Compounds for treating 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. The present application also describes pharmaceutical composition comprising a compound of Formula (A), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for treating diseases, such as cancer.

Description

[0001] COMPOUNDS FOR TREATING CANCER

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Application No. 63 / 609,175, filed on December 12, 2023, the contents of which are hereby incorporated by reference.

[0004] TECHNICAL FIELD

[0005] This present application relates to compounds, processes to prepare the compounds, compositions comprising the compounds, and methods of treating disorders (such as cancer) with the compounds or compositions.

[0006] BACKGROUND

[0007] Cyclin-dependent kinases (CDKs) perform essential functions in regulating eukaryotic cell division and proliferation. The cyclin-dependent kinase catalytic units are activated by regulatory subunits known as cyclins. 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 likely other heterodynes regulate cell cycle progression. Additional functions of cyclin / CDK heterodynes include regulation of transcription, DNA repair, differentiation and apoptosis. See Morgan D.O., Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291. Overexpression of CDK2 is associated with abnormal regulation of cell-cycle. The cyclin E / CDK2 complex plays and important role in regulation of the Gl / S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of Rb by cyclin E / Cdk2 releases the G1 transcription factor, E2F, and promotes S-phase entry. Activation of cyclin A / CDK2 during early S-phase promotes phosphorylation of endogenous substrates that permit DNA replication and inactivation of E2F, for S-phase completion. See Asghar et al., Nat. Rev. Drug. Discov. 2015; 14(2): 130-146.

[0008] Cyclin E is a regulatory cyclin for 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, gastric, endometrial and other cancers. See Nakayama et al., Cancer (2010) 116: 2621-34; Etemadmoghadam et al., Clin. Cancer Res. (2013) 19: 5960-71; Au-Yeung et al., Clin. Cancer Res. (2017) 23: 1862-1874; Ayhan et al., Modern Pathology (2017) 30: 297-303; Ooi et al., Hum. Pathol. (2017) 61 : 58-67; Noske et al., Oncotarget (2017) 8: 14794-14805. CDK2 in complex with cyclin E phosphorylates the tumor suppressor RBI during the G1 phase of the cell cycle. Fully phosphorylated RBI de-represses the E2F transcription factors which regulate transcription of DNA synthesis and repair genes including cyclin A2. CDK2 complexes with cyclin A2 to phosphorylate and regulate DNA-synthesis / repair processes during S-phase progression.

[0009] Amplification or overexpression of cyclin A (CCNA2) is known to be involved in several cancer types, including breast, liver, lung, and cervical. See, e.g., 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, Cyclin E2 (CCNE2) overexpression 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. Accordingly, inhibition of CDK2 can provide beneficial effects to cancers associated with aberrations in the cell cycle.

[0010] SUMMARY

[0011] Some embodiments provide a compound of Formula (A), or a pharmaceutically acceptable salt thereof, wherein:

[0012] R1is -NRARB, -C(=O)NRARB, -OC(=O)NRARB, an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each RAand RBare independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0013] Ring A is a 4-8 membered heterocyclyl; each Rxis independently halogen, C1-C6 alkyl, or C1-C6 alkoxy; m is 0, 1, or 2;

[0014] X1is N or CRX1; X2is N or CRX2;

[0015] CRX1and CRX2are 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;

[0016] Y is -NRC-, *-C(=O)NRc(CRDRE)n-, *-NRcC(=O)(CRDRE)n-, or -O-, wherein * indicates the point of connection to the X'-X2ring;

[0017] Rcis hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each RDand REare independently hydrogen, fluoro, or C1-C6 alkyl;

[0018] R2is phenyl optionally substituted with 1-4 independently selected R3, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R3, C3-C10 cycloalkyl optionally substituted with 1-4 independently selected R3, or 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3; each R3is independently selected from halogen, cyano, optionally substituted Cl -C6 alkyl, optionally substituted C1-C6 alkoxy, -NR3AR3B, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 haloalkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, -C(=O)NR3AR3B, -NR3AC(=O)R3B, -C(=O)R3C, -(SO2)NR3AR3B, - (SO2)R3C, optionally substituted 5-9 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;

[0019] R3Aand R3Bare independently selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0020] R3Cis optionally substituted alkyl, optionally substituted 5-9 membered heterocyclyl, optionally substituted C1-C6 alkoxy, or optionally substituted 5-10 membered heteroaryl.

[0021] 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.

[0022] 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.

[0023] Some embodiments provide a method for treating a cancer in a subject in need thereof, comprising: (a) identifying the cancer as being a CDK2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0024] Some embodiments provide a method for treating a cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the subject has been identified as having a CDK2-associated cancer.

[0025] Some embodiments provide a method of treating a CDK2-associated cancer, comprising administering 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, to a subject identified or diagnosed as having a CDK2-associated cancer.

[0026] Some embodiments provide a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with a dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity or level of any of the same; 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.

[0027] Some embodiments provide a method for inhibiting metastasis of a cancer in a subject having a 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.

[0028] Some embodiments provide a method for inhibiting cancer cell invasiveness in a subject having a 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.

[0029] Some embodiments provide a method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0030] 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.

[0031] Some embodiments provide a method for inducing apoptosis in mammalian cancer cells, comprising contacting the mammalian cell with a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entireties. In case of conflict, the present specification, including definitions, will control.

[0033] Other features and advantages of the disclosure will be apparent from the following detailed description and from the claims.

[0034] DETAILED DESCRIPTION

[0035] Definitions

[0036] The term “about,” when applied to a specific value or range, refers to ±10% of the specified value or range, e g., to account for experimental variance.

[0037] The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0038] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.

[0039] The term “tautomer,” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer. The following are examples of included tautomeric forms:

[0040] It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.

[0041] The term “halogen” refers to one of the halogens, group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0042] The term “alkyl” refers to a linear or branched hydrocarbon chain containing from 1-20 carbon atoms. The alkyl group may be denoted as, for example, a C1-12 alkyl group, which contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Examples of a C1-C6 alkyl group include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

[0043] The term “alkylene” refers to an alkyl group, as defined herein, which is a biradical and is connected to two other moieties. Non-limiting examples of alkylene groups include: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (IUPAC: (methyl)ethylene) (-CH2-CH(CH3)-), and isobutylene (IUPAC: 2-(methyl)propylene) (-CH2- CH(CH3)-CH2-). Alkylene groups can optionally include a C3-C4 cycloalkyl, as defined herein, that shares a carbon atom with the backbone of the alkylene chain, for example

[0044] The term “alkenyl” refers to an alkyl group as described herein containing carbon double bond(s) including, but not limited to, 1 -propenyl, 2-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2- butenyl and the like.

[0045] The term “alkynyl” refers to an alkyl group as described herein containing carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like.

[0046] The term “haloalkyl” refers to an alkyl group, as defined herein, substituted with at least one halogen atom independently chosen at each occurrence, 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 e.g., 1-chloroethyl and 2-chloroethyl, tri chloroethyl e.g., 1, 2, 2-tri chloroethyl, 2,2,2- tri chloroethyl, fluoroethyl e.g., 1 -fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g., 1,2,2- trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, tri chloropropyl, fluoropropyl, tri fluoropropyl.

[0047] The term “alkoxy” refers to an alkyl group, as defined herein, which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n- hexoxy.

[0048] As used herein, “haloalkoxy” refers to a O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, dihaloalkoxy and tri- haloalkoxy). In some instances, a haloalkoxy can be -OR, wherein R is a C1-4 alkyl substituted by 1, 2 or 3 halogens. Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2-fluoromethoxy and 2 -fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0049] As used herein, the term “aryl” refers to a 6-10 all carbon mono- or bicyclic group wherein at least one ring in the system is aromatic, i.e., a C6-C10 aryl. Non-limiting examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl. In bicyclic ring systems where only one ring is aromatic, the non-aromatic ring can be a cycloalkyl group, as defined herein.

[0050] As used herein, the term “heteroaryl” refers to a 5-10 membered mono- or bicyclic group wherein the ring system is aromatic; wherein one or more carbon atoms in at least one ring in the system is / are replaced with a heteroatom independently selected from N, O, and S. Heteroaryl groups include rings where one or more groups are oxidized, such as a pyridone moiety. Non- limiting examples of heteroaryl groups include pyridine, pyrimidine, pyrrole, imidazole, and indole.

[0051] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated 3-10 mono- or bicyclic hydrocarbon group; wherein bicyclic systems include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[l.l. l]pentyl.

[0052] The term “cycloalkoxy” refers to a cycloalkyl group, as defined herein, which is attached to a molecule via oxygen. This includes moieties where the cycloalkyl is saturated or partially unsaturated 3-10 mono- or bicyclic hydrocarbon group; wherein bicyclic systems include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkoxy groups include cyclopropoxyl, cyclobutoxyl, cyclopentyloxyl, and octahydropentalen-2-yl.

[0053] The term “heterocyclyl” refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system, that is not aromatic, having at least one heteroatom within the ring selected from N, O and S. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. The heterocyclyl ring system may include oxo substitution at one or more C, N, or S ring members. The heterocyclyl group may be denoted as, for example, a “5- 10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, azetidinyl, oxetanyl, 2- azaspiro[3.3]heptanyl, pyrrolidin-2-one, sulfolane, isothiazoline S,S-dioxide, and decahydronaphthalenyl.

[0054] The term “hydroxyl” refers to an -OH moiety.

[0055] The term “cyano” refers to a -CN moiety.

[0056] The term “nitro” refers to an -NO2moiety.

[0057] The term “azido” refers to an -N3moiety.

[0058] The term “isocyanato” group refers to a -NCO moiety.

[0059] The term “thiocyanato” group refers to a -CNS moiety. The term “isothiocyanate” group refers to an -NCS moiety.

[0060] The term “oxo” refers to an “=O” group attached to a carbon atom.

[0061] The term “acyl” refers to an alkyl group, connected as a substituent, via an oxo group. Examples include, but are not limited to, acetyl.

[0062] The term “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.

[0063] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy.

[0064] The term “thiocarb onyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy.

[0065] The term “O-carbamyl” group refers to a “-OC(=O)N(R R )” group in which R and R are independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0066] The term “N-carbamyl” group refers to an “ROC(=O)N(R ’)-” group in which R and R are independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0067] The term “O-thiocarbamyl” group refers to a “-OC(=S)-N(R’R”)” group in which R’ and R” are independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0068] The term “N-thiocarbamyl” group refers to an “ROC(=S)N(R’)-” group in which R and R’ are independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0069] The term “C-amido” group refers to a “-C(=O)N(R’R”)” group in which R’ and are independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cyclo alky l(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0070] The term “N-amido” group refers to a “RC(=O)N(R’)-” group in which R and R’ are independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0071] The term “S-sulfonamido” group refers to a “-SO2N(R’R”)” group in which R’ and R” independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl are, heterocyclyl, cyclo alky l(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.

[0072] The term “N-sulfonamido” group refers to a “RSO2N(R’)-” group in which R and R’ are independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0073] The term “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0074] The term “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl.

[0075] The term “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.

[0076] The term “aryl(alkyl)” refers to an aryl group connected, as a substituent, via an alkylene group as described herein. Examples include but are not limited to benzyl.

[0077] The term “heteroaryl(alkyl)” refers to a heteroaryl group connected, as a substituent, an alkylene group.

[0078] The term “heterocyclyl(alkyl)” refers to a heterocyclyl group connected, as a substituent, via an alkylene group.

[0079] The term “amino” refers to a -NH2group.

[0080] The term “mono-substituted amine” group refers to a “-NHR”’ group in which R’ can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. Examples of mono- substituted amine groups include, but are not limited to, -NH(methyl), -NH(phenyl) and the like.

[0081] The term “di-substituted amine” group refers to a “-NR’R”” group in which R’ and R” are independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. Examples of di-substituted amine groups include, but are not limited to, -N(methyl)2, - N(phenyl)(methyl), -N (ethyl)(methyl) and the like. As used herein, an asterisk (*) depicts the point of attachment of an atom or moiety to the indicated atom or group in the remainder of the molecule.

[0082] Whenever a group is described herein as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the 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 group(s) (such as 1, 2, 3, or 4) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O- carbamyl, N-carbamyl, O -thiocarb amyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N- sulfonamido, C-carboxy, O-carboxy, cyanate, isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, phosphine oxide, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amine group and a di-substituted amine group, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and (heterocyclyl)alkyl groups can be additionally substituted with one or more group(s) (such as 1, 2, 3, or 4) individually and independently selected from alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, cyanate, isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, phosphine oxide, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono- substituted amine group and a di-substituted amine group.

[0083] The compounds of Formula (A) include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula (A) also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and / or purifying compounds of Formula (A) and / or for separating enantiomers of compounds of Formula (A).

[0084] The term “pharmaceutically acceptable” indicates that the compound, or salt or composition thereof is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the subject being treated therewith.

[0085] Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (A), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to1H,2H,3H or mixtures thereof; when carbon is mentioned, it is understood to refer to "C,12C,13C,14C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to13N,14N,15N or mixtures thereof; when oxygen is mentioned, it is understood to refer to14O,15O,16O,17O,18O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to18F,19F or mixtures thereof; unless expressly noted otherwise. For example, in deuteroalkyl and deuteroalkoxy groups, where one or more hydrogen atoms are specifically replaced with deuterium (2H). AS some of the aforementioned isotopes are radioactive, the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0086] The ability of selected compounds to act as CDK2 inhibitors may be demonstrated by the biological assays described herein. Ki values are shown in Table A.

[0087] A “CDK2 inhibitor” as defined herein includes any compound exhibiting CDK2 inhibition activity. In some embodiments, a CDK2 inhibitor is selective for a CDK2 protein. Exemplary CDK2 inhibitors can exhibit inhibition activity (Ki) against CDK2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured in an assay as described herein. In some embodiments, a CDK2 inhibitor can exhibit inhibition activity (Ki) against CDK2 of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.

[0088] The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a CDK2-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular CDK2- associated cancer, and / or (iii) delay the onset of one or more symptoms of the particular CDK2- associated cancer described herein. A therapeutically effective amount can have the effect of, for example, reducing tumor size, inhibiting tumor growth, inhibiting cancer cell invasiveness, inhibiting metastasis, or a combination of any of the foregoing. The amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment.

[0089] Compounds of Formula (A), or a pharmaceutically acceptable salt thereof, are useful for treating diseases and disorders which can be treated with a CDK2 inhibitor, such as CDK2- associated cancers, such as solid tumors.

[0090] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0091] 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 exhibited at least one symptom of the cancer to be treated.

[0092] In certain embodiments, compounds of Formula (A), or a pharmaceutically acceptable salt thereof are useful for preventing diseases and disorders as defined herein. The term “preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0093] The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0094] The term “CDK2-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a CDK2 gene, a CDK2 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a CDK2 gene, a CDK2 protein, or the expression or activity or level of any of the same described herein). CDK2- associated cancers also include cancers associated with or having a dysregulation of a cyclin A2 gene, a cyclin A2 protein, or the expression or activity or level of any of the same, cancers associated with or having a dysregulation of a cyclin E 1 gene, a cyclin E1 protein, or the expression or activity or level of any of the same, and cancers associated with or having a dysregulation of a cyclin E2 gene, a cyclin E2 protein, or the expression or activity or level of any of the same. In some embodiments, a CDK-associated cancer is characterized by amplification or overexpression of CDK2. In some embodiments, a CDK-associated cancer is characterized by amplification or overexpression of cyclin A2 (CCNA2), cyclin E1 (CCNE1), and / or cyclin E2 (CCNE2). In some embodiments, a CDK-associated cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some embodiments, a CDK-associated cancer is characterized by amplification or overexpression of cyclin A2 (CCNA2). In some embodiments, a CDK-associated cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1). In some embodiments, a CDK-associated cancer is characterized by amplification or overexpression of cyclin E2 (CCNE2). Non-limiting examples of a CDK2-associated cancer are described herein.

[0095] An exemplary sequence of human CDK2 is shown below: SEQ ID NO: 1 (UniProt Accession No. P24941)

[0096] An exemplary sequence of human Cyclin E1 is shown below:

[0097] SEQ ID NO: 2 (UniProt Acession No. E1B9U2)

[0098] An exemplary sequence of human Cyclin E2 is shown below:

[0099] SEQ ID NO: 3 (UniProt Accession No. 096020)

[0100]

[0101] An exemplary sequence of human Cyclin A2 is shown below:

[0102] SEQ ID NO: 4 (UniProt Accession No. P20248)

[0103] Compounds of Formula (A)

[0104] Provided herein are compounds of Formula (A), or a pharmaceutically acceptable salt thereof, wherein:

[0105] R1is -NRARB, -C(=O)NRARB, -OC(=O)NRARB, an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each RAand RBare independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0106] Ring A is a 4-8 membered heterocyclyl; each Rxis independently halogen, C1-C6 alkyl, or C1-C6 alkoxy; m is 0, 1, or 2;

[0107] X1is N or CRX1;

[0108] X2is N or CRX2;

[0109] CRX1and CRX2are 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;

[0110] Y is -NRC-, *-C(=O)NRc(CRDRE)n-, *-NRcC(=O)(CRDRE)„-, or -O-, wherein * indicates the point of connection to the X'-X2ring;

[0111] Rcis hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each RDand REare independently hydrogen, fluoro, or C1-C6 alkyl;

[0112] R2is phenyl optionally substituted with 1-4 independently selected R3, 5-10 membered heteroaryl optionally substituted with 1-4 independently selectedR3, C3-C10 cycloalkyl optionally substituted with 1-4 independently selected R3, or 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3; each R3is independently selected from halogen, cyano, optionally substituted Cl -C6 alkyl, optionally substituted C1-C6 alkoxy, -NR3AR3B, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 haloalkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, -C(=O)NR3AR3B, -NR3AC(=O)R3B, -C(=O)R3C, -(SO2)NR3AR3B, - (SO2)R3C, optionally substituted 5-9 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;

[0113] R3Aand R3Bare independently selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0114] R3Cis optionally substituted alkyl, optionally substituted 5-9 membered heterocyclyl, optionally substituted C1-C6 alkoxy, or optionally substituted 5-10 membered heteroaryl.

[0115] In some embodiments, Ring A is a 4-6 membered heterocyclyl.

[0116] In some embodiments, Ring A is a 4 membered heterocyclyl. In some embodiments, the Ring A is selected from the group consisting of oxetanyl, azetidinyl, thietanyl, azetyl, oxetyl, and thietyl.

[0117] In some embodiments, Ring A is a 5-6 membered heterocyclyl. In some embodiments, Ring A is a 5 membered heterocyclyl. In some embodiments, Ring A is selected from the group consisting of pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydantionyl, thiohydantionyl, imidazolidinonyl, oxazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanethionyl, oxazolidinethionyl, imidazolidinethionyl, and isothiazolidinonyl. In some embodiments, Ring A is selected from the group consisting of pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl. In some embodiments, Ring A is tetrahydrofuryl. In some embodiments, Ring A is pyrrolidinyl. In some embodiments, Ring A is pyrrolinyl. In some embodiments, Ring A is thiolanyl. In some embodiments, Ring A is pyrazolidinyl.

[0118] In some embodiments, Ring A is a 6 membered heterocyclyl. In some embodiments, the Ring A is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidindione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, di oxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl. In some embodiments, Ring A is morpholinyl. In some embodiments, Ring A is thiomorpholinyl. In some embodiments, Ring A is dioxanyl. In some embodiments, Ring A is tetrahydropyranonyl.

[0119] In some embodiments, Ring A is a 7-8 membered heterocyclyl.

[0120] In some embodiments, Ring A is a 7 membered heterocyclyl. In some embodiments, Ring A is a 8 membered heterocyclyl. In some embodiments, the Ring A is selected from the group consisting of pyrrolizinyl, hexahydro- 1 f-pyrrolizinyl, 1 ,4,5,6- tetrahydrocyclopenta[b]pyrrolyl, l,3a,4,6a-tetrahydropyrrolo[3,2-b]pyrrolyl.

[0121] In some embodiments, R1is -NRARB.

[0122] In some embodiments, R1is -C(=O)NRARB.

[0123] In some embodiments, R1is -OC(=O)NRARB.

[0124] In some embodiments, RAand RBare the same. In some embodiments, RAand RBare each hydrogen.

[0125] In some embodiments, RAand RBare each unsubstituted C1-C6 alkyl. In some embodiments, RAand RBare each substituted C1-C6 alkyl.

[0126] In some embodiments, RAand RBare each unsubstituted C1-C6 haloalkyl. In some embodiments, RAand RBare each substituted C1-C6 haloalkyl.

[0127] In some embodiments, RAand RBare different.

[0128] In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted C1-C6 alkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted C1-C3 alkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis methyl, ethyl, or propyl.

[0129] In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted C1-C6 haloalkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted C1-C3 haloalkyl.

[0130] In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis substituted C1-C6 alkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis C1-C6 alkyl substituted with 1-5 halogen. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis C1-C4 alkyl substituted with 1-3 halogen.

[0131] In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis selected from the group consisting of In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis substituted C1-C6 haloalkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis C1-C6 haloalkyl with 1-5 halogen. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis C1-C4 haloalkyl with 1-3 halogen.

[0132] In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis selected from the group consisting of

[0133] In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis C3- C10 cycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis C3-C4 cycloalkyl optionally substituted with C1-C3 alkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis C3-C4 cycloalkyl substituted with C1-C3 alkyl. In some embodiments, one of RAand RDis hydrogen, and the other of RAand RBis

[0134] In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted C3-C10 cycloalkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted C3-C7 cycloalkyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted cyclopropyl.

[0135] In some embodiments, R1is an optionally substituted 5-10 membered heteroaryl oxy. In some embodiments, R1is a substituted 5-10 membered heteroaryloxy. In some embodiments, R1is an optionally monosubstituted 5-10 membered heteroaryloxy. In some embodiments, R1is an optionally disubstituted 5-10 membered heteroaryl oxy. In some embodiments, R1is an optionally tri substituted 5-10 membered heteroaryloxy. In some embodiments, R1is a substituted 5-10 membered heteroaryloxy. In some embodiments, R1is a monosubstituted 5-10 membered heteroaryl oxy. In some embodiments, R1is a disubstituted 5-10 membered heteroaryl oxy. In some embodiments, R1is a tri substituted 5-10 membered heteroaryl oxy. In some embodiments, tthe 5-10 membered heteroaryl oxy of R1is substituted with one or more independently selected C1-C6 alkyl (e.g., isopropyl and / or t-butyl). In some embodiments, the 5-10 membered heteroaryloxy of R1is substituted with one or more independently selected C2-C6 alkenyl (e.g., isopropenyl). In some embodiments, the 5-10 membered heteroaryloxy of R1is substituted with one or more independently selected C3-C6 cycloalkyl optionally substituted with an optionally substituted Cl -C6 alkyl. For example, the 5-10 membered heteroaryloxy of R1is substituted with . For example, the 5-10 membered heteroaryloxy of R1is substituted with . In some embodiments, R1is an unsubstituted 5-10 membered heteroaryl oxy. In some embodiments, the 5-10 membered heteroaryloxy of R1is a 5-6 membered heteroaryloxy. In some embodiments, the 5-10 membered heteroaryloxy of R1is isothiazolyl, pyridyl, or 1,3,4-triazolyl.

[0136] In some embodiments, R1is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R1is an unsubstituted 5-10 membered heteroaryl. In some embodiments, R1is a substituted 5-10 membered heteroaryl. In some embodiments, R1is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R1is an optionally substituted 5-6 membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatri azolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R1is unsubstituted 5-6 membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0137] In some embodiments, one or two Rxis independently halogen. In some embodiments, one Rxis halogen. In some embodiments, two Rxis halogen. In some embodiments, one or two Rxis F, Cl, or Br. In some embodiments, one Rxis F, Cl, or Br. In some embodiments, one Rxis F. In some embodiments, one Rxis Cl.

[0138] In some embodiments, one or two Rxis C1-C6 alkyl. In some embodiments, one Rxis C1- C6 alkyl. In some embodiments, two Rxis C1-C6 alkyl. In some embodiments, one or two Rxis C1-C3 alkyl. In some embodiments, one or two Rxis methyl, ethyl, or isopropyl. In some embodiments, one or two Rxis C1-C6 alkoxy. In some embodiments, one Rxis C1-C6 alkoxy. In some embodiments, two Rxis C 1-C6 alkoxy. In some embodiments, one or two Rxis C1-C3 alkoxy. In some embodiments, one or two Rxis methoxy or ethoxy.

[0139] In some embodiments, Rxis C1-C6 alkyl. In some embodiments, RX2is methyl. In some embodiments, RX2is C1-C6 alkoxy. In some embodiments, RX2is methoxy.

[0140] In some embodiments, m is 0.

[0141] In some embodiments, m is 1.

[0142] In some embodiments, m is 2. In some embodiments, R2is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R3. In some embodiments, R2is 5-10 membered heteroaryl substituted with 1-4 independently selected R3. In some embodiments, R2is unsubstituted 5-10 membered heteroaryl. In some embodiments, R2is 5-10 membered heteroaryl substituted with 1-2 independently selected R3. In some embodiments, R2is 5-10 membered heteroaryl substituted with 1 R3. In some embodiments, R2is 5-6 membered heteroaryl substituted with 1-2 independently selected R3. In some embodiments, R2is 5-6 membered heteroaryl substituted with 1 R3.

[0143] In some embodiments, R2is an optionally substituted 5-10 membered heteroaryl.

[0144] In some embodiments, R2is an optionally substituted 5-6 membered heteroaryl.

[0145] In some embodiments, R2is an optionally substituted 5 membered heteroaryl. In some embodiments, R2is an unsubstituted 5 membered heteroaryl. In some embodiments, R2is a substituted 5 membered heteroaryl. In some embodiments, the 5 membered heteroaryl of R2is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or 1,2,5-oxadiazolyl. In some embodiments, the 5 membered heteroaryl of R2is pyrazol-5-yl.

[0146] In some embodiments, R2is an optionally substituted 6 membered heteroaryl. In some embodiments, R2is an unsubstituted 6 membered heteroaryl. In some embodiments, R2is a substituted 6 membered heteroaryl. In some embodiments, the 6 membered heteroaryl of R2is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0147] In some embodiments, R2is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R2is a substituted 9-10 membered heteroaryl. In some embodiments, R2is an unsubstituted 9-10 membered heteroaryl. In some embodiments, the 9-10 membered heteroaryl of R2is pyrido[2,3-d]pyrimidine, imidazo[l,2-c]pyrimidine, imidazo[l,2-b]pyridazine, thiazolo[5,4-c]pyridine, quinoline, pyrazolo[l,5-a]pyrazine, or pyrazolo[l,5-a]pyridine. In some embodiments, R2is 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3. In some embodiments, R2is 5-9 membered heterocyclyl substituted with 1-4 independently selected R3. In some embodiments, R2is unsubstituted 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3. In some embodiments, R2is 5-9 membered heterocyclyl substituted with 1-2 independently selected R3. In some embodiments, R2is 5-9 membered heterocyclyl substituted with 1 R3. In some embodiments, R2is 5-6 membered heterocyclyl substituted with 1-2 independently selected R3. In some embodiments, R2is 5-6 membered heterocyclyl substituted with 1 R3.

[0148] In some embodiments, R2is an optionally substituted 5-9 membered heterocyclyl.

[0149] In some embodiments, R2is an optionally substituted 5-6 membered heterocyclyl.

[0150] In some embodiments, R2is an optionally substituted 5 membered heterocyclyl. In some embodiments, R2is an unsubstituted 5 membered heterocyclyl. In some embodiments, R2is a substituted 5 membered heterocyclyl. In some embodiments, the 5 membered heterocyclyl of R2is selected from the group consisting of pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydantionyl, thiohydantionyl, imidazolidinonyl, oxazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanethionyl, oxazolidinethionyl, imidazolidinethionyl, and i sothi azoli dinony 1.

