Cancer Treatment Compounds

Abstract

This application relates to compounds of Formula (A), as defined herein, and pharmaceutically acceptable salts thereof, as well as processes for preparing compounds of Formula (A), and pharmaceutically acceptable salts thereof. This application also describes pharmaceutical compositions comprising compounds of Formula (A), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions to treat diseases, such as cancer. Some embodiments provide a method for treating cancer in a subject in need thereof, comprising: (a) identifying the cancer as a CDK2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Patent Application No. 63 / 406,081, filed September 13, 2022, U.S. Patent Application No. 63 / 419,451, filed October 26, 2022, U.S. Patent Application No. 63 / 435,170, filed December 23, 2022, and U.S. Patent Application No. 63 / 536,249, filed September 1, 2023, the entire contents of which are incorporated herein by reference.

[0002] This application relates to compounds, processes for preparing the compounds, compositions containing the compounds, and methods of treating disorders (such as cancer) with the compounds or compositions. [Background technology]

[0003] Cyclin-dependent kinases (CDKs) play essential roles in regulating eukaryotic cell division and proliferation. The cyclin-dependent kinase catalytic units are activated by regulatory subunits known as cyclins. At least 16 mammalian cyclins have been identified. See Johnson, et al., Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312. Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin CDK4, cyclin D / CDK6, and potentially other heterodynes regulate cell cycle progression. Additional functions of cyclin / CDK heterodynes include regulating transcription, DNA repair, differentiation, and apoptosis. See Morgan DO, Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291. Overexpression of CDK2 is associated with dysregulation of the cell cycle. The cyclin E / CDK2 complex plays a key role in regulating the G1 / S transition, histone biosynthesis, and centrosome replication. Progressive phosphorylation of Rb by cyclin E / Cdk2 releases the G1 transcription factor E2F and promotes entry into S phase. Activation of cyclin A / CDK2 during early S phase promotes phosphorylation of endogenous substrates that enable DNA replication and inactivation of E2F for completion of S phase. See Asghar et al., Nat. Rev. Drug. Discov. 2015;14(2):130-146.

[0004] Cyclin E is a regulatory cyclin of CDK2. Amplification or overexpression of cyclin E has long been associated with poor outcome in breast cancer. See Keyomarsi et al., N Engl J Med. (2002) 347:1566-75. Cyclin E has at least two types, cyclin E1 and cyclin E2. Amplification or overexpression of cyclin E1 (CCNE1) has been associated with poor outcome in ovarian, gastric, endometrial, and other cancers. See Nakayama et al., Cancer (2010) 116:2621-34; Etemadmoghadam et al., Clin. Cancer Res. (2013) 19:5960-71; Au-Yeung et al., Clin. Cancer Res. (2017) 23:1862-1874; Ayhan et al., Modern Pathology (2017) 30:297-303; Ooi et al., Hum. Pathol. (2017) 61:58-67; Noske et al., Oncotarget (2017) 8:14794-14805. CDK2, in complex with cyclin E, phosphorylates the tumor suppressor RB1 during the G1 phase of the cell cycle. Fully phosphorylated RB1 derepresses E2F transcription factors that regulate the transcription of DNA synthesis and repair genes, including cyclin A2. CDK2 forms a complex with cyclin A2 and phosphorylates it, regulating the DNA synthesis / repair process during S phase progression. Amplification or overexpression of cyclin A (CCNA2) is known to be involved in several types of cancer, including breast cancer, liver cancer, lung cancer, and cervical cancer. See, for example, Yam et al., Cell Mol. Life Sci. 2002;59,1317-1326 and Burkholm et al., Int. J. Cancer, 2001;93(2)283-287. Increased cyclin A activity is also associated with poor clinical prognosis in non-small cell lung cancer. See Volm, et al., Br. J. Cancer, 1997;75(12)1774-1778. Similarly, overexpression of cyclin E2 (CCNE2) is associated with endocrine resistance in breast cancer cells. See Caldon et al., Mol. Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Cancer Res. (2016) 76:2301-2313. Thus, inhibition of CDK2 may have beneficial effects in cancers associated with cell cycle abnormalities. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Johnson, et al., Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312 [Non-patent document 2] Morgan DO,Annu.Rev.Cell.Dev.Biol.(1997)13:261-291 [Non-patent document 3] Asghar et al.,Nat.Rev.Drug.Discov.2015;14(2):130-146 [Non-patent document 4] Keyomarsi et al.,N Engl J Med.(2002)347:1566-75 [Non-patent document 5] Nakayama et al.,Cancer(2010)116:2621-34 [Non-patent document 6] Etemadmoghadam et al., Clin. Cancer Res. (2013) 19:5960-71 [Non-Patent Document 7] Au-Yeung et al., Clin. Cancer Res. (2017) 23:1862-1874 [Non-patent document 8] Ayhan et al.,Modern Pathology(2017)30:297-303 [Non-Patent Document 9] Ooi et al.,Hum. Pathol.(2017)61:58-67 [Non-Patent Document 10] Noske et al.,Oncotarget(2017)8:14794-14805 Summary of the Invention [Means for solving the problem]

[0006] In some embodiments, the compound of formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 Ga-NR A R B , -C(=O)NR A R B , -OC(=O)NR A R B , optionally substituted 5-10 membered heteroaryloxy, or optionally substituted 5-10 membered heteroaryl; Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl; X is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; a C3-C8 cycloalkylene-(CH2) b -; -(CH2) optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl a C5-C8 cycloalkenylene-(CH2) b -;-(CH2) a Phenylene-(CH2) b -;-(CH2) a Heteroarylene-(CH2) b -; -(CH2) a Heterocyclylene-(CH2) b -; and C2-C6 alkylene, a and b are independently 0, 1, or 2; X 1 But N or CR X1 and X 2 But N or CR X2 and CR X1 and CR X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy; Y is -NR C -, *-C(=O)NR C (CR D R E ) n -, *-NR C C(=O)(CR D R E ) n - or -O-, wherein * is X 1 ~X 2 Show the connection points to the ring, R C is hydrogen or C1-C6 alkyl, n is 0, 1, or 2; Each R Dand R E are independently hydrogen, fluoro, or C1-C6 alkyl; R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the compound of formula (AI): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 Ga-NR A R B , -C(=O)NR A R B , -OC(=O)NR A R B or an optionally substituted 5-10 membered heteroaryl; Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl; X 1 But N or CR X1 and X 2 But N or CR X2 and CR X1 and CR X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy; Y is -NR C -, *-C(=O)NR C (CR D R E ) n -, *-NR C C(=O)(CR DR E ) n - or -O-, wherein * is X 1 ~X 2 Show the connection points to the ring, R C is hydrogen or C1-C6 alkyl, m is 0, 1, or 2; n is 0, 1, or 2; Each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl; R 2 is an optionally substituted phenyl, an optionally substituted 5- to 6-membered heteroaryl, or an optionally substituted 5- to 6-membered heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0008] Some embodiments provide pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0009] Some embodiments provide a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0010] Some embodiments provide a method for treating cancer in a subject in need thereof, comprising: (a) identifying the cancer as a CDK2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0011] Some embodiments provide a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the subject has been identified as having a CDK2-associated cancer.

[0012] Some embodiments provide a method of treating a CDK2-associated cancer, comprising administering to a subject identified or diagnosed as having a CDK2-associated cancer a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0013] Some embodiments provide methods for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the CDK2 gene, the CDK2 protein, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0014] Some embodiments provide a method for inhibiting cancer metastasis in a subject having cancer in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0015] Some embodiments provide a method for inhibiting cancer cell invasiveness in a subject having cancer in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0016] Some embodiments provide a method for inhibiting the proliferation of a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0017] Some embodiments provide a method for inhibiting CDK2 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0018] Some embodiments provide a method for inducing apoptosis in mammalian cancer cells, comprising contacting the mammalian cells with a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0019] 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 to which this disclosure belongs. Methods and materials for use in this disclosure are described herein. Other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0020] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition The term "about," when applied to a particular value or range, refers to ±10% of the specified value or range, for example, to account for experimental variation.

[0022] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0023] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that may be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof.

[0024] As used herein, the term "tautomer" refers to a compound that differs significantly in the arrangement of atoms in its structure, but exists in easy and rapid equilibrium; the compounds provided herein may be depicted as different tautomers; it will be understood that if a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of the compound does not exclude any tautomer. The following are examples of tautomeric forms that are included: [ka]

[0025] It will be understood that certain compounds provided herein may contain one or more asymmetric centers and, therefore, may be prepared and isolated in a mixture of isomers, such as a racemic mixture, or in enantiomerically pure form.

[0026] The term "halogen" refers to one of the halogens of group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0027] The term "alkyl" refers to a straight or branched hydrocarbon chain containing 1 to 20 carbon atoms. An alkyl group can be represented as a C1-12 alkyl group, containing, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Examples of C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0028] The term "alkylene" refers to an alkyl group, as defined herein, that is a biradical and is linked to two other moieties. Non-limiting examples of alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (IUPAC: (methyl)ethylene) (-CH2-CH(CH3)-), and isobutylene (IUPAC: 2-(methyl)propylene) (-CH2-CH(CH3)-CH2-). The alkylene group may optionally be a C3-C4 cycloalkyl, as defined herein, sharing a carbon atom with the backbone of the alkylene chain, e.g. [ka] may include:

[0029] The term "alkenyl" refers to an alkyl group as described herein containing a carbon double bond(s), including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0030] The term "alkynyl" refers to an alkyl group as described herein containing a carbon-carbon triple bond(s), including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, and the like.

[0031] The term "haloalkyl" refers to an alkyl group, as defined herein, substituted with at least one independently selected halogen atom at each occurrence, such as fluorine, chlorine, bromine, and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-C3 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloroethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl and 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, or trifluoropropyl.

[0032] The term "alkoxy" refers to an alkyl group, as defined herein, attached to a molecule through an oxygen. It includes moieties such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy, where the alkyl portion may be straight or branched.

[0033] As used herein, "haloalkoxy" refers to an O-alkyl group in which one or more hydrogen atoms are replaced by halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). In some cases, the haloalkoxy can be -OR, where R is a C alkyl substituted with 1, 2, or 3 halogens. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. The haloalkoxy can be substituted or unsubstituted.

[0034] As used herein, the term "aryl" refers to a 6-10 all-carbon monocyclic or bicyclic group in which at least one ring in the system is aromatic, i.e., C6-C10 aryl. Non-limiting examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl. In bicyclic ring systems in which only one ring is aromatic, the non-aromatic ring may be a cycloalkyl group, as defined herein.

[0035] As used herein, the term "heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic group in which the ring system is aromatic and one or more carbon atoms in at least one ring in the system are replaced with a heteroatom independently selected from N, O, and S. Heteroaryl groups include rings in which one or more groups are oxidized, such as a pyridone moiety. Non-limiting examples of heteroaryl groups include pyridine, pyrimidine, pyrrole, imidazole, and indole.

[0036] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated 3-10 monocyclic or bicyclic hydrocarbon group, where bicyclic systems include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0037] The term "cycloalkoxy" refers to a cycloalkyl group, as defined herein, attached to a molecule via an oxygen atom. This includes moieties where cycloalkyl is a saturated or partially unsaturated 3-10 monocyclic or bicyclic hydrocarbon group, where bicyclic systems include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkoxy groups include cyclopropoxyl, cyclobutoxyl, cyclopentyloxyl, and octahydropentalen-2-yl.

[0038] The term "heterocyclyl" refers to a non-aromatic, saturated or partially unsaturated 3- to 12-membered hydrocarbon monocyclic or bicyclic ring system having at least one heteroatom selected from N, O, and S in the ring. In bicyclic ring systems, one ring can be aromatic. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. Heterocyclyl ring systems can include oxo substitution at one or more C, N, or S ring members. A heterocyclyl group can be, for example, a "5- to 10-membered heterocyclyl group," which is a ring system containing 5, 6, 7, 8, 9, or 10 atoms, with at least one heteroatom. For example, there can be 1, 2, or 3 heteroatoms, optionally 1 or 2. A heterocyclyl group can be attached to the remainder of the molecule through any carbon atom or heteroatom, such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptanyl, pyrrolidin-2-one, sulfolane, isothiazolidine S,S-dioxide, and decahydronaphthalenyl.

[0039] The term "hydroxyl" refers to an --OH moiety.

[0040] The term "cyano" refers to a -CN moiety.

[0041] The term "nitro" refers to a -NO2 moiety.

[0042] The term "azido" refers to the -N3 moiety.

[0043] The term "isocyanato" group refers to an --NCO moiety.

[0044] The term "thiocyanato" group refers to a -CNS moiety.

[0045] The term "isothiocyanato" group refers to an -NCS moiety.

[0046] The term "oxo" refers to a "=O" group attached to a carbon atom.

[0047] The term "acyl" refers to an alkyl group linked as a substituent through an oxo group. Examples include, but are not limited to, acetyl.

[0048] The term "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein.

[0049] The terms "ester" and "C-carboxy" refer to the group "-C(=O)OR", where R can be the same as defined for O-carboxy.

[0050] The term "thiocarbonyl" group refers to a "-C(=S)R" group, where R can be the same as defined for O-carboxy.

[0051] The term "O-carbamyl group" refers to the group "-OC(=O)N(R ’ R ’’ ) group, where R ’ and R ’’is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0052] The term "N-carbamyl group" refers to the group ROC(=O)N(R ’ )-" group, where R ’ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0053] The term "O-thiocarbamyl" group refers to an "-O-C(=S)-N(R'R'')" group, where R' and R'' are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0054] The term "N-thiocarbamyl" group refers to an "ROC(=S)N(R')-" group, where R and R' are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0055] The term "C-amido" group refers to a "-C(=O)N(R'R'')" group, where R' and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0056] The term "N-amido" group refers to an "RC(=O)N(R')-" group, where R and R' are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0057] The term "S-sulfonamido" group refers to a "-SON(R'R") group, where R' and R" are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). In some embodiments, R' and R" are both alkyl. In some embodiments, R' and R" are both hydrogen.

[0058] The term "N-sulfonamido" group refers to an "RSON(R')-" group, where R and R' are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0059] The term "sulfenyl" group refers to an "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl).

[0060] The term "sulfinyl" group refers to a "-S(=O)-R" group, where R can be the same as defined for sulfenyl.

[0061] The term "sulfonyl" group refers to an "SO2R" group, where R can be the same as defined for sulfenyl.

[0062] The term "aryl(alkyl)" refers to an aryl group, as described herein, linked as a substituent via an alkylene group. Examples include, but are not limited to, benzyl.

[0063] The term "heteroaryl(alkyl)" refers to a heteroaryl group linked, as a substituent, via an alkylene group.

[0064] The term "heterocyclyl(alkyl)" refers to a heterocyclyl group linked, as a substituent, via an alkylene group.

[0065] The term "amino" refers to a group of formula -NH2.

[0066] The term "monosubstituted amine" group refers to an "-NHR" group, where R' can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. Examples of monosubstituted amine groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

[0067] The term "disubstituted amine" group refers to a "-NR'R" group, where R' and R" can independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. Examples of disubstituted amine groups include, but are not limited to, -N(methyl), -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0068] As used herein, an asterisk (*) indicates the point of attachment of an atom or moiety to the indicated atom or group in the remainder of the molecule.

[0069] Whenever a group is described herein as "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted" if it is substituted, the substituent(s) can be selected from one or more of the indicated substituents. If no substituents are specified, the indicated "optionally substituted" or "substituted" group can be selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N- It means that it can be substituted with one or more group(s) (such as 1, 2, 3, or 4) individually and independently selected from amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, cyanato, isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinylsulfonyl, phosphine oxide, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amine groups, and disubstituted amine groups.

[0070] Compounds of formula (A) include pharmaceutically acceptable salts thereof. In addition, compounds of formula (A) also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and may be useful as intermediates for the preparation and / or purification of compounds of formula (A) and / or for the separation of enantiomers of compounds of formula (A).

[0071] The term "pharmaceutically acceptable" indicates that a compound, or a salt thereof, or composition thereof is chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the subject being treated therewith.

[0072] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, particularly when referred to with respect to compounds of formula (A), includes all isotopes and isotopic mixtures of that atom, whether naturally occurring or synthetically produced, either at natural abundance or in isotopically enriched form. For example, unless expressly stated otherwise, when hydrogen is referred to, it is 1 H, 2 H, 3 H, or mixtures thereof, and when carbon is mentioned, it is understood to refer to 11 C. 12 C. 13 C. 14 C, or mixtures thereof, and when nitrogen is mentioned, it is understood to refer to 13 N, 14 N, 15 N, or mixtures thereof, and when oxygen is mentioned, it is understood to refer to 14 O. 15 O. 16 O. 17 O. 18 Fluoro is understood to refer to fluoro, fluoro, or mixtures thereof. 18 F, 19 F, or mixtures thereof. For example, in deuteroalkyl and deuteroalkoxy groups, one or more hydrogen atoms are replaced with deuterium ( 2H). Some of the aforementioned isotopes are radioactive, and therefore the compounds provided herein also include compounds and mixtures thereof having one or more isotopes of one or more atoms, including radioactive compounds in which one or more non-radioactive atoms are replaced by one of their radio-enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0073] The ability of selected compounds to act as CDK2 inhibitors can be demonstrated by the biological assays described herein. Ki values ​​are shown in Table 3.

[0074] As defined herein, a "CDK2 inhibitor" includes any compound that exhibits CDK2 inhibitory activity. In some embodiments, the CDK2 inhibitor is selective for the CDK2 protein. Exemplary CDK2 inhibitors may exhibit an inhibitory activity (Ki) against CDK2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, as measured in the assays described herein. In some embodiments, the CDK2 inhibitor may exhibit an inhibitory activity (Ki) against CDK2 of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured in the assays provided herein.

[0075] The phrase "therapeutically effective amount" refers to an amount of a compound sufficient, when administered to a subject in need of such treatment, to (i) treat a CDK2-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular CDK2-associated cancer, and / or (iii) delay the onset of one or more symptoms of a particular CDK2-associated cancer described herein. A therapeutically effective amount may have the effect of, for example, reducing tumor size, inhibiting tumor growth, inhibiting cancer cell invasion, inhibiting metastasis, or any combination of the foregoing. The amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof corresponding to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, and the identity (e.g., body weight) of the subject requiring treatment.

[0076] The compounds of formula (A) or pharmaceutically acceptable salts thereof are useful in the treatment of diseases and disorders treatable with CDK2 inhibitors, such as CDK2-associated cancers, eg solid tumors.

[0077] As used herein, the term "treat" or "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of all or part of the symptoms associated with a disease or disorder or condition, whether detectable or undetectable, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total). "Treatment" can also mean prolonging survival compared to the expected survival if not receiving treatment.

[0078] As used herein, the term "subject" refers to any animal, including mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the cancer to be treated.

[0079] In certain embodiments, the compounds of Formula (A) or pharmaceutically acceptable salts thereof are useful for preventing the diseases and disorders defined herein. As used herein, the term "prevent" means preventing the onset, recurrence, or spread of all or part of a disease or condition described herein, or a symptom thereof.

[0080] The term "regulatory agency" refers to a national agency that approves pharmaceutical products for medical use in a country. For example, a non-limiting example of a regulatory agency is the US Food and Drug Administration (FDA).

[0081] As used herein, the term "CDK2-associated cancer" refers to a cancer associated with or having dysregulated expression, activity, or levels of the CDK2 gene, CDK2 protein, or any of these (e.g., one or more) (e.g., any of the types of dysregulated expression, activity, or levels of the CDK2 gene, CDK2 protein, or any of these described herein). CDK2-associated cancers also include cancer associated with or having dysregulated expression, activity, or levels of the cyclin A2 gene, cyclin A2 protein, or any of these, cancer associated with or having dysregulated expression, activity, or levels of the cyclin E1 gene, cyclin E1 protein, or any of these, and cancer associated with or having dysregulated expression, activity, or levels of the cyclin E2 gene, cyclin E2 protein, or any of these. In some embodiments, CDK-associated cancers are characterized by CDK2 amplification or overexpression. In some embodiments, the CDK-associated cancer is characterized by amplification or overexpression of cyclin A2 (CCNA2), cyclin E1 (CCNE1), and / or cyclin E2 (CCNE2). In some embodiments, the CDK-associated cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some embodiments, the CDK-associated cancer is characterized by amplification or overexpression of cyclin A2 (CCNA2). In some embodiments, the CDK-associated cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1). In some embodiments, the CDK-associated cancer is characterized by amplification or overexpression of cyclin E2 (CCNE2). Non-limiting examples of CDK2-associated cancers are described herein.

[0082] An exemplary human CDK2 sequence is shown below: [ka]

[0083] The sequence of an exemplary human cyclin E1 is shown below: [ka]

[0084] The sequence of an exemplary human cyclin E2 is shown below: [ka]

[0085] The sequence of an exemplary human cyclin A2 is shown below: [ka]

[0086] Compound of formula (A) Provided herein are compounds of formula (A) [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 Ga-NR A R B , -C(=O)NR A R B , -OC(=O)NR A R B , optionally substituted 5-10 membered heteroaryloxy, or optionally substituted 5-10 membered heteroaryl; Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl; X is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; a C3-C8 cycloalkylene-(CH2) b- or -(CH2) optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl a C5-C8 cycloalkenylene-(CH2) b - and a and b are independently 0, 1, or 2; X 1 But N or CR X1 and X 2 But N or CR X2 and CR X1 and CR X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy; Y is -NR C -, *-C(=O)NR C (CR D R E ) n -, *-NR C C(=O)(CR D R E ) n - or -O-, wherein * is X 1 ~X 2 Show the connection points to the ring, R C is hydrogen or C1-C6 alkyl, n is 0, 1, or 2; Each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl; R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl.

[0087] Provided herein are compounds of formula (AI), or a pharmaceutically acceptable salt thereof: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 Ga-NR A R B , -C(=O)NR A R B , -OC(=O)NR A R B or an optionally substituted 5-10 membered heteroaryl; Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl; X 1 But N or CR X1 and X 2 But N or CR X2 and R X1 and R X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy; Y is -NR C -, *-C(=O)NR C (CR D R E ) n -, *-NR C C(=O)(CR D R E ) n - or -O-, wherein * is X 1 ~X 2 Show the connection points to the ring, R C is hydrogen or C1-C6 alkyl, m is 0, 1, or 2; n is 0, 1, or 2; Each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl; R2 is optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, or optionally substituted 5- to 6-membered heterocyclyl.

[0088] In some embodiments, R 1 Ha-NR A R B is.

[0089] In some embodiments, R 1 is -C(=O)NR A R B is.

[0090] In some embodiments, R 1 is -OC(=O)NR A R B is.

[0091] In some embodiments, R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl.

[0092] In some embodiments, R A and R B In some embodiments, R A and R B are hydrogen atoms.

[0093] In some embodiments, R A and R B Each is an unsubstituted C1-C6 alkyl. In some embodiments, R A and R B are each substituted C1-C6 alkyl.

[0094] In some embodiments, R A and R B Each is an unsubstituted C1-C6 haloalkyl. In some embodiments, R Aand R B are each substituted C1-C6 haloalkyl.

[0095] In some embodiments, R A and R B is different.

[0096] In some embodiments, R A and R B one of which is hydrogen and R A and R B and the other of R is unsubstituted C1-C6 alkyl. A and R B one of which is hydrogen and R A and R B and the other of R is unsubstituted C1-C3 alkyl. A and R B one of which is hydrogen and R A and R B The other of is methyl, ethyl, or propyl.

[0097] In some embodiments, R A and R B one of which is hydrogen and R A and R B and the other of R is unsubstituted C1-C6 haloalkyl. A and R B one of which is hydrogen and R A and R B The other of is unsubstituted C1-C3 haloalkyl.

[0098] In some embodiments, R A and R B one of which is hydrogen and R A and R B and the other of R is a substituted C1-C6 alkyl. A and R B one of which is hydrogen and R A and R Band the other of R is C1-C6 alkyl substituted with 1-5 halogens. A and R B one of which is hydrogen and R A and R B The other of the above is C1-C4 alkyl substituted with 1 to 3 halogens.

[0099] In some embodiments, R A and R B one of which is hydrogen and R A and R B The other is, [ka] is selected from the group consisting of:

[0100] In some embodiments, R A and R B one of which is hydrogen and R A and R B and the other of R is a substituted C1-C6 haloalkyl. A and R B one of which is hydrogen and R A and R B and the other of R is C1-C6 haloalkyl substituted with 1-5 halogens. A and R B one of which is hydrogen and R A and R B The other of is C1-C4 haloalkyl substituted with 1 to 3 halogens.

[0101] In some embodiments, R A and R B one of which is hydrogen and R A and R B The other is, [ka] is selected from the group consisting of:

[0102] In some embodiments, R A and R B one of which is hydrogen and R A and R B and the other of R is C-C cycloalkyl optionally substituted with C-C alkyl. A and R B one of which is hydrogen and R A and R B and the other of R is C-C cycloalkyl substituted with C-C alkyl. A and R B one of which is hydrogen and R A and R B and the other of R is C-C cycloalkyl optionally substituted with C-C alkyl. A and R B one of which is hydrogen and R A and R B and the other of R is C-C cycloalkyl substituted with C-C alkyl. A and R B one of which is hydrogen and R A and R B The other of [ka] is.

[0103] In some embodiments, R A and R B one of which is hydrogen and R A and R B and the other of R is unsubstituted C-C cycloalkyl. A and R B one of which is hydrogen and R A and R B and the other of R is unsubstituted C-C cycloalkyl. A and RB one of which is hydrogen and R A and R B and the other of R is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. A and R B one of which is hydrogen and R A and R B The other of is unsubstituted cyclopropyl.

[0104] In some embodiments, R 1 is an optionally substituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is a substituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is an optionally monosubstituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is an optionally disubstituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is an optionally trisubstituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is a substituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is a monosubstituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is a disubstituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is a trisubstituted 5-10 membered heteroaryloxy. In some embodiments, R 1 is substituted with one or more independently selected C1-C6 alkyl (e.g., isopropyl and / or t-butyl). 1 is substituted with one or more independently selected C2-C6 alkenyl (e.g., isopropenyl). 1The 5-10 membered heteroaryloxy is substituted with one or more independently selected C3-C6 cycloalkyl, which is optionally substituted with an optionally substituted C1-C6 alkyl. For example, R 1 The 5- to 10-membered heteroaryloxy is [ka] For example, R 1 The 5- to 10-membered heteroaryloxy is [ka] In some embodiments, R 1 is unsubstituted 5-10 membered heteroaryloxy. In some embodiments, R 1 In some embodiments, the 5- to 10-membered heteroaryloxy is a 5- to 6-membered heteroaryloxy. 1 The 5- to 10-membered heteroaryloxy is isothiazolyl, pyridyl, or 1,3,4-triazolyl.

[0105] In some embodiments, R 1 is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 1 is unsubstituted 5-10 membered heteroaryl. In some embodiments, R 1 is a substituted 5-10 membered heteroaryl. In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R1 is an unsubstituted 5-6 membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, fluzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0106] In some embodiments, R 2 is an optionally substituted 5-10 membered heteroaryl.

[0107] In some embodiments, R 2 is an optionally substituted 5-6 membered heteroaryl.

[0108] In some embodiments, R 2 is an optionally substituted 5-membered heteroaryl. In some embodiments, R 2 is an unsubstituted 5-membered heteroaryl. In some embodiments, R 2 is a substituted 5-membered heteroaryl. In some embodiments, R 2 The 5-membered heteroaryl of R is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or 1,2,5-oxadiazolyl. 2 The 5-membered heteroaryl is pyrazol-5-yl.

[0109] In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl. In some embodiments, R 2 is an unsubstituted 6-membered heteroaryl. In some embodiments, R 2 is a substituted 6-membered heteroaryl. In some embodiments, R 2 The 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0110] In some embodiments, R 2 is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R 2 is a substituted 9-10 membered heteroaryl. In some embodiments, R 2 is unsubstituted 9-10 membered heteroaryl. In some embodiments, R 2 The 9- to 10-membered heteroaryl is pyrido[2,3-d]pyrimidine, imidazo[1,2-c]pyrimidine, imidazo[1,2-b]pyridazine, thiazolo[5,4-c]pyridine, quinoline, pyrazolo[1,5-a]pyrazine, or pyrazolo[1,5-a]pyridine.

[0111] In some embodiments, R 2 is an optionally substituted 5- to 9-membered heterocyclyl.

[0112] In some embodiments, R 2 is an optionally substituted 5-6 membered heterocyclyl.

[0113] In some embodiments, R 2 is an optionally substituted 5-membered heterocyclyl. In some embodiments, R 2 is an unsubstituted 5-membered heterocyclyl. In some embodiments, R 2 is a substituted 5-membered heterocyclyl. In some embodiments, R 2The 5-membered heterocyclyl is pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, thiazolidin ... and thiazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanthioneyl, oxazolidinethionyl, imidazolidinethionyl, and isothiazolidinonyl.

[0114] In some embodiments, R 2 is an optionally substituted 6-membered heterocyclyl. In some embodiments, R 2 is an unsubstituted 6-membered heterocyclyl. In some embodiments, R 2 is a substituted 6-membered heterocyclyl. In some embodiments, R 2 and the 6-membered heterocyclyl is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidinedione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl. In some embodiments, R 2is piperidin-4-yl.

[0115] In some embodiments, R 2 is an optionally substituted 9-membered heterocyclyl. In some embodiments, R 2 is a substituted 9-membered heterocyclyl. In some embodiments, R 2 is an unsubstituted 9-membered heterocyclyl. In some embodiments, R 2 The 9-membered heterocyclyl is 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.

[0116] In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is unsubstituted phenyl. In some embodiments, R 2 is a substituted phenyl. In some embodiments, R 2 is monosubstituted phenyl. In some embodiments, R 2 is a disubstituted phenyl.

[0117] In some embodiments, R 2 The group is substituted with 1 to 3 substituents selected from the group consisting of -SO2NH2, -F, cyano, -CHOMe, -CO2NH2, methyl, -CH2OCF3, pyrazolyl optionally substituted with 1 to 2 methyls, pyrazolyl optionally substituted with 1 to 2 substituents selected from methyl and isopropoxymethyl, 1,2,4-triazolyl optionally substituted with 1 to 2 methyls, and tetrazolyl optionally substituted with 1 to 2 methyls.

[0118] In some embodiments, R 2 The group is substituted with an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2 In some embodiments, the R group is substituted with an unsubstituted 5-10 membered heteroaryl. 2In some embodiments, the R group is substituted with a 5-10 membered heteroaryl. 2 The group is substituted with a 5-10 membered heteroaryl that is substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.

