Indazole derivatives as cannabinoid receptor partial agonists

Abstract

To provide indazole derivatives as cannabinoid receptor partial agonists.SOLUTION: The invention includes modulation of CB2, including peripheral partial agonists of one or more CB receptors, with and without CB1 selectivity. The disclosed compounds may be useful in the treatment of diseases and disorders mediated by CB signaling pathways, including, but not limited to, pains, gastrointestinal disorders, metabolic disorders, and hepatic disorders such as alcoholic fat hepatitis or non-alcoholic fat hepatitis (NASH). The present invention provides novel cannabinoid (CB) receptor partial agonists and uses thereof. The compounds of the invention are believed to be useful in the treatment of diseases and conditions caused by physiological processes associated with cannabinoid receptors, including appetite control, cardiovascular regulation, metabolic syndrome, liver disease, pain control, learning and memory, gastrointestinal disorders, inflammatory diseases, and drug addiction.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Federally funded research This invention was made with government support under No. R01 DK100414 and No. R01 AA022235, both awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 967,713, filed January 30, 2020, the contents of which are incorporated herein by reference in their entirety.

[0003] FIELD OF THE INVENTION The present invention provides novel cannabinoid (CB) receptor partial agonists and uses thereof. The compounds of the present invention are believed to be useful in treating diseases and conditions resulting from physiological processes associated with cannabinoid receptors, including appetite control, cardiovascular control, metabolic syndrome, liver disease, pain control, learning and memory, gastrointestinal disorders, inflammatory diseases, and drug addiction. [Background technology]

[0004] Background of the Invention Cannabinoid CB1 and CB2 receptors are components of the endocannabinoid system, which is involved in important physiological processes such as cardiovascular regulation, learning and memory, appetite, and pain management. See, for example, Mackie, K. Cannabinoid receptors as therapeutic targets, Annu. Rev. Pharmacol. Toxicol., 46, 101-122; Howlett, AC (2006) (Non-Patent Document 1); Breivogel, C.S.; SR, C.; Deadwyler, S.A.; Hampson, R.E.; Porrino, L.J. Cannabinoid physiology and pharmacology: 30 years of progress, Neuropharmacology, 47 Suppl 1, 345-358 (2004) (Non-Patent Document 2); and Di, M.; Bisogno, T.; De Petrocellis, L. Endocannabinoids: new targets for drug development, Curr Pharm Des, 6, 1361-80 (2000) (Non-Patent Document 3), each of which is incorporated herein by reference for its teaching of the background art.

[0005] CB receptors have been demonstrated to be viable targets in numerous disorders, including obesity, drug addiction, pain, inflammation, gastrointestinal disease, liver disease, multiple sclerosis, psychosis, schizophrenia, and osteoporosis. Pertwee, R.G. The therapeutic See AAPS Journal, 7, E625-54 (2005) (which is incorporated herein by reference for its teachings) for potential drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. A wide range of selective and non-selective agonists and antagonists for cannabinoids have been developed to date. All of the currently approved cannabinoid drugs are tetrahydrocannabinol (Δ 9 These drugs contain CB1-THC, the basic psychoactive component of the plant Cannabis sativa, or its synthetic analog (nabilone). However, they are prescribed with many limitations due to adverse effects such as marijuana-like psychoactivity and addictive tendencies. Rimonabant (SR141716A), a CB1-selective antagonist / inverse agonist, was first approved for the treatment of obesity but was subsequently withdrawn due to the risk of suicidal ideation. The narrow therapeutic window due to psychoactive effects limits the potential of CB-mediated therapies.

[0006] One alternative approach to targeting CB1-mediated signaling pathways is to develop allosteric modulators that bind to uncover binding sites from orthosteric sites. See, e.g., Christopoulos, A. Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov, 1, 198-210 (2002) (Non-Patent Document 5); and Bridges, TM; Lindsley, CWG-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem. Biol., 3, 530-541 (2008) (Non-Patent Document 6), each of which is incorporated herein for its background teachings. Another alternative approach to targeting CB1-mediated signaling pathways is to develop peripherally restricted full agonists. For example, Adam et al., Low Brain Penetrant CB1 Receptor Agonists for the Treatment of Neuropathic Pain. Bioorganic & Medicinal Chemistry Letters, 22, 2932-2937 (2012) (Non-Patent Document 7); and Cumella et al., Chromenopyrazoles: Non-psychoactive and Selective See CB1 Cannabanoid Agonists with Peripheral Antinociceptive Properties. ChemMedChem, 7, 452-463 (2012) (each of which is incorporated by reference herein for its background teachings regarding peripherally restricted full agonists). There is a need to develop additional alternative approaches to achieve the beneficial effects of CB-mediated therapeutics without the negative side effects associated with CNS permeability regulators. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Mackie, K. Cannabinoid receptors as therapeutic targets, Annu. Rev. Pharmacol. Toxicol., 46, 101-122; Howlett, AC (2006). [Non-patent document 2] Breivogel, CS; SR, C.; Deadwyler, SA; Hampson, RE; Porrino, LJCannabinoid physiology and pharmacology: 30 years of progress, Neuropharmacology, 47 Suppl 1, 345-358 (2004). [Non-patent document 3] Di, M.; Bisogno, T.; De Petrocellis, L. Endocannabinoids: new targets for drug development, Curr Pharm Des, 6, 1361-80 (2000). [Non-patent document 4] Pertwee, RG The therapeutic potential of drugs that target cannabinoid receptors or modulate the cannabinoid tissue levels or actions of endocannabinoids. AAPS Journal, 7, E625-54 (2005). [Non-patent document 5] Christopoulos, A. Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov, 1, 198-210 (2002). [Non-patent document 6] Bridges, TM; Lindsley, CWG-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem. Biol., 3, 530-541 (2008). [Non-Patent Document 7] Adam et al., Low Brain Penetrant CB1 Receptor Agonists for the Treatment of Neuropathic Pain. Bioorganic & Medicinal Chemistry Letters, 22, 2932-2937 (2012). [Non-patent document 8] Cumella et al., Chromenopyrazoles: Non-psychoactive and Selective CB1 Cannabanoid Agonists with Peripheral Antinociceptive Properties. ChemMedChem, 7, 452-463 (2012). Summary of the Invention [Means for solving the problem]

[0008] Summary of the Invention The present disclosure includes peripheral partial agonists of CB receptors, including CB1, with and without CB2 selectivity. The compounds of the present disclosure may be useful in treating diseases and disorders mediated by the CB signaling pathway, including, but not limited to, pain, gastrointestinal disorders, and metabolic disorders, including liver disorders, such as both non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH).

[0009] One embodiment of the present disclosure is a compound of formula (I): [ka] And, R1 is unsubstituted or substituted C 1-10 Alkyl, C 1-10 Haloalkyl, (CH2) n -cycloalkyl, (CH2) n -heterocyclyl, (CH2) n -aryl or (CH2) n -heteroaryl, n is 1, 2, or 3; X is CH or N; Y is CHR 3 or CR 4 R 5 and R 3 is C 1-4 is alkyl, R 4 and R 5 are each independently C 1-4 alkyl, or R 4 and R 5 can be taken together with the carbon atom to which they are attached to form a 3- to 7-membered cycloalkyl or heterocycloalkyl ring; L is a divalent C 1-3 Alkyl or C 2-3 is alkenyl, o is 0 or 1, V is a divalent aryl, heteroaryl, cycloalkyl, heterocyclyl, C 2-3 Alkyl or C 2-3 is alkenyl, Z is H, F, Cl, CF3, Me, CN, OMe, OCF3 or OCHF2; R 2 teeth, (i)(CH2) p C(O)NHR a , (ii) NHC(O)R b , (iii)NR c C(O)NHR a , or (iv) NH(C=NR d )NHR a and p is 0, 1 or 2; R a is H, C 1-4 Alkyl, C 3-6 is cycloalkyl, heterocyclyl, aryl or heteroaryl; R b is C 1-4 Alkyl, C 3-6 is cycloalkyl, heterocyclyl, aryl or heteroaryl; R c is H or C 1-4 is alkyl, R d are H, CN, and C 1-4 Alkyl or C 3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0010] One embodiment includes where X is N. One embodiment includes where Y is CR 4 R 5 An embodiment includes that Y is C(CH3)2. An embodiment includes that V is a divalent aryl, heteroaryl, cycloalkyl, or heterocyclyl. An embodiment includes that R 2 is (CH2) p C(O)NHR a , NHC(O)R b , or NHC(O)NHR a and R a is H, C 1-4 Alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; R b is C 1-4 Alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl. 2 is (CH2) p C(O)NHR a , or NHC(O)NHR a and R a is H, C 1-4 Alkyl, C 3-6cycloalkyl, heterocyclyl, aryl, or heteroaryl. One embodiment includes that o is 0. One embodiment includes that o is 1 and L is a divalent C 1-3 In one embodiment, n is 1. In one embodiment, Z is H or F.

