KHK inhibitors

Abstract

To provide methods for treating a disease and provide KHK inhibitors.SOLUTION: The invention provides compounds of formula (I) in the figure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 167,331, filed March 29, 2021, which is incorporated herein by reference in its entirety for all purposes. [Background technology]

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

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

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

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

[0006] An example of the consequences of unregulated fructose metabolism via KHK is hereditary fructose intolerance (HFI, OMIM#229600). Caused by a deficiency in Aldolase B (GENE:ALDOB) ALDOB is the enzyme immediately downstream of KHK and converts F1P to dihydroxyacetone phosphate (DH). Conversion to glyceraldehyde phosphate (GAP) and glyceraldehyde phosphate (GAP) ALDOB deficiency leads to the accumulation of F1P, ATP depletion, and increased uric acid. HFI is a rare disorder with a prevalence of approximately 1 in 20,000 (Simons et al., 2019). Individuals with HFI are severely intolerant to dietary fructose and exhibit acute symptoms such as vomiting, hypoglycemia, diarrhea, and abdominal distension. These symptoms contribute to the development of hypoglycemia, hyperuricemia, lactic acidosis, hepatic steatosis, and features reminiscent of Fanconi syndrome, and in severe cases, death (Aldamiz-Echevarria et al., 2020; Simons et al., 2019). Currently, the only treatment for patients with HFI is strict restriction of dietary fructose. However, this is not entirely sufficient to slow the deterioration of symptoms over time, and patients often exhibit features of liver and kidney disease throughout their life due to unaffected endogenous fructose production and metabolism (Aldamiz-Echevarria et al., 2020).

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

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

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

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

[0011] There is a need for KHK inhibitors with advantageous properties, such as equal tissue distribution, high target binding, and good pharmacokinetic properties. Although progress has been made, there remains a need for new, more potent KHK inhibitors with low tissue asymmetry, low drug-drug interaction propensity, reduced off-target propensity, and minimal toxicity. References: Aldamiz-Echevarria,L.,de Las Heras,J.,Couce,ML,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 Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice.Nat Commun,8,14181.doi:10.1038 / ncomms14181 Properties of normal and mutant recombinant human ketohexokinases and implications for pathogenesis of essential fructosuria.Diabetes,52(9),2426-2432.doi:10.2337 / diabetes.52.9.2426 Bantle,JP(2009).Dietary fructose and the metabolic syndrome and diabetes.J Nutr,139(6),1263S-1268S.doi:10.3945 / jn.108.098020 Bonthron , DT , Brady , N , Donaldson , IA , & Steinmann,B.(1994).Molecular basis of essential fructosuria:molecular cloning and mutational analysis of human ketohexokinase(fructokinase).Hum Mol Genet,3(9),1627-1631.doi:10.1093 / hmg / 3.9.1627 Diggle,C.P.,Shires,M.,Leitch,D.,Brooke,D.,Carr,I.M.,Markham,A.F.,.Bonthron,D.T.(2009).Ketohexokinase:expression and localization of the principal fructose-metabolizing enzyme.J Histochem Cytochem,57(8),763-774.doi:10.1369 / jhc.2009.953190 Geidl-Flueck,B.,&Gerber,P.A.(2017).Insights into the Hexose Liver Metabolism-Glucose versus Fructose.Nutrients,9(9).doi:10.3390 / nu9091026 Hayward,B.E.,&Bonthron,D.T.(1998).Struc ture and alternative splicing of the ketohexokinase gene.Eur J Biochem,257(1),85-91.doi:10.1046 / j.1432-1327.1998.2570085.x Helsley,R.N.,Moreau,F.,Gupta,M.K.,Radulescu,A.,DeBosch,B.,& Softic,S.(2020).Tissue-Specific Fructose Metabolism in Obesity and Diabetes.Curr Diab Rep,20(11),64.doi:10.1007 / s11892-020-01342-8 Ishimoto,T.,Lanaspa,M.A.,Le,M.T.,Garcia,G.E.,Diggle,C.P.,Maclean,P.S.,.Johnson,R.J.(2012).Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice.Proc Natl Acad Sci U S A,109(11),4320-4325.doi:10.1073 / pnas.1119908109 Jensen,T.,Abdelmalek,M.F.,Sullivan,S.,Nadeau,K.J.,Green,M.,Roncal,C.,.Johnson,R.J.(2018).Fructose and sugar:A major mediator of non-alcoholic fatty liver disease.J Hepatol,68(5),1063-1075.doi:10.1016 / j.jhep.2018.01.019 Johnson,R.J.,Nakagawa,T.,Sanchez-Lozada,L.G.,Shafiu,M.,Sundaram,S.,Le,M.,.Lanaspa,M.A.(2013).Sugar,uric acid,and the etiology of diabetes and obesity.Diabetes,62(10),3307-3315.doi:10.2337 / db12-1814 Lanaspa,M.A.,Ishimoto,T.,Li,N.,Cicerchi,C.,Orlicky,D.J.,Ruzycki,P.,.Johnson,R.J.(2013).Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome.Nat Commun,4,2434.doi:10.1038 / ncomms3434 Merino,B.,Fernandez-Diaz,C.M.,Cozar-Castellano,I.,&Perdomo,G.(2019).Intestinal Fructose and Glucose Metabolism in Health and Disease.Nutrients,12(1).doi:10.3390 / nu12010094 Montrose,D.C.,Nishiguchi,R.,Basu,S.,Staab,H.A.,Zhou,X.K.,Wang,H.,.Dannenberg,A.J.(2020).Dietary Fructose Alters the Composition,Localization,and Metabolism of Gut Microbiota in Association With Worsening Colitis.Cell Mol Gastroenterol Hepatol.doi:10.1016 / j.jcmgh.2020.09.008 Schapira,F.,Nordmann,Y.,& Gregori,C.(1972).Hereditary alterations of fructose metabolizing enzymes.Studies on essential fructosuria and on hereditary fructose intolerance.Acta Med Scand Suppl,542,77- 83。 Simons,N.,Debray,F.G.,Schaper,N.C.,Kooi,M.E.,Feskens,E.J.M.,Hollak,C.E.M.,.Brouwers,M.(2019).Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content.J Clin Endocrinol Metab,104(11),5056-5064.doi:10.1210 / jc.2018-02795 Todoric,J.,Di Caro,G.,Reibe,S.,Henstridge,DC,Green,CR,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 [Preliminary Technology Documents] [License]

[0012] [License 1] U.S. Patent and Trademark Office Publication No. 2017 / 183328 [License 2] China Patent Publication No. 111978296 [License 3] International Publication No. 2020 / 067735 [License 4] International Publication No. 2020 / 051058 [Patent Document 5] China Patent Publication No. 111423420 [License 6] International Publication No. 2020 / 156445 [License 7] International Publication No. 18 / 170517 [License 8] International Publication No. 11 / 133750 [Non-licensed literature]

[0013] [Non-licensed Document 1] Futatsugi et al.,J.Med.Chem.,2020,63,13546-13560 [Non-licensed Document 2] Lassila et al.,Chem.Res.Toxicol.,2015,28,12,2292-2303 [Non-licensed Document 3] Vleet Van et al.,Toxicology Letters,2017,272,1-7 [Non-patent document 4] Sekine et al.,Am.J.Physiol.Renal Physiol.,2006,290,F251-F261 [Non-Patent Document 5] Kalliokoski et al.,Br.J.Pharmacol.,2009,158,693-705 [Non-patent document 6] McFeely et al.,Clin.Transl.Sci.,2019,12,379-387 [Non-Patent Document 7] Zhang et al.,Bioorg.Med.Chem.Lett.,2011,21,4762-4767 [Non-patent document 8] Maryanoff et al.,Bioorg.Med.Chem.Lett.,2012,22,5326-532 [Non-Patent Document 9] Maryanoff et al.,ACS Med.Chem.Lett.,2011,2,538-543 [Non-Patent Document 10] Yukawa et al.,ACS Med.Chem.Lett.,2020,11,203-209 Summary of the Invention [Means for solving the problem]

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

[0015] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 teeth, A 4- to 10-membered heterocyclic moiety, wherein the heterocyclic ring contains 1 to 3 heteroatoms and up to four R 1aa heterocyclic moiety optionally substituted with 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 oxo, 3~7 is cycloalkyl, Each R 1a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, OH, OR 1b , CH2OH, CO2R 12 , halogen, oxo, 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 Haloalkyl is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or an alkyl-NHSOR 13 , alkyl-NHCOR 13 , alkoxy, or haloalkyl may have up to three R 1c or two R 1a can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, fused, or bridged ring; R 1b is H or C 1~6 alkyl, optionally substituted with up to three halogens, CN, or OH; Each R 1c are independently OH, OR 11 , halogen, oxo, SOR 13 , SO2R 13 , S.R. 13, SO2NH2, CONH2, CN, C 1~6 Alkoxy, C 6~10 Aryl, C 6~10 aryloxy, 5- to 11-membered heteroaryl, or C 3~7 is cycloalkyl, R 2 is C 6~10 aryl or 6- to 14-membered heteroaryl, and the aryl or heteroaryl may be up to 8 R 2a optionally substituted with R 2 is R 2 is attached to the core through a carbon atom of Each R 2a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, CONH2, COR 2c ,CONHR 2e , CON(R 2c )2, halogen, oxo, 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)(NHR 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 , S.R.2c , C 3~7 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl, or 5- to 11-membered heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, An aryl or heteroaryl may have up to seven R 2b and the cycloalkyl can be fused to a heteroaryl or form a spiro, or the cycloalkyl can be fused to an aryl, or two R 2a can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2b independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, OH, halogen, oxo, 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 1~6Alkyl-SO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3~7 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, alkyl, C 1~6 Alkyl-CO2R 12 , C 1~6 Alkyl-CONH2, C 1~6 Alkyl-NHSO2R 2c , C 1~6 Alkyl-SO2R 2c , alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be up to four R 2d or two R 2b can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2c independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 3~7 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 aryl, 5- to 11-membered heteroaryl, or 4- to 7-membered heterocyclyl, and the alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, alkyl-aryl, heteroaryl, or heterocyclyl may be substituted with up to four R 2d or two R 2c can combine with the atoms to which they are attached to form a 3- to 7-membered ring, Each R 2d are independently OH, halogen, NH2, C 1~6 Alkoxy, CONH2, COR 2e , SO2NH2, NR 11 COR 13 , NCH2OR 11 , C 1~6 Alkyl, C1~6 Haloalkyl, C 3~7 Cycloalkyl, 4-7 membered heterocyclyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-CO2R 12 , oxo, or CN; R 2e is C 1~6 Alkyl, C 3~7 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 aryl, 4- to 7-membered heterocyclyl, or 5- to 11-membered heteroaryl, and the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl may be substituted with up to three R 10 optionally replaced by Each X is independently 7 R 8 , oxo, S, SO, SO2, or O; Z 1 is CR 3 R 4 , N.R. 9 , S, SO, SO2, C=O, or O; Z 2 is CR 5 R 6 , N.R. 9 , S, SO, SO2, C=O, or O; n is 0, 1, or 2; When n is 0, Z 1 is CR 3 R 4 and Z 2 is CR 5 R 6 and When n is 2, only one X can be oxo, S, SO, SO, or O; Z 1 or Z 2 When any of is O, SO, or SO2, X is CR 7 CR 8 and Z 1 and Z 2 When both are O, SO, or SO2, X is CR7 CR 8 and The dashed circle represents one or more optional double bonds; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 independently, there is no 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 combine with the atoms to which they are attached to form 3- to 6-membered spiro , bridged, or fused rings may be formed; R 9 Does not exist or H, C 1~6 Alkyl, or C 3~7 is cycloalkyl, Each R 10 independently, C 1~6 Alkoxy, CN, halogen, OH, NH2, NHR 11 , CONH2, SO2NH2, or NHCO2-C 1~6 is alkyl, R 11 is H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 12 is C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, C 6~10 aryl or 5- to 11-membered heteroaryl; R 13 is C 1~6 Alkyl or C 1~6 It is haloalkyl.

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

[0017] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 teeth, A 4- to 10-membered heterocyclic moiety, wherein the heterocyclic ring contains 1 to 3 heteroatoms and up to four R 1a a heterocyclic moiety optionally substituted with 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 oxo, 3~7 is cycloalkyl, Each R 1a independently C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, OH, OR 1b , CH2OH, COOH, CO2R 12 , halogen, oxo, 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 haloalkyl, and alkyl, alkenyl, or alkynyl may have up to three R 1c or two R 1a can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, fused, or bridged ring; R 1b is H or C 1~6 alkyl, optionally substituted with up to three halogens, CN, or OH; Each R 1care independently OH, OR 11 , halogen, oxo, SOR 13 , SO2R 13 , S.R. 13 , SO2NH2, CONH2, C 1~6 Alkoxy, C 6~10 Aryl, C 6~10 aryloxy, 5- to 11-membered heteroaryl, or C 3~7 is cycloalkyl, R 2 is C 6~10 aryl or 6- to 14-membered heteroaryl, and the aryl or heteroaryl may be up to 8 R 2a optionally substituted with R 2 is R 2 is attached to the core through a carbon atom of Each R 2a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH 2, COOH, CO2R 12 , CONH2, COR 2c ,CONHR 2e , CON(R 2c )2, halogen, oxo, 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)(NR2c )NH2, S(O)(NH)NHR 2c , S(O)(NR 2c )NH(R 2c ), OR 2c , C 3~7 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to 7 R 2b and the cycloalkyl can be fused to a heteroaryl or form a spiro, or the cycloalkyl can be fused to an aryl, or two R 2a can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2b independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, OH, halogen, oxo, 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 16 Alkyl-CO2R 12 , C 1~6 Alkyl-CONH2, C1~6 Alkyl-NHSO2R 2c , CN, COR 2c , NHCO2R 2c , SO2NH2, SO2NHR 2c , SO2R 2c , C 3~7 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to four R 2d or two R 2b can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2c independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 aryl, 5- to 11-membered heteroaryl, or 4- to 7-membered heterocyclyl, and the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclyl may be substituted with up to four R 2d optionally replaced by Each R 2d are 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 , oxo, or CN; R 2e is C 1~6 Alkyl, C 3~7 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10aryl, 4- to 7-membered heterocyclyl, or 5- to 11-membered heteroaryl, and the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl may be substituted with up to three R 10 optionally replaced by Each X is independently 7 R 8 , N.R. 9 , oxo, S, SO, SO2, or O; Z 1 is CR 3 R 4 , N.R. 9 , S, SO, SO2, C=O, or O; Z 2 is CR 5 R 6 , N.R. 9 , S, SO, SO2, C=O, or O; n is 0, 1, or 2; When n is 0, Z 1 is CR 3 R 4 and Z 2 is CR 5 R 6 and When n is 2, only one X can be oxo, S, SO, SO, or O; Z 1 or Z 2 When any of is O, SO, or SO2, X is CR 7 CR 8 , or NR 9 and Z 1 and Z 2 When both are O, SO, or SO2, X is CR 7 CR 8 and The dashed circle represents one or more optional double bonds; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 independently, there is no H, C 1~6 Alkyl, halogen, or C3~7 cycloalkyl, or R 3 , R 4 , R 5 , R 6 , R 7 , or R 8 can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, bridged, or fused ring; R 9 Does not exist or H, C 1~6 Alkyl, or C 3~7 is cycloalkyl, Each R 10 independently, C 1~6 Alkoxy, CN, halogen, OH, NH2, NHR 11 ,CONH2,SO2NH2,COOH,CO2R 12 , or NHCO2-C 1~6 is alkyl, R 11 is H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 12 is H, C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, C 6~10 aryl or 5- to 11-membered heteroaryl; R 13 is C 1~6 Alkyl or C 1~6 It is haloalkyl.