[0119] In some embodiments, R 2 The group is substituted with 1 to 3 substituents selected from the group consisting of -SO2NH2, -F, -CH2OMe, and -CO2NH2.

[0120] In some embodiments, R 2 The group is substituted with 1 to 3 substituents, where one is -(SO2)NR'R", where R' and R" are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-9 membered heterocyclyl, or optionally substituted 3-10 membered cycloalkyl.

[0121] In some embodiments, R ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is unsubstituted C1-C6 alkyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is unsubstituted C1-C3 alkyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’ The other of is methyl, ethyl, or propyl.

[0122] In some embodiments, R ’ and R ’’ one of which is hydrogen and R’ and R ’’ and the other of R is a substituted C1-C6 alkyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is C1-C6 alkyl substituted with 1-5 halogens. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ The other of the above is C1-C4 alkyl substituted with 1 to 3 halogens.

[0123] In some embodiments, R ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is unsubstituted C1-C6 alkoxy. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ The other of these is unsubstituted C1-C3 alkoxy.

[0124] In some embodiments, R ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is a substituted C1-C6 alkoxy. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is C1-C6 alkoxy substituted with 1-5 halogens. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ The other is C1-C4 alkoxy substituted with 1 to 3 halogens.

[0125] In some embodiments, R ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is C-C cycloalkyl optionally substituted with C-C alkyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is C-C cycloalkyl substituted with C-C alkyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ The other of the is C3-C6 cycloalkyl substituted with 1 to 3 halogens.

[0126] In some embodiments, R ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is unsubstituted C-C cycloalkyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is unsubstituted C-C cycloalkyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ The other of is unsubstituted cyclopropyl.

[0127] In some embodiments, R ’ and R ’’ is hydrogen, and R ’and R ” and the other of R is an optionally substituted 5-10 membered heteroaryl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is unsubstituted 5-10 membered heteroaryl. ’ and R ’’ is hydrogen, and R ’ and R ” and the other of R is a substituted 5-10 membered heteroaryl. ’ and R ’’ is hydrogen, and R ’ and R ” and the other of R is an optionally substituted 5-6 membered heteroaryl. ’ and R ’’ is hydrogen, and R ’ and R ” and the other of R is an optionally substituted 5-6 membered heteroaryl substituted with an optionally substituted C1-C6 alkyl. ’ and R ’’ is hydrogen, and R ’ and R ” The other of is an optionally substituted 5-6 membered heteroaryl substituted with C1-C6 alkyl.

[0128] In some embodiments, R ’ and R ’’ is hydrogen, and R ’ and R ” and the other of R is an optionally substituted 5-9 membered heterocyclyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is unsubstituted 5-9 membered heterocyclyl. ’ and R’’ one of which is hydrogen and R ’ and R ’’ and the other of R is a substituted 5- to 9-membered heterocyclyl. ’ and R ’’ one of which is hydrogen and R ’ and R ’’ and the other of R is an optionally substituted 5- to 6-membered heterocyclyl. ’ and R ’’ is hydrogen, and R ’ and R ” and the other of R is an optionally substituted 5-6 membered heterocyclyl substituted with an optionally substituted C1-C6 alkyl. ’ and R ’’ is hydrogen, and R ’ and R ” The other of is an optionally substituted 5- to 6-membered heterocyclyl substituted with C1-C6 alkyl.

[0129] In some embodiments, R 2 The group is substituted with 1 to 3 substituents, where one is -(SO2)R', where R' is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-9 membered heterocyclyl, or optionally substituted 3-8 membered cycloalkyl.

[0130] In some embodiments, R' is unsubstituted C1-C6 alkyl. In some embodiments, R' is unsubstituted C1-C3 alkyl. In some embodiments, R' is methyl, ethyl, or propyl.

[0131] In some embodiments, R' is a substituted C1-C6 alkyl. In some embodiments, R' is a C1-C6 alkyl substituted with 1-5 halogens. In some embodiments, R' is a C1-C4 alkyl substituted with 1-3 halogens.

[0132] In some embodiments, R' is unsubstituted C1-C6 alkoxy. In some embodiments, R' is unsubstituted C1-C3 alkoxy.

[0133] In some embodiments, R' is a substituted C1-C6 alkoxy. In some embodiments, R' is a C1-C6 alkoxy substituted with 1-5 halogens. In some embodiments, R' is a C1-C4 alkoxy substituted with 1-3 halogens.

[0134] In some embodiments, R' is C3-C10 cycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, R' is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, R' is C3-C6 cycloalkyl substituted with 1-3 halogens.

[0135] In some embodiments, R' is unsubstituted C3-C10 cycloalkyl. In some embodiments, R' is unsubstituted C3-C7 cycloalkyl. In some embodiments, R' is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R' is unsubstituted cyclopropyl.

[0136] In some embodiments, R' is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R' is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R' is a substituted 5-10 membered heteroaryl. In some embodiments, R' is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R' is an optionally substituted 5-6 membered heteroaryl substituted with an optionally substituted C1-C6 alkyl. In some embodiments, R' is an optionally substituted 5-6 membered heteroaryl substituted with a C1-C6 alkyl.

[0137] In some embodiments, R' is an optionally substituted 5-9 membered heterocyclyl. In some embodiments, R' is an unsubstituted 5-9 membered heterocyclyl. In some embodiments, R' is a substituted 5-9 membered heterocyclyl. In some embodiments, R' is an optionally substituted 5-6 membered heterocyclyl. In some embodiments, R' is an optionally substituted 5-6 membered heterocyclyl substituted with an optionally substituted C1-C6 alkyl. In some embodiments, R' is an optionally substituted 5-6 membered heterocyclyl substituted with a C1-C6 alkyl.

[0138] In some embodiments, R 2 The group is substituted with one -SO2NH2 and one -F.

[0139] In some embodiments, R 2 The group is substituted with one -SO2NH2.

[0140] In some embodiments, R 2 The group is substituted with one —(SO)C-C cycloalkyl. In some embodiments, R 2 The base is one [ka] is replaced by .

[0141] In some embodiments, R 2 The group is substituted with one —(SO2)NHC3—C6 cycloalkylCF3. In some embodiments, R 2 The base is one [ka] is replaced by .

[0142] In some embodiments, R 2 The group is substituted with one -(C=O)C1-C6 alkyl. In some embodiments, R 2 The base is It is substituted with one -(C=O)CH3.

[0143] In some embodiments, R 2 The group is substituted with one -(C=O)C3-C6 cycloalkyl.

[0144] In some embodiments, R 2 The group is substituted with one -(C=O)NH2.

[0145] In some embodiments, R 2 The group is substituted with one -NH(SO2)C1-C6 alkyl. In some embodiments, R 2 The group is substituted with one -NH(SO2)C1-C3 alkyl. In some embodiments, R 2 The base is one [ka] is replaced by .

[0146] In some embodiments, R 2 The group is substituted with one -NH(SO)- optionally substituted C-C cycloalkyl. In some embodiments, R 2The group is substituted with one -NH(SO)- optionally substituted C-C cycloalkyl. In some embodiments, R 2 The group is substituted with one -NH(SO2)C3-C6 cycloalkyl. In some embodiments, R 2 The group is substituted with one -NH(SO2)-substituted C3-C6 cycloalkyl. In some embodiments, R 2 The group is substituted with one -NH(SO2)-halogen substituted C3-C6 cycloalkyl. In some embodiments, R 2 The group is substituted with one -NH(SO2)-fluoro substituted C3-C6 cycloalkyl.

[0147] In some embodiments, R 2 The group is one -(S(=NR L )(=O)) is substituted with C1-C6 alkyl, wherein R L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R 2 The group is one -(S(=NR L )(=O)) is substituted with C1-C3 alkyl, wherein R L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R 2 The base is one [ka] wherein R L is H or C1-C6 alkyl optionally substituted with hydroxyl.

[0148] In some embodiments, R 2 The group is one -(S(=NR L )(=O)) is substituted with C1-C6 haloalkyl, wherein R L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R 2The group is one -(S(=NR L )(=O)) is substituted with C1-C3 haloalkyl, wherein R L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R 2 The base is one [ka] wherein R L is H or C1-C6 alkyl optionally substituted with hydroxyl.

[0149] In some embodiments, R 2 The group is one -(S(=NR L )(=O))C-C cycloalkyl. In some embodiments, R 2 The base is one [ka] wherein R L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R L is hydrogen. In some embodiments, R L is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R L is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, R L teeth, [ka] In some embodiments, R L is unsubstituted C1-C6 alkyl. In some embodiments, R L is methyl.

[0150] In some embodiments, R 2 The base is [ka] is substituted with one substituent selected from the group consisting of:

[0151] In some embodiments, R 2 The group is one -(SO2)NR H R I wherein R H and R I are independently H and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, R 2 The group is one -(SO2)NR H R I wherein R H and R I One of R is H and the other is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. 2 The group is one -(SO2)NR H R I wherein R H and R I One of R is H and the other is C1-C6 alkyl. 2 The group is one -(SO2)NR H R I wherein R H and R I One of R is H and the other is C1-C6 alkyl substituted with hydroxyl. In some embodiments, R 2 The base is one [ka] is substituted with, i.e., R H and R I are hydrogen atoms.

[0152] In some embodiments, R 2 The base is [ka] is substituted with one selected from the group consisting of:

[0153] In some embodiments, X is —(CH) optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0154] In some embodiments, X is —(CH) optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0155] In some embodiments, X is —(CH) optionally substituted with three substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0156] In some embodiments, X is —(CH) optionally substituted with two substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0157] In some embodiments, X is —(CH) optionally substituted with one substituent independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0158] In some embodiments, X is —(CH) substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. aC3-C8 cycloalkylene-(CH2) b -It is.

[0159] In some embodiments, X is —(CH) substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0160] In some embodiments, X is —(CH) substituted with three substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0161] In some embodiments, X is —(CH) substituted with two substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0162] In some embodiments, X is —(CH) substituted with one substituent independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. a C3-C8 cycloalkylene-(CH2) b -It is.

[0163] In some embodiments, X is unsubstituted -(CH) a C3-C8 cycloalkylene-(CH2) b -It is.

[0164] In some embodiments, X is —(CH) a C3-C8 cycloalkylene-(CH2) b - is -(CH2) a C4-C6 cycloalkylene-(CH2) b -It is.

[0165] In some embodiments, X is —(CH) a C3-C8 cycloalkylene-(CH2) b - is cyclopentylene.

[0166] In some embodiments, X is —(CH) optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl. a C5-C8 cycloalkenylene-(CH2) b -It is.

[0167] In some embodiments, X is —(CH) optionally substituted with two substituents independently selected from halogen and C1-C6 alkyl. a C5-C8 cycloalkenylene-(CH2) b -It is.

[0168] In some embodiments, X is —(CH) optionally substituted with one substituent independently selected from halogen and C1-C6 alkyl. a C5-C8 cycloalkenylene-(CH2) b -It is.

[0169] In some embodiments, X is —(CH) substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl. a C5-C8 cycloalkenylene-(CH2) b -It is.

[0170] In some embodiments, X is —(CH) substituted with two substituents independently selected from halogen and C1-C6 alkyl. a C5-C8 cycloalkenylene-(CH2) b -It is.

[0171] In some embodiments, X is —(CH) substituted with one substituent independently selected from halogen and C1-C6 alkyl. a C5-C8 cycloalkenylene-(CH2) b-It is.

[0172] In some embodiments, X is unsubstituted -(CH) a C5-C8 cycloalkenylene-(CH2) b -It is.

[0173] In some embodiments, X is —(CH) a Phenylene-(CH2) b -It is.

[0174] In some embodiments, X is —(CH) a (4-8 membered heteroarylene)-(CH2) b -It is.

[0175] In some embodiments, X is —(CH) a (4-8 membered heterocyclylene)-(CH2) b -It is.

[0176] In some embodiments, X is C2-C6 alkylene.

[0177] In some embodiments, X is C2-C4 alkylene.

[0178] In some embodiments, X is [ka] is.

[0179] In some embodiments, X is [ka] is.

[0180] In some embodiments, X is [ka] is.

[0181] In some embodiments, X is [ka] is.

[0182] In some embodiments, X is [ka] is.

[0183] In some embodiments, X is [ka] is.

[0184] In some embodiments, X is [ka] is.

[0185] In some embodiments, X is [ka] is.

[0186] In some embodiments, X is [ka] is.

[0187] In some embodiments, X is [ka] is.

[0188] In some embodiments, X is [ka] is.

[0189] In some embodiments, X is [ka] is.

[0190] In some embodiments, X is [ka] is.

[0191] In some embodiments, X is [ka] is.

[0192] In some embodiments, X is [ka] is.

[0193] In some embodiments, (CH) a -(CH2) linked to a C3-C8 cycloalkylene-(CH2) b When the -cycloalkylene ring member is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, (CH) a -(CH2) linked to a C3-C8 cycloalkylene-(CH2) b When the -cycloalkylene ring member is a stereocenter, the stereochemical configuration of said stereocenter is (S).

[0194] In some embodiments, (CH) b -(CH2) linked to a C3-C8 cycloalkylene-(CH2) b When the -cycloalkylene ring member is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, (CH) b-(CH2) linked to a C3-C8 cycloalkylene-(CH2) b When the -cycloalkylene ring member is a stereocenter, the stereochemical configuration of said stereocenter is (S).

[0195] In some embodiments, (CH) a -(CH2) linked to a C3-C8 cycloalkenylene-(CH2) b When the -cycloalkenylene ring member is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, (CH) a -(CH2) linked to a C3-C8 cycloalkenylene-(CH2) b When the -cycloalkenylene ring member is a stereocenter, the stereochemical configuration of said stereocenter is (S).

[0196] In some embodiments, (CH) b -(CH2) linked to a C3-C8 cycloalkenylene-(CH2) b When the -cycloalkenylene ring member is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, (CH) b -(CH2) linked to a C3-C8 cycloalkenylene-(CH2) b When the -cycloalkenylene ring member is a stereocenter, the stereochemical configuration of said stereocenter is (S).

[0197] In some embodiments, (CH) b -(CH2) linked to a C3-C8 Heterocyclylene-(CH2) b When the - heterocyclylene ring member is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, (CH) b -(CH2) linked to a C3-C8 Heterocyclylene-(CH2) bWhen the - heterocyclylene ring member is a stereocenter, the stereochemical configuration of said stereocenter is (S).

[0198] In some embodiments, a is 0 or 1. In some embodiments, a is 1 or 2. In some embodiments, a is 0 or 2. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, a is 2.

[0199] In some embodiments, b is 0 or 1. In some embodiments, b is 1 or 2. In some embodiments, b is 0 or 2. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2.

[0200] In some embodiments, a is 0 and b is 0. In some embodiments, a is 0 and b is 1. In some embodiments, a is 0 and b is 2. In some embodiments, a is 1 and b is 0. In some embodiments, a is 1 and b is 1. In some embodiments, a is 1 and b is 2. In some embodiments, a is 2 and b is 0. In some embodiments, a is 2 and b is 1. In some embodiments, a is 2 and b is 2.

[0201] In some embodiments, X 1 is CR X1 is.

[0202] In some embodiments, X 2 is CR X2 In some embodiments, R X1 is C1-C6 alkyl. In some embodiments, R X1 is methyl. In some embodiments, R X1 is C1-C6 alkoxy. In some embodiments, R X1 is methoxy. In some embodiments, RX1 is C1-C6 haloalkyl. In some embodiments, R X1 is trifluoromethyl. In some embodiments, R X1 is C1-C6 haloalkoxy. In some embodiments, R X1 is trifluoromethoxy.

[0203] In some embodiments, R X1 is C-C cycloalkyl. In some embodiments, R X1 is cyclopropyl. In some embodiments, R X1 is C-C cycloalkoxy. In some embodiments, R X1 is cyclopropoxy. In some embodiments, R X1 is cyano. In some embodiments, R X1 is halogen. In some embodiments, R X1 is hydrogen.

[0204] In some embodiments, R X2 is C1-C6 alkyl. In some embodiments, R X2 is methyl. In some embodiments, R X2 is C1-C6 alkoxy. In some embodiments, R X2 is methoxy. In some embodiments, R X2 is C1-C6 haloalkyl. In some embodiments, R X2 is trifluoromethyl. In some embodiments, R X2 is C1-C6 haloalkoxy. In some embodiments, R X2 is trifluoromethoxy. In some embodiments, R X2 is C-C cycloalkyl. In some embodiments, R X2 is cyclopropyl. In some embodiments, R X2 is C-C cycloalkoxy. In some embodiments, R X2is cyclopropoxy. In some embodiments, R X2 is cyano. In some embodiments, R X2 is halogen. In some embodiments, R X2 is hydrogen.

[0205] In some embodiments, X 1 is N.

[0206] In some embodiments, X 2 is N.

[0207] In some embodiments, X 1 is N and X 2 is N.

[0208] In some embodiments, Y is —C(═O)NR C (CR D R E ) n -, where * represents X 1 ~X 2 Indicates the connection points to the ring.

[0209] In some embodiments, Y is *-NR C C(=O)(CR D R E ) n -, where * represents X 1 ~X 2 Indicates the connection points to the ring.

[0210] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0211] In some embodiments, each R D and R E In some embodiments, each R D and R E is R D and R E are the same except for one of the

[0212] In some embodiments, each R D and R E is hydrogen.

[0213] In some embodiments, each R D and R E is fluoro.

[0214] In some embodiments, R D and R E is methyl.

[0215] In some embodiments, R D and R E One of the R D and R E is hydrogen.

[0216] In some embodiments, Y is —NR C -It is.

[0217] In some embodiments, R C is a C1-C6 alkyl.

[0218] In some embodiments, R C is methyl.

[0219] In some embodiments, R C is hydrogen.

[0220] In some embodiments, Y is —O—.

[0221] In some embodiments, m is 0.

[0222] In some embodiments, m is 1.

[0223] In some embodiments, m is 2.

[0224] In some embodiments, R 2is an optionally substituted 5-6 membered heteroaryl.

[0225] In some embodiments, R 2 is an optionally substituted 5-membered heteroaryl.

[0226] In some embodiments, R 2 is an unsubstituted 5-membered heteroaryl.

[0227] In some embodiments, R 2 is a substituted 5-membered heteroaryl.

[0228] In some embodiments, R 2 The 5-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or 1,2,5-oxadiazolyl.

[0229] In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl.

[0230] In some embodiments, R 2 is an unsubstituted 6-membered heteroaryl.

[0231] In some embodiments, R 2 is a substituted 6-membered heteroaryl.

[0232] In some embodiments, R 2 The 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0233] In some embodiments, R 2 is an optionally substituted 5-6 membered heterocyclyl.

[0234] In some embodiments, R 2 is an optionally substituted 5-membered heterocyclyl.

[0235] In some embodiments, R 2 is an unsubstituted 5-membered heterocyclyl.

[0236] In some embodiments, R 2 is a substituted 5-membered heterocyclyl.

[0237] In some embodiments, R 2 The 5-membered heterocyclyl is pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, thiazolidin ... and thiazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanthioneyl, oxazolidinethionyl, imidazolidinethionyl, and isothiazolidinonyl.

[0238] In some embodiments, R 2 is an optionally substituted 6-membered heterocyclyl.

[0239] In some embodiments, R 2 is an unsubstituted 6-membered heterocyclyl.

[0240] In some embodiments, R 2 is a substituted 6-membered heterocyclyl.

[0241] In some embodiments, R 2The 6-membered heterocyclyl is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidinedione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl.

[0242] In some embodiments, R 2 is optionally substituted phenyl.

[0243] In some embodiments, R 2 is unsubstituted phenyl.

[0244] In some embodiments, R 2 is a substituted phenyl. In some embodiments, R 2 is monosubstituted phenyl. In some embodiments, R 2 is a disubstituted phenyl.

[0245] In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof is a compound of formula (AA): [ka] or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is a compound of Formula (AA1): [ka] or a pharmaceutically acceptable salt thereof.

[0247] Further provided herein is a compound of formula (B): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 Ga-NR A R B , -C(=O)NR A R B , -OC(=O)NR A R B , optionally substituted 5-10 membered heteroaryloxy, or optionally substituted 5-10 membered heteroaryl; Each R A and R B are independently hydrogen, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl; X is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; a C3-C8 cycloalkylene-(CH2) b -; -(CH2) optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl a C5-C8 cycloalkenylene-(CH2) b -;-(CH2) a Phenylene-(CH2) b -;-(CH2) a Heteroarylene-(CH2) b -;-(CH2) a Heterocyclylene-(CH2) b -; and C2-C6 alkylene, a and b are independently 0, 1, or 2; Ring A is an optionally substituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl, or an optionally substituted 9-10-membered heteroaryl; Y is -NR C -, *-C(=O)NR C (CRD R E ) n -, *-NR C C(=O)(CR D R E ) n -, or -O-, where * indicates the point of attachment to ring A; R C is hydrogen or C1-C6 alkyl, n is 0, 1, or 2; Each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl; R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl.

[0248] R 1 , R 2 , R A , R B , R C , R D , R E , X, Y, a, b, m, and n are further defined as disclosed in formula (A) above.

[0249] In some embodiments, ring A is an optionally substituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl. In some embodiments, ring A is a substituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl. In some embodiments, ring A is an unsubstituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrazinonyl. In some embodiments, ring A is pyridazinyl.

[0250] In some embodiments, ring A is an optionally substituted 9-10 membered heteroaryl. In some embodiments, ring A is a substituted 9-10 membered heteroaryl. In some embodiments, ring A is an unsubstituted 9-10 membered heteroaryl. In some embodiments, the 9- to 10-membered heteroaryl is pyrido[2,3-d]pyrimidine, quinazoline, cinnoline, isoquinolin-1(2H)-one, quinolin-2(1H)-one, imidazo[1,2-c]pyrimidine, imidazo[1,2-b]pyridazine, thiazolo[5,4-c]pyridine, quinoline, isoquinoline, pyrazolo[1,5-a]pyrazine, pyrrolo[1,2-a]pyrazine, 7-azaindole, 4-azaindole, 5-azaindole, 6-azaindole, benzimidazole, or pyrazolo[1,5-a]pyridine. In some embodiments, the 9- to 10-membered heteroaryl is pyrrolo[1,2-a]pyrazine.

[0251] Provided herein is a compound of formula (BI) or a compound of formula (B-II), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 Ga-NR A R B , -C(=O)NR A R B , -OC(=O)NR A R B or an optionally substituted 5-10 membered heteroaryl; Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl; X is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; a C3-C8 cycloalkylene-(CH2) b-; -(CH2) optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl a C5-C8 cycloalkenylene-(CH2) b -;-(CH2) a Phenylene-(CH2) b -;-(CH2) a Heteroarylene-(CH2) b -;-(CH2) a Heterocyclylene-(CH2) b -; and C2-C6 alkylene, a and b are independently 0, 1, or 2; Y is -NR C -, *-C(=O)NR C (CR D R E ) n -, *-NR C C(=O)(CR D R E ) n -, or -O-, where * indicates the point of attachment to the pyrazinyl ring; R C is hydrogen or C1-C6 alkyl, n is 0, 1, or 2; Each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl; R 2 is optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, or optionally substituted 5- to 6-membered heterocyclyl.

[0252] Provided herein is a compound of formula (B-IIIA), a compound of formula (B-IIIB), a compound of formula (B-IVA), or a compound of formula (B-IVA), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 Ga-NR A RB , -C(=O)NR A R B , -OC(=O)NR A R B or an optionally substituted 5-10 membered heteroaryl; Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl; X is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; a C3-C8 cycloalkylene-(CH2) b -; -(CH2) optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl a C5-C8 cycloalkenylene-(CH2) b -;-(CH2) a Phenylene-(CH2) b -;-(CH2) a Heteroarylene-(CH2) b -;-(CH2) a Heterocyclylene-(CH2) b -; and C2-C6 alkylene, a and b are independently 0, 1, or 2; Y is -NR C -, *-C(=O)NR C (CR D R E ) n -, *-NR C C(=O)(CR D R E ) n -, or -O-, where * indicates the point of attachment to the pyrazinonyl ring; R C is hydrogen or C1-C6 alkyl, n is 0, 1, or 2; Each R D and R Eare independently hydrogen, fluoro, or C1-C6 alkyl; R 2 is optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, or optionally substituted 5- to 6-membered heterocyclyl.

[0253] Provided herein is a compound of formula (BV) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 Ga-NR A R B , -C(=O)NR A R B , -OC(=O)NR A R B or an optionally substituted 5-10 membered heteroaryl; Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl; X is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; a C3-C8 cycloalkylene-(CH2) b -; -(CH2) optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl a C5-C8 cycloalkenylene-(CH2) b -;-(CH2) a Phenylene-(CH2) b -;-(CH2) a Heteroarylene-(CH2) b -;-(CH2) a Heterocyclylene-(CH2) b -; and C2-C6 alkylene, a and b are independently 0, 1, or 2; Y is -NR C -, *-C(=O)NR C (CR D R E ) n -, *-NR C C(=O)(CR D R E ) n -, or -O-, where * indicates the point of attachment to the pyrrolo[1,2-a]pyrazine ring; R C is hydrogen or C1-C6 alkyl, n is 0, 1, or 2; Each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl; R 2 is optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, or optionally substituted 5- to 6-membered heterocyclyl.

[0254] In some embodiments, the compound of Formula (A) is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-122

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-129

Table 1-131

Table 1-133

Table 1-136

Table 1-138

Table 1-139

Table 1-141

Table 1-145

Table 1-147

Table 1-149

Table 1-150

Table 1-151

Table 1-152

Table 1-153

Table 1-154

Table 1-155

Table 1-156

Table 1-157

Table 1-158

Table 1-159

Table 1-161

Table 1-166

Table 1-171

Table 1-176

Table 1-177

Table 1-178

Table 1-179

Table 1-186

Table 1-191

[0255] Treatment method Some embodiments provide a method of treating cancer (e.g., a CDK2-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein is a method for treating a CDK2-associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation in the expression or activity or level of the CDK2 gene, CDK2 protein, or any of them in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the CDK2 gene, CDK2 protein, or expression or activity or levels of any of them (a CDK2-associated cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the cyclin A2 gene, cyclin A2 protein, or expression or activity or levels of any of them (a CDK2-associated cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the cyclin E1 gene, cyclin E1 protein, or expression or activity or levels of any of them (a CDK2-associated cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). In some embodiments, the subject has been identified or diagnosed with cancer involving dysregulated expression or activity or levels of the cyclin E2 gene, cyclin E2 protein, or any of them (CDK2-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has been identified or diagnosed with cancer involving dysregulated expression or activity or levels of the CDK2 gene, CDK2 protein, cyclin A2 gene, cyclin A2 protein, cyclin E1 gene, cyclin E1 protein, cyclin E2 gene, cyclin E2 protein, or any of them (or any combination thereof).

[0257] In some embodiments, the subject has a tumor that is positive for dysregulation of the CDK2 gene, CDK2 protein, or expression or activity or levels of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). The subject may be a subject whose tumor is positive for dysregulation of the CDK2 gene, CDK2 protein, or expression or activity or levels of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). The subject may be a subject whose tumor has dysregulation of the CDK2 gene, CDK2 protein, or expression or activity or levels of any of them (e.g., the tumor is identified as such using an assay or kit approved by a regulatory agency, e.g., approved by the FDA).

[0258] In some embodiments, the subject has a tumor that is positive for dysregulation of the cyclin A2 gene, the cyclin A2 protein, or any of their expression, activity, or levels (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). The subject may be a subject whose tumor is positive for dysregulation of the cyclin A2 gene, the cyclin A2 protein, or any of their expression, activity, or levels (e.g., identified as positive using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). The subject may be a subject whose tumor has dysregulation of the cyclin A2 gene, the cyclin A2 protein, or any of their expression, activity, or levels (e.g., the tumor is identified as such using an assay or kit approved by a regulatory agency, e.g., approved by the FDA).

[0259] In some embodiments, the subject has a tumor that is positive for dysregulation of the cyclin E1 gene, the cyclin E1 protein, or expression or activity or levels of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). The subject may be a subject whose tumor is positive for dysregulation of the cyclin E1 gene, the cyclin E1 protein, or expression or activity or levels of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). The subject may be a subject whose tumor has dysregulation of the cyclin E1 gene, the cyclin E1 protein, or expression or activity or levels of any of them (e.g., the tumor is identified as such using an assay or kit approved by a regulatory agency, e.g., approved by the FDA).

[0260] In some embodiments, the subject has a tumor that is positive for dysregulation of the cyclin E2 gene, the cyclin E2 protein, or expression or activity or levels of either of them (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). The subject may be a subject whose tumor is positive for dysregulation of the cyclin E2 gene, the cyclin E2 protein, or expression or activity or levels of either of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, e.g., approved by the FDA). The subject may be a subject whose tumor has dysregulation of the cyclin E2 gene, the cyclin E2 protein, or expression or activity or levels of either of them (e.g., the tumor is identified as such using an assay or kit approved by a regulatory agency, e.g., approved by the FDA).

[0261] In some embodiments, the subject has a tumor that is positive for dysregulation of expression or activity or levels of the CDK2 gene, CDK2 protein, cyclin A2 gene, cyclin A2 protein, cyclin E1 gene, cyclin E1 protein, cyclin E2 gene, cyclin E2 protein, or any of them (or any combination thereof).

[0262] In some embodiments, the dysregulation can be dysregulation that results in abnormal activation of the gene, protein, or any of their expression, activity, or levels. Activation can be via any suitable mechanism, including, but not limited to, gene amplification, activating mutations, activating translocations, activating transcription, epigenetic changes, and / or overexpression of the protein product of an oncogene. In some embodiments, the dysregulation can be dysregulation that results in abnormal inactivation of the gene, protein, or any of their expression, activity, or levels. Inactivation can be via any suitable mechanism, including, but not limited to, gene deletion, inactivating mutations, inactivating translocations, silencing transcription, epigenetic changes, and degradation of the gene's mRNA and / or protein product. Typically, as used herein, dysregulation results in abnormalities in the cell cycle.

[0263] In some embodiments, the subject is suspected of having a CDK2-associated cancer.

[0264] In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the CDK2 gene, CDK2 protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the cyclin A2 gene, cyclin A2 protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the cyclin E1 gene, cyclin E1 protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the cyclin E2 gene, cyclin E2 protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the CDK2 gene, CDK2 protein, cyclin A2 gene, cyclin A2 protein, cyclin E1 gene, cyclin E1 protein, cyclin E2 gene, cyclin E2 protein, or any of them (or any combination thereof).