[0011] One embodiment of the present disclosure includes a method of treating a disease in a mammal susceptible to modulation of one or more CB receptors, the method comprising administering an effective amount of a compound of the present disclosure. In one aspect, the disease is selected from the group consisting of angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmotrophic small round cell tumor, renal cell carcinoma, and the like. The diseases include cystic carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher's disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry's disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. In one embodiment, the disease is a liver disorder or liver disease, such as fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

[0012] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable carriers.

[0013] One embodiment of the present disclosure includes the use of a compound of the present disclosure for the preparation of a medicament for treating a disease in a mammal sensitive to modulation of one or more CB receptors, wherein the treatment comprises administering an effective amount of the compound. In one aspect, the disease is angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, obesity, liver injury, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or nonalcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. In one embodiment, the disease is a liver injury or liver disease, such as fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

[0014] One embodiment of the present disclosure includes a compound of the present disclosure for use as an active therapeutic substance.One embodiment includes a compound of the present disclosure for use in the treatment of diseases mediated by one or more CB receptors.In one aspect, the disease is angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, obesity, liver injury, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. In one embodiment, the disease is a liver injury or liver disease, such as fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing biliary tract infection. It's tube inflammation.

[0015] One embodiment of the present disclosure includes a method of treating one or more diseases selected from angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH), comprising administering an effective amount of a compound of the present disclosure. In one embodiment, the disease is a metabolic disorder, obesity, liver injury, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or nonalcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. In one embodiment, the disease is a liver injury or liver disease, such as fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

[0016] One embodiment of the present disclosure includes use of a compound of the present disclosure for the preparation of a medicament for treating one or more diseases selected from angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH), wherein the treating comprises administering an effective amount of the compound. In one embodiment, the disease is a metabolic disorder, obesity, liver injury, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or nonalcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. In one embodiment, the disease is a liver injury or liver disease, such as fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

[0017] One embodiment of the present disclosure includes a compound of the present disclosure for use in the treatment of one or more diseases selected from angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). In one embodiment, the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). The disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. In one embodiment, the disease is a liver disorder or liver disease, such as fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

[0018] Preferably, the compounds of the present disclosure may be used in cases where CB receptor agents exhibit superior efficacy and experience reduced side effects, resulting in improved efficacy, pharmacokinetics, and safety.

[0019] The compounds of the present disclosure are believed to be useful as peripheral partial agonists of one or more CB receptors, including modulation of CB1 with or without CB2 selectivity. The compounds of the present disclosure may be useful in treating diseases and disorders mediated by the CB signaling pathway, including, but not limited to, pain, gastrointestinal disorders, and metabolic disorders, including liver disorders (e.g., nonalcoholic steatohepatitis (NASH)).

[0020] The scope of the present invention includes all combinations of aspects, embodiments and preferences described herein.

[0021] Detailed Description of the Invention The following definitions are meant to clarify, but not limit, the defined terms. As used herein, if a particular term is not specifically defined, that term should not be considered indefinite. Rather, the term is used in its generally accepted sense.

[0022] As used throughout this specification, suitable numbers of atoms, such as carbon atoms, are used, for example, as "C x-y The term "alkyl" refers to an alkyl group having a specified number of carbon atoms as defined herein. Similar terminology applies to other suitable terms and ranges as well. Thus, for example, C 1-4 Alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms.

[0023] The term "alkyl," as used herein alone or in combination with other terms, refers to a straight-chain or branched-chain hydrocarbon. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, sec-butyl, isopentyl, n-pentyl, n-hexyl, and the like. An alkyl group can be substituted or unsubstituted.

[0024] As used herein, the term "alkenyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-carbon double bonds, which can be optionally substituted, with multiple degrees of substitution allowed. Examples of "alkenyl" as used herein include, but are not limited to, vinyl and allyl.

[0025] As used herein, the term "alkylene" refers to an optionally substituted straight-chain divalent hydrocarbon radical. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

[0026] As used herein, the term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-carbon triple bonds, with multiple carbon-carbon triple bonds being permitted. It may be optionally substituted, with varying degrees of substitution. Examples of "alkynyl" as used herein include, but are not limited to, ethynyl.

[0027] As used herein, the term "cycloalkyl" refers to a fully saturated, optionally substituted monocyclic, bicyclic, or bridged hydrocarbon ring, with multiple degrees of substitution permitted. Exemplary "cycloalkyl" groups as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0028] As used herein, the term "heterocycle" or "heterocyclic," as used herein, refers to a cycloalkyl group in which one or more carbon atoms have been replaced by N, O, S, or Si. The heterocycle can be attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Representative examples of monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxa Representative examples of bicyclic heterocycles include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also includes bridged heterocyclic systems such as, for example, azabicyclo[3.2.1]octane and azabicyclo[3.3.1]nonane.

[0029] As used herein, the term "heterocyclyl" refers to a non-aromatic monocyclic ring or a fused non-aromatic polycyclic ring having one or more heteroatoms independently selected from N, S, and O, the remaining ring atoms being carbon, with at least one heteroatom present in each non-aromatic ring. The heterocyclyl group can be a three-, four-, five-, six-, or seven-membered ring. In certain embodiments, the heterocyclyl group is 1,4-dioxane, 1,3-dioxolane, 1,4-dithiane, imidazolidine, morpholine, piperidine, piperidone, piperazine, pyrrolidone, pyrrolidine, or 1,3,5-trithiane. It may contain an imide. Heterocyclyl groups can be bicyclic, e.g., heterospiro groups, such as heterospiro[3.3]heptanyl, heterospiro[3.4]octanyl, or heterospiro[5.5]undecanyl. Heterocyclyl groups can be substituted or unsubstituted. Thus, heterocyclyl groups include heterocycloalkyl groups substituted with one or more halogens, e.g., 3,3-difluoropiperidine or 4,4-difluoropiperidine. Furthermore, heterocyclyl groups can be substituted with a C1-C4 alkyl group or a C1-C4 haloalkyl group, e.g., a -CF3 group.

[0030] As used herein, the term "aryl" refers to a single benzene ring or a fused benzene ring system, which may be optionally substituted, with multiple degrees of substitution permitted. Examples of "aryl" groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, anthracene, and phenanthrene. Suitable aryl rings have 6 to 10 members.

[0031] As used herein, fused benzene ring systems included within the scope of the term "aryl" include fused multi-membered cyclic hydrocarbons, i.e., cyclic hydrocarbons having fewer than the maximum number of non-cumulative double bonds, such as a saturated hydrocarbon ring (a cycloalkyl, e.g., a cyclopentyl ring) fused to an aromatic ring (an aryl, e.g., a benzene ring) to form groups such as indanyl and acenaphthalenyl, and also include, by way of non-limiting example, groups such as dihydronaphthalene and tetrahydronaphthalene.

[0032] As used herein, the term "heteroaryl" refers to a monocyclic 5- to 7-membered aromatic ring, or a fused bicyclic aromatic ring system containing two such aromatic rings, which may be optionally substituted, with multiple degrees of substitution permitted. Preferably, the ring contains 5 to 10 members. These heteroaryl rings contain one or more nitrogen, sulfur, and / or oxygen atoms, with N-oxides, sulfur oxides, and dioxides being permissible heteroatom substituents. Examples of "heteroaryl" groups as used herein include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzoxazole, benzothiophene, indole, indazole, benzimidazole, imidazopyridine, pyrazolopyridine, and pyrazolopimidimidine.

[0033] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0034] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted with at least one halogen. Examples of branched or straight-chain "haloalkyl" groups, as used herein, include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl, each independently substituted with one or more halogens (e.g., fluoro, chloro, bromo, and iodo). The term "haloalkyl" should be interpreted to include substituents such as perfluoroalkyl groups (e.g., -CF).

[0035] As used herein, the term "substituted" refers to a functional group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Exemplary substituents include CN, NO, OH, oxo, C-C alkoxy, O-C-C haloalkyl, SC-C alkyl, SC-C haloalkyl, halogen, C-C alkyl, C-C haloalkyl, COH, NH, NH(C-C alkyl), N(C 1-3 alkyl), SO, H, NHSO, C-C alkyl, SO, NH, SO, C-C alkyl, NHC(O)(C-C alkyl), and C-C cycloalkyl.

[0036] Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. The salts encompassed by "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention. Salts of the compounds of the present invention may include acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, and napsylate. Salts include salts such as nitrates, N-methylglucamine, oxalates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, potassium salts, salicylates, sodium salts, stearates, diacetates, succinates, sulfates, tannates, tartrates, teoclates, tosylates, triethiodide, trimethylammonium salts, and valerates. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and are to be considered to form a further aspect of the invention.

[0037] The compounds of formula (I) may crystallize in more than one form, a property known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism can generally occur as a function of temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical properties, such as, for example, x-ray diffraction patterns, solubility, and melting point.

[0038] As used herein, the term "effective amount" refers to an amount of a drug or pharmaceutical agent that elicits the biological or medical response of a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. The term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject who does not receive such amount. This term also includes within its scope an amount effective to enhance normal physiological function.

