Compounds for treatment of cancer

Abstract

The present 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. Also described are pharmaceutical compositions comprising compounds of Formula (A) and pharmaceutically acceptable salts thereof, as well as methods of using the compounds and compositions in the treatment of diseases such as cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. application No. 63 / 406,081 filed on September 13, 2022, U.S. application No. 63 / 419,451 filed on October 26, 2022, U.S. application No. 63 / 435,170 filed on December 23, 2022, and U.S. application No. 63 / 536,249 filed on September 1, 2023, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present application relates to compounds, methods of making the compounds, compositions comprising the compounds, and methods of treating disorders (such as cancer) with the compounds or compositions. Background Art

[0004] Cyclin-dependent kinases (CDKs) play an important role in regulating eukaryotic cell division and proliferation. The cyclin-dependent kinase catalytic unit is activated by a regulatory subunit called a cyclin. At least sixteen 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 D / CDK4, cyclin D / CDK6 and other possible heterologous proteins (heterodyne) regulate cell cycle progression. Additional functions of cyclin / CDK heterologous proteins 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 abnormal cell cycle regulation. The cyclin E / CDK2 complex plays an important role in regulating the G1 / S transition, histone biosynthesis, and centrosome duplication. Progressive phosphorylation of Rb by cyclin E / Cdk2 releases the G1 transcription factor E2F and promotes entry into the S phase. Activation of cyclin A / CDK2 in the early S phase promotes phosphorylation of endogenous substrates, allowing DNA replication and E2F inactivation to complete the S phase. See Asghar et al., Nat. Rev. Drug. Discov. 2015; 14(2): 130-146.

[0005] Cyclin E is a regulatory cyclin of CDK2. Amplification or overexpression of cyclin E has long been associated with poor outcomes 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) is associated with poor outcomes in ovarian cancer, gastric cancer, endometrial cancer, 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. During the G1 phase of the cell cycle, CDK2 complexes with cyclin E to phosphorylate the tumor suppressor RB1. Fully phosphorylated RB1 removes inhibition of the E2F transcription factor, which regulates the transcription of DNA synthesis and repair genes, including cyclin A2. CDK2, in complex with cyclin A2, is phosphorylated during S phase progression and regulates the DNA synthesis / repair process.

[0006] Amplification or overexpression of cyclin A (CCNA2) is known to be associated with several cancer types, including breast cancer, liver cancer, lung cancer, and cervical cancer. See Yam et al., Cell Mol. Life Sci. 2002; 59, 1317-1326 and Burkholm et al., Int. J. Cancer, 2001; 93 (2) 283-287. Increased activity of cyclin A 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. Therefore, inhibition of CDK2 may provide beneficial effects in cancers associated with abnormalities in the cell cycle. Summary of the invention

[0007] Some embodiments provide a compound of formula (A),

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] R 1 For –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;

[0011] Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl or optionally substituted C3-C10 cycloalkyl;

[0012] X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -; optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl -(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;

[0013] a and b are independently 0, 1 or 2;

[0014] X 1 N or CR X1 ;

[0015] X 2 N or CR X2 ;

[0016] CRX1 and CR X2 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;

[0017] 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 same as X 1 -X 2 The connection point of the ring;

[0018] R C is hydrogen or C1-C6 alkyl;

[0019] n is 0, 1 or 2;

[0020] Each R D and R E are independently hydrogen, fluorine or C1-C6 alkyl; and

[0021] R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl or optionally substituted 5-9 membered heterocyclyl.

[0022] Some embodiments provide a compound of formula (AI),

[0023]

[0024] or a pharmaceutically acceptable salt thereof, wherein:

[0025] R 1 For –NR A R B 、–C(=O)NR A R B 、–OC(=O)NR A R B or optionally substituted 5-10 membered heteroaryl;

[0026] Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl or optionally substituted C3-C10 cycloalkyl;

[0027] X 1 N or CRX1 ;

[0028] X 2 N or CR X2 ;

[0029] CR X1 and CR X2 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;

[0030] 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 same as X 1 -X 2 The connection point of the ring;

[0031] R C is hydrogen or C1-C6 alkyl;

[0032] m is 0, 1 or 2;

[0033] n is 0, 1 or 2;

[0034] Each R D and R E are independently hydrogen, fluorine or C1-C6 alkyl; and

[0035] R 2 is optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl or optionally substituted 5-6-membered heterocyclyl.

[0036] Some embodiments provide a pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0037] 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.

[0038] Some embodiments provide a method for treating cancer in a subject in need thereof, comprising: (a) identifying the cancer as a CDK2-related 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.

[0039] 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-related cancer.

[0040] Some embodiments provide a method of treating a CDK2-related cancer, comprising administering to a subject identified or diagnosed as having a CDK2-related 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.

[0041] Some embodiments provide 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 a CDK2 gene, a 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.

[0042] Some embodiments provide a method for inhibiting cancer metastasis in a subject with cancer in need of such treatment, 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.

[0043] Some embodiments provide a method for inhibiting cancer cell invasion in a subject with cancer in need of such treatment, 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.

[0044] Some embodiments provide a method for inhibiting proliferation of mammalian cells, comprising contacting the mammalian cells with a compound of formula (A) or a pharmaceutically acceptable salt thereof.

[0045] 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.

[0046] 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.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those of ordinary skill in the art to which the present disclosure belongs. Methods and materials for use in the present 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 limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0048] Other features and advantages of the disclosure will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0049] definition

[0050] The term "about" when applied to a particular value or range means ± 10% of the stated value or range, for example, to account for experimental variance.

[0051] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. Unless otherwise indicated, a compound identified herein by name or structure as a particular tautomeric form is intended to include other tautomeric forms.

[0052] It should be understood that in any compound with one or more chiral centers as described herein, if the absolute stereochemical structure is not clearly indicated, each center can independently have the R configuration or the S configuration or a mixture thereof. Therefore, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched or stereoisomer mixtures. In addition, it should be understood that in any compound with one or more double bonds as described herein, if the double bonds produce geometric isomers that can be defined as E or Z, each double bond can independently be E or Z or a mixture thereof.

[0053] As used herein, the term "tautomer" refers to a compound whose structure is significantly different in atomic arrangement but exists in a facile and rapid equilibrium manner, and it is understood that the compounds provided herein can be depicted as different tautomers, and when a compound has a tautomeric form, 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 included:

[0054]

[0055] It will be appreciated that specific compounds provided herein may contain one or more asymmetric centers and therefore can be prepared and isolated as mixtures of isomers (such as racemic mixtures) or in enantiomerically pure form.

[0056] The term "halogen" refers to one of the halogens of Group 17 of the Periodic Table of Elements. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0057] The term "alkyl" refers to a straight or branched hydrocarbon chain containing 1 to 20 carbon atoms. Alkyl can be represented, for example, as a C1-12 alkyl group, which contains 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.

[0058] The term "alkylene" refers to an alkyl group as defined herein that is a diradical and is linked to two other moieties. Non-limiting examples of alkylene groups include: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylidene (IUPAC: (methyl)ethylene) (-CH 2 -CH(CH 3 )-) and isobutylene (IUPAC: 2-(methyl)propylene)(-CH 2 -CH(CH 3 )-CH 2 -). The alkylene group may optionally include a C3-C4 cycloalkyl group as defined herein, which shares one carbon atom with the backbone of the alkylene chain, e.g.

[0059] The term "alkenyl" refers to an alkyl group containing a carbon double bond as described herein, including but not limited to 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0060] The term "alkynyl" refers to an alkyl group containing a carbon triple bond as described herein, including but not limited to 1-propynyl, 1-butynyl, 2-butynyl, and the like.

[0061] The term "haloalkyl" refers to an alkyl group as defined herein, which is substituted at each occurrence by at least one halogen atom independently selected from, for example, 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, 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, trifluoropropyl.

[0062] The term "alkoxy" refers to an alkyl group as defined herein attached to a molecule via an oxygen. This includes moieties where the alkyl portion may be straight or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0063] As used herein, "haloalkoxy" refers to an O-alkyl group (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy) in which one or more hydrogen atoms are replaced by halogen. In some cases, the haloalkoxy group can be -OR, wherein R is a C1-4 alkyl group 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 group can be substituted or unsubstituted.

[0064] As used herein, the term "aryl" refers to a 6-10 all-carbon monocyclic or bicyclic group, wherein at least one ring in the system is aromatic, i.e., a C6-C10 aryl. Non-limiting examples of aryl include phenyl, naphthyl, tetrahydronaphthyl. In a bicyclic system where only one ring is aromatic, the non-aromatic ring may be a cycloalkyl as defined herein.

[0065] As used herein, the term "heteroaryl" refers to a 5-10 membered monocyclic or bicyclic group, wherein the ring system is aromatic; wherein one or more carbon atoms of at least one ring in the ring system are replaced by heteroatoms independently selected from N, O and S. Heteroaryl includes rings in which one or more groups are oxidized, such as pyridone moieties. Non-limiting examples of heteroaryl include pyridine, pyrimidine, pyrrole, imidazole and indole.

[0066] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated 3-10 monocyclic or bicyclic hydrocarbon group; wherein the bicyclic system includes fused rings, spiro rings and bridged ring systems. Non-limiting examples of cycloalkyl include cyclopropyl, cyclohexyl, spiro[2.3]hexyl and bicyclo[1.1.1]pentyl.

[0067] The term "cycloalkoxy" refers to a cycloalkyl group as defined herein attached to a molecule via an oxygen. This includes portions where the cycloalkyl group is a saturated or partially unsaturated 3-10 monocyclic or bicyclic hydrocarbon group; wherein bicyclic systems include fused rings, spirocyclic and bridged ring systems. Non-limiting examples of cycloalkoxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and octahydropentalen-2-yl.

[0068] The term "heterocyclyl" refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system which is not aromatic and has at least one heteroatom selected from N, O and S in the ring. In a bicyclic ring system, one ring may be aromatic. Bicyclic heterocyclyls include fused rings, spirocyclic rings and bridged ring systems. Heterocyclyl ring systems may include oxo substitutions at one or more C, N or S ring members. For example, a heterocyclyl may be represented as a "5-10 membered heterocyclyl", which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. For example, 1, 2 or 3 heteroatoms may be present, optionally 1 or 2. The heterocyclyl may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2-azaspiro[3.3]heptyl, pyrrolidin-2-one, sulfolane, isothiazolinyl S,S-dioxide, and decahydronaphthyl.

[0069] The term "hydroxyl" refers to an -OH moiety.

[0070] The term "cyano" refers to a -CN moiety.

[0071] The term "nitro" refers to -NO 2 part.

[0072] The term "azido" refers to -N 3 part.

[0073] The term "isocyanato" refers to a -NCO moiety.

[0074] The term "thiocyanato" refers to a -CNS moiety.

[0075] The term "isothiocyanato" refers to a -NCS moiety.

[0076] The term "oxo" refers to a "=0" group attached to a carbon atom.

[0077] The term "acyl" refers to an alkyl group attached via an oxo group as a substituent. Examples include, but are not limited to, acetyl.

[0078] The term "O-carboxy" refers to a "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.

[0079] The terms "ester" and "C-carboxy" refer to a "-C(=O)OR" group, where R may be the same as defined for O-carboxy.

[0080] The term "thiocarbonyl" refers to a "-C(=S)R" group, where R may be the same as defined for O-carboxyl.

[0081] The term "O-carbamyl" refers to a "-OC(=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).

[0082] The term "N-carbamyl" refers to a "ROC(=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).

[0083] The term "O-thiocarbamyl" refers to a "-OC(=S)-N(R'R")" group, wherein R' and R" are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0084] The term "N-thiocarbamyl" refers to a "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).

[0085] The term "C-amido" 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).

[0086] The term "N-amido" refers to a "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).

[0087] The term "S-sulfonamido" refers to "-SO 2 N(R'R")" group, wherein 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.

[0088] The term "N-sulfonylamino" refers to "RSO 2 N(R')-" group, wherein R and R' are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0089] The term "sulfenyl" refers to a "-SR" group where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0090] The term "sulfinyl" refers to a "-S(=O)-R" group, wherein R may be the same as defined for a hydrocarbylthio group.

[0091] The term "sulfonyl" refers to "SO 2 R" group, wherein R may be the same as defined for the hydrocarbon thio group.

[0092] The term "aryl(alkyl)" refers to an aryl group attached as a substituent via an alkylene group as described herein. Examples include, but are not limited to, benzyl.

[0093] The term "heteroaryl(alkyl)" refers to a heteroaryl group attached as a substituent to an alkylene group.

[0094] The term "heterocyclyl(alkyl)" refers to a heterocyclyl group attached via an alkylene group as a substituent.

[0095] The term "amino" refers to -NH 2 Group.

[0096] The term "monosubstituted amine" group refers to a "-NHR'" group, where R' can be an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. Examples of monosubstituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl), etc.

[0097] The term "disubstituted amine" group refers to a "-NR'R"" group, where R' and 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 disubstituted amino groups include, but are not limited to, -N(methyl) 2 , -N(phenyl)(methyl), -N(ethyl)(methyl), etc.

[0098] As used herein, an asterisk (*) delineates the point of attachment of an atom or moiety to the indicated atom or group in the rest of a molecule.

[0099] When a group is described herein as "optionally substituted", the group may be unsubstituted or substituted with one or more indicated substituents. Similarly, when a group is described as "unsubstituted or substituted", if substituted, the substituent may be selected from one or more indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more (such as 1, 2, 3 or 4) groups individually and independently selected from the following: deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, cyanate, isocyanate, thiocyanate, nitro, azido, silyl, alkylthio, sulfinyl, sulfonyl, phosphine oxide, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonylamino, amino, monosubstituted amino and disubstituted amino.

[0100] The compound of formula (A) includes its pharmaceutically acceptable salt. In addition, the compound of formula (A) also includes other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, but can be used as intermediates for preparing and / or purifying the compound of formula (A) and / or separating the enantiomers of the compound of formula (A).

[0101] The term "pharmaceutically acceptable" indicates that the compound or its salt or composition is chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the subject to be treated therewith.

[0102] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. That is, an atom, particularly when referred to in relation to a compound according to formula (A), includes all isotopes and isotopic mixtures of said atom, whether naturally occurring or synthetically produced, with natural abundance or in isotopically enriched form. For example, when referring to hydrogen, it is understood to refer to 1 H. 2 H. 3 H or mixtures thereof; when carbon is mentioned, it is understood to refer to 11 C. 12 C. 13 C. 14 C or mixtures thereof; when nitrogen is mentioned, it is understood to mean 13 N. 14 N. 15 N or mixtures thereof; when oxygen is mentioned, it is understood to mean 14 O. 15 O. 16O. 17 O. 18 O or mixtures thereof; when fluorine is mentioned, it is understood to mean 18 F. 19 F or mixtures thereof; unless otherwise expressly stated. For example, in deuterated alkyl and deuterated alkoxy, one or more hydrogen atoms are specifically replaced by deuterium ( 2 H) replacement. Since some of the above isotopes are radioactive, the compounds provided herein also include compounds and mixtures thereof having one or more isotopes of one or more atoms, including radioactive compounds, wherein one or more non-radioactive atoms have been replaced by one of their radioactive enriched isotopes. Radiolabeled compounds can be used 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 variants of the compounds provided herein, whether or not radioactive, are intended to be included within the scope of the present disclosure.

[0103] The ability of selected compounds to act as CDK2 inhibitors can be demonstrated by biological assays as described herein. The Ki values ​​are shown in Table 3.

[0104] As defined herein, "CDK2 inhibitors" include any compound expressing CDK2 inhibitory activity. In some embodiments, the CDK2 inhibitor is selective for CDK2 protein. Exemplary CDK2 inhibitors may exhibit an inhibitory activity (Ki) for CDK2 of less than about 1000nM, less than about 500nM, less than about 200nM, less than about 100nM, less than about 50nM, less than about 25nM, less than about 10nM, or less than about 1nM, as measured in an assay described herein. In some embodiments, the CDK2 inhibitor may exhibit an inhibitory activity (Ki) for CDK2 of less than about 25nM, less than about 10nM, less than about 5nM, or less than about 1nM, as measured in an assay described herein.

[0105] The phrase "therapeutically effective amount" means an amount of a compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a CDK2-related cancer, (ii) alleviate, improve or eliminate one or more symptoms of a specific CDK2-related cancer, and / or (iii) delay the onset of one or more symptoms of a specific CDK2-related 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 a combination of any of the foregoing effects. The amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof that will correspond to the amount will vary depending on factors such as the specific compound, the disease state and its severity, and the characteristics of the subject in need of treatment (e.g., body weight).

[0106] The compounds of formula (A) or pharmaceutically acceptable salts thereof can be used to treat diseases and conditions treatable by CDK2 inhibitors, such as CDK2-related cancers, such as solid tumors.

[0107] As used herein, the terms "treat" and "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, all or partial relief of symptoms associated with a disease or disorder or condition, reduction in the extent of the disease, stabilization (i.e., non-exacerbation) of the disease state, delay or slowing of disease progression, improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete) (whether detectable or undetectable). "Treatment" may also mean prolonging survival compared to the expected survival if not receiving treatment.

[0108] 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 has experienced and / or exhibits at least one symptom of the cancer to be treated.

[0109] In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof can be used to prevent diseases and disorders as defined herein. As used herein, the term "preventing" refers to the total or partial prevention of the occurrence, recurrence or spread of a disease or disorder or its symptoms as described herein.

[0110] The term "regulatory agency" refers to an agency in a country that is responsible for approving pharmaceutical products for medical use in that country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0111] As used herein, the term "CDK2-related cancer" refers to a cancer associated with or having a disorder of the expression or activity or level of a CDK2 gene, a CDK2 protein, or any of them (e.g., one or more thereof) (such as any type of disorder of the expression or activity or level of a CDK2 gene, a CDK2 protein, or any of them as described herein). CDK2-related cancers also include cancers associated with or having a disorder of the expression or activity or level of a cyclin A2 gene, a cyclin A2 protein, or any of them, a cancer associated with or having a disorder of the expression or activity or level of a cyclin E1 gene, a cyclin E1 protein, or any of them, and a cancer associated with or having a disorder of the expression or activity or level of a cyclin E2 gene, a cyclin E2 protein, or any of them. In some embodiments, a CDK-related cancer is characterized by amplification or overexpression of CDK2. In some embodiments, a CDK-related cancer is characterized by amplification or overexpression of cyclin A2 (CCNA2), cyclin E1 (CCNE1), and / or cyclin E2 (CCNE2). In some embodiments, CDK-related cancers are characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some embodiments, CDK-related cancers are characterized by amplification or overexpression of cyclin A2 (CCNA2). In some embodiments, CDK-related cancers are characterized by amplification or overexpression of cyclin E1 (CCNE1). In some embodiments, CDK-related cancers are characterized by amplification or overexpression of cyclin E2 (CCNE2). Non-limiting examples of CDK2-related cancers are described herein.

[0112] An exemplary sequence of human CDK2 is shown below:

[0113] SEQ ID NO: 1 (UniProt accession number P24941)

[0114] MENFQKVEKIGEGTYGVVYKARNKLTGEVVALKKIRLDTETEGVPSTAIREISLLKELNHPNIVKLLDVIHTENKLYLVFEFLHQDLKKFMDASALTGIPLPLIKSYLFQLLQGLAFCHSHRVLHRDLKPQNLLINTEGAIKLADFGLA RAFGVPVRTYTHEVVTLWYRAPEILLGCKYYSTAVDIWSLGCIFAEMVTRRALFPGDSEIDQLFRIFRTLGTPDEVVWPGVTSMPDYKPSFPKWARQDFSKVVPPLDEDGRSLLSQMLHYDPNKRISAKAALAHPFFQDVTKPVPHLRL

[0115] An exemplary sequence of human cyclin E1 is shown below:

[0116] SEQ ID NO:2 (UniProt accession number E1B9U2)

[0117] MPREKERDAKEPDTMKEESGTDVSVRSRKRKANVAVFLQDPDEEIAKIDRTVRSQCGSQPWDSNRACENPCSLIPTPDKEEDELLYPHAAYKPQRSTPSSSR ASPLPVLNWANREEVWKIMLNKEKTYLRDKHLMQRHPLLQPKMRAILLDWLMEVCEVYKLHRETFYLAQDFFDRYMATQQNVVKTLLQLIGISSLFIAAKLEE IYPPKLHQFAYVTDGACSGDEILTMELIIMKALKWHLSPLTIVSWLNVYMQVAYLNDVYEVLLPQYPQQIFIQIAELLDLCVLDVGCLEFSYGVLAASALYHF SSSELMQKVSGYQWCDIEKCVKWMVPFAIVIRETGSSKLKHFRGVPAEDAHNIQTHINSLDLLDKAQAKKAILSEENRISPLPTGVLTPPQSSKKQSSGQGSA

[0118] An exemplary sequence of human cyclin E2 is shown below:

[0119] SEQ ID NO:3 (UniProt accession number O96020)

[0120] MSRRSSRLQAKQQPQPSQTESPQEAQIIQAKKRKTTQDVKKRREEVTKKHQYEIRNCWPPVLSGGISPCIIIETPHKEIGTSDFSRFTNYRFKNLFINPSPLPDLSWGCSKEVWLNMLKKESRYVHDKHFEVLHSDLEPQMRSILLDWLLEVCEVYTLHRETFYLAQDFFDRFMLTQKDINKNMLQLIGITSLFIASKLEEIYAPKLQEFAYVTDGACSEEDILRMELIILKALKWELCPVTIISWLNLFLQVDALKDAPKVLLPQYSQETFIQIAQLLDLCILAIDSLEFQYRILTAAALCHFTSIEVVKKASGLEWDSISECVDWMVPFVNVVKSTSPVKLKTFKKIPMEDRHNIQTHTNYLAMLEEVNYINTFRKGGQLSPVCNGGIMTPPKSTEKPPGKH

[0121] An exemplary sequence of human cyclin A2 is shown below:

[0122] SEQ ID NO:4 (UniProt accession number P20248)

[0123] MLGNSAPGPATREAGSALLALQQTALQEDQENINPEKAAPVQQPRTRAALAVLKSGNPRG

[0124] LAQQQRPKTRRVAPLKDLPVNDEHVTVPPWKANSKQPAFTIHVDEAEKEAQKKPAESQKI

[0125] EREDALAFNSAISLPGPRKPLVPLDYPMDGSFESPHTMDMSIILEDEKPVSVNEVPDYHE

[0126] DIHTYLREMEVKCKPKVGYMKKQPDITNSMRAILVDWLVEVGEEYKLQNETLHLAVNYID

[0127] RFLSSMSVLRGKLQLVGTAAMLLASKFEEIYPPEVAEFVYITDDTYTKKQVLRMEHLVLK

[0128] VLTFDLAAPTVNQFLTQYFLHQQPANCKVESLAMFLGELSLIDADPYLKYLPSVIAGAAF

[0129] HLALYTVTGQSWPESLIRKTGYTLESLKPCLMDLHQTYLKAPQHAQQSIREKYKNSKYHG

[0130] VSLLNPPETLNL

[0131] Compound of formula (A)

[0132] Provided herein are compounds of formula (A),

[0133]

[0134] or a pharmaceutically acceptable salt thereof, wherein:

[0135] R 1 For –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;

[0136] Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl or optionally substituted C3-C10 cycloalkyl;

[0137] X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -; or -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -;

[0138] a and b are independently 0, 1 or 2;

[0139] X 1 N or CR X1 ;

[0140] X 2N or CR X2 ;

[0141] CR X1 and CR X2 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;

[0142] 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 same as X 1 -X 2 The connection point of the ring;

[0143] R C is hydrogen or C1-C6 alkyl;

[0144] n is 0, 1 or 2;

[0145] Each R D and R E are independently hydrogen, fluorine or C1-C6 alkyl; and

[0146] R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl or optionally substituted 5-9 membered heterocyclyl.

