HSD17B13 inhibitors and / or degraders

Abstract

Described herein are compounds of Formula I, where the variables are defined herein, their use as HSD17B13 inhibitors and / or degraders, pharmaceutical compositions containing such compounds, and their use for treating, for example, NAFLD and NASH. [Formula 1] TIFF2025533088000139.tif98164

Description

[Technical Field]

[0001] The present application provides compounds that are hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) inhibitors and / or degraders, pharmaceutical compositions containing such compounds, and their use for treating conditions, diseases, or disorders associated with HSD17B13 activity. [Background technology]

[0002] Hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated steroid dehydrogenase family enzyme. From 2018 to present, multiple human genetic variants of HSD17B13 have been identified as protective against NASH progression, resulting in reduced liver inflammation, ballooning, and fibrosis. Abul-Husn et al. (2018) reported that truncating variants were over-enriched in individuals with simple steatosis and under-enriched in individuals with NASH and NASH+fibrosis, suggesting their protection against disease progression. Abul-Husn et al., "Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease," N Engl J Med 2018;378:1096–1106. Later that same year, a second truncating variant was reported by Kozlitina et al. with reduced allele frequency in Blacks and Hispanics with chronic liver disease. Kozlitina et al., "HSD17B13 and Chronic Liver Disease in Blacks and Hispanics," N Engl J Med 2018;379:1876-1877. In 2019, Ma et al. found that a coding variant, P260S, was associated with reduced inflammation and ballooning. HSD17B13 expression was found to be significantly upregulated in humans with nonalcoholic fatty liver disease (NAFLD). Ma et al., "17-Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease," Hepatology 2019;69(4):1504-1519. A mouse model placed on a NASH-promoting diet also demonstrates upregulation of the protein.Therefore, inhibition or degradation of HSD17B13 enzymatic activity is hypothesized to slow or prevent the progression of liver diseases such as non-alcoholic fatty liver disease (NAFLD), including NASH (non-alcoholic steatohepatitis), liver inflammation, fibrosis, cirrhosis, and the development of hepatocellular carcinoma. Summary of the Invention [Problem to be solved by the invention]

[0003] Although there has been some initial research on HSD17B13, there remains a need for pharmaceutical agents that have HSD17B13 inhibitory / degrading activity and that are useful in treating, preventing or attenuating the manifestations of the diseases described herein. [Means for solving the problem]

[0004] The present application relates to a compound of formula I

[0005] [ka] [In the formula, A is —NH—C(O)— or heteroaryl having 1, 2, 3, or 4 heteroatoms selected from O, N, and S; A is selected from one or two R 4 may be substituted with B is absent or H, aryl, heteroaryl, heterocyclyl, fluoro, chloro, bromo, oxo, cyano, hydroxyl, (C-C)alkyl, (C-C)cycloalkyl, (C-C)fluoroalkyl, (C-C)alkoxy, or (C-C)fluoroalkoxy, where the heteroaryl or heterocyclyl has 1, 2, or 3 heteroatoms selected from O, N, and S, and B is selected from 1 or 2 R 5 may be substituted with C is absent or H, -NH-C(O)-R 7 , -S(O)2-R 7 , -OS(O)2-R 7, fluoro, chloro, bromo, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloether, (C1-C6)fluoroalkyl, (C1-C6)fluoroalkoxy, aryl, heteroaryl, or heterocyclyl, wherein heteroaryl or heterocyclyl has 1, 2, or 3 heteroatoms selected from O, N, and S, and C is selected from 1, 2, or 3 R 6 may be substituted with R 1 , R 2 , and R 3 are each independently selected from H and fluoro; Each R 4 , R 5 and R 6 are independently selected from oxo, hydroxyl, chloro, fluoro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl, (C3-C6)cycloalkyl, and heterocyclyl having 1, 2, or 3 heteroatoms selected from O and N; R 7 is hydroxyl, chloro, fluoro, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) fluoroalkyl, or (C3-C6) cycloalkyl; n is 0, 1, or 2. or a pharmaceutically acceptable salt of said compound.

[0006] The present application also relates to the treatment of fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, non-alcoholic steatohepatitis with cirrhosis, hepatocellular carcinoma, alcoholic fatty liver disease, alcoholic steatohepatitis, hepatitis B, hepatitis C, biliary cirrhosis, renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, gastric adenocarcinoma, adrenocortical carcinoma, papillary renal cell carcinoma, cervical and endocervical carcinoma carcinoma, urothelial carcinoma of the bladder, lung adenocarcinoma, type 1 diabetes, idiopathic type 1 diabetes (type 1b), latent autoimmune diabetes of adults (LADA), early-onset type 2 diabetes (EOD), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and impaired vascular compliance The present invention is directed to a method for treating chronic kidney disease (CKD), kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, and maple syrup urine disease by administering to a human in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt of said compound.

[0007] The present application is also directed to a method of reducing the incidence of cirrhosis, cirrhotic decompensation, progression to a Model for End-Stage Liver Disease (MELD) score of 15 or greater, liver transplantation, liver-related death, and hepatocellular carcinoma by administering to a human in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0008] The present application is also directed to pharmaceutical compositions having a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier, vehicle, or diluent.

[0009] The present application also a first compound which is a compound of formula I or a pharmaceutically acceptable salt of said compound; a second compound which is an antidiabetic agent; an agent for treating non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, or an anti-heart failure agent; and a pharmaceutical carrier, vehicle, or diluent. The present invention is directed to a pharmaceutical combination composition comprising a therapeutically effective amount of a composition having:

[0010] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present application may be understood more readily by reference to the following detailed description of exemplary embodiments and examples of the invention contained herein.

[0012] It should be understood that the present invention is not limited to the specific synthetic methods used to make them, which may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. In this specification and in the claims that follow, reference will be made to several terms that shall be defined to have the following meanings:

[0013] As used herein in this specification, "a" or "an" may mean one or more. As used herein in the claims, when used in conjunction with the word "comprising," the words "a" or "an" may mean one or more than one. As used herein, "another" may mean at least a second or more.

[0014] The term "about" refers to a relative term indicating an approximation of ±10%, in one embodiment ±5%, and in another embodiment ±2% of the associated nominal value. Within the scope of this disclosure, this level of approximation is appropriate unless the value is specifically stated to require a more precise range.

[0015] The term "and / or" means one or more. For example, "X and / or Y" shall be understood to mean either "X and Y" or "X or Y," and shall be interpreted as providing clear support for both meanings or for either meaning. Similarly, when more than two designations are listed, such as in "X, Y and / or Z," this shall be understood to mean either i) "X and Y," "X, Y and Z," "X and Z," or "Y and Z," or ii) "X or Y or Z," and shall be interpreted as providing clear support for all meanings.

[0016] The term “alkyl”, alone or in combination, refers to a group of the formula C, which may be linear or branched. n H 2n+1 "Alkyl" refers to an acyclic saturated hydrocarbon group of the formula: ##STR1## Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl, and t-butyl. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by prefixes that specify the lower and upper number of carbon atoms in the moiety, i.e., the prefix C i ~C j denotes a moiety from integer "i" to integer "j" carbon atoms, inclusive. Thus, for example, C1-C3 alkyl refers to an alkyl of 1 to 3 carbon atoms, inclusive.

[0017] "Fluoroalkyl" means alkyl, as defined herein, substituted with 1, 2, or 3 fluoro atoms. Exemplary (C1) fluoroalkyl compounds include fluoromethyl, difluoromethyl, and trifluoromethyl; exemplary (C2) fluoroalkyl compounds include 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, 1,1,2-trifluoroethyl, and the like.

[0018] "Cycloalkyl" refers to a group of the formula C n H 2n-1 refers to a non-aromatic ring that is a fully hydrogenated group of the formula: Examples of such carbocyclic rings include cyclopropyl and cyclobutyl.

[0019] "Fluorocycloalkyl" means a non-aromatic cycloalkyl ring, as defined herein, substituted with one, two, or three fluoro atoms. Exemplary (C3) fluorocycloalkyl compounds include fluorocyclopropyl, difluorocyclopropyl, and trifluorocyclopropyl; exemplary (C4) fluorocycloalkyl compounds include 1-fluorocyclobutyl, 2-fluorocyclobutyl, 1,1-difluorocyclobutyl, 1,2-difluorocyclobutyl, 1,1,1-trifluorocyclobutyl, 1,1,2-trifluorocyclobutyl, and the like.

[0020] "Alkoxy" means a straight-chain saturated alkyl or branched-chain saturated alkyl bonded through an oxy. Illustrative of such alkoxy groups (assuming the specified length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, hexoxy, isohexoxy, heptoxy, and octoxy.

[0021] "Fluoroalkoxy" means alkoxy, as defined herein, substituted with one, two, or three fluoro atoms. Exemplary (C1) fluoroalkoxy compounds include fluoromethoxy, difluoromethoxy, and trifluoromethoxy; exemplary (C2) fluoroalkyl compounds include 1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 1,1,1-trifluoroethoxy, 1,1,2-trifluoroethoxy, and the like.

[0022] "Halo" refers to bromo, chloro, fluoro or iodo.

[0023] The term "heteroaryl" refers to a monovalent or divalent group that contains at least one aromatic ring and at least one ring member that is a heteroatom (e.g., 1 to 5 heteroatoms, each independently N, O, or S). The total number of ring members is sometimes indicated (e.g., 5-10 membered heteroaryl). A heteroaryl group can include two fused rings where at least one of the rings is aromatic and the other is aromatic, saturated, or partially unsaturated, and at least one of the fused rings contains a heteroatom.

[0024] When "ene" is added to the end of a term after "yl" to form a new term, the new term refers to a diradical formed by removing one hydrogen atom from the original term from which the new term is derived. For example, alkylene refers to a diradical group formed by removing one hydrogen atom from an alkyl group, and "methylene" refers to the divalent radical -CH2- derived by removing one hydrogen atom from methyl. Further examples of such diradicals include, but are not limited to: alkenylene, alkynylene, cycloalkylene, phenylene, heterocyclylene, and heteroarylene, which are derived from alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, and heteroarylene. "C 1~3Non-limiting examples of "alkylene" include: -CH2-, -CH(CH3)-, -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, and -CH(CH2CH3)-. In cyclic moieties, hydrogen removal can occur at any atom with sufficient valence.

[0025] As used herein, "compound" includes conformational isomers (e.g., cis and trans isomers), atropisomers (i.e., stereoisomers resulting from hindered rotation), and all optical isomers (e.g., enantiomers and diastereoisomers), racemic, diastereomeric, and other mixtures of such isomers, as well as any pharmaceutically acceptable derivatives or modifications, including solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The term "prodrug" refers to a compound that is a drug precursor that, upon administration, releases the drug in vivo through some chemical or physiological process (e.g., upon reaching physiological pH or through enzymatic action, the prodrug is converted to the desired drug form). Upon cleavage, exemplary prodrugs release the corresponding free acid, and such hydrolyzable ester-forming residues of compounds of Formula I include, but are not limited to, those in which the free hydrogen is (C1-C4) alkyl, (C2-C7) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms. N,N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and those having a carboxyl moiety replaced by piperidino-, pyrrolidino-, or morpholino(C2-C3)alkyl.

[0026] As used herein, an arrow

[0027] [ka] or wavy line

[0028] [ka] indicates the point of attachment of a substituent to another group.

[0029] As used herein, "deuterium enrichment factor" refers to the ratio between the deuterium abundance and the natural abundance of deuterium, respectively, relative to the hydrogen abundance. Atomic locations designated as having deuterium typically have an atomic ratio of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 ( deuterium incorporation rate of at least 67.5%, at least 5000 (75% deuterium incorporation rate), at least 5500 (82.5% deuterium incorporation rate), at least 6000 (90% deuterium incorporation rate), at least 6333.3 (95% deuterium incorporation rate), at least 6466.7 (97% deuterium incorporation rate), at least 6600 (99% deuterium incorporation rate), or at least 6633.3 (99.5% deuterium incorporation rate).

[0030] The term "mammal" refers to humans, domestic animals or companion animals.

[0031] The term "companion animal" or "companion animals" refers to animals kept as pets or household animals. Examples of companion animals include dogs, cats, and rodents, including hamsters, guinea pigs, gerbils, etc., rabbits, and ferrets.

[0032] The term "livestock" refers to animals that are kept or raised in an agricultural environment to produce products such as food or fiber, or for their labor. In some embodiments, livestock are suitable for consumption by mammals, e.g., humans. Examples of livestock animals include cows, goats, horses, pigs, sheep, including lambs, and rabbits.

[0033] "Patient" refers to warm-blooded animals such as, for example, guinea pigs, minipigs, mice, rats, gerbils, cats, rabbits, dogs, cows, goats, sheep, horses, monkeys, chimpanzees, and humans.

[0034] The term "treating" or "treatment" refers to the alleviation of symptoms associated with a disease, disorder, or condition, or the halting of further progression or worsening of those symptoms. Depending on the patient's disease and condition, the term "treatment" as used herein may include one or more of curative, palliative, and preventive treatment. Treatment may also include administering a pharmaceutical preparation in combination with other therapies.

[0035] "Therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

[0036] The term "pharmaceutically acceptable" means a substance (e.g., a compound of the invention) and any salt thereof, or a composition containing a substance or salt of the invention, that is suitable for administration to a patient. It is understood that when referring to a compound of Formula I, pharmaceutically acceptable salts of said compound are also contemplated, unless otherwise stated.

[0037] In one embodiment of the compound, the compound has formula IA

[0038] [ka] or a pharmaceutically acceptable salt of said compound.

[0039] In one embodiment of the compound, the compound has formula IB

[0040] [ka] or a pharmaceutically acceptable salt of said compound.

[0041] In one embodiment of the compound, R 2 is F, or a pharmaceutically acceptable salt of said compound.

[0042] In one embodiment of the compound, A is thiazolyl, pyrazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, imidazotriazinyl, imidazopyridazinyl, imidazopyridinyl, benzimidazolyl, benzothiazolyl, purinyl, pyridopyridazinyl, quinazolinyl, indazolyl, imidazopyridinyl, benzoxazolyl, pyrazolopyridinyl, isoindolinonyl, triazolyl, or oxadiazolyl, or a pharmaceutically acceptable salt thereof.

[0043] In another embodiment of the compound, A is

[0044] [ka] is.

[0045] In another embodiment of the compound, B is absent or H, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, piperazinyl, quinoxalinyl, phenyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, imidazolyl, indazolyl, (C1-C6)alkyl, (C1-C6)fluoroalkyl, (C1-C6)alkoxy, bromo, chloro, fluoro, or oxo, and B is optionally substituted with one or two fluoro, oxo, hydroxyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)fluoroalkyl, (C1-C6)alkoxy, or (C3-C6)cycloether; or a pharmaceutically acceptable salt of said compound.

[0046] In another embodiment of the compound, B is pyrimidinyl, (C1-C3)fluoroalkyl-substituted pyrimidinyl, (C1-C3)alkyl-substituted pyrazolyl, methoxy-substituted pyridazinyl, difluoromethyl-substituted pyrazinyl, trifluoromethyl-substituted pyrimidinyl, or methoxy-substituted pyrimidinyl; or a pharmaceutically acceptable salt of said compound.

[0047] In another embodiment of the compound, C is absent or H, pyridinyl, piperazinyl, oxolanyl, (C-C)cycloalkyl, (C-C)alkyl, (C-C)fluoroalkyl, (C-C)alkoxy, cyano, bromo, chloro, fluoro, or oxo, and C is optionally substituted with one, two, or three fluoro, oxo, hydroxyl, (C-C)alkyl, (C-C)cycloalkyl, (C-C)fluoroalkyl, or (C-C)alkoxy; or a pharmaceutically acceptable salt of said compound.

[0048] In another embodiment of the compound, C is absent or is pyridinyl, piperazinyl, (C-C)cycloalkyl, (C-C)alkyl, (C-C)fluoroalkyl, C optionally substituted with 1, 2, or 3 fluoro, oxo, hydroxyl, or (C-C)alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment of the compound, the compound is 2,3,5-trifluoro-4-hydroxy-N-[(4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide; 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide; ,3,5-Trifluoro-4-hydroxy-N-({4-[6-(pyrimidin-2-yl)-2H-indazol-2-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide; 2,3,5-Trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide; 2,3,5-Trifluoro-4-hydroxy-N-({4-[3-(6-methoxypyridazin-3-yl)pyridazin-3-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide N-[(4-{5-[5-(difluoromethyl)pyrazin-2-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]-3,5-difluoro-4-hydroxybenzamide;3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1 ,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide;3,5-difluoro-4-hydroxy-N-({(1r,4r)-4-[6-(2-methoxypyrimidin-5-yl)-2H-pyrazolo[4,3-c]pyridin-2-yl]cyclohexyl}methyl)benzamide;2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(piperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide or 2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide, or a pharmaceutically acceptable salt of said compound.

[0049] In one compound embodiment, the compound is 2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment of the present invention, a method for treating fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma comprises administering to a human in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0051] In one embodiment of the present invention, the method comprises treating non-alcoholic steatohepatitis.

[0052] In one embodiment of the present invention, a pharmaceutical composition comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

[0053] In one embodiment of the present invention, the pharmaceutical combination composition comprises a therapeutically effective amount of a composition comprising: a first compound which is a compound of Formula I or a pharmaceutically acceptable salt of said compound; a second compound which is an antidiabetic agent; an agent for treating non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, or an anti-heart failure agent; and a pharmaceutical carrier, vehicle, or diluent.

[0054] In one embodiment of the present invention, the non-alcoholic steatohepatitis treating agent or non-alcoholic fatty liver disease treating agent in the pharmaceutical combination composition is an ACC inhibitor, a KHK inhibitor, a DGAT-2 inhibitor, an FXR agonist, metformin, an incretin analog, or an incretin receptor modulator.

[0055] In one embodiment of the present disclosure, the antidiabetic agent is an SGLT-2 inhibitor, metformin, an incretin analog, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist.

[0056] The present invention includes compounds of the present invention that are E3 ligase ligands or targeting protein ligands that are covalently linked to ligands known to interact with ubiquitin proteasome system (Degron) via linkers of various lengths and functional groups.When the compounds of the present invention are linked to Degron in this way, they are referred to herein as bifunctional compounds of the present invention.Compounds of the present invention are generally referred to as targeting ligands within the scope of these bifunctional compounds of the present invention.These bifunctional compounds of the present invention can be used as therapeutics to treat various diseases, including various liver diseases.

[0057] The bifunctional compounds of the present invention have the general structure: Degron-Linker-Targeting Ligand, where the Linker is covalently attached to at least one Degron and at least one Targeting Ligand, the Degron is a compound capable of binding to a ubiquitin ligase such as an E3 ubiquitin ligase (e.g., cereblon (CRBN), von Hippel-Lindau (VHL), etc.), and the Targeting Ligand is capable of binding to the targeting protein HSD17B13, and are compounds of the present invention as represented in any embodiment described herein. Such bifunctional compounds of the present invention are generally represented as compounds of Formula II, where L is a Linker and D is a Degron:

[0058]

change

[0059] Degrons are small in size and highly effective in recruiting target proteins for degradation. Degrons are compounds that serve to link target proteins to ubiquitin ligase for proteasomal degradation via a linker and a targeting ligand. In certain embodiments, Degrons are compounds that can bind to or bind to ubiquitin ligase. In further embodiments, Degrons are compounds that can bind to or bind to E3 ubiquitin ligase, including cereblon, and Degrons are thalidomide, lenalidomide, pomalidomide, or iverdomide, or novel IMiD CRBN ligands or analogs thereof disclosed in WO2019 / 060693, WO2019 / 140387, and WO2019 / 236483. In a further embodiment, a Degron is a compound that can bind to or that binds to an E3 ubiquitin ligase, including a von Hippel-Lindau ligand.For example, WO2020 / 092907;WO2013106643;Buckley et al., J.Am.Chem.Soc. 2012, 134, 4465~4468, “Targeting the Von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt the VHL / Hif-1alpha 2019, 61, 599-618, "Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase:Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298). In a further embodiment, Degron is a compound that can bind to or binds to E3 ubiquitin ligases, including inhibitors of apoptosis protein ligases (IAP1, IAP2, XIAP).See, e.g., Itoh et al., J. Am. Chem. Soc. 2010, 132, 5820-5826, "Protein Knockdown Using Methyl Bestatin-Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins," Mares et al., Commun. Biol. 2020, 3, 140, "Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2," and Tinworth et al., ACS Chem. Biol. 2019, 14, 342-347, "PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase Is Inhibited by Covalent Binding." In further embodiments, Degrons are compounds that can bind to or bind to other ubiquitin proteasome proteins that can induce degradation, including, but not limited to, the Hsp70 / 90 chaperone complex (WO2020 / 207395), Usp14 (WO2019 / 238886), UchL5 (WO2019238816), BILO (WO201719705), and Rpn11 (WO2019 / 238817).

[0060] In certain embodiments, the Linker is designed and optimized based on the SAR (structure-activity relationship) and X-ray crystallography of the Targeting Ligand with respect to the binding site for the Linker.

[0061] In certain embodiments, the optimal linker length and composition vary depending on the target and can be estimated based on the X-ray structure of the original targeting ligand bound to that target. Linker length and composition can also be altered to modulate metabolic stability and pharmacokinetic (PK) and pharmacodynamic (PD) parameters.

[0062] In certain embodiments, when a Target Ligand binds to multiple targets, selectivity can be achieved by varying the Linker length, such that the Ligand binds to some of its targets in different binding pockets, e.g., deeper or shallower binding pockets than others.

[0063] The Linker ("L") provides a covalent bond between the Targeting Ligand and the Degron. The Linker has two terminal groups, one of which binds to the Degron and the other to the Targeting Ligand. The structure of the Linker is not critical, provided that it does not substantially interfere with the activity of the Targeting Ligand or the Degron. In some embodiments, the Linker is an alkyl chain (e.g., having 2-20 alkyl units) or a polyethylene glycol (PEG) chain (CH2CH2-O or (O-CH2CH2)). In other embodiments, the Linker may be an alkylene chain, a PEG chain, or a divalent alkylene chain, any of which may contain at least one of the following: -O-, -S-, -N(R L )-, -C=C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR L )-, -C(O)N(R L )-, -C(O)N(R L )C(O)-, -C(O)N(R L )C(O)N(R L )-, -N(R L )C(O)-, -N(R L )C(O)N(R L )-, -N(R L )C(O)O-, -OC(O)N(R L)-, -C(NR L )-, -N(R L )C(NR L )-, -C(NR L )N(R L )-, -N(R L )C(NR L )N(R L )-, -OB(CH3)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R L )S(O)2-, -S(O)2N(R L )-, -N(R L )S(O)-, -S(O)N(R L )-, -N(R L )S(O)2N(R L )-, -N(R')S(O)N(R')-, C 3~12 may be interrupted and / or terminated (at either or both termini) by carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or arylene, or any combination thereof; R L is H or C 1~6 It is alkyl, and the interrupting and one or both terminal groups may be the same or different.

[0064] In some embodiments, the Linker is a C 1~10 The nitrogen may be an alkylene chain, the nitrogen of which is also bonded to a Degron, or the Linker may be a C 1~10 It may be an alkylene chain or a PEG chain having 1 to 8 PEG units, -(CH2) n’ It may be interrupted or terminated by -C(O)-NH-, and n' is 0 to about 5. In Linker, "carbocyclene" refers to an optionally substituted divalent carbocyclic radical. "heterocyclylene" refers to an optionally substituted divalent heterocyclyl radical. "heteroarylene" refers to an optionally substituted divalent heteroaryl radical.

[0065] Non-limiting examples of Linkers include -(CH2) n’-, -(CH2CH2-O) n’’ -(CH2) n’ -C(O)-, (CH2) n’ -C(O)-N(R L )-(CH2CH2-O) n’’ -(CH2) n’ -C(O)-, -(CH2CH2-O) n’’ -(CH2) n’ -N(R L )-C(O)-, -(CH2CH2-O) n’’ -(CH2) n’ -C(O)-N(R L )-, -(CH2) n’ -phenylene-N(R L )-C(O)-(CH2) n’ -, -N(R L )-(CH2) n’ -O-phenylene-(CH2) n’’ -N(R L )-(CH2) n’ -, -(CH2) n’ -C(O)-N(R L )-phenylene-C(O)-, -N(R L )-(CH2) n’ -phenylene-(CH2) n” -Heterocyclylene-, -(CH2) n’ -phenylene-N(R L )-C(O)-(CH2CH2-O) n” -(CH2) n’ -,-(CH2) n’ -phenylene-(CH2) n” -Heterocyclylene-(CH2) n” C(O)-N(R L )-(CH2) n’ -, -(CH2) n’ -phenylene-O-(CH2) n’ -Heterocyclylene-(CH2) n’ -, -(CH2) n’ -phenylene-(CH2) n’ -Heterocyclylene-(CH2) n’ -O-, -(CH2) n’ -Heterocyclylene-(CH2) n’ Contains RL is H or C 1~6 alkyl, n' is 0 to about 10, and n'' is 1 to about 10.

[0066] Another embodiment includes a compound selected from any of the examples described herein, or a pharmaceutically acceptable salt thereof.

[0067] Another embodiment includes a prodrug of any of the examples described herein, or a pharmaceutically acceptable salt thereof.

[0068] Another embodiment includes a phosphate ester prodrug of any of the examples described herein, or a pharmaceutically acceptable salt thereof.

[0069] Another embodiment includes any novel genus of intermediates described in the general schemes or examples.

[0070] Another embodiment includes any novel specific intermediates described in the preparations and examples described herein.

[0071] Another embodiment includes any of the novel processes described herein.

[0072] All pharmaceutically acceptable isotopically labeled compounds of Formula I in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature are within the scope of this application.

[0073] Examples of isotopes suitable for inclusion in the compounds of the invention include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 chlorine such as Cl, 18 Fluorine such as F, 13 N and 15 Nitrogen such as N15 O. 17 O and 18 Oxygen, such as O, 35 It contains isotopes of sulfur such as S.

[0074] Certain isotopically-labeled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and rapid means of detection.

[0075] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may be preferable in some cases as they may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0076] 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0077] Isotopically labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying Examples and Preparations, substituting the appropriate isotopically labeled reagent for the previously used unlabeled reagent.

[0078] Certain compounds of Formula I and intermediates described herein may exist in more than one crystalline form (generally referred to as "polymorphs").Polymorphs can be prepared under various conditions, for example, by crystallization using different solvents or different solvent mixtures for recrystallization; crystallization at various temperatures; and / or by various cooling modes ranging from very fast to very slow cooling during crystallization.Polymorphs can also be obtained by heating or melting a compound, followed by gradual or rapid cooling.The presence of polymorphs can also be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other such techniques.

[0079] The salts encompassed by the term "pharmaceutically acceptable salts" generally refer to compounds of the present invention prepared by reacting a free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to obtain a salt of the compound of the present invention that is suitable for administration to a patient. Base salts are preferred; however, some compounds can also form acid salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, and lactate. , malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0080] Suitable base salts are formed from bases that form non-toxic salts.Examples include aluminum, arginine, calcium, choline, diethylamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.Half-salts of acids and bases, such as hemisulfate and hemi-calcium salts, can also be formed.For a general overview of suitable salts, refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0081] Hemisalts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0082] Pharmaceutically acceptable salts of compounds of formula I can be prepared in three ways: (i) by reacting a compound of formula I with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) by converting one salt of a compound of the invention into another salt by reaction with an appropriate acid or base or using a suitable ion exchange column. Each of the compounds can be prepared by one or more of the following methods.

