KHK inhibitor

Abstract

A compound of the formula: TIFF2024512646001064.tif51128 where the variable substituents are defined herein.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 167,331, filed Mar. 29, 2021, the entire content of which is hereby incorporated by reference for all purposes.

Background Art

[0002] Excessive fructose is associated with several comorbidities related to diabetes and metabolic syndrome, including insulin resistance, the onset of hyperglycemia, and non - alcoholic fatty liver disease (NAFLD), non - alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), liver disease, liver fibrosis, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, hypertension, fibrosis, steatosis, cirrhosis, cardiometabolic syndrome, insulin resistance, cardiovascular disease, heart failure, type 1 and type 2 diabetes mellitus, chronic kidney disease (CKD), diabetic kidney disease (DKD), kidney disease, kidney fibrosis, renal insufficiency, irritable bowel syndrome disease (IBD), ulcerative colitis, Crohn's disease, hyperuricemia, gout, diseases driven by inflammasome activation, arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, or cancer (Bantle, 2009, Jensen et al., 2018, Johnson et al., 2013, Merino, Fernandez - Diaz, Cozar - Castellano, & Perdomo, 2019).

[0003] Food intake is a significant source of fructose, but fructose is also produced endogenously, particularly during cell stress, injury, tissue damage, or an increase in glucose concentration. This endogenous fructose production occurs via the polyol pathway in the liver, intestine, and kidney, where it contributes to the exacerbation of injury and metabolic dysfunction (Andres-Hernando et al., 2017; Lanaspa et al., 2013). In the small intestine, excessive dietary fructose is associated with the accumulation of fructose-1-phosphate (F1P), leading to the loss and disruption of tight junctions of the mucosal barrier that lines the intestine, contributing to increased intestinal permeability, inflammation, endotoxemia, and diarrhea (Merino et al., 2019; Montrose et al., 2020). In the liver and kidney, increased fructose metabolism causes the accumulation of metabolic intermediates such as fructose-1-phosphate (F1P), glyceraldehyde, dihydroxyacetone phosphate, and methylglyoxal, which contribute to increased glucose production, de novo lipogenesis, insulin resistance, and triglyceride synthesis (Todoric et al., 2020). Importantly, increased fructose production and / or metabolism results in rapid adenosine triphosphate (ATP) depletion, leading to cell apoptosis and injury, as well as increased levels of pro-inflammatory uric acid (Helsley et al., 2020).

[0004] Current drug therapies for the treatment of metabolic syndrome and related co - morbidities generally target the regulation of insulin secretion or activity, lipid metabolism, cholesterol levels, blood pressure, glucose homeostasis, and dietary intake of high - fat or high - fructose diets. Currently, there are no approved therapies to reduce fructose metabolism, and eliminating fructose intake from the diet is not practically achievable. Ketohexokinase (GENE:KHK) is a major rate - limiting enzyme in both dietary and endogenous fructose metabolism and thus represents a promising drug target for pharmacological intervention in diseases where fructose and the polyol pathway contribute to metabolic diseases and related comorbidities.

[0005] KHK is expressed as two major mRNA splice variants. The KHK mRNA variant 3C (isoform-C, KHK-C) is preferentially expressed in the small intestine (enterocytes), liver (hepatocytes), and kidney (proximal tubule cells) (Diggle et al., 2009; Hayward & Bonthron, 1998). These organs metabolize most of the dietary and endogenously produced fructose. The alternative splice variant of KHK (variant 3A, isoform-A, KHK-A) is more ubiquitously expressed in other organs including, but not limited to, the heart, brain, and skeletal muscle. KHK catalyzes the ATP-dependent conversion of fructose to F1P. Increased metabolism of fructose by KHK-C causes the accumulation of F1P and uric acid, and rapid ATP depletion. KHK-C has a higher affinity for fructose than KHK-A and results in more rapid metabolism of fructose than KHK-A. Furthermore, neither KHK-A nor KHK-C is subject to negative feedback inhibition or allosteric regulation, and thus, fructose is immediately and continuously metabolized by KHK (Ishimoto et al., 2012). Alternative enzymes such as hexokinase can metabolize fructose to fructose-6-phosphate, but this does not result in rapid ATP depletion because hexokinase is subject to negative feedback regulation (Geidl-Flueck & Gerber, 2017).

[0006] Examples of the consequences of unregulated fructose metabolism via KHK are seen in subjects with severe disorders caused by a deficiency in Aldolase B (GENE:ALDOB) in Hereditary Fructose Intolerance (HFI, OMIM#229600). ALDOB is an enzyme immediately downstream of KHK and is involved in the conversion of F1P to dihydroxy acetone phosphate (DHAP) and Glyceraldehyde phosphate (GAP). Deficiency of ALDOB results in the accumulation of F1P, depletion of ATP, and an increase in uric acid. HFI is a rare disorder with a prevalence of about 1 in 20,000 individuals (Simons et al., 2019). Individuals with HFI are severely intolerant to dietary fructose and exhibit acute symptoms such as vomiting, hypoglycemia, diarrhea, and abdominal distress. These contribute to features reminiscent of hypoglycemia, hyperuricemia, lactic acidosis, hepatic steatosis, and Fanconi syndrome, and in the worst cases, the onset of death (Aldamiz-Echevarria et al., 2020, Simons et al., 2019). Currently, the only treatment for HFI patients is strict restriction of dietary fructose. However, this is not completely sufficient to delay the worsening of symptoms over time, and patients often exhibit features of liver and kidney disease throughout their lives because it does not affect endogenous fructose production and metabolism (Aldamiz-Echevarria et al., 2020).

[0007] Genetic defects in the human KHK gene that result in loss of function or decreased enzyme stability of the enzyme lead to a benign condition known as essential fructosuria (EF, OMIM#229800), supporting KHK inhibition as a therapeutic strategy. EF is a rare benign disorder that affects approximately 1 in 100,000 people. Patients with EF appear normal and exhibit increased urinary excretion of fructose (Asipu, Hayward, O’Reilly, & Bonthron, 2003, Bonthron, Brady, Donaldson, & Steinmann, 1994, Schapira, Nordmann, & Gregori, 1972). The benign nature and lack of symptoms of EF emphasize the potential safety of long-term KHK inhibition. Furthermore, KHK-A / C homozygous knockout mice appear normal and healthy and, like humans with EF, excrete excessive fructose in their urine. In addition, KHK-A / C null mice are protected from features of liver and kidney diseases such as renal tubular cell injury, inflammation, hepatic steatosis, and fibrosis (Andres-Hernando et al., 2017, Lanaspa et al., 2013).

[0008] Currently, two classes of known KHK inhibitors exist, and both utilize the presence of charged residues for potency and / or metabolic stability and / or acceptable pharmacokinetic properties.

[0009] One class (U.S. Patent Application Publication No. 2017 / 183328, Chinese Patent Application Publication No. 111978296, International Publication No. 2020 / 067735, International Publication No. 2020 / 051058, Chinese Patent Application Publication No. 111423420, International Publication No. 2020 / 156445, Futatsugi et al., J. Med. Chem., 2020, 63, 13546 - 13560) contains a negatively charged carboxylic acid that mimics the gamma phosphate residue of the natural substrate ATP. Many carboxylic acid-containing drugs are associated with idiosyncratic drug toxicities that can be caused by reactive acyl glucuronide metabolites (Lassila et al., Chem. Res. Toxicol., 2015, 28, 12, 2292 - 2303). Acyl glucuronide metabolites can be chemically reactive and lead to covalent binding to macromolecules and cumulative toxicity (Vleet Van et al., Toxicology Letters, 2017, 272, 1 - 7). Compounds containing carboxylic acid tend to be substrates of the organic anion transporter (OAT) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLC21A (SLCO), and the multidrug resistance-associated protein (MRP) family encoded by ABCC (Sekine et al., Am. J. Physiol. Renal Physiol., 2006, 290, F251 - F261). This can result in asymmetric tissue exposure (i.e., tissue accumulation by active uptake and decreased tissue exposure by active efflux). Different tissue levels (e.g., toxicity due to accumulation or lack of efficacy due to active efflux) can represent risks specific to KHK-C inhibitors, where higher KHK-C inhibition in one organ can lead to higher circulating fructose concentrations in plasma, which can result in enhanced KHK-C-mediated fructose metabolism (and subsequent enhanced ATP depletion and tissue damage) in organs with decreased or lower inhibitor concentrations (free drug concentrations).Carboxylic acids are not only substrates of OATP but also tend to be inhibitors of OATP, which can lead to drug-drug interactions (DDIs) with some essential drugs (Kalliokoski et al., Br. J. Pharmacol., 2009, 158, 693 - 705; McFeely et al., Clin. Transl. Sci., 2019, 12, 379 - 387).

[0010] Other known inhibitors of KHK are dependent on the presence of positively charged basic amines (International Publication No. 18170517, International Publication No. 11133750, Zhang et al., Bioorg. Med. Chem. Lett., 2011, 21, 4762 - 4767, Maryanoff et al., Bioorg. Med. Chem. Lett., 2012, 22, 5326 - 532, Maryanoff et al., ACS Med. Chem. Lett., 2011, 2, 538 - 543, International Publication No. 2020 / 215022, International Publication No. 2020 / 046481, US Patent Application Publication No. 2020 / 392118). Basic drugs tend to be stored in tissues with a pH lower than their pKa values, such as in the lungs. Therefore, basic amines are well known to have a high risk of hERG inhibition or phospholipidosis, disorders such as organ - to - organ variability in exposure or lack of biological selectivity, or high safety risks. Compounds containing basic amines are often sequestered in acidic organelles of many different cell types, thereby contributing to various toxicities and can be further metabolized to form reactive iminium species (Yukawa et al., ACS Med. Chem. Lett., 2020, 11, 203 - 209, Charifson et al., J. Med. Chem., 2014, 57, 9701 - 9717). Both acids and bases are generally subject to significantly greater renal clearance than neutral molecules (Charifson et al., Chem., 2014, 57, 9701 - 9717).

[0011] There is a need for KHK inhibitors having advantageous properties, such as equal tissue distribution, high target binding, and good pharmacokinetic properties. Although progress has been made, there is still a need for more potent novel KHK inhibitors having low tissue asymmetry, low drug-drug interaction propensity, reduced off-target propensity, and minimal toxicity. References: Aldamiz-Echevarria,L.,de Las Heras,J.,Couce,M.L.,Alcalde,C.,Vitoria,I.,Bueno,M.,.Villate,O.(2020).Non-alcoholic fatty liver in hereditary fructose intolerance.Clin Nutr,39(2),455-459.doi:10.1016 / j.clnu.2019.02.019 Andres-Hernando,A.,Li,N.,Cicerchi,C.,Inaba,S.,Chen,W.,Roncal-Jimenez,C.,.Lanaspa,M.A.(2017).Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice.Nat Commun,8,14181.doi:10.1038 / ncomms14181 Asipu,A.,Hayward,B.E.,O’Reilly,J.,& Bonthron,D.T.(2003).Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria.Diabetes,52(9),2426-2432.doi:10.2337 / diabetes.52.9.2426 Bantle, J.P. (2009). Dietary fructose and metabolic syndrome and diabetes. J Nutr, 139(6), 1263S - 1268S. doi:10.3945 / jn.108.098020 Bonthron, D.T., Brady, N., Donaldson, I.A., & Steinmann, B. (1994). Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet, 3(9), 1627 - 1631. doi:10.1093 / hmg / 3.9.1627 Diggle, C.P., Shires, M., Leitch, D., Brooke, D., Carr, I.M., Markham, A.F.,. Bonthron, D.T. (2009). Ketohexokinase: expression and localization of the principal fructose - metabolizing enzyme. J Histochem Cytochem, 57(8), 763 - 774. doi:10.1369 / jhc.2009.953190 Geidl - Flueck, B., & Gerber, P.A. (2017). Insights into the Hexose Liver Metabolism - Glucose versus Fructose. Nutrients, 9(9). doi:10.3390 / nu9091026 Hayward, B.E., & Bonthron, D.T. (1998). Structure and alternative splicing of the ketohexokinase gene. Eur J Biochem, 257(1), 85 - 91. doi:10.1046 / j.1432 - 1327.1998.2570085.x Helsley, R. N., Moreau, F., Gupta, M. K., Radulescu, A., DeBosch, B., & Softic, S. (2020). Tissue-Specific Fructose Metabolism in Obesity and Diabetes. Curr Diab Rep, 20(11), 64. doi:10.1007 / s11892-020-01342-8 Ishimoto, T., Lanaspa, M. A., Le, M. T., Garcia, G. E., Diggle, C. P., Maclean, P. S.,. Johnson, R. J. (2012). Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci U S A, 109(11), 4320-4325. doi:10.1073 / pnas.1119908109 Jensen, T., Abdelmalek, M. F., Sullivan, S., Nadeau, K. J., Green, M., Roncal, C.,. Johnson, R. J. (2018). Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol, 68(5), 1063-1075. doi:10.1016 / j.jhep.2018.01.019 Johnson, R. J., Nakagawa, T., Sanchez-Lozada, L. G., Shafiu, M., Sundaram, S., Le, M.,. Lanaspa, M. A. (2013). Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes, 62(10), 3307-3315. doi:10.2337 / db12-1814 Lanaspa, M.A., Ishimoto, T., Li, N., Cicerchi, C., Orlicky, D.J., Ruzycki, P.,... Johnson, R.J. (2013). Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun, 4, 2434. doi:10.1038 / ncomms3434 Merino, B., Fernandez-Diaz, C.M., Cozar-Castellano, I., & Perdomo, G. (2019). Intestinal Fructose and Glucose Metabolism in Health and Disease. Nutrients, 12(1). doi:10.3390 / nu12010094 Montrose, D.C., Nishiguchi, R., Basu, S., Staab, H.A., Zhou, X.K., Wang, H.,... Dannenberg, A.J. (2020). Dietary Fructose Alters the Composition, Localization, and Metabolism of Gut Microbiota in Association With Worsening Colitis. Cell Mol Gastroenterol Hepatol. doi:10.1016 / j.jcmgh.2020.09.008 Schapira, F., Nordmann, Y., & Gregori, C. (1972). Hereditary alterations of fructose metabolizing enzymes. Studies on essential fructosuria and on hereditary fructose intolerance. Acta Med Scand Suppl, 542, 77 - 83。 Simons, N., Debray, F. G., Schaper, N. C., Kooi, M. E., Feskens, E. J. M., Hollak, C. E. M.,. Brouwers, M. (2019). Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content. J Clin Endocrinol Metab, 104(11), 5056 - 5064. doi:10.1210 / jc.2018 - 02795 Todoric, J., Di Caro, G., Reibe, S., Henstridge, D. C., Green, C. R., Vrbanac, A.,. Karin, M. (2020). Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat Metab, 2(10), 1034 - 1045. doi:10.1038 / s42255 - 020 - 0261 - 2

Prior Art Documents

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Non-Patent Literature

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Summary of the Invention

Means for Solving the Problems

[0014] In one embodiment, the present disclosure provides a compound of formula I

[0015]

Chemical formula

[0016] In another embodiment, the present disclosure provides a compound of formula I

[0017]

Chemical formula

[0018] In another embodiment, the present disclosure provides a compound of formula II

[0019]

Chemical Formula

[0020] In another embodiment, the disclosure provides a compound of formula V,

[0021]

Chemical formula

[0022] In another embodiment, the disclosure provides a compound of formula V,

[0023]

Chemical formula

Mode for Carrying Out the Invention

[0024] Definition As used herein, "core" is represented in its broadest sense by the following structure:

[0025]

Chemical Formula

[0026] "Alkyl" is a straight-chain or branched-chain saturated monovalent hydrocarbon. For example, an alkyl group has 1 to 18 carbon atoms (i.e., C 1~18 alkyl) or 1 to 8 carbon atoms (i.e., C 1~8 alkyl) or 1 to 6 carbon atoms (i.e., C 1~6 alkyl) or 1 to 4 carbon atoms (i.e., C 1~4It may have an (alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3). Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0027] "Alkenyl" is a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group has 2 to 8 carbon atoms (i.e., C 2~8(alkenyl) or 2 to 6 carbon atoms (i.e., C 2~6 (alkenyl) or 2 to 4 carbon atoms (i.e., C 2~4 (alkenyl) may be possessed. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. The alkenyl group can be either unsubstituted or substituted.

[0028] "Alkynyl" is a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group has 2 to 8 carbon atoms (i.e., C 2~8 (alkynyl) or 2 to 6 carbon atoms (i.e., C 2~6 (alkynyl) or 2 to 4 carbon atoms (i.e., C 2~4 (alkynyl) may be possessed. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and -CH2-C≡C-CH3. The alkynyl group can be either unsubstituted or substituted.

[0029] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group at the bonding point: alkyl-O-. Regarding the alkyl group, the alkoxy group can have any suitable number of carbon atoms such as C 1~6 . Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, OCF3, OCHF2, and the like.

[0030] As used herein, "aryl" refers to a fully carbon aromatic monocyclic or polycyclic system in which at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of aryl include phenyl radicals. As aryl, a polycyclic system having at least one aromatic ring and other rings that may or may not be aromatic (i.e., carbocyclic), having 9 to 20 carbon atoms (e.g., a ring system containing 2, 3, or 4 rings) is also included. In such a polycyclic system, any carbocyclic moiety of the polycyclic system is optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups. The rings of the polycyclic system may be linked to each other by fused bonds, spiro bonds, and cross-link bonds when permitted by valence requirements. When referring to aryl with a specific range of atomic numbers (e.g., 6- to 10-membered aryl), it should also be understood that the atomic range is for the total ring atoms of the aryl. For example, 6-membered aryl includes phenyl, and 10-membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like. Specific examples of polycyclic carbocycles include, but are not limited to, the following:

[0031] [Chemical formula]

[0032] "Cycloalkyl" has 3 to 20 cyclic carbon atoms (i.e., C 3~20"(Cycloalkyl)", for example, refers to a saturated or partially unsaturated all-carbon monocyclic ring having 3 to 12 ring atoms, for example, 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 3 to 4 ring atoms. The term "cycloalkyl" also encompasses saturated and partially unsaturated all-carbon polycondensed ring systems (for example, ring systems containing 2, 3, or 4 carbon rings). Thus, examples of cycloalkyl include polycyclic carbon rings, for example, bicyclic carbon rings (for example, bicyclic carbon rings having 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane, and bicyclo[2.1.1]hexane) and polycyclic carbon rings (for example, tricyclic and tetracyclic carbon rings having up to 20 ring carbon atoms). The rings of the polycondensed ring system may be linked to each other by fused bonds, spiro bonds, and crosslink bonds, if permitted by the valence requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

[0033] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene for the alkyl component to link the cycloalkyl component and the point of attachment. In some cases, the alkyl component may not be present. The alkyl component is C 1~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C 3~6 、C 4~5 、C 4~6 、and C5~6 It may contain any number of carbons such as. The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0034] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene for connecting the aryl component and the point of attachment. In some cases, the alkyl component may not be present. The alkyl component may contain any number of carbons such as C 1~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C 3~6 、C 4~5 、C 4~6 、and C 5~6 etc. The aryl component is as defined herein. Exemplary alkyl-aryl groups include, but are not limited to, methyl-phenyl or ethyl-phenyl.

[0035] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" or "heterocyclic" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic ring system having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur) in the ring, where the polycyclic ring system includes at least one non-aromatic ring containing at least one heteroatom. The polycyclic ring system may also include other aromatic and non-aromatic rings. Unless otherwise specified, a heterocyclyl group has 3 to 20 ring atoms, such as 3 to 12 ring atoms, such as 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term encompasses a saturated or partially unsaturated monocyclic ring (e.g., 3-, 4-, 5-, 6-, or 7-membered ring) having 1 to 6 cyclic carbon atoms in the ring and 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroatom may optionally be oxidized to form -N(-OH)-, =N(-O) - )-, -S(=O)-, or -S(=O)2-. The rings of a polycondensed ring (e.g., bicyclic heterocyclyl) system may be linked to each other by a fused bond, a spiro bond, and a bridging bond, if permitted by the valence requirements. Examples of heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinacridine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, and the like.

[0036] Examples of the heterocyclic group include, but are not limited to, the following:

[0037] [Chemical formula]

[0038] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (I).

[0039] As used herein, "oxo" refers to =O, SO, SO2, or SO(NH). Examples of compounds containing an oxo group include, but are not limited to, for example, the following:

[0040] [Chemical formula]

[0041] As used herein, "haloalkyl" refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by the same or different halo substituents. For example, C 1~4 haloalkyl is C 1~4 alkyl, wherein one or more of the hydrogen atoms of the C 1~4 alkyl are replaced by halo substituents, and is C 1~4 alkyl. Examples of the haloalkyl group include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0042] As used herein, "heteroaryl" refers to a monocyclic aromatic ring having at least one atom other than carbon in the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur, and "heteroaryl" also encompasses a polycondensed ring system having at least one such aromatic ring, which polycondensed ring system is further described below. Thus, "heteroaryl" encompasses a monocyclic aromatic ring having 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur atoms and nitrogen atoms may be in an oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl.

[0043] "Heteroaryl" also encompasses polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a heteroaryl group as defined above may be condensed with one or more rings selected from heteroaryl (e.g., forming 1,8-naphthyridinyl), heterocycle (e.g., forming 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., forming 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., forming indazolyl) to form a polycondensed ring system. Thus, heteroaryl (an aromatic monocyclic or polycondensed ring system) has 1 to 20 carbon atoms and 1 to 6 heteroatoms within the heteroaryl ring. Such a condensed polycyclic system may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moiety of the condensed ring. The rings of the polycondensed ring system may be linked to each other by condensation bonds, spiro bonds, and bridging bonds, if permitted by the valence requirements. It should be understood that the individual rings of the polycondensed ring system may be linked to each other in any order. The point of attachment to the heteroaryl or the polycondensed ring system of heteroaryl may be at any suitable atom of the heteroaryl or the polycondensed ring system of heteroaryl that contains carbon atoms and heteroatoms (e.g., nitrogen). When referring to heteroaryl with a specific range of atomic numbers (e.g., 5- to 10-membered heteroaryl), the atomic range is for the total ring atoms of the heteroaryl and is understood to include carbon atoms and heteroatoms. For example, 5-membered heteroaryl includes thiazolyl, and 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthylenyl, pyrrolo[2,3-b]pyridinyl, quinazolin-4(3H)-one, and triazolyl.