[0147] Provided herein are compounds of formula (AI), or pharmaceutically acceptable salts thereof:

[0148]

[0149] or a pharmaceutically acceptable salt thereof, wherein:

[0150] R 1 For –NR A R B 、–C(=O)NR A R B 、–OC(=O)NR A R B or optionally substituted 5-10 membered heteroaryl;

[0151] Each R A and R Bare independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl or optionally substituted C3-C10 cycloalkyl;

[0152] X 1 N or CR X1 ;

[0153] X 2 N or CR X2 ;

[0154] R X1 and R X2 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;

[0155] 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 same as X 1 -X 2 The connection point of the ring;

[0156] R C is hydrogen or C1-C6 alkyl;

[0157] m is 0, 1 or 2;

[0158] n is 0, 1 or 2;

[0159] Each R D and R E are independently hydrogen, fluorine or C1-C6 alkyl; and

[0160] R 2 is optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl or optionally substituted 5-6-membered heterocyclyl.

[0161] In some embodiments, R 1 For –NR A R B .

[0162] In some embodiments, R 1 –C(=O)NR A R B .

[0163] In some embodiments, R1 = –OC(=O)NR A R B .

[0164] In some embodiments, R A and R B and R is independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl.

[0165] In some embodiments, R A and R B In some embodiments, R A and R B Each is hydrogen.

[0166] In some embodiments, R A and R B Each is an unsubstituted C1-C6 alkyl. A and R B Each is a substituted C1-C6 alkyl group.

[0167] In some embodiments, R A and R B Each is an unsubstituted C1-C6 haloalkyl. A and R B Each is a substituted C1-C6 haloalkyl group.

[0168] In some embodiments, R A and R B different.

[0169] In some embodiments, R A and R B One of them is hydrogen, and R A and R B The other of is unsubstituted C1-C6 alkyl. A and R B One of them is hydrogen, and R A and R B The other of is unsubstituted C1-C3 alkyl. A and R B One of them is hydrogen, and R A and R B The other one of them is methyl, ethyl or propyl.

[0170] In some embodiments, R A and R B One of them is hydrogen, and R A and RB The other of is unsubstituted C1-C6 haloalkyl. A and R B One of them is hydrogen, and R A and R B The other one of them is unsubstituted C1-C3 haloalkyl.

[0171] In some embodiments, R A and R B One of them is hydrogen, and R A and R B The other of is a substituted C1-C6 alkyl. A and R B One of them is hydrogen, and R A and R B The other of is C1-C6 alkyl substituted by 1-5 halogens. A and R B One of them is hydrogen, and R A and R B The other one is C1-C4 alkyl substituted by 1-3 halogens.

[0172] In some embodiments, R A and R B One of them is hydrogen, and R A and R B Another one of the group consisting of:

[0173]

[0174] In some embodiments, R A and R B One of them is hydrogen, and R A and R B The other of is substituted C1-C6 haloalkyl. A and R B One of them is hydrogen, and R A and R B The other of is C1-C6 haloalkyl having 1-5 halogens. A and R B One of them is hydrogen, and R A and R B The other one of the above is C1-C4 haloalkyl having 1 to 3 halogens.

[0175] In some embodiments, R A and R B One of them is hydrogen, and RA and R B Another one of the group consisting of:

[0176]

[0177] In some embodiments, R A and R B One of them is hydrogen, and R A and R B The other of is a C3-C10 cycloalkyl group optionally substituted with a C1-C6 alkyl group. A and R B One of them is hydrogen, and R A and R B The other of is C3-C6 cycloalkyl substituted by C1-C6 alkyl. A and R B One of them is hydrogen, and R A and R B The other of is C3-C4 cycloalkyl optionally substituted with C1-C3 alkyl. A and R B One of them is hydrogen, and R A and R B The other of is C3-C4 cycloalkyl substituted by C1-C3 alkyl. A and R B One of them is hydrogen, and R A and R B The other one is

[0178] In some embodiments, R A and R B One of them is hydrogen, and R A and R B The other of is unsubstituted C3-C10 cycloalkyl. A and R B One of them is hydrogen, and R A and R B The other of is unsubstituted C3-C7 cycloalkyl. A and R B One of them is hydrogen, and R A and R B The other of is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R A and R B One of them is hydrogen, and R A and RB The other one is unsubstituted cyclopropyl.

[0179] In some embodiments, R 1 is an optionally substituted 5-10 membered heteroaryloxy. 1 is a substituted 5-10 membered heteroaryloxy. 1 is an optionally monosubstituted 5-10 membered heteroaryloxy. 1 is an optionally disubstituted 5-10 membered heteroaryloxy. 1 is an optionally trisubstituted 5-10 membered heteroaryloxy. 1 is a substituted 5-10 membered heteroaryloxy. 1 is a monosubstituted 5-10 membered heteroaryloxy. 1 is a disubstituted 5-10 membered heteroaryloxy. 1 is a trisubstituted 5-10 membered heteroaryloxy. 1 The 5-10 membered heteroaryloxy is substituted with one or more independently selected C1-C6 alkyl groups (e.g., isopropyl and / or tert-butyl). 1 The 5-10 membered heteroaryloxy is substituted with one or more independently selected C2-C6 alkenyl (e.g., isopropenyl). 1 The 5-10 membered heteroaryloxy is substituted by one or more independently selected C3-C6 cycloalkyl groups, which are optionally substituted by optionally substituted C1-C6 alkyl groups. 1 The 5-10 membered heteroaryloxy group is For example, R 1 The 5-10 membered heteroaryloxy group is In some embodiments, R 1 is an unsubstituted 5-10 membered heteroaryloxy group. 1 The 5-10 membered heteroaryloxy of is a 5-6 membered heteroaryloxy. 1 The 5-10 membered heteroaryloxy is isothiazolyl, pyridyl or 1,3,4-triazolyl.

[0180] In some embodiments, R 1 is an optionally substituted 5-10 membered heteroaryl. 1 is an unsubstituted 5-10 membered heteroaryl. 1is a substituted 5-10 membered heteroaryl. 1 is an optionally substituted 5-6 membered heteroaryl. 1 is an optionally substituted 5-6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl. In some embodiments, R 1 is an unsubstituted 5-6 membered heteroaryl group selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl and thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl.

[0181] In some embodiments, R 2 is an optionally substituted 5-10 membered heteroaryl group.

[0182] In some embodiments, R 2 is an optionally substituted 5-6 membered heteroaryl group.

[0183] In some embodiments, R 2 is an optionally substituted 5-membered heteroaryl. 2 is an unsubstituted 5-membered heteroaryl. 2 is a substituted 5-membered heteroaryl. 2 The 5-membered heteroaryl of is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl or 1,2,5-oxadiazolyl. 2 The 5-membered heteroaryl group is pyrazol-5-yl.

[0184] In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl. 2 is an unsubstituted 6-membered heteroaryl. 2 is a substituted 6-membered heteroaryl. 2 The 6-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0185] In some embodiments, R 2 is an optionally substituted 9-10 membered heteroaryl. 2 is a substituted 9-10 membered heteroaryl. 2is an unsubstituted 9-10 membered heteroaryl. 2 The 9-10 membered heteroaryl is pyrido[2,3-d]pyrimidine, imidazo[1,2-c]pyrimidine, imidazo[1,2-b]pyridazine, thiazo[5,4-c]pyridine, quinoline, pyrazolo[1,5-a]pyrazine or pyrazolo[1,5-a]pyridine.

[0186] In some embodiments, R 2 is an optionally substituted 5-9 membered heterocyclic group.

[0187] In some embodiments, R 2 is an optionally substituted 5-6 membered heterocyclic group.

[0188] In some embodiments, R 2 is an optionally substituted 5-membered heterocyclyl. 2 is an unsubstituted 5-membered heterocyclic group. 2 is a substituted 5-membered heterocyclyl. 2 The 5-membered heterocyclic group is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidonyl, pyrazolidinyl, imidazolinyl, dioxolane, sulfolane, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinone, hydantoin, thiohydantoin, imidazolidinone, oxazolidinone, thiazolidinone, oxathiolanone, dioxolanone, dioxazolidinone, oxadiazolidinone, triazolidinone, triazolidinethione, oxadiazolidinone, dioxazolidinone, dioxolanonethione, oxazolidinone, imidazolidinone and isothiazolidinone.

[0189] In some embodiments, R 2 is an optionally substituted 6-membered heterocyclyl. 2 is an unsubstituted 6-membered heterocyclic group. 2 is a substituted 6-membered heterocyclyl. 2The 6-membered heterocyclic group of R is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidonyl, piperidinedione, oxazinanedione, dihydropyrimidinedione, tetrahydropyridazinone, triazinanedione, oxadiazinanedione, dioxazinanedione, morpholinedione, piperazinedione, piperazinetrione and triazinanedione. In some embodiments, R 2 It is piperidin-4-yl.

[0190] In some embodiments, R 2 is an optionally substituted 9-membered heterocyclyl. 2 is a substituted 9-membered heterocyclyl. 2 is an unsubstituted 9-membered heterocyclic group. 2 The 9-membered heterocyclic group is 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.

[0191] In some embodiments, R 2 is an optionally substituted phenyl. 2 is unsubstituted phenyl. In some embodiments, R 2 In some embodiments, R 2 is a monosubstituted phenyl. 2 It is a disubstituted phenyl group.

[0192] In some embodiments, R 2 The group is substituted with 1 to 3 substituents selected from the group consisting of: -SO 2 NH 2 , -F, cyano, -CH 2 OMe, -CO 2 NH 2 , methyl, -CH 2 OCF 3 , pyrazolyl optionally substituted by 1-2 methyl groups, pyrazolyl optionally substituted by 1-2 substituents selected from methyl and isopropoxymethyl, 1,2,4-triazolyl optionally substituted by 1-2 methyl groups, and tetrazolyl optionally substituted by 1-2 methyl groups.

[0193] In some embodiments, R 2 The group is substituted with an optionally substituted 5-10 membered heteroaryl. 2 The group is substituted with an unsubstituted 5-10 membered heteroaryl. 2The group is substituted with a substituted 5-10 membered heteroaryl. 2 The group is substituted with a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is substituted with 1 to 3 substituents selected from the group consisting of a C1-C6 alkyl group and a C1-C6 haloalkyl group.

[0194] In some embodiments, R 2 The group is substituted with 1 to 3 substituents selected from the group consisting of: -SO 2 NH 2 、-F、-CH 2 OMe and -CO 2 NH 2 .

[0195] In some embodiments, R 2 The group is substituted by 1 to 3 substituents, one of which is -(SO 2 )NR'R", wherein 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.

[0196] In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is unsubstituted C1-C6 alkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is unsubstituted C1-C3 alkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is methyl, ethyl, or propyl.

[0197] In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is substituted C1-C6 alkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is C1-C6 alkyl substituted with 1-5 halogens. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is C1-C4 alkyl substituted with 1-3 halogens.

[0198] In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is unsubstituted C1-C6 alkoxy. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is unsubstituted C1-C3 alkoxy.

[0199] In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is a substituted C1-C6 alkoxy. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is a C1-C6 alkoxy substituted with 1-5 halogens. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is a C1-C4 alkoxy substituted with 1-3 halogens.

[0200] In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is C3-C10 cycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is C3-C6 cycloalkyl substituted with 1-3 halogens.

[0201] In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is unsubstituted C3-C10 cycloalkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is unsubstituted C3-C7 cycloalkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is unsubstituted cyclopropyl.

[0202] In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an optionally substituted 5-10 membered heteroaryl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an unsubstituted 5-10 membered heteroaryl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is a substituted 5-10 membered heteroaryl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an optionally substituted 5-6 membered heteroaryl substituted with an optionally substituted C1-C6 alkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an optionally substituted 5-6 membered heteroaryl substituted with a C1-C6 alkyl.

[0203] In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an optionally substituted 5-9 membered heterocyclyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an unsubstituted 5-9 membered heterocyclyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is a substituted 5-9 membered heterocyclyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an optionally substituted 5-6 membered heterocyclyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an optionally substituted 5-6 membered heterocyclyl substituted with an optionally substituted C1-C6 alkyl. In some embodiments, one of R' and R" is hydrogen, and the other of R' and R" is an optionally substituted 5-6 membered heterocyclyl substituted with a C1-C6 alkyl.

[0204] In some embodiments, R 2 The group is substituted by 1 to 3 substituents, one of which is -(SO 2 )R', wherein 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.

[0205] In some embodiments, R' is an unsubstituted C1-C6 alkyl. In some embodiments, R' is an unsubstituted C1-C3 alkyl. In some embodiments, R' is methyl, ethyl or propyl.

[0206] 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.

[0207] In some embodiments, R' is an unsubstituted C1-C6 alkoxy group. In some embodiments, R' is an unsubstituted C1-C3 alkoxy group.

[0208] 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.

[0209] In some embodiments, R' is a C3-C10 cycloalkyl optionally substituted by a C1-C6 alkyl. In some embodiments, R' is a C3-C6 cycloalkyl substituted by a C1-C6 alkyl. In some embodiments, R' is a C3-C6 cycloalkyl substituted by 1-3 halogens.

[0210] In some embodiments, R' is an unsubstituted C3-C10 cycloalkyl. In some embodiments, R' is an unsubstituted C3-C7 cycloalkyl. In some embodiments, R' is an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R' is an unsubstituted cyclopropyl.

[0211] 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.

[0212] 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.

[0213] In some embodiments, R 2 The group is replaced by a -SO 2 NH 2 and a –F substitution.

[0214] In some embodiments, R 2 The group is replaced by a -SO 2 NH 2 replace.

[0215] In some embodiments, R 2 The group is replaced by a –(SO 2 ) is substituted with C3-C6 cycloalkyl. In some embodiments, R 2 The group is a replace.

[0216] In some embodiments, R 2 The group is replaced by a –(SO 2 )NHC3-C6 cycloalkylCF3 substituted. In some embodiments, R 2 The group is a replace.

[0217] In some embodiments, R 2 The group is substituted with a -(C=O)C1-C6 alkyl. 2 The group is replaced by a –(C=O)CH 3 replace.

[0218] In some embodiments, R 2 The group is substituted with a -(C=O)C3-C6 cycloalkyl group.

[0219] In some embodiments, R 2 The group is replaced by a –(C=O)NH 2 replace.

[0220] In some embodiments, R 2 The group is replaced by a –NH(SO 2 ) is substituted with C1-C6 alkyl. In some embodiments, R 2 The group is replaced by a –NH(SO 2 ) is substituted with C1-C3 alkyl. In some embodiments, R 2 The group is a replace.

[0221] In some embodiments, R 2 The group is replaced by a –NH(SO 2 )-optionally substituted C3-C8 cycloalkyl. In some embodiments, R 2 The group is replaced by a –NH(SO 2 )- optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2 The group is replaced by a –NH(SO 2 ) is substituted with C3-C6 cycloalkyl. In some embodiments, R 2 The group is replaced by a –NH(SO 2 )-substituted C3-C6 cycloalkyl. In some embodiments, R 2 The group is replaced by a –NH(SO 2 )-halogen-substituted C3-C6 cycloalkyl. In some embodiments, R 2 The group is replaced by a –NH(SO 2 )-fluoro-substituted C3-C6 cycloalkyl.

[0222] In some embodiments, R 2 The group is replaced by a –(S(=NR L )(=O))C1-C6 alkyl substituted, wherein R L is H or a C1-C6 alkyl group optionally substituted with a hydroxyl group.2 The group is replaced by a –(S(=NR L )(=O))C1-C3 alkyl substituted, wherein R L is H or a C1-C6 alkyl group optionally substituted with a hydroxyl group. 2 The group is a Substitution, where R L is H or a C1-C6 alkyl group optionally substituted by a hydroxy group.

[0223] In some embodiments, R 2 The group is replaced by a –(S(=NR L )(=O))C1-C6 haloalkyl substituted, wherein R L is H or a C1-C6 alkyl group optionally substituted with a hydroxyl group. 2 The group is replaced by a –(S(=NR L )(=O))C1-C3 haloalkyl substituted, wherein R L is H or a C1-C6 alkyl group optionally substituted with a hydroxyl group. 2 The group is a Substitution, where R L is H or a C1-C6 alkyl group optionally substituted by a hydroxy group.

[0224] In some embodiments, R 2 The group is replaced by a –(S(=NR L )(=O))C3-C6 cycloalkyl substitution. In some embodiments, R 2 The group is a Substitution, where R L is H or a C1-C6 alkyl group optionally substituted with a hydroxyl group. L In some embodiments, R L is a C1-C6 alkyl group optionally substituted with a hydroxyl group. L is a C1-C3 alkyl group optionally substituted with a hydroxyl group. L for In some embodiments, R L is an unsubstituted C1-C6 alkyl. L It is methyl.

[0225] In some embodiments, R 2 The group is substituted with a substituent selected from the group consisting of:

[0226]

[0227] In some embodiments, R 2 The group is replaced by a -(SO 2 )NR H R I Substitution, where R H and R I R is independently H and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. 2 The group is replaced by a -(SO 2 )NR H R I Substitution, where R H and R I One of the R is H and the other is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. 2 The group is replaced by a -(SO 2 )NR H R I Substitution, where R H and R I One of is H and the other is C1-C6 alkyl. In some embodiments, R 2 The group is replaced by a -(SO 2 )NR H R I Substitution, where R H and R I One of the R is H and the other is a C1-C6 alkyl substituted with a hydroxyl group. 2 The group is a Substitution, i.e. R H and R I Each is hydrogen.

[0228] In some embodiments, R 2 The group is substituted with one selected from the group consisting of:

[0229]

[0230] In some embodiments, X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0231] In some embodiments, X is -(CH 2 ) aC3-C8 cycloalkylene-(CH 2 ) b -.

[0232] In some embodiments, X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0233] In some embodiments, X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0234] In some embodiments, X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0235] In some embodiments, X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0236] In some embodiments, X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0237] In some embodiments, X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0238] In some embodiments, X is -(CH2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0239] In some embodiments, X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0240] In some embodiments, X is unsubstituted -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

[0241] In some embodiments, X's -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -for–(CH 2 ) a C4-C6 cycloalkylene-(CH 2 ) b -.

[0242] In some embodiments, X's -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b - is cyclopentylene.

[0243] In some embodiments, X is -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

[0244] In some embodiments, X is -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

[0245] In some embodiments, X is -(CH 2 ) aC5-C8 cycloalkenylene-(CH 2 ) b -.

[0246] In some embodiments, X is -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

[0247] In some embodiments, X is substituted with 2 substituents independently selected from halogen and C1-C6 alkyl. 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

[0248] In some embodiments, X is -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

[0249] In some embodiments, X is unsubstituted -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

[0250] In some embodiments, X is -(CH 2 ) a Phenylene-(CH 2 ) b -.

[0251] In some embodiments, X is -(CH 2 ) a (4-8 membered heteroarylene)-(CH 2 ) b -

[0252] In some embodiments, X is -(CH 2 ) a (4-8 membered heterocyclylene)-(CH 2 ) b -

[0253] In some embodiments, X is C2-C6 alkylene.

[0254] In some embodiments, X is C2-C4 alkylene.

[0255] In some embodiments, X is

[0256]

[0257] In some embodiments, X is

[0258] In some embodiments, X is

[0259] In some embodiments, X is

[0260] In some embodiments, X is

[0261] In some embodiments, X is

[0262] In some embodiments, X is

[0263] In some embodiments, X is

[0264] In some embodiments, X is

[0265] In some embodiments, X is

[0266] In some embodiments, X is

[0267] In some embodiments, X is

[0268] In some embodiments, X is

[0269] In some embodiments, X is

[0270] In some embodiments, X is

[0271] In some embodiments, when attached to (CH 2 ) a of –(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -When the ring member of the cycloalkylene is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when attached to (CH2 ) a of –(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b When the ring member of the cycloalkylene group of - is a stereocenter, the stereochemical configuration of the stereocenter is (S).

[0272] In some embodiments, when attached to (CH 2 ) b of –(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -When the ring member of the cycloalkylene is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when attached to (CH 2 ) b of –(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b When the ring member of the cycloalkylene group of - is a stereocenter, the stereochemical configuration of the stereocenter is (S).

[0273] In some embodiments, when attached to (CH 2 ) a of –(CH 2 ) a C3-C8 cycloalkenylene-(CH 2 ) b -cycloalkenylene ring member is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when attached to (CH 2 ) a of –(CH 2 ) a C3-C8 cycloalkenylene-(CH 2 ) b When the ring member of the cycloalkenylene of - is a stereocenter, the stereochemical configuration of the stereocenter is (S).

[0274] In some embodiments, when attached to (CH 2 ) b of –(CH 2 ) a C3-C8 cycloalkenylene-(CH 2 ) b -cycloalkenylene ring member is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when attached to (CH 2 ) bof –(CH 2 ) a C3-C8 cycloalkenylene-(CH 2 ) b When the ring member of the cycloalkenylene of - is a stereocenter, the stereochemical configuration of the stereocenter is (S).

[0275] In some embodiments, when attached to (CH 2 ) b of –(CH 2 ) a C3-C8 heterocyclylene-(CH 2 ) b -When the ring member of the heterocyclylene is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when attached to (CH 2 ) b of –(CH 2 ) a C3-C8 heterocyclylene-(CH 2 ) b When the ring member of the heterocyclylene group of - is a stereocenter, the stereochemical configuration of the stereocenter is (S).

[0276] 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.

[0277] 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.

[0278] 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.

[0279] In some embodiments, X 1 CR X1 .

[0280] In some embodiments, X 2 CR X2 In some embodiments, R X1is C1-C6 alkyl. X1 In some embodiments, R X1 is C1-C6 alkoxy. X1 In some embodiments, R X1 is C1-C6 haloalkyl. X1 In some embodiments, R X1 is C1-C6 haloalkoxy. In some embodiments, wherein R X1 It is trifluoromethoxy.

[0281] In some embodiments, R X1 is a C3-C6 cycloalkyl group. X1 In some embodiments, R X1 is C3-C6 cycloalkoxy. X1 In some embodiments, R X1 In some embodiments, R X1 In some embodiments, R X1 For hydrogen.

[0282] In some embodiments, R X2 is C1-C6 alkyl. X2 In some embodiments, R X2 is C1-C6 alkoxy. X2 In some embodiments, R X2 is C1-C6 haloalkyl. X2 In some embodiments, R X2 is C1-C6 haloalkoxy. X2 In some embodiments, R X2 is a C3-C6 cycloalkyl group. X2 In some embodiments, R X2 is C3-C6 cycloalkoxy. X2 In some embodiments, R X2 In some embodiments, R X2 In some embodiments, R X2 For hydrogen.

[0283] In some embodiments, X 1 is N.

[0284] In some embodiments, X 2 is N.

[0285] In some embodiments, X 1 is N and X 2 is N.

[0286] In some embodiments, Y is *—C(═O)NR C (CR D R E ) n –, where * indicates 1 -X 2 The connection point of the ring.

[0287] In some embodiments, Y is *—NR C C(=O)(CR D R E ) n –, where * indicates 1 -X 2 The connection point of the ring.

[0288] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0289] In some embodiments, each R D and R E In some embodiments, except for R D and R E Except for one difference in each R D and R E same.

[0290] In some embodiments, each R D and R E For hydrogen.