[0151] In some embodiments, R2is an optionally substituted 6 membered heterocyclyl. In some embodiments, R2is an unsubstituted 6 membered heterocyclyl. In some embodiments, R2is a substituted 6 membered heterocyclyl. In some embodiments, the 6 membered heterocyclyl of R2is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidindione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, di oxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl. In some embodiments, R2is piperidin- 4-yl. In some embodiments, R2is an optionally substituted 9 membered heterocyclyl. In some embodiments, R2is a substituted 9 membered heterocyclyl. In some embodiments, R2is an unsubstituted 9 membered heterocyclyl. In some embodiments, the 9 membered heterocyclyl of R2is 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one.

[0152] In some embodiments, R2is phenyl optionally substituted with 1-4 independently selected R3. In some embodiments, R2is phenyl substituted with 1-4 independently selected R3. In some embodiments, R2is unsubstituted phenyl. In some embodiments, R2is phenyl substituted with 1- 2 independently selected R3. In some embodiments, R2is phenyl substituted with 1 R3. In some embodiments, R2is an optionally substituted phenyl. In some embodiments, R2is an unsubstituted phenyl. In some embodiments, R2is a substituted phenyl. In some embodiments, R2is monosubstituted phenyl. In some embodiments, R2is disubstituted phenyl.

[0153] In some embodiments, R2is C3-C10 cycloalkyl optionally substituted with 1-4 independently selected R3. In some embodiments, R2is C3-C10 cycloalkyl substituted with 1-4 independently selected R3. In some embodiments, R2is unsubstituted C3-C10 cycloalkyl. In some embodiments, R2is C3-C10 cycloalkyl substituted with 1-2 independently selected R3. In some embodiments, R2is C3-C10 cycloalkyl substituted with 1 R3.

[0154] In some embodiments, 1, 2, 3, or 4 R3is independently halogen. In some embodiments, 1 or 2 R3is independently halogen. In some embodiments, 1 R3is independently halogen. In some embodiments, 1 or 2 R3is independently fluoro or chloro.

[0155] In some embodiments, 1, 2, 3, or 4 R3is cyano. In some embodiments, 1 or 2 R3is independently cyano. In some embodiments, 1 R3is independently cyano.

[0156] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted C1-C6 alkyl. In some embodiments, 1 or 2 R3is optionally substituted C1-C3 alkyl. In some embodiments, 1 R3is optionally substituted C1-C3 alkyl. In some embodiments, 1, 2, 3, or 4 R3is unsubstituted C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 R3is substituted C1-C6 alkyl.

[0157] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted C1-C6 alkoxy. In some embodiments, 1 or 2 R3is optionally substituted C1-C3 alkoxy. In some embodiments, 1 R3is optionally substituted C1-C3 alkoxy. In some embodiments, 1, 2, 3, or 4 R3is unsubstituted C1- C6 alkoxy. In some embodiments, 1, 2, 3, or 4 R3is substituted C1-C6 alkoxy.

[0158] In some embodiments, 1, 2, 3, or 4 R3is -NR3AR3B. In some embodiments, 1 or 2 R3is - NR3AR3B jn someembodiments, 1 R3is -NR3AR3B. In some embodiments, R3Aand R3Bare independently selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl.

[0159] In some embodiments, each of R3Aand R3Bis hydrogen.

[0160] In some embodiments, one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis optionally substituted C1-C6 alkyl.

[0161] In some embodiments, one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis C1- C6 haloalkyl.

[0162] In some embodiments, one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis optionally substituted C3-C10 cycloalkyl.

[0163] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted C1-C6 haloalkyl. In some embodiments, 1 or 2 R3is optionally substituted C1-C3 haloalkyl. In some embodiments, 1 R3is optionally substituted C1-C3 haloalkyl. In some embodiments, 1, 2, 3, or 4 R3is unsubstituted C1- C6 haloalkyl. In some embodiments, 1, 2, 3, or 4 R3is substituted C1-C6 haloalkyl.

[0164] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted Cl -C6 haloalkoxy. In some embodiments, 1 or 2 R3is optionally substituted C1-C3 haloalkoxy. In some embodiments, 1 R3is optionally substituted C1-C3 haloalkoxy. In some embodiments, 1, 2, 3, or 4 R3is unsubstituted C1-C6 haloalkoxy. In some embodiments, 1, 2, 3, or 4 R3is substituted C1-C6 haloalkoxy.

[0165] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted C3-C6 cycloalkyl. In some embodiments, 1 or 2 R3is optionally substituted C3-C6 cycloalkyl. In some embodiments, 1 R3is optionally substituted C3-C6 cycloalkyl. In some embodiments, 1, 2, 3, or 4 R3is unsubstituted C3-C6 cycloalkyl. In some embodiments, 1, 2, 3, or 4 R3is substituted C3-C6 cycloalkoxy.

[0166] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted C3-C6 cycloalkyl. In some embodiments, 1 or 2 R3is optionally substituted C3-C6 cycloalkoxy. In some embodiments, 1 R3is optionally substituted C3-C6 cycloalkoxy. In some embodiments, 1, 2, 3, or 4 R3is unsubstituted C3-C6 cycloalkoxy. In some embodiments, 1, 2, 3, or 4 R3is substituted C3-C6 cycloalkoxy.

[0167] In some embodiments, 1, 2, 3, or 4 R3is -C(=O)NR3AR3B. In some embodiments, 1 or 2 R3is -C(=O)NR3AR3B. In some embodiments, 1 R3is -C(=O)NR3AR3B.

[0168] In some embodiments, 1, 2, 3, or 4 R3is -NR3AC(=O)R3B. In some embodiments, 1 or 2 R3is -NR3AC(=O)R3B. In some embodiments, 1 R3is -NR3AC(=O)R3B.

[0169] In some embodiments, 1, 2, 3, or 4 R3is -C(=O)R3C. In some embodiments, 1 or 2 R3is - C(=O)R3C. In some embodiments, 1 R3is -C(=O)R3C. In some embodiments, R3Cis optionally substituted alkyl, optionally substituted 5-9 membered heterocyclyl, optionally substituted C1-C6 alkoxy, or optionally substituted 5-10 membered heteroaryl.

[0170] In some embodiments, R3Cis optionally substituted alkyl.

[0171] In some embodiments, R3Cis optionally substituted 5-9 membered heterocyclyl.

[0172] In some embodiments, R3Cis optionally substituted C1-C6 alkoxy.

[0173] In some embodiments, R3Cis optionally substituted 5-10 membered heteroaryl.

[0174] In some embodiments, 1, 2, 3, or 4 R3is -(SO2)NR3AR3B. In some embodiments, 1 or 2 R3is -(SO2)NR3AR3B. In some embodiments, 1 R3is -(SO2)NR3AR3B.

[0175] In some embodiments, 1, 2, 3, or 4 R3is -(SO2)R3C. In some embodiments, 1 or 2 R3is - (SO2)R3C. In some embodiments, 1 R3is -(SO2)R3C.

[0176] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted 5-9 membered heterocyclyl. In some embodiments, 1 or 2 R3is optionally substituted 5-9 membered heterocyclyl. In some embodiments, 1 R3is optionally substituted 5-9 membered heterocyclyl. In some embodiments, 1 R3is a substituted 5-9 membered heterocyclyl. In some embodiments, 1 R3is unsubstituted 5-9 membered heterocyclyl.

[0177] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted phenyl. In some embodiments, 1 or 2 R3is optionally substituted phenyl. In some embodiments, 1 R3is optionally substituted phenyl. In some embodiments, 1 R3is a substituted phenyl. In some embodiments, 1 R3is unsubstituted phenyl.

[0178] In some embodiments, 1, 2, 3, or 4 R3is optionally substituted 5-10 membered heteroaryl. In some embodiments, 1 or 2 R3is optionally substituted 5-10 membered heteroaryl. In some embodiments, 1 R3is optionally substituted 5-10 membered heteroaryl. In some embodiments, 1 R3is a substituted 5-10 membered heteroaryl. In some embodiments, 1 R3is unsubstituted 5-10 membered heteroaryl. In some embodiments, the R2group is substituted with 1-3 substituents selected from the group consisting of -SO2NH2, -F, cyano, -CH2OMe, -CO2NH2, methyl, - CH2OCF3, pyrazolyl optionally substituted with 1-2 methyl, pyrazolyl optionally substituted with 1-2 substituents selected from methyl and isopropoxymethyl, 1,2,4-triazolyl optionally substituted with 1-2 methyl, and tetrazolyl optionally substituted with 1-2 methyl.

[0179] In some embodiments, the R2group is substituted with an optionally substituted 5-10 membered heteroaryl. In some embodiments, the R2group is substituted with an unsubstituted 5- 10 membered heteroaryl. In some embodiments, the R2group is substituted with a substituted 5- 10 membered heteroaryl. In some embodiments, the R2group is substituted with a 5-10 membered heteroaryl substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.

[0180] In some embodiments, the R2group is substituted with 1-3 substituents selected from the group consisting of -SO2NH2, -F, -CH2OMe, and -CO2NH2.

[0181] In some embodiments, the R2group is substituted with 1-3 substituents, where one is -(SO2)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 heterocylyl, or optionally substituted 3-10 membered cycloalkyl.

[0182] 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.

[0183] 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 halogen. 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 halogen.

[0184] 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.

[0185] In some embodiments, one of R and R is hydrogen, and the other of R and R is substituted C1-C6 alkoxy. In some embodiments, one of R and R is hydrogen, and the other of R and R is C1-C6 alkoxy substituted with 1-5 halogen. In some embodiments, one of R and R is hydrogen, and the other of R and R is C1-C4 alkoxy substituted with 1-3 halogen.

[0186] 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 halogen. 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.

[0187] 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.

[0188] 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.

[0189] In some embodiments, the R2group is substituted with 1-3 substituents, where one is -(SO2)R’, wherein R’ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted Cl -C 6 alkoxy, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-9 membered heterocylyl, or optionally substituted 3-8 membered cycloalkyl. In some embodiments, R’ is unsubstituted C1-C6 alkyl. In some embodiments, R’ is unsubstituted C1-C3 alkyl. In some embodiments, R’ is methyl, ethyl, or propyl.

[0190] In some embodiments, R’ is substituted C1-C6 alkyl. In some embodiments, R’ is C1-C6 alkyl substituted with 1-5 halogen. In some embodiments, R’ is C1-C4 alkyl substituted with 1-3 halogen.

[0191] In some embodiments, R’ is unsubstituted C1-C6 alkoxy. In some embodiments, R’ is unsubstituted C1-C3 alkoxy.

[0192] In some embodiments, R’ is substituted C1-C6 alkoxy. In some embodiments, R’ is C1- C6 alkoxy substituted with 1-5 halogen. In some embodiments, R’ is C1-C4 alkoxy substituted with 1-3 halogen.

[0193] In some embodiments, R’ is C3-C10 cycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, R’ is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, R’ is C3-C6 cycloalkyl substituted with 1-3 halogen.

[0194] In some embodiments, R’ is unsubstituted C3-C10 cycloalkyl. In some embodiments, R’ is unsubstituted C3-C7 cycloalkyl. In some embodiments, R’ is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R’ is unsubstituted cyclopropyl.

[0195] 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.

[0196] 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.

[0197] In some embodiments, the R2group is substituted with one -SO2NH2and one F.

[0198] In some embodiments, the R2group is substituted with one -SO2NH2. In some embodiments, the R2group is substituted with one -(SO2)C3-C6 cycloalkyl. In some embodiments, the R2group is substituted with one

[0199] In some embodiments, the R2group is substituted with one -(SO2)NHC3-C6 cycloalkyl

[0200] CF3. In some embodiments, the R2group is substituted with one

[0201] In some embodiments, the R2group is substituted with one -(C=O)C1-C6 alkyl. In some embodiments, the R2group is substituted with one -(C=O)CH3.

[0202] In some embodiments, the R2group is substituted with one -(C=O)C3-C6 cycloalkyl.

[0203] In some embodiments, the R2group is substituted with one -(C=0)NH2.

[0204] In some embodiments, the R2group is substituted with one -NH(SO2)C1-C6 alkyl. In some embodiments, the R2group is substituted with one -NH(SO2)C1-C3 alkyl. In some embodiments, the R2group is substituted with one

[0205] In some embodiments, the R2group is substituted with one -NH(SO2)-optionally substituted C3-C8 cycloalkyl. In some embodiments, the R2group is substituted with one - NH(SO2)-optionally substituted C3-C6 cycloalkyl. In some embodiments, the R2group is substituted with one -NH(SO2)C3-C6 cycloalkyl. In some embodiments, the R2group is substituted with one -NH(SO2)-substituted C3-C6 cycloalkyl. In some embodiments, the R2group is substituted with one -NH(SC>2)-halogen substituted C3-C6 cycloalkyl. In some embodiments, the R2group is substituted with one -NH(SO2)-fluoro- substituted C3-C6 cycloalkyl.

[0206] In some embodiments, the R2group is substituted with one -(S(=NRL)(=O))C1-C6 alkyl, wherein RLis H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R2group is substituted with one -(S(=NRL)(=O))C1-C3 alkyl, wherein RLis H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R2group is substituted with one or , wherein RLis H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R2group is substituted with one -(S(=NRL)(=O))C1-C6 haloalkyl, wherein RLis H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R2group is substituted with one -(S(=NRL)(=O))C1-C3 haloalkyl, wherein RLis H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R2group is substituted with one , wherein RLis H or C1-C6 alkyl optionally substituted with hydroxyl.

[0207] In some embodiments, the R2group is substituted with one -(S(=NRL)(=O))C3-C6 cycloalkyl. In some embodiments, the R2group is substituted with one wherein RLis

[0208] H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RLis hydrogen. In some embodiments, RLis C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments,

[0209] RLis C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, RLis .

[0210] In some embodiments, RLis unsubstituted C1-C6 alkyl. In some embodiments, RLis methyl.

[0211] In some embodiments, the R2group is substituted with one substituent selected from the group consisting of

[0212] In some embodiments, the R2group is substituted with one -(SO2)NRHRT, wherein RHand R1are independently H and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, the R2group is substituted with one -(SO2)NRHRI, wherein one of RHand R1is H and the other is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, the R2group is substituted with one -(SO2)NRHRI, wherein one of RHand R1is H and the other is C1-C6 alkyl. In some embodiments, the R2group is substituted with one - (SO2)NRHRI, wherein one of RHand R1is H and the other is C 1 -C6 alkyl substituted with hydroxyl .

[0213] In some embodiments, the R2group is substituted with one , i.e., RHand R1are each hydrogen. In some embodiments, the R2group is substituted with one selected from the group

[0214] In some embodiments, X1is CRX1.

[0215] In some embodiments, X2is CRX2. In some embodiments, RX1is C1-C6 alkyl. In some embodiments, RX1is methyl. In some embodiments, RX1is C1-C6 alkoxy. In some embodiments, RX1is methoxy. In some embodiments, RX1is C1-C6 haloalkyl. In some embodiments, RX1is trifluoromethyl. In some embodiments, RX1is C1-C6 haloalkoxy. In some embodiments, wherein RX1is trifluoromethoxy.

[0216] In some embodiments, RX1is C3-C6 cycloalkyl. In some embodiments, RX1is cyclopropyl. In some embodiments, RX1is C3-C6 cycloalkoxy. In some embodiments, RX1is cyclopropoxy. In some embodiments, RX1is cyano. In some embodiments, RX1is halogen. In some embodiments, RX1is hydrogen.

[0217] In some embodiments, RX2is C1-C6 alkyl. In some embodiments, RX2is methyl. In some embodiments, RX2is C1-C6 alkoxy. In some embodiments, RX2is methoxy. In some embodiments, RX2is C1-C6 haloalkyl. In some embodiments, RX2is trifluoromethyl. In some embodiments, RX2is C1-C6 haloalkoxy. In some embodiments, RX2is trifluoromethoxy. In some embodiments, RX2is C3-C6 cycloalkyl. In some embodiments, RX2is cyclopropyl. In some embodiments, RX2is C3-C6 cycloalkoxy. In some embodiments, RX2is cyclopropoxy. In some embodiments, RX2is cyano. In some embodiments, RX2is halogen. In some embodiments, RX2is hydrogen.

[0218] In some embodiments, X1is N.

[0219] In some embodiments, X2is N.

[0220] In some embodiments, X1is N and X2is N.

[0221] In some embodiments, Y is *-C(=O)NRc(CRDRE)n-, wherein * indicates the point of connection to the X'-X2ring.

[0222] In some embodiments, Y is *-NRcC(=O)(CRDRE)n- wherein * indicates the point of connection to the X'-X2ring. In some embodiments, n is 0. In some embodiments, n is i . In some embodiments, n is 2.

[0223] In some embodiments, each RDand REare the same. In some embodiments, each RDand REare the same except one of the RDand REis different.

[0224] In some embodiments, each RDand REis hydrogen.

[0225] In some embodiments, each RDand REis fluoro.

[0226] In some embodiments, RDand REis methyl.

[0227] In some embodiments, one of RDand REis methyl or fluoro, and the remaining RDand REare hydrogen.

[0228] In some embodiments, Y is -NRC-

[0229] In some embodiments, Rcis C1-C6 alkyl.

[0230] In some embodiments, Rcis methyl.

[0231] In some embodiments, Rcis hydrogen.

[0232] In some embodiments, Y is -O-.

[0233] In some embodiments, R2is an optionally substituted 5-6 membered heteroaryl.

[0234] In some embodiments, R2is an optionally substituted 5 membered heteroaryl.

[0235] In some embodiments, R2is an unsubstituted 5 membered heteroaryl.

[0236] In some embodiments, R2is a substituted 5 membered heteroaryl.

[0237] In some embodiments, the 5 membered heteroaryl of R2is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or 1,2,5-oxadiazolyl.

[0238] In some embodiments, R2is an optionally substituted 6 membered heteroaryl.

[0239] In some embodiments, R2is an unsubstituted 6 membered heteroaryl.

[0240] In some embodiments, R2is a substituted 6 membered heteroaryl.

[0241] In some embodiments, the 6 membered heteroaryl of R2is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0242] In some embodiments, R2is an optionally substituted 5-6 membered heterocyclyl.

[0243] In some embodiments, R2is an optionally substituted 5 membered heterocyclyl.

[0244] In some embodiments, R2is an unsubstituted 5 membered heterocyclyl.

[0245] In some embodiments, R2is a substituted 5 membered heterocyclyl.

[0246] In some embodiments, the 5 membered heterocyclyl of R2is seleted from the group consisting of pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazoli di nonyl, oxazolidinyl, isoxazolidinonyl, hydantionyl, thiohydantionyl, imidazolidinonyl, oxazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanethionyl, oxazolidinethionyl, imidazolidinethionyl, and isothiazolidinonyl.

[0247] In some embodiments, R2is an optionally substituted 6 membered heterocyclyl.

[0248] In some embodiments, R2is an unsubstituted 6 membered heterocyclyl.

[0249] In some embodiments, R2is a substituted 6 membered heterocyclyl.

[0250] In some embodiments, the 6 membered heterocyclyl of R2is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholi nonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidindione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl..

[0251] In some embodiments, R2is an optionally substituted phenyl.

[0252] In some embodiments, R2is an unsubstituted phenyl.

[0253] In some embodiments, R2is a substituted phenyl. In some embodiments, R2is a monosubstituted phenyl. In some embodiments, R2is a disubstituted phenyl.

[0254] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is a compound of Formula (AA): or a pharmaceutically acceptable salt thereof. Ring A, R1, Rx, and m are further defined as disclosed above in Formula (A).

[0255] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is a compound of Formula (AA1): or a pharmaceutically acceptable salt thereof. Ring A, R1, Rx, and m are further defined as disclosed above in Formula (A).

[0256] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is a compound of Formula (AA2): or a pharmaceutically acceptable salt thereof. R1, Y, and R2are further defined as disclosed above in Formula (A).

[0257] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is a compound of Formula (AA3): or a pharmaceutically acceptable salt thereof. R1and R2are further defined as disclosed above in Formula (A).

[0258] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is a compound of Formula (AA4): or a pharmaceutically acceptable salt thereof. R2, Y, RA, and RBare further defined as disclosed above in Formula (A).

[0259] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, is a compound of Formula (AA5): or a pharmaceutically acceptable salt thereof. R2, RA, and RBare further defined as disclosed above in Formula (A).

[0260] Also provided herein are compounds of Formula (B), or a pharmaceutically acceptable salt thereof, wherein:

[0261] R1is -NRARB, -C(=O)NRARB, -OC(=O)NRARB, an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each RAand RBare independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0262] Ring A is a 4-8 membered heterocyclyl;

[0263] Ring B is an optionally substituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl, or an optionally substituted 9-10 membered heteroaryl; each Rxis independently halogen, C1-C6 alkyl, or C1-C6 alkoxy; m is 0, 1, or 2;

[0264] X1is N or CRX1;

[0265] X2is N or CRX2;

[0266] CRX1and CRX2are 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 -NRC- *-C(=O)NRc(CRDRE)n- *-NRcC(=O)(CRDRE)n- or -O-, wherein * indicates the point of connection to the X'-X2ring;

[0267] Rcis hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each RDand REare independently hydrogen, fluoro, or C1-C6 alkyl; and

[0268] R2is phenyl optionally substituted with 1-4 independently selected R3, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R3, C3-C10 cycloalkyl optionally substituted with 1-4 independently selected R3, or 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3; each R3is independently selected from halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -NR3AR3B, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 haloalkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, -C(=O)NR3AR3B, -NR3AC(=O)R3B, -C(=O)R3C, -S(=O)2NR3AR3B, -S(=O)2R3C, optionally substituted 5-9 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;

[0269] R3Aand R3Bare independently selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0270] R3Cis optionally substituted alkyl, optionally substituted 5-9 membered heterocyclyl, optionally substituted C1-C6 alkoxy, or optionally substituted 5-10 membered heteroaryl. .

[0271] R1, R2, R3, R3A, R3B, R3CRA, RB, Rc, RD, RE, X, Y, a, b, m, and n are further defined as disclosed above in Formula (A).

[0272] In some embodiments, ring B is an optionally substituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl. In some embodiments, ring B is a substituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl. In some embodiments, ring B is an unsubstituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl. In some embodiments, ring B is pyrazinyl. In some embodiments, ring B is pyrazinonyl. In some embodiments, ring B is pyridazinyl.

[0273] In some embodiments, ring B is an optionally substituted 9-10 membered heteroaryl. In some embodiments, ring B is a substituted 9-10 membered heteroaryl. In some embodiments, ring B is an unsubstituted 9-10 membered heteroaryl. In some embodiments, the 9-10 membered heteroaryl is pyrido[2,3-d]pyrimidine, quinazoline, cinnoline, isoquinolin- l(2 / / )-one, quinolin- 2(l / / )-one, imidazo[l,2-c]pyrimidine, imidazo[l,2-b]pyridazine, thiazolo[5,4-c]pyridine, quinoline, isoquinoline, pyrazolo[l,5-a]pyrazine, pyrrolo[l,2-a]pyrazine, 7-azaindole, 4- azaindole, 5-azaindole, 6-azaindole, benzimidazole, or pyrazolo[l,5-a]pyridine9-membered heteroaryl. In some embodiments, the 9-10 membered heteroaryl is pyrrolo[l,2-a]pyrazine.

[0274] Provided herein are compounds of Formula (B-I) or compounds of Formula (B-II), or a pharmaceutically acceptable salt thereof: wherein:

[0275] R1is -NRARB, -C(=O)NRARB, -OC(=O)NRARB, an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each RAand RBare independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0276] Ring A is a 4-8 membered heterocyclyl; each Rxis independently halogen, C1-C6 alkyl, or C1-C6 alkoxy; m is 0, 1, or 2;

[0277] Rcis hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each RDand REare independently hydrogen, fluoro, or C1-C6 alkyl; and

[0278] R2is phenyl optionally substituted with 1-4 independently selected R3, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R3, C3-C10 cycloalkyl optionally substituted with 1-4 independently selected R3, or 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3; each R3is independently selected from halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -NR3AR3B, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 haloalkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, -C(=O)NR3AR3B, -NR3AC(=O)R3B, -C(=O)R3C, -S(=O)2NR3AR3B, -S(=O)2R3C, optionally substituted 5-9 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl; R3Aand R3Bare independently selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0279] R3Cis optionally substituted alkyl, optionally substituted 5-9 membered heterocyclyl, optionally substituted C1-C6 alkoxy, or optionally substituted 5-10 membered heteroaryl.

[0280] Provided herein are compounds of Formula (B-IIIA), compounds of Formula (B-IIIB), compounds of Formula (B-IVA), or compounds of Formula (B-IVA), or a pharmaceutically acceptable salt thereof wherein:

[0281] R1is -NRARB, -C(=O)NRARB, -OC(=O)NRARB, or an optionally substituted 5-10 membered heteroaryl; each RAand RBare independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0282] Y is -NRC-, *-C(=O)NRc(CRDRE)n-, *-NRcC(=O)(CRDRE)n -, or -O-, wherein * indicates the point of connection to the pyrazinonyl ring;

[0283] Rcis hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each Ruand REare independently hydrogen, fluoro, or C1-C6 alkyl; and

[0284] R2is phenyl optionally substituted with 1-4 independently selected R3, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R3, C3-C10 cycloalkyl optionally substituted with 1-4 independently selected R3, or 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3; each R3is independently selected from halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -NR3AR3B, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 haloalkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, -C(=O)NR3AR3B, -NR3AC(=O)R3B, -C(=O)R3C, -S(=O)2NR3AR3B, -S(=O)2R3C, optionally substituted 5-9 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;

[0285] R3Aand R3Bare independently selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0286] R3Cis optionally substituted alkyl, optionally substituted 5-9 membered heterocyclyl, optionally substituted C1-C6 alkoxy, or optionally substituted 5-10 membered heteroaryl.

[0287] Provided herein are compounds of Formula (B-V) or a pharmaceutically acceptable salt thereof: wherein:

[0288] R1is -NRARB, -C(=O)NRARB, -OC(=O)NRARB, an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each RAand RBare independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0289] Ring A is a 4-8 membered heterocyclyl; each Rxis independently halogen, C1-C6 alkyl, or C1-C6 alkoxy; m is 0, 1, or 2;

[0290] Y is NRC, * C(=O)NRc(CRDRE)n , * NRcC(=O)(CRDRE)n, or O , wherein * indicates the point of connection to the X'-X2ring;

[0291] Rcis hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each RDand REare independently hydrogen, fluoro, or C1-C6 alkyl; and R2is phenyl optionally substituted with 1-4 independently selected R3, 5-10 membered heteroaryl optionally substituted with 1-4 independently selectedR3, C3-C10 cycloalkyl optionally substituted with 1-4 independently selected R3, or 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3; each R3is independently selected from halogen, cyano, optionally substituted C 1 -C6 alkyl, optionally substituted C1-C6 alkoxy, -NR3AR3B, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 haloalkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkoxy, -C(=O)NR3AR3B, -NR3AC(=O)R3B, -C(=O)R3C, -S(=O)2NR3AR3B, -S(=O)2R3C, optionally substituted 5-9 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;

[0292] R3Aand R3Bare independently selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

[0293] R3Cis optionally substituted alkyl, optionally substituted 5-9 membered heterocyclyl, optionally substituted C1-C6 alkoxy, or optionally substituted 5-10 membered heteroaryl. In some embodiments, the compound of Formula (A) is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0294] Table 1: Exemplary Compounds of Formula (A)

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304] Methods of Treatment

[0305] Some embodiments provide a method of treating cancer (e.g., a CDK2-associated 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 or a pharmaceutical composition thereof, to the subject. For example, provided herein are methods for treating a CDK2-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of a CDK2 gene, a CDK2 protein, or the expression or activity or level of any of the same 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.