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

[0019] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: m is 0 to 4; Each R 1a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, OH, OR1b , CH2OH, COOH, CO2R 12 , halogen, oxo, 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 haloalkyl, and alkyl, alkenyl, or alkynyl may be any group having up to three R 1c or two R 1a can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, fused, or bridged ring; R 1b is H or C 1~6 alkyl, optionally substituted with up to three halogens, CN, or OH; Each R 1c are independently OH, OR 11 , halogen, oxo, SOR 13 , SO2R 13 , S.R. 13 , SO2NH2, CONH2, C 1~6 Alkoxy, C 6~10 Aryl, C 6~10 aryloxy, 5- to 11-membered heteroaryl, or C 3~7 is cycloalkyl, R 2 is C 6~10 aryl or 6- to 14-membered heteroaryl, and the aryl or heteroaryl may be up to 8 R 2a optionally substituted with R 2 is R 2 Through the carbon atoms of It is bound to the core Each R 2a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, COOH, CO2R12 , CONH2, COR 2c ,CONHR 2e , CON(R 2c )2, halogen, oxo, 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, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to 7 R 2b and the cycloalkyl can be fused to a heteroaryl or form a spiro, or the cycloalkyl can be fused to an aryl, or two R 2a can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2b independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, OH, halogen, oxo, COOH, CO2R 12 , CONH2, NHCOR 2c , N(R 2c )COR2c , 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, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to four R 2d or two R 2b can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2c independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 aryl, 5- to 11-membered heteroaryl, or 4- to 7-membered heterocyclyl, and the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclyl may be substituted with up to four R 2doptionally replaced by Each R 2d are 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 , oxo, or CN; R 2e is C 1~6 Alkyl, C 3~7 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 aryl, 4- to 7-membered heterocyclyl, or 5- to 11-membered heteroaryl, and the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl may be substituted with up to three R 10 optionally replaced by R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are 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 can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, bridged, or fused ring; Each R 10 independently, C 1~6 Alkoxy, CN, halogen, OH, NH2, NHR 11 ,CONH2,SO2NH2,COOH,CO2R 12 , or NHCO2-C 1~6 is alkyl, R 11 is H, C 1~6 Alkyl, or C1~6 is haloalkyl, R 12 is H, C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, C 6~10 aryl or 5- to 11-membered heteroaryl; R 13 is C 1~6 Alkyl or C 1~6 It is haloalkyl.

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

[0021] [ka] During the ceremony, R 1 teeth, A 4- to 10-membered heterocyclic moiety, wherein the heterocyclic ring contains 1 to 3 heteroatoms and up to four R 1a a heterocyclic moiety optionally substituted with 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 oxo, 3~7 is cycloalkyl, Each R 1a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, OH, OR 1b , CH2OH, CO2R 12 , halogen, oxo, CONH2, CN, NH2, NHR 11 , C 1~6 Alkyl-NHSO2R13 , C 1~6 Alkyl-NHCOR 13 , C 1~6 Alkoxy or C 1~6 Haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkyl-NHSOR 13 , alkyl-NHCOR 13 , alkoxy, or haloalkyl may have up to three R 1c or two R 1a can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, fused, or bridged ring; R 1b is H or C 1~6 alkyl, optionally substituted with up to three halogens, CN, or OH; Each R 1c are independently OH, OR 11 , halogen, oxo, SOR 13 , SO2R 13 , S.R. 13 , SO2NH2, CONH2, CN, C 1~6 Alkoxy, C 6~10 Aryl, C 6~10 aryloxy, 5- to 11-membered heteroaryl, or C 3~7 is cycloalkyl, R 2 is a 5-membered heteroaryl, the heteroaryl being a group consisting of up to three R 2a optionally substituted with R 2 is R 2 is attached to the core through a carbon atom of Each R 2a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, CONH2, COR 2c ,CONHR 2e , CON(R 2c )2, halogen, oxo, OH, CN, NH2, NHR2c , 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)(NHR 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 , S.R. 2c , C 3~7 Cycloalkyl, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to 7 R 2b and the cycloalkyl can be fused to a heteroaryl or form a spiro, or the cycloalkyl can be fused to an aryl, or two R 2a can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2b independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, OH, halogen, oxo, CONH2, CONHR 2e , CON(R 2c )2, NHCOR 2c , N(R 2c )COR 2c , NHCO2R 2c , NH2, N(R2c )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, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, alkyl, C 1~6 Alkyl-CO2R 12 , C 1~6 Alkyl-CONH2, C 1~6 Alkyl-NHSO2R 2c , C 1~6 Alkyl-SO2R 2c , alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be up to four R 2d or two R 2b can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2c independently, C 1~6 Alkyl, C 1~6Haloalkyl, C 1~6 Alkoxy, C 3~7 Cycloalkyl, C 6~10 Aryl, alkyl-C 6~10 aryl, 5- to 11-membered heteroaryl, or 4- to 7-membered heterocyclyl, and the alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, alkyl-aryl, heteroaryl, or heterocyclyl may be substituted with up to four R 2d or two R 2c can combine with the atoms to which they are attached to form a 3- to 7-membered ring, Each R 2d are 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, 4-7 membered heterocyclyl, C 1~6 Alkyl-NH2, C 1~6 Alkyl-CO2R 12 , oxo, or CN; R 2e is C 1~6 Alkyl, C 3~7 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 aryl, 4- to 7-membered heterocyclyl, or 5- to 11-membered heteroaryl, and the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl may be substituted with up to three R 10 optionally replaced by Each X is independently 7 R 8 , oxo, S, SO, SO2, or O; Z 1 is CR 3 R 4 , N.R. 9 , S, SO, SO2, C=O, or O; Z 2 is CR5 R 6 , N.R. 9 , S, SO, SO2, C=O, or O; n is 0, 1, or 2; When n is 0, Z 1 is CR 3 R 4 and Z 2 is CR 5 R 6 and When n is 2, only one X can be oxo, S, SO, SO, or O; Z 1 or Z 2 When any of is O, SO, or SO2, X is CR 7 CR 8 and Z 1 and Z 2 When both are O, SO, or SO2, X is CR 7 CR 8 and The dashed circle represents one or more optional double bonds; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 independently, there is no 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 can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, bridged, or fused ring; R 9 Does not exist or H, C 1~6 Alkyl, or C 3~7 is cycloalkyl, Each R 10 independently, C 1~6 Alkoxy, CN, halogen, OH, NH2, NHR 11, CONH2, SO2NH2, or NHCO2-C 1~6 is alkyl, R 11 is H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 12 is C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, C 6~10 aryl or 5- to 11-membered heteroaryl; R 13 is C 1~6 Alkyl or C 1~6 It is haloalkyl.

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

[0023] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 teeth, A 4- to 10-membered heterocyclic moiety, wherein the heterocyclic ring contains 1 to 3 heteroatoms and up to four R 1a a heterocyclic moiety optionally substituted with 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 C optionally substituted with up to four substituents independently selected from 3~7 is cycloalkyl, Each R 1a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, OH, OR1b , CH2OH, COOH, CO2R 12 , halogen, oxo, 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 haloalkyl, and alkyl, alkenyl, or alkynyl may be any group having up to three R 1c or two R 1a can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, fused, or bridged ring; R 1b is H or C 1~6 alkyl, optionally substituted with up to three halogens, CN, or OH; Each R 1c are independently OH, OR 11 , halogen, oxo, SOR 13 , SO2R 13 , S.R. 13 , SO2NH2, CONH2, C 1~6 Alkoxy, C 6~10 Aryl, C 6~10 aryloxy, 5- to 11-membered heteroaryl, or C 3~7 is cycloalkyl, R 2 is a 5-membered heteroaryl, the heteroaryl being a group consisting of up to three R 2a optionally substituted with R 2 is R 2 is attached to the core through a carbon atom of Each R 2a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, SO2R 2c , SOR 2c , SO2NH2, COOH, CO2R 12 , CONH2, COR 2c ,CONHR2e , CON(R 2c )2, halogen, oxo, 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, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to 7 R 2b The cycloalkyl can be fused to the heteroaryl or form a spiro group, or two R 2a can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2b independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, OH, halogen, oxo, 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, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to four R 2d or two R 2b can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2c independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 aryl, 5- to 11-membered heteroaryl, or 4- to 7-membered heterocyclyl, and the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclyl may be substituted with up to four R 2d optionally replaced by Each R 2d are 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 , oxo, or CN; R 2e is C 1~6 Alkyl, C 3~7 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 aryl, 4- to 7-membered heterocyclyl, or 5- to 11-membered heteroaryl, and the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl may be substituted with up to three R 10 optionally replaced by Each X is independently 7 R 8 , N.R. 9 , oxo, S, SO, SO2, or O; Z 1 is CR 3 R 4 , N.R. 9 , S, SO, SO2, C=O, or O; Z 2 is CR 5 R 6 , N.R. 9 , S, SO, SO2, C=O, or O; n is 0, 1, or 2; When n is 0, Z 1 is CR 3 R 4 and Z 2 is CR 5 R 6 and When n is 2, only one X can be oxo, S, SO, SO, or O; Z 1 or Z 2 When any of is O, SO, or SO2, X is CR 7 CR 8 , or NR9 and Z 1 and Z 2 When both are O, SO, or SO2, X is CR 7 CR 8 and The dashed circle represents one or more optional double bonds; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 independently, there is no 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 can combine with the atoms to which they are attached to form a 3- to 6-membered spiro, bridged, or fused ring; R 9 Does not exist or H, C 1~6 Alkyl, or C 3~7 is cycloalkyl, Each R 10 independently, C 1~6 Alkoxy, CN, halogen, OH, NH2, NHR 11 ,CONH2,SO2NH2,COOH,CO2R 12 , or NHCO2-C 1~6 is alkyl, R 11 is H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 12 is H, C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, C 6~10 aryl or 5- to 11-membered heteroaryl; R 13 is C 1~6 Alkyl or C 1~6 It is haloalkyl. DETAILED DESCRIPTION OF THE INVENTION

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

[0025] [ka] In the formula, R 1 , R 2 , Z 1 , Z 2 , and X n is defined herein.

[0026] "Alkyl" refers to a straight- or branched-chain saturated monovalent hydrocarbon. For example, an alkyl group may contain 1 to 18 carbon atoms (i.e., C 1~18 alkyl) or 1 to 8 carbon atoms (i.e., C 1~8 alkyl) or 1 to 6 carbon atoms (i.e., C 1~6 alkyl) or 1 to 4 carbon atoms (i.e., C 1~4Examples of alkyl groups include, but are not limited to, methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCH), 2-propyl (i-Pr, i-propyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, -CH(CH)CHCH), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH) ), 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 (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2 and 3,3-dimethyl-2-butyl (-C(CH)CH(CH)), 2-methyl-2-pentyl (-C(CH)CHCHCH), 3-methyl-2-pentyl (-CH(CH)CH(CH)CHCH), 4-methyl-2-pentyl (-CH(CH)CHCHCH(CH)), 3-methyl-3-pentyl (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), and 3,3-dimethyl-2-butyl (-CH(CH)C(CH)). Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0027] "Alkenyl" refers to a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can be an alkyl group having 2 to 8 carbon atoms (i.e., C2~8 alkenyl) or 2 to 6 carbon atoms (i.e., C 2~6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2~4 Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH), allyl (-CHCH=CH), and -CH-CH=CH-CH. Alkenyl groups can be unsubstituted or substituted.

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

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

[0030] As used herein, "aryl" refers to an all-carbon aromatic monocyclic ring or an all-carbon multiple condensed ring system in which at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having 9 to 20 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbocyclic). Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the multiple condensed ring system. The rings of the multiple condensed ring system may be connected to each other by fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. When an aryl having a particular range of atom members (e.g., a 6- to 10-membered aryl) is referred to, it is also understood that the atom range is for the total ring atoms of the aryl. For example, 6-membered aryls include phenyl, and 10-membered aryls 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, and the like. Specific examples of polycyclic carbocycles include, but are not limited to:

[0031] [ka]

[0032] "Cycloalkyl" refers to a group of 3 to 20 cyclic carbon atoms (i.e., C 3~20Cycloalkyl) refers to a saturated or partially unsaturated all-carbon monocyclic ring, e.g., having 3 to 12 ring atoms, e.g., 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 3 to 4 ring atoms. The term "cycloalkyl" also encompasses saturated and partially unsaturated all-carbon multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 carbocyclic rings). Thus, cycloalkyl includes polycyclic carbocycles, e.g., bicyclic carbocycles (e.g., bicyclic carbocycles having 6 to 12 ring 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 up to 20 ring carbon atoms). Rings in multiple condensed ring systems may be connected to each other by fused, spiro, and bridged bonds, where permitted by valency 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.

[0033] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect the cycloalkyl component and the point of attachment. In some cases, the alkyl component can be absent. The alkyl component can be any of C 1~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C5~6 The cycloalkyl moiety is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0034] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect the aryl component and the point of attachment. In some cases, the alkyl component can be absent. The alkyl component can be any of 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 The aryl moiety is as defined herein. Exemplary alkyl-aryl groups include, but are not limited to, methyl-phenyl or ethyl-phenyl.

[0035] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" or "heterocyclic" refers to a saturated or partially unsaturated non-aromatic mono- or multiple ring system having at least one heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur) in the ring, where the multiple ring system includes at least a non-aromatic ring containing at least one heteroatom. The multiple ring system may also include other aromatic and non-aromatic rings. Unless otherwise specified, a heterocyclyl group may have 3 to 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 3 to 10 ring atoms, or 3 to 8 ring atoms. The term "saturated" or "partially unsaturated" monocyclic ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) has 1 to 6 ring carbon atoms and 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroatoms are optionally oxidized to form -N(-OH)-, =N(-O)-, or -N(-OH)-. - )-, -S(=O)-, or -S(=O)2-. The rings of multiple condensed ring (e.g., bicyclic heterocyclyl) systems may be connected to each other by fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. Heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinacridine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl , 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, and the like.

[0036] Examples of heterocyclyl groups include, but are not limited to, the following:

[0037] [ka]

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

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

[0040] [ka]

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

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

[0043] "Heteroaryl" also encompasses multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a heteroaryl group as defined above is fused with one or more rings selected from heteroaryl (e.g., to form 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl) to form a multiple condensed ring system. Thus, a heteroaryl (aromatic monocyclic or multiple condensed ring system) has 1 to 20 carbon atoms and 1 to 6 heteroatoms in the heteroaryl ring. Such fused polycyclic ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of a multiple condensed ring system may be connected to each other through fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. It is understood that the individual rings of a multiple condensed ring system may be connected to each other in any order. It is understood that the point of attachment of a heteroaryl or heteroaryl to a multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). When a heteroaryl having a specific range of atom members (e.g., a 5- to 10-membered heteroaryl) is referred to, it is understood that the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl.

