KHK inhibitor

Abstract

Compound of chemical formula (I): [Chemical Formula (I)] In the above formula, variable substituents are defined in this specification and claims.

Description

Technology Field

[0001] Cross-reference of related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 167,331 filed March 29, 2021, under 35 USC § 119(e), which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0003] Excessive fructose is associated with insulin resistance, hyperglycemia, and the development of several comorbidities associated with diabetes and metabolic syndrome, such as: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), liver disease, hepatic fibrosis, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, hypertension, fibrosis, steatosis, cirrhosis, cardiometabolic syndrome, insulin resistance, cardiovascular disease, heart failure, type 1 and type 2 diabetes, chronic kidney disease (CKD), diabetic nephropathy (DKD), kidney disease, renal fibrosis, renal failure, irritable bowel syndrome (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).

[0004] Although dietary intake is the primary source of fructose, fructose is also endogenously produced during cellular stress, injury, tissue damage, or increased glucose concentration. This endogenous fructose production occurs via polyol pathways in the liver, intestines, and kidneys, contributing to the exacerbation of damage and metabolic dysfunction (Andres-Hernando et al., 2017; Lanaspa et al., 2013). Excessive dietary fructose in the small intestine is associated with the accumulation of fructose-1-phosphate (F1P), leading to a loss of tight binding integrity and the disruption of the intestinal mucosal barrier, which causes increased intestinal permeability, inflammation, dysbiosis, and diarrhea (Merino et al., 2019; Montrose et al., 2020). Increased fructose metabolism in the liver and kidneys leads to the accumulation of metabolic intermediates such as fructose-1-phosphate (F1P), glyceraldehyde, dihydroxyacetone phosphate, and methylglyoxal, contributing to increased glucose production, de novo lipid production, insulin resistance, and triglyceride synthesis (Todoric et al., 2020). Importantly, increased fructose production and / or metabolism rapidly depletes adenosine triphosphate (ATP), leading to cellular apoptosis and damage, and increases levels of uric acid, a pro-inflammatory molecule (Helsley et al., 2020).

[0005] Current pharmacotherapy for the treatment of metabolic syndrome and related comorbidities generally targets the regulation of insulin secretion or activity, lipid metabolism, cholesterol level control, 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 practically unattainable. Since ketohexokinase (gene: KHK) is the primary and rate-limiting enzyme for dietary and endogenous fructose metabolism, it represents a promising drug target for pharmacological intervention in diseases where fructose and polyol pathways contribute to metabolic disorders and related comorbidities.

[0006] 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 (intestinal cells), liver (hepatocytes), and kidney (proximal tubular cells) (Diggle et al., 2009; Hayward & Bonthron, 1998). These organs metabolize most of dietary and endogenously produced fructose. The alternative splice variants of KHK (variant 3A, isoform-A, KHK-A) are more universally 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 fructose metabolism by KHK-C leads to the accumulation of F1P and uric acid and rapid ATP depletion. Because KHK-C has a higher affinity for fructose than KHK-A, fructose metabolism occurs more rapidly. Furthermore, since neither KHK-A nor KHK-C undergo negative feedback inhibition or allosteric regulation, fructose is metabolized immediately and continuously by KHK (Ishimoto et al., 2012). Alternative enzymes such as hexokinase can metabolize fructose into fructose-6-phosphate, but because hexokinase undergoes negative feedback regulation, it does not lead to rapid ATP depletion (Geidl-Flueck & Gerber, 2017).

[0007] In subjects suffering from hereditary fructose intolerance (HFI, OMIM #229600), a severe disease caused by a defect in aldolase B (gene: ALDOB), unregulated fructose metabolism via KHK can be observed. ALDOB is an enzyme located immediately downstream of KHK and is involved in converting F1P into dihydroxyacetone phosphate (DHAP) and glyceraldehyde phosphate (GAP). A defect in ALDOB leads to F1P accumulation, ATP depletion, and increased uric acid levels. HFI is a rare disease with a prevalence of approximately 1 in 20,000 people (Simons et al., 2019). Patients with HFI exhibit severe dietary fructose intolerance and display acute symptoms such as vomiting, hypoglycemia, diarrhea, and abdominal pain. This contributes to the onset of symptoms reminiscent of hypoglycemia, hyperuricemia, lactic acidosis, hepatic steatosis, and Fanconi's Syndrome, and in the worst cases, becomes a cause of death (Aldamiz-Echevarria et al., 2020; Simons et al., 2019). Currently, the only treatment for HFI patients is the strict restriction of dietary fructose. However, this is not entirely sufficient to delay the worsening of symptoms over time, and patients often exhibit signs of liver and kidney disease throughout their lives because they are not affected by endogenous fructose production and metabolism (Aldamiz-Echevarria et al., 2020).

[0008] Genetic defects in the human KHK gene lead to a loss of enzymatic function or reduced enzymatic stability, resulting in a benign condition known as essential hypertonia (EF, OMIM #229800), which supports KHK inhibition as a therapeutic strategy. EF is a rare benign disease affecting approximately 1 in 100,000 people. Patients with EF appear normal and exhibit increased urinary fructose excretion (Asipu, Hayward, O'Reilly, & Bonthron, 2003; Bonthron, Brady, Donaldson, & Steinmann, 1994; Schapira, Nordmann, & Gregori, 1972). The benign nature of EF and the absence of symptoms highlight the potential safety of long-term KHK inhibition. Furthermore, KHK-A / C homozygous knockout mice appear normal and healthy and excrete excessive fructose in their urine, similar to individuals with EF. In addition, KHK-A / C null mice are protected from signs of liver and kidney disease such as renal tubular cell damage, inflammation, hepatic steatosis, and fibrosis (Andres-Hernando et al., 2017; Lanaspa et al., 2013).

[0009] Currently, there are two known types of KHK inhibitors, both of which utilize the presence of charged residues for efficacy and / or metabolic stability and / or acceptable pharmacokinetic properties.

[0010] One type (US2017183328, CN111978296, WO2020067735, WO2020051058, CN111423420, WO2020156445, 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 toxicity that can be induced by reactive acyl glucuronide metabolites (Lassila et al., Chem. Res. Toxicol., 2015, 28, 12, 2292-2303). Acyl glucuronide metabolites can chemically react to form covalent bonds with macromolecules and induce cumulative toxicity (Vleet Van et al., Toxicology Letters, 2017, 272, 1-7). Compounds containing carboxylic acids tend to be substrates of the organic anion transporter (OAT) family encoded by SLC22A, the organic anion transport 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 lead to asymmetric tissue exposure (i.e., tissue accumulation through active uptake and reduced tissue exposure through active efflux). Tissue-level differences (e.g., toxicity due to accumulation or lack of efficacy due to active excretion) mean that higher KHK-C inhibition in one organ leads to higher circulating fructose concentrations in the plasma, which may result in decreased inhibitor concentrations (free drug concentrations) or enhanced KHK-C-mediated fructose metabolism in organs with lower inhibition (subsequently, ATP depletion and tissue damage may be intensified). Carboxylic acids are not only substrates but also OATP inhibitors that cause drug-drug interactions (DDI) with some essential drugs (Kalliokoski et al., Br.J. Pharmacol., 2009, 158, 693-705; McFeely et al., Clin. Transl. Sci., 2019, 12, 379-387).

[0011] Other types of known KHK inhibitors depend on the presence of positively charged basic amines (WO18170517, WO11133750, 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, WO2020215022, WO2020046481, US2020392118). Basic amines are well known to carry a high risk of indiscriminate use, lack of bioselectivity, safety risks such as hERG inhibition or phospholipidosis, and inter-organ exposure variability, because basic drugs tend to be stored in tissues (e.g., lungs) where the pH is lower than the pKa value. Compounds containing basic amines are often sequestered in acidic organelles of various cell types, causing various toxicities, and furthermore, can be 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 generally have much higher renal clearance than neutral molecules (Charifson et al., J. Med. Chem., 2014, 57, 9701-9717).

[0012] There is a need for KHK inhibitors with favorable characteristics (e.g., uniform tissue distribution, high target engagement, and excellent pharmacokinetic properties). Although progress has been made, there is still a need for more potent and novel KHK inhibitors that possess low tissue asymmetry, low drug-drug interaction liability, minimal off-target liability, and minimal toxicity.

[0013] References:

[0014] 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

[0015] 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

[0016] 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

[0017] Bantle, J. P. (2009). Dietary fructose and metabolic syndrome and diabetes. J Nutr, 139 (6), 1263S-1268S. doi:10.3945 / jn.108.098020

[0018] 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

[0019] 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

[0020] Geidl-Flueck, B., & Gerber, P. A. (2017). Insights into the Hexose Liver Metabolism-Glucose versus Fructose. Nutrients, 9 (9). doi:10.3390 / nu9091026

[0021] 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

[0022] 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

[0023] 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 USA, 109 (11), 4320-4325. doi:10.1073 / pnas.1119908109

[0024] 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

[0025] 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

[0026] 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

[0027] 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

[0028] 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

[0029] 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.

[0030] 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

[0031] 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

[0032] In one embodiment, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof:

[0033] [Chemical Formula I]

[0034]

[0035] In the above formula,

[0036] R 1 The heterocycle contains 1 to 3 heteroatoms, and 4 or fewer R 1a A 4- to 10-membered heterocyclic portion arbitrarily substituted with; or

[0037] C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, CN, OH, CH2OH, CH2OR 11 , CONH2, CONHR 11 , NHCOR 13 , SO2NH2, SO2NHR 11 , NHSO2R 13 or C optionally substituted with four or fewer substituents independently selected from iodine 3-7 It is cycloalkyl;

[0038] Each R 1a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-7 Cycloalkyl, OH, OR1b , CH2OH, CO2R 12 , Halogen, Iodine, CONH2, CN, NH2, NHR 11 , C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkyl-NHCOR 13 , C 1-6 Alkoxy or C 1-6 It is a haloalkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkyl-NHSO2R 13 , Alkyl-NHCOR 13 , alkoxy or haloalkyl groups of 3 or fewer R 1c Arbitrarily substituted with; 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings;

[0039] R 1b is H or C 1-6 It is alkyl, wherein the alkyl is optionally substituted with three or fewer halogens, CN, or OH;

[0040] Each R 1c is independently OH, OR 11 , Halogen, Iodine, SOR 13 , SO2R 13 , SR 13 , SO2NH2, CONH2, CN, C 1-6 Alkoxy, C 6-10 Aril, C 6-10 Aryloxy, 5- to 11-membered heteroaryl or C 3-7 It is cycloalkyl;

[0041] R 2 is C 6-10 It is an aryl, or a 6- to 14-membered heteroaryl, wherein the aryl or heteroaryl has 8 or fewer R 2a It is arbitrarily substituted with, and R 2 is R 2 Attached to the core through carbon atoms;

[0042] Each R 2a C independently1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , N(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c, NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , SR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl can be fused to a heteroaryl or spiro, or the cycloalkyl can be fused to an aryl; or two R 2aThey can bond with atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings;

[0043] Each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, OH, halogen, iodine, CONH2, CONHR 2e , CON(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , C 1-6 Alkyl-SO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl or a 5- to 11-membered heteroaryl, wherein alkyl, C 1-6 Alkyl-CO2R12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , C 1-6 Alkyl-SO2R 2c , alkoxy, haloalkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl have 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings;

[0044] Each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclil, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, alkyl-aryl, heteroaryl, or heterocyclil has 4 or fewer R 2d Arbitrarily substituted with; 2 R 2c They can bond with the atoms to which they are attached to form a ternary to seven-membered ring;

[0045] Each R 2d is independently OH, halogen, NH2, C 1-6 Alkoxy, CONH2, COR 2e , SO2NH2, NR 11 COR 13 , NCH2OR 11 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , is oxo or CN;

[0046] R2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 It is arbitrarily replaced with;

[0047] Each X is independently CR 7 R 8 , iodine, S, SO, SO2 or O and;

[0048] Z 1 is CR 3 R 4 , NR 9 , S, SO, SO2, C=O or O and;

[0049] Z 2 is CR 5 R 6 , NR 9 , S, SO, SO2, C=O or O and;

[0050] n is 0, 1, or 2, and;

[0051] Here,

[0052] When n is 0, Z 1 is CR 3 R 4 Igo, Z 2 is CR 5 R 6 is;

[0053] When n is 2, only one X can be oxo, S, SO, SO2 or O;

[0054] Z 1 or Z 2 If is O, SO, or SO2, then X is CR 7 CR 8 is;

[0055] Z 1 and Z 2If all are O, SO, or SO2, then X is CR 7 CR 8 And;

[0056] Here, dashed circles represent one or more arbitrary double combinations;

[0057] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 does not exist independently, or H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, crosslinks, or fused rings;

[0058] R 9 is not present, or H, C 1-6 alkyl or C 3-7 It is cycloalkyl;

[0059] Each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2 or NHCO2-C 1-6 It is alkyl;

[0060] R 11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl;

[0061] R 12 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl;

[0062] R 13 C1-6 alkyl or C 1-6 It is a haloalkyl.

[0063] In another embodiment, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof:

[0064] [Chemical Formula I]

[0065]

[0066] In the above formula,

[0067] R 1 The heterocycle contains 1 to 3 heteroatoms, and 4 or fewer R 1a A 4- to 10-membered heterocyclic portion arbitrarily substituted with; or

[0068] C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, CN, OH, CH2OH, CH2OR 11 , CONH2, CONHR 11 , NHCOR 13 , SO2NH2, SO2NHR 11 , NHSO2R 13 or C optionally substituted with four or fewer substituents independently selected from iodine 3-7 It is cycloalkyl;

[0069] Each R 1a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, OR 1b , CH2OH, COOH, CO2R 12 , Halogen, Iodine, CONH2, CN, NH2, NHR 11 , C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkyl-NHCOR 13 , C 1-6 Alkoxy or C 1-6It is a haloalkyl, wherein the alkyl, alkenyl, or alkynyl is three or fewer Rs 1c Arbitrarily substituted with; 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings;

[0070] R 1b is H or C 1-6 It is alkyl, wherein the alkyl is optionally substituted with three or fewer halogens, CN, or OH;

[0071] Each R 1c is independently OH, OR 11 , Halogen, Iodine, SOR 13 , SO2R 13 , SR 13 , SO2NH2, CONH2, C 1-6 Alkoxy, C 6-10 Aril, C 6-10 Aryloxy, 5- to 11-membered heteroaryl or C 3-7 It is cycloalkyl;

[0072] R 2 is C 6-10 It is an aryl, or a 6- to 14-membered heteroaryl, wherein the aryl or heteroaryl has 8 or fewer R 2a It is arbitrarily substituted with, and R 2 is R 2 Attached to the core through carbon atoms;

[0073] Each R 2a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, COOH, CO2R 12 , CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c, N(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl can be fused to a heteroaryl or spiro, or the cycloalkyl can be fused to an aryl; or two R 2a They can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0074] Each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, OH, halogen, iodine, CO2H, CO2R 12 , CONH2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0075] Each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclil, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclil has 4 or fewer R 2dIt is arbitrarily replaced with;

[0076] Each R 2d is independently OH, halogen, NH2, C 1-6 Alkoxy, CONH2, SO2NH2, CO2H, CO2R 12 , NHCOR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , iodine or CN, and;

[0077] R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 Arbitrarily replaced with;

[0078] Each X is independently CR 7 R 8 , NR 9 , iodine, S, SO, SO2 or O;

[0079] Z 1 is CR 3 R 4 , NR 9 , S, SO, SO2, C=O or O and;

[0080] Z 2 is CR 5 R 6 , NR 9 , S, SO, SO2, C=O or O and;

[0081] n is 0, 1, or 2, and;

[0082] Here,

[0083] When n is 0, Z 1 is CR 3 R4 Igo, Z 2 is CR 5 R 6 is;

[0084] When n is 2, only one X can be oxo, S, SO, SO2 or O;

[0085] Z 1 or Z 2 If is O, SO, or SO2, then X is CR 7 CR 8 or NR 9 is;

[0086] Z 1 and Z 2 If all are O, SO, or SO2, then X is CR 7 CR 8 And;

[0087] Here, dashed circles represent one or more arbitrary double combinations;

[0088] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 does not exist independently, or H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, crosslinks, or fused rings;

[0089] R 9 is not present, or H, C 1-6 alkyl or C 3-7 It is cycloalkyl;

[0090] Each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11, CONH2, SO2NH2, COOH, CO2R 12 or NHCO2-C 1-6 It is alkyl;

[0091] R 11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl;

[0092] R 12 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl;

[0093] R 13 C 1-6 alkyl or C 1-6 It is a haloalkyl.

[0094] In another embodiment, the present invention provides a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof:

[0095] [Chemical Formula II]

[0096]

[0097] In the above formula,

[0098] m is 0 to 4;

[0099] Each R 1a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, OR 1b , CH2OH, COOH, CO2R 12 , Halogen, Iodine, CONH2, CN, NH2, NHR 11 , C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkyl-NHCOR 13 , C 1-6 Alkoxy or C 1-6 It is a haloalkyl, wherein the alkyl, alkenyl, or alkynyl is three or fewer Rs 1cArbitrarily substituted with, or 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings;

[0100] R 1b is H or C 1-6 It is alkyl, wherein the alkyl is optionally substituted with three or fewer halogens, CN, or OH;

[0101] Each R 1c is independently OH, OR 11 , Halogen, Iodine, SOR 13 , SO2R 13 , SR 13 , SO2NH2, CONH2, C 1-6 Alkoxy, C 6-10 Aril, C 6-10 Aryloxy, 5- to 11-membered heteroaryl or C 3-7 It is cycloalkyl;

[0102] R 2 is C 6-10 It is an aryl, or a 6- to 14-membered heteroaryl, wherein the aryl or heteroaryl has 8 or fewer R 2a It is arbitrarily substituted with, and R 2 is R 2 Attached to the core through carbon atoms;

[0103] Each R 2a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, COOH, CO2R 12 , CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , N(R 2c )2, NHCOR 2c , N(R2c )COR 2c , NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl can be fused to a heteroaryl or spiro, or the cycloalkyl can be fused to an aryl; or two R 2a They can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0104] Each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, OH, halogen, iodine, COOH, CO2R 12 ,CONH2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , S(O)(NH)R 2c, S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings;

[0105] Each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclile, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclile has 4 or fewer R 2d Arbitrarily replaced with;

[0106] Each R2d is independently OH, halogen, NH2, C 1-6 Alkoxy, CONH2, SO2NH2, COOH, CO2R 12 , NHCOR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , is oxo or CN;

[0107] R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 It is arbitrarily replaced with;

[0108] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is independently H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, crosslinks, or fused rings;

[0109] Each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2, COOH, CO2R 12 or NHCO2-C 1-6 It is alkyl;

[0110] R 11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl;

[0111] R 12 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl;

[0112] R 13 C 1-6 alkyl or C 1-6 It is a haloalkyl.

[0113] In another embodiment, the present invention provides a compound of formula V:

[0114] [Chemical Formula V]

[0115]

[0116] In the above formula,

[0117] R 1 The heterocycle contains 1 to 3 heteroatoms, and 4 or fewer R 1a A 4- to 10-membered heterocyclic portion arbitrarily substituted with; or

[0118] C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, CN, OH, CH2OH, CH2OR 11 , CONH2, CONHR 11 , NHCOR 13 , SO2NH2, SO2NHR 11 , NHSO2R 13 or C optionally substituted with four or fewer substituents independently selected from iodine 3-7 It is cycloalkyl;

[0119] Each R 1a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C3-7 Cycloalkyl, OH, OR 1b , CH2OH, CO2R 12 , Halogen, Iodine, CONH2, CN, NH2, NHR 11 , C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkyl-NHCOR 13 , C 1-6 Alkoxy or C 1-6 It is a haloalkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkyl-NHSO2R 13 , Alkyl-NHCOR 13 , alkoxy or haloalkyl groups of 3 or fewer R 1c Arbitrarily substituted with; 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings;

[0120] R 1b is H or C 1-6 It is alkyl, wherein the alkyl is optionally substituted with three or fewer halogens, CN, or OH;

[0121] Each R 1c is independently OH, OR 11 , Halogen, Iodine, SOR 13 , SO2R 13 , SR 13 , SO2NH2, CONH2, CN, C 1-6 Alkoxy, C 6-10 Aril, C 6-10 Aryloxy, 5- to 11-membered heteroaryl or C 3-7 It is cycloalkyl;

[0122] R 2 is a pentagonal heteroaryl, where the heteroaryl consists of three or fewer R atoms. 2a It is arbitrarily substituted with, and R 2 is R 2 Attached to the core through carbon atoms;

[0123] Each R 2a C independently 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , N(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c, NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , SR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl can be fused to a heteroaryl or spiro, or the cycloalkyl can be fused to an aryl; or two R 2aThey can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0124] Each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, OH, halogen, iodine, CONH2, CONHR 2e , CON(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , C 1-6 Alkyl-SO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein alkyl, C 1-6Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , C 1-6 Alkyl-SO2R 2c , alkoxy, haloalkyl, cycloalkyl, heterocyclil, aryl, or heteroaryl have 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0125] Each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclil, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, alkyl-aryl, heteroaryl, or heterocyclil has 4 or fewer R 2d Arbitrarily substituted with; 2 R 2c They can bond with the atoms to which they are attached to form ternary to seven-membered rings;

[0126] Each R 2d is independently OH, halogen, NH2, C 1-6 Alkoxy, CONH2, COR 2e , SO2NH2, NR 11 COR 13 , NCH2OR 11 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , iodine or CN, and;

[0127] R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 Arbitrarily replaced with;

[0128] Each X is independently CR 7 R 8 , iodine, S, SO, SO2 or O;

[0129] Z 1 is CR 3 R 4 , NR 9 , S, SO, SO2, C=O or O and;

[0130] Z 2 is CR 5 R 6 , NR 9 , S, SO, SO2, C=O or O and;

[0131] n is 0, 1, or 2, and;

[0132] Here,

[0133] When n is 0, Z 1 is CR 3 R 4 Igo, Z 2 is CR 5 R 6 is;

[0134] When n is 2, only one X can be oxo, S, SO, SO2 or O;

[0135] Z 1 or Z 2 If is O, SO, or SO2, then X is CR 7 CR 8 is;

[0136] Z 1 and Z 2If all are O, SO, or SO2, then X is CR 7 CR 8 And;

[0137] Here, dashed circles represent one or more arbitrary double combinations;

[0138] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 does not exist independently, or H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, crosslinks, or fused rings;

[0139] R 9 is not present, or H, C 1-6 alkyl or C 3-7 It is cycloalkyl;

[0140] Each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2 or NHCO2-C 1-6 It is alkyl;

[0141] R 11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl;

[0142] R 12 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl;

[0143] R 13 C1-6 alkyl or C 1-6 It is a haloalkyl.

[0144] In another embodiment, the present invention provides a compound of formula V, or a pharmaceutically acceptable salt or stereoisomer thereof:

[0145] [Chemical Formula V]

[0146]

[0147] In the above formula,

[0148] R 1 The heterocycle contains 1 to 3 heteroatoms, and 4 or fewer R 1a A 4- to 10-membered heterocyclic portion arbitrarily substituted with; or

[0149] C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, CN, OH, CH2OH, CH2OR 11 , CONH2, CONHR 11 , NHCOR 13 , SO2NH2, SO2NHR 11 , NHSO2R 13 or C optionally substituted with four or fewer substituents independently selected from iodine 3-7 It is cycloalkyl;

[0150] Each R 1a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, OR 1b , CH2OH, COOH, CO2R 12 , Halogen, Iodine, CONH2, CN, NH2, NHR 11 , C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkyl-NHCOR 13 , C 1-6 Alkoxy or C 1-6 It is a haloalkyl, wherein the alkyl, alkenyl, or alkynyl is three or fewer Rs1c Arbitrarily substituted with; 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings;

[0151] R 1b is H or C 1-6 It is alkyl, wherein the alkyl is optionally substituted with three or fewer halogens, CN, or OH;

[0152] Each R 1c is independently OH, OR 11 , Halogen, Iodine, SOR 13 , SO2R 13 , SR 13 , SO2NH2, CONH2, C 1-6 Alkoxy, C 6-10 Aril, C 6-10 Aryloxy, 5- to 11-membered heteroaryl or C 3-7 It is cycloalkyl;

[0153] R 2 is a pentagonal heteroaryl, where the heteroaryl consists of three or fewer R atoms. 2a It is arbitrarily substituted with, and R 2 is R 2 Attached to the core through carbon atoms;

[0154] Each R 2a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, COOH, CO2R 12 , CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , N(R 2c )2, NHCOR 2c , N(R 2c )COR2c , NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl group can be fused to a heteroaryl or spironed; or two R 2a They can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0155] Each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, OH, halogen, iodine, CO2H, CO2R 12 , CONH2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0156] Each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclil, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclil has 4 or fewer R 2d It is arbitrarily replaced with;

[0157] Each R 2d is independently OH, halogen, NH2, C 1-6Alkoxy, CONH2, SO2NH2, CO2H, CO2R 12 , NHCOR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , iodine or CN, and;

[0158] R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 Arbitrarily replaced with;

[0159] Each X is independently CR 7 R 8 , NR 9 , iodine, S, SO, SO2 or O;

[0160] Z 1 is CR 3 R 4 , NR 9 , S, SO, SO2, C=O or O and;

[0161] Z 2 is CR 5 R 6 , NR 9 , S, SO, SO2, C=O or O and;

[0162] n is 0, 1, or 2, and;

[0163] Here,

[0164] When n is 0, Z 1 is CR 3 R 4 Igo, Z 2 is CR 5 R 6 is;

[0165] When n is 2, only one X can be oxo, S, SO, SO2 or O;

[0166] Z 1 or Z 2 If is O, SO, or SO2, then X is CR 7 CR 8 or NR 9 is;

[0167] Z 1 and Z 2 If all are O, SO, or SO2, then X is CR 7 CR 8 And;

[0168] Here, dashed circles represent one or more arbitrary double combinations;

[0169] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 does not exist independently, or H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, crosslinks, or fused rings;

[0170] R 9 is not present, or H, C 1-6 alkyl or C 3-7 It is cycloalkyl;

[0171] Each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2, COOH, CO2R 12 or NHCO2-C 1-6 It is alkyl;

[0172] R11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl;

[0173] R 12 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl;

[0174] R 13 C 1-6 alkyl or C 1-6 It is a haloalkyl. Specific details for implementing the invention

[0175] definition

[0176] As used in this specification, "core" is represented in the broadest sense by the following structure:

[0177] (here, R 1 , R 2 , Z 1 , Z 2 and X n (as defined in this specification).