[0039] For use in therapy, therapeutically effective amounts of the compounds of formula (I) and their salts or solvates may be administered as the raw chemical. Additionally, the active ingredients may be presented as pharmaceutical compositions.

[0040] Accordingly, the present invention further provides pharmaceutical compositions comprising an effective amount of one or more compounds of formula (I), or salts or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I) and salts or solvates thereof are as described herein. The carrier, diluent, or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.

[0041] The compounds of this invention can be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are shown below, and specific compounds of the invention are prepared in the working examples.

[0042] In all examples shown below, protecting groups for sensitive or reactive groups are used where necessary in accordance with general principles of synthetic chemistry. Protecting groups are used according to standard methods of organic synthesis (T.W. Green and P.G.M. Butts (1999), Protecting Groups in Organic Synthesis, 3 rdProtecting groups are typically manipulated according to the principles of the present invention (see, e.g., Protecting Groups, vol. 1, pp. 111-115, 1997, John Wiley & Sons, Inc., incorporated by reference with respect to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes and reaction conditions and the order in which they are carried out are consistent in the preparation of compounds of the present invention.

[0043] The present invention also provides methods for the synthesis of novel compounds that are useful as synthetic intermediates in the preparation of compounds of formula (I) and compounds of the present invention.

[0044] As shown below, the compounds can be prepared according to methods using readily available starting materials and reagents. In these reactions, variants known per se to those skilled in the art can occur, but the details of which will not be mentioned.

[0045] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. The replacement of a hydrogen atom by deuterium or tritium, or 13 C or 14 Compounds with existing structures, except for the replacement of a carbon atom with a C-enriched carbon, are included within the scope of the present invention. For example, deuterium is widely used to investigate the pharmacokinetics and metabolism of biologically active compounds. Although deuterium behaves similarly to hydrogen from a chemical standpoint, there are significant differences in bond energy and bond distance between deuterium-carbon bonds and hydrogen-carbon bonds. As a result, the replacement of hydrogen with deuterium in a biologically active substance can result in compounds with significantly different absorption, distribution, metabolism, and / or excretion (ADME) properties compared to their non-isotopic counterparts, while retaining biochemical potency and selectivity. Thus, deuterium substitution can result in improved efficacy, safety, and / or tolerability in some biologically active compounds.

[0046] According to another aspect of the present invention there is also provided a process for preparing a pharmaceutical formulation, which process comprises admixing a compound of formula (I) or salts, solvates and physiologically functional derivatives thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0047] The therapeutically effective amount of a compound of the present invention depends on several factors. For example, the recipient's species, age, and weight, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to consider. The therapeutically effective amount should ultimately be at the discretion of the attending physician or veterinarian. Nevertheless, an effective amount of a compound of Formula (I) for treating a human suffering from frailty should generally be in the range of 0.1 to 100 mg per kg of recipient (mammal) body weight per day. More generally, the effective amount should be in the range of 0.1 to 20 mg / kg body weight / day. Thus, for a 70 kg adult mammal, an example of a practical amount per day would typically be 10 to 2000 mg. This amount can be given as a single dose per day or in a number of divided doses (e.g., 2, 3, 4, 5, or more) per day so that the total daily dose is the same. The effective amount of a salt or solvate thereof can be determined as a percentage of the effective amount of the compound of Formula (I) itself. Similar dosages should be appropriate for treating other conditions mentioned herein. Pharmaceutical formulations may be presented in unit dosage forms containing a predetermined amount of active ingredient per unit dosage. Such units may contain, by way of non-limiting example, 1 mg to 2 g of a compound of formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose as described herein above, or an appropriate fraction thereof, of the active ingredient. Such pharmaceutical formulations may be prepared by any method well known in the art of pharmacy.

[0048] Pharmaceutical formulations may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such formulations may be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient into association with the carrier(s) or excipient(s). By way of example, and not meant to limit the invention, for certain conditions and disorders for which the compounds of the present invention are believed to be useful, certain routes may be preferred over others. Furthermore, pharmaceutical formulations may be used to allow delayed or prolonged exposure to the compound of formula (I) in circumstances where such delayed or prolonged exposure would improve treatment.

[0049] Pharmaceutical formulations suitable for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids, respectively; edible foams or whips; or oil-in-water or water-in-oil liquid emulsions. For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with an oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Generally, powder is prepared by grinding the compound to a suitable fine size and mixing it with a suitable pharmaceutical carrier, such as an edible carbohydrate, for example, starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents can also be present.

[0050] Capsules can be made by preparing a powder, liquid, or suspension mixture and encapsulating it with gelatin or some other suitable shell material. Before encapsulation, glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the mixture. Disintegrating or solubilizing agents such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Examples of suitable binders include starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth, or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants useful for these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

[0051] Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and compressing into tablets. Powder mixtures can be prepared by mixing appropriately comminuted compounds with the diluents or bases described above. Optional ingredients include binders (e.g., carboxymethylcellulose, alginates, gelatin, or polyvinylpyrrolidone), solution retarders (e.g., paraffin), resorption accelerators (e.g., quaternary salts), and / or absorbents (e.g., bentonite, kaolin, or dicalcium phosphate). The powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulose or polymer materials and forced through a screen. As an alternative to granulation, the powder mixture can be run through a tablet machine, resulting in imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet-forming dies by the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.The compounds of the present invention can also be combined with a free-flowing inert carrier and directly compressed into tablets without granulating or slugging.A transparent or opaque protective coating can be provided, consisting of a shellac sealing coat, a sugar or polymer material coating, and a wax polish coating.Dyes can be added to these coatings to distinguish different unit dosages.

[0052] Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given amount contains a predetermined amount of compound.Syrups can be prepared, for example, by dissolving the compound in a suitable flavored aqueous solution, and elixirs are prepared by using a non-toxic alcoholic vehicle.Suspensions can generally be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers (e.g., ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives; flavoring additives (e.g., peppermint oil), or natural sweeteners, saccharin, or other artificial sweeteners, etc., can also be added.

[0053] Where appropriate, dosage unit formulations for oral administration can be microencapsulated. Formulations can also be, for example, coated or embedded with particulate material in polymers, wax, or the like. The release can also be formulated to be extended or sustained by administration of the compound.

[0054] Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouthwashes.

[0055] The compounds of the present invention, or their salts or solvates, may be used alone or in combination with other therapeutic agents. The compound of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately, and when administered separately, administration may occur simultaneously or sequentially in any order. The amounts of the compound of formula (I) and the other pharmaceutically active agent(s) and the relative timing of administration are selected to achieve the desired combined therapeutic effect. The administration of the compound of formula (I) or its salts or solvates in combination with the other therapeutic agent(s) may be by simultaneous administration (1) in a single pharmaceutical composition containing the combination of compounds; or (2) in separate pharmaceutical compositions, each containing one of the compounds. Alternatively, the combination may be administered separately in a sequential manner, with one therapeutic agent being administered first and the other therapeutic agent being administered second, or vice versa. Such sequential administration may be close in time or remote in time.

[0056] Those skilled in the art of organic synthesis will appreciate that there are multiple means to prepare radiolabeled compounds of the present invention suitable for a variety of uses.

[0057] Compound synthesis

[0058] One method for preparing the imidazoles of the present disclosure involves the synthesis of intermediate 3 according to Scheme 1 below. Preparation of compound 3 began with commercially available imidazole 3-carboxy ester 1, which was N-alkylated and then hydrolyzed to provide carboxylic acid 2 (reactions a and b). Carboxylic acid 2 was coupled with an amine to provide amide 3 (reaction c).

[0059] Scheme 1 [ka]

[0060] In Scheme 1, the reagents and conditions include: (a) RBr, K2CO3, MeCN, 60°C; (b) 2N NaOH, dioxane, 50°C; and (c) R'NH2, HBTU, NEt3, MeCN, 50°C.

[0061] Amides and ureas were then prepared from intermediate 3 using the procedures shown in Scheme 2. As shown, arylcarboxamide products were synthesized from aryl bromides such as 4. The aryl bromides were converted to aryl nitriles using a palladium catalyzed reaction (reaction a, part 1). The aryl nitriles were then hydrolyzed to arylcarboxamides 5 using aqueous base and hydrogen peroxide (reaction a, part 2).

[0062] Alternatively, aryl bromides 4 were readily converted to carboxamides via lithiation with n-BuLi followed by reaction with trimethylsilyl-isocyanate (TMS-NCO, reaction b).

[0063] For piperidine-containing products such as 7, a Boc-protected piperidine intermediate such as 6 can be used. The compound was hydrolyzed with aqueous acid (reaction c), reacted with TMS-NCO to give the urea (reaction d, R'' = C(=O)NH2), or alkylated with chloroacetamide to give the carboxamide (reaction e, R'' = CH2C(=O)NH2).

[0064] Aryl ureas such as 9 were prepared from anilines such as 8. Unsubstituted aryl ureas 9 (R' = H) were prepared by the reaction of TMS-NCO with aniline 8 (reaction f). Substituted aryl ureas 9 were prepared by the reaction of 8 with carbamoyl chloride (reaction g).

