3-Phenyl-1-benzothiophene-2-carboxylic acid derivatives as branched-chain alpha-ketoacid dehydrogenase kinase inhibitors for treating diabetes, kidney disease, NASH and heart failure

Abstract

The present invention relates to compounds of formula (I) as branched chain alpha keto acid dehydrogenase kinase inhibitors and / or decomposers, for example, for treating diabetes, kidney disease, NASH and heart failure.Preferred compounds are, for example, 3-phenyl-1-benzothiophene-2-carboxylic acid derivatives.Exemplary compounds are, for example, 3-(5,7-difluoro-3,4-dihydro-2H-1-benzopyran-6-yl)-fluoro-1-benzothiophene-2-carboxylic acid (Example 1).The present application discloses the synthesis and characterization of exemplary compounds, as well as their pharmacological data. [Case 1] TIFF2024543938000160.tif5562 [C2] TIFF2024543938000161.tif5950 [Figure 1] TIFF2024543938000162.tif83153

Description

Technical Field

[0001] The present application provides compounds that are branched-chain alpha-ketoacid dehydrogenase kinase inhibitors and / or degraders, pharmaceutical compositions containing such compounds, and their use for treating, for example, diabetes, NASH, kidney diseases, and heart failure.

Background Art

[0002] Branched-chain amino acids (BCAAs) account for approximately 40% of the essential amino acids in healthy subjects and need to be acquired through a balanced diet. Although BCAAs are toxic in excess, they are required for protein synthesis and cell signaling processes. BCAAs undergo aminotransfer by branched-chain aminotransferase (BCAT) to their alpha-keto acid forms: alpha-ketoisocaproate (KIC / keto-leucine), 2-keto-3-methylvalerate (KMV / keto-isoleucine), and alpha-ketoisovalerate (KIV / keto-valine). The branched-chain keto acids (BCKAs) are then oxidatively decarboxylated by the branched-chain keto acid dehydrogenase (BCKDH) enzyme complex, which consists of multiple copies of the BCKDH E1α / β tetramer, BCKDH E2, and BCKDH E3 subunits. This complex is regulated by inhibitory phosphorylation mediated by BCKDH kinase (BCKDK), and the same phosphorylation site is dephosphorylated by the phosphatase PPM1K. Inhibition of this complex phosphorylation promotes BCKDH activity and thus the irreversible catabolism of BCKA (Lynch CJ, Adams SH: Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 2014, 10:723~36). Deletion of Bckdk in mice resulted in increased BCKDH activity in multiple tissues, confirming this regulation (Joshi MA, Jeoung NH, Obayashi M, Hattab EM, Brocken EG, Liechty EA, Kubek MJ, Vattem KM, Wek RC, Harris RA: Impaired growth and neurological abnormalities in branched-chain alpha-keto acid dehydrogenase kinase-deficient mice. Biochem J 2006, 400:153~62).

[0003] U.S. Patent No. 9,078,865 is, for example, a method of reducing the plasma levels of one or more branched-chain amino acids or branched-chain alpha-keto acids, for example, to treat inborn errors of metabolism in neonates known as maple syrup urine disease (MSUD), to an individual in need thereof, a therapeutically effective amount of a compound of the formula: phenyl-CH2-(CH2) n -COOH (wherein n is 0, 2, 4, 6 or 8), comprising administering at least one such compound. MSUD, also known as branched-chain ketoaciduria, is an autosomal recessive disorder.

[0004] There is a strong correlation between BCAA catabolism and cardiometabolic health. Increases in BCAA / BCKA levels have been observed in the plasma of type 2 diabetes patients in multiple studies (Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, O’Donnell CJ, Carr SA, Mootha VK, Florez JC, Souza A, Melander O, Clish CB, Gerszten RE: Metabolite profiles and the risk of developing diabetes. Nat Med 2011, 17:448~53; Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS, Jr., Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP: A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009, 9:311~26).

[0005] Reductions in PPM1K levels and increases in BCKDK levels have been observed in human NASH (Lake AD, Novak P, Shipkova P, Aranibar N, Robertson DG, Reily MD, Lehman-McKeeman LD, Vaillancourt RR, Cherrington NJ: Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 2015, 47:603~15).

[0006] Reductions in mRNA levels of enzymes in the catabolic pathway have also been observed in the skeletal muscle of human diabetic patients (Lerin C, Goldfine AB, Boes T, Liu M, Kasif S, Dreyfuss JM, De Sousa-Coelho AL, Daher G, Manoli I, Sysol JR, Isganaitis E, Jessen N, Goodyear LJ, Beebe K, Gall W, Venditti CP, Patti ME: Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Mol Metab 2016, 5:926~36).

[0007] Similarly, metabolomics and RNA profiling data from mouse hearts also suggest that genes in the BCAA / BCKA catabolic pathway are downregulated in heart failure (Lai L, Leone TC, Keller MP, Martin OJ, Broman AT, Nigro J, Kapoor K, Koves TR, Stevens R, Ilkayeva OR, Vega RB, Attie AD, Muoio DM, Kelly DP: Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach. Circ Heart Fail 2014, 7:1022~31; Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn JY, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui WJ, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y: Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 2016, 133:2038~49).

[0008] Collectively, these data suggest that BCAA catabolism is impaired in multiple human pathologies. One mechanism to increase BCAA catabolism is a BCKDK inhibitor and / or a BCKDK degrader. By inhibiting and / or degrading BCKDK, BCKDH activity is increased and BCAA catabolism is increased. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0009] In recent years, inhibitors of BCKDK have been reported in the literature and patent applications, including the PCT applications PCT / IB2020 / 056066 and PCT / IB2020 / 055974, both of which were assigned to the assignee of the present application and published as WO2020 / 261205 and WO2020 / 261144, respectively, on December 30, 2020. Although there are some initial studies on BCKDK, there is still a need for pharmaceutical agents that have BCKDK inhibitory / degrading activity and are useful in the treatment, prevention, or reduction of symptoms of the diseases described herein.

Means for Solving the Problems

[0010] This application relates to a compound of formula I

[0011]

Chem.

[0012]

Chem.

[0013]

Chemical formula

[0014] This application relates to a compound of formula I

[0015]

Chemical formula

[0016]

Chem.

[0017]

Chem.

[0018] This application provides a method for treating fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with hepatic fibrosis, non-alcoholic steatohepatitis with cirrhosis, non-alcoholic steatohepatitis with cirrhosis, hepatocellular carcinoma, renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, gastric adenocarcinoma, adrenocortical carcinoma, papillary renal cell carcinoma, carcinoma in the cervix and endocervix, bladder urothelial carcinoma, lung adenocarcinoma, type I diabetes, type II true diabetes, idiopathic type I diabetes (type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary artery disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial lipemia, impaired glucose tolerance (IGT) state, impaired fasting plasma glucose state, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, glucose metabolism disorder, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and vascular compliance disorders, high apolipoprotein B lipoproteinemia, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, and maple syrup urine disease in a human in need of such treatment by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt of said compound.

[0019] This application also relates to a method for treating heart failure, cardiovascular death, congestive heart failure, heart failure with New York Heart Association Class I-IV symptoms, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with mid-range ejection fraction (HF-mrEF), cardiovascular death, heart failure in patients with type II diabetes mellitus, coronary artery disease, unstable angina, peripheral artery disease, peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, acute coronary syndrome, or reducing the risk of hospitalization therefrom, and modifying cardiovascular risk, by administering to a human in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt of said compound.

[0020] This application also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or excipient.

[0021] This application a first compound which is a compound of formula I or a pharmaceutically acceptable salt of said compound; an antidiabetic agent; a second compound which is a non-alcoholic steatohepatitis treatment agent, a non-alcoholic fatty liver disease treatment agent or an anti-heart failure treatment agent, and a pharmaceutical carrier, vehicle or excipient This application also relates to a pharmaceutical combination composition comprising a therapeutically effective amount of a composition having the same.

[0022] This application also relates to a crystalline form of a compound of formula I.

[0023] It should be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not limitations of the invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS

[0024]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0025] This application can be more easily understood by referring to the following detailed description of exemplary embodiments of the present invention and the examples included therein.

[0026] It should be understood that the present invention is not limited to specific synthetic methods for production, and they can of course vary. It should also be understood that the terms used in this specification are for the sole purpose of describing specific embodiments and are not intended to be limiting. In this specification and in the claims hereinafter, several terms will be referred to, and these are defined as having the following meanings.

[0027] As used in this specification, "a" or "an" can mean one or more. When used in a claim in conjunction with the term "comprising", the term "a" or "an" can mean one or more than one. As used in this specification, "another" can mean at least a second or more.

[0028] The term "about" refers to a relative term indicating an approximation of plus or minus 10% of a nominal value, and in one embodiment, plus or minus 5%, and in another embodiment, plus or minus 2%. In the field of this disclosure, this level of approximation is appropriate unless the value is specifically stated to require a narrower range.

[0029] The term "and / or" means one or more. For example, "X and / or Y" is understood to mean either "X and Y" or "X or Y", and is interpreted to provide clear support for both meanings or for either meaning. Similarly, when more than two designations are listed, such as in "X, Y and / or Z", this is understood to mean either i) "X and Y", "X, Y and Z", "X and Z", or "Y and Z", or ii) "X or Y or Z", and is interpreted to provide clear support for all meanings.

[0030] The term "alkyl", alone or in combination, means an acyclic saturated hydrocarbon group of the formula CnH2n+1, which may be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl and t-butyl. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix specifying the lower and upper numbers of carbon atoms in the moiety, i.e., the prefix Ci~Cj refers to a moiety of integer "i" to integer "j" carbon atoms including the boundaries. Thus, for example, C1~C3 alkyl refers to alkyl having 1 to 3 carbon atoms including the boundaries.

[0031] "Fluoroalkyl" means an alkyl as defined herein, substituted with one, two or three fluoro atoms. Exemplary (C1) fluoroalkyl compounds include fluoromethyl, difluoromethyl and trifluoromethyl; exemplary (C2) fluoroalkyl compounds include 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, 1,1,2-trifluoroethyl, etc.

[0032] "Cycloalkyl" refers to a non-aromatic ring that is a fully hydrogenated group of the formula CnH2n-1. Examples of such carbocyclic rings include cyclopropyl and cyclobutyl.

[0033] "Fluorocycloalkyl" means a non-aromatic cycloalkyl ring as defined herein, substituted with one, two or three fluoro atoms. Exemplary (C3) fluorocycloalkyl compounds include fluorocyclopropyl, difluorocyclopropyl and trifluorocyclopropyl; exemplary (C4) fluorocycloalkyl compounds include 1-fluorocyclobutyl, 2-fluorocyclobutyl, 1,1-difluorocyclobutyl, 1,2-difluorocyclobutyl, 1,1,1-trifluorocyclobutyl, 1,1,2-trifluorocyclobutyl, etc.

[0034] "Alkoxy" means a straight-chain saturated alkyl or branched-chain saturated alkyl bonded through oxygen. Exemplifications of such alkoxy groups (assuming that the specified length encompasses a particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.

[0035] "Fluoroalkoxy" means an alkoxy as defined herein substituted with one, two or three fluoro atoms. Exemplary (C1) fluoroalkoxy compounds include fluoromethoxy, difluoromethoxy and trifluoromethoxy; exemplary (C2) fluoroalkyl compounds include 1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 1,1,1-trifluoroethoxy, 1,1,2-trifluoroethoxy, etc.

[0036] "Halo" refers to bromo, chloro, fluoro or iodo.

[0037] "Compound", as used herein, includes conformational isomers (e.g., cis and trans isomers), atropisomers (i.e., stereoisomers from restricted rotation), and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers and other mixtures of such isomers, as well as solvates, hydrates, polymorphs, pseudopolymorphs, tautomers, esters, salt forms and prodrugs, including any pharmaceutically acceptable derivatives or variants thereof. The expression "prodrug" refers to a compound that is a drug precursor which releases the drug in vivo via some chemical or physiological process after administration (e.g., the prodrug is converted to the desired drug form at physiological pH or via enzymatic action). When cleaved, exemplary prodrugs release the corresponding free acid, and such hydrolysable ester-forming residues of the compounds of formula I have a carboxyl moiety replaced by hydrogen that is (C1-C4)alkyl, (C2-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as beta-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and carboxyl moieties replaced by piperidino-, pyrrolidino-, or morpholino(C2-C3)alkyl, including but not limited to those having such substitutions.

[0038] As used herein, the arrow, "

[0039] [Chemistry] 」 or a wavy line, "

[0040] [Chemistry] 」 indicates the bonding point of the substituent to another group.

[0041] The term "mammal" refers to a human, a domestic animal or a companion animal.

[0042] The term "companion animal" or "companion animals" refers to an animal that is kept as a pet or a household animal. Examples of companion animals include dogs, cats, and rodents such as hamsters, guinea pigs, and gerbils, rabbits, ferrets.

[0043] The term "domestic animal" refers to an animal that is raised or bred in an agricultural environment for the production of products such as food or fiber, or for its labor. In some embodiments, domestic animals are suitable for consumption by humans, for example, mammals. Examples of domestic animals include cows, goats, horses, pigs, sheep including lambs, and rabbits.

[0044] "Patient" refers to warm-blooded animals such as guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cows, goats, sheep, horses, monkeys, chimpanzees, and humans.

[0045] The term "treating" or "treatment" means alleviating the symptoms associated with a disease, disorder or condition, or halting the further progression or worsening of those symptoms. Depending on the disease and condition of the patient, the term "treatment" as used herein may include one or more of curative, palliative, and prophylactic treatments. Treatment may also include administering a pharmaceutical formulation in combination with other therapies.

[0046] "Therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

[0047] The term "pharmaceutically acceptable" means a substance (e.g., a compound of the present invention) and any salt thereof, or a composition containing the substance or salt of the present invention that is suitable for administration to a patient.

[0048] In one embodiment of the compound, Z is S, and A is

[0049]

Chemical formula

[0050] In another embodiment of the compound, R 1 , R 3 and R 4 are each H, and R 2 is fluoro or a pharmaceutically acceptable salt thereof.

[0051] In another embodiment of the compound, R 5 is fluoro, chloro, cyano or (C1-C4) alkyl, and R 10 is H, fluoro or chloro or a pharmaceutically acceptable salt thereof.

[0052] In another embodiment of the compound, R 6 and R 7 are each independently selected from H, fluoro, chloro, cyano, (C1-C4) alkyl, and (C1-C4) alkoxy; or a pharmaceutically acceptable salt thereof.

[0053] In another embodiment of the compound, R 11 is H, fluoro, chloro, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy, or a pharmaceutically acceptable salt thereof.

[0054] In one embodiment of the treatment method, the method comprises administering to a human in need of such treatment a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt of said compound, for treating fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with hepatic fibrosis, non-alcoholic steatohepatitis with cirrhosis, or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma.

[0055] In another embodiment of the treatment method, non-alcoholic steatohepatitis is treated.

[0056] In another embodiment of the treatment method, the method comprises administering to a human in need of such treatment a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt of said compound, for treating heart failure, cardiovascular death, congestive heart failure, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), cardiovascular death, heart failure in patients with type II diabetes mellitus, coronary artery disease, peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, acute coronary syndrome, or reducing the risk of hospitalization thereby, and modifying cardiovascular risk.

[0057] In another embodiment of the treatment method, heart failure is treated.

[0058] In another embodiment of the treatment method, the method comprises administering to a human in need of such treatment a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt of said compound, for treating type I diabetes, type II true diabetes, idiopathic type I diabetes (type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial lipemia, impaired glucose tolerance (IGT) state, fasting plasma glucose abnormality state, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, glucose metabolism disorder, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and vascular compliance abnormalities, high apoB lipoproteinemia, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, and maple syrup urine disease.

[0059] In another embodiment of the treatment method, kidney disease is treated.

[0060] In another embodiment of the treatment method, the method comprises administering to a human in need of such treatment a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, for treating hepatocellular carcinoma, renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, gastric adenocarcinoma, adrenocortical carcinoma, papillary renal cell carcinoma, cancers in the cervix and endocervical canal, bladder urothelial carcinoma, and lung adenocarcinoma.

[0061] In another embodiment of the treatment method, hepatocellular carcinoma is treated.

[0062] In one embodiment of the pharmaceutical composition, the composition comprises a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier, vehicle or excipient.

[0063] In another embodiment of the pharmaceutical composition, the composition is a first compound that is a compound as described herein or a pharmaceutically acceptable salt of said compound; an antidiabetic agent; a second compound that is a non-alcoholic steatohepatitis treatment agent, a non-alcoholic fatty liver disease treatment agent, a kidney disease treatment agent, or an anti-heart failure treatment agent, and a pharmaceutical carrier, vehicle or excipient and includes a pharmaceutical combination comprising a therapeutically effective amount of the composition.

[0064] In another embodiment of the pharmaceutical composition, the combination composition includes, as the second compound, 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid; [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid; 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid; (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; or 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0065] In another embodiment of the pharmaceutical composition, in the combination composition, the non-alcoholic steatohepatitis treatment agent or non-alcoholic fatty liver disease treatment agent is an ACC inhibitor, a GLP1 receptor agonist, a DGAT-2 inhibitor, an FXR agonist, metformin, an incretin analog, or an incretin receptor modulator.

[0066] In another embodiment of the pharmaceutical composition, in the combination composition, the anti-diabetic agent is an SGLT-2 inhibitor, metformin, an incretin analog, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist.

[0067] In another embodiment of the pharmaceutical composition, in the combination composition, the anti-diabetic agent is metformin, sitagliptin or ertuglifozin.

[0068] In another embodiment of the pharmaceutical composition, the anti-heart failure agent is an ACE inhibitor, an SGLT-2 inhibitor, an angiotensin receptor blocker, an angiotensin receptor neprilysin inhibitor, a beta-adrenergic receptor blocker, a calcium channel blocker, or a vasodilator.

[0069] In another embodiment of the pharmaceutical composition, the anti-heart failure agent is valsartan, sacubitril, dapagliflozin, empagliflozin, canagliflozin or ertuglifozin.

[0070] In one embodiment of the crystalline form, the powder X-ray diffraction pattern has 2-theta values of 7.6 ± 0.2, 14.6 ± 0.2, and 27.9 ± 0.2 (CuKα radiation, wavelength of 1.54056 Å).

[0071] In another embodiment of the crystalline form, the powder X-ray diffraction pattern has 2-theta values of 10.2 ± 0.2, 13.9 ± 0.2, and 24.7 ± 0.2 (CuKα radiation, wavelength of 1.54056 Å).

[0072] One embodiment includes the use of a compound of formula I or a pharmaceutically acceptable salt of said compound for the manufacture of a medicament for treating fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with hepatic fibrosis, non-alcoholic steatohepatitis with cirrhosis or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma, which comprises administering a therapeutically effective amount to a mammal such as a human in need of such treatment.

[0073] Another embodiment includes the use of a compound of formula I or a pharmaceutically acceptable salt of said compound for the manufacture of a medicament for treating heart failure, cardiovascular death, congestive heart failure, heart failure with New York Heart Association Class I-IV symptoms, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with mid-range ejection fraction (HF-mrEF), cardiovascular death, heart failure in patients with type II diabetes mellitus, coronary artery disease, unstable angina, peripheral artery disease, peripheral vascular disease, renal vascular disease, pulmonary hypertension, vasculitis, acute coronary syndrome, or reducing the risk of hospitalization therefor, and modifying cardiovascular risk, which comprises administering a therapeutically effective amount to a mammal such as a human in need of such treatment.

[0074] Another embodiment involves administering to a mammal such as a human in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound, for the manufacture of a medicament for treating type I diabetes, type II true diabetes, idiopathic type I diabetes (type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary artery disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial lipemia, impaired glucose tolerance (IGT) state, fasting plasma glucose abnormality state, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, glucose metabolism disorder, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and vascular compliance disorder, high apoB lipoproteinemia, kidney disease, end-stage renal disease, chronic kidney disease at risk of progression, and maple syrup urine disease, including the use of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0075] Another embodiment involves administering to a mammal such as a human in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound, for the manufacture of a medicament for treating hepatocellular carcinoma, renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, gastric adenocarcinoma, adrenocortical carcinoma, papillary renal cell carcinoma, carcinoma in the cervix and endocervical canal, bladder urothelial carcinoma, and lung adenocarcinoma, including the use of a composition comprising a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0076] Another embodiment includes a compound selected from any of the examples described herein or a pharmaceutically acceptable salt thereof.

[0077] Another embodiment includes a prodrug of any of the examples described herein or a pharmaceutically acceptable salt thereof.

[0078] Another embodiment includes any of the examples described herein or a phosphate ester prodrug of a pharmaceutically acceptable salt thereof.

[0079] Another embodiment includes any novel genus of the intermediates described in the general scheme or examples.

[0080] Another embodiment includes any novel specific intermediate described in the preparation examples and examples described herein.

[0081] Another embodiment includes any novel process described herein.

[0082] All pharmaceutically acceptable isotope-labeled compounds of Formula I in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature but having the same number of atoms are within the scope of this application.

[0083] Examples of isotopes suitable for inclusion in the compounds of the invention are 2 H and 3 hydrogen such as 11 C, 13 C and 14 carbon such as 36 chlorine such as 18 fluorine such as 13 N and 15 nitrogen such as 15 O, 17 O and 18 oxygen such as 35 sulfur isotopes such as

[0084] Certain isotope-labeled compounds of Formula I, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. Radioactive isotope tritium, namely 3 H, and carbon-14, namely 14C is particularly useful for this purpose considering the ease of their incorporation and immediate detection means.

[0085] Deuterium, i.e. 2 substitution with a heavier isotope such as

[0086] 11 C, 18 F, 15 O and 13 substitution with a positron-emitting isotope such as N can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy.

[0087] The isotope-labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the accompanying examples and preparations, using appropriate isotope-labeled reagents in place of the unlabeled reagents used previously.

[0088] Certain compounds of formula I and the intermediates described herein can generally exist in multiple crystalline forms (generally referred to as "polymorphs"). Polymorphs can be prepared by crystallization using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and / or various cooling modes ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound followed by slow or rapid cooling. The presence of polymorphs can be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

[0089] The salts encompassed by the term "pharmaceutically acceptable salts" generally refer to the salts of the compounds of the present invention which are prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, and are suitable for administration to a patient. Base salts are preferred, however, some compounds may also form acid salts. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharinate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

[0090] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, calcium, choline, diethylamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, trimethamine and zinc salts. Hemisalts of acids and bases, for example, hemisulfate and hemicalcium salts can also be formed. For a general overview of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0091] Half salts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed. For an overview of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0092] Pharmaceutically acceptable salts of the compounds of formula I can be prepared by one or more of the following three methods: (i) A method by reacting a compound of formula I with a desired acid or base; (ii) A method by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the present invention using a desired acid or base, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam; or (iii) A method by reacting with a suitable acid or base or by converting one salt of the compound of the present invention to another salt using a suitable ion exchange column.

[0093] All three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration, or recovered by evaporating the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost non-ionized.

[0094] The compounds of formula I, and pharmaceutically acceptable salts thereof, can exist in both non-solvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.

[0095] The currently approved classification system for organic hydrates defines isolated-site, channel, or metal-ion coordinated hydrates. See Polymorphism in Pharmaceutical Solids, by K.R. Morris (edited by H.G. Brittain, Marcel Dekker, 1995). Isolated-site hydrates have water molecules isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules are in lattice channels where they are adjacent to other water molecules. In metal-ion coordinated hydrates, the water molecules are bound to metal ions.

[0096] When the solvent or water is tightly bound, the complex can have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water / solvent content can depend on humidity and drying conditions. In such cases, non-stoichiometry becomes the norm.

[0097] Within the scope of the present invention are also included multi-component complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular components bound to each other via non-covalent interactions, but can also be complexes of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, recrystallization from solvents, or physically grinding the components together. See Chem Commun, 17, 1889 - 1896, by O. Almarsson and M.J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64(8), 1269 - 1288, by Haleblian (August 1975).

[0098] Compounds of formula I (including prodrugs), i.e., active metabolites of compounds that are often formed in vivo by oxidation or dealkylation upon administration of the drug, are also included within the scope of the present invention. Some examples of metabolites according to the present invention are: (i) When the compound of formula I contains a methyl group, its hydroxymethyl derivative (-CH3 → -CH2OH) and (ii) When the compound of formula I contains an alkoxy group, its hydroxy derivative (-OR → -OH) are included.

[0099] The compounds of the present invention can exist in a continuous solid state ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and can exhibit physical properties of a solid or a liquid depending on temperature. Typically, such a material does not show a characteristic X-ray diffraction pattern and, while showing solid properties, is more formally described as a liquid. When heated, a change from solid properties to liquid properties occurs, which is typically characterized by a secondary state change ("glass transition"). The term "crystalline" refers to a solid phase in which the material has an internal structure that is regularly arranged at the molecular level and shows a characteristic X-ray diffraction pattern with defined peaks. Such a material also shows liquid properties when sufficiently heated, but the change from solid to liquid is typically characterized by a primary phase change ("melting point").

[0100] Compounds of formula I can also exist in an intermediate state (mesophase or liquid crystal) when placed under suitable conditions. The intermediate state is intermediate between a true crystalline state and a true liquid state (melt or solution). Liquid crystallinity resulting from a temperature change is described as "thermotropic", and liquid crystallinity resulting from the addition of a second component such as water or another solvent is described as "lyotropic". Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic" and ionic (-COO - Na + , -COO - K + , or -SO3 - Na +etc.) or nonionic (-N - N + (such as (CH3)3) and consists of molecules having a polar head group. For further information, see Crystals and the Polarizing Microscope, 4th edition (Edward Arnold, 1970) by N.H. Hartshorne and A. Stuart.

[0101] The compounds of formula I may exhibit polymorphism and / or one or more isomers (e.g., optical, geometric, or tautomeric). The compounds of formula I may be isotopically labeled. Such variations are implied by the compounds of formula I as defined by reference to their structural features and are thus within the scope of the present invention.

[0102] The term "room temperature" or "ambient temperature" means a temperature between 18 °C and 25 °C, "HPLC" refers to high performance liquid chromatography, "MPLC" refers to medium pressure liquid chromatography, "TLC" refers to thin layer chromatography, "MS" refers to mass spectrum or mass spectrometry or mass spectrometric method, "NMR" refers to nuclear magnetic resonance spectroscopy, "DCM" refers to dichloromethane, "DMSO" refers to dimethyl sulfoxide, "DME" refers to 1,2-dimethoxyethane, "EtOAc" refers to ethyl acetate, "MeOH" refers to methanol, "Ph" refers to phenyl group, "Pr" refers to propyl, "trityl" refers to triphenylmethyl group, "ACN" refers to acetonitrile, "DEAD" refers to diethyl azodicarboxylate, "DIAD" refers to diisopropyl azodicarboxylate.

[0103] Generally, the compounds of the present invention can be prepared by processes involving procedures similar to those known in the chemical art, particularly in light of the descriptions contained herein. Certain processes for the manufacture of the compounds of the present invention are provided as a further feature of the present invention and are illustrated by the following reaction schemes. Other processes may be described in the Experimental section. A specific synthetic scheme for preparing the compounds of formula I is outlined below.

[0104] As used herein, the expressions "reaction-inert solvent" and "inert solvent" refer to a solvent or mixture thereof that does not interact with the starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.

[0105] As a first note in the preparation of the compounds of formula I, it should be noted that some of the preparative methods useful in the preparation of the compounds described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls in the formula I precursors). The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparative method. The need for such protection can be readily determined by one of ordinary skill in the art. The use of such protection / deprotection methods is also within the scope of the skills possessed by one of ordinary skill in the art. For an overview of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0106] For example, a particular compound, if left unprotected, contains a primary amine or carboxylic acid functional group that can interfere with reactions at other sites of the molecule. Thus, such functional groups may be protected by appropriate protecting groups that can be removed in subsequent steps. Suitable protecting groups for amine and carboxylic acid protection include those commonly used in peptide synthesis (such as N-tert-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethyleneoxycarbonyl for amines, and lower alkyl or benzyl esters for carboxylic acids, etc.), which are generally not chemically reactive under the described reaction conditions and can typically be removed without chemically altering other functional groups in the compound of formula I.

