Inhibitor and / or degradation agent containing 3-fluoro-4-hydroxybenzamide and use thereof

Abstract

Described herein are inhibitors and / or degradation agents comprising a 3-fluoro-4-hydroxybenzamide, and pharmaceutical compositions comprising inhibitors and / or degradation agents comprising a 3-fluoro-hydroxybenzamide. In some embodiments, the 3-fluoro-4-hydroxybenzamide-containing compounds of the present invention are useful in the treatment of conditions, such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Formula (II).

Description

Background Art

[0001] Hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) is an enzyme in the hepatic lipid droplet-associated steroid dehydrogenase family. Since 2018, multiple human genetic variants in HSD17B13 have been identified that protect against NASH progression, with some variants resulting in reduced liver inflammation, bloating, and fibrosis. In 2018, Abul-Husn et al. reported that a truncating variant was over-enriched in individuals with simple steatosis and under-enriched in individuals with NASH and NASH plus fibrosis, suggesting a protective effect 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 year, Kozlitina et al. reported a second truncating variant with reduced allele frequency in blacks and Hispanics with chronic liver disease. Kozlitina et al., “HSD17B13 and Chronic Liver Disease in Blacks and Hispanics”, NEngl J Med 2018;379:1876-1877. In 2019, Ma et al. found that the coding variant P260S was associated with reduced inflammation and bloating. HSD17B13 expression has been shown to be significantly upregulated in humans with non-alcoholic 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. Mouse models fed a NASH-promoting diet also showed upregulation of HSD17B13. Therefore, it is hypothesized that inhibition or degradation of HSD17B13 enzyme activity may 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 hepatocellular carcinoma development.

[0002] Although there have been some early studies related to HSD17B13, there is still a need for pharmaceutical agents with HSD17B13 inhibitory and / or degrading activity. HSD17B13 inhibitors and / or degraders can be used to treat, prevent or attenuate the manifestations of the diseases described herein. Summary of the Invention

[0003] In some embodiments, disclosed herein is a compound of Formula I:

[0004]

[0005] Formula II

[0006] in:

[0007] A is -NH-C(O)-, -C(O)- or heteroaryl, wherein heteroaryl has 1, 2, 3 or 4 heteroatoms selected from O, N and S, and wherein A is optionally substituted by one or two R 4 replace;

[0008] R 1 、R 2 and R 3 are each independently selected from H and fluorine;

[0009] R 4 is selected from oxo, hydroxy, chloro, fluoro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl, (C3-C6)cycloalkyl and heterocyclyl, wherein the heterocyclyl has 1, 2 or 3 heteroatoms selected from O and N;

[0010] n is 0, 1, or 2;

[0011] L is a linker; and

[0012] E is an E3 ubiquitin ligase binder,

[0013] or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, disclosed herein is a compound having the structure:

[0015]

[0016] Further disclosed herein are pharmaceutically acceptable salts of N-{[4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide. Also disclosed herein is N-{[4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide hydrochloride. In some embodiments, disclosed herein is N-{[4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide.

[0017] In some embodiments, disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, vehicle, or diluent. Further disclosed herein is a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising: a first compound, wherein the first compound is a compound of Formula II or a pharmaceutically acceptable salt thereof; a second compound, wherein the second compound is an antidiabetic agent; a therapeutic agent for nonalcoholic steatohepatitis, a therapeutic agent for nonalcoholic fatty liver disease, or an anti-heart failure therapeutic agent; and a pharmaceutical carrier, vehicle, or diluent.

[0018] In some embodiments, disclosed herein is a method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, nonalcoholic 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, renal papillary cell carcinoma, cervical cancer and endocervical cancer, bladder urothelial carcinoma, lung adenocarcinoma, type 1 diabetes, idiopathic type 1 diabetes (type 1b), latent autoimmune diabetes of adulthood (LADA), early-onset type 2 diabetes (EOD), juvenile-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (maturity-onset diabetes of the young) 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, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, and maple syrup urine disease.

[0019] In some embodiments, disclosed herein is a method of reducing the progression of a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cirrhosis, decompensated cirrhosis, progression to the Model for End-Stage Liver Disease (MELD), liver transplantation, liver-related death, and hepatocellular carcinoma.

[0020] Disclosed herein is a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating 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, adrenal cortical carcinoma, renal papillary cell carcinoma, cervical cancer and endocervical cancer, bladder urothelial carcinoma, lung adenocarcinoma, type I diabetes, idiopathic type I diabetes (type Ib), latent autoimmune disease in adults Diabetes mellitus (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, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, or maple syrup urine disease.

[0021] In some embodiments, disclosed herein is a use of a compound of the present invention or a pharmaceutically acceptable salt thereof as a medicament. In some embodiments, disclosed herein is a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating 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, adrenal cortical carcinoma, renal papillary cell carcinoma, cervical cancer and endocervical cancer, bladder urothelial carcinoma, lung adenocarcinoma, type 1 diabetes, idiopathic type 1 diabetes (type 1b) ), latent autoimmune diabetes in 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, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, or maple syrup urine disease.

[0022] In some embodiments, disclosed herein is a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for treating a condition selected from the group consisting of: fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, nonalcoholic 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, renal papillary cell carcinoma, cervical cancer and endocervical cancer, bladder urothelial carcinoma, lung adenocarcinoma, type 1 diabetes, idiopathic type 1 diabetes (type 1b), ), latent autoimmune diabetes in 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, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, and maple syrup urine disease. It is to be understood that 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

[0023] The present application may be understood more readily by reference to the following detailed description of exemplary embodiments of the invention and the Examples included therein.

[0024] It should be understood that the present invention is not limited to a particular synthetic manufacturing method, which may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. Throughout this specification and the claims that follow, reference will be made to several terms that are defined to have the following meanings.

[0025] As used in this specification, "a" or "an" may refer to one or more. As used in the claims, when used in conjunction with the word "comprising," the word "a" or "an" may refer to one or more than one. As used herein, "another" may refer to at least a second or more.

[0026] The term "about" is a relative term indicating an approximate value of plus or minus 10% of the nominal value, which in one embodiment means plus or minus 5%, and in another embodiment means plus or minus 2%. In the field of the present invention, this level of approximation is appropriate unless a closer range of the value is specifically stated.

[0027] The term "and / or" refers to one or more. For example, "X and / or Y" should be understood to mean "X and Y" or "X or Y," and should be considered to provide clear support for both meanings or either meaning. Similarly, when more than two meanings are listed, as in "X, Y, and / or Z," it should be understood to mean i) "X and Y," "X, Y, and Z," "X and Z," or "Y and Z," or ii) "X or Y or Z," and should be considered to provide clear support for all meanings.

[0028] Unless otherwise stated, any open valencies appearing on carbon, oxygen, sulfur, or nitrogen atoms in structures disclosed herein assume the presence of hydrogen.

[0029] Terminology C1-C x Including C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. For example, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0030] The term "bicyclic ring system" refers to two rings fused to each other via a common single or double bond (fused bicyclic ring system), via a series of three or more common single atoms (bridged bicyclic ring system), or via a common single atom (spirobicyclic ring system). The bicyclic ring system may be saturated, partially saturated, unsaturated, or aromatic. The bicyclic ring may contain heteroatoms selected from N, O, and S.

[0031] The term "bridged" refers to any ring structure having two or more rings that contain a bridge connecting two bridgehead atoms. A bridgehead atom is defined as an atom that is part of the backbone framework of a molecule and is bonded to three or more other backbone atoms. A bridgehead atom can be C, N, or P. A bridge can be a single atom or a chain of atoms connecting two bridgehead atoms. For example, a bridged ring system can be a cycloalkyl or heterocycloalkyl group.

[0032] The term "fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced by one or more N, S, and O atoms. Non-limiting examples of fused heterocyclyl rings include 6-5 fused heterocycles, 6-6 fused heterocycles, 5-6 fused heterocycles, 5-5 fused heterocycles, 7-5 fused heterocycles, and 5-7 fused heterocycles. Non-limiting examples of fused heteroaryl rings include 6-5 fused heteroaryls, 6-6 fused heteroaryls, 5-6 fused heteroaryls, 5-5 fused heteroaryls, 7-5 fused heteroaryls, and 5-7 fused heteroaryls.

[0033] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. This term is distinguished from a "heterocyclic" ring or "heterocycle" in which the ring backbone contains at least one atom that is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. For example, carbocycles include cycloalkyl and aryl.

[0034] The term "alkyl" refers to a group of formula C n H 2n+1 A non-cyclic saturated hydrocarbon group which may be straight or branched. The carbon atom content of an alkyl group and various other hydrocarbon-containing moieties is indicated by a prefix that specifies the lower and upper limits of the number of carbon atoms in the moiety, i.e., the prefix Ci-Cj indicates a moiety having an integer "i" to an integer "j" carbon atoms (inclusive of i and j). Thus, for example, a C1-C3 alkyl group refers to an alkyl group having from one to three carbon atoms (inclusive of 1 and 3). For example, an alkyl group containing up to 10 carbons is referred to as a C1-C 10 Alkyl. For example, an alkyl group containing up to 6 carbon atoms is referred to as a C1-C6 alkyl group. Alkyl groups containing other numbers of carbon atoms (and other moieties as defined herein) are similarly represented. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Alkyl groups may be optionally substituted or unsubstituted, as further defined herein.

[0035] The term "heteroalkyl" refers to an alkyl group whose one or more backbone atoms are selected from atoms other than carbon, such as N, S, O, or a combination thereof. Representative examples of heteroalkyl groups include, but are not limited to, -NH-, -N(alkyl)-, -N(aryl)-, -S-, -S(=O)-, or -S(=O)-, thioethers, -OCHTOMe, -OCHCHOH, -OCHCHOMe, or -OCHCHOCHCHNH, or a combination thereof. Heteroalkyl groups can be connected to the remainder of the molecule at a carbon atom of the heteroalkyl group. Heteroalkyl groups can also be connected to the remainder of the molecule at a heteroatom of the heteroalkyl group.

[0036] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by at least one of the same or different halogen atoms. For example, a "fluoroalkyl" refers to an alkyl group as defined herein that is substituted by one, two, or three fluorine 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. Examples of fully substituted fluoroalkyl groups (also known as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0037] "Cycloalkyl" refers to a fully hydrogenated alkyl radical having the formula C n H 2N-1 The cycloalkyl group may be a monocyclic, bridged or fused bicyclic or polycyclic non-aromatic ring. The cycloalkyl group may be a spirocyclic or bridged compound. The cycloalkyl group may be fused to an aromatic system, in which case the cycloalkyl group is bonded via a non-aromatic ring carbon atom. The cycloalkyl group may also be fused to a second cycloalkyl group. The cycloalkyl group may contain, but is not limited to, 3 to 12 carbon atoms ("C3-C 12 Representative cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetraenyl, decalinyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Cycloalkyl groups may be optionally substituted as defined herein.

[0038] "Fluoroalkyl" refers to a non-aromatic cycloalkyl ring as defined herein that is substituted with one, two, or three fluorine 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.

[0039] The term "alkoxy" refers to a straight-chain or branched saturated alkyl group bonded via an oxygen group, i.e., -OR x , where R x is an alkyl group as defined above. In some embodiments, the term "alkoxy" refers to an alkylene group comprising an oxy group, i.e., alkylene-O-alkylene, -O-alkylene, or alkylene-O-. Representative alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, heptyloxy, and octyloxy. Alkoxy groups may be optionally substituted or unsubstituted, as further defined herein.

[0040] "Fluoroalkoxy" refers to an alkoxy group as defined herein substituted with one, two, or three fluorine 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.

[0041] The terms "halo," "halogen," and "halide" are used interchangeably herein and refer to bromine, chlorine, fluorine, or iodine.

[0042] "Cyano" refers to a substituent in which a carbon atom is triple-bonded to a nitrogen atom, ie, -C≡N.

[0043] "Hydroxy" refers to an -OH group.

[0044] "Oxo" refers to a double-bonded oxygen (=0).

[0045] When "ene" is added before "yl" at the end of a term to form a new term, the new term refers to a diradical formed by removing a hydrogen atom from the original term from which the new term is derived. For example, "alkylene" refers to a divalent radical formed by removing a hydrogen atom from an alkyl group, and "methylene" refers to a divalent radical -CH2- resulting from removing a hydrogen atom from a methyl group, i.e., a straight or branched divalent hydrocarbon chain to which the rest of the molecule is attached a radical group. Examples of such diradicals include, but are not limited to, alkylene, alkenylene, alkynylene, cycloalkylene, phenylene, heterocyclylene, and heteroarylene, which are derived from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, and heteroarylene groups. "C 1-3 Non-limiting examples of "alkylene" include: -CH2-, -CH(CH3)-, -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, and -CH(CH2CH3)-. For cyclic moieties, removal of a hydrogen may occur at any atom of sufficient valence.

[0046] "Alkenyl" refers to an alkyl group as defined herein, and refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, an alkenyl group has 2 to 6 carbon atoms. In some embodiments, an alkenyl group has 2 to 4 carbon atoms. For example, as used herein, the term "C 2-6 "Alkenyl" refers to a straight or branched unsaturated group of 2 to 6 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like, optionally substituted with 1 to 5 suitable substituents. When the compounds of the present invention contain alkenyl, the alkenyl may exist in the form of pure E form, pure Z form or any mixture thereof.

[0047] "Alkynyl" refers to an alkyl group as defined herein consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl, and the like.

[0048] "Heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O and S as a ring member, wherein the ring S atoms are optionally substituted with one or two oxy groups (i.e., S(O) q, wherein q is 0, 1 or 2) and wherein the heterocycloalkyl ring is attached to the base molecule via a ring atom which may be C or N. Heterocycloalkyl rings include monocyclic, spirocyclic, bridged or fused rings to one or more other heterocycloalkyl rings or carbocyclic rings, wherein such spirocyclic, bridged or fused rings may themselves be saturated, partially unsaturated or aromatic, the degree of unsaturation or aromaticity being chemically reasonable, provided that the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. The heterocycloalkyl ring may contain from 1 to 4 atoms selected from N, O and S(O) qThe heteroatoms of the present invention are as ring members, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl ring does not contain two continuous oxygen atoms or sulphur atoms. The heterocycloalkyl ring may be optionally substituted or unsubstituted, as further defined herein. These substituents may be present in the heterocycle connected to the base molecule or in a spirocycle, bridged ring or fused ring connected thereto. According to the definition herein, the heterocycloalkyl ring may include but is not limited to 3 to 8 yuan of heterocyclic radicals, such as 4 to 7 yuan or 4 to 6 yuan of heterocycloalkyls. Illustrative examples of heterocycloalkyl rings include, but are not limited to, the following monovalent groups: oxirane (oxiranyl), thioethane (thioethaneyl), aziridine (aziridinyl), oxetane (oxetanyl), thietane (thietanyl), azetidine (azetidinyl), tetrahydrofuran (tetrahydrofuranyl), tetrahydrothiophene (tetrahydrothienyl), pyrrolidine (pyrrolidinyl), tetrahydropyran (tetrahydropyranyl), tetrahydrothiopyran (tetrahydrothiopyranyl), ), piperidine (piperidinyl), 1,4-dioxane (1,4-dioxanyl), 1,4-oxathietane (1,4-oxathietane), morpholine (morpholinyl), 1,4-dithiane (1,4-dithianyl), piperazine (piperazinyl), thiomorpholine (thiomorpholinyl), oxepane (oxepanyl), thioepane (thioepanyl), azepane (azepanyl), 1,4-dioxepane (1,4- dioxepane), 1,4-oxathiepane (1,4-oxathiepane), 1,4-oxazepane (1,4-oxazepane), 1,4-thiazepane (1,4-thiazepane), 1,4-diazepane (1,4-diazepane), 1,4-dithiepane (1,4-dithiepane), dioxolane, thienyl [1,3] dithianyl, tetrahydroquinone In some embodiments, the fused bicyclic heterocyclic group may include a first heterocyclic group fused to a second heterocyclic group. Illustrative examples of bridged and fused heterocycloalkyl groups include, but are not limited to, the monovalent radicals of 1-oxa-5-azabicyclo-[2.2.1]heptane, 3-oxa-8-azabicyclo-[3.2.1]octane, 3-azabicyclo-[3.1.0]hexane, or 2-azabicyclo-[3.1.0]hexane.Illustrative examples of spiroheterocyclic compounds include, but are not limited to, substituted or unsubstituted spiro[3.4]nonanyl, spiro[3.5]decyl, spiro[5.4]undecyl, spiro[4.5]undecyl, or spiro[5.5]tetradecyl, wherein the spiroheterocyclic compound contains at least one heteroatom selected from N, O, and S as a ring member.

[0049] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. Aromatic groups may be optionally substituted. The term "aromatic" includes monocyclic or fused bicyclic aromatic groups (e.g., phenyl, naphthyl) and monocyclic or fused bicyclic heteroaryl groups (e.g., pyridyl, quinolinyl).

[0050] "Aryl" means a monocyclic, fused bicyclic, or polycyclic ring system containing the specified number of ring atoms, in which all carbon atoms in the rings are sp 2 Hybridized and wherein the π electrons are conjugated. Aryl groups may contain, but are not limited to, 6 to 20 carbon atoms ("C6-C 20 aryl”), 6 to 14 carbon atoms (“C6-C 14 aryl”), 6 to 12 carbon atoms (“C6-C 12 aryl”) or 6 to 10 carbon atoms (“C6-C 10 Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Fused aryl rings may also include an aryl ring (e.g., a phenyl ring) fused to a cycloalkyl group. In some embodiments, a fused aryl ring may include an aryl ring (e.g., a phenyl ring) fused to a heterocyclyl group. In one embodiment, a fused aryl ring may include an aryl ring (e.g., a phenyl ring) fused to a heteroaryl ring. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted, or substituted, as further defined herein.

[0051] The term "heteroaryl" refers to a monocyclic, heterobiaryl, or fused bicyclic or polycyclic ring system containing the specified number of ring atoms and including at least one heteroatom selected from N, O, and S as a ring member, wherein all carbon atoms in the ring are sp 2Hybridized and wherein π electrons are conjugated. The total number of ring members (e.g., 5- to 10-membered heteroaryl) can be indicated. Heteroaryl can contain, but is not limited to, 5 to 20 ring atoms ("5- to 20-membered heteroaryl"), 5 to 14 ring atoms ("5- to 14-membered heteroaryl"), 5 to 12 ring atoms ("5- to 12-membered heteroaryl"), 5 to 10 ring atoms ("5- to 10-membered heteroaryl"), 5 to 9 ring atoms ("5- to 9-membered heteroaryl") or 5 to 6 ring atoms ("5- to 6-membered heteroaryl"). The heteroaryl ring is connected to the base molecule via the ring atoms of the heteroaromatic ring. Therefore, a 5- or 6-membered heteroaryl ring (alone or in a fused structure) can be connected to the base molecule via a ring C or N atom. The heteroaryl group can include two fused rings, wherein at least one ring is aromatic and the other is aromatic, saturated or partially unsaturated, and at least one fused ring contains heteroatoms. In some embodiments, the heteroaryl ring may be fused to a cycloalkyl ring. In some embodiments, the heteroaryl ring may be fused to an aryl ring. In some embodiments, the first heteroaryl ring may be fused to the second heteroaryl ring. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, and carbazolyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted, or substituted as further defined herein.

[0052] Illustrative examples of monocyclic heteroaryl groups include the following monovalent radicals: pyrrole (pyrrolyl), furan (furyl), thiophene (thienyl), pyrazole (pyrazolyl), imidazole (imidazolyl), isoxazole (isoxazolyl), oxazole (oxazolyl), isothiazole (isothiazolyl), thiazole (thiazolyl), 1,2,3-triazole (1,2,3-triazolyl), 1,3,4-triazole (1,3,4-triazolyl), 1-oxa-2,3-oxadiazole (1-oxa-2,3-oxadiazole), 1-oxa-2,4-oxadiazole (1-oxa-2,4-oxadiazole), 1-oxa-2,3-oxadiazole (1-oxa-2,3-oxadiazole). oxadiazole (1-oxa-2,5-oxadiazole), 1-oxa-3,4-oxadiazole (1-oxa-3,4-oxadiazole), 1-thia-2,3-oxadiazole (1-thia-2,3-oxadiazole), 1-thia-2,4-oxadiazole (1-thia-2,4-oxadiazole), 1-thia-2,5-oxadiazole (1-thia-2,5-oxadiazole), 1-thia-3,4-oxadiazole (1-thia-3,4-oxadiazole), tetrazole (tetrazolyl), pyridine (pyridinyl), pyridazine (pyridazinyl), pyrimidine (pyrimidinyl) or pyrazine (pyrazinyl).

[0053] Illustrative examples of fused-ring heteroaryl groups include, but are not limited to, benzofuran (benzofuranyl), benzothiophene (benzothienyl), indole (indolyl), benzimidazole (benzimidazolyl), indazole (indazolyl), benzotriazole (benzotriazolyl), pyrrolo[2,3-b]pyridine (pyrrolo[2,3-b]pyridinyl), pyrrolo[2,3-c]pyridine (pyrrolo[2,3-c]pyridinyl), pyrrolo[3,2-c]pyridine (pyrrolo[3,2-c]pyridinyl), pyrrolo[3,2-b]pyridine (pyrrolo[3,2-b]pyridinyl), imidazo[4,5-b]pyridine (imidazo[4,5-b]pyridinyl), imidazo[4,5-c]pyridine ( imidazo[4,5-c]pyridinyl), pyrazolo[4,3-d]pyridine(pyrazolo[4,3-d]pyridinyl), pyrazolo[4,3-c]pyridine(pyrazolo[4,3-c]pyridinyl), pyrazolo[3,4-c]pyridine(pyrazolo[3,4-c]pyridinyl), pyrazolo[3,4-b]pyridine(pyrazolo[3,4-b]pyridinyl), isoindole(isoindolyl), indazole(indazolyl), purine(purinyl), indolizine(indolizinyl), imidazo[1,2-a]pyridine(imidazo[1,2-a]pyridinyl), imidazo[1,5-a]pyridine(imidazo[1,5-a]pyridinyl), pyrazolo[1,5-a]pyridine(pyrazolo [1,5-a]pyridinyl), pyrrolo[1,2-b]pyridazine (pyrrolo[1,2-b]pyridazinyl), imidazo[1,2-c]pyrimidine (imidazo[1,2-c]pyrimidinyl), quinoline (quinolyl), isoquinoline (isoquinolyl), cinnoline (cinnolinyl), quinazoline (azaquinazoline), quinoxaline (quinoxalinyl), phthalazine (phthalazinyl), 1,6-naphthyridine (1,6-naphthyridinyl), 1,7-naphthyridine (1,7-naphthyridinyl), 1,8-naphthyridine (1,8-naphthyridinyl), 1,5-naphthyridine (1,5-naphthyridinyl), 2,6-naphthyridine (2,6-naphthyridinyl), 2,7-naphthyridine (2,7-naphthyridinyl), pyrido[3,2-d]pyrimidine (pyrido [3,2-d]pyrimidinyl), pyrido[4,3-d]pyrimidine(pyrido[4,3-d]pyrimidinyl), pyrido[3,4-d]pyrimidine(pyrido[3,4-d]pyrimidinyl), pyrido[2,3-d]pyrimidine(pyrido[2,3-d]pyrimidinyl), pyrido[2,3-b]pyrazine(pyrido[2,3-b]pyrazine), pyrido[3,4-b]pyrazine(pyrido[3,4-b]pyrazine), pyrimido[5,4-d]pyrimidine(pyrimido[5,4-d]pyrimidinyl), pyrazino[2,3-b]pyrazine(pyrazino[2,3-b]pyrazinyl) or pyrimido[4,5-d]pyrimidine(pyrimido[4,5-d]pyrimidinyl).