[0083] All three reactions are typically carried out in solution. The resulting salts can be precipitated and collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the resulting salts can vary from completely ionized to nearly non-ionized.

[0084] The compound of formula I and its pharmaceutically acceptable salts can exist in unsolvated and solvated forms.The term "solvate" is used herein to describe a molecular complex comprising the compound of formula I or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable solvent molecules, such as ethanol.The term "hydrate" is used when the solvent is water.

[0085] The currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal ion coordinated hydrates. See Polymorphism in Pharmaceutical Solids by KR Morris (HGBrittain, ed., Marcel Dekker, 1995). Isolated site hydrates are hydrates in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules reside in lattice channels where they are adjacent to other water molecules. In metal ion coordinated hydrates, the water molecules are bound to the metal ion.

[0086] When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may depend on humidity and drying conditions. In such cases, non-stoichiometry becomes the norm.

[0087] Multicomponent complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts are also included within the scope of the present invention. This type of complex includes clathrates (drug-host inclusion complexes) and cocrystals. The latter are typically defined as crystalline complexes of neutral molecular components bound together by noncovalent interactions, but could also be complexes of neutral molecules and salts. Cocrystals can be prepared by melt crystallization, recrystallization from solvents, or physical grinding of the components together. See O. Almarsson and MJ Zaworotko (2004), Chem Commun, 17; 1889-1896. For a general review of multicomponent complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975).

[0088] Active metabolites of compounds of Formula I (including prodrugs), i.e., compounds formed in vivo upon administration of the drug, often by oxidation or dealkylation, are also included within the scope of the present invention. Some examples of metabolites according to the present invention include: (i) When the compound of formula I contains a methyl group, its hydroxymethyl derivative (-CH- → -CHOH): and (ii) If the compound of formula I contains an alkoxy group, its hydroxy derivative (-OR → -OH) Includes:

[0089] The compounds of the present invention can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid, depending on temperature. Typically, such materials do not exhibit a distinctive X-ray diffraction pattern and, while exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, which is typically characterized by a second-order change of state ("glass transition"). The term "crystalline" refers to a solid phase in which the material has an internal structure that is regularly ordered at the molecular level and exhibits a distinctive X-ray diffraction pattern with defined peaks. When such materials are heated sufficiently, they also exhibit the properties of a liquid, but the change from solid to liquid is typically characterized by a first-order phase change ("melting point").

[0090] Compounds of Formula I may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. A mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphic states that arise as a result of a change in temperature are described as "thermotropic," while those that arise upon the addition of a second component, such as water or another solvent, are described as "lyotropic." Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic," and those that form ionic (-COO - Na + , -COO - K + , or -SO3 - Na + ) or non-ionic (-N - N + They consist of molecules with polar head groups (e.g., (CH3)3). For more information, see Crystals and the Polarizing Microscope, 4th Edition, by N.H. Hartshorne and A. Stuart (Edward Arnold, 1970).

[0091] Compounds of Formula I may exhibit polymorphism and / or one or more types of isomerism (e.g., optical, geometric, or tautomerism). Compounds of Formula I may also be isotopically labeled. Such variations are implicit in compounds of Formula I as defined by reference to their structural features and, therefore, are within the scope of the present invention.

[0092] The terms "concentrated," "evaporated," and "concentrated in vacuo" refer to the removal of solvent at reduced pressure in a rotary evaporator with a bath temperature below 60°C. The abbreviations "min" and "h" stand for "minutes" and "hours," respectively. The term "room or ambient temperature" refers to a temperature between 18 and 25°C. "GCMS" refers to gas chromatography-mass spectrometry, "LCMS" refers to liquid chromatography-mass spectrometry, "UPLC" refers to ultra-performance liquid chromatography, "SFC" refers to supercritical fluid chromatography, "HPLC" refers to high-pressure liquid chromatography, "MPLC" refers to medium-pressure liquid chromatography, "TLC" refers to thin-layer chromatography, and "MS" refers to mass spectrometry or mass spectrometry or mass spectrometry. "NMR" refers to nuclear magnetic resonance spectroscopy, "DCM" refers to dichloromethane, "DMSO" refers to dimethyl sulfoxide, "DME" refers to 1,2-dimethoxyethane, "EtOAc" refers to ethyl acetate, "MeOH" refers to methanol, "Ph" refers to a phenyl group, "Pr" refers to propyl, "trityl" refers to a triphenylmethyl group, "ACN" refers to acetonitrile, "DEAD" refers to diethyl azodicarboxylate, and "DIAD" refers to diisopropyl azodicarboxylate.

[0093] In general, the compounds of the present invention can be made by processes that include processes similar to those known in the chemical arts, particularly in light of the description contained herein.Certain processes for producing the compounds of the present invention are provided as further features of the present invention and are illustrated by the following reaction schemes.Other processes may also be described in the experimental section.Specific synthetic schemes for preparing compounds of formula I are outlined below.

[0094] As used herein, the expressions "reaction-inert solvent" and "inert solvent" refer to a solvent or mixture thereof that does not interact with the starting materials, reagents, intermediates, or products in a manner that adversely affects the yield of the desired product.

[0095] As an initial note on the preparation of compounds of Formula I, it should be noted that some of the preparation methods useful for preparing the compounds described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls in the precursors of Formula I). ​​The need for such protection will vary depending on the nature of the remote functional group and the conditions of its preparation method. Those skilled in the art will readily determine the need for such protection. The use of such protection / deprotection methods is also within the skill of the art. For a review of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0096] For example, if a certain compound contains a primary amine or carboxylic acid functional group, if it remains unprotected, it may interfere with reactions at other sites of the molecule. Therefore, such functional groups can be protected with a suitable protecting group that can be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include protecting groups commonly used in peptide synthesis (such as N-tert-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethyleneoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids), which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functional groups in the compound of Formula I.

[0097] The compounds and intermediates of formula I may contain asymmetric or chiral centers, and therefore may exist in various stereoisomeric forms.Unless otherwise specified, all stereoisomeric forms of compounds, as well as mixtures thereof, including racemic mixtures, are intended to be included herein.In addition, all geometric and positional isomers are included within the scope of the compounds.For example, if a compound has a double bond or a fused ring, both cis and trans forms, as well as mixtures, are included within the scope of the present invention.

[0098] In addition, the compounds and intermediates of Formula I encompass all atropisomers and stereoisomeric mixtures thereof, including racemic mixtures. Atropisomers include those that can be isolated as separate stereoisomers and maintain their stereoisomeric purity over various periods of time, including medium and long term. Atropisomers also include isomers that cannot be readily separated as separate stereoisomers by interconversion over some period of time, including short to medium term.

[0099] The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically high-pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC), on a resin using an asymmetric stationary phase and a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50%, typically 2-20%, isopropanol and 0-5% alkylamine, typically diethylamine (DEA) or 0.1% isopropylamine. The eluent is concentrated to obtain the enriched mixture.

[0100] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using chiral HPLC columns. Alternatively, specific stereoisomers can be synthesized by using optically active starting materials, by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by asymmetric transformation to convert one stereoisomer into another.

[0101] Where a compound has two or more asymmetric centers and the absolute or relative stereochemistry is indicated in the name, the symbols R and S each refer to each asymmetric center in ascending numerical order (1, 2, 3, etc.) according to the conventional IUPAC numbering scheme for each molecule. Where a compound has one or more asymmetric centers and the stereochemistry is not indicated in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemate.

[0102] The compounds of the present invention may contain olefin-like double bonds. When such bonds are present, the compounds of the present invention exist as cis and trans configurations, as well as mixtures thereof. The term "cis" refers to the orientation of two substituents relative to each other and to the plane of the ring (either both "up" or both "down"). Similarly, the term "trans" refers to the orientation of two substituents relative to each other and to the plane of the ring (these substituents are on opposite sides of the ring).

[0103] It is also possible that intermediates and compounds of Formula I may exist in different tautomeric forms, and all such forms are encompassed within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is a tetrazole moiety, in which a proton can migrate between the four ring nitrogens as follows:

[0104] [ka]

[0105] Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0106] All stereoisomers, geometric isomers, and tautomeric forms of the compounds of Formula I, including compounds exhibiting more than one type of isomerism and mixtures thereof, are included within the scope of the claimed compounds of the present invention. Also included are acid addition or base salts in which the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine.

[0107] Compounds of formula I can be prepared according to the general schemes and examples provided herein.

[0108] General Scheme In general, the compounds of the present invention can be made by the processes described herein and by similar processes known to those skilled in the art. Certain processes for producing the compounds of the present invention are described in the following reaction schemes. Other processes are described in the experimental section. The schemes and examples provided herein (including corresponding explanations) are for illustrative purposes only. The substituents labeled in Schemes 1-7 are as described in the present application, PMB is p-methoxybenzyl ether, and Boc is tert-butyloxycarbonyl.

[0109] Scheme 1 relates to the preparation of compounds of formula IA. Compounds of formula IA can be readily prepared from intermediates IV, VI, and VIII. Intermediate IV can be prepared from an amide bond formation reaction between carboxylic acid intermediate II and amine intermediate III. Similarly, intermediates VI and VIII can be prepared from an amide bond formation reaction between intermediate II and intermediates V and VII, respectively. This type of amide bond formation reaction can be achieved by combining a carboxylic acid (such as II) with an amine (such as III, V, or VII) in a suitable solvent (such as dichloromethane) in the presence of an activating reagent (such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HATU) and a base (such as N,N-diisopropylethylamine).

[0110] [ka]

[0111] Scheme 2 relates to the preparation of compounds of formulae IA-1, IA-2, IA-3, and IA-4 from intermediate IV. Hydrolysis of the ester in intermediate IV can provide intermediate IX. The carboxylic acid functionality in intermediate IX can be converted to various heteroaryl ring systems by methods known to those skilled in the art. For example, intermediate IX can be reacted with an aminophenol such as X under suitable conditions to provide a compound of formula IA-1 after removal of the PMB protecting group. Alternatively, intermediate IX can be coupled with an intermediate of structure XI, and the resulting compound can be further dehydrated and deprotected to provide a compound of formula IA-2. Those skilled in the art will also recognize that the carboxylic acid in intermediate IX can be converted to another functional group that may have additional functionality for constructing other heteroaryl ring systems. For example, the carboxylic acid in compound IX can be converted to a bromoketone by methods known in the art to provide intermediate XII. Intermediate XII can be reacted with an aminopyridine (XIII) followed by deprotection to prepare a compound of formula IA-3. Alternatively, the carboxylic acid in IX can be converted to a primary amide, followed by dehydration to provide a nitrile-containing intermediate of structure XIV. Intermediate XIV can be reacted with hydroxylamine to provide compound XV. Compounds of structure XV can be reacted with carboxylic acids of structure XVI. The resulting compounds can be dehydrated and deprotected to form oxadiazole-containing compounds of formula IA-4.

[0112] [ka]

[0113] Scheme 3 relates to the preparation of compounds of formula IA-5 and IA-6 from intermediate VI. The Boc protecting group in intermediate VI can be selectively removed to give intermediate XVII. Intermediate XVII can be reacted with a nitroaldehyde-containing compound (XVIII) in the presence of a trialkylphosphine to give a compound of formula IA-5 after removal of the PMB protecting group. Alternatively, compound XVII can be reacted with a bromoester-containing compound (XIX) followed by deprotection to give a compound of formula IA-6.

[0114] [ka]

[0115] Scheme 4 relates to the preparation of compounds of formula IA and IA-7 from intermediate VIII. Intermediates of structure VIII can be reacted with aryl and heteroaryl halides (XX) in the presence of a suitable metal-containing catalyst and ligand to give compounds of formula IA after removal of the PMB protecting group. Alternatively, the bromide can be displaced from intermediate VIII with sodium azide. The resulting intermediate can be reacted with an alkyne-containing compound (XXI) in the presence of a copper catalyst to give compounds of formula IA-7.

[0116] [ka]

[0117] Scheme 5 relates to an alternative preparation of a compound of formula IA-5. In some instances, compounds can be prepared by the methods described herein containing substituents that can be utilized synthetically to prepare alternative compounds of formula IA. For example, an intermediate of structure XXII can be prepared by the methods described for preparing a compound of formula IA-5. The bromine substituent in intermediate XXII can be reacted with a boronic acid (XXIII) or a boronic ester (XXIII) via a Suzuki reaction to obtain a compound of formula IA-5. Additionally, a compound of structure XXII can be reacted with an intermediate of structure XXIV, in which BH represents a primary or secondary amine. In this example, XXII and XXIV can be reacted with each other under Buchwald reaction conditions to obtain another variant of the compound of formula IA-5. Alternatively, the bromine substituent in XXII can be converted to a boronic acid (XXV; R = H) or a boronic ester (XXV; R = alkyl). A compound of structure XXV can be reacted with an aryl or heteroaryl halide of structure XXVI to obtain a compound of formula IA-5. Additionally, compounds of structure XXV can be reacted with an NH-bearing aromatic heterocycle (XXIV') under Cham-Lam coupling conditions to give compounds of formula IA-5. The examples of transformations presented in Scheme 5 are not intended to be comprehensive. The examples provided are merely isolated examples of synthetic sequences that can be used to vary the B- and C-substituents of compounds of formula IA. Those skilled in the art will also recognize that similar transformations can be achieved with compounds containing alternative A-substituents from those depicted in Scheme 5.

[0118] [ka]

[0119] Scheme 6 relates to the preparation of compounds of formula IB. Compounds of formula IB can be readily prepared from intermediates XXIX and XXX. Intermediate XXIX can be prepared from an amide bond formation reaction between carboxylic acid intermediate II and amine intermediate XXVII. Similarly, intermediate XXX can be prepared from an amide bond formation reaction between intermediate II and intermediate XXVIII. This type of amide bond formation reaction can be achieved by combining a carboxylic acid (such as II) with an amine (such as XXVII or XXVIII) in a suitable solvent (such as dichloromethane) in the presence of an activating reagent (such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HATU) and a base (such as N,N-diisopropylethylamine). Compounds of formula IB can be prepared from intermediate XXIX by methods similar to those described for preparing compounds of formula IA from intermediate IV in Schemes 2 and 5. Similarly, the preparation of compounds of formula IB can be achieved from intermediate XXX by methods similar to those described for the preparation of compounds of formula IA from intermediate VI in Scheme 3 and Scheme 5.

[0120] [ka]

[0121] Scheme 7 relates to another sequence of synthetic steps that can be used to prepare a compound of formula IA or a compound of formula IB. For example, intermediates such as XXXI, XXXII, or XXXIII can be converted to intermediates of structure XXXIV by the methods described herein. Amine intermediates of structure XXXIV can be reacted with carboxylic acids of structure II in an amide bond formation reaction. The resulting product can be deprotected to give compounds of formula IA. Similarly, intermediates such as XXXV and XXXVI can be converted to intermediates of structure XXXVII. Amine intermediates of structure XXXVII can be reacted with carboxylic acids of structure II, followed by deprotection to give compounds of formula IB.

[0122] [ka]

[0123] The starting materials and reagents for the compounds of formula I above are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis.For example, many of the compounds used herein are related to or derived from compounds of great scientific importance and commercial need, and therefore many such compounds are commercially available, or have been reported in the literature, or can be easily prepared from other commercially available materials by methods reported in the literature.

[0124] The present application is also directed to pharmaceutical compositions having a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier, vehicle, or diluent.

[0125] The compounds of the present invention may also be used in conjunction with other pharmaceutical agents (e.g., anti-atherosclerotic and anti-thrombotic agents) to treat the diseases / conditions described herein. a first compound which is any compound of formula I or a pharmaceutically acceptable salt of said compound; a second compound that is a treatment for kidney disease, an antidiabetic agent; a treatment for nonalcoholic steatohepatitis, a treatment for nonalcoholic fatty liver disease, or an anti-heart failure treatment; and a pharmaceutical carrier, vehicle or diluent; The present invention is directed to a pharmaceutical combination composition comprising a therapeutically effective amount of a composition having:

[0126] In one embodiment, the therapeutic agent for kidney disease is useful for treating acute and / or chronic kidney disease.

[0127] In one embodiment, the drug treating non-alcoholic steatohepatitis or non-alcoholic fatty liver disease is an ACC inhibitor, a KHK inhibitor, a DGAT-2 inhibitor, an FXR agonist, a GLP-1R agonist, metformin, an incretin analog, or an incretin receptor modulator.

[0128] In another embodiment, the antidiabetic agent is an SGLT-2 inhibitor, metformin, an incretin analog, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist. In another embodiment, the antidiabetic agent is metformin, sitagliptin, or ertugliflozin.

[0129] In another embodiment, the anti-heart failure agent is an ACE inhibitor, angiotensin receptor blocker, angiotensin-receptor neprilysin inhibitor, beta adrenergic receptor blocker, calcium channel blocker, or vasodilator.

[0130] Combination drugs The compound can be administered alone or in combination with one or more additional therapeutic agents. "Administered in combination" or "combined treatment" means that the compound and one or more additional therapeutic agents are administered to the mammal being treated at the same time. When administered in combination, each component can be administered simultaneously or sequentially in any order at different times. Thus, each component can be administered separately, but within a time period sufficiently close enough to achieve the desired therapeutic effect. The phrases "co-administration," "co-administration," "simultaneous administration," and "administered simultaneously" mean that the compound is administered in combination. Therefore, the prevention and treatment methods described herein include the use of combination drugs.

[0131] The combination is administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" is meant the amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat the desired disease / condition (e.g., NASH, heart failure, kidney disease, or diabetes).

[0132] Given the NASH / NAFLD activity of the compounds of the present invention, they may be used in combination with other agents for treating non-alcoholic steatohepatitis (NASH) and / or non-alcoholic fatty liver disease (NAFLD) and related diseases / conditions, such as orlistat, TZDs and other insulin sensitizers, FGF21 analogs, metformin, omega-3-acid ethyl esters (e.g., Lovaza), fibrates, HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104, (also known as itavastatin or nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin or atavastatin or visastatin)), ezetimibe, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors (e.g., evolocumab, alirocumab), probucol, ursodeoxycholic acid, TGR5 agonists, FXR agonists, vitamin E, betaine, pentazocine xifylline, CB1 antagonists, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, naltrexone in combination with bupropion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin, ASP-1941, THR1474, TS-071, ISIS388626 and LX4211, as well as those in WO2010023594), phentermine, topiramate, GLP-1 receptor agonists, GIP receptor agonists, dual GLP -1 receptor / glucagon receptor agonists (i.e., OPK88003, MEDI0382, JNJ-64565111, NN9277, BI456906), dual GLP-1 receptor / GIP receptor agonists (i.e., tirzepatide (LY3298176), NN9423), angiotensin-receptor blockers, acetyl-CoA carboxylase (ACC) inhibitors, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors, such as those described in WO09016462 or WO2010086820,It may be co-administered with AZD7687 or LCQ908, a diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, a PNPLA3 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, an SCD1 inhibitor, or an MPO inhibitor.

[0133] Exemplary GLP-1 receptor agonists include liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, HM15211, LY3298176, Medi-0382, NN-9924, TTP-054, TTP-273, epheglenatide, those described in WO2018109607, and 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; and These include those described in PCT / IB2019 / 054867, filed June 11, 2019, which includes 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0134] Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-1′H-spiro[indazol-5,4′-piperidine]-1′-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid; and filsocostat (GS-0976), and pharmaceutically acceptable salts thereof.

[0135] Exemplary FXR agonists include tropifexor (2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid); cilofexor (GS-9674); obeticholic acid; LY2562175; Met409; TERN-101; and EDP-305, and pharmaceutically acceptable salts thereof.

[0136] Exemplary DGAT2 inhibitors include (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; and 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof.

[0137] Exemplary KHK inhibitors include [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid and pharmaceutically acceptable salts thereof.

[0138] Considering the antidiabetic activity of the compounds of the present invention, they can be co-administered with other antidiabetic drugs.Suitable antidiabetic drugs include insulin, metformin, GLP-1 receptor agonists (as described herein above), acetyl-CoA carboxylase (ACC) inhibitors (as described herein above), SGLT2 inhibitors (as described herein above), monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors, AMPK activators, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabine, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), meglitinides, α-amylase inhibitors (e.g., tendamistat, trestatin, and AL-3 688), α-glucoside hydrolase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), PPARγ agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), PPARα / γ agonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hiruthiosal extract, and Zhang, S.Drug Discovery Today, 12(9 / 10), 373-381(2007)), SIRT-1 activators (e.g., resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., those in WO2005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-Jun amino-terminal kinase (JNK) inhibitors, glucokinase inhibitors, glycogen phosphorylase activators (GKa), such as those described in WO2010103437, WO201010343f8, WO2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, insulin mimetics, glycogen phosphorylase inhibitors (e.g., GSK1362885), VPAC2 receptor agonists, glucagon receptor modulators, such as those described in Demong, DE et al., Annual Reports in Medicinal Chemistry 2008, 43, 119-137; GPR119 modulators, particularly agonists, for example, those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, RM et al., Medicinal Chemistry 2009, 44, 149-170 (e.g., MBX-2982, GSK1292263, APD597 and PSN821); FGF21 derivatives or analogs, for example, those described in Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, 10(4) 359-364; TGR5 (also called GPBAR1) receptor modulators, particularly agonists, for example, those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, JC, Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including, but not limited to, TAK-875, GPR120 modulators, particularly agonists, high-affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. Further representative lists of antidiabetic agents that can be combined with the compounds of the present application can be found, for example, on page 28, line 35 to page 30, line 19 of WO2011005611.

[0139] Other antidiabetic agents include inhibitors or modulators of the enzyme carnitine palmitoyltransferase, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5, inhibitors of PKC isoforms (e.g., PKC□, PKC□, PKC□), inhibitors of fatty acid synthetase, and inhibitors of serine palmitoyltransferase. These drugs may include inhibitors of enzymes such as GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol-binding protein 4, glucocorticoid receptors, modulators of somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of the IL1 family, including IL1 beta, and modulators of RXR alpha. Additionally, suitable antidiabetic drugs include those listed by Carpino, PA, Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

[0140] Considering the anti-heart failure activity of the compounds of the present application, they may be used in combination with other anti-heart failure drugs, such as ACE inhibitors (e.g., captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril), angiotensin II receptor blockers (e.g., candesartan, losartan, valsartan), angiotensin-receptor neprilysin inhibitors (sacubitril / valsartan), I f It may be co-administered with the channel blocker ivabradine, beta-adrenergic blockers (e.g., bisoprolol, metoprolol succinate, carvedilol), SGLT2 inhibitors, aldosterone antagonists (e.g., spironolactone, eplerenone), cardiac myosin activators (e.g., omecamtiv mecarbil), guanylate cyclase stimulators (e.g., vericiguat), cardiac myosin inhibitors (e.g., mavacamten), SERCA2a activators (e.g., istaloxime), hydralazine and isosorbide dinitrate, diuretics (e.g., furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, indapamide, metolazone, triamterene), or digoxin.

[0141] The compounds of formula I can also be used in combination with antihypertensive agents, and such antihypertensive activity is readily determined by those skilled in the art by standard assays (e.g., blood pressure measurements). Examples of suitable antihypertensive agents include alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine); vasodilators (e.g., hydralazine), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cirazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); dual ET / A11 antagonists (e.g., WO 00 / 01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary anti-anginal agent is ivabradine.

[0142] Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine and mibefradil.

[0143] Examples of suitable cardiac glycosides include digitalis and ouabain.

[0144] In one embodiment, a compound of Formula I can be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics, such as furosemide (such as LASIX™), torsemide (such as DEMADEX™), bumetanide (such as BUMEX™), and ethacrynic acid (such as EDECRIN™); (b) thiazide diuretics, such as chlorothiazide (such as DIURIL™, ESIDRIX™, or HYDRODIURIL™), hydrochlorothiazide (such as MICROZIDE™ or ORETIC™), benzothiazides, hydroflumethiazide (SALUR™), and thiazides. ON™), bendroflumethiazide, methychlorothiazide, polythiazide, trichlormethiazide, and indapamide (LOZOL™, etc.); (c) phthalimidine diuretics, such as chlorthalidone (HYGROTON™, etc.) and metolazone (ZAROXOLYN™, etc.); (d) quinazoline diuretics, such as quinethazone; and (e) potassium-sparing diuretics, such as triamterene (DYRENIUM™, etc.) and amiloride (MIDAMOR™ or MODURETIC™, etc.).

[0145] In another embodiment, a compound of Formula I can be co-administered with a loop diuretic. In yet another embodiment, the loop diuretic is selected from furosemide and torsemide. In yet another embodiment, one or more compounds of Formula I can be co-administered with furosemide. In yet another embodiment, one or more compounds of Formula I can be co-administered with torsemide, which may be a controlled-release or modified-release form of torsemide.

[0146] In another embodiment, a compound of Formula I can be co-administered with a thiazide diuretic. In yet another embodiment, the thiazide diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In yet another embodiment, one or more compounds of Formula I can be co-administered with chlorothiazide. In yet another embodiment, one or more compounds of Formula I can be co-administered with hydrochlorothiazide.

[0147] In another embodiment, one or more compounds of Formula I can be co-administered with a phthalimidine diuretic, hi yet another embodiment, the phthalimidine diuretic is chlorthalidone.

[0148] Examples of suitable mineralocorticoid receptor antagonists include spironolactone and eplerenone.

[0149] Examples of suitable phosphodiesterase inhibitors include PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

[0150] Those skilled in the art will appreciate that the compounds of the present invention can also be used in conjunction with other cardiovascular or cerebrovascular procedures, including PCI, stenting, drug-eluting stents, stem cell therapy and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.

[0151] The compounds of Formula I may be used in combination with drugs used in the management of chronic kidney disease, including phosphate binders (e.g., sucroferric oxyhydroxide, sevelamer, calcium acetate), sodium bicarbonate, erythropoietin stimulators, oral or intravenous iron medications (e.g., iron sucrose, ferric carboxymaltose, ferumoxytol), potassium binders, calcitriol, or SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin, or other SGLT2 inhibitors listed herein).

[0152] Especially when provided as a single dosage unit, there may be chemical interactions between the combined active ingredients.For this reason, when the compound of formula I and a second therapeutic agent are combined in a single dosage unit, they can be formulated so that the active ingredients are combined in a single dosage unit, but the physical contact between the active ingredients is minimized (i.e., reduced).For example, one active ingredient can be enteric coated.By enteric coating one of the active ingredients, it is not only possible to minimize the contact between the combined active ingredients, but also to control the release of one of these ingredients in the digestive tract, so that one of these ingredients is not released in the stomach but is released in the intestinal tract.One of the active ingredients can also be coated with a material that brings about sustained release through the digestive tract and also helps to minimize the physical contact between the combined active ingredients.In addition, the sustained-release component can be additionally enteric coated so that the release of this component only occurs in the intestinal tract. Yet another approach would involve formulating a combination product in which one component is coated with a sustained and / or enteric release polymer to further separate the active ingredients, and the other component is coated with a polymer such as low viscosity grades of hydroxypropylmethylcellulose (HPMC) or other suitable material as known in the art. The polymer coating serves to form an additional barrier to interaction with the other component.