[0107] The compounds and intermediates of formula I may contain asymmetric or chiral centers and thus can exist in various stereoisomeric forms. Unless otherwise specified, all stereoisomeric forms of the compounds, including mixtures thereof including racemic mixtures, are intended to be included herein. In addition, all geometric and positional isomers are included within the scope of the compounds. For example, when a double bond or a fused ring is introduced into the compound, both cis and trans forms, as well as mixtures, are included within the scope of the present invention.

[0108] In addition, the compounds and intermediates of formula I include all atropisomers and mixtures of their stereoisomers including racemic mixtures. Atropisomers can be isolated as separate stereoisomers and include those that maintain their stereoisomeric purity over various periods including medium and long term. Atropisomers also include isomers that cannot be easily separated as separate stereoisomers by interconversion over a certain period including short to medium term.

[0109] Using chromatography, typically high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC), on a resin, with an enantioselective stationary phase and a mobile phase consisting of hydrocarbons containing from 0 to 50%, typically from 2 to 20% isopropanol and from 0 to 5%, typically 0.1% diethylamine (DEA) or isopropylamine, typically heptane or hexane, the chiral compounds (and their chiral precursors) of the present invention can be obtained in enantiomerically enriched form. By concentrating the eluent, an enriched mixture is obtained.

[0110] A mixture of diastereoisomers can be separated into its individual diastereoisomers by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization, based on their physicochemical differences. By reacting a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) to convert a mixture of enantiomers into a mixture of diastereoisomers, separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis), enantiomers can be separated. Enantiomers can also be separated by use of a chiral HPLC column. Alternatively, by using an optically active starting material, by asymmetric synthesis using an optically active reagent, substrate, catalyst, or solvent, or by asymmetric transformation to convert certain stereoisomers into others, certain stereoisomers can be synthesized.

[0111] When a compound has two or more chiral centers and the absolute or relative stereochemistry is indicated in the name, the symbols R and S refer to the ascending numerical values (1, 2, 3, etc.) according to the conventional IUPAC numbering scheme for each molecule for each chiral center. When a compound has one or more chiral centers and the stereochemistry is not indicated in the name or structural formula, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemic form.

[0112] The compounds of the present invention may contain olefin-like double bonds. When such bonds are present, the compounds of the present invention exist as cis and trans configurations, as well as mixtures thereof. The term "cis" refers to the orientation of two substituents relative to each other and to the plane of the ring (either both "above" or both "below"). Similarly, the term "trans" refers to the orientation of two substituents relative to each other and to the plane of the ring (where the substituents are on opposite sides of the ring).

[0113] The intermediates and compounds of Formula I can also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion via the movement of a proton, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the tetrazole moiety where a proton can move among four ring nitrogens as follows.

[0114]

Chemical formula

[0115] Valence tautomers involve interconversion by rearrangement of some bonding electrons.

[0116] All stereoisomers, geometric isomers, and tautomeric forms of the compounds of Formula I, including compounds that exhibit more than one type of isomerism and one or more mixtures thereof, are included within the scope of the claimed compounds of the present invention. Also included are acid addition salts or base salts where the counterion is optically active, such as D-lactate or L-lysine, or racemates, such as DL-tartrate or DL-arginine.

[0117] The compounds of Formula I can be prepared by the general schemes and examples provided herein.

[0118] General scheme The compounds of formula I can be prepared according to Schemes I - X, with variable groups A, X1, X2, X3, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and Z are given the meanings already described, unless otherwise noted. Further, in Schemes I - X, the variable group R 14 is H or C1 - C6(alkyl), R 15 is C1 - C6(alkyl), R * is H or C1 - C6(alkyl), R ** is H or C1 - C6(alkyl), or R * and R ** together with the O atom and the B group form a heterocyclic compound which may be substituted with 1, 2, 3, 4, 5 or 6 C1 - C6(alkyl).

[0119]

Chemical formula

[0120] The compound of formula I can be prepared by hydrolysis of the compound of formula H as shown in Scheme I. One of ordinary skill in the art will appreciate that there are various methods for ester hydrolysis. The formula I benzothiophene acid compound or benzofuran acid compound can be prepared from the formula H ester by a hydrolysis reaction with a suitable hydroxide source. Conditions for this conversion include, but are not limited to, reactions of esters with inorganic hydroxides, including the following exemplary procedures. The formula H ester is hydrolyzed, for example, by reaction with sodium hydroxide or with lithium hydroxide to the corresponding formula I. Suitable solvents include methanol, ethanol, water, 2-methyltetrahydrofuran, and tetrahydrofuran. The reaction mixture is heated at a temperature from about 25 °C to about 90 °C, typically at about 25 °C, for about 1 hour to about 16 hours, typically for about 16 hours.

[0121]

Chemical formula

[0122] The formula I benzothiophene acid compound or benzofuran acid compound is

[0123]

Chemical formula

[0124]

Chemical formula

[0125] As shown in Scheme III, the formula H ester can be prepared from the corresponding compounds of formula E or formula F by various methods known to those skilled in the art. For example, a Suzuki reaction with a coupling partner such as the compounds of formula D and formula G could result in the compound of formula H. This derivatization can be achieved using various reagents including potassium fluoride, tripotassium phosphate, potassium carbonate, potassium hydrogen carbonate and cesium carbonate, preferably potassium fluoride, in a wide range of solvents including tetrahydrofuran, 1,4-dioxane, toluene and water. The reaction can be carried out using many suitable catalysts and catalyst-ligand combinations. Exemplary catalysts and catalyst-ligand combinations include chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) (XPhos Pd G2), tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), methanesulfonyl[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) [P(t-Bu)3Pd G3], allylpalladium(II) chloride dimer, [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) [Pd(amphos)2Cl2] and / or chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) [P(t-Bu)3Pd G2]. Exemplary ligands include tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate and 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl. To carry out the reaction, heating may be required at a temperature from about 60 °C to about 120 °C, usually about 80 °C, for about 1 to 24 hours, usually about 16 hours. If atropisomerism is observed, separation using chiral techniques known to those skilled in the art can result in a single atropisomer.

[0126] [Chemistry]

[0127] Alternatively, as shown in Scheme IV, the ester of formula H can be synthesized by additional methods available to those skilled in the art. For example, the compound of formula K can be obtained by brominating the compound of formula J using a suitable reagent such as N-bromosuccinimide in various suitable polar solvents such as N,N-dimethylformamide, acetonitrile, or preferably acetic acid. A suitable temperature for the reaction is about 80 °C for 16 hours. The compound of formula H can be prepared from the corresponding compound of formula K by various methods known to those skilled in the art. As shown in Scheme IV, a Suzuki coupling reaction with a corresponding coupling partner such as the compound of formula D can result in the compound of formula H. This derivatization can be achieved with various reagents including, but not limited to, cesium carbonate and tetrakis(triphenylphosphine)palladium(0) in a suitable solvent system such as 1,4-dioxane and water. The reaction can proceed at a temperature of 80 °C for 16 hours. Further exemplary Suzuki coupling reaction conditions are described in Scheme III.

[0128] Aryl bromides such as the compound of formula M can be prepared by various methods available to those skilled in the art. For example, the compound of formula L can be brominated using a suitable reagent such as N-bromosuccinimide in various suitable organic solvents, preferably dichloromethane. A suitable temperature for the reaction is from about 25 °C to about 35 °C for 20 hours. The aryl bromide of formula M can be derivatized to the compound of formula H by catalytic esterification under a carbon monoxide atmosphere. A list of suitable catalyst-ligand combinations includes, but is not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex. Various bases, preferably N,N-diisopropylethylamine, can be used for this conversion. The reaction can proceed with heating at about 70 °C for 16 hours. Various protic solvents can be used for this esterification, but methanol is preferred.

[0129] The compound of formula H can also be prepared from the compound of formula N by metal-halogen exchange of the aryl halide of formula G to obtain the compound of formula O followed by reaction of a wine level amide compound such as those described by the compound of formula N. This metal-halogen exchange can be carried out under various conditions known to those skilled in the art. For example, reagents such as isopropylmagnesium chloride and tert-butyllithium can be used, but preferably n-butyllithium is used. Various aprotic solvents such as diethyl ether, 2-methyltetrahydrofuran, and tetrahydrofuran can be used for this reaction. The reaction can proceed at a temperature of about -78 °C for about 3 hours. The condensation of the compound of formula O and acetate as shown in Scheme IV can result in the compound of formula H. Examples of this transformation may involve the use of ethyl sulfanylacetate as well as other reagents such as potassium carbonate and N,N-dimethylformamide. When the reaction solution is heated to 100 °C for about 16 hours, the compound of formula H can be obtained.

[0130]

Chemical formula

[0131] The amino-benzothiophene and amino-benzofuran compounds of formula E2 can be prepared from the nitriles of formula P1 or formula P2 by alkylation followed by internal condensation with the nitrile group as shown in Scheme V. The conditions for this transformation include, but are not limited to, reacting a compound of formula P1 with an alkyl sulfanylacetate and treating with a base to obtain the desired amino-benzothiophene. A list of suitable bases for this reaction includes sodium hydroxide, potassium carbonate, and triethylamine. Dimethyl sulfoxide and N,N-dimethylformamide can be used as solvents, and the use of 18-crown-6 may promote this condensation. The reaction can be carried out at a temperature of from about 0 °C to about 130 °C in certain cases, typically at about 0 °C, for from about 3 hours to about 16 hours, typically for about 3 hours. Alkylation of the compound of formula P2 with alkyl bromoacetate can result in a compound of formula E1. As an example, this transformation can proceed with acetonitrile as a suitable solvent and potassium carbonate as a suitable base. The reaction can be carried out at a temperature of 15 °C for about 16 hours. The desired amino-benzofuran can be obtained from cyclization of the compound of formula E1 with tetrahydrofuran as a suitable solvent and potassium tert-butoxide as a suitable base. The reaction can proceed at a temperature of about 0 °C for about 2 hours.

[0132] The ester of formula E can be prepared, for example, by the Sandmeyer reaction of an amine of formula E2. This can be achieved using various reagents depending on the desired aryl halide of formula E. They include copper(II) bromide, copper(I) iodide, copper(II) chloride, diiodomethane, tert-butyl nitrite and 3-methylbutyl nitrite in a suitable solvent such as acetonitrile. The reaction can proceed at 0 °C or the reaction mixture can be heated to the reflux temperature of the appropriate solvent. Suitable reaction times are typically between about 1 hour and 16 hours. The arylboronic acid ester of formula F can then be prepared from the aryl halide of formula E by a Miyaura reaction with a boronic acid ester source such as 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane. The reaction can occur in various suitable solvents including 1,4-dioxane and a suitable base such as potassium acetate can be used. The conversion may require the use of a catalyst-ligand combination such as [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture can be heated to the reflux temperature of the appropriate solvent. Suitable reaction times are typically about 16 hours.

[0133]

Chemical formula

[0134] The necessary boronic acid or ester of formula D can be prepared by various methods known to those skilled in the art as shown in Scheme VI. For example, the compound of formula D can be obtained by the Miyaura borylation of an aryl halide of formula G1, typically an aryl bromide or aryl iodide. Various catalysts and catalyst-ligand combinations can be used, including but not limited to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II). Various ligands and reagents such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tetrahydroxydiboron, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, potassium acetate, sodium tert-butoxide, and ethane-1,2-diol can be used to affect the Miyaura transformation. Suitable solvents for this reaction can be N,N-dimethylformamide, 1,4-dioxane, and methanol. The reaction can proceed over about 16 hours at a temperature from about 50 °C to about 100 °C.

[0135] Alternatively, the boronic acid or ester of formula D can be prepared by metal-halogen exchange or deprotonation of the compound of formula G1. Reagents such as n-butyllithium and isopropylmagnesium chloride can be used to effect the exchange. Various reagents such as 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane and trimethyl borate can be used as the boronate source. The reaction can be carried out at a temperature from about -78 °C to about 25 °C, preferably at -78 °C, over about 1 hour. Aprotic solvents such as diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, but preferably tetrahydrofuran can be used.

[0136] An alternative method for obtaining the boronic acid or ester of formula D can be the borylation by CH activation of arenes such as the compound of formula G1. An example of this transformation can use (1,5-cyclooctadiene)(methoxy)iridium(I) dimer as the catalyst and 4,4'-di-tert-butyl-2,2'-bipyridine as the ligand. A suitable boronate source for this reaction can be 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and tetrahydrofuran can be used as a suitable solvent for this derivatization. A temperature of about 80 °C for about 16 hours may be required to obtain the desired boronic acid or ester.

[0137]

Chemical formula

[0138] Arenes of formula Q1, Q2, Q3 and Q4 can be prepared from various conventional modifications known to those skilled in the art as shown in Scheme VII. Examples of these modifications can include, but are not limited to, the reaction of an aldehyde of formula T with a suitable reagent such as methylmagnesium bromide in tetrahydrofuran at a temperature from about -78 °C to 0 °C for about 2 hours. Reacting a secondary alcohol of formula U with an activating group such as methanesulfonyl chloride gives a compound of formula V where LG is a leaving group such as mesylate, tosylate, or triflate. A suitable base for use in this reaction can be triethylamine, and a suitable solvent for this transformation can be dichloromethane at a temperature of about 0 °C for about 30 minutes. The reduction of the compound of formula V can be achieved using lithium triethylborohydride. Various aprotic solvents can be used for this reaction, but tetrahydrofuran may be preferred. A suitable reaction temperature can be about 0 °C for about 30 minutes to obtain a compound such as the arene of formula Q1.

[0139] The compound of formula Q2 can be prepared from the compound of formula W by iodination known to those skilled in the art, followed by a halogen dance reaction. The iodination of the compound of formula W can be carried out using an electrophilic reagent such as n-butyllithium and iodine at a temperature from about -78 °C to about 20 °C over about 3 hours. Many aprotic solvents can be used for this process, but tetrahydrofuran may be preferred. Treating the compound of formula X with a base such as lithium diisopropylamide in a suitable solvent such as tetrahydrofuran allows the halogen to be transferred. A typical temperature in this reaction can be from -65 °C to about 20 °C over 2 hours.

[0140] Benzoic acid of formula Y can be iodinated by a palladium-catalyzed process to obtain the compound of formula Z. This reaction can be carried out with various catalysts such as palladium(II) acetate and reagents such as iodine and (diacetoxyiodo)benzene. An aprotic solvent such as N,N-dimethylformamide may be required at a temperature of about 120 °C for about 16 hours to effect the conversion. The compound of formula AA can be prepared from the compound of formula Z under conditions known to those skilled in the art. As an example, the compound of formula Z can be treated with 1H-benzotriazol-1-ol, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 4-methylmorpholine and aqueous ammonium hydroxide. Many aprotic solvents can be used for this reaction, but tetrahydrofuran may be preferred. The reaction temperature can be about 15 °C over about 16 hours. The aryl nitrile of formula Q3 can be synthesized from the compound of formula AA under dehydration conditions. Various reagents such as trifluoroacetic anhydride and pyridine may be suitable for this conversion. Dichloromethane can be a suitable solvent for this reaction at a temperature of about 15 °C for about 16 hours.

[0141] The modification of the iodoarene of formula AB can be achieved with a suitable base such as lithium diisopropylamide at a temperature from about -78 °C to 25 °C. Then, to obtain the compound of formula Q4, many electrophiles, for example, iodomethane, can be used over about 1 hour. It may be necessary about 16 hours to cause derivatization.

[0142]

Chemical formula

[0143] In addition, a compound of formula Q5 in which R ’ is (C1-C4) alkyl or (C1-C4) fluoroalkyl can be prepared by an alternative route as shown in Scheme VIII. Nucleophilic substitution of a leaving group on the arene such as a compound of formula AC can result in a compound of formula AD. For example, when an aryl ether is shown for the compound of formula AD, it can be prepared using a suitable nucleophilic reagent such as sodium methoxide in methanol. A suitable temperature for the reaction can typically be about 25 °C over about 16 hours. Using various conditions known to those skilled in the art, the compound of formula AD can be mono-debrominated to obtain the compound of formula Q5. As an example, a base such as n-butyllithium can be used with a suitable solvent such as diethyl ether. A typical reaction temperature for this reaction can be -78 °C over about 5 hours.

[0144] Alternatively, the arene of formula Q5 can be prepared from the aryl bromide of formula AE. For example, borylation of a compound of formula AE with a base such as lithium diisopropylamide can afford the desired arylboronic acid of formula AF. This transformation can be carried out in many suitable solvents such as tetrahydrofuran and diethyl ether, preferably in methyl tert-butyl ether. The lithium-aryl complex can be quenched with an electrophilic reagent such as trimethyl borate, and treating it with an aqueous acid such as hydrogen chloride will afford the arene of formula AF. Typical temperatures for this reaction can be from about -70 °C to about 0 °C over about 4 hours. The phenol of formula AG can be prepared by hydroxylation of the boronic acid of formula AE using various reagents, preferably hydrogen peroxide. When a solvent is used, suitable solvents include ethanol, methanol, N,N-dimethylformamide, or preferably dichloromethane. Suitable temperatures for the above reaction are typically between 30 °C and 40 °C. Suitable reaction times are typically about 16 hours. The aryl ether of formula Q5 can be conveniently prepared from the corresponding phenol of formula AG with the addition of an inorganic base such as potassium carbonate in a suitable polar aprotic solvent such as acetone at a temperature between about -10 °C and 30 °C, preferably ambient temperature, over about 16 hours by reaction with iodomethane. In addition to those described, it will be apparent to those skilled in the art that there are other ways to effect this transformation.

[0145]

Chemical formula

[0146] As shown in Scheme IX where X represents halo, there are a wide variety of approaches that one skilled in the art can take to prepare the compound of formula R. For example, a compound of formula AH can be reacted with ethyl(triphenyl-λ 5- When reacted with phosphaniliden)acetate, arylethyl prop-2-enoate can be obtained. A typical temperature for this conversion can be about 25 °C over 16 hours. When the resulting alkene is reduced with a catalyst such as nickel(II) hexahydrate combined with sodium borohydride, a compound of formula AI can be produced. Various solvents or solvent combinations can be used, but preferably, a mixture of tetrahydrofuran and methanol can be used. The reaction can be carried out at a temperature of about 0 °C for about 1 hour. Acid-catalyzed condensation of the phenol of formula AI with an acid such as p-toluenesulfonic acid can result in a compound of formula AJ. A typical reaction time can be 16 hours at a suitable temperature of about 130 °C. The compound of formula AK can be prepared from the compound of formula AJ using a reducing reagent such as diisobutylaluminum hydride. A suitable solvent for this conversion can be dichloromethane over about 3 hours. A suitable temperature for the reaction is between about -78 °C and 0 °C, preferably about -78 °C.

[0147] In the compound of formula AK, further derivatization can be carried out by the addition of an alkylating agent including but not limited to methylmagnesium bromide in a suitable aprotic solvent such as diethyl ether to yield a diol of formula AL. A suitable temperature for the reaction is between about 0 °C and 25 °C, preferably about 0 °C. The reaction time is from about 3 to about 16 hours, typically about 3 hours. Acid-mediated dehydration of the compound of formula AL can finally result in a compound of formula R. An example of a reagent combination that can be used for this reaction is a mixture of sulfuric acid and acetic acid. Typically, the reaction can be carried out at a suitable temperature of about 100 °C for about 3 hours.

[0148] Additional methods for obtaining compounds of formula R may be derived from compounds of formula AM. As an example, alkylation of a phenol of formula AM with an electrophile such as 1,3-dibromopropane in a suitable solvent such as acetonitrile can be carried out in the presence of an inorganic base such as potassium carbonate. A suitable temperature for this derivatization can be about 80 °C over 16 hours. Compounds of formula R can be prepared from compounds of formula AN. This conversion can be carried out using a base such as n-butyllithium. This reaction can proceed in various aprotic solvents such as methyl tert-butyl ether, diethyl ether, 2-methyltetrahydrofuran, or preferably tetrahydrofuran. The reaction can afford compounds of formula R at a temperature from about -78 °C to nearly room temperature over 2 to about 16 hours. Alternatively, compounds of formula R can be synthesized using compounds of formula AP. Compounds of formula AQ can be prepared by treating compounds of formula AP with a reagent such as (2E)-but-2-enoic acid in the presence of an acid such as methanesulfonic acid. The reaction can proceed at a temperature of about 100 °C over about 16 hours. Reduction of compounds of formula AQ can be carried out with an organo-silane such as triethylsilane under acidic conditions. Typically, trifluoroacetic acid can be used. A suitable temperature for carrying out the reaction is about 25 °C over about 3 days.

[0149] Base-promoted condensation of a compound of formula AR with a suitable aldehyde can afford a compound of formula AQ. Typically, pyrrolidine can be used for this transformation in a suitable protic solvent such as ethanol. The temperature of the reaction can range from about 20 °C to about 70 °C over about 3 hours. The compound of formula R can be obtained after reduction of the compound of formula AQ under reaction conditions similar to those described above using an organo-silane reagent such as triethylsilane and an acid such as trifluoroacetic acid. In addition, the compound of formula AQ can be derivatized by treatment with an alkylating reagent such as methylmagnesium bromide in a suitable solvent such as tetrahydrofuran to afford a compound of formula AO. Cerium(III) chloride can be used to facilitate this transformation, which can be achieved over about 16 hours at a temperature from about -50 °C to about 25 °C. Reductive dehydration of the compound of formula AO can finally afford the compound of formula R by treatment with a reagent such as triethylsilane combined with boron trifluoride diethyl etherate. A typical reaction temperature can be about 0 °C over 30 minutes.

[0150]

Chemical formula

[0151] The compounds of formula AR can be further refined by various methods known to those skilled in the art prior to the Suzuki coupling. Such transformations include, but are not limited to, the examples shown in Scheme X. For example, the compounds of formula AR can be derivatized at the alpha position of the ketone by various methods. As an example, alkylation at the alpha position with respect to the ketone can be initiated by enolate formation with a combination of reagents such as lithium diisopropylamide and N,N,N’,N’,N”,N”-hexamethylphosphoric triamide. Various suitable polar aprotic solvents such as diethyl ether or preferably tetrahydrofuran can be used. A suitable temperature for the reaction is between about -78 °C and 0 °C. The addition of the electrophile can result in the compound of formula AQ after a typical reaction time of about 4 hours in total. The reduction of the carbonyl in the compound of formula AQ to yield the compound of formula S can be carried out using an organosilane such as triethylsilane under acidic conditions. Typically, trifluoroacetic acid can be used. A suitable temperature for carrying out the reaction is about 50 °C over about 16 hours. It will be apparent to those skilled in the art that many of these derivatives may themselves be suitable for further manipulations to access additional compounds of formula S.

[0152] Using a similar approach, derivatization of the compound of formula AS can also result in the compound of formula S. For example, for the metal-halogen exchange of the compound of formula AS with a suitable reagent such as (propan-2-yl)magnesium chloride in a suitable aprotic solvent such as tetrahydrofuran, a reaction with an electrophilic reagent in the presence of copper(I) iodide may follow to obtain the compound of formula AT. For similar transformations known to those skilled in the art, various electrophilic reagents can be used. As an example, the use of 3-bromo-2-methylprop-1-ene can result in the compound of formula AT at a typical temperature from about -20 °C to about 25 °C. The reaction may require about 16 hours. Hydroboration-oxidation of the compound of formula AT can result in the compound of formula AU. Many reagents can be used to achieve the above transformation; as an example, the use of borane in tetrahydrofuran can result in the compound of formula AU together with the use of sodium hydroxide and hydrogen peroxide. The typical reaction temperature can be from about 0 °C to about 60 °C over about 4 hours in a step approach. Intramolecular nucleophilic aromatic substitution of the compound of formula AU can result in the compound of formula S. As an example, the use of sodium hydride and the compound of formula AU under various solvents known to those skilled in the art, preferably a mixture of toluene and N,N-dimethylformamide, can result in the compound of formula S. A suitable temperature for carrying out the reaction is between about 0 °C and room temperature. A suitable reaction time is about 16 hours. It will be apparent to those skilled in the art that many of these derivatives may themselves be suitable for further manipulation to access additional compounds of formula S.

[0153] The starting materials and reagents for the above-described compounds of formula I are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related to or derived from compounds of great scientific interest and practical need, and thus many such compounds are commercially available or reported in the literature or can be readily prepared from other commercially available substances by methods reported in the literature.

[0154] This application also relates to a pharmaceutical composition having a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or excipient.

[0155] The compounds of the present invention can also be used in combination with other pharmaceutical agents (e.g., anti-atherosclerotic and antithrombotic agents) for treating the diseases / conditions described herein. This application a first compound which is any compound of formula I or a pharmaceutically acceptable salt of said compound; a second compound which is a therapeutic agent for renal diseases, an anti-diabetic agent; a therapeutic agent for non-alcoholic steatohepatitis, a therapeutic agent for non-alcoholic fatty liver disease or a therapeutic agent for heart failure, and a pharmaceutical carrier, vehicle or excipient also relates to a pharmaceutical combination composition comprising a therapeutically effective amount of a composition having

[0156] In one embodiment, said therapeutic agent for renal diseases is useful for treating acute and / or chronic renal diseases.

[0157] In one embodiment, said therapeutic agent for non-alcoholic steatohepatitis or non-alcoholic fatty liver disease is an ACC inhibitor, a KHK inhibitor, a DGAT-2 inhibitor, an FXR agonist, a GLP-1R agonist, metformin, an incretin analog, or an incretin receptor modulator.

[0158] In another embodiment, said anti-diabetic agent is an SGLT-2 inhibitor, metformin, an incretin analog, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist.

[0159] In another embodiment, said anti-diabetic agent is metformin, sitagliptin or ertuglifozin.

[0160] In another embodiment, the anti-heart failure agent is an ACE inhibitor, an angiotensin receptor blocker, an angiotensin-receptor neprilysin inhibitor, a beta adrenergic receptor blocker, a calcium channel blocker, or a vasodilator.

[0161] Combination agent The compound can be administered alone or in combination with one or more additional therapeutic agents. By "administered in combination" or "combination therapy" is meant that the compound and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination, each component may be administered sequentially in any order, either simultaneously or at different times. Thus, each component may be administered separately but sufficiently close in time to provide the desired therapeutic effect. The phrases "concurrent administration", "co-administration", "simultaneous administration" and "administered simultaneously" mean that the compound is administered in combination. Thus, the methods of prevention and treatment described herein include the use of combination agents.

[0162] The combination agent is administered to the mammal in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount of the compound of formula I effective to treat a desired disease / condition (e.g., NASH, heart failure, kidney disease or diabetes) when administered to a mammal alone or in combination with an additional therapeutic agent.

[0163] Considering the NASH / NAFLD activity of the compounds of the present invention, they are used in the treatment of non-alcoholic steatohepatitis (NASH) and / or non-alcoholic fatty liver disease (NAFLD) and related diseases / conditions together with other agents, such as orlistat, TZD and other insulin sensitizers, FGF21 analogs, metformin, omega-3-acid ethyl esters (e.g., Lovaza), fibrates, HMG-CoA reductase inhibitors (e.g., pravastatin , lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (also known as itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin, or atavasin or bisastatin)), ezetimibe, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors (e.g., evolocumab, alirocumab), probucol, ursodeoxycholic acid, TGR5 agonist, FXR agonist, vitamin E, betaine, pentoxifylline, CB1 antagonist, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone and buproprion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin, ASP-1941, THR1474, TS-071, ISIS388626 and LX4211 and those in WO2010023594), phentermine, topiramate, GLP-1 receptor agonists, GIP receptor agonists, dual GLP-1 receptor / glucagon receptor agonists (i.e., OPK88003, MEDI0382, JNJ-64565111, NN9277, BI456906), dual GLP-1 receptor / receptor / GIP receptor agonists (i.e., tirzepatide (LY3298176), NN9423), angiotensin receptor blockers acetyl-CoA carboxylase (ACC) inhibitors, diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors, e.g., those described in WO09016462 or WO2010086820, AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitors, PNPLA3 inhibitors, FGF21 analogs, FGF19 analogs, PPAR agonists, FXR agonists, AMPK activators, SCD1 inhibitors or MPO inhibitors may be co-administered.