[0054] "Amino" refers to the unsubstituted group -NH2. Where amino is described as substituted or optionally substituted, the term includes groups of the form -NR x R y A group in which R x and R y Each of is defined as further described herein.

[0055] The term "alkylamino" or "aminoalkyl" refers to a radical of the formula -NHR x or -NR x R y A group in which each R x and R y is independently H, alkyl, or alkylene. For example, "alkylamino" may refer to the group -NR x R y , where R x and R y One of the moieties is an alkyl group and the other is H; and "dialkylamino" may refer to -NR x R y , where R x and R y Both are alkyl moieties, wherein the alkyl moiety has the specified number of carbon atoms (e.g., -NH(C1-C4 alkyl) or -N(C1-C4 alkyl)2). In some embodiments, aminoalkyl refers to -NH-alkylene or alkylene-NH-alkylene, wherein each alkyl group is independently substituted or unsubstituted.

[0056] As used herein, "compound" includes any pharmaceutically acceptable derivative or variant, including conformational isomers (e.g., cis- and trans-isomers), atropisomers (i.e., stereoisomers resulting from hindered rotation), and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric, and other mixtures of these isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The expression "prodrug" refers to a compound that is a drug precursor that, after administration, releases the drug in vivo via some chemical or physiological process (e.g., when the prodrug reaches physiological pH or is converted to the desired drug form via enzymatic action). Exemplary prodrugs release the corresponding free acid upon cleavage, and such hydrolyzable ester-forming residues of the compounds of the invention include, but are not limited to, those having a carboxyl moiety in which the free hydrogen is replaced by (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 ethyl, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-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 N-piperidinyl(C2-C3)alkyl, N-pyrrolidinyl(C2-C3)alkyl or N-morpholinyl(C2-C3)alkyl.

[0057] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the others. Thus, each substituent may be the same as or different from the other substituents.

[0058] "Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0059] The terms "optionally substituted" and "substituted or unsubstituted" are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., is unsubstituted), or that the group may have one or more non-hydrogen substituents (i.e., is substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms that are present in the unsubstituted form of the group being described. When an optional substituent is attached via a double bond, such as an oxo (=O) substituent, the group takes up two available valencies, so the total number of other substituents included is reduced by two. Where the optional substituents are independently selected from a range of alternative substituents, the selected groups may be the same or different. Throughout this disclosure, it will be understood that the number and nature of the optional substituents will be limited to the extent that such substitutions are chemically reasonable for one of ordinary skill in the art. Examples of optional substituents include, but are not limited to, one or more of the following: D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2(alkyl), -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, or oxo(=O).

[0060] As used herein, arrows or wavy lines It indicates the point of attachment of a substituent to another group.

[0061] The term "formulation" in the Examples section that follows describes the formulation of compounds that may be useful in synthesizing intermediates that are useful to those skilled in the art in synthesizing the protein degrader compounds described herein.

[0062] The term "mammal" refers to humans, livestock, or companion animals.

[0063] The term "companion animal" or "companion animals" refers to an animal that is kept as a pet or domestic animal. Examples of companion animals include dogs, cats, and rodents (including hamsters, guinea pigs, gerbils, and the like), rabbits, and ferrets.

[0064] The term "livestock" refers to animals raised or cultivated in an agricultural environment to produce products such as food or fiber or to obtain their labor. In some embodiments, livestock are suitable for consumption by mammals (e.g., humans). Examples of livestock animals include cattle, goats, horses, pigs, sheep (including lambs), and rabbits.

[0065] "Patient" refers to warm-blooded animals such as guinea pigs, minipigs, mice, rats, gerbils, cats, rabbits, dogs, cows, goats, sheep, horses, monkeys, chimpanzees, and humans.

[0066] The term "treating" or "treatment" refers to relieving the symptoms associated with a disease, disorder, or condition, or stopping those symptoms from progressing or worsening. Depending on the patient's disease and condition, the term "treatment" as used herein may include one or more of curative, palliative, and preventative treatments. Treatment may also include administering a pharmaceutical formulation in combination with other therapies.

[0067] A "therapeutically effective amount" refers to an amount of a compound of the invention that (i) treats or prevents a particular disease, condition, or disorder; (ii) alleviates, ameliorates, 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.

[0068] The term "pharmaceutically acceptable" means that a substance (e.g., a compound of the invention) and any salt thereof, or a composition containing a substance or salt of the invention, is suitable for administration to a patient. When referring to a compound of the invention (e.g., a compound of Formula I or Formula II), unless otherwise indicated, it is understood that pharmaceutically acceptable salts of the compound are also contemplated.

[0069] Compounds of the present invention

[0070] In one embodiment of the compound, the compound has Formula IA

[0071]

[0072] or a pharmaceutically acceptable salt of the compound.

[0073] In one embodiment of the compound, the compound has Formula IB:

[0074]

[0075] or a pharmaceutically acceptable salt of the compound.

[0076] In one embodiment of the compound, R 2 is F, or a pharmaceutically acceptable salt of the compound.

[0077] In one embodiment of this 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 of said compound.

[0078] In another embodiment of the compound, A is

[0079]

[0080]

[0081] In another embodiment of this compound, B is absent or is 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 wherein B is optionally substituted with one or two fluoro, oxo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)fluoroalkyl, (C1-C6)alkoxy or (C3-C6)cyclic ether; or a pharmaceutically acceptable salt of said compound.

[0082] In another embodiment of this compound, B is pyrimidinyl, pyrimidinyl substituted by (C1-C3)fluoroalkyl, pyrazolyl substituted by (C1-C3)alkyl, pyridazinyl substituted by methoxy, pyrazinyl substituted by difluoromethyl, pyrimidinyl substituted by trifluoromethyl, or pyrimidinyl substituted by methoxy; or a pharmaceutically acceptable salt of said compound.

[0083] In another embodiment of this compound, C is absent or is H, pyridyl, piperazinyl, oxolanyl, (C3-C6)cycloalkyl, (C1-C6)alkyl, (C1-C6)fluoroalkyl, (C1-C6)alkoxy, cyano, bromo, chloro, fluoro, or oxo, and wherein C is optionally substituted with one, two, or three fluoro, oxo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)fluoroalkyl, or (C1-C6)alkoxy; or a pharmaceutically acceptable salt of said compound.

[0084] In another embodiment of this compound, C is absent or is pyridinyl, piperazinyl, (C3-C6)cycloalkyl, (C1-C6)alkyl, (C1-C6)fluoroalkyl; and wherein C is optionally substituted with one, two or three fluoro, oxo, hydroxy or (C1-C6)alkyl; or a pharmaceutically acceptable salt of said compound. 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; 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)-1,2-difluoromethyl] ... 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]pyridine-2-yl}bicyclo[2.2.2]octan-1-yl)methyl}benzamide 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; 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 the compound.

[0085] In one embodiment of the compound, 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 of the compound.

[0086] HSD17B13 protein degrader compounds

[0087] Disclosed herein are protein degrader compounds comprising: 1) a targeting protein ligand; 2) a linker of varying length and functionality; and 3) a ligand that interacts with the ubiquitin proteasome system (degrons). The protein degrader compounds of the present invention are bifunctional and comprise a targeting ligand. The bifunctional protein degrader compounds of the present invention can be used as therapeutic agents for treating various diseases, such as various liver diseases.

[0088] The protein degrader compounds of the present invention have the following general structure: [Targeting Ligand]-[Linker]-[Degradon], wherein the Linker is covalently bound to at least one Degradon and at least one Targeting Ligand. Degradons are compounds capable of binding to ubiquitin ligases (e.g., E3 ubiquitin ligases such as cereblon (CRBN) and VHL). Targeting Ligands are capable of binding to target proteins, such as HSD17B13.

[0089] In one embodiment of the compound, the compound has Formula II:

[0090]

[0091]

[0092] in:

[0093] A is -NH-C(O)-, -C(O)- or heteroaryl, wherein heteroaryl has 1, 2, 3 or 4 heteroatoms selected from O, N and S, and wherein A is optionally substituted by one or two R 4 replace;

[0094] R 1 、R 2 and R 3 are each independently selected from H and fluorine;

[0095] R 4 is selected from oxo, hydroxy, chloro, fluoro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl, (C3-C6)cycloalkyl and heterocyclyl, wherein the heterocyclyl has 1, 2 or 3 heteroatoms selected from O and N;

[0096] n is 0, 1, or 2;

[0097] L is a linker; and

[0098] E is an E3 ubiquitin ligase binder,

[0099] or a pharmaceutically acceptable salt thereof.

[0100] In one embodiment of the protein degrader compound, the HSD17B13 targeting ligand fragment of the compound has Formula II-I:

[0101]

[0102] in:

[0103] A is -NH-C(O)-, -C(O)- or heteroaryl, wherein heteroaryl has 1, 2, 3 or 4 heteroatoms selected from O, N and S, and wherein A is optionally substituted by one or two R 4 replace;

[0104] R 1 、R 2 and R 3 are each independently selected from H and fluorine;

[0105] R 4 is selected from oxo, hydroxy, chloro, fluoro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl, (C3-C6)cycloalkyl and heterocyclyl, wherein the heterocyclyl has 1, 2 or 3 heteroatoms selected from O and N; and

[0106] n is 0, 1, or 2;

[0107] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, 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.

[0109] In some embodiments, A is: In some embodiments, the linker is designed and optimized based on structure activity relationships (SAR) and X-ray crystallography of the targeting ligand with respect to the attachment position of the linker. In some embodiments, the optimal linker length and composition vary from target to target and can be estimated based on the X-ray structure of the original targeting ligand bound to its target. The linker length and composition can also be modified to modulate metabolic stability and pharmacokinetic (PK) and pharmacodynamic (PD) parameters. In some embodiments, when a targeting ligand binds to multiple targets, selectivity can be achieved by varying the linker length, where the ligand binds to some targets in different binding pockets thereof, such as a deeper or shallower binding pocket than other binding pockets.

[0110] The linker ("L") provides a covalent link between the targeting ligand and the degradon (i.e., E of Formula II). The linker has two terminal groups, one of which is connected to the degradon and the other is connected to the targeting ligand. The structure of the linker may not be critical, provided that it does not substantially interfere with the activity of the targeting ligand or the degradon.

[0111] In some embodiments, the linker is C2-C 20 Alkylene or polyethylene glycol (PEG) chain (e.g., CH2CH2-O or (O-CH2CH2)). In other embodiments, the linker may comprise at least one of the following and / or terminate (at one or both ends) with 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 carbocyclylene, 3-membered to 12-membered heterocyclylene, 5-membered to 12-membered heteroarylene or arylene, or any combination thereof, wherein R L is H or C1-C6 alkyl, wherein the interrupting group and one or both terminal groups may be the same or different.

[0112] In some embodiments, the linker can be a C1-C1-terminated NH-group. 10 In another embodiment, the linker can be a C1-C 10 an alkylene chain or a PEG chain comprising 1 to 8 PEG units, wherein the linker may comprise or terminate in -(CH2) n’ -C(O)-NH-, wherein n' is 0, 1, 2, 3, 4 or 5. With respect to the linker, "carbocyclylene" refers to an optionally substituted divalent carbocyclic group. "Heteroarylene" refers to an optionally substituted divalent heterocyclic group. "Heteroarylene" refers to an optionally substituted divalent heteroaryl group. 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’ , where R L H or C 1-6 alkyl; n' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and n" is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0113] In one embodiment of the protein degrader compound, the linker has Formula II-II:

[0114]

[0115] in:

[0116] B is absent; or is aryl, heteroaryl, heterocyclyl, -C(O)-, (C1-C6)alkylene, (C3-C6)cycloalkylene, (C1-C6)fluoroalkylene, (C1-C6)alkoxy or (C1-C6)fluoroalkoxy, wherein the heteroaryl or heterocyclyl has 1, 2 or 3 heteroatoms selected from O, N and S, and wherein B is optionally replaced by one or two R 5 replace;

[0117] C does not exist; or is -NH-C(O)-R 7 、-S(O)2-R 7 、-OS(O)2-R 7 , -C(O)-, (C1-C6)alkylene, (C1-C6)aminoalkylene, (C3-C6)cycloalkylene, (C1-C6)alkoxy, (C3-C6)cyclic ether, (C1-C6)fluoroalkylene, (C1-C6)fluoroalkoxy, aryl, heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group has 1, 2 or 3 heteroatoms selected from O, N and S, and wherein C is optionally replaced by one, two or three R 6 replace;

[0118] D is (C1-C6)alkylene, (C1-C6)aminoalkylene, -NH(C1-C6)alkylene, (C1-C6)alkoxy, -C(O)-, aryl, heteroaryl, heterocyclyl, (C0-C6)alkylene-heterocyclyl-C(O)-, -C(O)-(C1-C6)alkylene, heterocyclyl-(C1-C6)alkylene-aryl-(C1-C6)alkoxy, (C1-C6)heterocyclyl-(C1-C6)heterocyclyl-C(O)-, (C0-C2)alkylene-aryl-(C1-C6)alkoxy, -O-heterocyclyl-C(O)-, (C1-C6)cycloalkyl-(C1-C6)heterocyclyl, wherein the heteroaryl or heterocyclyl has 1, 2 or 3 heteroatoms selected from O, N and S, wherein D is optionally replaced by one or two R 8 Substitute; or be a bond;

[0119] R 5 、R 6 and R 8 are each independently selected from oxo, hydroxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl, (C3-C6)cycloalkyl, heteroaryl and heterocyclyl, wherein the heterocyclyl has 1, 2 or 3 heteroatoms selected from O and N;

[0120] R 7 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl or (C3-C6)cycloalkyl;

[0121] or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, B is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, piperazinyl, quinoxalinyl, phenyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, imidazolyl, indazolyl, (C1-C6)alkylene, (C1-C6)fluoroalkylene, (C1-C6)alkoxy, pyrrolopyridinyl, isoindolinyl, isoquinolinyl, tetrahydroisoquinolinyl, thiazolopyridinyl, tetrahydrothiazolopyridinyl, imidazopyrazinyl, tetrahydroimidazopyrazinyl, pyrazolopyrazinyl, tetrahydropyrazolopyrazinyl, phenyl, spiro[4.5]decyl, spiro[3.4]octanyl or spiro[4.5]decane-1-onyl, wherein B is optionally substituted with one or two halogen, oxo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)fluoroalkyl, (C1-C6)alkoxy or (C3-C6)cyclic ether. In some embodiments, B is (C1-C6)alkylene, (C1-C6)heteroalkylene, (C1-C6)alkoxy, phenyl, isoindolyl, pyrimidinyl, pyridazinyl, pyrazolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, tetrahydroisoquinolinyl, tetrahydrothiazolo[5,4-c]pyridinyl, tetrahydroimidazo[1,2-a]pyrazinyl, 6-oxa-2,9-diazaspiro[4.5]decanyl, 2,6-diazaspiro[3.4]octanyl, 7-diazaspiro[4.5]decan-1-one or tetrahydropyrazolo[1,5-a]pyrazinyl. In some embodiments, B is:

[0123]

[0124]

[0125] In some embodiments, B is absent. In some embodiments, B is (C1-C3)alkylene. In some embodiments, B is In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0126] In some embodiments, C is (C1-C3) alkylene, (C1-C6) aminoalkylene, (C1-C6) alkoxy, pyridyl, oxolanyl, (C3-C6) cycloalkyl, (C1-C6) fluoroalkylene, -C(O)-, piperazinyl, piperidinyl, azetidinyl, azaspiroundecyl, azaspironanyl, azaspiroundecyl, diazaspirooctane, diazaspirodecanyl, diazaspiro nonanyl, diazaspirododecanyl, diazaspiroundecyl, oxadiazaspironanyl, oxadiazaspiroundecyl, oxadiazaspirodecanyl, decahydronaphthyridinyl, octahydropyrrolopyridinyl or octahydropyridopyrazinyl; wherein C is optionally substituted with one, two or three halogen, oxo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)fluoroalkyl or (C1-C6)alkoxy. In some embodiments, C is (C1-C6)alkylene, (C1-C6)aminoalkylene, (C1-C6)alkoxy, piperazinyl, piperidinyl, azetidinyl, -C(O)-, 5-oxa-diazaspiro[3.5]nonanyl, 1-oxa-diazaspiro[5.5]undecyl, 3-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, 8-azaspiro[4.5]decyl, 7-azaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decyl, 1-oxa-4,9-diazaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecane 1-oxa-8-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 2-azaspiro[5.5]undecyl, 2,6-diazaspiro[3.4]octyl, 3,9-diazaspiro[5.6]dodecyl, 2,7-diazaspiro[3.5]nonyl, 2,9-diazaspiro[5.5]undecyl, decahydro-1,5-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,6-diazaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, octahydro-2H-pyrido[1,2-a]pyrazinyl.

[0127] In some embodiments, C is:

[0128]

[0129] In some embodiments, C is absent. In some embodiments, C is (C1-C6)alkylene, (C1-C6)aminoalkylene, or (C1-C6)alkoxy. In some embodiments, C is In some embodiments, C is In some embodiments, D is a bond. In some embodiments, D is (C1-C6)alkylene, (C1-C6)aminoalkylene, -NH(C1-C6)alkylene, (C1-C6)alkoxy, -C(O)-, or -C(O)-(C1-C6)alkylene. In some embodiments, D is methylene, ethylene, or propylene. In some embodiments, D is (C0-C6)alkylene-heterocyclyl-C(O)-, heterocyclyl-(C1-C6)alkylene-aryl-(C1-C6)alkoxy, (C1-C6)heterocyclyl-(C1-C6)heterocyclyl-C(O)-, (C0-C2)alkylene-aryl-(C1-C6)alkoxy, -O-heterocyclyl-C(O)-, (C1-C6)cycloalkyl-(C1-C6)heterocyclyl.

[0130] In some embodiments, D is methylene, ethylene, or propylene. In some embodiments, D is heterocyclyl-C(O)-. In some embodiments, D is -C(O)-(C1-C6)alkylene. In some embodiments, D is -C(O)-. In some embodiments, D is

[0131] In some embodiments, A is heteroaryl, B is heteroaryl, C is absent, and D is (C1-C6)alkylene. In some embodiments, A is heteroaryl, B is heteroaryl, C is heterocyclyl, and D is (C1-C3)alkylene. In some embodiments, A is indazolyl, oxadiazolyl, or thiazolyl; B is pyridazinyl, pyrazinyl, pyrimidinyl, piperazinyl, pyrazolyl, isoindolyl, or dihydropyrrolopyridinyl; C is absent, (C1-C3)alkylene, (C1-C3)alkoxy, or piperidinyl; and D is methylene, ethylene, or propylene. In some embodiments, A is indazolyl or oxadiazolyl; B is pyrimidinyl; C is piperazinyl; D is methylene, ethylene, or propylene. In some embodiments, A is indazolyl; B is pyrimidinyl; C is (C1-C3)alkoxy; and D is heterocyclyl-C(O)-. In some embodiments, A is oxadiazolyl, B is pyrimidinyl, C is piperazinyl, and D is propylene.

[0132] Degradon (i.e., "E" of Formula II) is small in size and very effective in recruiting target proteins for degradation. Degradon connects the target protein to a ubiquitin ligase to undergo proteasomal degradation via a linker and a targeting ligand. In certain embodiments, degradon is a compound that can be bound to a ubiquitin ligase. In other embodiments, degradon is a compound that can be bound to an E3 ubiquitin ligase (e.g., cereblon), and degradon can be thalidomide, lenalidomide, pomalidomide, or iberdomide, or the newer IMiD CRBN ligands disclosed in WO2019 / 060693, WO2019 / 140387, WO2019 / 236483, or their analogs. In other embodiments, degradon can be bound to an E3 ubiquitin ligase, such as a Hippel-Lindau ligand. See, for example, WO2020 / 092907; WO2013106643; Buckley et al. Interaction",Soares et al. J.Med.Chem.2019,61,599-618,,"Group-BasedOptimization ofPotent and Cell-Active Inhibitors of the von Hippel–Lindau(VHL)E3 Ubiquitin Ligase:Structure–Activity Relationships Leading to theChemical 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 additional embodiments, the degron can bind to E3 ubiquitin ligases, including inhibitors of apoptosis protein ligases (IAP1, IAP2, XIAP).See, for example, 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. 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 CovalentBinding". In additional embodiments, the degradons may bind to ubiquitin proteasome proteins that can induce degradation, including but not limited to Hsp70 / 90 chaperone complex (WO2020 / 207395), Usp14 (WO2019 / 238886), UchL5 (WO2019238816), BILO (WO201719705) and Rpn11 (WO2019 / 238817).

[0133] In some embodiments, E comprises a benzimidazolinone, a dihydropyrimidine-dione, or thalidomide.