[0178] "Alkyl" is a straight-chain or branched-chain saturated monovalent hydrocarbon. For example, an alkyl group consists of 1 to 18 carbon atoms (i.e., C 1-18 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 It may have an alkyl group. Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), and 1-propyl ( n -Pr, n -Profile, -CH2CH2CH3), 2-Profile( 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.

[0179] "Alkenyl" is a monovalent or divalent straight-chain or branched-chain hydrocarbon group having one or more carbon-carbon double bonds. For example, an alkenyl group has 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4It may have an alkenyl group. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. The alkenyl group may be unsubstituted or substituted.

[0180] "Alkynyl" is a monovalent or divalent straight-chain or branched-chain hydrocarbon group having one or more carbon-carbon triple bonds. For example, an alkynyl group has 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 It may have an alkynyl group. Examples of alkynyl groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CH2C≡CH), and -CH2-C≡C-CH3. The alkynyl group may be unsubstituted or substituted.

[0181] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to an attachment site: alkyl-O-. Like alkyl groups, alkoxy groups can have any suitable number of carbon atoms, e.g., C 1-6 It may have alkoxy groups, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, OCF3, OCHF2, etc.

[0182] As used herein, “aryl” refers to a single all-carbon aromatic ring, or a polycondensed all-carbon ring system in which at least one of the rings is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. The aryl includes a phenyl group. The aryl also includes a polycondensed ring system having 9 to 20 carbon atoms (e.g., a ring system comprising 2, 3, or 4 rings), in which at least one ring is aromatic and the other rings may be aromatic or non-aromatic (i.e., carbocycle). Such a polycondensed ring system is optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocycle portion of the polycondensed ring system. The rings of a polycondensed ring system may be connected to one another via fusion, spiro, and cross-linking, provided that valence requirements permit. Additionally, when a specific atomic range member aryl (e.g., hexa- to decimal aryls) is mentioned, the atomic range should be understood to refer to the total ring atoms of the aryl. For example, a hexa-aryl will include phenyl, and a decimal aryl will include 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, etc. Specific examples of polycyclic carbocycles include, but are not limited to, the following:

[0183] or .

[0184] "Cycloalkyl" is a monosaturated or partially unsaturated whole-carbon ring having 3 to 20 cyclic carbon atoms (i.e., C 3-20cycloalkyl), for example, referring to those having 3 to 12 cyclic atoms, for example, 3 to 10 cyclic atoms, 3 to 8 cyclic atoms, 3 to 6 cyclic atoms, 3 to 5 cyclic atoms, or 3 or 4 cyclic atoms. The term “cycloalkyl” also includes polycondensed saturated and partially unsaturated whole-carbon ring systems (for example, ring systems containing 2, 3, or 4 carbocyclic rings). Accordingly, cycloalkyls include multicyclic carbocycles such as bicyclic carbocycles (e.g., bicyclic carbocycles having 6 to 12 cyclic carbon atoms, e.g., bicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane and bicyclo[2.1.1]hexane) and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles having 20 or fewer cyclic carbon atoms). The rings of the multi-condensed ring system can be connected to each other through fusion, spiro, and cross-linking when permitted by valence requirements. Non-limiting examples of monocyclic cycloalkyls 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.

[0185] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, wherein the alkyl component links the cycloalkyl component to the attachment site. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene for linking to the cycloalkyl component and the attachment site. In some cases, the alkyl component may not be present. The alkyl component has any number of carbon atoms, e.g., C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C2-3 , 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 It may include. The cycloalkyl component is as defined in this specification. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0186] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, wherein the alkyl component links the aryl component to the attachment site. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene to link to the aryl component and the attachment site. In some cases, the alkyl component may not be present. The alkyl component has any number of carbon atoms, e.g., 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 It may include. The aryl component is as defined in this specification. Exemplary alkyl-aryl groups include, but are not limited to, methyl-phenyl or ethyl-phenyl.

[0187] As used herein, “heterocyclil,” “heterocycle,” “heterocycloalkyl,” or “heterocyclic” refers to a single saturated or partially unsaturated non-aromatic ring or a polycyclic system having one or more heteroatoms in the ring (i.e., one or more cyclic heteroatoms selected from oxygen, nitrogen, and sulfur)—say, the polycyclic system comprises at least one non-aromatic ring comprising one or more heteroatoms. The polycyclic system may also comprise other aromatic rings and non-aromatic rings. Unless otherwise specified, the heterocyclil group has 3 to 20 cyclic atoms, e.g., 3 to 12 cyclic atoms, e.g., 3 to 10 cyclic atoms, 3 to 8 cyclic atoms, 3 to 6 cyclic atoms, 3 to 5 cyclic atoms, 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Accordingly, the above term comprises a single saturated or partially unsaturated ring (e.g., a ternary, quaternary, pentary, hexavalent, or heptary ring) having one to six cyclic carbon atoms and one to three cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The heteroatoms are optionally oxidized to -N(-OH)-, =N(-O -They can form )-, -S(=O)-, or -S(=O)2-. Rings of a multi-condensed ring system (e.g., bicyclic heterocyclil) can be connected to each other through fusion, spiro, and cross-linking when permitted by valence requirements. Heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thiethane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidein, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 6-oxa-1-azaspiro[3.3]heptane-1-yl, 2-thi-6-azaspiro[3.3]heptane-6-yl, 2,6-diazaaspiro[3.3]heptane-2-yl, 2-azabicyclo[3.1.0]hexane-2-yl, Includes, but is not limited to, 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, etc.

[0188] Examples of heterocyclyl groups include, but are not limited to, the following:

[0189]

[0190] or .

[0191] "Halo" or "halogen" as used in this specification refers to fluoro(-F), chloro(-Cl), bromo(-Br), and iodo(-I).

[0192] As used herein, "oxo" refers to =O, SO, SO2, or SO(NH). Examples of compounds containing an oxo group include, for example,

[0193] or Includes, but is not limited to.

[0194] As used herein, "haloalkyl" refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a halo substituent that may be the same or different. For example, C 1-4 Haloalkyl is C 1-4 In alkyls, C 1-4 One or more hydrogen atoms of the alkyl group are replaced by a halo substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0195] As used herein, “heteroaryl” refers to a single aromatic ring having one or more atoms other than carbon in the ring, wherein the atoms are selected from the group consisting of oxygen, nitrogen, and sulfur; “heteroaryl” also includes a polycondensed ring system having one or more such aromatic rings, the polycondensed ring system is further described below. Thus, “heteroaryl” includes a single aromatic ring of 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also exist in an oxidized form if the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl.

[0196] "Heteroaryl" also comprises a polycondensed ring system (e.g., a ring system comprising 2, 3, or 4 rings), wherein the heteroaryl group as defined above condenses with one or more rings selected from heteroaryl (e.g., forming 1,8-naphthiridinyl), heterocycle (e.g., forming 1,2,3,4-tetrahydro-1,8-naphthiridinyl), carbocycle (e.g., forming 5,6,7,8-tetrahydroquinolyl) and aryl (e.g., forming indazolyl) to form a polycondensed ring system. Thus, the heteroaryl (a monoaromatic ring or a polycondensed ring system) has 1 to 20 carbon atoms and 1 to 6 heteroatoms within the heteroaryl ring. Such polycondensed ring systems may be optionally substituted with one or more (e.g., one, two, three, or four) oxo groups on the carbocyclic or heterocyclic portion of the condensed ring. The rings of the polycondensed ring system may be connected to one another through fusion, spiro, and cross-linking, where permitted by valence requirements. It should be understood that the individual rings of the polycondensed ring system may be connected to one another in any order. It should be understood that attachment points for a heteroaryl or heteroaryl polycondensed ring system may be on any suitable atom of the heteroaryl or heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Additionally, when a specific atomic range member heteroaryl (e.g., pentagonal to determinal heteroaryls) is mentioned, the atomic range refers to the total ring atoms of the heteroaryl and should be understood to include carbon atoms and heteroatoms. For example, a 5-membered heteroaryl will contain thiazolyl, and a 10-membered heteroaryl will contain quinolinyl.Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaptenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl.

[0197] The “heteroaryl” ring also comprises an 8- to 15-membered fused ring having two, three, or more rings, wherein one or more rings are aromatic rings and one or more rings are non-aromatic rings containing one or more heteroatoms. Representative fused bicyclic heteroaryls include, but are not limited to, indoline (dihydroindole), isoindoline (dihydroisoindole), indazoline (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxol, dihydrobenzo[b]dioxin, dihydrobenzo[d]oxazole, dihydrobenzo[b]thiophene, dihydroisobenzo[c]thiophene, dihydrobenzo[d]thiazole, dihydrobenzo[c]isothiazole, and benzo[b][1,4]thiazine, as shown in the structures below:

[0198]

[0199]

[0200] or .

[0201] An example of a bicyclic heteroaryl can also be represented by the following structure:

[0202] or

[0203] Here, X 1 , X 2 , X 3 , X 4 and X 5 are independently bonded (bond), -CH-, -CH2-, -CF2-, -N-, -NH-, -CO-, -SO2-, -O-, -S-, and X 1 , X 2 , X 3 , X 4 and X 5 One or more of them are -N-, -NH-, -CO-, -O-, -SO2- or -S-, and Y 1 , Y 2 , Y 3 , Y 4 Each is independently bonded to -CH-, -O-, -CO-, -S-, -NH-, or -N-, and Y 1 , Y 2 , Y 3 , Y 4 One or more of them are -CH-, -O-, -CO-, -S-, -NH- or -N-, and X 1 -X 5 or Y 1 -Y 4 Only one of them can be a bond, and the dashed circle or bond represents a saturated or partially unsaturated non-aromatic ring, Y 1 , Y 2 , Y 3 , Y 4 At least one of them is carbon, and the attachment point to the core is through carbon atoms. Fused bicyclic heteroaryls have 8 or fewer R atoms. 2a It is arbitrarily substituted as, and here

[0204] Each R 2a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c, SO2NH2, COOH, CO2R 12 , CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , N(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl can be fused to a heteroaryl or spiro, or the cycloalkyl can be fused to an aryl; or two R 2a They can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0205] Each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, OH, halogen, iodine, CO2H, CO2R 12 , CONH2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with atoms to which they are attached to form ternary to hypnaary spiros, fused or cross-linked rings;

[0206] Each R 2c C independently 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclil, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclil has 4 or fewer R 2d It is arbitrarily replaced with;

[0207] Each R 2d is independently OH, halogen, NH2, C 1-6 Alkoxy, CONH2, SO2NH2, CO2H, CO2R 12 , NHCOR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , iodine or CN, and;

[0208] R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 Arbitrarily replaced with;

[0209] Each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2, COOH, CO2R 12 or NHCO2-C 1-6 It is alkyl;

[0210] R 11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl;

[0211] R 12 is H, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl;

[0212] R 13 C 1-6 alkyl or C 1-6 It is a haloalkyl.

[0213] Examples of heteroaryl groups include, but are not limited to:

[0214]

[0215] or .

[0216] "Compounds of the present invention" include compounds disclosed herein, for example, compounds of the present invention include compounds of formula (I-VI).

[0217] As used herein, the term “composition” is intended to include not only a product comprising specified amounts of specified ingredients, but also any product produced directly or indirectly from a combination of specified amounts of specified ingredients. “Pharmaceuticalally acceptable” means that the carrier, diluent, or excipient is compatible with other components of the formulation and must not be harmful to the recipient thereof.

[0218] "Pharmaceutical effective amount" refers to an amount of a compound of the present invention or a combination thereof that provides a desired therapeutic or pharmaceutical result.

[0219] As used herein, “treatment,” “to treat,” or “treating” refers to an approach to obtain a beneficial or desired result. For the purposes of the invention, a beneficial or desired result includes, but is not limited to, the alleviation of symptoms associated with a disease or condition and / or a reduction in the severity of symptoms and / or prevention of worsening of symptoms. In one embodiment, “treatment” or “treating” comprises one or more of the following: a) suppressing the disease or condition (e.g., reducing and / or reducing one or more symptoms caused by the disease or condition, or lowering the severity of the disease or condition); b) slowing or stopping the manifestation of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, or delaying the worsening or progression of the disease or condition); and c) alleviating the disease or condition, e.g., causing a regression of clinical symptoms, improving the disease state and / or delaying the progression of the disease, increasing the quality of life and / or extending survival.

[0220] As used herein, “therapeutic effective dose” or “effective dose” refers to an amount effective in inducing a desired biological or medical response, which includes an amount of compound sufficient to achieve such treatment for a disease when administered to a subject to treat the disease. The effective dose may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. The effective dose may include various amounts. As understood in the art, the effective dose may be available in one or more doses; that is, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. The effective dose may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be provided in the effective dose if a desirable or beneficial result can or is achieved in combination with one or more other agents. The appropriate doses of any concomitantly administered compounds may be lowered at will due to the combined action of these compounds (e.g., additive or synergistic effects).

[0221] "Administration" refers to oral administration to a subject, administration as a suppository, local contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, nasal or subcutaneous administration, intrathecal administration, or implantation of a sustained-release device, e.g., a microosmotic pump. It may be administered according to a schedule specifying the frequency, dosage, and other factors.

[0222] As used herein, “concurrent administration” refers to administering a unit dose of the compound disclosed herein before or after the administration of a unit dose of one or more additional therapeutic agents, for example, administering the compound disclosed herein within seconds, minutes, or hours after the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound of the present invention is administered first, and then a unit dose of one or more additional therapeutic agents is administered within seconds or minutes. Alternatively, in other embodiments, a unit dose of the compound of the present invention is administered within seconds or minutes after a unit dose of one or more additional therapeutic agents is administered first. In some embodiments, a unit dose of one or more additional therapeutic agents is administered after a unit dose of the compound of the present invention is administered first, and then a unit dose of one or more additional therapeutic agents is administered after a few hours (e.g., 1 to 12 hours). In other embodiments, a unit dose of the compound of the present invention is administered after a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of the compound of the present invention is administered after a few hours (e.g., 1 to 12 hours). The combined administration of the compound disclosed herein and one or more additional therapeutic agents generally refers to administering the compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially so that a therapeutically effective amount of each agent is present in the patient's body.

[0223] "Object" refers to animals such as mammals, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the object is a human.

[0224] "Disease" or "pathological condition" refers to the state of existence or health condition of a patient or subject that can be treated by the compounds, pharmaceutical compositions, or methods provided herein.

[0225] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. “Pharmaceutically acceptable” or “physiologically acceptable” refers to compounds, salts, compositions, formulations, and other substances useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0226] The compounds described herein may be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. A pharmaceutically acceptable salt is a non-toxic salt in the free base form of a compound that possesses the desired pharmacological activity of a free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound containing basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting said compound with an inorganic acid or an organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogen-phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproate, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1,4-dioate, hexine-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, and methoxybenzoates. Includes phthalates, sulfonates, 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 is available in the literature [Remington: The Science and Practice of Pharmacy, 21 st It is found in Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0227] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 + Salts derived from (where X is a C1-C4 alkyl) are included. Base addition salts, such as sodium or potassium salts, are also included.

[0228] Compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which one to n hydrogen atoms attached to a carbon atom may be replaced with a deuterium atom or D, are also provided, wherein n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase metabolic resistance and thus may be useful in increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. For example, see the literature [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 a starting material in which one or more hydrogen atoms are replaced by deuterium.

[0229] Examples of isotopes that can be introduced into the disclosed compound also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, each 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 is included. Positron-emitting isotopes, for example 11 C, 18 F, 15 O and 13 Substitution with N may be useful for positron emission tomography (PET) studies to investigate substrate acceptor occupancy. The isotope-labeled compound of formula (I-VI) can be prepared by ordinary techniques generally known to those skilled in the art, or by a method similar to that described in the examples presented below, using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent.

[0230] The compounds of the embodiments disclosed herein or pharmaceutically acceptable salts thereof may comprise one or more asymmetric centers, and thus, in terms of absolute stereochemistry ( R )- or ( S Enantiomers, diastereomers, and other stereoisomers can be produced that can be defined as )-, or in the case of amino acids as (D)- or (L)-. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical activity (+) and (-), ( R )- and ( S)-, or (D)- and (L)- isomers may be prepared using chiral synthones or chiral reagents, or separated using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or, e.g., separation of racemics (or racemics of salts or derivatives) using chiral high-pressure liquid chromatography (HPLC). Where the compounds described in the present invention contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise specified, the compounds are intended to include both E geometric isomers and Z geometric isomers. Likewise, all tautomers are also intended to be included. Where a compound is represented by its chiral form, it is understood that embodiments encompass, but are not limited to, forms that are diastereomerically or enantiomerically abundant. Where chirality is not specified but is present, embodiments are understood to relate to forms that are diastereomerically or enantiomerically abundant in certain forms; or racemic or scalemic mixtures of such compound(s). As used herein, "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0231] "Racemic" refers to a mixture of enantiomers. Such a mixture may contain equal or unequal amounts of each enantiomer.

[0232] "Stereoisomers" and "stereoisomers" refer to compounds with different chiralities at one or more stereocenters. Stereoisomers include enantiomers and diastereomers. These compounds may exist as stereoisomers if they possess one or more asymmetric centers or double bonds with asymmetric substitutions, and thus may be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the foregoing description is intended to include mixtures as well as individual stereoisomers. Methods for measuring stereochemistry and separating 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).

[0233] "Tautomer" refers to an alternative form of a compound with different proton positions, such as enol-keto and imine-enamin tautomers, or a tautomer of a heteroaryl group containing a ring atom attached to both the ring -NH- and ring =N-, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0234] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Dashes before or after chemical groups are for convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in the structure indicate the attachment points of the groups. Dashed lines indicate arbitrary bonds. Unless chemically or structurally required, no orientation is indicated or implied in the order in which the chemical groups are listed or in the point where they are attached to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both may be connected in either direction. Similarly, for example, an "arylalkyl" group may be attached to the rest of the molecule at either the aryl or alkyl portion of the group. "C u-v " or (C u -C v Prefixes such as ) indicate that the following group has u to v carbon atoms. For example, "C 1-6 Both "alkyl" and "C1-C6alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0235] As used herein, "solvent" refers to the result of the interaction between a solvent and a compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0236] Exemplary compounds

[0237] Method for preparing a compound

[0238] The compounds of the present invention may be prepared by any method known in the art. The following exemplary general methods illustrate routes used to obtain the compounds of the present invention.

[0239] In some cases (reaction scheme 1), chemical formula 13Chemical formulas of compounds that are commercially available or known in the literature 1 (Here, LG 1 or LG 2 is a leaving group typically a halide or sulfone, but not limited thereto, was prepared from a compound. Chemical formula 1 The compound of appropriate R in the presence or absence of catalyst(s), in the presence or absence of base(s). 2 -M ( 4 By treating with ) and through a cross-coupling reaction, the chemical formula 2 A compound of was prepared. Suitable M groups are -B(OH)2, -B(pin), -Sn(alkyl)3, -ZnX or -MgX, but are not limited thereto. R 2 The functional groups of the phase may be protected by appropriate protecting groups as determined by those skilled in the art. The catalyst for this conversion was often Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, PdCl2Pd XPhos G1, G2, G3, or G4 precatalyst, Pd SPhos G1, G2, G3, or G4 precatalyst, or Pd2dba3 in the presence or absence of a phosphine ligand selected from, but not limited to, SPhos, XPhos, RuPhos, XantPhos, PCy3, PPh3, or dppf. 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 to.

[0240] R 1 In the case of this amine, the chemical formula 2 The compound of nucleophile HR in the presence of a base 1 By treating with, the chemical formula 13 A compound was obtained. Alternatively, the chemical formula 2 HR together with the compound 1 or MR1 Using in the presence of a catalyst and / or a base, the chemical formula 13 A compound was obtained. The catalyst and base were those described above, but were not limited thereto. R 1 The functional group of the upper part may be protected by an appropriate protective group as determined by those skilled in the art.

[0241] Reaction Schema 1

[0242]

[0243] MR that is not commercially available or is not known in the literature 2 ( 4 ) compounds are typically converted into the corresponding halide through catalytic activation in the presence of a base for nucleophile generation and an appropriate reagent. 3 It was derived from (Reaction Schema 2). The catalysts and bases were those listed above, but were not limited thereto. The reagents generating the nucleophile were B2pin2 or Sn2(alkyl)6, but were not limited thereto. Often, with exceptions, the chemical formula 4 The chemical formula of the compound 2 Directly using the compound and one-pot cross-coupling, chemical formula 13 A compound of was obtained.

[0244] Reaction Schema 2

[0245]

[0246] Chemical formulas not commercially available or known in the literature 1 The compound was synthesized according to the following reaction scheme 3. Chemical formula 5 The compound in the presence of a base S -Treated with a methylisothiourea source, chemical formula 6 A compound was obtained. Subsequently, the chemical formula 6 The compound is typically LG through treatment with POCl3. 2It was converted into the compound of Chemical Formula 7 through the activation of the hydroxyl group of Rho. Chemical Formula 7 The compound was converted into the compound of Chemical Formula 8 through cross-coupling as described above and in Reaction Schema 1. Chemical Formula 8 Typically, the thioether of the compound m - Chemical formula through treatment with an oxidizing agent, which was but not limited to chloroperbenzoic acid, peracetic acid, or Oxone® 9 LG of the compound 1 It was converted to. Then, the chemical formula 9 The compound of MR described above and in Reaction Schematic 1 1 or HR 1 By treating with, the chemical formula 13 A compound of was obtained.

[0247] Reaction Schema 3

[0248]

[0249] In some cases, chemical formula 13 The compound was prepared according to Reaction Schema 4. Chemical formula 1 The compound is treated with a hydroxide source, typically sodium hydroxide but not limited thereto, using the chemical formula 10 A compound was obtained. Then, the chemical formula 10 The compound of the above-described MR 1 or MR 2 By treating with, the chemical formula 11 A compound was obtained. As described above, the chemical formula 11 The chemical formula of the hydroxyl group of the compound 12 LG of the compound 2 Converted to. Chemical formula 12 The compound of the chemical formula through a cross-coupling reaction as described above 13 It was converted into a compound.

[0250] Reaction Schema 4

[0251]

[0252] Pharmaceutical preparations

[0253] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention (e.g., a compound of formulas I-VI), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0254] In some embodiments of the present invention, the pharmaceutical composition comprises, as described more fully below, a compound of formulas (I-VI), or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more additional therapeutic agents.

[0255] A pharmaceutical composition comprising the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, may be prepared with one or more pharmaceutically acceptable excipients selected according to ordinary practice. Tablets may contain excipients including flow promoters, fillers, binders, etc. Aqueous compositions may be prepared in a sterile form and may generally be isotonic when intended for delivery by means other than oral administration. In some embodiments, the composition [Rowe et al, Handbook of Pharmaceutical Excipients, 6 th It may contain excipients such as those described in [ed., American Pharmacists Association, 2009]. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc. In some embodiments, the composition is provided as a solid formulation including a solid oral formulation.

[0256] The composition includes those suitable for various routes of administration, including oral administration. The composition may be presented in unit formulations and may be prepared by any method well known in the pharmaceutical field. Such methods include the step of combining an active ingredient (e.g., a compound of the present invention or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The composition may be prepared by uniformly and closely combining the active ingredient with a liquid excipient or a fine solid excipient, or both, and then, if necessary, molding the product. Techniques and methods are generally described in the literature [Remington: The Science and Practice of Pharmacy, 21 st It appears in [Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006].

[0257] The compositions described herein suitable for oral administration may be provided as distinct units (unit formulations), each comprising, but not limited to, capsules, sachets, or tablets containing a predetermined amount of an active ingredient. In one embodiment, the pharmaceutical composition of the present invention is a tablet.

[0258] 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. Pharmaceutical compositions containing active ingredients may be in any form suitable for the intended method of administration. For oral use, tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared, for example. Compositions intended for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavorings, colorings, and preservatives, to provide a palatable formulation. Tablets containing active ingredients mixed with non-toxic, pharmaceutically acceptable excipients suitable for the preparation of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, sodium croscarmellose, povidone, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents, such as corn starch or alginic acid; binders, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants, such as magnesium stearate, stearic acid or talc. The tablets may not be coated, or may be coated by known techniques, including microencapsulation, to provide sustained action over a longer period by delaying disintegration and adsorption in the gastrointestinal tract. For example, time-delaying agents, such as glyceryl monostearate or glyceryl distearate, may be used alone or in combination with wax.

[0259] The amount of active ingredient that may be combined with the inactive ingredient to prepare a formulation may vary depending on the intended target of treatment and the method of administration. For example, in some embodiments, formulations for human oral administration may contain about 1 to 1000 mg of active substance formulated with an appropriate and convenient amount of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients vary from about 5 to about 95% (wt / wt) of the total composition.

[0260] In some embodiments, a composition comprising, in one variation, a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, does not contain a agent that affects the rate at which the active ingredient is metabolized. Accordingly, it is understood that a composition comprising a compound of the present invention in one embodiment does not contain a agent that affects (e.g., slows down, interferes with, or delays) the metabolism of the compound of the present invention or any other active ingredient administered individually, sequentially, or simultaneously with the compound of the present invention. Furthermore, it is understood that in one embodiment, any method, kit, manufactured article, etc. described in detail herein does not contain a agent that affects (e.g., slows down, interferes with, or delays) the metabolism of the compound of the present invention or any other active ingredient administered individually, sequentially, or simultaneously with the compound of the present invention.