[0164] Exemplary GLP-1 receptor agonists include liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, HM15211, LY3298176, Medi-0382, NN-9924, TTP-054, TTP-273, efpeglenatide, those described in WO2018109607 including the following, and those described in PCT / IB2019 / 054867 filed on June 11, 2019: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; and 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0165] Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-1’H-spiro[indazole-5,4’-piperidine]-1’-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid; and filsocostat (GS-0976) and pharmaceutically acceptable salts thereof.

[0166] Exemplary FXR agonists include tropifexor (2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid); cilofexor (GS-9674); obeticholic acid, LY2562175; Met409; TERN-101; and EDP-305 and pharmaceutically acceptable salts thereof.

[0167] Exemplary DGAT2 inhibitors include (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-Ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-Ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-Ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine-5-carboxamide; and 2-(5-((3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof.

[0168] Exemplary KHK inhibitors include [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hexan-6-yl]acetic acid and a pharmaceutically acceptable salt thereof.

[0169] Considering the antidiabetic activity of the compounds of the present invention, they may be co-administered with other antidiabetic agents. Suitable antidiabetic agents are insulin, metformin, GLP-1 receptor agonists (as described hereinabove), acetyl-CoA carboxylase (ACC) inhibitors (as described hereinabove), SGLT2 inhibitors (as described hereinabove), monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors, AMPK activators, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glyburide, glibide, glipizide, glimepiride, glyclazide, glipentide, gliclazide, glisolamide, tolazamide and tolbutamide), meglitinides, α-amylase inhibitors (e.g., tendamistat, trestatin and AL-3688), α-glucoside hydrolase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q and salbostatin), PPARγ agonists (e.g., balaglitazone, ciglitazone, daruglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), PPARα / γ agonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract, and Zhang, S.Compounds disclosed by, for example, Drug Discovery Today, 12(9 / 10), 373 - 381(2007), SIRT-1 activators (e.g., resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., those in WO2005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) inhibitors, glucokinase activators (GKa), such as those described in WO2010103437, WO201010343f8, WO2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, insulin mimetics, glycogen phosphorylase inhibitors (e.g., GSK1362885), VPAC2 receptor agonists, glucagon receptor modulators, such as those described by Demong, D.E. et al., Annual Reports in Medicinal Chemistry 2008, 43, 119 - 137, GPR119 modulators, particularly agonists, such as those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R.M. et al., Medicinal Chemistry 2009, 44, 149 - 170 (e.g., MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs, such as those described by Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, 10(4) 359 - 364, TGR5 (also referred to as GPBAR1) receptor modulators, particularly agonists, such as those described by Zhong, M., those described in Current Topics in Medicinal Chemistry, 2010, 10(4), 386 - 396 and INT777, GPR40 agonists, including but not limited to TAK - 875, those described in Medina, J.C., Annual Reports in Medicinal Chemistry, 2008, 43, 75 - 85, GPR120 modulators, particularly agonists, high - affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, including but not limited to GSK1614235. A further representative list of antidiabetic agents that can be combined with the compounds of the present application can be found, for example, on pages 28, line 35 to page 30, line 19 of WO2011005611.

[0170] Other antidiabetic agents include inhibitors or modulators of carnitine palmitoyltransferase enzymes, inhibitors of fructose 1,6 - diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5, inhibitors of PKC isoforms (e.g., PKCα, PKCβ, PKCγ), inhibitors of fatty acid synthase, inhibitors of serine palmitoyltransferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol - binding protein 4, glucocorticoid receptor, modulators of somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of the IL1 family including IL1 beta, and modulators of RXR alpha. Additionally, suitable antidiabetic agents include the mechanisms described by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627 - 51.

[0171] Considering the anti-heart failure activity of the compounds of the present application, they are ACE inhibitors (e.g., captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril,trandolapril), angiotensin II receptor blockers (e.g., candesartan, losartan, valsartan), angiotensin-receptor neprilysin inhibitors (sacubitril / valsartan), I f channel blocker ivabradine, beta-adrenergic blockers (e.g., bisoprolol, metoprolol succinate, carvedilol), SGLT2 inhibitors, aldosterone antagonists (e.g., spironolactone, eplerenone), cardiac myosin activator (e.g., omecamtiv mecarbil), guanylate cyclase stimulator (e.g., vericiguat), cardiac myosin inhibitor (e.g., mavacamten), SERCA2a activator (e.g., istaroxime), hydralazine and isosorbide dinitrate, diuretics (e.g., furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, indapamide, metolazone, triamterene), or may be co-administered with other anti-heart failure agents such as digoxin.

[0172] The compounds of formula I may be used in combination with an antihypertensive agent, and such antihypertensive activity can be readily determined by one of ordinary skill in the art according to standard assays (e.g., blood pressure measurement). Examples of suitable antihypertensive agents include alpha-adrenergic blockers; beta-adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine); vasodilators (e.g., hydralazine), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ticrynafen etacrynate, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan, and the compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265); dual ET / AII antagonists (e.g., the compounds disclosed in WO00 / 01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrate). An exemplary antianginal agent is ivabradine.

[0173] Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine, amlodipine, and mibefradil.

[0174] Examples of suitable cardiac glycosides include digitalis and ouabain.

[0175] In one embodiment, the compound of formula I may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (e.g., LASIX™), torsemide (e.g., DEMADEX™), bumetanide (e.g., BUMEX™), and ethacrynic acid (e.g., EDECRIN™); (b) thiazide diuretics such as chlorothiazide (e.g., DIURIL™, ESIDRIX™, or HYDRODIURIL™), hydrochlorothiazide (e.g., MICROZIDE™ or ORETIC™), benzthiazide, hydroflumethiazide (e.g., SALURON™), bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, and indapamide (e.g., LOZOL™); (c) phthalimidone diuretics such as chlorthalidone (e.g., HYGROTON™) and metolazone (e.g., ZAROXOLYN™); (d) quinazoline diuretics such as quinethazone; and (e) potassium-sparing diuretics such as triamterene (e.g., DYRENIUM™) and amiloride (e.g., MIDAMOR™ or MODURETIC™).

[0176] In another embodiment, the compound of formula I may be co-administered with a loop diuretic. In yet another embodiment, the loop diuretic is selected from furosemide and torsemide. In yet another embodiment, one or more compounds of formula I may be co-administered with furosemide. In yet another embodiment, one or more compounds of formula I may be co-administered with torsemide, which may be in a controlled or modified release form of torsemide.

[0177] In another embodiment, the compound of formula I may be co-administered with a thiazide diuretic. In yet another embodiment, the thiazide diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In yet another embodiment, one or more compounds of formula I may be co-administered with chlorothiazide. In yet another embodiment, one or more compounds of formula I may be co-administered with hydrochlorothiazide.

[0178] In another embodiment, one or more compounds of formula I may be co-administered with a phthalimidino diuretic. In yet another embodiment, the phthalimidino diuretic is chlorthalidone.

[0179] Examples of suitable mineralocorticoid receptor antagonists include spironolactone and eplerenone.

[0180] Examples of suitable phosphodiesterase inhibitors include PDE III inhibitors (such as cilostazol) and PDE V inhibitors (such as sildenafil).

[0181] Those skilled in the art will recognize that the compounds of the present invention may also be used in combination with other cardiovascular or cerebrovascular procedures, including PCI, stent placement, drug-eluting stents, stem cell therapy and implantable medical devices such as pacemakers, defibrillators, or cardiac resynchronization therapy.

[0182] The compounds of formula I may be used in combination with drugs used in the management of chronic kidney disease, including phosphate binders (e.g., sucroxy iron hydroxide, sevelamer, calcium acetate), sodium bicarbonate, erythropoietin stimulating agents, oral or intravenous iron agents (e.g., iron sucrose, ferric carboxymaltose, ferumoxytol), potassium binders, calcitriol, or SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin, or other SGLT2 inhibitors listed herein).

[0183] In particular, when provided as a single dosage unit, there is a potential for chemical interaction between the combined active ingredients. For this reason, when the compound of formula I and the second therapeutic agent are combined in a single dosage unit, they can be formulated such that physical contact between the active ingredients is minimized (i.e., reduced), even when the active ingredients are combined in a single dosage unit. For example, one of the active ingredients may be enteric-coated. By enteric-coating one of the active ingredients, it is possible not only to minimize contact between the combined active ingredients, but also to control the release of one of these components in the gastrointestinal tract such that these components are not released in the stomach but are released in the intestine. One of the active ingredients may also be coated with a material that serves to achieve sustained release throughout the gastrointestinal tract and also to minimize physical contact between the combined active ingredients. Additionally, the sustained release component can be further enteric-coated so that the release of this component occurs only in the intestine. Another approach would involve the formulation of a combination product in which one component is coated with a sustained and / or enteric release polymer and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropylmethylcellulose (HPMC) or other suitable material as known in the art. The polymer coating serves to form an additional barrier against interaction with other components.

[0184] These and other techniques for minimizing contact between the components of a combination product will be readily apparent to those skilled in the art upon understanding the present disclosure, whether administered in a single dosage form or in separate forms but simultaneously by the same method.

[0185] In combination therapy treatments, both the compounds of the invention and other drug therapies are administered to a mammal (e.g., a human, male or female) by conventional methods.

[0186] The compounds of formula I of the present invention, their prodrugs, and salts of such compounds and prodrugs are all suitable for therapeutic use as agents that inhibit and / or degrade BCKDK in mammals, particularly humans, and are therefore useful for the treatment of various conditions in which such an action is involved (e.g., those described herein).

[0187] Diseases / conditions that can be treated with the compounds of formula I include, but are not limited to, NASH / NAFLD, diabetes, kidney disease, and heart failure and related diseases / conditions.

[0188] In particular, inhibition and / or degradation of BCKDK is associated with NASH / NAFLD and related diseases / conditions because increased BCAA levels have been observed in human NASH samples (Lake AD, Novak P, Shipkova P, Aranibar N, Robertson DG, Reily MD, Lehman-McKeeman LD, Vaillancourt RR, Cherrington NJ: Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 2015, 47:603~15). Decreased levels of PPM1K mRNA and increased BCKDK protein levels have also been observed in human NASH (Lake AD, Novak P, Shipkova P, Aranibar N, Robertson DG, Reily MD, Lehman-McKeeman LD, Vaillancourt RR, Cherrington NJ: Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 2015, 47:603~15).Treatment of obese mice or rats with BCKDK inhibitors and / or degraders decreased fatty liver and triglyceride content, and overexpression of PPM1K in rats decreased hepatic triglyceride content (White PJ, McGarrah RW, Grimsrud PA, Tso SC, Yang WH, Haldeman JM, Grenier-Larouche T, An J, Lapworth AL, Astapova I, Hannou SA, George T, Arlotto M, Olson LB, Lai M, Zhang GF, Ilkayeva O, Herman MA, Wynn RM, Chuang DT, Newgard CB: The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase. Cell Metab 2018, 27(6), 1281-1293). Furthermore, conditional approval by regulatory authorities for Phase III studies in NASH is based on histological surrogate markers obtained by liver biopsy. These generally accepted surrogates are: i) resolution of NASH without worsening of fibrosis (i.e., numerical increase in fibrosis stage); ii) reduction of one or more stages in fibrosis without worsening of NASH. Details can be found in Ratziu, A critical review of endpoints for non-cirrhotic NASH therapeutic trials, Journal of Hepatology, 2018, 68.353-361 and references therein.

[0189] Accordingly, considering the positive correlation between the activation of BCKDK and the occurrence of NASH / NAFLD and related diseases / conditions, the compounds of formula I of the present invention, their prodrugs, and salts of such compounds and prodrugs are, by virtue of their pharmacological actions, useful for the prevention, arrest, and / or regression of fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with hepatic fibrosis, non-alcoholic steatohepatitis with cirrhosis, or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma.

[0190] In addition, the increase in BCKDK is associated with heart failure and related diseases / conditions because an increase in BCKA has been observed in the hearts of patients with heart failure (Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn JY, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui WJ, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y: Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 2016, 133:2038~49).

[0191] In heart failure, the regulatory phosphatase that activates BCKDH (PPM1K) is downregulated, and BCKDK is upregulated; thus, in heart failure, BCAA catabolism is probably impaired (Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn JY, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui WJ, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y: Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 2016, 133:2038-49).

[0192] Both BCKDH and BCKDK are ubiquitously expressed; however, the regulatory phosphatase PPM1K that dephosphorylates BCKDH is most highly expressed in heart tissue. Mice lacking PPM1K develop age-induced heart failure and have deteriorated cardiac function when subjected to the transverse aortic constriction (TAC) heart failure model (Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn JY, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui WJ, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y: Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 2016, 133:2038-49).

[0193] The use of inhibitors and / or degraders of BCKDK improved cardiac function in three different preclinical heart failure models (TAC, left anterior descending artery ligation / myocardial infarction, and ischemia / reperfusion) (Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn JY, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui WJ, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y: Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 2016, 133:2038~49; Wang W, Zhang F, Xia Y, Zhao S, Yan W, Wang H, Lee Y, Li C, Zhang L, Lian K, Gao E, Cheng H, Tao L: Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol 2016, 311:H1160-H9; Li T, Zhang Z, Kolwicz SC, Jr., Abell L, Roe ND, Kim M, Zhou B, Cao Y, Ritterhoff J, Gu H, Raftery D, Sun H, Tian R: Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury. Cell Metab 2017, 25:374~85).

[0194] Therefore, inhibition and / or degradation of BCKDK in the heart or peripheral tissues should demonstrate benefits for metabolic diseases and cardiac function.

[0195] Therefore, considering the positive correlation between the activation of BCKDK and the development of heart failure and related diseases / conditions, the compounds of formula I, their prodrugs, and salts of such compounds and prodrugs, by virtue of their pharmacological actions, congestive heart failure, heart failure with New York Heart Association Class I-IV symptoms, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with mid-range ejection fraction (HF-mrEF), unstable angina, peripheral arterial disease, pulmonary hypertension, vasculitis or, if the mammal has experienced a myocardial infarction, (secondary prevention (second myocardial infarction)) useful for reducing the risk of cardiovascular death and hospitalization for, including their prevention, arrest and / or regression.

[0196] In addition, reduced BCAA catabolism is associated with diabetes and related diseases / conditions, as plasma BCAA is upregulated in patients with elevated fasting glucose levels, and a 1 standard deviation increase in plasma BCKA concentration increases the likelihood of developing diabetes by more than 50% (Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, O’Donnell CJ, Carr SA, Mootha VK, Florez JC, Souza A, Melander O, Clish CB, Gerszten RE: Metabolite profiles and the risk of developing diabetes. Nat Med 2011, 17:448~53; Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS, Jr., Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP: A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.Cell Metab 2009, 9: 311 - 26; Menni C, Fauman E, Erte I, Perry JR, Kastenmuller G, Shin SY, Petersen AK, Hyde C, Psatha M, Ward KJ, Yuan W, Milburn M, Palmer CN, Frayling TM, Trimmer J, Bell JT, Gieger C, Mohney RP, Brosnan MJ, Suhre K, Soranzo N, Spector TD: Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach. Diabetes 2013, 62: 4270 - 6; White PJ, McGarrah RW, Grimsrud PA, Tso SC, Yang WH, Haldeman JM, Grenier - Larouche T, An J, Lapworth AL, Astapova I, Hannou SA, George T, Arlotto M, Olson LB, Lai M, Zhang GF, Ilkayeva O, Herman MA, Wynn RM, Chuang DT, Newgard CB: The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP - Citrate Lyase. Cell Metab 2018, 27(6), 1281 - 1293e7; Zhou M, Shao J, Wu C - Y, Shu L, Dong W, Liu Y, Chen M, Wynn RM, Wang J, Wang J, Gui W - J, Qi X, Lusis AJ, Li Z, Wang W, Ning G, Yang X, Chuang DT, Wang Y, Sun H: Targeting BCAA catabolism to treat obesity - associated insulin resistance. Diabetes 2019, 68(9), 1730 - 1746.Sjogren, RJO, Rizo-Roca D, Chibalin AV, Chorell E, Furrer R, Katayma S, Harada J, Karlsson HKR, Handschin C, Moritz T, Krook A, Naslund E, Zierath JR. Diabetologia, 2021, 64, 2077 - 2091).

[0197] Genetic analysis suggests that loss-of-function mutations at the PPM1K locus increase BCAA / BCKA levels and are associated with the development of type 2 diabetes (Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, Tillin T, Schmidt AF, Imamura F, Stewart ID, Perry JR, Marney L, Koulman A, Karoly ED, Forouhi NG, Sjogren RJ, Naslund E, Zierath JR, Krook A, Savage DB, Griffin JL, Chaturvedi N, Hingorani AD, Khaw KT, Barroso I, McCarthy MI, O’Rahilly S, Wareham NJ, Langenberg C: Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis. PLoS Med 2016, 13: e1002179).

[0198] Treatment of diabetic obese mice or rats with a BCKDK inhibitor and / or degrader improved fasting glycemia, glycemia in a glucose tolerance test, decreased insulin levels, and improved insulin sensitivity. Overexpression of PPM1K in rats also improved glycemia and decreased insulin levels (White PJ, McGarrah RW, Grimsrud PA, Tso SC, Yang WH, Haldeman JM, Grenier-Larouche T, An J, Lapworth AL, Astapova I, Hannou SA, George T, Arlotto M, Olson LB, Lai M, Zhang GF, Ilkayeva O, Herman MA, Wynn RM, Chuang DT, Newgard CB: The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase. Cell Metab 2018).

[0199] Accordingly, considering the positive correlation between BCKDK and the onset of diabetes and related diseases / conditions, the compounds of formula I of the present invention, their prodrugs, and salts of such compounds and prodrugs, by virtue of their pharmacological actions, are useful for the prevention, arrest, and / or regression of type I diabetes, type II true diabetes, idiopathic type I diabetes (type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), young-onset non-classical diabetes (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary artery disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial lipemia, impaired glucose tolerance (IGT) state, fasting plasma glucose abnormality state, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, abnormal glucose metabolism, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and abnormal vascular compliance, and hyperapoB lipoproteinemia.

[0200] Administration of the compounds of the present invention can be via any method that delivers the compounds of the present invention systemically and / or locally. These methods include oral route, parenteral, duodenal route, oral, intranasal, etc. Generally, the compounds of the present invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous, or intramedullary) can be utilized, for example, when oral administration is inappropriate for the target or when the patient is unable to ingest the drug.

[0201] For administration to human patients, the oral daily dosage of the compounds herein may, of course, be within the range of 1 mg to 5000 mg, depending on the mode and frequency of administration, the medical condition, and the age and condition of the patient, etc. The oral daily dosage is within the range of 3 mg to 3000 mg that can be used. A further oral daily dosage is within the range of 5 mg to 1000 mg. For convenience, the compounds of formula I may be administered in unit dosage forms. If desired, unit dosage forms of multiple dosages per day can be used to increase the total daily dosage. The unit dosage form may be, for example, a tablet or capsule containing about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 500 or 1000 mg of the compound. The total daily dosage may be administered in a single or divided dose and, at the discretion of the physician, may fall outside the typical ranges described herein.

[0202] For administration to human patients, the injection daily dosage of the compounds herein may, of course, be within the range of 1 mg to 2000 mg, depending on the mode and frequency of administration, the medical condition, and the age and condition of the patient, etc. A further injection daily dosage is within the range of 5 mg to 1000 mg. The total daily dosage may be administered in a single or divided dose and, at the discretion of the physician, may fall outside the typical ranges described herein.

[0203] These compounds may be administered to animals other than humans, for example, for the indications detailed above. The exact dosage of each active ingredient administered will vary depending on any number of factors including, but not limited to, the type of animal being treated and the type of medical condition, the age of the animal, and the route of administration.

[0204] The dosage of the combination pharmaceutical agent used in combination with the compound of formula I is one that is effective for the indication being treated. Such dosage can be determined by standard assays such as those referenced above and provided herein. The combination agent can be administered simultaneously or sequentially in any order.

[0205] These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. A physician will be able to readily determine dosages for subjects, such as infants and the elderly, whose weight falls outside this range.

[0206] The dosage regimen may be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the exigencies of the treatment situation. It is particularly advantageous to formulate the parenteral composition in dosage unit form for ease of administration and uniformity of dosage. As used herein, a dosage unit form refers to physically discrete units suitable as unit dosages for the mammalian subject to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present invention are determined by and directly depend on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds for the treatment of sensitivity in individuals.

[0207] Thus, one of ordinary skill in the art will appreciate that, based on the disclosure provided herein, the dosages and dosage regimens are adjusted according to methods well known in the therapeutic arts. That is, the maximum tolerated dose can be readily established, and an effective amount that provides a detectable therapeutic benefit to the patient can also be determined, similar to the primary requirement of administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, certain dosages and dosage regimens are exemplified herein, but these examples are not intended to limit in any way the dosages and dosage regimens that may be provided to a patient.

[0208] It should be noted that the dosage amount can vary with the type and severity of the condition to be alleviated and can include single or multiple dosages. For any particular subject, the specific dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and further understood that the dosage ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. For example, the dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or test values. Thus, as determined by one of ordinary skill in the art, dose escalation within the patient can be used. Determining suitable dosages and regimens for the administration of chemotherapeutic agents is well known in the relevant art and will be understood by one of ordinary skill in the art given the teachings disclosed herein.

[0209] This application further includes the use of the compound of Formula I for use as a medicament (such as unit dosage tablets or unit dosage capsules, etc.). In another embodiment, this application includes the use of the compound of Formula I for the manufacture of a medicament (such as unit dosage tablets or unit dosage capsules, etc.) for treating one or more of the conditions previously identified in the above sections discussing treatment methods.

[0210] The pharmaceutical composition of the present invention may be prepared, packaged, or bulk sold as a single unit dose or as multiple single unit doses. As used herein, "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject, or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0211] The compounds or combinations of the present invention can be administered alone, but generally will be administered in admixture with one or more suitable pharmaceutical additives, adjuvants, excipients or carriers known in the art and will be selected with regard to the intended route of administration and standard pharmaceutical practice. The compounds or combinations of the present invention may be formulated to provide immediate, delayed, modified, sustained, pulsed or controlled release dosage forms depending on the specificity of the desired route of administration and release profile appropriate to the therapeutic need.

[0212] The pharmaceutical composition generally contains the compound or combination of the present invention in an amount within the range of about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, usually within the range of about 1%, 2% or 3% to about 50%, 60% or 70%, more frequently within the range of about 1%, 2% or 3% to less than 50%, for example within the range of about 25%, 30% or 35%.

[0213] Methods for preparing various pharmaceutical compositions using specific amounts of the active compound are known to those skilled in the art. See, for example, Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore Md, 20th Edition, 2000.

[0214] Compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers or excipients (including solvents and vehicles) include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, triglycerides including vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Preferred carriers are Miglyol® brand caprylic / capric acid esters (e.g., Miglyol® 812, Miglyol® 829, Miglyol® 840) with added glycerin or propylene glycol, available from Condea Vista Co., Cranford, N.J. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0215] These compositions for parenteral injection may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial contamination of the compositions can be accomplished using various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents such as sugar, sodium chloride, etc. Sustained absorption of injectable pharmaceutical compositions can be achieved by the use of agents that can delay absorption, such as aluminum monostearate and gelatin.

[0216] Solid dosage forms for oral administration include capsules, tablets, chewable tablets, candies, pills, powders and multi-particulate preparations (granules). In such solid dosage forms, the compound or combination of formula I is admixed with at least one inert additive, excipient or carrier. Suitable additives, excipients or carriers include materials such as sodium citrate or dicalcium phosphate, and / or (a) one or more fillers or bulking agents (e.g., microcrystalline cellulose (available as Avicel® from FMC Corp.), starch, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, dextrose, calcium hydrogen phosphate, dextrin, alpha-cyclodextrin, beta-cyclodextrin, polyethylene glycol, medium-chain fatty acids, titanium oxide, magnesium oxide, aluminum oxide, etc.); (b) one or more binders (e.g., carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinyl pyrrolidone, sucrose, acacia, etc.); (c) one or more humectants (e.g., glycerol, etc.); (d) one or more disintegrants (e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, sodium lauryl sulfate, sodium starch glycolate (Edward Mendell Co.available as Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose sodium type A (available as Ac-di-sol®), polyacrilin potassium (ion exchange resin), etc.; (e) one or more solution retardants (e.g., paraffin, etc.); (f) one or more absorption accelerators (e.g., quaternary ammonium compounds, etc.); (g) one or more wetting agents (e.g., cetyl alcohol, glycerol monostearate, etc.); (h) one or more adsorbents (e.g., kaolin, bentonite, etc.); and / or (i) one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, stearic acid, polyoxyl stearate, cetanol, talc, hydrogenated castor oil, sucrose fatty acid ester, dimethylpolysiloxane, microcrystalline wax, yellow wax, white wax, solid polyethylene glycol, sodium lauryl sulfate, etc.). In the case of capsules and tablets, the dosage form may also include a buffering agent.

[0217] Solid compositions of the same kind can also be used as fillers in soft or hard filled gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycol, etc.

[0218] Solid dosage forms such as tablets, sugar-coated tablets, capsules, and granules can be prepared using enteric coatings and other coatings and outer shells well-known in the art. They may contain opacifying agents and may be of a composition that releases the compound of formula I and / or additional pharmaceutical agents in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The drug may, where appropriate, be in the form of microcapsules with one or more of the additives mentioned above added.

[0219] In tablets, the active agent typically constitutes less than 50% (by weight) of the formulation, for example, less than about 10% such as 5% or 2.5% by weight. The main part of the formulation includes fillers, excipients, disintegrants, lubricants, and may include flavoring agents. The composition of these additives is well known in the art. Frequently, the filler / excipient includes a mixture of two or more of the following components: microcrystalline cellulose, mannitol, lactose (all types), starch, and dicalcium phosphate. The filler / excipient mixture typically constitutes less than 98% of the formulation, preferably less than 95%, for example 93.5%. Preferred disintegrants include Ac-di-sol®, Explotab®, starch, and sodium lauryl sulfate. When present, the disintegrant usually constitutes less than 10% or less than 5% of the formulation, for example about 3%. The preferred lubricant is magnesium stearate. When present, the lubricant usually constitutes less than 5% or less than 3% of the formulation, for example about 1%.

[0220] Tablets can be manufactured by standard tableting processes such as direct compression or wet, dry, or melt granulation, melt solidification processes, and extrusion. The tablet core can be single or multi-layer and can be coated with a suitable protective film known in the art.

[0221] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds or combinations of formula I, liquid dosage forms may contain inert excipients commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame seed oil, etc.), Miglyol® (available from CONDEA Vista Co., Cranford, N.J.), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, or mixtures of these substances, etc.