[0265] In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulation of the CDK2 gene, CDK2 protein, or any of their expression, activity, or levels (CDK2-associated cancer) based on histological examination. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulation of the cyclin A2 gene, cyclin A2 protein, or any of their expression, activity, or levels (CDK2-associated cancer) based on histological examination. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulation of the cyclin E1 gene, cyclin E1 protein, or any of their expression, activity, or levels (CDK2-associated cancer) based on histological examination. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulation of the cyclin E2 gene, cyclin E2 protein, or any of their expression, activity, or levels (CDK2-associated cancer) based on histological examination. In some embodiments, the subject has been identified or diagnosed with a cancer that is determined to be associated with dysregulation of expression or activity or levels of the CDK2 gene, CDK2 protein, cyclin A2 gene, cyclin A2 protein, cyclin E1 gene, cyclin E1 protein, cyclin E2 gene, cyclin E2 protein, or any of them (or any combination thereof) based on histological examination.

[0266] In some embodiments, the subject has clinical documentation indicating that the subject has a tumor that is resistant to one or more previous therapies, e.g., resistant to CDK4 / CDK6 inhibition. In some embodiments, the subject has a cancer that is resistant to one or more previous therapies, e.g., resistant to CDK4 / CDK6 inhibition.

[0267] In some embodiments, the subject has a tumor that is resistant to one or more previous therapies, e.g., resistant to CDK4 / CDK6 inhibition. In some embodiments, the subject has a tumor suspected of being resistant to one or more previous therapies, e.g., suspected of being resistant to CDK4 / CDK6 inhibition.

[0268] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a pediatric tumor (e.g., neuroblastoma), brain tumor (e.g., glioblastoma), sarcoma, colorectal cancer, lung cancer (including small cell lung carcinoma, non-small cell carcinoma, squamous cell carcinoma, and adenocarcinoma), thyroid cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer, skin cancer (e.g., melanoma), bile duct cancer (e.g., cholangiocarcinoma), or brain cancer.

[0269] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a solid tumor. In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a pediatric tumor (e.g., a neuroblastoma). In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a brain tumor (e.g., a glioblastoma).

[0270] In some embodiments, the cancer (eg, a CDK2-associated cancer) is a sarcoma.

[0271] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is colorectal cancer, lung cancer (including small cell lung carcinoma, non-small cell carcinoma, squamous cell carcinoma, and adenocarcinoma), thyroid cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer (including renal cell carcinoma), liver cancer (including hepatocellular carcinoma), pancreatic cancer, stomach (i.e., gastric) cancer, skin cancer (e.g., melanoma), bile duct cancer (e.g., cholangiocarcinoma), or brain cancer. In some embodiments, the cancer (e.g., a CDK2-associated cancer) is small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, adenocarcinoma, renal cell carcinoma, hepatocellular carcinoma, gastric cancer, or melanoma, cholangiocarcinoma.

[0272] In some embodiments, the cancer (eg, a CDK2-associated cancer) is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and gastric cancer.

[0273] In some embodiments, the cancer (eg, a CDK2-associated cancer) is selected from the group consisting of breast cancer, ovarian cancer, and colorectal cancer.

[0274] In some embodiments, the cancer (eg, a CDK2-associated cancer) is colorectal cancer.

[0275] In some embodiments, the cancer (eg, a CDK2-associated cancer) is selected from the group consisting of breast cancer and ovarian cancer.

[0276] In some embodiments, the cancer (eg, a CDK2-associated cancer) is ovarian cancer.

[0277] In some embodiments, the cancer (eg, a CDK2-associated cancer) is breast cancer.

[0278] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a breast cancer selected from the group consisting of estrogen receptor (ER)-positive / hormone receptor (HR)-positive breast cancer, HER2-negative breast cancer, ER-positive / HR-positive breast cancer, HER2-positive breast cancer; triple-negative breast cancer (TNBC); and inflammatory breast cancer.

[0279] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a breast cancer selected from the group consisting of endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, and breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced breast cancer, metastatic breast cancer, or completely resected breast cancer.

[0280] As used herein, the term "resection" or "resected" refers to the surgical removal of malignant tissue characteristic of cancer from a patient (e.g., any of the cancer types described herein, such as solid tumors). According to one embodiment, resection refers to the removal of malignant tissue such that the presence of any remaining malignant tissue in the patient is no longer detectable by available methods. According to another embodiment of the invention, resection refers to the removal of breast cancer such that the presence of any remaining cancer in the patient is no longer detectable.

[0281] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a resected cancer. In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a resected breast cancer.

[0282] In some embodiments, a compound of Formula (A) is administered to a subject as adjuvant therapy. Adjuvant therapy is treatment given in addition to primary therapy to kill any cancer cells that may have spread, even if the spread is not detectable by radiological or clinical tests. See, e.g., Paik et al., J. Natl. Cancer Inst., 92(24):1991-1998 (2000) and Paik et al., J. Natl. Cancer Inst., 94:852-854 (2002). In some embodiments, a compound of Formula (A) is administered to a subject as adjuvant cancer therapy, wherein the cancer (e.g., a CDK2-associated cancer) is breast cancer selected from the group consisting of estrogen receptor (ER)-positive / hormone receptor (HR)-positive breast cancer, HER2-negative breast cancer, ER-positive / HR-positive breast cancer, HER2-positive breast cancer, triple-negative breast cancer (TNBC), and inflammatory breast cancer.

[0283] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a hematological cancer, which may also be referred to as a hematopoietic or blood cancer or malignancy. In some embodiments, the hematological cancer is a leukemia such as acute lymphocytic leukemia (ALL; e.g., B-cell ALL or T-cell ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL; e.g., B-cell CLL (e.g., hairy cell leukemia) or T-cell CLL), chronic neutrophilic leukemia (CNL), or chronic myelomonocytic leukemia (CMML).

[0284] In some embodiments, the hematological cancer is a lymphoma such as Hodgkin's lymphoma (HL; e.g., B-cell HL or T-cell HL), non-Hodgkin's lymphoma (NHL that may be considered aggressive, e.g., B-cell NHL or T-cell NHL), follicular lymphoma (FL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), e.g., B-cell lymphoma (e.g., splenic marginal zone B-cell lymphoma), primary mediastinal large cell lymphoma (e.g., splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma (BL), lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or primary central nervous system (CNS) lymphoma. B-cell NHL can be diffuse large cell lymphoma (DLCL; e.g., diffuse large B-cell lymphoma (DLBCL; e.g., germinal center B-cell-like (GCB) DLBCL, or activated B-cell-like (ABC) DLBCL), and T-cell NHL can be precursor T-lymphoblastic lymphoma or peripheral T-cell lymphoma (PTCL). In turn, PTCL can be cutaneous T-cell lymphoma (CTCL), e.g., mycosis fungoides or Sézary syndrome, angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like cell lymphoma, or anaplastic large cell lymphoma.

[0285] In some embodiments, the hematological cancer may be a myeloproliferative disorder, such as polycythemia vera (PV), essential thrombocytosis (ET), myeloid metaplasia of unknown etiology (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, or hypereosinophilic syndrome (HES).

[0286] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a myelodysplastic syndrome, including, but not limited to, refractory anemia with or without ringed sideroblasts, 5q-syndrome with or without ringed sideroblasts, refractory anemia with multilineage dysplasia with or without ringed sideroblasts, refractory anemia with excess blasts I and II, refractory anemia with excess blasts in transition, chronic myelomonocytic leukemia, or unclassifiable myelodysplastic syndrome.

[0287] In some embodiments, the subject is a human.

[0288] The compounds of formula (A) and pharmaceutically acceptable salts thereof are also useful in the treatment of CDK2-associated cancers. Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having a CDK2-associated cancer, such as any of the exemplary CDK2-associated cancers disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of formula (A), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0289] In some aspects, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating cancer in a subject in need thereof, comprising (a) identifying the cancer as a CDK2-associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0290] Identifying a cancer in a subject as a CDK2-associated cancer Identifying a cancer can be performed by any suitable method. In some embodiments, identifying a cancer in a subject as a CDK2-associated cancer includes performing an assay to detect dysregulation in the expression, activity, or level of the CDK2 gene, CDK2 protein, or any of them (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2) in a sample from the subject. In some embodiments, the method further includes obtaining a sample (e.g., a biopsy sample) from the subject. The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0291] Also provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject identified as having a CDK2-associated cancer a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof.

[0292] Also provided herein is a method of treating a CDK2-associated cancer, comprising administering to a subject identified or diagnosed as having a CDK2-associated cancer a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0293] In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor. The term "selective CDK2 inhibitor," as used in the context of the compounds described herein, refers to a compound that exhibits an IC50 or IC60 required to inhibit one or more of CDK4, CDK6, CDK1, and / or CDK9 activity to the same extent in a standard phosphorylation assay, e.g., any of the assays described herein. 50an IC that is at least about 10-fold, about 25-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 750-fold, about 1,000-fold, about 1,500-fold, or about 2,000-fold smaller than the value 50 The present invention includes compounds that inhibit CDK2 activity at low levels.

[0294] For example, the compound of formula (A) or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK1 activity (e.g., the compound of formula (A) or a pharmaceutically acceptable salt thereof has an IC50 of 100 or less required to inhibit CDK1 activity to the same extent in a standard phosphorylation assay). 50 IC at least about 50, 100, 200, 300, 400, or 500 times less (or, in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the molar concentration 50 In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK4 activity (e.g., the compound of Formula (A) or a pharmaceutically acceptable salt thereof has an IC50 of 100 or more required to inhibit CDK4 activity to the same extent in a standard phosphorylation assay, such as those described herein). 50 an IC at least about 50, 100, 200, 300, 400, or 500 times less (or, in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the value 50 In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK6 activity (e.g., the compound of Formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity at an IC value greater than or equal to 100 μg / mL, and more ... 50an IC at least about 50, 100, 200, 300, 400, or 500 times less (or, in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the value 50 In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A) or a pharmaceutically acceptable salt thereof selectively inhibits CDK2 activity while sparing CDK4 activity and CDK6 activity (e.g., the compound of Formula (A) or a pharmaceutically acceptable salt thereof has an IC50 required to inhibit CDK4 activity and CDK6 activity to the same extent in a standard phosphorylation assay, such as those described herein). 50 an IC at least about 50, 100, 200, 300, 400, or 500 times less (or, in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the value 50 In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK9 activity (e.g., the compound of Formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity at an IC value greater than or equal to 100 μg / mL, in a standard phosphorylation assay, such as those described herein). 50 an IC at least about 50, 100, 200, 300, 400, or 500 times less (or, in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the value 50In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A) or a pharmaceutically acceptable salt thereof selectively inhibits CDK2 activity while sparing CDK1 activity, CDK4 activity, CDK6 activity, and CDK9 activity (e.g., the compound of Formula (A) or a pharmaceutically acceptable salt thereof has an IC50 required to inhibit CDK1 activity, CDK4 activity, CDK6 activity, and CDK9 activity to the same extent in a standard phosphorylation assay, such as those described herein). 50 an IC at least about 50, 100, 200, 300, 400, or 500 times less (or, in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the value 50 Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the CDK2 gene, CDK2 protein, or expression or activity or level of any of them; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0295] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of expression or activity or levels of a cyclin A2 gene, a cyclin A2 protein, a cyclin E1 gene, a cyclin E1 protein, a cyclin E2 gene, a cyclin E2 protein, or any one of these (or a combination thereof); and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0296] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the cyclin A2 gene, the cyclin A2 protein, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0297] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the cyclin E1 gene, the cyclin E1 protein, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0298] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the cyclin E2 gene, the cyclin E2 protein, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0299] Determining that a cancer is associated with dysregulation of expression, activity, or level of a CDK2 gene, CDK2 protein, cyclin A2 gene, cyclin A2 protein, cyclin E1 gene, cyclin E1 protein, cyclin E2 gene, cyclin E2 protein, or any of them (or any combination thereof) can be performed using any suitable method. In some embodiments, determining that a cancer in a subject is a CDK2-associated cancer comprises performing an assay to detect dysregulation of expression, activity, or level of a CDK2 gene, CDK2 protein, cyclin A2 gene, cyclin A2 protein, cyclin E1 gene, cyclin E1 protein, cyclin E2 gene, cyclin E2 protein, or any of them (or any combination thereof) in a sample from the subject. In some embodiments, the method further comprises obtaining a sample (e.g., a biopsy sample) from the subject. The assay can be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next-generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). Further provided herein is a method of treating a CDK2-related cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) identifying the cancer as a CDK2-related disease or disorder; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof. Further provided herein is a method for treating cancer in a subject in need thereof, comprising administering to a subject identified as having a CDK2-related cancer a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0300] In some cases, a compound of Formula (A), or a pharmaceutically acceptable salt thereof, may be useful for inhibiting a cellular process, such as inhibiting cell proliferation. Further provided herein is a method for inhibiting mammalian cell proliferation, comprising contacting a mammalian cell with a compound of Formula (A), or a pharmaceutically acceptable salt thereof. Also provided herein is a method for inhibiting CDK2 activity in a mammalian cell, comprising contacting a mammalian cell with a compound of Formula (A), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. The mammalian cell can be any suitable cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian CDK2-associated cancer cell. In some embodiments, the mammalian cell has dysregulated expression or activity or levels of a CDK2 gene, a CDK2 protein, a cyclin A2 gene, a cyclin A2 protein, a cyclin E1 gene, a cyclin E1 protein, a cyclin E2 gene, a cyclin E2 protein, or any of them (or any combination thereof).

[0301] The compounds of formula (A), or pharmaceutically acceptable salts thereof, may also be useful in the manufacture of a medicament (ie, for use in the treatment of CDK2-associated cancers).

[0302] In some embodiments, assays used to determine whether a subject has dysregulated expression, activity, or levels of a gene (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene), or protein (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein), or any of them (or any combination thereof) using a sample from the subject, may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay can also use other detection methods known in the art for detecting dysregulation of expression or activity or levels of genes (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 genes), or proteins (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 proteins), or any of them (or any combination thereof). In some embodiments, the sample is a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample) from a subject. In some embodiments, the subject is a subject suspected of having a CDK2-associated cancer, a subject with one or more symptoms of a CDK2-associated cancer, and / or a subject at high risk for developing a CDK2-associated cancer.

[0303] In some embodiments, dysregulation of expression or activity or levels of genes (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 genes), or proteins (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 proteins), or any of them (or any combination thereof) can be identified using liquid biopsy (variously referred to as fluid biopsy or fluid-phase biopsy). Liquid biopsy methods can be used to detect total tumor tissue burden and / or dysregulation of expression or activity or levels of genes (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 genes), or proteins (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 proteins), or any of them (or any combination thereof). Liquid biopsies can be performed on biological samples that are relatively easily obtained from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulated expression or activity or levels of genes (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 genes), or proteins (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 proteins), or any of them (or any combination thereof). In some embodiments, liquid biopsies can be used to detect the presence of dysregulated expression or activity or levels of genes (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 genes), or proteins (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 proteins), or any of them (or any combination thereof) at an earlier stage than traditional methods. In some embodiments, biological samples used for liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs).In some embodiments, cell-free DNA can be detected using liquid biopsy. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using highly sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of the expression, activity, or levels of genes (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 genes), or proteins (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 proteins), or any of them (or any combination thereof).

[0304] In the field of medical oncology, it is common practice to use a combination of different forms of treatment to treat each subject with cancer.In medical oncology, other components (multiple) of this co-treatment or therapy other than the composition provided herein can be, for example, surgery, radiation therapy, and additional therapeutic agents such as those described herein.

[0305] For example, the surgery can be open surgery or minimally invasive surgery. Thus, the compounds of formula (A), or pharmaceutically acceptable salts thereof, can also be useful as adjuvants for cancer treatment, i.e., they can be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents that act by the same or different mechanisms of action.

[0306] In some embodiments, a compound of Formula (A), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, for a period of time, followed by at least partial tumor resection. In some embodiments, treatment with one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to at least partial tumor resection. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, for a period of time, followed by one or more radiation therapies. In some embodiments, treatment with one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to one or more radiation therapies.

[0307] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, can be used after the administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of the compound of Formula (A), or a pharmaceutically acceptable salt thereof, over a period of time after undergoing at least partial resection of a tumor. In some embodiments, treatment with one or more doses of the compound of Formula (A), or a pharmaceutically acceptable salt thereof, reduces the size (i.e., cell number) of any remaining tumor after at least partial resection of a tumor. In some embodiments, a subject in need thereof can be administered one or more doses of the compound of Formula (A), or a pharmaceutically acceptable salt thereof, over a period of time after undergoing one or more radiation therapies. In some embodiments, treatment with one or more doses of the compound of Formula (A), or a pharmaceutically acceptable salt thereof, reduces the size (i.e., cell number) of any remaining tumor after one or more radiation therapies.

[0308] In some embodiments, the subject has cancer (e.g., a locally advanced or metastatic tumor) that is resistant or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent), such as a kinase inhibitor (e.g., a CDK4 / CDK6 inhibitor, e.g., palbociclib, ribociclib, or abemaciclib), immunotherapy, and / or radiation. In some embodiments, the subject has cancer (e.g., a locally advanced or metastatic tumor) for which there is no standard therapy. In some embodiments, the subject is CDK2 inhibitor naive. For example, the subject is naive to treatment with a selective CDK2 inhibitor. In some embodiments, the subject is not CDK2 inhibitor naive (i.e., the subject has previously been administered one or more CDK2 inhibitors). In some embodiments, the subject is CDK4 / CDK6 inhibitor naive. For example, the subject is naive to treatment with a selective CDK4 / CDK6 inhibitor. In some embodiments, the subject is not CDK4 / CDK6 inhibitor naive (ie, the subject has previously been administered one or more CDK4 / CDK6 inhibitors).

[0309] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, may be administered in combination with a therapeutically effective amount of at least one additional therapeutic agent.

[0310] Non-limiting examples of additional therapeutic agents include other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapeutic agents such as EGFR, HER2, MEK, RAF, or KRAS inhibitors), cytotoxic chemotherapeutic agents, angiogenesis inhibitors, and radiation therapy.

[0311] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors can include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0312] In some embodiments, the additional therapeutic agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include trastuzumab and pertuzumab.

[0313] In some embodiments, the additional therapeutic agent is a Ras-Raf-MEK-ERK pathway inhibitor (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib), a PI3K-Akt-mTOR-S6K pathway inhibitor (e.g., everolimus, rapamycin, perifosine, temsirolimus), and other kinase inhibitors, e.g., baricitinib, brigatinib, capmatinib, danusitol, and thiazolinone. rutib, ibrutinib, mirciclib, regorafenib, ruxolitinib, semaxanib, mobocertinib, avapritinib, fisogatinib, itacitinib, palsaclisib, pemigatinib, glesatinib, pexidartinib, rilzabrutinib, PF-477736 ((R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3 ]benzodiazepin-8-yl]-cyclohexaneacetamide), PLX8394 ((3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide), PRN1371 (8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3, 5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one), TG101209 (Nt-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide), NMS-1286937, NMS-088, INCB52793, PLX7486, PLX9486, and INCB40093.

[0314] In some embodiments, the additional therapeutic agent is a cytotoxic chemotherapeutic agent, non-limiting examples of which include platinum agents such as bleomycin, bendamustine, fluorouracil, capecitabine, gemcitabine, vinorelbine, carboplatin, oxaliplatin, or cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, etoposide, irinotecan, lomustine, methotrexate, mitomycin C, pemetrexed, taxanes such as cabazitaxel, paclitaxel, or docetaxel, temozolomide, vinblastine, and vincristine.

[0315] In some embodiments, the additional therapeutic agent is an angiogenesis inhibitor, e.g., a VEGF inhibitor, a VEGFR inhibitor, a TIE-2 inhibitor, a PDGFR inhibitor, an angiopoietin inhibitor, a PKCβ inhibitor, a COX-2 (cyclooxygenase II) inhibitor, an integrin (alpha-v / beta-3), an MMP-2 (matrix-metalloproteinase 2) inhibitor, and an MMP-9 (matrix-metalloproteinase 9) inhibitor. Examples of specific angiogenesis inhibitors include, but are not limited to, sunitinib (Sutent), bevacizumab (Avastin), axitinib, SU-14813, AG-13958, vatalanib (CGP79787), sorafenib (Nexavar), pegaptanib octasodium (Macugen), vandetanib (Zactima), PF-0337210, SU-14843, AZD-2171, ranibizumab (Lucentis), neovastatin (AE941), tetrathiomolybdate (Coprexa), AMG706, VEGF Trap (AVE0005), CEP7055, XL880, telatinib, and CP-868,596. Other anti-angiogenic agents include enzastaurin, midostaurin, perifosine, teprenone (Selbex) and UCN01, lenalidomide (Revlimid), pomalidomide (Pomalyst), squalamine (Evizon), and thalidomide (Thalomid).

[0316] In some embodiments, the subject has a cancer that has been found to be resistant to one or more of the additional therapies described herein. Accordingly, some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has previously been administered one or more of a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen), a HER2 inhibitor (such as neratinib, trastuzumab, dacomitinib, lapatinib, tucatinib, pertuzumab, or margetuximab), a cytotoxic chemotherapeutic agent, an EGFR, MEK, RAF, or KRAS inhibitor, an inhibitor of the Ras-Raf-MEK-ERK pathway, or a combination of any of the foregoing.

[0317] In some embodiments, the subject has previously received one or more of a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen), a cytotoxic chemotherapeutic agent (as described herein), an EGFR, MEK, RAF, or KRAS inhibitor (as described herein), an inhibitor of the Ras-Raf-MEK-ERK pathway (as described herein), or a combination of any of the foregoing, and the previous therapy has failed to treat the cancer.

[0318] In some embodiments, the subject has previously received a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib) and endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen), and the previous therapy failed to treat the cancer. In some embodiments, the subject has previously received a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib) as monotherapy, and the previous therapy failed to treat the cancer.

[0319] Inhibition Methods Although the genetic basis of tumorigenesis may differ among different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar across all solid tumor types. During the metastatic cascade, cancer cells lose growth inhibitory responses, undergo changes in adhesion, and produce enzymes that can degrade extracellular matrix components. This leads to tumor cell detachment from the original tumor, invasion into the circulation via newly formed vasculature, and / or migration and extravasation at advantageous distant sites where they can establish colonies.

[0320] Accordingly, also provided herein is a method for inhibiting cancer metastasis in a subject having cancer in need of such treatment (e.g., a subject at risk of developing metastasis), comprising administering a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. In some embodiments, the cancer is a CDK2-associated cancer. In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is used in combination with an additional therapy or another therapeutic agent described herein.

[0321] The term "metastasis" is an art-recognized term that refers to the formation of additional tumors (e.g., solid tumors) at sites distant from a primary tumor in a subject, which additional tumors contain the same or similar cancer cells as the primary tumor.

[0322] Also provided is a method for reducing the risk of developing metastasis or additional metastasis in a subject having a CDK2-associated cancer, the method comprising selecting, identifying, or diagnosing the subject as having a CDK2-associated cancer, and administering to the subject selected, identified, or diagnosed as having a CDK2-associated cancer a therapeutically effective amount of a compound of formula (A), or a pharmaceutically acceptable salt thereof.

[0323] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject with a CDK2-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof. The reduced risk of developing metastasis or additional metastases in a subject with a CDK2-associated cancer can be compared to the risk of developing metastasis or additional metastases in the subject before treatment, or compared to a subject or population of subjects with a similar or same CDK2-associated cancer that has not been treated or has received a different treatment.

[0324] The phrase "risk of developing metastases" refers to the risk that a subject with a primary tumor will develop additional tumors (e.g., solid tumors) at sites distant from the primary tumor in the subject over a given period of time, the additional tumors containing the same or similar cancer cells as the primary tumor. Described herein are methods for reducing the risk of developing metastases in a subject with cancer.

[0325] The phrase "risk of developing additional metastases" refers to the risk that a subject who has a primary tumor and one or more additional tumors at sites distant from the primary tumor, where the one or more additional tumors contain the same or similar cancer cells as the primary tumor, will develop one or more further tumors distant from the primary tumor, where the further tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0326] Also provided is a method for inhibiting CDK2 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (A). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer described herein. In some embodiments, the mammalian cancer cell is a CDK2-associated mammalian cancer cell. In some embodiments, the amount of the compound of Formula (A) is a therapeutically effective amount.

[0327] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" a cell with a compound provided herein includes administering a compound provided herein to a subject, such as a human, and, for example, introducing a compound provided herein into a sample containing mammalian cells or a purified preparation containing the cells.

[0328] Also provided herein are methods of inhibiting mammalian cell proliferation in vitro or in vivo, comprising contacting the mammalian cell with a compound of Formula (A). In some embodiments, the amount of the compound of Formula (A) is a therapeutically effective amount.

[0329] Pharmaceutical compositions and kits When used as a pharmaceutical, the compound of formula (A), including its pharmaceutically acceptable salts, can be administered in the form of a pharmaceutical composition containing the compound of formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. These compositions can be prepared in a manner known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be, for example, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump.

[0330] Also provided herein are pharmaceutical compositions containing a compound of Formula (A) or a pharmaceutically acceptable salt thereof as an active ingredient and at least one pharmaceutically acceptable excipient. For example, a pharmaceutical composition prepared using a compound of Formula (A) or a pharmaceutically acceptable salt thereof. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. In some embodiments, the composition is formulated for oral administration.

[0331] Suitable pharmaceutically acceptable carriers are well known in the art, and descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0332] Methods for formulating pharmaceutical compositions are explained in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3 (eds. Lieberman et al.); Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2 (eds. Avis et al.); and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2 (eds. Lieberman et al.) (published by Marcel Dekker, Inc.).

[0333] The daily dosage of the compound of formula (A) or a pharmaceutically acceptable salt thereof can vary over a wide range from 1.0 to 10,000 mg per adult human per day, or any range therein.

[0334] Provided herein are pharmaceutical kits useful for treating a CDK2-related disease or disorder, e.g., cancer, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein. Such kits can further include one or more of various pharmaceutical kit components, as desired, e.g., a container with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as a package insert or label, indicating the amounts of components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. [Example]

[0335] Preparation of compounds Starting materials used in the synthesis were either synthesized or obtained from commercial sources, including, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, and VWR Scientific. Nuclear magnetic resonance (NMR) analyses were performed using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or a Bruker AVANCE NEO 400 MHz spectrometer with appropriate deuterated solvents. LCMS spectra were obtained using electrospray ionization in positive ion detection mode on a Shimadzu LCMS-2020 equipped with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS 2020 MS detector.

[0336] The general methods for preparing compounds of Formula (A) are described in an illustrative manner and are intended to be illustrative and not limiting. It will be understood, therefore, that conditions such as solvent selection, reaction temperature, amounts, and reaction time can be varied while still producing the desired compound. It will also be understood that many of the reagents provided in the following examples can be substituted with other suitable reagents. See, for example, Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including but not limited to those related to the chemical structures, substituents, derivatives, intermediates, synthesis, formulation, and / or methods of use provided herein, can be made without departing from the spirit and scope thereof.

[0337] Example 1: Synthesis of (1s,4s)-4-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclohexyl N-propylcarbamate (Compound 1) [ka] Step 1: Synthesis of 4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl trifluoromethanesulfonate To a stirred solution of 4-[(tert-butyldimethylsilyl)oxy]cyclohexan-1-one (2 g, 8.75 mmol, 1.00 equiv.) and LiHMDS (2 M in THF) (19.90 mL, 17.51 ​​mmol, 2.00 equiv.) in THF (100 mL) under a nitrogen atmosphere at −78° C., 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (6.3 g, 17.51 ​​mmol, 2.00 equiv.) was added dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl trifluoromethanesulfonate as a yellow solid, which was used crude in the next step without further purification.

[0338] Step 2: Synthesis of 5-{4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl}pyrimidin-2-amine To a stirred solution of 4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl trifluoromethanesulfonate (5 g, 13.87 mmol, 1.00 equiv.) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (4.60 g, 20.80 mmol, 1.50 equiv.) in 1,4-dioxane / HO (4:1) (20 mL) was added Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2.CHCl (2.26 g, 2.77 mmol, 0.2 equiv.) and KCO (5.75 g, 41.61 mmol, 3.00 equiv.) were added. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere overnight. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1 to 6:1) to give 5-{4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl}pyrimidin-2-amine (1.6 g, 38%, 2 steps) as a yellow solid. LC-MS: (ES+H, m / z) 306.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.22(s,2H),6.52(s,2H),5.83(dd,J=4.7,2.8Hz,1H),3.90-3.82(m,1H),2.36-2.2 5(m,3H),2.01-1.91(m,1H),1.78(d,J=12.0Hz,1H),1.55-1.30(m,1H),0.80(s,9H).

[0339] Step 3: Synthesis of 5-((1s,4s)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrimidin-2-amine To a stirred solution of 5-{4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl}pyrimidin-2-amine (1.6 g, 5.23 mmol, 1.00 equiv) in MeOH (150 mL) was added palladium under a hydrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (6:1 to 4:1) to give 5-[(1s,4s)-4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimidin-2-amine (500 mg, 31%) as a yellow solid. LC-MS: (ES+H, m / z) 308.2 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.01(s,2H),6.32(s,2H),3.99(s,1H),2.30(d,J=11.5Hz,1H),1.65(dd,J=23.4,11.8Hz,4H),1.48(q,J=11.9,10.8Hz,4H),0.85(s,9H).

[0340] Step 4: Synthesis of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate To a stirred solution of 5-[(1s,4s)-4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimidin-2-amine (200 mg, 0.65 mmol, 1.00 equiv.) and tert-butyl N-(4-bromo-3-fluorobenzenesulfonyl)carbamate (345.5 mg, 0.97 mmol, 1.50 equiv.) in t-BuOH (2 mL) was added EPhos Pd G (59.7 mg, 0.06 mmol, 0.10 equiv.) and KCO (269.6 mg, 1.95 mmol, 3.00 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1 to 3:1) to give tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate (150 mg, 40%) as a white solid. LC-MS: (ES+H, m / z) 581.3 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 11.75(s,1H),9.44(s,1H),8.35(s,1H),8.32-8.26(m,1H),7.95(dd,J=8.4,6.8Hz,1H),7.72-7.66(m,1H),7.61-7.55(m,2H) ),4.01-3.95(m,2H),1.93(s,2H),1.63-1.51(m,5H),1.26(s,4H),1.24(d,J=2.2Hz,9H),1.11(t,J=7.1Hz,2H),0.84(s,9H).