[0261] In some embodiments, the above-described pharmaceutical composition is intended for use in humans or animals.

[0262] The present invention further comprises a compound of the present invention 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 the active ingredient to a pharmaceutically acceptable therapeutic inert organic and / or inorganic carrier or excipient, or by mixing it with such carriers or excipients.

[0263] In one embodiment, the use of a compound of the present invention as a second or other active ingredient exhibiting a synergistic effect with another active ingredient in a known drug, or the administration of a compound of the present invention together with said drug, is provided herein.

[0264] The compound of the present invention may also be used in the form of a prodrug that releases an active ingredient in vivo or in other suitably modified forms.

[0265] Administration route

[0266] The compounds of the present invention (also referred to herein as active ingredients) may be administered by any route appropriate for the condition to be 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 preferred routes may vary, for example, depending on the condition of the recipient. An advantage of the specific compounds disclosed herein is that they are bioavailable orally and can be administered orally.

[0267] The compound of the present invention may be administered to an individual according to an effective administration plan for a desired period or continuous period, for example, 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 compound is administered daily or on an intermittent schedule for the lifetime of the individual.

[0268] The dosage or frequency of administration of the compound of the present invention may be adjusted throughout the course of treatment based on the judgment of the administering physician.

[0269] The compound may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once a day.

[0270] The compound may be administered by any useful route and means, for example, orally or parenterally (e.g., intravenously). The therapeutically effective amount of the compound may comprise about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example, about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or for example, about 0.3 mg to about 30 mg per day, or for example, about 30 mg to about 300 mg per day.

[0271] The compound of the present invention may be combined with one or more additional therapeutic agents at any dosage of the compound of the present invention (e.g., 1 mg to 1000 mg of the compound). The therapeutically effective dose may comprise about 1 mg to about 1000 mg per dose, e.g., about 50 mg to about 500 mg per dose, e.g., about 100 mg to about 400 mg per dose, e.g., about 150 mg to about 350 mg per dose, e.g., about 200 mg to about 300 mg per dose. Other therapeutically effective doses of the compound of the present invention are 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 doses of the compounds of the present invention are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose may be administered every hour, daily, or weekly. For example, a single dose may be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. A single dose may also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. A single dose may also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In some embodiments, a single dose may be administered once a week. A single dose may also be administered once a month.

[0272] A kit comprising a compound of the present invention, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any one of the above is also included in the present invention. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present invention, 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 regarding the use of the compound in the treatment of symptoms such as diseases or pathological conditions described herein. In one embodiment, a kit comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, is provided in combination with one or more additional therapeutic agents (e.g., one, two, three, four, one or two, one to three, or one to four).

[0273] Manufactured articles comprising a compound of the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterium analogue thereof in a suitable container are also provided herein. The container may be a vial, bottle, ampoule, pre-loaded syringe, and intravenous bag.

[0274] Combination therapy

[0275] NASH

[0276] In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, may be combined with a therapeutically effective amount of one or more additional therapeutic agents (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4). In some embodiments, the additional therapeutic agents comprise an apoptosis signal-modulating 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 a combination thereof.

[0277] The benefits of the combination product can be enhanced by the efficacy of the compound of the present invention, and the dosage of the corresponding component can be lowered to reduce side effects, thereby increasing the efficacy of the corresponding component and / or reducing side effects.

[0278] In some embodiments, the therapeutic agent or combination of therapeutic agents comprises an ACE inhibitor, a 2-acylglycerol O-acyltransferase 2 (DGAT2) inhibitor, an acetaldehyde dehydrogenase inhibitor, an acetyl CoA carboxylase inhibitor, an adrenergic receptor agonist, an Alstrom syndrome protein 1 (ALMS1) / PKC alpha 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, and a NAD-dependent deacetylase. Sirtuin-1 agonists, adrenergic receptor antagonists, androgen receptor agonists, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, peak sodium-dependent bile acid transport inhibitors, autophagy protein modulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein agonists, beta-catenin inhibitors, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 agonists, cathepsin inhibitors, caveolin 1 inhibitors, CCK receptor antagonists, CCL26 gene inhibitors, CCR1 chemokine antagonists, CCR2 chemokine antagonists, angiotensin II AT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, CDGSH iron-sulfur domain protein modulators, chitinase inhibitors, chloride channel agonists, chitotriosidase 1 inhibitor, CNR1 inhibitor, connective tissue growth factor ligand inhibitor, COT protein kinase inhibitor, cyclin D1 inhibitor, cytochrome P450 7A1 inhibitor, DGAT1 / 2 inhibitor, diacylglycerol 0 acyltransferase 1 inhibitor (DGAT1),Cytochrome P450 2E1 inhibitors (CYP2E1), cytochrome P450 reductase inhibitors, CXCR3 chemokine antagonists, CXCR4 chemokine antagonists, dihydroceramide delta 4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase IV inhibitors, endocyalin modulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, fibroblast activation protein inhibitors, free fatty acid receptor 1 agonists, galectin-3 inhibitors, GDNF family receptor alpha-like agonists, glucagon receptor agonists, glucagon-like peptide 1 agonists, glucocorticoid receptor antagonists, glucose 6-phosphate 1-dehydrogenase inhibitors, G protein-coupled bile acid receptor 1 agonists, G protein-coupled receptor-119 agonists, G protein-coupled receptor 84 antagonists, Hedgehog (Hh) modulators, Hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4 alpha modulators (HNF4A), hepatocyte growth factor modulators, histone deacetylase inhibitors, STAT-3 modulators, HMG CoA reductase inhibitors, HSD17B13 gene inhibitors, 5-HT2α receptor antagonists, hydrolase inhibitors, hypoxia-inducible factor-2 alpha inhibitors, IL-10 agonists, IL-17 antagonists, IL-22 agonists, ileal sodium bile acid cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, integrins Alpha-V / beta-1 antagonists, integrin alpha-V / beta-6 antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IL-6 receptor agonists, interleukin-17 ligand inhibitors, Jak2 tyrosine kinase inhibitors, Jun N-terminal kinase-1 inhibitors,Kelch-like ECH-associated protein 1 modulator, keto-hexokinase (KHK) inhibitor, clotho-beta 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 homologue 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) inhibitors, mitochondrial uncouplers, mixed lineage kinase-3 inhibitors, motile sperm domain protein 2 inhibitors, myelin basic protein stimulators, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin stimulators, NADPH oxidase inhibitors (NOX), NFE2L2 gene inhibitors, nicotinic acid receptor 1 agonists, opioid receptor mu antagonists, P2Y13 purine receptor stimulators, nuclear factor erythroid-2 related factor 2 stimulators, nuclear receptor modulators, nuclear transport of transcription factor regulators, P2X7 purine receptor modulators, PACAP type I receptor agonists, PDE 3 inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor beta modulators, phenylalanine hydroxylase stimulators, Phospholipase C inhibitors, phosphodiesterase inhibitors, PPAR alpha agonists, PPAR delta agonists, PPAR gamma agonists, peptidyl-prolyl cis-trans isomerase A inhibitors, PNPLA3 gene inhibitors, PPAR gamma 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, RNA polymerase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 inhibitors, spingolipid delta 4 desaturase DES1 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl CoA desaturase-1 inhibitors, STK25 inhibitors, cytokine signaling-1 stimulant, cytokine signaling-3 stimulant, type II taste receptor 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 beta agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, TLR-9 antagonists, vascular cell adhesion protein-1 (VAP-1) inhibitors, VDR agonists, vitamin D3 receptor modulators, WNT modulators, YAP / TAZ modulators, or zonulin inhibitors, and combinations thereof.

[0279] Non-limiting examples of one or more additional therapeutic agents include the following:

[0280] ACE inhibitors, e.g., enalapril;

[0281] Acetaldehyde dehydrogenase inhibitors, e.g., ADX-629;

[0282] Acetyl CoA carboxylase (ACC) inhibitors, e.g., NDI-010976 (firsocostat), DRM-01, gemcabene, GS-834356, PF-05175157, QLT-091382, PF-05221304;

[0283] Acetyl CoA carboxylase / diacylglycerol O acyltransferase 2 inhibitor, e.g., PF-07055341;

[0284] Adenosine receptor agonists, e.g., namodenoson (CF-102), piclidenoson (CF-101), CF-502, CGS21680;

[0285] Adenosine A3 receptor antagonists, e.g., FM-101;

[0286] Adiponectin receptor agonists, e.g., ADP-355, ADP-399, ALY668-SR;

[0287] Adrenergic receptor antagonists, e.g., bromocriptine, phentermine, VI-0521;

[0288] Aldehyde dehydrogenase 2 stimulants, e.g., FP-045;

[0289] Amylin / calcitonin receptor agonists, e.g., KBP-042, KBP-089;

[0290] AMP-activated protein kinase stimulants, e.g., C-455, PXL-770, O-304;

[0291] AMP kinase activators / ATP citrate lyase inhibitors, e.g., bempedoic acid (ETC-1002, ESP-55016);

[0292] AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulant, e.g., NS-0200 (leucine + metformin + sildenafil);

[0293] Androgen receptor agonists, e.g., LPCN-1144, LPCN-1148, testosterone prodrugs;

[0294] Angiotensin II AT-1 receptor antagonists, e.g., irbesartan; angiopoietin-related protein-3 inhibitors, e.g., vupanorsen (IONIS-ANGPTL3-LRx);

[0295] Apelin receptor agonists, e.g., CB-5064, MBT-2;

[0296] Peak sodium-dependent bile acid transport inhibitor, e.g., A-3907;

[0297] Autophagy protein regulators, e.g., A-2906, GM-90194;

[0298] Autotaxin (ectonucleotide pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2)) inhibitors, e.g., FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, BBT-877;

[0299] Axl tyrosine kinase receptor inhibitors, e.g., bemcentinib (BGB-324, R-428);

[0300] Bax protein stimulants, e.g., CBL-514;

[0301] Bioactive lipids, e.g., DS-102;

[0302] Cannabinoid receptor modulators, e.g., namacizumab (nimacimab), GWP-42004, REV-200, CRB-4001, INV-101, SCN-002;

[0303] Caspase inhibitors, e.g., emricasan;

[0304] Pan cathepsin B inhibitors, e.g., VBY-376;

[0305] Pan cathepsin inhibitors, e.g., VBY-825;

[0306] CCK receptor antagonists, e.g., proglumide;

[0307] CCL26 gene inhibitors, e.g., mosedipimod, KDDF-201410-10;

[0308] CCR2 / CCR5 chemokine antagonists, e.g., BMS-687681, cenicriviroc, maraviroc, CCX-872, leronlimab, WXSH-0213;

[0309] CCR2 / CCR5 chemokine antagonists and FXR agonists, e.g., LJC-242 (tropifexor + cenicriviroc);

[0310] CCR2 chemokine antagonists, e.g., propagermanium;

[0311] CCR2 chemokine / angiotensin II AT-1 receptor antagonists, e.g. DMX-200, DMX-250;

[0312] CCR3 chemokine antagonists, e.g., bertilimumab;

[0313] CD3 antagonists, e.g., NI-0401 (foralumab);

[0314] CDGSH iron-sulfur domain protein regulator, e.g., EYP-002;

[0315] Chitinase inhibitors, e.g., OATD-01;

[0316] Chitotriosidase 1 inhibitors, e.g., OAT-2068;

[0317] Chloride channel stimulants, e.g., cobiprostone and lubiprostone;

[0318] Casein kinase-1 (CK1) delta / epsilon inhibitor, e.g., PF-05006739;

[0319] Connective tissue growth factor ligand inhibitor, e.g., PBI-4050;

[0320] COT protein kinase inhibitors, e.g., GS-4875, GS-5290;

[0321] CXCR4 chemokine antagonists, e.g., AD-214;

[0322] Cytochrome P450 reductase inhibitors, e.g., SNP-630;

[0323] Diglyceride acyltransferase 2 (DGAT2) inhibitors, e.g., IONIS-DGAT2Rx, PF-06865571;

[0324] Diglyceride acyltransferase 1 (DGAT1) inhibitors, e.g., GSK-3008356;

[0325] Diacylglycerol O acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitor (CYP2E1), e.g., SNP-610;

[0326] Dihydroorotate dehydrogenase inhibitors, e.g., vidofludimus;

[0327] Dipeptidyl peptidase IV inhibitors, e.g., linagliptin, evogliptin;

[0328] Eotaxin ligand inhibitors, e.g., vertilimumab, CM-101;

[0329] Extracellular matrix protein regulators, e.g., CNX-024;

[0330] Farnesoid X receptor (FXR) agonists, e.g., AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, cilofexor 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, vonafexor (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266, HPD-001, alendronate;

[0331] Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, e.g., INT-767;

[0332] Fatty acid synthase inhibitors, e.g., TVB-2640, FT-8225;

[0333] Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, e.g., aldafermin (NGM-282);

[0334] Fibroblast growth factor 21 (FGF-21) ligand modulators, e.g., AP-025, BMS-986171, B-1654, BIO89-100, BOS-580, Pegbelfermin (BMS-986036), B-1344, NN-9499;

[0335] Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, e.g., YH-25723 (YH-25724; YH-22241), ephruxifermin (AKR-001);

[0336] FGF receptor agonists / cloto beta agonists, e.g., BFKB-8488A (RG-7992);

[0337] Free fatty acid receptor 1 agonist, e.g., SCO-267;

[0338] Galectin-3 inhibitors, e.g., belapectin (GR-MD-02), GB-1107 (Gal-300), GB-1211 (Gal-400), IMT-001;

[0339] GDNF family receptor alpha-like agonists, e.g., NGM-395;

[0340] Glucagon-like peptide 1 receptor (GLP1R) agonists, e.g., 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;

[0341] Glucagon-like peptide 1 receptor agonist; oxyntomodulin ligand; glucagon receptor agonist, e.g., epinofegdutide;

[0342] Gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP / GLP-1) receptor co-agonists, e.g., tirzepatide (LY-3298176);

[0343] PEG long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, e.g., DD-01;

[0344] Glucagon / GLP1 receptor agonists, e.g., BI-456906, NN-6177;

[0345] Glucocorticoid receptor antagonists, e.g., CORT-118335 (miricorilant);

[0346] Glucose 6-phosphate 1-dehydrogenase inhibitors, e.g., ST001;

[0347] Glucokinase stimulants, e.g., dorzagliatin, sinogliatin (RO-5305552);

[0348] G protein-coupled bile acid receptor 1 (TGR5) agonists, e.g., RDX-009, INT-777, HY-209;

[0349] G protein-coupled receptor 84 antagonists, e.g., PBI-4547;

[0350] G protein-coupled receptor-119 agonists, e.g., DA-1241;

[0351] Heat shock protein 47 (HSP47) inhibitors, e.g., ND-L02-s0201;

[0352] Hedgehog protein TGF beta ligand inhibitors, e.g., Oxy-210;

[0353] Histone deacetylase inhibitor / STAT-3 modulator, e.g., SFX-01;

[0354] HMG CoA reductase inhibitors, e.g., atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin;

[0355] HSD17B13 gene inhibitors, e.g., ALN-HSD, ARO-HSD;

[0356] Hydrolase inhibitors, e.g., ABD-X;

[0357] Hypoxia-inducible factor-2 alpha inhibitors, e.g., PT-2567;

[0358] IL-10 agonists, e.g., pegilodecakin;

[0359] Sodium bile acid co-transporter inhibitors, e.g., odevixibat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, elobixibat (A-3309);

[0360] Insulin sensitizers, e.g., KBP-042, azemiglitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), tolimidone, VVP-100X, CB-4211, ETI-101;

[0361] Insulin ligand / ds-insulin receptor agonist, e.g., ORMD-0801;

[0362] Integrin antagonists, e.g., IDL-2965;

[0363] IL-6 receptor agonists, e.g., KM-2702;

[0364] Integrin alpha-V / beta-6 and alpha-V / beta-1 dual inhibitors, e.g., PLN-74809;

[0365] Interleukin 17 ligand inhibitors, e.g., netakimab;

[0366] Jak1 / 2 tyrosine kinase inhibitors, e.g., baricitinib;

[0367] Jun N-terminal kinase-1 inhibitor, e.g., CC-90001;

[0368] Kelch-like ECH-associated protein 1 regulators, e.g., alpha-cyclodextrin-stabilized sulforaphane;

[0369] Keto-hexokinase (KHK) inhibitors, e.g., PF-06835919, LY-3478045, LY-3522348;

[0370] Beta-cloto (KLB)-FGF1c agonists, e.g., MK-3655 (NGM-313);

[0371] Leukotriene A4 hydrolase inhibitor, e.g. LYS-006;

[0372] 5-lipoxygenase inhibitors, e.g., tipelukast (MN-001), epeluton (DS-102 (AF-102));

[0373] Lipoprotein lipase inhibitors, e.g., CAT-2003;

[0374] LPL gene stimulators, e.g., alipogene tiparvovec;

[0375] Liver X receptor (LXR) inhibitors, e.g., PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238;

[0376] Lysophosphatidate-1 receptor antagonists, e.g., BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198;

[0377] Ricil oxidase homologue 2 inhibitors, e.g., simtuzumab, PXS-5382A (PXS-5338);

[0378] Macrophage mannose receptor 1 modulators, e.g., tilmanocept-Cy3 (technetium Tc 99m tilmanocept);

[0379] Matrix metalloprotease inhibitors, e.g., ALS-L1023;

[0380] Membrane copper amine oxidase (VAP-1) inhibitors, e.g., TERN-201, TT-01025;

[0381] MEKK-5 protein kinase (ASK-1) inhibitors, e.g., CJ-16871, CS-17919, selonsertib (GS-4997), SRT-015, GS-444217, GST-HG-151, TERN-301;

[0382] MCH receptor-1 antagonists, e.g., CSTI-100 (ALB-127158);

[0383] Semicarbazide-sensitive amine oxidase / vascular cell adhesion protein-1 (SSAO / VAP-1) inhibitors, e.g., PXS-4728A (BI-1467335);

[0384] Methionine aminopeptidase-2 inhibitors, e.g., ZGN-1061, ZGN-839, ZN-1345;

[0385] Methyl CpG-binding protein 2 regulators, e.g., mercaptamine;

[0386] Mineralocorticoid receptor antagonists (MCRA), e.g., MT-3995 (apararenone);

[0387] Mitochondrial uncoupler, e.g., 2,4-dinitrophenol, HU6, Mito-99-0053;

[0388] Mixed-line kinase-3 inhibitors, e.g., URMC-099-C;

[0389] Motile sperm domain protein 2 inhibitors, e.g., VB-601;

[0390] Myelin basic protein stimulants, e.g., olesoxime;

[0391] Myeloperoxidase inhibitors, e.g., PF-06667272, AZM-198;

[0392] NADPH oxidase inhibitors, e.g., GKT-831, GenKyoTex, APX-311, setanaxib;

[0393] Nicotinic acid receptor 1 agonists, e.g., ARI-3037MO;

[0394] NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, e.g., KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349);

[0395] NFE2L2 gene inhibitors, e.g., GeRP-amiR-144;

[0396] Nuclear transport of transcription factor regulators, e.g., AMTX-100;

[0397] Nuclear receptor modulators, e.g., DUR-928 (DV-928);

[0398] Opioid receptor mu antagonists, e.g., methylnaltrexone;

[0399] P2X7 purine receptor modulator, e.g., SGM-1019;

[0400] P2Y13 purine receptor stimulator, e.g., CER-209;

[0401] PDE 3 / 4 inhibitors, e.g., tipelukast (MN-001);

[0402] PDE 5 inhibitors, e.g., sildenafil, MSTM-102;

[0403] PDGF receptor beta modulators, e.g., BOT-191, BOT-509;

[0404] Peptidyl-prolyl cis-trans isomerase inhibitors, e.g., CRV-431 (CPI-432-32), NVP-018, NV-556 (NVP-025);

[0405] Phenylalanine hydroxylase stimulant, e.g., HepaStem;

[0406] Phosphodiester hydrolase inhibitors, e.g., ZSP-1601;

[0407] PNPLA3 gene inhibitors, e.g. AZD-2693;

[0408] PPAR agonists, e.g., Chiglitazar, elafibranor (GFT-505), seladelpar lysine (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;

[0409] Protease-activated receptor-2 antagonists, e.g., PZ-235;

[0410] Protein kinase modulators, e.g., CNX-014;

[0411] Protein NOV homologous regulator, e.g., BLR-200;

[0412] PTGS2 gene inhibitors, e.g., STP-705, STP-707;

[0413] Renin inhibitors, e.g., PRO-20;

[0414] Resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitors, e.g., DWJ-211;

[0415] Rev protein regulators, e.g., ABX-464;

[0416] Rho-associated protein kinase (ROCK) inhibitors, e.g., REDX-10178 (REDX-10325), KD-025, RXC-007, TDI-01;

[0417] RNA polymerase inhibitors, e.g., rifaximin;

[0418] S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, e.g., SL-891;

[0419] Sodium glucose transporter-2 (SGLT2) inhibitors, e.g., ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, sotagliflozin;

[0420] Sodium glucose transporter-1 / 2 (SGLT 1 / 2) inhibitors, e.g., licogliflozin bis(prolinate), LIK-066;

[0421] SREBP transcription factor inhibitors, e.g., CAT-2003, HPN-01, MDV-4463;

[0422] Stearoyl CoA desaturase-1 inhibitors, e.g., aramchol;

[0423] Type 2 taste receptor agonists, e.g., ARD-101;

[0424] Thyroid hormone receptor beta agonists, e.g., ALG-009, ASC-41, CNPT-101101, CNPT-101207, CS-27186, KY-41111, resmetirom (MGL-3196), MGL-3745, TERN-501, VK-2809, HP-515;

[0425] TLR-2 / TLR-4 antagonists, e.g., VB-201 (CI-201);

[0426] TLR-4 antagonists, e.g., JKB-121, JKB-122, naltrexone;

[0427] Tyrosine kinase receptor modulators, e.g., CNX-025, GFE-2137 (repurposed nitazoxanide);

[0428] TLR-9 antagonists, e.g., GNKS-356, AVO-101;

[0429] TNF antagonists, e.g., ALF-421;

[0430] GPCR modulators, e.g., CNX-023;

[0431] Nuclear hormone receptor modulators, e.g., Px-102;

[0432] VDR agonists, e.g., CK-15;

[0433] Xanthine oxidase inhibitors, e.g., ACQT-1127;

[0434] Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, e.g., RLBN-1001, RLBN-1127; or

[0435] Jonulin inhibitors, e.g., larazotide acetate (INN-202).

[0436] In a specific embodiment, one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, Alipogen Tiparvovec, AMX-342, AN-3015, anti-TAGE antibody, Aramcol, ARI-3037MO, ASP-8232, AXA-1125, betilimumab, anhydrous betaine, 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, Coviprostone, Colesevelam, 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), Emlicacic acid, Enalapril, Ertugliflozin, Evogliptin, F-351, Fluasterone (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 (icosabutate, PRC-4016), Icosapent ethyl ester, IMM-124-E, INT-767, INV-240, ION-455, IONIS-DGAT2Rx, Ipragliflozin, Irbesartan, 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) (Tropifexer), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX-8025, MDV-4463, Mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, Namacizumab, 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, olesoxim, PAT-505, PAT-048, pegilodecakin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, remogliflozin etabonate, RG-125 (AZD4076), RP-005, RPI-500, S-723595, Saroglitazar, SBP-301, Semaglutide, SH-2442, SHC-028, SHC-023, Simtuzumab, Solithromycin, Sotagliflozin, Statin (Atorvastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin), TCM-606F, TEV-45478, TQA-3526, TQA-3563, Tipelukast (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,It is selected from vismodegib, bolicsibart potassium 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.

[0437] In certain embodiments, examples of acetyl CoA carboxylase (ACC) inhibitors include, but are not limited to, those described in US2013123231, US2019134041, US2017267690, and US2018298025.

[0438] Examples of acetyl CoA carboxylase (ACC) inhibitors / farnesoid X receptor (FXR) agonists include, but are not limited to, those described in US2018280394.

[0439] 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 and US2018333401.

[0440] Examples of acetyl CoA carboxylase (ACC) / MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2018311244.

[0441] Examples of farnesoid X receptor (FXR) agonists include, but are not limited to, those described in US2014221659, US2020281911, and WO2020185685.

[0442] Examples of farnesoid X receptor (FXR) agonists / MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2017273952 and US201813320.

[0443] Examples of MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2011009410, US2013197037, US2016244430, and US2016280683.

[0444] CKD / DKD

[0445] Patients receiving treatment for psychorenal diseases, such as chronic kidney disease, can benefit from combination therapy.

[0446] In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, may be combined with a therapeutically effective amount of one or more additional therapeutic agents (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4). In some embodiments, the additional therapeutic agents may be angiotensin-converting enzyme (ACE) inhibitors, e.g., enalapril, captopril, ramipril, lisinopril, and quinapril; or angiotensin II receptor blockers (ARBs), e.g., losartan, olmesartan, and irbesartan; or antihypertensive agents, e.g., amlodipine, nifedipine, and felodipine; SGLT2 inhibitors, such as canagliflozin, dapagliflozin, empagliflozin and luceogliflozin; mineralocorticoid receptor antagonists, such as pinerone; NRF2 activators, such as bardoxolone methyl; LPAR antagonists; and apoptosis signaling kinase (ASK-1) inhibitors, such as selonsertip.

[0447] The benefits of the combination product can be enhanced by the efficacy of the compound of formula (I-VI) and / or other active ingredient(s), while the dose of the corresponding ingredient can be lowered to reduce side effects, thereby increasing the efficacy of the corresponding ingredient and / or reducing side effects.