[0222] In addition to such inert excipients, the composition may also contain additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0223] The oral liquid form of the compounds or combinations of the present invention comprises a solution in which the active compound is completely dissolved. Examples of solvents include all pharmaceutically pre - cedented solvents suitable for oral administration, in particular those in which the compounds of the present invention show good solubility, such as polyethylene glycol, polypropylene glycol, edible oils and glyceryl and glyceride - based systems. Glyceryl and glyceride - based systems include, for example, the following branded products (and corresponding generic products): Captex® 355EP (glyceryl tri - caprylate / caprate, manufactured by Abitec, Columbus Ohio), Crodamol™ GTC / C (medium - chain triglycerides, manufactured by Croda, Cowick Hall, UK) or Labrafac™ CC (medium - chain triglycerides, manufactured by Gattefosse), Captex® 500P (glyceryl tri - acetate, i.e. triacetin, manufactured by Abitec), Capmul® MCM (medium - chain mono - and diglycerides, manufactured by Abitec), Migyol® 812 (caprylic / capric triglyceride, manufactured by Condea, Cranford N.J.), Migyol® 829 (caprylic / capric / succinic triglyceride, manufactured by Condea), Migyol® 840 (dicaprylic / dicapric propylene glycol, manufactured by Condea), Labrafil® M1944CS (oleoyl macrogol - 6 glyceride, manufactured by Gattefosse), Peceol™ (glyceryl mono - oleate, manufactured by Gattefosse) and Maisine® 35 - 1 (glyceryl mono - oleate, manufactured by Gattefosse). Of particular interest are medium - chain (from about C8 to C 10 ) triglyceride oils. These solvents frequently constitute the major part of the composition, i.e. more than about 50%, usually about 80%, for example more than about 95% or 99%. Adjuvants and additives may be included together with the solvent, mainly as flavoring agents, palatability and fragrance agents, antioxidants, stabilizers, texture and viscosity modifiers and solubilizers.

[0224] In addition to the compound or combination of formula I, the suspending agent may further contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, or a carrier such as a mixture of these substances.

[0225] Compositions for rectal or vaginal administration preferably include suppositories, which are prepared by mixing a compound or combination of formula I with a suitable non-irritating additive or carrier such as cocoa butter, polyethylene glycol or suppository wax, which is solid at normal room temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity, thereby releasing the active ingredient.

[0226] Dosage forms for topical administration of the compound or combination of formula I include ointments, creams, lotions, powders and sprays. The drug is admixed with pharmaceutically acceptable additives, excipients or carriers, and any preservatives, buffers or propellants that may be required.

[0227] Many of the compounds of the present invention have poor solubility in water, for example less than about 1 μg / mL. Therefore, liquid compositions in solubilizing non-aqueous solvents such as the medium-chain triglyceride oil discussed above are preferred dosage forms for these compounds.

[0228] Solid amorphous dispersions containing a dispersion formed by a spray drying process are also a preferred dosage form for the poorly soluble compounds of the present invention. What is meant by "solid amorphous dispersion" is a solid material in which at least a portion of the poorly soluble compound is in an amorphous form and is dispersed in a water-soluble polymer. What is meant by "amorphous" is that the poorly soluble compound is not crystalline. What is meant by "crystalline" is that the compound exhibits a three-dimensional long-range order of at least 100 repeating units in each dimension. Thus, the term amorphous is intended to include not only materials that are essentially disordered but also materials that may have a slight degree of order but that order is less than three-dimensional and / or only short-range. Amorphous materials can be characterized by techniques known in the art, such as powder X-ray diffraction (PXRD) crystallography, solid-state NMR, or thermal techniques such as differential scanning calorimetry (DSC).

[0229] Preferably, at least the majority (i.e., at least about 60 wt%) of the poorly soluble compound in the solid amorphous dispersion is amorphous. The compound can exist as a solid solution of the compound homogeneously distributed throughout the polymer, or as any combination of these states or intermediate states between them, within a relatively pure amorphous domain or region within the solid amorphous dispersion. Preferably, the solid amorphous dispersion is substantially homogeneous, and thus the amorphous compound is dispersed as homogeneously as possible throughout the polymer. As used herein, "substantially homogeneous" means that the proportion of the compound present in a relatively pure amorphous domain or region within the solid amorphous dispersion is relatively small, less than approximately 20 wt%, preferably less than 10 wt%, of the total amount of the drug.

[0230] Water-soluble polymers suitable for use in solid amorphous dispersions should not chemically react in a detrimental manner with compounds of poor solubility, be pharmaceutically acceptable, and be inert in the sense of having at least some solubility in aqueous solution at physiologically relevant pHs (e.g., 1 - 8). The polymer can be neutral or ionizable and should have a water solubility of at least 0.1 mg / mL over at least a portion of the pH range of 1 - 8.

[0231] Water-soluble polymers suitable for use with the compounds of formula I may be cellulose or non-cellulose. The polymer may be neutral or ionizable in aqueous solution. Among these, ionizable and cellulose polymers are preferred, and ionizable cellulose polymers are more preferred.

[0232] Exemplary water-soluble polymers include hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO, also known as poloxamers), and mixtures thereof. Particularly preferred polymers include HPMCAS, HPMC, HPMCP, CMEC, CAP, CAT, PVP, poloxamers, and mixtures thereof. Most preferred is HPMCAS. Reference is made to European Patent Application Publication No. 0901786A2, the disclosure of which is incorporated herein by reference.

[0233] A solid amorphous dispersion can be prepared according to any process for forming a solid amorphous dispersion that results in at least the majority (at least 60%) of the poorly soluble compound being in an amorphous state. Such processes include mechanical, thermal, and solvent processes. Exemplary mechanical processes include milling and extrusion; melting processes including high temperature melting, solvent-modified fusion, and melt-solidification processes; and solvent processes including non-solvent precipitation, spray coating, and spray drying. For example, reference is made to the following U.S. patents, the relevant disclosures of which are incorporated herein by reference: U.S. Pat. Nos. 5,456,923 and 5,939,099, which describe forming a dispersion by an extrusion process; U.S. Pat. Nos. 5,340,591 and 4,673,564, which describe forming a dispersion by a milling process; and U.S. Pat. Nos. 5,707,646 and 4,894,235, which describe forming a dispersion by a melt-solidification process. In a preferred process, the solid amorphous dispersion is formed by spray drying, as disclosed in European Patent Application Publication No. 0901786A2. In this process, the compound and polymer are dissolved in a solvent such as acetone or methanol, and then the solvent is rapidly removed from the solution by spray drying to form the solid amorphous dispersion. The solid amorphous dispersion can be prepared to contain up to about 99 wt% of the compound, for example, 1 wt%, 5 wt%, 10 wt%, 25 wt%, 50 wt%, 75 wt%, 95 wt%, or 98 wt% as desired.

[0234] The solid dispersion may itself be used as a dosage form or may serve as a manufacturing-use product (MUP) in the preparation of other dosage forms such as capsules, tablets, solutions or suspensions. An example of an aqueous suspension is an aqueous suspension of a 1:1 (w / w) compound / HPMCAS-HF spray-dried dispersion containing 2.5 mg / mL of the compound in 2% polysorbate-80. Solid dispersions for use in tablets or capsules will generally typically be mixed with other additives or adjuvants found in such dosage forms. For example, an exemplary filler for capsules contains a 2:1 (w / w) compound / HPMCAS-MF spray-dried dispersion (60%), lactose (fast flow) (15%), microcrystalline cellulose (e.g., Avicel®-PH102) (15.8%), sodium starch (7%), sodium lauryl sulfate (2%) and magnesium stearate (1%).

[0235] The HPMCAS polymers are available in low, medium and high grades as Aqoa®-LF, Aqoat®-MF and Aqoat®-HF respectively from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan. The higher MF and HF grades are generally preferred.

[0236] In the following paragraphs, exemplary formulations, dosages, etc. useful in non-human animals are described. Administration of the compounds of formula I and combinations with anti-obesity agents can be carried out orally or parenterally.

[0237] Administer an amount of the compound of formula I or a combination of the compound of formula I with another anti-obesity agent such that an effective dose is administered. Generally, the daily dose administered orally to an animal is between about 0.01 and about 1,000 mg / kg body weight, for example between about 0.01 and about 300 mg / kg or between about 0.01 and about 100 mg / kg or between about 0.01 and about 50 mg / kg body weight, or between about 0.01 and about 25 mg / kg, or between about 0.01 and about 10 mg / kg or between about 0.01 and about 5 mg / kg.

[0238] Conveniently, the compound (or combination) of formula I can be carried in drinking water such that a therapeutically effective dose of the compound is ingested with normal drinking water. The compound can preferably be incorporated directly into drinking water in the form of a liquid water-soluble concentrate (such as an aqueous solution of a water-soluble salt).

[0239] Conveniently, the compound (or combination) of formula I can also be added directly to feed, either as such or in the form of an animal feed supplement, also referred to as a premix or concentrated feed. To incorporate the active substance into the feed, a premix or concentrated feed of the compound in an additive, excipient, or carrier is more commonly used. Suitable additives, excipients, or carriers can be various meals such as water, alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corn cob meal, and corn meal, molasses, urea, bone meal, and liquid or solid such as mineral mixes commonly used in poultry feed, as desired. Particularly effective additives, excipients, or carriers are the individual animal feeds themselves; i.e., small amounts of such feeds. The carrier facilitates the uniform distribution of the compound in the final feed into which the premix is mixed. Preferably, the compound is mixed well into the premix and then into the feed. In this regard, the compound can be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, or a volatile organic solvent and then mixed with the carrier. The amount of the compound in the final feed can be adjusted by blending an appropriate proportion of the premix with the feed so that the desired level of the compound is obtained, so it will be understood that the proportion of the compound in the concentrated feed can vary widely.

[0240] To produce a concentrated supplement suitable for direct supply to animals, feed manufacturers may blend a highly potent concentrated feed with a protein carrier such as soybean oil meal and other meals as described above. In such cases, the animals are allowed to consume normal feed. Alternatively, such concentrated supplements can be added directly to the feed to produce a nutritionally balanced final feed containing a therapeutically effective level of the compound. To ensure uniformity, the mixture is thoroughly blended by standard procedures, such as in a twin-shell blender.

[0241] When the supplement is used as a top dressing for the feed, this also serves to ensure uniformity in the distribution of the compound over the entire surface of the dressed feed.

[0242] Generally, by mixing a compound of Formula I in a sufficient amount with animal feed so as to provide from about 0.001 to about 500 ppm of the compound in the feed or in the water, a feed and drinking water effective for increasing the accumulation of lean meat and improving the ratio of lean meat to fat are prepared.

[0243] Preferred medicated feeds for pigs, cattle, sheep, and goats generally contain from about 1 to about 400 grams of the compound (or combination) of Formula I per ton of feed, and the optimal amount for these animals is usually from about 50 to about 300 grams per ton of feed.

[0244] Feeds for preferred poultry and household pets usually contain from about 1 to about 400 grams, preferably from about 10 to about 400 grams, of the compound (or combination thereof) per ton of feed.

[0245] For parenteral administration in animals, the compound (or combination) of Formula I can be prepared in the form of a paste or pellet and administered as an implant, usually subcutaneously in the head or ear, of the animals for which an increase in the accumulation of lean meat and an improvement in the ratio of lean meat to fat are desired.

[0246] A paste formulation can be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil, etc.

[0247] By mixing the compound or combination of formula I with excipients such as Carbowax, carnauba wax, etc., pellets containing an effective amount of the compound of formula I, a pharmaceutical composition, or a combination can be prepared, and lubricants such as magnesium stearate or calcium stearate can be added to improve the pelletization process.

[0248] It will of course be appreciated that more than one pellet can be administered to the animal to achieve the desired dosage level that results in an increase in the accumulation of desired lean meat and an improvement in the ratio of lean meat to fat. Furthermore, implants can also be performed periodically during the treatment period of the animal to maintain an appropriate drug level in the animal's body.

[0249] These agents and / or liposomes containing the compounds of the present invention are prepared by methods known in the art, such as those described in U.S. Patent Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation times are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be produced by the reverse phase evaporation method using a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with a defined pore size to produce liposomes with the desired diameter.

[0250] These agents and / or the compounds of the present invention may be encapsulated, for example, by coacervation techniques or by interfacial polymerization, for example, into colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or microcapsules prepared in macroemulsions by hydroxy methyl cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Edition, Mack Publishing (2000).

[0251] Sustained release preparations may be used. Suitable examples of sustained release preparations include a semipermeable matrix of a solid hydrophobic polymer containing the compound of the present invention, which matrix is in the form of a shaped article, for example, a film or a microcapsule. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and L-glutamic acid 7 ethyl, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as those used in LUPRON DEPOT (trademark) (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0252] Formulations for intravenous administration must be sterile. This is readily accomplished, for example, by filtration through sterile filtration membranes. The compounds of the present invention are generally placed in a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper penetrable by a hypodermic needle.

[0253] Suitable emulsions can be prepared using commercially available fat emulsions, such as Intralipid®, Liposyn®, Infonutrol™, Lipofundin® and Lipiphysan™. The active ingredient can be dissolved in a pre-mixed emulsion composition or alternatively dissolved in an emulsion formed upon mixing oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and phospholipids (e.g., egg phospholipids, soybean phospholipids or soy lecithin) with water. It will be appreciated that other ingredients, such as glycerol or glucose, may be added to adjust the isotonicity of the emulsion. Suitable emulsions will typically contain up to 20%, for example between 5 and 20%, oil. The fat emulsion can contain fat droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and can have a pH in the range of 5.5 to 8.0.

[0254] The emulsion composition can be one prepared by mixing the compound of the invention with Intralipid™ or its components (soybean oil, egg phospholipids, glycerol and water).

[0255] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid composition may contain suitable pharmaceutically acceptable additives as specified above. In some embodiments, the composition is administered by an oral or nasal inhalation route for local or systemic effects. Preferably, the composition in a sterile pharmaceutically acceptable solvent can be nebulized by the use of a gas. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing apparatus. The solution, suspension or powder composition can be administered from a device that delivers the formulation in a suitable manner, preferably orally or intranasally.

[0256] The compound particles in this specification can be formulated in a form suitable for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or for administration by inhalation. The compounds of the present invention may be formulated for sustained delivery.

[0257] Methods for preparing various pharmaceutical compositions using a specific amount of active ingredient are known or will be apparent to those skilled in the art in light of the present disclosure. For examples of methods for preparing pharmaceutical compositions, see Remington’s Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000).

[0258] The pharmaceutical compositions according to the present invention may contain from 0.1% to 95%, preferably from 1% to 70% of the compound of the present invention. In any case, the composition to be administered will contain an amount of the compound according to the present invention effective to treat the disease / condition of the subject being treated.

[0259] Since this application has aspects related to the treatment of the diseases / conditions described herein using compounds of active ingredients that can be administered separately, the present invention also relates to combining separate pharmaceutical compositions in kit form. The kit includes two separate pharmaceutical compositions: a compound of formula I, a prodrug thereof or a salt of such a compound or prodrug, and a second compound as described above. The kit includes means for containing the separate compositions, such as a container, a divided bottle or a divided foil packet. Typically, the kit includes instructions for administering the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0260] An example of such a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). A blister pack generally consists of a sheet of a relatively rigid material, preferably covered with a foil of a transparent plastic material. During the packaging process, depressions are formed in the plastic foil. The depressions have the size and shape in which tablets or capsules are to be packed. Next, the tablets or capsules are placed in the depressions, and the sheet of the relatively rigid material is sealed to the plastic foil on the side of the foil opposite to the side where the depressions are formed. As a result, the tablets or capsules are sealed within the depressions between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the depressions, thereby forming an opening at the location of the depressions in the sheet. Then, the tablets or capsules can be removed through the opening.

[0261] It may be desirable to provide a memory aid to the kit, for example, in the form of numbers adjacent to the tablets or capsules that match the number of days of the regimen for which the so-designated tablets or capsules are to be taken. Another example of such a memory aid is, for example, a calendar printed on a card as follows: "First week, Monday, Tuesday, etc... Second week, Monday, Tuesday,...", etc. Other variations of the memory aid will readily become apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules taken on a given day. Also, the daily dose of the compound of formula I may consist of one tablet or capsule, while the daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0262] In another specific embodiment of the present invention, there is provided a dispenser designed to dispense the daily dose one at a time in their intended order of use. Preferably, the dispenser is equipped with a memory aid to further facilitate compliance with the regimen. Examples of such memory aids are mechanical counters indicating the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory linked to a liquid crystal display and / or an audible reminder signal, e.g., to read out the date when the previous daily dose was taken and / or to remind of the date when the next dose should be taken.

[0263] Also, since this application has aspects regarding the diseases / conditions described herein using combinations of active ingredients that can be administered together, the present invention also relates to combining separate pharmaceutical compositions in a single dosage form such as (but not limited to) a single tablet or capsule, a double-layer or multi-layer tablet or capsule, or by use of isolated ingredients or compartments within a tablet or capsule.

[0264] The active ingredient can be delivered as a solution in an aqueous or non-aqueous vehicle, with or without the addition of additional solvents, co-solvents, additives or complexing agents selected from pharmaceutically acceptable excipients, additives, vehicles or carriers.

[0265] The active ingredient can be formulated as a solid dispersion or as a self-emulsifying drug delivery system (SEDDS) with the addition of pharmaceutically acceptable additives.

[0266] The active ingredient can be formulated as an immediate release or modified release tablet or capsule. Alternatively, the active ingredient can be delivered alone as the active ingredient within a capsule shell without the addition of additional additives.

Examples

[0267] Experimental procedures The following illustrates the synthesis of various compounds of the present invention. Additional compounds within the scope of the present invention can be prepared either alone or in combination with techniques generally known in the art using the methods exemplified in these examples. All starting materials in these preparations and examples are either commercially available or can be prepared by methods known in the art or as described herein.

[0268] Unless otherwise noted, all reactions were carried out using continuous stirring under an atmosphere of nitrogen or argon gas. Where appropriate, reaction vessels were dried under dynamic vacuum using a heat gun and anhydrous solvents (Sure-Seal™ products from Aldrich Chemical Company, Milwaukee, Wisconsin, or DriSolv™ products from EMD Chemicals, Gibbstown, NJ) were used. In some cases, commercially available solvents were passed through columns packed with 4 Å molecular sieves until the following water QC criteria were reached: a) less than 100 ppm for dichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b) less than 180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For highly sensitive reactions, solvents were further treated with metallic sodium, calcium hydride, or molecular sieves and distilled immediately prior to use. Other commercially available solvents and reagents were used without further purification. In syntheses that refer to procedures in other examples or methods, the reaction conditions (solvent, reaction time, and / or temperature) may vary. Products were generally dried under vacuum and then carried over to further reactions or sent for biological testing.

[0269] When indicated, the reaction solution was heated by microwave irradiation using a Biotage initiator or Personal Chemistry Emrys Optimizer microwave. The reaction progress was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analysis. TLC was performed on pre-coated silica gel plates using a fluorescent indicator (254 nm excitation wavelength) and visualized under UV light and / or using I2, KMnO4, CoCl2, phosphomolybdic acid, and / or cerium ammonium molybdate staining. LCMS data were acquired on an Agilent 1100 series instrument using a Leap Technologies autosampler, Gemini C18 column, acetonitrile / water gradient, and one of trifluoroacetic acid, formic acid, ammonium acetate, or ammonium hydroxide modifiers. The column eluate was analyzed using a Waters ZQ mass spectrometer scan in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were generally acquired on an Agilent 1100 series instrument using the indicated column, acetonitrile / water gradient, and one of trifluoroacetic acid or ammonium hydroxide modifiers. GCMS data were acquired using a Hewlett Packard 6890 oven, HP6890 injector, HP-1 column (12 m × 0.2 mm × 0.33 μm), and helium carrier gas. Samples were analyzed using an HP5973 mass selective detector with electron ionization scanning from 50 to 550 Da. Purification was performed by medium-pressure liquid chromatography (MPLC) using an Isco Combiflash Companion, AnaLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instrument and a prepack Isco RediSep or Biotage Snap Silica cartridge.Chiral purification was generally carried out by chiral supercritical fluid chromatography (SFC) using a Berger or Thar instrument; a column such as a Chiralpak-AD, -AS, -IC, Chiralcel-OD or -OJ column; and a CO2 mixture with methanol, ethanol, propan-2-ol, or acetonitrile, modified with trifluoroacetic acid or propan-2-amine alone or in combination. UV detection was used to induce fractional collection. In syntheses referring to procedures in other examples or methods, the purification may vary: generally, the solvents and solvent ratios used in the eluent / gradient were selected to provide an appropriate R. fS or retention time.

[0270] Mass spectrometry data was reported by LCMS analysis. Mass spectrometry (MS) was carried out via an atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI) or electron scattering ionization (ES) source. Proton magnetic resonance spectroscopy ( 1 1H NMR) chemical shifts were recorded in parts per million downfield from tetramethylsilane and recorded on a Varian, Bruker or Jeol spectrometer at 300, 400, 500, or 600 MHz. Chemical shifts are expressed in parts per million (ppm, δ) relative to the deuterated solvent residual peak (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-d2, 1.94 ppm; dimethyl sulfoxide-d5, 2.50 ppm; DHO, 4.79 ppm). Peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; brs, broad singlet; app, apparent. Analytical SFC data was obtained on a Berger instrument as described above. Optical rotation data was generally obtained on a PerkinElmer model 343 polarimeter using a 1 dm cell. Microanalysis was carried out by Quantitative Technologies Inc. and was within 0.4% of the calculated value.

[0271] Unless otherwise noted in the procedure, chemical reactions were carried out at room temperature (about 23 degrees Celsius).

[0272] Unless otherwise noted, all reactants were obtained and used without further commercial purification or were prepared using methods known in the literature.

[0273] The terms "concentrated", "evaporated", and "concentrated in vacuo" refer to the removal of solvent under reduced pressure on a rotary evaporator with a bath temperature below 60 °C. The abbreviations "min" and "h" represent "minute" and "hour", respectively. The term "TLC" refers to thin-layer chromatography, "room temperature or ambient temperature" means a temperature between 18 °C and 25 °C, "GCMS" refers to gas chromatography–mass spectrometry, "LCMS" refers to liquid chromatography–mass spectrometry, "UPLC" refers to ultra-performance liquid chromatography, "HPLC" refers to high-performance liquid chromatography, and "SFC" refers to supercritical fluid chromatography.

[0274] Hydrogenation can be carried out under pressurized hydrogen gas in a Parr shaker or in a Thales-nano H-cube flow hydrogenation apparatus at the specified temperature with a flow rate between 1 and 2 mL / min of pure hydrogen.

[0275] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods noted in the procedure.

[0276] In some embodiments, chiral separation was performed to isolate enantiomers, diastereoisomers, or atropisomers (or atropenantiomers) of certain compounds of the present invention [in some embodiments, the isolated enantiomers were designated as ENANT-1 and ENANT-2 according to their elution order; similarly, the isolated diastereoisomers were designated as DIAST-1 and DIAST-2 according to their elution order, and the isolated atropisomers (or atropenantiomers) were designated as ATROP-1 and ATROP-2 according to their elution order]. In some embodiments, the optical rotation of the enantiomers or atropisomers (or atropenantiomers) was measured using a polarimeter. According to the observed rotation data (or its specific rotation data), the enantiomers or atropisomers (or atropenantiomers) with clockwise rotation were designated as (+)-enantiomers or (+)-atropisomers [or (+)-atropenantiomers], and the enantiomers or atropisomers (or atropenantiomers) with counterclockwise rotation were designated as (-)-enantiomers or (-)-atropisomers [or (-)-atropenantiomers]. Racemic compounds were indicated either by the absence of depicted or described stereochemistry or by the presence of (+ / -) adjacent to the structure; in the latter case, the indicated stereochemistry represents only one of the two enantiomers that make up the racemic mixture.

[0277] The compounds and intermediates described below were named using the naming rules provided by ACD / ChemSketch 2019.1.1, file version C05H41, build 110712 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming rules provided by ACD / ChemSketch 2019.1.1 are well-known to those skilled in the art, and the naming rules provided by ACD / ChemSketch 2019.1.1 are generally considered to be in accordance with the IUPAC (International Union of Pure and Applied Chemistry) recommendations and CAS index rules in the nomenclature of organic compounds.

[0278] Preparation Example P1 Methyl 3-bromo-6-fluoro-1-benzothiophene-2-carboxylate (P1)

[0279]

Chem.

[0280] Step 2. Synthesis of methyl 3-bromo-6-fluoro-1-benzothiophene-2-carboxylate (P1). To a solution of tert-butyl nitrite (23.3 g, 226 mmol) and copper(II) bromide (40.5 g, 181 mmol) in acetonitrile (500 mL) was added C1 (34.0 g, 151 mmol). The reaction mixture was stirred at 20 °C for 3 h and then combined with a similar reaction carried out using C1 (33.0 g, 146 mmol) and filtered. The filtrate was concentrated under vacuum and subjected to silica gel chromatography (eluent: petroleum ether) to afford P1 as a white solid. Combined yield: 20 g, 69 mmol, 23%. GCMS m / z 290 (bromine isotope pattern observed) [M + . 1 H NMR (400 MHz, chloroform-d) δ 7.96 (dd, J = 9.0, 5.0 Hz, 1H), 7.52 (dd, J = 8.3, 2.3 Hz, 1H), 7.29 - 7.22 (m, 1H, putative; partly obscured by solvent peak), 3.97 (s, 3H).

[0281] Preparation Example P2 Methyl 6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophene-2-carboxylate (P2)

[0282]

Chemical Structure

[0283] Preparation Example P3 Ethyl 3-bromo-6,7-difluoro-1-benzothiophene-2-carboxylate (P3)

[0284] [Chemical formula] Step 1. Synthesis of ethyl 3-amino-6,7-difluoro-1-benzothiophene-2-carboxylate (C2). Ethyl sulfanylacetate (0.768 mL, 7.00 mmol) was added dropwise to a 0 °C solution of 2,3,4-trifluorobenzonitrile (1.00 g, 6.37 mmol) in N,N-dimethylformamide (6.4 mL). The reaction mixture was stirred at 0 °C for 30 minutes, after which an aqueous sodium hydroxide solution (5 M; 1.91 mL, 9.55 mmol) was added and stirring was continued for 2 hours. Then, water (30 mL) was added and the resulting precipitate was collected by filtration, washed with water, and dried in a vacuum dryer. Chromatography on silica gel (gradient: 0% to 10% ethyl acetate in petroleum ether) gave C2 as a white solid. Yield: 788 mg, 3.06 mmol, 48%. 1 1H NMR (400 MHz, chloroform-d) δ 7.37 (br dd, J = 8.8, 3.9 Hz, 1H), 7.26 - 7.18 (m, 1H), 5.88 (br s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).

[0285] Step 2. Synthesis of ethyl 3-bromo-6,7-difluoro-1-benzothiophene-2-carboxylate (P3). C2 (400 mg, 1.55 mmol) was added portionwise to a 0 °C suspension of copper(II) bromide (417 mg, 1.87 mmol) and tert-butyl nitrite (0.280 mL, 2.35 mmol) in acetonitrile (15.5 mL). The reaction mixture was then stirred at 0 °C for 15 minutes and at room temperature (26 °C) for 1 hour, and then immediately poured into hydrochloric acid (0.5 M; 200 mL) and extracted with ethyl acetate (100 mL). The organic layer was successively washed with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Chromatography on silica gel (gradient: 0% to 5% ethyl acetate in petroleum ether) gave P3 as a pale yellow solid. Yield: 334 mg, 1.04 mmol, 67%. 11H NMR (400 MHz, chloroform-d) δ 7.73 (ddd, J = 9.0, 4.0, 1.3 Hz, 1H), 7.37 (ddd, J = 10.1, 9.0, 7.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0286] Preparation Example P4 Ethyl 3-bromo-4,6-difluoro-1-benzothiophene-2-carboxylate (P4)

[0287]

Chemical formula

[0288] Step 2. Synthesis of ethyl 3-bromo-4,6-difluoro-1-benzothiophene-2-carboxylate (P4). To a 0 °C suspension of copper(II) bromide (996 mg, 4.46 mmol) and tert-butyl nitrite (0.668 mL, 5.62 mmol) in acetonitrile (37 mL) was added C3 (956 mg, 3.72 mmol) portionwise. The reaction mixture was stirred at 0 °C for 15 minutes and then at room temperature (26 °C) for 16 hours, and then immediately poured into hydrochloric acid (0.5 M; 200 mL) and extracted with ethyl acetate (100 mL). The organic layer was successively washed with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Chromatography on silica gel (gradient: 0% to 5% ethyl acetate in petroleum ether) afforded P4 as a white solid. Yield: 674 mg, 2.11 mmol, 57%. 1 H NMR (400 MHz, chloroform-d) δ 7.32 (ddd, J = 7.7, 2.2, 1.1 Hz, 1H), 6.93 (ddd, J = 11.3, 9.1, 2.2 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).