[0306] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity, or level of any of the same (a CDK2-associated-associated cancer) (e.g., as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a cyclin A2 gene, a cyclin A2 protein, or expression or activity, or level of any of the same (a CDK2-associated-associated cancer) (e.g., as determined using a regulatory agency -approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a cyclin E1 gene, a cyclin E1 protein, or expression or activity, or level of any of the same (a CDK2-associated-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a cyclin E2 gene, a cyclin E2 protein, or expression or activity, or level of any of the same (a CDK2-associated-associated cancer) (e.g., as determined using a regulatory agency-approved, e g., FDA-approved, assay or kit). In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation 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 expression or activity, or level of any of the same (or any combination thereof).

[0307] In some embodiments, the subject has a tumor that is positive for a dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency -approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity, or level of any of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).

[0308] In some embodiments, the subj ect has a tumor that is positive for a dysregulation of a cyclin A2 gene, a cyclin A2 protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a cyclin A2 gene, a cyclin A2 protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency -approved, e g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a cyclin A2 gene, a cyclin A2 protein, or expression or activity, or level of any of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).

[0309] In some embodiments, the subject has a tumor that is positive for a dysregulation of a cyclin E1 gene, a cyclin E1 protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a cyclin E1 gene, a cyclin E1 protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency -approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a cyclin E1 gene, a cyclin E1 protein, or expression or activity, or level of any of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).

[0310] In some embodiments, the subj ect has a tumor that is positive for a dysregulation of a cyclin E2 gene, a cyclin E2 protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a cyclin E2 gene, a cyclin E2 protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency -approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a cyclin E2 gene, a cyclin E2 protein, or expression or activity, or level of any of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).

[0311] In some embodiments, the subject has a tumor that is positive for a dysregulation 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 expression or activity, or level of any of the same (or any combination thereof).

[0312] In some embodiments, a dysregulation can be a dysregulation that results in aberrant activation of a gene, protein, or expression or activity or level of any of the same. Activation can be through any appropriate mechanism, including, but not limited to, gene amplification, activating mutation, activating translocation, transcriptional activation, epigenetic alteration, and / or overexpression of the protein product of the oncogene. In some embodiments, a dysregulation can be a dysregulation that results in aberrant inactivation of a gene, protein, or expression or activity or level of any of the same. Inactivation can be through any appropriate mechanism, including, but not limited to, gene deletion, inactivating mutation, inactivating translocation, transcriptional silencing, epigenetic alteration, and degradation of mRNA and / or protein products of the gene. Typically, as used herein, a dysregulation results in aberrations in the cell cycle.

[0313] In some embodiments, the subject is suspected of having a CDK2-associated-associated cancer.

[0314] In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a cyclin A2 gene, a cyclin A2 protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a cyclin E1 gene, a cyclin E1 protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a cyclin E2 gene, a cyclin E2 protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation 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 expression or activity, or level of any of the same (or any combination thereof).

[0315] In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with a dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity, or level of any of the same (a CDK2-associated- associated cancer). In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with a dysregulation of a cyclin A2 gene, a cyclin A2 protein, or expression or activity, or level of any of the same (a CDK2-associated-associated cancer). In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with a dysregulation of a cyclin E1 gene, a cyclin E1 protein, or expression or activity, or level of any of the same (a CDK2-associated-associated cancer). In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with a dysregulation of a cyclin E2 gene, a cyclin E2 protein, or expression or activity, or level of any of the same (a CDK2-associated- associated cancer). In some embodiments, the subject has been identified or diagnosed as having a cancer that, based on histological examination, is determined to be associated with a dysregulation 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 expression or activity, or level of any of the same (or any combination thereof).

[0316] In some embodiments, the subject has a clinical record indicating that the subject has a tumor resistant to one or more previous therapies, for example, resistance to CDK4 / CDK6 inhibition. In some embodiments, the subject has a cancer resistant to one or more previous therapies, for example, resistance to CDK4 / CDK6 inhibition.

[0317] In some embodiments, the subject has a tumor resistant to one or more previous therapies, for example, resistance to CDK4 / CDK6 inhibition. In some embodiments, the subject has a tumor that is suspected of being resistant to one or more previous therapies, for example, resistance to CDK4 / CDK6 inhibition.

[0318] In some embodiments, the cancer (e.g., CDK2-associated cancer) is pediatric tumors (e.g., neuroblastoma), a brain tumor (e.g., glioblastoma), sarcoma, colorectal cancer, lung cancer (including small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, and adenocarcinoma), thyroid cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer, skin cancer (e.g., melanoma), bile duct cancers (e.g., cholangiocarcinoma) or brain cancer.

[0319] In some embodiments, the cancer (e.g., CDK2-associated cancer) is a solid tumor. In some embodiments, the cancer (e.g., CDK2-associated cancer) is pediatric tumors (e.g., neuroblastoma). In some embodiments, the cancer (e.g., CDK2-associated cancer) is a brain tumor (e.g., glioblastoma).

[0320] In some embodiments, the cancer (e.g., CDK2-associated cancer) is sarcoma.

[0321] In some embodiments, the cancer (e.g., CDK2-associated cancer) is colorectal cancer, lung cancer (including small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, and adenocarcinoma), thyroid cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, esophageal cancer, head and neck cancer, kidney cancer (including renal cell cancer), liver cancer (including hepatocellular carcinoma), pancreatic cancer, stomach (i.e., gastric) cancer, skin cancer (e.g., melanoma), bile duct cancers (e.g., cholangiocarcinoma) or brain cancer. In some embodiments, the cancer (e.g., CDK2-associated cancer) is small cell lung carcinoma, non-small cell lung carcinoma, squamous cell carcinoma, adenocarcinoma, renal cell cancer, hepatocellular carcinoma, gastric cancer, or melanoma, cholangiocarcinoma.

[0322] In some embodiments, the cancer (e.g., CDK2-associated cancer) is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and stomach cancer.

[0323] In some embodiments, the cancer (e.g., CDK2-associated cancer) is selected from the group consisting of breast cancer, ovarian cancer, and colorectal cancer.

[0324] In some embodiments, the cancer (e.g., CDK2-associated cancer) is colorectal cancer.

[0325] In some embodiments, the cancer (e.g., CDK2-associated cancer) is selected from the group consisting of breast cancer and ovarian cancer.

[0326] In some embodiments, the cancer (e.g., CDK2-associated cancer) is ovarian cancer.

[0327] In some embodiments, the cancer (e.g., CDK2-associated cancer) is breast cancer.

[0328] In some embodiments, the cancer (e.g., CDK2-associated cancer) is a breast cancer selected from the group consisting of: estrogen receptor (ER)-positive / hormone receptor (HR)- positive breast cancer, HER2 -negative breast cancer; ER-positive / HR-positive breast cancer, HER2-positive breast cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer.

[0329] In some embodiments, the cancer (e.g., CDK2-associated cancer) is a breast cancer selected from the group consisting of: endocrine resistant breast cancer, trastuzumab -resistant breast cancer, and breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced breast cancer, metastatic breast cancer, or fully resected breast cancer.

[0330] As used herein, the term “resection” or “resected” means surgical removal of malignant tissue characteristic of cancer from a patient (e g., any of the cancer types, such as solid tumors, described herein). According to one embodiment, resection means removal of malignant tissue such that the presence of remaining malignant tissue within said patient is undetectable with available methods. According to another embodiment of the invention resection means removal of breast cancer such that the presence of remaining cancer with said patient is undetectable.

[0331] In some embodiments, the cancer (e.g., CDK2-associated cancer) is a cancer that has been resected. In some embodiments, the cancer (e.g., CDK2-associated cancer) is a breast cancer that has been resected.

[0332] In some embodiments, the subject is administered a compound of Formula (A) as an adjuvant therapy. Adjuvant therapy is treatment given in addition to the primary therapy to kill any cancer cells that may have spread, even if the spread cannot be detected by radiologic or laboratory tests. See, e.g., Paik et al., J. Natl. Cancer Inst., 92(24): 1991-1998 (2000) and Paik et al., J. Natl. Cancer Inst., 94:852-854 (2002). In some embodiments, the subject is administered a compound of Formula (A) as a cancer adjuvant therapy, wherein the cancer (e.g., CDK2-associated cancer) is a breast cancer selected from the group consisting of: estrogen receptor (ER)- positive / hormone receptor (HR)-positive breast cancer, HER2-negative breast cancer; ER- positive / HR-positive breast cancer, HER2-positive breast cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer.

[0333] In some embodiments, the cancer (e.g., CDK2-associated cancer) is a blood cancer, which may also be referred to as a hematopoietic or a hematological cancer or 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 myelocytic leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL; e.g., B cell CLL (e.g., hairy cell leukemia) or T cell CLL), chronic neutrophilic leukemia (CNL), or chronic myelomonocytic leukemia (CMML). 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 deemed 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), a marginal zone lymphoma (MZL), such as a 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), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, or primary central nervous system (CNS) lymphoma. The 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 the T cell NHL can be precursor T lymphoblastic lymphoma or a peripheral T cell lymphoma (PTCL). In turn, the PTCL can be a 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.

[0334] In some embodiments, the blood cancer can be a myeloproliferative disorder, such as, polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, hypereosinophilic syndrome (HES).

[0335] In some embodiments, the cancer (e.g., CDK2-associated cancer) is a myelodysplastic syndrome, including but not limited to, refractory anemia with or without ringed sideroblasts, 5q- syndrome with or without ringed sideroblasts, refractory anemia with multilineage dysplasia with or without ringed sideroblasts, refractory anemia with excess blasts I and II, refractory anemia with excess blasts in transformation, chronic myelo-monocytic leukemia, or an unclassifiable myelodysplastic syndrome.

[0336] In some embodiments, the subject is a human.

[0337] Compounds of Formula (A) and pharmaceutically acceptable salts thereof are also useful for treating a CDK2-associated cancer. Accordingly, also provided herein is a method for treating a subject diagnosed with or identified as having a CDK2-associated cancer, e.g., any of the exemplary CDK2-associated cancers disclosed herein, 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 as defined herein.

[0338] In some aspects, provided herein is a method for treating cancer in a subject in need thereof, including 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 a cancer in a subject in need thereof, including (a) identifying the cancer as being a CDK2- associated cancer; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0339] Identifying the cancer identifying the cancer in the subject as a CDK2-associated cancer can be performed by any appropriate method. In some embodiments, the step of identifying the cancer in the subject as a CDK2-associated cancer includes performing an assay to detect dysregulation in a CDK2 gene, a CDK2 protein, or expression or activity or level of any of the same in a sample from the subject (e.g., CDK2, cyclin A2, cyclin E1, and / or cyclin E2. In some embodiments, the method further includes obtaining a sample from the subject (e.g., a biopsy sample). An assay can be any appropriate assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0340] Also provided herein is a method for treating a cancer in a subject in need thereof, including administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof to a subject identified as having a CDK2-associated cancer.

[0341] Also provided herein is a method of treating a CDK2-associated cancer, comprising administering 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, to a subject identified or diagnosed as having a CDK2-associated cancer.

[0342] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor. The term “selective CDK2 inhibitor” used in the context of the compounds described herein includes compounds that inhibit CDK2 activity at an IC50value 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 less than the IC50value necessary to inhibit to the same degree of one or more of CDK4, CDK6, CDK1, and / or CDK9 activity in a standard phosphorylation assay, for example, any of the assays described herein.

[0343] For example, the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK1 activity (e.g., the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity at an IC50molar concentration at least about 50, 100, 200, 300, 400, or 500 times less (or in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the IC50molar concentration necessary to inhibit to the same degree of CDK1 activity in a standard phosphorylation assay). In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK4 activity (e.g., the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity at an IC50value of at least about 50, 100, 200, 300, 400, or 500 times less (or in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the IC50value necessary to inhibit to the same degree of CDK4 activity in a standard phosphorylation assay, such as those described herein). In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK6 activity (e.g., the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity at an IC50value of at least about 50, 100, 200, 300, 400, or 500 times less (or in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the IC50value necessary to inhibit to the same degree of CDK6 activity in a standard phosphorylation assay, such as those described herein). In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A), or a pharmaceutically acceptable salt thereof selectively inhibits CDK2 activity while sparing CDK4 activity and CDK6 activity (e.g., the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity at an IC50value of at least about 50, 100, 200, 300, 400, or 500 times less (or in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the IC50value necessary to inhibit to the same degree of CDK4 activity and CDK6 activity in a standard phosphorylation assay, such as those described herein). In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK9 activity (e.g., the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity at an IC50value of at least about 50, 100, 200, 300, 400, or 500 times less (or in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the IC50value necessary to inhibit to the same degree of CDK9 activity in a standard phosphorylation assay, such as those described herein). In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor, wherein the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK1 activity, CDK4 activity, CDK6 activity, and CDK9 activity (e.g., the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity at an IC50value of at least about 50, 100, 200, 300, 400, or 500 times less (or in alternative embodiments, at least 750, 1000, 1500, or 2000 times less) than the IC50value necessary to inhibit to the same degree of CDK1 activity, CDK4 activity, CDK6 activity, and CDK9 activity in a standard phosphorylation assay, such as those described herein). Provided herein is also a method for treating cancer in a subject in need thereof, including: (a) determining that the cancer is associated with a dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0344] Provided herein is also a method for treating cancer in a subject in need thereof, including: (a) determining that the cancer is associated with a dysregulation 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 expression or activity or level of any of the same (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.

[0345] Provided herein is also a method for treating cancer in a subject in need thereof, including: (a) determining that the cancer is associated with a dysregulation of a cyclin A2 gene, a cyclin A2 protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0346] Provided herein is also a method for treating cancer in a subject in need thereof, including: (a) determining that the cancer is associated with a dysregulation of a cyclin E1 gene, a cyclin E1 protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0347] Provided herein is also a method for treating cancer in a subject in need thereof, including: (a) determining that the cancer is associated with a dysregulation of a cyclin E2 gene, a cyclin E2 protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[0348] Determining that the cancer is associated with a dysregulation 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 expression or activity or level of any of the same (or any combination thereof), can be performed using any appropriate method. In some embodiments, the step of determining that the cancer in the subject is a CDK2-associated cancer includes performing an assay to detect dysregulation in a CDK2 gene, a CDK2protein, 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 expression or activity or level of any of the same (or any combination thereof), in a sample from the subject. In some embodiments, the method further includes obtaining a sample from the subject (e.g., a biopsy sample). An assay can be any appropriate assay. In some embodiments, the assay is selected from the group consisting of sequencing (e.g., pyrosequencing or next generation sequencing), immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH). Additionally provided herein is a method for treating a CDK2-associated cancer in a subject in need thereof, including 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, including: (a) identifying the cancer as being a CDK2-associated disease or disorder; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof. In addition, provided herein is a method for treating cancer in a subj ect in need thereof, including: administering to the subject a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof to a subject identified as having a CDK2-associated cancer.

[0349] In some cases, compounds of Formula (A), or a pharmaceutically acceptable salt thereof can be useful for inhibiting the processes of cells, such as inhibiting the proliferation of cells. Accordingly, provided herein is a method for inhibiting mammalian cell proliferation, including contacting the mammalian cell with a compound of Formula (A), or a pharmaceutically acceptable salt thereof. Also provided herein is a method for inhibiting CDK2 activity in a mammalian cell, including contacting the mammalian cell with a compound of Formula (A), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. A mammalian cell can be any appropriate cell. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is a mammalian CDK2 -associated cancer cell. In some embodiments, the mammalian cell has dysregulation of a CDK2 gene, a CDK2protein, 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 expression or activity or level of any of the same (or any combination thereof).

[0350] Compounds of Formula (A), or a pharmaceutically acceptable salt thereof can also be useful in the manufacture of medicaments, i.e., for use in the treatment of a CDK2-associated cancer.

[0351] In some embodiments, an assay used to determine whether the subject has a dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein), or expression or activity or level of any of the same (or any combination thereof), using a sample from a 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 assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein), or expression or activity or levels of any of the same (or any combination thereof). In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a CDK2-associated cancer, a subject having one or more symptoms of a CDK2-associated cancer, and / or a subject that has an increased risk of developing a CDK2-associated cancer).

[0352] In some embodiments, dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein), or the expression or activity or level of any of the same (or any combination thereof) can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). Liquid biopsy methods can be used to detect total tumor burden and / or the dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein), or expression or activity or level of any of the same (or any combination thereof). Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein), or expression or activity or level of any of the same (or any combination thereof). In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein), or expression or activity or level of any of the same (or any combination thereof), at an earlier stage than traditional methods. In some embodiments, the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin E1, and / or cyclin E2 protein), or expression or activity or level of any of the same (or any combination thereof). In the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and additional therapeutic agents such as those described herein.

[0353] For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (A), or a pharmaceutically acceptable salt thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action.

[0354] In some embodiments, a compound of Formula (A), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the 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., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof for a period of time and undergo one or more rounds of radiation therapy. In some embodiments, the 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., the tumor burden) prior to the one or more rounds of radiation therapy.

[0355] In some embodiments, a compound of Formula (A), or a pharmaceutically acceptable salt thereof, can be used after administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof for a period of time after undergoing at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof reduces the size (i.e. number of cells) of any remaining tumor after the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof for a period of time after undergoing one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (A), or a pharmaceutically acceptable salt thereof reduces the size (i.e. number of cells) of any remaining tumor after the one or more rounds of radiation therapy.

[0356] In some embodiments, a 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, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is CDK2 inhibitor naive. For example, the subject is naive to treatment with a selective CDK2 inhibitor. In some embodiments, a subject is not CDK2 inhibitor naive (i.e., the subject has been previously administered one or more CDK2 inhibitors). In some embodiments, a subject is CDK4 / CDK6 inhibitor naive. For example, the subject is naive to treatment with a selective CDK4 / CDK6 inhibitor. In some embodiments, a subject is not CDK4 / CDK6 inhibitor naive (i.e., the subject has been previously administered one or more CDK4 / CDK6 inhibitors).

[0357] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof, may be administered in combination with a therapeutically effective amount of at least one additional therapeutic agent.

[0358] Non-limiting examples of additional therapeutic agents include: other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents such as EGFR, HER2, MEK, RAF, or KRAS inhibitors), cytotoxic chemotherapeutics, angiogenesis inhibitors, and radiotherapy.

[0359] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor typrosine kinase inhibitor (EGFR). For example, EGFR inhibitors can include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0360] In some embodiments, the additional therapeutic agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include trastuzumab and pertuzumab.

[0361] In some embodiments, the additional therapeutic agent is a Ras-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., everolimus, rapamycin, perifosine, temsirolimus), and other kinase inhibitors, such as baricitinib, brigatinib, capmatinib, danusertib, ibrutinib, milciclib, regorafenib, ruxolitinib, semaxanib, mobocertinib, avapritinib, fisogatinib, itacitinib, parsaclisib, pemigatinib, glesatinib, pexidartinib, rilzabrutinib, PF-477736 ((R)-amino-N-[5,6- dihydro-2-(l-methyl-1H-pyrazol-4-yl)-6-oxo-l / / -pyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]- cyclohexaneacetamide), PLX8394 ((3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)- 17 / -pyrrolo[2,3- b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-l -sulfonamide), PRN1371 (8-(3- (4-acryloylpiperazin-l-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2- (methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one), TGI 01209 (N-t-butyl-3-(5-methyl-2-(4-(4- methylpiperazin-l-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide), NMS- 1286937, NMS-088, INCB52793, PLX7486, PLX9486, and INCB40093.

[0362] In some embodiments, the additional therapeutic agent is a cytotoxic chemotherapeutic. Non-limiting example of cytotoxic chemotherapeutics 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.

[0363] In some embodiments, the additional therapeutic agent is an angiogenesis inhibitor, for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors. Examples of specific angiogenesis inhibitors include, but are not limited to, sunitinib (Sutent), bevacizumab (Avastin), axitinib, SU-14813, AG-13958, vatalanib (CGP79787), sorafenib (Nexavar), pegaptanib octasodium (Macugen), vandetanib (Zactima), PF-0337210, SU- 14843, AZD-2171, ranibizumab (Lucentis), Neovastat (AE941), tetrathiomolybdata (Coprexa), AMG706, VEGF Trap (AVE0005), CEP 7055, XL 880, telatinib, and CP-868,596. Other anti- angiogenesis agents include enzastaurin, midostaurin, perifosine, teprenone (Selbex) and UCN 01, lenalidomide (Revlimid), pomalidomide (Pomalyst), squalamine (Evizon), and thalidomide (Thalomid).

[0364] In some embodiments, the subject has a cancer that is known to be resistant to one of more of the additional therapies described herein. Accordingly, 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 was previously administered one or more of a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib), an endocrine therapy (such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen), a HER2 inhibitor (such as neratinib, trastuzumab, dacomitinib, lapatinib, tucatinib, pertuzumab, or margetuximab), cytotoxic chemotherapeutic, an EGFR, MEK, RAF or KRAS inhibitor, an inhibitor of the Ras- Raf-MEK-ERK pathway, or a combination of any of the foregoing.

[0365] In some embodiments, the subject was previously administered one or more of 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 (as described herein), an EGFR, MEK, RAF or KRAS inhibitor (as described herein), an inhibitor of the Ras-Raf-MEK-ERK pathway (as described herein), or a combination of any of the foregoing, and the previous therapy was unsuccessful in treating the cancer.

[0366] In some embodiments, the subject was previously 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 was unsuccessful in treating the cancer. In some embodiments, the subject was previously administered a CDK4 / CDK6 inhibitor (such as palbociclib, ribociclib, or abemaciclib) as a monotherapy, and the previous therapy was unsuccessful in treating the cancer.

[0367] Methods of Inhibiting

[0368] Although the genetic basis of tumorigenesis may vary between different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During a metastatic cascade, the cancer cells lose growth inhibitory responses, undergo alterations in adhesiveness and produce enzymes that can degrade extracellular matrix components. This leads to detachment of tumor cells from the original tumor, infdtration into the circulation through newly formed vasculature, and / or migration and extravasation of the tumor cells at favorable distant sites where they may form colonies.

[0369] Accordingly, also provided herein are methods for inhibiting metastasis of a cancer in a subject having a cancer in need of such treatment (e.g., a subject at risk of developing metastasis), 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-associated cancer. In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent, as described herein.

[0370] The term “metastasis” is an art known term and means the formation of an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject, where the additional tumor includes the same or similar cancer cells as the primary tumor.

[0371] Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a CDK2-associated cancer that include: selecting, identifying, or diagnosing a subject as having a CDK2-associated 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-associated cancer.

[0372] Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a CDK2-associated cancer that includes administering a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof to a subject having a CDK2-associated cancer. The decrease in the risk of developing a metastasis or an additional metastasis in a subject having a CDK2-associated cancer can be compared to the risk of developing a metastasis or an additional metastasis in the subject prior to treatment, or as compared to a subject or a population of subjects having a similar or the same CDK2-associated cancer that has received no treatment or a different treatment.

[0373] The phrase “risk of developing a metastasis” means the risk that a subject having a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject over a set period of time, where the additional tumor includes the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing a metastasis in a subject having a cancer are described herein.

[0374] The phrase “risk of developing additional metastases” means the risk that a subject having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors include the same or similar cancer cells as the primary tumor) will develop one or more further tumors distant from the primary tumor, where the further tumors include the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastasis are described herein.

[0375] Also provided is a method for inhibiting CDK2 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (A). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a CDK2-associated mammalian cancer cell. In some embodiments, the amount of the compound of Formula (A) is a therapeutically effective amount.

[0376] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing the cell.

[0377] Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo. comprising contacting a mammalian cell with a compound of Formula (A). In some embodiments, the amount of the compound of Formula (A) is a therapeutically effective amount.

[0378] Pharmaceutical Compositions and Kits

[0379] When employed as pharmaceuticals, compounds of Formula (A), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. These compositions can be prepared n a manner known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be, for example, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g.. intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump.

[0380] Also provided herein are pharmaceutical compositions which contain, as the active ingredient, a compound of Formula (A) or pharmaceutically acceptable salt thereof, 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. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. In some embodiments, the composition is formulated for oral administration.

[0381] 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.

[0382] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, 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.

[0383] The daily dosage of the compound of Formula (A) or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or any range therein.

[0384] Provided herein are pharmaceutical kits useful, for example, in the treatment of CDK2- associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0385] EXAMPLES

[0386] Preparation of Compounds

[0387] The starting materials used for the syntheses are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or Bruker AVANCE NEO 400 MHz spectrometer with an appropriate deuterated solvent. LCMS spectra were obtained on a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector.

[0388] The general methods for the preparation of the compounds of Formula (A) have been described in an illustrative manner and are intended to be descriptive, rather than limiting. Thus, it will be appreciated that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, it will be appreciated that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including without limitation, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use provided herein, may be made without departing from the spirit and scope thereof.

[0389] Example 1: Synthesis of rac-(3R,5R)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl (l-methylcyclopropyl)carbamate (Compound 1)

[0390] Step 1; Preparation of ethyl 4-hydroxytetrahydrofuran-2-carboxylate

[0391] A solution of ethyl 4-oxotetrahydrofuran-2-carboxylate (30 g, 190 mmol, 1 equiv) in EtOH (500 mL) was treated with NaBH4(7.18 g, 190 mmol, 1 equiv) for 30 min at -60 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at -60 °C under nitrogen atmosphere. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CHChTPA = 1 : 1 (3 x 500mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl 4-hydroxytetrahydrofuran-2-carboxylate (26 g, crude) as a yellow oil. LC-MS: (ES+H, m / z) 161.0 [M +H]+;1H NMR (400 MHz, DMSO-d6) δ 4.91 - 4.73 (brs, 1H) 4.41 (dd, J= 9.1, 4.2 Hz, 1H), 4.31 - 4.25 (m, 1H), 4.14 - 4.04 (m, 2H), 3.85 - 3.76 (m, 1H), 3.68 - 3.63 (m, 1H), 2.34 - 2.25 (m, 1H), 2.03 - 1.91 (m, 1H), 1.19 (t, J= 7.1 Hz, 3H).

[0392] Step 2: Preparation of ethyl 4-(benzyloxy)tetrahydrofuran-2-carboxylate

[0393] A solution of NaH (5.84 g, 243 mmol, 1.5 equiv) in THF (300 mL) was treated with ethyl 4-hydroxytetrahydrofuran-2-carboxylate (26 g, 162 mmol, 1 equiv) for 30 min at 0 °C under nitrogen atmosphere followed by the addition of BnBr (30.5 g, 179 mmol, 1.1 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl 4-(benzyloxy)tetrahydrofuran-2-carboxylate (25 g, crude) as a yellow oil.

[0394] Step 3: Preparation of 4-(benzyloxy)tetrahydrofuran-2-carboxylic acid

[0395] A solution of ethyl 4-(benzyloxy)tetrahydrofuran-2-carboxylate (25 g, 99.9 mmol, 1 equiv) and NaOH (12.0 g, 300 mmol, 3 equiv) in MeOH (20 mL) : H2O (20 mL) was stirred for 1.5 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was neutralized to pH 7 with citric acid. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1 - LA) to afford 4-(benzyloxy)tetrahydrofuran-2-carboxylic acid (17 g, 67 %) as a yellow oil. LC-MS: (ES+H, m / z) 224.0 [M +H]+;1H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.18 (m, 5H), 4.49 - 4.36 (m, 2H), 4.15 - 4.07 (m, 1H), 4.05 - 3.88 (m, 1H), 3.85 - 3.77 (m, 1H), 3.67 - 3.58 (m, 1H), 2.35 - 2.27 (m, 1H), 1.85 - 1.74 (m, 1H).