[0065] Scheme 2 [ka]

[0066] In Scheme 2, the reagents and conditions include: (a)(1) Zn(CN), Pd(PPh), DMF, 70°C; (a)(2) 6N NaOH, 50% HO, EtOH, room temperature; (b) n-BuLi, THF, -78°C, followed by TMS-CN, room temperature; (c) 6N HCl, EtOH, 55°C; (d) TMS-NCO, DCE, room temperature; (e) ClCHCONH, KCO, MeCN, 50°C; (f) TMS-NCO, DCE, 60°C; and (g) R'NHCOCl, pyridine, DCE, room temperature.

[0067] Indole-based products were prepared using similar procedures as for indazoles and similar commercially available starting materials. [Example]

[0068] Table 1: Synthetic Examples [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0069] The present disclosure includes pharmaceutically acceptable salt forms of the exemplified compounds.

[0070] Abbreviations: As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with the symbols and conventions used in contemporary scientific literature (e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry). Specifically, the following abbreviations may be used: g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliter); psi (pounds per square inch); M (molar); mM (millimolar); Hz (Hertz); MHz (Megahertz); mol (mole); mmol (millimol); RT or rt (room temperature); hr (hours); min (minutes); TLC (thin layer chromatography); mp (melting point); RP (reverse phase); T r (retention time); TFA (trifluoroacetic acid); TEA (triethylamine); THF (tetrahydrofuran); TFAA (trifluoroacetic anhydride); CD3OD (deuterated methanol); CDCl3 (deuterated chloroform); DMSO (dimethyl sulfoxide); SiO2 (silica gel); atm (atmospheric pressure); EtOAc (ethyl acetate); CHCl3 (chloroform); HCl (hydrochloric acid); Ac (acetyl); DMF (N,N-dimethylformamide); Me (methyl); Cs2CO3 (cesium carbonate); EtOH (ethanol); Et(ethyl); t-Bu(tert-butyl); MeOH (methanol); p-TsOH (p-toluenesulfonic acid); DCM (dichloromethane); DCE (dichloroethane) Et2O (diethyl ether); K2CO3 (potassium carbonate); Na2CO3 (sodium carbonate); i-PrOH (isopropyl alcohol) NaHCO3 (sodium bicarbonate); ACN (acetonitrile); Pr(propyl); i-Pr(isopropyl); PE (petroleum ether); Hex (hexane); H2SO4 (sulfuric acid); HCl (hydrochloric acid); Et3N (triethylamine); Na2SO4 (sodium sulfate); MTBE (methyl tert-butyl ether); Boc (tert-butoxycarbonyl); DIPEA (diisopropylethylamine); IPA (isopropanol); HMDS (hexamethyldisilazane); NH4Cl (ammonium chloride); NH4CO3 (ammonium carbonate); MgSO4 (magnesium sulfate); NH4OH (ammonium hydroxide).

[0071] General chemistry.

[0072] Compound purity and characterization was performed by a combination of LC / MS, NMR, HPLC and TLC analytical techniques as shown below. Unless otherwise stated, 1 H spectra were recorded on a Bruker Avance DPX-300 (300 MHz) spectrometer and determined in chloroform-d (7.26 ppm) and methanol-d (3.31 ppm) using trimethylsilane (TMS, 0.00 ppm) as an internal standard. Chemical shifts are reported in ppm relative to the TMS signal, and coupling constant (J) values ​​are reported in hertz (Hz). Thin-layer chromatography (TLC) was performed on precoated silica gel 60 F plates. TLC spots were visualized by UV light or I detection.

[0073] LC / MS was performed using an Agilent InfinityLab MSD single quadrupole gravimetric spectrometer equipped with an API-ES and an Agilent Infinity II 1260 HPLC equipped with an Agilent Infinity 1260 variable wavelength detector and a Phenomenex Synergi 2.5 m Hydro-RP 100A C18 30x2 mm column. HPLC method: 20% solvent B starting at 0.6 mL / min for 0.4 min, followed by a gradient of 20% to 95% solvent B at 0.6 mL / min for 1.3 min, followed by 95% solvent B at 0.6 mL / min for 0.3 min, and then a final stepwise increase in flow rate at 1.2 mL / min (solvent A: water with 0.1% formic acid; solvent B: acetonitrile with 0.1% formic acid and 5% water; absorbance was monitored at 220 nm and 280 nm). MS method: Electrospray ionization was performed under atmospheric pressure, and positive and negative ions were monitored in the range of 70 to 700.

[0074] Unless otherwise specified, all test compounds were at least 95% pure as determined by HPLC. HPLC method: Waters 2695 Separation Module equipped with a Waters 2996 Photodiode Array Detector and a Phenomenex Synergi 4 μm Hydro-RP 80A C18 250 x 4.6 mm column. Starting with 5% solvent B at a flow rate of 1 mL / min for 1 minute, followed by a 5% to 95% solvent B gradient for 15 minutes, followed by 95% solvent B for 9 minutes (Solvent A: water with 0.1% TFA; Solvent B: acetonitrile with 0.1% TFA and 5% water; absorbance monitored at 220 nm and 280 nm).

[0075] General Procedure A: N-Alkylation of Indazole 1 or Similar Indoles. A mixture of indazole 1 (4 mmol) or the analogous indole, alkyl bromide (2.2 mmol, 1.1 equiv.), K2CO3 (1.7 g, 3 equiv.), and MeCN (6 mL) was stirred at room temperature for 15 min, followed by 15 h at 60 °C for the indazole and 15 h at 70 °C for the indole. Ethyl acetate (40 mL) was added, followed by water (8 mL) and brine (16 mL). After 10 min, the aqueous layer was removed. Celite (5 g) and toluene (4 mL) were added to the organic layer, and the solvent was evaporated. Flash chromatography on silica gel using a gradient of EtOAc / hexane afforded the purified N-alkylated indazole or analogous indole.

[0076] General Procedure B: Hydrolysis of Indazole-3-carboxymethyl Ester or Similar Indoles. To a solution of N-alkylated indazole-3-carboxymethyl ester (3 mmol) or similar indoles in dioxane (6 mL) was added 2N NaOH (3 mL, 2 equiv.). The resulting mixture was heated to 50°C for 15 hours for indazoles and 60°C for 15 hours for indoles. The mixture was acidified with 6N HCl (1.1 mL, 2.1 equiv.). Ethyl acetate (30 mL) and brine (6 mL) were added. The aqueous layer was saturated with sodium chloride and the layers were separated. The aqueous layer was extracted with ethyl acetate (1 x 3 mL). The combined organic layers were dried (sodium sulfate, 20 min) and filtered. Toluene (3 mL) was added, and the solvent was evaporated to give N-alkylated indazole-3-carboxylic acid 2 or similar indoles.

[0077] General Procedure C: Hydrolysis of Indazole Amide 3 or Similar Indoles. To a heterogeneous mixture of N-alkylated indazole 3-carboxylic acid 2 (0.2 mmol) or similar indole, HBTU (84 mg, 1.1 equiv.), and MeCN (1 mL) was added NEt (0.061 mL, 2.2 equiv.). The mixture was stirred at room temperature for 30 min. An amine (1.1 equiv.) was added, and after 30 min, the mixture was heated to 50 °C for 15 h. Water (0.8 mL) was added, and after 5 min, EtOAc (3 mL) was added, followed by brine (0.8 mL). After 10 min, the aqueous layer was removed and the organic layer was washed with 0.5 M NaHCO solution (0.8 mL). Celite (600 mg) was added to the organic layer, and the solvent was evaporated. Purified indazole amide 3 or similar indole was obtained by flash chromatography on silica gel with an EtOAc / hexane gradient.

[0078] General Procedure D: Aryl Nitriles from Aryl Bromides 4. Under dim light and nitrogen, Pd(PPh3)4 (70 mg, 0.2 equiv.) was added to a solution of aryl bromide 4 (0.3 mmol) or the analogous indole with Zn(CN)2 (110 mg, 3 equiv.) in DMF (1 mL). The mixture was stirred at room temperature for 10 min and then heated at 70–75 °C for 20 h. Ethyl acetate (4 mL) was added, followed by water (1 mL), and then saturated NaHCO3 solution (2 mL). After 10 min, the aqueous layer was removed and the organic layer was washed with brine (2 × 1 mL). Celite (800 mg) was added to the organic layer, and the solvent was evaporated. The purified nitrile was obtained by flash chromatography on silica gel with a gradient of EtOAc / hexanes.

[0079] General Procedure E: Arylcarboxamide 5 from Aryl Nitrile. To a mixture of arylnitrile (0.2 mmol) in EtOH (0.8 mL) was added 50% HO (0.2 mL), followed by 6N NaOH (0.2 mL). The mixture was stirred vigorously at room temperature for 20 h. Ethyl acetate (3 mL) was added, followed by brine (0.6 mL). After 10 min, the aqueous layer was removed, Celite (500 mg) was added to the organic layer, and the solvent was evaporated. Flash chromatography on silica gel with a gradient containing up to 4% MeOH in EtOAc / hexanes afforded the purified arylcarboxamide 5.