[0289] Preparation Example P5 Ethyl 3-bromo-6-chloro-5-fluoro-1-benzothiophene-2-carboxylate (P5)

[0290]

Chemical formula

[0291] Step 2. Synthesis of ethyl 3-bromo-6-chloro-5-fluoro-1-benzothiophene-2-carboxylate (P5). To a 0 °C suspension of copper(II) bromide (408 mg, 1.83 mmol) and tert-butyl nitrite (0.263 mL, 2.21 mmol) in acetonitrile (10 mL) was added C4 (from the preceding step; 500 mg, <1.83 mmol) in small portions. The reaction mixture was stirred at 0 °C for 15 minutes and at room temperature (28 °C) for 3 hours, and then immediately poured into hydrochloric acid (1 M; 2 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (5 mL) and with a saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Chromatography on silica gel (gradient: 0% to 5% ethyl acetate in petroleum ether) gave P5 as a white solid. Yield: 175 mg, 0.518 mmol, 20% over 2 steps. 11H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 6.3 Hz, 1H), 7.73 (d, J = 9.1 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0292] Preparation Example P6 Methyl 6-fluoro-3-iodo-1-benzothiophene-2-carboxylate (P6)

[0293]

Chemical Structure

[0294] Separation and Characterization of C5 and C1 A portion (644 mg, 2.86 mmol) of this mixture of C5 and C1 was separated by reverse-phase HPLC (column: YMC-Actus Triart C18, 50×250 mm, 7 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: from 34% to 74% B). Both components were isolated as pale yellow solids. C5 - Yield: 52 mg, 0.23 mmol. LCMS m / z 225.9 [M+H] + . 1 1H NMR (400 MHz, chloroform-d) δ 7.54 - 7.48 (m, 1H), 7.18 - 7.13 (m, 2H), 3.78 (s, 3H), 3.75 (s, 2H). Retention time: 4.38 min [column: Welch Ultisil XB-C18, 3.0×50 mm, 3 μm; mobile phase A: water containing 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: from 1% to 5% B over 1.0 min, then from 5% to 100% B over 5 min; flow rate: 1.2 mL / min].[[]END] C1 - Yield: 55 mg, 0.24 mmol. LCMS m / z 226.0 [M+H] + . 1 1H NMR (400 MHz, chloroform-d) δ 7.59 (dd, J = 8.9, 4.9 Hz, 1H), 7.41 (dd, J = 8.7, 2.4 Hz, 1H), 7.12 (ddd, J = 8.8, 8.8, 2.3 Hz, 1H), 5.89 (br s, 2H), 3.89 (s, 3H). Retention time: 4.70 min (same analytical conditions as those used for C5).

[0295] Step 2. Synthesis of methyl 3-amino-6-fluoro-1-benzothiophene-2-carboxylate (C1). A mixture of C5 and C1 (from the previous step; 490 g, 2.18 mol), potassium carbonate (601 g, 4.35 mol), and 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6; 28.8 g, 109 mmol) in N,N-dimethylformamide (2 L) was heated to 98 °C and stirred at 98 °C for 16 h. The reaction mixture was cooled to 25 °C, added to ice water (6 L), and the resulting mixture was filtered. The filter cake was washed with water (3 × 1.5 L), then suspended in water (2 L), stirred at 25 °C for 12 h, filtered, and C1 was obtained as a green solid. Yield: 382 g, 1.70 mol, 78%. 1 H NMR (400 MHz, chloroform-d) δ 7.59 (dd, J = 8.9, 4.9 Hz, 1H), 7.40 (dd, J = 8.7, 2.3 Hz, 1H), 7.11 (ddd, J = 8.8, 8.8, 2.3 Hz, 1H), 5.90 (br s, 2H), 3.88 (s, 3H).

[0296] Step 3. Synthesis of methyl 6-fluoro-3-iodo-1-benzothiophene-2-carboxylate (P6). To a solution of C1 (351 g, 1.56 mol) in acetonitrile (2 L) was added diiodomethane (188 mL, 2.33 mol), and immediately thereafter the mixture was heated to 70 °C. 3-Methylbutyl nitrite (314 mL, 2.34 mol) was added at a rate that maintained the reaction temperature between 70 °C and 80 °C over 1.5 h. At the end of the addition, the reaction mixture was stirred at 70 °C for an additional 2 h. After cooling it to 25 °C, the reaction mixture was concentrated under vacuum and purified using silica gel chromatography (gradient: 0% to 2.5% ethyl acetate in petroleum ether). The resulting material was stirred with methanol (500 mL) at 25 °C for 1.5 h and filtered to obtain P6 as a pale yellow solid. Yield: 184 g, 0.547 mmol, 35%. LCMS m / z 336.9 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.94 (dd, J = 9.0, 5.0 Hz, 1H), 7.52 (dd, J = 8.3, 2.3 Hz, 1H), 7.28 - 7.20 (m, 1H, putative; partially obscured by solvent peak), 3.97 (s, 3H).

[0297] Preparation Example P7 Ethyl 3-bromo-6-chloro-1-benzothiophene-2-carboxylate (P7)

[0298]

Chemical Structure

[0299] Step 2. Synthesis of ethyl 3-bromo-6-chloro-1-benzothiophene-2-carboxylate (P7). A suspension of copper(II) bromide (3.69 g, 16.5 mmol) and tert-butyl nitrite (2.48 mL, 20.8 mmol) in acetonitrile (140 mL) at 0 °C was added C7 (3.52 g, 13.8 mmol) portionwise. The reaction mixture was stirred at 0 °C for 15 minutes, then stirred at room temperature (26 °C) for 1 hour, and then immediately poured into hydrochloric acid (0.5 M; 200 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (gradient: 0% to 5% ethyl acetate in petroleum ether) gave the material, which was combined with the product from a similar reaction carried out using C7 (3.00 g, 11.7 mmol) to give P7 as a yellow solid. Combined yield: 5.69 g, 17.8 mmol, 70%. LCMS m / z 320.7 (bromochloro isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.90 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.46 (dd, J = 8.7, 1.9 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0300] Preparation Example P8 Methyl 6-chloro-3-iodo-1-benzothiophene-2-carboxylate (P8)

[0301]

Chemical Structure

[0302] Step 2. Synthesis of methyl 6-chloro-3-iodo-1-benzothiophene-2-carboxylate (P8). tert-Butyl nitrite (0.372 mL, 3.10 mmol) was added dropwise to a suspension of C8 (500 mg, 2.07 mmol) and copper(I) iodide (591 mg, 3.10 mmol) in acetonitrile (10 mL). After the reaction mixture was stirred at 20 °C for 16 hours, the pH was adjusted to approximately 3, and the reaction mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (50 mL), concentrated under vacuum, and purified using silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) to obtain P8 as a white solid. Yield: 200 mg, 0.567 mmol, 27%. 11H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 1.9 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.7, 2.0 Hz, 1H), 3.91 (s, 3H).

[0303] Preparation Example P9 Ethyl 6-fluoro-3-iodo-1-benzofuran-2-carboxylate (P9)

[0304]

Chemical Structure

[0305] Step 2. Synthesis of ethyl 3-amino-6-fluoro-1-benzofuran-2-carboxylate (C10). A solution of C9 (8.00 g, 35.8 mmol) in tetrahydrofuran (50 mL) was added dropwise to a 0 °C solution of potassium tert-butoxide (6.44 g, 57.4 mmol) in tetrahydrofuran (100 mL), and the reaction mixture was stirred at 0 °C for 2 hours. It was then diluted with water and extracted with ethyl acetate (3 × 150 mL); the combined organic layers were washed with saturated aqueous sodium chloride (2 × 150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give C10 as a yellow solid. Yield: 6.68 g, 29.9 mmol, 84%. LCMS m / z 224.0 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.49 (dd, J = 8.7, 5.3 Hz, 1H), 7.15 (dd, J = 8.9, 2.3 Hz, 1H), 7.01 (ddd, J = 8.9, 8.9, 2.2 Hz, 1H), 4.98 (br s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).

[0306] Step 3. Synthesis of ethyl 6-fluoro-3-iodo-1-benzofuran-2-carboxylate (P9). To a suspension of copper(I) iodide (2.56 g, 13.4 mmol) and C10 (2.00 g, 8.96 mmol) in acetonitrile (60 mL) was added tert-butyl nitrite (1.61 mL, 13.5 mmol) portionwise, and immediately thereafter, the reaction mixture was stirred at 0 °C for 15 minutes and at room temperature (15 °C) for 16 hours. It was then poured into hydrochloric acid (1 M; 15 mL) and extracted with ethyl acetate (50 mL). The organic layer was successively washed with aqueous sodium sulfite (3 × 40 mL) and saturated aqueous sodium chloride (2 × 30 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (gradient: 0% to 5% ethyl acetate in petroleum ether) to give P9 as a yellow solid. Yield: 190 mg, 0.569 mmol, 6%. 11H NMR (400 MHz, chloroform-d) δ 7.50 (dd, J = 8.7, 5.3 Hz, 1H), 7.29 (dd, J = 8.5, 2.2 Hz, 1H), 7.15 (ddd, J = 9.0, 9.0, 2.2 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H).

[0307] Preparation Example P10 Ethyl 6-chloro-3-iodo-1-benzofuran-2-carboxylate (P10)

[0308] [Chemical Structure Diagram] Step 1. Synthesis of ethyl (5-chloro-2-cyanophenoxy)acetate (C11). To a solution of 4-chloro-2-hydroxybenzonitrile (9.00 g, 58.6 mmol) in acetonitrile (290 mL) was added potassium carbonate (16.2 g, 117 mmol), followed by ethyl bromoacetate (11.7 g, 70.1 mmol), and the reaction mixture was stirred at 15 °C for 16 h. It was then filtered; the filtrate was concentrated under vacuum to give C11 as a white solid. Yield: 13.5 g, 56.3 mmol, 96%. 1 1H NMR (400 MHz, chloroform-d) δ 7.53 (d, J = 8.3 Hz, 1H), 7.06 (dd, J = 8.3, 1.8 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 4.76 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0309] Step 2. Synthesis of ethyl 3-amino-6-chloro-1-benzofuran-2-carboxylate (C12). A solution of C11 (13.5 g, 56.3 mmol) in tetrahydrofuran (25 mL) was added dropwise to a 0 °C solution of potassium tert-butoxide (10.1 g, 90.0 mmol) in tetrahydrofuran (200 mL). The reaction mixture was stirred at 0 °C for 2 hours, then diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 × 50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give C12 as a solid. Yield: 8.70 g, 36.3 mmol, 64%. LCMS m / z 239.9 (chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.50 - 7.44 (m, 2H), 7.24 (dd, J = 8.4, 1.8 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0310] Step 3. Synthesis of ethyl 6-chloro-3-iodo-1-benzofuran-2-carboxylate (P10). A suspension of C12 (7.40 g, 30.9 mmol) and copper(I) iodide (8.82 g, 46.3 mmol) in acetonitrile (150 mL) was heated to 45 °C, and immediately thereafter, a solution of tert-butyl nitrite (5.55 mL, 46.7 mmol) in acetonitrile (4 mL) was added. The reaction mixture was stirred at 45 °C for 2 hours, then concentrated under vacuum and treated with dilute hydrochloric acid until the pH of the mixture was approximately 3. After extraction with ethyl acetate (3 × 50 mL), the combined organic layers were washed with saturated aqueous sodium chloride solution (2 × 50 mL), concentrated under reduced pressure, and purified by silica gel chromatography (gradient: 0% to 20% ethyl acetate in petroleum ether) to give P10 as a white solid. Yield: 1.12 g, 3.20 mmol, 10%. LCMS m / z 350.9 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 7.58 (d, J = 1.7 Hz, 1H), 7.47 (d, half of AB quartet, J = 8.4 Hz, 1H), 7.36 (dd, component of ABX system, J = 8.5, 1.7 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H).

[0311] Preparation Example P11 5,7-Difluoro-2-methyl-3,4-dihydro-2H-1-benzopyran (P11)

[0312]

Chemical Structure

[0313] Step 2. Synthesis of ethyl 3-(2,4-difluoro-6-hydroxyphenyl)propanoate (C14). Nickel(II) chloride hexahydrate (3.39 g, 14.3 mmol) was added to a 0 °C solution of C13 (2.71 g, 11.9 mmol) in a mixture of tetrahydrofuran (90 mL) and methanol (16 mL). After the nickel(II) chloride hexahydrate had completely dissolved, sodium borohydride (1.80 g, 47.6 mmol) was added slowly in small portions, and the reaction mixture was stirred at 0 °C for 1 hour. Water (50 mL) was carefully added, and the resulting mixture was extracted with ethyl acetate (2 × 80 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 × 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give C14 as a yellow oil. Yield: 2.88 g; corrected with residual ethyl acetate: 2.35 g, 10.2 mmol; 86%. 1 H NMR (400 MHz, chloroform-d) δ 8.42 (br s, 1H), 6.47 (ddd, J = 10.1, 2.6, 1.8 Hz, 1H), 6.38 (ddd, J = 10.0, 8.9, 2.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 2.87 - 2.81 (m, 2H), 2.73 - 2.67 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H).

[0314] Step 3. Synthesis of 5,7-difluoro-3,4-dihydro-2H-1-benzopyran-2-one (C15). To a solution of C14 (from the preceding step; 2.88 g, 10.2 mmol containing 2.35 g of C14) in toluene (60 mL) was added p-toluenesulfonic acid (215 mg, 1.25 mmol), and immediately thereafter, the reaction mixture was stirred at 130 °C for 16 h. After the mixture was concentrated under vacuum, it was treated with water (50 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 × 50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography [gradient: 0% to 20% ethyl acetate in (5:1 petroleum ether / dichloromethane)] gave C15 as a yellow solid. Yield: 1.70 g, 9.23 mmol, 90%. 1 H NMR (400 MHz, chloroform-d) δ 6.68 - 6.61 (m, 2H), 3.03 - 2.96 (m, 2H), 2.82 - 2.76 (m, 2H).

[0315] Step 4. Synthesis of 5,7-difluoro-3,4-dihydro-2H-1-benzopyran-2-ol (C16). A solution of diisobutylaluminum hydride in toluene (DIBAL, 1 M; 7.82 mL, 7.82 mmol) was slowly added to a -78 °C solution of C15 (1.20 g, 6.52 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at -78 °C for 2.5 h and then immediately added to hydrochloric acid (1 M; 20 mL) at 0 °C; the resulting mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (26 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Chromatography on silica gel [gradient: 0% to 20% ethyl acetate in (5:1 petroleum ether / dichloromethane)] gave C16 as a yellow oil. Yield: 700 mg, 3.76 mmol, 58%. 1 H NMR (400 MHz, chloroform-d) δ 6.44 - 6.34 (m, 2H), 5.64 - 5.60 (m, 1H), 3.15 (broad d, J = 3.5 Hz, 1H), 2.85 - 2.67 (m, 2H), 2.10 - 2.00 (m, 1H), 1.99 - 1.87 (m, 1H).

[0316] Step 5. Synthesis of 3,5-difluoro-2-(3-hydroxybutyl)phenol (C17). A solution of methylmagnesium bromide in diethyl ether (3.0 M; 3.76 mL, 11.3 mmol) was added dropwise to a 0 °C solution of C16 (700 mg, 3.76 mmol) in tetrahydrofuran (18 mL). The reaction mixture was stirred at 0 °C for 20 minutes, then at 25 °C for 2.5 hours, and then immediately poured into hydrochloric acid (1 M; 15 mL) and extracted with ethyl acetate (2 × 12 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give C17 as a yellow oil. Yield: 540 mg, 2.67 mmol, 71%. 1 H NMR (400 MHz, chloroform-d) δ 6.43 (ddd, J = 10.2, 2.1, 2.1 Hz, 1H), 6.41 - 6.34 (m, 1H), 3.78 - 3.68 (m, 1H), 2.85 - 2.65 (m, 2H), 1.82 - 1.63 (m, 2H), 1.25 (d, J = 6.2 Hz, 3H).

[0317] Step 6. Synthesis of 5,7-difluoro-2-methyl-3,4-dihydro-2H-1-benzopyran (P11). A solution of C17 (540 mg, 2.67 mmol) in acetic acid (6 mL) was treated with sulfuric acid (50%; 6 mL), and the reaction mixture was stirred at 100 °C for 3 h. It was then diluted with water (10 mL) and extracted with a mixture of petroleum ether and ethyl acetate (5:1 ratio; 3 × 6 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to afford P11 as a brown oil. Yield: 350 mg, 1.90 mmol, 71%. 1 H NMR (400 MHz, chloroform-d) δ 6.38 - 6.29 (m, 2H), 4.17 - 4.07 (m, 1H), 2.83 - 2.72 (m, 1H), 2.67 - 2.54 (m, 1H), 2.05 - 1.96 (m, 1H), 1.72 - 1.59 (m, 1H), 1.39 (d, J = 6.2 Hz, 3H).

[0318] Alternative Preparation Example of P11 5,7-Difluoro-2-methyl-3,4-dihydro-2H-1-benzopyran (P11)

[0319]

Chemical Structure

[0320] Step 2. Synthesis of 5,7-difluoro-2-methyl-3,4-dihydro-2H-1-benzopyran (P11). To a solution of C18 (569 mg, 2.87 mmol) in trifluoroacetic acid (10 mL) was added triethylsilane (2.29 mL, 14.3 mmol), and then immediately the reaction mixture was stirred at 25 °C for 3 days. After adjusting the pH to 7 by the addition of aqueous sodium hydrogen carbonate solution, the reaction mixture was extracted with ethyl acetate (3 × 6 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (eluent: petroleum ether) gave P11 as a colorless oil. Yield: 416 mg, 2.26 mmol, 79%. 1 H NMR (400 MHz, chloroform-d), performed from a similar, smaller-scale reaction using C18: δ 6.37 - 6.30 (m, 2H), 4.12 (dqd, J = 10.1, 6.3, 2.1 Hz, 1H), 2.82 - 2.72 (m, 1H), 2.66 - 2.55 (m, 1H), 2.00 (dddd, J = 13.8, 6.3, 3.1, 2.2 Hz, 1H), 1.65 (dddd, J = 13.7, 11.3, 10.1, 5.8 Hz, 1H), 1.39 (d, J = 6.3 Hz, 3H).

[0321] Preparation Example P12 Methyl 3-bromo-6-chloro-1-benzothiophene-2-carboxylate (P12)

[0322] [Chemical Structure] To a 0 °C solution of tert-butyl nitrite (0.385 mL, 3.24 mmol) in acetonitrile (10 mL) was added copper(II) bromide (806 mg, 3.61 mmol), followed by the addition of C8 (560 mg, 2.32 mmol) portionwise. The reaction mixture was then warmed to 25 °C and stirred at that temperature for 2 hours, after which it was immediately treated with hydrochloric acid (1 M; 30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with hydrochloric acid (1 M; 2 × 10 mL), dried over sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (gradient: 0% to 2% ethyl acetate in petroleum ether) to afford P12 as a white solid. Yield: 350 mg, 1.15 mmol, 50%. LCMS m / z 304.9 (bromochloro isotope pattern observed) [M+H] + . 1 1H NMR (400 MHz, chloroform-d) δ 7.91 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 8.8, 1.8 Hz, 1H), 3.97 (s, 3H).

[0323] Preparation Example P13 5-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P13)

[0324]

Chem.

[0325] Step 2. Synthesis of 5-fluoro-3,4-dihydro-2H-1-benzopyran (C20). A solution of C19 (5.56 g, 17.8 mmol) in tetrahydrofuran (15 mL) at -78 °C was added to a solution of n-butyllithium in hexane (2.5 M; 9.27 mL, 23.2 mmol), and the reaction mixture was stirred at -78 °C for 2 h. Then it was warmed to 25 °C and stirred at that temperature for 16 h, and immediately thereafter, LCMS analysis showed conversion to C20: LCMS m / z 153.1 [M+H] + . Water (30 mL) was added, and the resulting mixture was extracted with methyl tert-butyl ether (3 × 50 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum to give C20 as a yellow oil. Yield: 2.70 g, 17.7 mmol, 99%. 1 H NMR (400 MHz, chloroform-d) δ 7.06 - 6.99 (m, 1H), 6.62 - 6.54 (m, 2H), 4.20 - 4.15 (m, 2H), 2.74 (t, J = 6.6 Hz, 2H), 2.04 - 1.96 (m, 2H).

[0326] Step 3. Synthesis of 6-bromo-5-fluoro-3,4-dihydro-2H-1-benzopyran (C21). N-Bromosuccinimide (2.34 g, 13.1 mmol) was added to a solution of C20 (2.00 g, 13.1 mmol) in acetonitrile (20 mL). After the mixture was stirred at 25 °C for 16 h, it was concentrated under reduced pressure, diluted with water (10 mL), and extracted with methyl tert-butyl ether (3 × 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum, and immediately thereafter, C21 was obtained as a colorless oil by silica gel chromatography (gradient: 0% to 1% ethyl acetate in petroleum ether). Yield: 1.60 g, 6.92 mmol, 53%. 1 H NMR (400 MHz, chloroform-d) δ 7.21 (br dd, J = 8.8, 8.0 Hz, 1H), 6.53 (dd, J = 8.8, 1.6 Hz, 1H), 4.19 - 4.13 (m, 2H), 2.77 (t, J = 6.6 Hz, 2H), 2.03 - 1.95 (m, 2H).

[0327] Step 4. Synthesis of 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P13). A mixture of C21 (200 mg, 0.866 mmol), potassium acetate (297 mg, 3.03 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane (330 mg, 1.30 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (63 mg, 86 μmol) in N,N-dimethylformamide (2 mL) was stirred at 100 °C for 16 h. Immediately thereafter, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered. The filtrate was washed with water (30 mL) and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under vacuum, and purified using silica gel chromatography (gradient: 0% to 5% ethyl acetate in petroleum ether) to obtain P13 as a white solid. Yield: 120 mg, 0.431 mmol, 50%. LCMS m / z 279.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.45 (dd, J = 8, 8 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 4.18 (dd, J = 5.8, 4.5 Hz, 2H), 2.73 (t, J = 6.6 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.34 (s, 12H).

[0328] Preparation Example P14 3-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P14)

[0329]

Chem.

[0330] A solution of 7-bromo-2,3-dihydro-4H-1-benzopyran-4-one (5.00 g, 22.0 mmol) and N,N,N’,N’,N”,N”-hexamethylphosphoric triamide (HMPA; 19.1 mL, 110 mmol) in tetrahydrofuran (70 mL) was cooled to -78 °C and treated with the lithium diisopropylamide solution prepared above. After the reaction mixture was stirred at -78 °C for 1 hour, a solution of iodomethane (15.6 g, 110 mmol) in tetrahydrofuran (20 mL) was added dropwise. At the end of this addition, the reaction mixture was warmed to 0 °C and stirred at 0 °C for 2 hours. After the addition of a saturated aqueous ammonium chloride solution (50 mL), the resulting mixture was extracted with ethyl acetate (3 × 40 mL), and the combined organic layers were washed with a saturated aqueous sodium chloride solution and concentrated under vacuum. Purification by silica gel chromatography (gradient: 0% to 15% ethyl acetate in petroleum ether) gave C22 as a yellow solid. Yield: 2.50 g, 10.4 mmol, 47%. LCMS m / z 240.9 (bromine isotope pattern was observed) [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 7.75 (d, J = 8.3 Hz, 1H), 7.19 - 7.13 (m, 2H), 4.51 (dd, J = 11.4, 5.1 Hz, 1H), 4.15 (dd, J = 11.3, 11.1 Hz, 1H), 2.92 - 2.80 (m, 1H), 1.21 (d, J = 7.0 Hz, 3H).

[0331] Step 2. Synthesis of 7-bromo-3-methyl-3,4-dihydro-2H-1-benzopyran (C23). To a solution of C22 (3.50 g, 14.5 mmol) in trifluoroacetic acid (30 mL) was added triethylsilane (25 mL, 160 mmol). The reaction mixture was stirred at 50 °C for 16 h, then immediately concentrated under vacuum and partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum; the residue was purified by silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) to afford C23 as a white solid. Yield: 3.01 g, 13.3 mmol, 92%. 1 1H NMR (400 MHz, chloroform-d) δ 6.98 - 6.92 (m, 2H), 6.87 (br d, half of AB quartet, J = 7.8 Hz, 1H), 4.16 (ddd, J = 10.6, 3.4, 2.0 Hz, 1H), 3.67 (dd, J = 10.6, 9.4 Hz, 1H), 2.77 (ddd, J = 16.2, 5.2, 2.0 Hz, 1H), 2.36 (dd, J = 16.2, 9.8 Hz, 1H), 2.19 - 2.05 (m, 1H), 1.03 (d, J = 6.7 Hz, 3H).

[0332] Step 3. Synthesis of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P14). A mixture of C23 (3.0 g, 13 mmol), potassium acetate (4.54 g, 46.3 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane (5.03 g, 19.8 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (967 mg, 1.32 mmol) in N,N-dimethylformamide (60 mL) was stirred at 100 °C for 16 h. Then, ethyl acetate (150 mL) was added and the resulting mixture was filtered. The filtrate was washed with water (2 × 300 mL) and then with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% to 15% ethyl acetate in petroleum ether) gave P14 as a white solid. Yield: 2.70 g, 9.85 mmol, 76%. LCMS m / z 275.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.29 - 7.23 (m, 2H), 7.03 (br d, J = 7.4 Hz, 1H), 4.16 (ddd, J = 10.6, 3.4, 2.0 Hz, 1H), 3.67 (dd, J = 10.6, 9.4 Hz, 1H), 2.84 (ddd, J = 16.4, 5.3, 1.9 Hz, 1H), 2.45 (dd, J = 16.5, 9.7 Hz, 1H), 2.20 - 2.07 (m, 1H), 1.32 (s, 12H), 1.03 (d, J = 6.7 Hz, 3H).

[0333] Preparation Example P15 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P15)

[0334]

Chem.

[0335] Step 2. Synthesis of 6-bromo-2-methyl-3,4-dihydro-2H-1-benzopyran (C25). Triethylsilane (25 mL, 160 mmol) was added to a solution of C24 (3.94 g, 16.3 mmol) in trifluoroacetic acid (25 mL). The reaction mixture was heated at 50 °C for 16 h, then concentrated under vacuum, diluted with ethyl acetate (100 mL), and basified to pH 8 by addition of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layers were washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. C25 was obtained as a pale yellow solid by silica gel chromatography (gradient: 0% to 5% ethyl acetate in petroleum ether). Yield: 3.00 g, 13.2 mmol, 81%. 1 H NMR (400 MHz, chloroform-d) δ 7.18 - 7.13 (m, 2H), 6.67 (d, J = 9.3 Hz, 1H), 4.11 (dqd, J = 10.1, 6.2, 2.1 Hz, 1H), 2.83 (br ddd, ABXY system component, J = 16.6, 11.5, 6.1 Hz, 1H), 2.71 (ddd, ABXY system component, J = 16.7, 5.6, 3.1 Hz, 1H), 1.97 (dddd, J = 13.6, 6.1, 3.2, 2.2 Hz, 1H), 1.68 (dddd, J = 13.6, 11.5, 10.1, 5.6 Hz, 1H), 1.39 (d, J = 6.2 Hz, 3H).