[0396] Step 4: Preparation of l,3-dioxoisoindolin-2-yl 4-(benzyloxy)tetrahydrofuran-2-carboxylate

[0397] To a stirred solution of 4-(benzyloxy)tetrahydrofuran-2-carboxylic acid (16 g, 72 mmol, 1 equiv) and A-hydroxyphthalimide (11.7 g, 72.0 mmol, 1 equiv) in 2-methyloxolane (200 mL) were added 2,4,6-tripropyl-l,3,5,2λ5,4λ5,6λ5-trioxatriphosphinane-2,4,6-trione (229 g, 360 mmol, 5 equiv, 50 %) and Et3N (21 .9 g, 216 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 6 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1~1 : 1) to afford l,3-dioxoisoindolin-2-yl 4- (benzyloxy)tetrahydrofuran-2-carboxylate (8 g, 24 %) as a colorless oil. LC-MS: (ES+H, m / z) 368.1 [M +H]+.

[0398] Step 5; Preparation of tert-butyl (5-(4-(benzyloxy)tetrahydrofuran-2-yl)pyrimidin-2- yl)carbamate

[0399] To a stirred solution of l,3-dioxoisoindolin-2-yl 4-(benzyloxy)tetrahydrofuran-2- carboxylate (4.01 g, 10.9 mmol, 1.3 equiv) and tert-butyl (2-bromopyrimidin-5-yl)carbamate (2.3 g, 8.39 mmol, 1 equiv) in DMAC (50 mL) were added 5-methoxypyridine-2-carboxamidine hydrochloride (0.16 g, 0.83 mmol, 0.1 equiv), nickel (II) chloride ethylene glycol dimethyl ether complex (184 mg, 0.83 mmol, 0.1 equiv) and Zn (5.49 g, 83.91 mmol, 10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1~1 : 1) to afford tert-butyl (5-(4-(benzyloxy)tetrahydrofuran-2-yl)pyrimidin-2- yl)carbamate (1.3 g, 38 %) as a yellow oil. LC-MS: (ES+H, m / z) 372.1 [M +H]+;1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.58 (s, 2H), 7.38 - 7.26 (m, 5H), 5.08 - 4.83 (m, 1H), 4.52 (dt, J = 26.3, 13.6 Hz, 2H), 4.34 (d, J = 17.4 Hz, 1H), 4.22 - 3.98 (m, 1H), 3.88 (d, J= 9.8 Hz, 1H), 2.06 - 1.83 (m, 1H), 1.46 (s, 9H), 1.27 (d, J = 27.5 Hz, 1H).

[0400] Step 6: Preparation of 5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-ol

[0401] A solution of tert-butyl (5-(4-(benzyloxy)tetrahydrofuran-2-yl)pyrimidin-2-yl)carbamate (1.3 g, 3.50 mmol, 1 equiv) in methanesulfonic acid (10 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1-5:1) to afford 5-(2-aminopyrimidin-5- yl)tetrahydrofuran-3-ol (500 mg, 71 %) as a yellow solid. LC-MS: (ES+H, m / z) 182.1 [M +H]+;1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J= 5.7 Hz, 2H), 5.76 (s, 3H), 5.01 - 4.93 (m, 1H), 4.43 (dd, J= 12.6, 7.7 Hz, 1H), 4.07 (dd, J= 9.1, 4.2 Hz, 1H), 3.87 - 3.61 (m, 1H), 2.17 (dd, J = 13.2, 5.6 Hz, 1H), 1.98 - 1.75 (m, 1H).

[0402] Step 7; Preparation of 5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (4-nitrophenyl) carbonate

[0403] To a stirred solution of 5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-ol (500 mg, 2.75 mmol, 1 equiv) and bis(4-nitrophenyl) carbonate (1007 mg, 3.31 mmol, 1.2 equiv) in DCM (20 mL) were added DIEA (1070 mg, 8.27 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with DCM (3 x 50mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-(2-aminopyrimidin-5- yl)tetrahydrofuran-3-yl (4-nitrophenyl) carbonate as a yellow oil. LC-MS: (ES+H, m / z) 347.0 [M +H]+.

[0404] Step 8; Preparation of rac-(3R,5R)-5-(2-aniinopyrimidin-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate & rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3- yl (l-methylcyclopropyl)carbamate

[0405] To a stirred solution of 5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (300 mg, 0.86 mmol, 1 equiv) and DIEA (336 mg, 2.59 mmol, 3 equiv) in DMF (5 mL) was added 1-methylcyclopropan-l -amine hydrochloride (140 mg, 1.29 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (200 mg) was purified by prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 20% B in 10 min; RTl(min): 8.65 / 9.58) to afford rac- (3R,5R)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (l-methylcyclopropyl)carbamate (25 mg, 10 %) as a white solid (LC-MS: (ES+H, m / z) 279.0 [M +H]+;1H NMR (400 MHz, DMSO- d6) δ 8.20 (s, 2H), 7.54 (s, 1H), 6.59 (s, 2H), 5.19 (d, J= 39.0 Hz, 1H), 4.86 - 4.56 (m, 1H), 3.81 (dd, J = 47.4, 7.4 Hz, 2H), 2.64 (dt, J= 14.4, 7.5 Hz, 1H), 1.81 - 1.66 (m, 1H), 1.23 (s, 3H), 0.68 - 0.41 (m, 4H)) and rac-(3R,5S)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (30 mg, 12 %) as a white solid (LC-MS: (ES+H, m / z) 279.0 [M +H]+;1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 2H), 7.55 (s, 1H), 6.62 (s, 2H), 5.21 (t, J= 5.3 Hz, 1H), 4.75 (dd, J= 10.4, 5.5 Hz, 1H), 4.27 - 4.15 (m, 1H), 3.67 (d, J= 10.2 Hz, 1H), 2.32 - 2.00 (m, 2H), 1.25 (s, 3H), 0.56 (dd, J= 52.1, 5.2 Hz, 4H)).

[0406] Step 9: Preparation of rac-(3R,5R)-5-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropy ylc)arbamate

[0407] To a stirred solution of rac- (3R,5R)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (28 mg, 0.10 mmol, 1 equiv) and tert-butyl N-(4- bromobenzenesulfonyl)carbamate (40.6 mg, 0.121 mmol, 1.2 equiv) in t-BuOH (3 mL) were added K2CO3(41.7 mg, 0.303 mmol, 3 equiv) and EPhos Pd G4 (9.24 mg, 0.010 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (9: 1), the resulting mixture was concentrated under reduced pressure to afford rac-(3R,5R)-5-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (32 mg, 60 %) as a yellow oil. LC-MS: (ES+H, m / z) 534.1 [M+H]+.

[0408] Step 10: Preparation of rac-(3R,5R)-5-(2-((4-siilfaiiioylplieiiyl)aiiiiiio)pyriniidin-5- yl)tetrahydrofuran-3-yl ( l-methylcyclopropyDcarbamate A solution of rac-(3R,5R)-5-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate (32 mg, 0.060 mmol, 1 equiv) in HCOOH (4 mL) was stirred for 1 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by prep- HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 17% B to 37% B in 10 min; RTl(min): 8.55 / 9.18), the resulting mixture was concentrated under reduced pressure by lyophilization to afford rac- (3R,5R)-5-(2-((4- sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl (l-methylcyclopropyl)carbamate (4 mg, 15 %) as a white solid. LC-MS: (ES+H, m / z) 434.1 [M+H]+;1H NMR (400 MHz, DMSO- d6) 8 10.09 (s, 1H), 8.68 - 8.44 (m, 2H), 7.95 - 7.88 (m, 2H), 7.82 -7.72 (m, 2H), 7.55 (s, 1H), 7.17 (s, 2H), 5.35 - 5.13 (m, 1H), 5.02 - 4.73 (m, 1H), 4.00 - 3.90 (m, 1H), 3.87 - 3.76 (m, 1H), 2.79 - 2.65 (m, 1H), 1.88 - 1.75 (m, 1H), 1.28 - 1.21 (m, 3H), 0.71 - 0.55 (m, 2H), 0.54 - 0.40 (m, 2H).

[0409] Example 2: (3S,5S)-5-(2-((4-carbamoyl-3-fluorophenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 24)

[0410] Step 1 - Synthesis of (S)-5-(2,3-dihydrofuran-2-yl)-N,N-bis(2,4- dimethoxybenzyl)pyrimidin-2-amine:

[0411] A mixture of 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]pyrimidin-2-amine (0.5 g, 1.05 mmol), 2, 3 -dihydrofuran (221 mg, 3.16 mmol), Pd(OAc)2(9 mg, 42 μmol), (S)-DTBM- SEGPHOS (74 mg, 63 μmol) and silver trifluoroacetate (232 mg, 1.05 mmol), DIEA (408 mg, 3.16 mmol) in MeOH (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90 °C for 12 h under N2atmosphere. After cooling to room temperature, the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (0.25 g, 38%) as a white solid. NMR (400 MHz, CDCI3) δ 8.35 (s, 2H), 7.04 - 7.00 (m, 2H), 6.44 (d, J= 2.4 Hz, 2H), 6.41 - 6.38 (m, 3H), 5.39 - 5.33 (m, 1H), 5.01 - 4.97 (m, 1H), 4.83 (s, 4H), 3.79 (s, 6H), 3.75 (s, 6H), 3.08 - 2.93 (m, 1H), 2.69 - 2.59 (m, 1H). LCMS (ESI) m / z: 464.2 [M+H]+. SFC showed 90%ee.

[0412] Step 2 - Synthesis of (3R,5S)-5-(2-(bis(2,4-dimethoxybenzyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-oI:

[0413] To a solution of 5-[(2S)-2,3-dihydrofuran-2-yl]- / V, / V-bis[(2,4- dimethoxyphenyl)methyl]pyrimidin-2-amine (2. 1 g, 4.53 mmol) in THF (40 mL) was added 9- BBN (0.5 M in THF, 20 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. Then the reaction mixture was cooled to 0 °C, quenched aqueous NaOH (3 M, 4.53 mL), then H2O2(1.54 g, 13.59 mmol, 30% in H2O) were added, and the resulting solution was stirred at 20 °C for 1 h. The reaction mixture was quenched by sat.aq. Na2SO3(20 mL), and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (1.7 g, 74%) as a yellow solid.1H NMR (400 MHz, CDCI3) δ 8.31 (s, 2H), 7.04 - 6.98 (m, 2H), 6.45 - 6.42 (m, 2H), 6.41 - 6.37 (m, 2H), 5.02 - 4.95 (m, 1H), 4.81 (s, 4H), 4.65 ( t, J= 4.8 Hz, 1H), 4.23 - 4.18 (m, 1H), 3.86 - 3.82 (m, 1H), 3.78 (s, 6H), 3.74 (s, 6H), 2.26 - 2.20 (m, 1H), 2.03 - 1.98 (m, 1H). LCMS (ESI) m / z: 482.2 [M+H]+.

[0414] Step 3 - Synthesis of (3S,5S)-5-(2-(bis(2,4-dimethoxybenzyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl 4-nitrobenzoate:

[0415] A solution of (3R,5S)-5-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]pyrimidin-5- yl]tetrahydrofuran-3-ol (1.7 g, 3.39 mmol), PPh3(1.78 g, 6.78 mmol) and 4-nitrobenzoic acid (1.13 g, 6.78 mmol) in toluene (20 mL) was degassed and purged with N2for 3 times, then DEAD (1.18 g, 6.78 mmol, 1.23 mL) was added. The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched by addition water (10 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (1.2 g, 49%) as a yellow oil. LCMS (ESI) m / z: 631.2 [M+H]+..

[0416] Step 4 - Synthesis of (3S,5S)-5-(2-(bis(2,4-dimethoxybenzyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-ol:

[0417] To a solution of [(3S,5S)-5-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]pyrimidin-5- yl]tetrahydrofuran-3-yl] 4-nitrobenzoate (1.2 g, 1.90 mmol) in MeOH (20 mL) was added K2CO3(789 mg, 5.71 mmol), the mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction was diluted with ethyl acetate (80 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (0.7 g, 71%) as a colorless oil.1H NMR (400 MHz, CDCI3) δ 8.40 (s, 2H), 7.05 - 6.95 (m, 2H), 6.44 - 6.36 (m, 4H), 4.81 (s, 4H), 4.72 (t, J= 7.6 Hz, 1H), 4.60 - 4.55 (m, 1H), 4.01 - 3.96 (m, 1H), 3.84 - 3.79 (s, 1H), 3.78 (s, 6H), 3.74 (s, 6H), 2.62 - 2.53 (m, 1H), 1.98 - 1.89 (m, 1H). LCMS (ESI) m / z 482.2 [M+H]+.

[0418] Step 5 - Synthesis of (3S,5S)-5-(2-(bis(2,4-diniethoxybenzyl)aniino)pyriniidin-5- yl)tetrahydrofuran-3-yl (4-nitrophenyl) carbonate

[0419] To a solution of (3S,5S)-5-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]pyrimidin-5- yl]tetrahydrofuran-3-ol (3 g, 4.36 mmol), pyridine (1.03 g, 13.08 mmol) and DMAP (266 mg, 2.18 mmol) in DCM (30 mL) was added 4-Nitrophenyl chloroformate (1.32 g, 6.54 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition water (10 mL) at 25 °C, and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (1.1 g, 41%) as a colorless oil. LCMS (ESI) m / z: 647.2 [M+H]+

[0420] Step 6 - Synthesis of (3S,5S)-5-(2-(bis(2,4-dimethoxybenzyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yI isopropylcarbamate:

[0421] To a solution of [(3S,5S)-5-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]pyrimidin-5- yl]tetrahydrofuran-3-yl] (4-nitrophenyl) carbonate (1.8 g, 2.78 mmol) in THF (30 mL) was added TEA (1.41 g, 13.92 mmol) and propan-2-amine (551 mg, 4.18 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition water (10 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (750 mg, 44%) as a yellow solid. LCMS (ESI) m / z: 567.3 [M+H]+.

[0422] Step 7 - Synthesis of (3S,5S)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0423] To a solution of [(3S,5S)-5-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]pyrimidin-5- yl]tetrahydrofuran-3-yl] A-isopropylcarbamate (0.75 g, 1.33 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 mixture was concentrated in vacuo and adjusted pH to 10 with NH4OH. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 3% MeOH in DCM) to give the title compound (300 mg, 85%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 2H), 7.15 (d, J= 7.2 Hz, 1H), 6.71 (s, 2H), 5.18 - 5.13 (m, 1H), 4.68 - 4.59 (m, 1H), 3.91 - 3.87 (m, 1H), 3.77 - 3.71(m, 1H), 3.62 - 3.55 (m, 1H), 2.70 - 2.60 (m, 1H), 1.79 - 1.69 (m, 1H), 1.10 - 0.95 (m, 6H). LCMS (ESI) m / z: 267.1 [M+H]+.

[0424] Step 8 - Synthesis of methyl 2-fluoro-4-((5-((2S,4S)-4- ((isopropylcarbamoyl)oxy)tetrahydrofuran-2-yl)pyrimidin-2-yl)amino)benzoate:

[0425] A mixture of [(3S,5S)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl] N- isopropylcarbamate (100 mg, 375 μmol), methyl 4-bromo-2-fluoro-benzoate (175 mg, 751 μmol), BrettPhos (40 mg, 75 μmol), CS2CO3(612 mg, 1.88 mmol) and BrettPhos Pd G3 (34 mg, 37 μmol) in dioxane (4 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 16 h under N2atmosphere. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (109 mg, 82%) as a colorless oil. LCMS (ESI) m / z: 419.1 [M+H]+.

[0426] Step 9 - Synthesis of 2-fluoro-4-((5-((2S,4S)-4- ((isopropylcarbamoyl)oxy)tetrahydrofuran-2-yl)pyrimidin-2-yl)amino)benzoic acid:

[0427] To a solution of methyl 2-fluoro-4-[[5-[(2S,45)-4- (isopropylcarbamoyloxy)tetrahydrofuran-2-yl]pyrimidin-2-yl]amino]benzoate (109 mg, 260 μmol) in MeOH (2 mL), H2O (2 mL) and THF (2 ml) was added LiOH.H2O (21.86 mg, 521 μmol). The reaction mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction was adjusted pH to 2 with aq. HC1 (IM) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (100 mg, crude) as a white solid. LCMS (ESI) m / z: 405.1 [M+H]+

[0428] Step 10 - Synthesis of (3A,55)-5-(2-((4-carbamoyl-3-fluorophenyl)amino)pyrimidin- 5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0429] To a solution of 2-fluoro-4-[[5-[(25',4S)-4-(isopropylcarbamoyloxy)tetrahydrofuran-2- yl]pyrimidin-2-yl]amino]benzoic acid (50 mg, 123 μmol), NH4CI (20 mg, 371 μmol) and DIPEA (48 mg, 371 μmol) in DMF (250 mL) was added HATU (71 mg, 185 μmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered and purified by reverse phase chromatography (acetonitrile 21% - 51% / 0.225% formic acid in water) to give the title compound (72 mg, 56%) as a white solid

[0430] Compound 24:1H NMR (400 MHz, DMSO de) 5 10.20 (s, 1H), 8.56 (s, 2H), 7.89 (d, J = 14.4 Hz, 1H), 7.67-7.63 (m, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.48 - 7.36 (m, 2H), 7.17 (d, J= 6.4 Hz, 1H), 5.26 - 5.14 (m, 1H), 4.81 (t, J= 7.2, 1H), 3.99 - 3.91 (m, 1H), 3.85 - 3.76 (m, 1H), 3.65 - 3.52 (m, 1H), 2.78 - 2.66 (m, 1H), 1.89 - 1.76 (m, 1H), 1.07 - 1.01 (m, 6H). LCMS (ESI) m / z: 404.1[M+H]‘-

[0431] SFC Method: Column: Chiralcel OI-3 100x4.6mm I D., 3um; Mobile phase: A: CO2B:ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 3 min and hold 40% for 0.5 min, then 5% of B for 1.5 min; Flow rate: 2.8mL / min; Column temp.: 35°C; ABPR: 1500psi. Analytical data of compounds is shown in Table A below. The compounds in Table A were prepared using procedures analogous to those described above with appropriate modifications within the purview of one skilled in the art.

[0432] Table A. Compounds of Formula (A)

[0433] Example 3: (3S,5S)-5-(2-((l-(2-aminopyridin-4-yl)-l / / -pyrazol-4-yl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 32) Step 1 - Synthesis of (3S,5S)-5-(2-chloropyrimidin-5-yl)tetrahydrofuran-3-yI isopropylcarbamate:

[0434] A mixture of [(3 ,5S)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl] N- isopropylcarbamate (0.3 g, 1.13 mmol), HC1 (12 M, 751 μL) and ZnCI2(460 mg, 3.38 mmol) in DCM (10 mL) was stirred at 0 °C for 0.5 h. Then NaNCh (233 mg, 3.38 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. After the reaction was completed, the mixture was adjusted pH to 7 with sat.aq. NaHCO3, extracted with ethyl acetate (50 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (0.12 g, 35%) as a yellow solid.1H NMR (400 MHz, CDCI3) δ 8.65 (s, 2H), 5.38 - 5.30 (m, 1H), 5.06 - 4.99 (m, 1H), 4.24 - 4.17 (m, 1H), 4.03 - 3.95 (m, 1H), 3.85 - 3.69 (m, 1H), 2.83 - 2.72 (m, 1H), 2.05 - 1.99 (m, 1H), 1.19 - 1.08 (m, 6H). LCMS (ESI) m / z 286.1 [M+H]+. Step 2 - Synthesis of tert-butyl (4-(4-nitro-1H-pyrazol-l-yl)pyridin-2-yl)carbamate

[0435] To a solution of tert-butyl A-(4-fluoro-2-pyridyl)carbamate (2.82 g, 13.27 mmol) and 4- nitro-1H-pyrazole (750 mg, 6.63 mmol) in NMP (25 mL) was added K2CO3(2.75 g, 19.90 mmol). The mixture was stirred at 60 °C for 24 h. The reaction was quenched by addition H2O (50 mL) and filtered, the filter cake was added di chloromethane (50 mL), stirred for 0.5 h, then filtered, the filter cake was washed by dichloromethane, and then the filter cake was dried under reduced pressure to give the title compound (1.424 g, 66%) as a white solid that required no further purification.1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.63 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (d, J= 5.6 Hz, 1H), 7.66 - 7.64 (m, 1H), 1.49 (s, 9H). LCMS (ESI) m / z: 249.8[M- / Bu+H]

[0436] Step 3 - Synthesis of tert-butyl (4-(4-amino-LH-pyrazol-l-yl)pyridin-2-yl)carbamate:

[0437] To a solution of tert-butyl A-[4-(4-nitropyrazol-l-yl)-2-pyridyl]carbamate (600 mg, 1.97 mmol) in EtOH (6 mL) and H2O (1 mL) was added Fe (1.10 g, 19.65 mmol) and NH4CI (3.15 g, 58.96 mmol). The mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered, the filtrate was extracted with ethyl acetate 60 mL (20 mL x3 ). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (370 mg, 64%) as a yellow solid that required no further purification. 'H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.24 - 8.08 (m, 2H), 7.68 (s, 1H), 7.36 (s, 1H), 7.28 (dd, J= 2.0, 5.6 Hz, 1H), 4.36 (s, 2H), 1.48 (s, 9H). LCMS (ESI) m / z: 275.9 [M+H]+.

[0438] Step 4 - Synthesis of (3S,5S)-5-(2-((l-(2-aminopyridin-4-yl)-l / / -pyrazol-4- yl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate

[0439] A mixture of tert-butyl A-[4-(4-aminopyrazol-l-yl)-2-pyridyl]carbamate (29 mg, 105 μmol), [(3S,5S)-5-(2-chloropyrimidin-5-yl)tetrahydrofuranN-3-yl]-isopropylcarbamate (20 mg, 70 μmol), BrettPhos Pd G3 (6 mg, 7.00 μmol), Brettphos (4 mg, 7.00 μmol) and CS2CO3(68 mg, 210 μmol) in dioxane (2 mL) was degassed and purged with N2for 3 times, the mixture was stirred at 100 °C for 16 h under N2atmosphere. After the reaction was completed, the reaction mixture filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 10% - 40% / 0.225% formic acid in water) to give the title compound (1.65 mg, 5.5%) as a white solid. Compound 32:1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.52 (s, 1H), 8.49 (s, 2H), 7.94 (d, .7 = 5.6 Hz, 1H), 7.85 (s, 1H), 7.18 (d, J= 8.0 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.82 (d, J= 1.6 Hz, 1H), 6.13 (s, 2H), 5.20 - 5.18 (m, 1H), 4.82 - 4.71 (m, 1H), 3.96 - 3.90 (m, 1H), 3.86 - 3.75 (m, 1H), 3.57 - 3.51 (m, 1H), 2.76 - 2.68 (m, 1H), 1.87 - 1.73 (m, 1H), 1.06 - 1.03 (m, 6H). LCMS (ESI) m / z: 425.3 [M+H]+

[0440] SFC Method: Column: Chiralcel OJ-3 50x4.6mm I.D., 3um; Mobile phase: A: CO2B:ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min; Flow rate: 3mL / min; Column temp.: 35°C; ABPR: 1500ps.

[0441] Analytical data of compounds is shown in Table B below. The compounds in Table B were prepared using procedures analogous to those described above with appropriate modifications within the purview of one skilled in the art.

[0442] Table B. Compounds of Formula (A)

[0443] Example 4: Cis-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)- sec-butyl)carbamate (Compound 37) Step 1 - Synthesis of l-(2-chloropyrimidin-5-yl)but-3-en-l-ol

[0444] To a solution of 2-chloropyrimidine-5-carbaldehyde (5 g, 35.08 mmol) in DMF (100 mL) was added Indium power (4.83 g, 42.09 mmol) and Nal (10.52 g, 70.15 mmol) at 0 °C. After addition, then 3 -bromoprop- 1-ene (8.49 g, 70.15 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction mixture was filtered and the filtrate was diluted with water (50 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (5 g, 77%) as yellow oil.1H NMR (400 MHz, CDCI3) δ 8.64 (s, 2H), 5.84 - 5.77 (m, 1H), 5.26 - 5.16 (m, 2H), 4.90 - 4.80 (m, 1H), 2.65 - 2.49 (m, 2H). LCMS (ESI) m / z: 185.1 [M+H]+.

[0445] Step 2 - Synthesis of l-(2-chloropyrimidin-5-yl)-2-(oxiran-2-yl)ethan-l-ol

[0446] A mixture of l-(2-chloropyrimidin-5-yl)but-3-en-l-ol (5 g, 27.08 mmol) in DCM (50 mL) was added m-CPBA (11.00 g, 54.16 mmol, 85% purity) at 0 °C, the mixture was stirred at 25 °C for 16 h under N2atmosphere. The reaction mixture was quenched with sat.aq. Na2S2O3(50 mL), and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (30 mL x 5), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (1.4 g, 25%) as white solid.1H NMR (400 MHz, CDCI3) δ 8.69 (d, J = 5.2 Hz, 2H), 5.18 - 5.01 (m, 1H), 3.29 - 3.13 (m, 1H), 3.10 - 2.99 (m, 1H), 2.96 - 2.86 (m, 1H), 2.81 - 2.58 (m, 1H), 2.39 - 2.21 (m, 1H), 1.89 - 1.70 (m, 1H). LCMS (ESI) m / z: 201.0 [M+H]+.

[0447] Step 3 - Synthesis of 5-(2-chloropyrimidin-5-yl)tetrahydrofuran-3-ol

[0448] To a solution of l-(2-chloropyrimidin-5-yl)-2-(oxiran-2-yl)ethanol (1.1 g, 5.48 mmol) in dioxane (50 mL) was added the solution of H2SO4(538 mg, 5.48 mmol) in dioxane (5 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. After the reaction was completed, the mixture was quenched by addition sat. aq. NaHCO3(40 mL) at 0 °C, extracted with with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 10% - 50% EtOAc in petroleum ether) to give the title compound (300 mg, 18%) as yellow oil.1H NMR (400 MHz, CDCI3) δ 8.69 - 8.61 (m, 2H), 5.23 - 5.14 (m, 0.5H), 5.04 - 4.99 (m, 0.5H), 4.75 - 4.64 (m, 1H), 4.29 - 4.22 (m, 0.5H), 4.14 - 4.09 (m, 0.5H), 3.97 - 3.90 (m, 1H), 2.73 - 2.66 (m, 0.5H), 2.47- 2.40 (m, 0.5H), 2.01 - 1.87 (m, 2H). LCMS (ESI) m / z: 201.0 [M+H]+.

[0449] Step 4 - Synthesis of 4-((5-(4-hydroxytetrahydrofuran-2-yl)pyrimidin-2- yl)amino)benzenesulfonamide To a solution of 5-(2-chloropyrimidin-5-yl)tetrahydrofuran-3-ol (0.3 g, 1 .50 mmol) and

[0450] 4-aminobenzenesulfonamide (515 mg, 2.99 mmol) in dioxane (4 mL) was added HCl / water (3 M, 1 mL). The reaction mixture was stirred at 110 ° C for Ih. After the reaction was completed, the mixture was adjust pH to 8 by addition sat. aq. NaHCO3at 0 °C, extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 10% - 80% EtOAc in petroleum ether) to give the title compound (230 mg, 33%) as white solid. LCMS (ESI) m / z: 337.0 [M+H]+.