[0080] General Procedure F: Arylcarboxamide 5 from Aryl Bromide 4. To a solution of aryl bromide 4 (0.2 mmol) in THF (1 mL) was added dropwise 2.5 M n-BuLi in hexane (0.16 mL, 2 equiv.) at −78 °C (IPA / dry ice bath). After 5 min, TMS-NCO (0.041 mL, 1.5 equiv.) was added in one portion. After 1 h, 2 N HCl (0.24 mL) was added dropwise, and the IPA / dry ice bath was removed. The mixture was stirred at room temperature for 30 min. Ethyl acetate (3 mL) was added, followed by brine (0.6 mL). After 10 min, the aqueous layer was removed, Celite (600 mg) was added to the organic layer, and the solvent was evaporated. Purified arylcarboxamide 5 was obtained by flash chromatography on silica gel with a gradient of EtOAc / hexane containing up to 4% MeOH.

[0081] General Procedure G: Deprotection of Boc-Piperidine 6. To a mixture of Boc-protected piperidine 6 (0.2 mmol) and ethanol (1 mL) was added 6N HCl (0.5 mL). The mixture was stirred at room temperature for 10 minutes and then at 55°C for 15 hours. Chloroform (3 mL) followed by brine (0.5 mL) was added, followed by the slow addition of 6N NaOH (0.55 mL). After 10 minutes, the organic and aqueous layers were separated. The aqueous layer was saturated with NaCl and extracted with CHCl (2 x 1 mL). The combined organic layers were dried (NaSO for 20 minutes) and filtered. Toluene (1 mL) was added, and the solvent was evaporated to give the deprotected piperidine.

[0082] General Procedure H: Reaction of TMS-NCO with piperidine. To a solution of piperidine (0.15 mmol) in DCE (1 mL) was added TMS-NCO (0.025 mL, 1.2 equiv.). The mixture was stirred at room temperature for 15 h. Water (0.1 mL) and EtOAc (1 mL) were added. After 15 min, Celite (600 mg) was added and the solvent was evaporated. Flash chromatography on silica gel with a gradient containing up to 6% MeOH in EtOAc / hexanes afforded the purified piperidine urea 7.

[0083] General Procedure I: Alkylation of piperidine with chloroacetamide. A mixture of piperidine (0.2 mmol), chloroacetamide (23 mg, 1.2 equiv.), KCO (83 mg, 3 equiv.), and MeCN (1 mL) was stirred at room temperature for 15 min and then heated at 50 °C for 15 h. EtOAc (3 mL) was added, followed by water (0.8 mL), and then brine (0.8 mL). After 10 min, the aqueous layer was removed, Celite (600 mg) was added, and the solvent was evaporated. Flash chromatography on silica gel with a gradient containing up to 8% MeOH in EtOAc / hexanes afforded the purified carboxamide 7.

[0084] General Procedure J: Reaction of aniline 5 with TMS-NCO. To a solution of aniline 8 (0.15 mmol) in DCE (1 mL) was added TMS-NCO (0.025 mL, 1.2 equiv.). The mixture was stirred at room temperature for 1 h and then at 60 °C for 20 h. Water (0.1 mL), MeOH (0.1 mL), and EtOAc (1 mL) were added. After 15 min, Celite (600 mg) was added and the solvent was evaporated. Flash chromatography on silica gel with a gradient containing up to 4% MeOH in EtOAc / hexanes afforded the purified aryl urea 9.

[0085] General Procedure K: Reaction of aniline 8 with an acid chloride or chloroformate. To a solution of aniline 8 (0.15 mmol) in DCE (1 mL) was added the acid chloride or chloroformate (1.2 equiv.), followed by pyridine (0.18 mL, 1.5 equiv.). The mixture was stirred at room temperature for 15 h. EtOAc (3 mL) was added, followed by water (0.8 mL), and then brine (0.8 mL). After 10 min, the aqueous layer was removed and the organic layer was washed with 0.5 M NaHCO3 solution (0.6 mL). Celite (600 mg) was added to the organic layer and the solvent was evaporated. Silica gel was used with a gradient of EtOAc / hexane containing up to 4% MeOH. Purified aryl amide or urea 9 was obtained by flash chromatography.

[0086] Synthesis Examples

[0087] N-[(1R)-1-(3-carbamoylphenyl)ethyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 10). The title compound was prepared according to general procedure E to yield 25 mg (95%) of a white amorphous solid. f = 0.22 (2% MeOH / 60% EtOAc / hexane; UV active). 1H NMR(300MHz,CDCl3)δ 8.35(d,J=8.1Hz,1H),7.93(s,1H),7.68(d,J=7.5Hz,1H),7.61(d,J=7.5Hz,1H),7.28-7.48(m,5H) ,7.11-7.21(m,2H),6.94-7.07(m,2H),5.57(s,2H),5.27-5.48(m,1H),1.65(d,J=7.0Hz,3H).LC / MS (m / z)417.4(M+1),>97% at 2.50min.HPLC>98% at 14.60min.

[0088] N-[(1S)-1-(3-carbamoylphenyl)ethyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 11). The title compound was prepared according to general procedure E to yield 13 mg (82%) of a white amorphous solid. f = 0.22 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ8.35(d,J=8.1Hz,1H),7.93(s,1H),7.68(d,J=7.5Hz,1H),7.60(d,J=7.5Hz,1H),7.28-7.49(m,5H), 7.10-7.20(m,2H),6.92-7.07(m,2H),5.56(s,2H),5.27-5.48(m,1H),1.65(d,J=7.0Hz,3H).LC / MS(m / z)417.4(M+1),>97% at 2.50min.HPLC 99% at 14.60min.

[0089] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 12). The title compound was prepared according to general procedure E to yield 87 mg (84%) of a white crystalline solid. f = 0.27 (2% MeOH / 60% EtOAc / Hexane; UV active). 1H NMR(300MHz,CDCl3)δ8.28(d,J=8.1Hz,1H),8.00(s,1H),7.65(d,J=7.5Hz,1H),7.59(d,J=7.4Hz,1H),7.46(s,1H) ,7.28-7.41(m,3H),7.13-7.25(m,3H),6.95-7.08(m,2H),5.58(s,2H),1.85(s,6H).LC / MS(m / z)431.4(M+1),>98% at 2.54min.HPLC >98% at 15.12min.

[0090] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-[(2,4-difluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 13). The title compound was prepared according to general procedure E to yield 104 mg (77%) of a white crystalline solid. f = 0.26 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.31(d,J=8.3Hz,1H),8.02(s,1H),7.69(d,J=7.8Hz,1H),7.62(d,J=7.3Hz,1H),7 .37-7.48(m,4H),7.21-7.27(m,1H),7.02-7.11(m,1H),6.76-6.94(m,2H),6.20(br HPLC 99% at 15.34min.

[0091] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-[1-(4-phenyl)- [Fluorophenyl]ethyl-1H-indazole-3-carboxamide (Example 14). The title compound was prepared according to general procedure E to yield 32 mg (83%) of a white crystalline solid. f = 0.40 (2% MeOH / 60% EtOAc / hexane; UV active). 1H NMR(300 MHz,CDCl3)δ 8.27(d,J=8.1Hz,1H),8.02(s,1H),7.68(d,J=7.7Hz,1H),7.61(d,J=7.4Hz,1H),7. 48(s,1H),7.37(t,J=7.7Hz,1H),7.17-7.31(m,5H),7.01(t,J=8.6Hz,2H),6.46(br s,1H),5.85(q,J=6.8Hz,2H),2.50(br s,1H),2.06(d,J=7.0Hz,3H),1.80-1.95(m,6H).LC / MS(m / z)445.0(M+1),489.2(M-1+HCO2H),>98% at 2.75 min. HPLC>99% at 15.70 min.

[0092] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-[(4,4-difluorocyclohexyl)methyl]-1H-indazole-3-carboxamide (Example 15). The title compound was prepared according to general procedure F to yield 47 mg (43%) of a white crystalline solid. f = 0.19 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.26(d,J=8.1Hz,1H),8.00(s,1H),7.66(d,J=7.9Hz,1H),7.60(d,J=7.7Hz,1H),7.32-7.47(m,4H),7.16-7.25(m,1H),4.28(d,J=7 .4Hz,2H),2.06-2.26(m,3H),1.86(s,6H),1.57-1.78(m,4H),1.21-1.55(m,4H).LC / MS(m / z)455.0(M+1),499.0(M-1+HCO2H),>98% at 2.73min.HPLC>99% at 15.34min.

[0093] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-(oxan-4-ylmethyl)-1H-indazole-3-carboxamide (Example 16). The title compound was prepared according to general procedure E to yield 31 mg (62%) of a white crystalline solid. f= 0.14 (2% MeOH / 70% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.27(d,J=8.1Hz,1H),8.00(s,1H),7.67(d,J=7.9Hz,1H),7.60(d,J=7.5Hz,1H),7.33-7.49(m,4H),7.15-7.24(m,1H),4.28(d,J=7.2Hz,2H) ,3.91-4.05(m,2H),3.25-3.47(m,2H),2.25-2.41(m,1H),1.87(s,6H),1.42-1.59(m,4H).LC / MS(m / z)421.0(M+1),465.2(M-1+HCO2H),>98% at 2.56min.HPLC>99% at 13.38min.