[0134] In some embodiments, the degron (ie, "E" of Formula II) has Formula II-IIIaa or II-IIIab:

[0135]

[0136] Where: R A1 、R A2 and R A3 are each independently H, hydroxy, halogen, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2; R B is H or (C1-C6)alkyl; and R C1 、R C2 、R C3 and R C4Each is independently H, hydroxy, halogen, (C1-C6) alkyl, (C1-C6) heteroalkyl, (C1-C6) alkoxy or NH2. In some embodiments, R C5 is H, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2. In some embodiments, R A1 、R A2 and R A3 Each independently represents H; R B is (C1-C3)alkyl; and R C1 、R C2 、R C3 、R C4 are each independently H; and R C5 is H. In some embodiments, E is In some embodiments, E is

[0137] In some embodiments, the degron (ie, "E" of Formula II) has Formula II-IIIb:

[0138]

[0139] Where: R A1 、R A2 and R A3 are each independently H, hydroxy, halogen, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2; R B is H or (C1-C6)alkyl; and R C1 、R C2 、R C3 、R C4 and R C5 Each is independently H, hydroxy, halogen or (C1-C6) alkyl, (C1-C6) heteroalkyl, (C1-C6) alkoxy or NH2. In some embodiments, E is

[0140] In some embodiments, the degron (ie, "E" of Formula II) has Formula II-IIIc:

[0141]

[0142] Where: R A1 、R A2 、R A3 and R A4 are each independently H, hydroxy, halogen, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2; and R C1 、RC2 、R C3 and R C4 Each is independently H, hydroxy, halogen, (C1-C6) alkyl, (C1-C6) heteroalkyl, (C1-C6) alkoxy or NH2. In some embodiments, R C5 is H, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2. In some embodiments, R A1 、R A2 and R A3 Each independently represents H; R A4 is (C1-C3)alkyl or halogen; and

[0143] R C1 、R C2 、R C3 、R C4 and R C5 Each is independently H. In some embodiments, E is

[0144] In some embodiments, the degron (ie, "E" of Formula II) has Formula II-IIId:

[0145]

[0146] Where: R A1 、R A2 and R A3 are each independently H, hydroxy, halogen, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2; R B is H or (C1-C6)alkyl; and R C1 、R C2 、R C3 and R C4 Each is independently H, hydroxy, halogen, (C1-C6) alkyl, (C1-C6) heteroalkyl, (C1-C6) alkoxy or NH2. In some embodiments, R C5 is H, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2. In some embodiments, R A1 、R A2 and R A3 Each independently represents H; R B is H; and R C1 、R C2 、R C3 、R C4 and R C5 Each is independently H. In some embodiments, E is

[0147] In some embodiments, the degron (ie, "E" of Formula II) has Formula II-IIIe:

[0148]

[0149] Where: R A1 、R A2 and R A3 are each independently H, hydroxy, halogen, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2; R C1 、R C2 、R C3 and R C4 Each is independently H, hydroxy, halogen, (C1-C6) alkyl, (C1-C6) heteroalkyl, (C1-C6) alkoxy or NH2. In some embodiments, R C5 is H, (C1-C6)alkyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy or NH2. In some embodiments, E is

[0150]

[0151] In some embodiments, the compound has Formula IIA:

[0152]

[0153] or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the compound has Formula IIB:

[0155]

[0156] or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the compound is selected from the group consisting of:

[0158] N-{[(1r,4r)-4-{6-[2-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)-2,3-dihydro-1H-isoindol-5-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0159] N-{[4-(7-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-5-yl}imidazo[1,2-a]pyridin-2-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0160] N-{[(1r,4r)-4-(6-{2-[8-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl}-2H-indazol-2-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0161] N-{[(1r,4r)-4-{6-[6-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0162] N-{[4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0163] N-{[(1r,4r)-4-(6-{5-[4-(2-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}ethyl)piperazin-1-yl]pyrazin-2-yl}-2H-indazol-2-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0164] N-{[(1r,4r)-4-(6-{6-[4-(2-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}ethyl)piperazin-1-yl]pyrazin-2-yl}-2H-indazol-2-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0165] N-{[(1r,4r)-4-{6-[4-(2-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}ethyl)piperazin-1-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0166] N-{[(1r,4r)-4-{6-[5-(4-{3-[3-(2,4-dioxo-1,3-diazacycloinan-1-yl)pyrazolo[1,5-a]pyridin-6-yl]propyl}piperazin-1-yl)pyrazin-2-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide hydrochloride;

[0167] N-{[4-(4-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,3-thiazol-2-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0168] N-{[4-(3-{6-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyridazin-3-yl}-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0169] N-{[4-(2-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,3-thiazol-4-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0170] N-{[(1r,4r)-4-{5-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]-2H-pyrazolo[4,3-b]pyridin-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0171] N-{[(1r,4r)-4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0172] N-{[4-(2-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,3-oxazol-5-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0173] N-{[(1r,4r)-4-{6-[2-(4-{3-[3-(2,4-dioxo-1,3-diazacycloinan-1-yl)imidazo[1,2-a]pyridin-7-yl]propyl}piperazin-1-yl)pyrimidin-5-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0174] N-{[(1r,4r)-4-{6-[2-(4-{8-[3-(2,4-dioxo-1,3-diazacyclohexan-1-yl)-4-methylbenzoyl]-1-oxa-8-azaspiro[4.5]decan-3-yl}piperazin-1-yl)pyrimidin-5-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide;

[0175] N-{[(1r,4r)-4-{6-[4-({4-[({2-[(3RS)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)methyl]phenyl}methyl)piperazin-1-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide; and

[0176] N-{[(1r,4r)-4-{6-[2-(2-{4-[3-(2,4-dioxo-1,3-diazacycloinan-1-yl)-4-methylbenzoyl]piperazin-1-yl}ethoxy)pyrimidin-5-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide,

[0177] or a pharmaceutically acceptable salt thereof.

[0178] In one embodiment, the compound has the following structure:

[0179]

[0180] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a pharmaceutically acceptable salt of N-{[4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide. In one embodiment, the compound is N-{[4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide hydrochloride. In some embodiments, the compound is N-{[4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide. Another embodiment includes a compound selected from any one of the Examples described herein, or a pharmaceutically acceptable salt thereof.

[0181] Another embodiment includes a prodrug of any of the Examples described herein, or a pharmaceutically acceptable salt thereof.

[0182] Another embodiment includes a phosphate prodrug of any one of the Examples described herein, or a pharmaceutically acceptable salt thereof.

[0183] Another embodiment includes any novel genera of the intermediates described in the general schemes or examples.

[0184] Another embodiment includes any novel specific compound described in the formulations and / or compounds or intermediates as described in the Examples described herein.

[0185] Another embodiment includes any of the novel processes described herein.

[0186] All pharmaceutically acceptable isotopically labeled compounds of Formula I or Formula II, wherein 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 the present application.

[0187] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen (e.g. 2 H and 3 H), carbon isotopes (such as 11 C. 13 C and 14 C), isotopes of chlorine (such as 36 Cl), fluorine isotopes (such as 18 F), nitrogen isotopes (such as 13 N and 15 N), oxygen isotopes (such as 15 O. 17 O and 18 O) and sulfur isotopes (such as 35 S).

[0188] Certain isotopically-labeled compounds of Formula I or Formula II, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) is particularly well-suited for this purpose due to its ease of incorporation and readily available detection means.

[0189] Use deuterium (i.e. 2 Substitution with heavier isotopes of H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0190] Positron-emitting isotopes (such as 11 C. 18 F. 15 O and 13 N) substitutions may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0191] Isotopically labeled compounds of Formula I or Formula II can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0192] Certain compounds of Formula I or Formula II and intermediates described herein may exist in more than one crystalline form (often referred to as a "polymorph"). Polymorphs can be prepared by crystallization under various conditions, such as recrystallization using different solvents or different solvent mixtures; crystallization at different temperatures; and / or various cooling patterns during crystallization, ranging from very fast to very slow cooling. Polymorphs can also be obtained by heating or melting the compound followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or such other techniques.

[0193] Salts encompassed within the term "pharmaceutically acceptable salts" refer to compounds of the invention which are generally 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 provide salts of the compounds of the invention suitable for administration to patients. Basic salts are preferred, however, some compounds may also form acid salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene dicarboxylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and hydroxynaphthoate.

[0194] Suitable alkali salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, calcium salts, choline salts, diethylamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, trimethylamine salts, and zinc salts. Hemi-salts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed. For a review of suitable salts, see Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0195] Hemi-salts of acids and bases can also be formed, such as hemisulphate and hemicalcium salts. For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0196] Pharmaceutically acceptable salts of compounds of Formula I or Formula II can be prepared by one or more of three methods:

[0197] (i) reacting a compound of formula I or formula II with a desired acid or base;

[0198] (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or ring-opening a suitable cyclic precursor (e.g., a lactone or lactam), using a desired acid or base; or

[0199] (iii) A salt of the compound of the present invention is reacted with a suitable acid or base or converted into another salt with the aid of a suitable ion exchange column.

[0200] All three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration, or can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

[0201] The compounds of Formula I or Formula II and their pharmaceutically acceptable salts can exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

[0202] The currently recognized classification system for organic hydrates is a system defining isolated site hydrates, channel hydrates, or metal-ion coordinated hydrates - see KR Morris's Polymorphism in Pharmaceutical Solids (HG Brittain, ed., Marcel Dekker, 1995). Isolated site hydrates are hydrates in which water molecules are separated from each other by intervening organic molecules and are not in direct contact. In channel hydrates, water molecules are in lattice channels next to other water molecules. In metal-ion coordinated hydrates, water molecules are bound to metal ions.

[0203] When the solvent or water is tightly bound, the complex can have a well-defined stoichiometry that is 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 these cases, non-stoichiometry will be the norm.

[0204] Also included within the scope of the present invention are multi-component complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and cocrystals. The latter are generally defined as crystalline complexes of neutral molecular components bound together by non-covalent interactions, but can also be complexes of neutral molecules with salts. Cocrystals can be prepared by melt crystallization, recrystallization from a solvent, or by physically grinding the components together - see O. Almarsson and MJ Zaworotko, Chem Commun, 17, 1889-1896, (2004). For a general review of multi-component complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975).

[0205] Also included within the scope of the present invention are active metabolites of compounds of Formula I or Formula II (including prodrugs), i.e., compounds formed in vivo following administration of the drug, often by oxidation or dealkylation. Some examples of metabolites according to the present invention include:

[0206] (i) wherein the compound of formula I or formula II contains a methyl group, a hydroxymethyl derivative thereof (-CH3->-CH2OH) and

[0207] (ii) wherein the compound of formula I or formula II contains an alkoxy group, or a hydroxyl derivative thereof (-OR->-OH).

[0208] The compounds of the present invention can exist in a continuum of solid forms ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and exhibits the physical properties of a solid or liquid depending on the temperature. Such materials do not produce a unique X-ray diffraction pattern and, while exhibiting the characteristics of a solid, are more formally described as liquids. Upon heating, a change from solid-like to liquid-like properties occurs, characterized by a change of state, typically second order ("glass transition"). The term "crystalline" refers to a solid phase in which a material has a regularly ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with well-defined peaks. These materials will also exhibit the characteristics of a liquid when fully heated, but the change from solid to liquid is characterized by a phase change, typically first order ("melting point").

[0209] Compounds of Formula I or Formula II may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is an intermediate state between a true crystalline state and a true liquid state (melt or solution). Mesomorphism that occurs due to temperature changes is described as "thermotropic", while mesomorphism that occurs due to the addition of a second component (such as water or another solvent) is described as "lyotropic". Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic" and are composed of molecules with ionic polar head groups (such as -COO - Na + 、-COO - K + or -SO 3- Na + ) or nonionic polar head groups (such as -NN + (CH3)3) For more information, see Crystals and the Polarizing Microscope, 4th edition, by NH Hartshorne and A. Stuart (Edward Arnold, 1970).

[0210] Compounds of Formula I or Formula II may exhibit polymorphism and / or one or more isomers (e.g., optical isomers, geometric isomers, or tautomers). Compounds of Formula I or Formula II may also be isotopically labeled. Such variations are implicit in the compounds of Formula I or Formula II defined with reference to their structural features and are therefore within the scope of the present invention.

[0211] The terms "concentrate", "evaporate" and "concentrate in vacuo" refer to the removal of solvent under reduced pressure on a rotary evaporator with a bath temperature below 60° C. The abbreviations "min" and "h" stand for "minutes" and "hours", respectively. The term "room temperature or ambient temperature" means a temperature between 18 and 25°C, "GCMS" means gas chromatography-mass spectrometry, "LCMS" means liquid chromatography-mass spectrometry, "UPLC" means ultra-performance liquid chromatography, "SFC" means supercritical fluid chromatography; "HPLC" means high performance liquid chromatography, "MPLC" means medium pressure liquid chromatography, "TLC" means thin layer chromatography, "MS" means mass spectrum or mass spectroscopy or mass spectrometry, "NMR" means nuclear magnetic resonance spectroscopy, "DCM" means dichloromethane, "DMSO" means dimethyl sulfoxide, "DME" means 1,2-dimethoxyethane, "EtOAc" means ethyl acetate, "MeOH" means methanol, "Ph" means phenyl, "Pr" means propyl, "trityl" means triphenylmethyl, "ACN" means acetonitrile, "DEAD" means diethyl azodicarboxylate, and "DIAD" means diisopropyl azodicarboxylate.

[0212] In general, the compounds of the present invention can be manufactured by processes including those similar to those known in the chemical art, particularly according to the description contained herein. Certain processes for manufacturing 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 can be described in the experimental section. Specific synthetic schemes for preparing compounds of Formula I or Formula II are summarized below.

[0213] As used herein, the expressions "reaction inert solvent" and "inert solvent" refer to a solvent or mixtures thereof that do not interact with the starting materials, reagents, intermediates, or products in a manner that adversely affects the yield of the desired product.

[0214] As an initial note, when preparing compounds of Formula I or Formula II, it should be noted that some preparation methods suitable for preparing compounds described herein may require protection of distal functional groups (e.g., primary amines, secondary amines, carboxyl groups in Formula I or Formula II precursors). The need for such protection will vary depending on the properties of the distal functional groups and the conditions of the preparation method. The need for such protection is easily determined by those skilled in the art. The use of such protection / deprotection methods is also within the technical scope of this area. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0215] For example, some compounds contain primary amine or carboxylic acid functional groups, which, if unprotected, may interfere with reactions at other sites of the molecule. Therefore, such functional groups may be protected by suitable protecting groups that can be removed in subsequent steps. Protective groups suitable for amine and carboxylic acid protection include those commonly used in peptide synthesis (such as N-tert-butyloxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl of amine, and low carbon number alkyl or benzyl esters of carboxylic acid), which are generally not chemically reactive under the described reaction conditions and can be removed without chemically changing other functional groups in the compound of Formula I or Formula II.

[0216] Compounds and intermediates of Formula I or Formula II may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. Unless otherwise specified, it is intended herein to include all stereoisomeric forms of the compound and mixtures thereof, including racemic mixtures. In addition, all geometric and positional isomers are included within the scope of the compound. For example, if the compound incorporates a double bond or a fused ring, the cis- and trans-forms and mixtures are encompassed within the scope of the present invention.

[0217] In addition, compounds and intermediates of Formula I or Formula II encompass all atropisomers and stereoisomeric mixtures thereof, including racemic mixtures. Atropisomers include those that can be separated into individual stereoisomers and maintain their stereoisomeric purity for various lengths of time (including medium and long periods of time). Atropisomers also include those that cannot be easily separated into individual stereoisomers due to interconversion over a period of time (including short to medium periods of time).

[0218] The chiral compounds of the present invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form by chromatography (typically high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC)) on a resin having an asymmetric stationary phase and a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0 to 50% isopropanol (typically 2% to 20%) and 0 to 5% alkylamine (typically 0.1% diethylamine (DEA)) or isopropylamine. Concentration of the eluate yields an enriched mixture.

[0219] Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art (such as by chromatography and / or fractional crystallization). Enantiomers can be separated as follows: by reacting with an appropriate optically active compound (such as a chiral auxiliary, such as a chiral alcohol or Moshers acid chloride), the enantiomeric mixture is converted into a diastereomeric mixture, the diastereomers are separated and the individual diastereomers are converted (such as hydrolyzed) into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column. Alternatively, specific stereoisomers can be synthesized by using optically active starting materials, by using an asymmetric synthesis of optically active reagents, substrates, catalysts or solvents, or by asymmetric transformation and converting one stereoisomer into another stereoisomer.

[0220] When a compound has two or more stereocenters and the absolute or relative stereochemistry is given in the name, the designations R and S refer, respectively, to each stereocenter in ascending numerical order (1, 2, 3, etc.) according to the conventional IUPAC numbering scheme for each molecule. When a compound has one or more stereocenters and the stereochemistry is not given in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including racemic forms.

[0221] The compounds of the present invention may contain olefinic double bonds. When these bonds are present, the compounds of the present invention exist in cis and trans configurations and mixtures thereof. The term "cis" refers to the orientation of two substituents relative to each other and the plane of the ring (both "up" or both "down"). Similarly, the term "trans" refers to the orientation of two substituents relative to each other and the plane of the ring (substituents are located on opposite sides of the ring).

[0222] Intermediates and compounds of formula I or formula II can also exist in different tautomeric forms, and all of these forms are encompassed within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include mutual conversion via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is a tetrazole moiety, in which a proton can migrate between the following four ring nitrogens.

[0223]

[0224] Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0225] Included within the scope of the claimed compounds of the present invention are all stereoisomers, geometric isomers, and tautomeric forms of the compounds of Formula I or Formula II, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition salts or base salts where the counterion is optically active, such as D-lactate or L-lysine; or racemic, such as DL-tartrate or DL-arginine.

[0226] Compounds of Formula I or Formula II can be prepared according to the general schemes and examples provided herein.

[0227] General solution

[0228] In general, the compounds of this invention can be prepared by methods described herein and similar methods known to those skilled in the art. Some methods for making the compounds of this invention are described in the following reaction schemes. Other methods are described in the experimental section. The schemes and embodiments (including corresponding descriptions) provided herein are for illustration only. The substituents marked in schemes 1 to 7 are as described in the application, wherein PMB is p-methoxyanisole and Boc is tert-butyloxycarbonyl.

[0229] 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 by an amide bond forming reaction between carboxylic acid intermediate II and amine intermediate III. Similarly, intermediates VI and VIII can be prepared by an amide bond forming reaction between intermediate II and intermediates V and VII, respectively. This type of amide bond forming reaction can be achieved by combining a carboxylic acid (such as II) and 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).

[0230]

[0231] Scheme 2 involves the preparation of compounds of Formulas IA-1, IA-2, IA-3, and IA-4 from intermediate IV. The ester in intermediate IV can be hydrolyzed to produce intermediate IX. The carboxylic acid functional group 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 obtain 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 obtain 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 an alternative functional group that can have other functionalities useful 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 produce intermediate XII. Intermediate XII can be reacted with an aminopyridine (XIII) and subsequently deprotected to produce a compound of Formula IA-3. Alternatively, the carboxylic acid in IX can be converted to a primary amide and then dehydrated to obtain a nitrogen-containing intermediate of structure XIV. Intermediate XIV can be reacted with hydroxylamine to give 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.

[0232]

[0233] Scheme 3 involves the preparation of compounds of formula IA-5 and formula IA-6 from intermediate VI. The Boc protecting group in intermediate VI can be selectively removed to provide intermediate XVII. Intermediate XVII can be reacted with a nitroaldehyde-containing compound (XVIII) in the presence of a trialkylphosphine to provide 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) and subsequently deprotected to provide a compound of formula IA-6.

[0234]

[0235] Scheme 4 relates to the preparation of compounds of Formula IA and Formula 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 obtain 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 obtain compounds of Formula IA-7.

[0236]

[0237] Scheme 5 relates to alternative preparations of compounds of formula IA-5. In some cases, compounds can be prepared by methods described herein containing substituents that can be used synthetically to prepare alternative compounds of formula IA. For example, intermediates of structure XXII can be prepared by methods described for preparing compounds of formula IA-5. The bromine substituent in intermediate XXII can react with boronic acid (XXIII) or boronic ester (XXIII) by Suzuki reaction to obtain compounds of formula IA-5. In addition, compounds of structure XXII can react with intermediates of structure XXIV, where BH represents a primary or secondary amine. In this case, XXII and XXIV can react with each other under Buchwald reaction conditions to obtain compounds or another variation of formula IA-5. Alternatively, the bromine substituent in XXII can be converted to boronic acid (XXV; R=H) or boronic ester (XXV; R=alkyl). Compounds of structure XXV can react with aryl and heteroaryl halides of structure XXVI to obtain compounds of formula IA-5. In addition, compounds of structure XXV can be reacted with aromatic heterocycles bearing NH(XXIV) under Cham-Lam coupling conditions to provide compounds of formula IA-5. The example transformations provided in Scheme 5 are not intended to be comprehensive. The examples provided are merely isolated examples of synthetic sequences that can be used to modify the B-substituents and C-substituents of compounds of formula IA. One skilled in the art will also recognize that similar transformations can be achieved using compounds containing alternative A-substituents as depicted in Scheme 5.

[0238]

[0239] 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 by an amide bond forming reaction between carboxylic acid intermediate II and amine intermediate XXVII. Similarly, intermediate XXX can be prepared by an amide bond forming reaction between intermediate II and intermediate XXVIII. This type of amide bond forming 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). The preparation of compounds of Formula IB can be achieved from intermediate XXIX by methods similar to those described for the preparation of 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 IV in Schemes 3 and 5.

[0240]

[0241] Scheme 7 relates to an alternative ordering of the synthetic steps that can be used to prepare compounds of Formula IA or Formula IB. For example, intermediates such as XXXI, XXXII, or XXXIII can be converted to intermediates of structure XXXIV via the methods described herein. The amine intermediate of structure XXXIV can be reacted with a carboxylic acid of structure II in an amide bond-forming reaction. The resulting product can be deprotected to yield a compound of Formula IA. Similarly, intermediates such as XXXV and XXXVI can be converted to an intermediate of structure XXXVII. The amine intermediate of structure XXXVII can be reacted with a carboxylic acid of structure II and subsequently deprotected to yield a compound of Formula IB.

[0242]

[0243] The starting materials and reagents for the above-mentioned compounds of Formula I or Formula II are also readily available or can be readily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein relate to or are derived from compounds in which there is a great scientific interest and commercial demand, and therefore many such compounds are commercially available or reported in the literature or are readily prepared from other commonly available substances by methods reported in the literature.

[0244] The present application also relates to pharmaceutical compositions having a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier, vehicle or diluent.

[0245] In one embodiment of the present invention, a method for treating fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, or nonalcoholic 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 Formula II, or a pharmaceutically acceptable salt of said compound.

[0246] In one embodiment of the invention, the method comprises treating nonalcoholic steatohepatitis.

[0247] In one embodiment of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

[0248] 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 Formula II or a pharmaceutically acceptable salt of said compound; a second compound, which is an antidiabetic agent; a non-alcoholic fatty liver hepatitis therapeutic agent, a non-alcoholic fatty liver disease therapeutic agent or an anti-heart failure therapeutic agent; and a pharmaceutical carrier, vehicle or diluent.

[0249] In one embodiment of the present invention, the therapeutic agent for nonalcoholic steatohepatitis or nonalcoholic fatty liver disease in the pharmaceutical combination composition is an ACC inhibitor, a KHK inhibitor, a DGAT-2 inhibitor, a FXR agonist, metformin, an incretin analog, or an incretin receptor modulator.

[0250] In one embodiment of the present disclosure, the antidiabetic agent is a SGLT-2 inhibitor, metformin, an incretin mimetic, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist.

[0251] The compounds of the present invention may also be used in combination with other pharmaceutical agents (e.g., anti-atherosclerotic agents and anti-thrombotic agents) for treating the diseases / conditions described herein. The present application also relates to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition having:

[0252] A first compound, which is any compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof;

[0253] a second compound which is a therapeutic agent for kidney disease, an antidiabetic agent, a therapeutic agent for nonalcoholic steatohepatitis, a therapeutic agent for nonalcoholic fatty liver disease, or an anti-heart failure therapeutic agent, and

[0254] Pharmaceutical carrier, vehicle or diluent.

[0255] In one embodiment, the agent treating kidney disease is suitable for treating acute and / or chronic kidney disease.

[0256] In one embodiment, the non-alcoholic steatohepatitis therapeutic agent or non-alcoholic fatty liver disease therapeutic agent is an ACC inhibitor, a KHK inhibitor, a DGAT-2 inhibitor, a FXR agonist, a GLP-1R agonist, metformin, an incretin analog, or an incretin receptor modulator.

[0257] In another embodiment, the antidiabetic agent is an SGLT-2 inhibitor, metformin, an incretin mimetic, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist.

[0258] In another embodiment, the antidiabetic agent is metformin, sitagliptin, or ertuglifozin.

[0259] 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.

[0260] Combination Potion

[0261] The compounds can be administered alone or in combination with one or more additional therapeutic agents. "Administered in combination" or "combination therapy" refers to the simultaneous administration of a compound and one or more additional therapeutic agents to a mammal being treated. When administered in combination, the components can be administered simultaneously or sequentially in any order at different time points. Thus, the components can be administered separately but sufficiently close in time to provide the desired therapeutic effect. The phrases "administered in parallel," "administered together," "simultaneous administration," and "administered simultaneously" refer to the compounds being administered in combination. Thus, the methods of prevention and treatment described herein include the use of combination agents.

[0262] The combination is administered to a mammal in a therapeutically effective amount. "Therapeutically effective amount" means an amount of a compound of Formula I or Formula II that is effective in treating the intended disease / condition (e.g., NASH, heart failure, kidney disease, or diabetes) when administered to a mammal alone or in combination with another therapeutic agent.