[0153] Sustained-release preparations can be used.Suitable examples of sustained-release preparations include the semipermeable matrix of solid hydrophobic polymer containing the compound of the present invention, and this matrix is ​​in the form of shaped article, for example, film or microcapsule.Examples of sustained-release matrix include polyester, hydrogel (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (US Pat. No. 3,773,919), L-glutamic acid and 7-ethyl-L-glutamate copolymer, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer (such as that used in LUPRONDEPOT™, which is composed of lactic acid-glycolic acid copolymer and leuprolide acetate, sucrose acetate isobutyrate and poly-D-(-)-3-hydroxybutyric acid.

[0154] These and other methods of minimizing contact between the components of the combination product, whether administered in a single dosage form or in separate forms but simultaneously and by the same technique, will be readily apparent to those of skill in the art given the present disclosure.

[0155] For combination therapy treatment, both the compounds of this invention and the other drug therapies are administered to mammals (eg, humans, male or female) by conventional methods.

[0156] The compounds of formula I of the present invention, their prodrugs and salts of such compounds and prodrugs are all suitable for therapeutic use as agents that inhibit and / or degrade HSD17B13 in mammals, particularly humans, and are therefore useful for treating a variety of conditions in which such action is implicated (e.g., conditions described herein).

[0157] Diseases / conditions that can be treated with compounds of Formula I include, but are not limited to, NASH / NAFLD, diabetes, kidney disease, and heart failure and related diseases / conditions.

[0158] Therefore, in view of the positive correlation between activation of HSD17B13 and the occurrence of NASH / NAFLD and related diseases / conditions, the compounds of formula I of the present invention, their prodrugs and salts of such compounds and prodrugs, by their pharmacological actions, are useful for preventing, arresting and / or regressing fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma.

[0159] The administration of the compounds of the present invention can be via any method that delivers the compounds of the present invention systemically and / or locally.These methods include oral route, parenteral route, intraduodenal route, buccal route, intranasal route, etc. Generally, the compounds of the present invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intramedullary) can also be used, for example, when oral administration is inappropriate for the target or the patient cannot take the drug.

[0160] For administration to human patients, the oral daily dose of the compounds herein may range from 1 mg to 5000 mg, depending, of course, on the mode and frequency of administration, the disease state, and the age and condition of the patient. Oral daily doses ranging from 3 mg to 3000 mg can be used. Additional oral daily doses range from 5 mg to 1000 mg. For convenience, the compound of Formula I can be administered in unit dosage form. If desired, the unit dosage form can be used in multiple doses per day to increase the total daily dose. The unit dosage form can be, for example, a tablet or capsule containing about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 500, or 1000 mg of the compound. The total daily dose may be administered in single or divided doses and, at the physician's discretion, may fall outside of the typical range given herein.

[0161] For administration to human patients, the daily infusion dose of the compounds herein may range from 1 mg to 2000 mg, depending, of course, on the mode and frequency of administration, the disease state, and the age and condition of the patient. Further daily infusion doses range from 5 mg to 1000 mg. The total daily dose may be administered in single or divided doses and, at the physician's discretion, may fall outside the typical ranges given herein.

[0162] These compounds can also be administered to non-human animals, for example, for the indications detailed above. The exact dosage of each active ingredient administered will vary depending on any number of factors, including, but not limited to, the type of animal and type of condition being treated, the age of the animal, and the route of administration.

[0163] The dosage of the combination drug used in conjunction with Formula I compound is that which is effective for the indication being treated.Such dosage can be determined by standard assays such as those referred to above and provided herein.The combination drug can be administered simultaneously or sequentially in any order.

[0164] These dosages are based on an average human subject weighing approximately 60 kg to 70 kg. A physician will be able to readily determine dosages for subjects whose weight falls outside this range, such as infants and the elderly.

[0165] Dosage regimen can be adjusted to obtain the optimum desired response.For example, a single bolus can be administered, or several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to a physically discrete unit suitable as a unit dosage for the mammalian subject to be treated; each unit containing a predetermined amount of active compound is calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier.The specifications for the dosage unit form of the present invention are determined by and directly depend on (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or preventive effect to be achieved, and (b) the inherent limitations in the art of compounding such active compound for the treatment of susceptibility in individuals.

[0166] Thus, based on the disclosure provided herein, one skilled in the art will understand that doses and administration regimens will be adjusted according to methods well known in the therapeutic field. That is, the maximum tolerated dose can be readily established, and the effective amount that provides a detectable therapeutic effect in a patient can be determined, as well as the primary requirement for administering each agent to provide a detectable therapeutic effect in a patient. Thus, although certain doses and administration regimens are exemplified herein, these examples in no way limit the doses and administration regimens that can be provided to a patient.

[0167] It should be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It should be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the dosage ranges specified herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. For example, dosages may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Therefore, intrapatient dose escalation can be used as determined by those skilled in the art. Determining appropriate dosages and regimens for administering chemotherapeutic agents is well known in the relevant fields and will be understood to be encompassed by those skilled in the art given the teachings disclosed herein.

[0168] The present application further includes the use of a compound of formula I for use as a medicament (such as a unit dose tablet or unit dose capsule). In another embodiment, the present application includes the use of a compound of formula I for manufacturing a medicament (such as a unit dose tablet or unit dose capsule) for treating one or more of the conditions previously identified in the section above discussing methods of treatment.

[0169] The pharmaceutical composition of the present invention can be prepared, packaged or sold in bulk as a single unit dose or as a plurality of single unit doses.As used herein, " unit dose " is the discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is generally equal to the dosage of active ingredient that will be administered to subject, or the convenient proportion of this dosage, for example, half or one-third of this dosage.

[0170] The compounds or combinations of the present invention can be administered alone, but will generally be administered in admixture with one or more suitable pharmaceutical excipients, adjuvants, diluents, or carriers known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice. Depending on the specifics of the desired route of administration and release profile, the compounds or combinations of the present invention can be formulated to provide immediate, delayed, modified, sustained, pulsed, or controlled release dosage forms to suit the needs of the treatment.

[0171] Pharmaceutical compositions generally contain a compound or combination of the invention in an amount ranging from about 1% to about 75%, 80%, 85%, 90%, or even 95% (by weight) of the composition, usually from about 1%, 2%, or 3% to about 50%, 60%, or 70%, and more often from about 1%, 2%, or 3% to less than 50%, for example, about 25%, 30%, or 35%.

[0172] Methods for preparing various pharmaceutical compositions containing specific amounts of active compounds are known to those skilled in the art. See, for example, Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore, Md. 20th ed. 2000.

[0173] Compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers or diluents (including solvents and vehicles) include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, triglycerides, including vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. A preferred carrier is Miglyol® brand caprylic / capric acid esters with glycerin or propylene glycol (e.g., Miglyol® 812, Miglyol® 829, Miglyol® 840), available from Condea Vista Co., Cranford, NJ. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0174] These compositions for parenteral injection may contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial contamination of the compositions can be achieved by using various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical compositions can be achieved by using agents that delay absorption, for example, aluminum monostearate and gelatin.

[0175] Solid dosage forms for oral administration include capsules, tablets, chewing gum, lozenges, pills, powders, and multiparticulate formulations (granules). In such solid dosage forms, the compound of Formula I or combination is mixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include substances such as sodium citrate or dicalcium phosphate, and / or (a) one or more fillers or extenders (e.g., microcrystalline cellulose (available as Avicel®, FMC), (b) one or more binders (e.g., carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.); (c) one or more humectants (e.g., glycerol, etc.); (d) one or more disintegrants (e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, sodium lauryl sulfate, sodium starch glycolate (available from Edward Mendell Co. under the trademark Explotab®)).(available from Pharmacy), cross-linked polyvinylpyrrolidone, croscarmellose sodium type A (available as Ac-di-sol®), polyacrilin potassium (an ion exchange resin), etc.; (e) one or more solution retardants (e.g., paraffin, etc.); (f) one or more absorption enhancers (e.g., quaternary ammonium compounds, etc.); (g) one or more wetting agents (e.g., cetyl alcohol, glycerol monostearate, etc.); (h) one or more adsorbents (e.g., kaolin, bentonite, etc.); and / or (i) one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, stearic acid, polyoxyl stearate, cetanol, talc, hydrogenated castor oil, sucrose esters of fatty acids, dimethylpolysiloxane, microcrystalline wax, yellow wax, white wax, solid polyethylene glycol, sodium lauryl sulfate, etc.). In the case of capsules and tablets, the dosage form may also include buffering agents.

[0176] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0177] Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art.They can also contain opacifying agents, and can be formulated to release the compound of Formula I and / or additional pharmaceutical agents in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.The drug can also be in the form of a microencapsulation, if appropriate, containing one or more of the above-mentioned additives.

[0178] In tablets, the active agent typically constitutes less than 50% (by weight) of the formulation, e.g., less than about 10% by weight, e.g., 5% or 2.5% by weight. The major proportions of the formulation are composed of fillers, diluents, disintegrants, lubricants, and, optionally, flavorings. The compositions of these additives are well known in the art. Often, the filler / diluent is composed of a mixture of two or more of the following ingredients: microcrystalline cellulose, mannitol, lactose (all types), starch, and dicalcium phosphate. The filler / diluent mixture typically constitutes less than 98% of the formulation, preferably less than 95%, e.g., 93.5%. Preferred disintegrants include Ac-di-sol®, Explotab®, starch, and sodium lauryl sulfate. When present, the disintegrant usually constitutes less than 10% or less than 5% by weight, e.g., about 3% by weight, of the formulation. A preferred lubricant is magnesium stearate. When present, lubricants typically comprise less than 5% or less than 3% by weight of the formulation, for example about 1% by weight.

[0179] Tablets can be manufactured by standard tableting processes, such as direct compression, or wet-, dry-, or melt-granulation, melt-congealing processes, and extrusion. The tablet cores may be single- or multi-layered(s) and may be coated with suitable overcoats known in the art.

[0180] The liquid dosage form for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.In addition to the compound of formula I or combination, the liquid dosage form can contain water or other solvent, solubilizer and emulsifier, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (for example, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.), Miglyol (available from CONDEA Vista Co., Cranford, NJ), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, or mixtures of these substances, and other inert diluents commonly used in the art.

[0181] Besides such inert diluents, compositions can also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0182] Oral liquid forms of the compounds or combinations of the present invention include solutions in which the active compound is sufficiently dissolved. Examples of solvents include all pharmaceutically precedent solvents suitable for oral administration, especially those in which the compounds of the present invention exhibit good solubility, such as polyethylene glycol, polypropylene glycol, edible oils, and glyceryl and glyceride-based systems. Glyceryl and glyceride based systems may include, for example, the following trademarked products (and corresponding generic products): Captex® 355 EP (glyceryl tricaprylate / caprate, manufactured by Abitec, Columbus, Ohio), Crodamol™ GTC / C (medium chain triglyceride, manufactured by Croda, Cowick Hall, UK) or Labrafac™ CC (medium chain triglyceride, manufactured by Gattefosse), Captex® 500P (glyceryl triacetate, i.e., triacetin, manufactured by Abitec), Capmul® MCM (medium chain mono- and diglycerides, manufactured by Abitec), Migyol® 812 (caprylic / capric triglyceride, manufactured by Condea, Cranford, OH). NJ), Migyol® 829 (caprylic / capric / succinic triglyceride, manufactured by Condea), Migyol® 840 (propylene glycol dicaprylate / dicaprate, manufactured by Condea), Labrafil® M1944CS (oleoyl macrogol-6 glyceride, manufactured by Gattefosse), Peceol™ (glyceryl monooleate, manufactured by Gattefosse), and Maisine® 35-1 (glyceryl monooleate, manufactured by Gattefosse). Of particular interest are medium chain (approximately C8 to C9) 10 ) triglyceride oils. These solvents often constitute a major proportion of the composition, i.e., greater than about 50% by weight, usually greater than about 80% by weight, e.g., about 95% or 99% by weight. Adjuvants and additives may be included with the solvents, primarily taste masking agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers, and solubilizers.

[0183] Suspensions may further comprise, in addition to a compound of formula I or a combination, a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances.

[0184] Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound of formula I or a combination with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at normal room temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity to release the active ingredient(s).

[0185] Dosage forms for topical administration of a compound or combination of Formula I include ointments, creams, lotions, powders, and sprays. The drug is mixed with a pharmaceutically acceptable excipient, diluent, or carrier, and any preservatives, buffers, or propellants that may be required.

[0186] Many of the present compounds are poorly soluble in water, e.g., less than about 1 μg / mL, and therefore liquid compositions in solubilizing non-aqueous solvents such as the medium chain triglyceride oils discussed above are preferred dosage forms for these compounds.

[0187] Solid amorphous dispersions, including dispersions formed by spray drying processes, are also preferred dosage forms for poorly soluble compounds of the present invention. "Solid amorphous dispersion" refers to a solid material in which at least a portion of the poorly soluble compound is in amorphous form and dispersed in a water-soluble polymer. "Amorphous" means that the poorly soluble compound is not crystalline. "Crystalline" means that the compound exhibits three-dimensional long-range order of at least 100 repeat units in each dimension. Thus, the term amorphous is intended to include not only materials that are essentially disordered, but also materials that may have some small-scale order, but that order is less than three-dimensional and / or only over a short distance. Amorphous materials can be characterized by techniques known in the art, such as powder X-ray diffraction (PXRD) crystallography, solid-state NMR, or thermal techniques such as differential scanning calorimetry (DSC).

[0188] Preferably, at least a majority (i.e., at least about 60% by weight) of the poorly soluble compound in the solid amorphous dispersion is amorphous. The compound may exist in the solid amorphous dispersion in relatively pure amorphous domains or regions, as a solid solution of the compound uniformly dispersed throughout the polymer, or in any combination of these states, or in any intermediate state therebetween. Preferably, the solid amorphous dispersion is substantially homogeneous, so that the amorphous compound is dispersed as uniformly as possible throughout the polymer. As used herein, "substantially homogeneous" means that the fraction of the compound present in the solid amorphous dispersion in relatively pure amorphous domains or regions is relatively small, on the order of less than 20% by weight, preferably less than 10% by weight, relative to the total amount of drug.

[0189] Water-soluble polymers suitable for use in solid amorphous dispersions should be inert, in the sense that they do not adversely react chemically with poorly soluble compounds, and have at least some solubility in aqueous solutions at pharmaceutically acceptable and physiologically relevant pHs (e.g., 1 to 8). The polymers may be neutral or ionizable and should have an aqueous solubility of at least 0.1 mg / mL over at least a portion of the pH range from 1 to 8.

[0190] Suitable water-soluble polymers for use with the compounds of Formula I may be cellulosic or non-cellulosic. The polymers may be neutral or ionizable in aqueous solution. Of these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.

[0191] Exemplary water-soluble polymers include hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO, also known as poloxamer), and mixtures thereof. Particularly preferred polymers include HPMCAS, HPMC, HPMCP, CMEC, CAP, CAT, PVP, poloxamer, and mixtures thereof. Most preferred is HPMCAS. See European Patent Application Publication No. 0 901 786 A2, the disclosure of which is incorporated herein by reference.

[0192] The solid amorphous dispersion can be prepared according to any process for forming a solid amorphous dispersion in which at least a majority (at least 60% by weight) of the poorly soluble compounds are in an amorphous state. Such processes include mechanical, thermal, and solvent processes. Exemplary mechanical processes include milling and extrusion; melt processes, including high-temperature fusion, solvent-modified fusion, and melt-congealing processes; and solvent processes, including non-solvent precipitation, spray coating, and spray drying. See, for example, the following U.S. patents, the relevant disclosures of which are incorporated herein by reference: U.S. Patent Nos. 5,456,923 and 5,939,099, which describe forming dispersions by an extrusion process; U.S. Patent Nos. 5,340,591 and 4,673,564, which describe forming dispersions by a milling process; and U.S. Patent Nos. 5,707,646 and 4,894,235, which describe forming dispersions by a melt-congealing process. In a preferred process, the solid amorphous dispersion is formed by spray drying as disclosed in European Patent Application Publication No. 0 901 786 A2. In this process, the compound and polymer are dissolved in a solvent such as acetone or methanol, and then the solvent is rapidly removed from the solution by spray drying to form the solid amorphous dispersion. The solid amorphous dispersion can be prepared to contain up to about 99% by weight of the compound, for example, 1%, 5%, 10%, 25%, 50%, 75%, 95%, or 98% by weight, as desired.

[0193] The solid dispersion can be used directly as a dosage form or can serve as a manufacturing-use-product (MUP) in preparing other dosage forms, such as capsules, tablets, liquids, or suspensions. An example of an aqueous suspension is an aqueous suspension of 1:1 (w / w) compound / HPMCAS-HF spray-dried dispersion containing 2.5 mg / mL of compound in 2% polysorbate-80. Solid dispersions for use in tablets or capsules are generally mixed with other additives or adjuvants typically present in such dosage forms. For example, exemplary fillers for capsules are 2:1 (w / w) compound / HPMCAS-MF spray-dried dispersion (60%), lactose (high flow) (15%), microcrystalline cellulose (e.g., Avicel). (R0-102) (15.8%), sodium starch (7%), sodium lauryl sulfate (2%), and magnesium stearate (1%).

[0194] HPMCAS polymers are available in low, medium, and high quality from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan) as Aqoat® LF, Aqoat® MF, and Aqoat® HF, respectively. The higher MF and HF qualities are generally preferred.

[0195] The compounds of Formula I or pharmaceutically acceptable salts of said compounds can be used to treat non-human animals. Administration of the compounds of Formula I in combination with another active agent used to treat related conditions can be oral or parenteral.

[0196] The compound of Formula I or the combination of the compound of Formula I and another active agent is administered in an amount such that an effective dose is administered. Generally, the daily dose administered orally to an animal is about 0.01 to about 1,000 mg / kg body weight, e.g., about 0.01 to about 300 mg / kg body weight, or about 0.01 to about 100 mg / kg body weight, or about 0.01 to about 50 mg / kg body weight, or about 0.01 to about 25 mg / kg, or about 0.01 to about 10 mg / kg, or about 0.01 to about 5 mg / kg.

[0197] Conveniently, the compound of formula I (or combination) can be placed in drinking water so that a therapeutic dosage of the compound is received in the daily water supply. The compound can be metered directly into the drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).

[0198] Advantageously, the compound of formula I (or combination) can be added directly to feed, as is, or in the form of an animal feed supplement, also called premix or concentrate.To include the drug in feed, a premix or concentrate of the compound in an additive, diluent, or carrier is more commonly used.Suitable additives, diluents, or carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corn cob meal, and corn meal, molasses, urea, bone meal, and mineral mixes commonly used in poultry feed.A particularly effective additive, diluent, or carrier is the individual animal feed itself; that is, a small amount of such feed.The carrier facilitates the uniform distribution of the compound in the final feed to be blended with the premix.Preferably, the compound is thoroughly blended into the premix, and then into the feed.In this regard, the compound can be dispersed or dissolved in a suitable oil vehicle such as soybean oil, corn oil, cottonseed oil, or in a volatile organic solvent, and then blended with the carrier. It will be appreciated that the proportion of compound in the concentrate feed can vary widely, as the amount of compound in the final feed can be adjusted by blending the appropriate proportion of premix with the feed to obtain the desired level of compound.

[0199] To produce a concentrated supplement suitable for direct feeding to animals, feed manufacturers may blend high-potency concentrated feed with protein carriers such as soybean oil meal and other meals as described above.In such cases, animals are allowed to consume normal diets.Alternatively, such concentrated supplements can be added directly to feed to produce a nutritionally balanced final feed containing therapeutically effective levels of compounds.To ensure uniformity, the mixture is thoroughly blended using standard procedures, such as in a twin-shell blender.

[0200] When the supplement is used as a top dressing for a feed, this also helps to ensure uniformity of distribution of the compound throughout the top of the top dressed feed.

[0201] Drinking water and feed effective for increasing lean meat deposition and improving the lean meat to fat ratio are generally prepared by mixing a compound of Formula I with a sufficient amount of animal feed to provide from about 0.001 to about 500 ppm of the compound in the feed or water.

[0202] Preferred medicated feeds for swine, cattle, sheep, and goats generally contain from about 1 to about 400 grams of a compound of Formula I (or combination) per ton of feed, with the optimum amount for these animals usually being from about 50 to about 300 grams per ton of feed.

[0203] Preferred poultry and domestic pet feeds typically contain from about 1 to about 400 grams, preferably from about 10 to about 400 grams of compound (or combination) per ton of feed.

[0204] For parenteral administration in animals, the compound of formula I (or combination) can be prepared in the form of a paste or pellet and administered as an implant, usually subcutaneously in the head or ear, of an animal seeking to increase lean meat deposition and improve the lean meat to fat ratio.

[0205] Paste formulations can be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

[0206] Pellets containing an effective amount of a compound of Formula I, pharmaceutical composition, or combination can be prepared by mixing the compound of Formula I or combination with a diluent such as carbowax, carnauba wax, etc., and a lubricant such as magnesium stearate or calcium stearate can be added to improve the pelleting process.

[0207] It will of course be appreciated that one or more pellets can be administered to an animal to achieve the desired dosage level that results in the desired increased lean meat accumulation and improved lean meat to fat ratio. Additionally, implants can be administered periodically during the administration period to the animal to maintain the proper drug level in the animal's body.

[0208] Liposomes containing these drugs and / or compounds of the present invention can be prepared by methods known in the art, such as those described in U.S. Patent Nos. 4,485,045 and 4,544,545. Liposomes with improved circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be produced by reverse phase evaporation using a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters with defined pore sizes to obtain liposomes with the desired diameter.

[0209] These drugs and / or compounds of the present invention can also be encapsulated in microcapsules, such as hydroxymethylcellulose or gelatin microcapsules and polymethylmethacrylate microcapsules, prepared by coacervation techniques or by interfacial polymerization, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Edition, Mack Publishing (2000).

[0210] Preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. The compound of the present invention is generally placed into a container with a sterile access port, for example, an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic injection needle.

[0211] Suitable emulsions can be prepared using commercially available lipid emulsions, such as Intralipid®, Liposyn®, Infonutrol™, Lipofundin®, and Lipiphysan™. The active ingredient can be dissolved in a premixed emulsion composition, or alternatively, in an emulsion formed by mixing water with an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and a phospholipid (e.g., egg phospholipid, soybean phospholipid, or soybean lecithin). It will be appreciated that other ingredients, such as glycerol or glucose, can be added to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, e.g., between 5 and 20%. Lipid emulsions contain lipid droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and may have a pH in the range of 5.5 to 8.0.

[0212] Emulsion compositions may be prepared by mixing a compound of the present invention with Intralipid™ or its components (soybean oil, egg phospholipids, glycerol and water).

[0213] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions, preferably in sterile pharmaceutically acceptable solvents, can be nebulized by using gas. Nebulized solutions can be inhaled directly from nebulizing devices, or the nebulizing devices can be attached to face masks, tents, or intermittent positive pressure respirators. Solution, suspension, or powder compositions can be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0214] The compounds herein can be formulated in a form suitable for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous) or rectal administration, or for administration by inhalation. The compounds of the invention can also be formulated for sustained delivery.

[0215] Methods of preparing various pharmaceutical compositions containing a particular amount of active ingredient are known, or will be apparent to those skilled in the art in light of this disclosure. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000).

[0216] Pharmaceutical compositions according to the invention may contain 0.1% to 95% by weight, preferably 1% to 70%, of a compound of the invention. In any event, the composition administered will contain a quantity of a compound according to the invention in an amount effective to treat the disease / condition of the subject being treated.

[0217] Since the present application has an aspect related to the treatment of the diseases / conditions described herein using a combination of active ingredients that may be administered separately, the present invention also relates to combining separate pharmaceutical compositions in the form of a kit. The kit may include a composition containing a compound of Formula I, or may contain at least two separate pharmaceutical compositions: a compound of Formula I, a prodrug thereof, or a salt of such a compound or prodrug, and a second compound as described above. The kit includes a means for containing the separate compositions, such as a container, a divided bottle, or a divided foil packet. Typically, the kit includes instructions for administering the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) or at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0218] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil, preferably a transparent plastic material. During the packaging process, recesses are formed in the plastic foil, the recesses having the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses, and the sheet of relatively stiff material is sealed to the plastic foil on the side of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through the openings.

[0219] It may be desirable to provide a memory aid in the kit, for example, in the form of numbers next to the tablets or capsules that correspond to the planned days on which the designated tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, e.g., "Week 1, Monday, Tuesday, etc.... Week 2, Monday, Tuesday..." Other variations on memory aids will be readily apparent. A "daily dose" may be a single tablet or capsule to be taken on a given day, or several pills or capsules. Also, a daily dose of a Formula I compound may consist of one tablet or capsule, while a daily dose of an optional second compound may consist of several tablets or capsules, or vice versa. The memory aid should reflect this.

[0220] Another specific embodiment of the present invention provides a dispensing device designed to dispense daily doses one at a time in the order of their intended use. Preferably, the dispensing device is equipped with a memory aid to further promote compliance with the regimen. One example of such a memory aid is a mechanical counter that displays the number of daily doses that have been dispensed. Another example of such a memory aid is a battery-powered microchip memory coupled with a liquid crystal display, or an audible reminder signal that, for example, reads out the date the most recent daily dose was taken and / or reminds the person when the next dose is due.

[0221] Also, since the present application has aspects relating to the treatment of diseases / conditions described herein with combinations of active ingredients that can be administered together, the present invention also relates to combining separate pharmaceutical compositions in a single dosage form, for example (but not limited to) in a single tablet or capsule, a bilayer or multilayer tablet or capsule, or by using separate components or compartments within a tablet or capsule.

[0222] The active ingredient may also be delivered as a solution in an aqueous or non-aqueous vehicle with or without additional solvents, co-solvents, additives, or complexing agents selected from pharmaceutically acceptable diluents, additives, vehicles, or carriers.

[0223] The active ingredient may also be formulated as a solid dispersion or as a self-emulsifying drug delivery system (SEDDS) with pharmaceutically acceptable excipients.

[0224] The active ingredient may also be formulated as an immediate-release or modified-release tablet or capsule, or may be delivered as the sole active ingredient within a capsule shell, without additional excipients.

[0225] Experimental procedure The synthesis of various compounds of the present invention is described below. Additional compounds within the scope of the present invention can also be prepared using the methods described in these examples alone or in combination with techniques generally known in the art. All starting materials in these preparations and examples are commercially available or can be prepared by methods known in the art or as described herein.