[0094] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-pentyl-1H-indazole-3-carboxamide (Example 17). The title compound was prepared according to general procedure F to yield 34 mg (48%) of a white amorphous solid. f = 0.28 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.26(d,J=8.3Hz,1H),7.98(s,1H),7.68(d,J=7.7Hz,1H),7.61(d,J=7.5Hz,1H),7.33-7.48(m,4H),7.16-7.24(m,1H),4.3 9(t,J=7.2Hz,2H),1.92-2.04(m,2H),1.86(s,6H),1.28-1.45(m,4H),0.92(t,J=6.7Hz,3H).LC / MS(m / z)393.0(M+1),>98% at 2.78min.HPLC 99% at 16.21min.

[0095] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-(5-fluoro Pentyl)-1H-indazole-3-carboxamide (Example 18). The title compound was prepared according to general procedure F to yield 34 mg (30%) of a white amorphous solid. f= 0.18 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.27(d,J=8.1Hz,1H),7.98(s,1H),7.68(d,J=7.7Hz,1H),7.61(d,J=7.4Hz,1H),7.33-7.47(m,4H),7.15-7.24(m,1H),4.53(t,J=5 .8Hz,1H),4.34-4.47(m,3H),1.96-2.12(m,2H),1.87(s,6H),1.25-1.80(m,6H).LC / MS(m / z)411.0(M+1),455.2(M-1+HCO2H),>97% at 2.68min.HPLC 99% at 14.66min.

[0096] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-(5,5,5-trifluoropentyl)-1H-indazole-3-carboxamide (Example 19). The title compound was prepared according to general procedure F to yield 14 mg (12%) of a white amorphous solid. f = 0.21 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3,CD3OD)δ 8.23(d,J=8.1Hz,1H),7.94(s,1H),7.66(d,J=7.7Hz,2H),7.36-7.46(m,3H),7.19-7.27(m,1H),4.45(t,J=6. 9Hz,2H),2.01-2.25(m,4H),1.86(s,6H),1.57-1.70(m,2H).LC / MS(m / z)447.0(M+1),491.0(M-1+HCO2H),>98% at 2.72min.HPLC 99% at 14.93min.

[0097] N-[2-(3-acetamidophenyl)propan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 20). The title compound was prepared according to general procedure K to yield 21 mg (91%) of a white crystalline solid. f = 0.38 (2% MeOH / 60% EtOAc / Hexane; UV active).1 H NMR(300MHz,CDCl3)δ 8.31(d,J=7.7Hz,1H),7.57(br s,1H),7.28-7.50(m,6H),7.11-7.24(m,4H),6.95-7.09(m,2H),5.59(s,2H) ,2.05(s,3H),1.81(s,6H).LC / MS(m / z)445.0(M+1),489.2(M-1+HCO2H),>98% at 2.75min.HPLC>99% at 15.58min.

[0098] N-{2-[3-(carbamoylamino)phenyl]propan-2-yl}-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 21). The title compound was prepared according to general procedure J to yield 56 mg (63%) of a white crystalline solid. f = 0.38 (5% MeOH / 65% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3,CD3OD)δ 8.24(d,J=8.1Hz,1H),7.54(s,1H),7.31-7.43(m,3H),7.14-7.27(m,5H),6.97-7.10 (m,2H),5.60(s,2H),1.80(s,6H).LC / MS(m / z)446.0(M+1),490.2(M-1+HCO2H),>98% at 2.70min.HPLC >99% at 14.99min.

[0099] N-{2-[3-(carbamoylamino)phenyl]propan-2-yl}-1-[(4,4-difluorocyclohexyl)methyl]-1H-indazole-3-carboxamide (Example 22). The title compound was prepared according to general procedure J to yield 33 mg (54%) of a white crystalline solid. f = 0.14 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3,CD3OD)δ 8.23(d ,J=7.9Hz,1H),7.50(s,1H),7.32-7.44(m,2H),7.14-7.28(m,4H),4.30(d,J=6.8Hz,2H),2.07-2.19(m,2H),1.82( s,6H),1.59-1.80(m,4H),1.38-1.56(m,2H),1.21-1.35(m,1H).LC / MS(m / z)470.0(M+1),514.2(M-1+HCO2H),>98% at 2.74min.HPLC 99% at 14.83min.

[0100] N-{2-[3-(carbamoylamino)phenyl]propan-2-yl}-1-(oxan-4-ylmethyl)-1H-indazole-3-carboxamide (Example 23). The title compound was prepared according to general procedure J to yield 49 mg (100%) of a white crystalline solid. f =0.15 (5% MeOH / 65% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3,CD3OD)δ 8.23(d,J=8.3Hz,1H),7.38-7.48(m,2H),7.36(s,1H),7.16-7.28(m,4H),4.29(d,J=7.0Hz,2H),3.91-4.06(m,2H),3. 33-3.45(m,2H),1.83(s,6H),1.43-1.60(m,4H),0.64-0.88(m,1H).LC / MS(m / z)436.0(M+1),480.2(M-1+HCO2H),>98% at 2.57min.HPLC >99% at 12.82 min.

[0101] N-{2-[3-(carbamoylamino)phenyl]propan-2-yl}-1-pentyl-1H-indazole-3-carboxamide (Example 24). The title compound was prepared according to general procedure J to yield 16 mg (51%) of a white crystalline solid. f = 0.17 (2% MeOH / 60% EtOAc / Hexane; UV active). 1H NMR(300MHz,CDCl3,CD3OD)δ 8.20(d,J=8.1Hz,1H),7.32-7.47(m,3H),7.11-7.27(m,4H),4.40(t,J=7.2Hz,2H),1.91-2.07(m,2H),1 .77(s,6H),1.20-1.44(m,4H),0.92(t,J=6.6Hz,3H).LC / MS(m / z)408.0(M+1),452.2(M-1+HCO2H),>98% at 2.77min.HPLC 99% at 15.73min.

[0102] N-{2-[3-(carbamoylamino)phenyl]propan-2-yl}-1-pentyl-1H-indazole-3-carboxamide (Example 25). The title compound was prepared according to general procedure J to yield 24 mg (77%) of a white crystalline solid. f = 0.13 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3,CD3OD)δ 8.20(d,J=8.3Hz,1H),7.34-7.49(m,3H),7.16-7.28(m,4H),4.54(t,J=5.8Hz,1H),4.32-4.48(m,3H),1. 95-2.12(m,2H),1.67-1.87(m,8H),1.44-1.57(m,2H).LC / MS(m / z)426.0(M+1),470.2(M-1+HCO2H),>98% at 2.68min.HPLC>98% at 14.15min.

[0103] 1-[(4,4-Difluorocyclohexyl)methyl]-N-(2-{3-[(methylcarbamoyl)amino]phenyl}propan-2-yl)-1H-indazole-3-carboxamide (Example 26). The title compound was prepared according to general procedure K to yield 30 mg (48%) of a white amorphous solid. f = 0.22 (2% MeOH / 60% EtOAc / Hexane; UV active). 1H NMR(300MHz,CDCl3)δ 8.24(d,J=8.1Hz,1H),7.56(s,1H),7.49(s,1H),7.36-7.44(m,2H),7.22(dt,J=8.1,3.9Hz,1H),7. 02-7.15(m,3H),6.71-6.84(m,2H),4.30(d,J=7.2Hz,2H),2.61(s,3H),2.07-2.23(m,2H),1.62-1. 89(m,10H),1.37-1.56(m,2H),1.19-1.31(m,1H).LC / MS(m / z)484.0(M+1),528.2(M-1+HCO2H),>98% at 2.76min.HPLC>98% at 15.38min.

[0104] N-(2-{3-[(methylcarbamoyl)amino]phenyl}propan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (Example 27). The title compound was prepared according to general procedure K to give 9 mg (28%) of a colorless residue. f = 0.24 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.23(d,J=8.1Hz,1H),7.49-7.59(m,1H),7.33-7.49(m,3H),7.03-7.24(m,3H),6.84-6.99(m,2H),4.41(t,J=7.2Hz,2H),2.59(s ,3H),1.93-2.04(m,2H),1.75(s,6H),1.21-1.45(m,4H),0.92(t,J=6.8Hz,3H).LC / MS(m / z)422.2(M+1),466.2(M-1+HCO2H),>97% at 2.81min.HPLC95% at 16.30min.

[0105] 1-(5-Fluoropentyl)-N-(2-{3-[(methylcarbamoyl)amino]phenyl}propan-2-yl)-1H-indazole-3-carboxamide (Example 28). The title compound was prepared according to general procedure K to give 11 mg (34%) of a colorless residue. f= 0.19 (2% MeOH / 60% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.23(d,J=8.1Hz,1H),7.35-7.58(m,4H),7.05-7.25(m,3H),6.81-6.93(m,2H),4.54(t,J=5.8Hz,1H),4.32-4.49(m,3H) ,2.59(s,3H),1.96-2.14(m,2H),1.69-1.86(m,8H),1.45-1.58(m,2H).LC / MS(m / z)440.0(M+1),484.2(M-1+HCO2H),>97% at 2.74min.HPLC 96% at 14.68 min.