[0291] In some embodiments, each R D and R E For fluorine.

[0292] In some embodiments, R D and R E It is methyl.

[0293] In some embodiments, R D and R E One of them is methyl or fluorine, and the other R D and R E For hydrogen.

[0294] In some embodiments, Y is -NR C –.

[0295] In some embodiments, R C It is a C1-C6 alkyl group.

[0296] In some embodiments, R C It is methyl.

[0297] In some embodiments, R C For hydrogen.

[0298] In some embodiments, Y is —O—.

[0299] In some embodiments, m is 0.

[0300] In some embodiments, m is 1.

[0301] In some embodiments, m is 2.

[0302] In some embodiments, R 2 is an optionally substituted 5-6 membered heteroaryl group.

[0303] In some embodiments, R 2 is an optionally substituted 5-membered heteroaryl group.

[0304] In some embodiments, R 2 is an unsubstituted 5-membered heteroaryl group.

[0305] In some embodiments, R 2 is a substituted 5-membered heteroaryl.

[0306] In some embodiments, R 2 The 5-membered heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl or 1,2,5-oxadiazolyl.

[0307] In some embodiments, R 2 is an optionally substituted 6-membered heteroaryl group.

[0308] In some embodiments, R 2 It is an unsubstituted 6-membered heteroaryl group.

[0309] In some embodiments, R 2 is a substituted 6-membered heteroaryl.

[0310] In some embodiments, R 2 The 6-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0311] In some embodiments, R 2 is an optionally substituted 5-6 membered heterocyclic group.

[0312] In some embodiments, R2 is an optionally substituted 5-membered heterocyclic group.

[0313] In some embodiments, R 2 It is an unsubstituted 5-membered heterocyclic group.

[0314] In some embodiments, R 2 It is a substituted 5-membered heterocyclic group.

[0315] In some embodiments, R 2 The 5-membered heterocyclic group is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolane, thiazolidinedione, succinimidyl, dihydrofuranonyl, pyrazolidinone, oxazolidinyl, isoxazolidinone, hydantoinyl, thiohydantoinyl, imidazolidinone, oxazolidinone, thiazolidinone, oxathiolanyl, dioxolanone, dioxazolidinone, oxadiazolidinone, triazolidinone, triazolidinethione, oxadiazolidinone, dioxazolidinone, dioxolanone, oxazolidinone, imidazolidinone and isothiazolidinone.

[0316] In some embodiments, R 2 is an optionally substituted 6-membered heterocyclic group.

[0317] In some embodiments, R 2 It is an unsubstituted 6-membered heterocyclic group.

[0318] In some embodiments, R 2 It is a substituted 6-membered heterocyclic group.

[0319] In some embodiments, R 2 The 6-membered heterocyclic group is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidonyl, piperidinedione, oxazinanedione, dihydropyrimidinedione, tetrahydropyridazinone, triazinanedione, oxadiazinanedione, dioxazinanedione, morpholinedione, piperazinedione, piperazinetrione and triazinanedione.

[0320] In some embodiments, R 2 is optionally substituted phenyl.

[0321] In some embodiments, R 2 It is an unsubstituted phenyl group.

[0322] In some embodiments, R2 In some embodiments, R 2 is a monosubstituted phenyl. 2 It is a disubstituted phenyl group.

[0323] In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof is a compound of formula (AA):

[0324]

[0325] or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof is a compound of formula (AA1):

[0327]

[0328] or a pharmaceutically acceptable salt thereof.

[0329] Also provided herein are compounds of formula (B),

[0330]

[0331] or a pharmaceutically acceptable salt thereof, wherein:

[0332] R 1 For –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;

[0333] Each R A and R B are independently hydrogen, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl;

[0334] X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -; optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl -(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;

[0335] a and b are independently 0, 1 or 2;

[0336] Ring A is an optionally substituted 6-membered heteroaryl group other than pyridyl and pyrimidinyl, or an optionally substituted 9-10-membered heteroaryl group;

[0337] 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 ring A;

[0338] R C is hydrogen or C1-C6 alkyl;

[0339] n is 0, 1 or 2;

[0340] Each R D and R E are independently hydrogen, fluorine or C1-C6 alkyl; and

[0341] R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl or optionally substituted 5-9 membered heterocyclyl.

[0342] 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 above in formula (A).

[0343] In some embodiments, ring A is an optionally substituted 6-membered heteroaryl other than pyridyl and pyrimidyl. In some embodiments, ring A is a substituted 6-membered heteroaryl other than pyridyl and pyrimidyl. In some embodiments, ring A is an unsubstituted 6-membered heteroaryl other than pyridyl and pyrimidyl. In some embodiments, ring A is pyrazinyl. In some embodiments, ring A is pyrazinonyl. In some embodiments, ring A is pyridazinyl.

[0344] 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 9-10 membered heteroaryl is pyrido [2,3-d] pyrimidine, quinazoline, octylline, isoquinolin-1 (2H) -one, quinolin-2 (1H) -one, imidazo [1,2-c] pyrimidine, imidazo [1,2-b] pyridazine, thiazo [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 9 membered heteroaryl. In some embodiments, the 9-10 membered heteroaryl is pyrrolo[1,2-a]pyrazine.

[0345] Provided herein are compounds of formula (BI) or (B-II), or pharmaceutically acceptable salts thereof:

[0346]

[0347] in:

[0348] R 1 For –NR A R B 、–C(=O)NR A R B 、–OC(=O)NR A R B or optionally substituted 5-10 membered heteroaryl;

[0349] Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl or optionally substituted C3-C10 cycloalkyl;

[0350] X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b-; optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl -(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;

[0351] a and b are independently 0, 1 or 2;

[0352] 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;

[0353] R C is hydrogen or C1-C6 alkyl;

[0354] n is 0, 1 or 2;

[0355] Each R D and R E are independently hydrogen, fluorine or C1-C6 alkyl; and

[0356] R 2 is optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl or optionally substituted 5-6-membered heterocyclyl.

[0357] Provided herein are compounds of formula (B-IIIA), (B-IIIB), (B-IVA), or (B-IVA), or pharmaceutically acceptable salts thereof:

[0358]

[0359]

[0360] in:

[0361] R 1 For –NR A R B 、–C(=O)NR A R B 、–OC(=O)NR A R B or optionally substituted 5-10 membered heteroaryl;

[0362] Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl or optionally substituted C3-C10 cycloalkyl;

[0363] X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -; optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl -(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;

[0364] a and b are independently 0, 1 or 2;

[0365] 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;

[0366] R Cis hydrogen or C1-C6 alkyl;

[0367] n is 0, 1 or 2;

[0368] Each R D and R E are independently hydrogen, fluorine or C1-C6 alkyl; and

[0369] R 2 is optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl or optionally substituted 5-6-membered heterocyclyl.

[0370] Provided herein are compounds of formula (BV) or pharmaceutically acceptable salts thereof:

[0371]

[0372] in:

[0373] R 1 For –NR A R B 、–C(=O)NR A R B 、–OC(=O)NR A R B or optionally substituted 5-10 membered heteroaryl;

[0374] Each R A and R B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl or optionally substituted C3-C10 cycloalkyl;

[0375] X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -; optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl -(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-(CH2 ) b -; and C2-C6 alkylene;

[0376] a and b are independently 0, 1 or 2;

[0377] 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;

[0378] R C is hydrogen or C1-C6 alkyl;

[0379] n is 0, 1 or 2;

[0380] Each R D and R E are independently hydrogen, fluorine or C1-C6 alkyl; and

[0381] R 2 is optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl or optionally substituted 5-6-membered heterocyclyl.

[0382] In some embodiments, the compound of formula (A) is selected from the group consisting of compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0383] Table 1: Exemplary compounds of formula (A)

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492] Treatment

[0493] Some embodiments provide a method for treating cancer (e.g., 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 or a pharmaceutical composition thereof. For example, provided herein is a method for treating a subject in need thereof CDK2-related cancer, comprising a) detecting a disorder of expression or activity or level of a CDK2 gene, a CDK2 protein, or any one thereof 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.

[0494] In some embodiments, the subject has been identified or diagnosed as having a cancer with a disordered expression or activity or level of a CDK2 gene, a CDK2 protein, or any thereof (a CDK2-associated cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, such as FDA). In some embodiments, the subject has been identified or diagnosed as having a cancer with a disordered expression or activity or level of a cyclin A2 gene, a cyclin A2 protein, or any thereof (a CDK2-associated cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, such as FDA). In some embodiments, the subject has been identified or diagnosed as having a cancer with a disordered expression or activity or level of a cyclin E1 gene, a cyclin E1 protein, or any thereof (a CDK2-associated cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, such as FDA). In some embodiments, the subject has been identified or diagnosed as having a cancer with a disordered expression or activity or level of a cyclin E2 gene, a cyclin E2 protein, or any thereof (a CDK2-associated cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, such as FDA). In some embodiments, the subject has been identified or diagnosed as having a cancer in which the expression or activity or level 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) is dysregulated.

[0495] In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or levels of a CDK2 gene, CDK2 protein, or any thereof (e.g., determined using an assay or kit approved by a regulatory agency, such as the FDA). The subject may be a subject having a tumor that is positive for dysregulated expression or activity or levels of a CDK2 gene, CDK2 protein, or any thereof (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as the FDA). The subject may be a subject whose tumor has dysregulated expression or activity or levels of a CDK2 gene, CDK2 protein, or any thereof (e.g., where the tumor is identified as such using an assay or kit approved by a regulatory agency, such as the FDA).

[0496] In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or levels of a cyclin A2 gene, a cyclin A2 protein, or any thereof (e.g., determined using an assay or kit approved by a regulatory agency, such as the FDA). The subject may be a subject having a tumor that is positive for dysregulated expression or activity or levels of a cyclin A2 gene, a cyclin A2 protein, or any thereof (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as the FDA). The subject may be a subject whose tumor has dysregulated expression or activity or levels of a cyclin A2 gene, a cyclin A2 protein, or any thereof (e.g., where the tumor is identified as such using an assay or kit approved by a regulatory agency, such as the FDA).

[0497] In some embodiments, the subject has a tumor that is positive for cyclin E1 gene, cyclin E1 protein, or any of them, expression or activity or level disorder (e.g., determined using an assay or kit approved by a regulatory agency, such as FDA). The subject may be a subject with a tumor that is positive for cyclin E1 gene, cyclin E1 protein, or any of them, expression or activity or level disorder (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as FDA). The subject may be a subject whose tumor has cyclin E1 gene, cyclin E1 protein, or any of them, expression or activity or level disorder (e.g., where the tumor is identified as such using an assay or kit approved by a regulatory agency, such as FDA).

[0498] In some embodiments, the subject has a tumor that is positive for cyclin E2 gene, cyclin E2 protein, or any of them with expression or activity or level disorder (e.g., determined using an assay or kit approved by a regulatory agency, such as FDA). The subject may be a subject with a tumor that is positive for cyclin E2 gene, cyclin E2 protein, or any of them with expression or activity or level disorder (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as FDA). The subject may be a subject whose tumor has cyclin E2 gene, cyclin E2 protein, or any of them with expression or activity or level disorder (e.g., where the tumor is identified as such using an assay or kit approved by a regulatory agency, such as FDA).

[0499] In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level 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).

[0500] In some embodiments, imbalance can be the imbalance that causes the expression or activity or abnormal activation of gene, protein or any one thereof.Activation can be carried out by any suitable mechanism, including but not limited to the overexpression of gene amplification, activating mutation, activating translocation, transcriptional activation, epigenetic change and / or oncogene protein product.In some embodiments, imbalance can be the imbalance that causes the expression or activity or abnormal inactivation of gene, protein or any one thereof.Inactivation can be carried out by any suitable mechanism, including but not limited to the degradation of mRNA and / or protein product of gene, including but not limited to gene deletion, inactivating mutation, inactivating translocation, transcriptional silencing, epigenetic change and gene.Generally, as used herein, imbalance can cause the abnormality in cell cycle.

[0501] In some embodiments, the subject is suspected of having a CDK2-related cancer.

[0502] In some embodiments, the subject's clinical record indicates that the subject suffers from a tumor with an unregulated expression or activity or level of a CDK2 gene, a CDK2 protein, or any thereof (and optionally, the clinical record indicates that the subject is treated with any of the compositions provided herein). In some embodiments, the subject's clinical record indicates that the subject suffers from a tumor with an unregulated expression or activity or level of a cyclin A2 gene, a cyclin A2 protein, or any thereof (and optionally, the clinical record indicates that the subject is treated with any of the compositions provided herein). In some embodiments, the subject's clinical record indicates that the subject suffers from a tumor with an unregulated expression or activity or level of a cyclin E1 gene, a cyclin E1 protein, or any thereof (and optionally, the clinical record indicates that the subject is treated with any of the compositions provided herein). In some embodiments, the subject's clinical record indicates that the subject suffers from a tumor with an unregulated expression or activity or level of a cyclin E2 gene, a cyclin E2 protein, or any thereof (and optionally, the clinical record indicates that the subject is treated with any of the compositions provided herein). In some embodiments, the subject's clinical record indicates that the subject has a tumor in which the expression or activity or level 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 is dysregulated (or any combination thereof).

[0503] In some embodiments, the subject has been identified or diagnosed as having cancer, and the cancer is determined to be associated with a dysregulated expression or activity or level of a CDK2 gene, a CDK2 protein, or any of them based on histological examination (CDK2-associated cancer). In some embodiments, the subject has been identified or diagnosed as having cancer, and the cancer is determined to be associated with a dysregulated expression or activity or level of a cyclin A2 gene, a cyclin A2 protein, or any of them based on histological examination (CDK2-associated cancer). In some embodiments, the subject has been identified or diagnosed as having cancer, and the cancer is determined to be associated with a dysregulated expression or activity or level of a cyclin E1 gene, a cyclin E1 protein, or any of them based on histological examination (CDK2-associated cancer). In some embodiments, the subject has been identified or diagnosed as having cancer, and the cancer is determined to be associated with a dysregulated expression or activity or level of a cyclin E2 gene, a cyclin E2 protein, or any of them based on histological examination (CDK2-associated cancer). In some embodiments, the subject has been identified or diagnosed as having a cancer that is determined, based on histological examination, to be associated with 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).

[0504] In some embodiments, the subject's clinical record indicates that the subject has a tumor that is resistant to one or more prior therapies, e.g., resistant to a CDK4 / CDK6 inhibitor. In some embodiments, the subject has a cancer that is resistant to one or more prior therapies, e.g., resistant to CDK4 / CDK6 inhibition.

[0505] In some embodiments, the subject has a tumor that is resistant to one or more prior therapies, e.g., resistant to CDK4 / CDK6 inhibition. In some embodiments, the subject has a tumor that is suspected of being resistant to one or more prior therapies, e.g., resistant to CDK4 / CDK6 inhibition.

[0506] In some embodiments, the cancer (e.g., a CDK2-associated cancer) is a pediatric tumor (e.g., neuroblastoma), a brain tumor (e.g., glioblastoma), a sarcoma, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, 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.

[0507] In some embodiments, the cancer (e.g., CDK2-related cancer) is a solid tumor. In some embodiments, the cancer (e.g., CDK2-related cancer) is a pediatric tumor (e.g., neuroblastoma). In some embodiments, the cancer (e.g., CDK2-related cancer) is a brain tumor (e.g., glioblastoma).

[0508] In some embodiments, the cancer (eg, a CDK2-related cancer) is a sarcoma.

[0509] In some embodiments, cancer (e.g., CDK2-related cancer) is colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, 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, cancer (e.g., CDK2-related cancer) is small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, renal cell carcinoma, hepatocellular carcinoma, gastric cancer or melanoma, cholangiocarcinoma.

[0510] In some embodiments, the cancer (eg, a CDK2-related 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.

[0511] In some embodiments, the cancer (eg, a CDK2-related cancer) is selected from the group consisting of breast cancer, ovarian cancer, and colorectal cancer.

[0512] In some embodiments, the cancer (eg, a CDK2-related cancer) is colorectal cancer.

[0513] In some embodiments, the cancer (eg, a CDK2-related cancer) is selected from the group consisting of breast cancer and ovarian cancer.

[0514] In some embodiments, the cancer (eg, a CDK2-related cancer) is ovarian cancer.

[0515] In some embodiments, the cancer (eg, a CDK2-related cancer) is breast cancer.

[0516] In some embodiments, the cancer (e.g., a CDK2-related 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.

[0517] In some embodiments, cancer (e.g., CDK2-related cancer) is breast cancer selected from the group consisting of endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, and breast cancer showing primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, breast cancer is advanced breast cancer, metastatic breast cancer, or completely resected breast cancer.

[0518] As used herein, the term "resection" or "resected" means surgically removing malignant tissue having cancer characteristics (e.g., any cancer type described herein, such as a solid tumor) from a patient. According to one embodiment, resection means removing malignant tissue such that the presence of residual malignant tissue in the patient cannot be detected by available methods. According to another embodiment of the invention, resection means removing breast cancer such that the presence of residual cancer in the patient cannot be detected.

[0519] In some embodiments, the cancer (eg, CDK2-related cancer) is a cancer that has been resected. In some embodiments, the cancer (eg, CDK2-related cancer) is a breast cancer that has been resected.

[0520] In some embodiments, the compound of formula (A) is administered to the subject as an adjuvant therapy. Adjuvant therapy is a treatment other than primary therapy, the purpose of which is to kill any cancer cells that may have spread, even if radioactivity or laboratory tests cannot detect the spread. See, for example, 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, the compound of formula (A) is administered to the subject as an adjuvant therapy for cancer, wherein the cancer (e.g., CDK2-related 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.

[0521] In some embodiments, the cancer (e.g., CDK2-related cancer) is a blood cancer, which may also be referred to as a hematopoietic cancer or a blood cancer or a malignancy. In some embodiments, the blood cancer is a leukemia, such as acute lymphocytic leukemia (ALL; e.g., B-cell ALL or T-cell ALL), acute myeloid leukemia (AML), chronic myeloid 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).

[0522] In some embodiments, the blood cancer is a lymphoma, such as Hodgkin's lymphoma (HL; e.g., B-cell HL or T-cell HL), non-Hodgkin's lymphoma (NHL, which can 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) (such as B-cell lymphoma (e.g., splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma (e.g., splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma), Burkitt lymphoma (BL), lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia (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). Conversely, PTCL can be cutaneous T-cell lymphoma (CTCL), such as mycosis fungoides or Sezary syndrome, angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous anniculitis-like T-cell lymphoma, or anaplastic large cell lymphoma.

[0523] In some embodiments, the blood cancer can be a myeloproliferative disorder such as polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown etiology (AMM) (also known as myelofibrosis (MF)), chronic idiopathic myelofibrosis, hypereosinophilic syndrome (HES).

[0524] In some embodiments, the cancer (e.g., a CDK2-related cancer) is a myelodysplastic syndrome, including but not limited to refractory anemia with or without ring sideroblasts, 5q syndrome with or without ring sideroblasts, refractory anemia with multilineage dysplasia with or without ring sideroblasts, refractory anemia with excess blasts I and II, refractory anemia with excess transformed blasts, chronic myelomonocytic leukemia, or unclassifiable myelodysplastic syndrome.

[0525] In some embodiments, the subject is a human.

[0526] The compound of formula (A) and its pharmaceutically acceptable salt can also be used to treat CDK2-related cancer. Therefore, the present invention also provides a method for treating a subject diagnosed with or identified as having a CDK2-related cancer (e.g., any exemplary CDK2-related cancer 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.

[0527] In certain aspects, a method for treating cancer in a subject in need is provided herein, comprising administering to the subject a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof. A method for treating cancer in a subject in need is also provided, comprising: (a) identifying the cancer as a CDK2-related cancer; and (b) administering to the subject a therapeutically effective amount of a compound of formula (A) or a pharmaceutical composition thereof.

[0528] Cancer can be identified by any appropriate method, and the subject's cancer is identified as a CDK2-related cancer. In some embodiments, the step of identifying the subject's cancer as a CDK2-related cancer includes performing an assay to detect the expression or activity or level of a 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 appropriate assay. In some embodiments, the assay is selected from the group consisting of: sequencing (e.g., pyrophosphate sequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0529] Also provided herein is a method for 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 a subject identified as having a CDK2-related cancer.

[0530] Also provided is a method for treating CDK2-related cancer, comprising administering to a subject identified or diagnosed as having CDK2-related 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.

[0531] 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 includes an IC of 1 to 200 μg / mL that inhibits CDK2 activity in a standard phosphorylation assay (e.g., any assay described herein). 50The value is greater than the IC required to inhibit one or more of the activities of CDK4, CDK6, CDK1 or CDK9 to the same extent. 50 Compounds having a value 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 lower.

[0532] 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 retains CDK1 activity while inhibiting CDK2 activity (for example, in a standard phosphorylation assay, the compound of formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity with an IC of 1:1. 50 Molar concentration ratio required to inhibit CDK1 activity to the same extent as IC 50 In some embodiments, the molar concentration of the compound of formula (A) or a pharmaceutically acceptable salt thereof is at least about 50, 100, 200, 300, 400, or 500 times lower (or in another embodiment, at least 750, 1000, 1500, or 2000 times lower). 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 retaining CDK4 activity (e.g., in a standard phosphorylation assay (such as those described herein), the compound of formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity with an IC of 1.0 50 The IC value is higher than that required to inhibit CDK4 activity to the same extent 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 retaining CDK6 activity (e.g., in a standard phosphorylation assay (such as those described herein), the compound of formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity with an IC of 0.05. 50 The IC value is higher than that required to inhibit CDK6 activity to the same extent 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 inhibits CDK2 activity while retaining CDK4 activity and CDK6 activity (e.g., in a standard phosphorylation assay (such as those described herein), the compound of formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity with an IC of 0.05. 50 The IC values ​​required to inhibit CDK4 and CDK6 activities to the same extent 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 retaining CDK9 activity (e.g., in a standard phosphorylation assay (such as those described herein), the compound of formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity with an IC of 0.01. 50 The IC value is higher than that required to inhibit CDK9 activity to the same extent 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 retaining CDK1 activity, CDK4 activity, CDK6 activity, and CDK9 activity (e.g., in a standard phosphorylation assay (such as those described herein), the compound of formula (A) or a pharmaceutically acceptable salt thereof inhibits CDK2 activity with an IC of 0.05. 50 The IC values ​​were compared to the IC values ​​required to inhibit CDK1, CDK4, CDK6, and CDK9 activities to the same extent. 50 The value is at least about 50, 100, 200, 300, 400 or 500 times lower (or in another embodiment, at least 750, 1000, 1500 or 2000 times lower). Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with a disorder in the expression or activity or level of a CDK2 gene, a CDK2 protein or any thereof; and (b) administering to the subject a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof.

[0533] 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 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 thereof (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.

[0534] 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, activity or level of a cyclin A2 gene, a 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.

[0535] 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, 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.

[0536] 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, activity or level of a cyclin E2 gene, a 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.

[0537] Any suitable method may be used to determine that the cancer is associated with a disorder of expression or activity or level 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). In some embodiments, the step of determining that the subject's cancer is a CDK2-related cancer comprises performing an assay to detect a disorder of expression or activity or level (or any combination thereof) 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 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 may be any suitable assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrophosphate sequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). Also provided herein is a method for 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 is a method for treating cancer in a subject in need thereof, comprising (a) identifying the cancer as a CDK2-related disease or condition; and (b) administering to the subject a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof. In addition, a method for treating cancer in a subject in need thereof is also provided, comprising administering to the subject identified as having a CDK2-related cancer a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof.