[0226] Reactions were carried out in air or, when oxygen- or moisture-sensitive reagents or intermediates were used, under an inert atmosphere (nitrogen or argon). Where appropriate, the reactor was dried under dynamic vacuum using a heat gun, and anhydrous solvents (Sure-Seal™ products from Aldrich Chemical Company, Milwaukee, Wisconsin, or DriSolv™ products from EMD Chemicals, Gibbstown, NJ) were used. In some cases, commercially available solvents were passed through columns packed with 4 Å molecular sieves until the following QC standards were achieved with water: a) <100 ppm by weight for dichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For very sensitive reactions, solvents were further treated with sodium metal, calcium hydride, or molecular sieves and distilled immediately before use. Other commercially available solvents and reagents were used without further purification. In syntheses that refer to procedures in other examples or methods, reaction conditions (reaction times and temperatures) may vary. Products were generally dried under vacuum before further reaction or biological testing.

[0227] Where indicated, reactions were heated by microwave irradiation using a Biotage Initiator or Personal Chemistry Emrys Optimizer microwave instrument. Reaction progress was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analysis. TLC was performed on precoated silica gel plates with a fluorescent indicator (excitation wavelength 254 nm) and visualized under UV light and / or with I2, KMnO4, CoCl2, phosphomolybdic acid, or cerium ammonium molybdate stains. LCMS data were acquired on an Agilent 1100 Series instrument using a Leap Technologies autosampler, a Gemini C18 column, an acetonitrile / water gradient, and either trifluoroacetic acid, formic acid, or ammonium hydroxide modifiers. Column eluents were analyzed using a Waters ZQ mass spectrometer scanning from 100 to 1200 Da in both positive and negative ion modes. Other similar instruments were also used. HPLC data were generally acquired on an Agilent 1100 Series instrument using a Gemini or XBridge C18 column, an acetonitrile / water gradient, and either trifluoroacetic acid or ammonium hydroxide modifier. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP 6890 injector, an HP-1 column (12 m × 0.2 mm × 0.33 μm), and helium carrier gas. Samples were analyzed on an HP 5973 mass-selective detector scanning from 50 to 550 Da using electron ionization. Purification was performed by medium-pressure liquid chromatography (MPLC) using an Isco CombiFlash Companion, AnalogLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instrument and pre-packed Isco RediSep or Biotage Snap silica cartridges.Chiral purification was typically performed by chiral supercritical fluid chromatography (SFC) using a Berger or Thar instrument; a column such as a ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or -OJ column; and CO mixtures with methanol, ethanol, propan-2-ol, or acetonitrile, either alone or conditioned with trifluoroacetic acid or propan-2-amine. UV detection was used to drive fraction collection. For syntheses referred to in other examples or methods, purification may vary: generally, the solvents and solvent ratios used in the eluents / gradients were adjusted to the appropriate R. f or retention time was selected.

[0228] Mass spectrometry data are reported from LCMS analysis. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI), or electron scattering (ES) ion sources. Proton nuclear magnetic spectroscopy ( 1H NMR (H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on 300, 400, 500, or 600 MHz Varian, Bruker, or Jeol spectrometers. Chemical shifts are expressed in parts per million (ppm, d) referenced to deuterated solvent residual peaks (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-d2, 1.94 ppm; dimethyl sulfoxide-d5, 2.50 ppm; DHO, 4.79 ppm). Peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were obtained on a Berger analytical instrument as described above. Optical rotation data were obtained on a PerkinElmer Model 343 polarimeter using a 1 dm cell. Silica gel chromatography was primarily performed using medium pressure Biotage or ISCO systems using pre-packed columns from various commercial vendors, including Biotage and ISCO. Trace analyses were performed by Quantitative Technologies Inc. and were within 0.4% of calculated values.

[0229] Unless otherwise indicated, chemical reactions were carried out at room temperature (approximately 23 degrees Celsius).

[0230] Unless otherwise indicated, all reactants were either commercially obtained without further purification or prepared using methods known in the literature.

[0231] Hydrogenation can be carried out in a Parr Shaker under pressurized hydrogen gas or in a Thales-nano H-Cube flow hydrogenator with total hydrogen and a flow rate of 1-2 mL / min at the specified temperature.

[0232] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods indicated in the procedures.

[0233] In some examples, chiral separations were performed to separate enantiomers or diastereoisomers of certain compounds of the invention (in some examples, the separated enantiomers are designated ENANT-1 and ENANT-2 according to their order of elution; similarly, the separated diastereoisomers are designated DIAST-1 and DIAST-2 according to their order of elution). In some examples, the optical rotations of the enantiomers were measured using a polarimeter. According to its observed rotational data (or its specific rotational data), the enantiomer with clockwise rotation was designated the (+)-enantiomer, and the enantiomer with counterclockwise rotation was designated the (-)-enantiomer. A racemate is indicated by the absence of a depicted or depicted stereochemistry or by the presence of (+ / -) adjacent to the structure; in the latter case, the depicted stereochemistry represents only one of the two enantiomers comprising the racemic mixture.

[0234] The compounds and intermediates described below were named using the naming conventions provided with ACD / ChemSketch 2017.2.1, File Version C40H41, Build 99535 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming conventions provided with ACD / ChemSketch 2017.2.1 are well known to those skilled in the art, and the naming conventions provided with ACD / ChemSketch 2012.2.1 are generally believed to be compatible with the IUPAC (International Union of Pure and Applied Chemistry) recommendations for organic chemistry nomenclature and the CAS indexing rules. [Example]

[0235] Preparation Example P1: 3,5-Difluoro-4-[(4-methoxyphenyl)methoxy]benzoic acid (P1)

[0236] [ka] Step 1. Synthesis of methyl 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzoate (C1). To a 0°C solution of sodium hydride (60% dispersion in mineral oil; 1.60 g, 40.0 mmol) in tetrahydrofuran (200 mL) was added (4-methoxyphenyl)methanol (5.25 g, 38.0 mmol). After stirring the reaction mixture at 0°C for 30 minutes, a solution of methyl 3,4,5-trifluorobenzoate (7.00 g, 36.8 mmol) in tetrahydrofuran (50 mL) was added, whereupon the reaction mixture was warmed to 25°C and stirred for 1 hour. It was then quenched by the addition of saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate; the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give C1 as a solid (11.2 g). This material was carried on directly to the next step.

[0237] Step 2. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzoic acid (P1) To a solution of C1 (from the previous step; 11.2 g, ≦36.3 mmol) in methanol (200 mL) was added a solution of sodium hydroxide (4.36 g, 109 mmol) in water (20 mL), whereupon the reaction mixture was stirred at 26° C. for 4 h. It was then concentrated in vacuo, and the aqueous residue was washed with dichloromethane (2×150 mL). After acidifying the aqueous layer to pH 5, it was extracted with dichloromethane (3×300 mL), and these three dichloromethane layers were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give P1 as a white solid. Yield: 10 g, 34 mmol, 92% for two steps. 1 H NMR (400 MHz, DMSO-d6) 7.61 - 7.53 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 5.20 (s, 2H), 3.74 (s, 3H).

[0238] Preparation Example P2: 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzoic acid (P2)

[0239] [ka] Step 1. Synthesis of ethyl 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzoate (C2) 1-(Chloromethyl)-4-methoxybenzene (40.1 g, 256 mmol) was added to a mixture of ethyl 2,3,5-trifluoro-4-hydroxybenzoate (51.3 g, 233 mmol) and potassium carbonate (64.3 g, 465 mmol) in acetonitrile (100 mL). After stirring the reaction mixture at 80° C. for 16 h, LCMS analysis showed conversion to C2: LCMS m / z 363.1 [M+Na + The solids were removed by filtration and the filtrate was concentrated in vacuo to give C2 as a yellow oil. Yield: 71.0 g, 209 mmol, 90%.

[0240] Step 2. Synthesis of 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzoic acid (P2). To a solution of C2 (71.0 g, 209 mmol) in methanol (500 mL) was added an aqueous solution of sodium hydroxide (3 M; 300 mL). The reaction mixture was stirred at 50° C. for 4 h before being concentrated in vacuo. The aqueous residue was acidified by the addition of 1 M hydrochloric acid, and the resulting solid was collected by filtration to give P2 as a white solid. Yield: 51.7 g, 166 mmol, 79%. LCMS m / z 335.1 [M+Na + ]. 1 H NMR (400 MHz, DMSO-d6) d 7.38 - 7.29 (m, 1H), 7.34 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 5.18 (s, 2H), 3.75 (s, 3H).

[0241] Preparation Example P3: N-{[(1r,4r)-4-aminocyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P3)

[0242] [ka] Step 1. Synthesis of tert-butyl [(1r,4r)-4-({3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)cyclohexyl]carbamate (C3). To a solution of P1 (19.3 g, 65.6 mmol), N,N-diisopropylethylamine (25.4 g, 197 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 27.5 g, 72.3 mmol) in dichloromethane (700 mL) was added tert-butyl [(1r,4r)-4-(aminomethyl)cyclohexyl]carbamate (15.0 g, 65.7 mmol). After stirring the reaction mixture at 25 °C for 16 h, LCMS analysis indicated the presence of C3: LCMS m / z 527.3 [M+Na + Filtration followed by washing of the filter cake with water and a mixture of dichloromethane and ethyl acetate gave C3 as a white solid. Yield: 26.5 g, 52.5 mmol, 80%. 1 H NMR (400 MHz, DMSO-d6) 8.48 (br t, J = 6 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.67 (br d, J = 8.0 Hz, 1H), 5.16 (s, 2H), 3.74 (s, 3H), 3.22 - 3.10 (m, 1H), 3.06 (dd, J = 6.1, 6.1 Hz, 2H), 1.83 - 1.65 (m, 4H), 1.48 - 1.36 (m, 1H), 1.36 (s, 9H), 1.16 - 1.02 (m, 2H), 1.00 - 0.85 (m, 2H).

[0243] Step 2. Synthesis of N-{[(1r,4r)-4-aminocyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P3). To a 0° C. solution of C3 (21.5 g, 42.6 mmol) and pyridine (27.0 g, 341 mmol) in dichloromethane (500 mL) was added trimethylsilyl trifluoromethanesulfonate (37.9 g, 170 mmol) dropwise. After the reaction mixture was stirred at 25° C. for 16 h, aqueous sodium bicarbonate (100 mL) was added and the mixture was filtered. The filter cake was washed with water and a mixture of dichloromethane and ethyl acetate to give P3 as a white solid. Yield: 10.0 g, 24.7 mmol, 58%. LCMS m / z 405.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.50 (br t, J = 6 Hz, 1H), 7.71 - 7.41 (m, 4H), 7.33 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 5.17 (s, 2H), 3.74 (s, 3H), 3.09 (dd, J = 6 Hz, 2H), 3.00 - 2.86 (m, 1H), 1.96 - 1.85 (m, 2H), 1.82 - 1.70 (m, 2H), 1.54 - 1.38 (m, 1H), 1.31 - 1.15 (m, 2H), 1.07 - 0.92 (m, 2H).

[0244] Preparation Example P4: (1r,4r)-4-({3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)cyclohexane-1-carboxylic acid (P4)

[0245] [ka] Step 1. Synthesis of methyl (1r,4r)-4-({3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)cyclohexane-1-carboxylate (C4). To a solution of P1 (18.0 g, 61.2 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (14.1 g, 73.5 mmol), and 1H-benzotriazol-1-ol (9.92 g, 73.4 mmol) in dichloromethane (500 mL) was added triethylamine (7.41 g, 73.2 mmol) and methyl (1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylate (10.5 g, 61.3 mmol). The reaction mixture was stirred at 28 °C for 4 hours and then extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (eluent: 6% methanol in dichloromethane) to give C4 as a white solid. Yield: 22.0 g, 49.2 mmol, 80%. LCMS m / z 448.2 [M+H] + .

[0246] Step 2. Synthesis of (1r,4r)-4-({3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)cyclohexane-1-carboxylic acid (P4). A solution of sodium hydroxide (8.05 g, 201 mmol) in water (20 mL) was added to a solution of C4 (18.0 g, 40.2 mmol) in methanol (200 mL). The reaction mixture was stirred at 26 °C for 6 h, whereupon the methanol was removed under reduced pressure and the aqueous residue was washed with dichloromethane (2 x 20 mL). The aqueous layer was then adjusted to pH 5 and extracted with dichloromethane (3 x 50 mL); these three extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to give P4 as a white solid. Yield: 14.0 g, 32.3 mmol, 80%. LCMS m / z 434.2 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) d 8.50 (br t, J = 5.7 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.33 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 5.16 (s, 2H), 3.74 (s, 3H), 3.08 (dd, J = 6, 6 Hz, 2H), 2.18 - 2.05 (m, 1H), 1.95 - 1.82 (m, 2H), 1.80 - 1.68 (m, 2H), 1.54 - 1.39 (m, 1H), 1.33 - 1.16 (m, 2H), 1.02 - 0.85 (m, 2H).

[0247] Preparation Example P5: 3,5-Difluoro-N-{[(1r,4r)-4-(N-hydroxycarbamimidoyl)cyclohexyl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P5)

[0248] [ka] Step 1. Synthesis of N-{[(1r,4r)-4-cyanocyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C5). A solution of hydrogen chloride in 1,4-dioxane (4 M; 50 mL, 200 mmol) was added to a solution of tert-butyl {[(1r,4r)-4-cyanocyclohexyl]methyl}carbamate (4.86 g, 20.4 mmol) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature overnight. After removing the solvent by concentration under reduced pressure, the residue was triturated with diethyl ether to give (1r,4r)-4-(aminomethyl)cyclohexane-1-carbonitrile, hydrochloride.

[0249] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 95%, 8.16 g, 20.4 mmol) was added to a solution of P1 (5.0 g, 17 mmol) in dichloromethane (113 mL). After stirring for 1 hour, the mixture was treated with N,N-diisopropylethylamine (8.88 mL, 51.0 mmol) and (1r,4r)-4-(aminomethyl)cyclohexane-1-carbonitrile, hydrochloride salt from above. The reaction mixture was stirred at room temperature for 3 days, whereupon it was washed successively with water, 1 M hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in a small amount of a warm 10:1 mixture of ethyl acetate and heptane; after cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. Silica gel chromatography afforded C5 as a white solid. Yield: 5.80 g, 14.0 mmol, 82%. LCMS m / z 415.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.50 (br t, J = 5.8 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.16 (s, 2H), 3.74 (s, 3H), 3.08 (dd, J = 6, 6 Hz, 2H), 2.62 (tt, J = 11.9, 3.6 Hz, 1H), 2.04 - 1.95 (m, 2H), 1.77 - 1.67 (m, 2H), 1.60 - 1.37 (m, 3H), 1.04 - 0.89 (m, 2H).

[0250] Step 2. Synthesis of 3,5-difluoro-N-{[(1r,4r)-4-(N-hydroxycarbamimidoyl)cyclohexyl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P5). Hydroxylamine hydrochloride (8.38 g, 121 mmol) and triethylamine (16.8 mL, 121 mmol) were added to a solution of C5 (5.00 g, 12.1 mmol) in methanol (50 mL). The reaction mixture was heated at 50° C. for 24 hours, whereupon it was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), and the mixture was stirred vigorously for 15 minutes. Filtration, followed by rinsing the collected solid with water (50 mL) and ethyl acetate (50 mL), afforded P5 as a white solid. Yield: 4.50 g, 10.1 mmol, 83%. LCMS m / z 448.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6), Characteristic peaks: d 9.42 (s, 1H), 8.47 (br t, J = 5.8 Hz, 1H), 8.19 (br s, 1H), 7.81 (br s, 1H), 7.63 - 7.54 (m, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 5.16 (s, 2H), 3.74 (s, 3H), 3.09 (dd, J = 6, 6 Hz, 2H), 2.5 - 2.40 (m, 1H, estimated; partially obscured by solvent peak), 1.96 - 1.84 (m, 2H), 1.56 - 1.41 (m, 1H), 1.02 - 0.87 (m, 2H).

[0251] Preparation Example P6: N-{[(1s,4s)-4-bromocyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P6)

[0252] [ka] Step 1. Synthesis of tert-butyl {[(1s,4s)-4-bromocyclohexyl]methyl}carbamate (C6). To a 0°C solution of tert-butyl {[(1r,4r)-4-hydroxycyclohexyl]methyl}carbamate (5.00 g, 21.8 mmol) in dichloromethane (150 mL) was added carbon tetrabromide (10.8 g, 32.6 mmol). Triphenylphosphine (8.58 g, 32.7 mmol) was added portionwise, and the reaction mixture was stirred at 25°C for 48 h. After removal of the solvent in vacuo, purification by silica gel chromatography (gradient: 0% to 20% ethyl acetate in petroleum ether) afforded C6. Yield: 1.30 g, 4.45 mmol, 20%. LCMS m / z 314.1 (bromine isotope pattern observed) [M+Na + ]. 1 H NMR (400 MHz, DMSO-d6) d 6.86 (br t, J = 6.0 Hz, 1H), 4.78 - 4.71 (m, 1H), 2.82 (dd, J = 6, 6 Hz, 2H), 1.99 - 1.89 (m, 2H), 1.87 - 1.75 (m, 2H), 1.57 - 1.26 (m, 5H), 1.37 (s, 9H).

[0253] Step 2. Synthesis of 1-[(1s,4s)-4-bromocyclohexyl]methanamine, hydrochloride (C7). To a solution of C6 (1.30 g, 4.45 mmol) in dichloromethane (20 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 15 mL). After stirring the reaction mixture at 25 °C for 2.5 h, LCMS analysis showed conversion to C7: LCMS m / z 192.1 (bromine isotope pattern observed) [M+H]. + The solvent was removed in vacuo to give C7 (900 mg), which was used directly in the next step.

[0254] Step 3. Synthesis of N-{[(1s,4s)-4-bromocyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P6). To a solution of P1 (1.65 g, 5.61 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 2.67 g, 7.02 mmol), and N,N-diisopropylethylamine (1.82 g, 14.1 mmol) in dichloromethane (80 mL), C7 (from the previous step; 900 mg, ≦4.45 mmol) was added, whereupon the reaction mixture was stirred at room temperature for 3 h. After concentration of the reaction mixture in vacuo, chromatography on silica gel (gradient: 0% to 30% ethyl acetate in petroleum ether) afforded P6. Yield: 1.40 g, 2.99 mmol, 67% over two steps. LCMS m / z 490.0 (bromine isotope pattern observed [M+Na + ]. 1 H NMR (400 MHz, DMSO-d6) d 8.55 (br t, J = 5.8 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.33 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.17 (s, 2H), 4.80 - 4.72 (m, 1H), 3.74 (s, 3H), 3.15 (dd, J = 6, 6 Hz, 2H), 2.02 - 1.91 (m, 2H), 1.89 - 1.77 (m, 2H), 1.70 - 1.53 (m, 3H), 1.47 - 1.33 (m, 2H).

[0255] Preparation Example P7: 3,5-Difluoro-N-{[4-(N-hydroxycarbamimidoyl)bicyclo[2.2.2]octan-1-yl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P7)

[0256] [ka] Step 1. Synthesis of tert-butyl [(4-carbamoylbicyclo[2.2.2]octan-1-yl)methyl]carbamate (C8). To a solution of 4-{[(tert-butoxycarbonyl)amino]methyl}bicyclo[2.2.2]octane-1-carboxylic acid (1.50 g, 5.29 mmol) in dichloromethane (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 3.02 g, 7.94 mmol), N,N-diisopropylethylamine (2.05 g, 15.9 mmol), and aqueous ammonium hydroxide (0.3 M; 22.9 mL, 6.87 mmol). The reaction mixture was stirred at 25 °C for 2 hours, then diluted with dichloromethane (25 mL), washed successively with water (2 × 20 mL) and saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Trituration with water (20 mL) gave C8 as a white solid. Yield: 1.20 g, 4.25 mmol, 80%. LCMS m / z 283.2 [M+H] + .

[0257] Step 2. Synthesis of tert-butyl [(4-cyanobicyclo[2.2.2]octan-1-yl)methyl]carbamate (C9). (Methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (Burgess reagent; 1.86 g, 7.81 mmol) was added to a solution of C8 (1.10 g, 3.90 mmol) in a mixture of pyridine (15 mL) and dichloromethane (10 mL). The reaction mixture was stirred at 25 °C for 2 h and then concentrated in vacuo; the residue was diluted with water (30 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 × 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give C9 as a white solid. Yield: 1.00 g, 3.78 mmol, 97%. LCMS m / z 209.2 [(M - 2-methylprop-1-ene) + H] + . 1 H NMR (400 MHz, DMSO-d6) 6.80 (br t, J = 6.4 Hz, 1H), 2.66 (d, J = 6.4 Hz, 2H), 1.86 - 1.76 (m, 6H), 1.36 (s, 9H), 1.36 - 1.27 (m, 6H).

[0258] Step 3. Synthesis of 4-(aminomethyl)bicyclo[2.2.2]octane-1-carbonitrile, hydrochloride (C10). To a 0° C. solution of C9 (1.00 g, 3.78 mmol) in dichloromethane (15 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 3.8 mL, 15 mmol), whereupon the reaction mixture was stirred at 25° C. for 16 h. The solvent was removed in vacuo to give C10 as a white solid. Yield: 750 mg, 3.74 mmol, 99%. LCMS m / z 165.2 [M+H] + .

[0259] Step 4. Synthesis of N-[(4-cyanobicyclo[2.2.2]octan-1-yl)methyl]-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C11). O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 1.60 g, 4.21 mmol) and N,N-diisopropylethylamine (1.81 g, 14.0 mmol) were added to a solution of P1 (1.13 g, 3.84 mmol) in N,N-dimethylformamide (10 mL). After stirring the reaction mixture at 25 °C for 10 minutes, C10 (700 mg, 3.49 mmol) was added, and stirring was continued at 25 °C for 4 hours. Water (25 mL) was then added, and the resulting mixture was extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed successively with water (2 × 10 mL) and saturated aqueous sodium chloride solution (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 50% ethyl acetate in petroleum ether) afforded C11 as a pale yellow solid. Yield: 1.29 g, 2.93 mmol, 84%. LCMS m / z 441.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.36 (br t, J = 6.3 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.34 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.17 (s, 2H), 3.75 (s, 3H), 3.01 (d, J = 6.2 Hz, 2H), 1.87 - 1.78 (m, 6H), 1.46 - 1.36 (m, 6H).

[0260] Step 5. Synthesis of 3,5-difluoro-N-{[4-(N-hydroxycarbamimidoyl)bicyclo[2.2.2]octan-1-yl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P7). To a solution of C11 (1.20 g, 2.72 mmol) in methanol (25 mL) was added hydroxylamine hydrochloride (1.14 g, 16.4 mmol) and N,N-diisopropylethylamine (2.82 g, 21.8 mmol), whereupon the reaction mixture was stirred at 70° C. for 16 h. The solvent was removed in vacuo to give a residue which was purified by silica gel chromatography (gradient: 0% to 5% methanol in dichloromethane) to give P7 as a white solid. Yield: 748 mg, 1.58 mmol, 58%. LCMS m / z 474.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.85 (s, 1H), 8.30 (br t, J = 6.2 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.34 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 5.16 (s, 2H), 5.11 (br s, 2H), 3.74 (s, 3H), 3.01 (d, J = 6.2 Hz, 2H), 1.66 - 1.56 (m, 6H), 1.41 - 1.31 (m, 6H).

[0261] Preparation Example P8: N-[(4-aminobicyclo[2.2.2]octan-1-yl)methyl]-2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P8)

[0262] [ka] Step 1. Synthesis of tert-butyl [4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octan-1-yl]carbamate (C12). N,N-Diisopropylethylamine (826 mg, 6.39 mmol) was added to a solution of P2 (1.00 g, 3.20 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 1.46 g, 3.84 mmol) in N,N-dimethylformamide (20 mL). After stirring the mixture at 25 °C for 2 minutes, tert-butyl [4-(aminomethyl)bicyclo[2.2.2]octan-1-yl]carbamate (855 mg, 3.36 mmol) was added, and stirring was continued at 20 °C for 1 hour. The reaction mixture was then extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (eluent: 1:1 petroleum ether / ethyl acetate) afforded C12 as a white solid. Yield: 1.35g, 2.46mmol, 77%. LCMS m / z 549.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.25 (t, J = 6.3 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.30 (ddd, J = 10.9, 6.0, 2.3 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.32 (br s, 1H), 5.21 (s, 2H), 3.75 (s, 3H), 2.96 (d, J = 6.2 Hz, 2H), 1.76 - 1.64 (m, 6H), 1.46 - 1.37 (m, 6H), 1.35 (s, 9H).

[0263] Step 2. Synthesis of N-[(4-aminobicyclo[2.2.2]octan-1-yl)methyl]-2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P8). To a solution of C12 (1.30 g, 2.37 mmol) and pyridine (1.50 g, 19.0 mmol) in dichloromethane (20 mL), trimethylsilyl trifluoromethanesulfonate (3.69 g, 16.6 mmol) was added, whereupon the reaction mixture was stirred at 20 °C for 30 min. Aqueous sodium bicarbonate (2 M; 50 mL) was then added, and the resulting mixture was extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo; purification using silica gel chromatography (gradient: 13% to 17% methanol in dichloromethane) afforded P8 as a white solid. Yield: 765 mg, 1.71 mmol, 72%. LCMS m / z 449.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) d 7.57 (ddd, J = 11.8, 6.8, 2.3 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.55 - 6.44 (m, 1H), 5.24 (s, 2H), 3.80 (s, 3H), 3.23 (d, J = 6.1 Hz, 2H), 1.71 - 1.60 (m, 6H), 1.59 - 1.49 (m, 6H).

[0264] Preparation Example P9: 4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octane-1-carboxylic acid (P9)

[0265] [ka] Step 1. Synthesis of methyl 4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octane-1-carboxylate (C13). To a solution of P2 (8.00 g, 25.6 mmol) and methyl 4-(aminomethyl)bicyclo[2.2.2]octane-1-carboxylate (5.05 g, 25.6 mmol) in N,N-dimethylformamide (60 mL) was added N,N-diisopropylethylamine (4.97 g, 38.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 11.7 g, 30.8 mmol). After stirring the reaction mixture at room temperature for 4 h, LCMS analysis showed conversion to C13: LCMS m / z 492.2 [M+H]. + The reaction mixture was poured into ice water, and the solid was collected by filtration and washed with water to give C13 as a gray solid. Yield: 11.6 g, 23.6 mmol, 92%.

[0266] Step 2. Synthesis of 4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octane-1-carboxylic acid (P9). A solution of C13 (11.6 g, 23.6 mmol) in methanol (120 mL) was treated with aqueous sodium hydroxide (3 M; 120 mL). The reaction mixture was stirred at 50° C. for 6 hours and then acidified by the addition of hydrochloric acid. The resulting solid was collected by filtration, washed with water, and then suspended in a mixture of ethyl acetate and methanol (10:1 ratio, 80 mL). This was stirred at 80° C. and slowly treated with methanol until a solution was obtained, whereupon it was cooled to room temperature. The resulting precipitate was collected by filtration and washed with ethyl acetate to give P9 as a white solid. Yield: 9.0 g, 18.8 mmol, 80%. LCMS m / z 478.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.26 (br t, J = 6.2 Hz, 1H), 7.42 - 7.23 (m, 3H), 6.94 (d, J = 8.3 Hz, 2H), 5.21 (s, 2H), 3.75 (s, 3H), 2.98 (d, J = 6.2 Hz, 2H), 1.71 - 1.55 (m, 6H), 1.44 - 1.29 (m, 6H).