[0451] Step 5 - Synthesis of [5-[2-[4-[bis( tert-butoxycarbonyl)sulfamoyl]anilino]pyrimidin-

[0452] 5-yl]tetrahydrofuran-3-yl] tert-butyl carbonate

[0453] To a solution of 4-((5-(4-hydroxytetrahydrofuran-2-yl)pyrimidin-2- yl)amino)benzenesulfonamide (0.23 g, 684 μmol) in THF (5 mL) was added DMAP (17 mg, 137 μmol) and TEA (207 mg, 2.05 mmol), then Boc2O (746 mg, 3.42 mmol) was added. The mixture was stirred at 25 °C for 16 h. After the reaction was completed, the mixture was quenched with water (10 mL) at 25 °C, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (0.3 g, 69%) as yellow oil that required no further purification. LCMS (ESI) m / z: 637.2 [M+H]+.

[0454] Step 6 - Synthesis of tert-butyl ((4-((5-(4-hydroxytetrahydrofuran-2-yl)pyrimidin-2- yl)amino)phenyl)sulfonyl)carbamate

[0455] To a solution of [5-[2-[4-[bis(terLbutoxycarbonyl)sulfamoyl]anilino]pyrimidin-5- yl]tetrahydrofuran-3-yl] tert-butyl carbonate (0.3 g, 471 μmol) in EtOH (5 mL) and water (1 mL) was added NaOH (94 mg, 2.36 mmol). The reaction was stirred at 25 °C for 5 h. After the reaction was completed, the mixture was diluted with addition water (10 mL) at 25 °C, extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 10% - 30% EtOAc in petroleum ether) to give the title compound (0.2 g, 97%) as white solid.1H NMR (400 MHz, DMSO-d6) 11.39 ( s, IH), 10.24 - 10.22 (m, IH), 8.60 - 8.54 (m, 2H), 8.01 - 7.95 (m, 2H), 7.79 - 7.74 (m, 2H), 5.09 - 5.01 (m, IH), 5.00 - 4.80 (m, 1H), 4.50 - 4.39 (m, 1H), 4.12 - 4.07 (m, 0.5H), 3.84 - 3.79 (m, 0.5H), 3.76 - 3.72 (m, 0.5H), 3.67 - 3.61 (m, 0.5H), 2.47 - 2.44 (m, 0.5H), 2.20 - 2.14 (m, 0.5H), 1.94 - 1.88 (m, 0.5H), 1.80 -1.73 (m, 0.5H). LCMS (ESI) m / z: 437.1 [M+H]+.

[0456] Step 7 - Synthesis of cis-tert-butyl ((4-((5-(4-(((4- nitrophenoxy)carbonyl)oxy)tetrahydrofuran-2-yl)pyrimidin-2- yl)amino)phenyl)sulfonyl)carbamate and trans-tert-butyl ((4-((5-(4-(((4- nitrophenoxy)carbonyl)oxy)tetrahydrofuran-2-yl)pyrimidin-2- yl)amino)phenyl)sulfonyl)carbamate

[0457] To a solution of tert-butyl A-[4-[[5-(4-hydroxytetrahydrofuran-2-yl)pyrimidin-2- yl]amino]phenyl]sulfonylcarbamate (0.2 g, 458 μmol) in DCM (10 mL) was added DMAP (11 mg, 91.64 μmol), py (108 mg, 1.37 mmol) and (4-nitrophenyl) carbonochloridate (138.54 mg, 687.31 μmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition water (5 mL) at 20 °C, and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give cis-tert-butyl ((4-((5-(4-(((4- nitrophenoxy)carbonyl)oxy)tetrahydrofuran-2-yl)pyrimidin-2- yl)amino)phenyl)sulfonyl)carbamate (30 mg, 9%, larger polarity) as a white solid.1H NMR (400 MHz, CDCI3) δ 10.00 (s, 1H), 8.62 (s, 2H), 8.28 - 8.22 (m, 2H), 7.93 - 7.87 (m, 4H), 7.38 - 7.33 (m, 2H), 5.49 - 5.44 (m, 1H), 4.95 (t, J= 7.6 Hz, 1H), 4.38 - 4.32 (m, 1H), 4.04 - 3.99 (m, 1H), 2.93 - 2.83 (m, 1H), 2.23 - 2.15 (m, 1H), 1.41 (s, 9H). LCMS (ESI) m / z: 602.1 [M+H]+. And trans-tert-bu\y\ ((4-((5-(4-(((4-nitrophenoxy)carbonyl)oxy)tetrahydrofuran-2-yl)pyrimidin-2- yl)amino)phenyl)sulfonyl)carbamate (40 mg, 12%, lower polarity) was obtained as a white solid.1H NMR (400 MHz, CDCI3) δ 9.25 (s, 1H), 8.57 (s, 2H), 8.40 (s, 1H), 8.31 (d, J= 9.2 Hz, 2H), 7.98 - 7.87 (m, 4H), 7.43 (d, J= 9.2 Hz, 2H), 5.56 - 5.50 (m, 1H), 5.15 - 5.08 (m, 1H), 4.49 - 4.42 (m, 1H), 4.15 - 4.10 (m, 1H), 2.69 - 2.61 (m, 1H), 2.22 - 2.11 (m, 1H), 1.42 (s, 9H). LCMS (ESI) m / z: 602.1 [M+H]+.

[0458] Step 8 - Synthesis of cis- 5-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyriniidin-5-yl)tetrahydrofuran-3-yl ((.V)-sec- butyl)carbamate: To a solution of cis-tert-butyl ((4-((5-(4-(((4-nitrophenoxy)carbonyl)oxy)tetrahydrofuran- 2-yl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate (30 mg, 49 μmol) in THF (2 mL) was added TEA (33 mg, 332 μmol) and (2S)-butan-2-amine HC1 salt (14 mg, 133 μmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition water (10 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (25 mg, 72%) as a yellow solid. LCMS (ESI) m / z: 536.2 [M+H]+.

[0459] Step 9 - Synthesis of Cis-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate

[0460] To a solution of cis- 5-(2-((4-N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec- butyl)carbamate (25 mg, 46 μmol) in DCM (6 mL) was added TFA (2 mL, 26.9 mmol). The reaction mixture was stirred at 25 °C for 1 h. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with NH4OH, then adjusted pH to 6 with formic acid. The residue was purified by reverse phase chromatography (acetonitrile 30% - 60% / 0.225% formic acid in water) to give the title compound (5 mg, 24%) as white solid. Compound 37:1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.55 (s, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.72 (d, J= 8.8 Hz, 2H), 7.18 (s, 2H), 7.11 (d, J= 8.8 Hz, 1H), 5.23 - 5.14 (m, 1H), 4.86 - 4.76 (m, 1H), 3.99 - 3.90 (m, 1H), 3.85 - 3.80 (m, 1H), 3.58 - 3.51 (m, 1H), 2.77 - 2.68 (m, 1H), 1.88 - 1.78 (m, 1H), 1.42 - 1.31 (m, 2H), 1.01 (t, J= 6.0 Hz, 3H), 0.85 - 0.74 (m, 3H). LCMS (ESI) m / z: 436.1 [M+H]+.

[0461] SFC methods: Column: (S,S)Whelk-01 100><4.6mm I.D., 5.0 um; Mobile phase: A: CO2BMethanol (0.05% DEA); Isocratic: 50% B; Flow rate: 2.5mL / min; Column temp.:40°C; ABPR: 100 bar.

[0462] Preparing of INT A: 5-(2-aminopyrimidin-5-yl) oxolan-3-ol (cis / trans mixture) (Method 1, for scaling up):

[0463] Step 1: Preparation of l-(2-aminopyrimidin-5-yl) but-3-en-l-ol:

[0464] To a stirred solution of 2-aminopyrimidine-5-carbaldehyde (200.00 g, 1624.49 mmol, 1.00 equiv) and In (149.22 g, 1299.59 mmol, 0.80 equiv) in DMF (2.00 L) was added Nal (365.25 g, 2436.74 mmol, 1.50 equiv) in portions at 0°C under nitrogen atmosphere. To the above mixture was added allyl bromide (294.79 g, 2436.74 mmol, 1.50 equiv) at 0°C. The resulting mixture was stirred for additional 2h at room temperature. Desired product could be detected by LCMS. The reaction was quenched by the addition of sat. NaHCO3(2.00 L) at 0°C. The precipitated solids were collected by filtration and washed with EA (2 x 1.00 L). The resulting mixture was extracted with CH3C1 / IPA(2: 1) (5 x 1.00 L). The combined organic layers were washed with brine (5 x 1.00 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (9: 1) to afford to afford l-(2-aminopyrimidin-5-yl)but-3-en-l-ol (180.00 g, 67.07%) as a light yellow solid. LC-MS: (ES+H, m / z\. [M+H]+=166.15

[0465] Step 2: Preparation of l-(2-aminopyrimidin-5-yl)-3,4-dibromobutan-l-ol:

[0466] To a stirred solution of l-(2-aminopyrimidin-5-yl)but-3-en-l-ol (180.00 g, 1089.61 mmol, 1.00 equiv) in THF (2.00 L) was added Bromine (55.83 mL, 1089.61 mmol, 1.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for additional 2 h. Desired product could be detected by LCMS. The reaction was quenched with Sodium thiosulfate(aq.) at 0°C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CH2CI2 / IPA (2: 1) (3 x 1.00 L). The combined organic layers were washed with brine (2 x 400.00 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2MeOH (9: 1) to afford l-(2-aminopyrimidin-5-yl)-3,4- dibromobutan-l-ol (162.00 g, 45.75%) as a yellow oil. LC-MS: (ES+H, m / zy. [M+H] =325.9 / 323.9 / 327.9.

[0467] Step 3: Preparation of 5-(4-bromooxolan-2-yI) pyrimidin-2-amine: A solution of l-(2-aminopyrimidin-5-yl)-3,4-dibromobutan-l-ol (162.00 g, 498.45 mmol, 1.00 equiv) and K2CO3(275.56 g, 1993.82 mmol, 4.00 equiv) in MeOH (1.00 L) was stirred at room temperature for 6 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was fdtered, the filter cake was washed with MeOH (2 x 200.00 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with CH2CI2 / IPA (2: 1) (3 x 700.00 mL). The combined organic layers were washed with brine (2 x 200.00 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6: 1) to afford 5-(4-bromooxolan-2-yl) pyrimidin- 2-amine (76.00 g, 62.46%) as a yellow oil. LC-MS: (ES+H, m / z\. [M+H]+=243.9 / 245.9.

[0468] Step 4: Preparation of 5-(2-aminopyrimidin-5-yl) oxoIan-3-yl acetate:

[0469] A solution of 5-(4-bromooxolan-2-yl)pyrimidin-2-amine (76.00 g, 311.35 mmol, 1.00 equiv) and AcOK (74.79 g, 1245.43 mmol, 4.00 equiv) in DMSO (300.00 mL) was stirred at 80°C for overnight under nitrogen atmosphere. Desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with DCM (3 x 100.00 mL). The filtrate was concentrated under reduced pressure and was diluted with water (1 L), The filtrate was extracted with CH2CI2 / IPA (2: 1) (3 x 600.00 mL). The combined organic layers were washed with brine (5 x 100.00 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 5-(2-aminopyrimidin-5-yl) oxolan-3-yl acetate (87.00 g, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LC-MS: (ES+H, m z)\ [M+H]+=224.0.

[0470] Step 5: Preparation of 5-(2-aminopyrimidin-5-yl) oxolan-3-ol (INT A, cis / trans mixture):

[0471] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl acetate (76.00 g, 340.45 mmol, 1.00 equiv) in MeOH (500.00 mL) was added K2CO3(188.21 g, 1361.81 mmol, 4.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CHjCL / MeOH (7: 1), the pure fraction was concentrated under vacuum to afford 5-(2-aminopyrimidin-5-yl) oxolan-3-ol (26.00 g, 41.23%) as a white solid. LC- MS: (ES+H, m / z) [M+H]+=182.0.1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.19 (s, 1H), 6.58 (s, 2H), 5.07 - 4.58 (m, 2H), 4.46 - 4.35 (m 1H), 4.14 - 3.56 (m, 2H), 2.49 - 2.02 (m, 1H), 1.90 - 1.62 (m, 1H).

[0472] Preparing of INT A: 5-(2-aminopyrimidin-5-yl) oxolan-3-ol (cis / trans mixture) (Method 2):

[0473] Step 1: Preparation of ethyl 4-hydroxyoxolane-2-carboxylate:

[0474] A solution of ethyl 4-oxooxolane-2-carboxylate (30 g, 189.690 mmol, 1 equiv) in EtOH (500 mL) was treated with NaBH4 (7.18 g, 189.69 mmol, 1 equiv) for 30min at -60°C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at -60°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4Q (aq.) at 0°C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CHCI3:IPA = 1.1 (3 x 500mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethyl 4-hydroxyoxolane-2-carboxylate (26 g, crude) as a yellow oil. LC-MS: (ES+H, m / z): [M +H]+=161.0.1H NMR (400 MHz, DMSO-d6) δ 4.82 (br, 1H) 4.41 (dd, J= 9.1, 4.2 Hz, 1H), 4.31 - 4.25 (m, 1H), 4.14 - 4.04 (m, 2H), 3.85 - 3.76 (m, 1H), 3.68 - 3.63 (m, 1H), 2.34 - 2.25 (m, 1H), 2.03 - 1.91 (m, 1H), 1.19 (t, J= 7.1 Hz, 3H).

[0475] Step 2&3: Preparation of 4-(benzyIoxy)oxolane-2-carboxylic acid:

[0476] A solution of NaH (9.7 g, 243.494 mmol, 1.5 equiv, 60%) in THF (300 mL) was treated with ethyl 4-hydroxyoxolane-2-carboxylate (26 g, 162.329 mmol, 1 equiv) and stirred for 30min at 0°C under nitrogen atmosphere followed by the addition of BnBr (30.54 g, 178.562 mmol, 1.1 equiv) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with Water / Ice at 0°C. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethyl 4-(benzyloxy)oxolane-2-carboxylate (25 g, crude) as a yellow oil.

[0477] A solution of ethyl 4-(benzyloxy)oxolane-2-carboxylate (25 g, 99.883 mmol, 1 equiv) and NaOH (11.99 g, 299.649 mmol, 3 equiv) in MeOH (20 mL):H2O (20 mL) was stirred for 1.5h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The mixture was neutralized to pH 7 with citric acid. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1 -EA) to afford 4-(benzyloxy)oxolane-2-carboxylic acid (17 g, 66.63%) as a yellow oil. LC-MS: (ES+H, m / z): [M +H]+=223.0.1H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.18 (m, 5H), 4.49 - 4.36 (m, 2H), 4.15 - 4.07 (m, 1H), 4.05 - 3.88 (m, 1H), 3.85 - 3.77 (m, 1H), 3.67 - 3.58 (m, 1H), 2.35 - 2.27 (m, 1H), 1.85 - 1.74 (m, 1H).

[0478] Step 4: Preparation of l,3-dioxoisoindol-2-yl 4-(benzyloxy)oxolane-2-carboxylate:

[0479] To a stirred solution of 4-(benzyloxy)oxolane-2-carboxylic acid (16 g, 71.994 mmol, 1 equiv) and NHPI (11.74 g, 71.994 mmol, 1 equiv) in 2-methyloxolane (200 mL) were added T3P in EA (229.07 g, 359.970 mmol, 5 equiv, 50%) and Et3N (21.86 g, 215.982 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 6h at 60°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200mL). The resulting mixture was extracted with EtOAc (3 x 150mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1— 1:1) to afford 1,3- dioxoisoindol-2-yl 4-(benzyloxy)oxolane-2-carboxylate (8 g, 24.20%) as a white oil. LC-MS: (ES+H, m / z): [M +H]+=368.1

[0480] Step 5: Preparation of tert-butyl N-{5-[4-(benzyloxy)oxolan-2-yl]pyrimidin-2- yl}carbamate: To a stirred solution of l ,3-dioxoisoindol-2-yl 4-(benzyloxy)oxolane-2-carboxylate (4.01 g, 10.90 mmol, 1.3 equiv) and tert-butyl N-(5-bromopyrimidin-2-yl)carbamate (2.3 g, 8.39 mmol, 1.00 equiv) in DMA (50 mL) were added 5-Methoxypyridine-2-carboxamidine hydrochloride (0.16 g, 0.83 mmol, 0.1 equiv), nickel(II) chloride ethylene glycol dimethyl ether complex (184.36 mg, 0.83 mmol, 0.1 equiv) and Zn (5.49 g, 83.91 mmol, 10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was fdtered, the filter cake was washed with EtOAc (3x100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1-1 :1) to afford tert-butyl N-{5-[4-(benzyloxy)oxolan-2-yl]pyrimidin-2-yl}carbamate (1.3 g, 37.54%) as a yellow oil.

[0481] LC-MS: (ES+H, m / z): [M +H]+=372.1.1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.58 (s, 2H), 7.38 - 7.26 (m, 5H), 5.08 - 4.83 (m, 1H), 4.62-4.40 (m, 2H), 4.44-4.24 (m, 1H), 4.22 - 3.98 (m, 1H), 3.98-3,80 (m, 1H), 2.06 - 1.83 (m, 1H), 1.46 (s, 9H), 1.37-1.20 (m, 1H).

[0482] Step 6: Preparation of 5-(2-aminopyrimidin-5-yl)oxolan-3-ol [INT A, cis / trans mixture]:

[0483] A solution of tert-butyl N-{5-[4-(benzyloxy)oxolan-2-yl]pyrimidin-2-yl}carbamate (1.3 g, 3.50 mmol, 1 equiv) in methanesulfonic acid (10 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1-5: 1) to afford 5-(2-aminopyrimidin-5-yl)oxolan-3-ol (500 mg, 70.96%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=182.1.1H NMR (400 MHz, DMSO- 6 8.65-8.58 (m, 2H), 5.76 (brs, 2H), 5.01 - 4.93 (m, 1H), 4.63-4.38 (m, 1H), 4.20-3.55 (m, 2H), 2.30-2.10 (m, 1H), 1.98 - 1.75 (m, 1H).

[0484] Example 5: rac-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l- methylcyclopropyl)carbamate (Compound 1), rel-(3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l-methylcyclopropyl)carbamate (Compound 39), and rel-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3- yl N-(l-methylcyclopropyl)carbamate (Compound 40):

[0485] Step 1: Preparation of 5-(2-aminopyrimidin-5-yl)oxoIan-3-yl 4-nitrophenyl carbonate:

[0486] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-ol (1 g, 5.519 mmol, 1 equiv) and bis(4-nitrophenyl) carbonate (2.01 g, 6.623 mmol, 1.2 equiv) in DCM (30 mL) was added DIEA (2.14 g, 16.557 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2CI2(3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2 g) was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=347.0.

[0487] Step 2: Preparation of rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (l-methylcyclopropyl)carbamate & (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-(l- methylcyclopropyl)carbamate:

[0488] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate (2 g, 5.775 mmol, 1 equiv) and 1 -methyl cyclopropan-1 -amine hydrochloride (1.24 g, 11.550 mmol, 2 equiv) in DMF (50 mL) was added DIEA (2.24 g, 17.325 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100mL). The resulting mixture was extracted with CH2CI2:IPA=3: 1 (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.5g) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 20% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.65 / 9.58) to afford rac-(3R,5R)-5-(2- aminopyrimidin-5-yl)oxolan-3-yl N-(l-methylcyclopropyl)carbamate (420 mg, 26.13%yield, 93%purity) as a light yellow solid [3A] and rac-(3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N- (l-methylcyclopropyl)carbamate (420 mg, 26.13%yield, 90%purity) as a light yellow solid [3B] : . rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (l-methylcyclopropyl)carbamate: LC-MS: (ES+H, m / z): [M +H]+=279.0.1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 2H), 7.54 (s, 1H), 6.59 (s, 2H), 5.31-5.09 (m, 1H), 4.86-4.56 (m, 1H), 4.00-3.67 (m, 2H), 2.71-2.56 (m, 1H), 1.81- 1.66 (m, 1H), 1.23 (s, 3H), 0.68 - 0.41 (m, 4H).

[0489] (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-(l-methylcyclopropyl)carbamate:

[0490] LC-MS: (ES+H, m / z): [M +H]+=279.0.1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 2H), 7.55 (s, 1H), 6.62 (s, 2H), 5.30-5.13 (m, 1H), 4.69-4.86 (m, 1H), 4.27 - 4.15 (m, 1H), 3.82-3.67 (m, 1H), 2.32 - 2.00(m, 2H), 1.25 (s, 3H), 0.71-0.40 (m, 4H).

[0491] Step 3: (3R,5R)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl] phenyl}amino)pyrimidin-5-yl] oxolan-3-yl N-(l- methylcyclopropyl)carbamate:

[0492] To a stirred solution of (3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-(l- methylcyclopropyl)carbamate (210 mg, 0.755 mmol, 1 equiv) and tert-butyl N-(4- bromobenzenesulfonyl)carbamate (304.42 mg, 0.906 mmol, 1.2 equiv) in t-BuOH (3 mL) were added K2CO3(312.85 mg, 2.265 mmol, 3 equiv)and EPhos Pd G4(69.31 mg, 0.076 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (9: 1), the resulting mixture was concentrated under reduced pressure to afford (3R,5R)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-(l- methylcyclopropyl)carbamate (240 mg, 59.61%) as a yellow oil. LC-MS: (ES+H, m / z) [M+H]+= 534.1.

[0493] Step 4: Preparation of rac-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-(l-methylcyclopropyl)carbamate:

[0494] A solution of rac-(3R,5R)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-(l- methylcyclopropyl)carbamate (32 mg, 0.060 mmol, 1 equiv) in HCOOH (4 mL) was stirred for Ih at 50°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30* 150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 17% B to 37% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.55 / 9.18), the resulting mixture was concentrated under reduced pressure by lyophilization to afford rac-(3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l-methylcyclopropyl)carbamate (4 mg, 15.39%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 434.1.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, IH), 8.68 - 8.44 (m, 2H), 7.95 - 7.88 (m, 2H), 7.82-7.72 (m, 2H), 7.55 (s, IH), 7.17 (s, 2H), 5.35 - 5.13 (m, IH), 5.02 - 4.73 (m, IH), 4.00-3.90 (m, IH), 3.87 - 3.76 (m, IH), 2.79 -2.65 (m, IH), 1.88-1.75 (m, IH), 1.24 (s, 3H), 0.71-0.55 (m, 2H), 0.54-0.40 (m, 2H).

[0495] Step 5: Preparation of rel-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-(l-methyIcyclopropyl)carbamate and rel-(3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l-methylcyclopropyl)carbamate:

[0496] The crude product (rac-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan- 3-yl N-(l-methylcyclopropyl)carbamate (200 mg) was purified by Chiral-HPLC with the following conditions (Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: MTBE: DCM=1 : l(10mMNH3), Mobile Phase B: MeOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 280 / 300 nm; RTl(min): 5.1; RT2(min): 7.2; Sample Solvent: MEOH: DCM=1 : l(0.1%FA); Injection Volume: 1 mL; Number Of Runs: 14), the resulting mixture was concentrated under reduced pressure and then lyophilization to afford rel-(3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l-methylcyclopropyl)carbamate (pre- peak, 72.6 mg, 36.30%) as a white solid and rel-(3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l-methylcyclopropyl)carbamate (post- peak, 76.9 mg, 38.45%) as a white solid. rel-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l- methylcyclopropyl)carbamate:

[0497] LC-MS: (ES+H, m / z): [M+H]+=434.0.1H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.53 (s, 2H), 7.98 - 7.87 (m, 2H), 7.77 - 7.68 (m, 2H), 7.57 (s, 1H), 7.17 (s, 2H), 5.36 - 5.13 (m, 1H), 5.06-4.67 (m, 1H), 4.08-3.71 (m, 2H), 2.81 - 2.63 (m, 1H), 1.90-1.68 (m, 1H), 1.25 (s, 3H), 0.65

[0498] - 0.53 (m, 2H), 0.52 - 0.41 (m, 2H). rel-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l- methylcyclopropyl)carbamate

[0499] LC-MS: (ES+H, m / z): [M+H]+=434.0.1H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.54 (s, 2H), 7.98 - 7.87 (m, 2H), 7.81 - 7.67 (m, 2H), 7.57 (s, 1H), 7.18 (s, 2H), 5.36 - 5.1 1 (m, 1H), 5.02

[0500] - 4.72 (m, 1H), 3.07-3.65 (m, 2H), 2.79 - 2.63 (m, 1H), 1.92 - 1.74 (m, 1H), 1.25 (s, 3H), 0.68 - 0.55 (m, 2H), 0.53 - 0.41 (m, 2H).

[0501] Analytical data of compounds is shown in Table C below. The compounds in Table C were prepared using procedures analogous to those described above with appropriate modifications within the purview of one skilled in the art.

[0502] Table C: Compounds of Formula (A).

[0503] Example 5: rac-(3RS,5SR)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 50), (3R*,5S*)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate (Compound 51) & (3R*,5S*)-5-(2-((4- sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2- yl)carbamate (Compound 52): Step 1: Preparation of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate:

[0504] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-ol (1.5 g, 8.278 mmol, 1 equiv) and bis(4-nitrophenyl) carbonate (3.02 g, 9.934 mmol, 1.2 equiv) in DCM (50 mL) was added DIEA (3.21 g, 24.834 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100mL). The resulting mixture was extracted with CH2C12 (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product(2 g) was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=347.0.

[0505] Step 2: Preparation of rac-(3RS,5RS)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3- yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate [cis racemic] & rac-(3RS,5SR)-5-(2- aminopyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate [trans racemic]:

[0506] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate (2 g, 5.775 mmol, 1 equiv) and (2S)-4,4,4-trifluorobutan-2-amine hydrochloride (1.89 g, 11.550 mmol, 2 equiv) in DMF (50 mL) was added DIEA (2.24 g, 17.325 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100mL). The resulting mixture was extracted with CH2C12:IPA=3: 1 (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2 g) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5μm; Mobile Phase A: Water(0. 1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 25% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.86 / 9.18) to afford (3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-4,4,4- trifluorobutan-2-yl]carbamate (500 mg, 25.90%yield, 90%purity) as a yellow green solid and (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-4,4,4-trifluorobutan-2-yl]carbamate (500 mg, 25.90%yield, 90%purity) as a yellow green solid. rac-(3RS,5RS)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2- yl)carbamate: LC-MS: (ES+H, m / z): [M+H]+= 335.1.1H NMR (400 MHz, DMSO-r / s) 6 8.22 (d, J= 2.5 Hz, 2H), 7.42 (d, J= 8.4 Hz, 1H), 6.63 (s, 2H), 5.22 - 5.11 (m, 1H), 4.72 - 4.56 (m, 1H), 3.94 - 3.71 (m, 3H), 2.74-2.60 (m, 1H), 2.48-2.28 (m, 2H), 1.80-1.69 (m, 1H), 1.20-1.07 (m, 3H). rac-(3RS,5SR)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2- yl)carbamate: LC-MS: (ES+H, m / z): [M+H]+= 335.1. 'H NV1R (400 MHz, DMSO-d6) δ 8.23 (s, 2H), 7.42 (d, J= 8.4 Hz, 1H), 6.64 (s, 2H), 5.28 - 5.22 (m,lH), 4.82 - 4.74 (m, 1H), 4.24 - 4.15 (m, 1H), 3.94 - 3.81 (m, 1H), 3.74 - 3.66 (m,lH), 2.48 - 2.32 (m, 2H), 2.28 - 2.17 (m, 1H), 2.14 -2.03 (m, 1H), 1.21 - 1.12 (m,3H).