[0538] In some cases, the compound of formula (A) or a pharmaceutically acceptable salt thereof can be used to inhibit cell processes, such as inhibiting cell proliferation. Therefore, a method for inhibiting mammalian cell proliferation is provided herein, comprising contacting the mammalian cell with a compound of formula (A) or a pharmaceutically acceptable salt thereof. A method for inhibiting CDK2 activity in a mammalian cell is also provided herein, comprising contacting the mammalian cell with a compound of formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, contact occurs in vivo. In some embodiments, contact 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 cell is a mammalian CDK2-related cancer cell. In some embodiments, the mammalian cell has a disorder of expression or activity or level (or any combination thereof) 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.

[0539] The compound of formula (A) or a pharmaceutically acceptable salt thereof can also be used for the manufacture of a medicament, ie for the treatment of CDK2-related cancers.

[0540] In some embodiments, the assay for determining whether the subject has a disorder of the expression or activity or level (or any combination thereof) of a gene (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene) or a protein (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein) or any of them using a sample from the subject can 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, the assay is typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay can utilize other detection methods known in the art to detect a disorder of the expression or activity or level (or any combination thereof) of a gene (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene) or a protein (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein) or any of them. In some embodiments, the sample is a biological sample or a 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-related cancer, a subject having one or more symptoms of a CDK2-related cancer, and / or a subject at increased risk of developing a CDK2-related cancer).

[0541] In some embodiments, the dysregulation of the expression or activity or level (or any combination thereof) 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 can be identified using a liquid biopsy (also referred to as a liquid biopsy or liquid phase biopsy). Liquid biopsy methods can be used to detect the dysregulation of the expression or activity or level (or any combination thereof) 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. Liquid biopsies can be performed on biological samples that are relatively easy to obtain from a subject (e.g., via a simple blood draw), and are generally less invasive than traditional methods for detecting tumor burden and / or dysregulation of the expression or activity or level (or any combination thereof) 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. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of the expression or activity or level (or any combination thereof) 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 at an earlier stage than traditional methods. In some embodiments, the biological sample for liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cystic fluid, feces, ascites and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTC). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA), which is derived from tumor cells. CtDNA analysis (e.g., using sensitive detection technology, such as but not limited to next generation sequencing (NGS), traditional PCR, digital PCR or microarray analysis) can be used to identify 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 the expression or activity or level (or any combination thereof) of any one thereof.

[0542] In the field of medical oncology, it is routine practice to treat each cancer patient with a combination of different treatment modalities. In medical oncology, in addition to the compositions provided herein, other components of such combined treatments or therapies may be, for example, surgery, radiation therapy, and additional therapeutic agents, such as those described herein.

[0543] For example, the surgery may be open surgery or minimally invasive surgery. Therefore, the compounds of formula (A) or their pharmaceutically acceptable salts may also be used as adjuvants for cancer treatment, i.e., they may be used in combination with one or more additional therapies or therapeutic agents (e.g., chemotherapeutic agents that act via the same or different mechanisms of action).

[0544] In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof may be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need may be administered one or more doses of a compound of formula (A) or a pharmaceutically acceptable salt thereof over a period of time, and then undergo at least partial tumor resection. In some embodiments, prior to at least partial resection of the tumor, treatment with one or more doses of a compound of formula (A) or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., tumor burden). In some embodiments, a subject in need may be administered one or more doses of a compound of formula (A) or a pharmaceutically acceptable salt thereof over a period of time, and undergo one or more rounds of radiotherapy. In some embodiments, prior to one or more rounds of radiotherapy, treatment with one or more doses of a compound of formula (A) or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., tumor burden).

[0545] In some embodiments, the compound of formula (A) or a pharmaceutically acceptable salt thereof may be used after administration of an additional therapeutic agent or additional therapy. For example, after undergoing at least partial tumor resection, a subject in need may be administered one or more doses of a compound of formula (A) or a pharmaceutically acceptable salt thereof over a period of time. In some embodiments, after at least partial resection of the tumor, treatment with one or more doses of a compound of formula (A) or a pharmaceutically acceptable salt thereof reduces the size (i.e., cell number) of any residual tumor. In some embodiments, after undergoing one or more rounds of radiotherapy, a subject in need may be administered one or more doses of a compound of formula (A) or a pharmaceutically acceptable salt thereof over a period of time. In some embodiments, after one or more rounds of radiotherapy, treatment with one or more doses of a compound of formula (A) or a pharmaceutically acceptable salt thereof reduces the size (i.e., cell number) of any residual tumor.

[0546] In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent), such as a kinase inhibitor (e.g., a CDK4 / CDK6 inhibitor, such as palbociclib, ribociclib, or abemaciclib), immunotherapy, and / or radiation. In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) for which there is no standard therapy. In some embodiments, the subject is a new user of a CDK2 inhibitor. For example, the subject has not been treated with a selective CDK2 inhibitor. In some embodiments, the subject is not a new user of a CDK2 inhibitor (i.e., the subject has previously been treated with one or more CDK2 inhibitors). In some embodiments, the subject is a new user of a CDK4 / CDK6 inhibitor. For example, the subject has not been treated with a selective CDK4 / CDK6 inhibitor. In some embodiments, the subject is not a new user of a CDK4 / CDK6 inhibitor (i.e., the subject has previously been treated with one or more CDK4 / CDK6 inhibitors).

[0547] In some embodiments, a 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.

[0548] Non-limiting examples of additional therapeutic agents include: other kinase inhibitors (eg, receptor tyrosine kinase targeted therapeutics such as EGFR, HER2, MEK, RAF or KRAS inhibitors), cytotoxic chemotherapeutics, angiogenesis inhibitors, and radiation therapy.

[0549] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR). For example, EGFR inhibitors may include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix) and vandetanib (Caprelsa).

[0550] In some embodiments, the additional therapeutic agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include trastuzumab and pertuzumab.

[0551] 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, mus) and other kinase inhibitors such as baricitinib, brigatinib, capmatinib, danusertib, ibrutinib, milciclib, regorafenib, ruxolitinib, semaxanib, mobocertinib, avapritinib, fisogatinib, itaciti nib), parsaclisib, 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]benzodiazepine-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 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide), NMS-1286937, NMS-088, INCB52793, PLX7486, PLX9486 and INCB40093.

[0552] In some embodiments, the additional therapeutic agent is a cytotoxic chemotherapeutic agent. Non-limiting examples of cytotoxic chemotherapeutic agents include bleomycin, bendamustine, fluorouracil, capecitabine, gemcitabine, vinorelbine, platinum agents (such as 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.

[0553] In some embodiments, the additional therapeutic agent is an angiogenesis inhibitor, such as a VEGF inhibitor, a VEGFR inhibitor, a TIE-2 inhibitor, a PDGFR inhibitor, an angiogenin inhibitor, a PKCβ inhibitor, a COX-2 (cyclooxygenase II) inhibitor, an integrin (α-v / β-3), a MMP-2 (matrix metalloproteinase 2) inhibitor, and a 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), pegaptaniboctasodium (Macugen), vandetanib (Zactima), PF-0337210, SU-14843, AZD-2171, ranibizumab (Lucentis), Neovastat (AE941), tetrathiomolybdate (Coprexa), AMG706, VEGF Trap (AVE0005), CEP 7055, XL Other anti-angiogenic agents include enzastaurin, midostaurin, perifosine, teprenone (Selbex) and UCN 01, lenalidomide (Revlimid), pomalidomide (Pomalyst), squalamine (Evizon), and thalidomide (Thalomid).

[0554] In some embodiments, the subject has a cancer known to be resistant to one or more additional therapies as described herein. Thus, some embodiments provide a method 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, wherein the subject has previously been administered one or more of the following: a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib or abemaciclib), an endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole and tamoxife), a HER2 inhibitor (such as neratinib, trastuzumab, dacomitinib, lapatinib, tucatinib, pertuzumab or margetuximab), a cytotoxic chemotherapeutic agent, an EGFR, MEK, RAF or KRAS inhibitor, a Ras-Raf-MEK-ERK pathway inhibitor, or a combination of any of the foregoing.

[0555] In some embodiments, the subject has previously been administered one or more of the following: a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), an 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), a Ras-Raf-MEK-ERK pathway inhibitor (as described herein), or a combination of any of the foregoing, and the previous therapy failed to successfully treat the cancer.

[0556] In some embodiments, the subject has previously been administered a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib) and an endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen), and the previous therapy failed to successfully treat the cancer. In some embodiments, the subject has previously been administered a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib) as a monotherapy, and the previous therapy failed to successfully treat the cancer.

[0557] Suppression methods

[0558] Although the genetic basis of tumorigenesis may differ between different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During the metastatic cascade, cancer cells lose growth inhibitory responses, undergo changes in adhesion, and produce enzymes that degrade components of the extracellular matrix. This results in tumor cells detaching from the original tumor, penetrating into the circulation through newly formed blood vessels, and / or tumor cell migration and extravasation to distant favorable sites where they form colonies.

[0559] Therefore, also provided herein is a method for inhibiting cancer metastasis in a subject with cancer (e.g., a subject at risk of metastasis) in need of such 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 thereof. In some embodiments, the cancer is a CDK2-related cancer. In some embodiments, a compound of formula (A) or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent as described herein.

[0560] The term "metastasis" is an art-recognized term referring to the formation of additional tumors (eg, solid tumors) at sites distant from a primary tumor in a subject, wherein the additional tumors include the same or similar cancer cells as the primary tumor.

[0561] Also provided is a method for reducing the risk of metastasis or additional metastasis in a subject with a CDK2-related cancer, comprising: selecting, identifying or diagnosing the subject as having a CDK2-related cancer, and administering a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof to the subject selected, identified or diagnosed as having a CDK2-related cancer.

[0562] Also provided is a method for reducing the risk of metastasis or additional metastasis in a subject with a CDK2-related cancer, comprising administering to the subject with the CDK2-related cancer a therapeutically effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof. The reduction in the risk of metastasis or additional metastasis in a subject with a CDK2-related cancer can be compared with the risk of metastasis or additional metastasis in the subject before treatment, or compared with a subject or subject population with a similar or identical CDK2-related cancer who has not received treatment or has received a different treatment.

[0563] The phrase "risk of developing a metastasis" means the risk that a subject with a primary tumor develops additional tumors (e.g., solid tumors) at a site distant from the primary tumor within a set period of time, wherein the additional tumors include cancer cells that are the same or similar to the primary tumor. Methods for reducing the risk of metastasis in a subject with cancer are described herein.

[0564] The phrase "risk of developing additional metastases" means that a subject having a primary tumor and one or more additional tumors distant from the primary tumor site (wherein the one or more additional tumors include cancer cells that are the same or similar to the primary tumor) will develop one or more other tumors distant from the primary tumor, wherein the other tumors include cancer cells that are the same or similar to the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0565] 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 contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a CDK2-related mammalian cancer cell. In some embodiments, the amount of the compound of formula (A) is a therapeutically effective amount.

[0566] As used herein, the term "contacting" refers to combining 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.

[0567] Also provided herein is an in vitro or in vivo method for inhibiting mammalian cell proliferation, 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.

[0568] Pharmaceutical compositions and kits

[0569] When used as a drug, the compound of formula (A), including its pharmaceutically acceptable salt, can be administered in the form of a pharmaceutical composition comprising the compound of formula (A) or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient. These compositions can be prepared in a manner known in the pharmaceutical technology and can be administered by a variety of routes, depending on the need for local treatment or systemic treatment and the area to be treated. For example, it can be administered orally or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose, or can be performed by a continuous infusion pump.

[0570] Also provided herein is a pharmaceutical composition containing a compound of formula (A) or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients. For example, a pharmaceutical composition prepared using a compound of formula (A) or a pharmaceutically acceptable salt thereof. When preparing the composition provided herein, the active ingredient is usually mixed with an excipient, diluted by an excipient, or encapsulated in such a carrier in the form of a capsule, a pouch, paper or other container. When an excipient is used as a diluent, it can be a solid, semisolid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient. In some embodiments, the composition is formulated for oral administration.

[0571] Suitable pharmaceutically acceptable carriers are well known in the art. 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.

[0572] Methods of formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, 2nd Edition, Revised and Expanded Edition, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0573] The daily dosage of the compound of formula (A) or a pharmaceutically acceptable salt thereof may vary over a wide range of 1.0 to 10,000 mg per adult human per day or any range therein.

[0574] Provided herein are pharmaceutical kits that can be used, for example, to treat CDK2-related diseases or disorders (such as cancer), comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein. If desired, such kits may further include one or more various pharmaceutical kit components, such as, for example, containers containing one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions for use as inserts or labels indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit.

[0575] Example

[0576] Preparation of compounds

[0577] The starting materials for the synthesis can be synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, etc. Nuclear magnetic resonance (NMR) analysis was performed using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or a Bruker AVANCE NEO 400 MHz spectrometer and appropriate deuterated solvents. LCMS spectra were obtained using electrospray ionization in positive ion detection mode on a Shimadzu LCMS-2020 with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS 2020MS detector.

[0578] The general method for preparing the compound of formula (A) has been described in an illustrative manner, intended to describe rather than limit. Therefore, it should be understood that conditions such as the selection of solvents, reaction temperature, volume, and reaction time can all be changed, but the desired compound can still be produced. In addition, it should be understood that other suitable reagents can also be used to replace many of the reagents provided in the following examples. For example, see Smith and March, Advanced Organic Chemistry, 7th edition (2013). Such changes and modifications can be made without departing from the spirit and scope of this article, including but not limited to those changes and modifications of the chemical structures, substituents, derivatives, intermediates, syntheses, preparations, and / or methods of use provided herein.

[0579] Example 1: Synthesis of (1s,4s)-4-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclohexyl N-propylcarbamate (Compound 1)

[0580]

[0581] Step 1: Synthesis of 4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl trifluoromethanesulfonate

[0582] To a stirred solution of 4-[(tert-butyldimethylsilyl)oxy]cyclohexan-1-one (2 g, 8.75 mmol, 1.00 equiv) and LiHMDS (2M in THF) (19.90 mL, 17.51 ​​mmol, 2.00 equiv) in THF (100 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (6.3 g, 17.51 ​​mmol, 2.00 equiv) dropwise under nitrogen atmosphere at -78 °C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (3x50 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. 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. The crude product was used in the next step without further purification.

[0583] Step 2: Synthesis of 5-{4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl}pyrimidin-2-amine

[0584] Trifluoromethanesulfonic acid 4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-en-1-yl ester (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) were added to 1,4-dioxane / H2O at room temperature under nitrogen atmosphere. 2 O=(4:1) (20 mL) was added to the stirred solution of Pd(dppf)Cl 2. CH 2 Cl 2 (2.26 g, 2.77 mmol, 0.2 eq.) and K 2 CO 3 (5.75 g, 41.61 mmol, 3.00 equiv). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (3x20 mL) and purified by anhydrous Na 2 SO 4The residue was purified by column chromatography on silica gel eluted 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% for two steps) as a yellow solid. LC-MS: (ES+H, m / z) 306.1 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 )δ8.22(s,2H),6.52(s,2H),5.83(dd,J=4.7,2.8Hz,1H),3.90-3.82(m,1H),2.36-2. 25(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).

[0585] Step 3: Synthesis of 5-((1s,4s)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrimidin-2-amine

[0586] Palladium was added to a stirred solution of 5-{4-[(tert-butyldimethylsilyl)oxy]cyclohex-1-ene-1-yl}pyrimidine-2-amine (1.6 g, 5.23 mmol, 1.00 equiv) in MeOH (150 mL) under a hydrogen atmosphere at room temperature. The resulting mixture was stirred for 1 h under a hydrogen atmosphere at room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3x100 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 eluted with PE / EA (6:1 to 4:1) to give 5-[(1s, 4s)-4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimidine-2-amine (500 mg, 31%) as a yellow solid. LC-MS: (ES+H, m / z) 308.2 [M+H] + ; 1 H NMR (300 MHz, DMSO-d 6 )δ8.01(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).

[0587] Step 4: Synthesis of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate

[0588] 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-fluorophenylsulfonyl)carbamate (345.5 mg, 0.97 mmol, 1.50 equiv) in t-BuOH (2 mL) was added EPhos Pd G4 (59.7 mg, 0.06 mmol, 0.10 equiv) and K 2 CO 3 (269.6 mg, 1.95 mmol, 3.00 equiv). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (3x5 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted 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 (300 MHz, DMSO-d 6 )δ11.75(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,2 H), 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).

[0589] Step 5: Synthesis of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-hydroxycyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate

[0590] 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 under nitrogen atmosphere at room temperature. The resulting mixture was stirred at 50 °C for 1 h under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (3x10 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted 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 (300 MHz, DMSO-d 6 )δ11.62(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).

[0591] Step 6: Synthesis of imidazole-1-carboxylic acid (1s, 4s)-4-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2-fluorophenyl}amino)pyrimidin-5-yl]cyclohexyl) ester

[0592] 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 nitrogen atmosphere at room temperature. The resulting mixture was stirred at 40 °C under nitrogen atmosphere for 12 h. The mixture was cooled to room temperature. The resulting mixture was washed with CH 2 Cl 2The combined organic layers were washed with water (3x5 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give imidazole-1-carboxylic acid (1s, 4s)-4-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2-fluorophenyl}amino)pyrimidin-5-yl]cyclohexyl ester (118 mg, crude product) as a light yellow solid. The crude product was used directly in the next step without further purification.

[0593] Step 7: Synthesis of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-[(propylcarbamoyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)benzenesulfonyl]carbamate

[0594] To a solution of (1s,4s)-4-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2-fluorophenyl}amino)pyrimidin-5-yl]cyclohexyl imidazole-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) under nitrogen at room temperature. The resulting mixture was stirred at 40 °C for 12 h under nitrogen. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water (10 mmol / LNH 4 HCO 3 ), gradient 30% to 50% in 10 min; detector, UV 254 nm. The 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 light yellow solid. 1 H NMR (300 MHz, DMSO-d 6 )δ11.68(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).

[0595] Step 8: Synthesis of N-propylcarbamic acid (1s, 4s)-4-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclohexyl ester (Compound 1)

[0596] 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 under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 3 h under nitrogen atmosphere at room temperature. The reaction was monitored by LCMS. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and washed with NH 3 ·H 2 O was neutralized to pH = 7. The mixture was purified by reverse phase combi-flash chromatography under the following conditions: column, C18; mobile phase, MeCN (10 mmol / L NH 4 HCO 3 ), 40% to 50% gradient in 10 min; detector, UV 254 nm. The pure fractions were concentrated under reduced pressure and freeze-dried to give N-propylcarbamic acid (1s, 4s)-4-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclohexyl ester (Compound 1, 19.4 mg, 62%) as a white solid. LC-MS: (ES+H, m / z) 452.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ9.32(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. 99-2.91(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 (376 MHz, DMSO-d 6 )δ-121.81.

[0597] Example 2: Synthesis of ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid (1RS,3SR)-3-(2-(imidazo[1,2-b]pyridazin-6-ylamino)pyrimidin-5-yl)cyclopentyl ester (Compound 40)

[0598]

[0599]

[0600] Step 1: Synthesis of cyclopent-2-en-1-ol

[0601] To a solution of cyclopent-2-en-1-one (10 g, 121.80 mmol, 10.20 mL) and trichlorocerium (47.70 g, 193.53 mmol) in MeOH (80 mL) was added NaBH at 0°C. 4 (5.10 g, 134.81 mmol). The mixture was stirred at 0 °C for 30 min, and then the reaction was warmed to 20 °C for 30 min. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were purified by anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo gave the title compound (4.5 g, crude) as a white solid which required no further purification. 1 H NMR (400 MHz, CDCl 3 )δ6.03-5.95(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).

[0602] Step 2: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-oxocyclopentyl)pyrimidin-2-yl]carbamate

[0603] To a solution of N-(5-bromopyrimidin-2-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (2 g, 2.67 mmol) and cyclopent-2-en-1-ol (900 mg, 5.34 mmol) in DMF (40 mL) were added tetrabutylammonium chloride (743 mg, 2.67 mmol), Pd(OAc) and 2 (60 mg, 0.27 mmol) and KOAc (1.57 g, 8.02 mmol). The reaction mixture was stirred at 80 °C under 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 x 5) and purified by anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (solvent gradient: 10%-50% EtOAc in petroleum ether) to give the title compound (0.52 g, 23%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.96(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).

[0604] Step 3: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-hydroxycyclopentyl)pyrimidin-2-yl]carbamate

[0605] 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 at -65 °C. 3 (1 M, 51 mL). The reaction mixture was stirred at -65 °C for 1 h. After the reaction was complete, saturated NaHCO 3 The mixture was quenched with aqueous solution (40 mL), and then the reaction was warmed to room temperature and diluted with EtOAc (150 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 10%-50% EtOAc in petroleum ether) to give the title compound (8 g, 66%) as a yellow oil. LCMS (ESI) m / z: 380.2 [M+H] + .

[0606] Step 4: Synthesis of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate

[0607] To a solution of N-tert-butyloxycarbonyl-N-[5-(3-hydroxycyclopentyl)pyrimidin-2-yl]carbamic acid tert-butyl ester (9g, 23.72mmol) in DCM (50mL) was added DMAP (580mg, 4.74mmol), pyridine (5.63g, 71.16mmol, 5.74mL) and chloroformic acid (4-nitrophenyl) ester (7.17g, 35.58mmol). The reaction mixture was stirred at 25°C for 1h. The reaction mixture was quenched by adding water (50mL) at 0°C and extracted with DCM (100mL x 3). The combined organic layer was washed with brine (50mL) and purified by anhydrous Na 2 SO 4 The mixture was dried, 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 as a white solid (cis isomer, random absolute configuration, 3.5 g, 27%). LCMS (ESI) m / z: 545.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ8.71(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,1H),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). And (tert-butoxycarbonyl)(5-((1R,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamic acid rac-tert-butyl ester was obtained as a white solid (trans isomer not shown, absolute configuration was randomly assigned, 1.5 g, 12%). 1 H NMR (400 MHz, CDCl 3 )δ8.66(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).

[0608] 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

[0609] 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 the addition of water (10 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), purified by chromatography on anhydrous Na 2 SO 4 Dry, filter and concentrate 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 (400 MHz, CDCl 3 )δ8.64(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).

[0610] Step 6: Synthesis of (1RS,3SR)-3-(2-aminopyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate

[0611] 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 without further purification. LCMS (ESI) m / z: 333.2 [M+H] + .

[0612] Step 7: Synthesis of ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid (1RS,3SR)-3-(2-(imidazo[1,2-b]pyridazin-6-ylamino)pyrimidin-5-yl)cyclopentyl ester (Compound 40)

[0613] ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid (1RS,3SR)-3-(2-aminopyrimidin-5-yl)cyclopentyl ester (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 Cs 2 CO 3 A mixture of (294 mg, 902 μmol) in dioxane (2 mL) was degassed and heated to 4 °C with N 2 Purge three times, and then the mixture is heated under N 2 Stir at 100 °C 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 x 3). The combined organic layers were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 22%-55% / 0.225% formic acid in water) 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-d 6)δ10.29(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).

