 (d, 2H, J= 8.7 Hz), 7.36 (dd, 1H, J= 2.4 Hz, J= 8.7 Hz), 4.37( s, 2H), 3.63 (s, 3H), 1.27 (s, 6H).). The intermediate 35B was synthesized from 35 A

(N-(4-bromophenyl)-6-chlorobenzo[d]thiazol-2-amine) and bis(pinacolato)diboron using a similar procedure described for intermediate IB in Example 1 (The MS data for 35B (ESI, m/z): [M+H] : 387.1). The intermediate 35A was synthesized from

2,6-dichlorobenzo[d]thiazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 4B in Example 4 (The MS and NMR data for 35 A (ESI, m/z):

[M+H]⁺: 338.9, 1H- NMR (300 MHz, DMSO-d₆) δ : 10.75 (s, 1H), 7.97 (d, 1H, J= 2.1 Hz), 7.73-7.78 (m, 2H), 7.60 (d, 1H, J= 8.7 Hz), 7.52-7.57 (m, 2H), 7.35 (dd, 1H, J= 2.4 Hz, J = 8.7 Hz).).

The MS and 1H-NMR data for Example 35:

MS (ESI, m/z): [M+H]⁺: 455.5; 1H-NMR (300 MHz, DMSO-<¾) δ: 8.84 (s, 2H), 7.81-7.84 (m, 3H), 7.65 (d, 2H, J= 8.4 Hz), 7,47 (d, 1H, J= 8.1 Hz), 7.26 (d, 1H, J= 9.0 Hz), 4.29 (s, 2H), 1.09 (s, 6H).

Example 36

Preparation of 2,2-dimethyl-3-((5-(4-(pyrimidin-2-ylamino)ph<

pyrimidin-2-yl)oxy)propanoic acid

The title compound was synthesized from intermediate 36B (methyl

2,2-dimethyl-3-((5-(4-(pyrimidin-2-ylamino)phenyl)pyrimidin-2-yl)oxy)propanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 36B was synthesized from intermediate 36A and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 2E in Example 2 (The MS data for 36B MS (ESI, m/z): [M+H]⁺: 380.2).

The intermediate 36A was synthesized from 2-chloropyrimidine and 4-bromoaniline similar to that described for intermediate 1 A in Example 1.

The MS and 1H-NMR data for Example 36:

MS (ESI, m/z): [M+H]⁺: 366.0; 1H-NMR (300 MHz,

δ: 12.43 (s, 1H), 9.81 (s, 1H), 8.89 (s, 2H), 8.51 (d, 2H, J= 4.8 Hz), 7.90 (d, 2H, J= 8.7 Hz), 7.68 (d, 2H, J= 8.7 Hz), 6.87 (m, 1H), 4.33 (s, 2H), 1.23 (s, 6H). Example 37

Preparation of l-(((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylic acid

Example 37

The title compound was synthesized from intermediate 37 A (ethyl

l-(((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropa necarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 37A was synthesized from intermediate 5B and intermediate 8B following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 37A (ESI, m/z): [M+H]⁺: 461.1).

The MS and 1H-NMR data for Example 37:

MS (ESI, m/z): [M+H]⁺: 433.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 8.91 (s, 2H), 7.91 (d, 2H, J= 8.7 Hz), 7.75 (d, 2H, J= 8.7 Hz), 7.62 (s, 1H), 7.54 (d, 1H, J= 8.1 Hz), 7.16 (d, 1H, J= 8.1 Hz), 4.44 (s, 2H), 2.37 (s, 3H),1.22 (m, 4H).

Example 38

Preparation of l-(((5-(4-((6-(trifluoromethyl)benzo[d]thiazol-2-yl) amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopentanecarboxylic acid

Example 38

The title compound was synthesized from intermediate 38 A (methyl

l-(((5-(4-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)c yclopentanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 38A was synthesized from intermediate 33B and intermediate 6C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 38A MS (ESI, m/z): [M+H]⁺: 529.3).

The MS and 1H-NMR data for Example 38:

MS (ESI, m/z): [M+H]⁺: 515.1 ; 1H-NMR (300 MHz, CD₃OD) δ: 8.82 (s, 2H), 8.06 (s, 1H), 7.91 (d, 2H, J= 8.7 Hz), 7.73 (d, 1H, J= 8.4 Hz), 7.66 (d, 2H, J= 8.7 Hz), 7.62 (m, 1H), 4.53 (s, 2H), 2.18-2.22 (m, 2H), 1.78-1.82 (m, 6H).

Example 39

Preparation of l-(((5-(4-((4-chlorobenzo[d]thiazol-2-yl)amino)phenyl)

pyrimidin-2-yl)oxy)methyl)cyclohexanecarboxylic acid

Example 39

The title compound was synthesized from intermediate 39 A (ethyl

l-(((5-(4-((4-chlorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexane carboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 39A was synthesized from intermediate 7B and intermediate 10A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 39A MS (ESI, m/z): [M+H]⁺: 523.3).

The MS and 1H-NMR data for Example 39:

MS (ESI, m z): [M+H]⁺: 495.1 ; 1H-NMR (300 MHz,

δ: 12.42 (s, 1H), 11.24 (s, 1H), 8.94 (s, 2H), 8.01 (d, 2H, J= 8.7 Hz), 7.80 (m, 3H), 7.43 (d, 1H, J= 7.2 Hz), 7.16 (t, 1H, J= 8.1 Hz), 4.40 (s, 2H), 1.99-2.01 (m, 2H), 1.23-1.56 (m, 8H).

Example 40

Preparation of l-(((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyrimidin

-2-yl)oxy)methyl)cyclobutanecarboxylic acid

Example 40

The title compound was synthesized from intermediate 40B (ethyl

l-(((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclobutanecarboxylat e) using a hydrolysis procedure similar to that described for Example 1. The intermediate 40B was synthesized from intermediate 40A (ethyl

l-(((5-bromopyrimidin-2-yl)oxy)methyl)cyclobutanecarboxylate) and intermediate IB following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 40B (ESI, m/z): [M+H]⁺: 461.1). The intermediate 40Awas synthesized from ethyl 1 -(hydro xymethyl)cyclobutanecarboxylate and 5-bromopyrimidin-2-ol using a similar synthetic procedure that was described for intermediate 5B in Example 5 (The MS and 1H-NMR data for 40A (ESI, m/z): [M+H]⁺: 315.1; 1H-NMR (300 MHz, CDC1₃) δ: 8.52 (s,2H), 4.61 (s,2H), 4.20 (m, 2H), 2.47-2.57 (m, 2H), 1.97-2.19 (m, 4H), 1.26 (m,3H).).

The MS and 1H-NMR data for Example 40:

MS (ESI, m/z): [M+H]⁺: 433.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 8.92 (s, 2H), 7.94 (d, 2H, J= 8.7 Hz), 7.82 (d, 1H, J= 7.5 Hz), 7.77 (d, 2H, J= 8.7 Hz), 7.65 (d, 1H, J= 7.8 Hz), 7.37 (t, 1H, J= 8.4 Hz), 7.21 (t, 1H, J= 8.4 Hz), 4.59 (s, 2H), 2.44 (m, 2H), 2.04 (m, 4H).

Example 41

Preparation of

3-(5-(4-(6-cyanobenzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)-2,2-dimethylpropa noic acid

Example 41

The title compound was synthesized from intermediate 41 A (methyl 3-(5-(4-(6-cyanobenzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)-2,2-dimethylpropanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 41 A was synthesized from intermediate 18B

and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 41A (ESI, m/z): [M+H]⁺: 460.0).

The MS and 1H-NMR data for Example 41 :

MS (ESI, m/z): [M+H]+: 446.3; 1H-NMR (300 MHz, CD₃OD) δ: 8.83 (s, 2H), 8,13 (s, 1H), 7.92 (d, 2H, J= 8.7 Hz), 7.69 (m, 4H), 4.46 (s, 2H), 1.33 (s, 6H).

Example 42

Preparation of l-(((5-(4-((6-chlorobenzo[d]thiazol-2-yl)amino

pyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylic acid

Example 42

The title compound was synthesized from intermediate 42A (ethyl

l-(((5-(4-((6-chlorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropan ecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 42A was synthesized from intermediate 35B and intermediate 5B following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 42A MS (ESI, m/z): [M+H]⁺: 481.2).

The MS and 1H-NMR data for Example 42:

MS (ESI, m z): [M+H]⁺: 453.1 ; 1H-NMR (300 MHz,

δ: 12.44 (s, 1H), 10.75 (s, 1H), 8.92 (s, 2H), 7.97 (d, 1H, J= 2.1 Hz), 7.90 (d, 2H, J= 8.7 Hz), 7.76 (d, 2H, J= 9.0 Hz), 7.62 (d, 1H, J= 8.4 Hz), 7.36 (dt, 1H, J= 2.1 Hz, J= 8.4 Hz), 4.45 (s, 2H), 1.20-1.24 (m, 2H), 1.05-1.09 (m, 2H).

Example 43 Preparation of l-(((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)meth l)cyclobutanecarboxylic acid

Example 43

The title compound was synthesized from intermediate 43 A (ethyl

l-(((5-(4-((6-methylbenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclobutan ecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 43 A was synthesized from intermediate 40A and intermediate 8B following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 43A (ESI, m/z): [M+H]⁺: 475.2).