[0263] In view of the NASH / NAFLD activity of the compounds of the present invention, they can be co-administered with other agents used to treat 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, ω-3-acid ethyl esters (e.g., Lovaza), fibrates, HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, dapoxetine ... in), 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 D Vitamin E, betaine, pentoxifylline, CB1 antagonists, L-carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, a combination of naltrexone and buproprion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, etogliflozin, ASP-1941, THR1474, TS-071, ISIS388626 and LX4211 and those in WO2010023594), phentermine , Topiramate, GLP-1 receptor agonist, GIP receptor agonist, dual GLP-1 receptor / glucagon receptor agonist (i.e., OPK88003, MEDI0382, JNJ-64565111, NN9277, BI456906), dual GLP-1 receptor / GIP receptor agonist (i.e., tezetribute (LY3298176), NN9423), angiotensin receptor blocker, acetyl-CoA carboxylase (ACC) inhibitor, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor (such as those described in WO09016462 or WO2010086820), AZD7687 or LCQ908,Diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitors, PNPLA3 inhibitors, FGF21 analogs, FGF19 analogs, PPAR agonists, FXR agonists, AMPK activators, SCD1 inhibitors, or MPO inhibitors.

[0264] Exemplary GLP-1 receptor agonists include liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, HM15211, LY3298176, Medi-0382, NN-9924, TTP-054, TTP-273, efpeglenatide, those described in WO2018109607, and those described in PCT / IB2019 / 054867, filed June 11, 2019, including the following:

[0265] 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0266] 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0267] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0268] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0269] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0270] 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0271] 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0272] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid;

[0273] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazo-1-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

[0274] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0275] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0276] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0277] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

[0278] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0279] 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0280] 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid;

[0281] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0282] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0283] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0284] 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0285] 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0286] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazo-1-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

[0287] 2-({4-[(2R)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0288] 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0289] 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazo-1-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid;

[0290] 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0291] 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0292] 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-1-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid;

[0293] 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

[0294] 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.

[0295] Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-1H-spiro[indazole-5,4-piperidin]-1-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid; and firsocostat (GS-0976) and pharmaceutically acceptable salts thereof.

[0296] 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.

[0297] Exemplary DGAT2 inhibitors include (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide;

[0298] 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide;

[0299] 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide;

[0300] 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide;

[0301] 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide;

[0302] 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; and

[0303] 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.

[0304] Exemplary KHK inhibitors include [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hexan-6-yl]acetic acid and pharmaceutically acceptable salts thereof.

[0305] In view of the anti-diabetic activity of the compounds of the present invention, they can be co-administered with other anti-diabetic agents. Suitable anti-diabetic agents include insulin; metformin; GLP-1 receptor agonists (described above); acetyl-CoA carboxylase (ACC) inhibitors (described above); SGLT2 inhibitors (described above); monoacylglycerol O-acyltransferase inhibitors; phosphodiesterase (PDE)-10 inhibitors; AMPK activators; sulfonylureas (e.g., acesulfame-3; chlorpropamide; diabinese; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide and tolbutamide); meglitinides; α-amylase inhibitors (e.g., tendamistat; trestatin; and AL-3688); α-glucosidase hydrolase inhibitors (e.g., acarbose); rbose); α-glucosidase inhibitors (e.g., adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; and salbostatin); PPARγ agonists (e.g., balaglitazone; ciglitazone; darglitazone; englitazone); litazone; 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; hyrtiosal extract; and Zhang; S.et al., 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; A 2 antagonists; c-jun N-terminal kinase (JNK) inhibitors; glucokinase 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 those described in Reports in Medicinal Chemistry 2008, 43, 119-137; GPR119 modulators, in particular agonists, such as those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, RM et al., in Medicinal Chemistry 2009, 44, 149-170 (e.g., MBX-2982; GSK1292263; APD597; and PSN821); FGF21 derivatives or analogs, such as those described in Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364; TGR5 (also known as GPBAR1) receptor modulators, in particular agonists, such as those described in Zhong, M., Current Topics in Medicinal those described in Chemistry, 2010, 10(4), 386-396, and INT777; GPR40 agonists such as 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. Another representative list 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.

[0306] Other antidiabetic agents may include inhibitors or modulators of carnitine palmitoyltransferase; inhibitors of fructose 1,6-bisphosphatase; inhibitors of aldose reductase; mineralocorticoid receptor inhibitors; inhibitors of TORC2; inhibitors of CCR2 and / or CCR5; inhibitors of PKC isoforms (e.g., PKCα, PKCβ, PKCγ); inhibitors of fatty acid synthase; inhibitors of serine palmitoyltransferase; modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, 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 IL1β); and modulators of RXRα. In addition, suitable antidiabetic agents include those listed in Carpino, PA, Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

[0307] In view of the anti-heart failure activity of the compounds of the present application, they can be co-administered with other anti-heart failure agents such as the following: 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), If channel blocker ivabradine, β-adrenergic blockers (e.g., bisoprolol, metoprolol succinate), 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., istaroxime), hydralazine, and isosorbide dinitrate. dinitrate), diuretics (e.g., furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, indapamide, metolazone, triamterene), or digoxin.

[0308] The compounds of Formula I or Formula II can also be used in combination with antihypertensive agents, and the activity of such antihypertensive agents can be readily determined by one skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of suitable antihypertensive agents include: α-adrenergic blockers; β-adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine); vasodilators (e.g., hydralazine); diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, benzflumethiazide, methylchlorothiazide, trichlorothiazide, polythiazide, benzthiazide, ethacrynic acid tricurenafine); acidtricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, il), pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrasentan, and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); dual ET / AII antagonists (e.g., compounds disclosed in WO 00 / 01389); neutral endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary anti-anginal agent is ivabradine.

[0309] Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine, amlodipine and mibefradil.

[0310] Examples of suitable cardiac glycosides include digitalis and ouabain.

[0311] In one embodiment, the compound of Formula I or Formula II may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics, such as furosemide (eg, LASIX TM), torasemide (such as DEMADEX Tm ), Bumetanide (such as BUMEX Tm ) and ethacrynic acid (such as EDECRIN TM ); (b) thiazide diuretics, such as chlorothiazide (such as DIURIL TM , ESIDRIX TM or HYDRODIURIL TM ), hydrochlorothiazide (such as MICROZIDE TM ORETIC TM ), benzylthiazide, hydroflumethiazide (such as SALURON TM ), benzflumethiazide, methylchlorothiazide, polythiazide, trichloromethiazide, and indapamide (such as LOZOL TM ); (cv phthalimide diuretics, such as chlorthalidone (such as HYGROTON TM ) and metolazone (such as ZAROXOLYN TM ); (d) quinazoline-type diuretics, such as quinethazolone; and (e) potassium-sparing diuretics, such as triamterene (such as DYRENIUM TM ) and amiloride (such as MIDAMOR TM or MODURETIC TM ).

[0312] In another embodiment, the compound of Formula I or Formula II may be co-administered with a loop diuretic. In another embodiment, the loop diuretic is selected from furosemide and torsemide. In yet another embodiment, one or more compounds of Formula I or Formula II may be co-administered with furosemide. In yet another embodiment, one or more compounds of Formula I or Formula II may be co-administered with torsemide, which may optionally be a controlled or modified release form of torsemide.

[0313] In another embodiment, the compound of Formula I or Formula II can be co-administered with a thiazide-type loop diuretic. In yet another embodiment, the thiazide-type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In yet another embodiment, one or more compounds of Formula I or Formula II can be co-administered with chlorothiazide. In another embodiment, one or more compounds of Formula I or Formula II can be co-administered with hydrochlorothiazide.

[0314] In another embodiment, one or more compounds of Formula I or Formula II may be co-administered with a phthalimide-type diuretic. In another embodiment, the phthalimide-type diuretic is chlorthalidone.

[0315] Examples of suitable mineralocorticoid receptor antagonists include spironolactone and eplerenone.

[0316] Examples of suitable phosphodiesterase inhibitors include: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

[0317] Those skilled in the art will recognize that the compounds of the present invention may also be used in combination with other cardiovascular or cerebrovascular treatments (including PCI, stenting, drug-eluting stents, stem cell therapy) and medical devices (such as implantable pacemakers, defibrillators) or cardiac resynchronization therapy.

[0318] Compounds of Formula I or Formula II can also be used in combination with drugs used to manage chronic kidney disease, including phosphate binders (e.g., sucroferric oxyhydroxide, sevelamer, calcium acetate), sodium bicarbonate, erythropoiesis stimulating agents, oral or intravenous iron (e.g., iron sucrose, ferric carboxymaltose, ferumoxytol), potassium binders, calcitriol, or SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin, or other SGLT2 inhibitors described herein).

[0319] Especially when provided in a single dosage unit form, there may be chemical interactions between the active ingredients of the combination. Therefore, when the compound of Formula I or Formula II and the second therapeutic agent are combined in a single dosage unit, it can be formulated so that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (i.e., reduced). For example, an active ingredient can be enteric coated. By enteric coating one of the active ingredients, not only can the contact between the active ingredients of the combination be minimized, but also the release of one of these components in the gastrointestinal tract can be controlled so that one of these components is not released in the stomach, but released in the intestine. One of the active ingredients can also be coated with a material that realizes sustained release in the entire gastrointestinal tract and is also used to minimize the physical contact between the active ingredients of the combination. In addition, the component of the sustained release can be additionally coated with an enteric coating so that the release of this component occurs only in the intestine. Another method will relate to the preparation of a combination product, wherein one component is coated with a continuous and / or enteric release polymer, and another component is also coated with a polymer such as hydroxypropyl methylcellulose (HPMC) of a low viscosity grade or other suitable materials known in the art to further separate the active ingredients. Polymer coatings serve to form additional barriers to interaction with another component.

[0320] Sustained-release formulations or formulations can be used. Suitable examples of sustained-release formulations or formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds of the invention in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as those used in LUPRON DEPOT TM (those in injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0321] These and other ways to minimize contact between the components of the combination product, whether administered in a single dosage form or in separate forms but administered simultaneously by the same means, will be readily apparent to those skilled in the art, consistent with the present disclosure.

[0322] In combination therapy treatment, a compound of the invention and the other pharmaceutical therapy are administered to a mammal (eg, a human, male or female) by conventional methods.

[0323] The compounds of formula I or formula II of the present invention, their prodrugs, and salts of such compounds and prodrugs are useful as agents for inhibiting and / or degrading HSD17B13 in mammals (particularly humans), and are therefore useful for treating various conditions involving such effects (e.g., those described herein).

[0324] Diseases / conditions that may be treated with compounds of Formula I or Formula II include, but are not limited to, NASH / NAFLD, diabetes, kidney disease, and heart failure, and related diseases / conditions.

[0325] Therefore, considering the positive correlation between the activation of HSD17B13 and the progression of NASH / NAFLD and related diseases / conditions, the compounds of formula I or formula II of the present invention, their prodrugs and salts of such compounds and prodrugs are suitable 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 by virtue of their pharmacological effects.

[0326] The compounds of the present invention may be administered by any method of systemic and / or local delivery of the compounds of the present invention. These methods include oral routes, parenteral, intraduodenal routes, buccal, intranasal, etc. Generally, the compounds of the present invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous, or intramedullary) may be used, for example, when oral administration is not suitable for the purpose or the patient is unable to ingest the drug.

[0327] For administration to human patients, the oral daily dose of the compound herein can be in the range of 1 mg to 5000 mg, of course, this depends on the mode of administration and frequency, disease state and patient's age and condition, etc. An oral daily dose in the range of 3 mg to 3000 mg can be used. Another oral daily dose is in the range of 5 mg to 1000 mg. For convenience, the compound of Formula I or Formula II can be administered in unit dosage form. If necessary, the unit dosage form of multiple doses per day can be used to increase the total daily dose. The unit dosage form can, for example, be 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 compound. The total daily dose may be administered in single or divided doses and, at the physician's discretion, may exceed the typical range given herein.

[0328] For administration to human patients, the daily infusion dose of the compounds herein may be in the range of 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. Another daily infusion dose is in the range of 5 mg to 1000 mg. The total daily dose may be administered in a single or divided dose and may exceed the typical ranges given herein at the discretion of the physician.

[0329] The compounds may also be administered to animals other than humans, 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 disease state being treated, the age of the animal, and the route of administration.

[0330] The dosage of the combination pharmaceutical agent used in combination with the compound of Formula I or Formula II is effective for the indication being treated. Such dosage can be determined by standard assays, such as those mentioned above and provided herein. The combination pharmaceutical agents can be administered simultaneously or sequentially in any order.

[0331] These dosages are based on an average human subject weighing about 60 kg to 70 kg. A physician will readily be able to determine dosages for subjects weighing outside this range, such as infants and the elderly.

[0332] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, 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 unit dosage form for ease of administration and uniform dosing. As used herein, a unit dosage form refers to a physically discrete unit suitable for use as a unit dose in a mammalian subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in combination with the desired pharmaceutical carrier. The specifications of the unit dosage forms of the present invention are dictated by and directly depend on: (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or prophylactic effect to be achieved, and (b) the inherent limitations in the art of formulating such active compounds for treating the sensitivity of an individual.

[0333] Therefore, it will be understood by those skilled in the art that, based on the disclosure provided herein, dosages and administration regimens can be adjusted according to methods well known in the therapeutic art. That is, the maximum tolerable dose can be easily determined, and the effective amount that provides a detectable therapeutic benefit to the patient can also be determined, and the temporary need for administering each agent can also be determined to provide a detectable therapeutic benefit to the patient. Therefore, although certain dosages and administration regimens are exemplified herein, these examples in no way limit the dosages and administration regimens that can be provided to a patient.

[0334] 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, a specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the personnel administering the composition or supervising the administration of the composition, and the dosage ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. For example, dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, such as toxic effects and / or experimental values. Therefore, intra-patient dose escalation may be used as determined by those skilled in the art. Determining the appropriate dosage and regimen for administering a chemotherapeutic agent is well known in the relevant art, and once provided with the teachings disclosed herein, those skilled in the art will understand its scope.

[0335] The present application further includes the use of a compound of Formula I or Formula II 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 or Formula II for the manufacture of a medicament (such as a unit dose tablet or unit dose capsule) for treating one or more conditions previously identified in the above discussion of treatment methods.

[0336] The pharmaceutical compositions 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, a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to an individual or a suitable fraction of such a dose, such as one-half or one-third of a dose.

[0337] 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 respect to the intended route of administration and standard pharmaceutical practice. Depending on the specificity of the desired route of administration and release profile (commensurate with therapeutic needs), the compounds or combinations of the present invention can be formulated to provide immediate release, delayed release, modified release, sustained release, pulsed release, or controlled release dosage forms.

[0338] Pharmaceutical compositions contain a compound or combination of the invention in an amount generally in the range of about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, typically in the range of about 1%, 2% or 3% to about 50%, 60% or 70%, more usually in the range of about 1%, 2% or 3% to less than 50%, such as about 25%, 30% or 35%.

[0339] Methods for preparing various pharmaceutical compositions having specific amounts of active compounds are known to those skilled in the art. For example, see Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore Md. 20.sup.th ed. 2000.

[0340] 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 and the like), suitable mixtures thereof, triglycerides (including vegetable oils such as olive oil) and injectable organic esters (such as ethyl oleate). Preferred carriers are those with glycerol or propylene glycol. Brand caprylate / caprate (e.g., 812, 829, 840), which is commercially 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 dispersion and by the use of surfactants.

[0341] These compositions for parenteral injection may also contain excipients such as preservatives, wetting agents, emulsifiers, and dispersants. Preventing microbial contamination of the compositions may be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be necessary to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions may be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin.

[0342] Solid dosage forms for oral administration include capsules, tablets, chewable tablets, lozenges, pills, powders, and multiparticulate formulations or formulations (granules). In such solid dosage forms, the compound of Formula I or Formula II, or a combination thereof, is blended with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include materials such as sodium citrate or dicalcium phosphate and / or (a) one or more fillers or extenders (e.g., microcrystalline cellulose (available from FMC Corp. as (a) one or more binders (e.g., carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, acacia, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinyl pyrrolidone, sucrose, acacia, and the like); (b) one or more humectants (e.g., glycerin, and the like); (c) one or more disintegrants (e.g., agar-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. Obtained), cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose type A (can (obtained), potassium polyacrylate (ion exchange resin) and the like); (e) one or more dissolution retardants (e.g., paraffin and the like); (f) one or more absorption promoters (e.g., quaternary ammonium compounds and the like); (g) one or more wetting agents (e.g., cetyl alcohol, glyceryl monostearate and the like); (h) one or more adsorbents (e.g., kaolin, bentonite and the like); and / or (i) one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, stearic acid, polyoxyethylene stearate, cetyl alcohol, talc, hydrogenated castor oil, sucrose fatty acid esters, dimethyl polysiloxane, microcrystalline wax, yellow beeswax, white beeswax, solid polyethylene glycol, sodium lauryl sulfate and the like). In the case of capsules and tablets, the dosage form may further contain a buffer.

[0343] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (milk sugar) as well as high molecular weight polyethylene glycols and the like.

[0344] Solid dosage forms, such as tablets, dragees, capsules and granules, can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. It can also contain an emulsifier, and can also have a composition that makes it release the compound of formula I or formula II and / or other pharmaceutical agents in a delayed manner. The example of operable embedding composition is polymeric material and wax. If suitable, medicine also can be in microencapsulated form with one or more of the above-mentioned excipients.

[0345] For tablets, the active agent will typically comprise less than 50% (by weight) of the formulation, e.g., less than about 10% by weight, such as 5% or 2.5% by weight. The major portion of the formulation comprises fillers, diluents, disintegrants, lubricants, and optional flavorings. The composition of these excipients is well known in the art. Frequently, the filler / diluent will comprise a mixture of two or more of the following components: microcrystalline cellulose, mannitol, lactose (all types), starch, and dicalcium phosphate. The filler / diluent mixture typically comprises less than 98% of the formulation, preferably less than 95%, e.g., 93.5%. Preferred disintegrants include Starch and sodium lauryl sulfate. When present, the disintegrant will generally comprise less than 10% or less than 5% by weight of the formulation, for example, about 3% by weight. A preferred lubricant is magnesium stearate. When present, the lubricant will generally comprise less than 5% or less than 3% by weight of the formulation, for example, about 1% by weight.

[0346] Tablets can be made by standard tableting techniques such as direct compression or wet, dry or melt granulation, melt congealing techniques and extrusion.Tablet cores may be single-layer or multi-layer and may be coated with appropriate outer coatings known in the art.

[0347] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of Formula I or Formula II or a combination thereof, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame seed oil and the like), (available from CONDEA Vista Co., Cranford, NJ), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof, and the like.

[0348] Besides such inert diluents, the composition may also include excipients such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0349] Oral liquid forms or combinations of the compounds of the invention include solutions in which the active compound is completely dissolved. Examples of solvents include all pharmaceutically established solvents suitable for oral administration, particularly those in which the compounds of the 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): 355 EP (tricaprylin / caprin, from Abitec, Columbus Ohio); Crodamol TM GTC / C (medium chain triglycerides from Croda, Cowick Hall, UK); or Labrafac TM CC (medium chain triglycerides, from Gattefosse); 500P (triacetin, also known as triacetin, from Abitec); MCM (medium-chain mono- and diglycerides, from Abitec); 812 (caprylic / capric triglyceride from Condea, Cranford N.J.); 829 (caprylic / capric / succinic triglycerides, from Condea); 840 (propylene glycol dicaprylate / dicaprate, from Condea); M1944CS (oleoyl macrogol-6 glyceride, from Gattefosse); Peceol TM(glyceryl monooleate from Gattefosse); and 35-1 (monoolein, from Gattefosse). Of particular interest are the medium chain (approximately C8 to C 10 ) triglyceride oil. These solvents often constitute the majority of the composition, i.e., greater than about 50% by weight, typically greater than about 80% by weight, for example, about 95% or 99% by weight. Adjuvants and additives may also be included with the solvent primarily as taste masking agents, palatants and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers, and solubilizers.

[0350] In addition to the compound or combination of Formula I or Formula II, the suspension may further contain carriers such as suspending agents, for example, ethoxylated isostearyl alcohols, polyethylene oxide sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[0351] Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound or combination of Formula I or Formula II with suitable non-irritating excipients or carriers, 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 rectum or vaginal cavity to release the active ingredient(s).

[0352] Dosage forms for topical administration of a compound or combination of Formula I or Formula II include ointments, creams, lotions, powders and sprays. The drug is blended with a pharmaceutically acceptable excipient, diluent or carrier and any preservatives, buffers or propellants that may be required.

[0353] Most of the compounds of the present invention are poorly soluble in water, for example, less than about 1 μg / mL. Therefore, liquid compositions in non-aqueous solvents, such as the solubility of medium chain triglyceride oils discussed above, are preferred dosage forms for these compounds.

[0354] 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 an amorphous form and dispersed in a water-soluble polymer. "Amorphous" means that the poorly soluble compound is not crystalline. "Crystallization" means that the compound exhibits long-range order in three dimensions of at least 100 repeating units in each dimension. Therefore, the term amorphous is intended not only to include substantially disordered materials, but also to include materials that may have a certain smaller degree of order, but have order in less than three dimensions and / or have order 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 analysis techniques such as differential scanning calorimetry (DSC).

[0355] 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 be present in a relatively pure amorphous domain or region within the solid amorphous dispersion, in a solid solution of the compound uniformly distributed throughout the polymer, or any combination of these states or a state in between. Preferably, the solid amorphous dispersion is substantially homogeneous such that the amorphous compound is dispersed as evenly as possible throughout the polymer. As used herein, "substantially homogeneous" refers to a relatively small proportion of the compound present in the relatively pure amorphous domain or region within the solid amorphous dispersion, being about less than 20% by weight of the total amount of the drug and preferably less than 10% by weight.

[0356] Water-soluble polymers suitable for use in solid amorphous dispersions should be inert, meaning that they do not react chemically with poorly soluble compounds in an adverse manner, be pharmaceutically acceptable, and have at least some solubility in aqueous solutions having a physiologically relevant pH (e.g., 1 to 8). The polymer can be neutral or ionizable and should have an aqueous solubility of at least 0.1 mg / mL in at least a portion of the pH range of 1 to 8.

[0357] The water-soluble polymers suitable for the compounds of Formula I or Formula II can be cellulosic or non-cellulosic. The polymer can be neutral or ionizable in aqueous solution. Of these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.

[0358] Exemplary water-soluble polymers include hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methyl cellulose (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. 0901786A2, the disclosure of which is incorporated herein by reference.

[0359] 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 compound is in an amorphous state. Such processes include mechanical, thermal, and solvent processes. Exemplary mechanical processes include grinding and extrusion; melt processes include high-temperature fusion, solvent-modified fusion, and melt-freeze processes; and solvent processes include non-solvent precipitation, spraying, and spray drying. See, for example, the following U.S. Patents, the relevant disclosures of which are incorporated herein by reference: Nos. 5,456,923 and 5,939,099, which describe dispersions formed by extrusion processes; Nos. 5,340,591 and 4,673,564, which describe dispersions formed by grinding processes; and Nos. 5,707,646 and 4,894,235, which describe dispersions formed by melt-freeze processes. In a preferred process, the solid amorphous dispersion is formed by spray drying, as disclosed in European Patent Application Publication No. 0901786A2. In this process, the compound and polymer are dissolved in a solvent such as acetone or methanol, and the solvent is then rapidly removed from the solution by spray drying to form a 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.