[0106] N-[2-(1-carbamoylpiperidin-3-yl)propan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 29). The title compound was prepared according to general procedure H to yield 51 mg (78%) of a white crystalline solid. f = 0.19 (5% MeOH / 65% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.33(d,J=8.1Hz,1H),7.28-7.43(m,3H),7.11-7.22(m,2H),6.96-7.08(m,2H),6.89(s,1H),5.57(s,2H),4.61(br s,2H),4.05-4.19(m,1H),3.89-4.03(m,1H),2.47-2.79(m,2H),1.91-2.03(m,1H),1.55 -1.81(m,3H),1.51(s,3H),1.42(s,3H),1.24-1.38(m,1H).LC / MS(m / z)438.4(M+1),>97% at 2.68 min.HPLC >99% at 15.37min.

[0107] N-{2-[1-(carbamoylmethyl)piperidin-3-yl]propan-2-yl}-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 30). The title compound was prepared according to general procedure H to yield 54 mg (80%) of a white amorphous solid. f = 0.19 (5% MeOH / 65% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.36(d,J=8.1Hz,1H),7.28-7.43(m,2H),7.09-7.23(m,3H),6.88-7.07(m,3H),5.56(s,2H),5.32(br s,1H),2.93-3.07(m,2H),2.80-2.91(m,1H),2.58-2.72(m,1H),1.96-2.19(m,2H),1.58-1.96(m,4H), 1.44(s,3H),1.48(s,3H),1.04-1.21(m,1H).LC / MS(m / z)452.6(M+1),>97% at 2.44min.HPLC>99% at 12.94min.

[0108] N-[2-(1-carbamoylpiperidin-4-yl)propan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 31). The title compound was prepared by general procedure H to yield 60 mg (92%) of a white amorphous solid. f =0.15 (5% MeOH / 65% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.37(d,J=7.9Hz,1H),7.28-7.42(m,3H),7.10-7.21(m,2H),6.94-7.06(m,2H),6.86(s,1H),5.57(s,2H),4.52(br s,2H),3.95-4.07(m,2H),2.75-2.91(m,2H),2.45-2.61(m,1H),1.73-1. 84(m,3H),1.45(s,6H),1.26-1.41(m,1H).LC / MS(m / z)438.4(M+1),>97% at 2.66min.HPLC>99% at 15.00min.

[0109] N-{2-[1-(carbamoylmethyl)piperidin-4-yl]propan-2-yl}-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (Example 32). The title compound was prepared according to general procedure I to yield 56 mg (83%) of a white crystalline solid. f =0.15 (5% MeOH / 65% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3)δ 8.38(d,J=8.1Hz,1H),7.28-7.43(m,3H),7.09-7.20(m,3H),6.94-7.06(m,2H),6.85(s,1H),5.56(s,2H),5.52(br s,1H),2.87-3.07(m,4H),2.14-2.36(m,2H),1.72-1.84(m,3H),1.37-1.54(m,8H).LC / MS(m / z)452.6(M+1),>97% at 2.42min.HPLC>99% at 12.77 min.

[0110] N-[2-(3-carbamoylphenyl)propan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indole-3-carboxamide (Example 33). The title compound was prepared according to general procedure E to yield 21 mg (80%) of a white crystalline solid. f =0.28 (4% MeOH / 66% EtOAc / Hexane; UV active). 1 H NMR(300MHz,CDCl3,CD3OD)δ 7.85-7.99(m,2H),7.74(s,1H),7.58-7.69(m,2H),7.34-7.46(m,1H),7.21-7.29(m,3H),7.08-7.19 (m,2H),6.95-7.06(m,2H),5.31(s,2H),1.84(s,6H).LC / MS(m / z)430.0(M+1),474.2(M-1+46),>98% at 2.70min.HPLC 99% at 14.28min.

[0111] Biological Examples

[0112] In vitro cannabinoid receptor activity assay. Chinese hamster ovary (CHO) cells stably expressing either human CB1 or CB2 cDNA and the promiscuous G protein Gαq16 were transferred to individual wells of black Costar 96-well optical bottom plates (Corning). Each plate was incubated at 37°C for 24 hours before harvesting. After removing the medium from the plate, the cells were incubated with a fluorescently labeled calcium probe (Ca(2+)) at a final loading concentration of 2 μM in a total volume of 255 μl of HBSS-based buffer containing 20 mM HEPES, 1% BSA, and 10 μM probenecid (Sigma). The cells were incubated at 37°C for 1 hour and then loaded with 5 dye (Molecular Devices). The plates were stimulated with various concentrations of test agents, where the FLIPR Tetra plate reader automatically added agonists at 10X concentrations to each well after a baseline reading of approximately 17 seconds. Agonist-mediated changes in fluorescence (excitation at 488 nm, emission at 525 nm) were monitored for 60 seconds at 1-second intervals per well and reported per well. Data were analyzed using Prism software (GraphPad). Nonlinear regression analysis was performed to fit the data and obtain the maximum response (Emax), 50% effective concentration (EC50), correlation coefficient (r2), and other parameters. All experiments were performed three to six times to ensure reproducibility.

[0113] Reference is made to the following references, which are incorporated herein by reference, regarding such assays: Seltzman, et al., Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain., J Med Chem. 2016 Aug 25;59(16):7525-43. doi: 10.1021 / acs.jmedchem.6b00516. Epub 2016 Aug 10.

[0114] In vitro binding affinity determination using radioligand displacement. Plasma membranes were isolated from HEK cells overexpressing either human CB1 or CB2. Binding was initiated by adding 40 μg of plasma membrane protein to assay tubes containing [H]CP-55,940 (approximately 130 Ci / mmol), test compound (for displacement studies), and sufficient buffer (50 mM Tris·HCl, 1 mM EDTA, 3 mM MgCl2, 5 mg / mL BSA, pH 7.4) to bring the total incubation volume to 0.5 mL. Nonspecific binding was determined by the inclusion of 10 μM unlabeled CP-55,940. After a 1-hour incubation at 30°C, binding was terminated by vacuum filtration through GF / C glass filter plates. The filter plates were washed extensively, air-dried, and the bottoms were sealed. Liquid scintillate was added to the wells, and the tops were sealed. Plates were incubated in the cocktail for at least 2 hours, and the radioactivity displayed was determined by liquid scintillation spectrometry. Assays were performed in duplicate, and results are presented as pooled data from 3 to 6 experiments. Saturation and displacement data were analyzed by unweighted nonlinear regression of receptor binding data. For displacement studies, curve fitting and IC50 calculations were performed using GraphPad Prism (GraphPad Software, Inc., San Diego, CA).

[0115] Reference is made to the following reference, which is incorporated herein by reference, regarding such assays: Zhang et al., Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor, J Med Chem. 2010 Oct 14;53(19):7048-60. doi: 10.1021 / jm1006676.

[0116] Biological data [Table 2-1] [Table 2-2] [Table 2-3]

[0117] The specific pharmacological response observed may vary depending on the particular active compound selected, the pharmaceutical carrier present, and the type of formulation and method of administration implemented. Such expected variations and differences are within the scope of the practice of the present invention.