[0044] "Heteroaryl" rings also include 8- to 15-membered fused rings having two, three, or more rings, where at least one ring is aromatic and at least one ring is non-aromatic containing at least one heteroatom. 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]dioxole, as shown in the following structures: These include dihydrobenzo[b]dioxin, dihydrobenzo[d]oxazole, dihydrobenzo[b]thiophene, dihydroisobenzo[c]thiophene, dihydrobenzo[d]thiazole, dihydrobenzo[c]isothiazole, and benzo[b][1,4]thiazine:

[0045] [ka]

[0046] A fused bicyclic heterocycloalkyl can also be represented by the following structure:

[0047] [ka] In the formula, X 1 , X 2 , X 3 , X 4 , and X 5 are each independently a bond, -CH-, -CH2-CF2-, -N-, -NH-, -CO-, -SO2-, -O-, or -S-; X 1 , X 2 , X 3 , X 4 , and X 5 at least one of Y is -N-, -NH-, -CO-, -O-, -SO2-, or -S-; 1 , Y2 , Y 3 , Y 4 are each independently a bond, —CH—, —O—, —CO—, —S—, —NH—, or —N—; Y 1 , Y 2 , Y 3 , Y 4 at least one of X is -CH-, -O-, -CO-, -S-, -NH, or -N-; 1 ~X 5 or Y 1 ~Y 4 can be a bond, the dashed circle or bond represents a saturated or partially unsaturated non-aromatic ring, and Y 1 , Y 2 , Y 3 , Y 4 At least one of R is carbon and the point of attachment to the core is through a carbon atom. A fused bicyclic heteroaryl can have up to eight R 2a optionally replaced by Each R 2a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 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, oxo, 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)(R2c )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, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to 7 R 2b and the cycloalkyl can be fused to a heteroaryl or form a spiro, or the cycloalkyl can be fused to an aryl, or two R 2a are combined with the atoms to which they are bonded. can be combined to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2b independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, OH, halogen, oxo, 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 )SO2R2c , 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, 4-7 membered heterocyclyl, C 6~10 aryl, or 5-11 membered heteroaryl, and the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with up to four R 2d or two R 2b can combine with the atoms to which they are attached to form a 3- to 7-membered spiro, fused, or bridged ring; Each R 2c independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 aryl, 5- to 11-membered heteroaryl, or 4- to 7-membered heterocyclyl, and the alkyl, haloalkyl, alkoxy, aryl, heteroaryl, or heterocyclyl may be substituted with up to four R 2d optionally replaced by Each R 2d are 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 , oxo, or CN; R 2e is C 1~6 Alkyl, C 3~7 Cycloalkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10aryl, 4- to 7-membered heterocyclyl, or 5- to 11-membered heteroaryl, and the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl, or heteroaryl may be substituted with up to three R 10 optionally replaced by Each R 10 independently, C 1~6 Alkoxy, CN, halogen, OH, NH2, NHR 11 ,CONH2,SO2NH2,COOH,CO2R 12 , or NHCO2-C 1~6 is alkyl, R 11 is H, C 1~6 Alkyl, or C 1~6 is haloalkyl, R 12 is H, C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, C 6~10 aryl or 5- to 11-membered heteroaryl; R 13 is C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0048] Examples of heteroaryl groups include, but are not limited to, the following:

[0049] [ka] is.

[0050] "Compounds of the present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of formulae (I-VI).

[0051] As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

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

[0053] As used herein, "treatment" or "treat" or "treating" refers to an approach for obtaining beneficial or desired results. For purposes of this disclosure, beneficial or Desired results include, but are not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the severity of the disease or condition), b) delaying the onset of or inhibiting one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, slowing the worsening or progression of the disease or condition), and c) palliating the disease or condition, e.g., causing regression of clinical symptoms, ameliorating the pathology, slowing disease progression, improving quality of life, and / or prolonging survival.

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

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

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

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

[0058] "Disease" or "condition" refers to a physical condition or state of health of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein.

[0059] 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, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

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

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

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

[0063] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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 can also be mentioned. 11 C. 18 F, 15 O, and 13Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formulas VI)-VI can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the Examples below, using appropriate isotopically labeled reagents in place of conventionally used non-labeled reagents.

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

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

[0066] "Stereoisomer" and "stereoisomers" refer to one or more "Asymmetric" refers to compounds that differ in the chirality of their stereocenters. Stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric forms if they have one or more asymmetric centers or double bonds with asymmetric substitution and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for determining 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).

[0067] "Tautomer" refers to alternative forms of a compound that differ in the location of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms attached to both the -NH- and =N- rings, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0068] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the front or end of chemical groups are for convenience, and chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is implied in the order in which chemical groups are written or their points of attachment to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be linked 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. u~v " or "(C u~C v A prefix such as "C" indicates that the following group has u to v carbon atoms. 1~6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has from 1 to 6 carbon atoms.

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

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

[0071] In some cases (Scheme 1), the compound of formula 13 is 1 or LG 2 are leaving groups, typically but not limited to halides or sulfones, were prepared from commercially available or literature-known compounds of formula 1. Compounds of formula 1 were reacted with the appropriate R 2 Treatment with -M(4) afforded a compound of formula 2 via a cross-coupling reaction. Suitable M groups include, but are not limited to, -B(OH)2, -B(pin), -Sn(alkyl)3, -ZnX, or -MgX. R 2 The above functional groups may require protection by appropriate protecting groups as determined by one skilled in the art. Catalysts for this transformation are often, but not limited to, Pd(PPh 34The catalysts used were, but are not limited to, Pd(dppf)Cl, Pd(OAc), PdCl, PdXPhos G1, G2, G3, or G4 catalyst, PdSPhos G1, G2, G3, or G4 precatalyst, or Pddba, and the phosphine ligand was selected from, but is not limited to, SPhos, XPhos, RuPhos, XantPhos, PCy, PPh, or dppf. The bases for this transformation were, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, cesium fluoride, triethylamine, diisopropylethylamine, or pyridine.

[0072] R 1 is an amine, the compound of formula 2 can be reacted with the nucleophile HR in the presence of a base 1 to give the compound of formula 13. Alternatively, HR 1 or MR 1 and a compound of formula 2 in the presence of a catalyst and / or a base to obtain a compound of formula 13. The catalyst and base were, but are not limited to, those described above. 1 The above functional groups may require protection by appropriate protecting groups as determined by one skilled in the art.

[0073] [ka]

[0074] MR not commercially available or known from literature 2 Compounds of formula (4) were typically derived from the corresponding halide 3 via catalytic activation in the presence of a base and an appropriate reagent to generate the nucleophile (Scheme 2). The catalysts and bases were, but are not limited to, those listed above. The reagent to generate the nucleophile was, but is not limited to, B2pin2 or Sn2(alkyl)6. Often, but not always, compounds of formula 4 were used directly in a one-pot cross-coupling with compounds of formula 2 to give compounds of formula 13.

[0075] [ka]

[0076] Compounds of formula 1, which are not commercially available or known in the literature, were synthesized according to Scheme 3 below. Compounds of formula 5 were treated with a source of S-methylisothiourea in the presence of a base to give compounds of formula 6. Compounds of formula 6 were then converted to LG-1 by the conversion of the hydroxy group. 2 The LG in compounds of formula 9 was converted to compounds of formula 1 by activation to 1, typically by treatment with POCl. Compounds of formula 7 were converted to compounds of formula 8 via cross-coupling as described above and in Scheme 1. The LG in compounds of formula 9 was converted to compounds of formula 1 by treatment of the thioether in compounds of formula 8 with an oxidizing agent, typically, but not limited to, m-chloroperbenzoic acid, peracetic acid, or Oxone®. 1 The compound of formula 9 was then converted to MR as described above and in Scheme 1. 1 or HR 1 to give the compound of formula 13.

[0077] [ka]

[0078] In some instances, compounds of formula 13 were prepared according to Scheme 4. Compounds of formula 1 were treated with a hydroxide source, typically sodium hydroxide, to give compounds of formula 10. Compounds of formula 10 were then reacted with MR as described above. 1 or MR 2 The hydroxy group of the compound of formula 11 was converted to LG in the compound of formula 12 as described above. 2 The compound of formula 12 was converted to MR as described above. 2 via a cross-coupling reaction with was converted to the compound of formula 13.

[0079] [ka]

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

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

[0082] Pharmaceutical compositions containing the compounds disclosed herein or pharmaceutically acceptable salts or stereoisomers thereof can be prepared with one or more pharmaceutically acceptable excipients, which can be selected according to conventional practice. Tablets may contain excipients, including lubricants, fillers, binders, etc. Aqueous compositions can be prepared in sterile form and, if intended for delivery by other than oral administration, may be generally isotonic. In some embodiments, the compositions can contain excipients such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. In some embodiments, the compositions are provided as solid dosage forms, including solid oral dosage forms.

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

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

[0085] 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 the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral administration, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating 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. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0086] The amount of active ingredient that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended therapeutic subject and mode of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain about 1 to 1000 mg of active agent, 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% (weight:weight) of the total composition.

[0087] In some embodiments, compositions comprising a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof in one variation do not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, in one aspect, it is understood that a composition comprising a compound of the present disclosure does not contain an agent that affects (e.g., slows, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compound of the present disclosure. It is also understood that in one aspect, none of the methods, kits, articles of manufacture, etc. detailed herein contain an agent that affects (e.g., slows, inhibits, or prevents) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compound of the present disclosure.

[0088] In some embodiments, the pharmaceutical compositions are for human or animal use.

[0089] The present disclosure further provides, for example, by combining or mixing the active ingredient with a pharmaceutically acceptable, therapeutically inert, organic and / or inorganic carrier or excipient. It includes the compounds of the present disclosure for administration as the sole active ingredient of a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art.

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

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

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

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

[0094] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

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

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

[0097] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., 1 mg to 1000 mg of compound). Therapeutically effective amounts can include about 1 mg per dose to about 1000 mg per dose, e.g., about 50 mg per dose to about 500 mg per dose, or e.g., about 100 mg per dose to about 400 mg per dose, or e.g., about 150 mg per dose to about 350 mg per dose, or e.g., about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure 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 amounts of the compounds of the present disclosure 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 can be administered hourly, daily, or weekly. For example, a single dose can be 1, 2, 3, 4, 6, 8, 12, 16, 18, 20, 22, 25, 27, 30, 35, 40, 45, or 500 mg. The single dose can be administered once every 1, 2, 3, 4, 5, 6, or 7 days. The single dose can also be administered once every 1, 2, 3, or 4 weeks. In some embodiments, the single dose can be administered once per week. The single dose can also be administered once per month.

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

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

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

[0101] The benefit of the combination can be increased efficacy and / or reduced side effects for the component, as the dose of the component can be adjusted to reduce its side effects while benefiting from its enhanced efficacy due to the efficacy of the compound of the present disclosure.

[0102] In some embodiments, the therapeutic agent or combination of therapeutic agents is selected from the group consisting of 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 Alström syndrome protein 1 (ALMS1) / PKCα protein interaction inhibitor, an apelin receptor agonist, a diacylglycerol O-acyltransferase 2 inhibitor, an adenosine A3 receptor agonist ... receptor antagonists, adiponectin receptor agonists, aldehyde dehydrogenase 2 stimulators, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), AMP kinase activators, ATP citrate lyase inhibitors, AMP-activated protein kinase stimulators, endothelial nitric oxide synthase stimulators, NAD-dependent deacetylase sirtuin-1 stimulators, adrenergic receptor antagonists, androgen receptor agonists, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, apical sodium-dependent bile acid transport inhibitors, autolysis protein modulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, β-catenin inhibitors, biologically active Lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors, caveolin-1 inhibitors, CCK receptor antagonists, CCL26 gene inhibitors, CCR2 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 stimulators, chitotriosidase 1 inhibitors, CNR1 inhibitors, connective tissue growth factor ligand inhibitors, COT protein kinase inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, DGAT1 / 2 inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (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, endosialin 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 Glucagon-1 agonist, galectin-3 inhibitor, GDNF family receptor α-like agonist, glucagon receptor agonist, glucagon-like peptide 1 agonist, glucocorticoid receptor antagonist, glucose 6-phosphate 1-dehydrogenase inhibitor, G protein-coupled bile acid receptor 1 agonist, G-protein-coupled receptor 119 agonist, G protein-coupled receptor 84 antagonist, hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 α modulator (HNF4A), hepatocyte growth factor modulator, histone deacetylase inhibitor, STAT-3 modulator, HMG CoA reductase inhibitor, HSD17B13 gene inhibitor, 5-HT2a receptor antagonists, hydrolase inhibitors, hypoxia-inducible factor-2α 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, integrin α-V / β-1 antagonists, integrin α-V / β-6 antagonists, interleukin-1 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-related protein 1 modulators, ketohexokinase (KHK) inhibitors, Klothoβ stimulators, leukotriene A4 hydrolase inhibitors, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor, LPL gene stimulators, lysophosphatidic acid receptor (LPAR) antagonists, lysophosphatidate-1 receptor antagonists, lysyl oxidase homolog 2 inhibitors, LXR inverse agonists, macrophage mannose receptor 1 modulators, mato Multimeric metalloproteinase (MMP) inhibitors, MEKK-5 protein kinase inhibitors, MCH receptor-1 antagonists, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl-CpG binding protein 2 modulators, microRNA-132 (miR-132) antagonists, 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 μ antagonists, P2Y13 purinergic receptor stimulators, nuclear erythroid 2-related factor 2 stimulators, nuclear receptor modulators, transcription factor modulators nuclear transport, P2X7 purinergic receptor modulators, PACAP type I receptor agonists, PDE 3 inhibitors, PDE 4 inhibitors, PDE5 inhibitor, PDGF receptor β modulator , phenylalanine hydroxylase stimulators, phospholipase C inhibitors, phosphorus diester hydrolase inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, peptidyl-prolyl cis-trans isomerase A inhibitors, PNPLA3 gene inhibitors, PPARγ modulators, protease-activated receptor-2 antagonists, protein kinase modulators, protein NOV homolog modulators, PTGS2 gene inhibitors, renin inhibitors, resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitors, Rho-associated protein kinase inhibitors, transcriptase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 inhibitors, sphingolipid delta-4 desaturase DES1 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase inhibitors and combinations thereof.