[0044] Examples of the "heteroaryl" ring also include 8- to 15-membered fused rings having two, three, or more rings, where at least one ring is an aromatic ring and at least one ring is a non-aromatic ring containing at least one heteroatom. Representative fused bicyclic heteroaryls include, but are not limited to, indoline (dihydroindole), isoindoline (dihydroisoindole), indazole (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxole, dihydrobenz[b]dioxin, dihydrobenz[d]oxazole, dihydrobenz[b]thiophene, dihydroisobenz[c]thiophene, dihydrobenz[d]thiazole, dihydrobenz[c]isothiazole, and benzo[b][1,4]thiazine, as shown in the following structures:

[0045]

Chem.

[0046] The fused bicyclic heterocycloalkyl can also be represented by the following structures:

[0047]

Chem.

[0048]

[0049]

Chemical Formula

[0050]

[0051] "Compounds of the present disclosure" include the compounds disclosed herein. For example, compounds of the present disclosure include compounds of formulas (I-VI). ​​As used herein, "composition" is intended to include a product containing specific ingredients in specific amounts, and any product directly or indirectly resulting from the combination of specific amounts of specific ingredients. "Pharmaceutically acceptable" means that a carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient.

[0052] "Pharmaceutically effective amount" refers to the amount of a compound of the present disclosure in a formulation or combination thereof that produces a desired therapeutic or pharmaceutical result.

[0053] As used herein, "treat" or "treating" or "treatment" refers to an approach for obtaining a beneficial or desired result. For the purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms, and / or reduction in the degree of symptoms, and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treat" or "treating" includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the degree of the disease or condition), b) delaying or suppressing the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition), and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the pathological condition, delaying the progression of the disease, improving the quality of life, and / or prolonging the survival period.

[0054] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount of a compound effective to induce a desired biological or medical response, which includes an amount of the compound sufficient to achieve such treatment of a disease when administered to a subject for treating the disease. The effective amount can vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated. The effective amount can include a range of amounts. As understood in the art, the effective amount can be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. The effective amount may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when used in combination with one or more other agents such that a desirable or beneficial result can be achieved, or is achieved. The preferred dosage of any co-administered compound can optionally be reduced due to the combined action of the compounds (e.g., additive or synergistic effects).

[0055] "Administering" refers to oral administration to a subject, administration as a suppository, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini osmotic pump. Administration can be carried out according to a schedule specifying the frequency of administration, the dosage administered, and other factors.

[0056] As used herein, "co-administration" refers to the administration of a unit dose of a compound disclosed herein, either before or after the administration of a unit dose of one or more additional therapeutic agents, e.g., the administration of a compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by the administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by the administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by the administration of a unit dose of one or more additional therapeutic agents hours (e.g., 1 to 12 hours) later. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by the administration of a unit dose of a compound of the present disclosure hours (e.g., 1 to 12 hours) later. Co-administration of a compound disclosed herein and one or more additional therapeutic agents generally refers to co-administering or sequentially administering a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0057] "Subject" refers to an animal such as a mammal including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0058] "Disease" or "condition" refers to a condition or state of health of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein.

[0059] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0060] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as the free base. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that have the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic bases. For example, a compound containing a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0061] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 +Salts derived from suitable bases such as (wherein X is C1-C4 alkyl) are also included. Base addition salts such as sodium salts or potassium salts are also included.

[0062] Also provided are the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may have enhanced resistance to metabolism and, thus, may be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. For example, it is described in Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527(1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0063] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I are also included. 11 C, 18 F, 15 O, and 13Substitution with a positron-emitting isotope such as N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotope-labeled compounds of formulas (I-VI) can generally be prepared by using appropriate isotope-labeled reagents in place of the conventionally used unlabeled reagents by conventional techniques known to those skilled in the art or by processes similar to those described in the examples below.

[0064] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and, accordingly, may give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- with respect to absolute stereochemistry, or as (D)- or (L)- with respect to amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagents or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of a racemic compound (or a racemic compound of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers and are not otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. When the compounds are represented in their chiral forms, it is understood that the embodiments include, but are not limited to, specifically diastereomerically or enantiomerically enriched forms. When chirality is not specified but is present, it is understood that the embodiments are directed to either a specifically diastereomerically or enantiomerically enriched form, or a racemic or scarmic mixture of such compounds. As used herein, a "scarmic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0065] A "racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0066] "Stereoisomer" and "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric forms if they have one or more asymmetric centers or double bonds with asymmetric substitution and can thus be produced as individual stereoisomers or mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0067] "Tautomers" refer to alternative forms of compounds where the position of a proton is different, such as enol-keto and imine-enamine tautomers, or to the tautomeric forms of heteroaryl groups containing ring atoms bonded to both ring-NH- and ring=N-.

[0068] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the front or end of a chemical group are for convenience, and chemical groups can be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of a group. A dashed line indicates an optional bond. Unless required chemically or structurally, the order in which a chemical group is written or the point at which it is attached to the rest of the molecule indicates neither directionality nor implies it. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be linked in either direction. Similarly, for example, an "arylalkyl" group can be attached to the rest of the molecule through either the aryl or alkyl portion of the group. "C u~v " or "(C u ~C vPrefixes such as "C 1~6 alkyl" and "C1-C6 alkyl" both indicate that the alkyl group has 1 to 6 carbon atoms.

[0069] As used herein, "solvate" refers to the result of the interaction between a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0070] Exemplary compounds Methods for preparing compounds The compounds of the present disclosure can be prepared by any method known in the art. The following exemplary general methods are exemplified as routes that can be used to obtain the compounds of the present disclosure.

[0071] In some cases (Scheme 1), the compound of formula 13 is prepared from a commercially available or literature-known compound of formula 1 where LG 1 or LG 2 is a leaving group, typically a halide or a sulfone, but not limited thereto. The compound of formula 1 is treated with an appropriate R 2 -M(4) in the presence or absence of a catalyst and in the presence or absence of a base to obtain the compound of formula 2 by a cross-coupling reaction. Suitable M groups include, but are not limited to, -B(OH)2, -B(pin), -Sn(alkyl)3, -ZnX, or -MgX. R 2 The above functional groups may need to be protected with appropriate protecting groups as determined by those skilled in the art. The catalyst for this transformation is often, but not limited to, Pd(PPh 34, Pd(dppf)Cl2, Pd(OAc)2, PdCl2, PdXPhos G1, G2, G3, or G4 catalyst, PdSPhos G1, G2, G3, or G4 precatalyst, or Pd2dba3, but not limited thereto, and the phosphine ligand is selected from SPhos, XPhos, RuPhos, XantPhos, PCy3, PPh3, or dppf, but not limited thereto. The base for this conversion was sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, cesium fluoride, triethylamine, diisopropylethylamine, or pyridine, but not limited thereto.

[0072] R 1 When R is an amine, the compound of formula 2 was treated with the nucleophile H-R in the presence of a base 1 to obtain the compound of formula 13. Alternatively, H-R 1 or M-R 1 and the compound of formula 2 were used in the presence of a catalyst and / or a base to obtain the compound of formula 13. The catalyst and the base were as described above, but not limited thereto. R 1 The above functional groups may require protection with appropriate protecting groups as determined by those skilled in the art.

[0073]

Chemical formula

[0074] M-R that is not commercially available or not known from the literature 2 (4) The compound was typically derived from the corresponding halide 3 via activation by a catalyst in the presence of a base and appropriate reagents for generating the nucleophile (Scheme 2). The catalyst and the base were as listed above, but not limited thereto. The reagents for generating the nucleophile were B2pin2 or Sn2(alkyl)6, but not limited thereto. Often, but not always, the compound of formula 4 was used directly in a one-pot cross-coupling with the compound of formula 2 to obtain the compound of formula 13.

[0075]

Chem.

[0076] A compound of formula 1 that is not commercially available or not known from the literature was synthesized according to Scheme 3 below. The compound of formula 5 was treated with an S-methylisothiourea source in the presence of a base to obtain a compound of formula 6. Then, the compound of formula 6 was converted to a compound of formula 7 by activating the hydroxy group to LG 2 , typically by treatment with POCl3. The compound of formula 7 was converted to a compound of formula 8 via the cross-coupling described above and in Scheme 1. The thioether of the compound of formula 8 was treated with an oxidizing agent, typically, but not limited to, m-chloroperbenzoic acid, peracetic acid, or Oxone® to convert LG 1 in the compound of formula 9. Then, the compound of formula 9 was treated with M-R 1 or H-R 1 as described above and in Scheme 1 to obtain a compound of formula 13.

[0077]

Chem.

[0078] In some examples, the compound of formula 13 was prepared according to Scheme 4. The compound of formula 1 was treated with a hydroxide source, typically sodium hydroxide, to obtain a compound of formula 10. Then, the compound of formula 10 was treated with M-R 1 or M-R 2 as described above to obtain a compound of formula 11. The hydroxy group of the compound of formula 11 was converted to LG 2 in the compound of formula 12 as described above. The compound of formula 12 was converted to a compound of formula 13 via a cross-coupling reaction with M-R 2 as described above.

[0079]

Chem.

[0080] Pharmaceutical preparation In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of Formulas I-VI), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0081] In some embodiments of the present disclosure, the pharmaceutical composition comprises a compound of Formulas (I-VI), or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more additional therapeutic agents, as more fully described hereinafter.

[0082] A pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof can be prepared with one or more pharmaceutically acceptable excipients selected according to ordinary practice. Tablets may contain excipients including lubricants, fillers, binders, and the like. Aqueous compositions can be prepared in a sterile form and may generally be isotonic if delivery other than oral administration is intended. In some embodiments, the composition may contain excipients such as those described in Rowe et al, Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. In some embodiments, the composition is provided as a solid dosage form including a solid oral dosage form.

[0083] The compositions are suitable for various routes of administration, including oral administration. The compositions may be presented in unit dosage forms and may be prepared by any of the methods known in the pharmaceutical art. Such methods include associating the active ingredient (e.g., a compound of the present disclosure or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by uniformly and intimately associating the active ingredient with a liquid excipient or a finely divided solid excipient or both, and then shaping the product, if necessary. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0084] The compositions described herein that are suitable for oral administration may be presented as discrete units (unit dosage forms), including, but not limited to, capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition of the present disclosure is a tablet.

[0085] The pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, together with pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient may be in any form appropriate for the intended method of administration. For example, when used for oral use, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients including sweetening agents, flavoring agents, coloring agents, and preserving agents to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients appropriate for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0086] The amount of the active ingredient that can be combined with the inert ingredients to produce a dosage form can vary depending on the intended treatment subject and mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 to 1000 mg of the active substance, formulated with a suitable and convenient amount of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients vary from about 5% to about 95% (weight: weight) of the total composition.

[0087] In some embodiments, a composition containing a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof in a single variant form does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, in one aspect, it is understood that a composition containing a compound of the present disclosure does not contain an agent that affects (e.g., delays, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, continuously, or simultaneously with the compound of the present disclosure. In one aspect, it is also understood that any of the methods, kits, articles of manufacture, etc. detailed herein do not contain an agent that affects (e.g., delays, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, continuously, or simultaneously with the compound of the present disclosure.

[0088] In some embodiments, the above pharmaceutical composition is for use in humans or animals.

[0089] The present disclosure further includes a compound of the present disclosure for administration as a single active ingredient of a pharmaceutically acceptable composition that can be prepared by conventional methods known in the art, for example, by binding or mixing the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient.

[0090] In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient having a synergistic effect with other active ingredients in a known drug, or the co-administration of a compound of the present disclosure with such a drug.

[0091] The compounds of the present disclosure can also be used in the form of prodrugs or in other suitably modified forms that release the active ingredient in vivo.

[0092] Route of administration The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to the health disorder being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, and epidural). It will be understood that the preferred route can vary, for example, depending on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0093] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen over a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In one variation, the compounds are administered daily or on an intermittent schedule over the lifetime of the individual.

[0094] The dosage or frequency of administration of the compounds of the present disclosure can be adjusted over the course of treatment based on the judgment of the administering physician.

[0095] The compounds can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compounds are administered once daily.

[0096] The compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can be from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or for example from about 0.3 mg per day to about 30 mg, or for example from about 30 mg per day to about 300 mg.

[0097] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of the compound). The therapeutically effective amount can be from about 1 mg per dose to about 1000 mg per dose, for example, from about 50 mg per dose to about 500 mg per dose, or for example, from about 100 mg per dose to about 400 mg per dose, or for example, from about 150 mg per dose to about 350 mg per dose, or for example, from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure can be about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure can be about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. The single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. The single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. The single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, the single dose can be administered once a week. The single dose can also be administered once a month.

[0098] Also included in the present disclosure are kits comprising a compound of the present disclosure, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the foregoing. In one embodiment, the kit further includes instructions for use. In one aspect, the kit includes a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a mixture of stereoisomers, a prodrug, or a deuterated analog, and a label and / or instructions for use of the compound in the treatment of indications such as the diseases or health disorders described herein. In one embodiment, provided is a kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents.

[0099] Also provided herein is a manufactured product comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, in a suitable container. The container can be a vial, a jar, an ampoule, a filled syringe, and an infusion bag.

[0100] Combination therapy NASH In some embodiments, a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof can be combined with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents in a therapeutically effective amount. In some embodiments, the additional therapeutic agents include an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-CoA carboxylase (ACC) inhibitor, a TGFβ antagonist, an LPAR antagonist, an SGLT2 inhibitor, a Tpl2 inhibitor, a VAP1 inhibitor, or a GLP-1 agonist, or combinations thereof.

[0101] The benefit of the combination can be an increase in efficacy and / or a reduction in side effects for the components, since the dosage of the components can be adjusted to reduce the side effects while obtaining the benefit from the efficacy enhanced by the efficacy of the compounds of the present disclosure.

[0102] In some embodiments, the therapeutic agent or combination of therapeutic agents is an ACE inhibitor, a 2-acylglycerol O-acyltransferase 2 (DGAT2) inhibitor, an aldehyde dehydrogenase inhibitor, an acetyl-CoA carboxylase inhibitor, an adrenergic receptor agonist, an Alstrom syndrome protein 1 (ALMS1) / PKCα protein interaction inhibitor, an apelin receptor agonist, a diacylglycerol O-acyltransferase 2 inhibitor, an adenosine A3 receptor agonist, an adenosine A3 receptor antagonist, an adiponectin receptor agonist, an aldehyde dehydrogenase 2 stimulator, an AKT protein kinase inhibitor, an AMP-activated protein kinase (AMPK), an AMP kinase activator, an ATP citrate lyase inhibitor, an AMP-activated protein kinase stimulator, an endothelial nitric oxide synthase stimulator, an NAD-dependent deacetylase sirtuin-1 stimulator, an adrenergic receptor antagonist, an androgen receptor agonist, an amylin receptor agonist, an angiotensin II AT-1 receptor antagonist, an apical sodium-dependent bile acid transport inhibitor, an autophagy protein modulator, an autotaxin inhibitor, an Axl tyrosine kinase receptor inhibitor, a Bax protein stimulator, a β-catenin inhibitor, a biologically active lipid, a calcitonin agonist, a cannabinoid receptor modulator, a caspase inhibitor, a caspase-3 stimulator, a cathepsin inhibitor, a caveolin-1 inhibitor, a CCK receptor antagonist, a CCL26 gene inhibitor, a CCR2 chemokine antagonist, a CCR2 chemokine antagonist, an angiotensin II AT-1 receptor antagonist, a CCR3 chemokine antagonist, a CCR5 chemokine antagonist, a CD3 antagonist, a CDGSH iron-sulfur domain protein modulator, a chitinase inhibitor, a chloride channel stimulator, a chitotriosidase 1 inhibitor, a CNR1 inhibitor, a connective tissue growth factor ligand inhibitor, a COT protein kinase inhibitor, a cyclin D1 inhibitor, a cytochrome P450 7A1 inhibitor, a DGAT1 / 2 inhibitor, a diacylglycerol O-acyltransferase 1 inhibitor (DGAT1), a cytochrome P450CYP2E1 inhibitor, cytochrome P450 reductase inhibitor, CXCR3 chemokine antagonist, CXCR4 chemokine antagonist, dihydroceramide delta 4 desaturase inhibitor, dihydroorotate dehydrogenase inhibitor, dipeptidyl peptidase IV inhibitor, endothelin modulator, eotaxin ligand inhibitor, extracellular matrix protein modulator, farnesoid X receptor agonist, fatty acid synthase inhibitor, FGF1 receptor agonist, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligand, fibroblast activation protein inhibitor, free fatty acid receptor 1 agonist, galectin-3 inhibitor, GDNF family receptor alpha-like agonist, glucagon receptor agonist, glucagon-like peptide 1 agonist, glucocorticoid receptor antagonist, glucose 6-phosphate 1-dehydrogenase inhibitor, G protein-coupled bile acid receptor 1 agonist, G-protein-coupled receptor 119 agonist, G protein-coupled receptor 84 antagonist, hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha modulator (HNF4A), hepatocyte growth factor modulator, histone deacetylase inhibitor, STAT-3 modulator, HMG CoA reductase inhibitor, HSD17B13 gene inhibitor, 5-HT 2a receptor antagonist, hydrolase inhibitor, hypoxia-inducible factor-2α inhibitor, IL-10 agonist, IL-17 antagonist, IL-22 agonist, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, insulin ligand agonist, insulin receptor agonist, integrin modulator, integrin antagonist, integrin alpha-V / beta-1 antagonist, integrin alpha-V / beta-6 antagonist, interleukin-1 kinase 4 (IRAK4) inhibitor, IL-6 receptor agonist, interleukin 17 ligand inhibitor, Jak2 tyrosine kinase inhibitor, JunN-terminal kinase-1 inhibitor, Kelch-like ECH-associated protein 1 modulator, ketohexokinase (KHK) inhibitor, Klothoβ stimulator, leukotriene A4 hydrolase inhibitor, 5-lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor, LPL gene stimulator, lysophosphatidic acid receptor (LPAR) antagonist, lysophosphatidate-1 receptor antagonist, lysyl oxidase homolog 2 inhibitor, LXR inverse agonist, macrophage mannose receptor 1 modulator, matrix metalloproteinase (MMP) inhibitor, MEKK-5 protein kinase inhibitor, MCH receptor-1 antagonist, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG-binding protein 2 modulator, microRNA-132 (miR-132) antagonist, microRNA-21 (miR-21) inhibitor, mitochondrial uncoupler, mixed lineage kinase-3 inhibitor, motility sperm domain protein 2 inhibitor, myelin basic protein stimulator, NACHT LRR PYD domain-containing protein 3 (NLRP3) inhibitor, NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), NFE2L2 gene inhibitor, nicotinic acid receptor 1 agonist, opioid receptor μ antagonist, P2Y13 purinergic receptor stimulator, nuclear erythroid 2-related factor 2 stimulator, nuclear receptor modulator, transcription factor modulator nuclear transport, P2X7 purinergic receptor modulator, PACAP type I receptor agonist, PDE 3 inhibitor, PDE 4 inhibitor, PDE5 inhibitors, PDGF receptor β modulators, phenylalanine hydroxylase stimulants, phospholipase C inhibitors, phosphodiesterase hydrolase inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, peptidyl-prolyl cis-trans isomerase A inhibitors, PNPLA3 gene inhibitors, PPARγ modulators, protease-activated receptor-2 antagonists, protein kinase modulators, protein NOV homolog modulators, PTGS2 gene inhibitors, renin inhibitors, resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitors, Rho-associated protein kinase inhibitors, transcription enzyme inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 inhibitors, sphingolipid delta4 desaturase DES1 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, STK25 inhibitors, suppressors of cytokine signal-1 stimulants, suppressors of cytokine signal-3 stimulants, taste receptor type 2 agonists, telomerase stimulants, TERT gene modulators, TGF beta (TGFB1) ligand inhibitors, TNF antagonists, transforming growth factor β (TGF-β), transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, TLR-9 antagonists, vascular adhesion protein-1 (VAP-1) inhibitors, VDR agonists, vitamin D3 receptor modulators, WNT modulators, YAP / TAZ modulators or zonulin inhibitors, and combinations thereof.

[0103] Non-limiting examples of one or more additional therapeutic agents include the following.