[0118] Although specific embodiments of the present invention have been described and illustrated in detail herein, the present invention is not limited to these aspects. The above detailed description is illustrative of the present invention and should not be construed as limiting. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present invention are intended to be included within the scope of the present invention. In one embodiment, for example, the following items are provided: (Item 1) Compounds of formula (I): [ka] And, R 1 is unsubstituted or substituted C 1-10 Alkyl, C 1-10 Haloalkyl, (CH2) n -cycloalkyl, (CH2) n -heterocyclyl, (CH2) n -aryl, or (CH2) n -heteroaryl, n is 1, 2 or 3; X is CH or N; Y is CHR 3 or CR 4 R 5 and R 3 is C 1-4is alkyl, R 4 and R 5 are each independently, C 1-4 alkyl, or R 4 and R 5 can be taken together with the carbon atom to which they are attached to form a 3- to 7-membered cycloalkyl or heterocycloalkyl ring; L is a divalent C 1-3 Alkyl or C 2-3 is alkenyl, o is 0 or 1, V is a divalent aryl, heteroaryl, cycloalkyl, heterocyclyl, C 2-3 Alkyl, or C 2-3 is alkenyl, Z is H, F, Cl, CF3, Me, CN, OMe, OCF3, or OCHF2; R 2 teeth, (i)(CH2) p C(O)NHR a , (ii) NHC(O)R b , (iii)NR c C(O)NHR a , or (iv) NH(C=NR d )NHR a and p is 0, 1 or 2; R a is H, C 1-4 Alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; R b is C 1-4 Alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; R c is H or C 1-4 is alkyl, R d are H, CN, and C 1-4 Alkyl, or C3-6 is cycloalkyl, The compound, or a pharmaceutically acceptable salt thereof. (Item 2) The compound according to item 1, wherein X is N. (Item 3) Y is CR 4 R 5 3. The compound according to item 1 or 2, wherein (Item 4) Item 3. The compound according to item 3, wherein Y is C(CH3)2. (Item 5) 5. The compound according to any one of items 1 to 4, wherein V is a divalent aryl, heteroaryl, cycloalkyl, or heterocyclyl. (Item 6) R 2 teeth, (i)(CH2) p C(O)NHR a , (ii) NHC(O)R b , or (iii) NHC(O)NHR a and R a is H, C 1-4 Alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; R b is C 1-4 Alkyl, C 3-6 6. The compound according to any one of items 1 to 5, which is cycloalkyl, heterocyclyl, aryl, or heteroaryl. (Item 7) R 2 teeth, (i)(CH2) p C(O)NHR a , or (ii) NHC(O)NHR a and R a is H, C 1-4 Alkyl, C 3-66. The compound according to any one of items 1 to 5, which is cycloalkyl, heterocyclyl, aryl, or heteroaryl. (Item 8) 8. The compound according to any one of items 1 to 7, wherein o is 0. (Item 9) o is 1 and L is a divalent C 1-3 8. The compound according to any one of items 1 to 7, wherein R is alkyl. (Item 10) 10. The compound according to any one of items 1 to 9, wherein n is 1. (Item 11) 11. The compound according to any one of items 1 to 10, wherein Z is H or F. (Item 12) A compound having the structure of any one of compounds 10 to 33 shown in Table 1. (Item 13) 13. A method for treating a disease in a mammal sensitive to modulation of one or more CB receptors, comprising administering an effective amount of a compound according to any one of items 1 to 12. (Item 14) Item 14. The method of item 13, wherein the disease is angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorder, intestinal hypomotility, metabolic disorder, obesity, liver disorder, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 15) 14. The method of claim 13, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 16) Item 14. The method according to item 13, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. (Item 17) Item 14. The method of item 13, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis. (Item 18) A pharmaceutical composition comprising a compound according to any one of items 1 to 12 and one or more pharmaceutically acceptable carriers. (Item 19) 13. Use of a compound according to any one of items 1 to 12 for the preparation of a medicament for treating a disease in a mammal sensitive to modulation of one or more CB receptors, said treatment comprising administering an effective amount of said compound. (Item 20) 20. The use according to item 19, wherein the disease is angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorder, intestinal hypomotility, metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 21) 20. The use according to item 19, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 22) 20. The use according to item 19, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. (Item 23) The disease is a liver disorder or liver disease, and includes fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary hepatitis, and the like. 20. The use according to item 19, wherein the liver disease is advanced biliary cirrhosis or primary sclerosing cholangitis. (Item 24) 13. A compound according to any one of items 1 to 12 for use as an active therapeutic substance. (Item 25) 13. A compound according to any one of items 1 to 12 for use in the treatment of diseases mediated by one or more CB receptors. (Item 26) 26. The compound according to item 25, wherein the disease is angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorder, intestinal hypomotility, metabolic disorder, obesity, liver disorder, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 27) 26. The compound according to item 25, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 28) 26. The compound according to item 25, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. (Item 29) 26. The compound according to item 25, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis. (Item 30) 1. A method of treating one or more diseases, comprising: 13. The method for treating angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver disorders, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or nonalcoholic steatohepatitis (NASH), comprising administering an effective amount of the compound according to any one of items 1 to 12. (Item 31) 31. The method of claim 30, wherein the disease is a metabolic disorder, obesity, liver disorder, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 32) 31. The method according to item 30, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. (Item 33) The disease is a liver disorder or liver disease, and includes fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFL), and the like. D), nonalcoholic steatohepatitis (NASH), liver fibrosis, liver cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis. (Item 34) 13. Use of a compound according to any one of items 1 to 12 for the preparation of a medicament for the treatment of one or more diseases, the disease is selected from angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH); The use, wherein the treatment comprises administering an effective amount of the compound. (Item 35) 35. The use according to item 34, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 36) 35. The use according to item 34, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. (Item 37) 35. The use according to Item 34, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis. (Item 38) A compound according to any one of items 1 to 12 for use in the treatment of one or more diseases, The disease is selected from the group consisting of angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH). (Item 39) 39. The compound according to item 38, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH). (Item 40) 39. The compound according to item 38, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity. (Item 41) 39. The compound according to item 38, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

Claims

1. Compounds of formula (I): 【Transformation 5】 And, R １ is unsubstituted or substituted C １－１０ Alkyl, C １－１０ Haloalkyl, (CH ２ ) ｎ -cycloalkyl, (CH ２ ) ｎ -heterocyclyl, (CH ２ ) ｎ -aryl, or (CH ２ ) ｎ -heteroaryl, n is 1, 2 or 3; Y is C(CH ３ ) ２ and V is a divalent aryl, heteroaryl, cycloalkyl, heterocyclyl, C ２－３ Alkyl, or C ２－３ is alkenyl, Z is H, F, Cl, CF ３ , Me, CN, OMe, OCF ３ , or OCHF ２ and R ２ teeth, (i)(CH ２ ) ｐ C(O)NHR ａ 、 (ii)NHC (O)R ｂ 、 (iii) NR ｃ C(O)NHR ａ , or (iv)NH(C=NR ｄ NHR ａ and p is 0, 1 or 2; R ａ is H, C １－４ Alkyl, C ３－６ cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ｂ is C １－４ Alkyl, C ３－６ cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ｃ is H or C １－４ is alkyl, R ｄ are H, CN, C １－４ Alkyl, or C ３－６ is cycloalkyl, The compound, or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein V is a divalent aryl, heteroaryl, cycloalkyl, or heterocyclyl.

3. R ２ teeth, (i)(CH ２ ) ｐ C(O)NHR ａ 、 (ii) NHC(O)R ｂ , or (iii)NHC(O)NHR ａ and R ａ is H, C １－４ Alkyl, C ３－６ cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ｂ is C １－４ Alkyl, C ３－６ The compound of any one of claims 1 to 2, which is cycloalkyl, heterocyclyl, aryl, or heteroaryl.

4. R ２ teeth, (i) (CH ２ ) ｐ C(O)NHR ａ , or (ii)NHC(O)NHR ａ and R ａ is H, C １－４ Alkyl, C ３－６ The compound of any one of claims 1 to 2, which is cycloalkyl, heterocyclyl, aryl, or heteroaryl.

5. The compound according to any one of claims 1 to 4, wherein n is 1.

6. The compound according to any one of claims 1 to 5, wherein Z is H or F.

7. The following compounds: 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 A compound having any one of the following structures:

8. 10. A composition comprising a compound according to any one of claims 1 to 7 for treating a disease in a mammal sensitive to modulation of one or more CB receptors, wherein the disease is selected from the group consisting of angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH).

9. 9. The composition of claim 8, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH).

10. 9. The composition of claim 8, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity.

11. 9. The composition of claim 8, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and one or more pharmaceutically acceptable carriers.

13. 10. Use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for treating a disease in a mammal sensitive to modulation of one or more CB receptors, said treatment comprising administering an effective amount of the compound, wherein the disease is selected from the group consisting of angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH).

14. 14. The use of claim 13, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH).

15. The use according to claim 13, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity.

16. 14. The use of claim 13, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

17. A composition comprising a compound according to any one of claims 1 to 7 for use as an active therapeutic substance.

18. 10. A composition comprising a compound according to any one of claims 1 to 7 for use in the treatment of a disease mediated by one or more CB receptors, wherein the disease is selected from the group consisting of angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, and non-alcoholic steatohepatitis (NASH).

19. 19. The composition of claim 18, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH).

20. 19. The composition of claim 18, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity.

21. 19. The composition of claim 18, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

22. A composition comprising a compound according to any one of claims 1 to 7 for treating one or more diseases, The disease is selected from angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH).

23. 23. The composition of claim 22, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH).

24. 23. The composition of claim 22, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity.

25. 23. The composition of claim 22, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

26. Use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of one or more diseases, comprising the disease is selected from angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmoplastic small round cell tumor, renal cell carcinoma, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, metabolic disorders, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH); The use, wherein the treatment comprises administering an effective amount of the compound.

27. 27. The use of claim 26, wherein the disease is a metabolic disorder, obesity, liver damage, liver disease, steatosis, steatohepatitis, alcoholic steatohepatitis, or non-alcoholic steatohepatitis (NASH).

28. 27. The use according to claim 26, wherein the disease is a metabolic disorder, such as diabetes, type 2 diabetes, Gaucher disease, glucose-galactose malabsorption, hemochromatosis, phenylketonuria, Niemann-Pick disease, Fabry disease, medium-chain acyl-CoA dehydrogenase deficiency, metabolic syndrome, or obesity.

29. 27. The use of claim 26, wherein the disease is a liver disorder or liver disease, and is fatty liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

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