The MS and 1H-NMR data for Example 43:

MS (ESI, m/z): [M+H]⁺: 447.2; 1H-NMR (300 MHz, DMSO- g) δ: 8.92 (s, 2H), 7.92 (d, 2H, J= 8.7 Hz), 7.76 (d, 2H, J=8.7 Hz), 7.76 (s, 1H), 7.54 (d, 1H, J= 8.4 Hz), 7.17 (dd, 1H, J= 1.2 Hz, J= 8.4 Hz), 4.59 (s, 2H), 2.40 (m, 5H), 2.02 (m, 4H).

Example 44

Preparation of 3-((5-(4-((6-chloro-4-fluorobenzo [d]thiazol-2-yl)

amino)phenyl)pyrimidin-2- l)oxy)-2,2-dimethylpropanoic acid

Example 44

The title compound was synthesized from intermediate 44C (methyl

3-((5-(4-((6-chloro-4-fluorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-d imethylpropanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 44C was synthesized from intermediate 44B

(6-chloro-4-fluoro-N-(4-(4,4,5,5- tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)benzo[d]thiazol-2-amine) and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 44 C (ESI, m/z): [M+H]⁺: 487.0). The intermediate 44B was synthesized from 44A (N-(4-bromophenyl)-6-chloro-4-fluorobenzo[d]thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The MS data for 44B (ESI, m/z):

[M+H] : 405.1). The intermediate 44A was synthesized from 4-chloro-2-fluoro-6-iodoaniline and l-bromo-4-isothiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3A in Example 3 (The MS data for 44A: (ESI, m z): [M+H]⁺: 356.9).

The MS and 1H-NMR data for Example 44:

MS (ESI, m/z): [M+H]⁺: 473.0; 1H-NMR (300 MHz, CD₃OD) δ: 8.84 (s, 2H), 7.93 (d, 2H, J = 8.7 Hz), 7.68 (d, 2H, J= 8.4 Hz), 7.60 (s, 1H), 7.20 (dd, 1H, J= 1.8 Hz, J= 10.5 Hz), 4.48 (s, 2H), 1.35 (s, 6H).

Example 45

Preparation of (ls,4s)-4-((5-(4-((6-chlorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)ox cyclohexanecarboxylic acid

Example 45

The title compound was synthesized from intermediate 45A ((ls,4s)-ethyl

4-((5-(4-((6-chlorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 45 A was synthesized from intermediate 35B and intermediate 13A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 45A: MS (ESI, m/z): [M+H]⁺: 409.1).

The MS and 1H-NMR data for Example 45:

MS (ESI, m/z): [M+H]⁺: 481.1 ; 1H-NMR (300 MHz,

δ: 12.16 (s, 1H), 10.73 (s, 1H), 8.90 (s, 2H), 7.97 (d, 1H, J= 2.1 Hz), 7.89 (d, 2H, J= 8.7 Hz), 7.74 (d, 2H, J= 8.7 Hz), 7.62 (d, lH, J= 8.7 Hz), 7.36 (dt, 1H, J= 2.4 Hz, J= 8.7 Hz), 5.17 (s, 1H), 2.41 (s, 1H), 1.67-1.99 (m, 8H).

Example 46

Preparation of sodium 3-((5-(4-(benzo[d]oxazol-2-ylamino)-3- fluorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 46

The title compound was synthesized from intermediate 46B (methyl

3-((5-(4-(benzo[d]oxazol-2-ylamino)-3-fluorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropano ate) using a procedure similar to that described for Example 3. The intermediate 46B was synthesized from intermediate 46A (N-(4-bromo-2-fluorophenyl)benzo[d]oxazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 46B (ESI, m/z): [M+H]⁺: 437.1). The intermediate 46Awas synthesized from 4-bromo-2-fluoroaniline and 2-chlorobenzo[d]oxazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The

MS data for 46A (ESI, m/z): [M+H] : 307.3).

The MS and 1H-NMR data for Example 46:

MS (ESI, m/z): [M+H]⁺: 423.0; 1H-NMR (300 MHz,

δ: 8.92 (s, 2H), 8.38 (t, 1H, J = 8.7 Hz, J= 8.7 Hz), 7.71 (d, 1H, J= 12.6 Hz), 7.61 (d, 1H, J= 8.4 Hz), 7.44 (m, 2H), 7.20 (m, 1H), 7.10 (m, 1H), 4.31 (s, 2H), 1.14 (s, 6H).

Example 47

Preparation of sodium 2,2-dimethyl-3-(5-(4-(thiazolo[4,5-b]pyridine

-2-ylamino)phenyl)pyrimidin-2-yloxy)propanoate ONa

Example 47

The title compound was synthesized from intermediate 47B (methyl

2,2-dimethyl-3-(5-(4-(thiazolo[4,5-b]pyridin-2-ylamino)

phenyl)pyrimidin-2-yloxy)propanoate) using a procedure similar to that described for Example 3. The intermediate 47B was synthesized from intermediate 47 A

(N-(4-bromophenyl)thiazolo[4,5-b]pyridin-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 2E in Example 2 (The MS data for 47B (ESI, m/z): [M+H] : 436.2). The intermediate 47A was synthesized from

3-bromopyridin-2-amine and potassium o-ethyl carbonodithioate and 4-bromoaniline using a similar procedure described for intermediate 2C in Example 2 (The MS data for 47A (ESI, m/z): [M+H]⁺: 307.9).

The MS and 1H-NMR data for Example 47:

MS (ESI, m/z): [M+H]⁺: 422.2; 1H-NMR (300 MHz, DMSO-<¾) 5:8.80 (s, 2H), 7.87 (dd, 1H, J= 1.5 Hz, J= 4.8 Hz), 7.48-7.51 (m, 5H), 6.51 (q, 1H, J= 5.1 Hz), 4.28 (s, 2H), 1.10 (s, 6H).

Example 48

Preparation of l-(((5-(4-((4,6-dichlorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)methyl)cyclohexanecarboxylic acid

Example 48

The title compound was synthesized from intermediate 48A (ethyl

l-(((5-(4-((4,6-dichlorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclohe xanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 48 A was synthesized from intermediate 30B and intermediate 1 OA following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 48A MS (ESI, m/z): [M+H]⁺: 557.3).

The MS and 1H-NMR data for Example 48:

MS (ESI, m/z): [M+H]⁺: 529.2; 1H-NMR (300 MHz, DMSO- g) δ: 12.42 (s, 1H), 11.37 (s, 1H), 8.93 (s, 2H), 7.98-8.00 (m, 3H), 7.78 (d, 2H, J = 9.0 Hz), 7.56 (d, 1H, J = 1.8 Hz), 4.38 (s, 2H), 1.99-2.03 (m, 2H), 1.41-1.56 (m, 8H).

Example 49

Preparation of 3-((5-(4-((4,6-dichlorobenzo[d] thiazol-2-yl)

phenyl)pyrimidin-2-yl)ox -2,2-dimethylpropanoic acid

Example 49

The title compound was synthesized from intermediate 49A (methyl

3-((5-(4-((4,6-dichlorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimeth ylpropanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 49A was synthesized from intermediate 30B and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 49 A: (ESI, m z): [M+H]⁺: 503.1).

The MS and 1H-NMR data for Example 49:

MS (ESI, m/z): [M+H]⁺: 489.1; 1H-NMR (300 MHz, CD₃OD) δ: 8.83 (s, 2H), 7.97 (d, 2H, J = 8.4 Hz), 7.70 (d, 1H, J= 1.8 Hz), 7.67 (d, 2H, J= 8.7 Hz), 7.41 (d, 1H, J= 1.8 Hz), 4.46 (s, 2H), 1.34 (s, 6H).

Example 50

Preparation of sodium 3-((5-(3-fluoro-4-((6-fluorobenzo[d]thiazol-2- yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 50

The title compound was synthesized from intermediate 5 OB (methyl

3-((5-(3-fluoro-4-((6-fluorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimeth ylpropanoate) using a procedure similar to that described for Example 3. The intermediate 50B was synthesized from intermediate 50A (N-(4-bromo-2-fluorophenyl)-6-fluorobenzo [d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 50B (ESI, m/z): [M+H]⁺: 471.1). The intermediate 50A was synthesized from 4-bromo-2-fluoroaniline and

2-chloro-6-fluorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate 1A in Example 1 (The MS data for 5 OA (ESI, m z): [M+H]⁺: 341.3).

The MS and 1H-NMR data for Example 50:

MS (ESI, m/z): [M+H]⁺: 457.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 8.91 (s, 2H), 8.63 (t, 1H, J = 8.7 Hz, J= 8.7 Hz), 7.72 (m, 2H), 7.61 (m, 2H), 7.16 (m, 1H), 4.31 (s, 2H), 1.11 (s, 6H).

Example 51

Preparation of sodium 2,2-dimethyl-3-(5-(4-(thiazolo[5,4-b]pyridin-2- ylamino)phenyl)pyrimidin-2-yloxy)propanoate

Example 51

The title compound was synthesized from intermediate 5 IB (methyl

2,2-dimethyl-3-(5-(4-(thiazolo[5,4-b]pyridin-2-ylamino)

phenyl)pyrimidin-2-yloxy)propanoate) using a procedure similar to that described for Example 3. The intermediate 5 IB was synthesized from intermediate 51 A (N-(4-bromophenyl)thiazolo

[5,4-b]pyridin-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 2E in Example 2 (The MS data for 5 IB MS (ESI, m/z): [M+H] : 436.3). The intermediate 51A was synthesized from 2-bromopyridin-3 -amine and potassium o-ethyl carbonodithioate and 4-bromoaniline using a similar procedure described for intermediate 2C in Example 2 (The MS data for 51A (ESI, m/z): [M+H]⁺: 307.9).