[0336] Step 3. Synthesis of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P15). 4,4,4’,4’,5,5,5’,5’-Octamethyl-2,2’-bi-1,3,2-dioxaborolane (5.03 g, 19.8 mmol), potassium acetate (4.55 g, 46.4 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (964 mg, 1.32 mmol) were added to a solution of C25 (3.00 g, 13.2 mmol) in N,N-dimethylformamide (40 mL). The reaction vessel was then evacuated and charged with nitrogen; this evacuation cycle was repeated twice, and then immediately, the reaction mixture was heated at 90 °C for 16 h. After adding water (100 mL) and ethyl acetate (100 mL), the resulting mixture was filtered, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed successively with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum. P15 was obtained as a pale yellow solid by silica gel chromatography (gradient: 5% to 10% ethyl acetate in petroleum ether). Yield: 2.56 g, 9.34 mmol, 71%. LCMS m / z 275.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.57 - 7.50 (m, 2H), 6.78 (d, J = 8.6 Hz, 1H), 4.16 (dqd, J = 10.1, 6.3, 2.2 Hz, 1H), 2.84 (br ddd, ABXY system component, J = 16.4, 11.3, 5.9 Hz, 1H), 2.75 (ddd, ABXY system component, J = 16.4, 5.5, 3.2 Hz, 1H), 1.99 (dddd, J = 13.6, 5.8, 3.3, 2.2 Hz, 1H), 1.71 (dddd, J = 13.6, 11.4, 10.0, 5.7 Hz, 1H), 1.39 (d, J = 6.3 Hz, 3H), 1.33 (s, 12H).

[0337] Preparation Example P16 4-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P16)

[0338]

Chem.

[0339] Step 2. Synthesis of 6-bromo-4-methyl-3,4-dihydro-2H-1-benzopyran (C27). Boron trifluoride diethyl etherate (98%, 2.14 g, 14.8 mmol) was added dropwise to a 0 °C solution of C26 (1.20 g, 4.94 mmol) and triethylsilane (2.87 g, 24.7 mmol) in dichloromethane (10 mL). After the reaction mixture was stirred at 0 °C for 30 minutes, it was treated with saturated aqueous sodium hydrogen carbonate; the aqueous layer was extracted with dichloromethane (3 × 30 mL), the combined organic layers were washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. C27 was obtained as a clear colorless liquid by silica gel chromatography (gradient: 0% to 1% ethyl acetate in petroleum ether). Yield: 801 mg, 3.53 mmol, 71%. GCMS m / z 226 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.25 (dd, J = 2.4, 1.0 Hz, 1H), 7.16 (ddd, J = 8.7, 2.4, 0.7 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 4.24 - 4.10 (m, 2H), 2.98 - 2.86 (m, 1H), 2.11 - 2.00 (m, 1H), 1.76 - 1.65 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H).

[0340] Step 3. Synthesis of 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P16). A mixture of C27 (300 mg, 1.32 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane (839 mg, 3.30 mmol), and potassium acetate (259 mg, 2.64 mmol) in 1,4-dioxane (12 mL) was degassed with nitrogen for 1 minute and then immediately [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (96.7 mg, 0.132 mmol) was added. The reaction mixture was heated at 100 °C for 16 hours. It was then filtered, the filtrate was concentrated under vacuum, diluted with water (40 mL), and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure; P16 was obtained as a clear yellow liquid by silica gel chromatography (eluent: petroleum ether). Yield: 350 mg.

[0341] Preparation Example P17 8-Fluoro-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P17)

[0342] [Chemical formula] Step 1. Synthesis of 1-bromo-2,3-difluoro-4-(2-methylprop-2-en-1-yl)benzene (C28). A solution of (propan-2-yl)magnesium chloride (2 M; 4.08 mL, 8.16 mmol) was added dropwise to a solution of 1-bromo-2,3-difluoro-4-iodobenzene (2.00 g, 6.27 mmol) in tetrahydrofuran (10 mL) at -20 °C. The reaction mixture was stirred for 10 minutes, then warmed to 0 °C and stirred for an additional 50 minutes. Immediately thereafter, copper(I) iodide (299 mg, 1.57 mmol) was added and stirring was continued at 0 °C for 10 minutes. Then, 3-bromo-2-methylprop-1-ene (931 mg, 6.90 mmol) was added; the reaction mixture was warmed to 25 °C and stirred for 16 hours. It was then treated with saturated aqueous ammonium chloride (30 mL), diluted with petroleum ether (8 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give C28 as a yellow oil. Yield: 1.48 g, 5.99 mmol, 96%. 1 H NMR (400 MHz, chloroform-d) δ 7.23 (ddd, J = 8.3, 6.1, 2.1 Hz, 1H), 6.89 - 6.83 (m, 1H), 4.85 (br s, 1H), 4.69 (br s, 1H), 3.33 (s, 2H), 1.71 (s, 3H).

[0343] Step 2. Synthesis of 3-(4-bromo-2,3-difluorophenyl)-2-methylpropan-1-ol (C29). A solution of C28 (1.48 g, 5.99 mmol) in tetrahydrofuran (10 mL) at 0 °C was added dropwise with a solution of borane in tetrahydrofuran (1 M; 8.39 mL, 8.39 mmol). After the reaction mixture was stirred for 30 minutes, it was warmed to room temperature, stirred for 2 hours, and then cooled back to 0 °C. An aqueous solution of sodium hydroxide (3 M; 9.98 mL, 29.9 mmol) was added, followed by hydrogen peroxide (30% in water; 3.06 mL, 30.0 mmol). Stirring was continued for 30 minutes, and immediately thereafter, the reaction mixture was heated to 60 °C and stirred at that temperature for an additional 1.5 hours. After cooling it to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL); the combined organic layers were washed with a saturated aqueous sodium chloride solution (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (gradient: 0% to 30% ethyl acetate in petroleum ether) gave C29 as a colorless oil. Yield: 800 mg, 3.02 mmol, 50%. 1 H NMR (400 MHz, chloroform-d) δ 7.22 (ddd, J = 8.2, 6.1, 2.0 Hz, 1H), 6.85 (ddd, J = 8.3, 6.9, 2.0 Hz, 1H), 3.51 (dd, J = 5.5, 5.5 Hz, 2H), 2.81 (ddd, J = 13.5, 6.1, 1.6 Hz, 1H), 2.48 (ddd, J = 13.6, 8.2, 1.6 Hz, 1H), 2.01 - 1.90 (m, 1H), 1.48 - 1.36 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H).

[0344] Step 3. Synthesis of 7-bromo-8-fluoro-3-methyl-3,4-dihydro-2H-1-benzopyran (C30). Sodium hydride (60% dispersion in mineral oil; 315 mg, 7.88 mmol) was added to a 0 °C solution of C29 (950 mg, 3.58 mmol) in a mixture of toluene (16 mL) and N,N-dimethylformamide (4 mL), and immediately thereafter, the reaction mixture was stirred at 25 °C for 16 hours. A saturated aqueous ammonium chloride solution (10 mL) was added, and the resulting mixture was diluted with water (15 mL) and petroleum ether (9 mL) and extracted with petroleum ether (3 × 9 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain crude C30 as a yellow solution (2.7 mL). A portion of this solution was carried forward as such to the next step.

[0345] The product of a similar reaction carried out using C29 was subjected to silica gel chromatography (eluent: petroleum ether) to obtain a purified sample of C30: 1 H NMR (400 MHz, chloroform-d) δ 6.96 (dd, J = 8.4, 6.2 Hz, 1H), 6.69 (br d, J = 8.3 Hz, 1H), 4.28 (ddd, J = 10.7, 3.5, 1.9 Hz, 1H), 3.74 (dd, J = 10.6, 9.4 Hz, 1H), 2.81 (ddd, J = 16.4, 5.1, 1.9 Hz, 1H), 2.40 (dd, J = 16.3, 9.7 Hz, 1H), 2.23 - 2.10 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H).

[0346] Step 4. Synthesis of 8-fluoro-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (P17). A mixture of C30 (a portion of the solution from the preceding step; 1.8 mL, ≤2.39 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane (361 mg, 1.42 mmol) in toluene (10 mL) was added with potassium acetate (232 mg, 2.36 mmol) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (86.6 mg, 0.118 mmol). The reaction vessel was then evacuated and charged with nitrogen; this evacuation cycle was repeated twice, and immediately thereafter, the reaction mixture was stirred at 100 °C for 16 h. It was then filtered, the filtrate was concentrated under vacuum, and purified using silica gel chromatography (eluent: petroleum ether) to obtain P17 as a yellow oil. Yield: 189 mg, 0.647 mmol, 27% over 2 steps. 1 H NMR (400 MHz, chloroform-d) δ 7.12 (dd, J = 7.6, 5.2 Hz, 1H), 6.79 (br d, J = 7.6 Hz, 1H), 4.25 (ddd, J = 10.5, 3.5, 2.0 Hz, 1H), 3.71 (dd, J = 10.6, 9.5 Hz, 1H), 2.85 (br dd, component of ABX system, J = 16.6, 5.0 Hz, 1H), 2.45 (dd, component of ABX system, J = 16.7, 9.7 Hz, 1H), 2.24 - 2.09 (m, 1H), 1.34 (s, 12H), 1.04 (d, J = 6.8 Hz, 3H).

[0347] Preparation Example P18 2-(3-Ethyl-2,4,5-trifluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (P18)

[0348]

Chemical Structure

[0349] Step 2. Synthesis of 1-(3-bromo-2,5,6-trifluorophenyl)ethyl methanesulfonate (C32). A solution of methanesulfonyl chloride (0.824 mL, 10.6 mmol) in dichloromethane (12 mL) was added dropwise to an ice-cooled solution of C31 (1.90 g, 7.45 mmol) and triethylamine (2.07 mL, 14.9 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at 0 °C for 30 minutes and then partitioned between dichloromethane (50 mL) and water (100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under vacuum, and purified using silica gel chromatography (gradient: 0% to 16% ethyl acetate in petroleum ether) to give C32 as a colorless oil. Yield: 2.40 g, 7.20 mmol, 97%. 1 H NMR (400 MHz, chloroform-d) δ 7.44 (ddd, J = 8.9, 8.1, 6.3 Hz, 1H), 6.08 (q, J = 6.8 Hz, 1H), 2.98 (s, 3H), 1.81 (d, J = 6.8 Hz, 3H).

[0350] Step 3. Synthesis of 1-bromo-3-ethyl-2,4,5-trifluorobenzene (C33). A solution of lithium triethylborohydride (1 M; 14.4 mL, 14.4 mmol) was added dropwise to an ice-cooled solution of C32 (2.40 g, 7.20 mmol) in tetrahydrofuran (24 mL). The reaction mixture was stirred at 0 °C for 30 minutes, then treated with water (50 mL) dropwise at 0 °C and diluted with petroleum ether (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated at 20 °C under reduced pressure. C33 was obtained as a colorless oil by silica gel chromatography (eluent: petroleum ether). Yield: 1.31 g, 5.48 mmol, 76%. 1 H NMR (400 MHz, chloroform-d) δ 7.24 (ddd, J = 9, 8, 6.5 Hz, 1H), 2.75 (qt, J = 7.6, 1.4 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H).

[0351] Step 4. Synthesis of 2-(3-ethyl-2,4,5-trifluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (P18). A mixture of C33 (400 mg, 1.67 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane (850 mg, 3.35 mmol), potassium acetate (328 mg, 3.34 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (122 mg, 0.167 mmol) in 1,4-dioxane (8.4 mL) was degassed with nitrogen for 2 minutes and then heated at 95 °C for 16 hours. It was concentrated under vacuum to give a residue, which was purified using silica gel chromatography (gradient: 0% to 5% ethyl acetate in petroleum ether) to give P18 as a yellow oil. Yield: 330 mg, 1.15 mmol, 69%. 1 H NMR (400 MHz, chloroform-d) δ 7.34 (ddd, J = 9.7, 9.7, 5.2 Hz, 1H), 2.70 (qt, J = 7.5, 1.6 Hz, 2H), 1.35 (s, 12H), 1.20 (t, J = 7.6 Hz, 3H).

[0352] Preparation Example P19 3-chloro-1,5-difluoro-2-iodo-4-methoxybenzene (P19)

[0353]

Chemical Structure

[0354] Step 2. Synthesis of 3-chloro-1,5-difluoro-2-iodo-4-methoxybenzene (P19). To a solution of C34 (1.68 g, 5.52 mmol) in tetrahydrofuran (30 mL) at -65 °C was added a solution of lithium diisopropylamide (2 M; 3.59 mL, 7.18 mmol), and the reaction mixture was stirred at 20 °C for 2 hours. After the reaction was quenched by the addition of an aqueous ammonium chloride solution (5 mL), the resulting mixture was extracted with petroleum ether (3 × 3 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (6 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to obtain P19 as a yellow oil. Yield: 1.23 g, 4.04 mmol, 73%. 1 H NMR (400 MHz, chloroform-d) δ 6.91 (dd, J = 10.4, 7.6 Hz, 1H), 3.92 (d, J = 1.0 Hz, 3H).

[0355] Preparation Example P20 3-Fluoro-6-iodo-2-methoxybenzonitrile (P20)

[0356]

Chem.

[0357] Step 2. Synthesis of 3-fluoro-6-iodo-2-methoxybenzamide (C36). A mixture of C35 (from the preceding step; 200 mg, <0.676 mmol), 1H-benzotriazol-1-ol (274 mg, 2.03 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (298 mg, 1.55 mmol) in tetrahydrofuran (3.5 mL) was stirred at 15 °C for 1 h, and then immediately, 4-methylmorpholine (226 mg, 2.23 mmol) and aqueous ammonium hydroxide (1.5 mL) were added; stirring was continued at 15 °C for 16 h. The reaction mixture was then diluted with water (4 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with saturated aqueous sodium chloride (5 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (gradient: 0% to 20% ethyl acetate in petroleum ether) to give C36 as a white solid. Yield: 86 mg, 0.29 mmol, 30% over 2 steps. 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (br s, 1H), 7.63 (br s, 1H), 7.55 (dd, J = 8.7, 4.5 Hz, 1H), 7.10 (dd, J = 11.5, 8.7 Hz, 1H), 3.83 (d, J = 1.3 Hz, 3H).

[0358] Step 3. Synthesis of 3-fluoro-6-iodo-2-methoxybenzonitrile (P20). Trifluoroacetic anhydride (306 mg, 1.46 mmol) was added to a 15 °C mixture of C36 (86.0 mg, 0.29 mmol) and pyridine (0.236 mL, 2.92 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at 15 °C for 16 h, then concentrated under reduced pressure, diluted with water (5 mL), and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. P20 was obtained as a colorless rubbery solid by silica gel chromatography (gradient: 0% to 20% ethyl acetate in petroleum ether). Yield: 79 mg, 0.285 mmol, 98%. 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (dd, J = 8.7, 4.4 Hz, 1H), 7.45 (dd, J = 12.1, 8.7 Hz, 1H), 4.06 (d, J = 2.8 Hz, 3H).

[0359] (Example 1) 3-(5,7-Difluoro-3,4-dihydro-2H-1-benzopyran-6-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (1)

[0360]

Chemical formula

[0361] Step 2. Synthesis of (5,7-difluoro-3,4-dihydro-2H-1-benzopyran-6-yl)boronic acid (C38). A reaction flask containing C37 (920 mg, 3.69 mmol), potassium acetate (906 mg, 9.23 mmol), sodium tert-butoxide (4 mg, 40 μmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos Pd G2; 29 mg, 37 μmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos; 53 mg, 0.11 mmol) was purged with nitrogen. Methanol (20 mL), ethane-1,2-diol (2 mL) and tetrahydroxydiborane (364 mg, 4.06 mmol) were added, and nitrogen was bubbled through the reaction mixture for 10 minutes, and then immediately it was heated to 50 °C (internal temperature) for 6 hours. The reaction mixture was then concentrated under vacuum, diluted with water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. After chromatography on silica gel (gradient: 0% to 50% ethyl acetate in petroleum ether), C38 was obtained as a yellow solid. 1 According to 1H NMR analysis, this material contained impurities. Yield: 243 mg, <1.14 mmol, <31%. 1 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 6.40 (dd, J = 9.9, 1.5 Hz, 1H), 4.18 - 4.10 (m, 2H), 2.62 - 2.56 (m, 2H), 1.94 - 1.85 (m, 2H).

[0362] Step 3. Synthesis of methyl 3-(5,7-difluoro-3,4-dihydro-2H-1-benzopyran-6-yl)-6-fluoro-1-benzothiophene-2-carboxylate (C39). To a solution of methyl 3-chloro-6-fluoro-1-benzothiophene-2-carboxylate (114 mg, 0.466 mmol) in 1,4-dioxane (1.5 mL) were added C38 (100 mg, 0.47 mmol), tripotassium phosphate (198 mg, 0.933 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) [Pd(amphos)2Cl2; 33 mg, 47 μmol], and water (0.25 mL). After nitrogen was bubbled through the reaction mixture for 2 minutes, it was stirred at 110 °C for 16 hours. Immediately thereafter, LCMS analysis indicated the presence of C39: LCMS m / z 379.3 [M+H] + The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, concentrated under vacuum, and subjected to silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) to afford C39 as a white solid. Yield: 10 mg, 26 μmol, 6%. 1 H NMR (400 MHz, methanol-d4) δ 7.75 (dd, J = 8.8, 2.3 Hz, 1H), 7.48 (br dd, J = 9.2, 5.2 Hz, 1H), 7.23 (ddd, J = 9.0, 9.0, 2.4 Hz, 1H), 6.54 (dd, J = 10.8, 1.9 Hz, 1H), 4.27 (dd, J = 5.9, 4.5 Hz, 2H), 3.80 (s, 3H), 2.75 (br dd, J = 6.5, 6.5 Hz, 2H), 2.09 - 2.00 (m, 2H).

[0363] Step 4. Synthesis of 3-(5,7-difluoro-3,4-dihydro-2H-1-benzopyran-6-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (1). A solution of lithium hydroxide (3.8 mg, 0.16 mmol) in water (1.0 mL) was added to a solution of C39 (10 mg, 26 μmol) in a mixture of methanol (1.0 mL) and tetrahydrofuran (1.0 mL). The reaction mixture was stirred at 60 °C for 16 h, and then immediately diluted with water (20 mL) and concentrated under vacuum to remove methanol and tetrahydrofuran, and washed with dichloromethane (3 × 25 mL). The aqueous layer was adjusted to pH 4 by the addition of 1 M hydrochloric acid and then extracted with ethyl acetate (3 × 15 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated under vacuum to give 3-(5,7-difluoro-3,4-dihydro-2H-1-benzopyran-6-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (1) as a yellow solid. Yield: 2.6 mg, 7.1 μmol, 27%. LCMS m / z 365.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.72 (dd, J = 8.8, 2.4 Hz, 1H), 7.44 (br dd, J = 9.0, 5.1 Hz, 1H), 7.20 (ddd, J = 9.0, 9.0, 2.4 Hz, 1H), 6.51 (dd, J = 10.7, 1.9 Hz, 1H), 4.28 - 4.22 (m, 2H), 2.75 (br dd, J = 6.5, 6.5 Hz, 2H), 2.08 - 2.00 (m, 2H).

[0364] (Example 2) 6-Fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (2)

[0365]

Chemical formula

[0366] Step 2. Synthesis of methyl 6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylate (C41). A suspension of C40 (100 mg, 0.347 mmol), P2 (117 mg, 0.348 mmol), potassium fluoride (40.3 mg, 0.694 mmol), and tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3; 15.9 mg, 17.4 μmol] in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL) was degassed with nitrogen for 1 minute and then immediately treated with tri-tert-butylphosphine (7.02 mg, 34.7 μmol). The reaction mixture was stirred at 75 °C for 16 hours and then concentrated under vacuum and purified by silica gel chromatography (gradient: 0% to 5% ethyl acetate in petroleum ether) to obtain C41 as a colorless rubbery solid. Yield: 40.0 mg, 0.108 mmol, 31%. 11H NMR (400 MHz, chloroform-d) δ 7.58 (dd, J = 8.5, 2.4 Hz, 1H), 7.44 (br dd, J = 9.1, 5.1 Hz, 1H), 7.17 (ddd, J = 8.9, 8.8, 2.3 Hz, 1H), 6.86 (ddd, J = 11.0, 9.1, 2.3 Hz, 1H), 4.00 (br s, 3H), 3.84 (s, 3H).

[0367] Step 3. Synthesis of 6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (2). Lithium hydroxide (25.9 mg, 1.08 mmol) was added to a solution of C41 (40.0 mg, 0.108 mmol) in a mixture of tetrahydrofuran (2 mL), methanol (1 mL), and water (1 mL). The reaction mixture was stirred at 25 °C for 2 h and then immediately acidified to approximately pH 3 by the addition of hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 × 3 mL), and the combined organic layers were concentrated in vacuo and purified by reverse-phase HPLC (column: Phenomenex Gemini C18, 50 × 250 mm, 10 μm; mobile phase A: water containing 0.225% formic acid; mobile phase B: acetonitrile; gradient: from 48% to 68% B; flow rate: 25 mL / min) to afford 6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (2) as a white solid. Yield: 10.4 mg, 29.2 μmol, 27%. LCMS m / z 354.9 [M-H] - . 1 1H NMR (400 MHz, chloroform-d) δ 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.45 (br dd, J = 9.0, 5.0 Hz, 1H), 7.18 (ddd, J = 8.8, 8.8, 2.4 Hz, 1H), 6.86 (ddd, J = 10.8, 9.0, 2.2 Hz, 1H), 4.00 (s, 3H).

[0368] (Example 3) 3-(5,7-Difluoro-2-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (3)

[0369] [Chemical formula] Step 1. Synthesis of 5,7-difluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1-benzopyran (C42). A solution of n-butyllithium in hexane (2.5 M; 1.63 mL, 4.08 mmol) was added dropwise to a solution of P11 (300 mg, 1.63 mmol) in tetrahydrofuran (8 mL) at -65 °C. After stirring the reaction mixture at -65 °C for 1 hour, 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (909 mg, 4.89 mmol) was added. The reaction mixture was warmed to 25 °C and stirred at that temperature for 1 hour. An aqueous ammonium chloride solution (15 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 × 20 mL); the combined organic layers were washed with a saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. C42 was obtained as a yellow oil by silica gel chromatography (0% to 10% ethyl acetate in petroleum ether). Yield: 350 mg, 1.13 mmol, 69%. 1 H NMR (400 MHz, chloroform-d) δ 6.31 (dd, J = 10.6, 1.7 Hz, 1H), 4.18 - 4.10 (m, 1H), 2.82 - 2.71 (m, 1H), 2.65 - 2.51 (m, 1H), 2.03 - 1.95 (m, 1H), 1.70 - 1.58 (m, 1H), 1.38 (d, J = 6.4 Hz, 3H), 1.36 (s, 12H).

[0370] Step 2. Synthesis of methyl 3-(5,7-difluoro-2-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-6-fluoro-1-benzothiophene-2-carboxylate (C43). A suspension of P1 (110 mg, 0.380 mmol), potassium fluoride (72.9 mg, 1.25 mmol), and C42 (165 mg, 0.532 mmol) in a mixture of tetrahydrofuran (2.0 mL) and water (0.2 mL) was degassed with nitrogen for 2 minutes and then immediately, tris(dibenzylideneacetone)dipalladium(0) (6.97 mg, 7.61 μmol) and tri-tert-butylphosphine (80 mg, 0.4 mmol) were added. The reaction mixture was stirred at 60 °C for 18 hours and then filtered. The filtrate was concentrated under vacuum and purified by silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) to obtain C43 as a colorless rubbery substance. 1 Investigation of the 1H NMR spectrum suggested that this material exists as a mixture of rotational isomers. Yield: 110 mg, 0.280 mmol, 74%. 1 1H NMR (400 MHz, chloroform-d) δ 7.55 (dd, J = 8.5, 2.3 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.17 - 7.10 (m, 1H), 6.55 - 6.49 (m, 1H), 4.25 - 4.17 (m, 1H), [3.84 (s) and 3.83 (s), total 3H], 2.90 - 2.78 (m, 1H), 2.77 - 2.64 (m, 1H), 2.11 - 2.01 (m, 1H), 1.80 - 1.65 (m, 1H), 1.44 (d, J = 6.3 Hz, 3H).

[0371] Step 3. Synthesis of 3-(5,7-difluoro-2-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (3). A solution of C43 (110 mg, 0.280 mmol) in a mixture of tetrahydrofuran (1 mL), methanol (1 mL), and water (0.2 mL) was added to lithium hydroxide monohydrate (82.3 mg, 1.96 mmol). After the reaction mixture was stirred at 25 °C for 16 h, it was adjusted to approximately pH 4 and extracted with ethyl acetate (3 × 4 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (8 mL), dried over sodium sulfate, filtered, concentrated under vacuum, and purified by preparative thin layer chromatography (eluent: 1:1 petroleum ether / ethyl acetate) to obtain 3-(5,7-difluoro-2-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (3) as a white solid. Yield: 100 mg, 0.26 mmol, 93%. LCMS m / z 379.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.60 (dd, J = 8.9, 2.4 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.10 (ddd, J = 9.0, 9.0, 2.4 Hz, 1H), 6.45 (dd, J = 10.7, 1.8 Hz, 1H), 4.25 - 4.13 (m, 1H), 2.90 - 2.76 (m, 1H), 2.76 - 2.61 (m, 1H), 2.13 - 2.03 (m, 1H), 1.74 - 1.61 (m, 1H), 1.41 (br d, J = 6.3 Hz, 3H).

[0372] (Example 4) 6,7-Difluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (4)

[0373]

Chemical Structure

[0374] Step 2. Synthesis of 6,7-difluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (4). A suspension of C44 (67.7 mg, 0.213 mmol) in a mixture of methanol (1 mL) and tetrahydrofuran (1 mL) was added with a solution of sodium hydroxide (42.5 mg, 1.06 mmol) in water (0.5 mL). The reaction mixture was stirred at room temperature (26 °C) for 16 h and then concentrated under vacuum. The residue was acidified to approximately pH 6 by the addition of 1 M hydrochloric acid. Filtration of the resulting suspension gave a solid, which was purified using reverse-phase HPLC (column: Phenomenex Gemini NX-C18, 30×75 mm, 3 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: 0% to 32% B; flow rate: 25 mL / min) to afford 6,7-difluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (4) as a white solid. Yield: 15.3 mg, 52.7 μmol, 25%. LCMS m / z 291.0 [M+H] + .1 1H NMR (400 MHz, DMSO-d6) δ 7.57 - 7.43 (m, 4H), 7.43 - 7.38 (m, 2H), 7.24 (br dd, J = 9, 4 Hz, 1H).

[0375] (Example 5) Ammonium 4,6-difluoro-3-phenyl-1-benzothiophene-2-carboxylate (5)

[0376] [Chemical formula] Step 1. Synthesis of ethyl 4,6-difluoro-3-phenyl-1-benzothiophene-2-carboxylate (C45). Cesium carbonate (1.22 g, 3.74 mmol) and tetrakis(triphenylphosphine)palladium(0) (144 mg, 0.125 mmol) were added to a suspension of P4 (400 mg, 1.25 mmol) and phenylboronic acid (228 mg, 1.87 mmol) in a mixture of 1,4-dioxane (8.0 mL) and water (2.0 mL). After stirring the reaction mixture at 90 °C for 16 h, LCMS analysis indicated the presence of C45: LCMS m / z 318.9 [M+H] + . The solvent was removed under vacuum and the residue was purified by silica gel chromatography (eluent: petroleum ether) to give C45 as a white solid. Yield: 282 mg, 0.886 mmol, 71%.

[0377] Step 2. Synthesis of ammonium 4,6-difluoro-3-phenyl-1-benzothiophene-2-carboxylate (5). A solution of sodium hydroxide (177 mg, 4.42 mmol) in water (2 mL) was added to a suspension of C45 (282 mg, 0.886 mmol) in a mixture of methanol (4 mL) and tetrahydrofuran (4 mL), and the reaction mixture was stirred at room temperature (26 °C) for 16 h. It was then concentrated under vacuum, and the residue was acidified to approximately pH 6 by the addition of 1 M hydrochloric acid. The solid was obtained by filtration and purified by reverse-phase HPLC (column: Phenomenex Gemini NX-C18, 30 × 75 mm, 3 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: 0% to 31% B; flow rate: 25 mL / min) to give ammonium 4,6-difluoro-3-phenyl-1-benzothiophene-2-carboxylate (5) as a white solid. Yield: 91.4 mg, 0.315 mmol, 36%. LCMS m / z 288.9 [M-H] - . 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (dd, J = 8.7, 2.3 Hz, 1H), 7.35 - 7.23 (m, 5H), 7.05 (ddd, J = 11.9, 9.6, 2.3 Hz, 1H), 6.74 (br s, approximately 4H).