[0267] Preparation Example P10: 2,3,5-trifluoro-N-{[4-(N-hydroxycarbamimidoyl)bicyclo[2.2.2]octan-1-yl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P10)

[0268] [ka] Step 1. Synthesis of 4-nitrophenyl 4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octane-1-carboxylate (C14). To a 0° C. suspension of P9 (962 mg, 2.01 mmol) in dichloromethane (8 mL) was added 4-nitrophenyl chloroformate (425 mg, 2.11 mmol), followed by triethylamine (0.842 mL, 6.04 mmol). The reaction mixture was allowed to warm to room temperature and then stirred overnight at room temperature, whereupon it was concentrated in vacuo to afford C14 as a solid (1.20 g). This material was used directly in the next step. LCMS m / z 599.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6), Characteristic peaks: d 5.21 (s, 2H), 3.75 (s, 3H), 3.05 (d, J = 6.3 Hz, 2H), 1.93 - 1.83 (m, 6H), 1.53 - 1.43 (m, 6H).

[0269] Step 2. Synthesis of 4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octane-1-carboxamide (C15). A solution of C14 (from the previous step; 1.20 g, ≦2.01 mmol) in N,N-dimethylformamide (10 mL) was treated with concentrated ammonium hydroxide (14.5 M; 0.415 mL, 6.02 mmol), and the reaction mixture was stirred at room temperature for 5 hours. It was then added to water (100 mL), and the resulting mixture was extracted with ethyl acetate (3×80 mL); the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to give C15 as an off-white solid. Yield: 919 mg, 1.93 mmol, 96% over two steps. LCMS m / z 477.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.27 (br t, J = 6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.30 (ddd, J = 11.0, 6.1, 2.4 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.88 (br s, 1H), 6.66 (br s, 1H), 5.21 (s, 2H), 3.75 (s, 3H), 2.99 (d, J = 6.2 Hz, 2H), 1.66 - 1.57 (m, 6H), 1.41 - 1.33 (m, 6H).

[0270] Step 3. Synthesis of N-[(4-cyanobicyclo[2.2.2]octan-1-yl)methyl]-2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C16). To a solution of C15 (797 mg, 1.67 mmol) in ethyl acetate (10 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (Burgess reagent; 997 mg, 4.18 mmol). The reaction mixture was stirred overnight at room temperature, whereupon it was diluted with ethyl acetate (40 mL) and washed successively with water (2×30 mL) and saturated aqueous sodium chloride (30 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give C16 as a solid. Yield: 658 mg, 1.44 mmol, 86%. LCMS m / z 459.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.32 (br t, J = 6.3 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.34 - 7.28 (m, 1H), 6.94 (d, J = 8.6 Hz, 2H), 5.21 (s, 2H), 3.75 (s, 3H), 2.99 (d, J = 6.3 Hz, 2H), 1.88 - 1.79 (m, 6H), 1.46 - 1.37 (m, 6H).

[0271] Step 4. Synthesis of 2,3,5-trifluoro-N-{[4-(N-hydroxycarbamimidoyl)bicyclo[2.2.2]octan-1-yl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P10). To a suspension of C16 (658 mg, 1.44 mmol) in methanol (8.0 mL) was added triethylamine (0.440 mL, 3.16 mmol), followed by hydroxylamine hydrochloride (219 mg, 3.15 mmol). No reaction was observed at room temperature for several hours. Hydroxylamine hydrochloride (219 mg, 3.15 mmol) was added again, and the reaction mixture was heated at 50° C. for 24 hours. After cooling, it was diluted with ethyl acetate (30 mL) and washed successively with water (2×40 mL) and saturated aqueous sodium chloride solution (30 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give P10 as a solid. Yield: 330 mg, 0.671 mmol, 47%. LCMS m / z 492.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.82 (br s, 1H), 10.64 (br s, 1H), 8.59 (v br s, 1H), 8.33 (br t, J = 6.3 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.34 - 7.28 (m, 1H), 6.94 (d, J = 8.6 Hz, 2H), 5.21 (s, 2H), 3.75 (s, 3H), 3.03 (d, J = 6.3 Hz, 2H), 1.78 - 1.67 (m, 6H), 1.49 - 1.38 (m, 6H).

[0272] Preparation Example P11: tert-butyl {[(1r,4r)-4-(7-bromoimidazo[1,2-a]pyridin-2-yl)cyclohexyl]methyl}carbamate (P11)

[0273] [ka] Step 1. Synthesis of tert-butyl({(1r,4r)-4-[methoxy(methyl)carbamoyl]cyclohexyl}methyl)carbamate (C17). To a solution of (1r,4r)-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexane-1-carboxylic acid (10.2 g, 39.6 mmol) in N,N-dimethylformamide (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (4.66 g, 47.8 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 19.7 g, 51.8 mmol), and triethylamine (16.7 mL, 120 mmol). After stirring the reaction mixture overnight at room temperature, LCMS analysis indicated the formation of C17: LCMS m / z 301.5 [M+H]. + In a pilot reaction carried out on a smaller scale, the reaction mixture was then concentrated under reduced pressure, diluted with a 1:1 mixture of ethyl acetate and dichloromethane, and filtered; the filtrate was concentrated in vacuo to give C17. The product from this 39.6 mmol-scale reaction was combined with that from a similar reaction carried out using (1r,4r)-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexane-1-carboxylic acid (9.50 g, 36.9 mmol) to give C17 as an oil. Combined yield: 22.8 g, 75.9 mmol, 99%. 1 H NMR (500 MHz, chloroform-d) d 4.56 (br s, 1H), 3.68 (s, 3H), 3.16 (s, 3H), 2.98 (br d, J = 6.4 Hz, 2H), 2.69 - 2.57 (m, 1H), 1.87 - 1.77 (m, 4H), 1.57 - 1.38 (m, 3H), 1.44 (s, 9H), 1.05 - 0.94 (m, 2H).

[0274] Step 2. Synthesis of tert-butyl {[(1r,4r)-4-acetylcyclohexyl]methyl}carbamate (C18). Methylmagnesium bromide (3.0 M; 81.7 mL, 245 mmol) was added dropwise to a 0° C. solution of C17 (23.0 g, 76.6 mmol) in tetrahydrofuran (219 mL), whereupon the reaction mixture was allowed to warm to room temperature. After 2 hours, it was cooled to 0° C., treated with water (50 mL), and then diluted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (eluent: 0%, then 10%, then 25%, then 50% ethyl acetate in heptane) afforded C18 as a solid. Yield: 13.3 g, 52.1 mmol, 68%. 1 H NMR (500 MHz, chloroform-d) d 4.56 (br s, 1H), 2.98 (br dd, J = 6, 6 Hz, 2H), 2.28 (tt, J = 12.2, 3.5 Hz, 1H), 2.13 (s, 3H), 1.98 - 1.91 (m, 2H), 1.88 - 1.81 (m, 2H), 1.44 (s, 9H), 1.44 - 1.37 (m, 1H), 1.37 - 1.26 (m, 2H), 1.02 - 0.92 (m, 2H).

[0275] Step 3. Synthesis of tert-butyl {[(1r,4r)-4-(bromoacetyl)cyclohexyl]methyl}carbamate (C19). Bromine (2.57 mL, 50.2 mmol) was added dropwise to a 0° C. solution of C18 (12.1 g, 47.4 mmol) in methanol (158 mL). The mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour, after which N,N-diisopropylethylamine (29.6 mL, 170 mmol) was added dropwise. Stirring was continued at room temperature for 20 minutes, whereupon the mixture was concentrated in vacuo and combined with the product of a similar reaction carried out using C18 (1.03 g, 4.03 mmol). Silica gel chromatography (eluent: 0%, then 10%, then 25% ethyl acetate in heptane) afforded C19 as a solid. Combined yield: 9.07 g, 27.1 mmol, 53%.1 H NMR (500 MHz, chloroform-d) d 4.56 (br s, 1H), 3.95 (s, 2H), 2.99 (dd, J = 6, 6 Hz, 2H), 2.68 (tt, J = 12.1, 3.4 Hz, 1H), 2.00 - 1.92 (m, 2H), 1.90 - 1.82 (m, 2H), 1.48 - 1.34 (m, 3H), 1.44 (s, 9H), 1.06 - 0.95 (m, 2H).

[0276] Step 4. Synthesis of tert-butyl {[(1r,4r)-4-(7-bromoimidazo[1,2-a]pyridin-2-yl)cyclohexyl]methyl}carbamate (P11). A suspension of C19 (1.00 g, 2.99 mmol) and 4-bromopyridin-2-amine (1.04 g, 6.01 mmol) in ethanol (20 mL) was heated at 70° C. overnight. After the reaction mixture was cooled to room temperature, it was poured into water (150 mL) with stirring and stirred for 20 minutes. The solid was collected by filtration and washed with water to give P11 as a white solid. Yield: 976 mg, 2.39 mmol, 80%. LCMS m / z 408.2 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.41 (br d, J = 7.1 Hz, 1H), 7.75 (br d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 6.97 (dd, J = 7.2, 2.0 Hz, 1H), 6.83 (br t, J = 5.9 Hz, 1H), 2.81 (dd, J = 6, 6 Hz, 2H), 2.64 - 2.53 (m, 1H), 2.09 - 1.99 (m, 2H), 1.82 - 1.73 (m, 2H), 1.45 - 1.29 (m, 3H), 1.38 (s, 9H), 1.08 - 0.94 (m, 2H).

[0277] Preparation Example P12: tert-Butyl ({(1r,4r)-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]cyclohexyl}methyl)carbamate (P12)

[0278] [ka] Step 1. Synthesis of tert-butyl {[(1r,4r)-4-(6-bromo-2H-indazol-2-yl)cyclohexyl]methyl}carbamate (C20). A suspension of tert-butyl {[(1r,4r)-4-aminocyclohexyl]methyl}carbamate (5.00 g, 21.9 mmol) and 4-bromo-2-nitrobenzaldehyde (5.04 g, 21.9 mmol) in propan-2-ol (70 mL) was heated at 80° C. for 4 hours. After the reaction mixture was cooled to room temperature, tributylphosphine (94%, 12 mL, 45 mmol) was added via syringe over 5 minutes; the reaction mixture was then heated at 80° C. overnight. Upon cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with heptane to afford C20 as a light brown solid. Yield: 6.52 g, 16.0 mmol, 73%. LCMS m / z 408.1 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) 8.45 (s, 1H), 7.86 - 7.82 (m, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.12 (dd, J = 8.8, 1.7 Hz, 1H), 6.89 (br t, J = 6.0 Hz, 1H), 4.50 - 4.38 (m, 1H), 2.85 (dd, J = 6.3, 6.3 Hz, 2H), 2.17 - 2.07 (m, 2H), 1.93 - 1.78 (m, 4H), 1.54 - 1.41 (m, 1H), 1.39 (s, 9H), 1.20 - 1.04 (m, 2H).

[0279] Step 2. Synthesis of tert-butyl ({(1r,4r)-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]cyclohexyl}methyl)carbamate (P12). A mixture of C20 (6.52 g, 16.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (6.08 g, 23.9 mmol), and potassium acetate (95%, 4.95 g, 47.9 mmol) in 1,4-dioxane (200 mL) was degassed with nitrogen for 10 min, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (Pd(dppf)Cl; 652 mg, 0.798 mmol) was added. The reaction mixture was heated at 100 °C for 1 h, then cooled and filtered through a pad of diatomaceous earth. The filter cake was rinsed with ethyl acetate and the combined filtrates were concentrated in vacuo; silica gel chromatography (gradient: 30% to 70% ethyl acetate in heptane; loaded as a solution in dichloromethane) afforded P12 as a colorless foam. Yield: 7.20 g, 15.8 mmol, 99%. LCMS m / z 456.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6), Characteristic peaks: d 8.40 (s, 1H), 7.96 - 7.93 (m, 1H), 7.65 (br d, J = 8.4 Hz, 1H), 7.25 (br d, J = 8.4 Hz, 1H), 6.89 (br t, J = 6.0 Hz, 1H), 4.53 - 4.39 (m, 1H), 2.85 (dd, J = 6, 6 Hz, 2H), 2.19 - 2.08 (m, 2H), 1.93 - 1.78 (m, 4H), 1.56 - 1.43 (m, 1H), 1.39 (s, 9H), 1.31 (s, 12H).

[0280] Preparation Example P13: 1-{(1r,4r)-4-[6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methanamine, hydrochloride (P13)

[0281] [ka] Step 1. Synthesis of tert-butyl ({(1r,4r)-4-[6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methyl)carbamate (C21). 4-Bromo-1-methyl-1H-pyrazole (233 mg, 1.45 mmol), P12 (600 mg, 1.32 mmol), aqueous potassium carbonate (2 M; 1.98 mL, 3.96 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) [Pd(dtbpf)Cl2; 85.9 mg, 0.132 mmol], ethanol (5 mL), and water (1 mL) were combined in a pressure relief vial, and the reaction mixture was heated at 85 °C for 1 h. After cooling the reaction mixture, ethanol was removed using concentration in vacuo, and the resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (eluent: ethyl acetate, then 5% methanol in ethyl acetate) afforded C21 as a colorless foam. Yield: 404 mg, 0.986 mmol, 75%. LCMS m / z 410.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.31 (br s, 1H), 8.15 (s, 1H), 7.91 - 7.89 (m, 1H), 7.76 - 7.72 (m, 1H), 7.65 (dd, J = 8.6, 0.9 Hz, 1H), 7.25 (dd, J = 8.7, 1.4 Hz, 1H), 6.90 (br t, J = 5.9 Hz, 1H), 4.47 - 4.34 (m, 1H), 3.87 (s, 3H), 2.85 (dd, J = 6, 6 Hz, 2H), 2.18 - 2.07 (m, 2H), 1.94 - 1.78 (m, 4H), 1.54 - 1.42 (m, 1H), 1.39 (s, 9H), 1.20 - 1.05 (m, 2H).

[0282] Step 2. Synthesis of 1-{(1r,4r)-4-[6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methanamine, hydrochloride (P13) A solution of hydrogen chloride in 1,4-dioxane (4 M; 6 mL) was added to C21 (404 mg, 0.986 mmol). Propan-2-ol (3 mL) was added to aid dissolution and stirring, and the reaction mixture was stirred overnight, whereupon it was diluted with diethyl ether (50 mL). The solid was collected by filtration and washed with diethyl ether to give P13 as a solid. Yield: 362 mg, assumed quantitative. LCMS m / z 310.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.37 (br s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.74 (br s, 1H), 7.66 (br d, J = 8.6 Hz, 1H), 7.27 (dd, J = 8.7, 1.4 Hz, 1H), 4.50 - 4.39 (m, 1H), 3.87 (s, 3H), 2.78 - 2.68 (m, 2H), 2.22 - 2.12 (m, 2H), 2.01 - 1.84 (m, 4H), 1.78 - 1.65 (m, 1H), 1.29 - 1.15 (m, 2H).

[0283] Preparation Example P14: 3,5-Difluoro-4-[(4-methoxyphenyl)methoxy]-N-({(1r,4r)-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (P14)

[0284] [ka] Step 1. Synthesis of 1-[(1r,4r)-4-(6-bromo-2H-indazol-2-yl)cyclohexyl]methanamine, hydrochloride (C22). A solution of hydrogen chloride in 1,4-dioxane (4 M; 25 mL, 100 mmol) was added to a solution of C20 (7.35 g, 18.0 mmol) in 1,4-dioxane (30 mL); the reaction mixture was stirred at room temperature for 3 hours, then at 50° C. overnight. After cooling, the reaction mixture was diluted with diethyl ether (100 mL). The solid was collected by filtration and washed with diethyl ether to give C22 as a solid. Yield: 6.20 g, 18.0 mmol, quantitative. LCMS m / z 308.5 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.49 (br s, 1H), 8.06 (br s, 3H), 7.86 - 7.83 (m, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.12 (dd, J = 8.8, 1.7 Hz, 1H), 4.47 (tt, J = 11.7, 3.9 Hz, 1H), 2.78 - 2.66 (m, 2H), 2.21 - 2.11 (m, 2H), 2.01 - 1.82 (m, 4H), 1.78 - 1.65 (m, 1H), 1.29 - 1.14 (m, 2H).

[0285] Step 2. Synthesis of N-{[(1r,4r)-4-(6-bromo-2H-indazol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C23). To a suspension of C22 (6.20 g, 18.0 mmol) and P1 (5.92 g, 20.1 mmol) in N,N-dimethylformamide (15 mL) was added N,N-diisopropylethylamine (14 mL, 80.4 mmol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 95%; 9.66 g, 24.1 mmol). The reaction mixture was stirred at room temperature for 3 days and then immediately poured into water (450 mL) with stirring. The resulting solid was isolated by filtration and washed with water to give C23 as a solid. Yield: 10.0 g, 17.1 mmol, 95%. LCMS m / z 584.2 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.57 (br t, J = 5.8 Hz, 1H), 8.45 (br s, 1H), 7.86 - 7.83 (m, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.12 (dd, J = 8.8, 1.7 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 5.17 (s, 2H), 4.53 - 4.41 (m, 1H), 3.74 (s, 3H), 3.17 (dd, J = 6, 6 Hz, 2H), 2.21 - 2.09 (m, 2H), 1.96 - 1.80 (m, 4H), 1.73 - 1.59 (m, 1H), 1.28 - 1.13 (m, 2H).

[0286] Step 3. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-({(1r,4r)-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (P14). A mixture of C23 (10 g, 17.1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (6.52 g, 25.7 mmol), and potassium acetate (95%, 5.30 g, 51.3 mmol) in 1,4-dioxane (250 mL) was degassed with nitrogen for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (700 mg, 0.857 mmol) was added, and the reaction mixture was purged with nitrogen for an additional 5 minutes, immediately followed by heating at 100 °C for 2 hours. After cooling, the reaction mixture was filtered through diatomaceous earth, and the filter pad was rinsed with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was purified by silica gel chromatography (gradient: 2% to 10% methanol in dichloromethane; loaded as a solution in dichloromethane) to give P14 as a light brown solid. Yield: 7.32 g, 11.6 mmol, 68%. LCMS m / z 632.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.57 (br t, J = 5.8 Hz, 1H), 8.40 (br s, 1H), 7.96 - 7.94 (m, 1H), 7.65 (dd, J = 8.4, 1 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.25 (br d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 4.55 - 4.43 (m, 1H), 3.74 (s, 3H), 3.18 (dd, J = 6, 6 Hz, 2H), 2.21 - 2.10 (m, 2H), 1.96 - 1.81 (m, 4H), 1.75 - 1.60 (m, 1H), 1.31 (s, 12H), 1.28 - 1.14 (m, 2H).

[0287] Preparation Example P15: N-{[(1r,4r)-4-(6-chloro-2H-pyrazolo[4,3-c]pyridin-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P15)

[0288] [ka] Step 1. Synthesis of tert-butyl {[(1r,4r)-4-(6-chloro-2H-pyrazolo[4,3-c]pyridin-2-yl)cyclohexyl]methyl}carbamate (C24). A mixture of 6-chloro-4-nitropyridine-3-carbaldehyde (2.00 g, 10.7 mmol) and tert-butyl {[(1r,4r)-4-aminocyclohexyl]methyl}carbamate (2.45 g, 10.7 mmol) in propan-2-ol (50 mL) was heated at 80°C for 4 hours, whereupon the reaction mixture was cooled to room temperature. Tributylphosphine (6.51 g, 32.2 mmol) was then added, and the reaction mixture was heated at 80°C for an additional 6 hours. After the solvent was removed in vacuo, the residue was purified by reverse-phase HPLC (column: Waters XBridge C18, 30 × 150 mm, 5 μm; mobile phase A: water containing 0.05% formic acid; mobile phase B: acetonitrile; gradient: 50% to 60% B; flow rate: 20 mL / min) to give C24 as a white solid. Yield: 260 mg, 0.713 mmol, 7%. LCMS m / z 365.2 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 9.01 (d, J = 1.2 Hz, 1H), 8.81 (br s, 1H), 7.68 (br s, 1H), 6.91 (br t, J = 5.9 Hz, 1H), 4.59 - 4.47 (m, 1H), 2.85 (dd, J = 6, 6 Hz, 2H), 2.20 - 2.08 (m, 2H), 1.95 - 1.78 (m, 4H), 1.54 - 1.40 (m, 1H), 1.38 (s, 9H), 1.20 - 1.04 (m, 2H).

[0289] Step 2. Synthesis of 1-[(1r,4r)-4-(6-chloro-2H-pyrazolo[4,3-c]pyridin-2-yl)cyclohexyl]methanamine, hydrochloride (C25). To a solution of C24 (260 mg, 0.713 mmol) in dichloromethane (4 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 1 mL, 4 mmol). The reaction mixture was stirred at 15° C. for 4 hours and then concentrated in vacuo to give C25 as a yellow oil. Yield: 170 mg, 0.564 mmol, 79%. LCMS m / z 265.1 (chlorine isotope pattern observed) [M+H] + .

[0290] Step 3. Synthesis of N-{[(1r,4r)-4-(6-chloro-2H-pyrazolo[4,3-c]pyridin-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P15). To a solution of P1 (186 mg, 0.632 mmol), N,N-diisopropylethylamine (163 mg, 1.26 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 288 mg, 0.757 mmol) in dichloromethane (10 mL), C25 (167 mg, 0.554 mmol) was added, whereupon the reaction mixture was stirred at 15 °C for 1 hour. It was then extracted with dichloromethane (3 × 30 mL), and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (eluent: 4% methanol in dichloromethane) afforded P15 as a yellow oil. Yield: 250 mg, 0.462 mmol, 83%. LCMS m / z 541.1 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6), characteristic peaks: d 9.01 (d, J = 1.2 Hz, 1H), 8.80 (br s, 1H), 8.58 (br t, J = 5.8 Hz, 1H), 7.68 (br s, 1H), 7.66 - 7.56 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 4.63 - 4.49 (m, 1H), 3.74 (s, 3H), 2.21 - 2.10 (m, 2H).

[0291] Preparation Example P16: N-{[4-(6-bromo-2H-indazol-2-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P16)

[0292] [ka] A solution of P8 (200 mg, 0.446 mmol) and 4-bromo-2-nitrobenzaldehyde (123 mg, 0.535 mmol) in propan-2-ol (10 mL) was stirred at 85° C. for 4 h, whereupon it was cooled to room temperature and treated with tributylphosphine (2 mL, 8 mmol). The reaction mixture was stirred at 85° C. overnight before being diluted with water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and chromatographed on silica gel (gradient: 0% to 10% methanol in dichloromethane) to afford P16 as a yellow solid. 1 H NMR data was obtained from a reaction carried out in a similar manner. Yield: 170 mg, 0.270 mmol, 61%. LCMS m / z 626.1 (bromine isotope pattern observed) [MH] - . 1 H NMR (400 MHz, DMSO-d6) d 8.46 (d, J = 1.0 Hz, 1H), 8.40 (br t, J = 6.3 Hz, 1H), 7.86 - 7.83 (m, 1H), 7.66 (br d, J = 8.8 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.11 (dd, J = 8.8, 1.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 5.22 (s, 2H), 3.75 (s, 3H), 3.10 (d, J = 6.2 Hz, 2H), 2.20 - 2.10 (m, 6H), 1.71 - 1.60 (m, 6H).

[0293] Example 1 N-{[(1r,4r)-4-(1,3-benzoxazol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide (1)

[0294] [ka] Step 1. Synthesis of N-{[(1r,4r)-4-(1,3-benzoxazol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C26). 1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (161 mg, 0.693 mmol) and P4 (1.00 g, 2.31 mmol) were added to a 0° C. mixture of triphenylphosphine (95%, 637 mg, 2.31 mmol) in 1,4-dioxane (40 mL). After stirring for 30 minutes, the reaction mixture was warmed to room temperature, 2-aminophenol (378 mg, 3.46 mmol) was added, and the reaction mixture was stirred overnight at 105° C. Upon cooling, the reaction mixture was filtered through a pad of diatomaceous earth, and the pad was rinsed successively with 1,4-dioxane, ethyl acetate, and dichloromethane. The combined filtrates were concentrated in vacuo to afford C26 as an orange oil, which was carried on directly to the next step. LCMS m / z 507.3 [M+H] + .

[0295] Step 2. Synthesis of N-{[(1r,4r)-4-(1,3-benzoxazol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide (1). A 0°C suspension of C26 (from the previous step; ≦2.31 mmol) in 1,4-dioxane (20 mL) was treated with a solution of hydrogen chloride in 1,4-dioxane (4 M; 20 mL). The reaction mixture was stirred at room temperature for 2 h before being concentrated in vacuo and purified by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane; sample loaded in dichloromethane containing a small amount of methanol). The resulting material was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, whereupon the organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (gradient: 0% to 100% ethyl acetate in heptane, followed by 0% to 10% methanol in dichloromethane; sample loaded in dichloromethane containing a small amount of methanol) to give N-{[(1r,4r)-4-(1,3-benzoxazol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide (1) as a white solid. Yield: 46 mg, 0.12 mmol, 5% over two steps. LCMS m / z 387.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) d 7.65 - 7.60 (m, 1H), 7.58 - 7.53 (m, 1H), 7.52 - 7.42 (m, 2H), 7.38 - 7.31 (m, 2H), 3.27 (d, J = 7.0 Hz, 2H), 2.98 (tt, J = 12.2, 3.6 Hz, 1H), 2.32 - 2.22 (m, 2H), 2.04 - 1.94 (m, 2H), 1.80 - 1.62 (m, 3H), 1.31 - 1.16 (m, 2H).

[0296] Example 2 3,5-Difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (2)

[0297] [ka] Step 1. Synthesis of N-hydroxy-5-(trifluoromethyl)pyridine-2-carboximidamide (C27). To a mixture of 5-(trifluoromethyl)pyridine-2-carbonitrile (200 mg, 1.16 mmol) and hydroxylamine hydrochloride (242 mg, 3.48 mmol) in ethanol (20 mL) was added sodium hydroxide (139 mg, 3.48 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo to give C27 as a white solid. Yield: 200 mg, 0.975 mmol, 84%. LCMS m / z 206.1 [M+H] + .

[0298] Step 2. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (C28). To a mixture of P4 (400 mg, 0.923 mmol), N,N-diisopropylethylamine (358 mg, 2.77 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 526 mg, 1.38 mmol) in dichloromethane (20 mL) at 0 °C, C27 (227 mg, 1.11 mmol) was added. The reaction mixture was stirred at room temperature for 6 h, whereupon it was diluted with water (20 mL) and extracted with dichloromethane (2 × 20 mL); the combined organic layers were washed with saturated aqueous sodium chloride (2 × 20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 7% methanol in dichloromethane) afforded the acylated intermediate (100 mg, 0.161 mmol, 17%), LCMS m / z 621.3 [M+H] + was obtained as a white solid.