[0507] Step 3: Preparation of rac-((3RS,5SR)-5-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate:

[0508] To a stirred mixture of (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-4,4,4- trifluorobutan-2-yl]carbamate (150 mg, 0.449 mmol, 1 equiv) and tert-butyl N-(4- bromobenzenesulfonyl)carbamate (181.02 mg, 0.539 mmol, 1.2 equiv) in t-BuOH (5 mL) were added K2CO3(186.04 mg, 1.347 mmol, 3 equiv) and EPhos Pd G4 (41.22 mg, 0.045 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Water was added and the resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in rac-(3R,5S)-5-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate (76 mg, 26.60%) as a brown solid. LC-MS: (ES+H, m / z): [M+H]+ =590.1.

[0509] Step 4: Preparation of rac-(3RS,5SR)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate:

[0510] Into a 20mL vial was added (3R,5S)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-[(2S)-4,4,4- trifluorobutan-2-yl]carbamate (76 mg, 0.129 mmol, 1 equiv) and formic acid (5 mL) at room temperature. The resulting mixture was stirred at 50°C for Ih under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed -phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure and lyophilization to afford rac-(3R,5S)-5-(2-((4- sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2- yl)carbamate (51.3 mg, 79.27%) as a white solid. rac-(3RS,5SR)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate: LC-MS: (ES+H, m / z): [M+H]+ =490.1.1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.53 (s, 2H), 7.95 - 7.89 (m, 2H), 7.75 - 7.68 (m, 2H), 7.40 (d, J= 8.5 Hz, 1H), 7.17 (s, 2H), 5.27-5.14 (m, 1H), 4.81 (t, J = 7.6 Hz, 1H), 4.01 - 3.94 (m, 1H), 3.90 - 3.78 (m, 2H), 2.73- 2.61 (m, 1H), 2.45-2.35 (m, 2H), 1.90-1.83 (m, 1H), 1.14 (d, J = 6.7 Hz, 3H).

[0511] 19F NMR (377 MHz, DMSO-d6) δ -62.60.

[0512] Step 5: Preparation of (3R*,5S*)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate & (3R*,5S*)-5-(2-((4- sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4-trifluorobutan-2- yl)carbamate:

[0513] The rac-(3RS,5SR)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N- [(2S)-4,4,4-trifluorobutan-2-yl]carbamate (50 mg, 0.102 mmol, 1 equiv) was separated by Chiral - HPLC with the following conditions (Column: CHIRALPAK ID, 2*25 cm, 5 μm; Mobile Phase A: MTBE: DCM=1: l(10mMNH3), Mobile Phase B: MeOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 224 / 292 nm; RTl(min): 5.5; RT2(min): 8.51; Sample Solvent: MeOH— HPLC; Injection Volume: 2 mL; Number Of Runs: 7). The pure fraction was concentrated under reduced pressure and lyophilization to afford (3R,5S)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-4,4,4-trifluorobutan-2-yl]carbamate (pre-peak, 18.9 mg, 36.25%, ee=100%) as a white solid and (3R,5S)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-4,4,4-trifluorobutan-2-yl]carbamate (post-peak ,18.4 mg, 35.91%, ee=100%) as a white solid.

[0514] (3R*,5S*)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate: LC-MS: (ES+H, m / z): [M+H]+=490.1.1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (s, 2H), 7.96-7.88 (m, 2H), 7.80 - 7.61 (m, 2H), 7.44 (d, J= 8.4 Hz, 1H), 7.17 (s, 2H), 5.33-5.22 (m, 1H), 4.98-4.89 (m, 1H), 4.32-4.16 (m, 1H), 3.95 - 3.59 (m, 2H), 2.46 - 2.32 (m, 3H), 2.19 - 2.04 (m, 1H), 1.16 (d, J = 6.7 Hz, 3H).19F NMR (377 MHz, DMSO-d6) δ -62.58.

[0515] (3R*,5S*)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate: LC-MS: (ES+H, m / z): [M+H]+=490.1.1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (s, 2H), 7.96-7.88 (m, 2H), 7.80 - 7.64 (m, 2H), 7.44 (d, J= 8.4 Hz, 1H), 7.17 (s, 2H), 5.31-5.21 (m, 1H), 4.99-4.88 (m, 1H), 4.31-4.18 (m, 1H), 3.91 - 3.76 (m, 1H), 3.81-3.71 (m, 1H), 2.51 - 2.19 (m, 3H), 2.19 - 2.12 (m, 1H), 1.16 (d, J = 6.7 Hz, 3H).19F NMR (377 MHz, DMSO-d6) δ -62.58. Analytical data of compounds is shown in Table D below. The compounds in Table D were prepared using procedures analogous to those described above with appropriate modifications within the purview of one skilled in the art.

[0516] Table D. Compounds of Formula (A)

[0517] Example 3: rac-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N- isopropylcarbamate (Compound 62), rel-(3R,5R)-5-{2-[(4- sulfamoylphenyl)aminoJpyrimidin-5-yl}oxolan-3-yl N-isopropylcarbamate (Compound 63) and rel-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N- isopropylcarbamate (Compound 64):

[0518] Step 1: Preparation of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate: To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-ol (4.5 g, 24.835 mmol, 1 equiv) and DIEA (9.63 g, 74.505 mmol, 3 equiv) in DCM (100 mL) was added bis(4-nitrophenyl) carbonate (9.07 g, 29.802 mmol, 1.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for Ih under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100mL). The resulting mixture was extracted with CH2C12 (3 x 100mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (6 g) was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M +H]+= 347.0.

[0519] Step 2: Preparation of rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N- isopropylcarbamate & rac-(3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N- isopropylcarbamate:

[0520] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate (6 g, 17.326 mmol, 1 equiv) and isopropylamine hydrochloride (3.31 g, 34.652 mmol, 2 equiv) in DMF (100 mL) was added DIEA (6.72 g, 51.978 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100mL). The resulting mixture was extracted with CH2C12:IPA=3:1 (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (6 g) was purified by Prep- HPLC with the following conditions (Column: Ultimate XB-C18, 50*250 mm, 10um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 100 mL / min mL / min; Gradient: 5% B to 30% B in 30min; Wave Length: 254nm / 220nm nm; RTl(min): 23, RT2(min): 26) to afford rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (2 g, 43.35%yield, 90%purity) as a light yellow solid and rac-(3R,5S)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3- yl isopropylcarbamate (2.1 g, 45.5 l%yield, 90%purity) as a light yellow solid. rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate: LC-MS: (ES+H, m / z) [M+H]+=267.0;1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 2H), 7.15 (d, J=7.8 Hz, IH), 6.62 (s, 2H), 5.23 -5.13 (m, 1H), 4.69-4.58 (m, 1H), 3.96-3.83 (m, 1H), 3.83-3.70 (m, 1H), 3.63 -3.53 (m, 1H), 2.70 -2.59 (m, 1H), 1.83 - 1.67 (m, 1H), 1.05 (d, J= 6.7 Hz, 6H). rac-(3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate: LC-MS: (ES+H, m zy [M+H]+=267.0;1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 2H), 7.16 (d, J = 7.8 Hz, 1H), 6.62 (s, 2H), 5.23 - 4.80 (m, 1H), 4.78 - 4.69 (m, 1H), 4.19 -4.10 (m, 1H), 3.75 - 3.54 (m, 2H), 2.30-2.18 (m, 1H), 2.06-2.01 (m, 1H), 1.05 (d, J= 6.5 Hz, 6H).

[0521] Step 3: Preparation of rac-(3R,5R)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N- isopropylcarbamate

[0522] To a stirred solution of rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N- isopropylcarbamate (30 mg, 0.113 mmol, 1 equiv) and tert-butyl N-(4- bromobenzenesulfonyl)carbamate (45.45 mg, 0.136 mmol, 1.2 equiv) in t-BuOH (3 mL) were added K2CO3(46.71 mg, 0.339 mmol, 3 equiv) and EPhos Pd G4 (10.35 mg, 0.011 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1), the resulting mixture was concentrated under reduced pressure to afford rac-(3R,5R)-5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimi din-5- yl]oxolan-3-yl N-isopropylcarbamate (50 mg, 85.09%) as a light yellow solid. LC-MS: (ES+H, m / z [M+H-]=522.1.

[0523] Step 4: Preparation of rac-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-isopropylcarbamate:

[0524] A solution of rac-(3R,5R)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N- isopropylcarbamate (50 mg, 0.096 mmol, 1 equiv) in HCOOH (4 mL) was stirred for Ih at 50°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 19% B to 34% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.27), the resulting mixture was concentrated under reduced pressure by lyophilization to afford rac-(3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-isopropylcarbamate (28 mg, 69.30%) as a white solid. rac-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N- isopropylcarbamate: LC-MS: (ES+H, m / z): [M+H]+=422.1.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.55 (s, 2H), 7.92 (d, J= 8.8 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.21 - 7.12 (m, 3H), 5.26 - 5.13 (m, 1H), 4.86-4.71 (m, 1H), 4.01-3.91 (m, 1H), 3.86 - 3.79 (m, 1H), 3.66-3.50 (m, 1H), 2.78 - 2.66 (m, 1H), 1.91 -1.76 (m, 1H), 1.10 - 1.87 (m, 6H).

[0525] Step 5: Preparation of rel-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-isopropylcarbamate and rel-(3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-isopropylcarbamate:

[0526] The crude product rac-(3A,5A)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan- 3-yl N-isopropylcarbamate (25 mg, 0.059 mmol, 1 equiv) was purified by Chiral-HPLC with the following conditions (Column: CHIRALPAK IA, 3*25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 30; Wave Length: 292 / 218 nm; RTl(min): 16.08; RT2(min): 23.22; Sample Solvent: MeOH: DCM=1 : 1- HPLC; Injection Volume: 1.3 mL; Number Of Runs: 6), the resulting mixture was concentrated under reduced pressure and then lyophilization to afford rel-(3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-isopropylcarbamate (pre-peak, 13.7 mg, 54.80%) as a white solid and rc / -(3A,5A)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-isopropylcarbamate ((post-peak, 7 mg, 28.00%) as a white solid. rel-(3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N- isopropylcarbamate: LC-MS: (ES+H, m / z): [M+H]+=422.1.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.55 (s, 2H), 7.93 (d, J= 8.1 Hz, 2H), 7.73 (d, J= 8.4 Hz, 2H), 7.30-7.07 (m, 3H), 5.27 - 5.14 (m, 1H), 4.88-4.74 (m, 1H), 4.03-3.91 (m, 1H), 3.87 - 3.79 (m, 1H), 3.64 - 3.55 (m, 1H), 2.77 - 2.67 (m, 1H), 1.91 - 1.77 (m, 1H), 1.13 - 0.99 (m, 6H). rel-(3R,5R)-5-{2-[(4-sulfamoylphenyl)aminolpyrimidin-5-yl}oxolan-3-yl N- isopropylcarbamate: LC-MS: (ES+H, m / z): [M+H]+=422.1.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (s, 2H), 7.93 (d, J= 8.4 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.32 - 7.07 (m, 3H), 5.36 - 5.10 (m, 1H), 4.91 - 4.71 (m, 1H), 4.07 - 3.75 (m, 2H), 3.70 - 3.54 (m, 1H), 2.85 - 2.65 (m, 1H), 2.09 - 1.79 (m, 1H), 1.14 - 0.88 (m, 6H).

[0527] Analytical data of compounds is shown in Table E below. The compounds in Table E were prepared using procedures analogous to those described above with appropriate modifications within the purview of one skilled in the art.

[0528] Table E. Compounds of Formula (A)

[0529] Example 4: (3RS,5RS)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3- yl ((S)-sec-butyl)carbamate (Compound 87), (3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl] carbamate (Compound 88), & (3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N- [(2S)-butan-2-yl]carbamate (Compound 89):

[0530]

[0531] Step 1: Preparation of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate:

[0532] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-ol (4 g, 22.076 mmol, 1 equiv) and bis(4-nitrophenyl) carbonate (8.06 g, 26.491 mmol, 1.2 equiv) in DCM (100 mL) was added DIEA (8.56 g, 66.228 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100mL). The resulting mixture was extracted with CH2C12 (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The crude product(5 g) was used in the next step directly without further purification. LC-MS: (ES+H, m / z): [M+H]+=347.0.

[0533] Step 2: Preparation of rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)- butan-2-yl] carbamate and rac-(3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan- 2-yl]carbamate:

[0534] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate (5 g, 14.438 mmol, 1 equiv) and (2S)-butan-2-amine hydrochloride (2.37 g, 21.657 mmol, 1.5 equiv) in DMF (100 mL) was added DIEA (5.60 g, 43.314 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2C12:IPA=3: 1 (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2.5g) was purified by Prep-HPLC with the following conditions (Column: Welch Ultimate XB- C18, 50*250 mm, 10um; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 100 mL / min mL / min; Gradient: 5% B to 35% B in 30 min; Wave Length: 220nm nm; RTl(min): 26, RT2(min): 29) to afford rac-(3R,5R)-5-(2-aminopyrimidin-5- yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate [3A] (1.3 g, 32.12%yield, 90%purity) as a yellow solid and rac-(37?,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate [3B] (1.2 g, 37.06%yield, 90%purity) as a yellow solid. rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N- [(2S)-butan-2-yl]carbamate: LC-MS : (ES+H, m / z): [M +H]+=281.1. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 2H), 7.08 (d, J = 8.3 Hz, 1H), 6.61 (s, 2H), 5.30-5.10 (m, 1H), 4.70-4.55 (m, 1H), 3.97 - 3.83 (m, 1H), 3.80 - 3.71 (m, 1H), 3.48 - 3.31 (m, 1H), 2.73 - 2.59 (m, 1H), 1.82 - 1.67 (m, 1H), 1.45 - 1.29 (m, 2H), 1.05 - 0.98 (m, 3H), 0.85 - 0.76 (m, 3H). rac-(3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbainate: LC-MS: (ES+H, m / z): [M +H]+=281.0.1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 2H), 7.09 (d, J= 8.3 Hz, 1H), 6.61 (s, 2H), 5.27 - 5.13 (m, 1H), 4.82 - 4.75 (m, 1H), 4.22 - 4.14 (m, 1H), 3.74 -3.60 (m, 1H), 3.47 - 3.35 (m, 1H), 2.29 -2.18 (m, 1H), 2.14 - 2.01 (m, 1H), 1.1.44 -1.32 (m, 2H), 1.09 - 0.98 (m, 3H), 0.88 - 0.77 (m, 3H).

[0535] Step 3: Preparation of rac-(3R,5R)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-[(2S)-butan-2- yl] carbamate:

[0536] To a stirred solution of (3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (24 mg, 0.086 mmol, 1 equiv) and tert-butyl N-(4-bromobenzenesulfonyl)carbamate (37.42 mg, 0.11 mmol, 1.3 equiv) in t-BuOH (3 mL) were added K2CO3(35.50 mg, 0.25 mmol, 3 equiv) and EPhos Pd G4 (15.73 mg, 0.017 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (0 to 10: 1) to afford rac-(3R,5R)-5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5- yl]oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (50 mg, 87.23%) as a yellow solid.

[0537] LC-MS: (ES+H, m / z): [M +H]+=536.1

[0538] Step 4: Preparation of (3RS,5RS)-5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate [Compound 87]:

[0539] A solution of rac-(3R,5R)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (50 mg, 0.093 mmol, 1 equiv) in formic acid (3 mL) was stirred for 30min at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 20% to 40% gradient in 10 min; detector, UV 220 nm. The pure fraction was concentrated under reduced pressure and lyophilization to afford (3RS,5RS)- 5-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl (S) -sec-butyl)carbamate (35 mg, 77.57%, 2.5 mg was submitted 2023-11-23) as a white solid. LC-MS: (ES+H, m / z): [M +H]+=436.1.1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.55 (s, 2H), 7.95 - 7.88 (m, 2H), 7.76 - 7.68 (m, 2H), 7.16 (s, 2H), 7.09 (d, J= 8.5 Hz, 1H), 5.28 - 5.12 (m, 1H), 4.85-4.78 (m, 1H), 4.02 - 3.77 (m, 2H), 3.49 - 3.37 (m, 1H), 2.79 - 2.66 (m, 1H), 1.89-1.79(m, 1H), 1.43 - 1.31 (m, 2H), 1.04 - 0.73 (m, 6H).

[0540] Step 5: Preparation of (3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (Compound 88) & (3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2*S)-butan-2-yl]carbamate

[0541] (Compound 89):

[0542] The (3RS,5RS)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)- butan-2-yl]carbamate (90 mg) was separated by Prep-Chiral -HPLC with the following conditions(Column: CHIRALPAK IA, 2*25 cm, 5 μm; Mobile Phase A: MTBE: DCM=1 : l(10mMNH3), Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 280 / 290 nm; RTl(min): 5.8; RT2(min): 7.5; Sample Solvent: MEOH(0.1%FA)). The pure fraction was concentrated under reduced pressure and by lyophilization to afford (isomer 1) (3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (36.1 mg, 39.79%) as a white solid with 100% ee and (isomer 2) (3R,5R)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (33.3 mg, 35.96%) as a white solid with 100% ee.

[0543] (3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- ylj carbarn ate: LC-MS: (ES+H, m / z): [M +H]+=436.15.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.55 (s, 2H), 7.96 - 7.88 (m, 2H), 7.76 - 7.69 (m, 2H), 7.17 (s, 2H), 7.10 (d, J= 8.3 Hz, 1H), 5.20 - 5.18 (m, 1H), 4.79 (t, J= 7.6 Hz, 1H), 3.96 - 3.94 (m, 1H), 3.83 - 3.81 (m, 1H), 3.44 - 3.35 (m, 1H), 2.76 - 2.65 (m, 1H), 1.89 - 1.79 (m, 1H), 1.45 - 1.31 (m, 2H), 1.01 (d, J= 6.6 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).

[0544] (3R,5R)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- yl]carbamate: LC-MS: (ES+H, m / z): [M +H]1=436.15.1H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.55 (s, 2H), 7.98 - 7.87 (m, 2H), 7.78 - 7.67 (m, 2H), 7.17 (s, 2H), 7.10 (d, J= 8.4 Hz, 1H), 5.19 - 5.16 (m, 1H), 4.82 (t, J= 7.5 Hz, 1H), 3.97 - 3.94 (m, 1H), 3.84 - 3.81 (m, 1H), 3.47 - 3.34 (m, 1H), 2.71 - 2.65 (m, 1H), 1.85 - 1.81 (m, 1H), 1.43 - 1.30 (m, 2H), 1.03 (d, J = 6.6 Hz, 3H), 0.80 (t, J= 7.4 Hz, 3H).

[0545] Example 5: Synthesis of (3R*,5S*)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan- 3-yl N-[(2S)-butan-2-yl]carbamate (Compound 91) and (3R*,5S*)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (Compound 92):

[0546] Step 1: Preparation of (3R,5S)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl] phenyl}amino)pyrimidin-5-yl] oxolan-3-yl N- [(2S)-butan-2- yl] carbamate: To a stirred solution of (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (36 mg, 0.128 mmol, 1 equiv) and tert-butyl N-(4- bromobenzenesulfonyl)carbamate (56.13 mg, 0.16 mmol, 1.3 equiv) in t-BuOH (3 mL) were added K2CO3(53.25 mg, 0.38 mmol, 3 equiv) and EPhos Pd G4 (23.59 mg, 0.026 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was fdtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (0 to 10: 1) to afford (3R,5S)-5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin- 5-yl]oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (60 mg, 78.51%) as a yellow solid.

[0547] LC-MS: (ES+H, m / z): [M +H]+=536.1

[0548] Step 2: Preparation of (3RS,5SR)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan- 3-yl N-[(2S)-butan-2-yl]carbamate:

[0549] A solution of (3R,5S)-5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5- yl]oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (50 mg, 0.093 mmol, 1 equiv) in formic acid (3 mL) was stirred for 30min at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure and lyophilization to afford (3RS,5SR)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (40 mg, 97.31%, 2.5 mg was submitted 2023-11- 23) as a white solid.

[0550] LC-MS: (ES+H, m / z): [M +H]+=436.1

[0551] 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (s, 2H), 7.92 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.16 (s, 2H), 7.13 (d, J = 8.2 Hz, 1H), 5.29 - 5.23 (m, 1H), 4.98 - 4.89 (m, 1H), 4.27 - 4.18 (m, 1H), 3.80 - 3.72 (m, 1H), 3.46 - 3.38 (m, 1H), 2.39 - 2.30 (m, 1H), 2.19 - 2.04 (m, 1H), 1.45 - 1.35 (m, 2H), 1.04 (d, J = 6.6 Hz, 3H), 0.87 - 0.79 (m, 3H). Step 3: Preparation of (3R*,5S*)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3- yl N-[(2S)-butan-2-yl]carbamate & (3R*,5S*)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin- 5-yl}oxolan-3-yl N- [(2S)-butan-2-yl] carbamate:

[0552] The (3RS,5SR)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (35 mg) wasisolated by Prep-Chiral -HPLC with the following conditions (Column: CHIRALPAK IA, 3*25 cm, 5 μm; Mobile Phase A: MTBE: DCM=1 : l(10mMNH3), Mobile Phase B: ETOH; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 292 / 222 nm; RTl(min): 7.68; RT2(min): 10.64; Sample Solvent: MeOH: DCM=1 : 1— HPLC; Injection Volume: 2.5 mL; Number Of Runs: 3). The pure fraction was concentrated under reduced pressure and lyophilization to afford (3R*,5S*)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (8.5 mg, 24.16%, ee=100%) as a white solid and (3R*,5S*)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (9.0 mg, 25.56%, ee=100%) as a white solid.

[0553] Compound 91:

[0554] LC-MS: (ES+H, m / z): [M +H]+=436.0

[0555] 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.57 (s, 2H), 7.95-7.90 (m, 2H), 7.75-7.69 (m, 2H), 7.18 (s, 2H), 7.14 (d, J = 8.3 Hz, 1H), 5.28-5.23 (m, 1H), 4.98-4.90 (m, 1H), 4.25-4.20 (m, 1H), 3.80-3.72 (m, 1H), 3.46-3.38 (m, 1H), 2.39-2.30 (m, 1H), 2.19 - 2.10 (m, 1H), 1.45 - 1.35 (m, 2H), 1.04 (d, J = 6.6 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H).

[0556] Compound 92:

[0557] LC-MS: (ES+H, m / z): [M +H]+=436.0

[0558] 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (s, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.18 (s, 2H), 7.14 (d, J = 8.3 Hz, 1H), 5.30-5.24 (m, 1H), 4.95-4.91 (m, 1H), 4.25- 4.20 (m, 1H), 3.80-3.72 (m, 1H), 3.46-3.38 (m, 1H), 2.37-2.30 (m, 1H), 2.19 - 2.09 (m, 1H), 1.47 - 1.29 (m, 2H), 1.04 (d, J = 6.6 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).

[0559] Analytical data of compounds is shown in Table F below. The compounds in Table F were prepared using procedures analogous to those described above with appropriate modifications within the purview of one skilled in the art. Table F. Compounds of Formula (A).

[0560] Example 6: Synthesis of (3S,5S)-5-(2-((3-cyano-4-fluorophenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate (Compound 135), (3S,5S)-5-(2-((3- carbamoyl-4-fluorophenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec- butyl)carbamate (Compound 136), (3S,5S)-5-(2-((3-carbamoyl-4- fluorophenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate (Compound 137), and (3R,5R)-5-(2-((3-carbamoyl-4-fluorophenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate (Compound 138):

[0561] Step 1: Preparation of (3S,5S)-5-(2-((3-cyano-4-fluorophenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate:

[0562] A solution of (3S,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (20 mg, 0.071 mmol, 1 equiv), 5-bromo-2-fluorobenzonitrile (17.12 mg, 0.085 mmol, 1.2 equiv), CS2CO3(46.49 mg, 0.142 mmol, 2 equiv) and (SP-4-l)-[l,3-BIs[2,6-bis(l-ethylpropyl)phenyl]- 4,5-dichloro-l,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (8.99 mg, 0.011 mmol, 0.15 equiv) in 1,4-dioxane (2 mL) was stirred at 100 °C for 1 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: CHIRALPAK IG, 3*25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 15; Wave Length: 274 / 216 nm; RTl(min): 26.21; RT2(min): 36.47; Sample Solvent: MeOH: DCM=1 : 1 — HPLC; Injection Volume: 2.0 mL; Number Of Runs: 3). The resulting liquid was dried by lyophilization to afford (3S,5S)-5-(2-((3-cyano-4-fluorophenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate (6.4 mg, 21.34%) as a white solid.

[0563] LCMS: (ES+H, m / z): [M+H]l= 400.11H NMR (400 MHz, DMSO-d6) δ 10.11-10.08 (m, 1H), 8.55 (s, 2H), 8.42-8.28 (m, 1H), 8.03- 7.04 (m, 1H), 7.48 (t, J = 9.2 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 5.18 (s, 1H), 5.02- 4.74 (m, 1H), 4.03-3.74 (m, 2H), 3.46-3.36 (m, 1H), 2.82-2.64 (m, 1H), 1.97-1.77 (m, 1H), 1.45-1.23 (m, 2H), 1.02 (t, J = 5.9 Hz, 3H), 0.90-0.74 (m, 3H).

[0564] 19F NMR (377 MHz, DMSO) δ -118.28, -118.29.

[0565] Step 2: Preparation of (3S,5S)-5-(2-((3-carbamoyl-4-fluorophenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate:

[0566] A solution of (3S,5S)-5-{2-[(3-cyano-4-fluorophenyl)amino]pyrimidin-5-yl}oxolan-3-yl N- [(2S)-butan-2-yl]carbamate (20 mg, 0.050 mmol, 1 equiv), NaOH (4.01 mg, 0.100 mmol, 2 equiv) and Hydrogen peroxide(30%) (1.70 mg, 0.050 mmol, 1 equiv) in DMSO (3 mL) was stirred at room temperature for 10 min under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. sodium metabisulfite (aq.) at room temperature. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 EXRS 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 41% B to 55% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.58). The resulting liquid was dried by lyophilization to afford (3S,5S)-5-(2-((3-carbamoyl-4- fluorophenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate (10.4 mg, 47.77%) as a white solid.

[0567] LCMS: (ES+H, m / z): [M+H]+= 418.151H NMR (400 MHz, DMSO-d6) δ 9.87-9.73 (m, 1H), 8.49 (s, 2H), 8.09-7.94 (m, 1H), 7.90-7.76 (m, 1H), 7.71-7.54 (m, 2H), 7.28-7.04 (m, 2H), 5.33-5.04 (m, 1H), 4.99-4.71 (m, 1H), 4.02-3.74 (m, 2H), 3.44-3.37 (m, 1H), 2.77-2.64 (m, 1H), 1.91-1.73 (m, 1H), 1.44-1.24 (m, 2H), 1.08- 0.92 (m, 3H), 0.86-0.68 (m, 3H).

[0568] F NMR (377 MHz, DMSO-d6) -1 δ22.64, -122.66. Step 3: Preparation of (isomer 1) (3S,5S)-5-(2-((3-carbamoyl-4- fluorophenyl)amino)pyrimidin-5-yI)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate and (isomer 2) (3R,5R)-5-(2-((3-carbamoyl-4-fluorophenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yI ((S)-sec-butyl)carbamate:

[0569] The (3RS,5RS)-5-{2-[(3-carbamoyl-4-fluorophenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)- butan-2-yl]carbamate (50 mg, 0.120 mmol, 1 equiv) was purified by prep-Chiral-HPLC with the following conditions(Column: CHIRALPAK IG, 3*25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 15; Wave Length: 274 / 216 nm; RTl(min): 26.21; RT2(min): 36.47; Sample Solvent: MeOH: DCM=1 : 1- HPLC; Injection Volume: 2.0 mL; Number Of Runs: 3). The pure fraction was concentrated under reduced pressure and lyophilization to afford (3S,5S)-5-(2-((3-carbamoyl-4- fluorophenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate (13.8 mg, 26.52%) and (isomer 2) (3R,5R)-5-(2-((3-carbamoyl-4-fluorophenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate (15.0 mg, 29.19%) as a white solid.