[0341] Step 5: Synthesis of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-hydroxycyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate A solution of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate (150 mg, 0.25 mmol, 1.00 equiv) in TBAF (4 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1 to 2:1) to give tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-hydroxycyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate (70 mg, 58%) as a yellow solid. LC-MS: (ES+H, m / z) 467.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 11.62(s,1H),9.47(s,1H),8.43(d,J=15.8Hz,2H),8.33(d,J=8.2Hz,1H),7.66-7.57(m,2H),4.38( d,J=3.7Hz,1H),3.89(s,1H),2.69(s,1H),1.84-1.70(m,4H),1.53(d,J=12.1Hz,4H),1.32(s,9H).

[0342] Step 6: Synthesis of (1s,4s)-4-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2-fluorophenyl}amino)pyrimidin-5-yl]cyclohexyl)imidazole-1-carboxylate To a mixture of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-hydroxycyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate (90 mg, 0.19 mmol, 1.00 equiv.) and carbonyldiimidazole (50.05 mg, 0.31 mmol, 1.60 equiv.) in DCM (5 mL) was added DMAP (1.18 mg, 0.01 mmol, 0.05 equiv.) and DIEA (49.87 mg, 0.39 mmol, 2.00 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 12 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with CHCl (3 × 10 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (1s,4s)-4-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2-fluorophenyl}amino)pyrimidin-5-yl]cyclohexylimidazole-1-carboxylate (118 mg, crude) as a pale yellow solid. The crude product was used directly in the next step without further purification.

[0343] Step 7: Synthesis of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-[(propylcarbamoyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate To a solution of (1s,4s)-4-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2-fluorophenyl}amino)pyrimidin-5-yl]cyclohexylimidazole-1-carboxylate (112 mg, 0.20 mmol, 1.00 equiv) in DCM (4 mL) was added propylamine (47.24 mg, 0.80 mmol, 4.00 equiv) and DIEA (77.47 mg, 0.60 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 40° C. under a nitrogen atmosphere for 12 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography under the following conditions: column, C18; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. Pure fractions were concentrated under reduced pressure to give tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-[(propylcarbamoyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate (38 mg, 36%) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 11.68(s,1H),9.47(s,1H),8.45(d,J=8.3Hz,2H),8.29(t,J=8.3Hz,1H),7.70-7.57(m,2H),7.06(s,1H),4.81-4.80(s,1H),2.95(q,J =6.6Hz,2H),2.60-2.57(m,1H),1.88(d,J=12.5Hz,2H),1.62-1.58(m,6H),1.43(q,J=7.3Hz,2H),1.32(s,9H),0.85(t,J=7.4Hz,3H).

[0344] Step 8: Synthesis of (1s,4s)-4-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclohexyl N-propylcarbamate (Compound 1) To a solution of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-[(propylcarbamoyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate (38 mg, 0.07 mmol, 1.00 equiv.) in HCOOH (2 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and neutralized to pH = 7 with NH3H2O. The mixture was purified by reverse-phase Combiflash chromatography under the following conditions: column, C18; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 40% to 50% in 10 min; detector, UV 254 nm. The pure fractions were concentrated under reduced pressure and lyophilized to give (1s,4s)-4-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclohexyl N-propylcarbamate (compound 1, 19.4 mg, 62%) as a white solid. LC-MS: (ES+H, m / z) 452.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.32(s,1H),8.42(s,2H),8.15(t,J=8.1Hz,1H),7.61-7.58(m,2H),7.35(s,2H),7.03-7.01(m,1H),4.80-4.78(s,1H),2.9 9-2.91(m,2H),2.57-2.52(m,1H),1.85(d,J=13.0Hz,2H),1.74-1.61(m,6H),1.42(q,J=7.4Hz,2H),0.84(t,J=7.5Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ -121.81.

[0345] Example 2: Synthesis of (1RS,3SR)-3-(2-(imidazo[1,2-b]pyridazin-6-ylamino)pyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 40) [ka] Step 1: Synthesis of cyclopent-2-en-1-ol To a solution of cyclopent-2-en-1-one (10 g, 121.80 mmol, 10.20 mL), cerium trichloride (47.70 g, 193.53 mmol) in MeOH (80 mL) was added NaBH (5.10 g, 134.81 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min, and the reaction was warmed to 20 °C over an additional 30 min. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (4.5 g, crude) as a white solid that did not require further purification. 1 H NMR(400MHz,CDCl3)δ 6.03-5.95(m,1H),5.88-5.78(m,1H),4.91-4.78(m,1H),2.59-2.39(m,1H),2.32-2.16(m,2H),1.96(s,1H)1.69-1.60(m,1H).

[0346] Step 2: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-oxocyclopentyl)pyrimidin-2-yl]carbamate To a solution of tert-butyl N-(5-bromopyrimidin-2-yl)-N-tert-butoxycarbonylcarbamate (2 g, 2.67 mmol) and cyclopent-2-en-1-ol (900 mg, 5.34 mmol) in DMF (40 mL) was added tetrabutylammonium chloride (743 mg, 2.67 mmol), Pd(OAc) (60 mg, 0.27 mmol), and KOAc (1.57 g, 8.02 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with EtOAc (150 mL) and water (50 mL). The organic layer was washed with brine (30 mL × 5), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 10% to 50% EtOAc in petroleum ether) to give the title compound (0.52 g, 23%) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ 9.96(s,1H),8.58(s,2H),3.38-3.35(m,1H),2.61-2.50(m,1H),2.41-2.22(m,4H),1.96-1.87(m,1H),1.45(s,9H).

[0347] Step 3: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-hydroxycyclopentyl)pyrimidin-2-yl]carbamate To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-oxocyclopentyl)pyrimidin-2-yl]carbamate (12 g, 31.79 mmol) in THF (30 mL) was added LiBHEt (1 M, 51 mL) at -65 °C. The reaction mixture was stirred at -65 °C for 1 h. After the reaction was complete, the mixture was quenched by adding saturated aqueous NaHCO (40 mL) at -65 °C. The reaction was then warmed to room temperature and diluted with EtOAc (150 mL). The organic layer was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 10% to 50% EtOAc in petroleum ether) to afford the title compound (8 g, 66%) as a yellow oil. LCMS (ESI) m / z: 380.2 [M+H] + .

[0348] Step 4: Synthesis of rac-tert-butyl(tert-butoxycarbonyl)(5-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-hydroxycyclopentyl)pyrimidin-2-yl]carbamate (9 g, 23.72 mmol) in DCM (50 mL) was added DMAP (580 mg, 4.74 mmol), pyridine (5.63 g, 71.16 mmol, 5.74 mL), and (4-nitrophenyl)carbonochloridate (7.17 g, 35.58 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by adding water (50 mL) at 0 °C and extracted with DCM (100 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (cis isomer; absolute configuration arbitrarily assigned; 3.5 g, 27%) as a white solid. LCMS (ESI) m / z: 545.2 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 8.71(s,2H),8.30(d,J=9.2Hz,2H),7.41(d,J=9.2Hz,2H),5.40-5.34(m,1H),3.17-3.32(m,1 H),2.80-2.68(m,1H),2.33-2.18(m,2H),2.16-2.04(m,1H),2.01-1.87(m,2H),1.49(s,18H). Also obtained was rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (trans isomer not shown; absolute configuration arbitrarily assigned; 1.5 g, 12%) as a white solid. 1H NMR(400MHz,CDCl3)δ 8.66(s,2H),8.30(d,J=9.2Hz,2H),7.41(d,J=9.2Hz,2H),5.40-5.34(m,1H),3.51- 3.37(m,1H),2.58-2.31(m,3H),2.12-1.98(m,2H),2.81-1.70(m,1H),1.49(s,18H).

[0349] Step 5: Synthesis of tert-butyl (tert-butoxycarbonyl) (5-((1RS,3SR)-3-((((S)-4,4,4-trifluorobutan-2-yl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate To a solution of rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (2 g, 3.7 mmol) in dioxane (20 mL) was added DIEA (3.8 mL, 22.0 mmol) and (2S)-4,4,4-trifluorobutan-2-amine (1 g, 6.1 mmol, HCl salt). The reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was quenched by adding water (10 mL) and subsequently extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (1.5 g, 87%) as a yellow solid. LCMS (ESI) m / z: 533.3 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 8.64(s,2H),5.28-5.20(m,1H),4.75-4.68(m,1H),4.10-4.00(m,1H),3.20-3.10(m,1H),2.64-2.53(m,1H),2. 51-2.34(m,1H),2.32-2.11(m,2H),2.03-1.94(m,2H),1.88-1.70(m,2H),1.46(s,18H),1.29(d,J=6.8Hz,3H).

[0350] Step 6: Synthesis of (1RS,3SR)-3-(2-aminopyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate To a solution of tert-butyl (tert-butoxycarbonyl) (5-((1RS,3SR)-3-((((S)-4,4,4-trifluorobutan-2-yl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (1.5 g, 2.8 mmol) in DCM (6 mL) was added TFA (2 mL, 26.9 mmol). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo to give the title compound (0.9 g, 89%, TFA salt) as a yellow oil which required no further purification. LCMS (ESI) m / z: 333.2 [M+H] + .

[0351] Step 7: Synthesis of (1RS,3SR)-3-(2-(imidazo[1,2-b]pyridazin-6-ylamino)pyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (compound 40) A mixture of (1RS,3SR)-3-(2-aminopyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (54 mg, 150 μmol), 6-chloroimidazo[1,2-b]pyridazine (34 mg, 225 μmol), BrettPhos Pd G3 (13 mg, 15 μmol), Brettphos (16 mg, 30 μmol), and CsCO3 (294 mg, 902 μmol) in dioxane (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C under a N2 atmosphere for 16 h. After cooling to room temperature, the reaction mixture was quenched by adding water (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase chromatography (22%-55% acetonitrile in water / 0.225% formic acid) to give compound 40 (14 mg, 20%) as a white solid. LCMS (ESI) m / z: 450.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.29(s,1H),8.52-8.41(m,2H),8.05-8.00(m,2H),7.90-7.85(m,1H),7 .63(d,J=0.8Hz,1H),7.30-7.25(m,1H),5.10-4.98(m,1H),3.91-3.79(m, 1H),3.09-2.95(m,1H),2.48-2.35(m,3H),2.12-2.03(m,1H),1.97-1.85( m,1H),1.84-1.65(m,2H),1.63-1.50(m,1H),1.15-1.10(d,J=6.8Hz,3H).

[0352] Example 3 Synthesis of rel-(1S,3R)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (Compound 151) and rel-(1R,3S)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (Compound 152) [ka] Step 1: Synthesis of 3-iodocyclopent-2-en-1-one To a stirred solution of I2 (15.52 g, 61.16 mmol, 1.2 equiv.) in MeCN (150 mL) was added PPh3 (16.04 g, 61.162 mmol, 1.2 equiv.) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for an additional 2 h at room temperature. A mixture of Et3N (6.19 g, 61.162 mmol, 1.2 equiv.) and 1,3-cyclopentanedione (5 g, 50.97 mmol, 1 equiv.) in MeCN (200 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1 to 3:5) to give 3-iodocyclopent-2-en-1-one (8 g, 75.46%) as a white solid. LC-MS (ES+H, m / z) 209.0 [M+H] + .

[0353] Step 2: Synthesis of 3-iodocyclopent-2-en-1-ol A mixture of 3-iodocyclopent-2-en-1-one (3.1 g, 14.90 mmol, 1 equiv.) and NaBH (0.57 g, 14.90 mmol, 1.2 equiv.) in EtOH (30 mL) was stirred at 0 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by H-NMR. The reaction was quenched at 0 °C by adding saturated NH Cl (aqueous) (20 mL). The resulting mixture was extracted with CHCl (3 × 200 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1 to 3:5) to give 3-iodocyclopent-2-en-1-ol (2.3 g, 73.5%) as a colorless liquid. LC-MS: (ES+H, m / z) 192.9 [M-OH] + ; 1H NMR(400MHz,DMSO-d6)δ 6.21-6.13(m,1H),4.97(d,J=6.1Hz,1H),4.55-4.47(m,1H),2.74-2.61(m,1H),2.49-2.42(m,1H),2.24-2.12(m,1H),1.65-1.56(m,1H)

[0354] Step 3: Synthesis of 3-(2-aminopyrimidin-5-yl)cyclopent-2-en-1-ol A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1000 mg, 4.523 mmol, 1 equiv.) and 3-iodocyclopent-2-en-1-ol (1140 mg, 5.42 mmol, 1.2 equiv.), Pd(dppf)Cl (661.97 mg, 0.905 mmol, 0.2 equiv.), and KCO (1875 mg, 13.57 mmol, 3 equiv.) in 1,4-dioxane (10 mL) and HO (1 mL) was stirred at 80 °C under a nitrogen atmosphere for 1 h. The resulting mixture was extracted with CHCl (5 × 100 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient from 8% to 16% in 10 min; detector, UV 254 nm. This gave 3-(2-aminopyrimidin-5-yl)cyclopent-2-en-1-ol (500 mg, 56.8%) as a yellow solid. LC-MS: (ES+H, m / z) 178.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.39(s,2H),6.76(s,2H),6.14-6.10(m,1H),4.81-4.70(m,2H),2.77- 2.64(m,1H),2.48-2.37(m,1H),2.31-2.17(m,1H),1.71-1.57(m,1H).

[0355] Step 4: Synthesis of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentan-1-ol To a solution of 3-(2-aminopyrimidin-5-yl)cyclopent-2-en-1-ol (2.8 g, 15.80 mmol, 1 equiv.) in MeOH (50 mL) in a 250 mL round-bottom flask under a nitrogen atmosphere was added Pd / C (10 wt%, 1.68 g). The reaction mixture was stirred under a hydrogen atmosphere at room temperature using a hydrogen balloon for 2 hours, filtered through a Celite pad, and concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 30*150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 1% B to 15% B, 15% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 7.92 / 8.82; run number: 0). The resulting mixture was concentrated under reduced pressure to give rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentan-1-ol (1.5 g, 53%; absolute configuration arbitrarily assigned) as a white solid. LC-MS: (ES+H, m / z) 180.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.14(s,2H),6.36(s,2H),4.65(d,J=3.9Hz,1H),4.24-4.13(m,1H),2.86-2.72(m,1H),2.29-2.17(m,1H),1.95 -1.84(m,1H),1.79-1.56(m,3H),1.44-1.33(m,1H).

[0356] Step 5: Synthesis of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(4-nitrophenyl)carbonate To a stirred solution of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentan-1-ol (1.5 g, 8.369 mmol, 1 equiv.) and DMAP (0.10 g, 0.837 mmol, 0.1 equiv.) in DCM (20 mL) was added DIEA (3.25 g, 25.107 mmol, 3 equiv.) and bis(4-nitrophenyl)carbonate (5.09 g, 16.738 mmol, 2 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN in water, gradient from 25% to 35% in 10 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This gave rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(4-nitrophenyl)carbonate (2.2 g, 76%) as a white solid. LC-MS: (ES+H, m / z) 345.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.36-8.28(m,2H),8.17(s,2H),7.62-7.54(m,2H),6.44(s,2H),5.27-5.17(m,1 H),3.00-2.86(m,1H),2.61-2.53(m,1H),2.10-1.93(m,3H),1.85-1.60(m,2H).

[0357] Step 6: Synthesis of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate A solution of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(4-nitrophenyl)carbonate (1.2 g, 3.49 mmol, 1 equiv.) in DMF (20 mL) was treated with 1-methylcyclopropan-1-amine hydrochloride (0.56 g, 5.23 mmol, 1.5 equiv.) at room temperature under a nitrogen atmosphere, followed by the dropwise addition of DIEA (1.35 g, 10.46 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 1.5 hours. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 30% to 40% gradient over 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This afforded rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (860 mg, 89%) as a white solid. LC-MS: (ES+H, m / z) 277.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.13(s,2H),7.40(s,1H),6.40(s,2H),5.03(d,J=37.8Hz,1H),2.85(t,J=9.1Hz,1H),2.46-2.34 (m,1H),2.02-1.79(m,2H),1.77-1.37(m,3H),1.24(s,3H),0.64-0.55(m,2H),0.54-0.43(m,2H).

[0358] Step 7: Synthesis of rac-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate To a stirred solution of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (150 mg, 0.543 mmol, 1 equiv.) and tert-butyl N-(4-bromobenzenesulfonyl)carbamate (218.99 mg, 0.652 mmol, 1.2 equiv.) in t-BuOH (5 mL) was added KCO (225.06 mg, 1.629 mmol, 3 equiv.) and EPhos Pd G (49.86 mg, 0.054 mmol, 0.1 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 30% to 45% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give rac-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (100 mg, 35%) as a white solid. LC-MS: (ES+H, m / z) 532.3 [M+H] + .

[0359] Step 8: Synthesis of rac-(1R,3S)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate A solution of rac-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (100 mg, 0.188 mmol, 1 equiv.) in HCl (gas) in 1,4-dioxane (5 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column 30*150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 40% B, 40% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 10; the resulting mixture was concentrated under reduced pressure by lyophilization to give rac-(1R,3S)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (7.6 mg, 9.4%) as a white solid. LC-MS: (ES+H, m / z) 432.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.98(s,1H),8.57-8.42(m,2H),7.95-7.88(m,2H),7.71(d,J=8.5Hz,2 H),7.43(s,1H),7.17(s,2H),5.18-4.95(m,1H),3.06-2.97(m,1H),2. 46(d,J=7.4Hz,1H),2.11-1.98(m,1H),1.96-1.85(m,1H),1.81-1.64( m,2H),1.61-1.50(m,1H),1.27-1.24(m,3H),0.61(s,2H),0.49(s,2H).

[0360] Step 9: Synthesis of rel-(1S,3R)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (Compound 151) and rel-(1R,3S)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (Compound 152) The product (75 mg) was purified by preparative chiral HPLC under the following conditions: Column: CHIRAL Cellulose-SB, 4.6*50 mm 3 um; Mobile phase A: (MtBE:Hex=1:1) (0.1% DEA):IPA=50:50; Flow rate: 1 mL / min; Gradient: 0% B to 0% B; Injection volume: 5 ul The pure fractions were concentrated under reduced pressure by lyophilization to give rel-(1S,3R)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (compound 151, 27.6 mg, 45.3%) as a white solid, and rel-(1R,3S)-3-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclopentyl N-(1-methylcyclopropyl)carbamate (compound 152, 29.3 mg, 48.1%) as a white solid. The absolute configuration was arbitrarily assigned to each enantiomer. Compound 151 - LC-MS: (ES+H, m / z) 432.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.98(s,1H),8.47(s,2H),7.95-7.87(m,2H),7.76-7.67(m,2H),7.44(s,1H) ),7.17(s,2H),5.18-4.95(m,1H),3.09-2.94(m,1H),2.49-2.42(m,1H),2. 12-2.00(m,1H),1.96-1.86(m,1H),1.81-1.64(m,2H),1.61-1.50(m,1H),1 .27-1.24(m,3H),0.65-0.46(m,4H).Compound 152-LC-MS:(ES+H,m / z)432.1[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 9.98(s,1H),8.47(s,2H),7.95-7.87(m,2H),7.74-7.67(m,2H),7.44(s,1H),7.17(s,2H),5.19-4.94(m,1H),3.08-2.94(m,1H),2.49 -2.42(m,1H),2.05(d,J=10.6Hz,1H),1.96-1.84(m,1H),1.81-1.65(m,2H),1.62-1.49(m,1H),1.27-1.24(m,3H),0.65-0.46(m,4H).

[0361] Example 4: Synthesis of rac-(1R,3S)-3-{2-[(1-sulfamoylpiperidin-4-yl)amino]pyrimidin-5-yl}cyclopentyl N-(1-methylcyclopropyl)carbamate (Compound 135) [ka] Step 1: Synthesis of rac-(1R,3S)-3-(2-chloropyrimidin-5-yl)cyclopentyl N-(1-methylcyclopropyl)carbamate To a stirred solution of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl N-(1-methylcyclopropyl)carbamate (150 mg, 0.543 mmol, 1 equiv.) and t-BuNO (167.93 mg, 1.629 mmol, 3 equiv.) in DCM (2 mL) was added tetrabutylazanium chloride (452.57 mg, 1.629 mmol, 3 equiv.) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 30% to 50% gradient in 10 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give rac-(1R,3S)-3-(2-chloropyrimidin-5-yl)cyclopentyl N-(1-methylcyclopropyl)carbamate (38 mg, 24%) as a white solid. LC-MS: (ES+H, m / z) 296.2 [M+H]+ .

[0362] Step 2: Synthesis of rac-tert-butyl 4-({5-[(1R,3S)-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]pyrimidin-2-yl}amino)piperidine-1-carboxylate To a stirred solution of rac-(1R,3S)-3-(2-chloropyrimidin-5-yl)cyclopentyl N-(1-methylcyclopropyl)carbamate (38 mg, 0.128 mmol, 1 equiv.) and tert-butyl 4-aminopiperidine-1-carboxylate (51.46 mg, 0.256 mmol, 2 equiv.) in dioxane (2 mL) was added Pd-PEPPSI-IpentCl at room temperature under a nitrogen atmosphere. 2-Methylpyridine (o-picoline (32.42 mg, 0.038 mmol, 0.3 equiv.) and CsCO (125.58 mg, 0.384 mmol, 3 equiv.) were added portionwise. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1 to 1:2) to give rac-tert-butyl 4-({5-[(1R,3S)-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (50 mg, 85%) as a white solid. LC-MS: (ES+H, m / z) 460.3 [M+H] + .

[0363] Step 3: Synthesis of rac-(1R,3S)-3-[2-(piperidin-4-ylamino)pyrimidin-5-yl]cyclopentyl N-(1-methylcyclopropyl)carbamate A solution of rac-tert-butyl 4-({5-[(1R,3S)-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (50 mg, 0.109 mmol, 1 equiv.) in HCOOH (3 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 8 with NH3H2O. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 30% to 60% in 10 minutes; detector, UV 254 nm. This gave rac-(1R,3S)-3-[2-(piperidin-4-ylamino)pyrimidin-5-yl]cyclopentyl N-(1-methylcyclopropyl)carbamate (30 mg, 77%) as a white solid. LC-MS: (ES+H, m / z) 360.2 [M+H] + .

[0364] Step 4: Synthesis of rac-(1R,3S)-3-{2-[(1-sulfamoylpiperidin-4-yl)amino]pyrimidin-5-yl}cyclopentyl N-(1-methylcyclopropyl)carbamate (Compound 135) To a stirred solution of rac-(1R,3S)-3-[2-(piperidin-4-ylamino)pyrimidin-5-yl]cyclopentyl N-(1-methylcyclopropyl)carbamate (30 mg, 0.083 mmol, 1 equiv.) and sulfamide (16.04 mg, 0.166 mmol, 2 equiv.) in dioxane (1 mL) was added EtN (25.34 mg, 0.249 mmol, 3 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: flow rate 60 mL / min; gradient: 21% B to 33% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.1. The resulting mixture was concentrated under reduced pressure by lyophilization to give rac-(1R,3S)-3-{2-[(1-sulfamoylpiperidin-4-yl)amino]pyrimidin-5-yl}cyclopentyl N-(1-methylcyclopropyl)carbamate (compound 135, 16 mg, 44%) as a white solid. LC-MS: (ES+H, m / z) 439.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.19(s,2H),7.40(s,1H),6.97(d,J=7.7Hz,1H),6.73(s,2H),4.99(s,1H),3.71(d,J=10.1Hz,1H),3.43(d,J=11.9Hz,2H),2. 87(s,1H),2.62(t,J=11.5Hz,2H),2.41(s,1H),2.07-1.84(m,4H),1.73-1.43(m,5H),1.24(s,3H),0.60(s,2H),0.48(s,2H).

[0365] Example 5 Synthesis of rac-(1R,3S)-3-(2-((1-((1-(trifluoromethyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 302) [ka] Step 1: Synthesis of 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-one To a stirred mixture of piperidin-4-one hydrochloride (190.75 mg, 1.407 mmol, 1.1 equiv.) and DIEA (330.58 mg, 2.558 mmol, 2 equiv.) in THF (5 mL) was added dropwise 1-(trifluoromethyl)pyrazole-4-sulfonyl chloride (300 mg, 1.279 mmol, 1 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by H-NMR. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-one (390 mg, crude) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ 9.31 (s, 1H), 8.39 (q, J=0.9Hz, 1H), 3.42-3.33 (m, 4H), 2.49-2.44 (m, 4H).

[0366] Step 2: Synthesis of 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-amine To a stirred mixture of 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-one (290 mg, 0.976 mmol, 1 equiv.) and NHOAc (225.61 mg, 2.928 mmol, 3 equiv.) in MeOH (5 mL) was added dropwise HOAc (0.05 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 20 minutes. To the above mixture was added NaBHCN (183.92 mg, 2.928 mmol, 3 equiv.) in portions over 5 minutes at room temperature. The resulting mixture was stirred at 50° C. for an additional 20 minutes. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (5:1 to 1:1) to give 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-amine (200 mg, 69%) as a yellow oil. LC-MS: (ES+H, m / z) 299.0 [M+H] + .

[0367] Step 3: Synthesis of rac-(1R,3S)-3-(2-((1-((1-(trifluoromethyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)cyclopentyl((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 302) To a stirred mixture of rac-(1R,3S)-3-(2-fluoropyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (80 mg, 0.239 mmol, 1 equiv.) and DIEA (123.35 mg, 0.956 mmol, 4 equiv.) in DMSO (3 mL) was added 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-amine (142.33 mg, 0.478 mmol, 2 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN (0.1% NH4HCO3) in water, 30% to 60% gradient in 10 min; detector, UV 254 nm. Pure fractions were concentrated under reduced pressure and lyophilized to give rac-(1R,3S)-3-(2-((1-((1-(trifluoromethyl)-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (compound 302, 36 mg, 25%) as a white solid. LC-MS: (ES+H, m / z) 614.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.25(s,1H),8.38-8.29(m,1H),8.22-8.08(m,2H),7.22(d,J=8.7Hz,1H),7 .03(d,J=7.7Hz,1H),5.11-4.88(m,1H),3.96-3.67(m,2H),3.61-3.42(m,2 H),2.87(p,J=9.2Hz,1H),2.73-2.57(m,2H),2.48-2.28(m,3H),2.03-1.81 (m,4H),1.80-1.68(m,1H),1.67-1.41(m,4H),1.13(dd,J=6.7,1.9Hz,3H); 19 F NMR (377MHz, DMSO) δ -59.50, -62.57.

[0368] Example 6: Synthesis of (1R*,3S*)-3-(2-((4-((S*)-cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate HCl salt (Compound 580) [ka] Step 1: Synthesis of rac-tert-butyl(tert-butoxycarbonyl)(5-((1R,3S)-3-(((1-methylcyclopropyl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate To a solution of 1-methylcyclopropanamine (2.3 g, 21.3 mmol) in dioxane (30 mL) and TEA (4.45 mL, 31.9 mmol) was added rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (5.8 g, 10.7 mmol). The mixture was stirred at 25 °C for 5 h. The reaction mixture was quenched by adding water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0–30% EtOAc in petroleum ether) to give the title compound (4.2 g, 83%) as a white solid. LCMS(ESI)m / z:477.4[M+H] + .

[0369] Step 2: Synthesis of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate To a solution of rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,3S)-3-(((1-methylcyclopropyl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (4.2 g, 8.8 mmol) in dioxane (10 mL) was added HCl / dioxane (30 mL, 4 M). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with MeOH (20 mL) and DCM (20 mL) and adjusted to pH = 8 with saturated aqueous NaHCO3, followed by stirring for 1 h. The solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (3.2 g, crude) as a white solid that required no further purification. LCMS (ESI) m / z: 277.2 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 8.45-8.01(m,2H),5.30-5.10(m,1H),5.02-4.90(m,2H),3.05-2.83(m,1H),2.64-2.45(m,1H),2.15-2.0 3(m,1H),1.99-1.90(m,2H),1.86-1.60(m,2H),1.50-1.24(m,3H),0.86-0.67(m,2H),0.65-0.49(m,2H).

[0370] Step 3: Synthesis of rac-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)phenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate To a solution of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (1.1 g, 3.0 mmol) and KPO (3.13 g, 14.73 mmol) in dioxane (20 mL) was added tert-butyl N-[(4-bromo-3-fluorophenyl)-cyclopropyl-oxo-sulfanylidene]carbamate (1.7 g, 4.4 mmol), BrettPhos (316 mg, 589 μmol), and BrettPhos Pd G (267 mg, 294 μmol). The reaction mixture was degassed and purged with N three times, and then the mixture was stirred at 80 °C under a N atmosphere for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (1.1 g, 52%) as a white solid. LCMS (ESI) m / z: 574.3 [M+H] + .

[0371] Step 4: Synthesis of rel-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate and rel-(1S,3R)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate rac-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (1.2 g, 1.7 mmol) was separated by using chiral SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); supercritical CO2 / i-PrOH+0.1%). NH3:HO=40 / 60; 80 mL / min), rel-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (397 mg, peak 1 and peak 2) was obtained as a white solid, and rel-(1S,3R)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (355 mg, peak 3 and peak 4) was obtained as a white solid. The absolute configuration was arbitrarily assigned to each isomer. LCMS (ESI) m / z: 574.3 [M+H] + .

[0372] Step 5: Synthesis of (1R*,3S*)-3-(2-((4-((R)-N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate and (1R*,3S*)-3-(2-((4-((S)-N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (397 mg, 692.0 μmol) was separated by using chiral SFC (Column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); supercritical CO2 / MeOH+0.1% NH3:HO=60 / 40; 150 mL / min), (1R*,3S*)-3-(2-((4-((R)-N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (147 mg, first peak) was obtained as a white solid, and (1R*,3S*)-3-(2-((4-((S)-N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (119 mg, second peak) was obtained as a white solid. The absolute configuration was arbitrarily assigned to each enantiomer. LCMS (ESI) m / z: 574.3 [M+H] + .

[0373] Step 6: Synthesis of (1R*,3S*)-3-(2-((4-((S*)-cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate HCl salt (Compound 580) To a solution of (1R*,3S*)-3-(2-((4-((S)-N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (147 mg, 255 μmol) in dioxane (5 mL), HCl / dioxane (5 mL, 4 M) was added. The reaction was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (30%-60% acetonitrile in water / 0.05% HCl) to give compound 580 (46 mg, 38%) as a white solid. The absolute configuration was arbitrarily assigned. LCMS (ESI) m / z: 474.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.80(s,1H),8.54-8.51(m,2H),8.02-7.98(m,1H),7.89-7.84(m,1H),7.43(s,1H) ),5.05-4.99(m,1H),3.55-3.40(m,1H),3.20-2.90(m,1H),2.49-2.36(m,2H),2. 12-2.00(m,1H),1.95-1.86(m,1H),1.82-1.64(m,2H),1.63-1.46(m,1H),1.46-1 .32(m,2H),1.24(s,3H),1.23-1.14(m,2H),0.65-0.56(m,2H),0.53-0.44(m,2H).