[0448] Patients with chronic kidney disease that can be treated with KHK inhibitors such as compounds of formulas (I-VI) may also be in a condition that benefits from the combination of antibiotics, analgesics, antidepressants and / or anxiolytics, or the combination of therapies (as directed by a qualified healthcare professional) in combination with compounds of formulas (I-VI). The combination therapy may be administered simultaneously or sequentially at intervals as directed by a qualified healthcare professional, or through a combination of fixed doses of two or more active agents (all active ingredients combined into a single formulation, e.g., a tablet).

[0449] In some embodiments, the therapeutic agent or combination of therapeutic agents comprises an ACE inhibitor, an adenosine A3 receptor antagonist, an atropin stimulator, an albumin modulator, an aldosterone antagonist, an AMP-activated protein kinase stimulator, angiotensin II AT-2 receptor agonist, angiotensin II receptor antagonist, angiotensinogen ligand inhibitor, APOA1 gene stimulator, 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, chemase inhibitor, complement C1s subcomponent inhibitor, CX3CR1 chemokine antagonist, cyclooxygenase 1 inhibitor, cyclooxygenase 2 inhibitor, cytochrome P450 11B2 inhibitor, and ectonucleotide. Pyrophosphatase-PDE-2 inhibitors, endothelin ET-A receptor antagonists, endothelin ET-B receptor antagonists, enteropeptidase inhibitors, epoxide hydrolase inhibitors, erythropoietin receptor antagonists, farnesoid X receptor agonists, FGF receptor antagonists, free fatty acid receptor 1 agonists, GHR gene inhibitors, glycoprotein Ib (GPIb) antagonists, GPR40 agonists, GPR84 antagonists, G-protein beta subunit inhibitors, G-protein coupled receptor 120 agonists, G-protein coupled receptor 84 modulators, growth hormone ligands, growth hormone receptor agonists, guanylate cyclase receptor agonists, guanylate cyclase stimulants, heme oxygenase 1 modulators, HIF proryl hydroxylase inhibitors, IGF1 gene inhibitors, IgG receptor FcRn large subunit p51 modulators, IL-6 receptors Antagonists, integrin alpha-V / beta-3 antagonists, interleukin 33 ligand inhibitors, Kelch-like ECH-associated protein 1 modulators, LDHA gene inhibitors, 5-lipoxygenase activating protein inhibitors, lysophosphatidate-1 receptor antagonists,Matrix extracell 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 factor erythroid-related factor 2 stimulator, nuclear factor kappa B inhibitor, opioid receptor kappa agonist, opioid receptor mu antagonist, p38 MAP kinase inhibitor, PDE4 inhibitor, PDGF receptor antagonist, PDGF receptor beta modulator, phosphatonin receptor agonist, PRKAA2 gene stimulator, proprotein convertase PC9 inhibitor, prostacyclin (PGI2) agonist, protein C activator, protein NOV homologous modulator, protein tyrosine phosphatase-1B inhibitor, active 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 synthesis inhibitors, tissue transglutaminase inhibitors, TRP cation channel C5 inhibitors, TRP cation channel C6 inhibitors, tryptophanase inhibitors, non-specific cell adhesion molecule inhibitors, urate anion exchanger 1 inhibitors, vasopressin V1a receptor antagonists, VEGF receptor antagonists, VIP 1 receptor agonists, VIP 2 receptor agonists, or xanthine oxidase inhibitors, and combinations thereof.

[0450] Non-limiting examples of one or more additional therapeutic agents include the following:

[0451] ACE inhibitors, e.g., benazepril, imidapril;

[0452] Adenosine A3 receptor antagonists, e.g., FM-101;

[0453] Adrenaline stimulants, e.g., RBT-2;

[0454] Albumin modulators, e.g., SYNT-002;

[0455] Aldosterone / mineralcorticoid receptor antagonists, e.g., MT-3995;

[0456] Allogeneic bone marrow-derived mesenchymal stromal cell therapy, e.g., ORBCEL-M™;

[0457] Allogeneic extended adipose-derived stem cell therapy, e.g., Elixcyte™;

[0458] AMP-activated protein kinase stimulants / protoprotein convertase PC9 inhibitors, e.g., O-304;

[0459] AMP-activated protein kinase stimulants, e.g., DZCY-01, MK-8722, PXL-770;

[0460] Angiotensin II AT-1 receptor / CCR2 chemokine antagonist, e.g. DMX-200;

[0461] Angiotensin II AT-2 receptor agonists, e.g., MOR-107, irbesartan;

[0462] Angiotensin II receptor antagonists, e.g., losartan;

[0463] Angiotensinogen ligand inhibitors, e.g., ALN-AGT;

[0464] Anti-C1 antibody, e.g., BIVV-009 (sutimlimab);

[0465] Anti-CB1 antibody, e.g., GFB-024;

[0466] Anti-CX3CR1 nanobody, e.g. BI-655088;

[0467] Anti-IL-6 antibody, e.g., COR-001;

[0468] Anti-VEGF-B antibody, e.g., CSL-346;

[0469] APOA1 gene stimulator / bromodomain-containing protein 2 / bromodomain-containing protein 4 inhibitor, e.g., apabetalone;

[0470] Bone morphogenetic protein-7 ligand modulators, e.g., BMP-7;

[0471] Calcium channel inhibitors, e.g., TBN (xiaotongqin);

[0472] Cannabinoid CB1 receptor antagonists, e.g., JNJ-2463;

[0473] CB1 inverse agents, e.g., CRB-4001;

[0474] Chemase inhibitors, e.g., fulacimstat (BAY-1142524);

[0475] Cyclooxygenase 1 inhibitors, e.g., GLY-230;

[0476] Cyclooxygenase 2 / epoxide hydrolase inhibitors, e.g., COX-2 / soluble epoxide hydrolase;

[0477] Cytochrome P450 11B2 inhibitors, e.g., aldosterone synthase inhibitors;

[0478] Ectonucleotide pyrophosphatase-PDE-2 inhibitors, e.g., BLD-0409;

[0479] Endothelin ET-A / endothelin ET-B receptor antagonists, e.g., aprocitentan;

[0480] Enteropeptidase inhibitors, e.g., SCO-792;

[0481] Erythropoietin receptor antagonists, e.g., EPO-018B;

[0482] Farnesoid X receptor (FXR) agonists, e.g., AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, cilofexer 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, Bonafexer (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266;

[0483] FGF / PDGF / beta receptor antagonists / p38 MAP kinase inhibitors, e.g., pirfenidone;

[0484] GHR / IGF1 gene inhibitors, e.g., atesidorsen sodium;

[0485] GPR40 agonists / GPR84 antagonists, e.g., PBI-4050;

[0486] G protein beta subunit inhibitors, e.g., galeons;

[0487] G protein-coupled receptor 84 modulators, e.g., PBI-4425;

[0488] Growth hormone ligands / growth hormone receptor agonists, e.g., Jintropin AQ™;

[0489] Growth hormone receptor agonists, e.g., LAT-8881;

[0490] Guanylate cyclase receptor agonists / guanylate cyclase stimulants, e.g., praliciguat;

[0491] Guanylate cyclase stimulants, e.g., MRL-001, runcaciguat;

[0492] Heme oxygenase 1 modulators, e.g., RBT-1;

[0493] HIF prolyl hydroxylase inhibitors, e.g., TRGX-154;

[0494] Insulin sensitizer / Kallikrein 1 regulator, e.g. DM-199;

[0495] Integrin alpha-V / beta-3 antagonists, e.g., VPI-2690B;

[0496] Interleukin 33 ligand inhibitors, e.g., MEDI-3506;

[0497] Kelch-like ECH-associated protein 1 regulators / nuclear factor erythroid 2-associated factor 2 stimulators, e.g., SFX-01;

[0498] LDHA gene inhibitors, e.g., nedosiran;

[0499] 5-lipoxygenase activating protein inhibitors, e.g., AZD-5718;

[0500] Lysophosphatidate-1 receptor antagonists, e.g., BMS-002, EPGN-696;

[0501] Matrix extracellular glycoprotein modulators / phosphatonin receptor agonists, e.g., TPX-200;

[0502] MEKK-5 protein kinase inhibitors, such as selonsertip

[0503] Membrane copper amine oxidase inhibitor, e.g., UD-014;

[0504] Midkine ligand inhibitors, e.g., CAB-101;

[0505] Mineralcorticoid receptor antagonists, e.g., AZD-9977, esaxerenone, finerenone, KBP-5074;

[0506] Myosin 2 inhibitors, e.g., DeciMab™;

[0507] NADPH oxidase 1 inhibitors / NADPH oxidase 4 inhibitors, e.g., cetanaxib;

[0508] NADPH oxidase inhibitors, e.g., APX-115;

[0509] NK1 receptor antagonists / opioid receptor kappa agonists / opioid receptor mu antagonists, e.g., AV-104;

[0510] Nuclear factor erythroid-associated factor 2 stimulants / TGF beta-ligand inhibitors, e.g., CU01-1001;

[0511] Nuclear factor kappa B inhibitors, e.g., mepunidone, bardoxolone methyl (NSC-713200);

[0512] PDE 4 inhibitors, e.g., ART-648, PCS-499;

[0513] PDGF receptor beta modulators, e.g., BOT-191;

[0514] PDGF / VEGF receptor antagonists, e.g., ANG-3070;

[0515] PR84 antagonists / GPR40 (FFAR1) / GPR120 (FFAR4) agonists / and partial activators of peroxisome proliferator-activated receptors (PPARs), e.g., PBI-4547;

[0516] PRKAA2 gene stimulators / AMPK activators, e.g., PF-06679142, PF-06685249;

[0517] Prostacyclin (PGI2) agonists, e.g., YS-1402;

[0518] Protein C activator / glycoprotein Ib (GPIb) antagonist, e.g. AB-002;

[0519] Protein NOV homologous regulator, e.g., BLR-200;

[0520] Protein tyrosine phosphatase-1B inhibitors, e.g., MSI-1436;

[0521] Reactive oxygen species regulator inhibitors, e.g., SUL-121;

[0522] Renin inhibitors, e.g., ima-marilene hydrochloride;

[0523] Rho-associated protein kinase 2 inhibitors, e.g., ANG-4201, RXC-007;

[0524] Sodium glucose transporter-2 inhibitors, e.g., canagliflozin, dapagliflozin, propanediol, empagliflozin;

[0525] Thromboxane A2 receptor antagonists / thromboxane synthesis inhibitors, e.g., SER-150;

[0526] Tissue transglutaminase inhibitors, e.g., ZED-1227;

[0527] TRP cation channel C5 inhibitor, e.g., GFB-887;

[0528] TRP cation channel C6 inhibitor, e.g., ALGX-2224;

[0529] Urate anion exchanger 1 (URAT1) / SLC22A12 inhibitor, e.g., verinurad (RDEA3170);

[0530] VIP 1 / VIP 2 receptor agonists, e.g., LBT-3627; or

[0531] Xanthine oxidase inhibitors, e.g., TMX-049, TMX-049DN.

[0532] In a specific embodiment, one or more additional 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 Targeted 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, Salvialolic Acid, SGF-3, SPD-01, It is selected from SZ-005, TCF-12, UMC119-06, VAR-400, Veverimer, VS-105, or XRx-221.

[0533] IBD

[0534] As used herein, the terms "inflammatory bowel disease" or "IBD" refer collectively to inflammatory diseases of the gastrointestinal tract, the most common forms being ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated by the compounds, compositions, and methods disclosed in the present invention include transformative colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagen-accumulating colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic colitis, indeterminate colitis, and Behcet's disease. Includes gastroduodenal CD, ileitis, ileitis, ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, ileum pouchitis, proctitis, chronic diarrhea, or endotoxemia due to intestinal barrier dysfunction.

[0535] The treatment method disclosed in the present invention may 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 period of remission (i.e., inactive disease). In such embodiments, the method of the present invention provides benefits by extending the period of remission (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 a period of active disease. Such a method provides benefits by shortening the duration of the period of active disease, reducing or improving one or more symptoms of IBD, or treating IBD.

[0536] The benefits of the combination product can be enhanced by the efficacy of the compound of the present invention, and the dosage of the corresponding component can be lowered to reduce side effects, thereby increasing the efficacy of the corresponding component and / or reducing side effects.

[0537] In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, may be combined with a therapeutically effective amount of one or more additional therapeutic agents (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4).

[0538] Examples of formulations for the treatment of inflammatory diseases or conditions that may be used in combination with the compounds described in this specification include alpha-fetoprotein modulators, adenosine A3 receptor antagonists, adrenomedulin ligands, AKT1 gene inhibitors, and antibiotics; Antifungal agents, ASK1 inhibitors, ATPase inhibitors, beta-adrenergic receptor antagonists, BTK inhibitors, calcineurin inhibitors, carbohydrate metabolism regulators, cathepsin S inhibitors, CCR9 chemokine antagonists, CD233 modulators, CD29 modulators, CD3 antagonists, CD40 ligand inhibitors, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, COT protein kinase inhibitors, CSF-1 agonists, CSF-1 antagonists, CX3CR1 chemokine modulators, DYRK-1 alpha protein kinase inhibitors, eotaxin ligand inhibitors, EP4 prostanoid receptor agonists, F1F0 ATP synthase modulators, farnesoid X receptor (FXR, NR1H4) agonists or modulators, fecal microbiota transplantation (FMT), fractalkine Ligand inhibitors, free fatty acid receptor 2 antagonists, GATA 3 transcription factor inhibitors, glucagon-like peptide 2 agonists, glucocorticoid agonists, glucocorticoid receptor modulators, guanylate cyclase receptor agonists HIF, prolyl hydroxylase inhibitors, histone deacetylase inhibitors, HLA class II antigen modulators, hypoxia-inducible factor-1 stimulators, ICAM1 gene inhibitors, IL-1 beta ligand modulators, IL-12 antagonists, IL-13 antagonists, IL-18 antagonists, IL-18 receptor accessory protein antagonists, IL-22 agonists, IL-23 antagonists, IL-23A inhibitors, IL-6 antagonists, IL-7 receptor antagonists, IL-8 receptor antagonists, IL-36 inhibitors, integrin alpha-4 / beta-1 antagonists, integrin alpha-4 / beta-7 antagonists, Integrin antagonists, interleukin ligand inhibitors,Interleukin receptor 17A antagonists, interleukin-1 beta ligands, interleukin 1-like receptor 2 inhibitors, IL-6 receptor modulators, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, lactoferrin stimulants, LanC-like protein 2 modulators, leukocyte elastase inhibitors, leukocyte protease-3 inhibitors, MAdCAM inhibitors, melanin agglutination hormone (MCH-1) antagonists, melanocortin agonists, metalloproteinase-9 inhibitors, microbiome targeted therapies, natriuretic peptide receptor C agonists; Neuregulin-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 purine receptor modulator, PDE 4 inhibitor, Pellino homolog 1 inhibitor, PPAR alpha / delta agonist, PPAR gamma agonist, protein arginine daminase IV inhibitor, protein fimH inhibitor, P-selectin glycoprotein ligand-1 inhibitor, Ret tyrosine kinase receptor inhibitor, RIP-1 kinase inhibitor, RIP-2 kinase inhibitor, RNA polymerase inhibitor, sphingosine 1-phosphate phosphatase 1 stimulant, sphingosine-1-phosphate receptor-1 agonist, sphingosine-1-phosphate receptor-5 agonist, sphingosine -1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, stem cell antigen-1 inhibitors, superoxide dismutase modulators, SYK inhibitors, tissue transglutaminase inhibitors, TLR-3 antagonists, TLR-4 antagonists, Toll-like receptor 8 (TLR8) inhibitors, TLR-9 agonists, TNF alpha ligand inhibitors, TNF ligand inhibitors, TNF alpha ligand modulators, TNF antagonists, TPL-2 inhibitors, tumor necrosis factor 14 ligand modulators, tumor necrosis factor 15 ligand inhibitors, Tyk2 tyrosine kinase inhibitors, type I IL-1 receptor antagonists,Includes vanilloid VR1 agonists or zonulin inhibitors, and combinations thereof.

[0539] A treatment method comprising administering a compound described herein in combination with an anti-inflammatory agent is included herein. The anti-inflammatory agent includes, but is not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

[0540] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozine, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetine sodium, and hydroxychloroquine. Examples of NSAIDs include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib, etoricoxib, and / or rofecoxib (i.e., COX-1 IC50 50 ICs that are at least 50 times lower than 50 Compounds that inhibit COX-2 are also included.

[0541] In additional embodiments, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, choline salicylate, and magnesium salicylate.

[0542] Anti-inflammatory agents can also be corticosteroids. For example, corticosteroids can be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.

[0543] In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (e.g., eculizumab or pexelizumab), a TNF antagonist (e.g., etanercept), or an anti-TNF alpha monoclonal antibody, infliximab.

[0544] A therapeutic method of administering a compound described herein in combination with an immunosuppressant is included in this specification. In some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, sodium mycophenolate, mercaptopurine, or mofetil mycophenolate.

[0545] Treatment methods

[0546] In some embodiments, a compound of formula (I-VI), or a pharmaceutically acceptable salt or stereoisomer thereof, is useful for a method of treating and / or preventing KHK (keto-hexokinase)-mediated diseases or conditions. In some embodiments, a method of treating and / or preventing KHK-mediated diseases or conditions comprises administering a pharmaceutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject requiring treatment and / or prevention of a KHK-mediated disease or condition.

[0547] In some embodiments, the disease or condition includes chronic kidney disease (CKD), diabetic kidney disease (DKD), kidney disease, renal fibrosis, renal failure, acute kidney injury, tubular insufficiency, lupus nephritis, 2,8-dihydroxydenine nephropathy, kidney transplant rejection, renal protection against drugs causing 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, irritable bowel syndrome (IBD), ulcerative colitis, Crohn's disease, hyperuricemia, gout, arthritis, osteoporosis, or cancer.

[0548] In some embodiments, a method for treating and / or preventing non-alcoholic fatty liver disease (NAFLD) comprises administering a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject requiring treatment and / or prevention of non-alcoholic fatty liver disease (NAFLD).

[0549] In some embodiments, a method for treating and / or preventing chronic kidney disease comprises administering a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject requiring treatment and / or prevention of chronic kidney disease.

[0550] In some embodiments, a method for treating and / or preventing irritable bowel syndrome (IBD) comprises administering a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject requiring treatment and / or prevention of irritable bowel syndrome (IBD).

[0551] A pharmaceutical composition for use in treating a KHK-mediated disease or condition described herein, comprising a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, is further provided herein.

[0552] The present invention also describes a use for manufacturing a medicine for treating KHK-mediated diseases or conditions, comprising a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof. The medicine mentioned herein may be manufactured by conventional methods comprising a combination of a compound according to the present invention and a pharmaceutically acceptable carrier.

[0553] Compounds of the present invention for the treatment of KHK-mediated diseases or conditions, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed. Compounds of the present invention for the prevention of KHK-mediated diseases or conditions, or pharmaceutically acceptable salts or stereoisomers thereof, are also disclosed.

[0554] Examples

[0555] Many general references are available that provide generally known chemical synthesis reaction schemes and conditions useful for synthesizing the disclosed compounds (e.g., the literature [Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th [See edition, Wiley-Interscience, 2013]).

[0556] The compounds described herein may be purified by any means known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase, including normal phase and reverse phase as well as ionic resins, may be used. For example, the disclosed compounds may be purified via silica gel and / or alumina chromatography. For example, see the literature [Introduction to Modern Liquid Chromatography, 2nd ed., ed. LR Snyder and JJ Kirkland, John Wiley and Sons, 1979]; and the literature [Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969].

[0557] In any method of preparing the compound of the present invention, it may be desirable to protect any sensitive or reactive group on any relevant molecule. This can be achieved by conventional protecting groups described in standard reference literature, such as [TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 4th ed., Wiley, New York 2006]. The protecting group may be removed in a convenient subsequent step using methods known in the art.

[0558] Exemplary chemical substances useful for the methods of the embodiments will now be described herein with reference to exemplary synthetic reaction schemes for their general production and specific examples below. Those skilled in the art will recognize that, in order to obtain the various compounds of this specification, the desired product can be obtained by appropriately selecting starting materials such that the ultimately desired substituent is transferred through the reaction scheme, either protected or unprotected as needed. Alternatively, instead of the ultimately desired substituent, it may be preferable to use a suitable group that can be transferred through the reaction scheme and substituted with the desired substituent as needed. Furthermore, those skilled in the art will recognize that the transformations shown in the reaction scheme below can be carried out in any order suitable for the functionality of the pendant group.

[0559] The examples provided herein describe the synthesis of the compounds disclosed in the present invention as well as the intermediates used to manufacture the compounds. It should be understood that the individual steps described herein may be combined. It should also be understood that individual batches of compounds may be performed in subsequent synthesis steps after being combined.

[0560] In the description of the following examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice specific embodiments of the invention. Other embodiments may be utilized, and logical and other modifications may be made without departing from the scope of the invention. The embodiments also relate to methods and intermediates useful for preparing compounds of the invention, or pharmaceutically acceptable salts or stereoisomers thereof. Accordingly, the following description is not intended to limit the scope of the invention.

[0561] In some embodiments, the present invention generally provides a specific enantiomer or diastereomer as a desired product, but the stereochemistry of the enantiomer or diastereomer is not determined in all cases. Where the stereochemistry of a specific stereocenter in an enantiomer or diastereomer is not determined, the compound is depicted as not exhibiting any stereochemistry at that specific stereocenter, even if the compound may be substantially enantiomerically or disatereomerically pure.

[0562] A representative synthesis of the compound of the present invention is described in the following reaction scheme and the following examples.

[0563] The compounds described in detail in the Examples were synthesized according to the general synthesis methods described below. Unless otherwise specified, compounds were named using ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.) or Biovia Notebook 2020 SP2 HF1 version 20.1.201.31.

[0564] abbreviation

[0565] Specific abbreviations and acronyms are used to describe experimental details. While most of these will be understood by those skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.

[0566] [Table 1]

[0567]

[0568]

[0569]

[0570]

[0571] Intermediate Synthesis and General Methods

[0572] Preparation of intermediates

[0573]

[0574] 2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-ol

[0575] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.00 g, 26.4 mmol, 1 equivalent) was injected into a flask, and THF (26 mL) and 5N sodium hydroxide (26 mL, 130 mmol) were added. The mixture was heated at 50°C for 2 days. It was diluted with water and washed twice with dichloromethane. The aqueous layer was acidified with 10% potassium hydrogen sulfate until the pH reached 5. The extract was extracted twice with dichloromethane, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The result was purified by flash chromatography (40 to 100% ethyl acetate / hexane linear gradient) to obtain the title compound.

[0576]

[0577] 2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-ol

[0578] 2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-ol (776 mg, 4.55 mmol, 1 equivalent) and (2S)-2-methylazetidine hydrochloride (587 mg, 5.46 mmol) were injected into a flask, and acetonitrile (12 mL) and N,N-diisopropylethylamine (2.38 mL, 13.6 mmol) were added. The mixture was sealed and heated to 80°C for 16 hours. After cooling to ambient temperature, the resulting solid was collected, washed with acetonitrile, and collected to obtain the title compound.

[0579]

[0580] 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0581] 2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (873 mg, 4.25 mmol, 1 equivalent) was injected into a flask, and phosphoryl chloride (12 mL, 128 mmol) was added. The mixture was heated to 80°C for 2 hours. It was cooled to ambient temperature, poured over ice, and neutralized with solid potassium carbonate until the pH reached > 9. It was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound.

[0582]

[0583] (2S,3R)-1-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-2-methylazetidine-3-yl benzoate

[0584] The title compound was prepared using (2S,3R)-2-methylazetidin-3-yl benzoate instead of (2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-ol in a similar manner.

[0585]

[0586] (S)-2-(2-methylazetidine-1-yl)-4-(tributylstantanyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0587] (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (23.0 g, 102 mmol) and PhMe (58 mL) were injected into a flask, followed by the injection of 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 to 120°C for 16 hours. The reaction mixture was cooled to ambient temperature, concentrated, and subjected to flash column chromatography (Al2O3, petroleum ether-ethyl acetate) to obtain the title compound.

[0588]

[0589] (S)-4-bromo-1-methoxy-2-(methylsulfinyl)benzene

[0590] After adding (-)-diethyl D-tartrate (15.4 g, 74.6 mmol) and DCM (400 mL) to a flask, Ti(OiPr)4 (10.6 g, 37.3 mmol) and H2O (0.67 mL, 37.3 mmol) were added. The mixture was stirred at ambient temperature for 30 minutes. (5-bromo-2-methoxyphenyl)(methyl)sulfane (8.70 g, 37.3 mmol) was added, and the mixture was stirred at ambient temperature for an additional 15 minutes. Afterward, the mixture was cooled to -20°C (ethylene glycol-dry ice bath), and tert-butyl hydrogen peroxide (5 to 6 M in decane, 8.96 mL, 44.8 mmol) was added dropwise over 5 minutes. The mixture was heated to ambient temperature over 18 hours. H2O (10 ml) was added, and the mixture was filtered using Celite®. The filtrate was washed with H2O (200 mL) and extracted with DCM (3 × 100 mL). The combined organic matter was dried with Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (hexane-ethyl acetate) to obtain a title product of 78% ee. The product was recrystallized with boiling hexane to obtain >99% ee.

[0591] general method

[0592] The general method represents the most commonly used method, but slight modifications, including reaction time processes and temperature, were often used.

[0593] 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 selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, PdCl2Pd XPhos G1, G2, G3 or G4 precatalyst, Pd SPhos G1, G2, G3 or G4 precatalyst, or Pd2dba3 in the presence or absence of a phosphine ligand, generally selected from SPhos, XPhos, RuPhos, XantPhos, PCy3, PPh3 or dppf, but not limited thereto. The base was generally selected from 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.

[0594] Stereochemistry was arbitrarily assigned to the isomers separated by chiral chromatography.