[0570] LCMS: (ES+H, m / z): [M+H]+= 418.20

[0571] 1H NMR (400 MHz, DMSO-d6) δ 9.85-9.73 (m, 1H), 8.49 (s, 2H), 8.05-7.97 (m, 1H), 7.91-7.80 (m, 1H), 7.67-7.57 (m, 2H), 7.20 (t, J = 9.5 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 5.28-5.13 (m, 1H), 4.82-4.68 (m, 1H), 4.00-3.74 (m, 2H), 3.43-3.35 (m, 1H), 2.78-2.65 (m, 1H), 2.04-1.77 (m, 1H), 1.41-1.31 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H).

[0572] 19F NMR (377 MHz, DMSO) δ -122.65, -122.82.

[0573] LCMS: (ES+H, m / z): [M+H]l= 418.20

[0574] 1H NMR (400 MHz, DMSO-d6) δ 9.82-9.75 (m, 1H), 8.49 (s, 2H)), 8.05-7.99 (m, 1H), 7.89- 7.80 (m, 1H), 7.65-7.57 (m, 2H), 7.20 (t, J = 9.5 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 5.24-5.14 (m, 1H), 4.81-4.70 (m, 1H), 4.01-3.75 (m, 2H), 3.44-3.35 (m, 1H), 2.78-62 (m, 1H), 1.87-1.73 (m, 1H), 1.44-1.32 (m, 2H), 1.01 (d, J = 6.6 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H).

[0575] 19F NMR (377 MHz, DMSO) δ -122.63, -122.82.

[0576] Example 7: Synthesis of rac-(3R,5R)-5-(2-((3-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl tert-pentylcarbamate (Compound 139), rel-(3R,5R)-5-(2-((3- sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl tert-pentylcarbamate (Compound 140) and rel-(3R,5R)-5-(2-((3-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl tert-pentylcarbamate (Compound 141):

[0577] Step 1: Preparation of 5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (4- nitrophenyl) carbonate:

[0578] A solution of 5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-ol (500.00 mg, 2.75 mmol, 1.00 equiv) in dichloromethane (10 mL) was treated with DIEA (1069.96 mg, 8.27 mmol, 3.00 equiv) and DMAP (33.71 mg, 0.27 mmol, 0.10 equiv) at room temperature for 2 min under nitrogen atmosphere followed by the addition of bis(4-nitrophenyl) carbonate (1007.36 mg, 3.31 mmol, 1.20 equiv) in portions at room temperature. The resulting mixture was stirred at 50 °C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with CH2CI2(2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. This resulted in 5-(2-aminopyrimidin-5-yl)tetrahydrofuran- 3-yl (4-nitrophenyl) carbonate (1.00 g, Crude) as a yellow oil. LC-MS: (ES-H, m / z . [M+H]+=347.1.

[0579] Step 2: Preparation of rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl tert-pentylcarbamate:

[0580] A solution of 5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (1.00 g, 2.88 mmol, 1.00 equiv) in THF (20 mL) was treated with DIEA (1.12 g, 8.66 mmol, 3.00 equiv) at room temperature for 1 min under nitrogen atmosphere followed by the addition of 2- butanamine, 2-methyl- (0.38 g, 4.33 mmol, 1.50 equiv) in portions at room temperature. The resulting mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (1 g) was purified by HP FLASH with the following conditions (Column: XB-C18 50*250 mm, 10 μm; Mobile Phase A: Water(0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 15% B to 45% B in 30 min; Wave Length: 254nm / 220nm; RTl(min): 25.5, RT2(min): 27). The pure fraction was concentrated under reduced pressure to afford rac-(37?,5R)-5-(2-aminopyrimidin-5- yl)tetrahydrofuran-3-yl tert-pentyl carbamate (500 mg, 61.55% over two steps, 90% purity) as a yellow oil. LC-MS: (ES-H, m / z): [M+H]+=295.1.

[0581] Step 3: Preparation of rac-(3R,5R)-5-(2-((3-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yI tert- pentylcarbamate:

[0582] A solution of rac-(3A,5A)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl tert- pentylcarbamate (140.00 mg, 0.47 mmol, 1.00 equiv) and K2CO3(197.20 mg, 1.427 mmol, 3.00 equiv) in tert-Butanol (4 mL) was treated with tert-butyl ((3-bromophenyl)sulfonyl)carbamate (207.87 mg, 0.619 mmol, 1.3 equiv) and Ephos Pd G4 (43.02 mg, 0.048 mmol, 0.10 equiv) at room temperature for 1 min under nitrogen atmosphere in portions at room temperature. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH2CI2(2 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1 : 1-1 :2) to afford rac-(3R,5R)- 5-(2-((3-(N-(ter / -butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl tert-pentylcarbamate (200.00 mg, 76.51% yield, 90% purity) as a yellow oil. LC-MS: (ES-H, TM / Z): [M+H]+=550.1.

[0583] Step 4: Preparation of r«c-(3R,5R)-5-(2-((3-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl tert-pentylcarbamate (Compound 139):

[0584] A solution of rac-(3A,5A)-5-(2-((3-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl tert- pentylcarbamate (100.00 mg, 0.073 mmol, 1.00 equiv) in HCOOH (1 mL) was stirred at 50 °C for 1 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 EXRS 30*150 mm, 5 gm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 34% B to 42% B in 8 min; Wave Length: 254nm / 220nm; RTl(min): 9.93 / 11.10). The pure fraction was obtained by lyophilization to afford rac-(3R,5R)-5-(2-((3- sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl tert-pentylcarbamate (70 mg, 85.71% yield, 97.7% purity)(Compound 139: 2.36 mg was submitted) as a white solid. LC-MS: (ES+H, m / z) [M+H]+= 450.1.1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.55-8.48 (m, 2H), 8.32-8.35 (m, 1H), 7.91 (d, .7 = 8.1 Hz, 1H), 7.50-7.36 (m, 2H), 7.31 (s, 2H), 6.86 (s, 1H), 5.16 (s, 1H), 4.79 - 4.82 (m, 1H), 3.98-3.75 (m, 2H), 2.72-2.69 (m, 1H), 1.81-1.76 (m, 1H), 1.57-1.53 (m, 2H), 1.19-1.09 (m, 6H), 0.75 (t, J= 7.4 Hz, 3H).

[0585] Step 5: Preparation of rel-(3R,5R)-5-(2-((3-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl tert-pentylcarbamate (isomer 1, Compound 140) and rel-(3R,5R)-5- (2-((3-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl tert-pentylcarbamate (isomer 2, Compound 141):

[0586] The crude product (50 mg) was isolated by CHIRAL-HPLC with the following conditions ( Column: CHIRALPAK IA, 3*25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH: ACN=5: 1; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 232 / 272 nm; RTl(min): 13.4; RT2(min): 18.1; Sample Solvent: EtOH: DCM=1 : 1--HPLC; Injection Volume: 1 mL; Number Of Runs: 4) The pure fraction was obtained by lyophilization to afford (isomer 1) rel-(3R,5R)-5-(2-((3-sulfamoylphcnyl)arnino)pyrimidin-5-yl)tctrahydrofuran-3-yl tert- pentylcarbamate (12.00 mg, 24.00% yield, 99.7% purity) as a white solid and (isomer 2) rel- (3R,5R)-5-(2-((3-sulfamoyl phenyl )amino)pyrimidin-5-yl)tetrahydrofuran-3-yl tert- pentylcarbamate (13.50 mg, 27.00% yield, 99.1% purity) as a white solid. rel-(3R,5R)-5-(2-((3-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl tert- pentylcarbamate: LC-MS: (ES+H, m z). [M+H]+= 450.2.1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.53 (s, 2H), 8.33-8.35 (m, 1H), 7.94-7.85 (m, 1H), 7.51-7.37 (m, 2H), 7.32 (s, 2H), 6.87 (s, 1H), 5.19-5.13 (m, 1H), 4.85-4.75 (m, 1H), 3.99-3.90 (m, 1H), 3.81-3.65 (m, 1H), 2.72- 2.64 (m, 1H), 1.87-1.75 (m, 1H), 1.51-1.64 (m, 2H), 1.20-1.10 (m, 6H), 0.75 (t, J= 7.4 Hz, 3H).

[0587] 19F NMR (377 MHz, DMSO) δ -120.5. rel-(3 / ?,5 / ?)-5-(2-((3-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl tert- pentylcarbamate: LC-MS: (ES+H, m / z . [M+H]+= 450.1.1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.53 (s, 2H), 8.34-8.27 (m, 1H), 7.92-7.87 (m, 1H), 7.50-7.36 (m, 2H), 7.32 (s, 2H), 6.87 (s, 1H), 5.16 (s, 1H), 4.78-4.64 (m, 1H), 3.94 (d, J= 10.3 Hz, 1H), 3.86 - 3.71 (m, 1H), 2.72- 2.63 (m, 1H), 1.81-1.75 (m, 1H), 1.52-1.64 (m, 2H), 1.19-1.11 (m, 6H), 0.74 (t, J= 7.4 Hz, 3H).

[0588] Example 8: Synthesis of rac-(3R,5R)-5-(2-((4-(2- (dimethylamino)ethoxy)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 141):

[0589] Step 1: Preparation of rac-(3R,5R)-5-(2-((4-(2- (dimethylamino)ethoxy)phenyl)amino)pyriinidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate:

[0590] A solution of (3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (70 mg, 0.263 mmol, 1.00 equiv), [2-(4-bromophenoxy)ethyl]dimethylamine (77.01 mg, 0.32 mmol, 1.2 equiv), K2CO3(108.99 mg, 0.79 mmol, 3.00 equiv) and EPhos Pd G4 (24.15 mg, 0.026 mmol, 0.1 equiv) in tert-Butanol (4 mL) was stirred at 100°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% NH3 • H2O), 30% to 50% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure and by lyophilization to afford rac-(3R,5R)-5- (2-((4-(2-(dimethylamino)ethoxy)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropyl carb am ate (77.2 mg, 68.38% yield, 99.3% purity, 3.7 mg was submitted) as a white solid.

[0591] LC-MS: (ES+H, m / z) [M+H]+= 430.21H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.42 (s, 2H), 7.66-7.57 (m, 2H), 7.18 (d, J = 7.8 Hz, 1H), 6.93-6.82 (m, 2H), 5.26-5.15 (m, 1H), 4.77-4.67 (m, 1H), 4.00 (t, J = 5.9 Hz, 2H), 3.83- 3.75 (m, 1H), 3.62-3.51 (m, 1H), 2.74-2.65 (m, 1H), 2.60 (t, J = 5.8 Hz, 2H), 2.21 (s, 6H), 1.87- 1.74 (m, 1H), 1.09-1.01 (m, 6H).

[0592] Example 9: Synthesis of rac-(3R,5R)-5-(2-((3-(4-methylpiperazin-l- yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 110), rel-(3R,5R)-5-(2-((3-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 85), and rel-(3R,5R)-5-(2-((3-(4- methylpiperazin-l-yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 86):

[0593] Step 1: Preparation of rac-(3R,5R)-5-(2-((3-(4-methylpiperazin-l- yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate:

[0594] To a stirred solution of 6-chloro-7-fluoro-3-methyl-2-(methylsulfanyl)imidazo[4,5-c]pyridine (70 mg, 0.302 mmol, 1 equiv) and (E)-N'-{3'-cyano-6',7'-dihydro-5'H-spiro[azetidine-3,4'- [l]benzothiophen]-2'-yl}-N,N-dimethylmethanimidamide (165.82 mg, 0.604 mmol, 2 equiv) in tert-Butanol (1 mL) were added K2CO3(72.66 mg, 0.526 mmol, 2 equiv) and EPhos Pd G4 (48.29 mg, 0.053 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for additional Ih. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.05% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure by lyophilization to afford rac-(3R,5R)-5-(2-((3-(4-methylpiperazin-l- yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (85.2 mg, 73.7%) as a white solid.

[0595] LC-MS: (ES+H, m / z): [M+H]+=441 .21H NMR (400 MHz, DMSO-d6) δ 9.47 (s, IH), 8.46 (s, 2H), 7.38 (s, IH), 7.27-7.15 (m, 2H), 7.09 (t, J= 8.1 Hz, IH), 6.58 - 6.51 (m, IH), 5.21-5.15 (m, IH), 4.75 (t, J= 7.6 Hz, IH), 3.94 (d, J= 10.2 Hz, IH), 3.84-3.75 (m, IH), 3.64 - 3.54 (m, IH), 3.13 - 3.07 (m, 4H), 2.75-2.64 (m, IH), 2.48 - 2.41 (m, 4H), 2.22 (s, 3H), 1.86-1.78 (m, IH), 1.05 (t, J= 5.8 Hz, 6H).

[0596] Step 2: Preparation of rel-(3R,5R)-5-(2-((3-(4-methylpiperazin-l- yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate and rel-(3R,5R)- 5-(2-((3-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate: rac-(3R,5R)-5-(2-((3-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (80mg) was purified by Prep-HPLC with the following conditions (Column: CHIRALPAK ID, 3*25 cm, 5 μm; Mobile Phase A: MtBE(10mM NH3-MeOH), Mobile Phase B: MEOH; Flow rate: 40 mL / min; Gradient: isocratic 10; Wave Length: 276 / 208 nm; RTl(min): 13.43; RT2(min): 17.30; Sample Solvent: MeOH: DCM=1 : 1-HPLC; Injection Volume: 1.0 mL; Number Of Runs: 4). The resulting mixture was concentrated under reduced pressure by lyophilization to afford rel-(3R,5R)-5-(2-((3-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl isopropylcarbamate (pre-peak, 33.5 mg, 41.88%) and rel-(3R,5R)-5-(2- ((3-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropyl carbamate (post-peak, 32.6 mg, 40.75%) as a white solid.

[0597] Compound 85 LC-MS: (ES+H, m / zy. [M+H]+=441 .2.1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.46 (s, 2H), 7.38 (s, 1H), 7.27-7.16 (m, 2H), 7.10 (t, J = 8.1 Hz, 1H), 6.55 (dd, J = 8.3, 2.3 Hz, 1H), 5.22-5.15 (m, 1H), 4.81-4.68 (m, 1H), 4.04-3.88 (m, 1H), 3.84 - 3.77 (m, 1H), 3.62-3.54 (m, 2H), 3.14-3.07 (m, 4H), 2.77-2.66 (m, 1H), 2.48-2.41 (m, 4H), 2.22 (s, 3H), 1.86-1.76 (m, 1H), 1.18-0.87 (m, 6H).

[0598] Compound 86

[0599] LC-MS: (ES+H, m / z): [M+H]+=441.2.1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.466 (s, 2H), 7.47-7.30 (s, 1H), 7.26-7.06 (m, 3H), 6.54 (d, J = 8.2 Hz, 1H), 5.22-5.15 (m, 1H), 4.85-4.67 (m, 1H), 3.98-3.76 (m, 2H), 3.63-3.57 (m, 1H), 3.16-3.08 (m, 4H), 2.77-2.66 (m, 1H), 2.49-2.42 (m, 4H), 2.22 (s, 3H), 1.86-1.76 (m, 1H), 1.16-0.81 (m, 6H).

[0600] Example 10: Synthesis of rac-(3R,5R)-5-(2-((3-(4-methylpiperazin-l- yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 161), rel-(3R,5R)-5-(2-((3-(4-methylpiperazin-l-yl)phenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 85), and rel-(3R,5R)-5-(2-((3-(4- methylpiperazin-l-yl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 86):

[0601] Step 1: Preparation of ethyl 4-hydroxyoxolane-2-carboxylate:

[0602] A solution of ethyl 4-oxooxolane-2-carboxylate (30 g, 189.690 mmol, 1 equiv) in EtOH (500 mL) was treated with NaBH4 (7.18 g, 189.69 mmol, 1 equiv) for 30min at -60°C under nitrogen atmosphere. The resulting mixture was stirred for 10min at -60°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CHC13:IPA=1: 1 (3 x 500mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethyl 4-hydroxyoxolane-2- carboxylate (26 g, crude) as a yellow oil.

[0603] LC-MS: (ES+H, m / z): [M +H]+=161.01H NMR (400 MHz, DMSO-d6) δ 4.91 - 4.73 (br, 1H) 4.41 (dd, J = 9.1, 4.2 Hz, 1H), 4.31 - 4.25 (m, 1H), 4.14 - 4.04 (m, 2H), 3.85 - 3.76 (m, 1H), 3.68 - 3.63 (m, 1H), 2.34 - 2.25 (m, 1H), 2.03 - 1.91 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H).

[0604] Step 2&3: Preparation of 4-(benzyloxy)oxolane-2-carboxylic acid:

[0605] A solution of NaH (5.84 g, 243.494 mmol, 1.5 equiv) in THF (300 mL) was treated with ethyl 4- hydroxyoxolane-2-carboxylate (26 g, 162.329 mmol, 1 equiv) for 30min at 0°C under nitrogen atmosphere followed by the addition of BnBr (30.54 g, 178.562 mmol, 1.1 equiv) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with Water / Ice at 0°C. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethyl 4-(benzyloxy)oxolane-2-carboxylate (25 g, crude) as a yellow oil.

[0606] A solution of ethyl 4-(benzyloxy)oxolane-2-carboxylate (25 g, 99.883 mmol, 1 equiv) and NaOH (11.99 g, 299.649 mmol, 3 equiv) in MeOH (20 mL):H20 (20 mL):H20 (20 mL) was stirred for 1.5h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The mixture was neutralized to pH 7 with citric acid. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1 - EA) to afford 4-(benzyloxy)oxolane-2-carboxylic acid (17 g, 66.63%) as a yellow oil.

[0607] LC-MS: (ES+H, m / z): [M +H]+=224.0

[0608] 1H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.18 (m, 5H), 4.49 - 4.36 (m, 2H), 4.15 - 4.07 (m, 1H), 4.05 - 3.88 (m, 1H), 3.85 - 3.77 (m, 1H), 3.67 - 3.58 (m, 1H), 2.35 - 2.27 (m, 1H), 1.85 - 1.74 (m, 1H).

[0609] Step 4: Preparation of l,3-dioxoisoindol-2-yl 4-(benzyloxy)oxolane-2-carboxylate:

[0610] To a stirred solution of 4-(benzyloxy)oxolane-2-carboxylic acid (16 g, 71.994 mmol, 1 equiv) and NHPI (11.74 g, 71.994 mmol, 1 equiv) in 2-methyloxolane (200 mL) were added 2,4,6-tripropyl- 1,3, 5, 2$lA{5},4$lA{5},6$lA{5}-trioxatriphosphinane-2, 4, 6-trione (229.07 g, 359.970 mmol, 5 equiv, 50%) and Et3N (21.86 g, 215.982 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 6h at 60°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (200mL). The resulting mixture was extracted with EtOAc (3 x 150mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1-1 : 1) to afford l,3-dioxoisoindol-2-yl 4- (benzyloxy)oxolane-2-carboxylate (8 g, 24.20%) as a white oil.

[0611] LC-MS: (ES+H, m / z): [M +H]+=368.1.

[0612] Step 5: Preparation of tert-butyl N-{5-[4-(benzyloxy)oxolan-2-yl]pyrimidin-2-yl}carbainate:

[0613] To a stirred solution of l,3-dioxoisoindol-2-yl 4-(benzyloxy)oxolane-2-carboxylate (4.01 g, 10.90 mmol, 1.3 equiv) and tert -butyl N-(5-bromopyrimidin-2-yl)carbamate (2.3 g, 8.39 mmol, 1.00 equiv) in DMAC (50 mL) were added 5-Methoxypyridine-2-carboxamidine hydrochloride (0.16 g, 0.83 mmol, 0.1 equiv), NICKEL(II) CHLORIDE ETHYLENE GLYCOL DIMETHYL ETHER COMPLEX (184.36 mg, 0.83 mmol, 0.1 equiv) and Zn (5.49 g, 83.91 mmol, 10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1-1 : 1) to afford tert-butyl N-{5-[4-(benzyloxy)oxolan-2-yl]pyrimidin-2-yl}carbamate (1.3 g, 37.54%) as a yellow oil.

[0614] LC-MS: (ES+H, m / z): [M +H]+=372.11H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.58 (s, 2H), 7.38 - 7.26 (m, 5H), 5.08 - 4.83 (m, 1H), 4.52 (dt, J = 26.3, 13.6 Hz, 2H), 4.34 (d, J = 17.4 Hz, 1H), 4.22 - 3.98 (m, 1H), 3.88(d, J = 9.8 Hz, 1H), 2.06 - 1.83 (m, 1H), 1.46 (s, 9H), 1.27 (d, J = 27.5 Hz, 1H).

[0615] Step 6: Preparation of 5-(2-aminopyrimidin-5-yl)oxolan-3-ol:

[0616] A solution of tert-butyl N-{5-[4-(benzyloxy)oxolan-2-yl]pyrimidin-2-yl}carbamate (1.3 g, 3.50 mmol, 1 equiv) in methanesulfonic acid (10 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1-5: 1) to afford 5-(2-aminopyrimidin-5-yl)oxolan-3-ol (500 mg, 70.96%) as a yellow solid.

[0617] LC-MS: (ES+H, m / z): [M +H]+=182.11H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 5.7 Hz, 2H), 5.76 (s, 3H), 5.01 - 4.93 (m, 1H), 4.43 (dd, J = 12.6, 7.7 Hz, 1H), 4.07 (dd, J = 9.1, 4.2 Hz, 1H), 3.87 - 3.61 (m,lH), 2.17 (dd, J = 13.2, 5.6 Hz, 1H), 1.98 - 1.75 (m, 1H).

[0618] Step 7: Preparation of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate:

[0619] To a stirred solutionof 5-(2-aminopyrimidin-5-yl)oxolan-3-ol (500 mg, 2.75 mmol, 1 equiv) and bis(4-nitrophenyl) carbonate (1007.35 mg, 3.31 mmol, 1.2 equiv) in DCM (20 mL) were added DIEA (1069.96 mg, 8.27 mmol, 3 equiv) and DIEA (1069.96 mg, 8.27 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50mL). The resulting mixture was extracted with CH2C12 (3 x 50mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 5-(2- aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate (400 mg, crude) as a yellow oil.

[0620] LC-MS: (ES+H, m / z): [M +H]l=347.0.

[0621] Step 8: Preparation of rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate & (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-(l- methylcyclopropyl)carbamate:

[0622] To a stirred solution of 5-(2-aminopyrimidin-5-yl)oxolan-3-yl 4-nitrophenyl carbonate (300 mg, 0.86 mmol, 1 equiv) and DIEA (335.90 mg, 2.59 mmol, 3 equiv) in DMF (5 mL) was added 1 - methylcyclopropan-1 -amine hydrochloride (139.80 mg, 1.29 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50mL). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 20% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.65 / 9.58) to afford (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-(l- methylcyclopropyl)carbamate (25 mg, 9.85%) as a white solid and (3R,5S)-5-(2-aminopyrimidin- 5-yl)oxolan-3-yl N-(l-methylcyclopropyl)carbamate (30 mg, 11.82%) as a white solid. rac-(3R,5R)-5-(2-aminopyrimidin-5-yl)tetrahydrofuran-3-yl (1- methylcyclopropyl)carbamate:

[0623] LC-MS: (ES+H, m / z): [M +H]+=279.0.1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 2H), 7.54 (s, 1H), 6.59 (s, 2H), 5.19 (d, J = 39.0 Hz, 1H), 4.86 - 4.56 (m, 1H), 3.81 (dd, J = 47.4, 7.4 Hz, 2H), 2.64 (dt, J = 14.4, 7.5 Hz, 1H), 1.81- 1.66 (m, 1H), 1.23 (s, 3H), 0.68 - 0.41 (m, 4H).

[0624] (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-(l-methylcyclopropyl)carbainate2 LC-MS: (ES+H, m / z): [M +H]+=279.0.

[0625] JH NMR (400 MHz, DMSO-d6) δ 8.22 (s, 2H), 7.55 (s, 1H), 6.62 (s, 2H), 5.21 (t, J = 5.3 Hz, 1H), 4.75 (dd, J = 10.4, 5.5 Hz, 1H), 4.27 - 4.15 (m, 1H), 3.67 (d, J = 10.2 Hz, 1H), 2.32 - 2.00(m, 2H), 1.25 (s, 3H), 0.56 (dd, J = 52.1, 5.2 Hz, 4H).

[0626] Step 9: Preparation of (3R,5S)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-(l- methylcyclopropyl)carbamate:

[0627] To a stirred solution of (3R,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-(l- methylcyclopropyl)carbamate (30 mg, 0.10 mmol, 1 equiv) and tert-butyl N-(4- bromobenzenesulfonyl)carbamate (47.11 mg, 0.14 mmol, 1.3 equiv) in t-BuOH (2 mL) were added K2CO3(44.69 mg, 0.324 mmol, 3 equiv) and EPhos Pd G4 (9.90 mg, 0.011 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20mL). The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (20: 1—10: 1) to afford (3R,5S)-5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3- yl N-(l-methylcyclopropyl)carbamate (40 mg, 62.59%) as a yellow solid.

[0628] LC-MS: (ES+H, m / z): [M +H] 534.1

[0629] Step 10: Preparation of rac-(3R,5S)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan- 3-yl N-(l-methylcyclopropyl)carbamate (Compound 41):

[0630] A solution of (3R,5S)-5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5- yl]oxolan-3-yl N-(l-methylcyclopropyl)carbamate (40 mg, 0.075 mmol, 1 equiv) in formic acid (1 mL) was stirred for 30min at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 10μm; Mobile Phase A: Water(10mmol / L NH4HCO3+ 0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 20% B to 35% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.87 / 9.40). The pure fraction was concentrated under reduced pressure and lyophilization to afford rac-(3R,5S)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l- methylcyclopropyl)carbamate (20 mg, 60.99%) as a white solid.

[0631] LC-MS: (ES+H, m / z): [M +H]+=434.1

[0632] 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (s, 2H), 7.96 - 7.88 (m, 2H), 7.77 - 7.68 (m, 2H), 7.58 (s, 1H), 7.16 (s, 2H), 5.35-5.18 (m, 1H), 5.02-5.48 (m, 1H), 4.28-4.16 (m, 1H), 3.81- 3.68 (m, 1H), 2.42 - 2.27 (m, 1H), 2.18 - 2.07 (m, 1H), 1.26 (s, 3H), 0.71-0.45 (m, 4H).

[0633] Step 11: Preparation of rel-(3R,5S)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan- 3-yl N-(l-methyIcyclopropyl)carbamate (Compound 42) and rel-(3R,5S)-5-{2-[(4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l-methylcyclopropyl)carbamate (Compound 43):

[0634] The rac-(3R,5S)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-(l- methylcyclopropyl)carbamate (16 mg) was isolated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IG, 3*25 cm, 5 μm; Mobile Phase A: MTBE: DCM=1 : l(10mMNH3), Mobile Phase B: MeOH— HPLC; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 280 / 292 nm; RTl(min): 5.3; RT2(min): 8.5; Sample Solvent: MeOH: DCM=4: 1; Injection Volume: 1.5 mL; Number Of Runs: 1). The pure fraction was concentrated under reduced pressure and lyophilization to afford rel-(3R,5S)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-(l-methylcyclopropyl)carbamate (3.2 mg, 18.42%, ee=100%) as a white solid and rel-(3R,5S)-5-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl }oxolan-3-yl N-(l- methylcyclopropyl)carbamate (2.2 mg, 13.56%, ee=100%) as a white solid..