[0374] Example 7 Synthesis of rel-4-((5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 52) and rel-4-((5-((1S,3R)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 392) [ka] Step 1: Synthesis of rac-tert-butyl (5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate To a solution of rac-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrimidin-2-yl)carbamate (200 mg, 0.72 mmol) in DMF (8 mL) was added NaH (71 mg, 1.79 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, followed by the addition of 4-isopropyl-3-methylsulfonyl-1,2,4-triazole (160 mg, 0.86 mmol). The mixture was stirred at 40 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction was quenched with saturated aqueous NH Cl (3 mL), diluted with HO (20 mL), and subsequently extracted with EtOAc (50 × 2 mL). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% methanol in ethyl acetate) to give the title compound (100 mg, 36%) as a yellow oil. LCMS (ESI) m / z: 389.2 [M+H] + .

[0375] Step 2: Synthesis of rac-5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt To a solution of rac-tert-butyl (5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (100 mg, 250 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give the title compound (70 mg, crude) as a yellow oil which required no further purification. LCMS (ESI) m / z 289.2 [M+H] + .

[0376] Step 3: Synthesis of rac-tert-butyl ((4-((5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate To a solution of rac-5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt (70.00 mg, 242 μmol), tert-butyl N-(4-bromophenyl)sulfonylcarbamate (122 mg, 364 μmol), and CsCO (476 mg, 1.46 mmol) in dioxane (3 mL) was added BrettPhos (13 mg, 24 μmol) and BrettPhos Pd G (22 mg, 24 μmol). The reaction was stirred at 100 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (50 mg, 53%) as a yellow solid. LCMS (ESI) m / z: 544.2 [M+H] + .

[0377] Step 4: Synthesis of rac-4-((5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide To a solution of rac-tert-butyl ((4-((5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (50 mg, 92 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give the title compound (40 mg, crude) as a yellow oil which required no further purification. LCMS (ESI) m / z 444.2 [M+H] + .

[0378] Step 5: Synthesis of rel-4-((5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 52) and rel-4-((5-((1S,3R)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 392) rac-4-((5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (40 g, 90 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); supercritical CO2 / iPrOH+0.1%). NH3:HO=50 / 50; 60 mL / min), affording rel-4-((5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (compound 52, 2.3 mg, first peak) as a white solid, and rel-4-((5-((1S,3R)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (compound 392, 2.1 mg, last peak) as a white solid. The absolute configuration was arbitrarily assigned to each enantiomer. Compound 52: LCMS (ESI) m / z: 444.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.02(s,1H),8.50(s,2H),8.25(s,1H),7.91(d,J=8.8Hz,2H),7.70(d,J=8.4Hz,2H),7.16(s,2H),5.37-5.29(m,1H),4.23-4.13(m,1H) ,3.19-3.09(m,1H),2.70-2.60(m,1H),2.17-1.93(m,3H),1.92-1.78(m,2H),1.33(d,J=6.8Hz,6H).Compound 392:LCMS(ESI)m / z:444.2[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 10.02(s,1H),8.50(s,2H),8.25(s,1H),7.91(d,J=8.8Hz,2H),7.70(d,J=8.8Hz,2H),7.16(s,2H),5.37-5.29(m,1H), 4.23-4.13(m,1H),3.19-3.10(m,1H),2.71-2.62(m,1H),2.17-1.94(m,3H),1.93-1.79(m,2H),1.33(d,J=6.8Hz,6H).

[0379] Example 8 Synthesis of rel-3-fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 449) [ka] Step 1: Synthesis of 4-(1-methylcyclopropyl)-4H-1,2,4-triazole-3-thiol To a solution of 1-isothiocyanato-1-methylcyclopropane (18 g, 159 mmol) in THF (200 mL) was added NaOH (3.6 g, 90 mmol) and formic acid hydrazide (18.0 g, 299.7 mmol). The mixture was stirred at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was quenched by adding water (20 mL) and subsequently extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0–50% ethyl acetate in petroleum ether) to afford the title compound (16 g, 64%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 12.49(s,1H),7.78(s,1H),1.59(s,3H),1.19-1.15(m,2H),1.05-0.99(m,2H).

[0380] Step 2: Synthesis of 4-(1-methylcyclopropyl)-3-(methylthio)-4H-1,2,4-triazole To a solution of 4-(1-methylcyclopropyl)-4H-1,2,4-triazole-3-thiol (16 g, 103.1 mmol) in acetone (100 mL) was added K2CO3 (15.7 g, 113.4 mmol) and MeI (13.2 g, 92.8 mmol). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-100% ethyl acetate in petroleum ether) to give the title compound (15 g, 86%) as a white solid. LCMS (ESI) m / z: 170.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ 8.22 (s, 1H), 2.77 (s, 3H), 1.51 (s, 3H), 1.18-1.13 (m, 2H), 1.03-0.94 (m, 2H).

[0381] Step 3: Synthesis of 4-(1-methylcyclopropyl)-3-(methylsulfonyl)-4H-1,2,4-triazole To a solution of 4-(1-methylcyclopropyl)-3-methylsulfanyl-1,2,4-triazole (14 g, 82.7 mmol) in DCM (100 mL) was added m-CPBA (61.2 g, 301.3 mmol, 85% purity). The mixture was stirred at 25 °C under a nitrogen atmosphere for 16 h. The reaction was quenched by adding 200 mL of saturated aqueous NaSO, followed by extraction with DCM (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 10% to 100% ethyl acetate in petroleum ether) to afford the title compound (14 g, 69%) as a white solid. LCMS (ESI) m / z: 202.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ 7.77 (s, 1H), 1.62 (s, 4H), 1.23-1.18 (m, 2H), 1.09-1.04 (m, 2H).

[0382] Step 4: Synthesis of rac-tert-butyl (5-((1R,3S)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate To a solution of rac-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrimidin-2-yl)carbamate (0.5 g, 1.8 mmol) in DMF (10 mL) was added NaH (214 mg, 5.4 mmol, 60% purity) under a nitrogen atmosphere at 0° C. The mixture was stirred at 0° C. for 30 minutes, followed by the addition of 4-(1-methylcyclopropyl)-3-(methylsulfonyl)-4H-1,2,4-triazole (721 mg, 3.6 mmol) over 5 minutes at 0° C., and then the mixture was heated to 40° C. for 16 hours. After cooling to room temperature, the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL), followed by extraction with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (solvent gradient: 5% to 10% MeOH in DCM) to give the title compound (0.4 g, 55%) as a white solid. LCMS (ESI) m / z: 401.1 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 8.55(s,2H),7.86(s,1H),7.47(s,1H),5.59-5.52(m,1H),3.23-3.09(m,1H),2.87-2.75(m,1H),2.34-2.20( m,2H),2.17-2.05(m,1H),2.03-1.81(m,2H),1.56(s,9H),1.48(s,3H),1.11-1.02(m,2H),0.99-0.90(m,2H).

[0383] Step 5: Synthesis of rac-5-((1R,3S)-(3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-amine To a solution of rac-tert-butyl (5-((1R,3S)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (0.3 g, 749 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo. The residue was diluted with MeOH (20 mL) and DCM (20 mL) and adjusted to pH = 8 with saturated aqueous NaHCO3, followed by stirring for 1 h, drying over anhydrous Na2SO4, filtering, and concentrating in vacuo to give the title compound (0.2 g, crude) as a yellow oil, which required no further purification. LCMS (ESI) m / z: 301.2 [M+H] + .

[0384] Step 6: Synthesis of rac-tert-butyl ((3-fluoro-4-((5-((1R,3S)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate rac-5-((1R,3S)-(3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-amine (150 mg, 499 μmol), tert-butyl N-(4-bromo-3-fluorophenyl)sulfonylcarbamate (265 mg, 749 μmol), BrettPhos Pd in ​​dioxane (8 mL). A mixture of G3 (45 mg, 49 μmol), Brettphos (54 mg, 99 μmol), and CsCO (976 mg, 3.0 mmol) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100 °C under nitrogen for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 20 mL). The organic layer was washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 3% to 5% methanol in ethyl acetate) to give the title compound (120 mg, 41%) as a yellow oil. LCMS (ESI) m / z: 574.1 [M+H] + .

[0385] Step 7: Synthesis of rel-tert-butyl ((3-fluoro-4-((5-((1R,3S)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate and rel-tert-butyl ((3-fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate rac-tert-butyl((3-fluoro-4-((5-((1R,3S)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (120 mg, 209 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); supercritical CO2 / EtOH+0.1%). NH3:HO=55 / 45; 80 mL / min), rel-tert-butyl ((3-fluoro-4-((5-((1R,3S)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (50 mg, first peak) was obtained as a colorless oil, and rel-tert-butyl ((3-fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (50 mg, second peak) was obtained as a colorless oil. The absolute configurations were arbitrarily assigned to each enantiomer.

[0386] Step 8: Synthesis of rel-3-fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 449) A solution of rel-tert-butyl ((3-fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (130 mg, 227 μmol) in HCl / dioxane (5 mL, 4 M) was stirred at 25° C. for 1 h. The reaction was then concentrated in vacuo. The residue was purified by reverse phase chromatography (36% to 60% acetonitrile in water / 0.05% HCl) to give the HCl salt compound. The HCl salt compound was diluted with MeOH (5 mL) and Amberlyst 15 was added. The mixture was then stirred at 25° C. for 1 h, filtered, and concentrated under reduced pressure to give compound 449 (40 mg, 96%) as a white solid. LCMS (ESI) m / z: 474.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.50(s,2H),8.17(s,1H),8.16-8.12(m,1H),7.61-7.59(m,2H),5.37-5.31(m,1H),3.21-3.10(m,1H),2.70-2.60(m,1H),2. 21-2.10(m,1H),2.08-1.99(m,2H),1.94-1.85(m,1H),1.85-1.77(m,1H),1.39(s,3H),1.05-1.01(m,2H),0.90-0.84(m,2H).

[0387] Example 9 Synthesis of rel-3-fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 480) and rel-3-fluoro-4-((5-((1R,3S)-3-((4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 551) [ka] Step 1: Synthesis of 2-butyryl-N-(1-methylcyclopropyl)hydrazine-1-carbothioamide To a solution of 1-isothiocyanato-1-methylcyclopropane (3 g, 26.5 mmol) in THF (20 mL) was added butane hydrazide (4.06 g, 39.8 mmol). The mixture was stirred at 60° C. for 16 h. The reaction was concentrated in vacuo to give the title compound (5.5 g, crude) as a yellow solid, which required no further purification. LCMS (ESI) m / z: 215.9 [M+H] + .

[0388] Step 2: Synthesis of 4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazole-3-thiol To a solution of 1-(butanoylamino)-3-(1-methylcyclopropyl)thiourea (5.5 g, 25.5 mmol) in EtOH (20 mL) was added TEA (10.7 mL, 76.6 mmol). The mixture was stirred at 100° C. for 16 h. The reaction was concentrated in vacuo to give the title compound (5 g, crude) as a yellow solid, which required no further purification. LCMS (ESI) m / z: 197.8 [M+H] + .

[0389] Step 3: Synthesis of rel-3-fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 480) and rel-3-fluoro-4-((5-((1R,3S)-3-((4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 551) rel-3-Fluoro-4-((5-((1S,3R)-3-((4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 480) and rel-3-fluoro-4-((5-((1R,3S)-3-((4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 551) were prepared in a manner similar to that of Compound 449, using 4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazole-3-thiol in place of 4-(1-methylcyclopropyl)-4H-1,2,4-triazole-3-thiol, with any suitable modifications. The absolute configuration was arbitrarily assigned to each enantiomer. Compound 449: LCMS (ESI) m / z: 516.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.39(s,1H),8.50(s,2H),8.21-8.10(m,1H),7.64-7.56(m,2H),7.36(s,2H),5. 34-5.25(m,1H),3.23-3.10(m,1H),2.66-2.58(m,3H),2.20-2.08(m,1H),2.06- 1.99(m,2H),1.92-1.78(m,2H),1.77-1.68(m,2H),1.33(s,3H),1.04-1.00(m,2 H),0.98(t,J=7.6Hz,3H),0.94-0.88(m,2H).Compound 551:LCMS(ESI)m / z:516.1[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 9.39(s,1H),8.50(s,2H),8.19-8.10(m,1H),7.64-7.56(m,2H),7.36( s,2H),5.35-5.25(m,1H),3.23-3.10(m,1H),2.68-2.58(m,3H),2.20-2 .07(m,1H),2.07-1.97(m,2H),1.92-1.77(m,2H),1.77-1.68(m,2H),1. 33(s,3H),1.05-1.00(m,2H),0.98(t,J=7.6Hz,3H),0.94-0.89(m,2H).

[0390] Example 10: Synthesis of rel-4-((5-((1S,3R)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 574) [ka] Step 1: Synthesis of rac-tert-butyl(tert-butoxycarbonyl)(5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate To a solution of 4-cyclopropylisothiazol-3-ol (555 mg, 3.93 mmol) and K2CO3 (1.09 g, 7.87 mmol) in DMF (10 mL) was added rac-(1R,3R)-3-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclopentylmethanesulfonic acid (1.5 g, 2.62 mmol). The reaction was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-100% ethyl acetate in petroleum ether) to give the title compound (1.1 g, 66%) as a white solid. LCMS (ESI) m / z: 503.2 [M+H] + .

[0391] Step 2: Synthesis of rac-5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt To a solution of rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (1.1 g, 1.75 mmol) in DCM (12 mL) was added TFA (4 mL). The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (550 mg, crude) as a yellow oil which required no further purification. LCMS (ESI) m / z: 303.2 [M+H] + .

[0392] Step 3: Synthesis of rac-tert-butyl ((4-((5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate To a solution of rac-5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt (100 mg, 330 μmol) and tert-butyl N-(4-bromophenyl)sulfonylcarbamate (133 mg, 396 μmol) in dioxane (5 mL) was added BrettPhos (18 mg, 33 μmol), BrettPhos Pd G3 (30 mg, 33 μmol), and K3PO4 (351 mg, 1.65 mmol). The reaction mixture was stirred at 80 °C under a N2 atmosphere for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 20 mL). The organic layer was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% methanol in ethyl acetate) to give the title compound (100 mg, 54%) as a yellow oil. LCMS (ESI) m / z: 558.2 [M+H] + .

[0393] Step 4: Synthesis of rel-tert-butyl ((4-((5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate and rel-tert-butyl ((4-((5-((1S,3R)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate rac-tert-butyl((4-((5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (256 mg, 466 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK IF (250 mm*30 mm, 10 μm); supercritical CO2 / heptane-EtOH+0.1%). NH3:HO=40 / 60; 80 ml / min), affording rel-tert-butyl ((4-((5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (70 mg, first peak) and rel-tert-butyl ((4-((5-((1S,3R)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (85 mg, second peak), both as white solids. The absolute configuration was arbitrarily assigned to each enantiomer. LCMS (ESI) m / z: 558.1 [M+H] + .

[0394] Step 5: Synthesis of rel-4-((5-((1S,3R)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 574) To a solution of tert-butyl N-[4-[[5-[(1S,3R)-3-(4-cyclopropylisothiazol-3-yl)oxycyclopentyl]pyrimidin-2-yl]amino]phenyl]sulfonylcarbamate (85 mg, 152 μmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography (52%-82% acetonitrile / 0.05% NH3).H2O + 10 mM aqueous NH4HCO3) to give compound 574 (20 mg, 35%) as a white solid. LCMS (ESI) m / z: 458.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.99(s,1H),8.52(s,2H),8.29(s,1H),7.90(d,J=8.0Hz,2H),7.70(d,J=8.0Hz,2H),7.15(s,2H),5.43-5.32(m,1H) ,3.20-3.11(m,1H),2.69-2.58(m,1H),2.17-1.95(m,3H),1.87-1.68(m,3H),0.93-0.84(m,2H),0.69-0.64(m,2H).

[0395] Example 11: Synthesis of rac-3-fluoro-4-((5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 55) [ka] Step 1: Synthesis of rac-tert-butyl (5-((1R,3S)-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)(tert-butoxycarbonyl)carbamate A solution of 4-bromopyridin-3-ol (75 mg, 0.4 mmol), K2CO3 (119 mg, 0.9 mmol), rac-(1R,3R)-3-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclopentyl methanesulfonate (237 mg, 0.5 mmol) in DMF (2 mL) was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-100% ethyl acetate in petroleum ether) to give the title compound (90 mg, 36%) as a white solid. LCMS (ESI) m / z: 537.1 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 8.76(s,2H),8.25(s,1H),8.06(d,J=5.2Hz,1H),7.52(d,J=5.2Hz,1H),5.10(s,1H),3.30-3.18( m,1H),2.80-2.70(m,1H),2.30-2.20(m,2H),2.10-2.06(m,1H),2.03-1.96(m,2H),1.46(s,18H).

[0396] Step 2: Synthesis of rac-5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-amine A solution of rac-tert-butyl (5-((1R,3S)-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)(tert-butoxycarbonyl)carbamate (50 mg, 93 μmol), KCO (40 mg, 0.3 mmol), Pd(dppf)Cl·CHCl (2 mg, 2 μmol), and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (31 mg, 0.2 mmol) in dioxane (0.8 mL) and HO (0.2 mL) was stirred at 130 °C under a N atmosphere for 16 h. The mixture was concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0–15% MeOH in DCM) to give the title compound (14 mg, 49%) as a colorless oil. LCMS(ESI)m / z:297.1[M+H] + .

[0397] Step 3: Synthesis of rac-tert-butyl ((3-fluoro-4-((5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate To a solution of rac-5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-amine (13 mg, 44 μmol) and tert-butyl N-(4-bromo-3-fluorophenyl)sulfonylcarbamate (47 mg, 0.14 mmol) in dioxane (2 mL) was added BrettPhos Pd G3 (8 mg, 9 μmol), BrettPhos (5 mg, 9 μmol), and Cs2CO3 (86 mg, 0.26 mmol). The reaction mixture was stirred at 100 °C under a N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 5 mL). The organic layer was washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% methanol in ethyl acetate) to give the title compound (14 mg, 31%) as a yellow oil. LCMS (ESI) m / z: 570.1 [M+H] + .

[0398] Step 4: Synthesis of rac-3-fluoro-4-((5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 55) To a solution of rac-tert-butyl ((3-fluoro-4-((5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (14 mg, 25 μmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 44%-74% / 0.05% NH).H2O + 10 mM aqueous NH4HCO3) to give compound 55 (2 mg, 16%) as a white solid. LCMS (ESI) m / z: 470.2 [M+H] + ; 1H NMR(400MHz,CDCl3)δ 8.90-8.80(m,1H),8.44(s,2H),8.30-8.17(m,2H),7.76-7.71(m,1H),7. 70-7.65(m,1H),7.59-7.51(m,1H),7.23-7.18(m,1H),5.34-5.26(m,2H), 5.09-4.99(m,1H),4.87-4.81(m,2H),3.23-3.04(m,1H),2.83-2.65(m,1 H),2.25-2.18(m,2H),2.15(s,3H),2.12-2.01(m,1H),1.97-1.90(m,2H).

[0399] Example 12: Synthesis of (1RS,3SR)-3-(5-chloro-6-((4-sulfamoylphenyl)amino)pyridin-3-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 353) [ka] Step 1: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[(1R)-3-oxocyclopentyl]-2-pyridyl]carbamate A mixture of tert-butyl N-(5-bromo-3-chloro-2-pyridyl)-N-tert-butoxycarbonylcarbamate (4 g, 9.8 mmol), cyclopent-2-en-1-ol (1.65 g, 19.62 mmol), Pd(OAc) (220 mg, 981 μmol), TBAC (2.73 g, 9.8 mmol), and KOAc (2.89 g, 29.4 mmol) in DMF (15 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 80° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (2 g, 49%) as a pale yellow oil. LCMS (ESI) m / z: 433.1 [M+Na] + .

[0400] Step 2: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[3-hydroxycyclopentyl]-2-pyridyl]carbamate To a mixture of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[3-oxocyclopentyl]-2-pyridyl]carbamate (2 g, 4.9 mmol) in THF (40 mL) under a N atmosphere at −65 °C, LiBHEt (1 M, 7.30 mL) was added. The reaction was stirred at the same temperature for 1 h. The reaction mixture was quenched by adding saturated aqueous NaHCO (50 mL) at −65 °C and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0–70% EtOAc in petroleum ether) to give the title compound (1 g, 49%) as a yellow solid. LCMS (ESI) m / z: 435.1 [M+Na] + .

[0401] Step 3: Synthesis of [3-[6-[bis(tert-butoxycarbonyl)amino]-5-chloro-3-pyridyl]cyclopentyl](4-nitrophenyl)carbonate To a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[(1R,3S)-3-hydroxycyclopentyl]-2-pyridyl]carbamate (1 g, 2.42 mmol), DMAP (30 mg, 242 μmol), and pyridine (0.6 mL, 7.3 mmol) in DCM (15 mL) was added (4-nitrophenyl)carbonochloridate (976 mg, 4.8 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was quenched by adding saturated aqueous NaHCO (10 mL) at 25° C. and extracted with DCM (100 mL). The organic layer was washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give the title compound (1.1 g, 78%) as a brown solid. LCMS (ESI) m / z: 600.1 [M+Na] + .

[0402] Step 4 - Synthesis of tert-butyl(tert-butoxycarbonyl)(3-chloro-5-(3-((((S)-4,4,4-trifluorobutan-2-yl)carbamoyl)oxy)cyclopentyl)pyridin-2-yl)carbamate To a mixture of [3-[6-[bis(tert-butoxycarbonyl)amino]-5-chloro-3-pyridyl]cyclopentyl](4-nitrophenyl)carbonate (1.1 g, 1.90 mmol) and (S)-4,4,4-trifluorobutan-2-amine (467 mg, 2.85 mmol, HCl salt) in THF (15 mL) under N at 25 °C, DIPEA (1 mL, 5.7 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by adding water (10 mL) at 25 °C and extracted with DCM (100 mL). The organic layer was washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-60% EtOAc in petroleum ether) to give the title compound (1.05 g, 97%) as a brown solid. LCMS (ESI) m / z: 588.2 [M+Na] + .

[0403] Step 5 - Synthesis of 3-(6-amino-5-chloropyridin-3-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate To a mixture of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[3-[[(1S)-3,3,3-trifluoro-1-methylpropyl]carbamoyloxy]cyclopentyl]-2-pyridyl]carbamate (1.05 g, 1.86 mmol) in DCM (10 mL) under a N atmosphere at 25 °C was added TFA (3 mL, 40.32 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo to give the title compound (0.69 g, crude, TFA salt) as a yellow oil that required no further purification. LCMS (ESI) m / z: 366.0 [M+H] + .

[0404] Step 6-Synthesis of 3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate To a mixture of 3-(6-amino-5-chloropyridin-3-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (0.5 g, 1.37 mmol) and tert-butyl N-(4-bromophenyl)sulfonylcarbamate (919 mg, 2.7 mmol) in dioxane (10 mL) was added BrettPhos Pd G3 (124 mg, 137 μmol), Brettphos (147 mg, 273 μmol), and Cs2CO3 (1.34 g, 4.1 mmol) under a N2 atmosphere at 25 °C. The reaction mixture was stirred at 100 °C under a N2 atmosphere for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (120 mg, 14%) as a white solid. LCMS (ESI) m / z 621.2 (M+H + ).

[0405] Step 7: Synthesis of (1RS,3SR)-3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl((S)-4,4,4-trifluorobutan-2-yl)carbamate and (1RS,3RS)-3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl((S)-4,4,4-trifluorobutan-2-yl)carbamate 3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl((S)-4,4,4-trifluorobutan-2-yl)carbamate (0.12 g, 193 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); supercritical CO2 / EtOH+0.1% NH3:HO=75 / 25; 60 ml / min), (1RS,3SR)-3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl((S)-4,4,4-trifluorobutan-2-yl)carbamate (cis isomer, 25 mg, mixture of the first and second peaks) as a white solid, and (1RS,3RS)-3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl((S)-4,4,4-trifluorobutan-2-yl)carbamate (trans isomer, 20 mg, mixture of the third and fourth peaks) as a white solid.

[0406] Step 8: Synthesis of (1RS,3SR)-3-(5-chloro-6-((4-sulfamoylphenyl)amino)pyridin-3-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 353) To a solution of (1RS,3SR)-3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (25 mg, 40 μmol) in dioxane (2 mL) under a N atmosphere at 25° C. was added HCl / dioxane (2 mL, 4 M). The mixture was stirred at 25° C. for 1 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (35%-63% acetonitrile in water / 0.05% HCl) to give compound 353 (7.2 mg, 34%) as a white solid. LCMS (ESI) m / z: 521.0 [M+H] + ;1 H NMR(400MHz,DMSO-d6)δ 8.72(s,1H),8.10(s,1H),7.85-7.79(m,3H),7.72-7.66(m,2H),7.37 -7.04(m,3H),5.15-5.07(m,1H),3.91-3.78(m,1H),3.31-3.10(m,1H ),2.44-2.32(m,2H),2.27-2.17(m,1H),2.15-2.07(m,1H),2.06-1.97(m,1H),1.94-1.83(m,1H),1.72-1.49(m,2H),1.13(d,J=6.4Hz,3H).

[0407] Example 13 Synthesis of (1RS,4RS)-4-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopent-2-en-1-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 412) [ka] Step 1: Synthesis of rac-tert-butyl(tert-butoxycarbonyl)(5-((1R,4R)-4-((tert-butyldiphenylsilyl)oxy)cyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate A mixture of tert-butyl N-(5-bromopyrimidin-2-yl)-N-tert-butoxycarbonylcarbamate (3 g, 8.0 mmol), tert-butylcyclopent-3-en-1-yloxydiphenylsilane (3.9 g, 12.0 mmol), Pd(OAc) (180 mg, 802 μmol), KOAc (1.57 g, 16.0 mmol), and PPh (420 mg, 1.60 mmol) in DMF (20 mL) was degassed and purged with N gas three times, and then the mixture was stirred in a microwave reactor under a N atmosphere at 140 °C for 1 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give the title compound (1 g, 20%) as a white solid. LCMS (ESI) m / z: 616.3 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 8.44(s,2H),7.70-7.67(m,4H),7.44-7.38(m,6H),5.93-5.86(m,2H),5.10-5.05(m,1H ),4.17-4.13(m,1H),2.46-2.37(m,1H),1.92-1.84(m,1H),1.45(s,18H),1.08(s,9H).

[0408] Step 2: Synthesis of rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,4R)-4-hydroxycyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate To a solution of rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,4R)-4-((tert-butyldiphenylsilyl)oxy)cyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate (1.0 g, 1.6 mmol) in THF (20 mL) was added TBAF (1 M, 1.6 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-60% ethyl acetate in petroleum ether) to give the title compound (530 mg, 84%) as a white solid. LCMS (ESI) m / z: 378.2 [M+H] + .

[0409] Step 3: Synthesis of rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,4R)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate To a solution of rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,4R)-4-hydroxycyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate (530 mg, 1.4 mmol), pyridine (333 mg, 4.2 mmol), DMAP (34 mg, 280 μmol) in DCM (10 mL) was added (4-nitrophenyl)carbonochloridate (424 mg, 2.1 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched at 25 °C by adding saturated aqueous NaHCO (10 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% ethyl acetate in petroleum ether) to give the title compound (700 mg, 92%) as a colorless oil. LCMS (ESI) m / z: 543.1 [M+H] + .

[0410] Step 4: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((1RS,4RS)-4-((((S)-4,4,4-trifluorobutan-2-yl)carbamoyl)oxy)cyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate To a solution of rac-tert-butyl (tert-butoxycarbonyl) (5-((1R,4R)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate (700 mg, 1.3 mmol), (S)-4,4,4-trifluorobutan-2-amine (316 mg, 1.9 mmol, HCl salt) in THF (10 mL) was added TEA (540 μL, 3.9 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched at 25 °C by adding saturated aqueous NaHCO (10 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% ethyl acetate in petroleum ether) to give the title compound (600 mg, 88%) as a yellow solid. LCMS (ESI) m / z: 531.2 [M+H] + .

[0411] Step 5: Synthesis of (1RS,4RS)-4-(2-aminopyrimidin-5-yl)cyclopent-2-en-1-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate To a solution of tert-butyl (tert-butoxycarbonyl)(5-((1RS,4RS)-4-((((S)-4,4,4-trifluorobutan-2-yl)carbamoyl)oxy)cyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate (600 mg, 1.1 mmol) in DCM (6 mL) was added TFA (2 mL) and the mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (500 mg, crude, TFA salt) as a yellow oil that required no further purification. LCMS (ESI) m / z: 331.3 [M+H] + .

[0412] Step 6: Synthesis of (1RS,4RS)-4-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopent-2-en-1-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 412) To a mixture of (1RS,4RS)-4-(2-aminopyrimidin-5-yl)cyclopent-2-en-1-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (0.15 g, 454 μmol), tert-butyl N-(4-bromophenyl)sulfonylcarbamate (305 mg, 908 μmol), and CsCO (296 mg, 908 μmol) in dioxane (5 mL) was added Brettphos (24 mg, 45 μmol), CsCO (296 mg, 908 μmol), and BrettPhos Pd G (41 mg, 45 μmol), and the mixture was stirred at 100° C. under a N atmosphere for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 0% to 35% / 0.04% HCl in water) to give compound 412 (2.1 mg) as a yellow solid. LCMS (ESI) m / z: 486.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,2H),10.05(s,1H),8.70(s,4H),8.39(s,2H),7.82-8.01(m,7H),7.65-7.77(m,7H),7 .30(d,J=8.8Hz,3H),7.12-7.23(m,6H),6.33(brs,2H),6.18-6.14(m,1H),6.05-6.00(m,1H),5 .74-5.67(m,1H),5.35-5.25(m,2H),4.09-4.01(m,1H),3.82-3.90(m,3H),3.00-3.08(m,2H),2 .84-2.93(m,2H),2.62-2.73(m,3H),2.34-2.42(m,6H),2.06-2.25(m,2H),1.05-1.18(m,11H).