[0595] General Method A:

[0596]

[0597] 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0598] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1 equivalent), 3-pyridylboronic acid (31 mg, 0.25 mmol, 1.2 equivalents), and Pd(PPh3)4 (25 mg, 0.021 mmol, 10 mol%) were injected into a vial and flushed with nitrogen. DME (10 mL) and Na2CO3 (2M aq, 0.53 mL, 4 equivalents) were added, and the mixture was heated to 90°C for 4 hours. The mixture was cooled to ambient temperature, concentrated, and subjected to flash column chromatography (ethyl hexane) to obtain the title compound (44 mg, 0.19 mmol).

[0599] General Method B:

[0600]

[0601] (S)-2-(2-methylazetidine-1-yl)-4-(pyridine-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0602] 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in a vial (44 mg, 0.19 mmol, 1.0 equivalent), (2S)-2-methylazetidine (R)-camposulfonate (86 mg, 0.29 mmol, 1.5 equivalents), and MeCN (1.5 mL) were injected. N(iPr)2Et (0.13 mL, 98 mg, 0.76 mmol, 4.0 equivalents) was added, and the mixture was heated at 90°C for 18 hours. The mixture was concentrated and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound (36 mg, 0.14 mol).

[0603] General method C:

[0604]

[0605] (S)-3-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)propanoic acid

[0606] Methyl (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)propanoate (20 mg, 0.057 mmol, 1 equivalent), MeOH (1 mL), and NaOH (2 M aq., 0.6 mL) were injected into a vial. The reaction mixture was heated to 60°C for 1 hour. The reaction 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 (3.3 mg, 0.0098 mmol).

[0607] General method D:

[0608]

[0609] Ethyl 2-tributylstanylimidazo[5,1-b]thiazole-7-carboxylate

[0610] Ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (500 mg, 1.82 mmol, 1.0 equivalent), Pd(OAc)2 (40.8 mg, 0.18 mmol, 10 mol%), PCy3 (102 mg, 0.36 mmol, 20 mol%), hexa-n-butylizutin (1.16 g, 2.00 mmol, 1.1 equivalent), and 1,4-dioxane (4.0 mL) were injected into a vial, and the mixture was sparged with nitrogen. The mixture was heated at 120°C for 18 hours. The mixture was concentrated and subjected to flash column chromatography (ethyl hexane-acetate) to obtain the title compound (258 mg, 0.53 mmol).

[0611] General Method E:

[0612]

[0613] Ethyl (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)imidazo[5,1-b]thiazole-7-carboxylate

[0614] Ethyl 2-tributylstanylimidazo[5,1-b]thiazole-7-carboxylate (100 mg, 0.21 mmol, 1.0 equivalent), (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (46 mg, 0.21 mmol, 1.0 equivalent), 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) were injected into a vial. The mixture was heated to 120°C for 4 hours. The mixture was concentrated and subjected to flash column chromatography (ethyl hexane) to obtain the title compound (50 mg, 0.13 mmol).

[0615] General method F:

[0616]

[0617] (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzo[d]isothiazole-3(2H)-one 1,1-dioxide

[0618] 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one (25.0 mg, 0.095 mmol), bis(pinacolato)diborone (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%) were injected into a microwave reaction tube. 1,4-dioxane (1 mL) was added, and the mixture was sparged with nitrogen for 5 minutes, then heated to 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). The filtrate and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine (21.3 mg, 0.095 mmol) were injected into a microwave reaction tube. An aqueous solution of Na2CO3 (2 M, 0.2 mL) was added, and the reaction mixture was sparged with nitrogen for 5 minutes, after which it was 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 obtain the title compound (5.3 mg, 0.014 mmol).

[0619] General method G:

[0620]

[0621] 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxamide

[0622] 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid (56 mg, 0.15 mmol, 1.0 equivalent), ammonia (0.4 M in 1,4-dioxane, 1.2 mL, 0.46 mmol, 3.0 equivalent), and HATU (70 mg, 0.18 mmol, 1.2 equivalent) were injected into a vial. DMF (2 mL), followed by N(i Pr)2Et (0.11 mL, 0.61 mmol, 4.0 equivalents) was added. 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 matter was dried with Na2SO4, filtered, and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound (45 mg, 0.12 mmol).

[0623] General method H:

[0624]

[0625] 2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine-4-ol

[0626] Methyl 2-oxobicyclo[3.1.0]hexane-3-carboxylate (300 mg, 1.95 mmol) and 2-methylisothiourea (557 mg, 3.89 mmol) were added to a vial, followed by sodium carbonate (2 M, aq., 3.89 mL, 7.78 mmol). The mixture was stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, treated with 1 N HCl, and then extracted with EA. The mixture was concentrated and subjected to flash column chromatography (ethyl hexane-acetate) to obtain the title compound (300 mg, 1.54 mmol).

[0627]

[0628] 4-chloro-2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine

[0629] 2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine-4-ol (300 mg, 1.54 mmol) was injected into a vial, followed by the addition of POCl3 (5 mL, 46.3 mmol). The mixture was heated to 110°C for 18 hours, cooled to ambient temperature, and poured over ice. The aqueous mixture was extracted twice with DCM. The combined organic layer was dried with MgSO4, filtered, and concentrated. The crude product was used without further purification.

[0630]

[0631] 3-(2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine-4-yl)benzamide

[0632] The title compounds were prepared in a manner similar 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 instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.

[0633]

[0634] 3-(2-(methylsulfonyl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine-4-yl)benzamide

[0635] 3-(2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine-4-yl)benzamide (135 mg, 0.454 mmol), mCPBA (261, 1.13 mmol), and DCM (2 mL) were injected into a flask. The mixture was stirred at ambient temperature for 2 hours. The mixture was extracted with EA, washed with an aqueous sodium bicarbonate solution, concentrated, and subjected to flash column chromatography (ethyl hexane-acetate) to obtain the title compound.

[0636]

[0637] 3-(2-((S)-2-methylazetidin-1-yl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine-4-yl)benzamide

[0638] The title compound was prepared in a manner similar to general method B using 3-(2-(methylsulfonyl)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine-4-yl)benzamide instead of 2-chloro-4-(pyridine-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0639] General Method I:

[0640]

[0641] (S)-2-(2-methylazetidine-1-yl)-4-(4-(piperazine-1-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0642] tert-butyl (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-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 obtain the title compound.

[0643] General method J:

[0644]

[0645] (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0646] (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzonitrile (30 mg, 0.10 mmol, 1.0 equivalent), EtOH (1 mL) and NaOH (2M aq., 0.5 mL) were injected into a vial and heated to 90°C for 1 hour. The reaction mixture was concentrated and passed through HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid.

[0647] General method K:

[0648]

[0649] (S)-1-methyl-N-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)-1H-imidazole-4-sulfonamide

[0650] (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)aniline (15 mg, 0.054 mmol, 1.0 equivalent), 4-dimethylaminopyridine (1 mg, 0.0054 mmol, 10 mol%), Et3N (0.022 mL, 0.16 mmol, 3.0 equivalent), and DCM (1 mL) were injected into a vial. Then, 1-methylimidazole-4-sulfonyl chloride (15 mg, 0.080 mmol, 1.5 equivalent) was added at ambient temperature, and the mixture was stirred for 4 hours. The mixture was concentrated and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[0651] General method L:

[0652]

[0653] 2-cyclopropyl-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0654] 2-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.17 mmol, 1.0 equivalent), Pd(P tBu3)2 (8.9 mg, 0.017 mmol, 10 mol%) and DMF (3 mL) were injected. After sparging the vial with argon, cyclopropyl zinc bromide (0.5 M in THF, 1.04 mL, 0.52 mmol, 3.0 equivalents) was added. The mixture was heated to 90°C for 30 minutes and then cooled to ambient temperature. NH4Cl (5 mL, sat. aq) was added, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic layer was dried with 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 obtain the title compound.

[0655] General method M:

[0656]

[0657] 4-(7,7-difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0658] 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide was prepared in a manner similar to general method A, using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-carbamoylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid.

[0659] To a vial containing 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide (136 mg, 0.42 mmol, 1.0 equivalent), 3-chloroperoxybenzoic acid (77% purity, 285 mg, 1.27 mmol, 3.0 equivalent) was added, followed by DCM (2 mL). The mixture was stirred at ambient temperature for 2 hours. NaHCO3 (sat. aq., 2 mL) was added, and the mixture was extracted with DCM (3 × 2 mL). The combined organic extract was dried with Na2SO4, filtered, and concentrated to obtain the title compound.

[0660] General method N:

[0661]

[0662] 4-(2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0663] 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide (50 mg, 0.18 mmol, 1.0 equivalent), 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (50 mg, 0.46 mmol, 2.5 equivalent), 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 equivalent) were added to a vial. 1,4-dioxane (2.0 mL) was added, and the mixture was sparged with nitrogen for 2 minutes. The mixture was heated to 120°C for 18 hours, 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 obtain the title compound.

[0664] General method O:

[0665]

[0666] 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzaldehyde

[0667] The title compounds were 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0668]

[0669] 2-[(2S)-2-methylazetidin-1-yl]-4-[3-(1-piperidylmethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0670] 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]pyrimidine-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 hours. NaHCO3 (1 mL, sat. aq.) was added, and the mixture was extracted with DCM (3 × 1 mL). The combined organic matter was dried with Na2SO4, filtered, and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[0671] General method P:

[0672]

[0673] 2-[(2S)-2-methylazetidin-1-yl]-4-vinyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0674] Potassium trifluoro(vinyl)boranude (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) were added 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). The reaction mixture was degassed with nitrogen, sealed, and heated at 70°C for 16 hours. It was cooled to ambient temperature, diluted with ethyl acetate, and washed with water and saturated sodium chloride. It was dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl-hexane acetate) to obtain the title compound.

[0675]

[0676] 2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carbaldehyde

[0677] Potassium osmium(VI)ate dihydrate (28 mg, 0.077 mmol) and sodium periodate (1.24 g, 5.8 mmol) were added 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), and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was filtered, diluted with EtOAc, and washed with water, saturated sodium thiosulfate, saturated sodium bicarbonate, and saturated sodium chloride. It was dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl-hexane acetate) to obtain the title compound.

[0678]

[0679] 2-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-1H-benzimidazole

[0680] 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), 2-nitroaniline (14 mg, 0.10 mmol) and a 1 M aqueous sodium adithionate solution (0.3 mL, 0.3 mmol) were added, and the reaction mixture was heated at 70°C for 16 hours. After cooling to ambient temperature and treatment with 5 N ammonium hydroxide, the resulting solid was collected by filtration. The residue was subjected to flash column chromatography (ethyl acetate-hexane) to obtain the title compound.

[0681] General method Q:

[0682]

[0683] Methyl (S)-4-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate

[0684] Methyl 4-bromo-2-hydroxy-benzoate (400 mg, 1.73 mmol), tert-butyl (S)-(1-hydroxypropane-2-yl)carbamate (303 mg, 1.73 mmol), and PhMe (4 mL) were injected into a vial. Diisopropyl azodicarboxylate (0.37 mL, 1.90 mmol) was then added dropwise with PPh3 (499 mg, 1.90 mmol). The mixture was heated at 90°C for 2 hours. The mixture was concentrated, and the residue was subjected to flash column chromatography (ethyl-hexane acetate) to obtain methyl (R)-4-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate.

[0685]

[0686] (S)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[0687] Methyl (S)-4-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate (672 mg, 1.73 mmol), TFA (2 mL), and DCM (2 mL) were injected into a vial. The mixture was stirred at ambient temperature for 30 minutes and then concentrated under vacuum. The residue was dissolved in EtOAc and washed with NaHCO3(sat, aq.). The organic layer was dried with Na2SO4, filtered, and concentrated. The resulting residue was dissolved in PhMe (4 mL) and heated at 110°C for 18 hours. The mixture was concentrated, and the residue was subjected to flash column chromatography (ethyl-hexane acetate) to obtain (S)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one.

[0688] General method R:

[0689]

[0690] 3-(4-(7,7-difluoro-2-((2S,3R)-3-fluoro-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)oxetane-3-amine

[0691] Benzyl (3-(4-(7,7-difluoro-2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)oxetane-3-yl)carbamate (100 mg, 0.19 mmol) and EtOH (3 mL) were injected into a vial. The vial was purged with nitrogen, and Pd / C (5 wt%, 41 mg, 0.019, 10 mol%) was added. The solution was sparged through an H2 gas balloon while stirring for 2 hours. The mixture was filtered through Celite®, concentrated, and subjected to reverse-phase HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[0692] General method S:

[0693]

[0694] 4-Bromo-1-methoxy-2-(methylsulfinyl)benzene

[0695] A suspension of (5-bromo-2-methoxyphenyl)(methyl)sulfane (4.00 g, 17.2 mmol) and sodium periodontate (3.97 g, 18.6 mmol) in methanol (37 mL) and water (37 mL, containing 0.5 M sodium periodontate) was stirred overnight at ambient temperature. The mixture was filtered, and the solid was washed with additional methanol. The filtrate was partitioned into dichloromethane and water, and the layers were separated. The aqueous layer was extracted three more times with dichloromethane, the organic matter was combined, dried with magnesium sulfate, filtered, and concentrated to obtain the title compound.

[0696] Alternatively, the starting material was dissolved in DCM (0.3 M), and mCBPA (1.5 equivalents) was added. The mixture was stirred for 30 minutes. K2CO3 (2 M aq) was added, and the mixture was extracted with DCM. The combined organic material was dried with Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl hexane) to obtain the desired product.

[0697]

[0698] tert-butyl ((5-bromo-2-methoxyphenyl)(methyl)(oxo)-λ 6 - Sulfanilidene) Carbamate

[0699] PhI(OAc)2 (8.14 mg, 25.3 mmol) was added 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). The resulting mixture was stirred at 40°C for 2 hours, then cooled to room temperature and filtered through a Celite® pad. The filtrate was concentrated under vacuum, and the resulting residue was subjected to flash column chromatography (ethyl hexane-acetate) to obtain the title compound.

[0700] General method T:

[0701]

[0702] Benzyl (3-(4-bromo-2-fluorophenyl)oxetane-3-yl)carbamate

[0703] 3-(4-bromo-2-fluorophenyl)oxetane-3-amine hydrochloride (300 mg, 1.06 mmol) and DCM (5 mL) were injected into a flask, followed by N(iPr)2Et (0.46 mL, 343 mg, 2.65 mmol). CbzCl (0.18 mL, 217 mg, 1.27 mmol) was added dropwise over 5 minutes. After stirring the mixture at ambient temperature for 4 hours, it was concentrated and subjected to flash column chromatography (ethyl hexane) to obtain the title compound.

[0704] General method U:

[0705]

[0706] Benzyl ((R)-6-(7,7-difluoro-2-((R)-2-(trifluoromethyl)azetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydrobenzofuran-3-yl)(oxetane-3-yl)carbamate

[0707] Benzyl (R)-(6-(7,7-difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydrobenzofuran-3-yl)(oxetane-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 injected into a microwave reaction tube. CH3CN (3 mL) and ( iPr)2EtN (139 mg, 1.08 mmol) was added to the 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 sat. aq. NaHCO3 (10 mL). The aqueous layer was extracted with DCM (3 × 10 mL). The organic matter was combined, dried with Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl hexane) to obtain the title compound.

[0708] General Method V:

[0709]

[0710] 5-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one oxime

[0711] 5-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one (1.00 g, 4.37 mmol), NaOAc-(H2O)3 (2.97 g, 21.8 mmol), and MeOH (20 mL) were added to a flask. Hydroxylamine hydrochloride (1.52 g, 21.8 mmol) was added, and the mixture was heated under reflux for 1 hour using a reflux condenser. The mixture was concentrated, and H2O (20 mL) was added. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic matter was dried with Na2SO4, filtered, and concentrated to obtain the title product.

[0712]

[0713] 5-Bromo-7-fluoro-2,3-dihydro-1H-indene-1-amine

[0714] Zn powder (1.43 g, 21.8 mmol) and HCl (aq. 6 M, 8.7 mL) were added to 5-bromo-7-fluoro-2,3-dihydro-1H-indene-1-one oxime (1.07 g, 4.37 mmol) in MeOH (10 mL). The mixture was heated to 60°C for 1 hour. After cooling to ambient temperature, KOH (aq. 2 M) was added to adjust the pH to 12. The obtained solid was filtered and dried under vacuum to obtain the title product.

[0715] General method W:

[0716]

[0717] 5-Bromo-7-methoxy-2,3-dihydro-1H-indene-1-ol

[0718] NaBH4 (156 mg, 4.13 mmol) was added to 5-bromo-7-methoxy-2,3-dihydro-1H-indene-1-one (498 mg, 2.07 mmol) in MeOH (10 mL). The mixture was stirred at ambient temperature for 18 hours, concentrated, and subjected to flash column chromatography (ethyl hexane) to obtain the title compound.

[0719]

[0720] 5-Bromo-7-methoxy-2,3-dihydro-1H-indene-1-amine

[0721] Diphenylphosphoryl azide (0.35 mL, 451 mg, 1.64 mmol) and DBU (0.31 mL, 312 mg, 2.05 mmol) were added dropwise over 5 minutes to 5-bromo-7-methoxy-2,3-dihydro-1H-indene-1-ol (332 mg, 1.37 mmol) in PhMe (6 mL). The mixture was stirred overnight at ambient temperature. H2O (10 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic matter was dried with 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 minutes. H2O (1 mL) was added, and the mixture was heated to 50°C for 4 hours. After cooling to ambient temperature, H2O (10 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic matter was dried with Na2SO4, filtered, concentrated, and subjected to flash column chromatography (ethyl hexane) to obtain the title compound.

[0722] General method X:

[0723]

[0724] 7-Bromospiro[chroman-4,4'-imidazolidine]-2',5'-dione

[0725] 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) were added to a flask. A reflux condenser was fitted to the flask, and it was heated to 90°C for 3 days. The mixture was cooled to ambient temperature, and the pH was adjusted to 6 using HCl (aq, 6 M). The resulting solid was collected by filtration, washed with H2O, and dried under vacuum to obtain the title compound.

[0726] General method Y:

[0727]

[0728] 5-bromo-2,3-dihydrospiro[indene-1,3'-morpholine]-5'-one

[0729] (1-amino-5-bromo-2,3-dihydro-1H-indene-1-yl)methanol (300 mg, 1.24 mmol) and DCM (12 mL) were added to a vial, 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 hours. H2O (10 mL) was added, and the mixture was extracted with DCM (3 × 10 mL). The combined organic matter was dried with Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl hexane-acetate) to obtain N-(5-bromo-1-(hydroxymethyl)-2,3-dihydro-1H-indene-1-yl)-2-chloroacetamide.

[0730] NaH (60% dispersion in mineral oil, 84 mg, 2.18 mmol) was added to a solution of N-(5-bromo-1-(hydroxymethyl)-2,3-dihydro-1H-indene-1-yl)-2-chloroacetamide (278 mg, 0.87 mmol) in THF (8 mL). 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 matter was dried with Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl hexane-acetate) to obtain the title compound.

[0731] General method Z:

[0732]

[0733] 5-bromo-2,3-dihydrospiro[indene-1,4'-oxazolidine]-2'-one

[0734] (1-amino-5-bromo-2,3-dihydro-1H-indene-1-yl)methanol (500 mg, 2.07 mmol) and THF (15 mL) were injected into a vial. Triphosgene (613 mg, 2.07 mmol) was slowly added. The resulting mixture was heated to 70°C for 2 hours. The mixture was cooled to ambient temperature. NaHCO3 (15 mL, sat. aq.) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was dried with Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (ethyl hexane-acetate) to obtain the title compound.

[0735] Alternatively, 1,1'-carbonyldiimidazole and N(iPr)2Et were used instead of triphosgene without heating.

[0736] General method AA:

[0737]

[0738] 4-ethynyl-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0739] 2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carbaldehyde (310 mg, 1.43 mmol) and methanol (12 mL) were injected into a vial. To this, potassium carbonate (197 mg, 1.43 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (0.278 mL, 1.85 mmol) were added, and the reaction mixture was stirred at ambient temperature for 16 hours. It was diluted with ethyl acetate and washed with saturated sodium bicarbonate and saturated sodium chloride. It was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound was obtained by purification by flash chromatography (hexane-ethyl acetate).

[0740]

[0741] 2-[(2S)-2-methylazetidin-1-yl]-4-[1-(oxetane-3-yl)triazole-4-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0742] Copper(I) thiophene-2-carboxylate (3 mg, 0.014 mmol) was added 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), and the reaction mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated and purified by flash chromatography (ethyl hexane-acetate) to obtain the title compound.

[0743] General method AB:

[0744]

[0745] tert-butyl N-(6-bromo-1,1-dioxo-2,3-dihydrobenzothiophen-3-yl)carbamate

[0746] Triethylamine (0.425 mL, 3 mmol) and tert-butoxycarbonyl tert-butyl carbonate (400 mg, 1.8 mmol) were added to a solution of 6-bromo-1,1-dioxo-2,3-dihydrobenzothiophen-3-amine (400 mg, 1.5 mmol) in tetrahydrofuran (8.3 mL), and the reaction mixture was stirred at ambient temperature for 16 hours. It was diluted with ethyl acetate and washed with 10% potassium hydrogen sulfate, saturated sodium bicarbonate, and saturated sodium chloride. It was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound was obtained by purification by flash chromatography (hexane-ethyl acetate).

[0747] General method AC:

[0748]

[0749] (2S,3R)-1-[4-[3-[(cyclopropyl-methyl-oxo-λ 6 -sulfanilidene)amino]phenyl]-7,7-difluoro-5,6-dihydrocyclopenta[d]pyrimidine-2-yl]-2-methyl-azetidine-3-ol

[0750] In a solution of (2S,3R)-1-[7,7-difluoro-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl]-5,6-dihydrocyclopenta[d]pyrimidine-2-yl]-2-methyl-azetidine-3-ol (50 mg, 0.11 mmol) in dimethylformamide (1 mL), cyclopropyl-imino-methyl-oxo-λ 6 - Sulfate (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 stirred at ambient temperature exposed to air for 16 hours. It was diluted with ethyl acetate and washed with 10% ammonium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. It was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound was obtained by purification by flash chromatography (DCM-MeOH).

[0751] General method AD:

[0752]

[0753] (5S)-5'-bromo-3-methyl-spiro[imidazolidine-5,1'-indane]-2,4-dione

[0754] Methyl iodide (0.022 mL, 0.36 mmol) was added to a suspension of (5S)-5'-bromospiro[imidazolidin-5,1'-indane]-2,4-dione (100 mg, 0.36 mmol) and potassium carbonate (49 mg, 0.36 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. Water was added to precipitate the solid, which was collected, washed with water, and dried under vacuum to obtain the title compound.

[0755] General method AE:

[0756]

[0757] Ethyl 3-(1-azido-5-bromo-2,3-dihydro-1H-indene-1-yl)propanoate

[0758] 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) were added to 5-bromo-1-methylene-2,3-dihydro-1H-indene (2500 mg, 12 mmol) in iPrOH (180 mL). The mixture was stirred at 50°C for 12 hours, concentrated, toluene (20 mL) was added, and concentrated again. The result was then subjected to flash column chromatography (DCM-MeOH) to obtain the title compound.

[0759]

[0760] Ethyl 3-(1-amino-5-bromo-2,3-dihydro-1H-indene-1-yl)propanoate

[0761] SnCl2 (1600 mg, 7.1 mmol), thiophenol (1.45 mL, 14.2 mmol), and TEA (2.47 mL, 17.7 mmol) were added to ethyl 3-(1-azido-5-bromo-2,3-dihydro-1H-indene-1-yl)propanoate (1200 mg, 3.55 mmol) in MeOH (60 mL). The mixture was stirred at ambient temperature for 30 minutes. Ethyl acetate (100 mL) was added, and the solid was filtered out. The organic layer was washed with aq. NaHCO3 and saline solution. The organic material was dried with Na2SO4, concentrated, and subjected to flash column chromatography (DCM-MeOH) to obtain the title compound.

[0762]

[0763] 5-bromo-2,3-dihydrospiro[indene-1,2'-pyrrolidine]-5'-one

[0764] Ethyl 3-(1-amino-5-bromo-2,3-dihydro-1H-indene-1-yl)propanoate (735 mg, 2.35 mmol) was heated at 100°C for 12 hours in toluene (8 mL). After cooling to ambient temperature, the solid was filtered to obtain the title compound.

[0765] General method AF:

[0766]

[0767] 5-Bromo-7-(methylthio)-2,3-dihydrobenzofuran

[0768] 5-bromo-7-iodo-2,3-dihydrobenzofuran (885 mg, 2.27 mmol, 1.0 equivalent), dimethyl disulfide (0.29 mL, 3.27 mmol, 1.2 mmol), cupric acetate (49.5 mg, 0.27 mmol, 0.10 equivalent), potassium hydroxide (306 mg, 5.45 mmol, 2.0 equivalent), and tetrabutylammonium bromide (43.9 mg, 0.14 mmol, 0.05 equivalent) were added to a vial. The vial was capped and heated to 100°C for 12 hours. After cooling to room temperature, the mixture was divided into water and EtOAc. The aqueous components were extracted twice with EtOAc, the organic matter was dried with magnesium sulfate, filtered, and concentrated to obtain the title compound.

[0769] General method AG:

[0770]

[0771] (2-(benzyloxy)-5-bromophenyl)(imino)(methyl)-λ 6 - Sulpanone

[0772] (2-(benzyloxy)-5-bromophenyl)(methyl)sulfane (618 mg, 2.00 mmol, 1.0 equivalent) and methanol (15 mL) were injected into a vial. Ammonium carbonate (288 mg, 3.00 mmol, 1.5 equivalent) was added, followed by iodobenzene diacetate (1482 mg, 4.60 mmol, 2.3 equivalent), the vial was rapidly sealed with a septum, and vigorously stirred at room temperature for 5 hours. Afterward, the solvent was removed under reduced pressure, and the residue was purified by silica gel flash column chromatography (0 to 5% MeOH in DCM) to obtain the title compound.