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

[0104] ACE inhibitors such as enalapril; acetaldehyde dehydrogenase inhibitors such as ADX-629; acetyl-CoA carboxylase (ACC) inhibitors such as NDI-010976 (filsocostat), DRM-01, gemcabene, GS-834356, PF-05175157, QLT-091382, and PF-05221304; acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341; adenosine receptor agonists such as namodenoson (CF-102), piclidenoson (CF-101), CF-502, and CGS21680; adenosine A3 receptor antagonists such as FM-101; adiponectin receptor agonists such as ADP-355, ADP-399, and ALY668-SR; Adrenergic receptor antagonists such as bromocriptine, phentermine, and VI-0521; aldehyde dehydrogenase 2 stimulators such as FP-045; amylin / calcitonin receptor agonists such as KBP-042, KBP-089; AMP-activated protein kinase stimulators such as C-455, PXL-770, and O-304; AMP kinase activators / ATP citrate lyase inhibitors such as bempedoic acid (ETC-1002, ESP-55016); AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators such as NS-0200 (leucine + metformin + sildenafil); androgen receptor agonists such as LPCN-1144, LPCN-1148, and testosterone prodrugs; Angiotensin II AT-1 receptor antagonists, such as irbesartan; angiopoietin-related protein-3 inhibitors (IONIS-ANGPTL3), such as bupanorsen; -LRx); apelin receptor agonists such as CB-5064, MBT-2; apical sodium-dependent bile acid transport inhibitors, e.g., A-3907; autophagy protein modulators such as A-2906, GM-90194; autotaxin (ectonucleotide pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2)) inhibitors such as FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, and BBT-877; Axl tyrosine kinase receptor inhibitors such as bemcentinib (BGB-324, R-428); Bax protein stimulators such as CBL-514; bioactive lipids such as DS-102; Nimacimab, GWP-42004, REV-200, CRB-400 Cannabinoid receptor modulators such as 1, INV-101, and SCN-002; caspase inhibitors, such as emricasan; pan-cathepsin B inhibitors such as VBY-376; pan-cathepsin inhibitors such as VBY-825; CCK receptor antagonists such as proglumide; CCL26 gene inhibitors such as mocedipimod and KDDF-201410-10; CCR2 / CCR5 chemokine antagonists such as BMS-687681, cenicriviroc, maraviroc, CCX-872, leronlimab, and WXSH-0213; CCR2 / CCR5 chemokine antagonists and FXR agonists such as LJC-242 (tropifexor + senibiliviroc); CCR2 chemokine antagonists such as propagermanium; CCR2 chemokine / angiotensin II inhibitors, such as DMX-200 and DMX-250 AT-1 receptor antagonists; CCR3 chemokine antagonists such as bertilimumab; CD3 antagonists such as NI-0401 (foralumab); CDGSH iron-sulfur domain protein modulators such as EYP-002; chitinase inhibitors such as OATD-01; chitotriosidase 1 inhibitors such as OAT-2068; Chloride channel stimulators such as cobiprostone and lubiprostone; casein kinase-1 (CK1) delta / epsilon inhibitors, such as PF-05006739; connective tissue growth factor ligand inhibitors such as PBI-4050; COT protein kinase inhibitors such as GS-4875, GS-5290; CXCR4 chemokine antagonists such as AD-214; cytochrome P450 reductase inhibitors such as SNP-630; diglyceride acyltransferase 2 (DGAT2) inhibitors such as IONIS-DGAT2Rx and PF-06865571; diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitors (C450 2E1 inhibitors), such as SNP-610 YP2E1); dihydroorotate dehydrogenase inhibitors, such as bidofludimus; Dipeptidyl peptidase IV inhibitors such as linagliptin and evogliptin; eotaxin ligand inhibitors such as bertilimumab and CM-101; extracellular matrix protein modulators such as CNX-024; AGN-242266, AGN-242256, ASC-42, EDP-297(EP-024297), RDX-023, BWL-200, AKN-083, EDP-305 Farnesoid X receptor (FXR) agonists such as 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, bonafexor (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266, HPD-001, and alendronate; farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767; fatty acid synthase inhibitors such as TVB-2640, FT-8225; fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as aldafermin (NGM-282); fibroblast growth factor 21 (FGF-21) ligands such as AP-025, BMS-986171, B-1654, BIO89-100, BOS-580, pegbelfermin (BMS-986036), B-1344, and NN-9499; fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists such as YH-25723 (YH-25724; YH-22241) and effluxifermin (AKR-001); FGF receptor agonists / Klotho beta stimulators such as BFKB-8488A (RG-7992); free fatty acid receptor 1 agonists, such as SCO-267; galectin-3 inhibitors such as Verapectin (GR-MD-02), GB-1107 (Gal-300), GB-1211 (Gal-400), and IMT-001; GDNF family receptor α-like agonists such as NGM-395; Glucagon-like peptide 1 (GLP1R) agonists such as ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, and semaglutide; -Glucagon-like peptide 1 receptor agonists; oxyntomodulin ligands; glucagon receptor agonists such as efinogdutide; gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP / GLP-1) receptor coagonists, such as tirzepatide (LY-3298176); PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, such as DD-01; glucagon / GLP1 receptor agonists such as BI-456906, NN-6177; glucocorticoid receptor antagonists such as CORT-118335 (milicorilant); glucose 6-phosphate 1-dehydrogenase inhibitors such as ST001; glucokinase stimulators such as dorzagliatin and sinogliatin (RO-5305552); G protein-coupled bile acid receptor 1 (TGR5) agonists such as RDX-009, INT-777, and HY-209; G protein-coupled receptor 84 antagonists such as PBI-4547; G protein-coupled receptor-119 agonists such as DA-1241; heat shock protein 47 (HSP47) inhibitors such as ND-L02-s0201; hedgehog protein TGFβ ligand inhibitors such as Oxy-210; histone deacetylase inhibitors / STAT-3 modulators such as SFX-01; HMG CoA reductase inhibitors such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; HSD17B13 gene inhibitors such as ALN-HSD and ARO-HSD; hydrolase inhibitors such as ABD-X; hypoxia-inducible factor-2 alpha inhibitors, such as PT-2567; IL-10 agonists such as peg-ilodecakin; ileal sodium-bile acid cotransporter inhibitors such as odebixibat (A-4250), borixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, or elobixibat (A-3309); insulin sensitizers such as KBP-042, azemiglitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), trimidone, VVP-100X, CB-4211, and ETI-101; insulin ligands / ds insulin receptor agonists such as ORMD-0801; integrin antagonists such as IDL-2965; IL-6 receptor agonists such as KM-2702; dual integrin α-V / β-6 and α-V / β-1 inhibitors such as PLN-74809; interleukin-17 ligand inhibitors such as netakimab; Jak1 / 2 tyrosine kinase inhibitors such as baricitinib; Jun N-terminal kinase-1 inhibitors such as CC-90001; Kelch-like ECH-associated protein 1 modulators, such as α-cyclodextrin-stabilized sulforaphane; ketohexokinase (KHK) inhibitors such as PF-06835919, LY-3478045, and LY-3522348; beta Klotho (KLB)-FGF1c agonists such as MK-3655 (NGM-313); leukotriene A4 hydrolase inhibitors such as LYS-006; 5-lipoxygenase inhibitors such as tipelukast (MN-001), epereuton (DS-102, (AF-102); lipoprotein lipase inhibitors such as CAT-2003; LPL gene stimulators such as alipogene tiparvovec; liver X receptor (LXR) inhibitors such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, and SR-9238; lysophosphatidic acid-1 receptor antagonists such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, and KI-16198; lysyl oxidase homolog 2 inhibitors such as simtuzumab and PXS-5382A (PXS-5338); macrophage mannose receptor 1 modulators such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept); matrix metalloproteinase inhibitors such as ALS-L1023; membrane copper amine oxidase (VAP-1) inhibitors such as TERN-201 and TT-01025; MEKK-5 protein kinase (ASK-1) inhibitors such as CJ-16871, CS-17919, selonsertib (GS-4997), SRT-015, GS-444217, GST-HG-151, and TERN-301; MCH receptor-1 antagonists such as CSTI-100 (ALB-127158); semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A (BI-1467335); methionine aminopeptidase-2 inhibitors such as ZGN-1061, ZGN-839, and ZN-1345; methyl-CpG binding protein 2 modulators such as mercaptamines; Mineralocorticoid receptor antagonists (MCRAs), such as MT-3995 (aparalenone); mitochondrial uncouplers such as 2,4-dinitrophenol, HU6, and Mito-99-0053; mixed lineage kinase-3 inhibitors such as URMC-099-C; motile sperm domain protein 2 inhibitors such as VB-601; myelin basic protein stimulators such as olesoxime; myeloperoxidase inhibitors such as PF-06667272, AZM-198; NADPH oxidase inhibitors such as GKT-831, GenKyoTex, APX-311, and setanaxib; nicotinic acid receptor 1 agonists such as ARI-3037MO; NACHT LRR PYD domain protein 3 (NLRP3) inhibitors such as KDDF-201406-03, NBC-6, IFM-514, and JT-194 (JT-349); NFE2L2 gene inhibitors such as GeRP-amiR-144; nuclear transport of transcriptional regulators such as AMTX-100; nuclear receptor modulators such as DUR-928 (DV-928); opioid receptor μ antagonists such as methylnaltrexone; P2X7 purinergic receptor modulators such as SGM-1019; P2Y13 purinergic receptor agonists such as CER-209; PDE 3 / 4 inhibitors such as tipelukast (MN-001); PDE 5 inhibitors such as sildenafil, MSTM-102; PDGF receptor β modulators such as BOT-191, BOT-509; peptidyl-prolyl cis-trans isomerase inhibitors such as CRV-431 (CPI-432-32), NVP-018, and NV-556 (NVP-025); phenylalanine hydroxylase stimulators such as HepaStem; phosphodiester hydrolase inhibitors such as ZSP-1601; PNPLA3 gene inhibitors such as AZD-2693; PPAR agonists such as tiglitazar, elafibranor (GFT-505), seladelparridine (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, PXL-065 (DRX-065), saroglitazar, lanifibranor (IVA-337), CHS-131, pemafibrate (K-877), ZG-0588, ZSP-0678; ZSYM-008; protease-activated receptor-2 antagonists such as PZ-235; protein kinase modulators such as CNX-014; protein NOV homologue modulators such as BLR-200; PTGS2 gene inhibitors such as STP-705 and STP-707; renin inhibitors such as PRO-20; resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitors, such as DWJ-211; Rev protein modulators such as ABX-464; Rho-associated protein kinase (ROCK) inhibitors such as REDX-10178 (REDX-10325), KD-025, RXC-007, and TDI-01; RNA polymerase inhibitors such as sapacitabine; S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891; sodium glucose transporter-2 (SGLT2) inhibitors such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, and sotagliflozin; sodium glucose transporter-1 / 2 (SGLT1 / 2) inhibitors, such as licogliflozin bis(prolinate) (LIK-066); SREBP transcription factor inhibitors such as CAT-2003, HPN-01, and MDV-4463 ; stearoyl-CoA desaturase-1 inhibitors such as aramchol; taste receptor type 2 agonists such as ARD-101; Thyroid hormone receptor beta agonists such as ALG-009, ASC-41, CNPT-101101; CNPT-101207, CS-27186, KY-41111, resmetirom (MGL-3196), MGL-3745, TERN-501, VK-2809, and HP-515; TLR-2 / TLR-4 antagonists such as VB-201 (CI-201); TLR-4 antagonists such as JKB-121, JKB-122, and naltrexone; tyrosine kinase receptor modulators such as CNX-025 and GFE-2137 (repurposed nitazoxanide); TLR-9 antagonists, e.g., GNKS-356, AVO-101; TNF antagonists such as ALF-421; GPCR modulators, e.g., CNX-023; nuclear hormone receptor modulators such as Px-102; VDR agonists, such as CK-15; xanthine oxidase inhibitors such as ACQT-1127; xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001 and RLBN-1127; or Examples include zonulin inhibitors such as lorazotide acetate (INN-202).

[0105] In certain specific embodiments, the one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogen tiparvovec, AMX-342, AN-3015, anti-TAGE antibody, aramchol, ARI-3037MO, ASP-8232, AXA-1125, bertilimumab, betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-05301 1, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dabigatran etexilate methanesulfonate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-Dinitrophenol, DRX-065, DS-102, DUR-928, edaravone (TTYP-01), EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fluasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-30 0, GS-4997, GS-9674, GS-4875, GS-5290, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, hydrochlorothiazide, icosabutate (PRC-4016), icosapentaenoic acid ethyl ester, IMM-124-E, INT-767, INV-240, ION-455, IONIS-DGAT2Rx, ipragliflozin, I Rubesarta, propagermanium, IVA-337, J2H-1702, JKB-121, KB-GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, (LJN-452) (Tropifexor), LM-011, LM-002 (CVI-LM-002), LMB -763, LYN-100, MB-N-008, MBX-8025, 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, Norurusodeoki, Cicholic acid, NV-422, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olesoxime, PAT-505, PAT-048, peg-ilodecaquin, 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, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV-454 78, 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, vismodegib, vorixib ethanol potassium hydroxybenzoate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, XZP-5610, ZGN-839, ZG-5216, ZSYM-008, or ZYSM-007.

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

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

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

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

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

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

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

[0113] CKD / DKD Patients being treated for cardiorenal conditions, such as chronic kidney disease, can benefit from combination drug therapy.

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

[0115] An advantage of the combination may be increased efficacy and / or reduced side effects of one component, as the dosage of that component may be adjusted to reduce its side effects while benefiting from its enhanced efficacy due to the efficacy of the compound of formula (I-VI) and / or other active component.

[0116] Patients presenting with chronic kidney disease treatable with KHK inhibitors, such as the compounds of Formulae (I-VI), may also present a condition that would benefit from the co-administration (as directed by a qualified caregiver) of therapeutic agent(s) that are antibiotics, analgesics, antidepressants, and / or anti-anxiety agents in combination with the compounds of Formulae (I-VI). Combination treatments may be administered simultaneously or sequentially within intervals directed by a qualified caregiver, or via fixed-dose combinations of two or more active agents (all active ingredients combined in a single dosage form, e.g., a tablet).

[0117] In some embodiments, the therapeutic agent or combination of therapeutic agents includes: ACE inhibitors, adenosine A3 receptor antagonists, adropin stimulators, albumin modulators, aldosterone antagonists, AMP-activated protein kinase stimulators, angiotensin II AT-2 receptor agonists, angiotensin II receptor antagonists, angiotensinogen ligand inhibitors, APOA1 gene stimulators, apolipoprotein L1 modulators, bone morphogenetic protein-7 ligand modulators, bromodomain-containing protein 2 inhibitors, bromodomain-containing protein 4 inhibitors, calcium channel inhibitors, cannabinoid CB1 receptor antagonists, CB1 inverse agonists, CCR2 chemokine antagonists, chymase inhibitors, complement C1s subcomponent inhibitors, CX3CR1 chemokine antagonists, cyclooxygenase 1 inhibitors, cyclooxygenase 2 inhibitors, cytochrome P450 11B2 inhibitors, 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 stimulators, heme oxygenase 1 modulators, HIF prolyl hydroxylase inhibitors, IGF1 gene inhibitors, IgG receptor FcRn large subunit p51 modulators, IL-6 receptor antagonists, integrin alpha-V / beta-3 antagonists, interleukin-33 ligand inhibitors, Kelch-like ECH-related proteins Protein 1 modulators, LDHA gene inhibitors, 5-lipoxygenase-activating protein inhibitors, lysophosphatidic acid-1 receptor antagonists, matrix extracellular phosphoglycoprotein modulators, membrane copper amine oxidase inhibitors, midkine ligand inhibitors, mineralocorticoid receptor antagonists, myosin 2 inhibitors, NADPH oxidase 1 inhibitors, NADPH oxidase 4 inhibitors, NADPH oxidase inhibitors, NK1 receptor antagonists, nuclear erythroid 2-related factor 2 stimulators, nuclear factor kappa B inhibitors, opioid receptor kappa agonists, opioid receptor mu antagonists p38 MAP kinase inhibitors, PDE4 inhibitors, PDGF receptor antagonists, PDGF receptor beta modulators, phosphatonin receptor agonists, PRKAA2 gene stimulators, proprotein convertase PC9 inhibitors, prostacyclin (PGI2) agonists, protein C activators, protein NOV homolog modulators, protein tyrosine phosphatase-1B inhibitors, reactive oxygen species modulator inhibitors, renin inhibitors, Rho-associated protein kinase 2 inhibitors, SLC22A12 inhibitors, sodium glucose transporter-2 inhibitors, solute carriers 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, VIP1 receptor agonists, VIP2 receptor agonists, and xanthine oxidase inhibitors, and combinations thereof.