[0614] Example 3: Synthesis of (1-methylcyclopropyl)carbamic acid rel-(1S,3R)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl ester (Compound 151) and (1-methylcyclopropyl)carbamic acid rel-(1R,3S)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl ester (Compound 152)

[0615]

[0616] Step 1: Synthesis of 3-iodocyclopent-2-en-1-one

[0617] In a nitrogen atmosphere at room temperature 2 (15.52 g, 61.16 mmol, 1.2 equiv) was added portionwise to a stirred solution of MeCN (150 mL) with PPh 3 (16.04 g, 61.162 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature for another 2 h. 1,3-Cyclopentanedione (5 g, 50.97 mmol, 1 eq.) was dissolved in Et 3 A mixture of N (6.19 g, 61.162 mmol, 1.2 eq.) and MeCN (200 mL) was stirred under nitrogen atmosphere at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1-3:5) to give 3-iodocyclopent-2-ene-1-one (8 g, 75.46%) as a white solid. LC-MS (ES+H, m / z) 209.0 [M+H] + .

[0618] Step 2: Synthesis of 3-iodocyclopent-2-en-1-ol

[0619] 3-Iodocyclopent-2-en-1-one (3.1 g, 14.90 mmol, 1 eq.) and NaBH 4A mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (0.57 g, 14.90 mmol, 1.2 equiv) in EtOH (30 mL) was stirred under nitrogen at 0°C for 1 h. The reaction was monitored by H-NMR. By adding saturated NH 4 Cl (aqueous solution) (20 mL) was used to quench the reaction. 2 Cl 2 The combined organic layers were washed with brine (1 x 100 mL) and purified by anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1-3:5) 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] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ6.21-6.13(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)

[0620] Step 3: Synthesis of 3-(2-aminopyrimidin-5-yl)cyclopent-2-en-1-ol

[0621] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1000 mg, 4.523 mmol, 1 eq.) and 3-iodocyclopent-2-en-1-ol (1140 mg, 5.42 mmol, 1.2 eq.), Pd(dppf)Cl 2 (661.97 mg, 0.905 mmol, 0.2 eq), K 2 CO 3 (1875 mg, 13.57 mmol, 3 eq.) in 1,4-dioxane (10 mL) and H 2 The mixture in 2% O (1 mL) was stirred at 80° C. under nitrogen atmosphere for 1 h. The resulting mixture was washed with CH 2 Cl 2 (5x100 mL) was extracted. 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 NH 4 HCO 3), 8% to 16% gradient in 10 min; detector, UV 254 nm. This produced 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 (400 MHz, DMSO-d 6 )δ8.39(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).

[0622] Step 4: Synthesis of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentan-1-ol

[0623] In a 250 mL round-bottom flask, Pd / C (10 wt %, 1.68 g) was added to a solution of 3-(2-aminopyrimidin-5-yl)cyclopent-2-ene-1-ol (2.8 g, 15.80 mmol, 1 eq) in MeOH (50 mL) MeOH under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h under a hydrogen atmosphere using a hydrogen balloon, 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 NH 4 HCO 3 +0.1% NH 3 .H 2 O), 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; number of runs: 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%, arbitrary absolute configuration) as a white solid. LC-MS: (ES+H, m / z) 180.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)δ8.14(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).

[0624] Step 5: Synthesis of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl (4-nitrophenyl) carbonate

[0625] To a stirred solution of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentan-1-ol (1.5 g, 8.369 mmol, 1 eq.) and DMAP (0.10 g, 0.837 mmol, 0.1 eq.) in DCM (20 mL) was added DIEA (3.25 g, 25.107 mmol, 3 eq.) and bis(4-nitrophenyl) carbonate (5.09 g, 16.738 mmol, 2 eq.) in a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 4 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water, 25% to 35% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in 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 (400 MHz, DMSO-d 6 )δ8.36-8.28(m,2H),8.17(s,2H),7.62-7.54(m,2H),6.44(s,2H),5.27-5.17(m, 1H),3.00-2.86(m,1H),2.61-2.53(m,1H),2.10-1.93(m,3H),1.85-1.60(m,2H).

[0626] Step 6: Synthesis of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate

[0627] A solution of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl (4-nitrophenyl) carbonate (1.2 g, 3.49 mmol, 1 eq) in DMF (20 mL) was treated with 1-methylcyclopropyl-1-amine hydrochloride (0.56 g, 5.23 mmol, 1.5 eq) at room temperature under nitrogen atmosphere, followed by dropwise addition of DIEA (1.35 g, 10.46 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 60 ° C under nitrogen atmosphere for 1.5 h. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (3x10 mL) and purified by anhydrous Na 2 SO 4 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 NH 4 HCO 3 ), 30% to 40% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This produced 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 (400 MHz, DMSO-d 6 )δ8.13(s,2H),7.40(s,1H),6.40(s,2H),5.03(d,J=37.8Hz,1H),2.85(t,J=9.1Hz,1H),2.46–2.3 4(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).

[0628] Step 7: Synthesis of rac-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate

[0629] To a stirred solution of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (150 mg, 0.543 mmol, 1 eq) and tert-butyl N-(4-bromobenzenesulfonyl)carbamate (218.99 mg, 0.652 mmol, 1.2 eq) in t-BuOH (5 mL) was added K in portions at room temperature under nitrogen atmosphere. 2 CO3 (225.06 mg, 1.629 mmol, 3 eq.) and EPhos Pd G4 (49.86 mg, 0.054 mmol, 0.1 eq.). The resulting mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3x20 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 NH 4 HCO 3 ), 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] + .

[0630] Step 8: Synthesis of rac-(1R,3S)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate

[0631] 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 eq.) in 1,4-dioxane (5 mL) containing HCl (gas) was stirred for 1 h at room temperature under nitrogen atmosphere. 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 NH 4 HCO 3 +0.1% NH 3 .H 2 O), 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 freeze drying 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 (400 MHz, DMSO-d 6 )δ9.98(s,1H),8.57-8.42(m,2H),7.95-7.88(m,2H),7.71(d,J=8.5Hz ,2H),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).

[0632] Step 9: Synthesis of (1-methylcyclopropyl)carbamic acid rel-(1S,3R)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl ester (Compound 151) and (1-methylcyclopropyl)carbamic acid rel-(1R,3S)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl ester (Compound 152)

[0633] 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 mL), the pure fractions were concentrated under reduced pressure by freeze drying to give (1-methylcyclopropyl)carbamic acid rel-(1S,3R)-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl ester (compound 151, 27.6 mg, 45.3%) as a white solid and N-(1-methylcyclopropyl)carbamic acid rel-(1R,3S)-3-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclopentyl ester (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 HNMR (400 MHz, DMSO-d 6)δ9.98(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] + ; 1 HNMR (400 MHz, DMSO-d 6 )δ9.98(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),2.4 9-2.42(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).

[0634] Example 4: Synthesis of rac-(1R,3S)-3-{2-[(1-sulfamoylpiperidin-4-yl)amino]pyrimidin-5-yl}cyclopentyl N-(1-methylcyclopropyl)carbamate (Compound 135)

[0635]

[0636] Step 1: Synthesis of rac-(1R,3S)-3-(2-chloropyrimidin-5-yl)cyclopentyl N-(1-methylcyclopropyl)carbamate

[0637] N-(1-methylcyclopropyl)carbamic acid rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl ester (150 mg, 0.543 mmol, 1 equivalent) and t-BuNO were added under nitrogen atmosphere at room temperature. 2To a stirred solution of DCM (2 mL) was added tetrabutylammonium chloride (452.57 mg, 1.629 mmol, 3 eq.) (167.93 mg, 1.629 mmol, 3 eq.) in portions. The resulting mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture 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 NH 4 HCO 3 ), 30% to 50% gradient in 10 min; 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] + .

[0638] Step 2: Synthesis of rac-tert-butyl 4-({5-[(1R,3S)-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]pyrimidin-2-yl}amino)piperidine-1-carboxylate

[0639] To a stirred solution of rac-(1R,3S)-3-(2-chloropyrimidin-5-yl)cyclopentyl N-(1-methylcyclopropyl)carbamate (38 mg, 0.128 mmol, 1 eq) and tert-butyl 4-aminopiperidine-1-carboxylate (51.46 mg, 0.256 mmol, 2 eq) in dioxane (2 mL) was added Pd-PEPPSI-IpentCl in portions at room temperature under nitrogen atmosphere; 2-methylpyridine (o-methylpyridine (32.42 mg, 0.038 mmol, 0.3 eq) and Cs 2 CO 3 (125.58 mg, 0.384 mmol, 3 equiv.). The resulting mixture was stirred for 2 h at 120 ° C under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1: 1-1: 2) to give 4-({5-[(1R, 3S)-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]pyrimidin-2-yl}amino)piperidine-1-carboxylic acid rac-tert-butyl ester (50 mg, 85%) as a white solid. LC-MS: (ES+H, m / z) 460.3[M+H] + .

[0640] Step 3: Synthesis of rac-(1R,3S)-3-[2-(piperidin-4-ylamino)pyrimidin-5-yl]cyclopentyl N-(1-methylcyclopropyl)carbamate

[0641] 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 eq.) in HCOOH (3 mL) was stirred under nitrogen atmosphere at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The mixture was washed with NH 3 · H2O basified to pH 8. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), gradient from 30% to 60% in 10 min; detector, UV 254 nm. This produced 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] + .

[0642] Step 4: Synthesis of rac-(1R,3S)-3-{2-[(1-sulfamoylpiperidin-4-yl)amino]pyrimidin-5-yl}cyclopentyl N-(1-methylcyclopropyl)carbamate (Compound 135)

[0643] 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 eq) and sulfonamide (16.04 mg, 0.166 mmol, 2 eq) in dioxane (1 mL) was added EtOH dropwise at room temperature under nitrogen atmosphere. 3 N (25.34 mg, 0.249 mmol, 3 eq.). The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was cooled 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 NH 4 HCO 3 ), mobile phase B: ; Flow rate: 60 mL / min mL / min; Gradient: 21% B to 33% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1 (min): 9.1. The resulting mixture was concentrated under reduced pressure by freeze drying 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 (400 MHz, DMSO-d 6 )δ8.19(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).

[0644] 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)

[0645]

[0646] Step 1: Synthesis of 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-one

[0647] To a stirred solution of piperidin-4-one hydrochloride (190.75 mg, 1.407 mmol, 1.1 equivalents) and DIEA (330.58 mg, 2.558 mmol, 2 equivalents) in THF (5 mL) was added dropwise 1-(trifluoromethyl)pyrazole-4-sulfonyl chloride (300 mg, 1.279 mmol, 1 equivalent) under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 2 h under nitrogen atmosphere at room temperature. The reaction was monitored by H-NMR. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layer was washed with brine (2x50 mL) and purified by anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure to obtain 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-one (390 mg, crude product) as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 )δ9.31(s,1H),8.39(q,J=0.9Hz,1H),3.42–3.33(m,4H),2.49–2.44(m,4H).

[0648] Step 2: Synthesis of 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-amine

[0649] 1-[1-(Trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-one (290 mg, 0.976 mmol, 1 eq) and NH 4 To a stirred solution of OAc (225.61 mg, 2.928 mmol, 3 eq.) in MeOH (5 mL) was added HOAc (0.05 mL) dropwise. The resulting mixture was stirred at room temperature under nitrogen for 20 min. NaBH was added to the above mixture in portions over 5 min at room temperature. 3 CN (183.92 mg, 2.928 mmol, 3 eq.). The resulting mixture was stirred at 50 °C for another 20 min. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. 2 Cl 2 The residue was purified by silica gel column chromatography eluting with 4-(4-nitropropene)-2-nitropropene / MeOH (5:1-1:1) 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] + .

[0650] 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)

[0651] To a stirred solution of ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid rac-(1R,3S)-3-(2-fluoropyrimidin-5-yl)cyclopentyl ester (80 mg, 0.239 mmol, 1 eq) and DIEA (123.35 mg, 0.956 mmol, 4 eq) in DMSO (3 mL) was added 1-[1-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-amine (142.33 mg, 0.478 mmol, 2 eq) in a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 ° C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x10 mL) and purified by anhydrous Na 2 SO 4 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 in water (0.1% NH 4 HCO 3 ), 30% to 60% gradient in 10 min; detector, UV 254 nm. The pure fractions were concentrated under reduced pressure and freeze-dried 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 as a white solid (Compound 302, 36 mg, 25%). LC-MS: (ES+H, m / z) 614.2 [M+H] + ; 1 HNMR (400 MHz, DMSO-d 6 )δ9.25(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, 2H),2.87(p,J=9.2Hz,1H),2.73–2.57(m,2H),2.48–2.28(m,3H),2.03–1.8 1(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.

[0652] Example 6: Synthesis of (1R*,3S*)-3-(2-((4-((S*)-cyclopropanesulfonyliminoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate HCl salt (Compound 580)

[0653]

[0654]

[0655] Step 1: Synthesis of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,3S)-3-(((1-methylcyclopropyl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate

[0656] To a solution of 1-methylcyclopropylamine (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 the addition of water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0657] Step 2: Synthesis of rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate

[0658] 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 washed with saturated NaHCO 3 The aqueous solution was adjusted to pH = 8 and then stirred for 1 h. 2 SO 4Dry, filter and concentrate in vacuo to give the title compound (3.2 g, crude) as a white solid without further purification. LCMS (ESI) m / z: 277.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ8.45-8.01(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. 03(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).

[0659] Step 3: Synthesis of rac-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonylimide)phenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate

[0660] To (1-methylcyclopropyl)carbamic acid rac-(1R,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl ester (1.1 g, 3.0 mmol) and K 3 PO 4 (3.13 g, 14.73 mmol) was added to a solution of N-[(4-bromo-3-fluoro-phenyl)-cyclopropyl-oxo-sulfhydryl]carbamic acid tert-butyl ester (1.7 g, 4.4 mmol), Brettphos (316 mg, 589 μmol), and BrettPhos Pd G3 (267 mg, 294 μmol). The reaction mixture was degassed and heated with N 2 Purge three times, and then the mixture is heated under N 2 Stir at 80°C 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) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0661] Step 4: Synthesis of rel-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonylimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate and rel-(1S,3R)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonylimidoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate

[0662] (1-Methylcyclopropyl)carbamic acid rac-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonylimide)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl ester (1.2 g, 1.7 mmol) was prepared by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); supercritical CO 2 / i-PrOH+0.1% NH 3 ·H 2 O=40 / 60;80mL / min) separation, to give (1-methylcyclopropyl)carbamic acid rel-(1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonylimide)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl ester (397mg, first peak and second peak) as a white solid and (1-methylcyclopropyl)carbamic acid rel-(1S,3R)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonylimide)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl ester (355mg, third peak and fourth peak) as a white solid. The absolute configuration was arbitrarily assigned to each isomer. LCMS(ESI)m / z:574.3[M+H] + .

[0663] Step 5: Synthesis of (1R*,3S*)-3-(2-((4-((R)-N-(tert-butoxycarbonyl)cyclopropanesulfonylimide)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate and (1R*,3S*)-3-(2-((4-((S)-N-(tert-butoxycarbonyl)cyclopropanesulfonylimide)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate

[0664] (1R,3S)-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonylimide)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (397 mg, 692.0 μmol) was prepared by chiral SFC (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); supercritical CO 2 / MeOH+0.1% NH 3 ·H 2 O=60 / 40;150mL / min) separation, (1-methylcyclopropyl) carbamic acid (1R *, 3S *)-3-(2-((4-((R)-N-(tert-butoxycarbonyl) cyclopropanesulfonylimide)-2-fluorophenyl)amino) pyrimidin-5-yl) cyclopentyl ester (147 mg, first peak) and (1-methylcyclopropyl) carbamic acid (1R *, 3S *)-3-(2-((4-((S)-N-(tert-butoxycarbonyl) cyclopropanesulfonylimide)-2-fluorophenyl)amino) pyrimidin-5-yl) cyclopentyl ester (119 mg, second peak) were obtained as white solids. The absolute configuration was arbitrarily assigned to each enantiomer. LCMS (ESI) m / z: 574.3 [M+H] + .

[0665] Step 6: Synthesis of (1R*,3S*)-3-(2-((4-((S)-cyclopropanesulfonyliminoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate HCl salt (Compound 580)

[0666] To a solution of (1R*,3S*)-3-(2-((4-((S)-N-(tert-butoxycarbonyl)cyclopropanesulfonylimide)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (147 mg, 255 μmol) in dioxane (5 mL) was added HCl / dioxane (5 mL, 4 M). The reaction was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 30%-60% / 0.05% HCl in water) to give Compound 580 (46 mg, 38%) as a white solid. The absolute configuration was assigned arbitrarily. LCMS (ESI) m / z: 474.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)δ9.80(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).

[0667] 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)

[0668]

[0669] 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

[0670] 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) at 0°C was added NaH (71 mg, 1.79 mmol, 60% purity). The mixture was stirred at 0°C for 0.5 h, and then 4-isopropyl-3-methylsulfonyl-1,2,4-triazole (160 mg, 0.86 mmol) was added. The mixture was stirred at 40°C under nitrogen for 16 h. After cooling to room temperature, the reaction was washed with saturated NH 4 The mixture was quenched with aqueous Cl solution (3 mL) and then treated with H 2 O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL x 3) and purified by anhydrous Na 2 SO 4Dry, filter and concentrate 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] + .

[0671] 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

[0672] 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 without further purification. LCMS (ESI) m / z 289.2 [M+H] + .

[0673] 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

[0674] To 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 Cs 2 CO 3 To a solution of 476 mg, 1.46 mmol) in dioxane (3 mL) was added BrettPhos (13 mg, 24 μmol) and BrettPhos Pd G3 (22 mg, 24 μmol). The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. 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) and filtered through anhydrous Na 2 SO 4Dry, filter and concentrate 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] + .

[0675] 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

[0676] 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 without further purification. LCMS (ESI) m / z 444.2 [M+H] + .

[0677] 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)

[0678] 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 prepared by chiral SFC (DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 um); supercritical CO 2 / iPrOH+0.1% NH 3 ·H 2O=50 / 50; 60mL / min) to give rel-4-((5-((1R,3S)-3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (compound 52, 2.3mg, 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, 2.1mg, 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 (400 MHz, DMSO-d 6 )δ10.02(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] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ10.02(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).

[0679] 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)

[0680]

[0681] Step 1: Synthesis of 4-(1-methylcyclopropyl)-4H-1,2,4-triazole-3-thiol

[0682] To a solution of 1-isocyanato-1-methyl-cyclopropane (18 g, 159 mmol) in THF (200 mL) was added NaOH (3.6 g, 90 mmol) and formic 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 then extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (50 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% ethyl acetate in petroleum ether) to give the title compound (16 g, 64%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ12.49(s,1H),7.78(s,1H),1.59(s,3H),1.19–1.15(m,2H),1.05–0.99(m,2H).

[0683] Step 2: Synthesis of 4-(1-methylcyclopropyl)-3-(methylthio)-4H-1,2,4-triazole

[0684] 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 K 2 CO 3 (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 x 3), and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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 (400 MHz, CDCl 3 )δ8.22(s,1H),2.77(s,3H),1.51(s,3H),1.18–1.13(m,2H),1.03–0.94(m,2H).

[0685] Step 3: Synthesis of 4-(1-methylcyclopropyl)-3-(methylsulfonyl)-4H-1,2,4-triazole

[0686] To a solution of 4-(1-methylcyclopropyl)-3-methylthiosulfanyl-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 under nitrogen at 25 °C for 16 h. The mixture was heated to 40 ℃ and then heated to 30 ℃ for 16 hours. The mixture was heated to 30 ℃ and then heated to 40 ℃ for 16 hours. The mixture was heated to 30 ℃ and then heated to 3 ... 2 SO 3 The reaction was quenched with aqueous solution and then extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 10%-100% ethyl acetate in petroleum ether) to give the title compound (14 g, 69%) as a white solid. LCMS (ESI) m / z: 202.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ7.77(s,1H),1.62(s,4H),1.23–1.18(m,2H),1.09–1.04(m,2H).

[0687] 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

[0688] 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 nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 30 min, then 4-(1-methylcyclopropyl)-3-(methylsulfonyl)-4H-1,2,4-triazole (721 mg, 3.6 mmol) was added at 0°C for 5 min, and then the mixture was heated to 40°C for 16 h. After cooling to room temperature, the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL), followed by extraction with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), purified by chromatography on anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by silica gel chromatography (solvent gradient: 5%-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 (400 MHz, CDCl 3 )δ8.55(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).

[0689] Step 5: Synthesis of rac-5-((1R,3S)-(3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-amine

[0690] 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 washed with saturated NaHCO 3 The aqueous solution was adjusted to pH 8 and then stirred for 1 h. 2 SO 4 Dry, filter and concentrate in vacuo to give the title compound as a yellow oil (0.2 g crude) which requires no further purification. LCMS (ESI) m / z: 301.2 [M+H] + .

[0691] 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

[0692] 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-fluoro-phenyl)sulfonylcarbamate (265 mg, 749 μmol), BrettPhos Pd G3 (45 mg, 49 μmol), Brettphos (54 mg, 99 μmol) and Cs 2 CO 3 A mixture of 4-(976 mg, 3.0 mmol) in dioxane (8 mL) was degassed and purged with a nitrogen atmosphere three times, and then the mixture was stirred under a nitrogen atmosphere at 100 ° C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with HCl aqueous solution (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3) and filtered through anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 3%-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] + .

[0693] 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

[0694] 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 prepared by chiral SFC (DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); supercritical CO 2 / EtOH+0.1% NH 3 ·H 2O=55 / 45;80mL / min) separation, ((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)carbamic acid rel-tert-butyl ester (50mg, first peak) was obtained as a colorless oil and ((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)carbamic acid rel-tert-butyl ester (50mg, second peak) was obtained as a colorless oil. The absolute configuration was arbitrarily assigned to each enantiomer.

[0695] 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)

[0696] 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 (acetonitrile 36–60% / 0.05% HCl in water) to give the HCl salt compound. The HCl salt compound was diluted with MeOH (5 mL) and Amberlyst 15 was added, then the mixture was 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 (400 MHz, DMSO-d 6 )δ8.50(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).

[0697] 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)

[0698]

[0699] Step 1: Synthesis of 2-butyryl-N-(1-methylcyclopropyl)hydrazine-1-carbothioamide

[0700] To a solution of 1-isothiocyanato-1-methyl-cyclopropane (3 g, 26.5 mmol) in THF (20 mL) was added butyric acid 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 did not require further purification. LCMS (ESI) m / z: 215.9 [M+H] + .

[0701] Step 2: Synthesis of 4-(1-methylcyclopropyl)-5-propyl-4H-1,2,4-triazole-3-thiol

[0702] To a solution of 1-(butyrylamino)-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 without further purification. LCMS (ESI) m / z: 197.8 [M+H] + .

[0703] 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)

[0704] 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 analogous to 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 and any appropriate modifications. The absolute configuration was arbitrarily assigned to each enantiomer. Compound 449: LCMS (ESI) m / z: 516.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.39(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,2H),0.98(t,J=7.6Hz,3H),0.94–0.88(m,2H). Compound 551: LCMS (ESI) m / z: 516.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.39(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).

[0705] Example 10: Synthesis of rel-4-((5-((1S,3R)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 574)

[0706]

[0707] Step 1: Synthesis of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate

[0708] 4-Cyclopropylisothiazol-3-ol (555 mg, 3.93 mmol) and K 2 CO 3 To a solution of rac-(1R,3R)-3-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclopentyl methanesulfonate (1.5 g, 2.62 mmol) (1.09 g, 7.87 mmol) in DMF (10 mL) was added. 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 x 3), and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0709] Step 2: Synthesis of rac-5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt

[0710] 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 without further purification. LCMS (ESI) m / z: 303.2 [M+H] + .