[0773] General method AH:

[0774]

[0775] 2-Benzyl-4-Bromobenzamide

[0776] 2-benzyl-4-bromobenzoic acid (200 mg, 0.69 mmol, 1.0 equivalent) and HATU (392 mg, 1.03 mmol, 1.5 equivalent) in DCM (5 mL) were injected into a vial. DIPEA (120 μL, 0.69 mmol, 1 equivalent) was added, and the reaction mixture was vigorously stirred at room temperature for 10 minutes. Subsequently, ammonia in 1,4-dioxane (6.87 mL, 5 equivalents of 0.5 M solution) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The solid was filtered out (washed with DCM), the combined solution was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound, 2-benzyl-4-bromobenzamide.

[0777] General Method AI:

[0778]

[0779] N-(6-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)chroman-4-yl)methanesulfonamide

[0780] 6-bromocroman-4-amine (50 mg, 0.19 mmol, 0.91 equivalents), DIPEA (146 μL, 0.84 mmol, 4 equivalents), and anhydrous NMP (1 mL) were injected into a vial under argon, and the reaction mixture was stirred at room temperature for 1 minute. Then, methanesulfonyl chloride (23 μL, 0.23 mmol, 1.1 equivalents) was added under argon, and the reaction mixture was stirred at room temperature for 20 minutes. Afterwards, (S)-2-(2-methylazetidin-1-yl)-4-(tributyltannyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100 mg, 0.21 mmol, 1.0 equivalent), Pd(PPh3)2Cl2 (15 mg, 0.021 mmol, 10 mol%), XPhos (9.4 mg, 0.021 mmol, 10 mol%), and CuI (3.9 mg, 0.021 mmol, 10 mol%) were added. The reaction mixture was purged with argon five times and heated at 110°C for 1 hour under argon. Afterwards, 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 removed by filtration, 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.

[0781] Compound Examples

[0782]

[0783] Example 1: Methyl (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H cyclopenta[d]pyrimidine-4-yl)phenyl)propanoate

[0784] The title compound was prepared using methyl 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl]propanoate instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0785]

[0786] Example 2: Methyl (S)-3-(2-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)propanoate

[0787] The title compound was prepared using methyl 3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl]propanoate instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0788]

[0789] Example 3: Methyl (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)acetate

[0790] The title compound was prepared using methyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl]acetate instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0791]

[0792] Example 4: (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)propanoic acid

[0793] The title compound was prepared according to general method C.

[0794]

[0795] Example 5: (S)-3-(2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)propanoic acid

[0796] The title compound was prepared in a manner similar to general method C using methyl (S)-3-(2-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)propanoate instead of (S)-3-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)propanoate.

[0797]

[0798] Example 6: (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)acetic acid

[0799] The title compound was prepared in a manner similar to general method C using methyl (S)-2-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)acetate instead of (S)-3-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)acetate.

[0800]

[0801] Example 7: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzonitrile

[0802] The title compound was prepared using (3-cyanophenyl)boronic acid instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[0803]

[0804] Example 8: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0805] Example 9: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid

[0806] The title compound was prepared according to general method J.

[0807]

[0808] Example 10: (S)-2-(2-methylazetidine-1-yl)-4-phenyl-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine

[0809] The title compounds were prepared using phenylboronic acid and 2,4-dichloro-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, in a manner similar to general method A, followed by general method B.

[0810]

[0811] Example 11: (S)-1-methyl-5-(2-methylazetidin-1-yl)-7-phenyl-1H-pyrazolo[4,3-d]pyrimidine

[0812] The title compounds were prepared using phenylboronic acid and 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, in a manner similar to general method A, followed by general method B.

[0813]

[0814] Example 12: (S)-2-(2-methylazetidin-1-yl)-4-phenylfuro[3,2-d]pyrimidine

[0815] The title compounds were prepared using phenylboronic acid and 2,4-dichlorofuro[3,2-d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, in a manner similar to general method A, followed by general method B.

[0816]

[0817] Example 13: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)isothiazole

[0818] The title compound was prepared using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0819]

[0820] Example 14: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)isothiazole

[0821] The title compound was prepared using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0822]

[0823] Example 15: (S)-2-(2-methylazetidin-1-yl)-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0824] The title compound was prepared according to general method A, followed by general method B.

[0825]

[0826] Example 16: (S)-2-(2-methylazetidin-1-yl)-4-(pyrimidine-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0827] The title compound was prepared using pyrimidine-5-ylboronic acid instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[0828]

[0829] Example 17: (S)-4-(1-methyl-1H-pyrazole-3-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0830] The title compound was prepared using 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0831]

[0832] Example 18: (S)-2-(2-methylazetidine-1-yl)-4-(1H-pyrazole-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0833] The title compound was prepared using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B. In the first step, tert-butyl carboxylate was decomposed under reaction conditions.

[0834]

[0835] Example 19: (S)-2-(2-methylazetidine-1-yl)-4-(1H-pyrazole-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0836] The title compound was prepared using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B. In the first step, tert-butyl carboxylate was decomposed under reaction conditions.

[0837]

[0838] Example 20: (S)-4-(1-methyl-1H-pyrazole-5-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0839] The title compound was prepared using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0840]

[0841] Examples 21: (S)-2-(2- Methylazetidine -1-day)-4-(pyridin-2-day)-6,7- Dihydro -5H- Cyclopenta[d]pyrimidine

[0842] 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 equivalent), 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 equivalent), and DMF (2 mL) were injected into a vial. The mixture was sparged with argon and heated to 100°C for 24 hours. The mixture was concentrated and subjected to flash column chromatography (ethyl hexane) to obtain 2-chloro-4-(2-pyridyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and then the title compound was obtained by general method B.

[0843]

[0844] Example 22: (S)-2-(2-methylazetidin-1-yl)-4-(pyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0845] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1.0 equivalent), 4-pyridylboronic acid (60.7 mg, 0.30 mmol, 1.4 equivalent), 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 equivalent), and DMF (2 mL) were injected into a vial. The mixture was sparged with argon and heated to 100°C for 24 hours. The mixture was concentrated and subjected to flash column chromatography (ethyl hexane) to obtain 2-chloro-4-(2-pyridyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and then the title compound was obtained by general method B.

[0846]

[0847] Example 23: (S)-4-(1-methyl-1H-pyrazole-4-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0848] The title compound was prepared using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0849]

[0850] Example 24: (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propanoic acid

[0851] (S)-2-(2-methylazetidin-1-yl)-4-(1H-pyrazole-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (12 mg, 0.033 mmol, 1 equivalent), K2CO3 (9.0 mg, 0.065 mmol, 2 equivalents), and MeCN (0.5 mL) were added to a vial, followed by methylprop-2-enoate (84 mg, 0.975 mmol, 30 equivalents). The sealed vial was heated to 120°C for 2 hours, then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL), and NaOH (2M aq., 0.5 mL) was added. The mixture was heated to 60°C for 20 minutes. The mixture was cooled to ambient temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[0852]

[0853] Example 25: (S)-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-pyrazole-1-yl)propanoic acid

[0854] 2-[(2S)-2-methylazetidin-1-yl]-4-(1H-pyrazole-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (6 mg, 0.016 mmol, 1 equivalent), K2CO3 (4.5 mg, 0.033 mmol, 2 equivalents), and MeCN (0.5 mL) were added to a vial, followed by methylprop-2-enoate (42 mg, 0.49 mmol, 30 equivalents). The sealed vial was heated to 120°C for 15 minutes, then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL), and NaOH (2M aq., 0.5 mL) was added. The mixture was heated to 60°C for 20 minutes. The mixture was cooled to ambient temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[0855]

[0856] Example 26: (S)-5-(2-methylazetidine-1-yl)-7-phenylthiazolo[5,4-d]pyrimidine

[0857] The title compounds were prepared using phenylboronic acid and 5,7-dichlorothiazolo[5,4-d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, in a manner similar to general method A, followed by general method B.

[0858]

[0859] Example 27: (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0860] The title compound was prepared using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0861]

[0862] Example 28: (S)-N-methyl-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0863] The title compound was prepared using [3-(methylcarbamoyl)phenyl]boronic acid instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[0864]

[0865] Example 29: (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)propenamide

[0866] Methyl 3-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]propanoate (35 mg, 0.10 mmol, 1.0 equivalent), EtOH (1 mL), and NH4OH (25% aq., 2 mL) were added to a vial and heated at 100°C for 18 hours. The reaction mixture was cooled to ambient temperature, concentrated, and subjected to HPLC to obtain the title compound.

[0867]

[0868] Example 30: 6-cyclopropyl-2-((S)-2-methylazetidine-1-yl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0869] The title compound was prepared in a manner similar to general method H by using methyl 4-cyclopropyl-2-oxocyclopentane-1-carboxylate instead of 2-oxobicyclo[3.1.0]hexane-3-carboxylate and phenylboronic acid instead of (3-carbamoylphenyl)boronic acid.

[0870]

[0871] Example 31: 2-((S)-2-methylazetidine-1-yl)-4-phenyl-5,6,7,8-tetrahydro-5,8-methanoquinazoline

[0872] The title compound was prepared in a manner similar to general method H by using methyl 3-oxobicyclo[2.2.1]heptane-2-carboxylate instead of 2-oxobicyclo[3.1.0]hexane-3-carboxylate and phenylboronic acid instead of (3-carbamoylphenyl)boronic acid.

[0873]

[0874] Example 32: 3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0875] The title compound was prepared in a manner similar to general method A using (3-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2S)-2-methylazetidine (R)-camposulfonate instead of (2S,3R)-2-methylazetidine-3-ol hydrochloride salt.

[0876]

[0877] Example 33: 3-(2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydro-5,8-methanoquinazolin-4-yl)benzamide

[0878] The title compound was prepared in a manner similar to general method H using methyl 3-oxobicyclo[2.2.1]heptane-2-carboxylate instead of 2-oxobicyclo[3.1.0]hexane-3-carboxylate.

[0879]

[0880] Example 34: (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)thiazole

[0881] The title compound was prepared using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0882]

[0883] Example 35: (S)-1-methyl-5-(2-methylazetidin-1-yl)-7-(1H-pyrazole-4-yl)-1H-pyrazole[4,3-d]pyrimidine

[0884] The title compounds were prepared in a manner similar to general method A, followed by general method B, using 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)pyrazol-1-carboxylate instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively. In the first step, tert-butyl carboxylate was decomposed under reaction conditions.

[0885]

[0886] Example 36: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)thiazole

[0887] The title compound was prepared in a manner similar to general method E by using tributyl(thiazole-4-yl)stanan instead of ethyl 2-tributylstanylimidazo[5,1-b]thiazole-7-carboxylate.

[0888]

[0889] Example 37: (S)-3-(1-methyl-5-(2-methylazetidin-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)benzenesulfonamide

[0890] The title compounds were prepared using 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, in a manner similar to general method A, followed by general method B.

[0891]

[0892] Example 38: 3-(5-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl)benzenesulfonamide

[0893] The title compounds were prepared in a manner similar to general method A, using 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and then using (2S,3R)-2-methylazetidine-3-ol hydrochloride salt instead of (2S)-2-methylazetidine, respectively.

[0894]

[0895] Example 39: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indazole

[0896] The title compound was prepared using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[0897]

[0898] Example 40: (S)-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)acetamide

[0899] The title compound was prepared using (3-acetamidophenyl)boronic acid instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[0900]

[0901] Example 41: N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)acetamide

[0902] The title compound was prepared in a manner similar to general method A using (3-acetamidophenyl)boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2S)-2-methylazetidin (R)-camposulfonate instead of (2S,3R)-2-methylazetidin-3-ol hydrochloride salt.

[0903]

[0904] Example 42: (S)-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)methanesulfonamide

[0905] The title compound was prepared using [3-(methanesulfonamido)phenyl]boronic acid instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[0906]

[0907] Example 43: N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)methanesulfonamide

[0908] The title compound was prepared in a manner similar to general method A using [3-(methanesulfonamido)phenyl]boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2S)-2-methylazetidine (R)-camposulfonate instead of (2S,3R)-2-methylazetidine-3-ol hydrochloride salt.

[0909]

[0910] Example 44: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indazole

[0911] The title compound was prepared using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[0912]

[0913] Example 45: (S)-2-(2-methylazetidine-1-yl)-4-(thiophene-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0914] The title compound was prepared in a manner similar to general method E using 5-tributylstanylthiophene-2-carbonitrile instead of ethyl 2-tributylstanylimidazo[5,1-b]thiazole-7-carboxylate, followed by general method B using 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0915]

[0916] Example 46: 2-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid

[0917] Ethyl (trans)-2-(3-bromophenyl)cyclopropanecarboxylate (200 mg, 0.74 mmol, 1.0 equivalent), Pd(dppf)Cl2-DCM complex (59 mg, 0.074 mmol, 10 mol%), B2pin2 (283 mg, 1.11 mmol, 1.5 equivalents), and KOAc (219 mg, 2.23 mmol, 3.0 equivalents) were injected into a vial. The vial was purged with nitrogen, and 1,4-dioxane (3.0 mL) was added. The mixture was heated to 100°C for 1 hour, cooled to ambient temperature, and subjected to flash column chromatography (0 to 100% hexane / ethyl acetate) to obtain ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate.

[0918] Ethyl 2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]cyclopropanecarboxylate was prepared by a method similar 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.

[0919] The title compound was prepared in a manner similar to general method C using ethyl 2-[3-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]cyclopropanecarboxylate instead of methyl (S)-3-(3-[2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]cyclopropanecarboxylate.

[0920]

[0921] Example 47: 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid

[0922] The title compound was prepared in a manner similar to general method A using 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl]cyclopropanecarboxylate instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-2-methylazetidine-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.

[0923]

[0924] Example 48: 2-(3-(2-((2S,3R)-3-fluoro-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid

[0925] The title compound was prepared in a manner similar to general method A using 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl]cyclopropanecarboxylate instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine (R)-camposulfonate.

[0926]

[0927] Example 49: (S)-5-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)thiophene-2-carbonitrile

[0928] The title compound was prepared in a manner similar to general method E, using 5-tributylstanylthiophene-2-carbonitrile instead of ethyl 2-tributylstanylimidazo[5,1-b]thiazole-7-carboxylate.

[0929]

[0930] Example 50: (S)-2-(2-methylazetidin-1-yl)-4-(4-(piperazine-1-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0931] tert-butyl (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)piperazine-1-carboxylate, respectively, 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 instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, and then preparing the title compound by a method similar to General Method A, followed by General Method I. I got it.

[0932]

[0933] Example 51: tert-butyl (S)-(2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamido)ethyl)carbamate

[0934] The title compounds were prepared in a manner similar to general method G, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and tert-butyl (2-aminoethyl)carbamate instead of ammonia.

[0935]

[0936] Example 52: (S)-N-(2-aminoethyl)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0937] The title compound was prepared in a manner similar to general method I using tert-butyl (S)-(2-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamido)ethyl)carbamate instead of (S)-4-(4-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamido)ethyl)carbamate.

[0938]

[0939] Example 53: (S)-N-(2-(methylamino)ethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0940] The title compounds were prepared using (S)-3-(2-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and tert-butyl (2-aminoethyl)(methyl)carbamate instead of ammonia, respectively, in a general method G, followed by a method similar to method I.

[0941]

[0942] Example 54: (S)-N-(2-hydroxyethyl)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide

[0943] The title compound was prepared in a manner similar to general method F using 3-bromo-N-(2-hydroxyethyl)benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[0944]

[0945] Example 55: (S)-2-(2-methylazetidin-1-yl)-4-(6-phenylpyridine-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0946] The title compounds were 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 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.

[0947]

[0948] Example 56: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)thiophene-2-carboxamide

[0949] The title compound was prepared according to general method J using (S)-5-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)thiophene-2-carbonitrile instead of (S)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzonitrile.

[0950]

[0951] Example 57: 5-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)thiophene-2-carboxamide

[0952] The title compounds were prepared in a manner similar to general method E, using 5-tributylstanylthiophene-2-carbonitrile and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of ethyl 2-tributylstanylimidazo[5,1-b]thiazole-7-carboxylate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidin, and general method B and general method J.

[0953]

[0954] Example 58: 5-(2-((2S,3R)-3-fluoro-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)thiophene-2-carboxamide

[0955] The title compounds were prepared in a manner similar to general method E, using 5-tributylstanylthiophene-2-carbonitrile and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of ethyl 2-tributylstanylimidazo[5,1-b]thiazole-7-carboxylate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by using (2S,3R)-3-fluoro-2-methylazetidin instead of (2S)-2-methylazetidin, and general method B and general method J.

[0956]

[0957] Example 59: N-((1S*,2S*)-2-hydroxycyclobutyl)-3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0958] The title compounds were prepared in a manner similar to general method G, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and rac-(1S*,2S*)-2-aminocyclobutanol instead of ammonia.

[0959]

[0960] Example 60: N-((1S*,2R*)-2-hydroxycyclobutyl)-3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0961] The title compounds were prepared in a manner similar to general method G, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and rac-(1S*,2R*)-2-aminocyclobutanol instead of ammonia.

[0962]

[0963] Example 61: (S)-N-(2-hydroxyethyl)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[0964] The title compounds were prepared in a manner similar to general method G, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and ethanolamine instead of ammonia.

[0965]

[0966] Example 62: 3-((5R,8S)-2-((S)-2-methylazetidine-1-yl)-5,6,7,8-tetrahydro-5,8-methanoquinazolin-4-yl)benzamide

[0967] Example 63: 3-((5S,8R)-2-((S)-2-methylazetidine-1-yl)-5,6,7,8-tetrahydro-5,8-methanoquinazolin-4-yl)benzamide

[0968] The isomers were separated by SFC (25% MeOH in CO2, CHIRALPAK IG, 100 × 4.6 mm, 3 mL / min) (see Example 33).

[0969]

[0970] Example 64: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-N-(1H-pyrazol-4-yl)benzamide

[0971] The title compounds were prepared in a manner similar to general method G, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and 1H-pyrazole-4-amine instead of ammonia.

[0972]

[0973] Example 65: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-N-(1H-pyrazol-3-yl)benzamide

[0974] The title compounds were prepared in a manner similar to general method G, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and 1H-pyrazole-3-amine instead of ammonia.

[0975]

[0976] Example 66: (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoyl)glycine

[0977] The title compounds were prepared in a manner similar to general method G, followed by general method C, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and methyl glycinate instead of ammonia.

[0978]

[0979] Example 67: (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamido)cyclopropane-1-carboxylic acid

[0980] The title compounds were prepared by a method similar to general method G, followed by general method C, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and methyl 1-aminocyclopropane-1-carboxylate hydrochloride salt instead of ammonia and (S)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid and methyl 1-aminocyclopropane-1-carboxylate hydrochloride salt, respectively.

[0981]

[0982] Example 68: (S)-1-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoyl)azetidine-3-carboxylic acid

[0983] The title compounds were prepared in a manner similar to general method G, followed by general method C, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and methylazetidine-3-carboxylate hydrochloride salt instead of ammonia.

[0984]

[0985] Example 69: (S)-2-(1-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoyl)azetidine-3-yl)acetic acid

[0986] The title compounds were prepared in a manner similar to general method G, followed by general method C, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and methyl 2-(azetidine-3-yl)acetate trifluoroacetate instead of ammonia.

[0987]

[0988] Example 70: (S)-2-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indazole-3-yl)acetic acid

[0989] tert-butyl (S)-2-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indazole-3-yl)acetate was prepared using tert-butyl 2-(5-bromo-1H-indazole-3-yl)acetate instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one in a manner similar to general method F.

[0990] 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]pyrimidine-4-yl)-1H-indazole-3-yl)acetate. The mixture was heated to 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.

[0991]

[0992] Example 71: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)aniline

[0993] The title compound was prepared using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[0994]

[0995] Example 72: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0996] The title compound was prepared in a manner similar to general method F using 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[0997]

[0998] Example 73: (S)-1-methyl-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)-1H-imidazole-4-sulfonamide

[0999] The title compound was prepared according to the general method K.

[1000]

[1001] Example 74: (S)-((3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)sulfonyl)glycine

[1002] The title compounds were prepared using 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]pyrimidine-4-yl)aniline, then general method F, using methyl ((3-bromophenyl)sulfonyl)glycinate instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one, then general method C, and similarly.

[1003]

[1004] Example 75: (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzyl)isothiazolidine 1,1-dioxide

[1005] The title compound was prepared in a manner similar to 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 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.

[1006]

[1007] Example 76: (S)-3,5-dimethyl-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)isooxazole-4-sulfonamide

[1008] The title compound was prepared using 3,5-dimethylisooxazole-4-sulfonyl chloride instead of 1-methylimidazole-4-sulfonyl chloride in a manner similar to general method K.

[1009]

[1010] Example 77: (S)-1-(3-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoyl)azetidine-2-carboxylic acid

[1011] The title compounds were prepared in a manner similar to general method G, followed by general method C, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and methyl (S)-azetidine-2-carboxylate hydrochloride salt instead of ammonia.

[1012]

[1013] Example 78: (R)-1-(3-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoyl)azetidine-2-carboxylic acid

[1014] The title compounds were prepared in a manner similar to general method G, followed by general method C, using (S)-3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and methyl (R)-azetidine-2-carboxylate hydrochloride salt instead of ammonia.

[1015]

[1016] Example 79: (rac)-3-(2-(6-azabicyclo[3.2.0]heptane-6-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide

[1017] The title compounds were prepared in a manner similar to general method B, using 6-azabicyclo[3.2.0]heptane and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1018]

[1019] Example 80: (rac)-3-(2-((1S*,5S*,6R*)-6-hydroxy-2-azabicyclo[3.2.0]heptane-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide

[1020] The title compounds were prepared in a manner similar to general method B using (rac)-(1S*,5S*,6R*)-2-azabicyclo[3.2.0]heptan-6-ol hydrochloride salt and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide, respectively.

[1021]

[1022] Example 81: (S)-2-(N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)sulfamoyl)acetic acid

[1023] The title compound was prepared using ethyl 2-(chlorosulfonyl)acetate instead of 1-methylimidazole-4-sulfonyl chloride in a manner similar to general method K, followed by general method C.

[1024]

[1025] Example 82: 2-(N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)sulfamoyl)acetic acid

[1026] The title compound was prepared using general method A using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline instead of 3-pyridylboronic acid, then general method K using ethyl 2-(chlorosulfonyl)acetate instead of 1-methylimidazole-4-sulfonyl chloride, then general method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidin, and then a method similar to general method C.

[1027]

[1028] Example 83: (S)-3-(N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)sulfamoyl)propanoic acid

[1029] The title compound was prepared using methyl 3-(chlorosulfonyl)propanoate instead of 1-methylimidazole-4-sulfonyl chloride in a manner similar to general method K, followed by general method C.

[1030]

[1031] Example 84: (S)-N-(5-(N-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)sulfamoyl)thiazole-2-yl)acetamide

[1032] The title compound was prepared using 2-acetamidothiazole-5-sulfonyl chloride instead of 1-methylimidazole-4-sulfonyl chloride in a manner similar to general method K.

[1033]

[1034] Example 85: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)isothiazole-3-carboxamide

[1035] The title compound was prepared in a manner similar to general method F using 5-bromoisothiazole-3-carboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1036]

[1037] Example 86: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzo[d]isothiazole-3(2H)-one 1,1-dioxide

[1038] The title compound was prepared according to general method F.

[1039]

[1040] Examples 87: (S)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1041] General method Q using tert-butyl (R)-(2-hydroxypropyl)carbamate instead of tert-butyl (S)-(1-hydroxypropane-2-yl)carbamate for the title compound, followed by general method F using (S)-8-bromo-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-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-benzothiazole-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by general method M, followed It was prepared using (2S,3R)-2-methylazetidine-3-ol instead of (S)-2-methylazetidine in a manner similar to general method B.

[1042]

[1043] Example 88: (S)-2-(2-methylazetidin-1-yl)-4-(3-((methylsulfonyl)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1044] The title compound was prepared in a manner similar to general method F, using 2-[(3-bromophenyl)methylsulfonyl]acetic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one. In situ decarboxylation ( In situIt was a limited product by decarboxylation.

[1045]

[1046] Example 89: (1S,2S)-2-(3-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid

[1047] Example 90: (1R,2R)-2-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid

[1048] The isomers were separated by SFC (25% MeOH in CO2, CHIRALPAK AD-H, 100 × 4.6 mm, 3 mL / min) (see Example 46).

[1049]

[1050] Example 91: (S)-N-(2-hydroxyethyl)-4-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1051] The title compounds were 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 N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid.

[1052]

[1053] Example 92: (R)-3-(2-(2-(hydroxymethyl)azetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide

[1054] The title compounds were prepared in a manner similar to general method B, using (R)-azetidine-2-ylmethanol and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridine-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1055]

[1056] Example 93: 4-(2-((2S,3R)-3-amino-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1057] The title compounds were prepared in a manner similar to general method B, followed by general method I, using tert-butyl ((2S,3R)-2-methylazetidin-3-yl)carbamate hydrochloride salt and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead of (2S)-2-methylazetidin and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide, respectively.

[1058]

[1059] Examples 94: (R)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1060] General method Q using tert-butyl (S)-(2-hydroxypropyl)carbamate instead of tert-butyl (S)-(1-hydroxypropane-2-yl)carbamate for the title compound, followed by general method F using (R)-8-bromo-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-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-benzothiazole-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by general method M, followed It was prepared using (2S,3R)-2-methylazetidine-3-ol instead of (S)-2-methylazetidine in a manner similar to general method B.

[1061]

[1062] Example 95: (R)-4-(2-(2-(hydroxymethyl)azetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1063] The title compounds were prepared in a manner similar to general method B, using (R)-azetidine-2-ylmethanol and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridine-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1064]

[1065] Example 96: 2-cyclopropyl-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1066] The title compound was prepared according to general method L.