[0118] Non-limiting examples of the one or more additional therapeutic agents include: ACE inhibitors such as benzepari and imidapril, adenosine A3 receptor antagonists such as FM-101, adrophin stimulants such as RBT-2, albumin modulators such as SYNT-002; adenosine / mineralocorticoid receptor antagonists such as MT-3995, allogeneic bone marrow-derived mesenchymal stromal cell therapy, such as ORBCEL-M™; allogeneic expanded adipose-derived stem cell therapy, such as Elixcyte™; AMP-activated protein kinase stimulators / proprotein convertase PC9 inhibitors, such as O-304; AMP-activated protein kinase stimulators such as DZCY-01, MK-8722, and PXL-770; angiotensin II AT-1 receptor / CCR2 chemokine antagonists such as DMX-200; angiotensin II AT-2 receptor antagonists such as MOR-107 and irbesartan; angiotensin II receptor antagonists such as losartan, angiotensinogen ligand inhibitors such as ALN-AGT, anti-C1 antibodies such as BIVV-009 (stimulimab); anti-CB1 antibodies such as GFB-024; anti-CX3CR1 nanobodies such as BI-655088, anti-IL-6 antibodies such as COR-001; anti-VEGF-B antibodies such as CSL-346; APOA1 gene stimulators / bromodomain-containing protein 2 / bromodomain-containing protein 4 inhibitors, such as apabetalone; bone morphogenetic protein-7 ligand modulators, such as BMP-7; calcium channel blockers such as TBN (xiaotongqin); cannabinoid CB1 receptor antagonists, such as JNJ-2463; CB1 inverse agonists such as CRB-4001, chymase inhibitors, such as fulacimstat (BAY-1142524); cyclooxygenase 1 inhibitors, such as GLY-230; cyclooxygenase-2 / epoxide hydrolase inhibitors, such as COX-2 / soluble epoxide hydrolase; cytochrome P450 11B2 inhibitors, such as aldosterone synthase inhibitors; ectonucleotide pyrophosphatase-PDE-2 inhibitors, such as BLD-0409; endothelin ET-A / endothelin ET-B receptor antagonists, such as aprocitentan; enteropeptidase inhibitors, such as SCO-792; erythropoietin receptor antagonists such as EPO-018B, 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- Farnesoid X receptor (FXR) agonists such as 102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, bonafexor (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, and ZG-5266; FGF / PDGF / beta receptor antagonists / p38 MAP kinase inhibitors such as pirfenidone; GHR / IGF1 gene inhibitors such as atesidorsen sodium; GPR40 antagonists / GPR84 antagonists such as PBI-4050; G protein beta subunit inhibitors such as gallon; G protein-coupled receptor 84 modulators, such as PBI-4425; growth hormone ligand / growth hormone receptor agonists such as Jintropin AQ™; growth hormone receptor agonists, such as LAT-8881; guanylate cyclase receptor agonists / guanylate cyclase stimulators such as praliciguat, guanylate cyclase stimulators such as MRL-001 and lancaciguat; heme oxygenase 1 modulators such as RBT-1, HIF prolyl hydroxylase inhibitors such as TRGX-154, insulin sensitizers / kallikrein 1 modulators such as DM-199; integrin alpha-V / beta-3 antagonists such as VPI-2690B; Interleukin-33 ligand inhibitors, such as MEDI-3506; Kelch-like ECH-associated protein 1 modulators / nuclear erythroid 2-related factor 2 stimulators, such as SFX-01; LDHA gene inhibitors such as nedosiran, 5-lipoxygenase-activating protein inhibitors, such as AZD-5718, lysophosphatidic acid-1 receptor antagonists such as BMS-002 and EPGN-696; matrix extracellular phosphoglycoprotein modulators / phosphatonin receptor agonists, such as TPX-200; MEKK-5 protein kinase inhibitors, such as selonsertib, membrane copper amine oxidase inhibitors, such as UD-014; Midkine ligand inhibitors such as CAB-101, mineralocorticoid receptor antagonists such as AZD-9977, esaxerenone, finerenone, and KBP-5074; myosin 2 inhibitors such as DeciMab™; NADPH oxidase 1 inhibitors / NADPH oxidase 4 inhibitors such as setanaxib Agent, NADPH oxidase inhibitors such as APX-115, NK1 receptor antagonists / opioid receptor kappa agonists / opioid receptor mu antagonists such as AV-104, nuclear erythroid 2-related factor 2 stimulators / TGF beta ligand inhibitors, such as CU01-1001; nuclear factor kappa B inhibitors such as mefnidone and bardoxolone methyl (NSC-713200); PDE 4 inhibitors such as ART-648 and PCS-499, PDGF receptor beta modulators such as BOT-191, PDGF / VEGF receptor antagonists such as ANG-3070; PR84 antagonists / GPR40 (FFAR1) / GPR120 (FFAR4) agonists / and partial activators of peroxisome proliferator-activated receptors (PPARs), such as PBI-4547; PRKAA2 gene stimulators / AMPK activators such as PF-06679142 and PF-06685249; prostacyclin (PGI2) agonists such as YS-1402; Protein C activators / glycoprotein Ib (GPIb) antagonists such as AB-002, protein NOV homologue modulators such as BLR-200, protein tyrosine phosphatase-1B inhibitors, such as MSI-1436; reactive oxygen species modulator inhibitors, such as SUL-121; renin inhibitors such as imarikiren hydrochloride, Rho-associated protein kinase 2 inhibitors such as ANG-4201 and RXC-007; sodium glucose transporter-2 inhibitors such as canagliflozin, dapagliflozin propanediol, and empagliflozin; thromboxane A2 receptor antagonists / thromboxane synthesis inhibitors, such as SER-150; tissue transglutaminase inhibitors, such as ZED-1227; TRP cation channel C5 inhibitors such as GFB-887, TRP cation channel C6 inhibitors such as ALGX-2224, urate anion exchanger 1 (URAT1) / SLC22A12 inhibitors, such as verinurad (RDEA3170); VIP1 / VIP2 receptor agonists such as LBT-3627, or Xanthine oxidase inhibitors such as TMX-049 and TMX-049DN.

[0119] In certain embodiments, the one or more therapeutic agents are selected from the group consisting of 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 Enhancement™ (Neo-Kidney Enhancement™), and others. Augment, NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, salvianolic acid, SGF-3, SPD-01, SZ-005, TCF-12, UMC119 ~ 06, VAR-400, Beverimer, VS-105, or XRx-221.

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

[0121] The therapeutic methods disclosed herein can also be applied at any point in the course of the disease. In some embodiments, the methods are applied to subjects suffering from IBD in remission (i.e., inactive disease). In such embodiments, the methods provide benefit 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 methods may be applied to subjects suffering from IBD during the active disease stage. Such methods provide benefit by shortening the duration of the active disease stage, reducing or ameliorating one or more symptoms of IBD, or treating IBD.

[0122] The benefit of the combination can be increased efficacy and / or reduced side effects for the component, as the dose of the component can be adjusted to reduce its side effects while benefiting from its enhanced efficacy due to the efficacy of the compound of the present disclosure.

[0123] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, can be combined with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0124] Examples of agents for the treatment of inflammatory diseases or conditions that can be used in combination with the compounds described herein include: Alpha-fetoprotein modulators, adenosine A3 receptor antagonists, adrenomedullin ligands, AKT1 gene inhibitors, antibiotics, antifungals, ASK1 inhibitors, ATPase inhibitors, beta-adrenoreceptor antagonists, BTK inhibitors, calcineurin inhibitors, carbohydrate metabolism modulators, 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-1beta 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 stimulators, LanC-like protein 2 modulators, leukocyte elastase inhibitors, leukocyte proteinase-3 inhibitors, MAdCAM inhibitors, melanin-concentrating hormone (MCH-1) antagonists, melanocortin agonists, metalloproteinase-9 inhibitors, microbiome-targeting therapeutics, natriuretic peptide receptor C agonists, activin-4 ligands, NLRP3 inhibitors, NKG2 D-activated NK receptor antagonist, NR1H4 receptor (FXR) agonist, nuclear factor kappa B inhibitor, opioid receptor antagonist, OX40 ligand inhibitor, oxidoreductase inhibitor, P2X7 purinoceptor modulator, PDE4 inhibitors, Pellino homolog 1 inhibitors, PPARα / δ agonists, PPARγ agonists, protein arginine deiminase IV inhibitors, protein fimH inhibitors, P-selectin glycoprotein ligand-1 inhibitors, Ret tyrosine kinase receptor inhibitors, RIP-1 kinase inhibitors, RIP-2 kinase inhibitors, RNA polymerase inhibitors, sphingosine 1 phosphate phosphatase 1 stimulators, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-5 agonists, sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate fate 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, TNFα ligand inhibitors, TNF ligand inhibitors, TNFα 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, vanilloid VR1 agonists, or zonulin inhibitors, and combinations thereof.

[0125] Included herein are methods of treatment in which the compounds described herein are administered in combination with anti-inflammatory agents, including, but not limited to, NSAIDs, nonspecific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

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

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

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

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

[0130] Included herein are methods of treatment in which a compound described herein is administered in combination with an immunosuppressant, hi some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, mycophenolate sodium, mercaptopurine, or mycophenolate mofetil.

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

[0132] In some embodiments, the disease or condition includes chronic kidney disease (CKD), diabetic kidney disease (DKD), kidney disease, renal fibrosis, renal insufficiency, acute kidney injury, tubular dysfunction, lupus nephritis, 2,8-dihydroxyadenine nephropathy, renal transplant rejection, Fanconi syndrome. induce kidney protection against drugs, 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), ulcerative colitis, Crohn's disease, hyperuricemia, gout, arthritis, osteoporosis or cancer.

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

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

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

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

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

[0138] The compounds of the present disclosure or pharmaceutically acceptable salts thereof for the treatment of KHK-mediated diseases or conditions. Salts or stereoisomers are also disclosed.Also disclosed are compounds of the present disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, for the prevention of KHK-mediated diseases or conditions. [Example]

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

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

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

[0142] Exemplary chemicals useful in the methods of the embodiments will now be described by reference to exemplary synthetic schemes for their general preparation herein and the specific examples below. To obtain the various compounds herein, the skilled artisan will recognize that starting materials can be appropriately selected to obtain the desired product such that the ultimately desired substituents are carried through the reaction scheme, with or without protection as necessary. Alternatively, it may be desirable to use, in place of the ultimately desired substituent, a suitable group that can be carried through the reaction scheme and appropriately replaced with the desired substituent. Furthermore, one skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the pendant groups.

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

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

[0145] In some embodiments, the present disclosure generally provides a particular enantiomer or diastereomer as the desired product, but the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is derived without indicating the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

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

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

[0148] Abbreviation Certain abbreviations and acronyms are used in describing the 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.

[0149] [Table 1-1]

[0150] [Table 1-2]

[0151] [Table 1-3]

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

[0153] [ka]

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

[0155] [ka]

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

[0157] [ka]

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

[0159] [ka]

[0160] (2S,3R)-1-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ylbenzoate The title compound was prepared in a similar manner to 2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol using (2S,3R)-2-methylazetidin-3-ylbenzoate instead of (2S)-2-methylazetidine hydrochloride.

[0161] [ka]

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

[0163] [ka]

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

[0165] General method The general methods represent the most commonly used methods, but were sometimes performed with slight modifications, including reaction time courses and temperatures.

[0166] The solvent is typically 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 is typically Pd(PPh 34 , Pd(dppf)Cl, Pd(OAc), PdCl, PdXPhos G1, G2, G3, or G4 precatalyst, PdSPhos G1, G2, G3, or G4 precatalyst, or Pddba with or without a phosphine ligand selected from, but not limited to, SPhos, XPhos, RuPhos, XantPhos, PCy, PPh, or dppf. The base is generally selected from, but is not limited to, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, cesium fluoride, triethylamine, diisopropylethylamine, or pyridine.

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

[0168] General method A:

[0169] [ka]

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

[0171] General method B:

[0172] [ka]

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

[0174] General method C:

[0175] [ka]

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

[0177] General method D:

[0178] [ka]

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

[0180] General method E:

[0181] [ka]

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

[0183] General method F:

[0184] [ka]

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

[0186] General method G:

[0187] [ka]

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

[0189] General method H:

[0190] [ka]

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

[0192] [ka]

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

[0194] [ka]

[0195] 3-(2-(methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-yl)benzamide The title compound was prepared in a 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 in place of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.

[0196] [ka]

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

[0198] [ka]

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

[0200] General method I:

[0201] [ka]

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

[0203] General method J:

[0204] [ka]

[0205] (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide A vial was charged with (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (30 mg, 0.10 mmol, 1.0 equiv), EtOH (1 mL), and NaOH (2 M aqueous solution, 0.5 mL) and heated to 90° C. for 1 h. The reaction mixture was concentrated and subjected to HPLC (0.1% TFA in MeCN-0.1% TFA in HO) to give S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide and S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid.

[0206] General method K:

[0207] [ka]

[0208] (S)-1-Methyl-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)-1H-imidazole-4-sulfonamide A vial was charged with (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline (15 mg, 0.054 mmol, 1.0 equiv.), 4-dimethylaminopyridine (1 mg, 0.0054 mmol, 10 mol%), EtN (0.022 mL, 0.16 mmol, 3.0 equiv.), and DCM (1 mL). 1-Methylimidazole-4-sulfonyl chloride (15 mg, 0.080 mmol, 1.5 equiv.) was then 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 HO) to provide the title compound.

[0209] General method L:

[0210] [ka]

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

[0212] General method M:

[0213] [ka]

[0214] 4-(7,7-Difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide 4-(7,7-Difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide was prepared in a 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, respectively.

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

[0216] General method N:

[0217] [ka]

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

[0219] General method O:

[0220] [ka]

[0221] 3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzaldehyde The title compound was prepared in a similar manner 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.

[0222] [ka]

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

[0224] General method P:

[0225] [ka]

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

[0227] [ka]

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

[0229] [ka]

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

[0231] General method Q:

[0232] [ka]

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

[0234] [ka]

[0235] (S)-8-Bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one A vial was charged with methyl (S)-4-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate (672 mg, 1.73 mmol), TFA (2 mL), and DCM (2 mL). The mixture was stirred at ambient temperature for 30 minutes and then concentrated in vacuo. The residue was dissolved in EtOAc and washed with NaHCO (sat. aq.). The organic layer was dried over NaSO, filtered, and concentrated. The resulting residue was dissolved in PhMe (4 mL) and heated to 110 °C for 18 hours. The mixture was concentrated, and the residue was subjected to flash column chromatography (ethyl acetate-hexanes) to give (S)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.

[0236] General method R:

[0237] [ka]

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

[0239] General method S:

[0240] [ka]

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

[0242] 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 aqueous solution) was added and the mixture was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was subjected to flash column chromatography (hexane-ethyl acetate) to obtain the desired product.

[0243] [ka]

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

[0245] General method:

[0246] [ka]

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

[0248] General method U:

[0249] [ka]

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

[0251] General method V:

[0252] [ka]

[0253] 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-1-one oxime In a flask, 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol A mixture of methylpropane (1.00 g, 4.37 mmol), NaOAc-(HO) (2.97 g, 21.8 mmol), and MeOH (20 mL) was charged. Hydroxylamine hydrochloride (1.52 g, 21.8 mmol) was added, and the mixture was fitted with a reflux condenser and heated to reflux for 1 h. The mixture was concentrated, and 20 mL of HO was added. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over NaSO and filtered to give the title product.

[0254] [ka]

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

[0256] General method W:

[0257] [ka]

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

[0259] [ka]

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

[0261] General method X:

[0262] [ka]

[0263] 7-Bromospiro[chroman-4,4'-imidazolidine]-2',5'-dione A flask was charged with 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 HO (10 mL). The flask was fitted with a reflux condenser and heated to 90 °C for 3 days. The mixture was cooled to ambient temperature and the pH was adjusted to 6 with HCl (aq, 6 M). The resulting solid was collected by filtration, washed with HO, and dried under vacuum to provide the title compound.

[0264] General method Y:

[0265] [ka]

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

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

[0268] General method Z:

[0269] [ka]

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

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

[0272] General method AA:

[0273] [ka]

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

[0275] [ka]

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

[0277] General method AB:

[0278] [ka]

[0279] tert-Butyl N-(6-bromo-1.1.-dioxo-2.3-dihydrobenzothiophen-3-yl)carbamate To a solution of 6-bromo-1,1-dioxo-2,3-dihydrobenzothiophen-3-amine (400 mg, 1.5 mmol) in tetrahydrofuran (8.3 mL) were added triethylamine (0.425 mL, 3 mmol) and tert-butoxycarbonyl tert-butyl carbonate (400 mg, 1.8 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. It was diluted with ethyl acetate and washed with 10% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride solutions. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography (hexane-ethyl acetate) to give the title compound.

[0280] General method AC:

[0281] [ka]

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

[0283] General method AD:

[0284] [ka]

[0285] (5S)-5'-Bromo-3-methyl-spiro[imidazolidine-5,1'-indan]-2,4-dione To a suspension of (5S)-5'-bromospiro[imidazolidine-5,1'-indan]-2,4-dione (100 mg, 0.36 mmol) and potassium carbonate (49 mg, 0.36 mmol) was added methyl iodide (0.022 mL, 0.36 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours. It was precipitated by the addition of water, and the solid was collected, washed with water, and dried under vacuum to give the title compound.