[0711] 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

[0712] 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) were added BrettPhos (18 mg, 33 μmol), BrettPhos Pd G3 (30 mg, 33 μmol) and K 3 PO 4 (351 mg, 1.65 mmol). The reaction mixture was stirred at N 2 Stir at 80°C 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 x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0713] 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

[0714] 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 prepared by chiral SFC (DAICELCHIRALPAK IF (250 mm*30 mm, 10 um); supercritical CO 2 / heptane-EtOH+0.1% NH 3 ·H 2O=40 / 60;80ml / min) separation, to give ((4-((5-((1R,3S)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamic acid rel-tert-butyl ester (70mg, first peak) and ((4-((5-((1S,3R)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamic acid rel-tert-butyl ester (85mg, second peak) as white solid. The absolute configuration was arbitrarily assigned to each enantiomer. LCMS (ESI) m / z: 558.1 [M+H] + .

[0715] Step 5: Synthesis of rel-4-((5-((1S,3R)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 574)

[0716] 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 (acetonitrile 52%-82% / 0.05% NH in water). 3 ·H 2 O + 10 mM NH 4 HCO 3 ) to obtain compound 574 (20 mg, 35%) as a white solid. LCMS (ESI) m / z: 458.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.99(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).

[0717] 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)

[0718]

[0719] Step 1: Synthesis of rac-tert-butyl (5-((1R,3S)-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)(tert-butoxycarbonyl)carbamate

[0720] 4-Bromopyridin-3-ol (75 mg, 0.4 mmol), K 2 CO 3 A solution of rac-(1R,3R)-3-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclopentyl methanesulfonate (119 mg, 0.9 mmol) and methanesulfonic acid rac-(1R,3R)-3-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclopentyl ester (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 x 3), and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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 (400 MHz, CDCl 3 )δ8.76(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).

[0721] Step 2: Synthesis of rac-5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-amine

[0722] Rac-tert-butyl (5-((1R,3S)-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)(tert-butoxycarbonyl)carbamate (50 mg, 93 μmol), K 2 CO3 (40 mg, 0.3 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (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 H 2 O (0.2 mL) in N 2 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] + .

[0723] 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

[0724] 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-fluoro-phenyl)sulfonylcarbamate (47 mg, 0.14 mmol) in dioxane (2 mL) were added BrettPhos Pd G3 (8 mg, 9 μmol), BrettPhos (5 mg, 9 μmol) and Cs 2 CO 3 (86 mg, 0.26 mmol). The reaction mixture was stirred at N 2 Stir under atmosphere at 100°C. 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 x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0725] 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)

[0726] 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 3 ·H 2 O + 10 mM NH 4 HCO 3 ) to obtain compound 55 (2 mg, 16%) as a white solid. LCMS (ESI) m / z: 470.2 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ8.90–8.80(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).

[0727] 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)

[0728]

[0729] Step 1 - Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[(1R)-3-oxocyclopentyl]-2-pyridyl]carbamate

[0730] N-(5-bromo-3-chloro-2-pyridyl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (4 g, 9.8 mmol), cyclopent-2-en-1-ol (1.65 g, 19.62 mmol), Pd(OAc) 2 A mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (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 heated with N 2 Purge three times, and then the mixture is heated under N 2 At 80°C, the mixture was stirred for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (30 mL x 3), and purified by anhydrous Na 2 SO 4 + .

[0731] Step 2 - Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[3-hydroxycyclopentyl]-2-pyridyl]carbamate

[0732] In N 2 LiBHEt was added to a mixture of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[3-oxocyclopentyl]-2-pyridinyl]carbamate (2 g, 4.9 mmol) in THF (40 mL) at -65°C. 3 (1 M, 7.30 mL). The reaction was stirred for 1 h. The mixture was stirred at -65 °C by adding saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and purified by anhydrous Na 2 SO 4 + .

[0733] Step 3 - Synthesis of [3-[6-[bis(tert-butoxycarbonyl)amino]-5-chloro-3-pyridyl]cyclopentyl]carbonate (4-nitrophenyl)

[0734] ​​To a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[(1R,3S)-3-hydroxycyclopentyl]-2-pyridinyl]carbamate (1 g, 2.42 mmol) and DMAP (30 mg, 242 μmol), pyridine (0.6 mL, 7.3 mmol) in DCM (15 mL) was added 4-nitrophenyl chloroformate (976 mg, 4.8 mmol) at 25° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was heated to 40° C. by adding saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (10 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0735] 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

[0736] In N 2 , DIPEA (1 mL, 5.7 mmol) was added to a mixture of [3-[6-[bis(tert-butoxycarbonyl)amino]-5-chloro-3-pyridyl]cyclopentyl]carbonate (4-nitrophenyl) (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) at 25°C. 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 x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0737] Step 5 Synthesis of 3-(6-amino-5-chloropyridin-3-yl)cyclopentyl(4,4,4-trifluorobutan-2-yl)carbamate

[0738] In N 2 To a mixture of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[3-[[(1S)-3,3,3-trifluoro-1-methyl-propyl]carbamoyloxy]cyclopentyl]-2-pyridinyl]carbamate (1.05 g, 1.86 mmol) in DCM (10 mL) was added TFA (3 mL, 40.32 mmol) at 25 °C. 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 without further purification. LCMS (ESI) m / z: 366.0 [M+H] + .

[0739] Step Synthesis of 3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl 6-((S)-4,4,4-trifluorobutan-2-yl)carbamate

[0740] In N 2 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), Cs 2 CO 3 (1.34 g, 4.1 mmol). The reaction mixture was stirred at N 2 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) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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 + ).

[0741] 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

[0742] 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 prepared by chiral SFC (DAICELCHIRALCEL OJ (250 mm*30 mm, 10 um); supercritical CO 2 / EtOH+0.1% NH 3 ·H 2 O=75 / 25; 60 mL / min)) to give ((S)-(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, a 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, a mixture of the third and fourth peaks) as a white solid.

[0743] 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)

[0744] In N 2To a solution of ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid (1RS,3SR)-3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl)cyclopentyl ester (25 mg, 40 μmol) in dioxane (2 mL) was added HCl / dioxane (2 mL, 4 M) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 35%-63% / 0.05% HCl in water) to give compound 353 (7.2 mg, 34%) as a white solid. LCMS (ESI) m / z: 521.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ8.72(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,1 H),2.44-2.32(m,2H),2.27-2.17(m,1H),2.15-2.07(m,1H),2.06-1.9 7(m,1H),1.94-1.83(m,1H),1.72-1.49(m,2H),1.13(d,J=6.4Hz,3H).

[0745] Example 13: Synthesis of ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid (1RS,4RS)-4-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopent-2-en-1-yl ester (Compound 412)

[0746]

[0747] Step 1: Synthesis of rac-tert-butyl (tert-butyloxycarbonyl)(5-((1R,4R)-4-((tert-butyldiphenylsilyl)oxy)cyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate

[0748] N-(5-bromopyrimidin-2-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (3 g, 8.0 mmol), tert-butyl-cyclopent-3-en-1-yloxy-diphenyl-silane (3.9 g, 12.0 mmol), Pd(OAc) 2 (180 mg, 802 μmol), KOAc (1.57 g, 16.0 mmol) and PPh 3A mixture of (420 mg, 1.60 mmol) in DMF (20 mL) was degassed and heated to 40 °C with N 2 The gas was purged three times, and then the mixture was heated in a microwave reactor under N 2 The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (30 mL x 3), and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate 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 HNMR (400MHz, CDCl 3 )δ8.44(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,1 H),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).

[0749] Step 2: Synthesis of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,4R)-4-hydroxycyclopent-2-en-1-yl)pyrimidin-2-yl)carbamate

[0750] (tert-Butyloxycarbonyl)(5-((1R,4R)-4-((tert-Butyldiphenylsilyl)oxy)cyclopent-2-en-1-yl)pyrimidin-2-yl)carbamic acid rac To a solution of -tert-butyl ester (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 x 3), and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0751] 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

[0752] 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) and DMAP (34 mg, 280 μmol) in DCM (10 mL) was added (4-nitrophenyl)chloroformate (424 mg, 2.1 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was heated to 40 °C by adding saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (10 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0753] 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

[0754] 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 heated to 40 °C by adding saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (10 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3) and purified by anhydrous Na 2 SO 4Dry, filter and concentrate 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] + .

[0755] Step 5: Synthesis of ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid (1RS,4RS)-4-(2-aminopyrimidin-5-yl)cyclopent-2-en-1-yl ester

[0756] To a solution of tert-butyl (tert-butoxycarbonyl)(5-((1RS,4RS)-4-((((S)-4,4,4-trifluorobut-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 without further purification. LCMS (ESI) m / z: 331.3 [M+H] + .

[0757] Step 6: Synthesis of ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid (1RS,4RS)-4-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopent-2-en-1-yl ester (Compound 412)

[0758] To ((S)-4,4,4-trifluorobutan-2-yl)carbamate (1RS,4RS)-4-(2-aminopyrimidin-5-yl)cyclopent-2-en-1-yl ester (0.15 g, 454 μmol), tert-butyl N-(4-bromophenyl)sulfonylcarbamate (305 mg, 908 μmol), Cs 2 CO 3 To a mixture of dioxane (5 mL) was added Brettphos (24 mg, 45 μmol), Cs 2 CO 3 (296 mg, 908 μmol) and BrettPhos Pd G3 (41 mg, 45 μmol), then in N 2 The mixture was stirred at 100° C. for 3 h under atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (10 mL×3), and dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 0-35% / 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 (400 MHz, DMSO-d 6 )δ10.18(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).

[0759] 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)

[0760]

[0761] Step 1: Synthesis of 5-(3-(benzyloxy)cyclobutyl)pyrimidin-2-amine

[0762] To a solution of (2-aminopyrimidin-5-yl)boronic acid (3.0 g, 21.6 mmol) in dioxane (100 mL) were added N-[(3-benzyloxycyclobutylidene)amino]-4-methyl-benzenesulfonamide (14.2 g, 43.2 mmol, prepared according to the procedure in WO 2021 / 155320, which is incorporated by reference in its entirety) and Cs 2 CO 3(14.1g, 43.2mmol). The mixture was stirred at 100°C for 16h. 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 (3.5g, crude product), which was further purified by reverse phase chromatography (acetonitrile 17-47% / 0.225% formic acid in water) to give the title compound (1.3g, 24%) as a yellow solid. LCMS (ESI) m / z: 256.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.21-8.08(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).

[0763] Step 2: Synthesis of 4-((5-(3-(benzyloxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluoro-N-isopropylbenzenesulfonamide

[0764] To a solution of 5-(3-benzyloxycyclobutyl)pyrimidin-2-amine (0.4 g, 1.33 mmol) and 4-bromo-3-fluoro-N-isopropyl-benzenesulfonamide (786 mg, 2.65 mmol) in dioxane (10 mL) was added Cs 2 CO 3 (1.30 g, 3.98 mmol), BrettPhos (71 mg, 132 μmol) and BrettPhos Pd G3 (120 mg, 132 μmol). The mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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 (400 MHz, DMSO-d 6)δ9.42(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),4.2 9-4.26(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).

[0765] Step 3: Synthesis of 3-fluoro-4-((5-(3-hydroxycyclobutyl)pyrimidin-2-yl)amino)-N-isopropylbenzenesulfonamide

[0766] 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) was slowly added BCl 3 (1M, 11.69 mL). After addition, the mixture was stirred at -78 °C for 2 h. The reaction mixture was washed with NH 3 / MeOH (1M, 5 mL) and then 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 (0.42 g, 95%) as a colorless oil. LCMS (ESI) m / z: 381.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.46-9.29(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).

[0767] Step 4: Synthesis of 3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl (4-nitrophenyl) carbonate

[0768] 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). Then (4-nitrophenyl)chloroformate (392 mg, 1.95 mmol) was slowly added. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with water (20 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (20 mL x 3) and purified by chromatography on anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (0.43 g, 81%) as a white solid. LCMS (ESI) m / z: 546.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.47(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).

[0769] 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)

[0770] To a mixture of 1-methylcyclopropylamine (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 h. The reaction mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 37-77% / 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, containing 8% cis isomer) as a white solid. The reaction mixture was purified by chiral SFC (DAICEL CHIRALCEL AS (250 mm*30 mm, 5 um); supercritical CO 2 / EtOH + 0.1% NH 3 ·H 2 O=65 / 35;80mL / min) to further separate the trans isomer to obtain (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] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.45(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 (400 MHz, DMSO-d 6)δ9.46(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,1 H),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).

[0771] 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)

[0772]

[0773] 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

[0774] 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 nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction was washed with saturated NH 4 The mixture was quenched with aqueous Cl solution (3 mL) and then treated with H 2 O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0775] Step 2: Synthesis of 5-((1s,3s)-3-((1-isopropyl-1H-1,2,4-triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-amine

[0776] 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 without further purification. LCMS (ESI) m / z 275.2 [M+H] + .

[0777] 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

[0778] To 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 Cs 2 CO 3 To a solution of 1,4-dioxane (267 mg, 820 μmol) was added BrettPhos (15 mg, 27 μmol) and BrettPhos PdG3 (25 mg, 27 μmol). The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. 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) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0779] 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)

[0780] 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 h. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 25%-55% / 0.225% formic acid in water) to give compound 367 (68 mg, 85%) as a white solid. LCMS (ESI) m / z: 448.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.39(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).

[0781] 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)

[0782]

[0783] Step 1: Synthesis of (4-bromo-3-fluorophenyl)dimethylphosphine oxide

[0784] To a solution of 1-bromo-2-fluoro-4-iodo-benzene (1 g, 3.32 mmol) and methylphosphonomethane (350 mg, 4.49 mmol) in THF (15 mL) and dioxane (15 mL) was added Pd 2 (dba) 3 (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 nitrogen for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and brine (30 mL). The organic layer was washed with anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to give the title compound (220 mg, 26%) as a white solid. LCMS (ESI) m / z: 251.1 [M+H] + .

[0785] 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)

[0786] 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 Cs 2 CO 3 1-Bromo-4-dimethylphosphoryl-2-fluoro-benzene (42 mg, 168 μmol), BrettPhos (8 mg, 16 μmol) and BrettPhos Pd G3 (14 mg, 16 μmol) were added to a solution of (204 mg, 629 μmol) in dioxane (2 mL). The reaction mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 20%-50% / 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 (400 MHz, DMSO-d 6 )δ9.30(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).

[0787] 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)

[0788]

[0789] Step 1: Synthesis of N-cyclobutylene-2-methylpropane-2-sulfenamide

[0790] To a solution of 5-bromo-2-methylsulfhydryl-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 min. N-cyclobutylene-2-methyl-propane-2-sulfinamide (454 mg, 2.62 mmol) in THF (1 mL) was then added to the reaction mixture and stirred at -78 °C for 2 h under a nitrogen atmosphere. The reaction was heated with saturated NH 4 The mixture was quenched with aqueous Cl solution (3 mL) and then treated with H 2 O (20 mL), and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0791] Step 2: Synthesis of 2-methyl-N-(1-(2-(methylsulfonyl)thiazol-5-yl)cyclobutyl)propane-2-sulfenamide

[0792] To 2-methyl-N-(1-(2-(methylthio)thiazol-5-yl)cyclobutyl)propane-2-sulfenamide (150 mg, 0.49 mmol) in MeCN (3 mL) and H 2 O (1 mL) was added to the mixture of 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 then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo gave the title compound (110 mg, crude) as a yellow oil without further purification.

[0793] 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

[0794] 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, and then 2-methyl-N-[1-(2-methylsulfonylthiazol-5-yl)cyclobutyl]propane-2-sulfenamide (110 mg, 0.34 mmol) was added. The mixture was stirred at 40°C under nitrogen for 16 h. The reaction was heated with saturated NH 4 The mixture was quenched with aqueous Cl solution (3 mL) and then treated with H 2 O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0795] Step 4: N-(1-(2-((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyloxy)thiazol-5-yl)cyclobutyl)-2-methylpropane-2-sulfenamide

[0796] 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 without further purification. LCMS (ESI) m / z: 422.1 [M+H] + .

[0797] 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

[0798] To N-(1-(2-((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyloxy)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 Cs 2 CO 3 To a solution of 186 mg, 569 μmol of 1% pyrrolidone (10 mg, 19 μmol) in dioxane (3 mL) was added BrettPhos (10 mg, 19 μmol) and BrettPhos Pd G3 (9 mg, 9 μmol). The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. 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) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0799] Step 6: 4-((5-((1s,3s)-3-((5-(1-aminocyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide (Compound 368)

[0800] 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, 4M) was stirred at room temperature for 2 h. This mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 15%-45% / 0.04% HCl in water) to give compound 368 (10.4 mg, 62%) as a white solid. LCMS (ESI) m / z: 513.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.45(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).

[0801] 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)

[0802]

[0803] Step 1: Synthesis of N-[[3-(benzyloxymethyl)cyclobutylidene]amino]-4-methyl-benzenesulfonamide

[0804] To a mixture of 3-(benzyloxymethyl)cyclobutanone (5 g, 26.28 mmol) in MeOH (50 mL) was added 4-methylbenzenesulfonylhydrazide (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 without further purification. LCMS (ESI) m / z: 359.0 [M+H] + . 1 HNMR (400MHz, CDCl 3 )δ7.87-7.60(m,2H),7.50-7.29(m,7H),4.59-4.47(m,2H),3.65-3.40(m,2H),319-3.05(m,1 H),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).

[0805] Step 2: Synthesis of 5-(3-((Benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine

[0806] To a mixture of (2-aminopyrimidin-5-yl)boronic acid (3.85 g, 27.72 mmol) in dioxane (150 mL) were added N-[[3-(benzyloxymethyl)cyclobutylidene]amino]-4-methyl-benzenesulfonamide (19.80 g, 55.24 mmol) and Cs 2 CO 3 (13.51g, 40.52mmol). The mixture was stirred at 105 ° C for 16h. 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: 0-50% EtOAc in petroleum ether) to give the title compound (3.5g, crude product). The crude product was further purified by reverse phase chromatography (acetonitrile 25-55% / 0.225% formic acid in water) to give the title compound (1.75g, 22%) as a yellow solid. LCMS (ESI) m / z: 270.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ8.23-8.15(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).

[0807] Step 3: Synthesis of tert-butyl ((4-((5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)carbamate

[0808] To a solution of 5-[3-(benzyloxymethyl)cyclobutyl]pyrimidin-2-amine (1.3 g, 4.83 mmol) in dioxane (40 mL) were added tert-butyl N-(4-bromo-3-fluoro-phenyl)sulfonylcarbamate (2.22 g, 6.27 mmol), Cs 2 CO 3 (4.72 g, 14.48 mmol), BrettPhos (259 mg, 482.66 μmol) and BrettPhos Pd G3 (437.53 mg, 482.66 μmol). The reaction was stirred at 100 ° C for 16 h under a nitrogen atmosphere. After cooling to room temperature, EtOAc (50 mL) was added, and then the pH was adjusted to 7 by gradually adding HCl aqueous solution (0.5 M). The mixture was washed with water (20 mL) and brine (20 mL). The organic layer was filtered through anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-40% EtOAc in petroleum ether) to give the title compound (1.9 g, 72%) as a brown solid. LCMS (ESI) m / z: 543.2 [M+H] + .

[0809] Step 4: Synthesis of 3-fluoro-4-((5-(3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0810] To a solution of tert-butyl N-[4-[[5-[3-(benzyloxymethyl)cyclobutyl]pyrimidin-2-yl]amino]-3-fluoro-phenyl]sulfonylcarbamate (1.9 g, 3.50 mmol) in DCM (10 mL) was added BCl under nitrogen atmosphere. 3 (1M, 17.51 ​​mL). The mixture was stirred at -78 °C for 2 h. The reaction mixture was washed with MeOH:NH 3 ·H 2 O=10:1 (5 mL) was quenched, and the mixture was then 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] + .

[0811] Step 5: Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl (4-nitrophenyl) carbonate

[0812] 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 chloroformic acid (4-nitrophenyl) ester (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 then washed with water (20 mL) and brine (20 mL). The organic layer was purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (82 mg, 43%) as a white solid. LCMS (ESI) m / z: 518.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.43-9.38(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),4.47-4.2 5(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).

[0813] Step 6: Synthesis of (S)-(3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl (4,4,4-trifluorobutan-2-yl)carbamate:

[0814] To a solution of [3-[2-(2-fluoro-4-sulfamoyl-phenylamino)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 Et 3 N (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 then washed with water (10 mL) and brine (10 mL). The organic layer was purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (36 mg, 74%) as a white solid. LCMS (ESI) m / z: 506.1 [M+H] + .

[0815] 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)

[0816] A mixture of (S)-(4,4,4-trifluorobutan-2-yl)carbamic acid (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ester (36 mg, 71.22 μmol) was prepared by chiral SFC (DAICEL CHIRALCEL AS (250 mm*30 mm, 5 um); supercritical CO 2 / EtOH+0.1% NH 3 ·H 2 O=60 / 40;100ml / min) to obtain ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid ((1s,3R)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ester (Compound 4, 8.82mg, first peak) as a white solid. LC-MS: (ES+H, m / z) 506.1 [M+H] + ; 1 HNMR (400 MHz, DMSO-d 6 )δ9.37(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. And ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid ((1r,3S)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ester (Compound 5, 18.10 mg, second peak) as a white solid. LC-MS: (ES+H, m / z) 506.1 [M+H] + ; 1 HNMR (400 MHz, DMSO-d 6)δ9.37(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.

[0817] 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)

[0818]

[0819] Step 1: Synthesis of 3-(Benzyloxy)isothiazole

[0820] To a solution of isothiazol-3-one (5 g, 49 mmol) in DMF (50 mL) was added K 2 CO 3 (13.67 g, 98.9 mmol) and BnBr (10.15 g, 59.3 mmol). 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 x 5) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% ethyl acetate in petroleum ether) to give the title compound (6.7 g, 71%) as a yellow oil. LCMS (ESI) m / z: 191.8 [M+H] + .

[0821] Step 2: Synthesis of 3-(Benzyloxy)-4-bromoisothiazole

[0822] 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 x 3). The combined organic layers were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% ethyl acetate in petroleum ether) to give the title compound (7.3 g, 77%) as a colorless oil. LCMS (ESI) m / z: 269.8, 271.8 [M+H] + .

[0823] Step 3: Synthesis of 3-(benzyloxy)-4-iodoisothiazole

[0824] To a mixture of 3-benzyloxy-4-bromo-isothiazole (1 g, 3.7 mmol) in THF (10 mL) was added chloro(isopropyl)magnesium (2 M, 2.8 mL) dropwise under nitrogen at 0° C. The mixture was stirred at 0° C. for 30 min, and then 1-(2-hydroxy-4-bromo-isothiazole) in THF (10 mL) was added dropwise at 0° C. 2 (1.41 g, 5.5 mmol) and stirred for 1 h. The resulting mixture was washed with saturated Na 2 SO 3 The aqueous solution (10 mL) was quenched and diluted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% ethyl acetate in petroleum ether) to give the title compound (1 g, 90%) as a yellow oil. LCMS (ESI) m / z: 317.8 [M+H] + .

[0825] Step 4: Synthesis of 3-(benzyloxy)-4-(trifluoromethyl)isothiazole

[0826] In N 2To a solution of CuI (528 mg, 2.77 mmol) in DMF (15 mL) was added 2,2-difluoro-2-fluorosulfonyl-acetic acid methyl ester (969 mg, 5.05 mmol) under atmosphere. The mixture was stirred at 25 ° C for 5 min, then 3-benzyloxy-4-iodo-isothiazole (0.8 g, 2.5 mmol) was added and the reaction was stirred at 80 ° C for 16 h. 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 x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% ethyl acetate in petroleum ether) to give the title compound (0.33 g, 50%) as a yellow oil. LCMS (ESI) m / z: 260.0 [M+H] + .