[1067]

[1068] Example 97: 2-cyclobutyl-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1069] The title compound was prepared using cyclobutyl zinc bromide instead of cyclopropyl zinc bromide in a manner similar to general method L.

[1070]

[1071] Example 98: 2-(bicyclo[2.2.1]heptane-2-yl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1072] The title compound was prepared using bicyclo[2.2.1]heptane-2-monozinc bromide instead of cyclopropylzinc bromide in a manner similar to general method L.

[1073]

[1074] Example 99: 2-(azetidine-3-yl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1075] The title compound was prepared using (1-(tert-butoxycarbonyl)azetidine-3-yl)zinc iodide instead of cyclopropylzinc bromide by general method L, followed by a method similar to general method I.

[1076]

[1077] Example 100: (S)-2-methyl-5-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)-1,3,4-oxadiazole

[1078] The title compound was prepared in a manner similar to general method F using 4-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1079]

[1080] Example 101: (S)-4-(4-(1-methyl-1H-imidazole-2-yl)phenyl)-2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1081] The title compound was prepared in a manner similar to general method F using [4-(1-methylimidazole-2-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1082]

[1083] Example 102: (S)-4-(4-(1H-pyrazole-1-yl)phenyl)-2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1084] The title compound was prepared in a manner similar to general method F using (4-pyrazole-1-ylphenyl)boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1085]

[1086] Example 103: (S)-4-(4-(1H-pyrazole-5-yl)phenyl)-2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1087] The title compound was prepared in a manner similar to general method F using [4-(1H-pyrazole-5-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1088]

[1089] Example 104: (S)-4-(4-(1H-tetrazole-5-yl)phenyl)-2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1090] The title compound was prepared in a manner similar to general method F using [4-(1H-tetrazole-5-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1091]

[1092] Example 105: 4-(2-(2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1093] The title compounds were prepared in a manner similar to general method B, using 2,3-dimethylazetidine hydrochloride salt and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1094]

[1095]

[1096] Example 106: 4-(2-((2S,3R)-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1097] Example 107: 4-(2-((2S,3S)-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1098] Example 108: 4-(2-((2R,3S)-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1099] Example 109: 4-(2-((2R,3R)-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1100] The isomers were separated using SFC (20% MeOH in CO2, CHIRALPAK IA, 100 × 4.6 mm, 3 mL / min).

[1101]

[1102] Example 110: (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzo[d]thiazole

[1103] The title compound was prepared in a manner similar to general method F using ethyl 2-(5-chlorobenzo[d]thiazole-2-yl)acetate instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one. It was a limited product by in situ decarboxylation.

[1104]

[1105] Example 111: 4-(2-(2-ethinylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1106] The title compounds were prepared in a manner similar to general method B, using (rac)-2-ethinylazetidine hydrochloride salt and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1107]

[1108] Example 112: 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxamide

[1109] The title compound was prepared according to general method G.

[1110]

[1111] Example 113: (1S,2S)-2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid

[1112] Example 114: (1R,2R)-2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid

[1113] The isomers were separated using SFC (35% MeOH in CO2, CHIRALPAK AD-H, 100 × 4.6 mm, 3 mL / min).

[1114]

[1115] Example 115: 1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)bicyclo[2.1.1]hexane-5-carboxylic acid

[1116] The title compound was prepared in a manner similar 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-benzothiazole-3-one. It was a limited product by in situ decarboxylation.

[1117]

[1118] Example 116: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)isophthalamide

[1119] The title compound was prepared using 5-bromoisophthalamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one in a manner similar to general method F.

[1120]

[1121] Example 117: 4-(2-(2-methyl-3-oxocyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1122] The title compounds were prepared in a manner similar 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]pyrimidine-4-yl)benzamide instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide, respectively.

[1123]

[1124] Example 118: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)imidazo[5,1-b]thiazole-7-carboxylic acid

[1125] The title compound was prepared according to general method E, followed by general method C.

[1126]

[1127] Example 119: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)imidazo[5,1-b]thiazole-7-carboxamide

[1128] The title compound was prepared in a manner similar to general method G using (S)-2-(2-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of (S)-2-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)imidazo[5,1-b]thiazole-7-carboxylic acid.

[1129]

[1130] Example 120: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indazole-3-ol

[1131] The title compound was prepared using 6-bromo-1H-indazole-3-ol instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate in a manner similar to general method D, followed by general method E.

[1132]

[1133] Example 121: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)imidazo[2,1-b]thiazole

[1134] The title compound was prepared using 2-bromoimidazo[2,1-b]thiazole in a manner similar to general method D, followed by general method E.

[1135]

[1136] Example 122: (S)-2-fluoro-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide

[1137] The title compound was prepared in a manner similar to general method F using 5-bromo-2-fluoro-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1138]

[1139] Example 123: (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide

[1140] The title compound was prepared in a manner similar to general method F using 5-bromo-2-methyl-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1141]

[1142] Example 124: (S)-4-(3-(2-methylazetidin-1-yl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene-5-yl)benzamide

[1143] The compound of the title was prepared in a manner similar to general method A, followed by general method B, 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.

[1144]

[1145] Example 125: 4-(3-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene-5-yl)benzamide

[1146] The title compound was prepared in a manner similar to 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, followed by (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidin, in a manner similar to general method B.

[1147]

[1148] Example 126: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-(trifluoromethoxy)benzenesulfonamide

[1149] The title compound was prepared in a manner similar to general method F using 5-bromo-2-(trifluoromethoxy)benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1150]

[1151] Example 127: (S)-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)oxetane-3-ol

[1152] The title compounds were prepared in a manner similar to general method A, using 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl]oxetan-3-ol and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[1153]

[1154] Examples 128: (S)-4-(7,7- difluoro -2-(2- Methylazetidine -1-day)-6,7- Dihydro -5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1155] The title compound was prepared by general method M, followed by a method similar to general method B.

[1156]

[1157] Example 129: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1158] The compound of the title was prepared by general method M, and then by a method similar to general method B, using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin.

[1159]

[1160] Example 130: (S)-2,4-difluoro-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide

[1161] The title compound was prepared in a manner similar to general method F using 5-bromo-2,4-difluoro-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1162]

[1163] Example 131: (S)-3-(4-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)oxetane-3-amine

[1164] The title compounds were prepared using tert-butyl N-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetane-3-yl]carbamate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, in a manner similar to general method A, followed by general method I.

[1165]

[1166] Example 132: (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)quinoline-2(1H)-one

[1167] The title compounds were prepared in a manner similar to general method A, using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-quinoline-2-one 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.

[1168]

[1169] Example 133: (S)-3-(7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-oxoquinoline-1(2H)-yl)propanoic acid

[1170] (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)quinoline-2(1H)-one trifluoroacetate (20 mg, 0.045 mmol, 1 equivalent), K2CO3 (16 mg, 0.112 mmol, 2.5 equivalents), and MeCN (1 mL) were added to a vial, followed by methylprop-2-enoate (116 mg, 0.121 mmol, 30 equivalents). The sealed vial was heated to 120°C for 2 hours, then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL), and NaOH (2M aq., 0.5 mL) was added. The mixture was heated to 60°C for 20 minutes. The mixture was cooled to ambient temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[1171]

[1172] Example 134: 2-(5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydro-1H-indene-2-yl)acetic acid

[1173] The title compound was prepared in a manner similar to general method F using 2-(5-bromoindane-2-yl)acetic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1174]

[1175] Example 135: 2-(5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydro-1H-indene-2-yl)acetamide

[1176] The title compound was prepared in a manner similar to general method G using 2-(5-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of 2-(5-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydro-1H-indene-2-yl)acetic acid.

[1177]

[1178] Example 136: 4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid

[1179] The title compound was prepared in a manner similar to 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-benzothiazole-3-one.

[1180]

[1181] Example 137: (1R,1aR*,6aS*)-4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide

[1182] Example 138: (1S,1aR*,6aS*)-4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide

[1183] The title compound was prepared by a method similar to general method G, using 4-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid. The isomers were separated by HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O).

[1184]

[1185] Example 139: 5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid

[1186] The title compound was prepared in a manner similar to general method F using 5-bromoindane-2-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1187]

[1188] Example 140: 5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydro-1H-indene-2-carboxamide

[1189] The title compound was prepared in a manner similar to general method G using 5-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid.

[1190]

[1191] Example 141: 4-(2-((2S,3R)-3-hydroxy-2,3-dimethylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1192] The title compounds were prepared in a manner similar to general method B using (2S,3R)-2,3-dimethylazetidin-3-ol (R)-camposulfonate and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead of (S)-2-methylazetidin and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide, respectively.

[1193]

[1194] Example 142: 4-(2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1195] The title compounds were prepared in a manner similar to general method B, using pyrrolidine and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead of (S)-2-methylazetidine and 2-chloro-4-(pyridine-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[1196]

[1197] Example 143: (S)-6-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)quinoline-2-amine

[1198] The title compounds were prepared in a manner similar to general method A, using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-amine 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.

[1199]

[1200] Example 144: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1-naftamide

[1201] The title compounds were prepared in a manner similar to general method A, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naftamide 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.

[1202]

[1203] Example 145: (3R,4S)-1-acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)pyrrolidine-3-carboxylic acid

[1204] Methyl (rac)-(3R*,4S*)-4-(3-bromophenyl)pyrrolidine-3-carboxylate (500 mg, 1.56 mmol, 1.0 equivalent), Et3N (0.87 mL, 6.24 mmol, 4.0 equivalent), and DCM (10 mL) were injected into a vial. Acetic anhydride (0.30 mL, 3.12 mmol, 2.0 equivalent) was added dropwise. The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated and subjected to flash column chromatography (ethyl acetate-methanol) to obtain methyl 1-acetyl-4-(3-bromophenyl)pyrrolidine-3-carboxylate (235 mg, 0.72 mmol).

[1205] The title compound was prepared using 1-acetyl-4-(3-bromophenyl)pyrrolidine-3-carboxylate instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one, in a manner similar to general method F, followed by general method C.

[1206]

[1207] Example 146: (3R*,4S*)-1-acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)pyrrolidin-3-carboxamide

[1208] The title compound was prepared in a manner similar to general method G using (3R*,4S*)-1-acetyl-4-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)pyrrolidine-3-carboxylic acid instead of 2-(3-(2-((S)-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)pyrrolidine-3-carboxylic acid.

[1209]

[1210] Example 147: (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)quinazolin-2,4-diamine

[1211] The title compound was prepared in a manner similar to general method F using 7-bromoquinazolin-2,4-diamine instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1212]

[1213] Example 148: 7'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carboxylic acid

[1214] The title compound was prepared in a manner similar to general method F using 7'-bromo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1215]

[1216] Example 149: (S)-8-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1217] The title compounds were prepared in a manner similar to general method A, using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, instead of 3-pyridylboronic acid and 2,4-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[1218]

[1219] Example 150: (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1220] The title compounds were prepared in a manner similar to general method A, using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1221]

[1222] Example 151: (S)-4-(1H-indole-2-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1223] The title compounds were prepared using (1-tert-butoxycarbonylindole-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, in a manner similar to general method A, followed by general method I.

[1224]

[1225] Example 152: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indole-5-carboxamide

[1226] Example 153: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indole-5-carboxylic acid

[1227] The title compounds were prepared using (1-tert-butoxycarbonyl-5-cyano-indole-2-yl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, in a manner similar to general method A, followed by general method I and general method J. A mixture of the two compounds was separated by HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O).

[1228]

[1229] Example 154: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indole-7-carboxamide

[1230] The title compounds were prepared using (1-tert-butoxycarbonyl-7-methoxycarbonyl-indole-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, in a manner similar to general method A, followed by general method I, general method C, and general method G.

[1231]

[1232] Example 155: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indole-4-carboxylic acid

[1233] The title compounds were prepared using (1-tert-butoxycarbonyl-4-ethoxycarbonyl-indole-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, in a manner similar to general method A, followed by general method I and general method C.

[1234]

[1235] Example 156: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indole-4-carboxamide

[1236] The title compound was prepared in a manner similar to general method G using (S)-2-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indole-4-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indole-4-carboxylic acid.

[1237]

[1238] Example 157: (S)-4-(8,8-difluoro-2-(2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)benzamide

[1239] The title compound was prepared using 4-chloro-8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazoline instead of 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide in a manner similar to general method M, followed by general method B.

[1240]

[1241] Example 158: 4-(8,8-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)benzamide

[1242] The title compound was prepared by general method M using 4-chloro-8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazolin instead of 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide, followed by a method similar to general method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin.

[1243]

[1244] Example 159: (2S,3R)-1-(4-(4-(3-aminooxetane-3-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-2-methylazetidine-3-ol

[1245] The title compound was prepared in a manner similar to general method A, using tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 3-pyridylboronic acid, followed by general method B and general method I using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin.

[1246]

[1247] Example 160: (S)-3-(4-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)oxetane-3-amine

[1248] The title compound was prepared using tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl)oxetane-3-yl)carbamate instead of (4-carbamoylphenyl)boronic acid, in a manner similar to general method M, followed by general method B and general method I.

[1249]

[1250] Example 161: (2S,3R)-1-(4-(4-(3-aminooxetane-3-yl)phenyl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-2-methylazetidine-3-ol

[1251] The title compound was prepared in a manner similar to general method M, using tert-butyl(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl)oxetan-3-yl)carbamate instead of (4-carbamoylphenyl)boronic acid, followed by general method B and general method I using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin.

[1252]

[1253] Example 162: 4-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid

[1254] The title compound was prepared using general method A with 4-bromobenzoic acid instead of 3-pyridylboronic acid, followed by a method similar to general method B with (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin.

[1255]

[1256] Example 163: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)isoquinoline

[1257] The title compounds were prepared in a manner similar to general method A, using 6-isoquinorylboronic 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.

[1258]

[1259] Example 164: 8-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1260] The title compound was prepared in a manner similar to general method A using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-2-methylazetidine-3-ol instead of (S)-2-methylazetidine.

[1261]

[1262] Example 165: (S)-8-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1263] The title compound was prepared using 8-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one instead of (4-carbamoylphenyl)boronic acid, in a manner similar to general method M, followed by general method B.

[1264]

[1265] Example 166: 8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1266] The title compound was prepared using general method M using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one instead of (4-carbamoylphenyl)boronic acid, followed by a method similar to general method B using (2S,3R)-2-methylazetidine-3-ol instead of (S)-2-methylazetidine.

[1267]

[1268] Example 167: (S)-4-(2-(1-methylisoindolin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1269] The title compounds were prepared in a manner similar to general method B, using (S)-1-methylisoindoline and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1270]

[1271] Example 168: 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)picolinamide

[1272] The title compound was prepared using general method M, using 5-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)picolinamide instead of (4-carbamoylphenyl)boronic acid, and then using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin, in a manner similar to general method B.

[1273]

[1274] Example 169: 4-(2-((2S,3S)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1275] The title compound was prepared using general method A with (4-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and then using (2S,3S)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin, in a manner similar to general method B.

[1276]

[1277] Example 170: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-ethoxybenzamide

[1278] The title compound was prepared using general method M, using 2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)benzamide instead of (4-carbamoylphenyl)boronic acid, and then using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin, in a manner similar to general method B.

[1279]

[1280] Example 171: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-N-methylbenzamide

[1281] The title compound was prepared using N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)benzamide instead of (4-carbamoylphenyl)boronic acid in a general method M, and then using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin in a manner similar to general method B.

[1282]

[1283] Example 172: 4-(2-(4-(hydroxymethyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1284] The title compound was prepared in a manner similar to general method A using (4-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4-yl)methanol instead of (S)-2-methylazetidine.

[1285]

[1286] Example 173: 4-(2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1287] The title compound was prepared according to the general method N.

[1288]

[1289] Example 174: 4-(2-(2,3-dihydro-1H-imidazo[1,5-a]imidazole-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1290] The title compound was prepared in a manner similar to general method N using 2,3-dihydro-1H-imidazo[1,5-a]imidazole instead of 2,3-dihydro-1H-imidazo[1,2-b]pirazol.

[1291]

[1292] Example 175: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)quinoline-2-ol

[1293] The title compounds were prepared in a manner similar to general method A, using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-ol 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.

[1294]

[1295] Example 176: 4-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-5,7-methanocyclopenta[d]pyrimidine-4-yl)benzamide

[1296] The title compounds were prepared in a manner similar to general method H, using ethyl 3-oxobicyclo[2.1.1]hexane-2-carboxylate and (3-carbamoylphenyl)boronic acid instead of methyl 2-oxobicyclo[3.1.0]hexane-3-carboxylate and (4-carbamoylphenyl)boronic acid.

[1297]

[1298] Example 177: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-methoxybenzamide

[1299] The title compound was prepared using general method M, using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)benzamide instead of (4-carbamoylphenyl)boronic acid, and then using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin, in a manner similar to general method B.

[1300]

[1301] Example 178: 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine-1-one

[1302] General method D using 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-1-one instead of ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate for the title compound, followed by general method E using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead A general method M was prepared using 7-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine-1-one, followed by a method similar to general method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin.

[1303]

[1304] Example 179: (S)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1305] The title compound was prepared according to general method Q, then general method F using (S)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-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-benzothiazole-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, then general method M, then general method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin.

[1306]

[1307] Example 180: (R)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[1308] General method Q using tert-butyl (R)-(1-hydroxypropane-2-yl)carbamate instead of tert-butyl (S)-(1-hydroxypropane-2-yl)carbamate for the title compound, followed by general method F using (R)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepine-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-benzothiazole-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by general method M, followed It was prepared using (2S,3R)-2-methylazetidine-3-ol instead of (S)-2-methylazetidine in a manner similar to general method B.

[1309]

[1310] Example 181: 2-acetamido-4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1311] The title compound was prepared using general method M, using 2-acetamido-4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)benzamide instead of (4-carbamoylphenyl)boronic acid, and then using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin, in a manner similar to general method B.

[1312]

[1313] Example 182: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-(difluoromethoxy)benzamide

[1314] General Method F, using methyl 4-bromo-2-(difluoromethoxy)benzoate and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine for the title compound, followed by 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide instead of methyl A method similar to the general method M using 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-(difluoromethoxy)benzoate, followed by the general method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin, followed by the general method C and the general method G.

[1315]

[1316] Example 183: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-(trifluoromethoxy)benzamide

[1317] The title compound was prepared using general method M, using methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)-2-(trifluoromethoxy)benzoate instead of (4-carbamoylphenyl)boronic acid, followed by general method B, using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidin, followed by general method C and general method G.

[1318]

[1319] Example 184: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-1H-indole-2-carboxamide

[1320] The title compounds were prepared in a manner similar to general method A, using 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1321]

[1322] Example 185: 4-[4-(1H-imidazole-2-yl)phenyl]-2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1323] The title compounds were prepared in a manner similar to general method A, using 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1324]

[1325] Example 186: 2-methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]isoindolin-1-one

[1326] The title compounds were prepared in a manner similar to general method A, using 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1327]

[1328] Example 187: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]isoindolin-1-one

[1329] The title compounds were prepared in a manner similar to general method A, using 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1330]

[1331] Example 188: [4-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methaneamine

[1332] The title compounds were prepared in a manner similar to general method A, using (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methaneamine 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.

[1333]

[1334] Example 189: 4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide

[1335] The title compounds were prepared in a manner similar 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1336]

[1337] Example 190: 2-[3-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]propane-2-amine

[1338] The title compounds were prepared in a manner similar to general method A, using 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-2-amine 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.

[1339]

[1340] Example 191: 4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzamide

[1341] The title compounds were prepared in a manner similar to general method A, using 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1342]

[1343] Examples 192: 3 -[2-[(2S)-2- Methylazetidine -1-day]-6,7- Dihydro -5H- Cyclopenta[d]pyrimidine -4-day] Benzenesulfonamide

[1344] The title compounds were prepared in a manner similar to general method A, using 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 instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[1345]

[1346] Example 193: (2S,3R)-1-[4-[4-(1H-imidazole-2-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl]-2-methyl-azetidine-3-ol

[1347] The title compound was prepared in a manner similar to general method A using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)phenyl)-1H-imidazole hydrochloride salt instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidin.

[1348]

[1349] Example 194: 5-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-2-methyl-isoindolin-1-one

[1350] The title compound was prepared in a manner similar to general method A using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-2-methylazetidine-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.

[1351]

[1352] Example 195: N-[[4-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methyl]methanesulfonamide

[1353] The title compound was prepared in a manner similar to general method A using (4-(methylsulfonamidomethyl)phenyl)boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-2-methylazetidine-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.

[1354]

[1355] Example 196: 5-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]isoindolin-1-one

[1356] The title compound was prepared in a manner similar 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, and then in general method B using (2S,3R)-2-methylazetidine-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.

[1357]

[1358] Example 197: 4-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzamide

[1359] The title compound was prepared in a manner similar to general method A using (4-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.

[1360]

[1361] Example 198: 4-[2-[(2S,3R)-3-fluoro-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide

[1362] The title compound was prepared in a manner similar to general method A using (4-sulfamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.

[1363]

[1364] Example 199: 4-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide

[1365] The title compound was prepared in a manner similar to general method A using (4-sulfamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-2-methylazetidine-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.

[1366]

[1367] Example 200: 4-[2-[(2S,3R)-3-fluoro-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzamide

[1368] The title compound was prepared in a manner similar to general method A using (4-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.

[1369]

[1370] Example 201: [4-[2-[(2S,3R)-3-fluoro-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methaneamine

[1371] The title compound was prepared in a manner similar to general method A using (4-(aminomethyl)phenyl)boronic acid hydrochloride instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.

[1372]

[1373] Example 202: (2S,3R)-1-[4-[4-(aminomethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl]-2-methyl-azetidine-3-ol

[1374] The title compound was prepared in a manner similar to general method A using (4-(aminomethyl)phenyl)boronic acid hydrochloride instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidin.

[1375]

[1376] Example 203: 6-[2-[(2S,3R)-3-fluoro-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-2-methyl-isoindolin-1-one

[1377] The title compound was prepared in a manner similar to general method A using 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.

[1378]

[1379] Example 204: 6-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-methyl-isoindolin-1-one

[1380] The title compound was prepared in a manner similar to 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 general method B using (2S,3R)-2-methylazetidine-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.

[1381]

[1382] Example 205: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]pyridine-3-sulfonamide

[1383] The title compound was prepared using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[1384]

[1385] Example 206: 2-methyl-6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]isoindolin-1-one

[1386] The title compound was prepared using 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, in a manner similar to general method A, followed by general method B.

[1387]

[1388] Example 207: 6-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)isoindolin-1-one

[1389] The title compound was prepared using (3-oxoisoindolin-5-yl)boronic acid instead of 3-pyridylboronic acid in a manner similar to general method A, followed by general method B.

[1390]

[1391] Example 208: 3-[2-[(2S,4S)-2,4-dimethylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide

[1392] The compound of the title was prepared in a manner similar to general method A using 3-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)benzenesulfonamide instead of 3-pyridylboronic acid, followed by general method B using (2S,4S)-2,4-dimethylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.

[1393]

[1394] Example 209: 3-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide

[1395] The title compound was prepared in a manner similar to general method A using 3-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)benzenesulfonamide instead of 3-pyridylboronic acid, and then in general method B using (2S,3R)-2-methylazetidine-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.

[1396]

[1397] Example 210: 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzenesulfonamide

[1398] The title compound was prepared in a manner similar to general method A using 3-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl)benzenesulfonamide instead of 3-pyridylboronic acid, followed by general method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.

[1399]

[1400] Example 211: 7-methyl-2-[(2S)-2-methylazetidine-1-yl]-6-phenyl-purine

[1401] The title compounds were prepared using phenylboronic acid and 2,6-dichloro-7-methyl-7H-purine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, in a manner similar to general method A, followed by general method B.

[1402]

[1403] Example 212: 2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-pyrido[2,3-d]pyrimidine

[1404] The title compounds were prepared using phenylboronic acid and 2,4-dichloropyrido[2,3-d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloropyrido[2,3-d]pyrimidine, respectively, in a manner similar to general method A, followed by general method B.

[1405]

[1406] Example 213: 2-[5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]thiazole-2-yl]propan-2-ol

[1407] The title compound was prepared in a manner similar to general method E, using 2-(5-(tributylstannyl)thiazole-2-yl)propan-2-ol instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate.

[1408]

[1409] Example 214: N-methyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide

[1410] 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide (42 mg, 0.12 mmol) was dissolved in DMF (10.5 mL) and then cooled to 0°C over 20 minutes. NaH (17.1 mg, 0.43) was slowly added, and the reaction mixture was carried out 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, slowly quenched with water, extracted with EtOAc, dried, filtered, concentrated, and purified by HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain N-methyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide.

[1411]

[1412] Example 215: N,N-dimethyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide

[1413] 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide (42 mg, 0.12 mmol) was dissolved in DMF (10.5 mL) and then cooled to 0°C over 20 minutes. NaH (17.1 mg, 0.43) was slowly added, and the reaction mixture was carried out 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, slowly quenched with water, extracted with EtOAc, dried, filtered, concentrated, and purified by HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain N,N-dimethyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzenesulfonamide.

[1414]

[1415] Example 216: N-(2-amino-2-oxo-ethyl)-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzamide

[1416] The title compounds were prepared in a manner similar to general method G, using 3-aminopropanoic acid and (S)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid.

[1417]

[1418] Example 217: 3-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzoyl]amino]propanoic acid

[1419] The title compounds were prepared in a manner similar to general method G, using 3-aminopropanoic acid and (S)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid.

[1420]

[1421] Example 218: N-benzyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzamide

[1422] The title compounds were prepared in a manner similar to general method G, using benzylamine and (S)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[1423]

[1424] Example 219: 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-N-(2-sulfamoylethyl)benzamide

[1425] The title compounds were prepared in a manner similar to general method G, using 2-aminoethane-1-sulfonamide and (S)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid.