The MS and 1H-NMR data for Example 51 :

MS (ESI, m z): [M+H]⁺: 422.2; 1H-NMR (300 MHz, DMSC ¾) 5: 11.11 (s, 1H), 8.86 (s, 2H), 8.19 (s, 1H), 7.87 (d, 3H, J= 8.1 Hz), 7.70 (d, 2H, J= 7.8 Hz), 7.33 (m, 1H), 4.28 (s, 2H), 1.05 (s, 6H).

Example 52

Preparation of 2-(((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyrimidin

-2-yl)oxy)methyl)-2-ethylbutanoic acid

Example 52

The title compound was synthesized from intermediate 52B (ethyl

2-(((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yl)oxy)methyl)-2-ethylbutanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 52B was synthesized from intermediate 52A( ethyl

2-(((5-bromopyrimidin-2-yl)oxy)methyl)-2- ethylbutanoate) and intermediate IB following a Suzuki coupling procedure similar to that described for intermediate ID in Example l(The MS data for 52B: MS (ESI, m/z):

[M+H] :477.3). The intermediate 52A was synthesized from diethyl 2,2-diethylmalonate and 5-bromopyrimidin -2-ol similar to that described for intermediate 5B in Example 5 (The MS data for 52A: MS (ESI, m/z): [M+H]⁺:331.0). The MS and 1H-NMR data for Example 52:

MS (ESI, m/z): [M+H]⁺: 449.2; 1H-NMR (300 MHz, DMSO- g) δ: 12.56 (s, 1H), 11.03 (s, 1H), 8.92 (s, 2H), 7.98 (d, 2H, J = 8.4 Hz), 7.83 (d, 1H, J = 7.8 Hz), 7.75 (d, 2H, J = 8.7 Hz), 7.63 (d, 1H, J = 7.5 Hz), 7.34 (t, 1H, J = 7.2 Hz), 7.17 (t, 1H, J = 7.8 Hz), 4.41 (m, 2H), 1.65 (m, 4H), 0.82 (t, 6H, J = 7.2 Hz).

Example 53

Preparation of sodium 3-((5-(2-fluoro-4-((6-fluorobenzo[d]thiazol-2- yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 53

The title compound was synthesized from intermediate 53B (methyl

3-((5-(2-fluoro-4-((6-fluorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-di methylpropanoate) using a procedure similar to that described for Example 3. The intermediate 53B was synthesized from intermediate 53A

(N-(4-bromo-3-fluorophenyl)-6-fluorobenzo

[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 53B (ESI, m/z): [M+H]⁺: 470.2). The intermediate 53 A was synthesized from 2-chloro-6-fluorobenzo

[d]thiazole and 4-bromo-3-fluoroaniline using a similar synthetic procedure that was described for intermediate lA in Example 1 (The MS data for 53A (ESI, m/z): [M+H]⁺: 342.1).

The MS and 1H-NMR data for Example 53:

MS (ESI, m/z): [M+H]⁺: 457.2; 1H-NMR (300 MHz, DMSO-<¾) 5: 11.38 (s, 1H), 8.72 (d, 2H, J = 1.2 Hz), 7.99 (d, 1H, J= 14.4 Hz), 7.70 (d, 1H, J= 7.2 Hz), 7.58 (m, 1H), 7.50 (m, 2H), 7.13 (t, 1H, J= 9.3 Hz), 4.13 (s, 2H), 1.09 (s, 6H).

Example 54 Preparation of sodium 3-((5-(4-(benzo[d]oxazol-2-ylamino)-2- fluorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 54

The title compound was synthesized from intermediate 54B (methyl

3-((5-(4-(benzo[d]oxazol-2-ylamino)-2-fluorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropano ate) using a procedure similar to that described for Example 3. The intermediate 54B was synthesized from intermediate 54A (N-(4-bromo-3-fluorophenyl)benzo[d]oxazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 54B (ESI, m/z): [M-H]^~: 435.1). The intermediate 54Awas synthesized from 4-bromo-3-fluoroaniline and 2-chlorobenzo[d]oxazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 54A (ESI, m/z): [M-H]^~: 305.3).

The MS and 1H-NMR data for Example 54:

MS (ESI, m/z): [M+H]⁺: 423.3; 1H-NMR (300 MHz, DMSO- g) δ: 8.73 (s, 2H), 7.93 (m, 1H), 7.60 (m, 2H), 7.45 (m, 2H), 7.23 (m, 1H), 7.14 (m, 1H), 4.30 (s, 2H), 1.11 (s, 6H).

Example 55

Preparation of sodium 3-(5-(4-(lH-benzo[d]imidazol-2-ylamino)

phenyl)pyrimidin-2-yloxy)- -dimethylpropanoate

Example 55

The title compound was synthesized from intermediate 55B (methyl

3-(5-(4-(lH-benzo[d]imidazol-2-ylamino)phenyl)pyrimidin-2-yloxy)-2,2-dimethylpropanoate) using a procedure similar to that described for Example 3. The intermediate 55B was synthesized from intermediate 55A (N-(4-bromophenyl)-lH-benzo[d]imidazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for

intermediate 3B in Example 3 (The MS data for 55B (ESI, m/z): [M+H]⁺: 418.2). The intermediate 55Awas synthesized from 2-bromo-lH-benzo[d]imidazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 2C in Example 2 (The MS data for 55A (ESI, m/z): [M+H]⁺: 289.1).

The MS and 1H-NMR data for Example 55:

MS (ESI, m/z): [M+H]⁺: 404.2; 1H-NMR (300 MHz, DMSO-<¾) 5: 14.49 (s, 1H), 12.26 (s, 1H), 8.69 (s, 2H), 7.57 (d, 2H, J= 8.4 Hz), 7.32 (d, 3H, J= 8.4 Hz), 7.18 (s, 1H), 6.93 (m, 2H), 4.50 (s, 2H), 1.24 (s, 6H).

Example 56

Preparation of (l s,4s)-4-((5-(4-((6-cyanobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylic acid

Example 56

The title compound was synthesized from intermediate 56 A ((ls,4s)-ethyl

4-((5-(4-((6-cyanobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 56A was synthesized from intermediate 18A and intermediate 13 A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS and 1H-NMR data for 56A MS (ESI, m/z):

[M+H]⁺:500.2; 1H-NMR (300 MHz,

δ: 11. 04 (s, 1H), 8.92 (s, 2H), 8.38 (s, 1H), 7.91 (d, 2H, J= 8.7 Hz), 7.72-7.79 (m, 4H), 5.18 (s, 1H), 4.06-4.13 (m, 2H), 1.69-1.99 (m, 8H), 1.20 (t, 3H, J= 7.2 Hz).).

The MS and 1H-NMR data for Example 56:

MS (ESI, m z): [M+H]⁺: 472.2; 1H-NMR (300 MHz,

δ: 12.19 (s, 1H), 11.58 (s, 1H), 8.92 (s, 2H), 8.38 (s, 1H), 7.98 (d, 2H, J= 8.7 Hz), 7.75 (m, 4H), 5.17 (s, 1H), 2.50 (s, 1H), 1.68-1.99 (m, 8H).

Example 57

Preparation of 3-((5-(4-((5-chlorobenzo[d]thiazol-2-yl)amino)]

pyrimidin-2-yl)oxy)-2,2-dimethylpropanoic acid

Example 57

The title compound was synthesized from intermediate 57B (methyl

3-((5-(4-((5-chlorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropan oate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 57B was synthesized from intermediate 57A

(N-(4-bromophenyl)-5-chlorobenzo[d]thiazol-

2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS and 1H-NMR data for 57B (ESI, m/z): [M+H]⁺: 469.1 , 1H-NMR(300MHz, CDC1₃) δ: 8.72 (s, 2H), 7.66-7.69 (m, 3H), 7.54-7.58 (m, 3H), 7.16-7.19 (m, 1H), 4.46 (s, 2H), 3.72 (s, 3H), 1.38 (s, 6H).). The intermediate 57Awas synthesized from 5-chloro-2-iodoaniline and l-bromo-4-isothiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3A in Example 3 (The MS and

1H-NMR data for 57A: (ESI, m z): [M+H]⁺: 340.9 , 1H-NMR (300 MHz, CD₃OD) δ:

7.64-7.70 (m, 3H), 7.58 (d, 1H, J= 1.8 Hz), 7.48 (d, 2H, J= 9.0 Hz), 7.13-7.17 (m, 1H).). The MS and 1H-NMR data for Example 57:

MS (ESI, m/z): [M+H]⁺: 454.1 ; 1H-NMR (300 MHz,

δ: 12.45 (s, 1H), 10.81 (s, 1H), 7.90 (d, 2H, J= 8.7 Hz), 7.86(d, 1H, J= 8.4 Hz), 7.76 (d, 2H, J= 8.7 Hz), 7.69 (d, 1H, J = 1.8 Hz), 7.22 (dt, 1H, J = 8.4 Hz, J₂ = 1.8 Hz), 4.35 (s, 2H), 1.24 (s, 6H).