[0299] This material was dissolved in a mixture of ethanol (4 mL) and water (1 mL), treated with sodium acetate (39.6 mg, 0.483 mmol), and stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was concentrated in vacuo and then purified using chromatography on silica gel (gradient: 0% to 5% methanol in dichloromethane) to afford C28 as a white solid. Yield: 60 mg, 0.10 mmol, 11% from P4. LCMS m / z 603.3 [M+H] + .

[0300] Step 3. Synthesis of 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (2). To a solution of C28 (60 mg, 0.10 mmol) in dichloromethane (5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 1 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo, diluted with dichloromethane (10 mL), treated with sodium bicarbonate (10 mg, 0.12 mmol), and concentrated under reduced pressure. Chromatography on silica gel (gradient: 0% to 5% methanol in dichloromethane) afforded 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (2) as a white solid. Yield: 11.6 mg, 24.0 μmol, 24%. LCMS m / z 483.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 9.19 - 9.14 (m, 1H), 8.48 - 8.39 (m, 2H), 8.27 (d, J = 8.2 Hz, 1H), 7.60 - 7.54 (m, 2H), 3.19 - 3.05 (m, 3H), 2.25 - 2.13 (m, 2H), 1.93 - 1.81 (m, 2H), 1.67 - 1.51 (m, 3H), 1.22 - 1.07 (m, 2H).

[0301] Example 3 2,3,5-Trifluoro-4-hydroxy-N-[(4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide (3)

[0302] [ka] Step 1. Synthesis of 5-(trifluoromethyl)pyrimidine-2-carbonitrile (C29). A solution of tetraethylammonium cyanide (1.88 g, 12.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (1.47 g, 13.1 mmol) in acetonitrile (8 mL) was added to a mixture of 2-chloro-5-(trifluoromethyl)pyrimidine (2.00 g, 11.0 mmol) in acetonitrile (8 mL), whereupon the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo to give a residue containing C29; this pale yellow solid was carried on directly to the next step.

[0303] Step 2. Synthesis of N-hydroxy-5-(trifluoromethyl)pyrimidine-2-carboximidamide (C30). A mixture of C29 (from the previous step; ≦11.0 mmol), hydroxylamine hydrochloride (1.52 g, 21.9 mmol), and N,N-diisopropylethylamine (4.26 g, 33.0 mmol) in methanol (20 mL) was stirred at 70° C. for 12 hours. The reaction mixture was concentrated in vacuo to give C30 (1.70 g), which was used directly in the next step. LCMS m / z 207.1 [M+H] + .

[0304] Step 3. Synthesis of tert-butyl [(4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methyl]carbamate (C31). To a solution of C30 (from the previous step; 1.70 g, ≤8.25 mmol) and 4-{[(tert-butoxycarbonyl)amino]methyl}bicyclo[2.2.2]octane-1-carboxylic acid (2.57 g, 9.07 mmol) in N,N-dimethylformamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 4.70 g, 12.4 mmol) and N,N-diisopropylethylamine (3.20 g, 24.8 mmol). The reaction mixture was stirred at 25 °C for 2 h, then diluted with water and filtered; the filtrate was concentrated in vacuo to give the acyl intermediate as a yellow solid. Yield: 1.90 g, 4.03 mmol, 37% over three steps. LCMS m / z 472.2 [M+H] + .

[0305] To a solution of the acyl intermediate (2.00 g, 4.24 mmol) in a mixture of ethanol (6 mL) and water (3 mL) was added sodium acetate (1.04 g, 12.7 mmol). The reaction mixture was stirred at 100° C. for 1 h under microwave irradiation before being concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% to 6% methanol in dichloromethane) afforded C31 as a white solid. Yield: 1.00 g, 2.21 mmol, 52% from the acyl intermediate. LCMS m / z 454.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) d 9.35 - 9.33 (m, 2H), 2.87 (s, 2H), 2.15 - 2.03 (m, 6H), 1.64 - 1.53 (m, 6H), 1.45 (s, 9H).

[0306] Step 4. Synthesis of 1-(4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methanamine (C32). A solution of hydrogen chloride in 1,4-dioxane (4 M; 5 mL, 20 mmol) was added to a solution of C31 (1.00 g, 2.21 mmol) in dichloromethane (15 mL), whereupon the reaction mixture was stirred at room temperature for 2 hours. It was then concentrated in vacuo, diluted with dichloromethane (10 mL), treated with sodium bicarbonate, and concentrated again under reduced pressure. Chromatography on silica gel (gradient: 0% to 7% methanol in dichloromethane) afforded C32 as a white solid. Yield: 800 mg, quantitative. LCMS m / z 354.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) d 9.35 (br s, 2H), 2.80 (s, 2H), 2.22–2.10 (m, 6H), 1.75 - 1.65 (m, 6H).

[0307] Step 5. Synthesis of 2,3,5-trifluoro-4-hydroxy-N-[(4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide (3). To a solution of C32 (100 mg, 0.283 mmol) and 2,3,5-trifluoro-4-hydroxybenzoic acid (65.2 mg, 0.339 mmol) in N,N-dimethylformamide (5 mL) was added 1H-benzotriazol-1-ol (57.4 mg, 0.425 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (81.4 mg, 0.425 mmol), and N,N-diisopropylethylamine (110 mg, 0.851 mmol). The reaction mixture was stirred at 25 °C for 4 h, then diluted with water (15 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride (100 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified by reverse-phase HPLC (Column: Waters XBridge C18, 19 × 150 mm, 5 μm; Mobile phase A: water containing 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 65% to 75% B; Flow rate: 20 mL / min) to give 2,3,5-trifluoro-4-hydroxy-N-[(4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide (3) as a white solid. Yield: 105 mg, 0.199 mmol, 70%. LCMS m / z 528.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.36 (br s, 1H), 9.49 (s, 2H), 8.20 (br t, J = 6 Hz, 1H), 7.28 (ddd, J = 11.0, 6.2, 2.3 Hz, 1H), 3.09 (d, J = 6.3 Hz, 2H), 2.06 - 1.93 (m, 6H), 1.61 - 1.50 (m, 6H).

[0308] Example 4 3,5-Difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (4)

[0309] [ka] Step 1. Synthesis of tert-butyl {[(1r,4r)-4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}carbamate (C33). To a solution of C30 (453 mg, 2.20 mmol) in N,N-dimethylformamide (8 mL) was added (1r,4r)-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexane-1-carboxylic acid (679 mg, 2.64 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 1.25 g, 3.29 mmol), and N,N-diisopropylethylamine (852 mg, 6.59 mmol). The reaction was stirred at 25 °C for 2 h, whereupon it was diluted with ice water (30 mL) and the solid collected by filtration to give the acyl intermediate as a brown solid. Yield: 510 mg, 1.14 mmol, 52%. LCMS m / z 446.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d), characteristic peaks, integrals approximately: d 9.08 (br s, 2H), 3.05 - 2.96 (m, 2H), 2.48 (tt, J = 12.3, 3.6 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.92 - 1.82 (m, 2H), 1.66 - 1.53 (m, 2H), 1.09 - 0.94 (m, 2H).

[0310] To a solution of the acyl intermediate (700 mg, 1.57 mmol) in dichloromethane (5 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M; 5 mL, 5 mmol), whereupon the reaction mixture was stirred at 25° C. for 4 h. It was then concentrated in vacuo and chromatographed on silica gel (gradient: 0% to 50% ethyl acetate in petroleum ether) to afford C33 as a white solid. Yield: 340 mg, 0.795 mmol, 51%. LCMS m / z 450.1 [M+Na + ]. 1 H NMR (400 MHz, chloroform-d) d 9.20 - 9.18 (m, 2H), 4.60 (br s, 1H), 3.11 - 2.99 (m, 3H), 2.34 - 2.24 (m, 2H), 2.00 - 1.91 (m, 2H), 1.84 - 1.69 (m, 2H), 1.6 - 1.50 (m, 1H, estimated; significantly obscured by water peak), 1.45 (s, 9H), 1.20 - 1.06 (m, 2H).

[0311] Step 2. Synthesis of 1-[(1r,4r)-4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methanamine, hydrochloride (C34). A solution of hydrogen chloride in 1,4-dioxane (4 M; 2 mL, 8 mmol) was added to a solution of C33 (340 mg, 0.795 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 25° C. for 2 h and then concentrated in vacuo to give C34 as a white solid. Yield: 200 mg, 0.550 mmol, 69%. LCMS m / z 328.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 9.51 - 9.49 (m, 2H), 8.00 (br s, 3H), 3.14 (tt, J = 12.1, 3.6 Hz, 1H), 2.75 - 2.65 (m, 2H), 2.27 - 2.17 (m, 2H), 1.97 - 1.87 (m, 2H), 1.73 - 1.53 (m, 3H), 1.23 - 1.09 (m, 2H).

[0312] Step 3. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (C35). To a 0° C. solution of P1 (27 mg, 91.8 μmol), C34 (30 mg, 82 μmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 52.3 mg, 0.138 mmol) in N,N-dimethylformamide (3 mL) was added N,N-diisopropylethylamine (35.5 mg, 0.275 mmol), whereupon the reaction mixture was stirred at 25° C. for 2 h. It was then treated with ice water (30 mL), and the resulting solid was collected by filtration to give C35 as a white solid (60 mg). This material was used directly in the next step. LCMS m / z 626.2 [M+Na + ]. 1 H NMR (400 MHz, DMSO-d6) d 9.49 (s, 2H), 8.56 (br t, J = 5.8 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 5.17 (s, 2H), 3.74 (s, 3H), 3.19 - 3.08 (m, 3H), 2.24 - 2.15 (m, 2H), 1.91 - 1.82 (m, 2H), 1.67 - 1.51 (m, 3H), 1.22 - 1.08 (m, 2H).

[0313] Step 4. Synthesis of 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (4). A solution of C35 (from the previous step; 60 mg, ≦82 μmol) in dichloromethane (4 mL) was treated with a solution of hydrogen chloride in 1,4-dioxane (4 M; 2 mL), and the reaction mixture was stirred at 25 °C for 2 h. After removal of volatiles in vacuo, the residue was purified using silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane) to afford 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (4) as a white solid. Yield: 14.3 mg, 29.6 μmol, 36% over two steps. LCMS m / z 484.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 10.84 (br s, 1H), 9.49 (s, 2H), 8.44 (br t, J = 5.8 Hz, 1H), 7.64 - 7.52 (m, 2H), 3.20 - 3.07 (m, 3H), 2.25 - 2.15 (m, 2H), 1.93 - 1.82 (m, 2H), 1.67 - 1.51 (m, 3H), 1.22 - 1.08 (m, 2H).

[0314] Example 5 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide, trifluoroacetate (5)

[0315] [ka] A mixture of 2,3,5-trifluoro-4-hydroxybenzoic acid (50 mg, 0.26 mmol), P13 (75 mg, 0.22 mmol), 2-hydroxypyridine 1-oxide (26.5 mg, 0.239 mmol), and 1-methyl-1H-imidazole (52 μL, 0.65 mmol) in a mixture of water (0.32 mL) and N,N-dimethylformamide (1.3 mL) was stirred at room temperature for 5 minutes, after which 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (45.7 mg, 0.238 mmol) was added in one portion, and the reaction mixture was stirred at room temperature overnight. After dilution with water, the reaction mixture was acidified by the addition of 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a solid that was purified by reverse-phase HPLC (Column: Waters Sunfire C18, 19 x 100 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v / v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v / v); Gradient: 5% to 95% B over 8.54 min, followed by 95% B for 1.46 min; Flow rate: 25 mL / min) to give 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide, trifluoroacetate salt (5). Yield: 46.3 mg, 95.8 μmol, 44%. LCMS m / z 484.6 [M+H] + Retention time: 2.51 min (analytical conditions: Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 min, then 95% B for 1.0 min; Flow rate: 2 mL / min).

[0316] Example 6 3,5-Difluoro-4-hydroxy-N-{[(1r,4r)-4-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methyl}benzamide (6)

[0317] [ka] Step 1. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-{[(1r,4r)-4-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methyl}benzamide (C36). A mixture of P3 (134 mg, 0.331 mmol) and 5-bromo-2-methoxypyridine-4-carbaldehyde (65 mg, 0.30 mmol) in toluene (8 mL) was stirred at 90 °C for 8 h. The reaction mixture was then concentrated under reduced pressure and diluted with dimethyl sulfoxide (8 mL); 1 ,N 1 ,N 2 ,N 2 To the resulting mixture were added tetramethylethane-1,2-diamine (3.49 mg, 30.0 μmol), and sodium azide (39.1 mg, 0.601 mmol). The reaction mixture was stirred at 100° C. for 8 hours, then treated with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride (2×20 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (gradient: 0% to 8% methanol in dichloromethane) to afford C36 as a brown solid. Yield: 50 mg, 93 μmol, 31%. LCMS m / z 537.3 [M+H] + .

[0318] Step 2. Synthesis of 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methyl}benzamide (6). To a solution of C36 (50 mg, 93 μmol) in dichloromethane (5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 1 mL). The reaction mixture was stirred at room temperature for 2 h, whereupon it was concentrated under reduced pressure, treated with dichloromethane (10 mL) and sodium bicarbonate (10 mg), and concentrated again in vacuo. Silica gel chromatography (gradient: 0% to 7% methanol in dichloromethane) afforded 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methyl}benzamide (6) as a white solid. Yield: 5.1 mg, 12 μmol, 13%. LCMS m / z 417.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 10.84 (s, 1H), 8.92 - 8.87 (m, 1H), 8.47 (br t, J = 5.8 Hz, 1H), 8.37 (s, 1H), 7.64 - 7.53 (m, 2H), 6.88 (d, J = 1.2 Hz, 1H), 4.59 - 4.49 (m, 1H), 3.84 (s, 3H), 3.17 (dd, J = 6, 6 Hz, 2H), 2.21 - 2.10 (m, 2H), 1.99 - 1.83 (m, 4H), 1.74 - 1.60 (m, 1H), 1.29 - 1.14 (m, 2H).

[0319] Example 7 2,3,5-Trifluoro-4-hydroxy-N-({4-[6-(pyrimidin-2-yl)-2H-indazol-2-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide (7)

[0320] [ka] Step 1. Synthesis of 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]-N-({4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide (C37). To a solution of P16 (100 mg, 0.159 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (48.5 mg, 0.191 mmol) in 1,4-dioxane (5 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.6 mg, 15.9 μmol) and potassium acetate (46.8 mg, 0.477 mmol) were added, whereupon the reaction mixture was stirred at 90° C. for 12 h. Concentration in vacuo afforded C37, which was carried on directly to the next step.

[0321] Step 2. Synthesis of 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]-N-({4-[6-(pyrimidin-2-yl)-2H-indazol-2-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide (C38). To a solution of C37 (from the previous step; ≦0.159 mmol) and 2-bromopyrimidine (28.2 mg, 0.177 mmol) in 1,4-dioxane (5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.8 mg, 14.8 μmol) and potassium carbonate (61.4 mg, 0.444 mmol). The reaction mixture was stirred at 90° C. for 12 h before being concentrated in vacuo and purified by silica gel chromatography (gradient: 0% to 60% ethyl acetate in petroleum ether) to give C38 as a white solid. Yield: 40 mg, 64 μmol, 40% over two steps. LCMS m / z 628.2 [M+H] + .

[0322] Step 3. Synthesis of 2,3,5-trifluoro-4-hydroxy-N-({4-[6-(pyrimidin-2-yl)-2H-indazol-2-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide (7). To a solution of C38 (40 mg, 64 μmol) in dichloromethane (10 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 2 mL, 8 mmol), and the reaction mixture was stirred at 25° C. for 2 h. It was then concentrated in vacuo, treated with dichloromethane (10 mL) and sodium bicarbonate (1 g), and concentrated under reduced pressure. Chromatography on silica gel (gradient: 0% to 7% methanol in dichloromethane) afforded 2,3,5-trifluoro-4-hydroxy-N-({4-[6-(pyrimidin-2-yl)-2H-indazol-2-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide (7) as a white solid. Yield: 6.0 mg, 12 μmol, 19%. LCMS m / z 508.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.38 (br s, 1H), 8.91 (d, J = 4.8 Hz, 2H), 8.67 - 8.65 (m, 1H), 8.47 (d, J = 1.0 Hz, 1H), 8.21 (br t, J = 6 Hz, 1H), 8.08 (dd, J = 8.8, 1.4 Hz, 1H), 7.79 (dd, J = 8.8, 0.9 Hz, 1H), 7.43 (t, J = 4.8 Hz, 1H), 7.29 (ddd, J = 11.1, 6.2, 2.3 Hz, 1H), 3.12 (d, J = 6.3 Hz, 2H), 2.25 - 2.15 (m, 6H), 1.74 - 1.63 (m, 6H).

[0323] Example 8 3,5-Difluoro-4-hydroxy-N-({(1r,4r)-4-[6-(2-methoxypyrimidin-5-yl)-2H-pyrazolo[4,3-c]pyridin-2-yl]cyclohexyl}methyl)benzamide (8)

[0324] [ka] To a solution of P15 (60 mg, 0.11 mmol), (2-methoxypyrimidin-5-yl)boronic acid (25.6 mg, 0.166 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos; 21.1 mg, 44.3 μmol), and potassium carbonate (46.0 mg, 0.333 mmol) in a mixture of 1,4-dioxane (2 mL) and water (0.4 mL) was added tris(dibenzylideneacetone)dipalladium(0) (20.3 mg, 22.2 μmol). The reaction mixture was stirred at 100 °C for 1 h under microwave irradiation and then immediately concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 mL), treated with a solution of hydrogen chloride in 1,4-dioxane (4 M; 1 mL, 4 mmol), and stirred at 15 °C for 1 h. After removal of the solvent in vacuo, purification by reverse-phase HPLC (column: Welch Xtimate C18, 30 × 250 mm, 10 μm; mobile phase A: water containing 0.05% formic acid; mobile phase B: acetonitrile; gradient: 43% to 95% B; flow rate: 50 mL / min) gave 3,5-difluoro-4-hydroxy-N-({(1r,4r)-4-[6-(2-methoxypyrimidin-5-yl)-2H-pyrazolo[4,3-c]pyridin-2-yl]cyclohexyl}methyl)benzamide (8) as a solid. Yield: 5.2 mg, 10 μmol, 9%. LCMS m / z 495.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 9.30 (s, 2H), 9.25 (d, J = 1.3 Hz, 1H), 8.76 (br s, 1H), 8.43 (br s, 1H), 8.23 - 8.20 (m, 1H), 7.62 - 7.49 (m, 2H), 4.64 - 4.50 (m, 1H), 3.98 (s, 3H), 3.18 (dd, J = 6, 6 Hz, 2H), 2.24 - 2.12 (m, 2H), 2.01 - 1.84 (m, 4H), 1.75 - 1.60 (m, 1H), 1.33 - 1.12 (m, 2H).

[0325] Example 9 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (9)

[0326] [ka] Step 1. Synthesis of N-{[(1r,4r)-4-(6-bromo-2H-indazol-2-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C39). To a solution of C22, free base (4.67 g, 15.2 mmol) and P2 (4.97 g, 15.9 mmol) in N,N-dimethylformamide (30 mL) was added 4-methylmorpholine (9.99 mL, 90.9 mmol). The suspension was then treated dropwise with chloro(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate (4.25 g, 15.1 mmol, divided into four equal portions), and the reaction mixture was stirred at room temperature for 5 hours, whereupon it was added dropwise to ice-cold water (300 mL). The resulting suspension was stirred for 20 minutes and filtered; the filter cake was washed three times with water to give C39 as a light brown solid. Yield: 9.20 g, quantitative. LCMS m / z 602.3 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.53 - 8.43 (m, 2H), 7.85 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.12 (dd, J = 8.8, 1.7 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 5.22 (s, 2H), 4.53 - 4.40 (m, 1H), 3.75 (s, 3H), 3.17 (dd, J = 6, 6 Hz, 2H), 2.20 - 2.09 (m, 2H), 1.97 - 1.81 (m, 4H), 1.72 - 1.58 (m, 1H), 1.29 - 1.13 (m, 2H).

[0327] Step 2. Synthesis of 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]-N-({(1r,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (C40). A mixture of C39 (700 mg, 1.16 mmol), pyrimidin-5-ylboronic acid (144 mg, 1.16 mmol), sodium carbonate (369 mg, 3.48 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (94.2 mg, 0.115 mmol) in a mixture of 1,4-dioxane (20 mL) and water (5 mL) was stirred at 90 °C for 16 h. The reaction mixture was then concentrated in vacuo and purified by silica gel chromatography (gradient: 0% to 100% ethyl acetate in petroleum ether) to afford C40 as a white solid. Yield: 300 mg, 0.499 mmol, 43%. LCMS m / z 602.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 9.20 (s, 2H), 9.18 (s, 1H), 8.53 - 8.46 (m, 2H), 8.08 (br s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 8.7, 1.6 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.35 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.22 (s, 2H), 4.59 - 4.45 (m, 1H), 3.75 (s, 3H), 3.18 (dd, J = 6, 6 Hz, 2H), 2.23 - 2.13 (m, 2H), 2.01 - 1.86 (m, 4H), 1.74 - 1.60 (m, 1H), 1.32 - 1.16 (m, 2H).

[0328] Step 3. Synthesis of 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (9). To a suspension of C40 (300 mg, 0.499 mmol) in dichloromethane (4.0 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 1 mL, 4 mmol). The reaction mixture was stirred at 25 °C for 2 h, whereupon it was concentrated in vacuo and purified using silica gel chromatography (gradient: 0% to 100% ethyl acetate in petroleum ether) to afford 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (9) as a white solid. Yield: 200 mg, 0.415 mmol, 83%. LCMS m / z 482.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.41 (br s, 1H), 9.21 (s, 2H), 9.18 (s, 1H), 8.49 (s, 1H), 8.37 - 8.30 (m, 1H), 8.09 (br s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 8.7, 1.6 Hz, 1H), 7.30 (ddd, J = 11.1, 6.3, 2.2 Hz, 1H), 4.58 - 4.46 (m, 1H), 3.21 - 3.14 (m, 2H), 2.23 - 2.13 (m, 2H), 2.02 - 1.86 (m, 4H), 1.75 - 1.61 (m, 1H), 1.33 - 1.16 (m, 2H).

[0329] Example 10 N-{[(1r,4r)-4-{6-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide, trifluoroacetate (10)

[0330] [ka] Step 1. Synthesis of tert-butyl {[(1r,4r)-4-{6-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methyl}carbamate (C41). To a mixture of 4-bromo-1-(2,2-difluoroethyl)-1H-pyrazole (46.1 mg, 0.218 mmol) and P12 (100 mg, 0.220 mmol), 1,4-dioxane (1.8 mL) and water (0.6 mL) were added, followed by potassium phosphate tribasic (140 mg, 0.660 mmol) and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) [Pd(amphos)Cl; 15.5 mg, 21.9 μmol]. The reaction mixture was heated at 85°C for 18 hours and immediately thereafter partitioned between water and ethyl acetate. After extracting the aqueous layer twice with ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 7.5% methanol in dichloromethane) afforded C41 as an oil. Yield: 80 mg, 0.17 mmol, 78%. LCMS m / z 460.3 [M+H] + . 1 H NMR (400 MHz, chloroform-d), characteristic peaks: d 7.91 (br s, 1H), 7.89 (s, 1H), 7.79 (br s, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.22 (dd, J = 8.7, 1.4 Hz, 1H), 6.13 (tt, J = 55.4, 4.3 Hz, 1H), 4.68 - 4.58 (m, 1H), 4.51 (td, J = 13.5, 4.3 Hz, 2H), 4.43 - 4.32 (m, 1H), 3.06 (dd, J = 6, 6 Hz, 2H), 2.39 - 2.28 (m, 2H), 1.46 (s, 9H).

[0331] Step 2. Synthesis of 1-[(1r,4r)-4-{6-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methanamine, trifluoroacetate (C42). Trifluoroacetic acid (0.5 mL, 6 mmol) was added dropwise to a solution of C41 (80 mg, 0.17 mmol) in dichloromethane (2 mL). The reaction mixture was stirred for 30 minutes at room temperature, whereupon it was concentrated to dryness in vacuo; the residue was azeotroped twice with dichloromethane to give C42 as a colorless oil (84 mg), the majority of which was used directly in the next step. LCMS m / z 360.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4), characteristic peaks: d 8.28 - 8.26 (m, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.75 (br s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.38 - 7.33 (m, 1H), 6.22 (tt, J = 55.2, 3.9 Hz, 1H), 4.61 (td, J = 14.4, 3.9 Hz, 2H), 4.56 - 4.44 (m, 1H), 2.90 (d, J = 7.0 Hz, 2H), 2.37 - 2.27 (m, 2H), 2.13 - 2.00 (m, 4H), 1.89 - 1.75 (m, 1H).

[0332] Step 3. Synthesis of N-{[(1r,4r)-4-{6-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide, trifluoroacetate (10). A solution of C42 (from the previous step; 82 mg, ≦0.17 mmol) in N,N-dimethylformamide (1.8 mL) was treated with water (0.4 mL). 3,5-Difluoro-4-hydroxybenzoic acid (36.2 mg, 0.208 mmol), 1-methyl-1H-imidazole (41.4 μL, 0.520 mmol), and 2-hydroxypyridine 1-oxide (64 mg, 5.76 mmol) were added sequentially, and the reaction mixture was stirred for 20 min at room temperature. 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 33.9 mg, 0.173 mmol) was then added, and stirring was continued for 18 h at room temperature. The reaction mixture was diluted with water (10 mL), acidified to pH 4 by the addition of 1 M hydrochloric acid, and then immediately extracted three times with ethyl acetate. The combined organic layers were washed five times with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by reverse-phase HPLC (column: Waters Sunfire C18, 19 × 100 mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid in water (v / v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v / v); gradient: 20% to 60% B over 8.5 min, then 60% to 95% B over 0.5 min; flow rate: 25 mL / min) afforded N-{[(1r,4r)-4-{6-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide, trifluoroacetate salt (10). Yield: 29.3 mg, 46.5 μmol, 27% over two steps). LCMS m / z 516.5 [M+H] + Retention time: 2.59 min (analytical conditions: Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 min, then 95% B for 1.0 min; Flow rate: 2 mL / min).

[0333] Example 11 2,3,5-trifluoro-4-hydroxy-N-{[(1r,4r)-4-{6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-2H-indazol-2-yl}cyclohexyl]methyl}benzamide, trifluoroacetate (11)

[0334] [ka] Step 1. Synthesis of tert-butyl {[(1r,4r)-4-{6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-2H-indazol-2-yl}cyclohexyl]methyl}carbamate (C43). A mixture of P12 (100 mg, 0.220 mmol), 4-(trifluoromethyl)-1H-pyrazole (120 mg, 0.882 mmol), and copper(II) acetate (53 mg, 0.29 mmol) in pyridine (1.3 mL) was heated at 90 °C for 18 hours. The reaction mixture was left open to air for the first hour; after which the cap was tightened, a needle was inserted through the cap to the atmosphere, and heating was continued for an additional 17 hours. The reaction mixture was concentrated to dryness in vacuo, and the residue was partitioned between dichloromethane and water. Silica gel chromatography (gradient: 0% to 7.5% methanol in dichloromethane) afforded C43 as a colorless oil. Yield: 80.0 mg, 0.173 mmol, 79%. LCMS m / z 464.3 [M+H] + . 1 H NMR (400 MHz, chloroform-d), characteristic peaks: d 8.21 (br s, 1H), 8.00 (br s, 1H), 7.92 (s, 1H), 7.91 - 7.89 (m, 1H), 7.77 (br d, J = 9.0 Hz, 1H), 7.49 (dd, J = 9.0, 1.9 Hz, 1H), 4.64 (br s, 1H), 4.42 (tt, J = 11.9, 3.7 Hz, 1H), 3.08 (dd, J = 6, 6 Hz, 2H), 2.40 - 2.28 (m, 2H), 2.07 - 1.89 (m, 4H), 1.70 - 1.55 (m, 1H), 1.46 (s, 9H).