[0104] ACE inhibitors such as enalapril; Aldehyde dehydrogenase inhibitors such as ADX-629; Inhibitors of acetyl-CoA carboxylase (ACC) such as NDI-010976 (filso-costat), DRM-01, gemcabene, GS-834356, PF-05175157, QLT-091382, PF-05221304; Inhibitors of acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 such as PF-07055341; Adenosine receptor agonists such as namodenoson (CF-102), picridenoson (CF-101), CF-502, CGS21680; Adenosine A3 receptor antagonists such as FM-101; Adiponectin receptor agonists such as ADP-355, ADP-399, ALY668-SR; Adrenergic receptor antagonists such as bromocriptine, phentermine, VI-0521; Aldehyde dehydrogenase 2 stimulants such as FP-045; Amylin / calcitonin receptor agonists such as KBP-042, KBP-089; AMP-activated protein kinase stimulants such as C-455, PXL-770, O-304; AMP kinase activators / ATP citrate lyase inhibitors such as bempedoic acid (ETC-1002, ESP-55016); AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulants such as NS-0200 (leucine + metformin + sildenafil); Androgen receptor agonists such as LPCN-1144, LPCN-1148, testosterone prodrugs; Angiotensin II AT-1 receptor antagonists such as irbesartan; inhibitors of angiopoietin-related protein-3 (IONIS-ANGPTL3-LRx) such as bupanolsen; Apelin receptor agonists such as CB-5064, MBT-2; Apical sodium-dependent bile acid transport inhibitors, for example A-3907; Autophagy protein modulators such as A-2906 and GM-90194; Autotaxin (ectonucleotide pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2)) inhibitors such as FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, and BBT-877; Axl tyrosine kinase receptor inhibitors such as bemcentinib (BGB-324, R-428); Bax protein stimulators such as CBL-514; Bioactive lipids such as DS-102; Cannabinoid receptor modulators such as namacimab, GWP-42004, REV-200, CRB-4001, INV-101, and SCN-002; Caspase inhibitors such as emricasan; Total cathepsin B inhibitors such as VBY-376; Total cathepsin inhibitors such as VBY-825; CCK receptor antagonists such as proglumide; CCL26 gene inhibitors such as mosedipimod and KDDF-201410-10; CCR2 / CCR5 chemokine antagonists such as BMS-687681, cenicriviroc, maraviroc, CCX-872, leronlimab, and WXSH-0213; CCR2 / CCR5 chemokine antagonists and FXR agonists such as LJC-242 (tropifexor + cenicriviroc); CCR2 chemokine antagonists such as propagermanium; CCR2 chemokine / angiotensin II AT-1 receptor antagonists such as DMX-200 and DMX-250; CCR3 chemokine antagonists such as belrimumab; CD3 antagonists such as NI-0401 (foralumab); CDGSH iron-sulfur domain protein modulators such as EYP-002; Chitinase inhibitors such as OATD-01; Chitotriosidase 1 inhibitors such as OAT-2068; Chloride channel stimulants such as cobiprostone and lubiprostone; Casein kinase-1 (CK1) δ / ε inhibitors such as PF-05006739; Connective tissue growth factor ligand inhibitors such as PBI-4050; COT protein kinase inhibitors such as GS-4875 and GS-5290; CXCR4 chemokine antagonists such as AD-214; Cytochrome P450 reductase inhibitors such as SNP-630; Diacylglycerol acyltransferase 2 (DGAT2) inhibitors such as IONIS-DGAT2Rx and PF-06865571; Diacylglycerol acyltransferase 1 (DGAT1) inhibitors such as GSK-3008356; Diacylglycerol O-acyltransferase 1 (DGAT1) / Cytochrome P450 2E1 inhibitors (Cytochrome P450 2E1 inhibitors, CYP2E1) such as SNP-610; Dihydroorotate dehydrogenase inhibitors such as vidofludimus; Dipeptidyl peptidase IV inhibitors such as linagliptin and evogliptin; Eotaxin ligand inhibitors such as belimumab and CM-101; Extracellular matrix protein modulators such as CNX-024; Farnesoid X receptor (FXR) agonists such as AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, silofexol tromethamine (GS-9674), HPG-1860, IOT-022, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, bonafexol (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266, HPD-001, alendronate; Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists such as INT-767; Fatty acid synthase inhibitors such as TVB-2640, FT-8225; Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors such as aldafermin (NGM-282); Fibroblast growth factor 21 (FGF-21) ligands such as AP-025, BMS-986171, B-1654, BIO89-100, BOS-580, pegbelfermin (BMS-986036), B-1344, NN-9499; Fibroblast growth factor 21 (FGF-21) / glucagon like peptide 1 (GLP-1) agonists such as YH-25723 (YH-25724; YH-22241), efruxifermin (AKR-001); FGF receptor agonists / Klotho beta stimulators such as BFKB-8488A (RG-7992); Free fatty acid receptor 1 agonists such as SCO-267; Galectin-3 inhibitors such as verapectin (GR-MD-02), GB-1107 (Gal-300), GB-1211 (Gal-400), IMT-001; GDNF family receptor alpha-like agonists such as NGM-395; Glucagon-like peptide-1 (GLP1R) agonists such as ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, semaglutide; - Glucagon-like peptide 1 receptor agonist; oxyntomodulin ligand; glucagon receptor agonists such as efineglucagon; Gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP / GLP-1) receptor coagonists such as tildesatide (LY-3298176); PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists such as DD-01; Glucagon / GLP1 receptor agonists such as BI-456906, NN-6177; Glucocorticoid receptor antagonists such as CORT-118335 (millicortilant); Glucose 6-phosphate 1-dehydrogenase inhibitors such as ST001; Glucokinase stimulators such as dorzagliatin, sinogliatin (RO-5305552); G protein-coupled bile acid receptor 1 (TGR5) agonists such as RDX-009, INT-777, HY-209; G protein-coupled receptor 84 antagonists such as PBI-4547; G protein-coupled receptor-119 agonists such as DA-1241; Heat shock protein 47 (HSP47) inhibitors such as ND-L02-s0201; Hedgehog protein TGFβ ligand inhibitors such as oxy-210; Histone deacetylase inhibitors / STAT-3 modulators such as SFX-01; HMG CoA reductase inhibitors such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; HSD17B13 gene inhibitors such as ALN-HSD and ARO-HSD; Hydrolase inhibitors such as ABD-X; Hypoxia-inducible factor-2 alpha inhibitors such as PT-2567; IL-10 agonists such as peg-ilodecakin; Ileal sodium-bile acid cotransporter inhibitors such as odesivabat (A-4250), polyxibat potassium ethanol adduct hydrate (SHP-262), GSK2330672, CJ-14199, or elobixibat (A-3309); Insulin sensitizers such as KBP-042, azemirolitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), trimidone, VVP-100X, CB-4211, ETI-101; Insulin ligand / ds insulin receptor agonists such as ORMD-0801; Integrin antagonists such as IDL-2965; IL-6 receptor agonists such as KM-2702; Integrin α-V / β-6 and α-V / β-1 dual inhibitors such as PLN-74809; Interleukin 17 ligand inhibitors such as netakimab; Jak1 / 2 tyrosine kinase inhibitors such as baricitinib; Jun N-terminal kinase-1 inhibitors such as CC-90001; Kelch-like ECH-associated protein 1 modulators such as α-cyclodextrin-stabilized sulforaphane; Ketone hexokinase (KHK) inhibitors such as PF-06835919, LY-3478045, LY-3522348; Beta Klotho (KLB)-FGF1c agonists such as MK-3655 (NGM-313); Leukotriene A4 hydrolase inhibitors such as LYS-006; 5-Lipoxygenase inhibitors such as tepelukast (MN-001), eproidone (DS-102, (AF-102); Lipoprotein lipase inhibitors such as CAT-2003; LPL gene stimulants such as alipogene tiparvovec; Liver X receptor (LXR) inhibitors such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238; Lysophosphatidic acid-1 receptor antagonists such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198; Lysyl oxidase homolog 2 inhibitors such as simtuzumab, PXS-5382A (PXS-5338); Macrophage mannose receptor 1 modulators such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept); Matrix metalloprotease inhibitors such as ALS-L1023; Membrane copper amine oxidase (VAP-1) inhibitors such as TERN-201, TT-01025; MEKK-5 protein kinase (ASK-1) inhibitors such as CJ-16871, CS-17919, seronesertib (GS-4997), SRT-015, GS-444217, GST-HG-151, TERN-301; MCH receptor-1 antagonists such as CSTI-100 (ALB-127158); Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors such as PXS-4728A (BI-1467335); Methionine aminopeptidase-2 inhibitors such as ZGN-1061, ZGN-839, ZN-1345; Methyl CpG binding protein 2 modulators such as mercaptamine; Mineralocorticoid receptor antagonists (MCRA) such as MT-3995 (apararenone); Mitochondrial uncouplers such as 2,4-dinitrophenol, HU6, Mito-99-0053; Mixed lineage kinase-3 inhibitors such as URMC-099-C; Motile sperm domain-containing protein 2 inhibitors such as VB-601; Myelin basic protein stimulants such as olesoxime; Myeloperoxidase inhibitors such as PF-06667272 and AZM-198; NADPH oxidase inhibitors such as GKT-831, GenKyoTex, APX-311, and setanaxib; Nicotinic acid receptor 1 agonists such as ARI-3037MO; NACHT LRR PYD domain-containing protein 3 (NLRP3) inhibitors such as KDDF-201406-03, NBC-6, IFM-514, and JT-194 (JT-349); NFE2L2 gene inhibitors such as GeRP-amiR-144; Nuclear transport of transcription regulators such as AMTX-100; Nuclear receptor modulators such as DUR-928 (DV-928); Opioid receptor μ antagonists such as methylnaltrexone; P2X7 purinergic receptor modulators such as SGM-1019; P2Y13 purinergic receptor stimulants such as CER-209; PDE 3 / 4 inhibitors such as tipepidust (MN-001); PDE 5 inhibitors such as sildenafil and MSTM-102; PDGF receptor β modulators such as BOT-191 and BOT-509; Peptidyl-prolyl cis-trans isomerase inhibitors such as CRV-431 (CPI-432-32), NVP-018, and NV-556 (NVP-025); Phenylalanine hydroxylase stimulants such as HepaStem; Phosphodiesterase hydrolase inhibitors such as ZSP-1601; PNPLA3 gene inhibitors such as AZD-2693; PPAR agonists such as ciglitazone, elafibranor (GFT-505), ceradelpariline (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, PXL-065 (DRX-065), saroglitazar, ranifibranor (IVA-337), CHS-131, pemafibrate (K-877), ZG-0588, ZSP-0678; ZSYM-008; Protease-activated receptor-2 antagonists such as PZ-235; Protein kinase modulators such as CNX-014; Protein NOV homolog modulators such as BLR-200; PTGS2 gene inhibitors such as STP-705, STP-707; Renin inhibitors such as PRO-20; Resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitors such as DWJ-211; Rev protein modulators such as ABX-464; Rho-associated protein kinase (ROCK) inhibitors such as REDX-10178 (REDX-10325), KD-025, RXC-007, TDI-01; RNA polymerase inhibitors such as sapacitabine; S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors such as SL-891; Sodium glucose transporter-2 (SGLT2) inhibitors such as ipragliflozin, empagliflozin, ertugliflozin, dapagliflozin, tofogliflozin, sotagliflozin; Sodium glucose transporter-1 / 2 (SGLT1 / 2) inhibitors such as licogliflozin bis (prolinate) (LIK-066); SREBP transcription factor inhibitors such as CAT-2003, HPN-01, MDV-4463; Stearoyl CoA desaturase-1 inhibitors such as alamchol; Taste receptor type 2 agonists such as ARD-101; Thyroid hormone receptor β agonists such as ALG-009, ASC-41, CNPT-101101; CNPT-101207, CS-27186, KY-41111, resmetirom (MGL-3196), MGL-3745, TERN-501, VK-2809, HP-515; TLR-2 / TLR-4 antagonists such as VB-201 (CI-201); TLR-4 antagonists such as JKB-121, JKB-122, naltrexone; Tyrosine kinase receptor modulators such as CNX-025, GFE-2137 (repurposed nitazoxanide); TLR-9 antagonists, for example, GNKS-356, AVO-101; TNF antagonists such as ALF-421; GPCR modulators, for example, CNX-023; Nuclear hormone receptor modulators such as Px-102; VDR agonists such as CK-15; Xanthine oxidase inhibitors such as ACQT-1127; Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors such as RLBN-1001, RLBN-1127; or Zonulin inhibitors such as lorazotide acetate (INN-202) may be mentioned.

[0105] In certain specific embodiments, one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342, AN-3015, anti-TAGE antibody, alamchol, ARI-3037MO, ASP-8232, AXA-1125, belimumab, betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colecalciferol, dabigatran etexilate mesylate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, edaravone (TTYP-01), EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fludroxycortide (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, GS-4875, GS-5290, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, hydrochlorothiazide,icosabutate (PRC-4016), ethyl ester of icosapent acid, IMM-124-E, INT-767, INV-240, ION-455, IONIS-DGAT2Rx, ipragliflozin, ilbesartan, propagermanium, IVA-337, J2H-1702, JKB-121, KB-GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, (LJN-452) (tropifexor), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX-8025,Selected from MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namasizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, norursodeoxycholic acid, NV-422, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, oleoxime, PAT-505, PAT-048, peg-ilotekin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, empagliflozin etabonate, RG-125 (AZD4076), RP-005, RPI-500, S-723595, saroglitazar, SBP-301, semaglutide, SH-2442, SHC-028, SHC-023, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV-45478, TQA-3526, TQA-3563, tipepidast (MN-001), TLY-012, TRX-318, TVB-2640, TXR-611, TXR-612, TS-20004, UD-009, UN-03, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, besimodegib, potassium volixibat ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, XZP-5610, ZGN-839, ZG-5216, ZSYM-008, or ZYSM-007.

[0106] In certain embodiments, examples of acetyl-CoA carboxylase (ACC) inhibitors include, but are not limited to, those described in US2013123231, US2019134041, US2017267690, US2018298025.

[0107] Examples of acetyl-CoA carboxylase (ACC) inhibitors / farnesoid X receptor (FXR) agonists include, but are not limited to, those described in US2018280394.

[0108] Examples of acetyl-CoA carboxylase (ACC) inhibitors / farnesoid X receptor (FXR) agonists / MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2018021341, US2018333401.

[0109] Examples of acetyl-CoA carboxylase (ACC) / MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2018311244.

[0110] Examples of farnesoid X receptor (FXR) agonists include, but are not limited to, those described in US2014221659, US2020281911, WO2020185685.

[0111] Examples of farnesoid X receptor (FXR) agonists / MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2017273952, US201813320.

[0112] Examples of MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2011009410, US2013197037, US2016244430, US2016280683.

[0113] CKD / DKD Patients receiving treatment for cardio-renal diseases such as chronic kidney disease can benefit from combination drug therapy.

[0114] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts or stereoisomers thereof can be combined with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents. In some embodiments, the additional therapeutic agents include the following: Angiotensin-converting enzyme (ACE) inhibitors such as enalapril, captopril, ramipril, lisinopril, and quinapril, or angiotensin II receptor blockers (ARBs) such as losartan, olmesartan, and irbesartan, antihypertensive agents such as amlodipine, nifedipine, and felodipine, SGLT2 inhibitors such as canagliflozin, dapagliflozin, empagliflozin, and luseogliflozin, mineralocorticoid receptor antagonists such as finerenone, NRF2 activators such as bardoxolone methyl, LPAR antagonists, and apoptosis signal-regulating kinase (ASK-1) inhibitors such as seronacib.

[0115] The advantage of the combination can be an increase in the effectiveness and / or a reduction in side effects of the components, since the dosage of a component can be adjusted to reduce its side effects while benefiting from the enhanced effectiveness of the compound of formula (I-VI) and / or other active ingredients.

[0116] Patients presenting with chronic kidney disease treatable with a KHK inhibitor such as a compound of formula (I-VI) may also benefit from co-administration (as directed by a qualified caregiver) of a therapeutic agent(s) that is / are an antibiotic, an analgesic, an antidepressant, and / or an antianxiety agent in combination with a compound of formula (I-VI). The combination therapy may be administered simultaneously or sequentially within intervals directed by a qualified caregiver, or via a combination of fixed doses of two or more active agents (where all active ingredients are combined in a single dosage form, e.g., a tablet).

[0117] In some embodiments, the therapeutic agent or combination of therapeutic agents may include the following: ACE inhibitor, adenosine A3 receptor antagonist, adropin stimulant, albumin modulator, aldosterone antagonist, AMP-activated protein kinase stimulant, angiotensin II AT-2 receptor agonist, angiotensin II receptor antagonist, angiotensinogen ligand inhibitor, APOA1 gene stimulant, apolipoprotein L1 modulator, bone morphogenetic protein-7 ligand modulator, bromodomain-containing protein 2 inhibitor, bromodomain-containing protein 4 inhibitor, calcium channel inhibitor, cannabinoid CB1 receptor antagonist, CB1 inverse agonist, CCR2 chemokine antagonist, chymase inhibitor, complement C1s subcomponent inhibitor, CX3CR1 chemokine antagonist, cyclooxygenase 1 inhibitor, cyclooxygenase 2 inhibitor, cytochrome P45011B2 inhibitor, ectonucleotide pyrophosphatase-PDE-2 inhibitor, endothelin ET-A receptor antagonist, endothelin ET-B receptor antagonist, enteropeptidase inhibitor, epoxide hydrolase inhibitor, erythropoietin receptor antagonist, farnesoid X receptor agonist, FGF receptor antagonist, free fatty acid receptor 1 agonist, GHR gene inhibitor, glycoprotein Ib (GPIb) antagonist, GPR40 agonist, GPR84 antagonist, G protein beta subunit inhibitor, G protein-coupled receptor 120 agonist, G protein-coupled receptor 84 modulator, growth hormone ligand, growth hormone receptor agonist, guanylate cyclase receptor agonist, guanylate cyclase stimulator, heme oxygenase 1 modulator, HIF prolyl hydroxylase inhibitor, IGF1 gene inhibitor, IgG receptor FcRn large subunit p51 modulator, IL-6 receptor antagonist, integrin alpha-V / beta-3 antagonist, interleukin 33 ligand inhibitor, Kelch-like ECH-associated protein 1 modulator, LDHA gene inhibitor, 5-lipoxygenase activating protein inhibitor, lysophosphatidic acid-1 receptor antagonist, matrix extracellular phosphoglycoprotein modulator, membrane copper amine oxidase inhibitor, midkine ligand inhibitor, mineralocorticoid receptor antagonist, myosin 2 inhibitor, NADPH oxidase 1 inhibitor, NADPH oxidase 4 inhibitor, NADPH oxidase inhibitor, NK1 receptor antagonist, nuclear erythroid 2-related factor 2 stimulator, nuclear factor kappa B inhibitor, opioid receptor kappa agonist, opioid receptor mu antagonist p38MAP kinase inhibitors, PDE4 inhibitors, PDGF receptor antagonists, PDGF receptor beta modulators, phosphatonin receptor agonists, PRKAA2 gene stimulants, proprotein convertase PC9 inhibitors, prostacyclin (PGI2) agonists, protein C activators, protein NOV homolog modulators, protein tyrosine phosphatase-1B inhibitors, reactive oxygen species modulator inhibitors, renin inhibitors, Rho-associated protein kinase 2 inhibitors, SLC22A12 inhibitors, sodium glucose transporter-2 inhibitors, solute carrier family inhibitors, TGF beta ligand inhibitors, TGF beta receptor antagonists, thromboxane A2 receptor antagonists, thromboxane synthase inhibitors, tissue transglutaminase inhibitors, TRP cation channel C5 inhibitors, TRP cation channel C6 inhibitors, tryptophanase inhibitors, unspecified cell adhesion molecule inhibitors, urate anion exchanger 1 inhibitors, vasopressin V1a receptor antagonists, VEGF receptor antagonists, VIP1 receptor agonists, VIP2 receptor agonists, and xanthine oxidase inhibitors, and combinations thereof.

[0118] Non-limiting examples of one or more additional therapeutic agents include the following. ACE inhibitors such as benazepril, imidapril, etc. Adenosine A3 receptor antagonists such as FM-101 Adropin stimulants such as RBT-2 Albumin modulators such as SYNT-002 Adenosine / mineralocorticoid receptor antagonists such as MT-3995 Allogeneic bone marrow-derived mesenchymal stromal cell therapies such as ORBCEL-M™ Allogeneic expanded adipose-derived stem cell therapies such as Elixcyte™ AMP-activated protein kinase stimulants / proprotein convertase PC9 inhibitors such as O-304 AMP-activated protein kinase stimulants such as DZCY-01, MK-8722, PXL-770, etc. Angiotensin II AT-1 receptor / CCR2 chemokine antagonists such as DMX-200, Angiotensin II AT-2 receptor antagonists such as MOR-107, irbesartan, Angiotensin II receptor antagonists such as losartan, Angiotensinogen ligand inhibitors such as ALN-AGT, Anti-C1 antibodies such as BIVV-009 (stimuvumab), Anti-CB1 antibodies such as GFB-024, Anti-CX3CR1 nanobodies such as BI-655088, Anti-IL-6 antibodies such as COR-001, Anti-VEGF-B antibodies such as CSL-346, APOA1 gene stimulators / bromodomain-containing protein 2 / bromodomain-containing protein 4 inhibitors such as apabetalone, Bone morphogenetic protein-7 ligand modulators such as BMP-7, Calcium channel inhibitors such as TBN (xiaotongqin), Cannabinoid CB1 receptor antagonists such as JNJ-2463, CB1 inverse agonists such as CRB-4001, Chymase inhibitors such as fulacimstat (BAY-1142524), Cyclooxygenase 1 inhibitors such as GLY-230, Cyclooxygenase 2 / epoxide hydrolase inhibitors such as COX-2 / soluble epoxide hydrolase, Cytochrome P450 11B2 inhibitors such as aldosterone synthase inhibitors, Ectonucleotide pyrophosphatase-PDE-2 inhibitors such as BLD-0409, Endothelin ET-A / endothelin ET-B receptor antagonists such as aprocitentan, Enteropeptidase inhibitors such as SCO-792, Erythropoietin receptor antagonists such as EPO-018B, Farnesoid X receptor (FXR) agonists such as AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, silofexol tromethamine (GS-9674), HPG-1860, IOT-022, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, bonafexol (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266, etc., FGF / PDGF / beta receptor antagonists / p38 MAP kinase inhibitors such as pirfenidone, GHR / IGF1 gene inhibitors such as atesidorsen sodium, GPR40 antagonists / GPR84 antagonists such as PBI-4050, G protein beta subunit inhibitors such as gallon, G protein-coupled receptor 84 modulators such as PBI-4425, Growth hormone ligands / growth hormone receptor agonists such as Jintropin AQ (trademark), Growth hormone receptor agonists such as LAT-8881, Guanylate cyclase receptor agonists / guanylate cyclase stimulants such as praliciguat, Guanylate cyclase stimulants such as MRL-001, lanciguat, etc., Heme oxygenase 1 modulators such as RBT-1, HIF prolyl hydroxylase inhibitors such as TRGX-154, Insulin sensitizers / kallikrein 1 modulators such as DM-199, Integrin alpha-V / beta-3 antagonists such as VPI-2690B, Interleukin 33 ligand inhibitors such as MEDI-3506, Kelch-like ECH-associated protein 1 modulator / nuclear erythroid 2-related factor 2 stimulator such as SFX-01, LDHA gene inhibitor such as nedoceran, 5-lipoxygenase activating protein inhibitor such as AZD-5718, Lysophosphatidic acid-1 receptor antagonist such as BMS-002, EPGN-696, Matrix extracellular phosphoglycoprotein modulator / phosphatonin receptor agonist such as TPX-200, MEKK-5 protein kinase inhibitor such as seroncertib, Membrane copper amine oxidase inhibitor such as UD-014, Midkine ligand inhibitor such as CAB-101, Mineralocorticoid receptor antagonist such as AZD-9977, esaxerenone, finerenone, KBP-5074, Myosin 2 inhibitor such as DeciMab™, NADPH oxidase 1 inhibitor / NADPH oxidase 4 inhibitor such as setanaxib, NADPH oxidase inhibitor such as APX-115, NK1 receptor antagonist / opioid receptor kappa agonist / opioid receptor mu antagonist such as AV-104, Nuclear erythroid 2-related factor 2 stimulator / TGF beta ligand inhibitor such as CU01-1001, Nuclear factor kappa B inhibitor such as mefenidone, bardoxolone methyl (NSC-713200), PDE 4 inhibitor such as ART-648, PCS-499, PDGF receptor beta modulator such as BOT-191, PDGF / VEGF receptor antagonist such as ANG-3070, PR84 antagonist / GPR40 (FFAR1) / GPR120 (FFAR4) agonist / and peroxisome proliferator-activated receptor (PPAR) partial activator such as PBI-4547, PRKAA2 gene stimulants / AMPK activators such as PF-06679142 and PF-06685249, Prostacyclin (PGI2) agonists such as YS-1402, Protein C activators / glycoprotein Ib (GPIb) antagonists such as AB-002, Protein NOV homolog modulators such as BLR-200, Protein tyrosine phosphatase-1B inhibitors such as MSI-1436, Reactive oxygen species modulator inhibitors such as SUL-121, Renin inhibitors such as imarigiren hydrochloride, Rho-associated protein kinase 2 inhibitors such as ANG-4201 and RXC-007, Sodium glucose transporter-2 inhibitors such as canagliflozin, dapagliflozin propanediol, and empagliflozin, Thromboxane A2 receptor antagonists / thromboxane synthesis inhibitors such as SER-150, Tissue transglutaminase inhibitors such as ZED-1227, TRP cation channel C5 inhibitors such as GFB-887, TRP cation channel C6 inhibitors such as ALGX-2224, Urate anion exchanger 1 (URAT1) / SLC22A12 inhibitors such as berinurad (RDEA3170), VIP1 / VIP2 receptor agonists such as LBT-3627, or Xanthine oxidase inhibitors such as TMX-049 and TMX-049DN.