[0286] General method AE:

[0287] [ka]

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

[0289] [ka]

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

[0291] [ka]

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

[0293] General method AF:

[0294] [ka]

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

[0296] General method AG:

[0297] [ka]

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

[0299] General method AH:

[0300] [ka]

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

[0302] General method AI:

[0303] [ka]

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

[0305] Compound example

[0306] [ka]

[0307] Example 1: Methyl (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate The title compound was prepared in a manner similar to general method A, using methyl 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0308] [ka]

[0309] Example 2: Methyl (S)-3-(2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate The title compound was prepared in a manner similar to general method A, using methyl 3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0310] [ka]

[0311] Example 3: Methyl (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetate The title compound was prepared in a manner similar to general method A, using methyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0312] [ka]

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

[0314] [ka]

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

[0316] [ka]

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

[0318] [ka]

[0319] Example 7: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzonitrile The title compound was prepared in a manner similar to general method A, using (3-cyanophenyl)boronic acid instead of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0320] [ka]

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

[0322] [ka]

[0323] Example 10: (S)-2-(2-methylazetidin-1-yl)-4-phenyl-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine The title compound was prepared in a manner similar to general method A, 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, followed by a manner similar to general method B.

[0324] [ka]

[0325] Example 11: (S)-1-Methyl-5-(2-methylazetidin-1-yl)-7-phenyl-1H-pyrazolo[4,3-d]pyrimidine The title compound was prepared in a manner similar to general method A, using phenylboronic acid and 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a manner similar to general method B.

[0326] [ka]

[0327] Example 12: (S)-2-(2-methylazetidin-1-yl)-4-phenylfuro[3,2-d]pyrimidine The title compound was prepared in a manner similar to general method A, using phenylboronic acid and 2,4-dichlorofuro[3,2-d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a manner similar to general method B.

[0328] [ka]

[0329] Example 13: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole 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)isothiazole in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0330] [ka]

[0331] Example 14: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole The title compound was prepared in a manner similar to general method A, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0332] [ka]

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

[0334] [ka]

[0335] Example 16: (S)-2-(2-methylazetidin-1-yl)-4-(pyridin-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method A, using pyrimidin-5-ylboronic acid instead of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0336] [ka]

[0337] Example 17: (S)-4-(1-methyl-1H-pyrazol-3-yl)-2-(2- Methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method A, using 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0338] [ka]

[0339] Example 18: (S)-2-(2-methylazetidin-1-yl)-4-(1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method A, using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate instead of 3-pyridylboronic acid, followed by a manner similar to general method B. In the first step, the tert-butyl carboxylate was cleaved under the reaction conditions.

[0340] [ka]

[0341] Example 19: (S)-2-(2-methylazetidin-1-yl)-4-(1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method A, using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate instead of 3-pyridylboronic acid, followed by a manner similar to general method B. In the first step, the tert-butyl carboxylate was cleaved under the reaction conditions.

[0342] [ka]

[0343] Example 20: (S)-4-(1-methyl-1H-pyrazol-5-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine In a similar manner to general method A, 1-methyl-5-(4-pyridylboronic acid was used instead of 3-pyridylboronic acid. The title compound was prepared using (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole, following a similar procedure to general method B.

[0344] [ka]

[0345] Example 21: (S)-2-(2-methylazetidin-1-yl)-4-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine A vial was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1.0 equiv.), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (60.7 mg, 0.30 mmol, 1.4 equiv.), Pd(dppf)Cl-DCM complex (8.8 mg, 0.011 mmol, 5 mol%), CuCl (20.9 mg, 0.21 mmol, 1 equiv.), CsCO (138 mg, 0.42 mmol, 2.0 equiv.), and DMF (2 mL). The mixture was sparged with argon and heated to 100 °C for 24 h. The mixture was concentrated and subjected to flash column chromatography (hexane-ethyl acetate) to give 2-chloro-4-(2-pyridyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by general procedure B to give the title compound.

[0346] [ka]

[0347] Example 22: (S)-2-(2-methylazetidin-1-yl)-4-(pyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine A vial was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1.0 equiv.), 4-pyridylboronic acid (60.7 mg, 0.30 mmol, 1.4 equiv.), Pd(dppf)Cl-DCM complex (8.8 mg, 0.011 mmol, 5 mol%), CuCl (20.9 mg, 0.21 mmol, 1 equiv.), CsCO (138 mg, 0.42 mmol, 2.0 equiv.), and DMF (2 mL). The mixture was sparged with argon and heated to 100 °C for 24 h. The mixture was concentrated and subjected to flash column chromatography (hexane-ethyl acetate) to give 2-chloro-4-(2-pyridyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by general procedure B to give the title compound.

[0348] [ka]

[0349] Example 23: (S)-4-(1-methyl-1H-pyrazol-4-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method A, using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0350] [ka]

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

[0352] [ka]

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

[0354] [ka]

[0355] Example 26: (S)-5-(2-methylazetidin-1-yl)-7-phenylthiazolo[5,4-d]pyrimidine The title compound was prepared in a manner similar to general method A, using phenylboronic acid and 5,7-dichlorothiazolo[5,4-d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a manner similar to general method B.

[0356] [ka]

[0357] Example 27: (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide 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)benzamide in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0358] [ka]

[0359] Example 28: (S)—N-methyl-3-(2-(2-methylazetidin-1-yl)- 6,7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method A, using [3-(methylcarbamoyl)phenyl]boronic acid in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0360] [ka]

[0361] Example 29: (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propenamide A vial was charged with methyl 3-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]propanoate (35 mg, 0.10 mmol, 1.0 equiv), EtOH (1 mL), and NHOH (25% aqueous solution, 2 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to ambient temperature, concentrated, and subjected to HPLC to provide the title compound.

[0362] [ka]

[0363] Example 30: 6-Cyclopropyl-2-((S)-2-methylazetidin-1-yl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method H, 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.

[0364] [ka]

[0365] Example 31: 2-((S)-2-methylazetidin-1-yl)-4-phenyl-5, 6,7,8-Tetrahydro-5,8-methanoquinazoline 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 and phenylboronic acid instead of (3-carbamoylphenyl)boronic acid.

[0366] [ka]

[0367] Example 32: 3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method A, using (3-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride instead of (2S)-2-methylazetidine (R)-camphorsulfonate.

[0368] [ka]

[0369] Example 33: 3-(2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydro-5,8-methanoquinazolin-4-yl)benzamide The title compound was prepared in a similar manner to general method H, using methyl 3-oxobicyclo[3.1.0]heptane-2-carboxylate instead of 2-oxobicyclo[2.2.1]hexane-3-carboxylate.

[0370] [ka]

[0371] Example 34: (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiazole In a similar manner to general method A, 2-methyl-5-(4-pyridylboronic acid was used instead of 3-pyridylboronic acid. The title compound was prepared using (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole, following a similar procedure to general method B.

[0372] [ka]

[0373] Example 35: (S)-1-Methyl-5-(2-methylazetidin-1-yl)-7-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidine The title compound was prepared in a manner similar to general method A, 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)pyrazole-1-carboxylate instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a manner similar to general method B. In the first step, the tert-butyl carboxylate was cleaved under the reaction conditions.

[0374] [ka]

[0375] Example 36: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiazole The title compound was prepared in a similar manner to general procedure E, using tributyl(thiazol-4-yl)stannane in place of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate.

[0376] [ka]

[0377] Example 37: (S)-3-(1-methyl-5-(2-methylazetidin-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)benzenesulfonamide In a similar manner to general method A, 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide were used in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively. , followed by a method similar to general method B to prepare the title compound.

[0378] [ka]

[0379] Example 38: 3-(5-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)benzenesulfonamide The title compound was 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 in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride in place of (2S)-2-methylazetidine.

[0380] [ka]

[0381] Example 39: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazole 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)-1H-indazole in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0382] [ka]

[0383] Example 40: (S)—N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetamide In a similar manner to general method A, 3-acetamidophenylboronic acid was used instead of 3-pyridylboronic acid. The title compound was prepared using (methyl)boronic acid followed by a method similar to general method B.

[0384] [ka]

[0385] Example 41: N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetamide 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 a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride instead of (2S)-2-methylazetidine (R)-camphorsulfonate.

[0386] [ka]

[0387] Example 42: (S)—N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanesulfonamide The title compound was prepared in a manner similar to general method A, using [3-(methanesulfonamido)phenyl)boronic acid in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0388] [ka]

[0389] Example 43: N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanesulfonamide In a similar manner to general method A, 3-pyridylboronic acid was replaced with [3-(methanesulfonyl)boronic acid]. The title compound was prepared using (2S,3R)-2-methylazetidin-3-ol hydrochloride in place of (2S)-2-methylazetidine (R)-camphorsulfonate in a manner similar to general method B.

[0390] [ka]

[0391] Example 44: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazole The title compound was prepared in a manner similar to general method A, using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0392] [ka]

[0393] Example 45: (S)-2-(2-methylazetidin-1-yl)-4-(thiophen-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method E, using 5-tributylstannylthiophene-2-carbonitrile in place of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general method B, using 2-chloro-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0394] [ka]

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

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

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

[0398] [ka]

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

[0400] [ka]

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

[0402] [ka]

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

[0404] [ka]

[0405] Example 50: (S)-2-(2-methylazetidin-1-yl)-4-(4-(piperazin-1-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (S)-tert-Butyl 4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate was reacted in a similar manner to general procedure A to afford (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl Using 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, respectively, followed by a procedure similar to general method I, the title compound was obtained.

[0406] [ka]

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

[0408] [ka]

[0409] Example 52: (S)—N-(2-aminoethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method I, using tert-butyl (S)-(2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamido)ethyl)carbamate in place of (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate.

[0410] [ka]

[0411] Example 53: (S)—N-(2-(methylamino)ethyl)-3-(2-(2-methyl) Azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and tert-butyl(2-aminoethyl)(methyl)carbamate in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, followed by a manner similar to method I.

[0412] [ka]

[0413] Example 54: (S)—N-(2-hydroxyethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was prepared in a similar manner to general procedure F, using 3-bromo-N-(2-hydroxyethyl)benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0414] [ka]

[0415] Example 55: (S)-2-(2-methylazetidin-1-yl)-4-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a similar manner to general method A, using (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.

[0416] [ka]

[0417] Example 56: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide The title compound was prepared according to general method J, using (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carbonitrile instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzonitrile.

[0418] [ka]

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

[0420] [ka]

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

[0422] [ka]

[0423] Example 59: N-((1S * ,2S * )-2-Hydroxycyclobutyl)-3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In a similar manner to general method G, (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and rac-(1S * ,2S * The title compound was prepared using 2-aminocyclobutanol.

[0424] [ka]

[0425] Example 60: N-((1S * ,2R *)-2-Hydroxycyclobutyl)-3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide In a similar manner to general method G, (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and rac-(1S * ,2R * The title compound was prepared using 2-aminocyclobutanol.

[0426] [ka]

[0427] Example 61: (S)—N-(2-hydroxyethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and ethanolamine in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0428] [ka]

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

[0430] [ka]

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

[0432] [ka]

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

[0434] [ka]

[0435] Example 66: (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)glycine The title compound was prepared in a manner similar to general method G using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl glycine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, followed by a manner similar to general method C.

[0436] [ka]

[0437] Example 67: (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide)cyclopropane-1-carboxylic acid The title compound was prepared in a manner similar to general method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl 1-aminocyclopropane-1-carboxylate hydrochloride in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, followed by a manner similar to general method C.

[0438] [ka]

[0439] Example 68: (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidine-3-carboxylic acid The title compound was prepared in a similar manner to general method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl azetidine-3-carboxylate hydrochloride in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, followed by a similar manner to general method C.

[0440] [ka]

[0441] Example 69: (S)-2-(1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidin-3-yl)acetic acid The title compound was prepared in a manner similar to general method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl 2-(azetidin-3-yl)acetate trifluoroacetate in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, followed by a similar procedure to general method C.

[0442] [ka]

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

[0444] To a vial containing tert-butyl (S)-2-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazol-3-yl)acetate was added TFA (0.5 mL) and DCM (0.5 mL). 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 HO) to provide the title compound.

[0445] [ka]

[0446] Example 71: (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole The title compound was prepared in a manner similar to general method A, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0447] [ka]

[0448] Example 72: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide The title compound was prepared in a similar manner to general procedure F, using 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0449] [ka]

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

[0451] [ka]

[0452] Example 74: (S)-((3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)sulfonyl)glycine The title compound was prepared in a manner similar to general method K, using 3-bromobenzenesulfonyl chloride and methyl glycinate in place of 1-methylimidazole-4-sulfonyl chloride and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline, respectively, followed by general method F, using methyl ((3-bromophenyl)sulfonyl)glycinate in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, followed by general method C.

[0453] [ka]

[0454] Example 75: (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzyl)isothiazolidine 1,1-dioxide In a manner similar to general procedure D, (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used in place of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general procedure E to obtain 2-(3-bromobenzyl)isothiazolidine 1,1-dioxide. was used in place of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine to make the title compound.

[0455] [ka]

[0456] Example 76: (S)-3,5-dimethyl-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)isoxazole-4-sulfonamide The title compound was prepared in a similar manner to general method K, using 3,5-dimethylisoxazole-4-sulfonyl chloride instead of 1-methylimidazole-4-sulfonyl chloride.

[0457] [ka]

[0458] Example 77: (S)-1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidine-2-carboxylic acid The title compound was prepared in a manner similar to general method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl (S)-azetidine-2-carboxylate hydrochloride in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, followed by a manner similar to general method C.

[0459] [ka]

[0460] Example 78: (R)-1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoyl)a Zetidine-2-carboxylic acid The title compound was prepared in a manner similar to general method G, using (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl (R)-azetidine-2-carboxylate hydrochloride in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, followed by a manner similar to general method C.

[0461] [ka]

[0462] Example 79: (rac)-3-(2-(6-azabicyclo[3.2.0]heptan-6-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was 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]pyrimidin-4-yl)benzenesulfonamide in place of (2S)-2-methylazetidine 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0463] [ka]

[0464] Example 80: (rac)-3-(2-((1S * ,5S * ,6R * )-6-Hydroxy-2-azabicyclo[3.2.0]heptan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide In a similar manner to general method B, (rac)-(1S)-azetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively. * ,5S * ,6R * The title compound was prepared using 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide.

[0465] [ka]

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

[0467] [ka]

[0468] Example 82: 2-(N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)acetic acid The title compound was prepared in a manner similar to general method A, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in place of 3-pyridylboronic acid, followed by general method K, using ethyl 2-(chlorosulfonyl)acetate in place of 1-methylimidazole-4-sulfonyl chloride, followed by general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (2S)-2-methylazetidine, followed by general method C.

[0469] [ka]

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

[0471] [ka]

[0472] Example 84: (S)—N-(5-(N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)thiazol-2-yl)acetamide The title compound was prepared in a similar manner to general method K, using 2-acetamidothiazole-5-sulfonyl chloride instead of 1-methylimidazole-4-sulfonyl chloride.

[0473] [ka]

[0474] Example 85: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isothiazole-3-carboxamide The title compound was prepared in a similar manner to general method F, using 5-bromoisothiazole-3-carboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0475] [ka]

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

[0477] [ka]

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

[0479] [ka]

[0480] Example 88: (S)-2-(2-methylazetidin-1-yl)-4-(3-((methylsulfonyl)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine 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-benzothiazol-3-one. The in situ decarboxylated oxide was the only product.

[0481] [ka]

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

[0483] [ka]

[0484] Example 91: (S)—N-(2-hydroxyethyl)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a similar manner to general method A, using (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine 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, respectively.