[0413] Example 14: Synthesis of (1s,3s)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (Compound 2) and (1r,3r)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (Compound 3) [ka] Step 1: Synthesis of 5-(3-(benzyloxy)cyclobutyl)pyrimidin-2-amine To a solution of (2-aminopyrimidin-5-yl)boronic acid (3.0 g, 21.6 mmol) in dioxane (100 mL) was added N-[(3-benzyloxycyclobutylidene)amino]-4-methylbenzenesulfonamide (14.2 g, 43.2 mmol, prepared according to the procedure of WO 2021 / 155320, the entire contents of which are incorporated herein by reference), and CsCO (14.1 g, 43.2 mmol). The mixture was stirred at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (3.5 g, crude), which was further purified by reverse phase chromatography (17-47% acetonitrile in water / 0.225% formic acid) to give the title compound (1.3 g, 24%) as a yellow solid. LCMS (ESI) m / z: 256.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.21-8.08(m,2H),7.47-7.14(m,5H),6.47(s,2H),4.42-4.36(m,2H),4.28-4.18(m,1H),4.02-3.90(m, 0.6H), 3.45-3.27 (m, 1H), 2.85-2.75 (m, 0.4H), 2.61-2.48 (m, 1H), 2.42-2.23 (m, 2H), 1.98-1.86 (m, 1H).

[0414] Step 2: Synthesis of 4-((5-(3-(benzyloxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluoro-N-isopropylbenzenesulfonamide To a solution of 5-(3-benzyloxycyclobutyl)pyrimidin-2-amine (0.4 g, 1.33 mmol) and 4-bromo-3-fluoro-N-isopropylbenzenesulfonamide (786 mg, 2.65 mmol) in dioxane (10 mL) was added CsCO (1.30 g, 3.98 mmol), BrettPhos (71 mg, 132 μmol), and BrettPhos Pd G (120 mg, 132 μmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give the title compound (0.6 g, 96%) as a yellow oil. LCMS (ESI) m / z: 471.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.42(s,1H),8.56-8.36(m,2H),8.28-8.15(m,1H),7.63-7.51(m,3H),7.40-7.31(m,4H),7.31-7.24(m,1H),4.46-4.38(m,2H),4.29 -4.26(m,0.6H),3.58-3.39(m,1H),3.29-3.21(m,2H),3.00-2.85(m,0.4H),2.69-2.54(m,1H),2.45-2.35(m,2H),0.99-0.93(m,6H).

[0415] Step 3: Synthesis of 3-fluoro-4-((5-(3-hydroxycyclobutyl)pyrimidin-2-yl)amino)-N-isopropylbenzenesulfonamide To a solution of 4-((5-(3-(benzyloxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluoro-N-isopropylbenzenesulfonamide (0.55 g, 1.17 mmol) in DCM (4 mL) at −78° C. was slowly added BCl (1 M, 11.69 mL). After the addition, the mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with NH / MeOH (1 M, 5 mL) and subsequently concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to afford the title compound (0.42 g, 95%) as a colorless oil. LCMS (ESI) m / z: 381.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.46-9.29(m,1H),8.55-8.37(m,2H),8.29-8.16(m,1H),7.69-7.39(m,3H),5.13(s,1H),4.35-4.21(m,0.6H),3.48-3.35(m, 1H),3.26-3.21(m,1H),2.90-2.78(m,0.4H),2.68-2.53(m,1H),2.38-2.25(m,2H),1.97-1.80(m,1H),0.96(d,J=6.4Hz,6H).

[0416] Step 4: Synthesis of 3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(4-nitrophenyl)carbonate To a solution of 3-fluoro-4-((5-(3-hydroxycyclobutyl)pyrimidin-2-yl)amino)-N-isopropylbenzenesulfonamide (0.37 g, 0.97 mmol) in DCM (20 mL) was added DMAP (24 mg, 0.19 mmol) and pyridine (230 mg, 2.92 mmol). Subsequently, (4-nitrophenyl)carbonochloridate (392 mg, 1.95 mmol) was added slowly. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with water (20 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0–50% EtOAc in petroleum ether) to afford the title compound (0.43 g, 81%) as a white solid. LCMS(ESI)m / z:546.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.47(s,1H),8.58-8.49(m,2H),8.35-8.30(m,2H),8.27-8.18(m,1H),7.64-7.53(m,5H),5.33-4.91(m,1H),3.78-3.63(m,0. 6H),3.30-3.21(m,1H),3.20-3.03(m,0.4H),2.87-2.76(m,1H),2.68-2.62(m,2H),2.42-2.29(m,1H),0.96(d,J=6.4Hz,6H).

[0417] Step 5: Synthesis of (1s,3s)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (Compound 2) and (1r,3r)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (Compound 3) To a mixture of 1-methylcyclopropanamine (170 mg, 1.58 mmol) and 3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(4-nitrophenyl)carbonate (0.43 g, 0.79 mmol) in THF (5 mL) was added triethylamine (240 mg, 2.36 mmol). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (37-77% acetonitrile / 0.225% formic acid in water) to give (1s,3s)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (compound 2, 57 mg, 15%) as a white solid and (1r,3r)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (130 mg, contained 8% of the cis isomer) as a white solid. The trans isomers were further separated using chiral SFC (DAICEL CHIRALCEL AS (250 mm * 30 mm, 5 μm); supercritical CO2 / EtOH + 0.1% NH3.H2O = 65 / 35; 80 mL / min) to give (1r,3r)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (compound 3, 116 mg, 51%) as a white solid. Compound 2: LCMS (ESI) m / z: 478.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 9.45(s,1H),8.45(s,2H),8.25-8.18(m,1H),7.63-7.53(m,3H),7.47 (s,1H),4.88-4.75(m,1H),3.29-3.21(m,1H),3.09-2.97(m,1H),2.71 -2.62(m,2H),2.13-1.99(m,2H),1.24(s,3H),0.96(d,J=6.4Hz,6H),0.64-0.56(m,2H),0.51-0.44(m,2H).Compound 3:LCMS(ESI)m / z:478.1[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.46(s,1H),8.51(s,2H),8.27-8.18(m,1H),7.62-7.55(m,3H),7.51(s,1H),5.07-4.95(m,1H),3.59-3.48(m,1H) ),3.29-3.21(m,1H),2.48-2.37(m,4H),1.24(s,3H),0.96(d,J=6.8Hz,6H),0.64-0.56(m,2H),0.51-0.45(m,2H).

[0418] Example 15: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 367) [ka] Step 1: Synthesis of tert-butyl (5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)carbamate To a solution of tert-butyl (5-((1s,3s)-3-hydroxycyclobutyl)pyrimidin-2-yl)carbamate (453 mg, 1.71 mmol) in DMF (8 mL) was added NaH (150 mg, 3.82 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then 1-isopropyl-3-nitro-1,2,4-triazole (400 mg, 2.56 mmol, prepared according to the procedure in Chem Hete Compounds., 2005, 41,861) was added. The mixture was stirred at 65 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction was quenched with saturated aqueous NH Cl (3 mL), diluted with HO (20 mL), and subsequently extracted with EtOAc (50 × 2 mL). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (106 mg, 17%) as a yellow oil. LCMS (ESI) m / z: 375.2 [M+H] + .

[0419] Step 2: Synthesis of 5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-amine To a solution of tert-butyl (5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)carbamate (105 mg, 280 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give the title compound (80 mg, crude) as a yellow oil which required no further purification. LCMS (ESI) m / z 275.2 [M+H] + .

[0420] Step 3: Synthesis of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate To a solution of 5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-amine (75 mg, 273 μmol), tert-butyl N-(4-bromo-3-fluoro-phenyl)sulfonylcarbamate (145 mg, 410 μmol), and CsCO (267 mg, 820 μmol) in dioxane (3 mL) was added BrettPhos (15 mg, 27 μmol) and BrettPhos Pd G (25 mg, 27 μmol). The reaction was stirred at 100 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (98 mg, 65%) as a yellow solid. LCMS (ESI) m / z: 548.2 [M+H] + .

[0421] Step 4: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 367) A solution of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (98 mg, 179 μmol) in HCl / dioxane (2 mL, 4 M) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography (25% to 55% acetonitrile in water / 0.225% formic acid) to give compound 367 (68 mg, 85%) as a white solid. LCMS (ESI) m / z: 448.0 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 9.39(s,1H),8.48(s,2H),8.20(s,1H),8.19-8.12(m,1H),7.63-7.57(m,2H),7.36(s,2H),4.96-4.85(m ,1H),4.45-4.35(m,1H),3.13-3.01(m,1H),2.86-2.75(m,2H),2.25-2.14(m,2H),1.39(d,J=6.4Hz,6H).

[0422] Example 16: Synthesis of (3-fluoro-4-((5-((1s,3s)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)phenyl)dimethylphosphine oxide (Compound 523) [ka] Step 1: Synthesis of 4-bromo-3-fluorophenyl)dimethylphosphine oxide To a solution of 1-bromo-2-fluoro-4-iodobenzene (1 g, 3.32 mmol) and methylphosphonoylmethane (350 mg, 4.49 mmol) in THF (15 mL) and dioxane (15 mL) was added Pd(dba) (152 mg, 166 μmol), Xantphos (192 mg, 332 μmol), and TEA (4.63 mL, 33.23 mmol). The reaction was stirred at 60 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and brine (30 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0–20% EtOAc in petroleum ether) to afford the title compound (220 mg, 26%) as a white solid. LCMS(ESI)m / z:251.1[M+H] + .

[0423] Step 2: Synthesis of (3-fluoro-4-((5-((1s,3s)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)phenyl)dimethylphosphine oxide (Compound 523) To a solution of 5-((1s,3s)-3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-amine (30 mg, 104.77 μmol) and CsCO (204 mg, 629 μmol) in dioxane (2 mL) was added 1-bromo-4-dimethylphosphoryl-2-fluorobenzene (42 mg, 168 μmol), BrettPhos (8 mg, 16 μmol), and BrettPhos Pd G (14 mg, 16 μmol). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (20%-50% acetonitrile / 0.225% formic acid in water) to give compound 523 (10 mg, 21%) as a white solid. LCMS (ESI) m / z: 457.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.30(s,1H),8.47(s,2H),8.19(s,1H),8.03-8.10(m,1H),7.50-7.63(m,2H),5.03-5.14(m,1H),3.05-3.17(m,1H) ,2.84-2.93(m,2H),2.21-2.33(m,2H),1.65(d,J=13.2Hz,6H),1.42(s,3H),1.03-1.09(m,2H),0.85-0.90(m,2H).

[0424] Example 17: Synthesis of 4-((5-((1s,3s)-3-((5-(1-aminocyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide HCl salt (Compound 368) [ka] Step 1: Synthesis of N-cyclobutylidene-2-methylpropane-2-sulfinamide To a solution of 5-bromo-2-methylsulfanyl-thiazole (500 mg, 2.38 mmol, prepared according to the procedure in WO2022105771) in THF (10 mL) was added n-BuLi (2.5 M, 1.05 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 20 minutes. N-Cyclobutylidene-2-methyl-propane-2-sulfinamide (454 mg, 2.62 mmol) in THF (1 mL) was added to the reaction mixture and stirred at −78° C. under a nitrogen atmosphere for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (3 mL), diluted with HO (20 mL), and subsequently extracted with EtOAc (20 × 2 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (200 mg, 27%) as a yellow solid. LCMS (ESI) m / z: 305.2 [M+H] + .

[0425] Step 2: Synthesis of 2-methyl-N-(1-(2-(methylsulfonyl)thiazol-5-yl)cyclobutyl)propane-2-sulfinamide To a mixture of 2-methyl-N-(1-(2-(methylthio)thiazol-5-yl)cyclobutyl)propane-2-sulfinamide (150 mg, 0.49 mmol) in MeCN (3 mL) and HO (1 mL) was added oxone (332 mg, 1.97 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford the title compound (110 mg, crude) as a yellow oil, which required no further purification.

[0426] Step 3: Synthesis of tert-butyl (5-((1s,3s)-3-((5-(1-((tert-butylsulfinyl)amino)cyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyrimidin-2-yl)carbamate To a solution of tert-butyl (5-((1s,3s)-3-hydroxycyclobutyl)pyrimidin-2-yl)carbamate (90 mg, 0.34 mmol) in DMF (5 mL) was added NaH (41 mg, 1.02 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, followed by the addition of 2-methyl-N-[1-(2-methylsulfonylthiazol-5-yl)cyclobutyl]propane-2-sulfinamide (110 mg, 0.34 mmol). The mixture was stirred at 40 °C under a nitrogen atmosphere for 16 h. The reaction was quenched with saturated aqueous NH Cl (3 mL), diluted with HO (20 mL), and subsequently extracted with EtOAc (50 × 2 mL). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to give the title compound (40 mg, 28%) as a yellow oil. LCMS (ESI) m / z: 522.3 [M+H] + .

[0427] Step 4: N-(1-(2-((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutoxy)thiazol-5-yl)cyclobutyl)-2-methylpropane-2-sulfinamide To a solution of tert-butyl (5-((1s,3s)-3-((5-(1-((tert-butylsulfinyl)amino)cyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyrimidin-2-yl)carbamate (40 mg, 43 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give the title compound (30 mg, crude) as a yellow oil which required no further purification. LCMS (ESI) m / z: 422.1 [M+H] + .

[0428] Step 5: tert-butyl ((4-((5-((1s,3s)-3-((5-(1-((tert-butylsulfinyl)amino)cyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)carbamate To a solution of N-(1-(2-((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutoxy)thiazol-5-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (30 mg, 71 μmol), tert-butyl ((4-bromo-3-fluorophenyl)sulfonyl)carbamate (50 mg, 142 μmol), and CsCO (186 mg, 569 μmol) in dioxane (3 mL) was added BrettPhos (10 mg, 19 μmol) and BrettPhos Pd G (9 mg, 9 μmol). The reaction was stirred at 100 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM) to give the title compound (30 mg, 46%) as a yellow solid. LCMS (ESI) m / z: 695.3 [M+H] + .

[0429] Step 6: 4-((5-((1s,3s)-3-((5-(1-aminocyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide (Compound 368) A solution of tert-butyl ((4-((5-((1s,3s)-3-((5-(1-((tert-butylsulfinyl)amino)cyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)carbamate (30 mg, 43 μmol) in HCl / dioxane (4 mL, 4 M) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography (acetonitrile in water 15% to 45% / 0.04% HCl) to give compound 368 (10.4 mg, 62%) as a white solid. LCMS (ESI) m / z: 513.2 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ 9.45(s,1H),8.85(s,3H),8.50(s,2H),8.13-8.09(m,1H),7.67-7.54(m,2H),7.39(s,2H),5.23-5.08(m,1H),3.18-3.04( m,1H),2.88-2.85(m,2H),2.66-2.59(m,2H),2.48-2.41(m,2H),2.37-2.21(m,2H),2.07-1.97(m,1H),1.90-1.77(m,1H).

[0430] Example 18: Synthesis of (1s,3R)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (Compound 4) and (1r,3S)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl(1-methylcyclopropyl)carbamate (Compound 5) [ka] Step 1: Synthesis of N-[[3-(benzyloxymethyl)cyclobutylidene]amino]-4-methyl-benzenesulfonamide To a mixture of 3-(benzyloxymethyl)cyclobutanone (5 g, 26.28 mmol) in MeOH (50 mL) was added 4-methylbenzenesulfonohydrazide (4.89 g, 26.28 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated in vacuo to give the title compound (8.4 g, crude) as a white solid, which required no further purification. LCMS (ESI) m / z: 359.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.87-7.60(m,2H),7.50-7.29(m,7H),4.59-4.47(m,2H),3.65-3.40(m,2H),319-3.05(m,1H ),3.01-2.90(m,1H),2.89-2.79(m,1H),2.74-2.64(m,1H),2.62-2.53(m,1H),2.43(s,3H).

[0431] Step 2: Synthesis of 5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine To a mixture of (2-aminopyrimidin-5-yl)boronic acid (3.85 g, 27.72 mmol) in dioxane (150 mL) was added N-[[3-(benzyloxymethyl)cyclobutylidene]amino]-4-methylbenzenesulfonamide (19.80 g, 55.24 mmol) and CsCO (13.51 g, 40.52 mmol). The mixture was stirred at 105 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 to 50% EtOAc in petroleum ether) to give the title compound (3.5 g, crude). The crude product was further purified by reverse phase chromatography (25-55% acetonitrile in water / 0.225% formic acid) to give the title compound (1.75 g, 22%) as a yellow solid. LCMS (ESI) m / z: 270.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ 8.23-8.15(m,2H),7.39-7.26(m,5H),5.11(s,2H),4.60-4.51(m,2H),3.64-3.59(m,1H),3. 50-3.20(m,2H),2.71-2.56(m,1H),2.52-2.41(m,1H),2.30-2.15(m,2H),1.95-1.84(m,1H).

[0432] Step 3: Synthesis of tert-butyl ((4-((5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)carbamate To a solution of 5-[3-(benzyloxymethyl)cyclobutyl]pyrimidin-2-amine (1.3 g, 4.83 mmol) in dioxane (40 mL) was added tert-butyl N-(4-bromo-3-fluorophenyl)sulfonylcarbamate (2.22 g, 6.27 mmol), CsCO (4.72 g, 14.48 mmol), BrettPhos (259 mg, 482.66 μmol), and BrettPhos Pd G (437.53 mg, 482.66 μmol). The reaction was stirred at 100 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, EtOAc (50 mL) was added, followed by the slow addition of aqueous HCl (0.5 M) to adjust the pH to 7. The mixture was then washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-40% EtOAc in petroleum ether) to afford the title compound (1.9 g, 72%) as a brown solid. LCMS (ESI) m / z: 543.2 [M+H] + .

[0433] Step 4: Synthesis of 3-fluoro-4-((5-(3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide To a solution of tert-butyl N-[4-[[5-[3-(benzyloxymethyl)cyclobutyl]pyrimidin-2-yl]amino]-3-fluorophenyl]sulfonylcarbamate (1.9 g, 3.50 mmol) in DCM (10 mL) was added BCl3 (1 M, 17.51 ​​mL) dropwise under a nitrogen atmosphere. The mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with MeOH:NH3.H2O = 10:1 (5 mL), and then the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM) to give the title compound (0.98 g, 79%) as a white solid. LCMS (ESI) m / z: 353.0 [M+H] + .

[0434] Step 5: Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl(4-nitrophenyl)carbonate To a solution of 3-fluoro-4-[[5-[3-(hydroxymethyl)cyclobutyl]pyrimidin-2-yl]amino]benzenesulfonamide (130 mg, 368.92 μmol) in DCM (5 mL) was added (4-nitrophenyl)carbonochloridate (148.72 mg, 737.83 μmol), DMAP (45 mg, 368.92 μmol), and pyridine (87.54 mg, 1.11 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (30 mL) and subsequently washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in DCM) to afford the title compound (82 mg, 43%) as a white solid. LCMS (ESI) m / z: 518.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.43-9.38(m,1H),8.52-8.45(m,2H),8.35-8.29(m,2H),8.15(t,J=8.4Hz,1H),7.63-7.55(m,4H),7.37(s,2H),4.47-4.25 (m,2H),3.64-3.38(m,1H),2.77-2.67(m,1H),2.47-2.36(m,1H),2.35-2.30(m,1H),2.28-2.24(m,1H),2.05-1.91(m,1H).

[0435] Step 6: Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl (S)-(4,4,4-trifluorobutan-2-yl)carbamate: To a solution of [3-[2-(2-fluoro-4-sulfamoylanilino)pyrimidin-5-yl]cyclobutyl]methyl(4-nitrophenyl)carbonate (50 mg, 96.62 μmol) in THF (4 mL) was added (2S)-4,4,4-trifluorobutan-2-amine (47.41 mg, 289.86 μmol, HCl salt) and EtN (29.33 mg, 289.86 μmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and subsequently washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in DCM) to afford the title compound (36 mg, 74%) as a white solid. LCMS (ESI) m / z: 506.1 [M+H] + .

[0436] Step 7: Synthesis of ((1s,3R)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 4) and ((1r,3S)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl (S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 5) A mixture of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl (S)-(4,4,4-trifluorobutan-2-yl)carbamate (36 mg, 71.22 μmol) was separated by chiral SFC (DAICEL CHIRALCEL AS (250 mm*30 mm, 5 μm); supercritical CO / EtOH+0.1% NH.HO=60 / 40; 100 ml / min) to give ((1s,3R)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (compound 4, 8.82 mg, first peak) as a white solid. LC-MS: (ES+H, m / z) 506.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),8.45(s,2H),8.15(t,J=8.2Hz,1H),7.66-7.55(m,2H),7.36(s,2H),7.30(d,J=8.4Hz,1H),4.07-3.91(m,2H), 3.89-3.79(m,1H),3.28-3.27(m,1H),2.66-2.61(m,1H),2.46-2.27(m,4H),1.89(q,J=10.3Hz,2H),1.14(d,J=6.7Hz,3H); 19 F NMR (377 MHz, DMSO) δ -121.67, -62.54. Subsequently, ((1r,3S)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (compound 5, 18.10 mg, second peak) was obtained as a white solid. LC-MS: (ES+H, m / z) 506.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),8.48(s,2H),8.17(t,J=8.1Hz,1H),7.65-7.57(m,2H),7.37(s,2H),7.30(d,J=8.4Hz,1H),4.19-4.06(m,2H),3.93-3 .81(m,1H),3.59-3.51(m,1H),2.62-2.54(m,1H),2.47-2.33(m,2H),2.31-2.20(m,2H),2.20-2.06(m,2H),1.15(d,J=6.7Hz,3H); 19 F NMR (377MHz, DMSO) δ -121.79, -62.55.

[0437] Example 19: Synthesis of 4-((5-((1s,3s)-3-(((4-(trifluoromethyl)isothiazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide HCl salt (Compound 586) [ka] Step 1: Synthesis of 3-(benzyloxy)isothiazole To a solution of isothiazol-3-one (5 g, 49 mmol) in DMF (50 mL) was added K2CO3 (13.67 g, 98.9 mmol) and BnBr (10.15 g, 59.3 mmol) at 0 °C. The mixture was then stirred at 25 °C for 16 h. The reaction was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was washed with water (20 mL × 5), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% ethyl acetate in petroleum ether) to afford the title compound (6.7 g, 71%) as a yellow oil. LCMS (ESI) m / z: 191.8 [M+H] + .

[0438] Step 2: Synthesis of 3-(benzyloxy)-4-bromoisothiazole To a solution of 3-benzyloxyisothiazole (6.7 g, 35.0 mmol) in MeCN (100 mL) was added NBS (6.86 g, 38.5 mmol). The mixture was stirred at 25 °C for 72 h. The resulting mixture was quenched by adding water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% ethyl acetate in petroleum ether) to afford the title compound (7.3 g, 77%) as a colorless oil. LCMS (ESI) m / z: 269.8, 271.8 [M+H] + .

[0439] Step 3: Synthesis of 3-(benzyloxy)-4-iodoisothiazole To a mixture of 3-benzyloxy-4-bromoisothiazole (1 g, 3.7 mmol) in THF (10 mL) was added dropwise chloro(isopropyl)magnesium (2 M, 2.8 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min, followed by the dropwise addition of I (1.41 g, 5.5 mmol) in THF (10 mL) at 0 °C and stirring for 1 h. The resulting mixture was quenched with saturated aqueous NaSO (10 mL) and diluted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0–5% ethyl acetate in petroleum ether) to afford the title compound (1 g, 90%) as a yellow oil. LCMS (ESI) m / z: 317.8 [M+H] + .

[0440] Step 4: Synthesis of 3-(benzyloxy)-4-(trifluoromethyl)isothiazole To a solution of CuI (528 mg, 2.77 mmol) in DMF (15 mL) was added methyl 2,2-difluoro-2-fluorosulfonylacetate (969 mg, 5.05 mmol) under anhydrous N2. The mixture was stirred at 25 °C for 5 minutes, then 3-benzyloxy-4-iodo-isothiazole (0.8 g, 2.5 mmol) was added, and the reaction was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% ethyl acetate in petroleum ether) to afford the title compound (0.33 g, 50%) as a yellow oil. LCMS (ESI) m / z: 260.0 [M+H] + .

[0441] Step 5: Synthesis of 4-(trifluoromethyl)isothiazol-3-ol A solution of 3-benzyloxy-4-(trifluoromethyl)isothiazole (0.33 g, 1.3 mmol) in aqueous HCl (2.12 mL, 12 M) was stirred at 50 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0–30% ethyl acetate in petroleum ether) to afford the title compound (190 mg, 88%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 12.57 (s, 1H), 9.44 (s, 1H). LCMS(ESI)m / z:169.8[M+H] + .

[0442] Step 6: Synthesis of 5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine To a mixture of (2-aminopyrimidin-5-yl)boronic acid (3.85 g, 27.72 mmol) in dioxane (150 mL) was added N-[[3-(benzyloxymethyl)cyclobutylidene]amino]-4-methylbenzenesulfonamide (19.80 g, 55.24 mmol) and CsCO (13.51 g, 40.52 mmol). The mixture was stirred at 105 °C for 16 h. After cooling to room temperature, the reaction was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 to 50% EtOAc in petroleum ether) to give the title compound (3.5 g, crude). The crude product was further purified by reverse phase chromatography (25% to 55% acetonitrile in water / 0.225% formic acid) to give the title compound (1.75 g, 22%) as a yellow solid. LCMS (ESI) m / z: 270.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.23-8.15(m,2H),7.39-7.26(m,5H),5.11(s,2H),4.60-4.51(m,2H),3.64-3.59(m,1H),3. 50-3.20(m,2H),2.71-2.56(m,1H),2.52-2.41(m,1H),2.30-2.15(m,2H),1.95-1.84(m,1H).

[0443] Step 7: Synthesis of 5-((1s,3s)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine and 5-((1r,3r)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine trans-5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine: A mixture of 5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (300 g, 1.12 mol) was separated by chiral SFC (DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm); supercritical CO2 / EtOH + 0.1% NH3.H2O = 60 / 40; 220 ml / min) to give 5-((1s,3s)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (125 g, first peak, cis isomer) and 5-((1r,3r)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (130 g, second peak, trans isomer), both as white solids. First peak (cis isomer): LCMS (ESI) m / z: 270.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.12(s,2H),7.29-7.37(m,5H),6.43(s,2H),4.46(s,2H),3.41(d,J=6.0Hz,2H ),3.09-3.20(m,1H),2.50-2.40(m,1H),2.24-2.34(m,2H),1.75-1.85(m,2H). 2nd peak (trans isomer): LCMS (ESI) m / z: 270.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.16(s,2H),7.31-7.38(m,5H),6.43(s,2H),4.50(s,2H),3.55(d,J=7.2Hz,2H),3.29-3.41(m,2H),2.06-2.16(m,4H).

[0444] Step 8: Synthesis of ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl)methanol To a solution of 5-((1s,3s)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (5 g, 18.56 mmol) in DCM (100 mL) was added BCl3 (1 M, 100 mL) dropwise under a nitrogen atmosphere. The mixture was stirred at -78 °C for 48 h. The reaction was quenched with NH3.MeOH (7 M, 40 mL). The mixture was then diluted with THF (200 mL). The solution was filtered and the filtrate was concentrated in vacuo to give the title compound (3 g, 90%) as a white solid. LCMS (ESI) m / z: 180.1 [M+H] + .

[0445] Step 9: Synthesis of tert-butyl (tert-butoxycarbonyl) (5-((1s,3s)-3-(((tert-butoxycarbonyl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate To a solution of ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl)methanol (4 g, 22.3 mmol) in THF (50 mL) was added DMAP (545 mg, 4.5 mmol) and BocO (24.4 g, 112 mmol). The mixture was stirred at 40 °C for 16 h. The reaction was concentrated in vacuo to give the title compound (10 g, crude) as a white solid. LCMS (ESI) m / z: 480.1 [M+H] + .

[0446] Step 10: Synthesis of tert-butyl (5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)carbamate A mixture of tert-butyl (tert-butoxycarbonyl) (5-((1s,3s)-3-(((tert-butoxycarbonyl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate (18 g, 37.5 mmol) and NaOH (7.1 g, 17.75 mmol) in EtOH (100 mL) and HO (10 mL) was stirred at 20 °C for 12 h. The residue was poured into water (10 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-100% ethyl acetate in petroleum ether) to afford the title compound (9 g, 85%) as a white solid. LCMS (ESI) m / z: 280.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.43(s,2H),3.38(d,J=5.6Hz,2H),3.28-3.24(m,1H),2.43-2.36(m,1H),2.34-2.27(m,2H),1.90-1.81(m,2H),1.44(s,9H).

[0447] Step 11: Synthesis of tert-butyl ((4-((5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate A mixture of tert-butyl (5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)carbamate (1 g, 5.6 mmol), tert-butyl N-(4-bromophenyl)sulfonylcarbamate (3.75 g, 11.2 mmol), BrettPhos Pd G3 (506 mg, 558 μmol), Brettphos (300 mg, 558 μmol), and Cs2CO3 (5.45 g, 16.7 mmol) in dioxane (20 mL) was degassed and purged with N2 three times. Subsequently, the mixture was stirred at 100 °C under a N2 atmosphere for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with aqueous HCl (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0-2% MeOH in DCM) to give the title compound (1.21 mg, 39%) as a white solid. LCMS (ESI) m / z: 435.2 [M+H] + .

[0448] Step 12: Synthesis of ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl methanesulfonate To a solution of tert-butyl ((4-((5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (1.21 g, 2.1 mmol) in DCM (30 mL) at 0 °C was added TEA (0.87 mL, 6.3 mmol) and MsCl (0.26 g, 2.3 mmol). The mixture was stirred at 0 °C for 1 h. The residue was poured into ice water (50 mL), stirred for 2 min, and then extracted with DCM (50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (1 g, crude) as a yellow oil that required no further purification. LCMS (ESI) m / z: 513.2 [M+H + ].

[0449] Step 13: Synthesis of tert-butyl ((4-((5-((1s,3s)-3-(((4-(trifluoromethyl)isothiazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate To a solution of ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl methanesulfonate (0.2 g, 390 μmol) in DMF (3 mL) was added 4-(trifluoromethyl)isothiazol-3-ol (132 mg, 780 μmol) and K2CO3 (162 mg, 1.2 mmol). The mixture was stirred at 90 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0–30% ethyl acetate in petroleum ether) to afford the title compound (160 mg, 70%) as a yellow oil. LCMS(ESI)m / z:586.1[M+H] + .