[0119] In certain embodiments, one or more therapeutic agents are A-717, ACF-TEI, alanyl-glutamine, ALLN-346, anti-SCF248 antibody, anti-TAGE monoclonal antibody, anti-TGF beta antibody, AST-120, BAY-2327949, BI-685509, DP-001, DZ-4001, GDT-01, LNP-1892, MEDI-8367, microRNA target antisense oligonucleotide therapy, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney Augment (NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, salvianolic acid, SGF-3, SPD-01, SZ-005, TCF-12, UMC119 ~ 06, VAR-400, bevelimer, VS-105, or selected from XRx-221.

[0120] IBD As used herein, the term "inflammatory bowel disease" or "IBD" is a collective term that describes inflammatory disorders of the gastrointestinal tract, and the most common forms of inflammatory disorders of the gastrointestinal tract are ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated using the compounds, compositions, and methods of the present disclosure include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), unclassified colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet's disease, gastroduodenal Crohn's disease, jejunoileitis, ileitis, ileocolitis, colonic Crohn's disease (granulomatous colitis), irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, ileal pouchitis, proctitis, chronic diarrhea, or endotoxemia due to intestinal barrier dysfunction.

[0121] The treatment methods disclosed herein can also be applied at any point in the course of the disease. In some embodiments, the method is applied to a subject suffering from IBD during a remission period (i.e., inactive disease). In such embodiments, the method provides a benefit by extending the remission period (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, the method may be applied to a subject suffering from IBD during an active disease episode. Such methods provide a benefit by shortening the duration of the active disease episode, reducing or ameliorating one or more symptoms of IBD, or treating IBD.

[0122] The benefit of the combination can be an increase in the effectiveness and / or a reduction in the side effects of the components, since the dosage of the components can be adjusted to reduce the side effects while obtaining the benefit from the effectiveness enhanced by the effectiveness of the compounds of the disclosure.

[0123] In some embodiments, the compounds of the disclosure or pharmaceutically acceptable salts or stereoisomers thereof can be combined with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 - 3, or 1 - 4) additional therapeutic agents in a therapeutically effective amount.

[0124] Examples of agents for the treatment of inflammatory diseases or conditions that can be used in combination with the compounds described herein include the following: α-Fetoprotein modulator, adenosine A3 receptor antagonist, adrenomedullin ligand, AKT1 gene inhibitor, antibiotic, antifungal agent, ASK1 inhibitor, ATPase inhibitor, beta-adrenergic receptor antagonist, BTK inhibitor, calcineurin inhibitor, carbohydrate metabolism modulator, cathepsin S inhibitor, CCR9 chemokine antagonist, CD233 modulator, CD29 modulator, CD3 antagonist, CD40 ligand inhibitor, CD40 ligand receptor antagonist, chemokine CXC ligand inhibitor, CHST15 gene inhibitor, collagen modulator, COT protein kinase inhibitor, CSF-1 agonist, CSF-1 antagonist, CX3CR1 chemokine modulator, DYRK-1 alpha protein kinase inhibitor, eotaxin ligand inhibitor, EP4 prostanoid receptor agonist, F1F0 ATP synthase modulator, farnesoid X receptor (FXR, NR1H4) agonist or modulator (fecal microbiota transplantation (FMT)), fractalkine ligand inhibitor, free fatty acid receptor 2 antagonist, GATATranscription factor inhibitor, glucagon-like peptide 2 agonist, glucocorticoid agonist, glucocorticoid receptor modulator, guanylate cyclase receptor agonist HIF, prolyl hydroxylase inhibitor, histone deacetylase inhibitor, HLA class II antigen modulator, hypoxia-inducible factor-1 stimulator, ICAM1 gene inhibitor, IL-1 beta ligand modulator, IL-12 antagonist, IL-13 antagonist, IL-18 antagonist, IL-18 receptor accessory protein antagonist, IL-22 agonist, IL-23 antagonist, IL-23A inhibitor, IL-6 antagonist, IL-7 receptor antagonist, IL-8 receptor antagonist, IL-36 inhibitor, integrin alpha-4 / beta-1 antagonist, integrin alpha-4 / beta-7 antagonist, integrin antagonist, interleukin ligand inhibitor, interleukin receptor 17A antagonist, interleukin-1 beta ligand, interleukin 1-like receptor 2 inhibitor, IL-6 receptor modulator, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, lactoferrin stimulator, LanC-like protein 2 modulator, leukocyte elastase inhibitor, leukocyte protease-3 inhibitor, MAdCAM inhibitor, melanin-concentrating hormone (MCH-1) antagonist, melanocortin agonist, metalloprotease-9 inhibitor, microbiome-targeting therapeutic agent, natriuretic peptide receptor C agonist, activin-4 ligand, NLRP3 inhibitor, NKG2 D-activated NK receptor antagonist, NR1H4 receptor (FXR) agonist, nuclear factor kappa B inhibitor, opioid receptor antagonist, OX40 ligand inhibitor, oxidoreductase inhibitor, P2X7 purinoceptor regulator, PDE4 inhibitors, Pellino homolog 1 inhibitors, PPARα / δ agonists, PPARγ agonists, protein arginine deiminase IV inhibitors, protein fimH inhibitors, P-selectin glycoprotein ligand-1 inhibitors, Ret tyrosine kinase receptor inhibitors, RIP-1 kinase inhibitors, RIP-2 kinase inhibitors, RNA polymerase inhibitors, sphingosine-1-phosphate phosphatase 1 stimulants, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-5 agonists, sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 regulators, stem cell antigen-1 inhibitors, superoxide dismutase regulators, SYK inhibitors, tissue transglutaminase inhibitors, TLR-3 antagonists, TLR-4 antagonists, Toll-like receptor 8 (TLR8) inhibitors, TLR-9 agonists, TNFα ligand inhibitors, TNF ligand inhibitors, TNFα ligand regulators, TNF antagonists, TPL-2 inhibitors, tumor necrosis factor 14 ligand regulators, tumor necrosis factor 15 ligand inhibitors, Tyk2 tyrosine kinase inhibitors, type I IL-1 receptor antagonists, vanilloid VR1 agonists, or zonulin inhibitors, and combinations thereof.

[0125] Also included herein are methods of treatment in which the compounds described herein are administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressive agents, and methotrexate.

[0126] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, the combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., compounds that inhibit COX-2 with an IC 50 that is at least 50-fold lower than the IC 50 for COX-1), such as celecoxib, valdecoxib, lumiracoxib, etoricoxib, and / or rofecoxib.

[0127] In a further embodiment, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline salicylate and magnesium salicylate.

[0128] The anti-inflammatory agent can also be a corticosteroid. For example, the corticosteroid can be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.

[0129] In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pegcetacoplan), a TNF antagonist such as etanercept, or infliximab, an anti-TNFα monoclonal antibody.

[0130] Also included herein are methods of treatment in which the compounds described herein are administered in combination with an immunosuppressive agent. In some embodiments, the immunosuppressive agent is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, mycophenolate sodium, mercaptopurine or mycophenolate mofetil.

[0131] Therapeutic method In some embodiments, the compounds of formulas (I-VI) or pharmaceutically acceptable salts or stereoisomers thereof are useful in methods for treating and / or preventing KHK (ketohexokinase)-mediated diseases or conditions. In some embodiments, a method for treating and / or preventing a KHK-mediated disease or condition comprises administering to a subject in need thereof a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, diseases or conditions include chronic kidney disease (CKD), diabetic kidney disease (DKD), kidney disease, renal fibrosis, renal insufficiency, acute kidney injury, tubulointerstitial dysfunction, lupus nephritis, 2,8-dihydroxyadenine nephropathy, kidney transplant rejection, renal protection against drugs including Fanconi syndrome, hereditary fructose intolerance, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), liver disease, liver fibrosis, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, hypertension, fibrosis, steatosis, cirrhosis, cardiometabolic syndrome, insulin resistance, cardiovascular disease, heart failure, type 1 and type 2 diabetes mellitus, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, hyperuricemia, gout, arthritis, osteoporosis or cancer.

[0133] In some embodiments, a method for treating and / or preventing non-alcoholic fatty liver disease (NAFLD) comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0134] In some embodiments, a method for treating and / or preventing chronic kidney disease comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0135] In some embodiments, a method of treating and / or preventing inflammatory bowel disease (IBD) comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0136] Also provided herein is a pharmaceutical composition for use in the treatment of a KHK-mediated disease or condition described herein, comprising a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.

[0137] The present disclosure also describes the use of a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof in the manufacture of a medicament for treating a KHK-mediated disease or condition. The medicaments referred to herein can be prepared by conventional processes involving a combination of a compound according to the present disclosure with a pharmaceutically acceptable carrier.

[0138] Also disclosed are a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof for the treatment of a KHK-mediated disease or condition. Also disclosed are a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof for the prevention of a KHK-mediated disease or condition.

Examples

[0139] Many general references are available that provide generally known chemical synthesis schemes and conditions useful for synthesizing the disclosed compounds (see, e.g., Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th edition, Wiley-Interscience, 2013).

[0140] The compounds described herein can be purified by any of the means known in the art, including chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, such as normal and reverse phases and ion exchange resins. For example, the disclosed compounds can be purified via silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd ed., ed. L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0141] During any of the processes for the preparation of the target compounds, it may be desirable to protect any sensitive or reactive groups on any of the relevant molecules. This can be accomplished by conventional protecting groups described in standard treatises such as T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 4th ed., Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known from the art.

[0142] Here, exemplary chemical substances useful in the methods of the embodiments are described by reference to exemplary synthetic schemes for their general preparation herein and the following specific examples. One of ordinary skill in the art will recognize that, in order to obtain the various compounds herein, the starting materials can be suitably selected such that the ultimately desired substituents are carried through the reaction scheme, with or without protection as necessary, to obtain the desired product. Alternatively, it may be desirable to use a suitable group that is carried through the reaction scheme and can be appropriately replaced with the ultimately desired substituent. Further, one of ordinary skill in the art will recognize that the transformations shown in the following schemes can be carried out in any order that is compatible with the functionality of the pendant groups.

[0143] The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that separate batches of the compounds can be combined and then carried forward to the next synthetic step.

[0144] In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail to enable one of ordinary skill in the art to practice certain embodiments of the disclosure. Other embodiments can be utilized and logical changes and other changes can be made without departing from the scope of the disclosure. The embodiments also are directed to processes and intermediates useful in preparing the subject compounds or pharmaceutically acceptable salts or stereoisomers thereof. Accordingly, the following description is not intended to limit the scope of the disclosure.

[0145] In some embodiments, the present disclosure generally provides a particular enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. If the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is drawn without indicating the stereochemistry at that particular stereocenter, even if the compound may be substantially enantiomerically or diastereomerically pure.

[0146] Representative syntheses of the compounds of the present disclosure are described in the following schemes and the following examples.

[0147] The compounds detailed in the examples were synthesized according to the general synthetic methods described below. The compounds were named using ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.) or BIOVIA Notebook 2020 SP2 HF1 version 20.1.201.31, unless otherwise indicated.

[0148] Abbreviations Certain abbreviations and acronyms are used when describing the details of the experiments. Most of these are understood by those skilled in the art, but Table 1 includes a list of many of these abbreviations and acronyms.

[0149]

Table 1-1

[0150]

Table 1-2

[0151]

Table 1-3

[0152] Synthesis of Intermediates and General Methods Preparation of Intermediates

[0153]

Chem.

[0154] 2-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.00 g, 26.4 mmol, 1 equiv) was placed in a flask, and THF (26 mL) and 5N sodium hydroxide (26 mL, 130 mmol) were added. This was heated at 50 °C for 2 hours. It was diluted with water and washed twice with dichloromethane. The aqueous layer was acidified with 10% potassium bisulfate until the pH reached 5. This was extracted twice with dichloromethane, and these extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This was purified by flash chromatography (40 - 100% ethyl acetate / hexane linear gradient) to obtain the title compound.

[0155]

Chem.

[0156] 2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol 2-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (776 mg, 4.55 mmol, 1 equiv) and (2S)-2-methylazetidine hydrochloride (587 mg, 5.46 mmol) were placed in a flask, and acetonitrile (12 mL) and N,N-diisopropylethylamine (2.38 mL, 13.6 mmol) were added. This was sealed and heated at 80 °C for 16 hours. It was cooled to ambient temperature, and the solid formed was collected, washed with acetonitrile, and recovered to obtain the title compound.

[0157]

Chem.

[0158] 4-Chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine Into a flask, 2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (873 mg, 4.25 mmol, 1 equiv) was placed, and phosphoryl chloride (12 mL, 128 mmol) was added. This was heated at 80 °C for 2 hours. This was cooled to ambient temperature, poured onto ice, and neutralized with solid potassium carbonate until pH>9 was reached. This was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound.

[0159]

Chemical formula

[0160] (2S,3R)-1-(4-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-yl benzoate In the same manner as 2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol, the title compound was prepared using (2S,3R)-2-methylazetidin-3-yl benzoate instead of (2S)-2-methylazetidine hydrochloride.

[0161]

Chemical formula

[0162] (S)-2-(2-Methylazetidin-1-yl)-4-(tributylstannyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine Into a flask were added (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (23.0 g, 102 mmol), PhMe (58 mL), followed by Sn2Bu6 (48.0 g, 82.7 mmol), Pd(OAc)2 (1.15 g, 5.14 mmol) and PCy3 (2.88 g, 10.2 mmol). The flask was purged with nitrogen and heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature, concentrated and subjected to flash column chromatography (Al2O3, petroleum ether - ethyl acetate) to give the title compound.

[0163] [Chemical formula]

[0164] (S)-4-bromo-1-methoxy-2-(methylsulfinyl)benzene Into a flask were added (-)-diethyl D-tartrate (15.4 g, 74.6 mmol) and DCM (400 mL), followed by Ti(OiPr)4 (10.6 g, 37.3 mmol) and H2O (0.67 mL, 37.3 mmol). The mixture was stirred at ambient temperature for 30 min. (5-Bromo-2-methoxyphenyl)(methyl)sulfane (8.70 g, 37.3 mmol) was added and stirring was continued for a further 15 min, after which the mixture was cooled to -20 °C (in an ethylene glycol - dry ice bath) and tert-butyl hydroperoxide (5 - 6 M in decane, 8.96 mL, 44.8 mmol) was added dropwise over 5 min. The mixture was warmed to ambient temperature over 18 h. H2O (10 mL) was added and the mixture was filtered through Celite®. The filtrate was washed with H2O (200 mL) and extracted with DCM (3 × 100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was subjected to flash column chromatography (hexane - ethyl acetate) to give the title product with 78% ee. The product was recrystallized from boiling hexane to achieve >99% ee.

[0165] General method The general method represents the most commonly used method, although slight modifications including reaction time elapsed and temperature were sometimes used.

[0166] The solvent was generally selected from, but not limited to, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, xylene, benzene, chlorobenzene, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, 2-propanol, or water. The palladium catalyst was generally selected from, but not limited to, Pd(PPh 34 , Pd(dppf)Cl2, Pd(OAc)2, PdCl2 PdXPhos G1, G2, G3, or G4 precatalyst, PdSPhos G1, G2, G3, or G4 precatalyst, or Pd2dba3 with or without a phosphine ligand selected from, but not limited to, SPhos, XPhos, RuPhos, XantPhos, PCy3, PPh3, or dppf. The base was generally selected from, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, cesium fluoride, triethylamine, diisopropylethylamine, or pyridine.

[0167] The isomers separated by chiral chromatography were arbitrarily assigned stereochemistry.

[0168] General Method A:

[0169]

Chem.

[0170] 2-Chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine Into a vial were placed 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1 equiv), 3-pyridylboronic acid (31 mg, 0.25 mmol, 1.2 equiv), and Pd(PPh3)4 (25 mg, 0.021 mmol, 10 mol%), and the vial was flushed with nitrogen. DME (10 mL) and Na2CO3 (2 M aqueous solution, 0.53 mL, 4 equiv) were added, and the mixture was heated at 90 °C for 4 h. The mixture was cooled to ambient temperature, concentrated, and subjected to flash column chromatography (hexane - ethyl acetate) to afford the title compound (44 mg, 0.19 mmol).

[0171] General method B:

[0172] [Chemical formula]

[0173] (S)-2-(2-Methylazetidin-1-yl)-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine Into a vial were placed 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (44 mg, 0.19 mmol, 1.0 equiv), (2S)-2-methylazetidine (R)-camphorsulfonate (86 mg, 0.29 mmol, 1.5 equiv), and MeCN (1.5 mL). N(iPr)2Et (0.13 mL, 98 mg, 0.76 mmol, 4.0 equiv) was added, and the mixture was heated at 90 °C for 18 h. The mixture was concentrated and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound (36 mg, 0.14 mmol).

[0174] General method C:

[0175] [Chemical formula]

[0176] (S)-3-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoic acid Into a vial were placed methyl (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate (20 mg, 0.057 mmol, 1 equiv), MeOH (1 mL), and NaOH (2 M aqueous solution, 0.6 mL). The reaction mixture was heated at 60 °C for 1 h. The reaction mixture was cooled to room temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to give the title compound (3.3 mg, 0.0098 mmol).

[0177] General method D:

[0178]

Chem.

[0179] Ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate Into a vial were placed ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (500 mg, 1.82 mmol, 1.0 equiv), Pd(OAc)2 (40.8 mg, 0.18 mmol, 10 mol%), PCy3 (102 mg, 0.36 mmol, 20 mol%), hexane-n-butylditin (1.16 g, 2.00 mmol, 1.1 equiv), and 1,4-dioxane (4.0 mL). The mixture was sparged with nitrogen. The reaction mixture was heated to 120 °C for 18 h. The mixture was concentrated and subjected to flash column chromatography (hexane - ethyl acetate) to give the title compound (258 mg, 0.53 mmol).

[0180] General method E:

[0181]

Chem.

[0182] Ethyl (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)imidazo[5,1-b]thiazole-7-carboxylate To a vial were added ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate (100 mg, 0.21 mmol, 1.0 equiv), (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (46 mg, 0.21 mmol, 1.0 equiv), Pd(PPh3)2Cl2 (15 mg, 0.021 mmol, 10 mol%), XPhos (9.4 mg, 0.021 mmol, 10 mol%), CuI (3.9 mg, 0.021 mmol, 10 mol%), and 1,4-dioxane (3 mL). The mixture was heated at 120 °C for 4 h. The mixture was concentrated and subjected to flash column chromatography (hexane-ethyl acetate) to afford the title compound (50 mg, 0.13 mmol).

[0183] General method F:

[0184]

Chemical formula

[0185] (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide To a microwave reaction tube were added 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one (25.0 mg, 0.095 mmol), bis(pinacolato)diboron (30.3 mg, 0.119 mmol), KOAc (23.4 mg, 0.238 mmol), and Pd(dppf)Cl2 (7.56 mg, 0.0095 mmol, 10 mol%). 1,4-Dioxane (1 mL) was added and the mixture was sparged with nitrogen for 5 minutes, then heated at 130 °C for 1 hour in a CEM microwave reactor. The mixture was cooled to ambient temperature, filtered, and washed with 1,4-dioxane (0.5 mL). To the microwave reaction tube were added the filtrate and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine (21.3 mg, 0.095 mmol). Aqueous Na2CO3 solution (2 M, 0.2 mL) was added and the reaction mixture was sparged with nitrogen for 5 minutes, then heated at 130 °C for 1 hour in a CEM microwave reactor. The mixture was cooled to ambient temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound (5.3 mg, 0.014 mmol).