Example 58

Preparation of sodium l-(((5-(3-fluoro-4-((6-fluorobenzo[d]thiazol-2- yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylate

Example 58

The title compound was synthesized from intermediate 58B (methyl

l-(((5-(3-fluoro-4-((6-fluorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyc lopropanecarboxylate) using a procedure similar to that described for Example 3. The intermediate 58B was synthesized from intermediate 58 A

(N-(4-bromo-3-fluorophenyl)benzo

[d]oxazol-2-amine) and intermediate 50A following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 58B (ESI, m/z): [M+H]⁺: 469.2). The intermediate 58A was synthesized from intermediate 5B using a similar synthetic procedure that was described for intermediate 2D in Example 2 (The MS data for 58A (ESI, m/z): [M+H]⁺: 349.2).

The MS and 1H-NMR data for Example 58:

MS (ESI, m z): [M+H]⁺: 455.1 ; 1H-NMR (300 MHz, DMSO- g) δ: 8.91 (s, 2H), 8.64 (t, 1H, J = 8.7 Hz), 7.70 (d, 2H, J= 10.8 Hz), 7.59 (d, 2H, J= 9.0 Hz), 7.14 (m, 1H), 4.46 (s, 2H), 0.91 (m, 2H) , 0.56 (m, 2H).

Example 59

Preparation of sodium 3-(5-(4-(7-fluorobenzo[d]thiazol-2-ylamino)

phenyl)pyrimidin-2-yloxy)- -dimethylpropanoate

Example 59

The title compound was synthesized from intermediate 59B (methyl

3-(5-(4-(7-fluorobenzo[d]thiazol-2-ylamino)phenyl) pyrimidin-2-yloxy)-2,2-dimethylpropanoate) using a procedure similar to that described for Example 3. The intermediate 59B was synthesized from intermediate 59A

(N-(4-bromophenyl)-7-fluorobenzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 59B (ESI, m/z): [M+H] : 453.2). The intermediate 59A was synthesized from

2-chloro-3-fluoroaniline and potassium o-ethyl carbonodithioate and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 2C in Example 2 (The MS data for 59A (ESI, m/z): [M+H]⁺: 324.9).

The MS and 1H-NMR data for Example 59:

MS (ESI, m z): [M+H]+: 439.2; 1H-NMR (300 MHz, DMSO-<¾) 5: 11.19 (s, 1H), 8.87 (s, 2H), 7.88 (d, 2H, J= 8.4 Hz), 7.71 (d, 2H, J= 8.7 Hz), 7.48(d, 1H, J= 8.1 Hz), 7.35 (q, 1H, J= 7.8 Hz), 7.04 (t, 1H, J= 8.7 Hz), 4.30 (s, 2H), l. l l(s, 6H).

Example 60

Preparation of (l-(((5-(4-((4-chlorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy methyl)cyclopropanecarboxylic acid

Example 60

The title compound was synthesized from intermediate 60A (ethyl

l-(((5-(4-((4-chlorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropan ecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 60A was synthesized from intermediate 7B and intermediate 5B following a Suzuki coupling procedure similar to that described for intermediate ID in Example l(The MS data for 60A MS (ESI, m/z): [M+H] :481.2).

The MS and 1H-NMR data for Example 60:

MS (ESI, m/z): [M+H]⁺: 453.2; 1H-NMR (300 MHz,

δ: 12.47 (s, 1H), 11.28 (s, 1H), 8.94 (s, 2H), 8.01 (d, 1H, J= 8.7 Hz), 7.80 (m, 3H), 7.43 (d, 2H, J= 7.8 Hz), 7.16 (t, 1H, J 7.8 Hz), 4.45 (s, 2H), 1.18-1.30 (m, 2H), 1.01-1.08 (m, 2H).

Example 61

Preparation of sodium l-(((5-(4-(benzo[d]thiazol-2-ylamino)-3- fluorophenyl)pyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylate

xamp e

The title compound was synthesized from intermediate 61 A (ethyl

l-(((5-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenyl)pyrimidin-2-yl)oxy)methyl)cyclopr opanecarboxylate) using a procedure similar to that described for Example 3. The intermediate 61 A was synthesized from intermediate 58 A and intermediate 31A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 61 A (ESI, m/z): [M+H]⁺: 465.1).

The MS and 1H-NMR data for Example 61 :

MS (ESI, m/z): [M+H]⁺: 437.2; 1H-NMR (300 MHz, DMSO-<¾) 5: 10.50 (s, 1H), 8.90(s, 2H), 8.61 (t, 1H, J= 9.0 Hz), 7.48-7.67 (m, 4H), 7.25 (m, 1H), 7.06 (s, 1H), 4.46 (s, 2H), 0.89 (s, 2H), 0.55 (d, 2H, J= 2.1 Hz).

Example 62

Preparation of sodium 3-((5-(4-(benzo[d]thiazol-2-ylamino)-2- methylphenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 62

The title compound was synthesized from intermediate 62B (methyl

3-((5-(4-(benzo[d]thiazol-2-ylamino)-2-methylphenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropan oate) using a procedure similar to that described for Example 3. The intermediate 62B was synthesized from intermediate 62A (N-(4-bromo-3-methylphenyl)benzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 62B (ESI, m/z): [M+H]⁺: 449.2). The intermediate 62Awas synthesized from 4-bromo-3-methylaniline and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS and 1H-NMR data for 62A (ESI, m/z): [M+H]⁺: 318.9 , 1H-NMR (300 MHz, DMSO-d₆) δ: 7.82 (dd, 1H, J= 7.2, 0.9 Hz), 7.72-7.73 (m,lH), 7.64-7.68 (m,lH), 7.60-7.63 (m,lH),

7.53-7.56 (m,lH), 7.31-7.37 (m,lH), 7.14-7.20 (m,lH), 2.36 (s,3H) ).

The MS and 1H-NMR data for Example 62:

MS (ESI, m z): [M+H]⁺: 435.3; 1H-NMR (300 MHz,

δ: 8.58 (s, 2H), 7.80-7.83 (m, 2H), 7.61-7.67 (m, 2H), 7.25-7.36 (m, 2H), 7.23-7.10 (m, 1H), 4.28 (s, 2H), 2.29 (s, 3H), 1.09 (s, 6H).

Example 63

Preparation of l-((5-(4-(4,6-dichlorobenzo[d]thiazol-2-ylamino)

phenyl)pyrimidin-2-yloxy)meth l)cyclopropanecarboxylic acid

Example 63

The title compound was synthesized from intermediate 63 A (ethyl

l-((5-(4-(4,6-dichlorobenzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)methyl)cyclopropa necarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 63 A was synthesized from intermediate 30B and intermediate 5B following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 63A (ESI, m/z): [M+H] : 515.2).

The MS and 1H-NMR data for Example 63:

MS (ESI, m/z): [M+H]+: 486.0; 1H-NMR (300 MHz, DMSO-<¾) δ: 12.47 (s, 1H), 10.99 (s, 1H), 8.94 (s, 2H), 7.98 (d, 1H, J= 2.1 Hz), 7.93(d, 2H, J= 8.7 Hz), 7.79 (d, 2H, J

1H, J= 2.1 Hz), 4.44 (s, 2H), 1.21-1.24 (m, 2H), 1.06-1.09 (m, 2H).

Example 64

Preparation of (l s,4s)-4-((5-(4-((4-chlorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylic acid

Example 64

The title compound was synthesized from intermediate 64 A ((ls,4s)-ethyl

4-((5-(4-((4-chlorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 64A was synthesized from intermediate 7B and intermediate 13A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The 1H-NMR data for 64A: 1H-NMR (300 MHz, DMSO-d₆) δ: 10.90 (s, 1H), 8.93 (s, 2H), 7.95 (d, 2H, J= 8.7 Hz), 7.76-7.83 (m, 3H), 7.44 (d, 1H, J= 7.5 Hz), 7.17 (t, 1H, J= 7.8 Hz), 5.18 (s, 1H), 4.06-4.13 (m, 2H), 1.69-1.99 (m, 8H), 1.20 (t, 3H, J= 7.2 Hz).).

The MS and 1H-NMR data for Example 64:

MS (ESI, m/z): [M+H]⁺: 481.2; Ή-NMR (300 MHz, CD₃OD) δ: 8.78 (s, 2H), 7.96 (d, 2H, J = 8.7 Hz), 7.62 (m, 3H), 7.35 (d, 1H, J= 7.5 Hz), 7.10 (t, 1H, J= 7.8 Hz), 5.26 (s, 1H), 2.47 (s, 1H), 1.94-2.08 (m, 4H), 1.76-1.84 (m, 4H).

Example 65

Preparation of sodium l-(((5-(4-(benzo[d]thiazol-2-ylamino)-2- fluorophenyl)pyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylate

Example 65

The title compound was synthesized from intermediate 65 A (ethyl

l-(((5-(4-(benzo[d]thiazol-2-ylamino)-2-fluorophenyl)pyrimidin-2-yl)oxy)methyl)cyclopr opanecarboxylate) using a procedure similar to that described for Example 3. The intermediate 65 A was synthesized from intermediate 58 A and intermediate 34A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 65A (ESI, m/z): [M+H]⁺: 465.1).