[0360] The solid dispersion can be used as a dosage form itself or it can serve as a manufacturing ready product (MUP) for preparing other dosage forms such as capsules, tablets, solutions, or suspensions. An example of an aqueous suspension is an aqueous suspension of a 1:1 (w / w) compound / HPMCAS-HF spray-dried dispersion containing 2.5 mg / mL of the compound in 2% polysorbate-80. Solid dispersions for tablets or capsules will generally be mixed with other excipients or adjuvants typically found in the dosage form. For example, an exemplary filler for a capsule contains a 2:1 (w / w) compound / HPMCAS-MF spray-dried dispersion (60%), lactose (fast flow) (15%), microcrystalline cellulose (e.g., Avicel.sup. (RO-102)) (15.8%), sodium starch glycolate (7%), sodium lauryl sulfate (2%), and magnesium stearate (1%).

[0361] HPMCAS polymers are commercially available from ShiN-Etsu Chemical Co., LTD, Tokyo, Japan as low, medium, and high grades Aqoat.sup.(R)-LF, Aqoat.sup.(R)-MF, and Aqoat.sup.(R)-HF, respectively. High grades MF and HF are generally preferred.

[0362] The compounds of formula I or II or pharmaceutically acceptable salts thereof can be used to treat non-human animals. The administration of the compounds of formula I or II and the combination with another effective agent for treating the relevant condition can be performed orally or parenterally.

[0363] An amount of a compound of Formula I or Formula II or a combination of a compound of Formula I or Formula II and another effective agent is administered so as to receive an effective dose. Generally speaking, the daily dose for oral administration to an animal is between about 0.01 and about 1,000 mg / kg body weight, for example, between about 0.01 and about 300 mg / kg, or between about 0.01 and about 100 mg / kg, or between about 0.01 and about 50 mg / kg body weight, or between about 0.01 and about 25 mg / kg, or about 0.01 to about 10 mg / kg or about 0.01 to about 5 mg / kg.

[0364] Suitably, the compound of Formula I or Formula II (or combination) can be carried in drinking water so that a therapeutic dose of the compound is taken with the daily water supply. The compound can be metered directly into the drinking water, preferably in the form of a liquid, water-soluble concentrate (e.g., an aqueous solution of a water-soluble salt).

[0365] Suitably, the compound (or combination) of Formula I or Formula II can also be added directly to the feed as is, or in the form of an animal feed supplement, also referred to as a premix or concentrate. Premixes or concentrates of the compounds in the excipients, diluents or carriers are more commonly used to include the medicament in the feed. Suitable excipients, diluents or carriers are liquid or solid as needed, such as water, various coarse meals (such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corn cob meal and corn flour, molasses, urea, bone meal) and mineral mixtures (such as materials commonly used in poultry feed). Particularly effective excipients, diluents or carriers are the individual animal feeds themselves; that is, the smaller portion of this feed. The carrier promotes uniform distribution of the compound in the finished feed blended with the premix. Preferably, the compound is fully blended into the premix and then blended into the feed. In this regard, the compound can be dispersed or dissolved in a suitable oily vehicle (such as soybean oil, corn oil, cottonseed oil and the like) or a volatile organic solvent and then blended with a carrier. It will be appreciated that the ratio of the compound in the concentrate can vary widely, as the amount of compound in the finished feed can be adjusted by blending the premix with the feed in appropriate proportions to obtain the desired level of compound.

[0366] As described above, the high potency concentrate can be blended with a protein carrier (such as soybean oil meal and other coarse meals) by the feed manufacturer to produce a concentrated supplement suitable for direct feeding to animals. In these cases, the animals are allowed to eat their usual diet. Alternatively, the concentrated supplement can be added directly to the feed to produce a nutritionally balanced finished feed containing therapeutically effective levels of the compound. The mixture is thoroughly blended by standard procedures, such as in a twin-shell blender, to ensure homogeneity.

[0367] If the supplement is used as a top dressing on feed, it will likewise help ensure that the compound is evenly distributed across the top of the dressing.

[0368] Drinking water and feed effective for increasing lean mass deposition and for improving lean to fat ratio are typically prepared by mixing a compound of Formula I or Formula II with sufficient animal feed to provide from about 0.001 to about 500 ppm of the compound in the feed or water.

[0369] Preferred medicinal pig, cattle, sheep and goat feeds typically contain from about 1 to about 400 grams of a compound of Formula I or Formula II (or combination) per ton of feed, with the optimum amount for these animals typically being from about 50 to about 300 grams per ton of feed.

[0370] Preferred poultry and domestic pet feeds typically contain from about 1 gram to about 400 grams, and preferably from about 10 grams to about 400 grams, of the compound (or combination) per ton of feed.

[0371] For parenteral administration in animals, the compounds of Formula I or Formula II (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 the animal in which increased lean mass deposition and improved lean to fat ratio are sought.

[0372] 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.

[0373] Pellets containing an effective amount of a compound of Formula I or Formula II, pharmaceutical composition, or combination can be prepared by mixing the compound of Formula I or Formula II, or combination, with a diluent such as carbowax, carnauba wax, and the like, and a lubricant such as magnesium stearate or calcium stearate can be added to improve the granulation process.

[0374] Of course, it has been recognized that more than one bolus can be administered to an animal to achieve the desired dosage level that will increase lean mass deposition and improve the desired lean to fat ratio. Additionally, implants can be performed periodically during the animal's treatment period to maintain appropriate drug levels in the animal's body.

[0375] Liposomes containing these agents and / or compounds of the present invention are 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 extended circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly suitable liposomes can be produced by reverse phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with a limited pore size to produce liposomes with the desired diameter.

[0376] These agents and / or compounds of the invention may also be encapsulated in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and polymethyl methacrylate microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. This technology is disclosed in The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0377] The formulations for intravenous administration must be sterile. This is easily achieved, for example, by filtration through a sterile filtration membrane. The compounds of the invention are typically placed in a container with a sterile access port, such as an intravenous solution bag or vial with a stopper pierceable by a hypodermic needle.

[0378] Suitable emulsions include commercially available fat emulsions, such as InfonutrolTM, and Lipiphysan™. The active ingredient can be dissolved in a premixed emulsion composition, or it can be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and in an emulsion formed when mixed with a phospholipid (e.g., lecithin, soybean lecithin, or soy lecithin) and water. It will be appreciated that other ingredients, such as glycerol or glucose, can be added to adjust the emulsion tension. Suitable emulsions will typically contain up to 20% oil, for example, between 5% and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and have a pH in the range of 5.5 to 8.0.

[0379] Emulsion compositions may be those prepared by mixing a compound of the present invention with Intralipid™ or its components (soybean oil, lecithin, glycerin and water).

[0380] 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 excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory routes for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents can be atomized using gases. Nebulized solutions can be inhaled directly from a nebulizing device, or the nebulizing device can be attached to a mask, hood, or intermittent positive pressure breathing machine. Solutions, suspensions, or powder compositions can be preferably administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0381] The compounds herein can be formulated for oral, buccal, intranasal, parenteral (eg, intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation. The compounds of the present invention can also be formulated for sustained delivery.

[0382] Methods for preparing various pharmaceutical compositions having a certain amount of active ingredient are known to those skilled in the art, or will be apparent in light of this disclosure. For examples of methods for preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, 20th edition (Lippincott Williams & Wilkins, 2000).

[0383] The pharmaceutical compositions of the present invention may contain from 0.1% to 95% by weight, preferably from 1% to 70% by weight of a compound of the present invention. In any case, the composition to be administered will contain an amount of one or more compounds according to the present invention that is effective in treating the disease / condition of the individual being treated.

[0384] Since one aspect of the present application relates to treating the diseases / conditions described herein with a combination of active ingredients that can be applied separately, the present invention also relates to combining separate pharmaceutical compositions in the form of a kit. The kit may include a composition comprising a compound of Formula I or Formula II, or it may contain at least two separate pharmaceutical compositions: a compound of Formula I or Formula II, a prodrug thereof, or a salt of this compound or prodrug, and a second compound as described above. The kit includes components for accommodating separate compositions, such as containers, separating bottles, or separating foil packets. The kit typically includes instructions for administering separate components. When separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when the prescribing physician needs to titrate the individual components of the combination, the kit form is particularly advantageous.

[0385] 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, and similar dosage forms). Blister packs generally consist of a sheet of relatively rigid material covered with a preferably transparent plastic material foil. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove and, relative to the plastic foil, sealed with the sheet of relatively rigid material on the side opposite to the direction in which the groove is formed. Therefore, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the sheet strength makes it possible to remove the tablet or capsule from the blister package by manually applying pressure on the groove, thereby forming an opening in the sheet at the position of the groove. The tablet or capsule can be removed subsequently via this opening.

[0386] It may be necessary to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, where the numbers correspond to the days of the regimen on which the specified tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, for example as follows "Week 1, Monday, Tuesday, etc. ... Week 2, Monday, Tuesday ... " etc. Other variations of memory aids are obvious. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a specified day. In addition, a daily dose of a compound of Formula I or Formula II can consist of one tablet or capsule, while a daily dose of an optional second compound can consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0387] In another specific embodiment of the present invention, a dispenser is provided that is designed to dispense daily doses one at a time in the order desired for use. Preferably, the dispenser is equipped with a memory aid to further facilitate compliance with the regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory coupled to a liquid crystal reader or an audible reminder signal that, for example, reads out the date the last daily dose was taken and / or reminds when the next dose should be taken.

[0388] Furthermore, since one aspect of the present application relates to treating the diseases / conditions described herein with a combination of co-administered active ingredients, the present invention also relates to combining separate pharmaceutical compositions into a single dosage form, such as, but not limited to, a single tablet or capsule, a double or multi-layer tablet or capsule, or by using separate components or compartments within a tablet or capsule.

[0389] The active ingredient may be delivered as a solution in an aqueous or non-aqueous vehicle, with or without additional solvents, co-solvents, excipients, or compounding agents selected from pharmaceutically acceptable diluents, excipients, vehicles, or carriers.

[0390] The active ingredient can be formulated together with pharmaceutically acceptable excipients as a solid dispersion or a self-emulsifying drug delivery system (SEDDS).

[0391] The active ingredient can be formulated as an immediate release or modified release tablet or capsule. Alternatively, the active ingredient can be delivered as the active ingredient alone within a capsule shell without additional excipients.

[0392] Experimental procedures

[0393] The synthesis of various compounds of the present invention is described below. Other compounds within the scope of the present invention can be prepared using the methods described in these examples (alone or in combination with techniques generally known in the art). The starting materials in all of these preparations and examples are commercially available or can be prepared by methods known in the art or as described herein.

[0394] Reactions were carried out in air or, when oxygen-sensitive or moisture-sensitive reagents or intermediates were used, under an inert atmosphere (nitrogen or argon). Where appropriate, reaction equipment was dried using a heat gun under dynamic vacuum, 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 removed by packing with 5-Methyl-2-thiazolyl ether (DMSO-1) was added to a column of 4-methylene zeolite until the following QC standards for water were reached: 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 extremely sensitive reactions, the solvent was further treated with sodium metal, calcium hydride, or molecular sieves and distilled just before use. Other commercially available solvents and reagents were used without further purification. For the synthetic reference procedures in other embodiments or methods, the reaction conditions (reaction time and temperature) may vary. The product was typically dried under vacuum before further reaction or submission for biological testing.

[0395] If indicated, then the reaction mixture is heated by microwave irradiation using a Biotage Initiator or Personal Chemistry EmrysOptimizer microwave instrument. Thin layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high performance liquid chromatography (HPLC) and / or gas chromatography-mass spectrometry (GCMS) analysis are used to monitor the reaction process. TLC is carried out on a pre-coated silica gel plate with a fluorescent indicator (254nm excitation wavelength) and observed under UV light and / or I , KMnO , CoCl , phosphomolybdic acid and / or ceric ammonium molybdate stain. LCMS data are obtained on an Agilent 1100 series instrument with a Leap Technologies automatic sampler, Gemini C18 columns, acetonitrile / water gradient and trifluoroacetic acid, formic acid or ammonium hydroxide modifier. Waters ZQ mass spectrometer is used to scan the column eluent in positive and negative ion modes from 100 to 1200Da. Other similar instruments are also used. HPLC data were obtained on an Agilent 1100 series instrument using Gemini or XBridge C18 columns, acetonitrile / water gradient and trifluoroacetic acid or ammonium hydroxide modifiers. GCMS data were obtained using a Hewlett Packard 6890 baking oven with an HP 6890 injector, HP-1 column (12m × 0.2mm × 0.33 μm) and helium carrier gas. Samples were analyzed using an electron ionization scan from 50 to 550 Da on an HP 5973 mass selective detector. Purification was performed using an Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1 or Biotage Isolera One instrument and pre-packed Isco RediSep or Biotage Snap silica cartridges. In general, chiral purification is performed by chiral supercritical fluid chromatography (SFC) using a Berger or Thar instrument; ChiralPAK-AD, ChiralPAK-AS, ChiralPAK-IC, Chiralcel-OD or Chiralcel-OJ column; and a CO mixture containing methanol, ethanol, propan-2-ol or acetonitrile (alone or conditioned with trifluoroacetic acid or propan-2-amine). UV detection is used to trigger fraction collection. For synthetic reference procedures in other embodiments or methods, purification may vary: In general, the solvent and solvent ratio for the eluent / gradient are selected to provide appropriate Rfs or retention times.

[0396] Mass spectrometry data are reported from LCMS analysis. Mass spectrometry (MS) was performed using atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI), or electron scattering (ES) ionization sources. Proton nuclear magnetic spectrometry ( 1 HNMR) chemical shifts are expressed 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 residual peaks of deuterated solvent (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; brs, broad singlet; app, apparent. Analytical SFC data were acquired on a Berger analytical instrument as described above. Optical rotation data were acquired on a PerkinElmer model 343 polarimeter using a 1 dm unit. Silica gel chromatography was primarily performed using medium pressure Biotage or ISCO systems using pre-packed columns from various commercial suppliers including Biotage and ISCO. Microscopic analysis was performed by Quantitative Technologies Inc. and was within 0.4% of the calculated value.

[0397] Unless otherwise stated, chemical reactions were performed at room temperature (approximately 23 degrees Celsius).

[0398] Unless otherwise stated, all reactants were either commercially available without further purification or prepared using methods known in the literature.

[0399] Hydrogenations can be performed under pressurized hydrogen in a Parr Shaker or under full hydrogen in a Thales-nano H-Cube flow hydrogenation apparatus at a flow rate between 1 and 2 ml / min at the specified temperature.

[0400] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods indicated in the procedures.

[0401] In some embodiments, chiral separations are performed to isolate individual enantiomers or diastereomers of certain compounds of the invention (in some embodiments, the separated enantiomers are designated as ENANT-1 and ENANT-2 based on their elution order; similarly, the separated diastereomers are designated as DIAST-1 and DIAST-2 based on their elution order). In some embodiments, the optical rotation of the enantiomers is measured using a polarimeter. Based on their observed rotation data (or their specific rotation data), the enantiomer that rotates clockwise is referred to as the (+)-enantiomer and the enantiomer that rotates counterclockwise is referred to as the (-)-enantiomer. Racemic compounds are indicated by the absence of a drawn or described stereochemistry or the presence of (+ / -) adjacent structures; in the latter case, the designated stereochemistry represents only one of the two enantiomers that make up the racemic mixture.

[0402] The compounds and intermediates described below are named using the nomenclature provided by ACD / ChemSketch 2017.2.1, file version C40H41, build 99535 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The nomenclature provided by ACD / ChemSketch 2017.2.1 is well known to those skilled in the art and is believed to generally conform to the recommendations of the International Union for Pure and Applied Chemistry (IUPAC) for organic nomenclature and CAS indexing rules.

[0403] Example

[0404] Preparation of P1

[0405] 3,5-Difluoro-4-[(4-methoxyphenyl)methoxy]benzoic acid (P1)

[0406]

[0407] 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 the reaction mixture had been stirred 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, after which 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 afford C1 (11.2 g) as a solid. This material was directly carried on to the next step.

[0408] 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), after which the reaction mixture was stirred at 26 ° C for 4 hours. It was then concentrated in vacuo, and the aqueous residue was washed with dichloromethane (2×150 mL). After the aqueous layer had been acidified to pH 5, it was extracted with dichloromethane (3×300 mL), and these three dichloromethane layers were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give P1 as a white solid. Yield: 10 g, 34 mmol, 92% over 2 steps. 1 HNMR (400MHz, DMSO-d6) δ7.61–7.53(m,2H),7.34(d,J=8.6Hz,2H),6.92(d,J=8.7Hz,2H),5.20(s,2H),3.74(s,3H).

[0409] Preparation of P2

[0410] 2,3,5-Trifluoro-4-[(4-methoxyphenyl)methoxy]benzoic acid (P2)

[0411]

[0412] 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 hours, LCMS analysis indicated conversion to C2: LCMS m / z 363.1 [M+Na + The solids were removed by filtration, and the filtrate was concentrated in vacuo to afford C2 as a yellow oil. Yield: 71.0 g, 209 mmol, 90%.

[0413] 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 aqueous sodium hydroxide solution (3 M; 300 mL). After stirring the reaction mixture at 50 ° C for 4 hours, it was concentrated in vacuo. The aqueous residue was acidified by adding 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 (400MHz, DMSO-d6) δ7.38–7.29(m,1H),7.34(d,J=8.6Hz,2H),6.93(d,J=8.7Hz,2H),5.18(s,2H),3.75(s,3H).

[0414] Preparation of P3

[0415] N-{[(1r,4r)-4-aminocyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P3)

[0416]

[0417]

[0418] 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 hours, LCMS analysis indicated the presence of C3: LCMS m / z 527.3 [M+Na + ]. Filtration and washing of the filter cake with water and a mixture of dichloromethane and ethyl acetate afforded C3 as a white solid. Yield: 26.5 g, 52.5 mmol, 80%. 1 H NMR (400MHz, DMSO-d6) δ8.48(br t,J=6Hz,1H),7.63–7.53(m,2H),7.33(d,J=8.6Hz,2H),6.92(d,J=8.7Hz,2H),6.67(br d,J=8.0Hz,1H),5.16(s,2H),3.74(s,3H),3.22–3.10(m,1H),3.06(dd,J=6.1,6.1Hz,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).

[0419] 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) in a dropwise manner. After the reaction mixture was stirred at 25°C for 16 hours, 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] + . 1HNMR(400MHz,DMSO-d6)δ8.50(br t,J=6Hz,1H),7.71–7.41(m,4H),7.33(d,J=8.2Hz,2H),6.92(d,J=8.2Hz,2H),5.17(s,2H),3.74(s,3H),3.09(dd,J=6Hz ,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).

[0420] Preparation of P4

[0421] (1r,4r)-4-({3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)cyclohexane-1-carboxylic acid (P4)

[0422]

[0423] 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) were added triethylamine (7.41 g, 73.2 mmol) and methyl (1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylate (10.5 g, 61.3 mmol). After stirring the reaction mixture at 28° C. for 4 hours, it was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated in vacuo, and purified via silica gel chromatography (eluent: 6% methanol / dichloromethane) to afford C4 as a white solid. Yield: 22.0 g, 49.2 mmol, 80%. LCMS m / z 448.2 [M+H] + .

[0424] 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 hours, after which the methanol was removed under reduced pressure and the aqueous residue was washed with dichloromethane (2×20 mL). The aqueous layer was then adjusted to pH 5 and extracted with dichloromethane (3×50 mL); these three extracts were combined, washed with saturated aqueous sodium chloride solution, 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 HNMR(400MHz,DMSO-d6)δ8.50(br t,J=5.7Hz,1H),7.64–7.54(m,2H),7.33(d,J=8.5Hz,2H),6.92(d,J=8.4Hz,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).

[0425] Preparation of P5

[0426] 3,5-Difluoro-N-{[(1r,4r)-4-(N-hydroxycarbamimidoyl)cyclohexyl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P5)

[0427]

[0428] 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 (4M; 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.

[0429] 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 this mixture for 1 hour, it was treated with N,N-diisopropylethylamine (8.88 mL, 51.0 mmol) and (1r,4r)-4-(aminomethyl)cyclohexane-1-carbonitrile hydrochloride from above. The reaction mixture was stirred at room temperature for 3 days, after which it was washed sequentially with water, 1M hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in a minimum amount of a hot mixture of ethyl acetate and heptane in a ratio of 10:1; after cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. Silica gel chromatography provided C5 as a white solid. Yield: 5.80 g, 14.0 mmol, 82%. LCMS m / z 415.3 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.50(brt,J=5.8Hz,1H),7.62–7.53(m,2H),7.33(d,J=8.6Hz,2H),6.92(d,J=8.6Hz,2H),5.16(s,2H),3.74(s ,3H),3.08(dd,J=6,6Hz,2H),2.62(tt,J=11.9,3.6Hz,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).

[0430] 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, after which it was allowed to cool 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. Filter and then rinse the collected solid with water (50 mL) and ethyl acetate (50 mL) to give P5 as a white solid. Yield: 4.50 g, 10.1 mmol, 83%. LCMS m / z 448.4 [M + H] + . 1HNMR (400 MHz, DMSO-d6), characteristic peaks: δ9.42 (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 the solvent peak), 1.96–1.84 (m, 2H), 1.56–1.41 (m, 1H), 1.02–0.87 (m, 2H).

[0431] Preparation of P6

[0432] N-{[(1s,4s)-4-bromocyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P6)

[0433]

[0434]

[00155] Step 1. 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 hours. After removal of the solvent in vacuo, purification via 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 HNMR(400MHz,DMSO-d6)δ6.86(br t,J=6.0Hz,1H),4.78–4.71(m,1H),2.82(dd,J=6,6Hz,2H),1.99–1.89(m,2H),1.87–1.75(m,2H),1.57–1.26(m,5H),1.37(s,9H).

[0435] 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 hours, LCMS analysis indicated conversion to C7: LCMS m / z 192.1 (bromine isotope pattern observed) [M+H] + The solvent was removed in vacuo to afford C7 (900 mg), which was used directly in the following step.

[0436] 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) was added C7 (from the previous step; 900 mg, ≤4.45 mmol), and the reaction mixture was stirred at room temperature for 3 hours. After concentration in vacuo, silica gel chromatography (gradient: 0% to 30% ethyl acetate in petroleum ether) afforded P6. Yield: 1.40 g, 2.99 mmol, 67% over 2 steps. LCMS m / z 490.0 (bromine isotope pattern [M+Na + ]. 1 HNMR(400MHz,DMSO-d6)δ8.55(br t,J=5.8Hz,1H),7.63–7.54(m,2H),7.33(d,J=8.7Hz,2H),6.92(d,J=8.6Hz,2H),5.17(s,2H),4.80–4.72(m,1H), 3.74(s,3H),3.15(dd,J=6,6Hz,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).

[0437] Preparation of P7

[0438] 3,5-Difluoro-N-{[4-(N-hydroxycarbamimidoyl)bicyclo[2.2.2]octan-1-yl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P7)

[0439]

[0440]

[0441] 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) were 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). After stirring the reaction mixture at 25°C for 2 hours, it was diluted with dichloromethane (25 mL), washed sequentially with water (2 x 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] + .

[0442]

[0146] Step 2. Synthesis of tert-butyl [(4-cyanobicyclo[2.2.2]octan-1-yl)methyl]carbamate (C9): (Methoxycarbonylaminosulfonyl)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). After stirring the reaction mixture at 25°C for 2 hours, it was concentrated in vacuo; the residue was diluted with water (30 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 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 (400MHz, DMSO-d6) 6.80 (br t, J=6.4Hz, 1H), 2.66 (d, J=6.4Hz, 2H), 1.86–1.76 (m, 6H), 1.36 (s, 9H), 1.36–1.27 (m, 6H).