[0186] General method G:

[0187] [Chemical formula]

[0188] 2-(3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide To a vial was added 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid (56 mg, 0.15 mmol, 1.0 equiv), ammonia (0.4 M in 1,4-dioxane, 1.2 mL, 0.46 mmol, 3.0 equiv), and HATU (70 mg, 0.18 mmol, 1.2 equiv). DMF (2 mL) was added, followed by N(iPr)2Et (0.11 mL, 0.61 mmol, 4.0 equiv). The mixture was heated to 50 °C for 30 minutes and cooled to ambient temperature. H2O (5 mL) was added and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound (45 mg, 0.12 mmol).

[0189] General Procedure H:

[0190]

Chem.

[0191] 2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-ol To a vial were added methyl 2-oxobicyclo[3.1.0]hexane-3-carboxylate (300 mg, 1.95 mmol) and 2-methylisothiourea (557 mg, 3.89 mmol), followed by sodium carbonate (2 M, aqueous solution, 3.89 mL, 7.78 mmol). The mixture was stirred at ambient temperature for 18 hours. The solid formed was collected by filtration, treated with 1N HCl, and then extracted with EA. The mixture was concentrated and subjected to flash column chromatography (hexane - ethyl acetate) to afford the title compound (300 mg, 1.54 mmol).

[0192]

Chem.

[0193] 4-Chloro-2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine Into a vial was placed 2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-ol (300 mg, 1.54 mmol), followed by the addition of POCl3 (5 mL, 46.3 mmol). The mixture was heated at 110 °C for 18 h, cooled to ambient temperature, and poured into ice. The aqueous mixture was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was used without further purification.

[0194]

Chem.

[0195] 3-(2-(Methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-yl)benzamide The title compound was prepared in a similar manner to General Method A using 4-chloro-2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine and (3-carbamoylphenyl)boronic acid in place of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.

[0196]

Chem.

[0197] 3-(2-(Methylsulfonyl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-yl)benzamide To a flask, 3-(2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-yl)benzamide (135 mg, 0.454 mmol), mCPBA (261, 1.13 mmol), and DCM (2 mL) were added. The mixture was stirred at ambient temperature for 2 hours. The mixture was extracted with EA, washed with aqueous sodium bicarbonate solution, concentrated, and subjected to flash column chromatography (hexane - ethyl acetate) to obtain the title compound.

[0198]

Chemical formula

[0199] 3-(2-((S)-2-methylazetidin-1-yl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-yl)benzamide The title compound was prepared in a similar manner to General Method B, using 3-(2-(methylsulfonyl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-yl)benzamide instead of 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0200] General Method I:

[0201]

Chemical formula

[0202] (S)-2-(2-methylazetidin-1-yl)-4-(4-(piperazin-1-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine tert-Butyl (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate was dissolved in TFA (1 mL) and DCM (1 mL), stirred at ambient temperature for 10 minutes, concentrated, and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound.

[0203] General method J:

[0204]

Chem.

[0205] (S)-3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide To a vial were added (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (30 mg, 0.10 mmol, 1.0 equiv), EtOH (1 mL), and NaOH (2 M aqueous solution, 0.5 mL), and the mixture was heated at 90 °C for 1 hour. The reaction mixture was concentrated and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid.

[0206] General method K:

[0207]

Chem.

[0208] (S)-1-Methyl-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)-1H-imidazole-4-sulfonamide Into a vial were placed (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline (15 mg, 0.054 mmol, 1.0 equiv), 4-dimethylaminopyridine (1 mg, 0.0054 mmol, 10 mol%), Et3N (0.022 mL, 0.16 mmol, 3.0 equiv), and DCM (1 mL). Then, 1-methylimidazole-4-sulfonyl chloride (15 mg, 0.080 mmol, 1.5 equiv) was added at ambient temperature and the mixture was stirred for 4 h. The mixture was concentrated and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound.

[0209] General method L:

[0210] [Chemical formula]

[0211] 2-Cyclopropyl-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine Into a vial were placed 2-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.17 mmol, 1.0 equiv), Pd(PtBu3)2 (8.9 mg, 0.017 mmol, 10 mol%), and DMF (3 mL). The vial was sparged with argon and then cyclopropylzinc bromide (0.5 M in THF, 1.04 mL, 0.52 mmol, 3.0 equiv) was added. The mixture was heated at 90 °C for 30 minutes and then cooled to ambient temperature. NH4Cl (5 mL, saturated aqueous solution) was added and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was subjected to flash column chromatography (hexane-ethyl acetate), followed by HPLC (0.1% TFA in MeCN-0.1% TFA in H2O) to afford the title compound.

[0212] General method M:

[0213]

Chemical formula

[0214] 4-(7,7-Difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide 4-(7,7-Difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide was prepared in a similar manner to General method A using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-carbamoylphenyl)boronic acid in place of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.

[0215] To a vial containing 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide (136 mg, 0.42 mmol, 1.0 equiv), 3-chloroperoxybenzoic acid (purity 77%, 285 mg, 1.27 mmol, 3.0 equiv) was added, followed by DCM (2 mL). The mixture was stirred at ambient temperature for 2 h. Saturated aqueous NaHCO3 (2 mL) was added and the mixture was extracted with DCM (3 × 2 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound.

[0216] General method N:

[0217] [Chemical formula]

[0218] 4-(2-(2,3-Dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide To a vial were added 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide (50 mg, 0.18 mmol, 1.0 equiv), 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (50 mg, 0.46 mmol, 2.5 equiv), Pd(OAc)2 (4.1 mg, 0.018 mmol, 10 mol%), XantPhos (16 mg, 0.027 mmol, 15 mol%), and Cs2CO3 (238 mg, 0.73 mmol, 4.0 equiv). 1,4-Dioxane (2.0 mL) was added and the mixture was sparged with nitrogen for 2 min. The mixture was heated at 120 °C for 18 h, cooled to ambient temperature, filtered through Celite® and washed with DCM. The mixture was concentrated and the residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to give the title compound.

[0219] General method O:

[0220] [Chemical formula]

[0221] 3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzaldehyde The title compound was prepared in a manner similar to General Method A, using (3-formylphenyl)boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0222]

Chemical formula

[0223] 2-[(2S)-2-Methylazetidin-1-yl]-4-[3-(1-piperidylmethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine Sodium triacetoxyborohydride (58 mg, 0.27 mmol) was added to a solution of 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzaldehyde (40 mg, 0.14 mmol) and piperidine (0.04 mL, 0.4 mmol) in 1,2-dichloroethane (0.5 mL), and the reaction mixture was stirred at ambient temperature for 18 h. NaHCO3 (1 mL, saturated aqueous solution) was added and the mixture was extracted with DCM (3 × 1 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound.

[0224] General Method P:

[0225]

Chemical formula

[0226] 2-[(2S)-2-Methylazetidin-1-yl]-4-vinyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine To a solution of 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.89 mmol) in THF (5 mL) and water (1 mL) were added potassium trifluoro(vinyl)boranuide (144 mg, 1.1 mmol), potassium carbonate (272 mg, 1.97 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (66 mg, 0.089 mmol). The reaction mixture was degassed with nitrogen, sealed, and heated at 70 °C for 16 h. It was cooled to ambient temperature, diluted with ethyl acetate, and washed with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl acetate - hexane) to afford the title compound.

[0227]

Chemical formula

[0228] 2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carbaldehyde To a solution of 2-[(2S)-2-methylazetidin-1-yl]-4-vinyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (415 mg, 1.93 mmol) in dioxane (22 mL) and water (22 mL) were added potassium osmate(VI) dihydrate (28 mg, 0.077 mmol) and sodium periodate (1.24 g, 5.8 mmol). The reaction mixture was stirred at ambient temperature for 16 h. It was filtered, diluted with EtOAc, and washed with water, saturated sodium thiosulfate, saturated sodium bicarbonate, and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl acetate - hexane) to afford the title compound.

[0229]

Chem.

[0230] 2-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1H-benzimidazole To a solution of 2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carbaldehyde (22 mg, 0.10 mmol) in ethanol (0.4 mL) was added 2-nitroaniline (14 mg, 0.10 mmol) and an aqueous solution of 1M sodium dithionite (0.3 mL, 0.3 mmol), and the reaction mixture was heated at 70 °C for 16 h. This was cooled to ambient temperature, treated with 5N ammonium hydroxide, and the resulting solid was collected by filtration. The residue was subjected to flash column chromatography (ethyl acetate - hexane) to afford the title compound.

[0231] General Method Q:

[0232]

Chem.

[0233] Methyl (S)-4-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate A vial was charged with methyl 4-bromo-2-hydroxy-benzoate (400 mg, 1.73 mmol), tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate (303 mg, 1.73 mmol), and PhMe (4 mL). Diisopropyl azodicarboxylate (0.37 mL, 1.90 mmol) was then added dropwise, followed by PPh3 (499 mg, 1.90 mmol). The mixture was heated at 90 °C for 2 h. The mixture was concentrated and the residue was subjected to flash column chromatography (ethyl acetate - hexane) to afford methyl (R)-4-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate.

[0234] [Chemical formula]

[0235] (S)-8-Bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one A vial was charged with methyl (S)-4-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate (672 mg, 1.73 mmol), TFA (2 mL), and DCM (2 mL). The mixture was stirred at ambient temperature for 30 min and then concentrated under vacuum. The residue was dissolved in EtOAc and washed with NaHCO3 (saturated aqueous solution). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was dissolved in PhMe (4 mL) and heated at 110 °C for 18 h. The mixture was concentrated and the residue was subjected to flash column chromatography (ethyl acetate - hexane) to afford (S)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

[0236] General method R:

[0237] [Chemical formula]

[0238] 3-(4-(7,7-Difluoro-2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine Into a vial were added benzyl (3-(4-(7,7-difluoro-2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-yl)carbamate (100 mg, 0.19 mmol) and EtOH (3 mL). The vial was purged with nitrogen and Pd / C (5 wt%, 41 mg, 0.019, 10 mol%) was added. A balloon of H2 gas was sparged into the solution with stirring for 2 h. The mixture was filtered through Celite® and concentrated, and subjected to reverse phase HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound.

[0239] General Method S:

[0240]

Chem.

[0241] 4-Bromo-1-methoxy-2-(methylsulfinyl)benzene A suspension of (5-bromo-2-methoxyphenyl)(methyl)sulfane (4.00 g, 17.2 mmol) and sodium periodate (3.97 g, 18.6 mmol) in methanol (37 mL) and water (37 mL, 0.5 M containing sodium periodate) was stirred at ambient temperature overnight. The mixture was filtered and the solid was washed with additional methanol. The filtrate was partitioned between dichloromethane and water and the layers were separated. The aqueous layer was extracted with dichloromethane three more times, the organic layers were combined, dried over magnesium sulfate, filtered and concentrated to afford the title compound.

[0242] Alternatively, the starting material was dissolved in DCM (0.3 M), and mCBPA (1.5 eq) was added. The mixture was stirred for 30 minutes. K2CO3 (2 M aqueous solution) was added, and the mixture was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (hexane - ethyl acetate) to afford the desired product.

[0243]

Chem.

[0244] tert - butyl ((5 - bromo - 2 - methoxyphenyl)(methyl)(oxo)-λ 6 -sulfanilidene)carbamate To a suspension of 4 - bromo - 1 - methoxy - 2 - (methylsulfinyl)benzene (4.20 g, 16.9 mmol), tert - butyl carbamate (2.96 g, 25.3 mmol), magnesium oxide (2.72 g, 67.4 mmol), and Rh2(OAc)4 (186 mg, 2.5 mol%) in dichloromethane (170 mL) was added PhI(OAc)2 (8.14 mg, 25.3 mmol). The resulting mixture was stirred at 40 °C for 2 hours, then cooled to room temperature and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash column chromatography (hexane - ethyl acetate) to afford the title compound.

[0245] General method T:

[0246]

Chem.

[0247] Benzyl (3 - (4 - bromo - 2 - fluorophenyl)oxetan - 3 - yl)carbamate To a flask, 3-(4-bromo-2-fluoro-phenyl)oxetan-3-amine hydrochloride (300 mg, 1.06 mmol), DCM (5 mL), and then N(iPr)2Et (0.46 mL, 343 mg, 2.65 mmol) were added. CbzCl (0.18 mL, 217 mg, 1.27 mmol) was added dropwise over 5 minutes. After the mixture was stirred at ambient temperature for 4 hours, it was concentrated and subjected to flash column chromatography (hexane-ethyl acetate) to give the title compound.

[0248] General method U:

[0249] [Chemical formula]

[0250] Benzyl ((R)-6-(7,7-difluoro-2-((R)-2-(trifluoromethyl)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)(oxetan-3-yl)carbamate To a microwave reaction tube, benzyl (R)-(6-(7,7-difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)(oxetan-3-yl)carbamate (150 mg, 0.269 mmol), (2R)-2-(trifluoromethyl)azetidine (160 mg, 0.538 mmol), and CsF (81.7 mg, 0.538 mmol) were added. CH3CN (3 mL) and (iPr)2EtN (139 mg, 1.08 mmol) were added to the reaction tube, and the reaction mixture was heated at 130 °C for 8 hours in a CEM microwave reactor. The mixture was cooled to ambient temperature and diluted with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with DCM (3 × 10 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (hexane-ethyl acetate) to give the title compound.

[0251] General method V:

[0252]

Chem.

[0253] 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-1-one oxime To a flask were added 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one (1.00 g, 4.37 mmol), NaOAc-(H2O)3 (2.97 g, 21.8 mmol), and MeOH (20 mL). Hydroxylamine hydrochloride (1.52 g, 21.8 mmol) was added, a reflux condenser was attached to the mixture, and the mixture was heated to reflux for 1 hour. The mixture was concentrated, 20 mL of H2O was added. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over Na2SO4, filtered, and the title product was obtained.

[0254]

Chem.

[0255] 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-1-amine To 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one oxime (1.07 g, 4.37 mmol) in MeOH (10 mL) were added Zn powder (1.43 g, 21.8 mmol) and HCl (aqueous solution, 6 M, 8.7 mL). The mixture was heated at 60 °C for 1 hour. After cooling to ambient temperature, KOH (aqueous solution, 2 M) was added to adjust the pH to 12. The resulting solid was collected by filtration and dried under vacuum to obtain the title product.

[0256] General method W:

[0257]

Chem.

[0258] 5-Bromo-7-methoxy-2,3-dihydro-1H-inden-1-ol To 5-bromo-7-methoxy-2,3-dihydro-1H-inden-1-one (498 mg, 2.07 mmol) in MeOH (10 mL) was added NaBH4 (156 mg, 4.13 mmol). The mixture was stirred at ambient temperature for 18 h, concentrated, and subjected to flash column chromatography (hexane - ethyl acetate) to afford the title compound.

[0259]

Chemical formula

[0260] 5-Bromo-7-methoxy-2,3-dihydro-1H-inden-1-amine To 5-bromo-7-methoxy-2,3-dihydro-1H-inden-1-ol (332 mg, 1.37 mmol) in PhMe (6 mL) were added diphenylphosphoryl azide (0.35 mL, 451 mg, 1.64 mmol) and DBU (0.31 mL, 312 mg, 2.05 mmol) dropwise over 5 min. The mixture was stirred at ambient temperature overnight. H2O (10 mL) was added and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was dissolved in THF (10 mL) and PPh3 (430 mg, 1.64 mmol) was added. The mixture was stirred at ambient temperature for 30 h. H2O (1 mL) was added and the mixture was heated at 50 °C for 4 h. After cooling to ambient temperature, H2O (10 mL) was added and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and subjected to flash column chromatography (hexane - ethyl acetate) to afford the title compound.

[0261] General method X:

[0262]

Chemical formula

[0263] 7-Bromospiro[chroman-4,4'-imidazolidine]-2',5'-dione To a flask were added 7-bromochroman-4-one (2.00 g, 8.81 mmol), ammonium carbonate (1.69 g, 17.6 mmol), KCN (860 mg, 13.2 mmol), EtOH (10 mL) and H2O (10 mL). A reflux condenser was attached to the flask and the mixture was heated at 90 °C for 3 days. The mixture was cooled to ambient temperature and the pH was adjusted to 6 with HCl (aqueous solution, 6 M). The resulting solid was collected by filtration, washed with H2O and dried under vacuum to obtain the title compound.

[0264] General method Y:

[0265]

Chemical formula

[0266] 5-Bromo-2,3-dihydrospiro[indene-1,3'-morpholin]-5'-one To a vial were added (1-amino-5-bromo-2,3-dihydro-1H-indene-1-yl)methanol (300 mg, 1.24 mmol) and DCM (12 mL), followed by N(iPr)2Et (0.86 mL, 641 mg, 4.96 mmol) and chloroacetyl chloride (0.12 mL, 168 mg, 1.49 mmol). The mixture was stirred at ambient temperature for 2 h. 10 mL of H2O was added and the mixture was extracted with DCM (3 × 10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was subjected to flash column chromatography (hexane - ethyl acetate) to obtain N-(5-bromo-1-(hydroxymethyl)-2,3-dihydro-1H-indene-1-yl)-2-chloroacetamide.

[0267] To a solution of N-(5-bromo-1-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)-2-chloroacetamide (278 mg, 0.87 mmol) in THF (8 mL) was added NaH (60% dispersion in mineral oil, 84 mg, 2.18 mmol). The mixture was stirred at ambient temperature for 15 minutes. H2O (10 mL) was added and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was subjected to flash column chromatography (hexane - ethyl acetate) to afford the title compound.

[0268] General method Z:

[0269]

Chemical formula

[0270] 5-Bromo-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one Into a vial were placed (1-amino-5-bromo-2,3-dihydro-1H-inden-1-yl)methanol (500 mg, 2.07 mmol) and THF (15 mL). Triphosgene (613 mg, 2.07 mmol) was added slowly. The resulting mixture was heated to 70 °C for 2 hours. The mixture was allowed to cool to ambient temperature. Aqueous NaHCO3 solution (15 mL, saturated aqueous solution) was added and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was subjected to flash column chromatography (hexane - ethyl acetate) to afford the title compound.

[0271] Alternatively, 1,1'-carbonyldiimidazole and N(iPr)2Et were used instead of triphosgene without heating.

[0272] General method AA:

[0273]

Chemical formula

[0274] 4-Ethynyl-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine To a vial were added 2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carbaldehyde (310 mg, 1.43 mmol) and methanol (12 mL). To this were added potassium carbonate (197 mg, 1.43 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (0.278 mL, 1.85 mmol), and the reaction mixture was stirred at ambient temperature for 16 h. This was diluted with ethyl acetate and washed with saturated sodium bicarbonate and saturated sodium chloride solutions. This was dried over anhydrous sodium sulfate, filtered, and concentrated. This was purified by flash chromatography (hexane - ethyl acetate) to give the title compound.

[0275]

Chemical formula

[0276] 2-[(2S)-2-Methylazetidin-1-yl]-4-[1-(oxetan-3-yl)-1,2,3-triazol-4-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine To a solution of 4-ethynyl-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30 mg, 0.14 mmol) and 3-azidooxetane (14 mg, 0.14 mmol) in tetrahydrofuran (0.7 mL) was added copper(I) thiophene-2-carboxylate (3 mg, 0.014 mmol), and the reaction mixture was stirred at ambient temperature for 3 h. This was concentrated and purified by flash chromatography (hexane - ethyl acetate) to give the title compound.

[0277] General method AB:

[0278]

Chemical formula

[0279] tert-Butyl N-(6-bromo-1,1-dioxo-2,3-dihydrobenzothiophen-3-yl)carbamate To a solution of 6-bromo-1,1-dioxo-2,3-dihydrobenzothiophen-3-amine (400 mg, 1.5 mmol) in tetrahydrofuran (8.3 mL) was added triethylamine (0.425 mL, 3 mmol) and tert-butoxycarbonyl tert-butyl carbonate (400 mg, 1.8 mmol), and the reaction mixture was stirred at ambient temperature for 16 h. This was diluted with ethyl acetate and washed with 10% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride solutions. This was dried over anhydrous sodium sulfate, filtered, and concentrated. This was purified by flash chromatography (hexane-ethyl acetate) to afford the title compound.

[0280] General method AC:

[0281]

Chemical formula

[0282] (2S,3R)-1-[4-[3-[(Cyclopropyl-methyl-oxo-λ 6 -sulfanylidene)amino]phenyl]-7,7-difluoro-5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol To a solution of (2S,3R)-1-[7,7-difluoro-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol (50 mg, 0.11 mmol) in dimethylformamide (1 mL) was added cyclopropyl-imino-methyl-oxo-λ 6- Sulfan (27 mg, 0.23 mmol), boric acid (14 mg, 0.23 mmol), and copper(II) acetate (10 mg, 0.056 mmol) were added, and the reaction mixture was opened to the atmosphere and stirred at ambient temperature for 16 h. This was diluted with ethyl acetate and washed with 10% ammonium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride solutions. This was dried over anhydrous sodium sulfate, filtered, and concentrated. This was purified by flash chromatography (DCM - MeOH) to give the title compound.

[0283] General method AD:

[0284]

Chemical formula

[0285] (5S)-5’-Bromo-3-methyl-spiro[imidazolidine-5,1’-indane]-2,4-dione (5S)-5’-Bromospiro[imidazolidine-5,1’-indane]-2,4-dione (100 mg, 0.36 mmol) and potassium carbonate (49 mg, 0.36 mmol) were suspended, and methyl iodide (0.022 mL, 0.36 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 h. This was precipitated by the addition of water, the solid was collected, washed with water, and dried under vacuum to give the title compound.