[0450] Step 14: Synthesis of 4-((5-((1s,3s)-3-(((4-(trifluoromethyl)isothiazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide HCl salt (Compound 586) A solution of tert-butyl ((4-((5-((1s,3s)-3-(((4-(trifluoromethyl)isothiazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (0.16 g, 273 μmol) in HCl / dioxane (5 mL, 4 M) was stirred at 25° C. for 1 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile in water 50% to 80% / HCl) to give compound 586 (25 mg, 17%) as a white solid. LCMS (ESI) m / z: 486.0 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),9.57(s,1H),8.50(s,2H),7.91(d,J=8.4Hz,2H),7.72(d,J=8.4Hz,2H),7.16(s,2H) ),4.46-4.39(m,2H),3.47-3.27(m,1H),2.90-2.70(m,1H),2.46-2.34(m,2H),2.13-1.99(m,2H).

[0451] Example 20: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-((5-(1-methylpyrrolidin-2-yl)-2-oxopyridin-1(2H)-yl)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide HCl salt (Compound 469) [ka] Step 1: Synthesis of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-((5-(1-methylpyrrolidin-2-yl)-2-oxopyridin-1(2H)-yl)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate A mixture of 5-(1-methylpyrrolidin-2-yl)pyridin-2-ol (144 mg, 808 μmol, prepared according to the procedure in Eur. J. Med. Chem. 1999, 34, 31), ((1s,3s)-3-(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl)methyl methanesulfonate (330 mg, 622 μmol), and K2CO3 (344 mg, 2.5 mmol) in DMF (5 mL) was stirred at 90 °C under a nitrogen atmosphere for 16 h. The reaction was diluted with EtOAc (50 mL) and water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (17% to 57% acetonitrile in water / 0.225% formic acid) to give the title compound (80 mg, 85%) as a yellow oil. LCMS(ESI)m / z:613.2[M+H] + .

[0452] Step 2: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-((5-(1-methylpyrrolidin-2-yl)-2-oxopyridin-1(2H)-yl)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide HCl salt (Compound 469) A solution of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-((5-(1-methylpyrrolidin-2-yl)-2-oxopyridin-1(2H)-yl)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (7 mg, 11 μmol) in HCl / dioxane (5 mL, 4 M) was stirred at 25° C. for 1 h. The reaction was concentrated in vacuo to give compound 469 (3 mg, 32%) as a white solid. LCMS (ESI) m / z: 513.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.08-10.93(m,1H),9.41(s,1H),8.46(s,2H),8.17-8.10(m,1H),8.05(d,J=2.4Hz,1H),7.76(d d,J=9.6,2.4Hz,1H),7.63-7.57(m,2H),7.38(s,2H),6.46(d,J=9.2Hz,1H),4.13-4.06(m,1H),3. 98(d,J=7.2Hz,2H),3.69-3.60(m,3H),3.31-3.23(m,1H),3.13-3.04(m,1H),2.75-2.66(m,1H),2 .59(d,J=4.8Hz,2H),2.37-2.28(m,3H),2.18-2.12(m,1H),2.12-2.04(m,2H),2.02-1.94(m,2H).

[0453] Example 21: Synthesis of 3-fluoro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 571) [ka] Step 1: Synthesis of tert-butyl (5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate To a solution of tert-butyl (5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)carbamate (0.5 g, 1.79 mmol) in DMF (5 mL) was added NaH (358 mg, 8.95 mmol, 60% purity) under a N atmosphere at 0° C. The mixture was stirred at 0° C. for 30 minutes. Subsequently, 3-chloro-4-isopropylpyridazine (560 mg, 3.58 mmol, prepared according to the procedure in WO2022 / 174031) was added at 0° C. The mixture was heated at 40° C. for 16 hours. The reaction was quenched by adding MeOH (10 mL) at 0° C. The solution was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EE in petroleum ether (30% ethanol in ethyl ether) to give the title compound (0.26 g, 36%) as a yellow oil. LCMS (ESI) m / z: 400.1 [M+H] + .

[0454] Step 2: Synthesis of 5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-amine To a solution of tert-butyl (5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate (0.25 g, 625 μmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 25° C. for 2 h. The solution was concentrated in vacuo. The crude residue was dissolved in MeOH (2 mL). The pH of the solution was adjusted to 10 with aqueous NaOH (2 M), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.18 g, crude) as a yellow oil that required no further purification. LCMS (ESI) m / z: 300.1 [M+H] + .

[0455] Step 3 - Synthesis of 3-fluoro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 571) A mixture of 5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-amine (170 mg, 567 μmol), 4-bromo-3-fluoro-N-[3-hydroxy-3-(trifluoromethyl)cyclobutyl]benzenesulfonamide (334 mg, 851 μmol), BrettPhos (30 mg, 56 μmol), BrettPhos Pd G3 (51 mg, 56 μmol), and K3PO4 (482 mg, 2.27 mmol) in dioxane (5 mL) was degassed and purged with N2 three times. Subsequently, the mixture was stirred at 80 °C under a N2 atmosphere for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL) and washed with aqueous HCl (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (51%-81% acetonitrile in water / 0.05% NH3.H2O + 10 mM NH4HCO3) to give compound 571 (0.2 mg, 80%) as a white solid. LCMS (ESI) m / z: 611.5 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.46(s,1H),8.77(d,J=4.8Hz,1H),8.50(s,2H),8.32-8.26(m,1H),8.12( s,1H),7.61-7.55(m,2H),7.44(d,J=4.8Hz,1H),6.60(s,1H),4.47(d,J=6 .0Hz,2H),3.47-3.35(m,1H),3.10-3.01(m,1H),2.89-2.78(m,1H),2.56- 2.52(m,1H),2.49-2.41(m,4H),2.14-1.96(m,4H),1.18(d,J=6.8Hz,6H).

[0456] Example 22: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 495) [ka] Step 1: Synthesis of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate To a stirred solution of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (0.3 g, 663 μmol) in DMF (5 mL) under a N atmosphere at 0° C. was added NaH (132 mg, 3.31 mmol, 60% purity). The mixture was stirred at 0° C. for 30 min. Subsequently, 3-chloro-4-isopropylpyridazine (156 mg, 994 μmol, prepared according to the procedure in WO 2022 / 174031) was added at 0° C. The mixture was heated at 40° C. for 16 h. The reaction was quenched by adding MeOH (10 mL) at 0° C. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography [solvent gradient: 0-20% in petroleum ether (ethyl acetate / EtOH=3:1)] to give the title compound (0.35 g, 92%) as a yellow oil. LCMS (ESI) m / z: 573.0 [M+H] + .

[0457] Step 2: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 495) To a solution of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (0.3 g, 524 μmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 2 h. The solution was concentrated in vacuo. The crude residue was dissolved in MeOH (2 mL). The pH of the solution was adjusted to 10 with aqueous NaOH (2 M), followed by adjustment to pH 6 with formic acid. The solution was purified by reverse-phase chromatography (29%-59% acetonitrile in water / 0.225% formic acid) to give compound 495 (0.1 g, 40%) as a white solid. LCMS (ESI) m / z: 473.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),8.78(d,J=4.4Hz,1H),8.47(s,2H),8.17-8.11(m,1H),7.63-7.57(m,2H),7.44(d,J=4.8Hz,1H),7.36(s,2H),4.47(d, J=6.0Hz,2H),3.47-3.36(m,1H),3.12-2.99(m,1H),2.90-2.75(m,1H),2.49-2.41(m,2H),2.15-2.02(m,2H),1.19(d,J=6.8Hz,6H).

[0458] Example 23: Synthesis of 4-((5-((1s,3s)-3-(((1-(1-(aminomethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide (Compound 504) [ka] Step 1: Synthesis of 1-azidocyclopropane-1-carboxamide To a mixture of N-diazosulfamoyl fluoride (4.5 g, 36.0 mmol), 1-aminocyclopropanecarboxamide (4 g, 40 mmol) in DMF (5 mL) and HO (8 mL) was added NaHCO (16.8 g, 200 mmol). The mixture was then stirred at 0 °C under a N atmosphere for 1 h. The reaction was filtered, and the filtrate was concentrated in vacuo. The crude residue was dissolved in ethyl acetate (100 mL), washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford the title compound (4.5 g, crude) as a yellow oil, which required no further purification.

[0459] Step 2: Synthesis of 1-(4-ethoxy-1H-1,2,3-triazol-1-yl)cyclopropane-1-carboxamide To a mixture of 1-azidocyclopropanecarboxamide (1.2 g, 9.52 mmol), ethynoxyethane (1.33 g, 9.52 mmol) in DMF (5 mL) was added sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (754 mg, 3.8 mmol) and copper sulfate (1.52 g, 9.5 mmol). The mixture was then stirred at 110 °C under a N atmosphere for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0–50% ethyl acetate in petroleum ether) to afford the title compound (1.08 g, 58%) as a yellow oil.

[0460] Step 3: Synthesis of 1-(4-ethoxy-1H-1,2,3-triazol-1-yl)cyclopropane-1-carbonitrile A mixture of 1-(4-ethoxytriazol-1-yl)cyclopropanecarboxamide (1.08 g, 5.50 mmol), 2,4,6-trichloro-1,3,5-triazine (2.23 g, 12.1 mmol) in DMF (20 mL) was stirred at 25 °C under a N atmosphere for 2 h. The reaction was quenched with water (30 mL). The solution was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0–50% ethyl acetate in petroleum ether) to afford the title compound (0.5 g, 51%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 4.15-4.10 (m, 2H), 2.06-1.98 (m, 2H), 1.97-1.88 (m, 2H), 1.32 (t, J = 8.0Hz, 3H).

[0461] Step 4: Synthesis of (1-(4-ethoxy-1H-1,2,3-triazol-1-yl)cyclopropyl)methanamine To a solution of 1-(4-ethoxytriazol-1-yl)cyclopropanecarbonitrile (0.3 g, 1.7 mmol) and NiCl2.6H2O (1.20 g, 5.05 mmol) in MeOH (5 mL) was added NaBH4 (0.24 g, 6.34 mmol). The mixture was stirred at 0 °C under a N2 atmosphere for 2 h. The reaction was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0–10% MeOH in DCM) to give the title compound (150 mg, 49%). 1 H NMR(400MHz,DMSO-d6)δ 7.69(s,1H),4.13-4.05(m,2H),2.88(s,2H),1.30(t,J=7.2Hz,4H),1.16-1.12(m,2H),1.09-1.06(m,2H).

[0462] Step 5: Synthesis of 1-(1-(aminomethyl)cyclopropyl)-1H-1,2,3-triazol-4-ol A mixture of [1-(4-ethoxytriazol-1-yl)cyclopropyl]methanamine (150 mg, 823 μmol) in AcOH (5 mL, 30.4 mmol, 33% purity) and HBr was stirred at 100 °C under a N atmosphere for 16 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0% to 10% MeOH in DCM) to afford the title compound (120 mg, 95%) as a yellow solid.

[0463] Step 6: Synthesis of tert-butyl ((1-(4-((tert-butoxycarbonyl)oxy)-1H-1,2,3-triazol-1-yl)cyclopropyl)methyl)carbamate To a solution of 1-[1-(aminomethyl)cyclopropyl]triazol-4-ol (120 mg, 778 μmol) in DCM (5 mL) was added DIEA (302 mg, 2.34 mmol) and BocO (170 mg, 778 μmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography (35% to 65% acetonitrile in water / 0.225% formic acid) to give the title compound (200 mg, 73%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.10(s,1H),7.16-7.08(m,1H),3.36(d,J=6.4Hz,2H),1.50(s,9H),1.31(s,9H),1.24-1.20(m,2H),1.18-1.14(m,2H).

[0464] Step 7: Synthesis of tert-butyl ((1-(4-hydroxy-1H-1,2,3-triazol-1-yl)cyclopropyl)methyl)carbamate A mixture of tert-butyl ((1-(4-((tert-butoxycarbonyl)oxy)-1H-1,2,3-triazol-1-yl)cyclopropyl)methyl)carbamate (180 mg, 508 μmol) and NaOH (61 mg, 1.52 mmol) in EtOH (1 mL) and HO (0.2 mL) was stirred at 25° C. for 2 h. The reaction was concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0% to 10% MeOH in DCM) to afford the title compound (120 mg, 93%) as a yellow solid. LCMS (ESI) m / z: 255.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ 9.97(s,1H),7.26(s,1H),7.10-7.01(m,1H),3.31(s,2H),1.34(s,9H),1.17-1.11(m,2H),1.11-1.04(m,2H).

[0465] Step 8: Synthesis of tert-butyl ((4-((5-((1s,3s)-3-(((1-(1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)carbamate A mixture of tert-butyl ((1-(4-hydroxy-1H-1,2,3-triazol-1-yl)cyclopropyl)methyl)carbamate (17 mg, 68 μmol), ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl methanesulfonate (30 mg, 57 μmol), and KCO (23 mg, 169 μmol) in DMF (2 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL), washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (40% to 80% acetonitrile in water / 0.225% formic acid) to give the title compound (20 mg, 25%) as a brown solid. LCMS (ESI) m / z: 689.3 [M+H] + .

[0466] Step 9: Synthesis of 4-((5-((1s,3s)-3-(((1-(1-(aminomethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide (Compound 504) A mixture of tert-butyl ((4-((5-((1s,3s)-3-(((1-(1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)carbamate (20 mg, 14 μmol) in HCl / dioxane (2 mL, 4 M) was stirred at 25° C. for 16 hours. The reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile in water 10% to 40% / 0.04% HCl) to give compound 504 (5.87 mg, 86%) as a white solid. LCMS (ESI) m / z: 489.0 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 9.45(s,1H),8.48(s,2H),8.30(s,3H),8.17-8.09(m,1H),7.85(s,1H),7.57-7.64(m,2H),7.40(s,2H),4.09(d,J=6. 0Hz,2H),3.35-3.42(m,1H),3.28-3.34(m,2H),2.67-2.78(m,1H),2.39-2.47(m,2H),1.91-2.03(m,2H),1.36(s,4H).

[0467] Example 24: Synthesis of ((1s,3R)-3-(2-((1-((1H-1,2,3-triazol-1-yl)methyl)-1H-indazol-6-yl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 524) [ka] Step 1: Synthesis of (6-bromo-1H-indazol-1-yl)methanol A mixture of 6-bromo-1H-indazole (2 g, 10.15 mmol), aqueous HCHO (7.6 mL, 101.51 mmol, 37% purity) in EtOH (7 mL) was degassed and purged with N three times. The reaction was stirred at 50 °C for 16 h. After cooling to room temperature, the reaction was quenched at 0 °C by adding saturated aqueous NH Cl (5 mL), followed by dilution with HO (15 mL) and extraction with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0–50% EtOAc in petroleum ether) to afford the title compound (2.1 g, 91%) as a white solid. 1 H NMR(400MHz, CDCl3)δ 8.06-7.98(m,1H),7.85-7.74(m,1H),7.61(d,J=8.4Hz,1H),7.38-7.30(m,1H),5.93-5.78(m,2H).

[0468] Step 2: Synthesis of 6-bromo-1-(chloromethyl)-1H-indazole A mixture of (6-bromoindazol-1-yl)methanol (500 mg, 2.20 mmol) in SOCl (0.5 mL) was degassed and purged with N three times. The mixture was then stirred at 0 °C for 30 min. The reaction was quenched at 0 °C by adding saturated aqueous NH Cl (5 mL), followed by dilution with HO (15 mL) and extraction with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0–50% EtOAc in petroleum ether) to afford the title compound (0.5 g, 9%) as a yellow oil.

[0469] Step 3: Synthesis of 1-((1H-1,2,3-triazol-1-yl)methyl)-6-bromo-1H-indazole A mixture of 1H-triazole (0.1 mL, 1.88 mmol) and t-BuOK (317 mg, 2.82 mmol) in THF (5 mL) was degassed and purged with N2 three times. After the mixture was stirred at 25 °C for 30 min, 6-bromo-1-(chloromethyl)indazole (462 mg, 1.88 mmol) was added, followed by stirring the mixture under a N2 atmosphere for 30 min. The reaction was quenched with water (30 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0–50% EtOAc in petroleum ether) to afford the title compound (0.18 g, 34%) as a yellow solid.

[0470] Step 4: Synthesis of ((1s,3R)-3-(2-((1-((1H-1,2,3-triazol-1-yl)methyl)-1H-indazol-6-yl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 524) To a solution of 6-bromo-1-(triazol-1-ylmethyl)indazole (63 mg, 226 μmol), ((1s,3R)-3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (50 mg, 150 μmol), and CsCO (294 mg, 903 μmol) in dioxane (2 mL) was added Brettphos (8 mg, 15 μmol) and BrettPhos Pd G (14 mg, 15 μmol). The mixture was stirred at 100 °C under a N atmosphere for 12 h. The reaction was diluted with ethyl acetate (10 mL) and washed with aqueous HCl (0.5 M, 5 mL). The organic layer was washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (23% to 63% acetonitrile in water / 0.025% formic acid) to give compound 524 (12.57 mg, 16%) as a white solid. LCMS (ESI) m / z: 530.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.88(s,1H),8.56(s,1H),8.50(s,2H),8.25(d,J=0.8Hz,1H),8.04(s,1H),7 .74(s,1H),7.62(d,J=8.8Hz,1H),7.40-7.36(m,1H),7.30(d,J=8.8Hz,1H), 6.95(s,2H),3.99(d,J=5.6Hz,2H),3.90-3.80(m,1H),3.39-3.35(m,1H),2. 60-2.54(m,1H),2.42-2.32(m,4H),1.97-1.88(m,2H),1.14(d,J=6.4Hz,3H).

[0471] Example 25 Synthesis of 5-((1s,3s)-3-(((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)methyl)cyclobutyl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine (Compound 477) [ka] Step 1: Synthesis of tert-butyl (5-((1s,3s)-3-(((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate To a solution of cis-tert-butyl N-[5-[3-(hydroxymethyl)cyclobutyl]pyrimidin-2-yl]carbamate (200 mg, 716 μmol) in DMF (6 mL) was added NaH (63 mg, 1.6 mmol, 60% purity) at 0 °C and stirred at 0 °C for 1 h. Subsequently, 4-isopropyl-3-methylsulfonyl-1,2,4-triazole (271 mg, 1.43 mmol) was added. The mixture was stirred at 40 °C under a N atmosphere for 72 h. After cooling to room temperature, the reaction was quenched with saturated aqueous NH Cl (3 mL), diluted with HO (20 mL), and subsequently extracted with EtOAc (50 × 2 mL). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in EtOAc) to give the title compound (172 mg, 53%) as a yellow oil. LCMS (ESI) m / z: 389.1 [M+H] + .

[0472] Step 2: Synthesis of 5-((1s,3s)-3-(((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-amine To a solution of tert-butyl (5-((1s,3s)-3-(((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate (172 mg, 443 μmol) in DCM (6 mL) at 25° C. was added TFA (2 mL). The mixture was stirred at 25° C. for 1 h. The reaction was concentrated in vacuo to give the title compound (127 mg, TFA salt) as a yellow oil which required no further purification. LCMS (ESI) m / z: 289.1 [M+H] + .

[0473] Step 3: Synthesis of 5-((1s,3s)-3-(((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)methyl)cyclobutyl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine (Compound 477) To a stirred solution of 5-((1s,3s)-3-(((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-amine (90 mg, 312 μmol) in DMF (5 mL) at 25 °C was added 1-methylsulfonylpiperidin-4-one (276 mg, 1.6 mmol) and TFA (0.25 mL, 3.12 mmol). The mixture was stirred at 25 °C for 2 h. Subsequently, NaBH(OAc) (661 mg, 3.1 mmol) was added. The mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction was quenched with saturated aqueous NaHCO (3 mL), diluted with HO (20 mL), and subsequently extracted with EtOAc (50 × 2 mL). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (20%-50% acetonitrile in water / 0.225% formic acid) to give compound 477 (2.06 mg, 1.5%) as a white solid. LCMS (ESI) m / z: 450.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.20-8.23(m,3H),7.05(d,J=8.0Hz,1H),4.37-4.32(m,2H),4.25-4.16(m,1H),3.86-3.76(m,1H),3.55-3.47(m,1H),3.51(d,J=11.6Hz,2H) ),3.28-3.19(m,2H),2.92-2.81(m,5H),2.77-2.67(m,1H),2.43-2.31(m,2H),1.96-1.89(m,3H),1.59-1.46(m,2H),1.34(d,J=6.8Hz,6H).

[0474] Example 26: Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate (Compound 321) [ka] Step 1: Synthesis of (5,8-dioxaspiro[3.4]octan-2-yl)methan-d2-ol To a stirred solution of methyl 5,8-dioxaspiro[3.4]octane-2-carboxylate (4 g, 23.23 mmol, 1 equiv.) in methanol-d (20 mL) under a nitrogen atmosphere at 0 °C, sodium borodeuteride (2.92 g, 69.69 mmol, 3 equiv.) was added portionwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with CHCl3:IPA (1:1) (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This afforded (5,8-dioxaspiro[3.4]octan-2-yl)methan-d2-ol (3.3 g, crude) as a yellow oil. LC-MS: (ES+H, m / z) 147.1 [M+H]+; 1 H NMR (400MHz, DMSO-d6) δ 4.60 (s, 1H), 3.85-3.70 (m, 4H), 2.25-2.16 (m, 2H), 2.10-2.00 (m, 1H), 2.00-1.91 (m, 2H).

[0475] Step 2: Synthesis of 2-((benzyloxy)methyl-d2)-5,8-dioxaspiro[3.4]octane A solution of NaH (0.64 g, 26.7 mmol, 1.3 equiv.) in THF (20 mL) was treated with (5,8-dioxaspiro[3.4]octan-2-yl)methan-d2-ol (3 g, 20.5 mmol, 1 equiv.) at 0 °C under a nitrogen atmosphere for 30 min, followed by the dropwise addition of BnBr (3.69 g, 21.5 mmol, 1.05 equiv.) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with CHCl3:IPA (3:1) (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN (0.1% NH4HCO3) in water, gradient from 30% to 60% in 10 min; detector, UV 254 nm. This gave 2-((benzyloxy)methyl-d2)-5,8-dioxaspiro[3.4]octane (3 g, 58%) as a yellow oil. LC-MS: (ES+H, m / z) 237.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ 7.41-7.20(m,5H),4.46(s,2H),3.83-3.71(m,4H),2.35-2.17(m,3H),2.03-1.91(m,2H).

[0476] Step 3: Synthesis of 3-((benzyloxy)methyl-d2)cyclobutan-1-one A solution of 2-((benzyloxy)methyl-d)-5,8-dioxaspiro[3.4]octane (3 g, 12.69 mmol, 1 equiv.) in HCl (2 mL) and HO (12 mL) was stirred at 60 °C under a nitrogen atmosphere for 1.5 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with CHCl:IPA (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN in water, 40% to 60% gradient in 10 min; detector, UV 200 nm. This gave 3-((benzyloxy)methyl-d)cyclobutan-1-one (2 g, 78%) as a pale yellow oil. LC-MS: (ES+H, m / z) 193.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ 7.45-7.21(m,5H),4.51(s,2H),3.14-3.03(m,2H),2.86-2.74(m,2H),2.80-2.60(m,1H).

[0477] Steps 4 and 5: Synthesis of 5-(3-((benzyloxy)methyl-d2)cyclobutyl)pyrimidin-2-amine To a stirred solution of 3-((benzyloxy)methyl-d2)cyclobutan-1-one (2 g, 10.40 mmol, 1 equiv.) in MeOH (20 mL) at room temperature under a nitrogen atmosphere was added tosylhydrazide (2.03 g, 10.92 mmol, 1.05 equiv.). The resulting mixture was stirred at RT under a nitrogen atmosphere for 20 min. The resulting mixture was concentrated under reduced pressure. The crude product (2.5 g) was used directly in the next step without further purification.

[0478] To a stirred solution of N'-(3-((benzyloxy)methyl-d2)cyclobutylidene)-4-methylbenzenesulfonohydrazide (2.5 g, 6.93 mmol, 1 equiv.) and 2-aminopyrimidin-5-ylboronic acid (1.45 g, 10.40 mmol, 1.5 equiv.) in 1,4-dioxane (30 mL) under a nitrogen atmosphere at room temperature was added Cs2CO3 (1.44 g, 10.40 mmol, 1.5 equiv.). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere overnight. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN (0.1% NH4HCO3) in water, gradient from 40% to 60% in 18 min; detector, UV 254 nm. This gave 5-(3-((benzyloxy)methyl-d2)cyclobutyl)pyrimidin-2-amine (330 mg, 14%) as a yellow oil. LC-MS: (ES+H, m / z) 272.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.14(d,J=17.5Hz,2H),7.34(dd,J=5.6,2.6Hz,5H),6.40(s,2H),4.51(d,J=1.9Hz,2 H),3.20-3.05(m,1H),2.84-2.74(m,1H),2.35-2.23(m,1H),2.16-2.07(m,2H),1.87 -1.77(m,1H).

[0479] Step 6: Synthesis of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methan-d2-ol A solution of 5-(3-((benzyloxy)methyl-d2)cyclobutyl)pyrimidin-2-amine (300 mg, 1.10 mmol, 1 equiv.) and methanesulfonic acid (3.19 g, 33.18 mmol, 30 equiv.) in DCM (1 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The residue was purified by silica gel column chromatography eluting with CHCl:MeOH (5:1 to 1:1) to give (3-(2-aminopyrimidin-5-yl)cyclobutyl)methan-d2-ol (130 mg, 62%) as a yellow oil. LC-MS: (ES+H, m / z) 182.1 [M+H] + .

[0480] Step 7: Synthesis of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl-d2(4-nitrophenyl)carbonate To a stirred solution of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methan-d2-ol (130 mg, 0.71 mmol, 1 equiv.) and bis(4-nitrophenyl)carbonate (262 mg, 0.86 mmol, 1.2 equiv.) in DCM (3 mL) was added DIEA (278 mg, 2.15 mmol, 3 equiv.) and DMAP (18 mg, 0.14 mmol, 0.2 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18, mobile phase, MeCN in water, gradient from 30% to 50% in 10 min, detector, UV 254 nm. This gave (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl-d2(4-nitrophenyl)carbonate (150 mg, 54.34%) as a yellow solid. LC-MS: (ES+H, m / z) 347.1 [M+H] + .

[0481] Step 8: Synthesis of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate To a stirred solution of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl-d2(4-nitrophenyl)carbonate (140 mg, 0.40 mmol, 1 equiv.) and DIEA (156.74 mg, 1.21 mmol, 3 equiv.) in DMF (2 mL) under a nitrogen atmosphere at room temperature, (2S)-4,4,4-trifluorobutan-2-amine hydrochloride (132.24 mg, 0.80 mmol, 2 equiv.) was added. The resulting mixture was stirred under a nitrogen atmosphere at 60 °C for 4 hours. The mixture was allowed to cool to room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. This gave (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate (110 mg, 73%) as a yellow solid. LC-MS: (ES+H, m / z) 335.0 [M+H] + .

[0482] Step 9: Synthesis of (3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate To a stirred solution of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate (100 mg, 0.29 mmol, 1 equiv.) and tert-butyl N-(4-bromo-3-fluorobenzenesulfonyl)carbamate (74.16 mg, 0.20 mmol, 0.7 equiv.) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (54.78 mg, 0.06 mmol, 0.2 equiv.), Cs2CO3 (292.36 mg, 0.89 mmol, 3 equiv.), and XantPhos (34.61 mg, 0.06 mmol, 0.2 equiv.) in portions at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18, mobile phase, MeCN in water, gradient from 30% to 50% in 10 min, detector, UV 254 nm. This afforded (3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate (120 mg, 59%) as a yellow solid. LC-MS: (ES+H, m / z) 608.0 [M+H] + .

[0483] Step 10: Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate (Compound 321) A solution of (3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate (120 mg, 0.19 mmol, 1 equiv.) in formic acid (3 mL) was stirred under a nitrogen atmosphere at 50° C. for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18; mobile phase, MeCN in water, gradient from 30% to 50% in 10 minutes; detector, UV 254 nm. The pure fractions were concentrated under reduced pressure and lyophilized to give (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-d2(S)-(4,4,4-trifluorobutan-2-yl)carbamate (compound 321, 75 mg, 71%) as a white solid. LC-MS: (ES+H, m / z) 508.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.36(s,1H),8.46(d,J=12.0Hz,2H),8.20-8.12(m,1H),7.64-7.56(m,2H),7.32(d,J=32.9Hz,3H),3.90-3.78(m,1H),3.62-3.28(m, 1H),2.55(s,1H),2.47-2.30(m,3H),2.29-2.18(m,1H),2.16(d,J=11.3Hz,1H),1.90(q,J=10.2Hz,1H),1.14(dd,J=6.8,3.2Hz,3H); 19 F NMR (376MHz, DMSO) δ -62.55, -121.72.

[0484] Example 27: Synthesis of ((1s,3s)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate (Compound 332) [ka] Step 1: Synthesis of 3-(hydroxymethyl-d2)cyclobutan-1-d-1-ol To a mixture of methyl 3-oxocyclobutanecarboxylate (10 g, 78.1 mmol) in THF (200 mL) was added LiAlD (5 g, 108.7 mmol) at 0 °C. The reaction was then degassed and purged with N three times, and the mixture was then stirred at 25 °C under a N atmosphere for 16 h. The reaction was quenched with HO (5 mL), aqueous NaOH (15%, 5 mL), and HO (15 mL), diluted with ethyl acetate (300 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 3-(hydroxymethyl-d)cyclobutan-1-d-1-ol (7.6 g, crude) as a colorless oil, which required no further purification. 1 H NMR (400MHz, DMSO-d6) δ 4.85 (s, 1H), 4.37 (s, 1H), 2.17-2.09 (m, 2H), 1.78-1.67 (m, 1H), 1.52-1.43 (m, 2H).

[0485] Step 2: Synthesis of 3-(((tert-butyldiphenylsilyl)oxy)methyl-d2)cyclobutan-1-d-1-ol To a mixture of 3-(hydroxymethyl-d2)cyclobutan-1-d-1-ol (7.6 g, 72.3 mmol) in DCM (150 mL) was added DMAP (883 mg, 7.2 mmol), TEA (20 mL, 144.6 mmol), and TBDPSCl (16.7 mL, 65.1 mmol) at 0 °C, followed by stirring the mixture at 0 °C for 2 h. The reaction was diluted with DCM (100 mL) and HO (25 mL). The organic layer was washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0–30% EtOAc in petroleum ether) to give 3-(((tert-butyldiphenylsilyl)oxy)methyl-d2)cyclobutan-1-d-1-ol (13.4 g, 54%) as a white oil.