[0485] [ka]

[0486] Example 92: (R)-3-(2-(2-(hydroxymethyl)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was prepared in a manner similar to general method B, using (R)-azetidin-2-ylmethanol and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide in place of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0487] [ka]

[0488] Example 93: 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method B, using tert-butyl ((2S,3R)-2-methylazetidin-3-yl)carbamate hydrochloride and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide in place of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a manner similar to general method I.

[0489] [ka]

[0490] Example 94: (R)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one In a manner similar to general procedure Q, using tert-butyl (S)-(2-hydroxypropyl)carbamate instead of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate, followed by a manner similar to general procedure F, using (R)-8-bromo-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by a procedure similar to general procedure F, using (R)-8-bromo-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by a procedure similar to general procedure F The title compound was prepared in a manner similar to Method M followed by General Method B using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0491] [ka]

[0492] Example 95: (R)-4-(2-(2-(hydroxymethyl)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method B, using (R)-azetidin-2-ylmethanol and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide in place of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0493] [ka]

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

[0495] [ka]

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

[0497] [ka]

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

[0499] [ka]

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

[0501] [ka]

[0502] Example 100: (S)-2-methyl-5-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)-1,3,4-oxadiazole The title compound was prepared in a similar manner to general method F, using 4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]boronic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0503] [ka]

[0504] Example 101: (S)-4-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a similar manner to general method F, using [4-(1-methylimidazol-2-yl)phenyl]boronic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0505] [ka]

[0506] Example 102: (S)-4-(4-(1H-pyrazol-1-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a similar manner to general method F, using (4-pyrazol-1-ylphenyl)boronic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0507] [ka]

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

[0509] [ka]

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

[0511] [ka]

[0512] Example 105: 4-(2-(2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method B, using 2,3-dimethylazetidine hydrochloride and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0513] [ka]

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

[0515] [ka]

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

[0517] [ka]

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

[0519] [ka]

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

[0521] [ka]

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

[0523] [ka]

[0524] Example 115: 1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)bicyclo[2.1.1]hexane-5-carboxylic acid The title compound was prepared in a 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-benzothiazol-3-one. The in situ decarboxylated oxide was the only product.

[0525] [ka]

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

[0527] [ka]

[0528] Example 117: 4-(2-(2-methyl-3-oxocyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a 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]pyrimidin-4-yl)benzamide in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0529] [ka]

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

[0531] [ka]

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

[0533] [ka]

[0534] Example 120: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indazol-3-ol The title compound was prepared in a manner similar to general method D, using 6-bromo-1H-indazol-3-ol instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general method E.

[0535] [ka]

[0536] Example 121: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)imidazo[2,1-b]thiazole In a manner similar to general method D, 2-bromoimidazo[2,1-b]thiazole was used. , followed by a method similar to general method E to prepare the title compound.

[0537] [ka]

[0538] Example 122: (S)-2-Fluoro-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was prepared in a similar manner to general method F, using 5-bromo-2-fluoro-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0539] [ka]

[0540] Example 123: (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was prepared in a similar manner to general method F, using 5-bromo-2-methyl-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0541] [ka]

[0542] Example 124: (S)-4-(3-(2-methylazetidin-1-yl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-trien-5-yl)benzamide In a manner similar to general procedure A, using 5-chloro-3-(methylsulfonyl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene and (4-carbamoylphenyl)boronic acid in place of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, followed by a manner similar to general procedure B: The title compound was prepared.

[0543] [ka]

[0544] Example 125: 4-(3-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-trien-5-yl)benzamide 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 in place of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (2S)-2-methylazetidine.

[0545] [ka]

[0546] Example 126: (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(trifluoromethoxy)benzenesulfonamide The title compound was prepared in a similar manner to general procedure F, using 5-bromo-2-(trifluoromethoxy)benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0547] [ka]

[0548] Example 127: (S)-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-ol The title compound was prepared in a manner similar to general method A, using 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-ol and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0549] [ka]

[0550] Example 128: (S)-4-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method M followed by general method B.

[0551] [ka]

[0552] Example 129: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method M followed by general method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.

[0553] [ka]

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

[0555] [ka]

[0556] Example 131: (S)-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine The title compound was prepared in a similar manner to general method A using tert-butyl N-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]carbamate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a similar manner to method I.

[0557] [ka]

[0558] Example 132: (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinolin-2(1H)-one In a manner similar to general procedure A, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-quinolin-2-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]piperidin were prepared. The title compound was prepared using pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0559] [ka]

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

[0561] [ka]

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

[0563] [ka]

[0564] Example 135: 2-(5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro- 1H-inden-2-yl)acetamide The title compound was prepared in a manner similar to general method G, using 2-(5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-2-yl)acetic acid in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[0565] [ka]

[0566] Example 136: 4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid The title compound was prepared in a similar manner 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-benzothiazol-3-one.

[0567] [ka]

[0568] Example 137: (1R, 1aR * ,6aS * )-4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide Example 138: (1S, 1aR * ,6aS *)-4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide The title compound was prepared in a manner similar to general method G, using 4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid. The isomers were separated by HPLC (0.1% TFA in MeCN-0.1% TFA in HO).

[0569] [ka]

[0570] Example 139: 5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid The title compound was prepared in a similar manner to general method F, using 5-bromoindan-2-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0571] [ka]

[0572] Example 140: 5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxamide The title compound was prepared in a manner similar to general method G, using 5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carboxylic acid in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[0573] [ka]

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

[0575] [ka]

[0576] Example 142: 4-(2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method B, using pyrrolidine and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide in place of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0577] [ka]

[0578] Example 143: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinolin-2-amine The title compound was prepared in a similar manner to general method A, using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0579] [ka]

[0580] Example 144: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1-naphthamide The title compound was prepared in a manner similar to general method A, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthamide and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0581] [ka]

[0582] Example 145: (3R,4S)-1-acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)pyrrolidine-3-carboxylic acid In a vial, methyl(rac)-(3R * ,4S * )-4-(3-bromophenyl)pyrrolidine-3-carboxylate (500 mg, 1.56 mmol, 1.0 equiv), EtN (0.87 mL, 6.24 mmol, 4.0 equiv), and DCM (10 mL) were added. Acetic anhydride (0.30 mL, 3.12 mmol, 2.0 equiv) 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 give methyl 1-acetyl-4-(3-bromophenyl)pyrrolidine-3-carboxylate (235 mg, 0.72 mmol).

[0583] The title compound was prepared in a manner similar to general method F, using 1-acetyl-4-(3-bromophenyl)pyrrolidine-3-carboxylate instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, followed by a manner similar to general method C.

[0584] [ka]

[0585] Example 146: (3R * ,4S * )-1-acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)pyrrolidine-3-carboxamide In a similar manner to general method G, 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid was replaced with (3R * ,4S * The title compound was prepared using 4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)pyrrolidine-3-carboxylic acid.

[0586] [ka]

[0587] Example 147: (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinazoline-2,4-diamine The title compound was prepared in a similar manner to general method F, using 7-bromoquinazoline-2,4-diamine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0588] [ka]

[0589] Example 148: 7'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carboxylic acid The title compound was prepared in a similar manner to general method F, using 7'-bromo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carboxylic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0590] [ka]

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

[0592] [ka]

[0593] Example 150: (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one The title compound was prepared in a similar manner to general method A, using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0594] [ka]

[0595] Example 151: (S)-4-(1H-indol-2-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method A, using (1-tert-butoxycarbonylindol-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, followed by a manner similar to general method I.

[0596] [ka]

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

[0598] [ka]

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

[0600] [ka]

[0601] Example 155: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-4-carboxylic acid In a similar manner to general method A, 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine were replaced with (1-tert-bromo-2-methyl-2-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively. The title compound was prepared using (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in a manner similar to general method I and general method C.

[0602] [ka]

[0603] Example 156: (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-4-carboxamide The title compound was prepared in a manner similar to general method G, using (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-4-carboxylic acid in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.

[0604] [ka]

[0605] Example 157: (S)-4-(8,8-difluoro-2-(2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)benzamide The title compound was prepared in a manner similar to general method M, 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]pyrimidin-4-yl)benzamide, followed by a manner similar to general method B.

[0606] [ka]

[0607] Example 158: 4-(8,8-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)benzamide The title compound was prepared in a manner similar to general method M, using 4-chloro-8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazoline in place of 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0608] [ka]

[0609] Example 159: (2S,3R)-1-(4-(4-(3-aminooxetan-3-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol The title compound was prepared in a manner similar to general method I, using tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate in place of 3-pyridylboronic acid, followed by general method B using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0610] [ka]

[0611] Example 160: (S)-3-(4-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine 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-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of (4-carbamoylphenyl)boronic acid, followed by general methods B and I.

[0612] [ka]

[0613] Example 161: (2S,3R)-1-(4-(4-(3-aminooxetan-3-yl)phenyl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol The title compound was prepared in a manner similar to general method I, using tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate in place of (4-carbamoylphenyl)boronic acid, followed by general method B using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0614] [ka]

[0615] Example 162: 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid The title compound was prepared in a manner similar to general method A, using 4-boronobenzoic acid instead of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.

[0616] [ka]

[0617] Example 163: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isoquinoline The title compound was prepared in a manner similar to general method A, using 6-isoquinolylboronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0618] [ka]

[0619] Example 164: 8-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one 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]oxazepin-5(2H)-one in place of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0620] [ka]

[0621] Example 165: (S)-8-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one In a similar manner to general method M, 8- The title compound was prepared using (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one followed by a method similar to general method B.

[0622] [ka]

[0623] Example 166: 8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one The title compound was prepared in a manner similar to general method M, using 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one in place of (4-carbamoylphenyl)boronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0624] [ka]

[0625] Example 167: (S)-4-(2-(1-methylisoindolin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method B, using (S)-1-methylisoindoline and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide in place of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0626] [ka]

[0627] Example 168: 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)picolinamide The title compound was prepared in a manner similar to general method M, using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide in place of (4-carbamoylphenyl)boronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0628] [ka]

[0629] Example 169: 4-(2-((2S,3S)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method A, using (4-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and subsequently in a manner similar to general method B, using (2S,3S)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.

[0630] [ka]

[0631] Example 170: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-ethoxybenzamide The title compound was prepared in a manner similar to general method M, using 2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in place of (4-carbamoylphenyl)boronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0632] [ka]

[0633] Example 171: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylbenzamide The title compound was prepared in a manner similar to general method M, using N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in place of (4-carbamoylphenyl)boronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0634] [ka]

[0635] Example 172: 4-(2-(4-(hydroxymethyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method A, using (4-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol instead of (S)-2-methylazetidine.

[0636] [ka]

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

[0638] [ka]

[0639] Example 174: 4-(2-(2,3-dihydro-1H-imidazo[1,5-a]imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in 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]pyrazole.

[0640] [ka]

[0641] Example 175: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)quinolin-2-ol The title compound was prepared in a similar manner to general method A, using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0642] [ka]

[0643] Example 176: 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-5,7-methanecyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method H, using ethyl 3-oxobicyclo[3.1.0]hexane-2-carboxylate and (3-carbamoylphenyl)boronic acid instead of methyl 2-oxobicyclo[2.1.1]hexane-3-carboxylate and (4-carbamoylphenyl)boronic acid, respectively.

[0644] [ka]

[0645] Example 177: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxybenzamide The title compound was prepared in a manner similar to general method M, using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in place of (4-carbamoylphenyl)boronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0646] [ka]

[0647] Example 178: 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one In a similar manner to general procedure D, using 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one in place of ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a similar manner to general procedure E, using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of (S)-4-chloro-2-(2-methylazepin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by general procedure M. The title compound was prepared in a similar manner using 7-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one in place of 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, followed by a similar procedure to general method B using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0648] [ka]

[0649] Example 179: (S)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one The title compound was prepared according to general method Q, followed by general method F, using (S)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by general method M, followed by general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0650] [ka]

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

[0652] [ka]

[0653] Example 181: 2-acetamido-4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide The title compound was prepared in a manner similar to general method M, using 2-acetamido-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in place of (4-carbamoylphenyl)boronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0654] [ka]

[0655] Example 182: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(difluoromethoxy)benzamide In a similar manner to general procedure F, methyl 4-bromo-2-(difluoromethoxy)benzoate and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine were used in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by a similar manner to general procedure M to obtain 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. The title compound was prepared in a manner similar to general method C and G, using methyl 4-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide in place of (7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, followed by general method B, and using (2S,3R)-2-methylazetidin-3-ol in place of (S)-2-methylazetidine.

[0656] [ka]

[0657] Example 183: 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(trifluoromethoxy)benzamide The title compound was prepared in a manner similar to general method M, using methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-methylazetidine, followed by general methods C and G.

[0658] [ka]

[0659] Example 184: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1H-indole-2-carboxamide The title compound was prepared in a similar manner to general method A, using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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.

[0660] [ka]

[0661] Example 185: 4-[4-(1H-imidazol-2-yl)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a similar manner 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.

[0662] [ka]

[0663] Example 186: 2-methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one The title compound was prepared in a similar manner to general method A, using 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.

[0664] [ka]

[0665] Example 187: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one The title compound was prepared in a similar manner to general method A, using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one 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.

[0666] [ka]

[0667] Example 188: [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine The title compound was prepared in a similar manner to general method A, using (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine 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.

[0668] [ka]

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

[0670] [ka]

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

[0672] [ka]

[0673] Example 191: 4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide In a similar manner to general method A, 4-(4,4,5,5-tetramethyl-1,3,2-di The title compound was prepared using (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.

[0674] [ka]

[0675] Example 192: 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide The title compound was prepared in a similar manner to general method A, using 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.

[0676] [ka]

[0677] Example 193: (2S,3R)-1-[4-[4-(1H-imidazol-2-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol The title compound was 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 hydrochloride in place of 3-pyridylboronic acid, followed by general method B, using (2S,3R)-2-methylazetidin-3-ol in place of (2S)-2-methylazetidine.

[0678] [ka]

[0679] Example 194: 5-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-methyl-isoindolin-1-one 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 in place of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride in place of (2S)-2-methylazetidine.

[0680] [ka]

[0681] Example 195: N-[[4-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]methanesulfonamide The title compound was prepared in a manner similar to general method A, using (4-(methylsulfonamidomethyl)phenyl)boronic acid instead of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride instead of (2S)-2-methylazetidine.

[0682] [ka]

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

[0684] [ka]

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

[0686] [ka]

[0687] Example 198: 4-[2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide The title compound was prepared in a manner similar to general method A, using (4-sulfamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and subsequently in a manner similar to general method B, using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride instead of (2S)-2-methylazetidine.

[0688] [ka]

[0689] Example 199: 4-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide The title compound was prepared in a manner similar to general method A, using (4-sulfamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride instead of (2S)-2-methylazetidine.

[0690] [ka]

[0691] Example 200: 4-[2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide The title compound was prepared in a manner similar to general method A, using (4-carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, and subsequently in a manner similar to general method B, using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride instead of (2S)-2-methylazetidine.

[0692] [ka]

[0693] Example 201: [4-[2-[(2S,3R)-3-Fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine The title compound was prepared in a manner similar to general method A, using (4-(aminomethyl)phenyl)boronic acid hydrochloride in place of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride in place of (2S)-2-methylazetidine.

[0694] [ka]

[0695] Example 202: (2S,3R)-1-[4-[4-(aminomethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol The title compound was prepared in a manner similar to general method A, using (4-(aminomethyl)phenyl)boronic acid hydrochloride in place of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride in place of (2S)-2-methylazetidine.

[0696] [ka]

[0697] Example 203: 6-[2-[(2S,3R)-3-Fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-methyl-isoindolin-1-one In a similar manner to general method A, 2-methyl-6-(4-pyridylboronic acid was used instead of 3-pyridylboronic acid. The title compound was prepared using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride in place of (2S)-2-methylazetidine in a manner similar to general method B, using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride.