[0335] Step 2. Synthesis of 1-[(1r,4r)-4-{6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-2H-indazol-2-yl}cyclohexyl]methanamine, hydrochloride (C44). To a solution of C43 (80.0 mg, 0.173 mmol) in 1,4-dioxane (2 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 1 mL, 4 mmol), whereupon the reaction mixture was stirred for 2 h. The solvent was removed in vacuo to give a residue that was azeotroped twice with dichloromethane to give C44 as a white solid (75 mg); most of the material was used directly in the next step. LCMS m / z 364.3 [M+H] + .

[0336] Step 3. Synthesis of 2,3,5-trifluoro-4-hydroxy-N-{[(1r,4r)-4-{6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-2H-indazol-2-yl}cyclohexyl]methyl}benzamide, trifluoroacetate (11). A solution of C44 (from the previous step; 69 mg, ≦0.16 mmol) in N,N-dimethylformamide (1.8 mL) was treated with water (0.4 mL), followed immediately by the sequential addition of the following reagents: 2,3,5-trifluoro-4-hydroxybenzoic acid (39.8 mg, 0.207 mmol), 1-methyl-1H-imidazole (55.0 μL, 0.690 mmol), and 2-hydroxypyridine 1-oxide (26.8 mg, 0.241 mmol). After stirring the reaction mixture for 20 min at room temperature, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 33.8 mg, 0.173 mmol) was added, and stirring was continued for 18 h. The reaction mixture was then diluted with water (10 mL), acidified to pH 4 by the addition of 1 M hydrochloric acid, and extracted three times with ethyl acetate. The combined organic layers were washed five times with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and purified using reverse-phase HPLC (Column: Waters Sunfire C18, 19 × 100 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v / v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v / v); Gradient: 5% to 95% B over 8.54 min, followed by 95% B for 1.46 min; Flow rate: 25 mL / min) to give 2,3,5-trifluoro-4-hydroxy-N-{[(1r,4r)-4-{6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]-2H-indazol-2-yl}cyclohexyl]methyl}benzamide, trifluoroacetate salt (11). Yield: 41.1 mg, 63.1 μmol, 39% over two steps. LCMS m / z 538.5 [M+H] + Retention time: 3.11 min (analytical conditions: column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); gradient: 5.0% to 95% B over 4.0 min, then 95% B for 1.0 min; flow rate: 2 mL / min).

[0337] Example 12 3,5-Difluoro-4-hydroxy-N-{[(1r,4r)-4-{6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methyl}benzamide (12)

[0338] [ka] Step 1. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-{[(1r,4r)-4-{6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methyl}benzamide (C45). This experiment was carried out in a library format.

[0339] A solution of P14 (60 mg, 100 μmol) in 1,4-dioxane (1 mL) was added to 4-bromo-1-(oxan-4-yl)-1H-pyrazole (150 μmol). Then, an aqueous solution of tripotassium phosphate (1.5 M; 0.20 mL, 300 μmol) was added, followed by chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium® A Pd G2; 5 μmol). The reaction vial was then capped and shaken at 100° C. for 16 hours. After removing the solvent using a Speedvac® concentrator, the residue was mixed with water (1 mL), extracted with ethyl acetate (3×1.5 mL), and concentrated again to give C45, which was carried on directly to the next step.

[0340] Step 2. Synthesis of 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methyl}benzamide (12). This experiment was carried out in a library format.

[0341] A solution of trifluoroacetic acid (0.2 mL) in dichloromethane (0.8 mL) was added to C45 (from the previous step; ≦100 μmol), after which the reaction vial was capped and shaken for 16 h at 30° C. After removal of the solvent using a Speedvac® concentrator, reverse-phase HPLC (column: YMC-Actus Triart C18, 30 × 150 mm, 5 μm; mobile phase A: water containing 0.225% formic acid; mobile phase B: acetonitrile; gradient: 35% to 75% B; flow rate: 35 mL / min) afforded 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{6-[1-(oxan-4-yl)-1H-pyrazol-4-yl]-2H-indazol-2-yl}cyclohexyl]methyl}benzamide (12). Yield: 13.7 mg, 22.2 μmol, 22% over two steps. LCMS m / z 536 [M+H] + Retention time: 2.77 min (Column: Waters XBridge C18, 2.1 × 50 mm, 5 μm; Mobile phase A: water containing 0.0375% trifluoroacetic acid; Mobile phase B: acetonitrile containing 0.01875% trifluoroacetic acid; Gradient: 1% to 5% B over 0.6 min; 5% to 100% B over 3.4 min; Flow rate: 0.8 mL / min).

[0342] Example 13 3,5-Difluoro-4-hydroxy-N-{[(1r,4r)-4-{5-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}cyclohexyl]methyl}benzamide (13)

[0343] [ka] Step 1. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-{[(1r,4r)-4-{5-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}cyclohexyl]methyl}benzamide (C46). To a 0°C mixture of 5-(trifluoromethyl)pyridine-2-carboxylic acid (47.0 mg, 0.246 mmol), N,N-diisopropylethylamine (86.6 mg, 0.670 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 127 mg, 0.334 mmol) in dichloromethane (20 mL) was added P5 (100 mg, 0.223 mmol), whereupon the reaction mixture was stirred at room temperature for 1 h. It was then diluted with water (20 mL) and extracted with dichloromethane (2 × 20 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (2 × 20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 5% methanol in dichloromethane) afforded the acyl intermediate as a white solid. Yield: 80 mg, 0.13 mmol, 58%. LCMS m / z 621.3 [M+H] + .

[0344] Sodium acetate (31.7 mg, 0.386 mmol) was added to a solution of the acyl intermediate (80 mg, 0.13 mmol) in a mixture of ethanol (4 mL) and water (1 mL). The reaction mixture was stirred at 100° C. for 1 h under microwave irradiation and then concentrated in vacuo. Silica gel chromatography (gradient: 0% to 7% methanol in dichloromethane) afforded C46 as a white solid. Yield: 40 mg, 66 μmol, 51% from the acyl intermediate. LCMS m / z 625.3 [M+Na + ].

[0345] Step 2. Synthesis of 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{5-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}cyclohexyl]methyl}benzamide (13). A solution of hydrogen chloride in 1,4-dioxane (4 M; 1 mL) was added to a solution of C46 (40 mg, 66 μmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 2 h, whereupon it was concentrated in vacuo, diluted with dichloromethane (10 mL), and treated with sodium bicarbonate (10 mg, 0.12 mmol). After removal of the solvent under reduced pressure, the residue was subjected to silica gel chromatography (gradient: 0% to 6% methanol in dichloromethane) followed by reverse-phase HPLC (column: Waters XBridge C18, 19 x 100 mm, 5 μm; mobile phase A: water containing 0.1% formic acid; mobile phase B: acetonitrile; gradient: 50% to 60% B; flow rate: 20 mL / min) to give 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{5-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}cyclohexyl]methyl}benzamide (13) as a white solid. Yield: 9.0 mg, 19 μmol, 29%. LCMS m / z 483.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) d 9.09 (br s, 1H), 8.45 (d, half of the AB quartet, J = 8.3 Hz, 1H), 8.40 (dd, components of the ABX system, J = 8.4, 2.3 Hz, 1H), 7.51 - 7.41 (m, 2H), 3.27 (d, J = 6.9 Hz, 2H), 2.91 (tt, J = 12.2, 3.4 Hz, 1H), 2.24 - 2.14 (m, 2H), 2.03 - 1.92 (m, 2H), 1.80 - 1.59 (m, 3H), 1.29 - 1.15 (m, 2H).

[0346] Example 14 N-[(4-{5-[5-(difluoromethyl)pyrazin-2-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]-3,5-difluoro-4-hydroxybenzamide, ammonium salt (14)

[0347] [ka] This reaction was carried out in a library format.

[0348] A stock solution of P7 (300 mg, 0.634 mmol) in ethyl acetate (6 mL) was used; 1 mL of this solution (0.106 mmol of P7) was treated with 5-(difluoromethyl)pyrazine-2-carboxylic acid (18.3 mg, 0.105 mmol), followed by triethylamine (42.2 μL, 0.303 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 wt% solution in ethyl acetate; 0.15 mL, 0.25 mmol). The reaction vial was heated at 100 °C until oxadiazole formation occurred, whereupon it was cooled to room temperature, diluted with ethyl acetate (3 mL), and washed successively with water (2 × 3 mL) and saturated aqueous sodium chloride (3 mL). The organic layer was concentrated in vacuo, and the residue was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol, treated with 1 equivalent of trifluoroacetic acid, and stirred until the phenol deprotection was complete. The solvent was removed under reduced pressure, followed by reverse-phase HPLC (Waters XBridge C18, 19 x 100 mm, 5 μm column; mobile phase A: water containing 0.03% ammonium hydroxide; mobile phase B: acetonitrile containing 0.03% ammonium hydroxide; gradient: 5% to 95% B; flow rate: 25 mL / min) to give N-[(4-{5-[5-(difluoromethyl)pyrazin-2-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]-3,5-difluoro-4-hydroxybenzamide, ammonium salt (14). Yield: 13.8 mg, 27.1 μmol, 26%. LCMS m / z 492.4 [M+H] +Retention time: 2.54 min (analytical conditions: Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 min, then 95% B for 1.0 min; Flow rate: 2 mL / min).

[0349] Example 15 2,3,5-Trifluoro-4-hydroxy-N-({4-[3-(6-methoxypyridazin-3-yl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide (15)

[0350] [ka] Step 1. Synthesis of N-hydroxy-6-methoxypyridazine-3-carboximidamide (C47). To a solution of 6-methoxypyridazine-3-carbonitrile (745 mg, 5.51 mmol) in methanol (3.7 mL) was added hydroxylamine hydrochloride (383 mg, 5.51 mmol), followed by triethylamine (0.776 mL, 5.57 mmol). The reaction mixture was stirred at room temperature for 4 days, whereupon it was cooled in an ice bath for 15 minutes; the precipitated solid was collected by filtration to give C47 as a purple solid. Yield: 690 mg, 4.10 mmol, 74%. LCMS m / z 169.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 10.13 (s, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.22 (d, J = 9.3 Hz, 1H), 5.98 (br s, 2H), 4.05 (s, 3H).

[0351] Step 2. Synthesis of tert-butyl ({4-[3-(6-methoxypyridazin-3-yl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octan-1-yl}methyl)carbamate (C48). O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 312 mg, 0.821 mmol) was added to a solution of C47 (155 mg, 0.547 mmol) in N,N-dimethylformamide (3 mL). After stirring the reaction mixture for 20 minutes, 4-{[(tert-butoxycarbonyl)amino]methyl}bicyclo[2.2.2]octane-1-carboxylic acid (101 mg, 0.601 mmol) and N,N-diisopropylethylamine (0.286 mL, 1.64 mmol) were added, and stirring was continued at room temperature for 18 hours. The reaction mixture was then diluted with water; the solid was collected by filtration and washed with water to give the acyl intermediate as a white solid. Yield: 134 mg, 0.309 mmol, 56%. LCMS m / z 434.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4) d 8.22 (d, J = 9.3 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 6.61 - 6.52 (m, 1H; presumed amide proton, slow exchange), 4.14 (s, 3H), 2.83 (d, J = 6.5 Hz, 2H), 2.00 - 1.91 (m, 6H), 1.54 - 1.45 (m, 6H), 1.44 (s, 9H).

[0352] The acyl intermediate (134 mg, 0.309 mmol) and sodium acetate (51.2 mg, 0.624 mmol) were placed in a mixture of water (0.1 mL) and ethanol (1 mL), and the reaction vial was heated at 120° C. under microwave irradiation for 2.5 hours. The reaction mixture was then diluted with water (approximately 0.5 mL) and filtered; the filter cake was washed with ethanol to give C48 as an off-white solid. Yield: 75 mg, 0.18 mmol, 58% from the acyl intermediate. LCMS m / z 416.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4) d 8.20 (d, J = 9.2 Hz, 1H), 7.33 (d, J = 9.2 Hz, 1H), 6.68 - 6.58 (m, 1H), 4.19 (s, 3H), 2.88 (d, J = 6.4 Hz, 2H), 2.13 - 2.02 (m, 6H), 1.63 - 1.53 (m, 6H), 1.45 (s, 9H).

[0353] Step 3. Synthesis of 1-{4-[3-(6-methoxypyridazin-3-yl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octan-1-yl}methanamine, trifluoroacetate (C49). Trifluoroacetic acid (0.15 mL, 1.9 mmol) was added dropwise to a 0° C. solution of C48 (75 mg, 0.18 mmol) in dichloromethane (2 mL). The reaction mixture was stirred for 30 minutes before trifluoroacetic acid (0.15 mL, 1.9 mmol) was added again; after 30 minutes, the reaction mixture was treated once more with trifluoroacetic acid (20 μL, 0.26 mmol) and stirred for an additional 5 minutes. It was then concentrated in vacuo, and the residue was azeotroped once with toluene and once with dichloromethane to give C49 as an oil (84 mg). The majority of this material was used in the next step. LCMS m / z 316.2 [M+H] + .

[0354] Step 4. Synthesis of 2,3,5-trifluoro-4-hydroxy-N-({4-[3-(6-methoxypyridazin-3-yl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide (15). A solution of C49 (from the previous step; 84 mg, ≦0.18 mmol) in a mixture of N,N-dimethylformamide (1.8 mL) and water (0.41 mL) was treated sequentially with 2,3,5-trifluoro-4-hydroxybenzoic acid (41.9 mg, 0.218 mmol), 1-methyl-1H-imidazole (43.4 μL, 0.544 mmol), and 2-hydroxypyridine 1-oxide (20.2 mg, 0.182 mmol). After stirring the reaction mixture for 20 min at room temperature, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (35.5 mg, 0.185 mmol) was added; stirring was continued at room temperature for 18 h, whereupon the reaction mixture was diluted with water (10 mL), acidified to pH 4 by the addition of methanesulfonic acid, and extracted three times with ethyl acetate. The combined organic layers were washed five times with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by reverse-phase HPLC (Column: Waters Sunfire C18, 19 × 100 mm, 5 μm; Mobile Phase A: 0.05% trifluoroacetic acid in water (v / v); Mobile Phase B: 0.05% trifluoroacetic acid in acetonitrile (v / v); Gradient: 5% to 95% B over 8.54 min, followed by 95% B for 1.46 min; Flow Rate: 25 mL / min) afforded 2,3,5-trifluoro-4-hydroxy-N-({4-[3-(6-methoxypyridazin-3-yl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide (15). Yield: 26.6 mg, 54.3 μmol, 30% over two steps. LCMS m / z 490.4 [M+H] +Retention time: 2.57 min (analytical conditions: Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 min, then 95% B for 1.0 min; Flow rate: 2 mL / min).

[0355] Example 16 3,5-Difluoro-N-{[(1r,4r)-4-(6-fluoro-2H-indazol-2-yl)cyclohexyl]methyl}-4-hydroxybenzamide, ammonium salt (16)

[0356] [ka] Step 1. Synthesis of 3,5-difluoro-N-{[(1r,4r)-4-(6-fluoro-2H-indazol-2-yl)cyclohexyl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (C50). This reaction was carried out in a library format.

[0357] A solution of P3 (60.7 mg, 0.150 mmol) in propan-2-ol (0.6 mL) was added to 4-fluoro-2-nitrobenzaldehyde (0.15 mmol). The reaction vial was capped, then evacuated and backfilled with nitrogen. This evacuation cycle was repeated twice, after which the reaction mixture was shaken at 80 °C for 4 h and then cooled to room temperature. After the addition of tributylphosphine (0.1 mL, 0.4 mmol), the reaction mixture was shaken at 80 °C for 18 h. It was then partitioned between half-saturated aqueous sodium bicarbonate (1.5 mL) and ethyl acetate (2.4 mL) and vortexed. The organic layer was eluted through a solid-phase extraction cartridge (6 mL) charged with sodium sulfate (approximately 1 g); this extraction procedure was repeated twice, and the combined eluents were concentrated in vacuo to give C50, which was used directly in the next step.

[0358] Step 2. Synthesis of 3,5-difluoro-N-{[(1r,4r)-4-(6-fluoro-2H-indazol-2-yl)cyclohexyl]methyl}-4-hydroxybenzamide, ammonium salt (16). This reaction was carried out in a library format.

[0359] A solution of p-toluenesulfonic acid (57.1 mg, 0.300 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (0.6 mL) was added to C50 (from the previous step; ≦0.150 mmol) and the reaction mixture was shaken at room temperature for 3 days. After removing the solvent using a Genevac concentrator, purification was carried out by reverse-phase HPLC (Column: Waters XBridge C18, 19 × 100 mm, 5 μm; Mobile phase A: water containing 0.03% ammonium hydroxide; Mobile phase B: acetonitrile containing 0.03% ammonium hydroxide; Gradient: 5% to 95% B over 8.54 min, then 95% B for 1.46 min; Flow rate: 25 mL / min) to give 3,5-difluoro-N-{[(1r,4r)-4-(6-fluoro-2H-indazol-2-yl)cyclohexyl]methyl}-4-hydroxybenzamide, ammonium salt (16). Yield: 11.4 mg, 27.1 μmol, 18% over two steps. LCMS m / z 404.4 [M+H] + Retention time: 2.61 min (analytical conditions: Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 min, then 95% B for 1.0 min; Flow rate: 2 mL / min).

[0360] Example 17 N-{[(1r,4r)-4-{3-[6-(2,2-dimethylpropanamido)pyridazin-3-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide, ammonium salt (17)

[0361] [ka] Step 1. Synthesis of 6-chloro-N-hydroxypyridazine-3-carboximidamide (C51). To a solution of 6-chloropyridazine-3-carbonitrile (698 mg, 5.00 mmol) in methanol (15 mL) was added hydroxylamine hydrochloride (382 mg, 5.50 mmol), followed by triethylamine (0.775 mL, 5.56 mmol). The reaction mixture was stirred for 2 hours, whereupon the solid was collected by filtration to afford C51 as a brown solid. Yield: 465 mg, 2.69 mmol, 54%. LCMS m / z 173.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 10.43 (s, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 6.15 (br s, 2H).

[0362] Step 2. Synthesis of N-({(1r,4r)-4-[3-(6-chloropyridazin-3-yl)-1,2,4-oxadiazol-5-yl]cyclohexyl}methyl)-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C52). A solution of P4 (595 mg, 1.37 mmol) in N,N-dimethylformamide (9 mL) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 783 mg, 2.06 mmol). After 30 min, C51 (261 mg, 1.51 mmol) and N,N-diisopropylethylamine (0.717 mL, 4.12 mmol) were added, whereupon the reaction mixture was stirred for 18 h at room temperature. The precipitate was collected by filtration and washed with dichloromethane to give the acyl intermediate as an off-white solid. Yield: 358 mg, 0.609 mmol, 44%. LCMS m / z 588.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) d 8.52 (br t, J = 5.8 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.29 (br s, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.17 (s, 2H), 3.74 (s, 3H), 3.12 (dd, J = 6, 6 Hz, 2H), 2.57 - 2.44 (m, 1H, estimated; almost completely obscured by solvent peak), 2.05 - 1.96 (m, 2H), 1.85 - 1.75 (m, 2H), 1.61 - 1.48 (m, 1H), 1.47 - 1.32 (m, 2H), 1.06 - 0.92 (m, 2H).

[0363] A portion of the acyl intermediate (219 mg, 0.372 mmol) and sodium acetate (61.7 mg, 0.752 mmol) in a mixture of ethanol (4.5 mL) and water (0.45 mL) was heated at 120° C. under microwave irradiation for 1 h. The resulting solid was isolated by filtration and washed with a 10:1 mixture of ethanol and water to give C52 as a white solid. Yield: 172 mg, 0.302 mmol, 81% from the acyl intermediate. LCMS m / z 570.3 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.55 (br t, J = 5.8 Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.17 (s, 2H), 3.74 (s, 3H), 3.20 - 3.09 (m, 3H), 2.25 - 2.14 (m, 2H), 1.92 - 1.83 (m, 2H), 1.69 - 1.51 (m, 3H), 1.23 - 1.08 (m, 2H).

[0364] Step 3. Synthesis of N-{[(1r,4r)-4-{3-[6-(2,2-dimethylpropanamido)pyridazin-3-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C53). A mixture of C52 (46 mg, 81 μmol), 2,2-dimethylpropanamide (9.8 mg, 97 μmol), palladium(II) acetate (0.906 mg, 4.04 μmol), ([1,1′-binaphthalene]-2,2′-diyl)bis(diphenylphosphane) (BINAP; 5.03 mg, 8.08 μmol), and cesium carbonate (65.7 mg, 0.202 mmol) in 1,4-dioxane (1 mL) was degassed under vacuum and charged with nitrogen. This evacuation cycle was repeated twice, after which the reaction vial was heated at 100° C. for 18 h. After partitioning the reaction mixture between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to give C53 as a brown oil (64 mg). This material was used directly in the next step. LCMS m / z 635.4 [M+H] + .

[0365] Step 4. Synthesis of N-{[(1r,4r)-4-{3-[6-(2,2-dimethylpropanamido)pyridazin-3-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide, ammonium salt (17). Trifluoroacetic acid (0.3 mL, 4 mmol) was added to a solution of C53 (from the previous step; 64 mg, ≦81 μmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1 h, whereupon it was concentrated in vacuo and azeotroped twice with dichloromethane. Reverse-phase HPLC (Column: Waters XBridge C18, 19 × 100 mm, 5 μm; Mobile phase A: Water containing 0.03% ammonium hydroxide; Mobile phase B: Acetonitrile containing 0.03% ammonium hydroxide; Gradient: 5% to 50% B over 8.5 min, then 50% to 95% B over 0.5 min, then 95% B for 1.0 min; Flow rate: 25 mL / min) gave N-{[(1r,4r)-4-{3-[6-(2,2-dimethylpropanamido)pyridazin-3-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide, ammonium salt (17). Yield: 4.2 mg, 7.9 μmol, 10% over two steps. LCMS m / z 515.3 [M+H] + Retention time: 2.83 min (analytical conditions: Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 min, then 95% B for 1.0 min; Flow rate: 2 mL / min).

[0366] Example 18 3,5-Difluoro-4-hydroxy-N-({(1r,4r)-4-[4-(quinoxalin-6-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}methyl)benzamide (18)

[0367] [ka] Step 1. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-({(1r,4r)-4-[4-(quinoxalin-6-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}methyl)benzamide (C54). This reaction was carried out in a library format.

[0368] A solution of P6 (100 μmol) in N,N-dimethylformamide (0.50 mL) was treated with a solution of sodium azide in water (2.0 M; 0.20 mL, 400 μmol), followed by a solution of sodium carbonate in water (0.2 M; 0.10 mL, 20 μmol). The reaction vial was capped, and the reaction mixture was heated at 125°C under microwave irradiation for 10 minutes. After the reaction mixture was cooled to room temperature, 6-ethynylquinoxaline (100 μmol) and copper(I) iodide (2.0 mg, 10 μmol) were added, and microwave irradiation was continued for 40 minutes at 125°C. When the reaction mixture returned to room temperature, it was treated with aqueous sodium hypochlorite (8%-10%; 1.0 mL), and the vial was shaken at 30°C for 5 minutes; the solvent was removed using a Speedvac® concentrator to give C54. This material was carried on to the next step as is.

[0369] Step 2. Synthesis of 3,5-difluoro-4-hydroxy-N-({(1r,4r)-4-[4-(quinoxalin-6-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}methyl)benzamide (18). This reaction was carried out in a library format.

[0370] To a solution of C54 (from the previous step; ≦100 μmol) in dichloromethane (0.8 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 0.2 mL, 800 μmol), whereupon the reaction vial was capped and shaken for 16 h at 30 °C. After removing the solvent using a Speedvac® concentrator, the residue was purified by reverse-phase HPLC (column: YMC-Actus Triart C18, 30 × 150 mm, 5 μm; mobile phase A: water containing ammonium hydroxide (pH 10); mobile phase B: acetonitrile; gradient: 10% to 50% B; flow rate: 35 mL / min) to give 3,5-difluoro-4-hydroxy-N-({(1r,4r)-4-[4-(quinoxalin-6-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}methyl)benzamide (18). Yield: 9.1mg, 20μmol, 20%. LCMS m / z 465 [M+H] + Retention time: 2.46 min (analytical conditions: column: Waters XBridge C18, 2.1 × 50 mm, 5 μm; mobile phase A: water containing 0.0375% trifluoroacetic acid; mobile phase B: acetonitrile containing 0.01875% trifluoroacetic acid; gradient: 1% to 5% B over 0.6 min; 5% to 100% B over 3.4 min; flow rate: 0.8 mL / min).

[0371] Example 19 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(4-methylpiperazin-1-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide, trifluoroacetate (19)

[0372] [ka] Step 1. Synthesis of 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]-N-({(1r,4r)-4-[6-(4-methylpiperazin-1-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (C55). In a glovebox under nitrogen, a scintillation vial was charged with C39 (100 mg, 0.166 mmol), cesium carbonate (162 mg, 0.497 mmol), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos Pd G3; 13.9 mg, 16.6 μmol). The contents of the vial were stirred for 2 min, after which toluene (1.7 mL) was added; to the resulting solution, 1-methylpiperazine (27.6 μL, 0.249 mmol) was added, and the vial was transferred to a heating block. The reaction mixture was slowly heated to 90 °C under vigorous stirring and then held at 90 °C overnight. It was then cooled to room temperature, concentrated in vacuo, taken up in ethyl acetate (50 mL), and washed successively with water (3 x 50 mL) and saturated aqueous sodium chloride (25 mL). The organic layer was concentrated under reduced pressure to give an oil (106 mg). LCMS analysis showed that both C55 and 19 were present in this material, and the bulk was used directly in the next step. LCMS m / z 622.5 and 502.4 [M+H] + .

[0373] Step 2. Synthesis of 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(4-methylpiperazin-1-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide, trifluoroacetate (19). Trifluoroacetic acid (50 μL, 0.65 mmol) was added to a solution of C55 and 19 (from the previous step; 103 mg, ≦0.161 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.5 mL). The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo and purified by reverse-phase HPLC [Column: Waters Sunfire C18, 19 x 100 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v / v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v / v); Gradient: 5% to 35% B over 8.5 min, then 35% to 95% B over 0.5 min; Flow rate: 25 mL / min] to give 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(4-methylpiperazin-1-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide, trifluoroacetate salt (19). Yield: 40 mg, 65 μmol, 40% over two steps. LCMS m / z 502.3 [M+H] + Retention time: 1.91 min (analytical conditions: Column: Waters Atlantis dC18, 4.6 × 50 mm, 5 μm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 min, then 95% B for 1.0 min; Flow rate: 2 mL / min).