The MS and 1H-NMR data for Example 65:

MS (ESI, m/z): [M+H]⁺: 437.2; 1H-NMR (300 MHz, DMSO-<¾) 5: 11.04 (s, 1H), 8.75 (d, 2H, J= 0.9 Hz), 8.04 (dd, 1H, J= 1.5 Hz, J= 13.5 Hz), 7.84 (d, 1H, J= 7.5 Hz), 7.52-7.68 (m, 3H), 7.35 (t, 1H, J= 8.4 Hz), 7.19 (t, 1H, J= 8.1 Hz), 4.48 (s, 2H), 1.01 (s, 2H), 0.70 (s, 2H).

Example 66

Preparation of sodium 3-((5-(4-(benzo[d]thiazol-2-ylamino)-2- chlorophenyl)pyrimidin-2-yl oxy)-2,2-dimethylpropanoate

Example 66

The title compound was synthesized from intermediate 66B (methyl

3-((5-(4-(benzo[d]thiazol-2-ylamino)-2-chlorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropano ate) using a procedure similar to that described for Example 3. The intermediate 66B was synthesized from intermediate 66A (N-(4-bromo-3-chlorophenyl)benzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 66B: (ESI, m z): [M+H]⁺: 469.2). The intermediate 66Awas synthesized from 4-bromo-3-chloroaniline and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 66A (ESI, m/z): [M+H]⁺: 337.0 ).

The MS and 1H-NMR data for Example 66:

MS (ESI, m/z): [M+H]⁺: 455.5; 1H-NMR (300 MHz, DMSO- g) δ: 8.65 (d, 2H), 8.23 (d, 1H, J= 1.8 Hz), 7.82 (d, 1H, J= 5.1 Hz), 7.72 (dd, 1H, J= 8.4, 1.8 Hz), 7.64 (d, 1H, J= 8.4 Hz), 7.41 (d, 1H, J= 8.4 Hz), 7.34 (t, 1H, J= 7.5 Hz), 7.17 (t, 1H, J= 7.5 Hz) 4.31 (s, 2H), 1.11 (s, 6H).

Example 67

l-((5-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)methyl )cyclopropanecarboxylic acid

Example 67

The title compound was synthesized from intermediate 67A (ethyl

l-((5-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)methyl)cycl opropanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 67A was synthesized from intermediate 33B and intermediate 5B following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 67A (ESI, m z): [M+H]⁺: 515.2).

The MS and 1H-NMR data for Example 67:

MS (ESI, m/z): [M+H]⁺: 486.10; 1H-NMR (300 MHz, DMSO-<¾) δ: 12.47 (s, 1H), 10.98 (s, 1H), 8.93 (s, 2H), 8.32 (s, 1H), 7.93 (d, 2H, J= 8.7 Hz), 7.78 (m, 3H), 7.65 (dt, 1H, J= 1.5 Hz, J= 8.7 Hz), 4.45 (s, 2H), 1.20-1.26 (m, 2H), 1.05-1.09 (m, 2H).

Example 68

Preparation of (l s,4s)-4-((5-(4-((6-(trifluoromethyl)benzo[d]thiazol

-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylic acid

Example 68

The title compound was synthesized from intermediate 68A ((ls,4s)-ethyl

4-((5-(4-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)

amino )phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 68A was synthesized from intermediate 33B and intermediate 13A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS and 1H-NMR data for 68A MS (ESI, m/z): [M+H]⁺:543.2; 1H-NMR (300 MHz, CD₃OD) δ: 8.82 (s, 2H), 8.06 (s, 1H), 7.91 (d, 2H, J = 8.7 Hz), 7.62-7.74 (m, 4H), 5.30 (s, 1H), 4.11-4.18 (m, 2H), 2.48-2.54 (m, 1H), 1.95-2.11 (m, 4H), 1.77-1.86 (m, 4H), 1.27 (t, 3H, J= 7.2 Hz).).

The MS and 1H-NMR data for Example 68:

MS (ESI, m/z): [M+H]⁺: 515.2; 1H-NMR (300 MHz,

δ: 11.00 (s, 1H), 8.92 (s, 2H), 8.32 (s, 1H), 7.93 (d, 2H, J= 8.7 Hz), 7.77(d, 2H, J= 8.7 Hz), 7.76 (s, 1H), 7.66 (m, 1H), 5.16 (s, 1H), 2.36 (s, 1H), 1.65-1.88 (m, 8H).

Example 69

Preparation of sodium l-(((5-(2-fluoro-4-((6-fluorobenzo [d]thiazol- 2-yl)amino)phenyl)pyrimidin-2-yl)oxy)methyl)cyclopropanecarboxylate

Example 69

The title compound was synthesized from intermediate 69A (ethyl

l-(((5-(2-fluoro-4-((6-fluorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)meth yl)cyclopropanecarboxylate) using a procedure similar to that described for Example 3. The intermediate 69 A was synthesized from intermediate 58A and intermediate 53 A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 69A (ESI, m/z): [M+H]⁺: 483.1).

The MS and 1H-NMR data for Example 69:

MS (ESI, m/z): [M+H]⁺: 455.3; 1H-NMR (300 MHz, DMSC ¾) 5: 11.42 (d, 1H, J= 3.0 Hz), 8.72 (d, 2H, J= 1.2 Hz), 8.02 (d, 1H, J= 14.1 Hz), 7.75 (dd, 1H, J= 2.7 Hz, J= 8.7 Hz), 7.66 (q, 1H, J= 4.8 Hz), 7.53 (d, 2H, J= 4.8 Hz), 7.18 (tq, 1H, J= 9.3 Hz, J= 9.3 Hz), 4.47 (s, 2H), 0.95 (s, 2H), 0.60 (s, 2H).

Example 70

Preparation of sodium 3-((5-(4-(benzo[d]thiazol-2-ylamino)-3- chlorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 70

The title compound was synthesized from intermediate 70B (methyl

3-((5-(4-(benzo[d]thiazol-2-ylamino)-3-chlorophenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropano ate) using a procedure similar to that described for Example 3. The intermediate 70B was synthesized from intermediate 70A (N-(4-bromo-2-chlorophenyl)benzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data and 1H-NMR for 70B (ESI, m/z): [M+H]⁺: 469.2; 1H-NMR (300 MHz,

δ: 8.05 (s, 2H), 8. 7.67-7.70 (m, 1H), 7.00-7.02 (m, 1H), 6.83-6.92 (m, 2H), 6.67-6.80 (m, 1H), 6.51-6.56 (m, 1H), 6.35-6.41 (m, 1H), 3.67 (s,2H), 2.89 (s, 3H), 0.84 (s, 6H)). The intermediate 70Awas synthesized from 4-bromo-2-chloroaniline and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for

intermediate lA in Example 1 (The MS and Ή-NMR data for 70A (ESI, m z): [M+H]⁺: 337.1 , 1H-NMR (300 MHz, OMSO-d₆) δ: 8.31 (d, 1H, J= 8.7 Hz), 7.82 (d, 1H, J= 7.2Hz ), 7.79 (d, 1H, J= 2.1Hz), 7.59-7.63 (m,lH), 7.54-7.57 (m,lH), 7.30-7.36 (m,lH), 7.15-7.21 (m,lH).). The MS and 1H-NMR data for Example 70:

MS (ESI, m/z): [M+H]⁺: 455.3; 1H-NMR (300 MHz, DMSO- g) δ: 8.92 (s, 2H), 8.45 (d, 1H, J= 8.4 Hz), 7.88 (s, 1H), 7.69-7.75 (m, 2H), 7.47-7.51 (m, 1H), 7.24-7.30 (m, 1H), 7.09-7.12 (m, 1H), 4.30 (s, 2H), 1.09 (s, 6H)

Example 71

Preparation of l-((5-(4-(6-(trifluoromethyl)benzo[d]thiazol-2- ylamino)phenyl)pyrimidin- -yloxy)methyl)cyclohexanecarboxylic acid

Example 71

The title compound was synthesized from intermediate 71 A (ethyl

l-((5-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)methyl)cycl ohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 71 A was synthesized from intermediate 33B and intermediate 10A following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 71A (ESI, m z): [M+H]⁺: 557.3).

The MS and 1H-NMR data for Example 71 :

MS (ESI, m/z): [M+H]+: 528.14; 1H-NMR (300 MHz, DMSO-<¾) δ: 12.42 (s, 1H), 10.94 (s, 1H), 8.92 (s, 2H), 8.32 (s, 1H), 7.93(d, 2H, J= 8.7 Hz), 7.78 (m, 3H), 7.65 (dt, 1H, J= 1.5 Hz, J = 8.7 Hz), 4.39 (s, 2H), 1.99-2.04 (m, 2H), 1.41-1.56 (m, 8H).