[0286] General method AE:

[0287]

Chemical formula

[0288] Ethyl 3-(1-azido-5-bromo-2,3-dihydro-1H-inden-1-yl)propanoate To 5-bromo-1-methylene-2,3-dihydro-1H-indene (2500 mg, 12 mmol) in iPrOH (180 mL) were added Fe(OAc)2 (104 mg, 0.6 mmol), TMS-N3 (3.2 mL, 24 mmol), ethyl diazoacetate (2.5 mL, 24 mmol), tBu-OOH (4.6 mL, 36 mmol), and TEA (3.3 mL, 24 mmol). The mixture was stirred at 50 °C for 12 h, concentrated, 20 mL of toluene was added, re-concentrated, and then subjected to flash column chromatography (DCM-MeOH) to afford the title compound.

[0289]

Chemical formula

[0290] Ethyl 3-(1-amino-5-bromo-2,3-dihydro-1H-indene-1-yl)propanoate To ethyl 3-(1-azido-5-bromo-2,3-dihydro-1H-indene-1-yl)propanoate (1200 mg, 3.55 mmol) in MeOH (60 mL) were added SnCl2 (1600 mg, 7.1 mmol), thiophenol (1.45 mL, 14.2 mmol), and TEA (2.47 mL, 17.7 mmol). The mixture was stirred at ambient temperature for 30 h. Ethyl acetate (100 mL) was added and the solid was filtered off. The organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, concentrated, and subjected to flash column chromatography (DCM-MeOH) to afford the title compound.

[0291]

Chemical formula

[0292] 5-Bromo-2,3-dihydrospiro[indene-1,2'-pyrrolidine]-5'-one Ethyl 3-(1-amino-5-bromo-2,3-dihydro-1H-inden-1-yl)propanoate (735 mg, 2.35 mmol) was heated in toluene (8 mL) at 100 °C for 12 h. After cooling to ambient temperature, the solid was filtered off to afford the title compound.

[0293] General method AF:

[0294]

Chem.

[0295] 5-Bromo-7-(methylthio)-2,3-dihydrobenzofuran To a vial were added 5-bromo-7-iodo-2,3-dihydrobenzofuran (885 mg, 2.27 mmol, 1.0 equiv), dimethyldisulfide (0.29 mL, 3.27 mmol, 1.2 mmol), copper(II) acetate (49.5 mg, 0.27 mmol, 0.10 equiv), potassium hydroxide (306 mg, 5.45 mmol, 2.0 equiv), and tetrabutylammonium bromide (43.9 mg, 0.14 mmol, 0.05 equiv). The vial was capped and heated at 100 °C for 12 h. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous component was extracted twice with EtOAc, the organic layer was dried over magnesium sulfate, filtered, and concentrated to afford the title compound.

[0296] General method AG:

[0297]

Chem.

[0298] (2-(Benzyloxy)-5-bromophenyl)(imino)(methyl)-λ 6 -sulfanone Into a vial were added (2-(benzyloxy)-5-bromophenyl)(methyl)sulfane (618 mg, 2.00 mmol, 1.0 equiv) and methanol (15 mL). Ammonium carbonate (288 mg, 3.00 mmol, 1.5 equiv) was added, followed by iodosobenzene diacetate (1482 mg, 4.60 mmol, 2.3 equiv). The vial was quickly sealed with a septum and stirred vigorously at room temperature for 5 h. Then, the solvent was removed under reduced pressure and the residue was purified by silica gel flash column chromatography (0 - 5% MeOH in DCM) to give the title compound.

[0299] General method AH:

[0300]

Chem.

[0301] 2-Benzyl-4-bromobenzamide Into a vial were added 2-benzyl-4-bromobenzoic acid (200 mg, 0.69 mmol, 1.0 equiv) and HATU (392 mg, 1.03 mmol, 1.5 equiv) in DCM (5 mL). DIPEA (120 μL, 0.69 mmol, 1 equiv) was added and the reaction mixture was stirred vigorously at room temperature for 10 min. Then, ammonia in 1,4-dioxane (0.5 M solution 6.87 mL, 5 equiv) was added and the reaction mixture was stirred at room temperature for 30 min. The solid was filtered off (washed with DCM), the combined solutions were concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (0 - 5% MeOH in DCM) to give the title compound 2-benzyl-4-bromobenzamide.

[0302] General method AI:

[0303]

Chem.

[0304] N-(6-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)chroman-4-yl)methanesulfonamide Into a vial were placed 6-bromochroman-4-amine (50 mg, 0.19 mmol, 0.91 eq), DIPEA (146 μL, 0.84 mmol, 4 eq) and dry NMP (1 mL) under argon, and the reaction mixture was stirred at room temperature for 1 minute. Then, methanesulfonyl chloride (23 μL, 0.23 mmol, 1.1 eq) was added under argon, and the reaction mixture was stirred at room temperature for 20 minutes. Thereafter, (S)-2-(2-Methylazetidin-1-yl)-4-(tributylstannyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100 mg, 0.21 mmol, 1.0 eq), Pd(PPh3)2Cl2 (15 mg, 0.021 mmol, 10 mol%), XPhos (9.4 mg, 0.021 mmol, 10 mol%), CuI (3.9 mg, 0.021 mmol, 10 mol%) were added. The reaction mixture was purged with argon 5 times and heated at 110 °C for 1 hour under argon. Then, the mixture was cooled to room temperature, diluted with DMSO (1 mL) and water (0.2 mL), and acidified with trifluoroacetic acid (16 μL, 0.21 mmol). The solid was filtered off, and the solution was purified by preparative reverse-phase HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[0305] Compound Example

[0306]

Chemical Structure

[0307] Example 1: Methyl (S)-3-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate In the same manner as General Method A, methyl 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0308]

Chemical formula

[0309] Example 2: Methyl (S)-3-(2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate In the same manner as General Method A, methyl 3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0310]

Chemical formula

[0311] Example 3: Methyl (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetate In the same manner as General Method A, methyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0312]

Chemical formula

[0313] Example 4: (S)-3-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoic acid The title compound was prepared according to General Method C.

[0314]

Chemical Structure

[0315] Example 5: (S)-3-(2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoic acid Using methyl (S)-3-(2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate instead of (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoic acid, the title compound was prepared in a similar manner to General Method C.

[0316]

Chemical Structure

[0317] Example 6: (S)-2-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetic acid Using methyl (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetate instead of (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoic acid, the title compound was prepared in a similar manner to General Method C.

[0318]

Chemical Structure

[0319] Example 7: (S)-3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzonitrile In the same manner as General Method A, (3-cyanophenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0320] [Chemical formula]

[0321] Example 8: (S)-3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide Example 9: (S)-3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid The title compound was prepared according to General Method J.

[0322] [Chemical formula]

[0323] Example 10: (S)-2-(2-Methylazetidin-1-yl)-4-phenyl-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine In the same manner as General Method A, phenylboronic acid and 2,4-dichloro-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently, the title compound was prepared in the same manner as General Method B.

[0324] [Chemical formula]

[0325] Example 11: (S)-1-Methyl-5-(2-methylazetidin-1-yl)-7-phenyl-1H-pyrazolo[4,3-d]pyrimidine In the same manner as General Method A, phenylboronic acid and 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and then the title compound was prepared in the same manner as General Method B.

[0326]

Chemical Structure

[0327] Example 12: (S)-2-(2-Methylazetidin-1-yl)-4-phenylfuro[3,2-d]pyrimidine In the same manner as General Method A, phenylboronic acid and 2,4-dichlorofuro[3,2-d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and then the title compound was prepared in the same manner as General Method B.

[0328]

Chemical Structure

[0329] Example 13: (S)-5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole In the same manner as General Method A, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole was used instead of 3-pyridylboronic acid, and then the title compound was prepared in the same manner as General Method B.

[0330]

Chemical Structure

[0331] Example 14: (S)-4-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole In the same manner as General Method A, 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0332]

Chemical formula

[0333] Example 15: (S)-2-(2-Methylazetidin-1-yl)-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared according to General Method A, followed by General Method B.

[0334]

Chemical formula

[0335] Example 16: (S)-2-(2-Methylazetidin-1-yl)-4-(pyridin-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In the same manner as General Method A, pyrimidin-5-ylboronic acid was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0336]

Chemical formula

[0337] Example 17: (S)-4-(1-Methyl-1H-pyrazol-3-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In the same manner as general method A, 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as general method B.

[0338]

Chemical formula

[0339] Example 18: (S)-2-(2-Methylazetidin-1-yl)-4-(1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In the same manner as general method A, tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as general method B. In the first step, the tert-butyl carboxylate was cleaved under the reaction conditions.

[0340]

Chemical formula

[0341] Example 19: (S)-2-(2-Methylazetidin-1-yl)-4-(1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In the same manner as general method A, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as general method B. In the first step, the tert-butyl carboxylate was cleaved under the reaction conditions.

[0342]

Chemical formula

[0343] Example 20: (S)-4-(1-Methyl-1H-pyrazol-5-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In the same manner as General Method A, 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, the title compound was prepared.

[0344]

Chemical Structure

[0345] Example 21: (S)-2-(2-Methylazetidin-1-yl)-4-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine Into a vial were added 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1.0 equivalent), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (60.7 mg, 0.30 mmol, 1.4 equivalents), Pd(dppf)Cl2-DCM complex (8.8 mg, 0.011 mmol, 5 mol%), CuCl (20.9 mg, 0.21 mmol, 1 equivalent), Cs2CO3 (138 mg, 0.42 mmol, 2.0 equivalents), and DMF (2 mL). The mixture was sparged with argon and heated at 100 °C for 24 hours. The mixture was concentrated and subjected to flash column chromatography (hexane - ethyl acetate) to obtain 2-chloro-4-(2-pyridyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, which was subsequently subjected to General Method B to obtain the title compound.

[0346]

Chemical Structure

[0347] Example 22: (S)-2-(2-Methylazetidin-1-yl)-4-(pyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine Into a vial were added 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1.0 equiv), 4-pyridylboronic acid (60.7 mg, 0.30 mmol, 1.4 equiv), Pd(dppf)Cl2-DCM complex (8.8 mg, 0.011 mmol, 5 mol%), CuCl (20.9 mg, 0.21 mmol, 1 equiv), Cs2CO3 (138 mg, 0.42 mmol, 2.0 equiv), and DMF (2 mL). The mixture was sparged with argon and heated at 100 °C for 24 h. The mixture was concentrated and subjected to flash column chromatography (hexane-ethyl acetate) to obtain 2-chloro-4-(2-pyridyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, which was subsequently subjected to General Method B to obtain the title compound.

[0348]

Chemical Structure

[0349] Example 23: (S)-4-(1-Methyl-1H-pyrazol-4-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In a manner similar to General Method A, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole was used instead of 3-pyridylboronic acid, and subsequently, in a manner similar to General Method B, the title compound was prepared.

[0350]

Chemical Structure

[0351] Example 24: (S)-3-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoic acid A vial was charged with (S)-2-(2-methylazetidin-1-yl)-4-(1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (12 mg, 0.033 mmol, 1 equiv), K2CO3 (9.0 mg, 0.065 mmol, 2 equiv) and MeCN (0.5 mL), followed by methyl prop-2-enoate (84 mg, 0.975 mmol, 30 equiv). The sealed vial was heated at 120 °C for 2 h, then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL), and NaOH (2 M aqueous solution, 0.5 mL) was added. The mixture was heated at 60 °C for 20 min. The mixture was cooled to ambient temperature, concentrated and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound.

[0352]

Chemical formula

[0353] Example 25: (S)-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoic acid A vial was charged with 2-[(2S)-2-methylazetidin-1-yl]-4-(1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (6 mg, 0.016 mmol, 1 equiv), K2CO3 (4.5 mg, 0.033 mmol, 2 equiv) and MeCN (0.5 mL), followed by methyl prop-2-enoate (42 mg, 0.49 mmol, 30 equiv). The sealed vial was heated at 120 °C for 15 min, then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL), and NaOH (2 M aqueous solution, 0.5 mL) was added. The mixture was heated at 60 °C for 20 min. The mixture was cooled to ambient temperature, concentrated and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound.

[0354]

Chemical formula

[0355] Example 26: (S)-5-(2-Methylazetidin-1-yl)-7-phenylthiazolo[5,4-d]pyrimidine In the same manner as General Method A, phenylboronic acid and 5,7-dichlorothiazolo[5,4-d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently, the title compound was prepared in the same manner as General Method B.

[0356]

Chemical Structure

[0357] Example 27: (S)-2-Methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method A, 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0358]

Chemical Structure

[0359] Example 28: (S)-N-Methyl-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method A, [3-(methylcarbamoyl)phenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0360]

Chemical Structure

[0361] Example 29: (S)-3-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propenamide Methyl 3-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]propanoate (35 mg, 0.10 mmol, 1.0 eq), EtOH (1 mL), and NH4OH (25% aqueous solution, 2 mL) were placed in a vial and heated at 100 °C for 18 h. The reaction mixture was cooled to ambient temperature, concentrated, and subjected to HPLC to afford the title compound.

[0362]

Chemical formula

[0363] Example 30: 6-Cyclopropyl-2-((S)-2-methylazetidin-1-yl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine Using a method similar to General Method H, methyl 4-cyclopropyl-2-oxocyclopentane-1-carboxylate was used instead of 2-oxobicyclo[3.1.0]hexane-3-carboxylate, and phenylboronic acid was used instead of (3-carbamoylphenyl)boronic acid to prepare the title compound.

[0364]

Chemical formula

[0365] Example 31: 2-((S)-2-Methylazetidin-1-yl)-4-phenyl-5,6,7,8-tetrahydro-5,8-methanoquinazoline In the same manner as General Method H, methyl 3-oxobicyclo[2.2.1]heptane-2-carboxylate was used instead of 2-oxobicyclo[3.1.0]hexane-3-carboxylate, and phenylboronic acid was used instead of (3-carbamoylphenyl)boronic acid to prepare the title compound.

[0366]

Chemical formula

[0367] Example 32: 3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method A, (3-carbamoylphenyl)boronic acid was used instead of 3-pyridylboronic acid, and then in General Method B, (2S,3R)-2-methylazetidin-3-ol hydrochloride was used instead of (2S)-2-methylazetidine (R)-camphorsulfonate to prepare the title compound.

[0368]

Chemical formula

[0369] Example 33: 3-(2-((S)-2-Methylazetidin-1-yl)-5,6,7,8-tetrahydro-5,8-methanoquinazolin-4-yl)benzamide In the same manner as General Method H, methyl 3-oxobicyclo[3.1.0]heptane-2-carboxylate was used instead of 2-oxobicyclo[2.2.1]hexane-3-carboxylate to prepare the title compound.

[0370]

Chemical formula

[0371] Example 34: (S)-2-Methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiazole In the same manner as General Method A, 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0372]

Chemical formula

[0373] Example 35: (S)-1-Methyl-5-(2-methylazetidin-1-yl)-7-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidine In the same manner as General Method A, 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently, the title compound was prepared in the same manner as General Method B. In the first step, the tert-butyl carboxylate was cleaved under the reaction conditions.

[0374]

Chemical formula

[0375] Example 36: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiazole The title compound was prepared in the same manner as General Method E, using tributyl(thiazol-4-yl)stannane instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate.

[0376] [Chemical formula]

[0377] Example 37: (S)-3-(1-Methyl-5-(2-methylazetidin-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)benzenesulfonamide In the same manner as General Method A, 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and then the title compound was prepared in the same manner as General Method B.

[0378] [Chemical formula]

[0379] Example 38: 3-(5-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)benzenesulfonamide In the same manner as General Method A, 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and then (2S,3R)-2-methylazetidin-3-ol hydrochloride was used instead of (2S)-2-methylazetidine in the same manner as General Method B to prepare the title compound.

[0380] [Chemical formula]

[0381] Example 39: (S)-5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazole In the same manner as General Method A, 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, the title compound was prepared.

[0382]

Chemical Structure

[0383] Example 40: (S)-N-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetamide In the same manner as General Method A, (3-Acetamidophenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, the title compound was prepared.

[0384]

Chemical Structure

[0385] Example 41: N-(3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetamide In the same manner as General Method A, (3-Acetamidophenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, (2S,3R)-2-Methylazetidin-3-ol hydrochloride was used instead of (2S)-2-methylazetidine (R)-camphorsulfonate to prepare the title compound.

[0386]

Chemical Structure

[0387] Example 42: (S)-N-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanesulfonamide In the same manner as General Method A, [3-(Methanesulfonamido)phenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0388]

Chemical Structure

[0389] Example 43: N-(3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanesulfonamide In the same manner as General Method A, [3-(Methanesulfonamido)phenyl]boronic acid was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, (2S,3R)-2-Methylazetidin-3-ol hydrochloride was used instead of (2S)-2-methylazetidine (R)-camphorsulfonate to prepare the title compound.

[0390]

Chemical Structure

[0391] Example 44: (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazole In the same manner as General Method A, 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0392]

Chemical Structure

[0393] Example 45: (S)-2-(2-Methylazetidin-1-yl)-4-(thiophen-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In a manner similar to General Method E, 5-tributylstannylthiophene-2-carbonitrile was used instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate, and then in a manner similar to General Method B, 2-chloro-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used instead of 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine to prepare the title compound.

[0394] [Chemical formula]

[0395] Example 46: 2-(3-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid Into a vial, ethyl (trans)-2-(3-bromophenyl)cyclopropanecarboxylate (200 mg, 0.74 mmol, 1.0 equiv), Pd(dppf)Cl2-DCM complex (59 mg, 0.074 mmol, 10 mol%), B2pin2 (283 mg, 1.11 mmol, 1.5 equiv), and KOAc (219 mg, 2.23 mmol, 3.0 equiv) were placed. The vial was purged with nitrogen and 1,4-dioxane (3.0 mL) was added. The mixture was heated at 100 °C for 1 h, cooled to ambient temperature, and subjected to flash column chromatography (0 - 100% hexane / ethyl acetate) to obtain ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate.

[0396] Ethyl 2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarboxylate was prepared in a similar manner to General Method A using 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0397] The title compound was prepared in a similar manner to General Method C using ethyl 2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarboxylate instead of methyl (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate.

[0398] [Chemical formula]

[0399] Example 47: 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid The title compound was prepared in a similar manner to General Method A using 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate instead of 3-pyridylboronic acid, and then in a similar manner to General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride instead of (2S)-2-methylazetidine.

[0400] [Chemistry]

[0401] Example 48: 2-(3-(2-((2S,3R)-3-Fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid Using 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate in place of 3-pyridylboronic acid in a manner similar to General Method A, and subsequently using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride in place of (2S)-2-methylazetidine (R)-camphorsulfonate in a manner similar to General Method B, the title compound was prepared.

[0402] [Chemistry]

[0403] Example 49: (S)-5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carbonitrile Using 5-tributylstannylthiophene-2-carbonitrile in place of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate in a manner similar to General Method E, the title compound was prepared.

[0404] [Chemistry]

[0405] Example 50: (S)-2-(2-Methylazetidin-1-yl)-4-(4-(piperazin-1-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (S)-tert-Butyl 4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate was prepared in a manner similar to General Method A using (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate in place of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by a method similar to General Method I to afford the title compound.

[0406] [Chemical Formula]

[0407] Example 51: (S)-tert-Butyl (2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide)ethyl)carbamate The title compound was prepared in a manner similar to General Method G using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and tert-butyl (2-aminoethyl)carbamate in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0408] [Chemical Formula]

[0409] Example 52: (S)-N-(2-Aminoethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in the same manner as General Method I, using tert-butyl (S)-(2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide)ethyl)carbamate instead of (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate.

[0410]

Chemical formula

[0411] Example 53: (S)-N-(2-(Methylamino)ethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in the same manner as General Method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and tert-butyl (2-aminoethyl)(methyl)carbamate instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, and then in the same manner as General Method I.

[0412]

Chemical formula

[0413] (S)-N-(2-Hydroxyethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was prepared in a similar manner to General Method F, using 3-bromo-N-(2-hydroxyethyl)benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0414]

Chemical formula

[0415] (S)-2-(2-Methylazetidin-1-yl)-4-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a similar manner to General Method A, using (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.

[0416]

Chemical formula

[0417] (S)-5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide According to the general method J, the title compound was prepared using (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carbonitrile instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzonitrile.

[0418] [Chemical formula]

[0419] Example 57: 5-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide In a manner similar to general method E, using 5-tributylstannylthiophene-2-carbonitrile and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and then in a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine, and in a manner similar to general method J, the title compound was prepared.

[0420] [Chemical formula]

[0421] Example 58: 5-(2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide In the same manner as general method E, 5-tributylstannylthiophene-2-carboxylic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively. Subsequently, in the same manner as general method B, (2S,3R)-3-fluoro-2-methylazetidine was used instead of (2S)-2-methylazetidine, and in the same manner as general method J, the title compound was prepared.

[0422]

Chemical formula

[0423] Example 59: N-((1S * ,2S * )-2-hydroxycyclobutyl)-3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as general method G, (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and rac-(1S * ,2S * )-2-aminocyclobutanol were used instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, to prepare the title compound.

[0424]

Chemical formula

[0425] Example 60: N-((1S * ,2R *)-2-Hydroxycyclobutyl)-3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and rac-(1S * ,2R * )-2-aminocyclobutanol instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia respectively, the title compound was prepared.

[0426]

Chemical formula

[0427] Example 61: (S)-N-(2-Hydroxyethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and ethanolamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia respectively, the title compound was prepared.

[0428]

Chemical formula

[0429] Example 62: 3-((5R,8S)-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydro-5,8-methanoquinazolin-4-yl)benzamide Example 63: 3-((5S,8R)-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydro-5,8-methanoquinazolin-4-yl)benzamide The isomers were separated by SFC (25% MeOH in CO2, CHIRALPAK IG, 100×4.6 mm, 3 mL / min) (see Example 33).

[0430]

Chemical Structure

[0431] Example 64: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-(1H-pyrazol-4-yl)benzamide The title compound was prepared in a similar manner to General Method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and 1H-pyrazol-4-amine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0432]

Chemical Structure

[0433] Example 65: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-(1H-pyrazol-3-yl)benzamide In the same manner as general method G, the title compound was prepared using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and 1H-pyrazol-3-amine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0434]

Chem.