[0827] Step 5: Synthesis of 4-(trifluoromethyl)isothiazol-3-ol

[0828] 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 x 3). The combined organic layers were washed with brine (10 mL x 2) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% ethyl acetate in petroleum ether) to give the title compound (190 mg, 88%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.57(s,1H),9.44(s,1H). LCMS(ESI)m / z:169.8[M+H] + .

[0829] Step 6: Synthesis of 5-(3-((Benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine

[0830] To a mixture of (2-aminopyrimidin-5-yl)boronic acid (3.85 g, 27.72 mmol) in dioxane (150 mL) were added N-[[3-(benzyloxymethyl)cyclobutylidene]amino]-4-methyl-benzenesulfonamide (19.80 g, 55.24 mmol) and Cs 2 CO 3(13.51g, 40.52mmol). The mixture was stirred at 105 ° C for 16h. 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: 0-50% EtOAc in petroleum ether) to give the title compound (3.5g, crude product). The crude product was further purified by reverse phase chromatography (acetonitrile 25%-55% / 0.225% formic acid in water) to give the title compound (1.75g, 22%) as a yellow solid. LCMS (ESI) m / z: 270.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ8.23-8.15(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).

[0831] 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:

[0832] A mixture of 5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (300 g, 1.12 mol) was prepared by using chiral SFC (DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); supercritical CO 2 / EtOH+0.1% NH 3 ·H 2 O=60 / 40;220ml / min) to obtain 5-((1s,3s)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (125g, first peak, cis isomer) and 5-((1r,3r)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (130g, second peak, trans isomer) both as white solids. First peak (cis isomer): LCMS (ESI) m / z: 270.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)δ8.12(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). Second peak (trans isomer): LCMS(ESI)m / z:270.0[M+H] + ; 1 HNMR (400 MHz, DMSO-d 6 )δ8.16(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).

[0833] Step 8: Synthesis of ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl)methanol

[0834] 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 BCl dropwise under nitrogen atmosphere. 3 (1M, 100 mL). The mixture was stirred at -78 °C for 48 h. The reaction was washed with NH 3 · Quench with MeOH (7M, 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] + .

[0835] Step 9: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((1s,3s)-3-(((tert-butoxycarbonyl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate

[0836] To a solution of ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl)methanol (4 g, 22.3 mmol) in THF (50 mL) were added DMAP (545 mg, 4.5 mmol) and Boc 2 O (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] + .

[0837] Step 10: Synthesis of tert-butyl (5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)carbamate

[0838] 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) were dissolved in EtOH (100 mL) and H 2 The mixture in 2% HCl (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 x 3). The combined organic layers were washed with brine (50 mL x 3) and purified by HPLC. 2 SO 4 Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-100% ethyl acetate in petroleum ether) to give the title compound (9 g, 85%) as a white solid. LCMS (ESI) m / z: 280.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.43(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).

[0839] Step 11: Synthesis of tert-butyl ((4-((5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate

[0840] tert-Butyl (5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2-yl)carbamate 1 (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 Cs 2 CO 3 A mixture of 2-nitropropene (5.45 g, 16.7 mmol) in dioxane (20 mL) was degassed and heated to 40 ℃ for 2 h. 2 The mixture was then purged three times under N 2The mixture was stirred at 100 °C 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) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0841] Step 12: Synthesis of ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl methanesulfonate

[0842] 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 extracted with DCM (50 mL). The organic layer was washed with brine (20 mL), purified by chromatography on anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give the title compound (1 g, crude) as a yellow oil without further purification. LCMS (ESI) m / z: 513.2 [M+H + ].

[0843] 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

[0844] 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 K 2 CO 3(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 x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% ethyl acetate in petroleum ether) to give the title compound (160 mg, 70%) as a yellow oil. LCMS (ESI) m / z: 586.1 [M+H] + .

[0845] 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)

[0846] 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 50%-80% / HCl in water) to give Compound 586 (25 mg, 17%) as a white solid. LCMS (ESI) m / z: 486.0 [M+H] + ; 1 HNMR (400 MHz, DMSO-d 6 )δ10.03(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,2 H),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).

[0847] 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)

[0848]

[0849] 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

[0850] 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 K 2 CO 3 A mixture of (344 mg, 2.5 mmol) in DMF (5 mL) was stirred for 16 h. The reaction was diluted with EtOAc (50 mL) and water (20 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 17%-57% / 0.225% formic acid in water) to give the title compound (80 mg, 85%) as a yellow oil. LCMS (ESI) m / z: 613.2 [M+H] + .

[0851] 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)

[0852] 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, 4M) 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 (400 MHz, DMSO-d 6)δ11.08-10.93(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( dd,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).

[0853] 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)

[0854]

[0855] Step 1: Synthesis of tert-butyl (5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate

[0856] In N 2 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) at 0 ° C. The mixture was stirred at 0 ° C for 30 min. Then 3-chloro-4-isopropyl-pyridazine (560 mg, 3.58 mmol, prepared according to the procedure in WO2022 / 174031) was added at 0 ° C. The mixture was heated to 40 ° C for 16 h. 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 (30% ethanol in ether) in petroleum ether) to give the title compound (0.26 g, 36%) as a yellow oil. LCMS (ESI) m / z: 400.1 [M+H] + .

[0857] Step 2: Synthesis of 5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-amine

[0858] 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 solution was adjusted to pH 10 with aqueous NaOH (2 M) and the residue was purified by chromatography on anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give the title compound (0.18 g, crude) as a yellow oil without further purification. LCMS (ESI) m / z: 300.1 [M+H] + .

[0859] 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)

[0860] 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 K 3 PO 4 A mixture of (482 mg, 2.27 mmol) in dioxane (5 mL) was degassed and heated to 40 °C with N 2 The mixture was then purged 3 times under N 2 Stir at 80°C 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) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue. The product was purified by reverse phase chromatography (acetonitrile 51%-81% / 0.05% NH 3 ·H 2 O + 10 mM NH 4 HCO3 ) to obtain compound 571 (0.2 mg, 80%) as a white solid. LCMS (ESI) m / z: 611.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.46(s,1H),8.77(d,J=4.8Hz,1H),8.50(s,2H),8.32–8.26(m,1H),8.1 2(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).

[0861] 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)

[0862]

[0863] 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

[0864] In N 2 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) was added NaH (132 mg, 3.31 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 30 min. 3-Chloro-4-isopropyl-pyridazine (156 mg, 994 μmol, prepared according to the procedure in WO2022 / 174031) was then added at 0 °C. The mixture was heated to 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% (ethyl acetate / EtOH=3:1) in petroleum ether] to give the title compound (0.35 g, 92%) as a yellow oil. LCMS (ESI) m / z: 573.0 [M+H]+ .

[0865] 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)

[0866] 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 solution was adjusted to pH 10 with aqueous NaOH (2 M) and then to pH 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 29%-59% / 0.225% formic acid in water) to give Compound 495 (0.1 g, 40%) as a white solid. LCMS (ESI) m / z: 473.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ9.40(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).

[0867] 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)

[0868]

[0869] Step 1: Synthesis of 1-azidocyclopropane-1-carboxamide

[0870] To N-diazosulfamoyl fluoride (4.5 g, 36.0 mmol), 1-aminocyclopropanecarboxamide (4 g, 40 mmol) in DMF (5 mL) and H 2O (8 mL) was added to the mixture of NaHCO 3 (16.8 g, 200 mmol). The mixture was then heated under N 2 Stir at 0 °C for 1 h under atmosphere. Filter the reaction and concentrate the filtrate in vacuo. The crude residue was dissolved in ethyl acetate (100 mL), washed with brine (50 mL), and purified by anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo gave the title compound (4.5 g, crude) as a yellow oil which required no further purification.

[0871] Step 2: Synthesis of 1-(4-ethoxy-1H-1,2,3-triazol-1-yl)cyclopropane-1-carboxamide

[0872] To a mixture of 1-azidocyclopropanecarboxamide (1.2 g, 9.52 mmol) and ethynyloxyethane (1.33 g, 9.52 mmol) in DMF (5 mL) were added sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-ol ester (754 mg, 3.8 mmol) and copper sulfate (1.52 g, 9.5 mmol). The mixture was then stirred at N 2 At room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (50 mL x 3), and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (solvent gradient: 0-50% ethyl acetate in petroleum ether) to give the title compound (1.08 g, 58%) as a yellow oil.

[0873] Step 3: Synthesis of 1-(4-ethoxy-1H-1,2,3-triazol-1-yl)cyclopropane-1-carbonitrile

[0874] A mixture of 1-(4-ethoxytriazol-1-yl)cyclopropanecarboxamide (1.08 g, 5.50 mmol) and 2,4,6-trichloro-1,3,5-triazine (2.23 g, 12.1 mmol) in DMF (20 mL) was stirred at N 2 Stir under atmosphere at 25°C for 2 h. Quench the reaction with water (30 ml). Extract the solution with ethyl acetate (50 mL x 3). Wash the combined organic layers with brine (50 mL x 2) and dry them over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (solvent gradient: 0-50% ethyl acetate in petroleum ether) to give the title compound (0.5 g, 51%) as a yellow solid.1 H NMR (400 MHz, DMSO-d 6 )δ8.05(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).

[0875] Step 4: Synthesis of (1-(4-ethoxy-1H-1,2,3-triazol-1-yl)cyclopropyl)methanamine

[0876] 1-(4-ethoxytriazol-1-yl)cyclopropanecarbonitrile (0.3 g, 1.7 mmol) and NiCl 2 6H 2 To a solution of O (1.20 g, 5.05 mmol) in MeOH (5 mL) was added NaBH 4 (0.24 g, 6.34 mmol). The mixture was stirred at N 2 The mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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 (400 MHz, DMSO-d 6 )δ7.69(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).

[0877] Step 5: Synthesis of 1-(1-(aminomethyl)cyclopropyl)-1H-1,2,3-triazol-4-ol

[0878] A mixture of [1-(4-ethoxytriazol-1-yl)cyclopropyl]methanamine (150 mg, 823 μmol) and HBr in AcOH (5 mL, 30.4 mmol, 33% purity) was stirred at N 2 Stir at 100 °C for 16 h. The mixture was poured into water (20 ml) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3) and purified by anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM) to give the title compound (120 mg, 95%) as a yellow solid.

[0879] Step 6: Synthesis of tert-butyl ((1-(4-((tert-butoxycarbonyl)oxy)-1H-1,2,3-triazol-1-yl)cyclopropyl)methyl)carbamate

[0880] 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 Boc 2 O (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 (acetonitrile 35%-65% / 0.225% formic acid in water) to give the title compound (200 mg, 73%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.10(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).

[0881] Step 7: Synthesis of tert-butyl ((1-(4-hydroxy-1H-1,2,3-triazol-1-yl)cyclopropyl)methyl)carbamate

[0882] 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) were dissolved in EtOH (1 mL) and H 2 The mixture in 0 (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: 0-10% MeOH in DCM) to give the title compound (120 mg, 93%) as a yellow solid. LCMS (ESI) m / z: 255.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.97(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).

[0883] 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

[0884] 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 K 2 CO 3 A mixture of (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 x 3), and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile in formic acid water 40%-80% / 0.225%) to give the title compound as a brown solid (20 mg, 25%). LCMS (ESI) m / z: 689.3 [M+H] + .

[0885] 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)

[0886] 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 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 10%-40% / 0.04% HCl in water) to give compound 504 (5.87 mg, 86%) as a white solid. LCMS (ESI) m / z: 489.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)δ9.45(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).

[0887] 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)

[0888]

[0889] Step 1: Synthesis of (6-bromo-1H-indazol-1-yl)methanol

[0890] 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 heated to 40 °C. 2 The reaction was stirred at 50 °C for 16 h. After cooling to room temperature, the mixture was stirred at 0 °C by adding saturated NH 4 The reaction was quenched with aqueous Cl (5 mL) and then treated with H 2 O (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (2.1 g, 91%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ8.06-7.98(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).

[0891] Step 2: Synthesis of 6-bromo-1-(chloromethyl)-1H-indazole

[0892] (6-Bromoindazol-1-yl)methanol (500 mg, 2.20 mmol) was dissolved in SOCl 2 The mixture was degassed and heated with N 2 The mixture was then stirred at 0°C for 30 min. The mixture was purged three times. 4 The reaction was quenched with aqueous Cl (5 mL) and then treated with H 2 O (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (0.5 g, 9%) as a yellow oil.

[0893] Step 3: Synthesis of 1-((1H-1,2,3-triazol-1-yl)methyl)-6-bromo-1H-indazole

[0894] A mixture of 1H-triazole (0.1 mL, 1.88 mmol), t-BuOK (317 mg, 2.82 mmol) in THF (5 mL) was degassed and heated to 40 ℃ for 2 h. 2 After the mixture was stirred at 25°C for 30 min, 6-bromo-1-(chloromethyl)indazole (462 mg, 1.88 mmol) was added, and the mixture was then stirred at N 2 Stir for 30 min under atmosphere. Quench the reaction with water (30 ml). Extract the mixture with ethyl acetate (50 mL x 3). Wash the combined organic layers with brine (50 mL x 2) and dry them with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (0.18 g, 34%) as a yellow solid.

[0895] 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)

[0896] To 6-bromo-1-(triazol-1-ylmethyl)indazole (63 mg, 226 μmol), ((S)-4,4,4-trifluorobutan-2-yl)carbamic acid ((1s,3R)-3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl ester (50 mg, 150 μmol) and Cs2 CO 3 To a solution of 1,2-dioxane (2 mL) and 1,4-dioxane (294 mg, 903 μmol) were added Brettphos (8 mg, 15 μmol) and BrettPhos Pd G3 (14 mg, 15 μmol). The mixture was stirred under N 2 The reaction mixture 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 x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 23%-63% / 0.025% formic acid in water) 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-d 6 )δ9.88(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).

[0897] 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)

[0898]

[0899] 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

[0900] 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. Then 4-isopropyl-3-methylsulfonyl-1,2,4-triazole (271 mg, 1.43 mmol) was added. The mixture was stirred at N 2 At 40 °C, the reaction mixture was stirred for 72 h. 4 The mixture was quenched with aqueous Cl solution (3 mL) and then treated with H 2 O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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] + .

[0901] Step 2: Synthesis of 5-((1s,3s)-3-(((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2-amine

[0902] 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 without further purification. LCMS (ESI) m / z: 289.1 [M+H] + .

[0903] 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)

[0904] 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. NaBH(OAc) was then added 3 (661 mg, 3.1 mmol). The mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction was washed with saturated NaHCO 3 The aqueous solution (3 mL) was quenched with H 2 O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 20%-50% / 0.225% formic acid in water) to give compound 477 (2.06 mg, 1.5%) as a white solid. LCMS (ESI) m / z: 450.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ8.20-8.23(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,2 H),3.28-3.19(m,2H),2.92-2.81(m,5H),2.77-2.67(m,1H),2.43-2.3 1(m,2H),1.96-1.89(m,3H),1.59-1.46(m,2H),1.34(d,J=6.8Hz,6H).

[0905] Example 26: (S)-(3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl (4,4,4-trifluorobutan-2-yl)carbamate 2 Synthesis of (Compound 321)

[0906]

[0907] Step 1: (5,8-dioxaspiro[3.4]octan-2-yl)methoxy-d 2 Synthesis of -alcohols

[0908] To a stirred solution of methyl 5,8-dioxaspiro[3.4]octane-2-carboxylate (4 g, 23.23 mmol, 1 eq.) in methanol-d (20 mL) was added sodium borodeuteride (2.92 g, 69.69 mmol, 3 eq.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with ice water at 0°C. The resulting mixture was washed with CHCl 3 :IPA (1:1) (3x100 mL). The combined organic layers were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. This gave (5,8-dioxaspiro[3.4]octan-2-yl)methan-d as a yellow oil. 2 -alcohol (3.3 g, crude product). LC-MS: (ES+H, m / z) 147.1 [M+H] +; 1 H NMR (400 MHz, DMSO-d 6 )δ4.60(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).

[0909] Step 2: 2-((Benzyloxy)methyl-d 2 Synthesis of )-5,8-dioxaspiro[3.4]octane

[0910] A solution of NaH (0.64 g, 26.7 mmol, 1.3 equiv) in THF (20 mL) was reacted with (5,8-dioxaspiro[3.4]octan-2-yl)methyl-d 2 -alcohol (3 g, 20.5 mmol, 1 eq.) was treated for 30 min, followed by the addition of BnBr (3.69 g, 21.5 mmol, 1.05 eq.) dropwise at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was washed with CHCl 3 :IPA (3:1) (3x100 mL). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 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 in water (0.1% NH 4 HCO 3 ), gradient 30% to 60% in 10 min; detector, UV 254 nm. This produced 2-((benzyloxy)methyl-d2 )-5,8-dioxaspiro[3.4]octane (3 g, 58%). LC-MS: (ES+H, m / z) 237.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ7.41-7.20(m,5H),4.46(s,2H),3.83-3.71(m,4H),2.35-2.17(m,3H),2.03-1.91(m,2H).

[0911] Step 3: 3-((Benzyloxy)methyl-d 2 )Synthesis of Cyclobutan-1-one

[0912] 2-((Benzyloxy)methyl-d 2 )-5,8-dioxaspiro[3.4]octane (3 g, 12.69 mmol, 1 eq.) in HCl (2 mL) and H 2 O (12 mL) was stirred at 60 °C for 1.5 h under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was washed with CHCl 3 :IPA (3x100mL) was extracted. The combined organic layers were washed with brine (50mL) and purified by anhydrous Na 2 SO 4 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 in water, 40% to 60% gradient in 10 min; detector, UV 200 nm. This produced 3-((benzyloxy)methyl-d 2 )Cyclobutan-1-one (2 g, 78%). LC-MS: (ES+H, m / z) 193.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ7.45-7.21(m,5H),4.51(s,2H),3.14-3.03(m,2H),2.86-2.74(m,2H),2.80-2.60(m,1H).

[0913] Steps 4 and 5: 5-(3-((Benzyloxy)methyl-d 2 Synthesis of 2-((cyclobutyl)pyrimidine)-2-amine

[0914] Under nitrogen atmosphere at room temperature, 3-((benzyloxy)methyl-d 2)cyclobutane-1-one (2 g, 10.40 mmol, 1 eq) was added to a stirred solution of MeOH (20 mL) with toluenesulfonyl hydrazide (2.03 g, 10.92 mmol, 1.05 eq). The resulting mixture was stirred at RT under 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.

[0915] In a nitrogen atmosphere at room temperature, N'-(3-((benzyloxy)methyl)-d 2 To a stirred solution of 1,4-dioxane (30 mL) was added Cs(2-(4-(cyclobutylene)-4-methylbenzenesulfonylhydrazide) (2.5 g, 6.93 mmol, 1 eq.) and 2-aminopyrimidin-5-ylboronic acid (1.45 g, 10.40 mmol, 1.5 eq.). 2 CO 3 (1.44 g, 10.40 mmol, 1.5 equiv.). The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The mixture was cooled 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 (3x100 mL). The combined organic layers were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4 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 in water (0.1% NH 4 HCO 3 ), gradient 40% to 60% in 18 min; detector, UV 254 nm. This produced 5-(3-((benzyloxy)methyl-d 2 )cyclobutyl)pyrimidin-2-amine (330 mg, 14%). LC-MS: (ES+H, m / z) 272.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ8.14(d,J=17.5Hz,2H),7.34(dd,J=5.6,2.6Hz,5H),6.40(s,2H),4.51(d,J=1.9Hz, 2H),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).

[0916] Step 6: (3-(2-aminopyrimidin-5-yl)cyclobutyl)methoxy-d 2 Synthesis of -alcohols

[0917] 5-(3-((Benzyloxy)methyl-d 2 A solution of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methan-2-amine (300 mg, 1.10 mmol, 1 eq.) and methanesulfonic acid (3.19 g, 33.18 mmol, 30 eq.) in DCM (1 mL) was stirred under nitrogen at room temperature for 1 h. The residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH (5:1-1:1) to afford (3-(2-aminopyrimidin-5-yl)cyclobutyl)methan-2-amine as a yellow oil. 2 -Alcohol (130 mg, 62%). LC-MS: (ES+H,m / z)182.1[M+H] + .

[0918] Step 7: (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl carbonate-d 2 Synthesis of (4-nitrophenyl) ester

[0919] Under nitrogen atmosphere at room temperature, (3-(2-aminopyrimidin-5-yl)cyclobutyl)methoxy-d 2 -alcohol (130 mg, 0.71 mmol, 1 eq.) and bis(4-nitrophenyl) carbonate (262 mg, 0.86 mmol, 1.2 eq.) were added DIEA (278 mg, 2.15 mmol, 3 eq.) and DMAP (18 mg, 0.14 mmol, 0.2 eq.) in a stirred solution of DCM (3 mL). The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 Dry. 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 in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. This produced (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl carbonate-d 2 (4-nitrophenyl) ester (150 mg, 54.34%). LC-MS: (ES+H, m / z) 347.1 [M+H] + .

[0920] Step 8: (S)-(3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl(4,4,4-trifluorobutan-2-yl)carbamate-d 2 Synthesis

[0921] To a stirred solution of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl)carbonate-d2(4-nitrophenyl)ester (140 mg, 0.40 mmol, 1 eq) and DIEA (156.74 mg, 1.21 mmol, 3 eq) in DMF (2 mL) was added (2S)-4,4,4-trifluorobutan-2-amine hydrochloride (132.24 mg, 0.80 mmol, 2 eq) under nitrogen atmosphere at room temperature. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 4 h. The mixture was allowed to cool to room temperature. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. This yielded (S)-(3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl(4,4,4-trifluorobutan-2-yl)carbamate-d as a yellow solid. 2 (110 mg, 73%). LC-MS:(ES+H,m / z)335.0[M+H] + .

[0922] Step 9: (S)-(3-(2-((4-(N-(tert-Butyloxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl(4,4,4-trifluorobutan-2-yl)carbamate 2 Synthesis

[0923] To (S)-(4,4,4-trifluorobutan-2-yl)carbamic acid (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl ester at room temperature 2 To a stirred solution of 1,4-dioxane (5 mL) was added Pd 2 (dba) 3 (54.78 mg, 0.06 mmol, 0.2 eq), Cs 2 CO 3 (292.36 mg, 0.89 mmol, 3 eq.) and XantPhos (34.61 mg, 0.06 mmol, 0.2 eq.). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4Dry. 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 in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. This produced (S)-(4,4,4-trifluorobutan-2-yl)carbamic acid (3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ester-d as a yellow solid 2 (120mg, 59%). LC-MS:(ES+H,m / z)608.0[M+H] + .

[0924] Step 10: (S)-(3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl(4,4,4-trifluorobutan-2-yl)carbamate 2 Synthesis of (Compound 321)

[0925] (S)-(4,4,4-trifluorobutan-2-yl)carbamic acid (3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ester 2 A solution of (120 mg, 0.19 mmol, 1 eq.) in formic acid (3 mL) was stirred at 50 °C for 30 min under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18; mobile phase, MeCN in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. The pure fractions were concentrated under reduced pressure and freeze-dried to give (S)-(4,4,4-trifluorobutan-2-yl)carbamic acid (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ester-d as a white solid. 2 (Compound 321, 75 mg, 71%). LC-MS: (ES+H, m / z) 508.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6)δ9.36(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.