Example 72

Preparation of 3-((5-(4-((4,6-dimethylbenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoic acid

Example 72

The title compound was synthesized from intermediate 72C (methyl

3-((5-(4-((4,6-dimethylbenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpr opanoate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 72C was synthesized from intermediate 72B

(4,6-dimethyl-N-(4-(4,4,5,5-tetramethyl

-l,3,2-dioxaborolan-2-yl)phenyl)benzo[d]thiazol-2-amine) and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS and 1H-NMR data for 72C: (ESI, m/z): [M+H]⁺: 463.2; 1H-NMR (300 MHz, DMSO-d₆) δ: 10.56 (s, 1H), 8.92 (s, 2H), 7.94 (d, 2H, J= 8.7 Hz), 7.75 (d, 2H, J= 8.7 Hz), 7.44 (s, 1H), 7.00 (s, 1H), 4.37 (s, 2H), 3.63 (s, 3H), 2.54 (s, 3H), 2.34 (s, 3H), 1.23-1.34 (m, 6H).). The intermediate 72B was synthesized from 72A

(N-(4-bromophenyl)-4,6-dimethylbenzo[d]thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The 1H-NMR data for 72B: 1H-NMR (300 MHz, CDC1₃) δ: 7.82 (d, 2H, J= 8.4 Hz), 7.48 (d, 2H, J= 8.4 Hz), 7.30 (s, 1H), 7.01 (s, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 1.35 (s, 12H).). The intermediate 72Awas synthesized from 2-iodo-4,6-dimethylaniline and l-bromo-4-isothiocyanatobenzene using a similar synthetic procedure that was described for intermediate 3 A in Example 3 (The MS and 1H-NMR data for 72A (ESI, m z): [M+H]⁺: 334.9; 1H-NMR (300 MHz, CDC1₃) δ: 7.43-7.50 (m, 4H), 7.29 (s, 1H), 7.01 (s, 1H), 2.59 (s, 3H), 2.39 (s, 3H). ).

The MS and 1H-NMR data for Example 72:

MS (ESI, m/z): [M+H]⁺: 448.2; 1H-NMR (300 MHz,

δ: 12.43 (s, 1H), 10.56 (s, 1H), 8.92 (s, 2H), 7.94 (d, 2H, J= 8.7 Hz), 7.75 (d, 2H, J= 8.7 Hz), 7.44 (s, 1H), 7.00 (s, 1H), 4.34 (s, 2H), 2.54 (s, 3H), 2.34 (s, 3H), 1.24 (s, 6H).

Example 73 Preparation of 3-((5-(4-((6-fluorobenzo[d]thiazol-2-yl)amino)phenyl)

pyrimidin-2-yl)oxy)-2,2-dimethylpropanoic acid

Example 73

The title compound was synthesized from intermediate 73 C (methyl

3-((5-(4-((6-fluorobenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropan oate) using a hydrolysis procedure similar to that described for Example 1. The

intermediate 73 C was synthesized from intermediate 73B

(6-fluoro-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan

-2-yl)phenyl)benzo[d]thiazol-2-amine) and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS data for 73C (ESI, m/z): [M+H] : 453.2). The intermediate 73B was synthesized from 73 A

(N-(4-bromophenyl)-6-fluorobenzo[d]thiazol-2-amine) using a similar procedure described for intermediate IB in Example 1 (The MS data for 73B (ESI, m/z): [M+H]⁺: 371.2). The intermediate 73Awas synthesized from 2-chloro-6-fluorobenzo[d]thiazole and 4-bromoaniline using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS data for 73A (ESI, m/z): [M+H]⁺: 324.9).

The MS and 1H-NMR data for Example 73:

MS (ESI, m z): [M+H]⁺: 439.2; 1H-NMR (300 MHz, DMSO- g) δ: 12.44 (s, 1H), 10.66 (s, 1H), 8.92 (s, 2H), 7.90 (d, 2H, J= 8.7 Hz), 7.74-7.79 (m, 3H), 7.61-7.66 (m, 1H), 7.16-7.22 (dt, 1H, J= 9.0 Hz, J= 2.7 Hz), 4.35 (s, 2H), 1.24 (s, 6H).

Example 74

Preparation of sodium 3-((5-(4-(benzo[d]thiazol-2-ylamino)-3- methylphenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 74

The title compound was synthesized from intermediate 74B (methyl

3 -((5 -(4-(benzo [d]thiazo l-2-ylamino)-3 -methylphenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropan oate) using a procedure similar to that described for Example 3. The intermediate 74B was synthesized from intermediate 74A (N-(4-bromo-2-methylphenyl)benzo[d]thiazol-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data and for 74B (ESI, m/z): [M+H]⁺: 449.2). The intermediate 74Awas synthesized from 4-bromo-2-methylaniline and 2-chlorobenzo[d]thiazole using a similar synthetic procedure that was described for intermediate 1 A in Example 1 (The MS and 1H-NMR data for 74A (ESI, m/z): [M+H]⁺: 319.0; 1H-NMR (300 MHz, DMSO-<¾) δ: 7.90 (d, 1H, J= 8.4 Hz), 7.81 (dd, 1H, J= 8.4,1.2 Hz), 7.50-7.53 (m, 2H), 7.43-7.47 (m,lH), 7.30-7.36 (m,lH), 7.14-7.20 (m,lH), 2.30(s,3H).).

The MS and 1H-NMR data for Example 74:

MS (ESI, m z): [M+H]⁺: 435.2; 1H-NMR (300 MHz,

δ: 8.89 (s, 2H), 8.09 (d, 1H, J= 8.4 Hz ), 7.77 (d, 1H, J= 7.5 Hz), 7.57-7.63 (m, 2H), 7.51 (d, 1H, J= 7.5 Hz), 7.26-7.32 (m, 1H), 7.09-7.15 (m, 1H), 4.34 (s, 2H), 2.30 (s, 3H), 1.15 (s, 6H).

Example 75

Preparation of sodium 1 -((5 -(4-(l -methyl- lH-benzo[d] imidazo 1-2- ylamino)phenyl)pyrimidin-2-yloxy)methyl)cyclopropanecarboxylate

Example 75 The title compound was synthesized from intermediate 75 A (ethyl

l-((5-(4-(l-methyl-lH-benzo[d]imidazol-2-ylamino)phenyl)pyrimidin-2-yloxy)methyl)cyclopr opanecarboxylate) using a procedure similar to that described for Example 3. The intermediate 75 A was synthesized from intermediate 29A and intermediate 58A following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 75A (ESI, m/z): [M+H]⁺: 444.2).

The MS and 1H-NMR data for Example 75:

MS (ESI, m/z): [M+H]⁺: 416.2; 1H-NMR (300 MHz, DMSO-<¾) δ: 9.51 (s, 1H), 8.84 (s, 2H), 8.04 (d, 2H, J= 8.7 Hz), 7.65 (d, 2H, J= 8.7 Hz), 7.40 (m, 1H), 7.31 (m, 1H), 7.06 (m, 2H), 4.48 (s, 2H), 3.75 (s, 3H), 0.96 (d, 2H, J= 2.4 Hz), 0.60 (d, 2H, J= 2.4 Hz).

Example 76

Preparation of (l s,4s)-4-((5-(4-((4,6-dichlorobenzo[d]thiazol-2-yl)

amino)phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylic acid

Example 76

The title compound was synthesized from intermediate 76 A ((ls,4s)-ethyl

4-((5-(4-((4,6-dichlorobenzo[d]thiazol-2-yl)amino)

phenyl)pyrimidin-2-yl)oxy)cyclohexanecarboxylate) using a hydrolysis procedure similar to that described for Example 1. The intermediate 76A was synthesized from intermediate 30B and intermediate 13A following a Suzuki coupling procedure similar to that described for intermediate ID in Example l(The MS and 1H-NMR data for 76A: MS (ESI, m z): [M+H]⁺: 543.2; 1H-NMR (300 MHz,

δ: 10.97 (s, 1H), 8.93 (s, 2H), 7.98 (d, 1H, J= 2.1 Hz), 7.93 (d, 2H, J= 8.7 Hz), 7.78 (d, 2H, J= 8.7 Hz), 7.57 (d, 1H, J= 1.8 Hz), 5.18 (s, 1H), 4.06-4.13 (m, 2H), 1.69-1.99 (m, 8H), 1.22 (t, 3H, J= 7.2 Hz)).

The MS and 1H-NMR data for Example 76:

MS (ESI, m/z): [M+H]⁺: 515.1 ; 1H-NMR (300 MHz,

δ: 12.24 (s, 1H), 11.05 (s, 1H), 8.92 (s, 2H), 7.98 (d, 1H, J = 2.1 Hz), 7.93(d, 2H, J = 8.7 Hz), 7.77 (d, 2H, J = 8.7 Hz), 7.56 (d, 1H, J = 2.1 Hz), 5.16 (s, 1H), 2.36 (s, 1H), 1.66-1.88 (m, 8H).

Example 77

Preparation of 3-((5-(4-((6-methoxybenzo[d]thiazol-2-yl)amino)

Lyl)pyrimidin-2-yl)oxy)- -dimethylpropanoic acid

Example 77

The title compound was synthesized from intermediate 77A (methyl

3-((5-(4-((6-methoxybenzo[d]thiazol-2-yl)amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylprop anoate) using a hydrolysis procedure similar to that described for Example 3. The intermediate 77 A was synthesized from intermediate 16B and intermediate 1C following a Suzuki coupling procedure similar to that described for intermediate ID in Example 1 (The MS and 1H-NMRdata for 77A (ESI, m/z): [M+H]⁺: 465.2, ¹ HNMR(300MHz, CDC1₃) δ: 8.71 (s, 2H), 7.66 (d, 2H, J= 8.7 Hz), 7.58 (d, 1H, J= 8.7 Hz), 7.52 (d, 2H, J= 8.4 Hz), 7.19 (d, 1H, J = 2.4 Hz), 6.96-6.99 (m, 1H), 4.45 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 1.38 (s, 6H)).