[0378] (Example 6) 6-Chloro-5-fluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (6)

[0379]

Chem.

[0380] Step 2. Synthesis of 6-chloro-5-fluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (6). A suspension of C46 (110 mg, 0.329 mmol) in a mixture of methanol (1 mL), water (1 mL), and tetrahydrofuran (1 mL) was treated with lithium hydroxide monohydrate (138 mg, 3.29 mmol). After the reaction mixture was stirred at 25 °C for 16 h, hydrochloric acid (1 M; 2 mL) was used to adjust the pH to approximately 3, and immediately thereafter, the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum. 6-Chloro-5-fluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (6) was obtained as a white solid by reverse-phase HPLC (column: Welch Xtimate C18, 30 × 100 mm, 3 μm; mobile phase A: water containing 0.225% formic acid; mobile phase B: acetonitrile; gradient: 45% to 85% B; flow rate: 30 mL / min). Yield: 31.6 mg, 0.103 mmol, 31%. LCMS m / z 261.1 (chlorine isotope pattern observed) [M-CO2H] - . 1 H NMR (400 MHz, methanol-d4) δ 8.14 (d, J = 6.6 Hz, 1H), 7.54 - 7.44 (m, 3H), 7.40 - 7.35 (m, 2H), 7.22 (d, J = 9.8 Hz, 1H).

[0381] (Example 7) 3-(4,5-Dichloro-2-fluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (7)

[0382]

Chemical formula

[0383] Step 2. Synthesis of 3-(4,5-dichloro-2-fluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (7). A mixture of C47 (214 mg, 0.573 mmol), an aqueous solution of lithium hydroxide (1.0 M; 1.15 mL, 1.15 mmol), and tetrahydrofuran (2.9 mL) was heated at 80 °C overnight. The reaction mixture was then partitioned between ethyl acetate and 1 M hydrochloric acid; the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with heptane containing a small amount of diethyl ether and then purified by silica gel chromatography (gradient: 0% to 20% methanol in dichloromethane). The resulting material was triturated with heptane to give 3-(4,5-dichloro-2-fluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (7) as a white solid. Yield: 94.8 mg, 0.264 mmol, 46%. LCMS m / z 358.8 (dichloro isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.77 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.49 (br dd, J = 9.0, 5.0 Hz, 1H), 7.25 (ddd, J = 9.0, 9.0, 2.4 Hz, 1H).

[0384] (Example 8) 3-(3,5-Difluoro-2-methylpyridin-4-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (8)

[0385]

Chemical Structure

[0386] Step 2. Synthesis of methyl 3-(3,5-difluoro-2-methylpyridin-4-yl)-6-fluoro-1-benzothiophene-2-carboxylate (C49). A suspension of C48 (from the previous step; 140 mg), P2 (185 mg, 0.550 mmol), and potassium fluoride (95.7 mg, 1.65 mmol) in a mixture of tetrahydrofuran (10 mL) and water (1.0 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (25.1 mg, 27.4 μmol), followed by addition of a solution of tri-tert-butylphosphine in toluene (1 M; 54.9 μL, 54.9 μmol). The reaction mixture was heated at 60 °C for 16 h and then immediately poured into water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. C49 was obtained as a yellow solid by preparative thin layer chromatography (eluent: 15:1 petroleum ether / ethyl acetate). Yield: 40.0 mg, 0.119 mmol, 3% over 2 steps. LCMS m / z 337.9 [M+H] + .

[0387] Step 3. Synthesis of 3-(3,5-difluoro-2-methylpyridin-4-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (8). Lithium hydroxide (28.4 mg, 1.19 mmol) was added to a suspension of C49 (40.0 mg, 0.119 mmol) in a mixture of tetrahydrofuran (3.0 mL), methanol (1.5 mL), and water (1.5 mL). The reaction mixture was stirred at 25 °C for 16 h and then immediately concentrated under reduced pressure, diluted with water (30 mL), and acidified to approximately pH 5 by the addition of 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2 × 15 mL), and the combined organic layers were concentrated under vacuum and purified by reverse-phase HPLC (column: YMC-Actus Triart C18, 30 × 150 mm, 5 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: 20% to 40% B; flow rate: 35 mL / min) to give 3-(3,5-difluoro-2-methylpyridin-4-yl)-6-fluoro-1-benzothiophene-2-carboxylic acid (8) as a white solid. Yield: 2.78 mg, 8.60 μmol, 7%. LCMS m / z 324.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.34 (s, 1H), 7.66 (dd, J = 8.9, 2.4 Hz, 1H), 7.42 (dd, J = 8.9, 5.2 Hz, 1H), 7.12 (ddd, J = 9.0, 9.0, 2.4 Hz, 1H), 2.34 (dd, J = 1.6, 1.6 Hz, 3H).

[0388] (Example 9) 6-Fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (9)

[0389] [Chemical formula] Step 1. Synthesis of 1,2-dibromo-3,4,6-trifluoro-5-methoxybenzene (C50). 1,2-Dibromo-3,4,5,6-tetrafluorobenzene (25.0 g, 81.2 mmol) was added to a mixture of sodium methoxide in methanol (25% by weight; 37.1 mL, 162 mmol) and methanol (125 mL). After the reaction mixture was stirred at room temperature overnight, it was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum to give C50 as a pale yellow oil. This material was estimated to show quantitative conversion and was carried forward to the next step without further purification. 1 H NMR (400 MHz, methanol-d4) δ 4.06 (t, J = 1.3 Hz, 3H).

[0390] Step 2. Synthesis of 1-bromo-2,4,5-trifluoro-3-methoxybenzene (C51). A solution of n-butyllithium in hexane (2.5 M; 32.5 mL, 81.2 mmol) was added to a -78 °C solution of C50 (26 g, 81 mmol) in diethyl ether (813 mL), and the reaction mixture was stirred at -78 °C for 5 hours. It was then diluted with water and extracted three times with diethyl ether; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered through a prepacked hydrogeneator filter cartridge containing silica gel. The filtrate was concentrated under vacuum using a 30 °C bath to give C51 as a clear yellow oil (20 g, estimated to be quantitative). This material was carried forward to the next step. 1 H NMR (400 MHz, methanol-d4) δ 7.36 (ddd, J = 9.7, 7.8, 6.1 Hz, 1H), 4.04 (t, J = 1.2 Hz, 3H).

[0391] Step 3. Synthesis of (2,4,5-trifluoro-3-methoxyphenyl)boronic acid (C52). C51 (from the preceding step; 20 g, ≤81 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane (52.7 g, 208 mmol), potassium acetate (16.3 g, 166 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.07 g, 8.30 mmol) in 1,4-dioxane (830 mL) were placed in a reaction vessel which was evacuated and charged with nitrogen. This evacuation cycle was repeated twice and then immediately afterwards, the reaction mixture was heated at 100 °C overnight. It was then filtered through a cartridge filled with diatomaceous earth and the cartridge was rinsed with ethyl acetate. The combined filtrates were concentrated in vacuo almost to dryness and then treated with 1 M hydrochloric acid. The resulting mixture was stirred for approximately 10 minutes and it was extracted three times with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give C52 as a black oil (17.1 g). This material was used as is in the next step. LCMS m / z 205.1 [M-H] - .

[0392] Step 4. Synthesis of methyl 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylate (C53). A reaction vessel containing a suspension of P6 (20.0 g, 59.5 mmol), C52 (from step 3; 17.1 g, ≤81 mmol), methanesulfonyl[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) [P(t-Bu)3Pd G3; 3.40 g, 5.94 mmol], cesium fluoride aqueous solution (1 M; 89.3 mL, 89.3 mmol), and tri-tert-butylphosphonium tetrafluoroborate (17.3 g, 59.6 mmol) in tetrahydrofuran was evacuated and charged with nitrogen. This evacuation cycle was repeated twice, and immediately thereafter, the reaction mixture was heated at 70 °C overnight. Then, it was poured into ethyl acetate and washed with water; the aqueous layer was extracted twice with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered through a cartridge packed with diatomaceous earth. The filtrate was concentrated under vacuum and purified twice by silica gel chromatography (gradient: 0% to 10% ethyl acetate in heptane) to obtain C53 as a pale brown oil. Yield: 17.3 g, 46.7 mmol, 78%. LCMS m / z 339.1 [M-OCH3] + . 1 H NMR (400 MHz, chloroform-d) δ 7.58 (dd, J = 8.4, 2.3 Hz, 1H), 7.46 (br dd, J = 8.9, 5.1 Hz, 1H), 7.16 (ddd, J = 8.9, 8.9, 2.3 Hz, 1H), 6.86 (ddd, J = 9.9, 8.1, 6.0 Hz, 1H), 4.09 (t, J = 1.2 Hz, 3H), 3.84 (s, 3H).

[0393] Step 5. Synthesis of 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (9). An aqueous solution of sodium hydroxide (50% by weight; 12.9 mL, 244 mmol) was added to a solution of C53 (43.4 g, 117 mmol) in a mixture of ethanol (360 mL) and 2-methyltetrahydrofuran (239 mL), and immediately thereafter, the reaction mixture was heated at 55 °C for 1 hour. It was then cooled to room temperature, diluted with ethyl acetate, and added to a 1:1 mixture of 1 M hydrochloric acid and saturated aqueous sodium chloride. After the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting material containing a small amount of residual solvent from the concentration was triturated with heptane and then purified by supercritical fluid chromatography {column: Chiral Technologies Chiralpak AD-H, 50.0 × 250 mm, 5 μm; mobile phase: 85:15 carbon dioxide / [methanol containing 0.2% (7 M ammonia in methanol)]; flow rate: 225 mL / min; back pressure: 175 bar} to obtain the ammonium salt of 9 as a white solid. Yield: 32.7 g, 87.6 mmol, 75%. Retention time 2.22 minutes [analysis conditions. Column: Chiral Technologies Chiralpak AD-H, 4.6 × 250 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: methanol containing 0.2% (7 M ammonia in methanol); gradient: 5% B over 1.00 minute, then from 5% B to 100% over 7.50 minutes; flow rate: 3.0 mL / min; back pressure: 120 bar].

[0394] This material was combined with the product of a similar reaction carried out using C53 (22.4 g, 60.5 mmol), dissolved in ethyl acetate, and added to a 1:1 mixture of 1 M hydrochloric acid and saturated aqueous sodium chloride. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue containing a small amount of residual ethyl acetate from the concentration was triturated with heptane to obtain 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (9) as a white solid. Combined yield: 44.67 g, 125.4 mmol, 71%. LCMS m / z 311.0 [M-CO2H] - . 1 H NMR (400 MHz, DMSO-d6) δ 13.59 (br s, 1H), 8.07 (dd, J = 9.2, 2.4 Hz, 1H), 7.56 (br dd, J = 9.0, 5.1 Hz, 1H), 7.44 - 7.32 (m, 2H), 4.02 (br s, 3H).

[0395] Preparation Example of Crystal Form 1, Anhydrous 6-Fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic Acid (Example 9)

[0396]

Chemical Structure

[0397] Step 2. Synthesis of 3-bromo-2,5,6-trifluorophenol (C55). An aqueous solution of hydrogen peroxide (30%, 15.2 kg, 134 mol) was added dropwise to a solution of C54 (22.8 kg, 89.5 mol) in dichloromethane (159 kg) at 30 °C to 40 °C. After the reaction mixture was stirred at 35 °C to 40 °C for 16 h, it was cooled to -10 °C and treated by dropwise addition with a 10% aqueous solution of sodium bisulfite (98 kg, 392 mmol) at a rate that maintained the temperature of the mixture between -15 °C and -10 °C. The resulting mixture was extracted with dichloromethane (2 × 336 kg); the combined organic layers were concentrated under vacuum at 30 °C to give a solution of C55 in dichloromethane (70 kg, assayed as 30.3% C55 by weight). This material was used in the next reaction. Data from a similar reaction carried out using C54: LCMS m / z 224.9 (bromine isotope pattern observed) [M-H] + . 1 H NMR (400 MHz, chloroform-d) δ 6.96 (ddd, J = 9.3, 7.7, 6.1 Hz, 1H).

[0398] Step 3. Synthesis of 1-bromo-2,4,5-trifluoro-3-methoxybenzene (C51). A solution of C55 (≤89.5 mol from the preceding step) in acetone (94.8 kg) was treated with potassium carbonate (38.7 kg, 280 mmol), cooled from -10 °C to 0 °C, and then immediately, iodomethane (19.9 kg, 140 mol) was added dropwise at -10 °C to 0 °C. The reaction mixture was stirred at 25 °C to 30 °C for 16 h and then filtered. The filter cake was washed with heptane (55 kg), and the combined filtrates were repeatedly diluted with heptane and subsequently exchanged into heptane by removing the solvent under reduced pressure to an approximate final weight of 100 kg. This heptane solution was washed with water (64 kg) and with an aqueous sodium sulfate solution (5%, 64 kg), filtered through silica gel (11 kg), and concentrated under vacuum at < 30 °C to give C51 as a solution in heptane (35.2 kg, assayed 51.4% C51 by weight). Yield: 18 kg, 75 mol, 84% over 2 steps. Data from a similar reaction carried out using C55: GCMS m / z 240.0 (bromine isotope pattern observed) [M + . 1 H NMR (400 MHz, methanol-d4) δ 7.37 (ddd, J = 9.7, 7.9, 6.1 Hz, 1H), 4.04 (t, J = 1.2 Hz, 3H).

[0399] Step 4. Synthesis of (2,4,5-trifluoro-3-methoxyphenyl)boronic acid (C52). A solution of (propan-2-yl)magnesium chloride (2 M; 45 L, 90 mol) was added dropwise to a solution of C51 (18.1 kg, 75.1 mol) in tetrahydrofuran (161 kg) at -70 °C to -65 °C. After the reaction mixture was stirred at -70 °C to -65 °C for 2 to 3 hours, trimethyl borate (10.1 kg, 97.2 mol) was added dropwise at a rate that maintained the internal reaction temperature between -70 °C and -65 °C. The reaction mixture was stirred at -50 °C to -40 °C for 1 to 2 hours and then immediately quenched with hydrochloric acid (1 M; 375 kg, 379 mol) at 0 °C to 5 °C. The resulting mixture was extracted with methyl tert-butyl ether (161 kg); the combined organic layers were successively washed with water (90 kg) and an aqueous sodium sulfate solution (10%, 90 kg) and concentrated under vacuum. The solvent was exchanged with tetrahydrofuran (180 to 360 kg), and the resulting mixture was filtered. The filtrate was concentrated under vacuum to a volume of 55 L at < 30 °C and then treated with heptane (90 kg) and concentrated to 55 L in the same manner. Heptane (90 kg) was added again, and the mixture was stirred at 15 °C to 25 °C for 1 to 2 hours, at which point the solid was collected by filtration and slurried with heptane (36 kg). Isolation of the solid obtained by filtration gave C52 as a solid. Yield: 10.2 kg, 49.5 mol, 66%. LCMS m / z 205.1 [M-H] - . 1 H NMR (400 MHz, chloroform-d) δ 7.36 - 7.27 (br ddd, J = 9, 9, 5.4 Hz, 1H), 5.07 - 5.02 (m, 2H), 4.03 (apparent br t, J = 1 Hz, 3H).

[0400] Step 5. Synthesis of 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (9). A mixture of P6 (1.00 g, 2.98 mmol), C52 (735 mg, 3.57 mmol), and potassium fluoride (520 mg, 8.95 mmol) in tetrahydrofuran (11 mL) and water (5 mL) was sparged with nitrogen for 2 minutes, and then immediately, tri-tert-butylphosphonium tetrafluoroborate (99%, 34.0 mg, 0.116 mmol) and allylpalladium(II) chloride dimer (10.7 mg, 29.2 μmol) were added. Sparging was continued for 1 minute, and then the reaction mixture was placed in a heating block at 50 °C with magnetic stirring at 700 rpm. After the reaction mixture was stirred at 50 °C for 1 hour, the organic layer was washed with a solution of sodium chloride in water (23.5 mass%; 3 mL, 14 mmol). It was then treated with a solution of sodium bisulfite (99%, 600 mg, 5.7 mmol) in water (2.4 mL) and stirred at 60 °C for 1 hour; the organic layer was washed by stirring with a solution of sodium chloride in water (23.5 mass%; 3 mL, 14 mmol) at 60 °C for 2 minutes. SiliCycle SiliaMetS® Thiol (Si-Thiol; 300 mg) was added to the organic layer, and the resulting mixture was stirred at 60 °C for 1 hour and then immediately cooled to 20 °C and filtered through a pad of diatomaceous earth. The filter cake was washed with tetrahydrofuran (6 mL), and the combined filtrates were concentrated under vacuum. The resulting material was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL) and treated with an aqueous solution of sodium hydroxide (3.0 M; 1.5 mL, 4.5 mmol). The reaction mixture was heated in a 50 °C heating block with magnetic stirring at 700 rpm for 1 hour, then cooled to 20 °C, acidified by the addition of hydrochloric acid (3.0 M, 2.0 mL, 6.0 mmol), and extracted with methyl tert-butyl ether (5 mL, then 3 mL); the combined organic layers were concentrated under reduced pressure, treated with propan-2-ol (7 mL), and concentrated again. The resulting oil was dissolved in propan-2-ol (4 mL), and water (4 mL) was slowly added to obtain a slurry, which was stirred at 20 °C and 500 rpm for 17 hours. The mixture was cooled in an ice bath, stirred for 10 minutes, and then filtered.The filter cake was washed with an ice-cold mixture of propan-2-ol (1 mL) and water (1 mL) and dried in vacuo at 50 °C to give 9 as an off-white solid, Form 1. Yield: 0.912 g, 99.3 mass% (determined by quantitative NMR), 2.54 mmol, 85%. 1 H NMR (400 MHz, DMSO-d6) δ 13.58 (br s, 1H), 8.06 (dd, J = 9.1, 2.4 Hz, 1H), 7.56 (dd, J = 9.0, 5.2 Hz, 1H), 7.44 - 7.31 (m, 2H), 4.02 (s, 3H). This material was analyzed for powder X-ray diffraction as described herein.

[0401] Amorphous Form 3 of 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid was prepared by heating Form 1 anhydrous 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid to 205 °C and holding at a constant temperature for approximately 2 minutes, then cooling to ambient temperature to obtain a glassy material. This material was analyzed for powder X-ray diffraction as described herein.

[0402] (Example 10) 6-Chloro-3-(2,4,5-trifluoro-3-methylphenyl)-1-benzothiophene-2-carboxylic acid (10)

[0403] [Chemical formula] Step 1. Synthesis of 4,4,5,5-tetramethyl-2-(2,4,5-trifluoro-3-methylphenyl)-1,3,2-dioxaborolane (C56). A mixture of 1-bromo-2,4,5-trifluoro-3-methylbenzene (250 mg, 1.11 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane (564 mg, 2.22 mmol), potassium acetate (218 mg, 2.22 mmol), and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (81.3 mg, 0.111 mmol) in 1,4-dioxane (5.6 mL) was degassed with nitrogen for 2 minutes and then immediately heated at 100 °C for 16 hours. The reaction mixture was concentrated under vacuum, diluted with ethyl acetate (20 mL), filtered, and concentrated under vacuum. C56 was obtained as a pale yellow oil by silica gel chromatography (gradient: 0% to 6% ethyl acetate in petroleum ether). Yield: 167 mg, 0.614 mmol, 55%. 1 1H NMR (400 MHz, chloroform-d) δ 7.33 (ddd, J = 9.7, 9.7, 5.2 Hz, 1H), 2.20 (dd, J = 1.9, 1.9 Hz, 3H), 1.35 (s, 12H).

[0404] Step 2. Synthesis of ethyl 6-chloro-3-(2,4,5-trifluoromethylphenyl)-1-benzothiophene-2-carboxylate (C57). A suspension of P7 (200 mg, 0.626 mmol), C56 (167 mg, 0.614 mmol), potassium fluoride (109 mg, 1.88 mmol), and tris(dibenzylideneacetone)dipalladium(0) (57.3 mg, 62.6 μmol) in a mixture of tetrahydrofuran (6 mL) and water (1.5 mL) was degassed with nitrogen for 1 minute and then immediately a solution of tri-tert-butylphosphine in toluene (1 M; 62.6 μL, 62.6 μmol) was added. The reaction mixture was heated at 60 °C for 16 hours, then concentrated under vacuum and purified using silica gel chromatography (eluent: petroleum ether) to obtain C57 as a yellow oil. Yield: 221 mg, 0.574 mmol, 92%. LCMS m / z 385.0 (chlorine isotope pattern observed) [M+H] + .

[0405] Step 3. Synthesis of 6-chloro-3-(2,4,5-trifluoro-3-methylphenyl)-1-benzothiophene-2-carboxylic acid (10). Lithium hydroxide monohydrate (241 mg, 5.74 mmol) was added to a solution of C57 (221 mg, 0.574 mmol) in a mixture of tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL), and the reaction mixture was stirred at 22 °C for 16 hours. It was then concentrated under vacuum, diluted with water (20 mL), acidified to approximately pH 5 by the addition of hydrochloric acid; filtered to obtain a solid, which was subjected to reverse-phase HPLC (column: YMC-Actus Triart C18, 50×250 mm, 7 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: from 43% to 83% B; flow rate: 60 mL / min) to obtain 6-chloro-3-(2,4,5-trifluoro-3-methylphenyl)-1-benzothiophene-2-carboxylic acid (10) as a white solid. Yield: 109 mg, 0.306 mmol, 53%. LCMS m / z 310.8 [M-COOH] - . 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 1.7 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.49 (dd, component of ABX system, J = 8.7, 1.8 Hz, 1H), 7.46 (d, half of AB quartet, J = 8.8 Hz, 1H), 2.27 (br s, 3H).

[0406] (Example 11) 5,6-Difluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (11)

[0407] [Chemical formula] Step 1. Synthesis of 3-bromo-5,6-difluoro-1-benzothiophene (C58). A solution of 5,6-difluoro-1-benzothiophene (R. Acharya et al.; see WO2016100184 A1, June 23, 2016; 1.60 g, 9.40 mmol) in acetic acid (47 mL) was treated portionwise with N-bromosuccinimide (2.01 g, 11.3 mmol). The reaction mixture was stirred at 80 °C for 16 h, and then immediately diluted with water and extracted with petroleum ether (3 × 30 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. C58 was obtained as a white solid by silica gel chromatography (eluent: petroleum ether). Yield: 1.26 g, 5.06 mmol, 54%. 1 1H NMR (400 MHz, chloroform-d) δ 7.64 (dd, J = 9.5, 6.9 Hz, 1H), 7.60 (dd, J = 10.3, 7.4 Hz, 1H), 7.46 (s, 1H).

[0408] Step 2. Synthesis of 5,6-difluoro-3-phenyl-1-benzothiophene (C59). A suspension of C58 (640 mg, 2.57 mmol) and phenylboronic acid (313 mg, 2.57 mmol) in a mixture of 1,4-dioxane (20 mL) and water (2 mL) was added with cesium carbonate (2.51 g, 7.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (297 mg, 0.257 mmol). The reaction mixture was stirred at 85 °C for 16 h, then filtered. The filtrate was concentrated under vacuum and purified by silica gel chromatography (eluent: petroleum ether) to afford C59 as a gummy substance. Yield: 561 mg, 2.28 mmol, 89%. 1 H NMR (400 MHz, chloroform-d) δ 7.70 - 7.62 (m, 2H), 7.56 - 7.47 (m, 4H), 7.46 - 7.40 (m, 2H).

[0409] Step 3. Synthesis of 2-bromo-5,6-difluoro-3-phenyl-1-benzothiophene (C60). A solution of N-bromosuccinimide (425 mg, 2.39 mmol) in ethanol (1 mL) was added dropwise to a solution of C59 (560 mg, 2.27 mmol) in a mixture of dichloromethane (20 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 25 °C for 16 h, then at 35 °C for 3 h, and then immediately diluted with water and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 × 15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. C60 was obtained as a colorless oil by silica gel chromatography (eluent: petroleum ether). Yield: 260 mg, 0.800 mmol, 35%. 1 H NMR (400 MHz, chloroform-d) δ 7.59 - 7.41 (m, 6H), 7.32 (dd, J = 10.8, 7.5 Hz, 1H).

[0410] Step 4. Synthesis of methyl 5,6-difluoro-3-phenyl-1-benzothiophene-2-carboxylate (C61). To a solution of C60 (260 mg, 0.800 mmol) and N,N-diisopropylethylamine (0.221 mL, 1.27 mmol) in methanol (5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (65.3 mg, 80.0 μmol), and immediately thereafter, the atmosphere was changed to carbon monoxide. The reaction mixture was stirred at 70 °C for 16 h, at which point analysis by thin layer chromatography indicated that the starting material had not been consumed. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a material which was then subjected to a second reaction: the residue was diluted with methanol (15 mL), treated with N,N-diisopropylethylamine (0.221 mL, 1.27 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (65.3 mg, 80.0 μmol), and placed under an atmosphere of carbon monoxide. This reaction mixture was stirred at 80 °C for 3 h, filtered; the filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (eluent: petroleum ether) to give C61 as a colorless rubbery solid. Yield: 52.0 mg, 0.171 mmol, 21%. 1 H NMR (400 MHz, chloroform-d) δ 7.65 (dd, J = 9.5, 7.0 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.39 - 7.34 (m, 2H), 7.29 (dd, J = 10.7, 7.6 Hz, 1H), 3.78 (s, 3H)

[0411] Step 5. Synthesis of 5,6-difluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (11). A solution of C61 (52.0 mg, 0.171 mmol) in a mixture of methanol (1 mL), tetrahydrofuran (1 mL), and water (0.5 mL) was added to lithium hydroxide monohydrate (71.7 mg, 1.71 mmol), and immediately thereafter, the reaction mixture was stirred at 20 °C for 4 h. Water was added and the resulting mixture was washed with petroleum ether (2 × 8 mL); then the aqueous layer was adjusted to approximately pH 3 by the addition of hydrochloric acid (1 mL). This aqueous mixture was extracted with ethyl acetate (3 × 8 mL), the combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by reverse-phase HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: 13% to 43% B; flow rate: 30 mL / min) gave 5,6-difluoro-3-phenyl-1-benzothiophene-2-carboxylic acid (11) as a white solid. Yield: 26.5 mg, 91.3 μmol, 53%. LCMS m / z 291.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.86 (dd, J = 10.2, 7.2 Hz, 1H), 7.51 - 7.36 (m, 5H), 7.24 (dd, J = 11.2, 7.6 Hz, 1H).

[0412] (Example 12) Ammonium 6-chloro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylate (12)

[0413]

Chemical formula

[0414] Step 2. Synthesis of methyl 6-chloro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylate (C63). A suspension of C62 (200 mg, 0.694 mmol), P8 (200 mg, 0.567 mmol), and potassium carbonate (235 mg, 1.70 mmol) in 1,4-dioxane (2 mL) was degassed with nitrogen for 1 minute and then immediately [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41.5 mg, 56.7 μmol) was added. The reaction mixture was stirred at 80 °C for 16 hours, then filtered; the filtrate was concentrated under vacuum and purified by silica gel chromatography (gradient: 0% to 5% ethyl acetate in petroleum ether) to afford C63 as a colorless gummy substance. Yield: 160 mg, 0.414 mmol, 73%. 1 H NMR (400 MHz, chloroform-d) δ 7.89 (br d, J = 1.9 Hz, 1H), 7.42 (br d, half of the AB quartet, J = 8.7 Hz, 1H), 7.37 (dd, component of the ABX system, J = 8.7, 1.8 Hz, 1H), 6.85 (ddd, J = 9.9, 8.1, 6.0 Hz, 1H), 4.09 (t, J = 1.2 Hz, 3H), 3.84 (s, 3H).