[0443] 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), followed by stirring the reaction mixture at 25°C for 16 hours. The solvent was removed in vacuo to afford C10 as a white solid. Yield: 750 mg, 3.74 mmol, 99%. LCMS m / z 165.2 [M+H] + .

[0444] 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 sequentially with water (2×10 mL) and saturated aqueous sodium chloride (2×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 50% ethyl acetate in petroleum ether) provided C11 as a pale yellow solid. Yield: 1.29 g, 2.93 mmol, 84%. LCMS m / z 441.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ8.36(br t,J=6.3Hz,1H),7.64–7.54(m,2H),7.34(d,J=8.7Hz,2H),6.92(d,J=8.6Hz,2H),5. 17(s,2H),3.75(s,3H),3.01(d,J=6.2Hz,2H),1.87–1.78(m,6H),1.46–1.36(m,6H).

[0445] 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), followed by stirring the reaction mixture at 70° C. for 16 hours. The solvent was removed in vacuo to give a residue, which was purified via 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 HNMR(400MHz,DMSO-d6)δ8.85(s,1H),8.30(br t,J=6.2Hz,1H),7.64–7.55(m,2H),7.34(d,J=8.7Hz,2H),6.92(d,J=8.7Hz,2H),5.16(s,2H),5.11(br s, 2H), 3.74 (s, 3H), 3.01 (d, J = 6.2Hz, 2H), 1.66–1.56 (m, 6H), 1.41–1.31 (m, 6H).

[0446] Preparation of P8

[0447] N-[(4-aminobicyclo[2.2.2]octan-1-yl)methyl]-2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P8)

[0448]

[0449] 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 the mixture was stirred 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. Silica gel chromatography (eluent: 1:1 petroleum ether / ethyl acetate) afforded C12 as a white solid. Yield: 1.35 g, 2.46 mmol, 77%. LCMS m / z 549.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.25(t,J=6.3Hz,1H),7.35(d,J=8.6Hz,2H),7.30(ddd,J=10.9,6.0,2.3Hz,1H),6.94(d,J=8.7Hz,2H),6.32(br s,1H),5.21(s,2H),3.75(s,3H),2.96(d,J=6.2Hz,2H),1.76–1.64(m,6H),1.46–1.37(m,6H),1.35(s,9H).

[0450] 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) was added trimethylsilyl trifluoromethanesulfonate (3.69 g, 16.6 mmol), followed by stirring the reaction mixture at 20° C. for 30 minutes. 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 solution (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo; purified using silica gel chromatography (Gradient: 13% to 17% methanol in dichloromethane) to give 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) δ 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).

[0451] Preparation of P9

[0452] 4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octane-1-carboxylic acid (P9)

[0453]

[0454] 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) were 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 hours, LCMS analysis indicated 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%.

[0455] 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 solution (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 and washed with water, then suspended in a mixture of ethyl acetate and methanol (10: 1 ratio, 80 mL). It was stirred at 80 ° C and slowly treated with methanol until a solution was obtained, after which 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 HNMR(400MHz,DMSO-d6)δ8.26(br t,J=6.2Hz,1H),7.42–7.23(m,3H),6.94(d,J=8.3Hz,2H),5.21(s,2H),3 .75(s,3H),2.98(d,J=6.2Hz,2H),1.71–1.55(m,6H),1.44–1.29(m,6H).

[0456] Preparation of P10

[0457] 2,3,5-Trifluoro-N-{[4-(N-hydroxycarbamimidoyl)bicyclo[2.2.2]octan-1-yl]methyl}-4-[(4-methoxyphenyl)methoxy]benzamide (P10)

[0458]

[0459]

[0460] 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 at room temperature overnight before being concentrated in vacuo to afford C14 (1.20 g) as a solid. This material was used directly in the following step. LCMS m / z 599.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 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).

[0461] 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 solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford C15 as an off-white solid. Yield: 919 mg, 1.93 mmol, 96% over 2 steps. LCMS m / z 477.3 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.27(br t,J=6Hz,1H),7.35(d,J=8.6Hz,2H),7.30(ddd,J=11.0,6.1,2.4Hz,1H),6.94(d,J=8.6Hz,2H),6.88(br s,1H),6.66(br s,1H),5.21(s,2H),3.75(s,3H),2.99(d,J=6.2Hz,2H),1.66–1.57(m,6H),1.41–1.33(m,6H).

[0462]

[0146] 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 (methoxycarbonylaminosulfonyl)triethylammonium hydroxide inner salt (Burgess reagent; 997 mg, 4.18 mmol). The reaction mixture was stirred at room temperature overnight before being diluted with ethyl acetate (40 mL) and washed sequentially with water (2 x 30 mL) and saturated aqueous sodium chloride solution (30 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford C16 as a solid. Yield: 658 mg, 1.44 mmol, 86%. LCMS m / z 459.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.32(br t,J=6.3Hz,1H),7.35(d,J=8.7Hz,2H),7.34–7.28(m,1H),6.94(d,J=8.6Hz,2H),5. 21(s,2H),3.75(s,3H),2.99(d,J=6.3Hz,2H),1.88–1.79(m,6H),1.46–1.37(m,6H).

[0463] 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 sequentially 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 afford P10 as a solid. Yield: 330 mg, 0.671 mmol, 47%. LCMS m / z 492.4 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.82(br s,1H),10.64(br s,1H),8.59(v br s,1H),8.33(br t,J=6.3Hz,1H),7.35(d,J=8.6Hz,2H),7.34–7.28(m,1H),6.94(d,J=8.6Hz,2H),5. 21(s,2H),3.75(s,3H),3.03(d,J=6.3Hz,2H),1.78–1.67(m,6H),1.49–1.38(m,6H).

[0464] Preparation of P11

[0465] Tert-butyl {[(1r,4r)-4-(7-bromoimidazo[1,2-a]pyridin-2-yl)cyclohexyl]methyl}carbamate (P11)

[0466]

[0467] 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 at room temperature overnight, LCMS analysis indicated the formation of C17: LCMS m / z 301.5 [M+H] + In a pilot reaction run 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 provide C17. The product from this 39.6 mmol scale reaction was combined with the product from a similar reaction performed using (1r,4r)-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexane-1-carboxylic acid (9.50 g, 36.9 mmol) to provide C17 as an oil. Combined yield: 22.8 g, 75.9 mmol, 99%. 1 HNMR (500 MHz, CHLOROFORM-d) δ 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).

[0468] 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), after which 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 solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (eluent: 0%, then 10%, then 25%, then 50% ethyl acetate in heptane) provided C18 as a solid. Yield: 13.3 g, 52.1 mmol, 68%. 1HNMR(500MHz,chloroform-d)δ4.56(br s,1H),2.98(br dd,J=6,6Hz,2H),2.28(tt,J=12.2,3.5Hz,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).

[0469] Step 3. Synthesis of tert-butyl {[(1r, 4r)-4-(bromoacetyl)cyclohexyl]methyl}carbamate (C19): Bromine (2.57 mL, 50.2 mmol) was added portionwise to a 0°C solution of C18 (12.1 g, 47.4 mmol) in methanol (158 mL). After the mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour, N,N-diisopropylethylamine (29.6 mL, 170 mmol) was added portionwise. Stirring was continued at room temperature for 20 minutes, after which the mixture was concentrated in vacuo and combined with the product of a similar reaction performed using C18 (1.03 g, 4.03 mmol). Silica gel chromatography (eluent: 0%, then 10%, then 25% ethyl acetate in heptane) gave C19 as a solid. Combined yield: 9.07 g, 27.1 mmol, 53%. 1 HNMR (500 MHz, chloroform-d) δ 4.56 (brs, 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).

[0470] 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] + . 1HNMR (400MHz, DMSO-d6) δ8.41(br d,J=7.1Hz,1H),7.75(br d,J=2.0Hz,1H),7.69(s,1H),6.97(dd,J=7.2,2.0Hz,1H),6.83(br t,J=5.9Hz,1H),2.81(dd,J=6,6Hz,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).

[0471] Preparation of P12

[0472] 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)

[0473]

[0474] 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 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. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with heptane to give C20 as a tan solid. Yield: 6.52 g, 16.0 mmol, 73%. LCMS m / z 408.1 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400MHz, DMSO-d6)8.45(s,1H),7.86–7.82(m,1H),7.67(d,J=8.8Hz,1H),7.12(dd,J=8.8,1.7Hz,1H),6.89(br t,J=6.0Hz,1H),4.50–4.38(m,1H),2.85(dd,J=6.3,6.3Hz,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).

[0475] 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 minutes before the addition of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (Pd(dppf)Cl2; 652 mg, 0.798 mmol). After heating the reaction mixture at 100°C for 1 hour, it was cooled and filtered through a Celite pad. 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; loading was as a solution in dichloromethane) provided P12 as a colorless foam. Yield: 7.20 g, 15.8 mmol, 99%. LCMS m / z 456.4 [M+H] + . 1 HNMR (400 MHz, DMSO-d6), characteristic peaks: δ8.40 (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).

[0476] Preparation of P13

[0477] 1-{(1r,4r)-4-[6-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methanamine hydrochloride (P13)

[0478]

[0479] 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 reduced pressure bottle and the reaction mixture was heated at 85°C for 1 hour. After the reaction mixture cooled, the ethanol was removed using vacuum concentration, 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, followed by 5% methanol in ethyl acetate) provided C21 as a colorless foam. Yield: 404 mg, 0.986 mmol, 75%. LCMS m / z 410.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.31(br s,1H),8.15(s,1H),7.91–7.89(m,1H),7.76–7.72(m,1H),7.65(dd,J=8.6,0.9Hz,1H),7.25(dd,J=8.7,1.4Hz,1H),6.90(br t,J=5.9Hz,1H),4.47–4.34(m,1H),3.87(s,3H),2.85(dd,J=6,6Hz,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).

[0480] 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 (4M; 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 before being diluted with diethyl ether (50 mL). The solid was collected by filtration and washed with diethyl ether to afford P13 as a solid. Yield: 362 mg, presumably total yield. LCMS m / z 310.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.37(br s,1H),8.17(s,1H),7.92(s,1H),7.74(br s,1H),7.66(br d,J=8.6Hz,1H),7.27(dd,J=8.7,1.4Hz,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).

[0481] Preparation of P14

[0482] 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)

[0483]

[0484]

[0485] 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 (4M; 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 and then stirred at 50 ° C overnight. After the reaction mixture was cooled, it 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 HNMR(400MHz,DMSO-d6)δ8.49(br s,1H),8.06(br s,3H),7.86–7.83(m,1H),7.68(d,J=8.8Hz,1H),7.12(dd,J=8.8,1.7Hz,1H),4.47(tt,J=11.7,3.9Hz ,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).

[0486] 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 before being poured into water (450 mL) with stirring. The resulting solid was isolated by filtration and washed with water to afford 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(400MHz,DMSO-d6)δ8.57(br t,J=5.8Hz,1H),8.45(brs,1H),7.86–7.83(m,1H),7.67(d,J=8.8Hz,1H),7.6 5–7.56(m,2H),7.34(d,J=8.6Hz,2H),7.12(dd,J=8.8,1.7Hz,1H),6.92(d,J=8 .6Hz,2H),5.17(s,2H),4.53–4.41(m,1H),3.74(s,3H),3.17(dd,J=6,6Hz,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).

[0487] 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 before being heated at 100° C. for 2 hours. After the reaction mixture cooled, it was filtered through celite 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 brown solid. Yield: 7.32 g, 11.6 mmol, 68%. LCMS m / z 632.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.57(br t,J=5.8Hz,1H),8.40(br s,1H),7.96–7.94(m,1H),7.65(dd,J=8.4,1Hz,1H),7.66–7.56(m,2H),7.34(d,J=8.6Hz,2H),7.25(br d,J=8.4Hz,1H),6.92(d,J=8.7Hz,2H),5.17(s,2H),4.55–4.43(m,1H),3.74(s,3H),3.18(dd,J=6, 6Hz,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).

[0488] Preparation of P15

[0489] 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)

[0490]

[0491]

[0492] 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, after which 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 removing the solvent 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 afford 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 (400MHz, DMSO-d6) δ9.01 (d, J=1.2Hz, 1H), 8.81 (br s, 1H), 7.68 (br s, 1H), 6.91 (br t,J=5.9Hz,1H),4.59–4.47(m,1H),2.85(dd,J=6,6Hz,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).

[0493] 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). After stirring the reaction mixture at 15° C. for 4 hours, it was concentrated in vacuo to afford C25 as a yellow oil. Yield: 170 mg, 0.564 mmol, 79%. LCMS m / z 265.1 (chlorine isotope pattern observed) [M+H] + .

[0494] 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 (C23): 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) was added C25 (167 mg, 0.554 mmol), and the reaction mixture was stirred at 15°C for 1 hour. It was then extracted with dichloromethane (3 x 30 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (eluent: 4% methanol in dichloromethane) gave 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: δ9.01 (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).

[0495] Preparation of P16

[0496] 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)

[0497]

[0498] 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 hours, after which it was cooled to room temperature and treated with tributylphosphine (2 mL, 8 mmol). After stirring the reaction mixture at 85 ° C overnight, it was 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 subjected to silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give P16 as a yellow solid. 1 H NMR data were obtained from a reaction performed in a similar manner. Yield: 170 mg, 0.270 mmol, 61%. LCMS m / z 626.1 (bromine isotope pattern observed) [MH] - . 1 HNMR(400MHz, DMSO-d6)δ8.46(d,J=1.0Hz,1H),8.40(br t,J=6.3Hz,1H),7.86–7.83(m,1H),7.66(br d,J=8.8Hz,1H),7.38–7.32(m,1H),7.36(d,J=8.7Hz,2H),7.11(dd,J=8.8,1.7Hz,1H),6.94(d,J= 8.7Hz,2H),5.22(s,2H),3.75(s,3H),3.10(d,J=6.2Hz,2H),2.20–2.10(m,6H),1.71–1.60(m,6H).

[0499] Preparation of P17

[0500] N-{[(1r,4r)-4-(1,3-benzoxazol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide (P17)

[0501]

[0502] 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 the reaction mixture for 30 minutes, it was allowed to warm to room temperature, 2-aminophenol (378 mg, 3.46 mmol) was added, and the reaction mixture was stirred at 105° C. overnight. Once cooled, the reaction mixture was filtered through a Celite filter pad and the filter pad was rinsed with 1,4-dioxane, ethyl acetate, and dichloromethane, in that order. The combined filtrates were concentrated in vacuo to afford C26 as an orange oil, which was directly carried on to the next step. LCMS m / z 507.3 [M+H] + .

[0503] Step 2. Synthesis of N-{[(1r,4r)-4-(1,3-benzoxazol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide (P17): 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). After the reaction mixture had been stirred at room temperature for 2 hours, it was concentrated in vacuo and purified via silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane; the sample was loaded in dichloromethane containing minimal methanol). The resulting material was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate, after which 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, then 0% to 10% methanol in dichloromethane; the sample was loaded in dichloromethane with minimal methanol) to afford N-{[(1r,4r)-4-(1,3-benzoxazol-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide (P17) as a white solid. Yield: 46 mg, 0.12 mmol, 5% over 2 steps. LCMS m / z 387.3 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 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).

[0504] Preparation of P18

[0505] 3,5-Difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (P18)

[0506]

[0507]

[0508] 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). After stirring the reaction mixture at room temperature for 3 hours, it was concentrated in vacuo to afford C27 as a white solid. Yield: 200 mg, 0.975 mmol, 84%. LCMS m / z 206.1 [M+H] + .

[0509] 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 0°C 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) was added C27 (227 mg, 1.11 mmol). The reaction mixture was stirred at room temperature for 6 hours, after which 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) provided the acylated intermediate (100 mg, 0.161 mmol, 17%) as a white solid. LCMS m / z 621.3 [M+H] + .

[0510] 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. under microwave irradiation for 1 hour. After the reaction mixture was concentrated in vacuo, it was purified using silica gel chromatography (gradient: 0% to 5% methanol in dichloromethane) to give C28 as a white solid. Yield: 60 mg, 0.10 mmol, 11% from P4. LCMS m / z 603.3 [M+H] + .

[0511] 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 (P18): 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 the reaction mixture at room temperature for 2 hours, it was concentrated in vacuo, diluted with dichloromethane (10 mL), treated with sodium bicarbonate (10 mg, 0.12 mmol), and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) provided 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{3-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}benzamide (P18) as a white solid. Yield: 11.6 mg, 24.0 μmol, 24%. LCMS m / z 483.2 [M+H] + . 1 HNMR(400MHz, DMSO-d6)δ9.19–9.14(m,1H),8.48–8.39(m,2H),8.27(d,J=8.2Hz,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).

[0512] Preparation of P19

[0513] 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 (P19)

[0514]

[0515]

[0516] 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), and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo to give a residue containing C29; this material (pale yellow solid) was directly carried on to the next step.

[0517] 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 afford C30 (1.70 g), which was used directly in the following step. LCMS m / z 207.1 [M+H] + .

[0518] Step 3. Synthesis of tert-butyl [(4-{3-[5-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octane-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) were 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). After the reaction mixture was stirred at 25°C for 2 hours, it was 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 3 steps.

[0519] LCMS m / z 472.2 [M+H] + .

[0520] 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). After the reaction mixture was stirred at 100 ° C under microwave irradiation for 1 hour, it was concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% to 6% methanol in dichloromethane) gave 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) δ 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).

[0521] 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), and 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. Silica gel chromatography (Gradient: 0% to 7% methanol in dichloromethane) gave C32 as a white solid. Yield: 800 mg, quantitative. LCMS m / z 354.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.35 (br s, 2H), 2.80 (s, 2H), 2.22–2.10 (m, 6H), 1.75–1.65 (m, 6H).

[0522] 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 (P19): 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). After stirring the reaction mixture at 25° C. for 4 hours, it was 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 via 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 afford 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 (P19) as a white solid. Yield: 105 mg, 0.199 mmol, 70%. LCMS m / z 528.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.36(br s,1H),9.49(s,2H),8.20(br t, J=6Hz, 1H), 7.28 (ddd, J=11.0, 6.2, 2.3Hz, 1H), 3.09 (d, J=6.3Hz, 2H), 2.06–1.93 (m, 6H), 1.61–1.50 (m, 6H).

[0523] Preparation of P20

[0524] 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)

[0525]

[0526]

[0527] 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 hours, after which it was diluted with ice water (30 mL) and the solid was 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, integration is approximate: δ9.08 (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).

[0528] 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), after which the reaction mixture was stirred at 25 ° C for 4 hours. It was then concentrated in vacuo and subjected to silica gel chromatography (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) δ 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; mostly obscured by water peak), 1.45 (s, 9H), 1.20–1.06 (m, 2H).

[0529] 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 (4M; 2 mL, 8 mmol) was added to a solution of C33 (340 mg, 0.795 mmol) in dichloromethane (5 mL). After stirring the reaction mixture at 25° C. for 2 hours, it was 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 HNMR(400MHz,DMSO-d6)δ9.51–9.49(m,2H),8.00(br s,3H),3.14(tt,J=12.1,3.6Hz,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).

[0530] 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), and the reaction mixture was stirred at 25°C for 2 hours. It was then treated with ice water (30 mL) and the resulting solid was collected by filtration to give C35 (60 mg) as a white solid. This material was used directly in the following step. LCMS m / z 626.2 [M+Na + ]. 1 H NMR(400MHz,DMSO-d6)δ9.49(s,2H),8.56(br t,J=5.8Hz,1H),7.66–7.56(m,2H),7.34(d,J=8.5Hz,2H),6.92(d,J=8.4Hz,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).

[0531] 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 (P20): 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 hours. After removing the 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 (P20) as a white solid. Yield: 14.3 mg, 29.6 μmol, 36% over 2 steps. LCMS m / z 484.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.84(br s,1H),9.49(s,2H),8.44(br t,J=5.8Hz,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).

[0532] Preparation of P21

[0533] 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 (P21)

[0534]

[0535] 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 adding 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, which was purified via 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 minutes, then 95% B for 1.46 minutes; 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 (P21). Yield: 46.3 mg, 95.8 μmol, 44%. LCMS m / z 484.6 [M+H] +Retention time: 2.51 minutes (Analytical conditions, column: Waters Atlantis dC18, 4.6 x 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 minutes, followed by 95% B for 1.0 minute; flow rate: 2 ml / min).

[0536] Preparation of P22

[0537] 3,5-Difluoro-4-hydroxy-N-{[(1r,4r)-4-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methyl}benzamide (P22)

[0538]

[0539]

[0540] 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 hours. The reaction mixture was then concentrated under reduced pressure and diluted with dimethyl sulfoxide (8 mL); copper (i) iodide (5.71 mg, 30.0 μmol), N 1 ,N 1 ,N 2 ,N 2 -tetramethylethane-1,2-diamine (3.49 mg, 30.0 μmol) and sodium azide (39.1 mg, 0.601 mmol). After stirring the reaction mixture at 100 ° C for 8 hours, it was treated with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (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 give C36 as a brown solid. Yield: 50 mg, 93 μmol, 31%. LCMSm / z537.3[M+H] + .

[0541] 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 (P22): 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, then concentrated under reduced pressure and washed with dichloromethane (10 The mixture was treated with 1 mL of 4-nitropropane (5% dextrose) 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 (P22) as a white solid. Yield: 5.1 mg, 12 μmol, 13%. LCMS m / z 417.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.92–8.87(m,1H),8.47(brt,J=5.8Hz,1H),8.37(s,1H),7.64–7.53(m,2H),6.88(d,J=1.2Hz,1H ),4.59–4.49(m,1H),3.84(s,3H),3.17(dd,J=6,6Hz,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).

[0542] Preparation of P23

[0543] 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 (P23)

[0544]

[0545] 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 P16 (100 mg, 0.159 mmol) and 4,4,4,4,5,5,5 To a solution of 5-octamethyl-2,2-bi-1,3,2-dioxaborolane (48.5 mg, 0.191 mmol) in 1,4-dioxane (5 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.6 mg, 15.9 μmol) and potassium acetate (46.8 mg, 0.477 mmol), followed by stirring the reaction mixture at 90° C. for 12 hours. Concentration in vacuo afforded C37, which was directly carried on to the next step.

[0546]

[0266] 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). After stirring the reaction mixture at 90° C. for 12 hours, it was concentrated in vacuo and purified via 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 2 steps. LCMS m / z 628.2 [M+H] + .

[0547] 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 (P23): 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 hours. It was then concentrated in vacuo, treated with dichloromethane (10 mL) and sodium bicarbonate (1 g), and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 7% methanol in dichloromethane) provided 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 (P23) as a white solid. Yield: 6.0 mg, 12 μmol, 19%. LCMS m / z 508.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.38(br s,1H),8.91(d,J=4.8Hz,2H),8.67–8.65(m,1H),8.47(d,J=1.0Hz,1H),8.21(br t,J=6Hz,1H),8.08(dd,J=8.8,1.4Hz,1H),7.79(dd,J=8.8,0.9Hz,1H),7.43(t,J=4.8Hz,1H),7 .29(ddd,J=11.1,6.2,2.3Hz,1H),3.12(d,J=6.3Hz,2H),2.25–2.15(m,6H),1.74–1.63(m,6H).

[0548] Preparation of P24

[0549] 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 (P24)

[0550]

[0551]

[0552] 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. under microwave irradiation for 1 hour, after which it was concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 mL), treated with a solution of hydrochloric acid in 1,4-dioxane (4 M; 1 mL, 4 mmol), and stirred at 15° C. for 1 hour. After removing the solvent in vacuo, the product was purified by reverse-phase HPLC (column: Welch Xtimate C18, 30 x 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) to afford 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 (P24) as a solid. Yield: 5.2 mg, 10 μmol, 9%. LCMS m / z 495.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 2H), 9.25 (d, J = 1.3Hz, 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 =6,6Hz,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).