The MS and 1H-NMR data for Example 77:

MS (ESI, m/z): [M+H]⁺: 450.1 ; 1H-NMR (300 MHz,

δ: 12.44 (s, 1H), 10.50 (s, 1H), 8.91 (s, 2H), 7.89 (d, 2H, J= 8.7 Hz), 7.73(d, 2H, J= 8.7 Hz), 7.55 (d, 1H, J= 8.7 Hz), 7.47 (d, 1H, J= 2.7 Hz), 6.94 (dt, 1H, J = 8.7 Hz, J₂ = 2.7 Hz), 4.34 (s, 2H), 3.79 (s, 3H), 1.24

(s, 6H).

Example 78

Preparation of sodium 2,2-dimethyl-3-((5-(4-(quinoxalin-2-ylamino)

yl)pyrimidin-2-yl)oxy)propanoate

Example 78

The title compound was synthesized from intermediate 78B (methyl

2,2-dimethyl-3-((5-(4-(quinoxalin-2-ylamino)phenyl)pyrimidin-2-yl)oxy)propanoate) using a procedure similar to that described for Example 3. The intermediate 78B was synthesized from intermediate 78A (N-(4-bromophenyl)quinoxalin-2-amine) and intermediate 2D following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data and for 78B (ESI, m/z): [M+H]⁺: 430.0). The intermediate 78Awas synthesized from 4-bromoaniline and 2-chloroquinoxaline using a similar synthetic procedure that was described for intermediate lA in Example l(The MS data for 78A (ESI, m/z): [M+H]⁺: 301.9).

The MS and 1H-NMR data for Example 78:

MS (ESI, m/z): [M+H]⁺: 416.2; 1H-NMR (300 MHz, DMSO- g) δ: 8.87 (s, 2H), 8.56-8.70 (m, 1H), 8.12 (d, 2H, J= 8.7 Hz), 7.86 (d, 1H, J= 7.8 Hz), 7.63-7.77 (m, 4H), 7.45-7.50 (m, 1H), 4.30 (s, 2H), 1.08 (s, 6H).

Example 79

Preparation of l-((5-(4-(6-methoxybenzo[d]thiazol-2-ylamino)phenyl)

pyrimidin-2-yloxy)methyl)cyclobutanecarboxylic acid

Example 79

The title compound was synthesized from intermediate 79A (ethyl

l-((5-(4-(6-methoxybenzo[d]thiazol-2-ylamino)phenyl)pyrimidin-2-yloxy)methyl)cyclobutanec arboxylate) using a hydrolysis procedure similar to that described for Example 3. The intermediate 79 A was synthesized from intermediate 16B and intermediate 40A following a Suzuki coupling procedure similar to that described for intermediate 3B in Example 3 (The MS data for 79A (ESI, m/z): [M+H]⁺: 491.1).

The MS and 1H-NMR data for Example 79:

MS (ESI, m/z): [M+H]⁺: 463.2; 1H-NMR (300 MHz, OMSO-d₆) δ: 8.92 (s, 2H), 7.90 (d, 2H, J = 9.0 Hz), 7.75 (d, 2H, J = 8.7 Hz), 7.56 (d, 1H, J = 8.7 Hz), 7.47 (d, 1H, J = 2.7 Hz), 6.96 (dd, 1H, J = 2.7 Hz, J = 9.0 Hz), 4.59 (s, 2H), 3.78 (s, 3H), 2.39 (m, 2H), 2.04 (m, 4H).

Example 80

Preparation of sodium 3-((5-(4-(benzo[d]thiazol-2-ylamino)

phenyl)pyridin-2-yl)oxy)-2,2-dimethylpropanoate

Example 80

The title compound was synthesized from intermediate 80B (methyl

3-((5-(4-(benzo[d]thiazol-2-ylamino)phenyl)pyridin-2-yl)oxy)-2,2-dimethylpropanoate) using a procedure similar to that described for Example 3. The intermediate 80B was synthesized from intermediate 80A (methyl 3-((5-bromopyridin-2-yl)oxy)-2,2-dimethylpropanoate) and intermediate IB following a Suzuki coupling procedure similar to that described for

intermediate ID in Example l(The MS data and for 80B (ESI, m z): [M+H]⁺: 434.1). The intermediate 80A was synthesized from 5-bromo-2-fluoropyridine and methyl

3-hydroxy-2,2-dimethylpropanoate using a similar synthetic procedure that was described for intermediate 1C in Example l(The MS data for 80A (ESI, m/z): [M+H] : 288.0).

The MS and 1H-NMR data for Example 80:

MS (ESI, m/z): [M+H]⁺: 420.2; 1H-NMR (300 MHz,

δ: 8.43 (d, 1H, J= 2.4 Hz), 7.94 (dd, lH, J= 2.7 Hz, 8.7 Hz), 7.89 (s, 1H), 7.86 (s, 1H), 7.81 (d, 1H, J= 8.1 Hz),

7.61-7.67 (m, 3H), 7.31-7.36 (m, 1H), 7.13-7.19 (m, 1H), 6.80 (d, 1H, J= 8.7 Hz), 4.21 (s, 2H), 1.06 (s, 6H).

Example 81

Preparation of sodium 3-((5-(4-(benzo[d]thiazol-2-ylamino)phi

p rimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 1 Example 81

Compound example 1 (4.2 g, 10 mmol) was dissolved in 42 mL of tetrahydroiuran, to which was added slowly 1 mL of 10 N sodium hydroxide aqueous solution. The reaction was carried out for 2 h. To the reaction solution was added 210 mL of ethyl acetate. The mixture was filtered and the obtained solid was recrystallized from a mixed solution of tetrahydroiuran and ethyl acetate to give 4.16 g of white flake crystals compound example 81. Yield: 94%. MS (ESI, m/z): [M+H]⁺: 421.2; 1H-NMR (300 MHz, DMSC /₆) δ: 10.88 (s, 1H), 8.86 (s, 2H), 7.92 (d, 2H, J= 8.4 Hz), 7.82 (d, 1H, J = 7.2 Hz), 7.71 (d, 2H, J= 8.7 Hz), 7.63 (d, 1H, J = 7.2 Hz), 7.45 (t, 2H, J= 7.5 Hz), 7.32 (t, 1H, J= 7.5 Hz), 4.29 (s, 2H), 1.08 (s, 6H).

Example 82

Preparation of sodium 2,2-dimethyl-3-((5-(4-(thiazolo[4,5-c]pyridin

-2-ylamino)phenyl)pyrimidin-2-yl)oxy)propanoate

Example 82

The title compound was synthesized from example 2 using a procedure similar to that described for Example 81.

MS (ESI, m/z): [M+H]⁺: 422.3; 1H-NMR (300 MHz, DMSO- g) 5: 11.28 (s, 1H), 8.83 (s, 2H), 8.57 (s, 1H), 8.05 (s, 1H), 7.60-7.74 (m, 5H), 4.28 (s, 2H), 1.08 (s, 6H).

Example 83

Preparation of sodium 3-((5-(4-((5-fluorobenzo[d]thiazol-2-yl)

amino)phenyl)pyrimidin- -yl)oxy)-2,2-dimethylpropanoate

Example 83

The title compound was synthesized from example 9 using a procedure similar to that described for Example 81.

MS (ESI, m/z): [M+H]⁺: 460.1; 1H-NMR (300 MHz, DMSO- g) δ: 11.01 (s, 1H), 8.86 (s, 2H), 7.85 (d, 2H, J = 8.1 Hz), 7.76 (m, 1H), 7.68 (d, 2H, J = 8.7 Hz), 7.37 (m, 1H), 6.96 (m, 1H), 4.29 (s, 2H), 1.09 (s, 6H).

Example 84

Preparation of sodium 3-((5-(4-((4,6-difluorobenzo[d]thiazol- amino)phenyl)pyrimidin-2-yl)oxy)-2,2-dimethylpropanoate

Example 84

The title compound was synthesized from example 15 using a procedure similar to that described for Example 81.

MS (ESI, m/z): [M+H]⁺: 478.5; 1H-NMR (300 MHz, DMSO- g) δ: 11.25 (s, 1H), 8.86 (s, 2H), 7.85 (d, 2H, J = 8.4 Hz), 7.69 (d, 2H, J= 8.4 Hz), 7.59 (s, 1H), 7.22 (m, 1H), 4.29 (s, 2H), 1.08

(s, 6H).

Evaluation of Biological Activities

In the following, in vivo and in vitro tests were conducted on compounds of the present invention to evaluate their inhibition on DGAT-1 enzyme and on the absorption of triglyceride downstream its pathway.

Example 85 : In vitro screening of DGAT-1 inhibitors (evaluating the inhibition on murine DGAT-1 enzyme in HEPG2 cell line^

The in vitro screening of DGAT-1 inhibitors employed human liver cancer cell line HEPG2 expressing DGAT-1. In brief, the process comprises: collecting cells, ultrasonically homogenizing the cells in a buffer containing 10 mM Tris-HCl [pH 7.4], 250 mM glucose and a protease inhibitor, centrifuging at 2000 g and 4°C for 10 min, collecting the supernatant, and storing at -80°C for further use.