[0435] Example 66: (S)-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)glycine In the same manner as general method G, (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and glycine methyl were used instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, and then the title compound was prepared in the same manner as general method C.

[0436]

Chem.

[0437] Example 67: (S)-1-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamido)cyclopropane-1-carboxylic acid In the same manner as General Method G, (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl 1-aminocyclopropane-1-carboxylate hydrochloride were used instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, and then the title compound was prepared in the same manner as General Method C.

[0438]

Chemical formula

[0439] Example 68: (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidine-3-carboxylic acid In the same manner as General Method G, (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl azetidine-3-carboxylate hydrochloride were used instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, and then the title compound was prepared in the same manner as General Method C.

[0440]

Chemical formula

[0441] Example 69: (S)-2-(1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidin-3-yl)acetic acid In the same manner as general method G, (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl 2-(azetidin-3-yl)acetate trifluoroacetate were used instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, and then the title compound was prepared in the same manner as general method C.

[0442]

Chemical formula

[0443] Example 70: (S)-2-(5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazol-3-yl)acetic acid tert-Butyl (S)-2-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazol-3-yl)acetate was prepared in the same manner as general method F, using tert-butyl 2-(5-bromo-1H-indazol-3-yl)acetate instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0444] TFA (0.5 mL) and DCM (0.5 mL) were added to a vial containing tert-butyl (S)-2-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazol-3-yl)acetate. The mixture was heated at 50 °C for 30 minutes. The mixture was cooled to room temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[0445]

Chemical formula

[0446] Example 71: (S)-3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole In the same manner as General Method A, 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole was used instead of 3-pyridylboronic acid, and subsequently, the title compound was prepared in the same manner as General Method B.

[0447]

Chemical Structure

[0448] Example 72: (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide The title compound was prepared in the same manner as General Method F, using 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0449]

Chemical Structure

[0450] Example 73: (S)-1-Methyl-N-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)-1H-imidazole-4-sulfonamide The title compound was prepared according to General Method K.

[0451]

Chemical Structure

[0452] Example 74: (S)-((3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)sulfonyl)glycine In the same manner as General Method K, using 3-bromobenzenesulfonyl chloride and methyl glycinate instead of 1-methylimidazole-4-sulfonyl chloride and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline respectively, and then in the same manner as General Method F, using methyl ((3-bromophenyl)sulfonyl)glycinate instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, and then in the same manner as General Method C, the title compound was prepared.

[0453]

Chemical Structure

[0454] Example 75: (S)-2-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzyl)isothiazolidine 1,1-dioxide In the same manner as General Method D, using (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and then in the same manner as General Method E, using 2-(3-bromobenzyl)isothiazolidine 1,1-dioxide instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine to prepare the title compound.

[0455]

Chemical Structure

[0456] Example 76: (S)-3,5-Dimethyl-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)isoxazole-4-sulfonamide The title compound was prepared in the same manner as General Method K, using 3,5-dimethylisoxazole-4-sulfonyl chloride instead of 1-methylimidazole-4-sulfonyl chloride.

[0457]

Chemical formula

[0458] Example 77: (S)-1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidine-2-carboxylic acid The title compound was prepared in the same manner as General Method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl (S)-azetidine-2-carboxylate hydrochloride instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, and then in the same manner as General Method C.

[0459]

Chemical formula

[0460] Example 78: (R)-1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidine-2-carboxylic acid In the same manner as General Method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl (R)-azetidine-2-carboxylate hydrochloride instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia respectively, and then in the same manner as General Method C, the title compound was prepared.

[0461]

Chemical formula

[0462] Example 79: (rac)-3-(2-(6-azabicyclo[3.2.0]heptan-6-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide In the same manner as General Method B, using 6-azabicyclo[3.2.0]heptane and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide instead of (2S)-2-methylazetidine 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine respectively, the title compound was prepared.

[0463]

Chemical formula

[0464] Example 80: (rac)-3-(2-((1S * ,5S * ,6R * )-6-hydroxy-2-azabicyclo[3.2.0]heptan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide In the same manner as general method B, using (rac)-(1S * ,5S * ,6R * )-2-azabicyclo[3.2.0]heptan-6-ol hydrochloride and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, the title compound was prepared.

[0465]

Chemical formula

[0466] Example 81: (S)-2-(N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)acetic acid In the same manner as general method K, using ethyl 2-(chlorosulfonyl)acetate instead of 1-methylimidazole-4-sulfonyl chloride, and then in the same manner as general method C, the title compound was prepared.

[0467]

Chemical formula

[0468] Example 82: 2-(N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)acetic acid In a manner similar to General Method A, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 3-pyridylboronic acid, and then in a manner similar to General Method K, ethyl 2-(chlorosulfonyl)acetate was used instead of 1-methylimidazole-4-sulfonyl chloride, and then in a manner similar to General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (2S)-2-methylazetidine, and then in a manner similar to General Method C, the title compound was prepared.

[0469] [Chemical formula]

[0470] Example 83: (S)-3-(N-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)propanoic acid In a manner similar to General Method K, methyl 3-(chlorosulfonyl)propanoate was used instead of 1-methylimidazole-4-sulfonyl chloride, and then in a manner similar to General Method C, the title compound was prepared.

[0471] [Chemical formula]

[0472] Example 84: (S)-N-(5-(N-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)thiazol-2-yl)acetamide In a manner similar to General Method K, 2-acetamidothiazole-5-sulfonyl chloride was used instead of 1-methylimidazole-4-sulfonyl chloride to prepare the title compound.

[0473] [Chemical formula]

[0474] Example 85: (S)-5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole-3-carboxamide The title compound was prepared in the same manner as General Method F, using 5-bromoisothiazole-3-carboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0475]

Chemical formula

[0476] Example 86: (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide The title compound was prepared according to General Method F.

[0477]

Chemical formula

[0478] Example 87: (S)-8-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one In a manner similar to General Method Q, using tert-butyl (R)-(2-hydroxypropyl)carbamate instead of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate, and subsequently in a manner similar to General Method F, using (S)-8-bromo-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and then subsequently in General Method M, and then in a manner similar to General Method B, using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine, the title compound was prepared.

[0479]

Chem.

[0480] Example 88: (S)-2-(2-Methylazetidin-1-yl)-4-(3-((methylsulfonyl)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In a manner similar to General Method F, using 2-[(3-bromophenyl)methylsulfonyl]acetic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, the title compound was prepared. The in situ decarboxylated product was the only product.

[0481]

Chem.

[0482] Example 89: (1S,2S)-2-(3-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid Example 90: (1R,2R)-2-(3-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid The isomers were separated by SFC (25% MeOH in CO2, CHIRALPAK AD-H, 100×4.6 mm, 3 mL / min). (See Example 46)

[0483]

Chemical formula

[0484] Example 91: (S)-N-(2-Hydroxyethyl)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as in General Method A, (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide were each used instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid to prepare the title compound.

[0485]

Chemical formula

[0486] Example 92: (R)-3-(2-(2-(Hydroxymethyl)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide In the same manner as General Method B, using (R)-azetidin-2-ylmethanol and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide in place of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, the title compound was prepared.

[0487]

Chem.

[0488] Example 93: 4-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method B, using tert-butyl ((2S,3R)-2-methylazetidin-3-yl)carbamate hydrochloride and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide in place of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and then in the same manner as General Method I, the title compound was prepared.

[0489]

Chem.

[0490] Example 94: (R)-8-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one In the same manner as general method Q, tert-butyl (S)-(2-hydroxypropyl)carbamate was used instead of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate, and subsequently, in the same manner as general method F, (R)-8-bromo-2-methyl-3,4-dihydrobenzof[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and subsequently, following general method M and then in the same manner as general method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0491]

Chemical formula

[0492] Example 95: (R)-4-(2-(2-(Hydroxymethyl)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as general method B, (R)-azetidin-2-ylmethanol and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide were used instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0493]

Chemical formula

[0494] Example 96: 2-Cyclopropyl-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared according to the general method L.

[0495]

Chemical formula

[0496] Example 97: 2-Cyclobutyl-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a similar manner to the general method L, using cyclobutylzinc bromide instead of cyclopropylzinc bromide.

[0497]

Chemical formula

[0498] Example 98: 2-(Bicyclo[2.2.1]heptan-2-yl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a similar manner to the general method L, using bicyclo[2.2.1]heptan-2-ylzinc bromide instead of cyclopropylzinc bromide.

[0499]

Chemical formula

[0500] Example 99: 2-(Azetidin-3-yl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a similar manner to the general method L, using (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc iodide instead of cyclopropylzinc bromide, and then in a similar manner to the general method I.

[0501]

Chemical formula

[0502] Example 100: (S)-2-Methyl-5-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)-1,3,4-oxadiazole The title compound was prepared in the same manner as General Method F, using 4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0503]

Chemical Structure

[0504] Example 101: (S)-4-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in the same manner as General Method F, using [4-(1-methylimidazol-2-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0505]

Chemical Structure

[0506] Example 102: (S)-4-(4-(1H-pyrazol-1-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in the same manner as General Method F, using (4-pyrazol-1-ylphenyl)boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0507]

Chemical Structure

[0508] Example 103: (S)-4-(4-(1H-Pyrazol-5-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in the same manner as General Method F, using [4-(1H-pyrazol-5-yl)phenyl]boronic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0509]

Chemical formula

[0510] Example 104: (S)-4-(4-(1H-Tetrazol-5-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in the same manner as General Method F, using [4-(1H-tetrazol-5-yl)phenyl]boronic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0511]

Chemical formula

[0512] Example 105: 4-(2-(2,3-Dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in the same manner as General Method B, using 2,3-dimethylazetidine hydrochloride and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide in place of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0513]

Chemical formula

[0514] Example 106: 4-(2-((2S,3R)-2,3-Dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide Example 107: 4-(2-((2S,3S)-2,3-Dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide Example 108: 4-(2-((2R,3S)-2,3-Dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide Example 109: 4-(2-((2R,3R)-2,3-Dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The isomers were separated by SFC (20% MeOH in CO2, CHIRALPAK IA, 100×4.6 mm, 3 mL / min).

[0515]

Chemical formula

[0516] Example 110: (S)-2-Methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]thiazole The title compound was prepared in a similar manner to General Method F, using ethyl 2-(5-chlorobenzo[d]thiazol-2-yl)acetate instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one. The in situ decarboxylation product was the only product.

[0517]

Chemical formula

[0518] Example 111: 4-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a similar manner to General Method B, using (rac)-2-ethynylazetidine hydrochloride and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0519]

Chemical formula

[0520] Example 112: 2-(3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide The title compound was prepared according to General Method G.

[0521]

Chemical formula

[0522] Example 113: (1S,2S)-2-(3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid Example 114: (1R,2R)-2-(3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid The isomers were separated by SFC (35% MeOH in CO2, CHIRALPAK AD-H, 100×4.6 mm, 3 mL / min).

[0523] [Chemical formula]

[0524] Example 115: 1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)bicyclo[2.1.1]hexane-5-carboxylic acid The title compound was prepared in a similar manner to General Method F using 1-(3-bromophenyl)bicyclo[2.1.1]hexane-5-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one. The in situ decarboxylated product was the only product.

[0525] [Chemical formula]

[0526] Example 116: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole The title compound was prepared in a similar manner to General Method F using 5-bromoisophthalamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0527] [Chemical formula]

[0528] Example 117: 4-(2-(2-methyl-3-oxocyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a similar manner to General Method A, using 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0529]

Chemical formula

[0530] Example 118: (S)-2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)imidazo[5,1-b]thiazole-7-carboxylic acid The title compound was prepared according to General Method E, followed by General Method C.

[0531]

Chemical formula

[0532] Example 119: (S)-2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)imidazo[5,1-b]thiazole-7-carboxamide The title compound was prepared in a similar manner to General Method G, using (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)imidazo[5,1-b]thiazole-7-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[0533]

Chemical formula

[0534] Example 120: (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazol-3-ol In the same manner as General Method D, 6-bromo-1H-indazol-3-ol was used instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and subsequently, the title compound was prepared in the same manner as General Method E.

[0535]

Chemical Structure

[0536] Example 121: (S)-2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)imidazo[2,1-b]thiazole In the same manner as General Method D, 2-bromoimidazo[2,1-b]thiazole was used, and subsequently, the title compound was prepared in the same manner as General Method E.

[0537]

Chemical Structure

[0538] Example 122: (S)-2-Fluoro-5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide In the same manner as General Method F, 5-bromo-2-fluoro-benzenesulfonamide was used instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one to prepare the title compound.

[0539]

Chemical Structure

[0540] Example 123: (S)-2-Methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was prepared in the same manner as General Method F, using 5-bromo-2-methyl-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0541]

Chemical formula

[0542] Example 124: (S)-4-(3-(2-methylazetidin-1-yl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene-5-yl)benzamide The title compound was prepared in the same manner as General Method A, using 5-chloro-3-(methylsulfonyl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene and (4-carbamoylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, and then in the same manner as General Method B.

[0543]

Chemical formula

[0544] Example 125: 4-(3-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene-5-yl)benzamide In the same manner as general method A, 5-chloro-3-(methylsulfonyl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene and (4-carbamoylphenyl)boronic acid were used instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, and then in the same manner as general method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0545]

Chem.

[0546] Example 126: (S)-5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(trifluoromethoxy)benzenesulfonamide In the same manner as general method F, 5-bromo-2-(trifluoromethoxy)benzenesulfonamide was used instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one to prepare the title compound.

[0547]

Chem.

[0548] Example 127: (S)-3-(4-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-ol In the same manner as general method A, 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-ol and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0549]

Chem.

[0550] Example 128: (S)-4-(7,7-Difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in the same manner as General Method M followed by General Method B.

[0551]

Chem.

[0552] Example 129: 4-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in the same manner as General Method M followed by General Method B, using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.

[0553]

Chem.

[0554] Example 130: (S)-2,4-Difluoro-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was prepared in the same manner as General Method F, using 5-bromo-2,4-difluoro-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0555]

Chem.

[0556] Example 131: (S)-3-(4-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine In a manner similar to General Method A, tert-Butyl N-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]carbamate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and then the title compound was prepared in a manner similar to Method I.

[0557]

Chemical formula

[0558] Example 132: (S)-7-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinolin-2(1H)-one In a manner similar to General Method A, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-quinolin-2-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0559]

Chemical formula

[0560] Example 133: (S)-3-(7-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxoquinolin-1(2H)-yl)propanoic acid Into a vial were placed (S)-7-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinolin-2(1H)-one trifluoroacetate (20 mg, 0.045 mmol, 1 equiv), K2CO3 (16 mg, 0.112 mmol, 2.5 equiv) and MeCN (1 mL), followed by methyl prop-2-enoate (116 mg, 0.121 mmol, 30 equiv). The sealed vial was heated at 120 °C for 2 h, then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL) and NaOH (2 M aqueous solution, 0.5 mL) was added. The mixture was heated at 60 °C for 20 min. The mixture was cooled to ambient temperature, concentrated and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound.

[0561]

Chemical formula

[0562] Example 134: 2-(5-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-2-yl)acetic acid The title compound was prepared in a similar manner to General Method F using 2-(5-bromoinden-2-yl)acetic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0563]

Chemical formula

[0564] Example 135: 2-(5-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-2-yl)acetamide The title compound was prepared in the same manner as General Method G, using 2-(5-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-2-yl)acetic acid instead of 2-(3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[0565]

Chemical Structure

[0566] Example 136: 4-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid The title compound was prepared in the same manner as General Method F, using 4-Bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid instead of 6-Bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0567]

Chemical Structure

[0568] Example 137: (1R,1aR * ,6aS * )-4-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide Example 138: (1S,1aR* ,6aS * )-4-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-carboxamide In the same manner as General Method G, 4-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-carboxylic acid was used instead of 2-(3-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid to prepare the title compound. The isomers were separated by HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O).

[0569]

Chemical formula

[0570] Example 139: 5-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-2-carboxylic acid In the same manner as General Method F, 5-Bromoindan-2-carboxylic acid was used instead of 6-Bromo-1,1-dioxo-1,2-benzothiazol-3-one to prepare the title compound.

[0571]

Chemical formula

[0572] Example 140: 5-(2-((S)-2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-2-carboxamide In the same manner as the general method G, the title compound was prepared using 5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-2-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[0573]

Chem.

[0574] Example 141: 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as the general method B, the title compound was prepared using (2S,3R)-2,3-dimethylazetidin-3-ol (R)-camphorsulfonate and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin, respectively.

[0575]

Chem.

[0576] Example 142: 4-(2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as general method B, pyrrolidine and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide were used instead of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0577]

Chemical formula

[0578] Example 143: (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinolin-2-amine In the same manner as general method A, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0579]

Chemical formula

[0580] Example 144: (S)-4-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1-naphthamide In the same manner as general method A, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthamide and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0581]

Chem.

[0582] Example 145: (3R,4S)-1-Acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)pyrrolidine-3-carboxylic acid In a vial, methyl (rac)-(3R * ,4S * )-4-(3-bromophenyl)pyrrolidine-3-carboxylate (500 mg, 1.56 mmol, 1.0 eq), Et3N (0.87 mL, 6.24 mmol, 4.0 eq), and DCM (10 mL) were added. Acetic anhydride (0.30 mL, 3.12 mmol, 2.0 eq) was added dropwise. The mixture was stirred at ambient temperature for 1 h. The mixture was concentrated and subjected to flash column chromatography (ethyl acetate - methanol) to afford methyl 1-acetyl-4-(3-bromophenyl)pyrrolidine-3-carboxylate (235 mg, 0.72 mmol).

[0583] Using 1-acetyl-4-(3-bromophenyl)pyrrolidine-3-carboxylate in a similar manner to General Method F, followed by a similar method to General Method C, the title compound was prepared.

[0584]

Chem.

[0585] Example 146: (3R * ,4S * )-1-Acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)pyrrolidine-3-carboxamide In the same manner as General Method G, instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, (3R * ,4S * )-1-acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)pyrrolidine-3-carboxylic acid was used to prepare the title compound.

[0586]

Chemical Structure

[0587] Example 147: (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinazoline-2,4-diamine In the same manner as General Method F, instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, 7-bromoquinazoline-2,4-diamine was used to prepare the title compound.

[0588]

Chemical Structure

[0589] Example 148: 7’-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3’,4’-dihydro-2’H-spiro[cyclopropane-1,1’-naphthalene]-2-carboxylic acid In the same manner as General Method F, instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, 7’-bromo-3’,4’-dihydro-2’H-spiro[cyclopropane-1,1’-naphthalene]-2-carboxylic acid was used to prepare the title compound.

[0590]

Chemical Structure

[0591] Example 149: (S)-8-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one The title compound was prepared in the same manner as General Method A, using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0592]

Chemical formula

[0593] Example 150: (S)-7-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one The title compound was prepared in the same manner as General Method A, using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0594]

Chemical formula

[0595] Example 151: (S)-4-(1H-Indol-2-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In the same manner as General Method A, (1-tert-butoxycarbonylindol-2-yl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently, the title compound was prepared in the same manner as General Method I.

[0596]

Chemical formula

[0597] Example 152: (S)-2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-5-carboxamide Example 153: (S)-2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-5-carboxylic acid In the same manner as General Method A, (1-tert-butoxycarbonyl-5-cyano-indol-2-yl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently, the title compound was prepared in the same manner as General Methods I and J. The mixture of the two compounds was separated by HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O).

[0598]

Chemical formula

[0599] Example 154: (S)-2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-7-carboxamide In a manner similar to General Method A, using (1-tert-butoxycarbonyl-7-methoxycarbonyl-indol-2-yl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently in a manner similar to General Method I, General Method C, and General Method G, the title compound was prepared.

[0600]

Chem.

[0601] Example 155: (S)-2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-4-carboxylic acid In a manner similar to General Method A, using (1-tert-butoxycarbonyl-4-ethoxycarbonyl-indol-2-yl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently in a manner similar to General Method I and General Method C, the title compound was prepared.

[0602]

Chem.

[0603] Example 156: (S)-2-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-4-carboxamide In the same manner as General Method G, the title compound was prepared using (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-4-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[0604]

Chemical Structure

[0605] Example 157: (S)-4-(8,8-Difluoro-2-(2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)benzamide In the same manner as General Method M, 4-chloro-8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazoline was used instead of 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, and subsequently, the title compound was prepared in the same manner as General Method B.

[0606]

Chemical Structure

[0607] Example 158: 4-(8,8-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)benzamide In the same manner as general method M, 4-chloro-8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazoline was used instead of 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, and subsequently, in the same manner as general method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0608]

Chemical formula

[0609] Example 159: (2S,3R)-1-(4-(4-(3-Aminooxetan-3-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol In the same manner as general method A, tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as general method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine, and in the same manner as general method I, the title compound was prepared.

[0610]

Chemical formula

[0611] Example 160: (S)-3-(4-(7,7-Difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine In the same manner as general method M, tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate was used instead of (4-carbamoylphenyl)boronic acid, and subsequently, the title compound was prepared in the same manner as general methods B and I.

[0612]

Chem.

[0613] Example 161: (2S,3R)-1-(4-(4-(3-Aminooxetan-3-yl)phenyl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol In the same manner as general method M, tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate was used instead of (4-carbamoylphenyl)boronic acid, and subsequently, in the same manner as general method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine, and in the same manner as general method I, the title compound was prepared.

[0614]

Chem.

[0615] Example 162: 4-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid In the same manner as general method A, 4-boronobenzoic acid was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as general method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0616] [Chemical formula]

[0617] Example 163: (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isoquinoline Using the same method as General Method A, 6-isoquinolylboronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine respectively to prepare the title compound.

[0618] [Chemical formula]

[0619] Example 164: 8-(2-((2S,3R)-3-Hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one Using the same method as General Method A, 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one was used instead of 3-pyridylboronic acid, and then using the same method as General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0620] [Chemical formula]

[0621] Example 165: (S)-8-(7,7-Difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one In the same manner as General Method M, 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one was used instead of (4-carbamoylphenyl)boronic acid, and subsequently, in the same manner as General Method B, the title compound was prepared.