[1426]

[1427] Example 220: N-(3-amino-3-oxo-propyl)-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]benzamide

[1428] The title compounds were prepared in a manner similar to general method G, using 3-aminopropanamide and (S)-3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzoic acid.

[1429]

[1430] Example 221: (S)-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)thiazole-2-yl)methaneamine

[1431] The title compound was prepared in a manner similar to 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, followed by general method E and general method I, using tert-butyl N-[(5-bromothiazole-2-yl)methyl]carbamate instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[1432]

[1433] Example 222: (S)-2-methyl-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,4-dihydroisoquinoline-1(2H)-one

[1434] The title compound was prepared in a manner similar to 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 general method E, using 6-bromo-2-methyl-3,4-dihydroisoquinoline-1(2H)-one instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[1435]

[1436] Example 223: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)pyridine-2-sulfonamide

[1437] The title compound was prepared in a manner similar to 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 general method E, using 6-bromopyridine-2-sulfonamide instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[1438]

[1439] Example 224: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)pyridine-2-sulfonamide

[1440] The title compound was prepared in a manner similar to 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 general method E, using 4-bromopyridine-2-sulfonamide instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[1441]

[1442] Example 225: (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-amine

[1443] The title compound was prepared in a manner similar to 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 general method E, using 1-(3-bromophenyl)cyclopropane-1-amine instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[1444]

[1445] Examples 226: 4 -(2-(( 2S, 3S )-3- fluoro -2- Methylazetidine -1-day)-6,7- Dihydro -5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1446] 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide (23.5 mg, 0.72 mmol) and DCM (0.24 mL) were injected into a vial. DAST (117 mg, 0.72 mmol) was slowly added, and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was slowly quenched to 0°C using an ice chip, extracted with 25% MeOH / DCM, washed with NaHCO3 (aq., sat.), dried with Na2SO4, filtered, and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the title compound.

[1447]

[1448] Example 227: 3-hydroxy-N-[[3-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methyl]propanamide

[1449] The title compounds were prepared in a manner similar to general method G, using 3-hydroxypropanoic acid and (S)-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and (S)-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)methaneamine instead of 2-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)methaneamine, respectively.

[1450]

[1451] Example 228: 2-hydroxy-2-methyl-N-[[3-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methyl]propanamide

[1452] The title compounds were prepared in a manner similar to general method G, using 2-hydroxy-2-methylpropanoic acid and (S)-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and (S)-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)methaneamine instead of ammonia.

[1453]

[1454] Example 229: (2R)-2-hydroxy-N-[[3-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methyl]propanamide

[1455] The title compounds were prepared in a manner similar to general method G, using (R)-2-hydroxypropanoic acid and (S)-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and (S)-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)methaneamine instead of ammonia.

[1456]

[1457] Example 230: (2S)-2-hydroxy-N-[[3-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methyl]propanamide

[1458] The title compounds were prepared in a manner similar to general method G, using (S)-2-hydroxypropanoic acid and (S)-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid and (S)-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)methaneamine instead of ammonia.

[1459]

[1460] Example 231: 2-hydroxy-N-[[3-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methyl]acetamide

[1461] The title compound was prepared in a manner similar to general method G using 2-hydroxyacetic acid and (S)-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)cyclopropane-1-carboxylic acid instead of 2-hydroxyacetic acid and (S)-(3-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)phenyl)methaneamine.

[1462]

[1463] Example 232: 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]naphthalene-2-carboxylic acid

[1464] 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 instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1465]

[1466] Example 233: 4-[4-(azetidine-3-yl)phenyl]-2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[1467] The title compound was prepared using tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one by general method F, followed by a method similar to general method I.

[1468]

[1469] Example 234: 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-1,1-dioxo-2,3-dihydro-1lambda6,3-benzothiazine-4-one

[1470] The title compound was prepared using 7-bromo-2,3-dihydro-4H-benzo[e][1,3]thiazine-4-one 1,1-dioxide instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate by a method similar to general method D, followed by general method E.

[1471]

[1472] Example 235: 4-(2-((2S,3R)-3-methoxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide

[1473] (2S,3R)-1-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-2-methylazetidin-3-ol (21 mg, 0.09 mmol) and DMF (1 mL) were injected into a vial and cooled to 0°C. NaH (60% dispersion in mineral oil, 12.3 mg, 0.31 mmol) was slowly added. The reaction mixture was stirred at 0°C for 20 minutes, then MeI (14.9 mg, 0.11 mmol) was slowly added, and the reaction mixture was heated 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 organic matter was dried with Na2SO4, filtered, and concentrated to obtain 4-(2-((2S,3R)-3-methoxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzamide, which was used without further purification.

[1474] The title compounds were prepared in a manner similar to general method A, using 4-chloro-2-[(2S,3R)-3-methoxy-2-methyl-azetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-carbamoylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.

[1475]

[1476] Example 236: 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2-methylisoindolin-1-one

[1477] The title compound was prepared in a manner similar to general method A, then general method M, and (2S,3R)-2-methylazetidin-3-ol, using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidin.

[1478]

[1479] Examples 237: (S)-2-amino-1-(5-(2-(2- Methylazetidine -1-day)-6,7- Dihydro -5H- Cyclopenta[d]pyrimidine -4-il)-1H-indazole-1-il)ethane-1-one

[1480] Example 238: (S)-2-amino-1-(5-(2-(2-methylazetidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-2H-indazole-2-yl)ethane-1-one

[1481] (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-1H-indazole (28 mg, 0.092 mmol), potassium carbonate (50.2 mg, 0.37 mmol), and MeCN (0.7 mL) were added to a vial. The mixture was heated at 40°C for 18 hours. NaHCO3 (1 mL, sat. aq.) was added, and the mixture was extracted with DCM (3 × 1 mL). The combined organic matter was dried with Na2SO4, filtered, and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN - 0.1% TFA in H2O) to obtain the respective title compounds.

[1482]

[1483] Example 239: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)benzo[d]isothiazole-3(2H)-one 1,1-dioxide

[1484] The title compound was prepared in a manner similar to general method F using 5-bromobenzo[d]isothiazole-3(2H)-one 1,1-dioxide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1485]

[1486] Example 240: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]isoindolin-1,3-dione

[1487] The title compound was prepared in a manner similar to general method F using 5-bromoisoindolin-1,3-dione instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1488]

[1489] Example 241: 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-2-(trifluoromethyl)-1H-benzimidazole

[1490] The title compound was prepared in a manner similar to general method F using 6-bromo-2-(trifluoromethyl)-1H-benzimidazole instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1491]

[1492] Example 242: [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]methanesulfonamide

[1493] The title compound was prepared in a manner similar to general method F using (4-bromophenyl)methanesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1494]

[1495] Example 243: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-3-(trifluoromethyl)-1H-indazole

[1496] The title compound was prepared in a manner similar to general method F using 5-bromo-3-(trifluoromethyl)-1H-indazole instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1497]

[1498] Example 244: 2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]acetamide

[1499] The title compound was prepared in a manner similar to general method F using 2-(3-bromophenyl)acetamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1500]

[1501] Example 245: 2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]acetamide

[1502] The title compound was prepared in a manner similar to general method F using 2-(4-bromophenyl)acetamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1503]

[1504] Example 246: 2,2,2-trifluoro-1-[3-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]ethanolamine

[1505] The title compound was prepared in a manner similar to general method F using 1-(3-bromophenyl)-2,2,2-trifluoro-ethanolamine instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1506]

[1507] Example 247: 5-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-1,3-dihydrobenzimidazole-2-one

[1508] The title compound was prepared in a manner similar to general method F using 5-bromo-1,3-dihydrobenzimidazole-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1509]

[1510] Example 248: 5-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]indolin-2-one

[1511] The title compound was prepared using 5-bromoindolin-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one in a manner similar to general method F.

[1512]

[1513] Example 249: 3-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]bicyclo[1.1.1]pentane-1-carboxylic acid

[1514] The title compound was prepared in a manner similar to general method F using 3-(4-bromophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1515]

[1516] Example 250: 3-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]bicyclo[1.1.1]pentane-1-carboxamide

[1517] The compound of the title was prepared in a manner similar to general method F using 3-(4-bromophenyl)bicyclo[1.1.1]pentan-1-carboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1518]

[1519] Example 251: 3-methyl-5-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]-1H-benzimidazole-2-one

[1520] The title compound was prepared in a manner similar to general method F using 5-bromo-3-methyl-1H-benzimidazole-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1521]

[1522] Example 252: 1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]cyclopropanecarboxamide

[1523] The title compound was prepared in a manner similar to general method F using 1-(4-bromophenyl)cyclopropanecarboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1524]

[1525] Example 253: 1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]cyclopropanecarboxylic acid

[1526] The title compound was prepared in a manner similar to general method F using 1-(3-bromophenyl)cyclopropanecarboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1527]

[1528] Example 254: 1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]cyclopropanecarboxamide

[1529] The title compound was prepared in a manner similar to general method F using 1-(3-bromophenyl)cyclopropanecarboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazole-3-one.

[1530]

[1531] Example 255: 1-[hydroxy-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]cyclopropanecarbonitrile

[1532] The title compounds were prepared in a manner similar to general method A, using 1-[hydroxy-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]cyclopropanecarbonitrile 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.

[1533]

[1534] Example 256: 2,2-Difluoro-1-[4-[2-[(2S)-2-methylazetidine-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl]phenyl]ethanol

[1535] The title compounds were prepared in a manner similar to general method A, using 2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabolololan-2-yl...

Claims

Claim 1 Compounds having the structure of Formula II, or pharmaceutically acceptable salts or stereoisomers thereof: [Formula II] In the above formula, m is 0 to 4; and each R 1a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, OR 1b , CH2OH, CO2R 12 , Halogen, Iodine, CONH2, CN, NH2, NHR 11 , C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkyl-NHCOR 13 , C 1-6 Alkoxy or C 1-6 It is a haloalkyl, wherein the alkyl, alkenyl, or alkynyl is three or fewer Rs 1c Arbitrarily substituted with, or 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings; R 1b is H or C 1-6 It is alkyl, wherein the alkyl group is optionally substituted with three or fewer halogens, CN, or OH; and each R 1c is independently OH, OR 11 , Halogen, Iodine, SOR 13 , SO2R 13 , SR 13 , SO2NH2, CONH2, C 1-6 Alkoxy, C 6-10 Aril, C 6-10 Aryloxy, 5- to 11-membered heteroaryl or C 3-7 It is cycloalkyl; R 2 is C 6-10 It is an aryl, or a 6- to 14-membered heteroaryl, wherein the aryl or heteroaryl has 8 or fewer R 2a It is arbitrarily substituted with, and R 2 is R 2 Attached to the core through carbon atoms; each R 2a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , N(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl can be fused to a heteroaryl or spiro, or the cycloalkyl can be fused to an aryl; or two R 2a They can bond with the atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings; and each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, OH, Halogen, Iodine, CONH2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with the atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings; and each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclil, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclil has 4 or fewer R 2d It is arbitrarily substituted with; each R 2d is independently OH, halogen, NH2, C 1-6 Alkoxy, CONH2, SO2NH2, NHCOR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , iodine or CN and;R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 Arbitrarily substituted with;R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is independently H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, cross-linked or fused rings; and each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2 or NHCO2-C 1-6 It is alkyl and;R 11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl; R 12 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl; R 13 C 1-6 alkyl or C 1-6 It is a haloalkyl. Claim 2 In paragraph 1, each R 1a C independently 1-6 Alkyl, C 1-6 Alkynyl, OH, OR 1b , CH2OH, halogen, iodine, CONH2, CN, C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkoxy or C 1-6 It is a haloalkyl, wherein the alkyl or alkynyl is three or fewer R 1c Arbitrarily substituted with; 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings; R 1b is H or C 1-6 It is alkyl; and each R 1c is independently OH, SR 13 or C 6-10 Aril and;R 2 is C 6-10 It is an aryl, or a 6- to 11-membered heteroaryl, wherein the aryl or heteroaryl has 3 or fewer R 2a It is arbitrarily substituted with, and R 2 is R 2 Attached to the core through carbon atoms; each R 2a C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SO2NH2, CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , NHCOR 2c , NO2, SO2NHR 2c , NHSO2R 2c , SO(NH)R 2c , OR 2c , C 3-7 It is a cycloalkyl, a tetrocycline to hypotyl, or a zetroaryl to elevenyl, wherein the alkyl, cycloalkyl, heterocycline, or heteroaryl comprises four or fewer Rs. 2b It is substituted with, and the cycloalkyl can be fused to a heteroaryl or spiro, or the cycloalkyl can be fused to an aryl; or two R 2a They can bond with the atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings; and each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, OH, halogen, oxo, CONH2, NHCOR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , CN, COR 2c , SO2NH2, SO2R 2c , C 3-7 It is a cycloalkyl, a tetrocycline to hypotyl, or a zetroaryl to elevenyl, wherein the alkyl, haloalkyl, cycloalkyl, heterocycline, or heteroaryl is four or fewer R 2d It can be arbitrarily substituted with; each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclile, wherein the alkyl, haloalkyl, aryl, heteroaryl, or heterocyclile has 4 or fewer R 2d It is arbitrarily substituted with; each R 2d is independently OH, NHCOR 13 , C 1-6 It is alkyl, oxo, or CN;R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, or heteroaryl has three or fewer Rs 10 Arbitrarily substituted with;R 3 , R 4 , R 5 , R 6 , R 7 , R 8 does not exist independently, or H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, cross-linked or fused rings; and each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2 or NHCO2-C 1-6 It is alkyl and;R 11 H or C 1-6 It is alkyl; R 12 is C 1-6 It is alkyl and;R 13 C 1-6 alkyl or C 1-6 A compound that is a haloalkyl, or a pharmaceutically acceptable salt or stereoisomer thereof. Claim 3 In claim 1, a compound having the structure of Formula III, or a pharmaceutically acceptable salt or stereoisomer thereof: [Formula III] In the above equation, p is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; and each R 1a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, OR 1b , CH2OH, CO2R 12 , Halogen, Iodine, CONH2, CN, NH2, NHR 11 , C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkyl-NHCOR 13 , C 1-6 Alkoxy or C 1-6 It is a haloalkyl, wherein the alkyl, alkenyl, or alkynyl is three or fewer R 1c Arbitrarily substituted with; 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings; R 1b is H or C 1-6 It is alkyl, wherein the alkyl is optionally substituted with three or fewer halogens, CN, or OH; and each R 1c is independently OH, OR 11 , Halogen, Iodine, SOR 13 , SO2R 13 , SR 13 , SO2NH2, CONH2, C 1-6 Alkoxy, C 6-10 Aril, C 6-10 Aryloxy, 5- to 11-membered heteroaryl or C 3-7 It is cycloalkyl; and each R 2a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , N(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl group can be fused to the aryl group; or two R 2a They can bond with the atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings; and each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, OH, Halogen, Iodine, CONH2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with the atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings; and each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclil, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclil has 4 or fewer R 2d It is arbitrarily substituted with; each R 2d is independently OH, halogen, NH2, C 1-6 Alkoxy, CONH2, SO2NH2, NHCOR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , iodine or CN and;R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 Arbitrarily substituted with;R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is independently H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, cross-linked or fused rings; and each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2 or NHCO2-C 1-6 It is alkyl and;R 11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl; R 12 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl; R 13 C 1-6 alkyl or C 1-6 It is a haloalkyl. Claim 4 In paragraph 1, (i) R 2 Is or and, where, p is 0, 1, 2 or 3 and; s is independently 0, 1 or 2 and; W 1 is CHF or CF2;W 2 is O, CF2, CHF, S, SO, SO(NH), SO(NR 2c ), CH2O, CH2OCH2, OCH2O, CH2SO2, CH2SO2CH2 or SO2 or; (ii) R 2 is R 2 Attached to the core through carbon atoms, and R 2 Is or and, where, p is 0, 1, 2 or 3 and s is 0, 1 or 2 or; (iii) R 2 Is or and, where, p is 0, 1, 2, 3 or 4 and; s is 0 or 1 and; W 3 O, NH, SO(NH), SO(NR 2c ), SO2 or NR 11 Or; (iv) R 2 Is or and, where, p is 0, 1, 2, 3 or 4, and s is independently 0 or 1, and W 2 is O, CF2, CHF, S, SO, SO(NH), SO(NR 2c ) or SO2 and;W 5 is SO(NH), SO(NR 2c ), SO2 or non-existent; (v) R 2 Is and, where, p is independently 0, 1, or 2; s is 0 or 1; t is independently 1, 2, or 3; and each W 3 are independently O, CH2, CHF, CF2, S, CO, SO, SO2, SO(NH), SO(NR 11 ) or NR 11 and here, 1 W 3 This NR 11 In this case, adjacent W 3 is O, S, or NR 11 This cannot be, and 1 W 3 This O, S, CO, SO, SO2, SO(NR 11 In the case of ) or SO(NH), adjacent W 3 It contains O, S, CO, SO, SO2, SO(NR 11 Cannot be ) or SO(NH); each W 4 is independently O, CO, SO(NR 11 ), SO(NH), CH2, CHF, CF2, SO2, or NR 11 and, here, 1 W 4 O, SO2, CO, SO(NR 11 In the case of ) or SO(NH), adjacent W 4 is O, SO2, CO, SO(NR 11 ) or SO(NH) cannot be;W 6 CO, SO, SO2, SO(NH), SO(NR 11 ) or CH2, where W 6 This CO, SO, SO2, SO(NH) or SO(NR 11 In the case of ), adjacent W 4 is CO, SO2, SO(NH), or SO(NR 11 ) cannot be; (vi) R 2 Is or and, here, Y 1 is a 6- to 14-membered heteroaryl, where Y 1 is Y 1 Attached to the core through carbon atoms; p is 0, 1, 2, or 3 and s is 0, 1, or 2 and W 2 is O, CF2, CHF, SO, SO(NH), SO(NR 2c ), CH2O, CH2OCH2, OCH2O, CH2SO2, CH2SO2CH2 or SO2 or; or (vii) R 2 Is or and, where, s is 0 or 1; p is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; W 4 is not present, or CH2, O, CF2, CH2NH, CH2NHCH2, OCH2, OCH2CH2, CONH or CONHCH2;W 6 CH2, O, SO2, SO(NH), or SO(NR 2c A compound, or a pharmaceutically acceptable salt or stereoisomer thereof. Claim 5 In paragraph 1, R 2 Is Phosphorus compound, or a pharmaceutically acceptable salt thereof. Claim 6 Compounds having the structure of Formula VI, or pharmaceutically acceptable salts or stereoisomers thereof: [Formula VI] In the above formula, m is 0 to 4; and each R 1a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, OH, OR 1b , CH2OH, CO2R 12 , Halogen, Iodine, CONH2, CN, NH2, NHR 11 , C 1-6 Alkyl-NHSO2R 13 , C 1-6 Alkyl-NHCOR 13 , C 1-6 Alkoxy or C 1-6 It is a haloalkyl, wherein the alkyl, alkenyl, or alkynyl is three or fewer Rs 1c Arbitrarily substituted with; 2 R 1a They can bond with atoms to which they are attached to form ternary to hexavalent spiros, fused or cross-linked rings; R 1b is H or C 1-6 It is alkyl, wherein the alkyl group is optionally substituted with three or fewer halogens, CN, or OH; and each R 1c is independently OH, OR 11 , Halogen, Iodine, SOR 13 , SO2R 13 , SR 13 , SO2NH2, CONH2, C 1-6 Alkoxy, C 6-10 Aril, C 6-10 Aryloxy, 5- to 11-membered heteroaryl or C 3-7 It is cycloalkyl and; (i) R 2 Is or and, here, Y 2 is a 5-membered heteroaryl, where Y 2 is Y 2 Attached to the core through carbon atoms; p is 0 or 1, s is 0, 1, or 2, and W 2 is O, CF2, CHF, SO, SO(NH), SO(NR 2c ), CH2O, CH2OCH2, OCH2O, CH2SO2, CH2SO2CH2 or SO2; or (ii) R 2 Is or and, each R 2a C independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, CONH2, COR 2c , CONHR 2e , CON(R 2c )2, halogen, iodine, OH, CN, NH2, NHR 2c , N(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NO2, SO2NHR 2c , SO2N(R 2c )2, NHSO2R 2c , N(R 2c )SO2R 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclil, aryl, or heteroaryl has 7 or fewer R 2b It is substituted with, and the cycloalkyl group can be fused to a heteroaryl or spironed; or two R 2a They can bond with the atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings; and each R 2b C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, OH, Halogen, Iodine, CONH2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R 2c )2, NHR 2c , S(O)(NH)R 2c , S(O)(NH)NH2, NHS(O)(NH)R 2c , NS(O)(NH2)R 2c , NS(O)(R 2c )2, S(O)(NR 2c )R 2c , S(O)(NR 2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , NHSO2R 2c , N(R 2c )SO2R 2c , C 1-6 Alkyl-CO2R 12 , C 1-6 Alkyl-CONH2, C 1-6 Alkyl-NHSO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has 4 or fewer R 2d It can be arbitrarily substituted with; or 2 R 2b They can bond with the atoms to which they are attached to form ternary to hepta-spiros, fused or cross-linked rings; and each R 2c C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 It is an aryl, a 5- to 11-membered heteroaryl, or a 4- to 7-membered heterocyclile, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclile has 4 or fewer R 2d arbitrarily substituted with; each R 2d is independently OH, halogen, NH2, C 1-6 Alkoxy, CONH2, SO2NH2, NHCOR 13 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-NH2, C 1-6 Alkyl-CO2R 12 , iodine or CN, and R 2e is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 6-10 Aril, C 1-6 Alkyl-C 6-10 It is an aryl, a tetanical to hypanical heterocyclyl, or a zetanical to elevenaryl heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl comprises three or fewer Rs. 10 It is arbitrarily replaced with;R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is independently H, C 1-6 Alkyl, halogen, or C 3-7 Cycloalkyl or; R 3 , R 4 , R 5 , R 6 , R 7 or R 8 They can bond with the atoms to which they are attached to form ternary to hexavalent spiros, cross-linked or fused rings; and each R 10 C independently 1-6 Alkoxy, CN, Halogen, OH, NH2, NHR 11 , CONH2, SO2NH2 or NHCO2-C 1-6 It is alkyl; R 11 H, C 1-6 alkyl or C 1-6 It is a haloalkyl and;R 12 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, quaternary to hypnotic heterocyclile, C 6-10 It is an aryl, or a 5- to 11-membered heteroaryl; R 13 C 1-6 alkyl or C 1-6 It is a haloalkyl. Claim 7 In paragraph 6, a compound having the structure shown below or a pharmaceutically acceptable salt thereof: or . Claim 8 In claim 1, a compound having the structure shown below or a pharmaceutically acceptable salt thereof: or . Claim 9 In claim 1, a compound having the structure shown below or a pharmaceutically acceptable salt thereof: or . Claim 10 In claim 1, a compound having the structure shown below or a pharmaceutically acceptable salt thereof: or . Claim 11 In claim 1, a compound having the structure shown below or a pharmaceutically acceptable salt thereof: or . Claim 12 In claim 1, a compound having the structure shown below or a pharmaceutically acceptable salt thereof: or . Claim 13 Compounds having the structure shown below or pharmaceutically acceptable salts thereof: . Claim 14 Compounds having the structure shown below or pharmaceutically acceptable salts thereof: Claim 15 Compounds having the structure shown below or pharmaceutically acceptable salts thereof: . Claim 16 Compounds having the structure shown below or pharmaceutically acceptable salts thereof: . Claim 17 Compounds having the structure shown below or pharmaceutically acceptable salts thereof: . Claim 18 Compounds having the structure shown below or pharmaceutically acceptable salts thereof: Claim 19 A pharmaceutically effective amount of a compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, comprising: renal protection against drugs causing chronic kidney disease (CKD), diabetic nephropathy (DKD), kidney disease, renal fibrosis, renal failure, acute renal injury, tubular insufficiency, lupus nephritis, 2,8-dihydroxydenine nephropathy, kidney transplant rejection, Fanconi's 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, irritable bowel syndrome (IBD). A pharmaceutical composition for treating ulcerative colitis, Crohn's disease, hyperuricemia, gout, arthritis, osteoporosis, or cancer. Claim 20 A pharmaceutical composition according to claim 19, further comprising one or more additional therapeutic agents. Claim 21 A pharmaceutical composition used to treat ketohexokinase (KHK)-mediated diseases or conditions in paragraph 20. Claim 22 A pharmaceutical composition for treating a KHK-mediated disease or condition in a subject requiring treatment for the KHK-mediated disease or condition, comprising a compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein the disease or condition is chronic kidney disease (CKD), diabetic nephropathy (DKD), kidney disease, renal fibrosis, renal failure, acute renal injury, tubular insufficiency, lupus nephritis, 2,8-dihydroxydenine nephropathy, kidney transplant rejection, renal protection against drugs causing Fanconi's 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 A pharmaceutical composition comprising type 2 diabetes, irritable bowel syndrome (IBD), ulcerative colitis, Crohn's disease, hyperuricemia, gout, arthritis, osteoporosis, or cancer. Claim 23 A pharmaceutical composition according to paragraph 22, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent. Claim 24 In claim 20, the additional therapeutic agent is a pharmaceutical composition comprising an SGLT2 inhibitor, empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, remogliflozin, ertugliflozin, an ACE inhibitor, benazepril, imidapril or enalapril and / or a pharmaceutically acceptable salt thereof. Claim 25 In paragraph 23, the additional therapeutic agent is a pharmaceutical composition comprising an SGLT2 inhibitor, empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, remogliflozin, ertugliflozin, an ACE inhibitor, benazepril, imidapril or enalapril and / or a pharmaceutically acceptable salt thereof. Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete

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