[0553] Preparation of P25

[0554] 2,3,5-Trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (P25)

[0555]

[0556]

[0557]

[0266] Step 1. 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 P229 (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 hours. The reaction mixture was then concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in petroleum ether) to give C40 as a white solid. Yield: 300 mg, 0.499 g, 43%. LCMS m / z 602.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.20(s,2H),9.18(s,1H),8.53–8.46(m,2H),8.08(br s,1H),7.85(d,J=8.7Hz,1H),7.45(dd,J=8.7,1.6Hz,1H),7.41–7.34(m,1H),7.35(d,J=8.6Hz,2H),6.94(d,J=8.6Hz,2H),5.22(s,2H ),4.59–4.45(m,1H),3.75(s,3H),3.18(dd,J=6,6Hz,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).

[0558]

[0266] Step 2. Synthesis of 2,3,5-trifluoro-4-hydroxy-N-({(lr,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (P25): 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 hours before it was concentrated in vacuo and purified using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in petroleum ether) to give 2,3,5-trifluoro-4-hydroxy-N-({(lr,4r)-4-[6-(pyrimidin-5-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide (P25) as a white solid. Yield: 200 mg, 0.415 mmol, 83%. LCMS m / z 482.2 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ11.41(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=8.7Hz,1H),7.45(dd,J=8.7,1.6Hz,1H),7.30(ddd,J=11.1,6.3,2.2Hz,1H),4.58–4.4 6(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).

[0559] Preparation of P26

[0560] 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 (P26)

[0561]

[0562]

[0563] 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) was added 1,4-dioxane (1.8 mL) and water (0.6 mL), followed by potassium phosphate (140 mg, 0.660 mmol) and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) [Pd(amphos)2Cl2; 15.5 mg, 21.9 μmol]. The reaction mixture was heated at 85°C for 18 hours before being 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) provided C41 as an oil. Yield: 80 mg, 0.17 mmol, 78%. LCMS m / z 460.3 [M+H] + . 1HNMR (400 MHz, chloroform-d), characteristic peaks: δ7.91 (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).

[0564] 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 at room temperature for 30 minutes before being concentrated to dryness in vacuo; the residue was azeotroped twice with dichloromethane to afford C42 (84 mg) as a colorless oil, most of which was used directly in the following step. LCMS m / z 360.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4), characteristic peaks: δ8.28–8.26 (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).

[0565] 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 (P26): 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 at room temperature for 20 minutes. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 33.9 mg, 0.173 mmol) was then added and stirring was continued at room temperature for 18 hours. The reaction mixture was diluted with water (10 mL) and acidified to pH 4 by addition of 1 M hydrochloric acid, after which it was 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; reverse phase HPLC (column: Waters Sunfire C18, 19 x 100 mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid / water (v / v); mobile phase B: 0.05% trifluoroacetic acid / acetonitrile (v / v); gradient: 20% to 60% B over 8.5 minutes, then 60% to 95% B over 0.5 minutes; 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 (P26). Yield: 29.3 mg, 46.5 μmol, 27% over 2 steps. LCMS m / z 516.5 [M+H] + Retention time: 2.59 minutes (Analytical conditions, column: Waters Atlantis dC18, 4.6 x 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 minutes, followed by 95% B for 1.0 minute; flow rate: 2 ml / min).

[0566] Preparation of P27

[0567] 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 (P27)

[0568]

[0569] 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-pyrazol (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. For the first hour, the reaction mixture was exposed to air; it was then capped, a needle was inserted through the cap to access the atmosphere, and heating was continued for an additional 17 hours. The reaction mixture was concentrated in vacuo to dryness and the residue was partitioned between dichloromethane and water. The organic layer was subjected to silica gel chromatography (gradient: 0% to 7.5% methanol in dichloromethane) to provide 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: δ8.21 (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).

[0570] 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), and the reaction mixture was stirred for 2 hours. The solvent was removed in vacuo to give a residue, which was azeotroped twice with dichloromethane to give C44 (75 mg) as a white solid; most of this material was used directly in the following step. LCMS m / z 364.3 [M+H] + .

[0571] 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 (P27): 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 by the 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 the reaction mixture was stirred at room temperature for 20 minutes, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 33.8 mg, 0.173 mmol) was added and stirring was continued for 18 hours. The reaction mixture was then diluted with water (10 mL), acidified to pH 4 by adding 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 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 minutes, then 95% B for 1.46 minutes; 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 (P27). Yield: 41.1 mg, 63.1 μmol, 39% over 2 steps. LCMS m / z 538.5[M+H] + Retention time: 3.11 minutes (Analytical conditions, column: Waters Atlantis dC18, 4.6 x 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 minutes, followed by 95% B for 1.0 minute; flow rate: 2 ml / min).

[0572] Preparation of P28

[0573] 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 (P28)

[0574]

[0575] 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 performed in a library format. 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). Subsequently, an aqueous solution of potassium phosphate (1.5 M; 0.20 mL, 300 μmol) was added, followed by the addition of chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) ( APdG2; 5 μmol), then the reaction vial was capped and shaken at 100 ° C for 16 hours. After removal of the solvent by concentrator, the residue was mixed with water (1 mL), extracted with ethyl acetate (3 x 1.5 mL), and concentrated again to afford C45; this material was directly carried on to the next step.

[0576] 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 (P28): This experiment was performed in a library format. 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 at 30°C for 16 hours. After removing the solvent using a concentrator, reverse-phase HPLC (column: YMC-Actus Triart C18, 30 x 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 (P28). Yield: 13.7 mg, 22.2 μmol, 22% over two steps. LCMS m / z 536 [M+H] +Retention time: 2.77 minutes (column: Waters XBridge C18, 2.1 x 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 minutes; 5% to 100% B over 3.4 minutes; flow rate: 0.8 mL / min).

[0577] Preparation of P29

[0578] 3,5-Difluoro-4-hydroxy-N-{[(1r,4r)-4-{5-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}cyclohexyl]methyl}benzamide (P29)

[0579]

[0580] 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), and the reaction mixture was stirred at room temperature for 1 hour. 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 (2×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 5% methanol in dichloromethane) provided the acyl intermediate as a white solid. Yield: 80 mg, 0.13 mmol, 58%. LCMS m / z 621.3 [M+H] + .

[0581] 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). After stirring the reaction mixture at 100 ° C under microwave irradiation for 1 hour, it was concentrated in vacuo. Silica gel chromatography (gradient: 0% to 7% methanol in dichloromethane) gave C46 as a white solid. Yield: 40 mg, 66 μmol, 51% from the acyl intermediate. LCMS m / z 625.3 [M + Na + ].

[0582] 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 (P29): A solution of hydrogen chloride in 1,4-dioxane (4M; 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 hours, after which it was concentrated in vacuo, diluted with dichloromethane (10 mL), and treated with sodium bicarbonate (10 mg, 0.12 mmol). After the solvent was removed 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 afford 3,5-difluoro-4-hydroxy-N-{[(1r,4r)-4-{5-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazol-3-yl}cyclohexyl]methyl}benzamide (P29) 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) δ 9.09 (br s, 1H), 8.45 (d, half of the AB quartet, J = 8.3 Hz, 1H), 8.40 (dd, component 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).

[0583] Preparation of P30

[0584] 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 (P30)

[0585]

[0586] This reaction was performed in a library format.

[0587] 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-trioxatriphosphaninane 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, after which it was cooled to room temperature, diluted with ethyl acetate (3 mL), and washed sequentially with water (2×3 mL) and saturated aqueous sodium chloride solution (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 phenol deprotection was complete. The solvent was removed under reduced pressure, and then reverse-phase HPLC (column: Waters XBridge C18, 19 x 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; flow rate: 25 mL / min) was performed to obtain 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 (P30). Yield: 13.8 mg, 27.1 μmol, 26%. LCMS m / z 492.4 [M+H] + Retention time: 2.54 minutes (Analytical conditions, column: Waters Atlantis dC18, 4.6 x 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 minutes, followed by 95% B for 1.0 minute; flow rate: 2 ml / min).

[0588] Preparation of P31

[0589] 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)

[0590]

[0591]

[0592] 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 before being cooled in an ice bath for 15 minutes; the precipitated solid was collected by filtration to afford C47 as a purple solid. Yield: 690 mg, 4.10 mmol, 74%. LCMS m / z 169.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.13 (s, 1H), 7.94 (d, J = 9.3Hz, 1H), 7.22 (d, J = 9.3Hz, 1H), 5.98 (br s, 2H), 4.05 (s, 3H).

[0593] 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) δ8.22 (d, J = 9.3 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 6.61–6.52 (m, 1H; presumed to be 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).

[0594] The acyl intermediate (134 mg, 0.309 mmol) and sodium acetate (51.2 mg, 0.624 mmol) were dissolved 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 afford 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 HNMR (400 MHz, methanol-d4) δ8.20 (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).

[0595] 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). After stirring the reaction mixture for 30 minutes, trifluoroacetic acid (0.15 mL, 1.9 mmol) was added again; after 30 minutes, the reaction mixture was treated with trifluoroacetic acid (20 μL, 0.26 mmol) again and stirred for another 5 minutes. It was then concentrated in vacuo, and the residue was azeotroped once with toluene and once with dichloromethane to give C49 (84 mg) as an oil. Most of this material was used in the following step. LCMS m / z 316.2 [M+H] + .

[0596] 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 (P31): 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 the reaction mixture was stirred at room temperature for 20 minutes, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (35.5 mg, 0.185 mmol) was added; stirring was continued at room temperature for 18 hours, after which the reaction mixture was diluted with water (10 mL), acidified to pH 4 by 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 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 minutes, then 95% B for 1.46 minutes; flow rate: 25 mL / min) gave 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 (P31). Yield: 26.6 mg, 54.3 μmol, 30% over 2 steps. LCMS m / z 490.4 [M+H] + Retention time: 2.57 minutes (Analytical conditions, column: Waters Atlantis dC18, 4.6 x 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 minutes, followed by 95% B for 1.0 minute; flow rate: 2 ml / min).

[0597] Preparation of P32

[0598] 3,5-Difluoro-N-{[(1r,4r)-4-(6-fluoro-2H-indazol-2-yl)cyclohexyl]methyl}-4-hydroxybenzamide ammonium salt (P32)

[0599]

[0600]

[0148] 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 performed in a library format. 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 filled with nitrogen. This evacuation cycle was repeated twice, after which the reaction mixture was shaken at 80°C for 4 hours 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 hours. It was then partitioned between half-saturated aqueous sodium bicarbonate solution (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 eluates were concentrated in vacuo to afford C50, which was used directly in the following step.

[0601] Step 2. Synthesis of 3,5-difluoro-N-{[(1r,4r)-4-(6-fluoro-2H-indazol-2-yl)cyclohexyl]methyl}-4-hydroxybenzamide ammonium salt (P32): This reaction was performed in a library format. 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 performed via reverse-phase HPLC (column: Waters XBridge C18, 19 x 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 minutes, then 95% for 1.46 minutes; flow rate: 25 mL / min) to afford 3,5-difluoro-N-{[(1r,4r)-4-(6-fluoro-2H-indazol-2-yl)cyclohexyl]methyl}-4-hydroxybenzamide ammonium salt (P32). Yield: 11.4 mg, 27.1 μmol, 18% over 2 steps. LCMS m / z 404.4 [M+H] + Retention time: 2.61 minutes (Analytical conditions, column: Waters Atlantis dC18, 4.6 x 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 minutes, then 95% B for 1.0 minute; flow rate: 2 ml / min).

[0602] Preparation of P33

[0603] N-{[(1r,4r)-4-{3-[6-(2,2-dimethylpropionamido)pyridazin-3-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide ammonium salt (P33)

[0604]

[0605]

[0606] 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 after which 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 HNMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.08 (d, J = 9.1Hz, 1H), 7.88 (d, J = 9.0Hz, 1H), 6.15 (br s, 2H).

[0607]

[0266] 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 minutes, C51 (261 mg, 1.51 mmol) and N,N-diisopropylethylamine (0.717 mL, 4.12 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. 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 (400MHz, DMSO-d6) δ8.52(br t,J=5.8Hz,1H),8.15(d,J=9.0Hz,1H),8.01(d,J=9.0Hz,1H),7.64–7.55(m,2H),7.34(d,J=8.6Hz,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 value; almost completely obscured by the 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).

[0608] 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 hour. The resulting solid was isolated by filtration and washed with a 10:1 mixture of ethanol and water to afford 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(400MHz,DMSO-d6)δ8.55(br t,J=5.8Hz,1H),8.32(d,J=9.0Hz,1H),8.14(d,J=8.9Hz,1H),7.65–7.56(m,2H),7.34(d,J=8.6Hz,2H),6.92(d,J=8.6Hz,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).

[0609] Step 3. Synthesis of N-{[(1r,4r)-4-{3-[6-(2,2-dimethylpropionamido)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-dimethylpropionamide (9.8 mg, 97 μmol), palladium(II) acetate (0.906 mg, 4.04 μmol), ([1,1-binaphthyl]-2,2-diyl)bis(diphenylphosphine) (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 filled with nitrogen. This evacuation cycle was repeated twice, after which the reaction vial was heated to 100° C. for 18 hours. After the reaction mixture was partitioned 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 afford C53 (64 mg) as a brown oil. This material was used directly in the following step. LCMS m / z 635.4 [M+H] + .

[0610] Step 4. Synthesis of N-{[(1r,4r)-4-{3-[6-(2,2-dimethylpropionamido)pyridazin-3-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide ammonium salt (P33): 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 hour before being concentrated in vacuo and azeotroped twice with dichloromethane. Reverse-phase HPLC (column: Waters XBridge C18, 19 x 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 minutes, then 50% to 95% B over 0.5 minutes, then 95% for 1.0 minutes, flow rate: 25 mL / min) afforded N-{[(1r,4r)-4-{3-[6-(2,2-dimethylpropionamido)pyridazin-3-yl]-1,2,4-oxadiazol-5-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide ammonium salt (P33). Yield: 4.2 mg, 7.9 μmol, 10% over 2 steps. LCMS m / z 515.3 [M+H] +Retention time: 2.83 minutes (Analytical conditions, column: Waters Atlantis dC18, 4.6 x 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 minutes, then 95% B for 1.0 minute; flow rate: 2 ml / min).

[0611] Preparation of P34

[0612] 3,5-Difluoro-4-hydroxy-N-({(1r,4r)-4-[4-(quinoxalin-6-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}methyl)benzamide (P34)

[0613]

[0614]

[0615]

[0146] Step 1. Synthesis of 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 performed in a library format. 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 at 125°C for 40 minutes. When the reaction mixture returned to room temperature, it was treated with aqueous sodium hypochlorite (8% to 10%; 1.0 mL) and the vial was shaken at 30° C. for 5 minutes; The solvent was removed by concentrator to afford C54. This material was directly carried on to the next step.

[0616] 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 (P34): This reaction was performed in a library format. 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), after which the reaction vial was capped and shaken at 30°C for 16 hours. After removing the solvent using a concentrator, the residue was purified via reverse-phase HPLC (column: YMC-Actus Triart C18, 30 x 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 provide 3,5-difluoro-4-hydroxy-N-({(1r,4r)-4-[4-(quinoxalin-6-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}methyl)benzamide (P34). Yield: 9.1 mg, 20 μmol, 20%. LCMS m / z 465 [M+H] + Retention time: 2.46 minutes (analytical conditions, column: Waters XBridge C18, 2.1 x 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 minutes; 5% to 100% B over 3.4 minutes; flow rate: 0.8 ml / min).

[0617] Preparation of P35

[0618] 2,3,5-Trifluoro-4-hydroxy-N-({(1r,4r)-4-[6-(4-methylpiperazin-1-yl)-2H-indazol-2-yl]cyclohexyl}methyl)benzamide trifluoroacetate (P35)

[0619]

[0620] 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 glove box under nitrogen, a scintillation vial was charged with P229 (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)]methanesulfonate palladium(II) (RuPhos PdG3; 13.9 mg, 16.6 μmol). The contents of the vial were stirred for 2 minutes, after which toluene (1.7 mL) was added; to the resulting solution was added 1-methylpiperazine (27.6 μL, 0.249 mmol), and the vial was transferred to a heating block. The reaction mixture was slowly heated to 90°C with vigorous stirring and then maintained at 90°C overnight. It was then allowed to cool to room temperature, concentrated in vacuo, dissolved in ethyl acetate (50 mL), and washed sequentially with water (3×50 mL) and saturated aqueous sodium chloride solution (25 mL). The organic layer was concentrated under reduced pressure to give an oil (106 mg). LCMS analysis indicated that both C55 and P35 were present in this material, most of which was used directly in the following step. LCMS m / z 622.5 and 502.4 [M+H] + .

[0621] 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 (P35): Trifluoroacetic acid (50 μL, 0.65 mmol) was added to a solution of C55 and P35 (from the previous step; 103 mg, ≤0.161 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.5 mL). After stirring the reaction mixture at room temperature overnight, it was concentrated in vacuo and purified via 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% over 8.5 minutes, then 35% to 95% over 0.5 minutes; 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 (P35). Yield: 40 mg, 65 μmol, 40% over 2 steps. LCMS m / z 502.3 [M+H] +Retention time: 1.91 minutes (Analytical conditions, column: Waters Atlantis dC18, 4.6 x 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 minutes, followed by 95% B for 1.0 minute; flow rate: 2 ml / min).

[0622] Preparation of P36

[0623] 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 (P36)

[0624]

[0625]

[0626] 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). After stirring the reaction mixture at 100° C. for 16 hours, it was concentrated in vacuo; silica gel chromatography (eluent: 5% methanol in dichloromethane) gave 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(400MHz,DMSO-d6)δ8.55(br t,J=5.6Hz,1H),7.84(s,1H),7.69–7.55(m,4H),7.33(d,J=8.5Hz,2H),6.92(d,J=8.4Hz,2H),5.17(s,2H),4.43(s,2 H),4.04–3.92(m,1H),3.74(s,3H),3.12(dd,J=6,6Hz,2H),1.89–1.70(m,4H),1.63–1.46(m,3H),1.19–1.04(m,2H).

[0627] 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) was added tetrakis(triphenylphosphine)palladium(0) (19.3 mg, 16.7 μmol), and the reaction mixture was stirred at 100°C for 16 hours. After removal of the solvent by vacuum concentration, 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] + .

[0628] 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 (P36): 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 hour, after which it was concentrated in vacuo and purified via 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: 25% to 45% B; flow rate: 20 mL / min) to afford 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 (P36). Yield: 15.8 mg, 32.9 μmol, 53%. LCMS m / z 481.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.37(br t,J=5.8Hz,1H),7.97(br s,1H),7.89(dd,J=7.9,1.4Hz,1H),7.77(d,J=2.3Hz,1H),7.66(d,J=7.9Hz,1H),7.59–7.47(m,2H),6.79(d,J=2.3Hz,1H),4.46(s ,2H),4.00(tt,J=12.2,3.8Hz,1H),3.90(s,3H),3.12(dd,J=6,6Hz,2H),1.90–1.73(m,4H),1.65–1.49(m,3H),1.20–1.05(m,2H).

[0629] Preparation of P37

[0630] 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 (P37)

[0631]

[0632]

[0633] 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), and the reaction mixture was stirred at 65° C. After 1.5 hours, 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 another hour and then diluted with water and extracted three times with dichloromethane. The combined organic layers were concentrated in vacuo to afford C58 (1.75 g) as a yellow solid, most of which was carried on to the next step. 1 H NMR (400MHz, 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).

[0634]

[0148] 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 hour, allowed to cool to room temperature, and concentrated in vacuo to remove most of the solvent. After the residue was acidified to pH 2 to 3 by the addition of 1 M hydrochloric acid, the mixture was extracted three times with ethyl acetate. At this time, the aqueous layer was acidified again to reach 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 light yellow solid. Yield: 1.42 g, 4.60 mmol, 90% over 2 steps. LCMS m / z 307.2 [MH] - . 1 HNMR (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).

[0635] 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, bis(pentafluorophenyl)carbonate (98%, 20 mg, 51 μmol) was added and stirring was continued for 10 minutes, followed by the addition of P10 (500 mg, 1.02 mmol) and stirring at room temperature for another 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 solution, 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 via silica gel chromatography (gradient: 30% to 100% ethyl acetate in heptane) to give C60 as a yellow solid. Yield: 474 mg (corrected for residual dichloromethane), 0.621 mmol, 61%. LCMSm / z 764.5 [M + H] + .1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=4.8Hz,1H),8.35(br t,J=6.3Hz,1H),7.38–7.31(m,1H),7.36(br d,J=8.6Hz,2H),7.30(d,J=4.8Hz,1H),6.94(brd,J=8.7Hz,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=6.2Hz,2H),1.94–1.84(m,6H),1.57–1.48(m,6H),1.43(s,9H).

[0636] 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 about -15°C and treated dropwise with trimethylsilyl trifluoromethanesulfonate (0.796 mL, 4.40 mmol). The reaction mixture was stirred at -15°C overnight, although the temperature of the cooling bath had reached 12°C by morning. The reaction mixture was then cooled in an ice bath, after which 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 sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was co-evaporated three times with dichloromethane to afford C61 as a yellow solid. Yield: 673 mg, 1.01 mmol, 92%. LCMS m / z 664.4 [M+H] + . 1 HNMR (400MHz, chloroform-d) δ8.51(d,J=4.8Hz,1H),7.59(ddd,J=11.7,6.8,2.3Hz,1H),7.34(d,J=8.6Hz,2H),7.22(d ,J=4.8Hz,1H),6.88(d,J=8.6Hz,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=6Hz,2H),3.04–2.91(m,4H),2.07–1.96(m,6H),1.66–1.56(m,6H).

[0637]

[0266] 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). After stirring the reaction mixture at 25 °C for 1 hour, it was treated with aqueous solution and extracted with dichloromethane (2 x 30 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (eluent: 5% methanol in dichloromethane) provided C62 as a yellow solid. Yield: 72.0 mg, 0.106 mmol, 70%. LCMS m / z 678.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ8.65(d,J=4.9Hz,1H),8.36(br t,J=6.2Hz,1H),7.37–7.30(m,1H),7.36(d,J=8.5Hz,2H),7.27(d,J=4.8Hz,1H),6.94(d,J=8.4Hz,2H),5.22(s,2H),3.8 4–3.76(m,4H),3.75(s,3H),3.06(d,J=6.2Hz,2H),2.45–2.34(m,4H),2.23(s,3H),1.92–1.84(m,6H),1.58–1.47(m,6H).

[0638] 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 (P37): A solution of hydrogen chloride in 1,4-dioxane (4M: 1 mL, 4 mmol) was added to a solution of C62 (72.0 mg, 0.106 mmol) in dichloromethane (4 mL). After stirring the reaction mixture at 25° C. for 1 hour, it was concentrated in vacuo and purified via reverse phase HPLC (column: Waters XBridge C18, 19×150 mm, 5 μm, 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 (P37) 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 peaks: δ8.75 (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).

[0639] Using similar procedures, compounds of preparations P38 to P226 were synthesized as described in Tables 1 and 2.

[0640] Table 1. Structures and IUPAC names of preparations P38 to P226.

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668] Table 2. Synthesis methods and physicochemical data of formulations P38 to P226.