[0374] Example 20 3,5-Difluoro-4-hydroxy-N-({(1r,4r)-4-[5-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]cyclohexyl}methyl)benzamide (20)

[0375] [ka] Step 1. Synthesis of N-{[(1r,4r)-4-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (C56). To a solution of P3 (400 mg, 0.989 mmol) and triethylamine (150 mg, 1.48 mmol) in toluene (10 mL) was added methyl 4-bromo-2-(bromomethyl)benzoate (305 mg, 0.990 mmol). The reaction mixture was stirred at 100° C. for 16 h and then concentrated in vacuo; silica gel chromatography (eluent: 5% methanol in dichloromethane) afforded C56 as a white solid. Yield: 332 mg, 0.554 mmol, 56%. LCMS m / z 599.0 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.55 (br t, J = 5.6 Hz, 1H), 7.84 (s, 1H), 7.69 - 7.55 (m, 4H), 7.33 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 5.17 (s, 2H), 4.43 (s, 2H), 4.04 - 3.92 (m, 1H), 3.74 (s, 3H), 3.12 (dd, J = 6, 6 Hz, 2H), 1.89 - 1.70 (m, 4H), 1.63 - 1.46 (m, 3H), 1.19 - 1.04 (m, 2H).

[0376] Step 2. Synthesis of 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-({(1r,4r)-4-[5-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]cyclohexyl}methyl)benzamide (C57). To a mixture of C56 (100 mg, 0.167 mmol), (1-methyl-1H-pyrazol-3-yl)boronic acid (25.2 mg, 0.200 mmol), and potassium carbonate (69.2 mg, 0.501 mmol) in 1,4-dioxane (10 mL), tetrakis(triphenylphosphine)palladium(0) (19.3 mg, 16.7 μmol) was added, whereupon the reaction mixture was stirred at 100° C. for 16 h. After the solvent was removed by concentration in vacuo, silica gel chromatography (eluent: 5% methanol in dichloromethane) afforded C57 as an oil. Yield: 42 mg, 70 μmol, 42%. LCMS m / z 601.2 [M+H] + .

[0377] Step 3. Synthesis of 3,5-difluoro-4-hydroxy-N-({(1r,4r)-4-[5-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]cyclohexyl}methyl)benzamide (20). To a solution of C57 (37 mg, 62 μmol) in dichloromethane (5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 1 mL). The reaction mixture was stirred at 25 °C for 1 h, whereupon it was concentrated in vacuo and purified by reverse-phase HPLC (column: Waters XBridge C18, 19 × 100 mm, 5 μm; mobile phase A: water containing 0.1% formic acid; mobile phase B: acetonitrile; gradient: 25% to 45% B; flow rate: 20 mL / min) to give 3,5-difluoro-4-hydroxy-N-({(1r,4r)-4-[5-(1-methyl-1H-pyrazol-3-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]cyclohexyl}methyl)benzamide (20). Yield: 15.8 mg, 32.9 μmol, 53%. LCMS m / z 481.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.37 (br t, J = 5.8 Hz, 1H), 7.97 (br s, 1H), 7.89 (dd, J = 7.9, 1.4 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.59 - 7.47 (m, 2H), 6.79 (d, J = 2.3 Hz, 1H), 4.46 (s, 2H), 4.00 (tt, J = 12.2, 3.8 Hz, 1H), 3.90 (s, 3H), 3.12 (dd, J = 6, 6 Hz, 2H), 1.90 - 1.73 (m, 4H), 1.65 - 1.49 (m, 3H), 1.20 - 1.05 (m, 2H).

[0378] Example 21 2,3,5-Trifluoro-4-hydroxy-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide, hydrochloride (21)

[0379] [ka] Step 1. Synthesis of methyl 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrimidine-4-carboxylate (C58). Potassium carbonate (2.18 g, 15.8 mmol) was added to a solution of methyl 2-chloropyrimidine-4-carboxylate (95%, 956 mg, 5.26 mmol) and tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol) in acetonitrile (26 mL), whereupon the reaction mixture was stirred at 65° C. After 1.5 h, LCMS analysis indicated the presence of C58: LCMS m / z 267.2 [(M − 2-methylprop-1-ene) + H] + The reaction mixture was stirred at 65° C. for an additional 1 h, then diluted with water and extracted three times with dichloromethane. The combined organic layers were concentrated in vacuo to give C58 as a yellow solid (1.75 g), the bulk of which was carried on to the next step. 1H NMR (400 MHz, chloroform-d) δ 8.51 (d, J = 4.8 Hz, 1H), 7.14 (d, J = 4.8 Hz, 1H), 3.96 (s, 3H), 3.92 - 3.84 (m, 4H), 3.55 - 3.47 (m, 4H), 1.49 (s, 9H).

[0380] Step 2. Synthesis of 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrimidine-4-carboxylic acid (C59). A solution of lithium hydroxide (1.26 g, 52.6 mmol) in a mixture of tetrahydrofuran (10 mL), water (10 mL), and methanol (5 mL) was added to C58 (from the previous step; 1.70 g, ≦5.11 mmol). The reaction mixture was heated at 50° C. for 1 h, cooled to room temperature, and concentrated in vacuo to remove most of the solvent. The residue was acidified to pH 2-3 by the addition of 1 M hydrochloric acid, after which the mixture was extracted three times with ethyl acetate. At this point, the aqueous layer was again acidified to pH 2 and extracted twice with ethyl acetate. All organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give C59 as a pale yellow solid. Yield: 1.42 g, 4.60 mmol, 90% over two steps. LCMS m / z 307.2 [M−H] - . 1 H NMR (400 MHz, chloroform-d) δ 8.62 (d, J = 4.7 Hz, 1H), 7.31 (d, J = 4.7 Hz, 1H), 3.90 - 3.82 (m, 4H), 3.58 - 3.51 (m, 4H), 1.50 (s, 9H).

[0381] Step 3. Synthesis of tert-butyl 4-(4-{3-[4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octan-1-yl]-1,2,4-oxadiazol-5-yl}pyrimidin-2-yl)piperazine-1-carboxylate (C60). N,N-Diisopropylethylamine (0.532 mL, 3.05 mmol) was added dropwise to a solution of C59 (345 mg, 1.12 mmol) and bis(pentafluorophenyl)carbonate (98%, 450 mg, 1.12 mmol) in tetrahydrofuran (5 mL). After stirring the reaction mixture at room temperature for 30 minutes, additional bis(pentafluorophenyl)carbonate (98%, 20 mg, 51 μmol) was added, and stirring was continued for 10 minutes. Immediately thereafter, P10 (500 mg, 1.02 mmol) was added, followed by stirring at room temperature for an additional 30 minutes. The reaction mixture was then treated with a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M; 5.09 mL, 5.09 mmol) and heated at 50° C. overnight. After cooling to room temperature, the reaction mixture was treated with a small amount of aqueous sodium bicarbonate, diluted with water, and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by chromatography on silica gel (gradient: 30% to 100% ethyl acetate in heptane) to afford C60 as a yellow solid. Yield: 474 mg (corrected for residual dichloromethane), 0.621 mmol, 61%. LCMS m / z 764.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.8 Hz, 1H), 8.35 (br t, J = 6.3 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.36 (br d, J = 8.6 Hz, 2H), 7.30 (d, J = 4.8 Hz, 1H), 6.94 (br d, J = 8.7 Hz, 2H), 5.22 (s, 2H), 3.83 - 3.77 (m, 4H), 3.75 (s, 3H), 3.47 - 3.40 (m, 4H), 3.07 (d, J = 6.2 Hz, 2H), 1.94 - 1.84 (m, 6H), 1.57 - 1.48 (m, 6H), 1.43 (s, 9H).

[0382] Step 4. Synthesis of 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]-N-[(4-{5-[2-(piperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide (C61). A solution of C60 (840 mg, 1.10 mmol) and pyridine (0.711 mL, 8.79 mmol) in dichloromethane (36 mL) was cooled to approximately −15° C. and treated dropwise with trimethylsilyl trifluoromethanesulfonate (0.796 mL, 4.40 mmol). The reaction mixture was stirred overnight at −15° C., but by the next morning, the cooling bath temperature had reached 12° C. The reaction mixture was then cooled in an ice bath, whereupon aqueous sodium bicarbonate (20 mL) was slowly added and the resulting mixture was stirred for 10 minutes. The aqueous layer was adjusted to pH 10 and extracted three times with dichloromethane; the combined organic layers were washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was coevaporated three times with dichloromethane to give C61 as a yellow solid. Yield: 673 mg, 1.01 mmol, 92%. LCMS m / z 664.4 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.51 (d, J = 4.8 Hz, 1H), 7.59 (ddd, J = 11.7, 6.8, 2.3 Hz, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 4.8 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.62 - 6.50 (m, 1H), 5.24 (s, 2H), 3.96 - 3.86 (m, 4H), 3.80 (s, 3H), 3.30 (br d, J = 6 Hz, 2H), 3.04 - 2.91 (m, 4H), 2.07 - 1.96 (m, 6H), 1.66 - 1.56 (m, 6H).

[0383] Step 5. Synthesis of 2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide (C62). To a solution of C61 (100 mg, 0.151 mmol) and formaldehyde (43 mg, 1.43 mmol) in 1,2-dichloroethane (8 mL) was added sodium triacetoxyborohydride (91 mg, 0.43 mmol). The reaction mixture was stirred at 25 °C for 1 h before being subjected to aqueous workup and extracted with dichloromethane (2 × 30 mL); the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (eluent: 5% methanol in dichloromethane) afforded C62 as a yellow solid. Yield: 72.0 mg, 0.106 mmol, 70%. LCMS m / z 678.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 4.9 Hz, 1H), 8.36 (br t, J = 6.2 Hz, 1H), 7.37 - 7.30 (m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 4.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H), 3.84 - 3.76 (m, 4H), 3.75 (s, 3H), 3.06 (d, J = 6.2 Hz, 2H), 2.45 - 2.34 (m, 4H), 2.23 (s, 3H), 1.92 - 1.84 (m, 6H), 1.58 - 1.47 (m, 6H).

[0384] Step 6. Synthesis of 2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide, hydrochloride (21). A solution of hydrogen chloride in 1,4-dioxane (4 M: 1 mL, 4 mmol) was added to a solution of C62 (72.0 mg, 0.106 mmol) in dichloromethane (4 mL). After stirring at 25 °C for 1 h, the reaction mixture was concentrated in vacuo and purified by reverse-phase HPLC (Waters XBridge C18, 19 × 150 mm, 5 μm column, mobile phase A: water containing 0.05% formic acid; mobile phase B: acetonitrile; gradient: 15% to 45% B; flow rate: 20 mL / min) to give 2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide, hydrochloride salt (21) as a white solid. Yield: 30.0 mg, 50.5 μmol, 48%. LCMS m / z 558.3 ​​[M+H] + . 1 H NMR (400 MHz, DMSO-d6), Characteristic peak: δ 8.75 (d, J = 4.9 Hz, 1H), 8.19 (br t, J = 6 Hz, 1H), 7.42 (d, J = 4.9 Hz, 1H), 7.27 (ddd, J = 11.0, 6.2, 2.4 Hz, 1H), 3.66 - 3.2 (m, 8H, estimated; completely obscured by water peak), 3.07 (d, J = 6.2 Hz, 2H), 2.84 (s, 3H), 1.96 - 1.83 (m, 6H), 1.60 - 1.47 (m, 6H).

[0385] Using similar procedures, the compounds of Examples 22-214 were synthesized as described in Tables 1 and 2.

[0386]

Table 1-1

[0387]

Table 1-2

[0388]

Table 1-3

[0389]

Table 1-4

[0390]

Table 1-5

[0391]

Table 1-6

[0392]

Table 1-7

[0393]

Table 1-8

[0394]

Table 1-9

[0395]

Table 1-10

[0396]

Table 1-11

[0397]

Table 1-12

[0398]

Table 1-13

[0399]

Table 1-14

[0400]

Table 1-15

[0401]

Table 1-16

[0402]

Table 1-17

[0403]

Table 1-18

[0404]

Table 1-19

[0405]

Table 1-20

[0406]

Table 1-21

[0407]

Table 1-22

[0408]

Table 1-23

[0409]

Table 1-24

[0410]

Table 1-25

[0411]

Table 1-26

[0412]

Table 1-27

[0413]

Table 1-28

[0414]

Table 1-29

[0415]

Table 1-30

[0416]

Table 1-31

[0417]

Table 1-32

[0418]

Table 1-33

[0419]

Table 1-34

[0420]

Table 1-35

[0421]

Table 1-36

[0422]

Table 1-37

[0423]

Table 1-38

[0424]

Table 1-39

[0425]

Table 1-40

[0426]

Table 1-41

[0427]

Table 1-42

[0428]

Table 1-43

[0429]

Table 2-1

[0430]

Table 2-2

[0431]

Table 2-3

[0432]

Table 2-4

[0433]

Table 2-5

[0434]

Table 2-6

[0435]

Table 2-7

[0436]

Table 2-8

[0437]

Table 2-9

[0438]

Table 2-10

[0439]

Table 2-11

[0440]

Table 2-12

[0441]

Table 2-13

[0442]

Table 2-14

[0443]

Table 2-15

[0444]

Table 2-16

[0445]

Table 2-17

[0446]

Table 2-18

[0447] [Table 2-19]

[0448] [Table 2-20]

[0449] [Table 2-21]

[0450] [Table 2-22]

[0451] [Table 2-23]

[0452] Those skilled in the art can of course modify the following protocol. hHSD17B13 IC 50 Assay (FAC beta-estradiol) The HSD17B13 enzyme inhibitory potency of test compounds was determined using a purified protein biochemical enzyme activity assay with NAD(P)H-Glo luciferase readout (Promega). During the metabolism of beta-estradiol (substrate) to estradiol (product), the HSD17B13 enzyme uses the oxidized form of nicotinamide adenine dinucleotide (NAD+) as a cofactor, converting NAD+ to its reduced form (NADH). The Promega NAD(P)H-Glo™ assay is a homogeneous bioluminescent assay that generates a light signal from a biochemical reaction involving NADH (or nicotinamide adenine dinucleotide phosphate, NADPH). In the presence of NADH (or NADPH), the enzyme reductase reduces the proluciferin reductase substrate to form luciferin. Luciferin was then quantified using Ultra-Glo™ Recombinant Luciferase (rLuciferase), and the light signal generated is proportional to the amount of NAD(P)H in the sample. A substrate mix consisting of 12 μM final assay concentration (FAC) beta-estradiol (Sigma, E8875) and 500 μM FAC NAD+ (Sigma, N8285) in assay buffer (25 mM Tris-HCl and 0.02% Triton, pH 7.6, Sigma T2444 and X-100) was added (2 μL / well) to a 384-well assay plate (Corning 3824) containing 80 nL of 50x FAC compound (each concentration included in duplicate) serially diluted 1 / 3.162 in 100% DMSO for an 11-point concentration-response curve (highest concentration 80 μM). The reaction was initiated by the addition of 2 μL / well of purified HSD17B13 protein (30 nM FAC in assay buffer). The compound, substrate mix, and HSD17B13 protein were incubated in the dark at room temperature for 2 hours, after which 3 μL / well of NAD(P)H-Glo detection reagent, prepared from luciferase detection reagent and reductase / reductase substrate according to the manufacturer's instructions (Promega, G9061), was added.The detection reagent was incubated in the dark for 1 hour at room temperature, after which the plate was read out on an Envision plate reader (Perkin Elmer) using the luminescence protocol. Data, displayed as relative luminescence units (RLU), were then normalized to control wells using Activity Base (IDBS). Zero percent effect (ZPE) was defined as the RLU generated from uninhibited HSD17B13 protein (vehicle control). 100 percent effect (HPE) was defined as the RLU generated from wells containing 40 μM FAC of a Pfizer proprietary compound known to cause 100% inhibition of HSD17B13 protein. Concentration and percent effect values ​​for each compound were plotted using Activity Base using a four-parameter logarithmic dose-response equation to determine 50% inhibition (IC). 50 The required concentration of

[0453] HEK_Beta-Est LCMS_IC 50 _Tekcel Inhibitory potency of test compounds was determined using a whole cell HEK-HSD17B13 inhibition assay utilizing an LCMS readout.

[0454] During the metabolism of beta-estradiol (substrate), HSD17B13 uses the oxidized form of nicotinamide adenine dinucleotide (NAD+) as a cofactor, converting NAD+ to its reduced form (NADH) and beta-estradiol to its product (estrone). Estrone production is quantified by LCMS and used as a measure of HSD17B13 enzyme activity.

[0455] HEK cells stably expressing wild-type human HSD17B13 were seeded at 10,000 cells / well into poly-D-lysine-coated 384-well plates (Corning Biocoat, 354663) in 50 μL growth medium (DMEM containing 10% heat-inactivated FBS, 400 μg / ml geneticin, 1x L-glutamine, and 1x non-essential amino acids; Invitrogen 11965-092, 16140-071, 10131-027, 25030-081, 11140-050) and incubated overnight (with lid) at 37°C (95% O2:5% CO2). After overnight incubation, an intermediate compound plate (Greiner, 781280) containing 160 nL of 375x FAC test compounds serially diluted 1 / 3.162 in 100% DMSO for an 11-point concentration-response curve (including duplicate points at each concentration) was diluted 1 / 187.5 with 30 μL of warm assay medium (DMEM, 1x L-glutamine, and 1x non-essential amino acids) to obtain 2x FAC compounds (maximum concentration 80 μM) in 0.53% DMSO. Growth medium was then removed from the cell plate and replaced with 10 μL of 2x FAC test compound and incubated for 1 hour (lid on) at 37°C (95% O2:5% CO2), after which 25 μM FAC beta-estradiol in assay medium / 0.2% DMSO was added. The reactions were incubated for 2 hours (lidded) at 37°C (95% O2:5% CO2), after which 10 μL of the reactions were transferred from the assay plate to a new 384-well deep well plate (Matrix 4325) and stopped with stop reagent (internal standard 17b-estradiol-2,3,4- 13The wells were diluted 1 / 10 with 90 μL of 50% methanol in water containing C3. The amount of product (estrone) was then quantified by LCMS. Data, expressed as product area ratio (PAR), were then normalized to control wells using Activity Base (IDBS). Zero percent effect (ZPE) was defined as the PAR generated from uninhibited HSD17B13 (vehicle control). 100 percent effect (HPE) was defined as the PAR generated from wells containing 20 μM FAC of a Pfizer proprietary compound known to cause 100% inhibition of HSD17B13. Concentration and % effect values ​​for each compound were plotted using a four-parameter logarithmic dose-response equation to determine the 50% inhibition (IC 50 The required concentration of

[0456] Table 3 shows the assay data (IC 50 ) are shown below (two key figures as geometric means based on the number of replicates tested).

[0457] [Table 3-1]

[0458] [Table 3-2]

[0459] [Table 3-3]

[0460] [Table 3-4]

[0461] [Table 3-5]

[0462] [Table 3-6]

[0463] [Table 3-7]

[0464] [Table 3-8]

[0465] [Table 3-9]

[0466] [Table 3-10]

[0467] [Table 3-11]

[0468] [Table 3-12]

[0469] [Table 3-13]

[0470] [Table 3-14]

[0471] Throughout this application, various publications are referenced, the disclosures of which are incorporated by reference into this application in their entireties for all purposes.

[0472] It will be apparent to those skilled in the art that various modifications and variations of the present invention can be made without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

1. Compounds of Formula I 【Chemical 1】 [In the formula, A is —NH—C(O)— or heteroaryl having 1, 2, 3, or 4 heteroatoms selected from O, N, and S; A is selected from one or two R ４ may be substituted with B is absent or is H, aryl, heteroaryl, heterocyclyl, fluoro, chloro, bromo, oxo, cyano, hydroxyl, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) fluoroalkyl, (C １ ~C ６ ) alkoxy, or (C １ ~C ６ ) fluoroalkoxy, wherein said heteroaryl or heterocyclyl has 1, 2, or 3 heteroatoms selected from O, N, and S, and B has 1 or 2 R ５ may be substituted with C is absent or is H, —NH—C(O)—R ７ , -S(O) ２ -R ７ , —O—S(O) ２ -R ７ , fluoro, chloro, bromo, oxo, cyano, hydroxyl, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) alkoxy, (C ３ ~C ６ ) cycloether, (C １ ~C ６ ) fluoroalkyl, (C １ ~C ６ ) fluoroalkoxy, aryl, heteroaryl, or heterocyclyl, wherein said heteroaryl or heterocyclyl has 1, 2, or 3 heteroatoms selected from O, N, and S; and C has 1, 2, or 3 R ６ may be substituted with R １ , R ２ , and R ３ are each independently selected from H and fluoro; Each R ４ , R ５ and R ６ are independently oxo, hydroxyl, chloro, fluoro, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) fluoroalkyl, (C ３ ~C ６ cycloalkyl, and heterocyclyl having 1, 2, or 3 heteroatoms selected from O and N; R ７ is hydroxyl, chloro, fluoro, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) fluoroalkyl, or (C ３ ~C ６ ) cycloalkyl; n is 0, 1 or 2. or a pharmaceutically acceptable salt of said compound.

2. Formula IA 【Chemistry 2】 2. The compound of claim 1, wherein:

3. Formula IB 【Chemistry 3】 2. The compound of claim 1, wherein:

4. R １ , R ２ , and R ３ 10. A compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, wherein at least one of is fluoro.

5. 10. A compound according to any preceding claim, wherein A is thiazolyl, pyrazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, imidazotriazinyl, imidazopyridazinyl, imidazopyridinyl, benzimidazolyl, benzothiazolyl, purinyl, pyridopyridazinyl, quinazolinyl, indazolyl, imidazopyridinyl, benzoxazolyl, pyrazolopyridinyl, isoindolinonyl, triazolyl, or oxadiazolyl; or a pharmaceutically acceptable salt thereof.

6. A is, 【Chemistry 4】 10. A compound according to any preceding claim, wherein:

7. B is absent or is selected from the group consisting of H, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, piperazinyl, quinoxalinyl, phenyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, imidazolyl, indazolyl, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) fluoroalkyl, (C １ ~C ６ ) alkoxy, bromo, chloro, fluoro, or oxo, and B is one or two fluoro, oxo, hydroxyl, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) fluoroalkyl, (C １ ~C ６ ) alkoxy, or (C ３ ~C ６ 2. A compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, optionally substituted with a cycloether.

8. B is pyrimidinyl, (C １ ~C ３ ) fluoroalkyl-substituted pyrimidinyl, (C １ ~C ３ 2. A compound according to any preceding claim, which is alkyl-substituted pyrazolyl, methoxy-substituted pyridazinyl, difluoromethyl-substituted pyrazinyl, trifluoromethyl-substituted pyrimidinyl, or methoxy-substituted pyrimidinyl, or a pharmaceutically acceptable salt thereof.

9. C is absent or is H, pyridinyl, piperazinyl, oxolanyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) fluoroalkyl, (C １ ~C ６ ) alkoxy, cyano, bromo, chloro, fluoro, or oxo, and C is 1, 2, or 3 fluoro, oxo, hydroxyl, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) fluoroalkyl, or (C １ ~C ６ 2. A compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, optionally substituted with .

10. C is absent or is selected from pyridinyl, piperazinyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) fluoroalkyl, and C is 1, 2, or 3 fluoro, oxo, hydroxyl, or (C １ ~C ６ 2. A compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, optionally substituted with alkyl.

11. 2,3,5-trifluoro-4-hydroxy-N-[(4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide; 2,3,5-trifluoro-4-hydroxy-N-({4-[6-(pyrimidin-2-yl)-2H-indazol-2-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide; 2,3,5-trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide; 2,3,5-trifluoro-4-hydroxy-N-({4-[3-(6-methoxypyridazin-3-yl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide: N-[(4-{5-[5-(difluoromethyl)pyrazin-2-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]-3,5-difluoro-4-hydroxybenzamide; 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide; 3,5-difluoro-4-hydroxy-N-({(1r,4r)-4-[6-(2-methoxypyrimidin-5-yl)-2H-pyrazolo[4,3-c]pyridin-2-yl]cyclohexyl}methyl)benzamide, 2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(piperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide, or 2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide or a pharmaceutically acceptable salt of said compound.

12. A compound which is 2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide, or a pharmaceutically acceptable salt thereof.

13. The compound is 2,3,5-trifluoro-4-hydroxy-N-[(4-{5-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-3-yl}bicyclo[2.2.2]octan-1-yl)methyl]benzamide, hydrochloride.

14. 【Chemical 5】 A compound which is

15. Fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, non-alcoholic steatohepatitis with cirrhosis, hepatocellular carcinoma, alcoholic fatty liver disease, alcoholic steatohepatitis, hepatitis B, hepatitis C, biliary cirrhosis, clear cell carcinoma of the kidney, squamous cell carcinoma of the head and neck, colorectal adenocarcinoma, mesothelioma, gastric adenocarcinoma, adrenocortical carcinoma, papillary renal cell carcinoma, cervical and endocervical carcinoma, urothelial carcinoma of the bladder, lung adenocarcinoma, type 1 diabetes, idiopathic type 1 diabetes (type lb), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), young-onset atypical diabetes (YOAD), young-onset adult 16. A method of treating type 2 diabetes mellitus (MODY), malnutrition-related diabetes, gestational diabetes, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, and maple syrup urine disease by administering a compound of any of claims 1 to 14 or a pharmaceutically acceptable salt of said compound to a human in need of such treatment.

16. 16. The method of claim 15, wherein alcoholic fatty liver disease, alcoholic steatohepatitis, hepatitis B, hepatitis C, or biliary cirrhosis is treated.

17. 16. The method of claim 15, wherein fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, or non-alcoholic steatohepatitis with cirrhosis, or hepatocellular carcinoma is treated.

18. 16. The method of claim 15, wherein nonalcoholic steatohepatitis is treated.

19. A method of reducing the incidence of cirrhosis, cirrhotic compensation, progression to model of end-stage liver disease (MELD), liver transplantation, liver-related death, or hepatocellular carcinoma by administering to a human a compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt of said compound.

20. 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier, vehicle or diluent.

21. a first compound which is a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt of said compound; a second compound that is an antidiabetic agent; an agent for treating non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, or an anti-heart failure agent; and a pharmaceutical carrier, vehicle or diluent; A pharmaceutical combination composition comprising a therapeutically effective amount of a composition comprising:

22. 22. The pharmaceutical combination composition of claim 21, wherein the drug for treating non-alcoholic steatohepatitis or non-alcoholic fatty liver disease is an ACC inhibitor, a KHK inhibitor, a DGAT-2 inhibitor, an FXR agonist, metformin, an incretin analog, or an incretin receptor modulator.

23. 22. The pharmaceutical combination composition of claim 21, wherein the antidiabetic agent is an SGLT-2 inhibitor, metformin, an incretin analog, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist.

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