[0486] Step 3: Synthesis of tert-butyl (5-(3-(((tert-butyldiphenylsilyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate To a mixture of 3-(((tert-butyldiphenylsilyl)oxy)methyl-d2)cyclobutan-1-d-1-ol (6 g, 17.5 mmol), 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (6.9 g, 17.5 mmol) in t-BuOMe (120 mL) was added pyridine (1.4 mL, 17.5 mmol). The reaction was stirred for 5 minutes. The mixture was filtered, and the filtrate was added to a solution of tert-butyl N-(5-bromopyrimidin-2-yl)carbamate (3.19 g, 11.6 mmol), NiBr(dtbbpy) (283.5 mg, 582 μmol), quinuclidine (1.94 g, 17.5 mmol), and Ir(ppy)(dtbbpy)PF (159.6 mg, 174 μmol) in DMA (120 mL) under a N atmosphere. The mixture was stirred at room temperature and irradiated with a blue LED for 16 hours. EtOAc (400 mL) was added to dilute the mixture, and the mixture was washed with brine (100 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-40% EtOAc in petroleum ether) to give tert-butyl (5-(3-(((tert-butyldiphenylsilyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate (2.9 g, 48%) as a colorless oil. LCMS (ESI) m / z: 521.3 [M+H] + .

[0487] Step 4: Synthesis of tert-butyl (5-(3-(hydroxymethyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate To a solution of tert-butyl (5-(3-(((tert-butyldiphenylsilyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate (2.5 g, 3.8 mmol) in THF (50 mL) was added TBAF (19.2 mL, 1 M). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc (200 mL) and washed with brine (50 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% ethyl acetate in petroleum ether) to give tert-butyl (5-(3-(hydroxymethyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate (800 mg, 66%) as a white solid. LCMS (ESI) m / z: 283.2 [M+H] + .

[0488] Step 5: Synthesis of tert-butyl (5-(3-((((4-nitrophenoxy)carbonyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate To a solution of tert-butyl (5-(3-(hydroxymethyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate (1 g, 3.5 mmol) and pyridine (0.1 mL, 10.6 mmol) in DCM (50 mL) was added (4-nitrophenyl)carbonochloridate (1.07 g, 5.3 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was washed with brine (50 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0–50% EtOAc in petroleum ether) to give tert-butyl (5-(3-((((4-nitrophenoxy)carbonyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate (660 mg, 37%) as a white solid. LCMS(ESI)m / z:392.2[M-56+H] + .

[0489] Step 6: Synthesis of tert-butyl (5-(3-((((3,3-difluoro-1-methylcyclobutyl)carbamoyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate To a solution of tert-butyl (5-(3-((((4-nitrophenoxy)carbonyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate (750 mg, 1.7 mmol) and 3,3-difluoro-1-methylcyclobutanamine (660 mg, 4.2 mmol) in THF (15 mL) was added TEA (2.3 mL, 16.8 mmol). The mixture was stirred at 50 °C for 5 h. After cooling to room temperature, the reaction was diluted with EtOAc (20 mL) and the mixture was washed with brine (15 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to give tert-butyl (5-(3-((((3,3-difluoro-1-methylcyclobutyl)carbamoyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate (710 mg, 91%) as a white solid. LCMS (ESI) m / z: 430.3 [M+H] + .

[0490] Step 7: Synthesis of ((1s,3s)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate and ((1r,3r)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate tert-Butyl (5-(3-((((3,3-difluoro-1-methylcyclobutyl)carbamoyl)oxy)methyl-d2)cyclobutyl-1-d)pyrimidin-2-yl)carbamate (710 mg, 1.7 mmol) was separated by using chiral SFC (Column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); supercritical CO2 / EtOH+0.1% NH3:HO = 85 / 15; 60 mL / min), ((1s,3s)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate (181 mg, first peak, cis isomer (desired)) as a white solid, and ((1r,3r)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate (260 mg, second peak, trans isomer) as a white solid. LCMS (ESI) m / z: 430.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),8.51(s,2H),7.70(s,1H),2.90-2.79(m,2H),2.60-2.55( m, 3H), 2.35-2.32 (m, 2H), 1.95-1.84 (m, 2H), 1.46 (s, 9H), 1.40 (s, 3H).

[0491] Step 8: Synthesis of ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate To a solution of ((1s,3s)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate (180 mg, 419 μmol) in DCM (6 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate (160 mg, crude) as a white solid, which required no further purification. LCMS (ESI) m / z: 330.2 [M+H] + .

[0492] Step 9: Synthesis of ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate To a mixture of ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl-3-d)methyl-d2 (3,3-difluoro-1-methylcyclobutyl)carbamate (80 mg, 243 μmol) and K3PO4 (309 mg, 1.5 mmol) in dioxane (6 mL), tert-butyl N-(4-bromo-3-fluorophenyl)sulfonylcarbamate (258 mg, 729 μmol), Brettphos (26 mg, 49 μmol), and BrettPhos Pd G3 (44 mg, 49 μmol) were added, degassed, and purged with N2 three times. The mixture was then stirred at 80 °C under a N2 atmosphere for 16 h. After cooling to room temperature, EtOAc (10 mL) was added, and the mixture was washed with HCl (0.5 M, 10 mL) and brine (10 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (solvent gradient: 0-20% MeOH in DCM) to give ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate (80 mg, 41%) as a white solid. LCMS (ESI) m / z: 603.3 [M+H] + .

[0493] Step 10: Synthesis of ((1s,3s)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2(3,3-difluoro-1-methylcyclobutyl)carbamate To a solution of ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl-d2 (3,3-difluoro-1-methylcyclobutyl)carbamate (80 mg, 100 μmol) in DCM (3 mL) was added TFA (1 mL) and the reaction was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo. The crude residue was dissolved in MeOH (2 mL) and the pH was adjusted to 10 with aqueous NaOH (2 M), followed by formic acid to pH 6. The solution was purified by reverse phase chromatography (36%-68% acetonitrile in water / 0.225% formic acid) to give compound 332 (26 mg, 51%) as a white solid. LCMS (ESI) m / z: 502.9 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.38(s,1H),9.33(s,1H),8.45(s,2H),8.18-8.10(m,1H),7.74-7.65(m,1H),7.62-7.58(m,2H),7. 36(s,2H),2.92-2.77(m,2H),2.61-2.52(m,3H),2.37-2.31(m,2H),1.97-1.82(m,2H),1.39(s,3H).

[0494] Example ...

Claims

1. A compound of formula (A), 【Chemical 76】 or a pharmaceutically acceptable salt thereof, wherein: R １ Ga-NR Ａ R Ｂ , —C(═O)NR Ａ R Ｂ , -OC(=O)NR Ａ R Ｂ , optionally substituted 5- to 10-membered heteroaryloxy, or optionally substituted 5- to 10-membered heteroaryl; Each R Ａ and R Ｂ are independently hydrogen, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl; X is —(CH ) optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. ２ ) ａ C3-C8 cycloalkylene-(CH ２ ) ｂ -; -(CH ２ ) ａ C5-C8 cycloalkenylene-(CH ２ ) ｂ -;-(CH ２ ) ａ Phenylene-(CH ２ ) ｂ -;-(CH ２ ) ａ Heteroarylene-(CH ２ ) ｂ -; - (CH ２ ) ａ Heterocyclylene-(CH ２ ) ｂ -; and C2-C6 alkylene, a and b are independently 0, 1, or 2; X １ But N or CR Ｘ１ and X ２ But N or CR Ｘ２ and R Ｘ１ and R Ｘ２ are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy; Y is -NR Ｃ -, *-C(=O)NR Ｃ (CR Ｄ R Ｅ ) ｎ -, *-NR Ｃ C(=O)(CR Ｄ R Ｅ ) ｎ - or -O-, wherein * is X １ ~X ２ Show the connection points to the ring, R Ｃ is hydrogen or C1-C6 alkyl, n is 0, 1, or 2; Each R Ｄ and R Ｅ are independently hydrogen, fluoro, or C1-C6 alkyl; R ２ is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl, or a pharmaceutically acceptable salt thereof.

2. R １ Ga-NR Ａ R Ｂ 2. The compound of claim 1, wherein:

3. R １ -C(=O)NR Ａ R Ｂ 2. The compound of claim 1, wherein:

4. R １ is -OC(=O)NR Ａ R Ｂ 2. The compound of claim 1, wherein:

5. R Ａ and R Ｂ is independently hydrogen, C1-C6 haloalkyl, unsubstituted C1-C6 alkyl, or unsubstituted C3-C10 cycloalkyl.

6. R Ａ and R Ｂ The compound according to any one of claims 1 to 5, wherein

7. R Ａ and R Ｂ The compound of any one of claims 1 to 6, wherein each is hydrogen.

8. R Ａ and R Ｂ The compound of any one of claims 1 to 6, wherein each is unsubstituted C1-C6 alkyl.

9. R Ａ and R Ｂ The compound according to any one of claims 1 to 5, wherein

10. R Ａ and R Ｂ one of R is hydrogen; Ａ and R Ｂ The compound according to any one of claims 1 to 5 and 9, wherein the other is a substituted C1-C6 alkyl.

11. R Ａ and R Ｂ one of R is hydrogen; Ａ and R Ｂ The compound according to any one of claims 1 to 5 and 9, wherein the other is unsubstituted C1-C6 alkyl.

12. R Ａ and R Ｂ one of R is hydrogen; Ａ and R Ｂ The compound according to any one of claims 1 to 5 and 9, wherein the other is C1-C6 haloalkyl.

13. R Ａ and R Ｂ one of R is hydrogen; Ａ and R Ｂ The compound according to any one of claims 1 to 5 and 9, wherein the other is a C2-C4 haloalkyl.

14. R Ａ and R Ｂ one of R is hydrogen; Ａ and R Ｂ The compound according to any one of claims 1 to 5 and 9, wherein the other is unsubstituted C3-C10 cycloalkyl.

15. R Ａ and R Ｂ one of R is hydrogen; Ａ and R Ｂ The compound according to any one of claims 1 to 5 and 9, wherein the other is a substituted C3-C10 cycloalkyl.

16. R １ The compound of claim 1, wherein is an optionally substituted 5-10 membered heteroaryloxy.

17. R １ 17. The compound of any one of claims 1 and 16, wherein is a substituted 5-10 membered heteroaryloxy.

18. R １ 17. The compound of any one of claims 1 and 16, wherein is unsubstituted 5-10 membered heteroaryloxy.

19. R １ 19. The compound according to any one of claims 1 and 16 to 18, wherein the 5- to 10-membered heteroaryloxy is a 5- to 6-membered heteroaryloxy.

20. R １ 20. The compound of any one of claims 1 and 16 to 19, wherein said 5 to 10 membered heteroaryloxy is isothiazolyloxy, pyridyloxy, or 1,3,4-triazolyloxy.

21. R １ The compound of claim 1, wherein is an optionally substituted 5-10 membered heteroaryl.

22. R １ 22. The compound of any one of claims 1 and 21, wherein is unsubstituted 5-10 membered heteroaryl.

23. R １ 22. The compound of any one of claims 1 and 21, wherein is a substituted 5-10 membered heteroaryl.

24. R ２ The compound of any one of claims 1 to 23, wherein is an optionally substituted 5-6 membered heteroaryl.

25. R ２ The compound of any one of claims 1 to 24, wherein is an optionally substituted 5-membered heteroaryl.

26. R ２ The compound of any one of claims 1 to 24, wherein is unsubstituted 5-membered heteroaryl.

27. R ２ The compound of any one of claims 1 to 24, wherein is a substituted 5-membered heteroaryl.

28. R ２ 28. The compound of any one of claims 1 to 27, wherein said 5-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or 1,2,5-oxadiazolyl.

29. R ２ The compound of any one of claims 1 to 24, wherein is an optionally substituted 6-membered heteroaryl.

30. R ２ 30. The compound of any one of claims 1 to 24 or 29, wherein is unsubstituted 6-membered heteroaryl.

31. R ２ 30. The compound of any one of claims 1 to 24 or 29, wherein is a substituted 6-membered heteroaryl.

32. R ２ 32. The compound of any one of claims 1-24 or 29-31, wherein said 6-membered heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

33. R ２ The compound of any one of claims 1 to 23, wherein is optionally substituted 5- to 6-membered heterocyclyl.

34. R ２ The compound of any one of claims 1 to 23 or 33, wherein is optionally substituted 5-membered heterocyclyl.

35. R ２ The compound of any one of claims 1 to 23 or 33 to 34, wherein is unsubstituted 5-membered heterocyclyl.

36. R ２ The compound of any one of claims 1-23 or 33-34, wherein is a substituted 5-membered heterocyclyl.

37. R ２ wherein the 5-membered heterocyclyl is pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfonyl, thiazolidinonyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydanthionyl, thiohydanthionyl, imidazolidino 37. The compound of any one of claims 1 to 23 or 33 to 36, wherein the compound is selected from the group consisting of oxazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanthioneyl, oxazolidinethionyl, imidazolidinethionyl, and isothiazolidinonyl.

38. R ２ The compound of any one of claims 1 to 23 or 33, wherein is an optionally substituted 6-membered heterocyclyl.

39. R ２ The compound of any one of claims 1 to 23 or 38, wherein is unsubstituted 6-membered heterocyclyl.

40. R ２ The compound of any one of claims 1 to 23 or 38, wherein is a substituted 6-membered heterocyclyl.

41. R ２ 41. The compound of any one of claims 1 to 23 or 38 to 40, wherein said 6-membered heterocyclyl is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidinedione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl.

42. R ２ The compound of any one of claims 1 to 23, wherein is optionally substituted phenyl.

43. R ２ The compound of any one of claims 1 to 23 or 42, wherein is unsubstituted phenyl.

44. R ２ The compound of any one of claims 1 to 23 or 42, wherein is substituted phenyl.

45. The R ２ The group is —SO ２ NH ２ , -F, cyano, -CH ２ OMe, -CO ２ NH ２ , methyl, —CH ２ OCF ３ 45. The compound of any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42, or 44, wherein the compound is substituted with 1 to 3 substituents selected from the group consisting of pyrazolyl optionally substituted with 1 to 2 methyl, pyrazolyl optionally substituted with 1 to 2 substituents selected from methyl and isopropoxymethyl, 1,2,4-triazolyl optionally substituted with 1 to 2 methyl, and tetrazolyl optionally substituted with 1 to 2 methyl.

46. The R ２ The group is —SO ２ NH ２ , -F, -CH ２ OMe, and -CO ２ NH ２ 46. ​​The compound of any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42, or 44 to 45, substituted with 1 to 3 substituents selected from the group consisting of:

47. The R ２ The group is one -(SO ２ 45. The compound of any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42, or 44, which is substituted with C3 to C6 cycloalkyl.

48. The R ２ The group is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, and C1-C6 haloalkyl. ２ ) The compound of any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42, or 44, substituted with NHC3-C6 cycloalkyl.

49. The R ２ The group is one -(SO ２ ) NR Ｈ R Ｉ wherein R Ｈ and R Ｉ is independently H and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

50. The R ２ The group is one -(SO ２ ) NR Ｈ R Ｉ wherein R Ｈ and R Ｉ 49. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, 44, or 48, wherein one of is H and the other is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

51. The R ２ The group is one -(SO ２ ) NR Ｈ R Ｉ wherein R Ｈ and R Ｉ 49. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, 44, or 48, wherein one of is H and the other is C1-C6 alkyl.

52. The R ２ The group is one -(SO ２ ) NR Ｈ R Ｉ wherein R Ｈ and R Ｉ 49. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, 44, or 48, wherein one of is H and the other is a C1-C6 alkyl substituted with hydroxyl.

53. The R ２ The base is 【Chemical 77】 45. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, or 44, substituted with one selected from the group consisting of:

54. The R ２ 45. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, or 44, wherein the group is substituted with one -(C=O)C1-C6 alkyl or -(C=O)C3-C6 cycloalkyl.

55. The R ２ The group is one -NH(SO ２ 45. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, or 44, wherein the compound is substituted with C1-C3 alkyl.

56. The R ２ The group is one -(S(=NR Ｌ )(=O)) is substituted with C1-C6 alkyl, wherein R Ｌ 45. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, or 44, wherein is H or C1-C6 alkyl optionally substituted with hydroxyl.

57. The R ２ The group is one -(S(=NR Ｌ )(=O)) is substituted with C1-C3 haloalkyl, wherein R Ｌ 45. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, or 44, wherein is H or C1-C6 alkyl optionally substituted with hydroxyl.

58. The R ２ The group is one -(S(=NR Ｌ 45. The compound of any one of claims 1-25, 27-29, 31-34, 36-38, 40-42, or 44, substituted with (=O)) C3-C6 cycloalkyl.

59. The substituted R ２ 58. The compound of any one of claims 44 to 57, wherein each H in the group is independently deuterium.

60. X is —(CH ) optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy. ２ ) ａ C3-C8 cycloalkylene-(CH ２ ) ｂ The compound according to any one of claims 1 to 59, wherein

61. X is —(CH ) substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; ２ ) ａ C3-C8 cycloalkylene-(CH ２ ) ｂ The compound according to any one of claims 1 to 60, wherein

62. X is unsubstituted -(CH ２ ) ａ C3-C8 cycloalkylene-(CH ２ ) ｂ The compound according to any one of claims 1 to 60, wherein

63. The X -(CH ２ ) ａ C3-C8 cycloalkylene-(CH ２ ) ｂ - is - (CH ２ ) ａ C4-C6 cycloalkylene-(CH ２ ) ｂ The compound according to any one of claims 1 to 62, wherein

64. The X -(CH ２ ) ａ C3-C8 cycloalkylene-(CH ２ ) ｂ 64. The compound of any one of claims 1 to 63, wherein - is cyclopentylene.

65. X is —(CH ) optionally substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl; ２ ) ａ C5-C8 cycloalkenylene-(CH ２ ) ｂ The compound according to any one of claims 1 to 59, wherein

66. X is —(CH ) substituted with 1 to 2 substituents independently selected from halogen and C1-C6 alkyl; ２ ) ａ C5-C8 cycloalkenylene-(CH ２ ) ｂ 66. The compound according to any one of claims 1 to 59 and 65, wherein

67. X is unsubstituted -(CH ２ ) ａ C5-C8 cycloalkenylene-(CH ２ ) ｂ 66. The compound according to any one of claims 1 to 59 and 65, wherein

68. X is -(CH ２ ) ａ Phenylene-(CH ２ ) ｂ The compound according to any one of claims 1 to 59, wherein

69. X is -(CH ２ ) ａ (4- to 8-membered heteroarylene)-(CH ２ ) ｂ The compound according to any one of claims 1 to 59, wherein

70. X is -(CH ２ ) ａ (4- to 8-membered heterocyclylene)-(CH ２ ) ｂ The compound according to any one of claims 1 to 59, wherein

71. The compound of any one of claims 1 to 70, wherein a is 0.

72. The compound of any one of claims 1 to 70, wherein a is 1.

73. The compound of any one of claims 1 to 70, wherein a is 2.

74. The compound of any one of claims 1 to 73, wherein b is 0.

75. 74. The compound of any one of claims 1 to 73, wherein b is 1.

76. 74. The compound of any one of claims 1 to 73, wherein b is 2.

77. 60. The compound of any one of claims 1 to 59, wherein X is C2 to C6 alkylene.

78. 60. The compound of any one of claims 1 to 59, wherein X is C2 to C4 alkylene.

79. X １ is CR Ｘ１ 79. The compound of any one of claims 1 to 78, wherein

80. X ２ is CR Ｘ２ 80. The compound of any one of claims 1 to 79, wherein

81. R Ｘ１ The compound of any one of claims 1 to 80, wherein is C1 to C6 alkyl.

82. R Ｘ１ The compound of any one of claims 1 to 81, wherein is methyl.

83. R Ｘ１ The compound of any one of claims 1 to 82, wherein is C1-C6 alkoxy.

84. R Ｘ１ 84. The compound of any one of claims 1 to 80 or 83, wherein is methoxy.

85. R Ｘ１ The compound of any one of claims 1 to 80, wherein is C1-C6 haloalkyl.

86. R Ｘ１ 86. The compound of any one of claims 1 to 80 or 85, wherein is trifluoromethyl.

87. R Ｘ１ The compound of any one of claims 1 to 80, wherein is C1-C6 haloalkoxy.

88. R Ｘ１ 88. The compound of any one of claims 1 to 80 or 87, wherein is trifluoromethoxy.

89. R Ｘ１ The compound of any one of claims 1 to 80, wherein is C3-C6 cycloalkyl.

90. R Ｘ１ 90. The compound of any one of claims 1 to 80 or 89, wherein is cyclopropyl.

91. R Ｘ１ The compound of any one of claims 1 to 80, wherein is C3 to C6 cycloalkoxy.

92. R Ｘ１ 92. The compound of any one of claims 1 to 80 or 91, wherein is cyclopropoxy.

93. R Ｘ１ The compound of any one of claims 1 to 80, wherein is cyano.

94. R Ｘ１ The compound of any one of claims 1 to 80, wherein is halogen.

95. R Ｘ１ The compound of any one of claims 1 to 80, wherein is hydrogen.

96. R Ｘ２ The compound of any one of claims 1 to 95, wherein is C1 to C6 alkyl.

97. R Ｘ２ 97. The compound of any one of claims 1 to 96, wherein is methyl.

98. R Ｘ２ The compound of any one of claims 1 to 95, wherein is C1-C6 alkoxy.

99. R Ｘ２ 99. The compound of any one of claims 1 to 95 or 98, wherein is methoxy.

100. R Ｘ２ The compound of any one of claims 1 to 95, wherein is C1-C6 haloalkyl.

101. R Ｘ２ 101. The compound of any one of claims 1 to 95 or 100, wherein is trifluoromethyl.

102. R Ｘ２ The compound of any one of claims 1 to 95, wherein is C1-C6 haloalkoxy.

103. R Ｘ２ 103. The compound of any one of claims 1 to 95 or 102, wherein is trifluoromethoxy.

104. R Ｘ２ The compound of any one of claims 1 to 95, wherein is C3-C6 cycloalkyl.

105. R Ｘ２ The compound of any one of claims 1 to 95 or 104, wherein is cyclopropyl.

106. R Ｘ２ The compound of any one of claims 1 to 95, wherein is C3 to C6 cycloalkoxy.

107. R Ｘ２ 107. The compound of any one of claims 1 to 95 or 106, wherein is cyclopropoxy.

108. R Ｘ２ 96. The compound of any one of claims 1 to 95, wherein is cyano.

109. R Ｘ２ The compound of any one of claims 1 to 95, wherein is halogen.

110. R Ｘ２ 96. The compound of any one of claims 1 to 95, wherein is hydrogen.

111. X １ The compound of any one of claims 1 to 78 or 80 to 95, wherein is N.

112. X ２ 112. The compound of any one of claims 1-79, 81-95, or 111, wherein is N.

113. Y is *-C(=O)NR Ｃ (CR Ｄ R Ｅ ) ｎ -, wherein * is X １ ~X ２ 113. The compound of any one of claims 1 to 112, showing a point of attachment to the ring.

114. Y is *-NR Ｃ C(=O)(CR Ｄ R Ｅ ) ｎ -, wherein * is X １ ~X ２ 113. The compound of any one of claims 1 to 112, showing a point of attachment to the ring.

115. The compound of any one of claims 1 to 114, wherein n is 0.

116. The compound of any one of claims 1 to 114, wherein n is 1.

117. The compound of any one of claims 1 to 114, wherein n is 2.

118. Each R Ｄ and R Ｅ The compound according to any one of claims 1 to 117, wherein

119. Each R Ｄ and R Ｅ is the same as above, except that Ｄ and R Ｅ The compound according to any one of claims 1 to 117, wherein one of

120. Each R Ｄ and R Ｅ The compound of any one of claims 1 to 117, wherein is hydrogen.

121. Each R Ｄ and R Ｅ The compound of any one of claims 1 to 117, wherein is fluoro.

122. Each R Ｄ and R Ｅ The compound of any one of claims 1 to 117, wherein is methyl.

123. R Ｄ and R Ｅ one of R is methyl or fluoro, and the remaining R Ｄ and R Ｅ The compound of any one of claims 1 to 117, wherein is hydrogen.

124. Y is -NR Ｃ The compound according to any one of claims 1 to 112, wherein

125. R Ｃ is C1-C6 alkyl.

126. R Ｃ The compound of any one of claims 1 to 125, wherein is methyl.

127. R Ｃ The compound of any one of claims 1 to 124, wherein is hydrogen.

128. The compound of any one of claims 1 to 112, wherein Y is -O-.

129. 2. The compound of claim 1, wherein the compound of formula (A) is selected from the group consisting of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

130. 130. A pharmaceutical composition comprising a compound according to any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

131. 130. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 130.

132. 1. A method for treating cancer in a subject in need thereof, comprising: (a) identifying the cancer as a CDK2-associated cancer; (b) administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 130.

133. The method of claim 132, wherein the step of identifying the cancer in the subject as a CDK2-associated cancer comprises performing an assay to detect dysregulation in the CDK2 gene, CDK2 protein, or expression or activity or level of either thereof in a sample from the subject.

134. The method of claim 132, wherein the step of identifying the cancer in the subject as a CDK2-associated cancer comprises performing an assay to detect dysregulation in the expression or activity or level of the cyclin A2 gene, cyclin A2 protein, or any of them in a sample from the subject.

135. The method of claim 132, wherein the step of identifying the cancer in the subject as a CDK2-associated cancer comprises performing an assay to detect dysregulation in the expression or activity or level of the cyclin E1 gene, the cyclin E1 protein, or any of them in a sample from the subject.

136. The method of claim 132, wherein the step of identifying the cancer in the subject as a CDK2-associated cancer comprises performing an assay to detect dysregulation in the expression or activity or level of the cyclin E2 gene, cyclin E2 protein, or any of them in a sample from the subject.

137. 137. The method of any one of claims 132 to 136, further comprising obtaining a sample from the subject.

138. 138. The method of claim 137, wherein the sample is a biopsy sample.

139. 139. The method of any one of claims 133 to 138, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

140. 140. The method of claim 139, wherein the sequencing is pyrosequencing or next generation sequencing.

141. 1. A method for treating cancer in a subject in need thereof, comprising:

130. The method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 130, wherein the subject has been identified as having a CDK2-associated cancer.

142. 130. A method for treating a CDK2-associated cancer, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 130, to a subject who has been identified or diagnosed as having a CDK2-associated cancer.

143. 1. A method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the CDK2 gene, CDK2 protein, or expression or activity or levels of either thereof; (b) administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 130.

144. The method of claim 143, wherein the step of determining that the cancer in the subject is a CDK2-associated cancer comprises performing an assay to detect dysregulation in the CDK2 gene, CDK2 protein, or expression or activity or level of either of them in a sample from the subject.

145. The method of claim 143, wherein the step of determining that the cancer in the subject is a CDK2-associated cancer comprises performing an assay to detect dysregulation in the expression or activity or level of the cyclin A2 gene, cyclin A2 protein, or any of them in a sample from the subject.

146. The method of claim 143, wherein the step of determining that the cancer in the subject is a CDK2-associated cancer comprises performing an assay to detect dysregulation in the expression or activity or level of the cyclin E1 gene, the cyclin E1 protein, or any of them in a sample from the subject.

147. The method of claim 143, wherein the step of determining that the cancer in the subject is a CDK2-associated cancer comprises performing an assay to detect dysregulation in the expression or activity or level of the cyclin E2 gene, cyclin E2 protein, or any of them in a sample from the subject.

148. 148. The method of any one of claims 143 to 147, further comprising obtaining a sample from the subject.

149. 149. The method of claim 148, wherein the sample is a biopsy sample.

150. 150. The method of any one of claims 143 to 149, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

151. 151. The method of claim 150, wherein the sequencing is pyrosequencing or next generation sequencing.

152. 130. A method for inhibiting metastasis in a subject having cancer in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 130.

153. 153. The method of any one of claims 131 to 152, further comprising administering to the subject an additional therapy or therapeutic agent.

154. 154. The method of claim 153, wherein the additional therapy or therapeutic agent is selected from an EGFR inhibitor, a HER2 inhibitor, a MEK inhibitor, a RAF inhibitor, a KRAS inhibitor, a cytotoxic chemotherapeutic agent, an angiogenesis inhibitor, and radiation therapy.

155. 155. The method of any one of claims 131 to 154, wherein the cancer is colorectal cancer, lung cancer, thyroid cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, pancreatic cancer, or gastric cancer.

156. 156. The method of any one of claims 131 to 155, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or gastric cancer.

157. 157. The method of any one of claims 131 to 156, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, and colorectal cancer.

158. 158. The method of any one of claims 131 to 157, wherein the cancer is selected from the group consisting of breast cancer and ovarian cancer.

159. 159. The method of any one of claims 131 to 158, wherein the cancer is breast cancer.

160. 160. The method of any one of claims 131 to 159, wherein the cancer is a breast cancer selected from the group consisting of estrogen receptor (ER) positive / hormone receptor (HR) positive breast cancer, HER2 negative breast cancer, ER positive / HR positive breast cancer, HER2 positive breast cancer, triple negative breast cancer (TNBC), and inflammatory breast cancer.

161. 160. The method of any one of claims 131 to 159, wherein the cancer is a breast cancer selected from the group consisting of endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, and breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition.

162. 159. The method of any one of claims 131 to 158, wherein the cancer is ovarian cancer.

163. 158. The method of any one of claims 131 to 157, wherein the cancer is colorectal cancer.

164. 130. A method for inhibiting the proliferation of mammalian cells, comprising contacting said mammalian cells with a compound of any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof.

165. 130. A method for inhibiting CDK2 activity in a mammalian cell, comprising contacting said mammalian cell with a compound of any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof.

166. 166. The method of claim 164 or 165, wherein the contacting occurs in vivo.

167. 166. The method of claim 164 or 165, wherein the contacting occurs in vitro.

168. 168. The method of any one of claims 164 to 167, wherein the mammalian cell is a mammalian cancer cell.

169. 169. The method of any one of claims 164 to 168, wherein the mammalian cell has a dysregulated CDK2 gene, CDK2 protein, or expression or activity or level of either thereof.

170. 170. The method of any one of claims 164 to 169, wherein the mammalian cells have a dysregulated cyclin A2 gene, cyclin A2 protein, or expression or activity or level of either thereof in a sample from the subject.

171. 171. The method of any one of claims 164 to 170, wherein the mammalian cell has a dysregulated cyclin E1 gene, cyclin E1 protein, or expression or activity or level of either thereof.

172. 172. The method of any one of claims 164 to 171, wherein the mammalian cell has a dysregulated cyclin E2 gene, cyclin E2 protein, or expression or activity or level of either thereof.

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