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683] 1. Reaction of P3 with 2-nitrobenzaldehyde followed by ring closure of the resulting imine with triethyl phosphite and deprotection using hydrogen chloride / 1,4-dioxane afforded preparation P38.

[0684] 2. Trifluoroacetic acid was used for the final deprotection instead of hydrogen chloride.

[0685] 3. Prepare the desired 1-[(1r,4r)-4-(6-methoxy-2H-indazol-2-yl)cyclohexyl]methanamine hydrochloride using the method described in Preparation P15 for the synthesis of C25.

[0686] 4. In this case, the boronate coupling is catalyzed by tetrakis(triphenylphosphine)palladium(0) rather than [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0687] 5. The desired chloro-substituted 1-[(1r,4r)-4-(2H-indazol-2-yl)cyclohexyl]methanamine hydrochloride was prepared using the method described for the synthesis of C25 in Preparation P15.

[0688] 6. Prepare the desired 1-{(1r,4r)-4-[6-(pyrimidin-2-yl)-2H-indazol-2-yl]cyclohexyl}methanamine hydrochloride using the method described for the synthesis of P13 in Preparation P13.

[0689] 7. Prepare the desired 1-{(1r,4r)-4-[6-(pyrazin-2-yl)-2H-indazol-2-yl]cyclohexyl}methanamine hydrochloride using the method described for the synthesis of P13 in Preparation P13.

[0690] 8. tert-Butyl {[(1r,4r)-4-(6-bromoimidazo[1,2-a]pyridin-2-yl)cyclohexyl]methyl}carbamate was synthesized from C19 using the method described for the synthesis of P11 in Preparation P11. This material was converted to the desired 1-{(1r,4r)-4-[6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl]cyclohexyl}methanamine hydrochloride by reaction with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in the presence of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium carbonate, followed by deprotection with hydrogen chloride.

[0691] 9. The desired N-{[(1r,4r)-4-(5-chloro-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide was synthesized according to the method described for Preparation P15.

[0692] 10. Cyclopropylmethanol was deprotected with sodium hydride / tetrahydrofuran at 0° C., followed by addition of N-{[(1r,4r)-4-(5-chloro-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (see footnote 9), and the reaction mixture was heated at 80° C. for 16 hours. Subsequent deprotection using trifluoroacetic acid afforded Preparation 32.

[0693] 11. Analytical HPLC conditions: Column: Waters XBridge C18, 2.1 x 50 mm, 5 μm; Mobile phase A: Water containing 0.0375% trifluoroacetic acid; Mobile phase B: Acetonitrile containing 0.01875% trifluoroacetic acid; Gradient: 10% B for 0.50 min; 10% to 100% B over 3.5 min; Flow rate: 0.8 ml / min.

[0694] 12. A mixture of N-{[(1r,4r)-4-(5-chloro-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide (see footnote 9), [6-(trifluoromethyl)pyridin-2-yl]methanol, tris(dibenzylideneacetone)dipalladium(0), 5-(di-tert-butylphosphanyl)-1,3,5-triphenyl-1H-1,4-bipyrazole (BippyPhos), and sodium hydroxide was heated in a 4:1 mixture of 2-methylbutan-2-ol and dichloromethane at 105° C. for 16 hours. Subsequent deprotection using trifluoroacetic acid afforded Preparation 33.

[0695] 13. Analytical HPLC conditions: Column: Waters XBridge C18, 2.1 x 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 minutes; 5% to 100% B over 3.4 minutes; Flow rate: 0.8 mL / min.

[0696] 14. Intermediate P14 is reacted with an appropriate aromatic bromide in the presence of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and tripotassium phosphate, followed by deprotection with hydrogen chloride.

[0697] 15. Column: Waters Atlantis dC18, 4.6 x 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 minutes, linear, then 95% B for 1.0 minute; Flow rate: 2 ml / min.

[0698] 16. In this case, 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was used instead of chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) ( A Pd G2).

[0699] 17. Coupling was performed using the conditions described in step 1 of the preparation of P26; subsequent deprotection of the product was achieved using trifluoroacetic acid.

[0700] 18. In this case, a chlorine reactant is used instead of a bromide.

[0701] 19. In this case, 5-bromo-1H-pyrrolo[2,3-b]pyridine is reacted with p-toluenesulfonyl chloride in the presence of N,N-diisopropylethylamine, and the resulting 5-bromo-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is used in the coupling reaction.

[0702] 20. In this case, the acyl intermediate was cyclized by treatment with sodium acetate rather than tetrabutylammonium fluoride.

[0703] 21. The desired 4-({3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octane-1-carboxylic acid was synthesized using the method described for Preparation P9, but using P1 as the starting material.

[0704] 22. The final deprotection was carried out using 1,1,1,3,3,3-hexafluoropropan-2-ol with methanesulfonic acid instead of hydrogen chloride.

[0705] 23. P1 was converted to the desired N-[(4-aminobicyclo[2.2.2]octan-1-yl)methyl]-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide using the method described for the preparation of P3. This intermediate was condensed with 2-nitro-5-(trifluoromethyl)benzaldehyde, followed by ring closure of the resulting imine with triethyl phosphite and deprotection with hydrogen chloride to afford Preparation P141.

[0706] 24. P7 was reacted with 4-[(fluorosulfonyl)oxy]benzoic acid (A. Baranczak et al., J. Am. Chem. Soc. 2015, 137, 7404–7414), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 1H-benzotriazol-1-ol, and N,N-diisopropylethylamine to give the acyl intermediate; this was treated with tetrabutylammonium fluoride to give 3,5-difluoro-N-({4-[5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]bicyclo[2.2.2]octan-1-yl}methyl)-4-[(4-methoxyphenyl)methoxy]benzamide. Reaction with (4-acetamidophenyl)imidodisulfonyl difluoride (AISF) and cesium carbonate followed by deprotection via treatment with hydrogen chloride afforded Preparation P142.

[0707] 25. Use p-toluenesulfonic acid instead of hydrogen chloride for the final deprotection.

[0708] 26. In this case, the acyl intermediate was cyclized by heating in 1-methylpyrrolidin-2-one rather than treatment with sodium acetate.

[0709] 27. Methyl 4-(aminomethyl)bicyclo[2.2.2]octane-1-carboxylate was protected by reaction with benzyl chloroformate and triethylamine, followed by ester cleavage using sodium hydroxide. The resulting 4-({[(benzyloxy)carbonyl]amino}methyl)bicyclo[2.2.2]octane-1-carboxylic acid was converted to benzyl [4-(1,3-benzoxazol-2-yl)bicyclo[2.2.2]octan-1-yl]methyl}carbamate using the method described for the synthesis of C26 from P4 in Preparation P17; subsequent hydrogenation over palladium / carbon afforded the desired 1-[4-(1,3-benzoxazol-2-yl)bicyclo[2.2.2]octan-1-yl]methanamine.

[0710] 28. The desired 1-(4-{3-[6-(trifluoromethyl)pyridazin-3-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methanamine was prepared using the method described in Preparation P19 for the synthesis of C32.

[0711] 29. The desired chloro-substituted 1-[(1r,4r)-4-(2H-indazol-2-yl)cyclohexyl]methanamine hydrochloride was prepared using the method employed for the synthesis of C25 in Preparation P15.

[0712] 30. The reaction of C49 with P1 was mediated by O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to give 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-({4-[3-(6-methoxypyridazin-3-yl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide. This material was demethylated using trimethylsilyl chloride and potassium iodide to give 3,5-difluoro-4-[(4-methoxyphenyl)methoxy]-N-({4-[3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,4-oxadiazol-5-yl]bicyclo[2.2.2]octan-1-yl}methyl)benzamide, which was N-methylated using methyl 4-nitrobenzene-1-sulfonate and cesium carbonate; deprotection using trifluoroacetic acid gave Preparation P162.

[0713] 31. Tert-butyl {[(1r,4r)-4-aminocyclohexyl]methyl}carbamate was converted to 1-{(1r,4r)-4-[5-(trifluoromethyl)-2H-pyrazolo[3,4-c]pyridin-2-yl]cyclohexyl}methanamine hydrochloride using the procedure described for the synthesis of P22 from P3 in the preparation of P22.

[0714] 32. 1-{(1r,4r)-4-[6-(1-ethyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methanamine hydrochloride was prepared from P12 using the method described for the synthesis of P13 in the preparation of P13.

[0715] 33. 1-{(1r,4r)-4-[6-(Difluoromethyl)-2H-indazol-2-yl]cyclohexyl}methanamine trifluoroacetate was prepared from C20 by reaction with 2-(difluoromethanesulfonyl)pyridine and zinc in the presence of nickel(II) chloride ethylene glycol dimethyl ether complex, 4-methylpyridine-2,6-dicarboximidamide (see JME Hughes and PSFier, Org. Lett. 2019, 21, 5650–5654) and tetraethylammonium iodide; subsequent deprotection was performed using trifluoroacetic acid.

[0716] 34. tert-Butyl ({(1r,4r)-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]cyclohexyl}methyl)carbamate was prepared in the same manner as in Preparation P12. It was then converted to the desired 1-{(1r,4r)-4-[5-(pyrimidin-2-yl)-2H-indazol-2-yl]cyclohexyl}methanamine hydrochloride using the method described in Preparation P13.

[0717] 35. Tert-butyl ({(1r,4r)-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]cyclohexyl}methyl)carbamate (see footnote 34) was converted to the desired 1-{(1r,4r)-4-[5-(1-methyl-1H-pyrazol-4-yl)-2H-indazol-2-yl]cyclohexyl}methanamine hydrochloride via the method described for the synthesis of C41 from P12 in Preparation P26, followed by deprotection using hydrogen chloride.

[0718] 36. P12 was converted to the desired 2-(4-{2-[(1r,4r)-4-(aminomethyl)cyclohexyl]-2H-indazol-6-yl}-1H-pyrazol-1-yl)ethan-1-ol using the method described for the synthesis of C41 from P12 in the preparation of P26, followed by deprotection with hydrogen chloride.

[0719] 37. Using the method described for the synthesis of C41 from P12 in the preparation of P26, P12 was reacted with 4-bromo-1-(oxetan-3-yl)-1H-pyrazole. Subsequent deprotection with hydrogen chloride also cleaved the oxetane ring to give 2-(4-{2-[(1r,4r)-4-(aminomethyl)cyclohexyl]-2H-indazol-6-yl}-1H-pyrazol-1-yl)-3-chloropropan-1-ol.

[0720] 38. Tert-butyl {[(1r,4r)-4-(6-bromoimidazo[1,2-a]pyridin-2-yl)cyclohexyl]methyl}carbamate was synthesized from C19 using the method described for the synthesis of P11 in Preparation P11. This material was coupled with 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in the presence of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and potassium carbonate, followed by deprotection with hydrogen chloride to give the desired 1-[(1r,4r)-4-{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridin-2-yl}cyclohexyl]methanamine hydrochloride.

[0721] 39. In this case, the final amide formation utilizes 2,3-difluoro-4-hydroxybenzoic acid instead of P1.

[0722] 40. The desired 1-(4-{3-[5-(trifluoromethyl)pyrazin-2-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methanamine hydrochloride was prepared as follows: 4-{[(tert-butoxycarbonyl)amino]methyl}bicyclo[2.2.2]octane-1-carboxylic acid was reacted with N'-hydroxy-5-(trifluoromethyl)pyrazine-2-carboximidamide using 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 1-methyl-1H-imidazole; the resulting acyl intermediate was cyclized by heating in 1-methylpyrrolidin-2-one at 120° C. and subsequently deprotected with hydrogen chloride.

[0723] 41. In this case, hydrogen chloride was used for intermediate deprotection rather than trifluoroacetic acid. In addition, the final coupling was performed using O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine rather than the reagents described in Preparation P31.

[0724] 42. Tert-butyl {[(1r,4r)-4-aminocyclohexyl]methyl}carbamate is condensed with 2-nitro-5-(trifluoromethyl)benzaldehyde, followed by ring closure of the resulting imine with triethyl phosphite and deprotection with hydrogen chloride to afford the desired 1-{(1r,4r)-4-[5-(trifluoromethyl)-2H-indazol-2-yl]cyclohexyl}methanamine hydrochloride.

[0725] 43. In this case, hydrogen chloride was used for deprotection of the intermediate instead of trifluoroacetic acid.

[0726] 44. Tert-butyl {[(1r,4r)-4-aminocyclohexyl]methyl}carbamate is reacted with methyl 2-(bromomethyl)-4-chlorobenzoate and triethylamine, followed by deprotection with hydrogen chloride to afford the desired 2-[(1r,4r)-4-(aminomethyl)cyclohexyl]-5-chloro-2,3-dihydro-1H-isoindol-1-one hydrochloride.

[0727] 45. The desired 1-[(1r,4r)-4-(5-chloro-2H-pyrazolo[3,4-c]pyridin-2-yl)cyclohexyl]methanamine hydrochloride was prepared using the method described in Preparation P15 for the synthesis of C25.

[0728] 46. ​​In this case, 3-hydroxybenzoic acid was used instead of 4-[(fluorosulfonyl)oxy]benzoic acid.

[0729] 47. Treatment of tert-butyl [4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]carbamate with methanesulfonyl chloride and triethylamine, followed by displacement of the resulting methanesulfonate group using sodium azide and potassium carbonate, affords tert-butyl [4-(azidomethyl)bicyclo[2.2.2]octan-1-yl]carbamate. This material is hydrogenated over palladium on carbon, and the resulting primary amine is acylated with P1 by reaction with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 1H-benzotriazol-1-ol. Deprotection of the product via hydrogenation over palladium on carbon affords Preparation P208.

[0730] 48. In this case, the acyl intermediate was cyclized by treatment with tetrabutylammonium fluoride rather than sodium acetate.

[0731] 49. The reaction of 4-{[(tert-butoxycarbonyl)amino]methyl}bicyclo[2.2.2]octane-1-carboxylic acid with N'-hydroxy-6-(trifluoromethyl)pyridine-3-carboximidamide N'-hydroxy-4-(trifluoromethyl)benzene-1-carboximidamide mediated by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 1-methyl-1H-imidazole, followed by heating the acyl intermediate in 1-methylpyrrolidin-2-one, yielded the desired 1-(4-{3-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}bicyclo[2.2.2]octan-1-yl)methanamine hydrochloride.

[0732] 50. In this case, hydrogen chloride was used for the final deprotection step.

[0733] 51. The desired N-{[4-(6-bromo-2H-indazol-2-yl)bicyclo[2.2.2]octan-1-yl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide was prepared using the methods described for the synthesis of P16 and P8.

[0734] 52. Deprotection of N-{[4-(6-bromo-2H-indazol-2-yl)bicyclo[2.2.2]octan-1-yl]methyl}-3,5-difluoro-4-[(4-methoxyphenyl)methoxy]benzamide described in footnote 51 using hydrogen chloride gave Preparation P221.

[0735] 53. The final coupling was performed with 2,3,5-trifluoro-4-hydroxybenzoic acid instead of P1.

[0736] Preparation of P227

[0737] N-{[4-(Bromoacetyl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamide (P227)

[0738]

[0739]

[0740] Step 1. Synthesis of N-methoxy-N-methyl-4-({2,3,5-trifluoro-4-[(4-methoxyphenyl)methoxy]benzamido}methyl)bicyclo[2.2.2]octane-1-carboxamide (C68): To a solution of P9 (8.00 g, 16.8 mmol), N-methoxymethylamine hydroch...

Claims

1. A compound of formula II or a pharmaceutically acceptable salt thereof, in: A is -NH-C(O)-, -C(O)- or heteroaryl, wherein heteroaryl has 1, 2, 3 or 4 heteroatoms selected from O, N and S, and wherein A is optionally substituted by one or two R 4 replace; R 1 、R 2 and R 3 are each independently selected from H and fluorine; R 4 is selected from oxo, hydroxy, chloro, fluoro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl, (C3-C6)cycloalkyl and heterocyclyl, wherein the heterocyclyl has 1, 2 or 3 heteroatoms selected from O and N; n is 0, 1, or 2; L is a linker; and E is an E3 ubiquitin ligase binder.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IIB:

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is:

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L has the formula: in: B is absent; or is aryl, heteroaryl, heterocyclyl, -C(O)-, (C1-C6)alkylene, (C3-C6)cycloalkylene, (C1-C6)fluoroalkylene, (C1-C6)alkoxy or (C1-C6)fluoroalkoxy, wherein the heteroaryl or heterocyclyl has 1, 2 or 3 heteroatoms selected from O, N and S, and wherein B is optionally replaced by one or two R 5 replace; C does not exist; or is -NH-C(O)-R 7 、-S(O)2-R 7 、-OS(O)2-R 7 , -C(O)-, (C1-C6)alkylene, (C1-C6)aminoalkylene, (C3-C6)cycloalkylene, (C1-C6)alkoxy, (C3-C6)cyclic ether, (C1-C6)fluoroalkylene, (C1-C6)fluoroalkoxy, aryl, heteroaryl or heterocyclic group, wherein the heteroaryl or heterocyclic group has 1, 2 or 3 heteroatoms selected from O, N and S, and wherein C is optionally replaced by one, two or three R 6 replace; D is (C1-C6)alkylene, (C1-C6)aminoalkylene, -NH(C1-C6)alkylene, (C1-C6)alkoxy, -C(O)-, aryl, heteroaryl, heterocyclyl, (C0-C6)alkylene-heterocyclyl-C(O)-, -C(O)-(C1-C6)alkylene, heterocyclyl-(C1-C6)alkylene-aryl-(C1-C6)alkoxy, (C1-C6)heterocyclyl-(C1-C6)heterocyclyl-C(O)-, (C0-C2)alkylene-aryl-(C1-C6)alkoxy, -O-heterocyclyl-C(O)-, (C1-C6)cycloalkyl-(C1-C6)heterocyclyl, wherein the heteroaryl or heterocyclyl has 1, 2 or 3 heteroatoms selected from O, N and S, wherein D is optionally replaced by one or two R 8 Substitute; or be a bond; R 5 、R 6 and R 8 are each independently selected from oxo, hydroxy, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl, (C3-C6)cycloalkyl, heteroaryl, and heterocyclyl, wherein the heterocyclyl has 1, 2, or 3 heteroatoms selected from O and N; R 7 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkyl or (C3-C6)cycloalkyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein B is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, piperazinyl, quinoxalinyl, phenyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, imidazolyl, indazolyl, (C1-C6)alkylene, (C1-C6)fluoroalkylene, (C1-C6)alkoxy, pyrrolopyridinyl, isoindolyl, isoquinolyl, tetrahydroisoquinolyl, thiazolopyridinyl , tetrahydrothiazolopyridinyl, imidazopyrazinyl, tetrahydroimidazopyrazinyl, pyrazolopyrazinyl, tetrahydropyrazolopyrazinyl, phenyl, oxadiazaspirodecanyl, diazaspirooctane or diazaspirodecan-1-one, wherein B is optionally substituted with one or two halogen, oxo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)fluoroalkyl, (C1-C6)alkoxy or (C3-C6)cyclic ether.

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein C is (C1-C3) alkylene, (C1-C6) aminoalkylene, (C1-C6) alkoxy, pyridyl, oxolanyl, (C3-C6) cycloalkyl, (C1-C6) fluoroalkylene, -C(O)-, piperazinyl, piperidinyl, azetidinyl, azaspiroundecyl, azaspironanyl, azaspiroundecyl, diazaspirooctane, diazaspiro decyl, diazaspironanyl, diazaspirododecanyl, diazaspiroundecyl, oxadiazaspironanyl, oxadiazaspiroundecyl, oxa-azaspirodecanyl, decahydronaphthyridinyl, octahydropyrrolopyridinyl or octahydropyridopyrazinyl; wherein C is optionally substituted with one, two or three halogen, oxo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)fluoroalkyl or (C1-C6)alkoxy.

8. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein D is (C1-C6)alkylene, (C1-C6)aminoalkylene, (C1-C6)alkoxy, -C(O)-, (C0-C6)alkylene-heterocyclyl-C(O)-, -C(O)-(C1-C6)alkylene, heterocyclyl-(C1-C6)alkylene-aryl-(C1-C6)alkoxy, (C1-C6)heterocyclyl-(C1-C6)heterocyclyl-C(O)-, (C0-C2)alkylene-aryl-(C1-C6)alkoxy, -O-heterocyclyl-C(O)-, (C1-C6)cycloalkyl-(C1-C6)heterocyclyl; or a bond.

9. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein: A is a heteroaryl group; B is a heteroaryl group; C is a heterocyclyl group; and D is (C1-C3)alkylene.

10. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein: A is indazolyl or oxadiazolyl; B is a pyrimidinyl group; C is piperazinyl; and D is methylene, ethylene or propylene.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein E comprises a benzimidazolinone, a dihydropyrimidine-dione or thalidomide.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein E is selected from the group consisting of:

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-{[(1r,4r)-4-{6-[2-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)-2,3-dihydro-1H-isoindol-5-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[4-(7-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-5-yl}imidazo[1,2-a]pyridin-2-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-(6-{2-[8-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl}-2H-indazol-2-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-{6-[6-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-(6-{5-[4-(2-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}ethyl)piperazin-1-yl]pyrazin-2-yl}-2H-indazol-2-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-(6-{6-[4-(2-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}ethyl)piperazin-1-yl]pyrazin-2-yl}-2H-indazol-2-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-{6-[4-(2-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}ethyl)piperazin-1-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-{6-[5-(4-{3-[3-(2,4-dioxo-1,3-diazacycloinan-1-yl)pyrazolo[1,5-a]pyridin-6-yl]propyl}piperazin-1-yl)pyrazin-2-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide hydrochloride; N-{[4-(4-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,3-thiazol-2-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[4-(3-{6-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyridazin-3-yl}-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[4-(2-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,3-thiazol-4-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-{5-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]-2H-pyrazolo[4,3-b]pyridin-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-(5-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,2,4-oxadiazol-3-yl)cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[4-(2-{2-[4-(3-{1-[(3RS)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl}propyl)piperazin-1-yl]pyrimidin-4-yl}-1,3-oxazol-5-yl)bicyclo[2.2.2]octan-1-yl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-{6-[2-(4-{3-[3-(2,4-dioxo-1,3-diazacycloinan-1-yl)imidazo[1,2-a]pyridin-7-yl]propyl}piperazin-1-yl)pyrimidin-5-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-{6-[2-(4-{8-[3-(2,4-dioxo-1,3-diazacyclohexan-1-yl)-4-methylbenzoyl]-1-oxa-8-azaspiro[4.5]decan-3-yl}piperazin-1-yl)pyrimidin-5-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide; and N-{[(1r,4r)-4-{6-[4-({4-[({2-[(3RS)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)methyl]phenyl}methyl)piperazin-1-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-3,5-difluoro-4-hydroxybenzamide; N-{[(1r,4r)-4-{6-[2-(2-{4-[3-(2,4-dioxo-1,3-diazacycloinan-1-yl)-4-methylbenzoyl]piperazin-1-yl}ethoxy)pyrimidin-5-yl]-2H-indazol-2-yl}cyclohexyl]methyl}-2,3,5-trifluoro-4-hydroxybenzamide.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, vehicle or diluent.

15. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in treating a condition selected from the group consisting 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, adrenal cortical carcinoma, renal papillary cell carcinoma, cervical cancer and endocervical cancer, bladder urothelial carcinoma, lung adenocarcinoma, type 1 diabetes, idiopathic type 1 diabetes (type 1b), adult Latent autoimmune diabetes mellitus (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, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, and maple syrup urine disease.

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