[0926] Example 27: ((1s,3s)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2 Synthesis of (Compound 332)

[0927]

[0928] Step 1: 3-(Hydroxymethyl-d 2 )Synthesis of Cyclobutane-1-d-1-ol

[0929] To a mixture of methyl 3-oxocyclobutanecarboxylate (10 g, 78.1 mmol) in THF (200 mL) was added LiAlD 4 (5 g, 108.7 mmol). The reaction was then degassed and heated to 40 °C. 2 The gas was purged 3 times, and then the mixture was kept under N 2 The reaction was stirred at 25 °C for 16 h. 2 O (5 mL), aqueous NaOH (15%, 5 mL) and H 2 O (15 mL), diluted with ethyl acetate (300 mL), and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to give 3-(hydroxymethyl-d 2 ) cyclobutane-1-d-1-ol (7.6 g, crude) which was not further purified. 1 H NMR (400 MHz, DMSO-d 6 )δ4.85(s,1H),4.37(s,1H),2.17-2.09(m,2H),1.78-1.67(m,1H),1.52-1.43(m,2H).

[0930] Step 2: 3-(((tert-butyldiphenylsilyl)oxy)methyl-d 2 )Synthesis of Cyclobutane-1-d-1-ol

[0931] At 0 °C, 3-(hydroxymethyl-d 2 )cyclobutane-1-d-1-ol (7.6 g, 72.3 mmol) was added to a mixture of DCM (150 mL) with DMAP (883 mg, 7.2 mmol), TEA (20 mL, 144.6 mmol) and TBDPSCl (16.7 mL, 65.1 mmol), and the mixture was stirred at 0 °C for 2 h. The reaction was washed with DCM (100 mL) and H 2 The organic layer was washed with brine (50 mL x 2) and purified by anhydrous Na 2 SO 4 The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to afford 3-(((tert-butyldiphenylsilyl)oxy)methyl-d-(((tert-butyldiphenylsilyl)oxy)methyl) ... 2 )cyclobutane-1-d-1-ol (13.4 g, 54%).

[0932] Step 3: (5-(3-(((tert-butyldiphenylsilyl)oxy)methyl-d 2 Synthesis of tert-butyl 1-(2-(cyclobutyl-1-d)pyrimidin-2-yl)carbamate

[0933] To 3-(((tert-butyldiphenylsilyl)oxy)methyl-d 2 )cyclobutane-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 with pyridine (1.4 mL, 17.5 mmol). The reaction was stirred for 5 min. The mixture was filtered and the filtrate was heated to 40 ℃ for 2 h. 2 Under atmosphere, tert-butyl N-(5-bromopyrimidin-2-yl)carbamate (3.19 g, 11.6 mmol), NiBr 2 (dtbbpy) (283.5 mg, 582 μmol), quinuclidine (1.94 g, 17.5 mmol), Ir(ppy) 2 (dtbbpy)PF 6(159.6 mg, 174 μmol) in DMA (120 mL). The mixture was stirred and irradiated under a blue LED at room temperature for 16 h. EtOAc (400 mL) was added to dilute the mixture, and the mixture was washed with brine (100 mL x 3). The organic layer was purified by anhydrous Na 2 SO 4 The crude residue was purified by silica gel chromatography (solvent gradient: 0-40% EtOAc in petroleum ether) to afford (5-(3-(((tert-butyldiphenylsilanyl)oxy)methyl-d 2 )cyclobutyl-1-d)pyrimidin-2-yl)carbamic acid tert-butyl ester (2.9 g, 48%). LCMS (ESI) m / z: 521.3 [M+H] + .

[0934] Step 4: (5-(3-(hydroxymethyl-d 2 Synthesis of tert-butyl 1-(2-(cyclobutyl-1-d)pyrimidin-2-yl)carbamate

[0935] To (5-(3-(((tert-butyldiphenylsilyl)oxy)methyl-d 2 To a solution of tert-butyl 1-(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 x 3). The organic layer was purified by anhydrous Na 2 SO 4 The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% ethyl acetate in petroleum ether) to afford (5-(3-(hydroxymethyl-d 2 )cyclobutyl-1-d)pyrimidin-2-yl)carbamic acid tert-butyl ester (800 mg, 66%). LCMS (ESI) m / z: 283.2 [M+H] + .

[0936] Step 5: (5-(3-((((4-nitrophenoxy)carbonyl)oxy)methyl-d 2 Synthesis of tert-butyl 1-(2-(cyclobutyl-1-d)pyrimidin-2-yl)carbamate

[0937] To (5-(3-(hydroxymethyl-d 2To a solution of tert-butyl)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)chloroformate (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 x 3). The organic layer was purified by anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to afford (5-(3-((((4-nitrophenoxy)carbonyl)oxy)methyl-d 2 )cyclobutyl-1-d)pyrimidin-2-yl)carbamic acid tert-butyl ester (660 mg, 37%). LCMS (ESI) m / z: 392.2 [M-56+H] + .

[0938] Step 6: (5-(3-((((3,3-difluoro-1-methylcyclobutyl)carbamoyl)oxy)methyl-d 2 Synthesis of tert-butyl 1-(2-(cyclobutyl-1-d)pyrimidin-2-yl)carbamate

[0939] To (5-(3-((((4-nitrophenoxy)carbonyl)oxy)methyl-d 2 To a solution of tert-butyl 3-((4-((2-((cyclobutyl-1-d)pyrimidin-2-yl)carbamate (750 mg, 1.7 mmol) and 3,3-difluoro-1-methyl-cyclobutylamine (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 x 3). The organic layer was purified by anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to afford (5-(3-((((3,3-difluoro-1-methylcyclobutyl)carbamoyl)oxy)methyl-d 2 )cyclobutyl-1-d)pyrimidin-2-yl)carbamic acid tert-butyl ester (710 mg, 91%). LCMS (ESI) m / z: 430.3 [M+H] + .

[0940] Step 7: (1s,3s)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate2 and ((1r,3r)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2 Synthesis

[0941] (5-(3-((((3,3-difluoro-1-methylcyclobutyl)carbamoyl)oxy)methyl-d 2 tert-Butyl)cyclobutyl-1-(d)pyrimidin-2-yl)carbamate (710 mg, 1.7 mmol) was prepared by chiral SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); supercritical CO 2 / EtOH+0.1% NH 3 ·H 2 O=85 / 15;60mL / min) was separated to give ((1s,3s)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate as a white solid. 2 (181 mg, first peak, cis isomer, desired) and ((1r,3r)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate-d 2 (260 mg, second peak, trans isomer). LCMS (ESI) m / z: 430.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.93(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).

[0942] Step 8: (1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2 Synthesis

[0943] To ((1s,3s)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2To a solution of 180 mg, 419 μmol of cyclobutyl-3-yl)-1-nitropropane (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 (3,3-difluoro-1-methylcyclobutyl)carbamate as a white solid. 2 (160 mg, crude product), which did not require further purification. LCMS (ESI) m / z: 330.2 [M+H] + .

[0944] Step 9: ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2 Synthesis

[0945] To ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2 (80 mg, 243 μmol) and K 3 PO 4 To a mixture of dioxane (6 mL) was added tert-butyl N-(4-bromo-3-fluoro-phenyl)sulfonylcarbamate (258 mg, 729 μmol), Brettphos (26 mg, 49 μmol), and BrettPhos Pd G3 (44 mg, 49 μmol). The mixture was degassed and heated with N 2 The mixture was then purged three times under N 2 At 80 °C, the mixture was stirred 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 x 3). The organic layer was purified by anhydrous Na 2 SO 4 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 (3,3-difluoro-1-methylcyclobutyl)carbamate as a white solid. 2 (80mg, 41%). LCMS(ESI)m / z:603.3[M+H] + .

[0946] Step 10: ((1s,3s)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2 Synthesis

[0947] To ((1s,3s)-3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2 (80 mg, 100 μmol) was added to a solution of DCM (3 mL) with TFA (1 mL). 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), the pH was adjusted to 10 with aqueous NaOH (2 M), and then the pH was adjusted to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 36%-68% / 0.225% formic acid in water) to give compound 332 (26 mg, 51%) as a white solid. LCMS (ESI) m / z: 502.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 )δ9.38(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).

[0948] Example 28: ((1s,3s)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl-3-d)methyl (3,3-difluoro-1-methylcyclobutyl)carbamate 2 Synthesis of (Compound 172)

[0949]

[0950] Step 1: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[5-[3-hydroxycyclopentyl]pyrazin-2-yl]carbamate

[0951] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-oxocyclopentyl)pyrazin-2-yl]carbamate (720 mg, 1.91 mmol) in THF (10 mL) was added LiBHEt at -65 °C. 3(1 M, 2.7 mL). The reaction mixture was stirred at -65 °C for 1 h. The mixture was purified by adding saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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 (400 mg, 55%) as a white solid. LCMS (ESI) m / z: 380.2 [M+H + ].

[0952] Step 2: Synthesis of [3-[5-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]cyclopentyl](4-nitrophenyl)carbonate

[0953] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-hydroxycyclopentyl)pyrazin-2-yl]carbamate (340 mg, 896 μmol) in DCM (30 mL) was added DMAP (22 mg, 179 μmol), pyridine (212 mg, 2.69 mmol) and (4-nitrophenyl) chloroformate (361 mg, 1.79 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was heated to 40 °C by adding saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (20 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (100 mL x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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 (370 mg, 75%) as a white solid. LCMS (ESI) m / z: 545.2 [M+H + ].

[0954] Step 3: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-(3-((isopropylcarbamoyl)oxy)cyclopentyl)pyrazin-2-yl)carbamate

[0955] To a solution of [3-[5-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]cyclopentyl](4-nitrophenyl)carbonate (370 mg, 679 μmol) and propan-2-amine (201 mg, 3.40 mmol) in THF (4 mL) was added DIPEA (264 mg, 2.04 mmol). The mixture was stirred at 25 °C for 2 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 x 3) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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 (300 mg, 95%) as a white solid. LCMS (ESI) m / z: 465.3 [M+H + ].

[0956] Step 4: Synthesis of 3-(5-aminopyrazin-2-yl)cyclopentyl isopropylcarbamate

[0957] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-[3-(isopropylcarbamoyloxy)cyclopentyl]pyrazin-2-yl]carbamate (200 mg, 430 μmol) in DCM (3 mL) was added TFA (1 mL, 13.44 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo to give the title compound (0.11 g, crude, TFA salt) as a yellow oil without further purification. LCMS (ESI) m / z: 265.2 [M+H + ].

[0958] Step 5: Synthesis of 3-(5-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopentyl isopropylcarbamate

[0959] To a solution of tert-butyl N-(4-bromophenyl)sulfonylcarbamate (954 mg, 2.84 mmol) and [3-(5-aminopyrazin-2-yl)cyclopentyl]N-isopropylcarbamate (250 mg, 946 μmol) in dioxane (4 mL) was added Cs 2 CO 3 (2.47 g, 7.57 mmol), BrettPhos Pd G3 (85 mg, 94 μmol) and Brettphos (50 mg, 94 μmol). The reaction mixture was stirred at N 2The reaction mix...

Claims

1. A compound of formula (A), or a pharmaceutically acceptable salt thereof, in: R 1 For –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 -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -; optionally substituted by 1-2 substituents independently selected from halogen and C1-C6 alkyl -(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 N or CR X1 ; X 2 N or CR X2 ; R X1 and R X2 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–, where * indicates the same as X 1 -X 2 The connection point of 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, fluorine or C1-C6 alkyl; and R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl or optionally substituted 5-9 membered heterocyclyl.

2. The compound of claim 1, wherein R 1 For –NR A R B .

3. The compound as claimed in claim 1, wherein R 1 –C(=O)NR A R B .

4. The compound of claim 1, wherein R 1 = –OC(=O)NR A R B .

5. The compound according to any one of claims 1 to 4, wherein R A and R B are independently hydrogen, C1-C6 haloalkyl, unsubstituted C1-C6 alkyl or unsubstituted C3-C10 cycloalkyl.

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

7. A compound as claimed in any one of claims 1 to 6, wherein R A and R B Each is hydrogen.

8. A compound as claimed in any one of claims 1 to 6, wherein R A and R B Each is an unsubstituted C1-C6 alkyl group.

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

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

11. A compound as described in any one of claims 1 to 5 and 9, wherein R A and R B One of them is hydrogen, and R A and R B The other one of them is unsubstituted C1-C6 alkyl.

12. A compound as described in any one of claims 1 to 5 and 9, wherein R A and R B One of them is hydrogen, and R A and R B The other one of them is C1-C6 haloalkyl.

13. A compound as described in any one of claims 1 to 5 and 9, wherein R A and R B One of them is hydrogen, and R A and R B The other one of them is C2-C4 haloalkyl.

14. A compound as described in any one of claims 1 to 5 and 9, wherein R A and R B One of them is hydrogen, and R A and R B The other one of them is unsubstituted C3-C10 cycloalkyl.

15. A compound as described in any one of claims 1 to 5 and 9, wherein R A and R B One of them is hydrogen, and R A and R B The other one of them is a substituted C3-C10 cycloalkyl group.

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

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

18. A compound as described in any one of claims 1 and 16, wherein R 1 is an unsubstituted 5-10 membered heteroaryloxy group.

19. A compound as described in any one of claims 1 and 16 to 18, wherein R 1 The 5-10 membered heteroaryloxy group is a 5-6 membered heteroaryloxy group.

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

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

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

23. A compound as described in any one of claims 1 and 21, wherein R 1 is a substituted 5-10 membered heteroaryl group.

24. A compound as described in any one of claims 1 to 23, wherein R 2 is an optionally substituted 5-6 membered heteroaryl group.

25. A compound as described in any one of claims 1 to 24, wherein R 2 is an optionally substituted 5-membered heteroaryl group.

26. A compound as described in any one of claims 1 to 24, wherein R 2 is an unsubstituted 5-membered heteroaryl group.

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

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

29. A compound as described in any one of claims 1 to 24, wherein R 2 is an optionally substituted 6-membered heteroaryl group.

30. A compound as described in any one of claims 1 to 24 or 29, wherein R 2 It is an unsubstituted 6-membered heteroaryl group.

31. A compound as described in any one of claims 1 to 24 or 29, wherein R 2 is a substituted 6-membered heteroaryl.

32. A compound as described in any one of claims 1 to 24 or 29 to 31, wherein R 2 The 6-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

33. A compound as described in any one of claims 1 to 23, wherein R 2 is an optionally substituted 5-6 membered heterocyclic group.

34. A compound as described in any one of claims 1 to 23 or 33, wherein R 2 is an optionally substituted 5-membered heterocyclic group.

35. A compound as described in any one of claims 1 to 23 or 33 to 34, wherein R 2 It is an unsubstituted 5-membered heterocyclic group.

36. A compound as described in any one of claims 1 to 23 or 33 to 34, wherein R 2 It is a substituted 5-membered heterocyclic group.

37. A compound as described in any one of claims 1 to 23 or 33 to 36, wherein R 2 The 5-membered heterocyclic group is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinone, pyrazolidinyl, imidazolinyl, dioxolane, sulfolane, thiazolidinedione, succinimidyl, dihydrofuranone, pyrazolidinone, oxazolidinyl, isoxazolidinone, hydantoin, thiohydantoin, imidazolidinone, oxazolidinone, thiazolidinone, oxathiolanone, dioxolane, dioxazolidinone, oxadiazolidinone, triazolidinone, triazolidinethione, oxadiazolidinethione, dioxazolidinone, dioxolanethione, oxazolidinone, imidazolidinone and isothiazolidinone.

38. A compound as described in any one of claims 1 to 23 or 33, wherein R 2 is an optionally substituted 6-membered heterocyclic group.

39. A compound as described in any one of claims 1 to 23 or 38, wherein R 2 It is an unsubstituted 6-membered heterocyclic group.

40. A compound as described in any one of claims 1 to 23 or 38, wherein R 2 It is a substituted 6-membered heterocyclic group.

41. A compound as described in any one of claims 1 to 23 or 38 to 40, wherein R 2 The 6-membered heterocyclic group is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidonyl, dioxanonyl, oxazinalonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidonyl, piperidinedione, oxazinanedione, dihydropyrimidinedione, tetrahydropyridazinone, triazinanedione, oxadiazinanedione, dioxazinanedione, morpholinedione, piperazinedione, piperazinetrione and triazinanedione.

42. A compound as described in any one of claims 1 to 23, wherein R 2 is optionally substituted phenyl.

43. A compound as described in any one of claims 1 to 23 or 42, wherein R 2 It is an unsubstituted phenyl group.

44. A compound as described in any one of claims 1 to 23 or 42, wherein R 2 is a substituted phenyl group.

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

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

47. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42 or 44, wherein R 2 The group is replaced by a –(SO 2 )C3-C6 cycloalkyl substituted.

48. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42 or 44, wherein R 2 The group is replaced by a –(SO 2 )NHC3-C6 cycloalkyl, which is optionally substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl and C1-C6 haloalkyl.

49. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42 or 44, wherein R 2 The group is replaced by a -(SO 2 )NR H R I Substitution, where R H and R I and C1-C6 alkyl optionally substituted with hydroxy or C1-C6 alkoxy.

50. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42, 44 or 48, wherein R 2 The group is replaced by a -(SO 2 )NR H R I Substitution, where R H and R I One of the groups is H and the other is a C1-C6 alkyl group optionally substituted by a hydroxy group or a C1-C6 alkoxy group.

51. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42, 44 or 48, wherein R 2 The group is replaced by a -(SO 2 )NR H R I Substitution, where R H and R I One of the is H and the other is C1-C6 alkyl.

52. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42, 44 or 48, wherein R 2 The group is replaced by a -(SO 2 )NR H R I Substitution, where R H and R I One of the is H and the other is a C1-C6 alkyl group substituted with a hydroxy group.

53. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42 or 44, wherein the R 2 The group is substituted with one selected from the group consisting of:

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

55. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42 or 44, wherein R 2 The group is replaced by a –NH(SO 2 )C1-C3 alkyl substituted.

56. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42 or 44, wherein R 2 The group is replaced by a –(S(=NR L )(=O))C1-C6 alkyl substituted, wherein R L is H or a C1-C6 alkyl group optionally substituted by a hydroxy group.

57. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42 or 44, wherein R 2 The group is replaced by a –(S(=NR L )(=O))C1-C3 haloalkyl substituted, wherein R L is H or a C1-C6 alkyl group optionally substituted by a hydroxy group.

58. A compound as described in any one of claims 1 to 25, 27 to 29, 31 to 34, 36 to 38, 40 to 42 or 44, wherein R 2 The group is replaced by a –(S(=NR L )(=O))C3-C6 cycloalkyl substituted.

59. The compound of any one of claims 44 to 57, wherein at the substituted R 2 Each H on the radical is independently deuterium.

60. A compound as described in any one of claims 1 to 59, wherein X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

61. A compound as described in any one of claims 1 to 60, wherein X is -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.

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

63. A compound as described in any one of claims 1 to 62, wherein the -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -for–(CH 2 ) a C4-C6 cycloalkylene-(CH 2 ) b -.

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

65. A compound as described in any one of claims 1 to 59, wherein X is -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

66. A compound as described in any one of claims 1 to 59 and 65, wherein X is -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

67. A compound as described in any one of claims 1 to 59 and 65, wherein X is unsubstituted -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.

68. A compound as described in any one of claims 1 to 59, wherein X is -(CH 2 ) a Phenylene-(CH 2 ) b -.

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

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

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. A compound as described in 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. The compound of any one of claims 1 to 73, wherein b is 1.

76. A compound as described in any one of claims 1 to 73, wherein b is 2.

77. A compound as described in any one of claims 1 to 59, wherein X is C2-C6 alkylene.

78. A compound as described in any one of claims 1 to 59, wherein X is C2-C4 alkylene.

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

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

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

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

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

84. A compound as described in any one of claims 1 to 80 or 83, wherein R X1 It is a methoxy group.

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

86. A compound as described in any one of claims 1 to 80 or 85, wherein R X1 It is trifluoromethyl.

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

88. A compound as described in any one of claims 1 to 80 or 87, wherein R X1 It is trifluoromethoxy.

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

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

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

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

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

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

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

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

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

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

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

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

101. A compound as described in any one of claims 1 to 95 or 100, wherein R X2 It is trifluoromethyl.

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

103. A compound as described in any one of claims 1 to 95 or 102, wherein R X2 It is trifluoromethoxy.

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

105. A compound as described in any one of claims 1 to 95 or 104, wherein R X2 It is cyclopropyl.

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

107. A compound as described in any one of claims 1 to 95 or 106, wherein R X2 It is cyclopropyloxy.

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

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

110. A compound as described in any one of claims 1 to 95, wherein R X2 For hydrogen.

111. A compound as described in any one of claims 1 to 78 or 80 to 95, wherein X 1 is N.

112. A compound as described in any one of claims 1 to 79, 81 to 95 or 111, wherein X 2 is N.

113. The compound of any one of claims 1 to 112, wherein Y is *—C(═O)NR C (CR D R E ) n –, where * indicates 1 -X 2 The connection point of the ring.

114. The compound of any one of claims 1 to 112, wherein Y is *—NR C C(=O)(CR D R E ) n –, where * indicates 1 -X 2 The connection point of 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. A compound as described in any one of claims 1 to 117, wherein each R D and R E same.

119. The compound of any one of claims 1 to 117, wherein except for R D and R E Except for one difference in each R D and R E same.

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

121. The compound of any one of claims 1 to 117, wherein each R D and R E For fluorine.

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

123. A compound as described in any one of claims 1 to 117, wherein R D and R E One of them is methyl or fluorine, and the other R D and R E For hydrogen.

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

125. A compound as described in any one of claims 1 to 124, wherein R C It is a C1-C6 alkyl group.

126. A compound as described in any one of claims 1 to 125, wherein R C It is methyl.

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

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

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

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

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

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

133. The method of claim 132, wherein the step of identifying the cancer in the subject as a CDK2-related cancer comprises performing an assay to detect dysregulation of expression or activity or levels of a CDK2 gene, CDK2 protein, or 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-related cancer comprises performing an assay to detect dysregulation of expression or activity or levels of a cyclin A2 gene, a cyclin A2 protein, or either thereof 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-related cancer comprises performing an assay to detect dysregulation of expression or activity or levels of a Cyclin E1 gene, a Cyclin E1 protein, or any thereof 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-related cancer comprises performing an assay to detect dysregulation of expression or activity or levels of a cyclin E2 gene, a cyclin E2 protein, or any thereof in a sample from the subject.

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

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

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

141. A method for treating cancer in a subject in need thereof, comprising: include: 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 the subject; wherein the subject has been identified as having a CDK2-related cancer.

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

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

144. The method of claim 143, wherein the step of determining that the cancer in the subject is a CDK2-related cancer comprises performing an assay to detect dysregulation of expression or activity or level of a CDK2 gene, CDK2 protein, or any thereof 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-related cancer comprises performing an assay to detect dysregulation of expression or activity or levels of a cyclin A2 gene, a cyclin A2 protein, or any thereof 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-related cancer comprises performing an assay to detect dysregulation of expression or activity or levels of a Cyclin E1 gene, a Cyclin E1 protein, or any thereof 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-related cancer comprises performing an assay to detect dysregulation of expression or activity or levels of a cyclin E2 gene, a cyclin E2 protein, or any thereof in a sample from the subject.

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

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

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

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

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

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. 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. 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, and gastric cancer.

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

160. The method of any one of claims 131 to 159, wherein the 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.

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

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

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

164. A method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a compound as described in any one of claims 1 to 129, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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