[0622]

Chemical formula

[0623] Example 166: 8-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one In the same manner as General Method M, 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one was used instead of (4-carbamoylphenyl)boronic acid, and subsequently, in the same manner as General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0624]

Chemical formula

[0625] Example 167: (S)-4-(2-(1-Methylisoindolin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method B, the title compound was prepared using (S)-1-methylisoindoline and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0626] [Chemical formula]

[0627] Example 168: 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)picolinamide In the same manner as General Method M, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide was used instead of (4-carbamoylphenyl)boronic acid, and then in the same manner as General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0628] [Chemical formula]

[0629] Example 169: 4-(2-((2S,3S)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method A, (4-carbamoylphenyl)boronic acid was used instead of 3-pyridylboronic acid, and then in the same manner as General Method B, (2S,3S)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0630] [Chemical formula]

[0631] Example 170: 4-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-ethoxybenzamide Using the same method as General Method M, 2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was used instead of (4-carbamoylphenyl)boronic acid, and then using the same method as General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0632] [Chemical formula]

[0633] Example 171: 4-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylbenzamide Using the same method as General Method M, N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was used instead of (4-carbamoylphenyl)boronic acid, and then using the same method as General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0634] [Chemical formula]

[0635] Example 172: 4-(2-(4-(Hydroxymethyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as General Method A, (4-carbamoylphenyl)boronic acid was used instead of 3-pyridylboronic acid, and then in the same manner as General Method B, (2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0636]

Chemical formula

[0637] Example 173: 4-(2-(2,3-Dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared according to General Method N.

[0638]

Chemical formula

[0639] Example 174: 4-(2-(2,3-Dihydro-1H-imidazo[1,5-a]imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in the same manner as General Method N, using 2,3-dihydro-1H-imidazo[1,5-a]imidazole instead of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole.

[0640]

Chemical formula

[0641] Example 175: (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinolin-2-ol In the same manner as general method A, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0642] [Chemical formula]

[0643] Example 176: 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-5,7-methanocyclopenta[d]pyrimidin-4-yl)benzamide In the same manner as general method H, ethyl 3-oxobicyclo[3.1.0]hexane-2-carboxylate and (3-carbamoylphenyl)boronic acid were used in place of methyl 2-oxobicyclo[2.1.1]hexane-3-carboxylate and (4-carbamoylphenyl)boronic acid, respectively, to prepare the title compound.

[0644] [Chemical formula]

[0645] Example 177: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxybenzamide In the same manner as general method M, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was used in place of (4-carbamoylphenyl)boronic acid, and then in the same manner as general method B, (2S,3R)-2-methylazetidin-3-ol was used in place of (S)-2-methylazetidine to prepare the title compound.

[0646]

Chem.

[0647] Example 178: 7-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one In the same manner as General Method D, 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one was used instead of ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and then in the same manner as General Method E, 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used instead of (S)-4-chloro-2-(2-methylazepin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and then in the same manner as General Method M, 7-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one was used instead of 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, and then in the same manner as General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0648]

Chem.

[0649] Example 179: (S)-8-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one According to General Method Q, followed by General Method F, instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, (S)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used, and then according to General Method M, followed by General Method B, instead of (S)-2-methylazetidine, (2S,3R)-2-methylazetidin-3-ol was used to prepare the title compound.

[0650]

Chemical Structure

[0651] Example 180: (R)-8-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one In a manner similar to General Method Q, tert-butyl (R)-(1-hydroxypropan-2-yl)carbamate was used instead of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate, and then in a manner similar to General Method F, (R)-8-bromo-3-methyl-3,4-dihydrobenzof[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and then followed by General Method M, and then in a manner similar to General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0652]

Chemical formula

[0653] Example 181: 2-Acetamido-4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In a manner similar to General Method M, 2-acetamido-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was used instead of (4-carbamoylphenyl)boronic acid, and then in a manner similar to General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine to prepare the title compound.

[0654]

Chemical formula

[0655] Example 182: 4-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(difluoromethoxy)benzamide Using methyl 4-bromo-2-(difluoromethoxy)benzoate and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in a manner similar to General Method F instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and then using methyl 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(difluoromethoxy)benzoate in a manner similar to General Method M instead of 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, and then using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine in a manner similar to General Method B, and then preparing the title compound in a manner similar to General Methods C and G.

[0656]

Chemical formula

[0657] Example 183: 4-(7,7-Difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(trifluoromethoxy)benzamide In the same manner as the general method M, methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)benzoate was used instead of (4-carbamoylphenyl)boronic acid, and subsequently, in the same manner as the general method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (S)-2-methylazetidine, and subsequently, in the same manner as the general methods C and G, the title compound was prepared.

[0658]

Chemical formula

[0659] Example 184: 5-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1H-indole-2-carboxamide In the same manner as the general method A, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0660]

Chemical formula

[0661] Example 185: 4-[4-(1H-Imidazol-2-yl)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine In the same manner as General Method A, 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0662]

Chemical formula

[0663] Example 186: 2-Methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one In the same manner as General Method A, 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin)-1-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0664]

Chemical formula

[0665] Example 187: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one In the same manner as General Method A, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0666]

Chemical formula

[0667] Example 188: [4-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine In the same manner as General Method A, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0668]

Chemical formula

[0669] Example 189: 4-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide The title compound was prepared in a similar manner to General Method A, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0670]

Chem.

[0671] Example 190: 2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]propan-2-amine The title compound was prepared in a similar manner to General Method A, using 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-amine and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0672]

Chem.

[0673] Example 191: 4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide In the same manner as general method A, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0674]

Chemical formula

[0675] Example 192: 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide In the same manner as general method A, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, to prepare the title compound.

[0676]

Chemical formula

[0677] Example 193: (2S,3R)-1-[4-[4-(1H-imidazol-2-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol In a manner similar to General Method A, 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole hydrochloride was used instead of 3-pyridylboronic acid, and subsequently, in a manner similar to General Method B, (2S,3R)-2-methylazetidin-3-ol was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0678]

Chemical formula

[0679] Example 194: 5-[2-[(2S,3R)-3-Hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-methyl-isoindolin-1-one In a manner similar to General Method A, 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one was used instead of 3-pyridylboronic acid, and subsequently, in a manner similar to General Method B, (2S,3R)-2-methylazetidin-3-ol hydrochloride was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0680]

Chemical formula

[0681] Example 195: N-[[4-[2-[(2S,3R)-3-Hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]methanesulfonamide In a manner similar to General Method A, (4-(methylsulfonamidomethyl)phenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, in a manner similar to General Method B, (2S,3R)-2-methylazetidin-3-ol hydrochloride was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0682]

Chem.

[0683] Example 196: 5-[2-[(2S,3R)-3-Hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one The title compound was prepared in a similar manner to General Method A using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, followed by using (2S,3R)-2-methylazetidin-3-ol hydrochloride instead of (2S)-2-methylazetidine in a similar manner to General Method B.

[0684]

Chem.

[0685] Example 197: 4-[2-[(2S,3R)-3-Hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide The title compound was prepared in a similar manner to General Method A using (4-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride instead of (2S)-2-methylazetidine in a similar manner to General Method B.

[0686]

Chem.

[0687] Example 198: 4-[2-[(2S,3R)-3-Fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide In the same manner as General Method A, (4-sulfamoylphenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, (2S,3R)-3-fluoro-2-methylazetidine hydrochloride was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0688]

Chemical formula

[0689] Example 199: 4-[2-[(2S,3R)-3-Hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide In the same manner as General Method A, (4-sulfamoylphenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, (2S,3R)-2-methylazetidin-3-ol hydrochloride was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0690]

Chemical formula

[0691] Example 200: 4-[2-[(2S,3R)-3-Fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide In the same manner as General Method A, (4-carbamoylphenyl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, (2S,3R)-3-fluoro-2-methylazetidine hydrochloride was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0692]

Chemical formula

[0693] Example 201: [4-[2-[(2S,3R)-3-Fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine In the same manner as General Method A, using (4-(aminomethyl)phenyl)boronic acid hydrochloride instead of 3-pyridylboronic acid, and subsequently in the same manner as General Method B, using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride instead of (2S)-2-methylazetidine, the title compound was prepared.

[0694]

Chemical formula

[0695] Example 202: (2S,3R)-1-[4-[4-(aminomethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol In the same manner as General Method A, using (4-(aminomethyl)phenyl)boronic acid hydrochloride instead of 3-pyridylboronic acid, and subsequently in the same manner as General Method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride instead of (2S)-2-methylazetidine, the title compound was prepared.

[0696]

Chemical formula

[0697] Example 203: 6-[2-[(2S,3R)-3-Fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-methyl-isoindolin-1-one The title compound was prepared in the same manner as general method A, using 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, and then in the same manner as general method B, using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride instead of (2S)-2-methylazetidine.

[0698]

Chem.

[0699] Example 204: 6-(2-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methyl-isoindolin-1-one The title compound was prepared in the same manner as general method A, using 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, and then in the same manner as general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride instead of (2S)-2-methylazetidine.

[0700]

Chem.

[0701] Example 205: 5-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]pyridine-3-sulfonamide The title compound was prepared in the same manner as general method A, using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide instead of 3-pyridylboronic acid, and then in the same manner as general method B.

[0702]

Chem.

[0703] Example 206: 2-Methyl-6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one In the same manner as General Method A, 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, the title compound was prepared.

[0704]

Chemical Structure

[0705] Example 207: 6-(2-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isoindolin-1-one In the same manner as General Method A, (3-oxoisoindolin-5-yl)boronic acid was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, the title compound was prepared.

[0706]

Chemical Structure

[0707] Example 208: 3-[2-[(2S,4S)-2,4-Dimethylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide In the same manner as General Method A, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide was used instead of 3-pyridylboronic acid, and subsequently, in the same manner as General Method B, (2S,4S)-2,4-dimethylazetidine hydrochloride was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0708]

Chemical Structure

[0709] Example 209: 3-[2-[(2S,3R)-3-Hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide In a manner similar to General Method A, 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide was used instead of 3-pyridylboronic acid, and then in a manner similar to General Method B, (2S,3R)-2-methylazetidin-3-ol hydrochloride was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0710] [Chemical formula]

[0711] Example 210: 3-(2-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide In a manner similar to General Method A, 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide was used instead of 3-pyridylboronic acid, and then in a manner similar to General Method B, (2S,3R)-3-fluoro-2-methylazetidine hydrochloride was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0712] [Chemical formula]

[0713] Example 211: 7-Methyl-2-[(2S)-2-methylazetidin-1-yl]-6-phenyl-purine In the same manner as General Method A, phenylboronic acid and 2,6-dichloro-7-methyl-7H-purine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently, the title compound was prepared in the same manner as General Method B.

[0714]

Chem.

[0715] Example 212: 2-[(2S)-2-Methylazetidin-1-yl]-4-phenyl-pyrido[2,3-d]pyrimidine In the same manner as General Method A, phenylboronic acid and 2,4-dichloropyrido[2,3-d]pyrimidine were used instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, and subsequently, the title compound was prepared in the same manner as General Method B.

[0716]

Chem.

[0717] Example 213: 2-[5-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]thiazol-2-yl]propan-2-ol In the same manner as General Method E, 2-(5-(Tributylstannyl)thiazol-2-yl)propan-2-ol was used instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate to prepare the title compound.

[0718]

Chem.

[0719] Example 214: N-Methyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide 3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide (42 mg, 0.12 mmol) was dissolved in 10.5 mL of DMF and then cooled to 0 °C over 20 minutes. NaH (17.1 mg, 0.43) was added slowly and the reaction mixture was reacted at ambient temperature for 20 minutes. Then methyl iodide (0.0095 mL, 0.15 mmol) was added and the reaction mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 0 °C, quenched slowly with water, extracted with EtOAc, dried, filtered, concentrated and purified by HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to give N-methyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide.

[0720]

Chemical formula

[0721] Example 215: N,N-Dimethyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide 3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide (42 mg, 0.12 mmol) was dissolved in 10.5 mL of DMF and then cooled to 0 °C over 20 minutes. NaH (17.1 mg, 0.43) was added slowly and the reaction mixture was reacted at 0 °C for 20 minutes. Then methyl iodide (0.0095 mL, 0.15 mmol) was added and the reaction mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was cooled to 0 °C, quenched slowly with water, extracted with EtOAc, dried, filtered, concentrated, and purified by HPLC (0.1% TFA in MeCN-0.1% TFA in H2O) to afford N,N-dimethyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide.

[0722]

Chemical Structure

[0723] Example 216: N-(2-Amino-2-oxo-ethyl)-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide Using 3-aminopropanoic acid and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively, in a manner similar to General Method G, the title compound was prepared.

[0724]

Chemical Structure

[0725] Example 217: 3-[[3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzoyl]amino]propanoic acid The title compound was prepared in the same manner as General Method G, using 3-aminopropanoic acid and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.

[0726]

Chemical formula

[0727] Example 218: N-Benzyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide The title compound was prepared in the same manner as General Method G, using benzylamine and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.

[0728]

Chemical formula

[0729] Example 219: 3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-N-(2-sulfamoylethyl)benzamide In the same manner as General Method G, the title compound was prepared using 2-aminoethane-1-sulfonamide and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.

[0730]

Chemical formula

[0731] Example 220: N-(3-Amino-3-oxo-propyl)-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide In the same manner as General Method G, the title compound was prepared using 3-aminopropanamide and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.

[0732]

Chemical formula

[0733] Example 221: (S)-(5-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiazol-2-yl)methanamine In the same manner as General Method D, (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and then, in the same manner as General Method E, tert-butyl N-[(5-bromothiazol-2-yl)methyl]carbamate was used instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and the title compound was prepared in the same manner as General Method I.

[0734]

Chemical formula

[0735] Example 222: (S)-2-Methyl-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one In the same manner as General Method D, (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and then, in the same manner as General Method E, 6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one was used instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine to prepare the title compound.

[0736]

Chemical formula

[0737] Example 223: (S)-6-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyridine-2-sulfonamide In the same manner as General Method D, (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and subsequently, in the same manner as General Method E, 6-bromopyridine-2-sulfonamide was used instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine to prepare the title compound.

[0738]

Chemical Structure

[0739] Example 224: (S)-4-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyridine-2-sulfonamide In the same manner as General Method D, (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and subsequently, in the same manner as General Method E, 4-bromopyridine-2-sulfonamide was used instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine to prepare the title compound.

[0740]

Chemical Structure

[0741] Example 225: (S)-1-(3-(2-(2-Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-amine In the same manner as General Method D, (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and then in the same manner as General Method E, 1-(3-bromophenyl)cyclopropane-1-amine was used instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine to prepare the title compound.

[0742]

Chemical Structure

[0743] Example 226: 4-(2-((2S,3S)-3-Fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide Into a vial, 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide (23.5 mg, 0.072 mmol) and DCM (0.24 mL) were added. DAST (117 mg, 0.72 mmol) was added slowly, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched slowly to 0 °C with ice chips, extracted with 25% MeOH / DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the title compound.

[0744]

Chemical Structure

[0745] Example 227: 3-Hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide In the same manner as General Method G, 3-hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine were used instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, to prepare the title compound.

[0746]

Chemical formula

[0747] Example 228: 2-Hydroxy-2-methyl-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide In the same manner as General Method G, 2-hydroxy-2-methylpropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine were used instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, to prepare the title compound.

[0748]

Chemical formula

[0749] Example 229: (2R)-2-Hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide In the same manner as General Method G, the title compound was prepared using (R)-2-hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0750]

Chemical formula

[0751] Example 230: (2S)-2-Hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide In the same manner as General Method G, the title compound was prepared using (S)-2-hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0752]

Chemical formula

[0753] Example 231: 2-Hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]acetamide The title compound was prepared in a manner similar to General Method G, using 2-hydroxyacetic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[0754]

Chem.

[0755] Example 232: 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]naphthalene-2-carboxylic acid The title compound was prepared in a manner similar to General Method F, using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0756]

Chem.

[0757] Example 233: 4-[4-(azetidin-3-yl)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to General Method F, using tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, and subsequently in a manner similar to General Method I.

[0758]

Chem.

[0759] Example 234: 7-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydro-1λ6,3-benzothiazin-4-one In a manner similar to General Method D, 7-bromo-2,3-dihydro-4H-benzo[e][1,3]thiazin-4-one 1,1-dioxide was used instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, and subsequently, the title compound was prepared in a manner similar to General Method E.

[0760]

Chemical formula

[0761] Example 235: 4-(2-((2S,3R)-3-Methoxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide Into a vial were placed (2S,3R)-1-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol (21 mg, 0.09 mmol) and DMF (1 mL), and the mixture was cooled to 0 °C. NaH (60% dispersion in mineral oil, 12.3 mg, 0.31 mmol) was added slowly. The reaction mixture was stirred at 0 °C for 20 minutes, then MeI (14.9 mg, 0.11 mmol) was added slowly, and the reaction mixture was warmed to ambient temperature over 15 minutes. The reaction mixture was cooled to 0 °C, quenched with ice water, and extracted with DCM (3 × 1 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give 4-(2-((2S,3R)-3-methoxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, which was used without further purification.

[0762] In the same manner as the general method A, 4-chloro-2-[(2S,3R)-3-methoxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-carbamoylphenyl)boronic acid were used instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, to prepare the title compound.

[0763] [Chemical formula]

[0764] Example 236: 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methylisoindolin-1-one In the same manner as the general method A, 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one were used instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, and then in the same manner as the general methods M and B, (2S,3R)-2-methylazetidin-3-ol was used instead of (2S)-2-methylazetidine to prepare the title compound.

[0765] [Chemical formula]

[0766] Example 237: (S)-2-amino-1-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazol-1-yl)ethan-1-one Example 238: (S)-2-Amino-1-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2H-indazol-2-yl)ethan-1-one Into a vial were placed (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazole (28 mg, 0.092 mmol), potassium carbonate (50.2 mg, 0.37 mmol), and MeCN (0.7 mL). The mixture was heated at 40 °C for 18 h. NaHCO3 (1 mL, saturated aqueous solution) was added, and the mixture was extracted with DCM (3 × 1 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to afford the respective title compounds.

[0767]

Chemical formula

[0768] Example 239: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide The title compound was prepared in a similar manner to General Method F, using 5-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0769]

Chemical formula

[0770] Example 240: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindoline-1,3-dione In the same manner as General Method F, the title compound was prepared using 5-bromoisoindoline-1,3-dione instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0771]

Chem.

[0772] Example 241: 6-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-(trifluoromethyl)-1H-benzimidazole In the same manner as General Method F, the title compound was prepared using 6-bromo-2-(trifluoromethyl)-1H-benzimidazole instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0773]

Chem.

[0774] Example 242: [4-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methanesulfonamide In the same manner as General Method F, the title compound was prepared using (4-bromophenyl)methanesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0775]

Chem.

[0776] Example 243: 5-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-3-(trifluoromethyl)-1H-indazole In the same manner as general method F, the title compound was prepared using 5-bromo-3-(trifluoromethyl)-1H-indazole instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0777]

Chem.

[0778] Example 244: 2-[3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]acetamide In the same manner as general method F, the title compound was prepared using 2-(3-bromophenyl)acetamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0779]

Chem.

[0780] Example 245: 2-[4-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]acetamide In the same manner as general method F, the title compound was prepared using 2-(4-bromophenyl)acetamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0781]

Chem.

[0782] Example 246: 2,2,2-Trifluoro-1-[3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]ethanamine The title compound was prepared in a similar manner to General Method F, using 1-(3-bromophenyl)-2,2,2-trifluoro-ethanamine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0783]

Chem.

[0784] Example 247: 5-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1,3-dihydrobenzimidazol-2-one The title compound was prepared in a similar manner to General Method F, using 5-bromo-1,3-dihydrobenzimidazol-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0785]

Chem.

[0786] Example 248: 5-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]indolin-2-one The title compound was prepared in a similar manner to General Method F, using 5-bromoindolin-...

Claims

**Claim 1**: A structure shown below: 【Chemical 1】 【Chemical Formula 2】 [Chemical Formula 3] 【Chemical Formula 4】 [Chemical Formula 5] 【Chemical Formula 6】 【Chemical Formula 7】 【Chemical Formula 8】 A compound having the same or a pharmaceutically acceptable salt thereof. **Claim 2** A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. **Claim 3** The pharmaceutical composition according to claim 2, further comprising one or more additional therapeutic agents. **Claim 4** The pharmaceutical composition according to claim 3, for use in the treatment of a ketohexokinase (KHK)-mediated disease or condition. **Claim 5** A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, for the treatment of a KHK-mediated disease or condition in a subject in need thereof, or the pharmaceutical composition according to claim 2 or 3. **Claim 6** The composition according to claim 5, wherein the disease or condition includes chronic kidney disease (CKD), diabetic kidney disease (DKD), kidney disease, renal fibrosis, renal insufficiency, acute kidney injury, tubular dysfunction, lupus nephritis, 2,8-dihydroxyadenine nephropathy, kidney transplant rejection, Fanconi syndrome, kidney protection against drugs including hereditary fructose intolerance, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), liver disease, liver fibrosis, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, hypertension, fibrosis, steatosis, cirrhosis, cardiometabolic syndrome, insulin resistance, cardiovascular disease, heart failure, type 1 and type 2 diabetes mellitus, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, hyperuricemia, gout, arthritis, osteoporosis or cancer. **Claim 7** The composition according to claim 5 or 6, wherein the composition is administered in combination with an additional therapeutic agent. **Claim 8** The pharmaceutical composition according to claim 3 or the composition according to claim 7, wherein the additional therapeutic agent comprises an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, remogliflozin, or ertugliflozin), an ACE inhibitor (e.g., benazepril, imidapril, or enalapril), and / or a pharmaceutically acceptable salt thereof.

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