[0415] Step 3. Synthesis of ammonium 6-chloro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylate (12). To a solution of C63 (160 mg, 0.414 mmol) in a mixture of methanol (2.0 mL) and tetrahydrofuran (2.0 mL) was added a solution of lithium hydroxide monohydrate (174 mg, 4.15 mmol) in water (1.0 mL). After the reaction mixture was stirred at room temperature for 16 h, it was diluted with water (5 mL) and adjusted to pH 4. The resulting mixture was extracted with ethyl acetate (3 × 5 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under vacuum, and purified by reverse-phase HPLC (column: YMC-Actus Triart C18, 30 × 150 mm, 7 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: from 3% to 43% B; flow rate: 25 mL / min). Ammonium 6-chloro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylate (12) was isolated as a white solid. Yield: 71.4 mg, 0.183 mmol, 44%. LCMS m / z 370.8 (chlorine isotope pattern observed) [M-H] - . 1 1H NMR (400 MHz, DMSO-d6) δ 8.12 (br s, 1H), 7.37 (dd, component of the ABX system, J = 8.7, 1.8 Hz, 1H), 7.34 (d, half of AB quartet, J = 8.8 Hz, 1H), 7.25 (br s, approximately 3H), 7.22 (ddd, J = 10.8, 8.5, 6.1 Hz, 1H), 4.00 (br s, 3H).

[0416] (Example 13) 6-Chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (13)

[0417] [Chemical formula] Step 1. Synthesis of 2-(2,4-difluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (C64). A mixture of 1-bromo-2,4-difluoro-3-methoxybenzene (330 mg, 1.48 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (752 mg, 2.96 mmol), and potassium acetate (290 mg, 2.95 mmol) in 1,4-dioxane (7 mL) was degassed with nitrogen for 1 minute and then immediately [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (108 mg, 0.148 mmol) was added and the reaction mixture was heated at 95 °C for 16 hours. It was then filtered; the filtrate was concentrated under vacuum and purified by silica gel chromatography (eluent: petroleum ether) to give C64 as a yellow rubbery solid. Yield: 370 mg, 1.37 mmol, 93%. 1 H NMR (400 MHz, chloroform-d) δ 7.37 (ddd, J = 8.5, 6.3, 6.3 Hz, 1H), 6.88 (ddd, J = 10.1, 8.5, 1.6 Hz, 1H), 3.97 (s, 3H), 1.35 (s, 12H).

[0418] Step 2. Synthesis of ethyl 6-chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylate (C65). A suspension of C64 (370 mg, 1.37 mmol), P7 (390 mg, 1.22 mmol), and potassium fluoride (193 mg, 3.32 mmol) in a mixture of tetrahydrofuran (10 mL) and water (1 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (50.8 mg, 55.5 μmol), followed by a solution of tri-tert-butylphosphine in toluene (1 M; 0.111 mL, 0.111 mmol). The reaction mixture was heated at 65 °C for 16 h, then filtered, concentrated under vacuum, and purified by silica gel chromatography (gradient: 0% to 2% ethyl acetate in petroleum ether) to give C65 as a gummy substance. Yield: 240 mg, 0.627 mmol, 51%. 1 H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 1.8 Hz, 1H), 7.41 (br d, component of an AB quartet, J = 8.7 Hz, 1H), 7.34 (dd, component of an ABX system, J = 8.7, 1.9 Hz, 1H), 7.03 (ddd, component of an ABXY system, J = 10.1, 8.7, 1.6 Hz, 1H), 6.95 (ddd, component of an ABXY system, J = 8.7, 7.1, 5.9 Hz, 1H), 4.32 - 4.21 (m, 2H), 4.05 (br s, 3H), 1.25 (t, J = 7.1 Hz, 3H).

[0419] Step 3. Synthesis of 6-chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (13). A solution of lithium hydroxide monohydrate (263 mg, 6.27 mmol) in water (1 mL) was added to a solution of C65 (240 mg, 0.627 mmol) in a mixture of methanol (2.5 mL) and tetrahydrofuran (2.5 mL). The reaction mixture was stirred at 25 °C for 2.5 h, then adjusted to approximately pH 3 and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride (2 × 15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was treated with acetonitrile and water and then lyophilized to give 6-chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (13) as a green solid. Yield: 160 mg, 0.451 mmol, 72%. LCMS m / z 372.0 (chlorine isotope pattern observed) [M+NH4 + . 1 H NMR (400 MHz, methanol-d4) δ 8.05 (br d, J = 1.6 Hz, 1H), 7.44 (br d, half of an AB quartet, J = 8.7 Hz, 1H), 7.41 (dd, component of an ABX system, J = 8.8, 1.8 Hz, 1H), 7.12 (ddd, component of an ABXY system, J = 10.4, 8.7, 1.6 Hz, 1H), 7.05 (ddd, component of an ABXY system, J = 8.7, 7.2, 5.8 Hz, 1H), 4.00 (br s, 3H).

[0420] (Examples 14, 15, and 16) 3-(6-Chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (14), 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-1 (15), and 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2 (16)

[0421]

Chem.

[0422] Step 2. Synthesis of methyl 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylate (C67). To a mixture of P1 (1.80 g, 6.23 mmol), C66 (3.03 g, 9.95 mmol), and tripotassium phosphate (3.96 g, 18.7 mmol) in toluene (30 mL) was added tris(dibenzylideneacetone)dipalladium(0), chloroform complex (322 mg, 0.311 mmol) and 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (SPhos; 383 mg, 0.933 mmol), and immediately thereafter, the reaction mixture was stirred at 100 °C for 2 h. It was then concentrated under vacuum and purified by silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) to afford C67 as a colorless oil (1.80 g). 1 1H NMR analysis showed that the product contained aliphatic impurities; it was carried on as such to the next step. 1 1H NMR (400 MHz, chloroform-d), only peaks of the product: δ 7.59 (dd, J = 8.4, 2.3 Hz, 1H), 7.36 (dd, J = 9.0, 5.0 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.03 (br s, 3H), 3.83 (s, 3H).

[0423] Step 3. Synthesis of 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (14). To a solution of C67 (from the preceding step; 1.80 g, <4.65 mmol) in a mixture of water (4 mL), tetrahydrofuran (6 mL), and methanol (8 mL) was added lithium hydroxide monohydrate (976 mg, 23.3 mmol). The reaction mixture was stirred at 20 °C for 16 h, and immediately thereafter, LCMS analysis showed conversion to 14: LCMS m / z 370.9 [M-H] -After concentrating the reaction mixture under vacuum, it was diluted with water (50 mL), acidified to approximately pH 4 by the addition of 1 M hydrochloric acid, and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were concentrated under reduced pressure and purified by reverse-phase HPLC (column: YMC-Actus Triart C18, 50 × 250 mm, 7 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: from 7% to 47% B; flow rate: 60 mL / min). The fractions containing 14 were combined, concentrated under vacuum to remove acetonitrile, and then acidified to approximately pH 4 by the addition of 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2 × 40 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (14) as a white solid. Yield: 1.01 g, 2.71 mmol, 43% over 2 steps. LCMS m / z 373.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.38 (dd, J = 8.9, 5.1 Hz, 1H), 7.31 (dd, J = 10.7, 2.1 Hz, 1H), 7.23 (ddd, J = 9.0, 8.9, 2.4 Hz, 1H), 4.00 (t, J = 0.9 Hz, 3H).

[0424] Step 4. Isolation of 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-1 (15) and 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2 (16). Using supercritical fluid chromatography (column: Chiral Technologies Chiralpak AD-H, 30×250 mm, 5 μm; mobile phase: 4:1 carbon dioxide / methanol; back pressure: 100 bar; flow rate: 80 mL / min), the product 14 (1.00 g, 2.68 mmol) from the previous step was separated into its constituent atropisomers. The first eluting atropisomer, an off-white solid, was designated as 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-1 (15), and the second eluting atropisomer, a white solid, was designated as 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2 (16). 15 - Yield: 0.45 g, 1.2 mmol, 45% by separation. LCMS m / z 373.2 (Chlorine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.66 (br s, 1H), 8.08 (dd, J = 9.1, 2.4 Hz, 1H), 7.65 (dd, J = 11.0, 2.0 Hz, 1H), 7.46 (dd, component of ABX system, J = 9.0, 5.2 Hz, 1H), 7.35 (ddd, component of ABXY system, J = 9.0, 9.0, 2.4 Hz, 1H), 3.97 (s, 3H). Retention time: 1.16 min (analysis conditions. Column: Chiral Technologies Chiralpak AD-H, 4.6×100 mm, 3 μm; mobile phase A: carbon dioxide; mobile phase B: methanol; gradient: B 5% over 0.25 min, then from B 5% to 70% over 2.25 min; back pressure: 100 bar; flow rate: 2.5 mL / min). 16 - Yield: 0.49 g, 1.3 mmol, 49% by separation. LCMS m / z 373.3 (Chlorine isotope pattern observed) [M+H] + .1 1H NMR (400 MHz, DMSO-d6) δ 13.66 (br s, 1H), 8.08 (dd, J = 9.2, 2.4 Hz, 1H), 7.65 (dd, J = 11.0, 2.0 Hz, 1H), 7.46 (dd, component of ABX system, J = 8.9, 5.2 Hz, 1H), 7.35 (ddd, component of ABXY system, J = 9.0, 9.0, 2.5 Hz, 1H), 3.97 (s, 3H). Retention time: 1.34 minutes (the same analysis conditions as those used for 15).

[0425] (Example 17) 6-Fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzofuran-2-carboxylic acid (17)

[0426]

Chemical formula

[0427] Step 2. Synthesis of 6-Fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzofuran-2-carboxylic acid (17). A solution of lithium hydroxide monohydrate (148 mg, 3.53 mmol) in water (1 mL) was added to a solution of C68 (130 mg, 0.353 mmol) in a mixture of methanol (2 mL) and tetrahydrofuran (2 mL). After the reaction mixture was stirred at room temperature for 4 hours, it was diluted with water (5 mL) and washed with petroleum ether (2 × 8 mL). The aqueous layer was acidified to pH 4 by the addition of hydrochloric acid (1 M; 3 mL) and extracted with ethyl acetate (3 × 8 mL); the combined ethyl acetate layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum. 6-Fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzofuran-2-carboxylic acid (17) was obtained as a white solid by reverse phase HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: from 8% to 38% B; flow rate: 30 mL / min). Yield: 48.4 mg, 0.142 mol, 40%. LCMS m / z 338.9 [M-H] - . 1 1H NMR (400 MHz, methanol-d4) δ 7.45 - 7.37 (m, 2H), 7.19 - 7.07 (m, 2H), 4.05 (br s, 3H).

[0428] (Example 18) 6-Chloro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzofuran-2-carboxylic acid (18)

[0429] [Chemical formula] Step 1. Synthesis of ethyl 6-chloro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzofuran-2-carboxylate (C69). A suspension of P10 (73.0 mg, 0.208 mmol), C62 (50 mg, 0.17 mmol), and potassium carbonate (72.0 mg, 0.521 mmol) in 1,4-dioxane (1 mL) was degassed with nitrogen for 1 minute and then immediately [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12.7 mg, 17.4 μmol) was added. The reaction mixture was stirred at 80 °C for 16 hours, then filtered; the filtrate was concentrated under vacuum and purified using silica gel chromatography (gradient: 0% to 7% ethyl acetate in petroleum ether) to obtain C69 as a colorless rubbery substance. Yield: 39.6 mg, 0.103 mmol, 61%. 1 H NMR (400 MHz, chloroform-d) δ 7.65 (d, J = 1.7 Hz, 1H), 7.40 (br d, half of an AB quartet, J = 8.7 Hz, 1H), 7.33 (dd, component of an ABX system, J = 8.5, 1.7 Hz, 1H), 6.99 (ddd, J = 10.0, 8.1, 6.0 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.10 (t, J = 1.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0430] Step 2. Synthesis of 6-chloro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzofuran-2-carboxylic acid (18). A solution of C69 (84.0 mg, 0.218 mmol) in a mixture of methanol (1 mL) and tetrahydrofuran (1 mL) was treated with a solution of lithium hydroxide monohydrate (91.6 mg, 2.18 mmol) in water (0.5 mL). The reaction mixture was stirred at room temperature for 1.5 h and then immediately diluted with water (5 mL) and washed with petroleum ether (4 mL). The aqueous layer was acidified to pH 4 by the addition of hydrochloric acid (1 M; 3 mL) and extracted with ethyl acetate (3 × 5 mL); the combined ethyl acetate layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase HPLC (column: YMC-Actus Triart C18, 30 × 150 mm, 7 μm; mobile phase A: water containing 0.05% ammonium hydroxide (v / v); mobile phase B: acetonitrile; gradient: 25% to 50% B; flow rate: 25 mL / min) followed by supercritical fluid chromatography [column: Chiral Technologies Chiralpak AD, 30 × 250 mm, 10 μm; mobile phase: 3:1 carbon dioxide / (2-propanol containing 0.1% ammonium hydroxide); flow rate: 70 mL / min] gave 6-chloro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzofuran-2-carboxylic acid (18) as a white solid. Yield: 9.71 mg, 27.2 μmol, 12%. LCMS m / z 356.9 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.72 (d, J = 1.8 Hz, 1H), 7.45 (br d, half of an AB quartet, J = 8.5 Hz, 1H), 7.35 (dd, component of an ABX system, J = 8.5, 1.8 Hz, 1H), 7.17 (ddd, J = 10.6, 8.3, 6.0 Hz, 1H), 4.06 (br s, 3H).

[0431] (Example 19) 6-Fluoro-3-(2,3,4-trifluorophenyl)-1-benzothiophene-2-carboxylic acid (19)

[0432]

Chem.

[0433] Step 2. Synthesis of 6-fluoro-3-(2,3,4-trifluorophenyl)-1-benzothiophene-2-carboxylic acid (19). A solution of lithium hydroxide (24.7 mg, 1.03 mmol) in water (1 mL) was added to a solution of C70 (70 mg, 0.21 mmol) in a mixture of methanol (5 mL) and tetrahydrofuran (1 mL). The reaction mixture was stirred at 25 °C for 16 h, then concentrated under vacuum, diluted with water (10 mL), and washed with dichloromethane (2 × 10 mL). The aqueous layer was adjusted to pH 2 and then immediately extracted with ethyl acetate (3 × 50 mL). The combined ethyl acetate layers were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6-fluoro-3-(2,3,4-trifluorophenyl)-1-benzothiophene-2-carboxylic acid (19) as a solid. Yield: 11.5 mg, 35.2 μmol, 17%. LCMS m / z 327.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (br d, J = 9.1 Hz, 1H), 7.52 - 7.37 (m, 2H), 7.37 - 7.23 (m, 2H).

[0434] (Example 20) 6-chloro-3-(4-chloro-3-fluorophenyl)-1-benzothiophene-2-carboxylic acid (20)

[0435]

Chemical formula

[0436] Step 2. Synthesis of ethyl 6-chloro-3-(4-chloro-3-fluorophenyl)-1-benzothiophene-2-carboxylate (C72). To a solution of C71 (120 mg, 0.418 mmol) in N,N-dimethylformamide (2 mL) was added ethyl sulfanylacetate (75 mg, 0.62 mmol) and potassium carbonate (173 mg, 1.25 mmol). The reaction mixture was heated at 100 °C for 16 h and then immediately diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo; C72 was obtained as a white solid by silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether), followed by preparative thin layer chromatography (eluent: 20:1 petroleum ether / ethyl acetate). This material was carried forward as such to the next step. Yield: 15 mg, 41 μmol, 10%. LCMS m / z 369.0 (dichloro isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.89 (d, J = 1.9 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.40 (d, half of AB quartet, J = 8.7 Hz, 1H), 7.34 (dd, component of ABX system, J = 8.7, 1.8 Hz, 1H), 7.25 - 7.18 (m, 2H), 4.34 - 4.17 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0437] Step 3. Synthesis of 6-chloro-3-(4-chloro-3-fluorophenyl)-1-benzothiophene-2-carboxylic acid (20). A solution of lithium hydroxide (10 mg, 0.42 mmol) in water (1.0 mL) was added to a solution of C72 (15 mg, 41 μmol) in a mixture of tetrahydrofuran (1.0 mL) and methanol (1.0 mL), and the reaction mixture was stirred at 20 °C for 16 h. After removing the volatile substances by concentration under vacuum, the residue was purified by reverse-phase HPLC (column: Nouryon Kromasil® C18, 21.2×100 mm, 5 μm; mobile phase A: water containing 0.1% formic acid; mobile phase B: acetonitrile; gradient: from 60% to 70% B) to give 6-chloro-3-(4-chloro-3-fluorophenyl)-1-benzothiophene-2-carboxylic acid (20) as a white solid. Yield: 3.2 mg, 9.4 μmol, 23%. LCMS m / z 294.9 (dichloro isotope pattern observed) [M-COOH] - . 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (br s, 1H), 7.74 - 7.66 (m, 1H), 7.52 - 7.32 (m, 4H).

[0438] (Example 21) 3-(2,6-Difluoro-4-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (21)

[0439]

Chemical Structure

[0440] Step 2. Synthesis of methyl 3-(2,6-difluoro-4-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylate (C74). A solution of P1 in 1,4-dioxane (0.1 M; 1.0 mL, 0.1 mmol) was added to C73 (from the preceding step; ≤0.20 mmol). Then water (0.2 mL) and potassium fluoride (174 mg, 2.99 mmol) were added, followed by chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) [P(t-Bu)3Pd G2; 2.6 mg, 5.1 μmol). The reaction vial was capped and the vial was shaken at 80 °C for 16 h. Immediately thereafter, the volatiles were removed using a Speedvac concentrator. The residue was diluted with water (1 mL) and extracted with ethyl acetate (3 × 1 mL); the combined organic layers were evaporated using a Speedvac concentrator to afford C74, which was carried forward directly to the next step.

[0441] Step 3. Synthesis of 3-(2,6-difluoro-4-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (21). Tetrahydrofuran (1 mL) and lithium hydroxide aqueous solution (1 M; 1.0 mL, 1.0 mmol) were added to C74 (from the preceding step; ≤0.20 mmol), followed by methanol (0.4 mL). Immediately thereafter, the cap of the reaction vial was tightened, and the vial was shaken at 30 °C for 2 hours. After evaporation using a Speedvac concentrator, the residue was purified by reverse-phase HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm; mobile phase A: water containing ammonium hydroxide (pH 10); mobile phase B: acetonitrile; gradient: from 12% to 52% B; flow rate: 30 mL / min) to obtain 3-(2,6-difluoro-4-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid (21). Yield: 8.4 mg, 25 μmol, 25% over 2 steps. LCMS m / z 339 [M+H] + . Retention time: 3.16 min (analysis conditions. Column: Waters XBridge C18, 2.1 × 50 mm, 5 μm; mobile phase A: water containing 0.0375% trifluoroacetic acid; mobile phase B: acetonitrile containing 0.01875% trifluoroacetic acid; gradient: 10% B over 0.50 min; from 10% to 100% B over 3.5 min; flow rate: 0.8 mL / min.

[0442] (Example 22) 6-Fluoro-3-(2,4,5-trifluoro-3-hydroxyphenyl)-1-benzothiophene-2-carboxylic acid (22)

[0443] [Chemical formula] A solution of boron tribromide in dichloromethane (1 M; 4.21 mL, 4.21 mmol) was slowly added to a 0 °C solution of 9 (0.500 g, 1.40 mmol) in dichloromethane (30 mL). The reaction mixture was then warmed to room temperature and stirred at that temperature for 16 h, and then immediately cooled to 0 °C and a solution of boron tribromide in dichloromethane (1 M, 2.81 mmol, 2.81 mL) was added again. The reaction mixture was warmed to room temperature; after stirring it at room temperature for an additional 16 h, it was poured into a mixture of chilled water (200 mL) and dichloromethane (100 mL). The resulting solid was collected by filtration, washed with dichloromethane (3 × 15 mL), then dissolved in a mixture of dichloromethane and methanol (9:1, 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and methanol (9:1, 10 mL) and subjected to silica gel chromatography [gradient: 5% to 15% in dichloromethane (5% acetic acid in methanol)] to afford 6-fluoro-3-(2,4,5-trifluoro-3-hydroxyphenyl)-1-benzothiophene-2-carboxylic acid (22) as a white solid. Yield: 217 mg, 0.634 mmol, 45%. LCMS m / z 343.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.75 (dd, J = 8.8, 2.4 Hz, 1H), 7.49 (dd, J = 9.0, 5.1 Hz, 1H), 7.23 (ddd, J = 9.0, 9.0, 2.4 Hz, 1H), 6.73 (ddd, J = 10.5, 8.1, 6.0 Hz, 1H).

[0444] (Example 23) 6-Fluoro-3-(2,4,5-trifluorophenyl)-1-benzothiophene-2-carboxylic acid (23)

[0445]

Chem.

Claims

1. A compound of formula I 【Chemical 1】 [wherein Z is S, A is 【Chemical Formula 3】 and X １ is CR １１ and R １ , R ３ and R ４ are each independently selected from H and fluoro, R ２ is fluoro or chloro, and R ５ 、 R ６ 、 R ７ and R １１ are each independently selected from H, halo, hydroxyl, amino, cyano, (C １ ~C ４ )alkyl, (C ３ ~C ６ )cycloalkyl, (C １ ~C ４ )alkoxy, (C １ ~C ４ )fluoroalkyl, (C ３ ~C ６ )fluorocycloalkyl, or (C １ ~C ４ )fluoroalkoxy, R １０ is H, fluoro, chloro, cyano, or (C １ ~C ４ )alkyl, A is [Chemical Formula 3] and X １ is CR １１ when, R １ R ２ R ３ R ４ R ５ R ６ R ７ R １０ and R １１ at least one of is a halo, and R １ R ２ R ３ R ４ R ５ R ６ R ７ R １０ and R １１ at least one of the others is other than H] or a pharmaceutically acceptable salt of said compound.

2. R １ 、 R ３ and R ４ are each H, and R ２ is fluoro, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ５ is fluoro, chloro, cyano or (C １ ~C ４ ) alkyl, and R １０ is H, fluoro or chloro, the compound or a pharmaceutically acceptable salt thereof according to claim 2.

4. R ６ and R ７ are each independently selected from H, fluoro, chloro, cyano, (C １ ~C ４ )alkyl, and (C １ ~C ４ )alkoxy, the compound according to claim 3 or a pharmaceutically acceptable salt thereof.

5. R １１ is H, fluoro, chloro, cyano, (C １ ~C ４ )alkyl, or (C １ ~C ４ )alkoxy, the compound according to claim 4 or a pharmaceutically acceptable salt thereof.

6. 6-Fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 6-Fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 6-Chloro-3-(2,4,5-trifluoro-3-methylphenyl)-1-benzothiophene-2-carboxylic acid; 6-Chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 3-(6-Chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 3-(6-Chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2; 3-(3-Chloro-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 3-(4-Chloro-2,6-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 6-Chloro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 6-Chloro-3-(3-ethyl-2,4,5-trifluorophenyl)-1-benzothiophene-2-carboxylic acid; or ammonium 3-(3-ethyl-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylate; or a pharmaceutically acceptable salt thereof.

7. 6-Fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; or 3-(6-Chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2; or a pharmaceutically acceptable salt thereof.

8. 【Fig. 8】 or a pharmaceutically acceptable salt thereof.

9. 【Fig. 9】 or a compound.

10. 【Fig. 10】 ； or a compound or a pharmaceutically acceptable salt of said compound.

11. 【Chemical Formula 11】 or a compound.

12. A pharmaceutical composition for treating fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with hepatic fibrosis, non-alcoholic steatohepatitis with cirrhosis, non-alcoholic steatohepatitis with cirrhosis or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma, comprising the compound according to claim 1 or a pharmaceutically acceptable salt of said compound.

13. The pharmaceutical composition according to claim 12 for treating non-alcoholic steatohepatitis.

14. A pharmaceutical composition for treating heart failure, cardiovascular death, congestive heart failure, heart failure with New York Heart Association Class I-IV symptoms, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with mid-range ejection fraction (HF-mrEF), cardiovascular death, heart failure in patients with type II true diabetes, coronary artery disease, unstable angina, peripheral artery disease, peripheral vascular disease, renal vascular disease, pulmonary hypertension, vasculitis, acute coronary syndrome, or reducing the risk of hospitalization thereby, and modifying cardiovascular risk, comprising the compound according to claim 1 or a pharmaceutically acceptable salt of said compound.

15. The pharmaceutical composition according to claim 14 for treating heart failure.

16. A pharmaceutical composition for treating type I diabetes, type II true diabetes, idiopathic type I diabetes (type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), young-onset non-typeable diabetes (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary artery disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial lipemia, impaired glucose tolerance (IGT) state, fasting plasma glucose abnormality state, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal insufficiency, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, glucose metabolism disorder, skin and connective tissue disorders, foot ulcers and ulcerative colitis, endothelial dysfunction and vascular compliance abnormalities, high apoB lipoproteinemia, renal disease, end-stage renal disease, chronic renal disease at risk of progression, and maple syrup urine disease, comprising the compound according to claim 1 or a pharmaceutically acceptable salt of said compound.

17. The pharmaceutical composition according to claim 16, which is used for treating kidney diseases.

18. The pharmaceutical composition containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof for treating hepatocellular carcinoma, clear cell renal cell carcinoma of the kidney, squamous cell carcinoma of the head and neck, colorectal adenocarcinoma, mesothelioma, gastric adenocarcinoma, adrenocortical carcinoma, papillary renal cell carcinoma, carcinoma in the neck and endocervical canal, urothelial carcinoma of the bladder, and lung adenocarcinoma.

19. The pharmaceutical composition according to claim 18, which is used for treating hepatocellular carcinoma.

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier, vehicle or excipient.

21. A first compound which is the compound according to claim 1 or a pharmaceutically acceptable salt of said compound; an antidiabetic agent; a second compound which is an agent for treating non-alcoholic steatohepatitis, an agent for treating non-alcoholic fatty liver disease, an agent for treating kidney diseases or an agent for treating heart failure, and a pharmaceutical carrier, vehicle or excipient A pharmaceutical combination composition comprising a therapeutically effective amount of a composition containing the above.

22. The pharmaceutical combination composition according to claim 21, wherein the second compound is 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid; [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid; 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid; (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; or 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical combination composition according to claim 21, wherein the non-alcoholic steatohepatitis treatment agent or non-alcoholic fatty liver disease treatment agent is an ACC inhibitor, a GLP1 receptor agonist, a DGAT-2 inhibitor, an FXR agonist, metformin, or an incretin receptor modulator.

24. The pharmaceutical combination composition according to claim 21, wherein the anti-diabetic agent is an SGLT-2 inhibitor, metformin, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist.

25. The pharmaceutical combination composition according to claim 21, wherein the anti-diabetic agent is metformin, sitagliptin, or ertugliflozin.

26. The pharmaceutical combination composition according to claim 21, wherein the anti-heart failure agent is an ACE inhibitor, an SGLT-2 inhibitor, an angiotensin receptor blocker, an angiotensin receptor-neprilysin inhibitor, a beta-adrenergic receptor blocker, a calcium channel blocker, or a vasodilator.

27. The pharmaceutical combination composition according to claim 21, wherein the anti-heart failure agent is valsartan, sacubitril, dapagliflozin, empagliflozin, canagliflozin, or ertugliflozin.

28. Structure: 【Chemical Formula 12】 A crystal of a compound having the structure: or a pharmaceutically acceptable salt thereof, having a powder X-ray diffraction pattern including 2 theta values of 7.6 ± 0.2, 14.6 ± 0.2, and 27.9 ± 0.2 (CuKα radiation, wavelength of 1.54056 Å).

29. Structure: 【Chemical 13】 An amorphous of a compound having the structure:

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