The test on the activities of DGAT-1 was based on an improvement of the prior art (Alan M. Birch, et al, Journal of Medicinal Chemistry, 52(6), 1558- 1568, 2009): the compound (final concentration of 0.0001 to 10 μΜ) was firstly co-incubated with 20 μg of HEPG2 protein for 10 min; then 1 ,2- dioleoyl-sn- glycerol (final concentration of 1 mM, dissolved in 12.5% ethanol solution) and ¹⁴C oleoyl co-enzyme A (final concentration of 30 μΜ) were added to initiate the reaction. After incubating at room temperature for 1 h, 300 μΐ_^ of a mixture of isopropanol: heptane (7: 1) was added to terminate the reaction. Then, 200 μΐ, of heptane and 200 μΐ, of 0.1 M carbonate buffer (pH 9.5) were added to the reaction system. Radioactive triglyceride was extracted into the organic phase. The upper layer heptane was quantified by liquid scintillation method to analyze the activities of DGAT-1. By calculating the inhibition percentage of the compound in comparison with the reference compound, the efficiency of inhibiting DGAT-1 was obtained.

By the above method, the half maximal inhibitory concentration IC50S of the compounds of Examples 1-84 were less than 1000 nM, the IC50S of the compounds of Examples 1 , 4, 5, 3 land 73 were less than 500 nM.

Example 86: In vitro screening of DGAT-1 inhibitors (evaluation of inhibition on human DGAT-1 enzyme in SF9 cell line^

The in vitro test of DGAT-1 inhibitors employed recombined human DGAT-1 protein expressed by insect cells as the source of enzyme. In brief, the process comprises: infecting SF9 cells with recombined baculo virus encoded with human DGAT-1, harvesting the cells, washing once with DPBS pre-cooled with ice, adding a homogenizing buffer [250 mM glucose, 10 mM Tris-HCl (pH 7.4), protease inhibitor] to re-suspend the cells, lysing the cells in a homogenizer, centrifuging at 10000 g for 30 min, removing cell fragments, collecting the mitochondrial membrane in the supernatant by ultracentrifugation (centrifuging at 100000 g for 60 min), re-suspending the mitochondrial membrane in the homogenizing buffer, and storing at -80 °C.

The test on the activities of DGAT-1 enzyme was based on an improvement of the prior art (J. Med. Chem. 2009, 52, 1558-1568). The compound having a final concentration of 0.0001-10 μΜ was pre-incubated for 15 min together with SF9 microsome protein having a final concentration of 10 μg and MgCl₂ having a final concentration of 100 mM. l,2-Dioleoyl-s/?-glycerol (dissolved in 12.5% ethanol solution) having a final concentration of 100 μΜ and isotope labeled ¹⁴C oleoyl coenzyme A having a final concentration of 30 μΜ were added to initiate the enzymatic reaction. The mixture was incubated at room temperature for 30 min. The reaction was terminated by 300 μΐ_^ of isopropanol: heptane 7: 1 solution. Radioactive triglyceride product was isolated with an organic phase 200 μΐ, of heptane and 200 μΐ, of 0.1 M carbonate buffer. The product in the upper layer heptane was quantified by liquid scintillation method. DGAT-1 inhibition activity was expressed as % inhibition rate in comparison with the reference compound.

By the above method, the IC50S of the compounds of Examples 1-84 were less than 1000 nM, wherein the exemplary compounds listed in Table 1 showed good inhibition activities on human DGAT-1 enzyme.

Table 1 : In vitro inhibition activities on human DGAT-1 enzyme in SF9 cell line

: 10 nM < IC₅₀ < 100 nM

Example 87: Oral Lipid Tolerance Test (OLTT

Materials and Methods:

Reagents: corn oil, purchased from Sigma; Blood triglyceride test kit (GPO-PAP method), purchased from Biosino Bio-Technology & Science Inc.

Animals: ICR mice, male, weight 20-22 g, purchased from Beijing HFK Bioscience Co. Ltd. The animals were fed in an SPF grade animal room at room temperature of 20-25°C under a humidity of 40-60%. The animal room was kept under a 12-hour light/dark cycle. The feeding and handling of the animals followed the national regulations for the administration of affairs concerning experimental animals.

Experimental method: normal ICR mice are grouped randomly before the experiment based on their body weights. After the mice were kept fasting overnight (16 h), blood samples were taken from tail tip (-30 min), followed by immediate oral gavage of a test compound in an amount of 5 mL/kg. At 30 minutes after the gavage of the test compound, blood samples were taken again from tail tip (0 min), followed by immediate oral gavage of corn oil in an amount of 5 mL/kg. Blood samples were taken from tail tip at 60, 120, 180 and 240 min after gastric perfusion of corn oil, respectively. Blood triglyceride was determined for the blood samples taken at the 6 time points, following the instructions in the kit, and a blood triglyceride-time curve was drawn.

Statistical method: One way ANOVA is used for data comparison among groups, and P < 0.05 was considered to be a statistically significant difference.

By the above method, it was determined that: 4 hours after using coin oil, comparing the AUC (areas under the curve) value of 10 mg/kg of the compounds of Examples 1-84 with that of the reference compound, the administration group showed activities of decreasing triglyceride in the serum. Some of the percentages of decrease of triglyceride in the serum in the administration groups in comparison with the blank group are illustrated in Table 2.

Table 2: Inhibition of triglyceride absorption by exemplary compounds

#: 10% < Decrease of Triglyceride (%) <30%

##: 30% < Decrease of Triglyceride (%) < 60% In summary, from the data shown in Tables 1 and 2, which showed the evaluation of the in vivo and in vitro biological activities of the compounds of formula I, the compounds of the present invention showed good inhibition on murine derived and human derived DGAT-1 enzymes.

Claims

Claims:

1. A compound of formula I,

Formulal

wherein:

A independently represents C3-C₁₀ heteroaryl, wherein the heteroaryl is selected from the group consisting of:

B each independently represents phenyl or C5-C₆ heteroaryl;

Qi and Q₂ each independently represent -CH- or N;

Q₃ each independently represents NR₃, O or S;

Ri and R₂ each independently represent hydrogen; halogen; cyano; optionally substituted Ci-C₆ alkyl, optionally substituted Ci-C₆ alkoxy, optionally substituted mono- or di-cyclic aryl or heteroaryl, wherein the substituent is selected from one or more of halogen, hydroxy and amino; and the numbers of Ri and R₂ are independently one or two;

R₃ each independently represents hydrogen or C₁-C₄ alkyl;

R_m and R_n each independently represent hydrogen, halogen or Ci-C₆ alkyl; and the numbers of R_m and R_n are independently one or two;

R_x independently represents hydrogen or C₁-C₄ alkyl;

L is selected from the group consisting of the following formula:

or a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

2. The compound of Claim 1 , wherein:

A independently represents C3-C 10 heteroaryl, wherein the heteroaryl is selected from the group consisting of:

wherein B each independently represents phenyl or pyridinyl,

or a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

3. The compound of Claim 1 or 2, wherein:

A re resents one of the following structures:

or a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

4. The compound of any one of Claims 1~3, wherein:

Ri and R₂ each independently represent hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, trifluoromethoxy or phenyl;

R3 independently represents hydrogen, methyl or ethyl;

R_m and R_n each independently represent hydrogen, fluoro, chloro or methyl;

R_x independently represents hydrogen, methyl or ethyl;

L is selected from one of the following structures,

ΚΉ wherein R₄ and R₅ each independently represent methyl or ethyl; or, R₄ and R₅ together form C3-C6 cycloalkyl,

or a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

5. The compound of any one of Claims 1~4, wherein:

A represents one of the following structures:

or a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

6. The compound of any one of Claims 1~5, wherein:

L is selected from one of the following structures:

5 6 7 or a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

7. The compound of any one of Claims 1~6, wherein the compound is selected from one of the following:

WO 2013/056679 PCT/CN2012/083248

or a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

8. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from sodium, potassium, calcium, lithium, magnesium, zinc, ammonium, tetramethyl ammonium, tetraethyl ammonium, dimethyl ammonium, triethyl ammonium, trimethyl ammonium, ethyl ammonium and diethanol ammonium salts, arginine salts, lysine salts, hydrochloride, hydrobromide, phosphate, sulfate, mesylate and p-toluene sulfonate.

9. The compound of Claim 8 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from sodium, potassium and calcium salts.

10. A pharmaceutical composition, comprising a compound of any one of Claims 1~9 or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, and a pharmaceutically acceptable excipient.

11. A drug combination, comprising a compound of any one of Claims 1~9 or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, in combination with another drug, said another drug is selected from at least one of the following: anti-obesity drug, hypoglycemic drug, hypolipidemic drug, antihypertensive drug, coagulation regulating drug, non-steroidal anti-inflammatory drug, steroidal anti-inflammatory drug and anti hepatitis C virus drug.

12. The drug combination of Claim 11 , wherein the hypolipidemic drug is selected from the group consisting of statins, fibrates, nicotinic acids, and fish oils.

13. Use of a compound of any one of Claims 1~9, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, in preparing a medicament for inhibiting DGAT-1 activities.

14. Use of claim 13, wherein the medicament is for treating and/or preventing a disease, disorder or condition selected from the group consisting of obesity, coronary disease, hypertension, hyperlipidemia, arteriosclerosis, type II diabetes, stroke and hepatitis C.