[0698] [ka]

[0699] Example 204: 6-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methyl-isoindolin-1-one The title compound was prepared in 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 in place of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride in place of (2S)-2-methylazetidine.

[0700] [ka]

[0701] Example 205: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]pyridine-3-sulfonamide The title compound was prepared in a manner similar to general method A, using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0702] [ka]

[0703] Example 206: 2-Methyl-6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindole On-1-On 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 in place of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0704] [ka]

[0705] Example 207: 6-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isoindolin-1-one The title compound was prepared in a manner similar to general method A, using (3-oxoisoindolin-5-yl)boronic acid instead of 3-pyridylboronic acid, followed by a manner similar to general method B.

[0706] [ka]

[0707] Example 208: 3-[2-[(2S,4S)-2,4-dimethylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide The title compound was prepared in a manner similar to general method A, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in place of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,4S)-2,4-dimethylazetidine hydrochloride in place of (2S)-2-methylazetidine.

[0708] [ka]

[0709] Example 209: 3-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl] benzenesulfonamide The title compound was prepared in a manner similar to general method A, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in place of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-2-methylazetidin-3-ol hydrochloride in place of (2S)-2-methylazetidine.

[0710] [ka]

[0711] Example 210: 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide The title compound was prepared in a manner similar to general method A, using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in place of 3-pyridylboronic acid, followed by a manner similar to general method B, using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride in place of (2S)-2-methylazetidine.

[0712] [ka]

[0713] Example 211: 7-Methyl-2-[(2S)-2-methylazetidin-1-yl]-6-phenyl-purine The title compound was prepared in a manner similar to general method A, using phenylboronic acid and 2,6-dichloro-7-methyl-7H-purine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a manner similar to general method B.

[0714] [ka]

[0715] Example 212: 2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-pyrido[2,3-d]pyrimidine The title compound was prepared in a manner similar to general method A, using phenylboronic acid and 2,4-dichloropyrido[2,3-d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by a manner similar to general method B.

[0716] [ka]

[0717] Example 213: 2-[5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]thiazol-2-yl]propan-2-ol The title compound was prepared in a similar manner to general method E using 2-(5-(tributylstannyl)thiazol-2-yl)propan-2-ol in place of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate.

[0718] [ka]

[0719] Example 214: N-methyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide 3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide (42 mg, 0.12 mmol) was dissolved in 10.5 mL of DMF and then cooled to 0° C. over 20 minutes. NaH (17.1 mg, 0.43) was added slowly and the reaction mixture was allowed to react 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 HO) to give N-methyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide.

[0720] [ka]

[0721] Example 215: N,N-dimethyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide 3-[2-[(2S)-2-Methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide (42 mg, 0.12 mmol) was dissolved in 10.5 mL of DMF and then cooled to 0° C. over 20 min. NaH (17.1 mg, 0.43) was added slowly and the reaction mixture was allowed to react at 0° C. for 20 min. Methyl iodide (0.0095 mL, 0.15 mmol) was then added and the reaction mixture was stirred at ambient temperature for 15 min. 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 HO) to give N,N-dimethyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide.

[0722] [ka]

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

[0724] [ka]

[0725] Example 217: 3-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzoyl]amino]propanoic acid The title compound was prepared in a manner similar to general method G, using 3-aminopropanoic acid and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid in place of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.

[0726] [ka]

[0727] Example 218: N-benzyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide The title compound was prepared in a manner similar to general method G, using benzylamine and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid in place of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.

[0728] [ka]

[0729] Example 219: 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-N-(2-sulfamoylethyl)benzamide The title compound was prepared in a manner similar to general method G, using 2-aminoethane-1-sulfonamide and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid in place of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.

[0730] [ka]

[0731] Example 220: N-(3-amino-3-oxo-propyl)-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]benzamide The title compound was prepared in a manner similar to general method G, using 3-aminopropanamide and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid in place of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.

[0732] [ka]

[0733] Example 221: (S)-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiazol-2-yl)methanamine 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 in place of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general method E, using tert-butyl N-[(5-bromothiazol-2-yl)methyl]carbamate in place of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, in a manner similar to general method I.

[0734] [ka]

[0735] Example 222: (S)-2-methyl-6-(2-(2-methylazetidin-1-yl) -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 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 in place of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general method E, using 6-bromo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one in place of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0736] [ka]

[0737] Example 223: (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyridine-2-sulfonamide 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 in place of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general method E, using 6-bromopyridine-2-sulfonamide in place of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0738] [ka]

[0739] Example 224: (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyridine-2-sulfonamide 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 in place of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general method E, using 4-bromopyridine-2-sulfonamide in place of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0740] [ka]

[0741] Example 225: (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropan-1-amine 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 in place of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general method E, using 1-(3-bromophenyl)cyclopropan-1-amine in place of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0742] [ka]

[0743] Example 226: 4-(2-((2S,3S)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide A vial was charged with 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide (23.5 mg, 0.0.72 mmol) and DCM (0.24 mL). DAST (117 mg, 0.72 mmol) was slowly added, and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was slowly quenched to 0 °C with ice chips, extracted with 25% MeOH / DCM, washed with NaHCO (saturated aqueous solution), dried over NaSO, filtered, and concentrated. The residue was subjected to HPLC (0.1% TFA in MeCN-0.1% TFA in HO) to give the title compound.

[0744] [ka]

[0745] Example 227: 3-hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide The title compound was prepared in a manner similar to general method G, using 3-hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0746] [ka]

[0747] Example 228: 2-hydroxy-2-methyl-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide The title compound was prepared in a manner similar to general method G, using 2-hydroxy-2-methylpropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0748] [ka]

[0749] Example 229: (2R)-2-hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide The title compound was prepared in a manner similar to general method G, using (R)-2-hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0750] [ka]

[0751] Example 230: (2S)-2-hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide The title compound was prepared in a manner similar to general method G, using (S)-2-hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine in place of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.

[0752] [ka]

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

[0754] [ka]

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

[0756] [ka]

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

[0758] [ka]

[0759] Example 234: 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydro-1λ6,3-benzothiazin-4-one The title compound was prepared in a manner similar to general method D, using 7-bromo-2,3-dihydro-4H-benzo[e][1,3]thiazin-4-one 1,1-dioxide in place of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by a manner similar to general method E.

[0760] [ka]

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

[0762] The title compound was prepared in a similar manner to general method A, using 4-chloro-2-[(2S,3R)-3-methoxy-2-methyl-azetidin-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.

[0763] [ka]

[0764] Example 236: 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methylisoindolin-1-one The title compound 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 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one in place of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, followed by general methods M and B, using (2S,3R)-2-methylazetidin-3-ol in place of (2S)-2-methylazetidine.

[0765] [ka]

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

[0767] [ka]

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

[0769] [ka]

[0770] Example 240: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]isoindoline-1,3-dione The title compound was prepared in a similar manner to general method F, using 5-bromoisoindoline-1,3-dione instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0771] [ka]

[0772] Example 241: 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2-(trifluoromethyl)-1H-benzimidazole The title compound was prepared in a similar manner to general method F, using 6-bromo-2-(trifluoromethyl)-1H-benzimidazole instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0773] [ka]

[0774] Example 242: [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methanesulfonamide The title compound was prepared in a similar manner to general method F, using (4-bromophenyl)methanesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0775] [ka]

[0776] Example 243: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-3-(trifluoromethyl)-1H-indazole The title compound was prepared in a similar manner to general method F, using 5-bromo-3-(trifluoromethyl)-1H-indazole instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0777] [ka]

[0778] Example 244: 2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]acetamide The title compound was prepared in a similar manner to general method F, using 2-(3-bromophenyl)acetamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0779] [ka]

[0780] Example 245: 2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]acetamide The title compound was prepared in a similar manner to general method F, using 2-(4-bromophenyl)acetamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0781] [ka]

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

[0783] [ka]

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

[0785] [ka]

[0786] Example 248: 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]indolin-2-one The title compound was prepared in a similar manner to general method F, using 5-bromoindolin-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0787] [ka]

[0788] Example 249: 3-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]bicyclo[1.1.1]pentane-1-carboxylic acid The title compound was prepared in a similar manner to general procedure F, using 3-(4-bromophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0789] [ka]

[0790] Example 250: 3-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]bicyclo[1.1.1]pentane-1-carboxamide The title compound was prepared in a similar manner to general procedure F, using 3-(4-bromophenyl)bicyclo[1.1.1]pentane-1-carboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0791] [ka]

[0792] Example 251: 3-methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1H-benzimidazol-2-one The title compound was prepared in a similar manner to general method F, using 5-bromo-3-methyl-1H-benzimidazol-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0793] [ka]

[0794] Example 252: 1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarboxamide The title compound was prepared in a similar manner to general method F, using 1-(4-bromophenyl)cyclopropanecarboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0795] [ka]

[0796] Example 253: 1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarboxylic acid The title compound was prepared in a similar manner to general procedure F, using 1-(3-bromophenyl)cyclopropanecarboxylic acid in place of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0797] [ka]

[0798] Example 254: 1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarboxamide The title compound was prepared in a similar manner to general procedure F, using 1-(3-bromophenyl)cyclopropanecarboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.

[0799] [ka]

[0800] Example 255: 1-[hydroxy-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]cyclopropanecarbonitrile In a manner similar to general procedure A, 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 were converted to 3-pyridylboronic acid and 4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively. and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine to prepare the title compound.

[0801] [ka]

[0802] Example 256: 2,2-Difluoro-1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]ethanol The title compound was prepared in a similar manner to general method A, using 2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol 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.

[0803] [ka]

[0804] Example 257: 2-Difluoro-1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]ethanol The title compound was prepared in a similar manner to general method A, using 2-fluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol 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.

[0805] [ka]

[0806] Example 258: 4-[3-(difluoromethoxy)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine The title compound was prepared in a manner similar to general method A, using 2-[3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine in place of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.

[0807] [ka]

[0808] Example 259: 4-[1-(difluoromethyl)pyrazol-4-yl]-2...

Claims

1. A compound having the structure shown below: 【Chemistry 1-1】 [Chemistry 1-2] [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] [Chemistry 1-6] [Chemistry 1-7] [Chemistry 1-8] [Chemistry 1-9] 【Chemistry 1-10】 【Chemistry 1-11】 【Chemistry 1-12】 【Chemistry 1-13】 [Chemistry 1-14] 【Chemistry 1-15】 【Chemistry 1-16】 【Chemistry 1-17】 【Chemistry 1-18】 【Chemistry 1-19】 【Chemistry 1-20】 【Chemistry 1-21】 【Chemistry 1-22】 [Chemistry 1-23] [Chemistry 1-24] [Chemistry 1-25] [Chemistry 1-26] [Chemistry 1-27] [Chemistry 1-28] [Chemistry 1-29] 【Chemistry 1-30】 【Chemistry 1-31】 【Chemistry 1-32】 【Chemistry 1-33】 [Chemistry 1-34] 【Chemistry 1-35】 [Chemistry 1-36] 【Chemistry 1-37】 [Chemistry 1-38] [Chemistry 1-39] 【Chemistry 1-40】 【Chemistry 1-41】 【Chemistry 1-42】 [Chemistry 1-43] [Chemistry 1-44] [Chemistry 1-45] [Chemistry 1-46] [Chemistry 1-47] [Chemistry 1-48] [Chemistry 1-49] 【Chemistry 1-50】 【Chemistry 1-51】 【Chemistry 1-52】 [Chemistry 1-53] [Chemistry 1-54] 【Chemistry 1-55】 [Chemistry 1-56] 【Chemistry 1-57】 [Chemistry 1-58] [Chemistry 1-59] 【Chemistry 1-60】 【Chemistry 1-61】 【Chemistry 1-62】 [Chemistry 1-63] [Chemistry 1-64] 【Chemistry 1-65】 【Chemistry 1-66】 【Chemistry 1-67】 【Chemistry 1-68】 [Chemistry 1-69] 【Chemistry 1-70】 【Chemistry 1-71】 【Chemistry 1-72】 【Chemistry 1-73】 [Chemistry 1-74] 【Chemistry 1-75】 【Chemistry 1-76】 【Chemistry 1-77】 【Chemistry 1-78】 【Chemistry 1-79】 【Chemistry 1-80】 【Chemistry 1-81】 【Chemistry 1-82】 【Chemistry 1-83】 [Chemistry 1-84] 【Chemistry 1-85】 【Chemistry 1-86】 【Chemistry 1-87】 【Chemistry 1-88】 【Chemistry 1-89】 【Chemistry 1-90】 【Chemistry 1-91】 【Chemistry 1-92】 【Chemistry 1-93】 【Chemistry 1-94】 【Chemistry 1-95】 【Chemistry 1-96】 【Chemistry 1-97】 【Chemistry 1-98】 【Chemistry 1-99】 【Chemistry 1-100】 【Chemistry 1-101】 【Chemistry 1-102】 【Chemistry 1-103】 【Chemistry 1-104】 【Chemistry 1-105】 【Chemistry 1-106】 【Chemistry 1-107】 【Chemistry 1-108】 【Chemistry 1-109】 【Chemistry 1-110】 【Chemistry 1-111】 【Chemistry 1-112】 【Chemistry 1-113】 【Chemistry 1-114】 【Chemistry 1-115】 【Chemistry 1-116】 【Chemistry 1-117】 or a pharmaceutically acceptable salt thereof.

2. A compound having the structure shown below: 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3] [Chemistry 2-4] 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8】 【Chemistry 2-9】 or a pharmaceutically acceptable salt thereof.

3. A compound having the structure shown below: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 [Chemistry 3-4] [Transformation 3-5] or a pharmaceutically acceptable salt thereof.

4. A compound having the structure shown below: 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] 【Chemistry 4-7】 【Chemistry 4-8】 【Chemistry 4-9】 【Chemistry 4-10】 【Chemistry 4-11】 【Chemistry 4-12】 【Chemistry 4-13】 【Chemistry 4-14】 【Chemistry 4-15】 【Chemistry 4-16】 【Chemistry 4-17】 【Chemistry 4-18】 【Chemistry 4-19】 【Chemistry 4-20】 【Chemistry 4-21】 【Chemistry 4-22】 【Chemistry 4-23】 【Chemistry 4-24】 or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

6. The pharmaceutical composition of claim 5, further comprising one or more additional therapeutic agents.

7. The pharmaceutical composition of claim 6 for use in treating a ketohexokinase (KHK)-mediated disease or condition.

8. A composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5 or 6, for treating a KHK-mediated disease or condition in a subject in need thereof.

9. The composition of claim 8, wherein the disease or condition comprises chronic kidney disease (CKD), diabetic kidney disease (DKD), kidney disease, renal fibrosis, renal insufficiency, acute kidney injury, tubular dysfunction, lupus nephritis, 2,8-dihydroxyadenine nephropathy, renal transplant rejection, renal protection against drugs inducing Fanconi syndrome, hereditary fructose intolerance, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), liver disease, liver fibrosis, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, hypertension, fibrosis, steatosis, cirrhosis, cardiometabolic syndrome, insulin resistance, cardiovascular disease, heart failure, type 1 and type 2 diabetes mellitus, irritable bowel syndrome (IBD), ulcerative colitis, Crohn's disease, hyperuricemia, gout, arthritis, osteoporosis or cancer.

10. The composition described in claim 8 or 9, characterized in that the composition is administered in combination with an additional therapeutic agent.

11. The pharmaceutical composition of claim 6 or the composition of claim 9, wherein the additional therapeutic agent comprises an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, remogliflozin, or ertugliflozin), an ACE inhibitor (e.g., benazepril, imidapril, or enalapril), and / or a pharmaceutically acceptable salt thereof.

Images