[0635] Compound 42:

[0636] LC-MS: (ES+H, m / z): [M +H]+=434.11H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (s, 2H), 7.98 - 7.89 (m, 2H), 7.77-7.68 (m, 2H), 7.58 (s, 1H), 7.17 (s, 2H), 5.33-5.18 (m, 1H), 5.01-4.83 (m, 1H), 4.31-4.18 (m, 1H), 3.83- 3.69 (m, 1H), 2.37 - 2.27 (m, 1H), 2.19 - 2.06 (m, 1H), 1.27 (s, 3H), 0.71-0.44 (m, 4H).

[0637] Compound 43:

[0638] LC-MS: (ES+H, m / z): [M +H]+=434.1

[0639] ^ NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.56 (s, 2H), 7.98 - 7.89 (m, 2H), 7.77-7.68 (m, 2H), 7.58 (s, 1H), 7.17 (s, 2H), 5.33-5.18 (m, 1H), 5.01-4.83 (m, 1H), 4.31-4.18 (m, 1H), 3.83- 3.69 (m, 1H), 2.40 - 2.27 (m, 1H), 2.18 - 2.06 (m, 1H), 1.27 (s, 3H), 0.71-0.44 (m, 4H).

[0640] Example 11: Synthesis of (3R,5S)-5-(2-(((lS,4R)-4-(((R)-l-methoxypropan-2- yl)amino)cyclohexyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate formate (Compound 157) and (3R,5S)-5-(2-(((lS,4R)-4-(((R)-l-methoxypropan-2- yl)amino)cyclohexyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate formate (Compound 158)

[0641] Step 1: Preparation of (3R,5S)-5-(2-(((lS,4R)-4-(((R)-l-methoxypropan-2- yl)amino)cyclohexyI)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate formate(isomer 2) and (3R,5S)-5-(2-(((lS,4R)-4-(((R)-l-methoxypropan-2- yl)amino)cyclohexyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate formate(isomer 2)

[0642] To a stirred mixture of (R)-N1-(l-methoxypropan-2-yl)cyclohexane-l,4-diamine (60.00 mg, 0.32 mmol, 1 .OOequiv) and 5-(2-chloropyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (96.54 mg, 0.32 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) were added (SP-4-l)-[l,3-BIs[2,6- bis(l -ethylpropyl)phenyl]-4,5-dichl oro-1, 3-dihydro-2H-imidazol-2-ylidene]di chi oro(2- methylpyridine)palladium (27.06 mg, 0.03 mmol, 0.10 equiv) and CS2CO3(314.80 mg, 0.96 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 4h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with 1,4-di oxane (3 x 3 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL). The residue was purified by reversed-phase flash chromatography with the following conditions: (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 8% B to 18% B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 8.91 / 10.35. The pure fraction was concentrated under reduced pressure and by lyophilization to afford (3R,5S)-5-(2-(((lS,4R)-4-(((R)-l- methoxypropan-2-yl)amino)cyclohexyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec- butyl)carbamate formate (12.40 mg, 7.71% yield, isomer 2, Assume cis) as a grey solid and (3R,5S)-5-(2-(((1R,4S)-4-(((R)-l-methoxypropan-2-yl)amino)cyclohexyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate formate (8.10 mg, 5.04 yield, isomer 2, Assume trans) as a off-white semi-solid.

[0643] Compound 157:

[0644] LC-MS: (ES+H, m / z): [M+H]+= 450.3

[0645] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.22 (s, 2H), 7.05 (d, J= 8.5 Hz, 1H), 5.24-5.13 (m, 1H), 4.82 - 4.75 (m, 1H), 4.19 - 4.11 (m, 1H), 3.74 - 3.53 (m, 2H), 3.52 - 3.32 (m, 4H), 3.29 (s, 3H), 3.11 - 2.99 (m, 1H), 2.25 - 2.15 (m, 1H), 2.09 - 1.89 (m, 5H), 1.50 - 1.24 (m, 6H), 1.17 (d, J= 6.2 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H), 0.78 (t, J= 7.4 Hz, 3H).

[0646] Compound 158:

[0647] LC-MS: (ES+H, m / z): [M+H]+= 450.31H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.24 (s, 2H), 7.03 (d, J= 8.4 Hz, 1H), 5.24-5.13 (m, 1H), 4.86-4.74 (m, 1H), 4.19 - 4.11 (m, 1H), 3.97-3.87 (m, 1H), 3.78-3.62 (m, 1H), 3.52 - 3.41 (m, 2H), 3.40 - 3.32 (m, 2H), 3.28 (s, 3H), 3.20-3.11 (m, 1H), 2.27 - 2.17 (m, 1H), 2.09 - 1.96 (m, 1H), 1.88 - 1.73 (m, 4H), 1.69 - 1.52 (m, 4H), 1.39 - 1.28 (m, 2H), 1.17 (d, J= 6.3 Hz, 3H), 1.00 (d, J= 6.6 Hz, 3H), 0.77 (t, J= 7.4 Hz, 3H). Example 12: Synthesis of rac-(3R,5R)-5-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin- 5-yl)tetrahydrofuran-3-yl isopropylcarbamate (Compound 68)

[0648] Step 1: Preparation of rac-(3R,5R)-5-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2-fluoroph enyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate:

[0649] To a stirred solution of (3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (150 mg, 0.563 mmol, 1 equiv) and tert-butyl N-(4-bromo-3-fluorobenzenesulfonyl)carbamate (399.01 mg, 1.126 mmol, 2 equiv) in dioxane (5 mL) were added K2CO3(233.54 mg, 1.689 mmol, 3 equiv) and EPhos Pd G4 (51.74 mg, 0.056 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C for additional 4h. The reaction was monitored by LCMS. LCMS was OK. The mixture was allowed to cool down to room temperature. The resulting mixture was fdtered, the fdter cake was washed with EtOAc (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8; mobile phase, MeCN in Water (0.1% FA), 40% to 60% gradient in 20 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure to afford rac-(3R,5R)-5-(2-((4- (N-(tert-butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropyl carbamate (150 mg, 49.3%) as a white solid. LC-MS: (ES+H, m z). [M+H]+=540.1.

[0650] Step 2: Preparation of rac-(3R,5R)-5-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-y l)tetrahydrofuran-3-yl isopropylcarbamate:

[0651] A solution of (3R,5R)-5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2- fluorophenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-isopropylcarbamate (150 mg, 0.278 mmol, 1 equiv) in HCOOH (2 mL) was stirred at 50°C for 30min under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: Xbridge Phenyl OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 23%B to 33%B in 10min; Wave Length: 254nm / 220nm nm;

[0652] RTl(min): 8.73). The pure fraction was obtained by lyophilization to afford rac-(3R,5R)-5-(2- ((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl isopropylcarbamate (2.1 mg, 1.7%) as a white solid. LC-MS: (ES+H, m 'z) [M+H]+=440.0.1H NMR (400 MHz, DMSO-d6) δ 9.52 (brs, 1H), 8.50 (s, 2H), 8.08 (t, J= 8.2 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.15 (d, J = 7.8 Hz, 1H), 5.24-5.14 (m, 1H), 4.85-4.74 (m, 1H), 4.01-3.90 (m, 1H), 3.87-3.76 (m, 1H), 3.63 - 3.54 (m, 1H), 2.77 - 2.66 (m, 1H), 1.86 - 1.76 (m, 1H), 1.08 - 0.89 (m, 6H).19F NMR (377 MHz, DMSO) δ -120.80.

[0653] Example 13: Synthesis of (3R*,5R*)-5-{2-[(4-{[(2R)-l-methoxypropan-2- yl]amino}cyclohexyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate; formic acid (Compound 150)

[0654] Step 1: Preparation of (3R*,5R*)-5-{2-[(4-{[(2R)-l-methoxypropan-2- yl]amino}cyclohexyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate; formic acid:

[0655] A solution of (3R*,5R*)-5-(2-chloropyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (30 mg, 0.100 mmol, 1 equiv)Nl-[(2R)-l-methoxypropan-2-yl]cyclohexane-l,4-diamine (46.61 mg, 0.250 mmol, 2.5 equiv), (SP-4-l)-[l,3-BIs[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-l,3- dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (8.41 mg, 0.010 mmol, 0.1 equiv) and CS2CO3(228.26 mg, 0.700 mmol, 7 equiv) in 1,4-dioxane (4 mL). The resulting mixture was stirred at 100°C for overnight under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1%FA, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 22% B in10min; Wave Length: 254nm / 220nm; RTl(min): 6.82 / 7.75). The pure fraction was concentrated under reduced pressure and lyophilized to afford (3R*,5R*)-5-{2-[(4-{[(2R)-l-methoxypropan-2- yl]amino}cyclohexyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate; formic acid (3.0 mg, 97.8%purity, 5.92%) as a black solid.

[0656] LC-MS: (ES+H, m / )z: [M+H]+= 450.3

[0657] 1H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.21 (m, 3H), 7.20 - 7.10 (m, 1H), 7.10 - 7.02 (m, 1H), 5.23 - 5.10 (m, 1H), 4.67 - 4.57 (m, 1H), 3.97 - 3.79 (m, 2H), 3.79 - 3.71 (m, 1H), 3.34 - 3.30 (m, 3H), 3.30 - 3.25 (m, 3H), 2.96 - 2.84 (m, 1H), 2.71 - 2.56 (m, 1H), 1.99 - 1.87 (m, 2H), 1.82 - 1.70 (m, 2H), 1.69 - 1.49 (m, 4H), 1.44 - 1.32 (m, 2H), 1.32 - 1.21 (m, 2H), 1.12 - 0.93 (m, 6H), 0.87 - 0.74 (m, 3H).

[0658] Example 14: Synthesis of (3R*,5S*)-5-{2-[(4-{[(2R)-l-methoxypropan-2- yl]amino}cyclohexyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate; formic acid (Compound 156)

[0659] Step 1: Preparation of (3R*,5S*)-5-{2-[(4-{[(2R)-l-methoxypropan-2- yl]amino}cyclohexyI)amino]pyrimidin-5-yI}oxoIan-3-yl N-[(2S)-butan-2-yl]carbamate; formic acid:

[0660] To a stirred mixture of Nl-[(2R)-l-methoxypropan-2-yl]cyclohexane-l,4-diamine (60 mg, 0.322 mmol, 1 equiv) and 5-(2-chloropyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (96.54 mg, 0.322 mmol, 1 equiv) in 1,4-dioxane (2 mL) were added (SP-4-l)-[l,3-BIs[2,6-bis(l- ethylpropyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2-ylidene]dichloro(2- methylpyridine)palladium (27.06 mg, 0.032 mmol, 0.1 equiv) and CS2CO3(314.80 mg, 0.966 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 4h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2mL). The residue was purified by reversed-phase flash chromatography with the following conditions:(Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(0. 1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 18% B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 8.91 / 10.35) to afford (3R*,5S*)-5-{2-[(4-{[(2R)-l-methoxypropan-2-yl]amino}cyclohexyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate; formic acid (11.2 mg, 99.4%purity, 6.97%) as an off-white semi-solid. LC-MS: (ES+H, m / z. [M+H]+= 450.31H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.10 (m, 3H), 7.24 - 6.90 (m, 2H), 5.33 - 5.10 (m, 1H), 4.90 - 4.71 (m, 2H), 4.29 - 4.08 (m, 1H), 3.92 - 3.56 (m, 2H), 3.49 - 3.36 (m, 1H), 3.34 - 3.19 (m, 5H), 3.18 - 2.96 (m, 1H), 2.89 - 2.62 (m, 1H), 2.33 - 2.02 (m, 2H), 2.02 - 1.80 (m, 2H), 1.81 - 1.65 (m, 1H), 1.65 - 1.48 (m, 2H), 1.46 - 1.12 (m, 5H), 1.12 - 0.92 (m, 6H), 0.90 - 0.70 (m, 3H).

[0661] Example 15: Synthesis of (3R*,5S*)-5-{2-[(4-{[(2R)-l-methoxypropan-2- yl] amino} cyclohexyl)am ino] pyrimidin-5-yl} oxolan-3-yl N- [(2S)-butan-2-ylJ carbarn ate; formic acid (Compound 153)

[0662] Step 1: Preparation of (3R*,5S*)-5-{2-[(4-{[(2R)-l-methoxypropan-2- yl]amino}cyclohexyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate; formic acid:

[0663] A solution of (3S,5R)-5-(2-chloropyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (50 mg, 0.167 mmol, 1 equiv), Nl-[(2R)-l-methoxypropan-2-yl]cyclohexane-l,4-diamine (77.69 mg, 0.418 mmol, 2.5 equiv), CS2CO3(380.43 mg, 1.169 mmol, 7 equiv) and (SP-4-l)-[l,3- BIs[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichl oro-1 , 3-dihydro-2H-imidazol-2-ylidene]dichloro(2- methylpyridine)palladium (14.01 mg, 0.017 mmol, 0.1 equiv) in 1,4-dioxane (3 mL). The resulting mixture was stirred at 100°C for overnight under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 19% B in 8 min; Wave Length: 254nm / 220nm; RTl(min): 6.62 / 7.67). The pure fraction was concentrated under reduced pressure and lyophilized to afford (3R*,5S*)-5-{2-[(4-{[(2R)-l- methoxypropan-2-yl]amino}cyclohexyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- yl]carbamate; formic acid (4.6 mg, 95.6%purity, 8.87%) as a colorless oil. LC-MS: (ES+H, m / z) [M+H]' = 450.3

[0664] 1H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.21 (m, 3H), 7.17 - 7.02 (m, 2H), 5.27 - 5.17 (m, 1H), 4.85 - 4.74 (m, 1H), 4.23 - 4.13 (m, 1H), 3.89 - 3.80 (m, 1H), 3.73 - 3.67 (m, 2H), 3.45 - 3.35 (m, 1H), 3.35 - 3.30 (m, 1H), 3.30 - 3.28 (m, 4H), 3.21 - 3.30 (m, 1H), 2.90 - 2.67 (m, 1H), 2.27 - 2.16 (m, 1H), 2.13 - 2.00 (m, 1H), 2.00 - 1.88 (m, 2H), 1.80 - 1.67 (m, 1H), 1.67 - 1.50 (m, 3H), 1.45 - 1.32 (m, 2H), 1.32 - 1.15 (m, 2H), 1.09 - 0.97 (m, 6H), 0.82 (t, J = 7.4 Hz, 3H).

[0665] Example 16: Synthesis of (3R,5S)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (Compound 97) and (3R,5S)-5-{2-[(2-fluoro-4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (Compound 98): Step 1: Preparation of (3R,5S)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate & (3R,5S)-5-{2-[(2-fluoro-4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate:

[0666] The crude product (3R,5S)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3- yl N-[(2S)-butan-2-yl]carbamate (95 mg) was purified by Chiral-HPLC with the following conditions (Column: CHIRALPAK ID, 3*25 cm, 5 μm; Mobile Phase A: MTBE: DCM=1 : l(10mMNH3), Mobile Phase B: MeOH— HPLC; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 280 / 290 nm; RTl(min): 9.5; RT2(min): 16.8; Sample Solvent: MEOH: DCM=1: l(0.1%FA); Injection Volume: 0.6 mL; Number Of Runs: 4 ). The pure fraction was obtained by lyophilization to afford (3R,5S)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (24.2 mg, 99.4%purity, prepeak) and (3R,5S)-5- {2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (17.7 mg, 98.1%purity, postpeak) as a white solid.

[0667] Compound 97:

[0668] LC-MS: (ES+H, mlz)-. [M+H]+=454.1.1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.52 (s, 2H), 8.10 (t, J= 8.0 Hz, 1H), 7.61 (d, J= 9.5 Hz, 2H), 7.38 (s, 2H), 7.15 (d, J= 8.3 Hz, 1H), 5.30-5.18 (m, 1H), 4.98-4.85 (m, 1H), 4.29-4.15 (m 1H), 3.82-3.69 (m, 1H), 3.49 - 3.37 (m, 1H), 2.40-2.25 (m, 1H), 2.19 - 2.03 (m, 1H), 1.45 - 1.32 (m, 2H), 1.03 (d, J= 6.6 Hz, 3H), 0.83 (t, J = 1A Hz, 3H).19F NMR (282 MHz, DMSO) δ -120.91.

[0669] Compound 98:

[0670] LC-MS: (ES+H, m / z): [M+H]1=454.1.1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.52 (s, 2H), 8.10 (t, J= 8.1 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.38 (s, 2H), 7.13 (d, J= 8.3 Hz, 1H), 5.30 - 5.22 (m, 1H), 4.93 (dd, J= 10.3, 5.6 Hz, 1H), 4.22 (dd, J= 10.2, 4.6 Hz, 1H), 3.76 (d, J= 10.2 Hz, 1H), 3.47 - 3.37 (m, 1H), 2.41-2.28 (m, 1H), 2.19 - 2.06 (m, 1H), 1.45 - 1.32 (m, 2H), 1.04 (d, J= 6.6 Hz, 3H), 0.83 (t, J= 7.4 Hz, 3H).19F NMR (377 MHz, DMSO) δ -120.96.

[0671] Example 17: Synthesis of (3S,5S)-5-(2-((3-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate (Compound 99), (3R,5R)-5-{2-[(3- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (Compound 100), and (3S,5S)-5-{2-[(3-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl

[0672] N-[(2S)-butan-2-yl]carbamate (Compound 101):

[0673] Step 1: Preparation of (3S,5S)-5-(2-((3-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)tetrahydrofuran-3-yl ((S)-sec- butyl)carbamate:

[0674] To a solution of tert-butyl N-(3-bromobenzenesulfonyl)carbamate (215.88 mg, 0.64 mmol, 1.2 equiv) and (3S,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (150 mg, 0.54 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) were added { l,3-bis[2,6-bis(heptan-4- yl)phenyl]-4,5-dichl oro-2, 3-dihy dro-lH-imidazol-2-yl}dichloro(3-chloro-llambda4-pyri din- 1- yl)palladium (52.11 mg, 0.054 mmol, 0.1 equiv) and K2CO3(147.90 mg, 1.07 mmol, 2.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for additional 3h. The reaction was monitored by LCMS. LCMS Was OK. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure to afford (3 S,5S)-5-[2-({3-[(tert- butoxycarbonyl)aminosulfonyl]phenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (120 mg, 41.8% yield, 97.0% purity) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =536.2. Step 2: Preparation of (3S,5S)-5-(2-((3-sulfamoylphenyl)amino)pyrimidin-5- yl)tetrahydrofuran-3-yl ((S)-sec-butyl)carbamate:

[0675] Into a 8 mL vial were added (3S,5S)-5-[2-({3-[(tert- butoxycarbonyl)aminosulfonyl]phenyl }amino)pyrimidin-5-yl]oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (120 mg, 0.224 mmol, 1.00 equiv) and HCOOH (2 mL) at room temperature. The resulting mixture was stirred at room temperature for additional 30min. The reaction was monitored by LCMS. LCMS Was OK. The mixture was neutralized to pH 8 with saturated NaHCO3(aq.). The aqueous layer was extracted with CH2CI2(2 x 10 mL). The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.05%NH3.H20), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 38% B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 9.1). The pure fraction was obtained by lyophilization to afford (3S,5S)-5-{2-[(3-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (70 mg, 71.7% yield, 98.7% purity) (2.7 mg was submitted) as a white solid. LC- MS: (ES+H, m / z): [M+H]+ =436.1. NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.55-8.48 (m, 2H), 8.36-8.30 (m, 1H), 7.96-7.88 (m, 1H), 7.51-7.29 (m, 4H), 7.14-7.07 (m, 1H), 5.26-5.15 (m, 1H), 4.84-4.75 (m, 1H), 3.99 - 3.91 (m, 1H), 3.86-3.77 (m, 1H), 3.43 - 3.36 (m, 1H), 2.78 - 2.66 (m, 1H), 1.89 - 1.79 (m, 1H), 1.44 - 1.31 (m, 2H), 1.05-0.97 (m, 3H), 0.88-0.75 (m, 3H).

[0676] Step 3: Preparation of (isomer 1) (3R,5R)-5-{2-[(3-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate & (isomer 2) (3S,5S)-5-{2-[(3- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yI N-[(2S)-butan-2-yl]carbamate:

[0677] The crude product (60 mg) was isolated by Prep-CHIRAL-HPLC with the following conditions (Column: CHIRALPAK-IK, 3*25mm, 5 μm; Mobile Phase A: Hex(10 mM NH3-MeOH), Mobile Phase B: IP A; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 276 / 254 nm; RTl(min): 14.264; RT2(min): 20.72; Sample Solvent: MEOH: DCM=1 :). The pure fraction was obtained by lyophilization to afford (isomer 1) (3R,5R)-5-{2-[(3- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (15.8 mg, 26.3% yield, 99.2% purity) and (isomer 2) (3S,5S)-5-{2-[(3-sulfamoylphenyl)amino]pyrimidin- 5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (20.1 mg, 33.5% yield, 98.2% purity) as a white solid.

[0678] Compound 100:

[0679] LC-MS: (ES+H, m / z): [M+H]+ =436.2.1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.52 (s, 2H), 8.33 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.33 (s, 2H), 7.11 (d, J = 8.4 Hz, 1H, 5.26-5.15 (m, 1H), 4.84-4.75 (m, 1H), 3.99-3.91 (m, 1H), 3.86- 3.77 (m, 1H), 3.43 - 3.36 (m, 1H), 2.78 - 2.66 (m, 1H), 1.89 - 1.79 (m, 1H), 1.44 - 1.31 (m, 2H), 1.03 (d, J = 6.6 Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H).

[0680] Compound 101:

[0681] LC-MS: (ES+H, m / z): [M+H]+ =436.1.1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.53 (s, 2H), 8.36-8.30 (m, 1H), 7.94-7.88 (m, 1H), 7.51-7.37 (m, 2H), 7.33 (s, 2H), 7.11 (d, J = 8.4 Hz, 1H), 5.26 - 5.15 (m, 1H), 4.84 - 4.75 (m, 1H), 3.99 - 3.91 (m, 1H), 3.86 - 3.77 (m, 1H), 3.40 - 3.38 (m, 1H), 2.78 - 2.66 (m, 1H), 1.89 - 1.79 (m, 1H), 1.44-1.31 (m, 2H), 1.01 (d, J = 6.6 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H).

[0682] Example 18: Synthesis of (3RS,5RS)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N- [(2S)-4, 4, 4-trifluorobutan-2-yl] carbamate (Compound 56), (3R*,5R*)-5- {2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-4,4,4- trifluorobutan-2-yl]carbamate (Compound 57), and (3R*,5R*)-5-{2-[(2-fluoro-4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-4,4,4-trifluorobutan-2- yljcarbamate (Compound 58) Step 1: Preparation of (3R,5R)-5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2- fluorophenyl} amino)pyrimidin-5-yl] oxoIan-3-yl N- [(2S)-4,4,4-trifluorobutan-2- yl] carbamate:

[0683] To a stirred solution of (3R,5R)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-4,4,4- trifluorobutan-2-yl]carbamate (100 mg, 0.299 mmol, 1 equiv) and tert-butyl N-(4-bromo-3- fluorobenzenesulfonyl)carbamate (105.95 mg, 0.299 mmol, 1 equiv) in 2-methylpropan-2-ol (4 mL) were added EPhos Pd G4 (27.48 mg, 0.030 mmol, 0.1 equiv) and K2CO3(124.03 mg, 0.897 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for additional 2 h. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:3 - 4:3) to afford (3R,5R)- 5-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2-fluorophenyl}amino)pyrimidin-5-yl]oxolan-3- yl N-[(2S)-4,4,4-trifluorobutan-2-yl]carbamate (125 mg, 68.7%) as a light brown solid.

[0684] LC-MS: (ES+H, m / z): [M+H]+=608.20.

[0685] Step 2: Preparation of (3RS,5RS)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N- [(2S)-4, 4, 4-trifluorobutan-2-yl] carbamate:

[0686] Into a 100 mL round-bottom flask were added (3R,5R)-5-[2-({4-[(tert- butoxycarbonyl)aminosulfonyl]-2-fluorophenyl}amino)pyrimidin-5-yl]oxolan-3-yl N-[(2S)- 4,4,4-trifluorobutan-2-yl]carbamate (125 mg, 0.206 mmol, 1 equiv) and HCOOH (3 mL) at room temperature. The resulting mixture was stirred at 50 °C for additional 1 h. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 8 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The pure fraction was obtained by lyophilization to afford (3RS,5RS)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N- [(2S)-4,4,4-trifluorobutan-2-yl]carbamate (85 mg, 77.5%) as a white solid.

[0687] LC-MS: (ES+H, m / z): [M+H]+=508.05. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 1.9 Hz, 2H), 8.06 (t, J = 8.1 Hz, 1H), 7.64-7.57 (m, 2H), 7.44-7.35 (m, 1H), 5.24-5.13 (m, 1H), 4.84-4.78 (m, 1H), 3.98-3.77 (m, 3H), 2.79-2.64 (m, 1H), 2.45-2.32 (m, 2H), 1.87-1.78 (m, 1H), 1.13 (t, J = 5.8 Hz, 3H).

[0688] 19F NMR (400 MHz, DMSO-d6) δ -61.59, -120.87.

[0689] Step 3: Preparation of (3R*,5R*)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N- [(2S)-4, 4, 4-trifluorobutan-2-yl] carbamate & (3R*,5R*)-5-{2-[(2-fluoro-4- suIfamoylphenyI)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-4,4,4-trifluorobutan-2- yl] carbamate:

[0690] The product (3RS,5RS)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-4,4,4-trifluorobutan-2-yl]carbamate (80 mg) was chiral by Prep-HPLC with the following conditions (Column: CHIRALPAK ID, 2*25 cm, 5 μm; Mobile Phase A: MTBE: DCM=1 : l(10mMNH3), Mobile Phase B: MeOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 280 / 300 nm; RTl(min): 8.2; RT2(min): 13.1; Sample Solvent: MEOH: DCM=1 : 1; Injection Volume: 1 mL; Number Of Runs: 10). The pure fraction was obtained by lyophilization to afford (3R*,5R*)-5-{2-[(2-fluoro-4- sulfamoylphenyl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-4,4,4-trifluorobutan-2-yl]carbamate (30.4 mg, 37.2%) and (3R*,5R*)-5-{2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-4,4,4-trifluorobutan-2-yl]carbamate (38.3 mg, 47.5%) as a white solid by lyophilization.

[0691] Compound 57:

[0692] LC-MS: (ES+H, m / z): [M+H]+= 508.0.1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.50 (s, 2H), 8.08 (t, J = 8.3 Hz, 1H), 7.65-7.57 (m, 2H), 7.51-7.30 (m, 2H), 5.24-5.13 (m, 1H), 4.84-4.78 (m, 1H), 3.98-3.77 (m, 3H), 2.79-2.64 (m, 1H), 2.45-2.32 (m, 2H), 1.87-1.78 (m, 1H), 1.13 (d, J = 6.7 Hz, 3H).19F NMR (377 MHz, DMSO) δ -62.59, -120.79.

[0693] Compound 58:

[0694] LC-MS: (ES+H, m / z): [M+H]1= 508.0. ' H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 2H), 8.09 (t, J = 8.3 Hz, 1H), 7.65-7.58 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), 5.25-5.15 (m, 1H), 4.85-4.76 (m, 1H), 4.06-3.75 (m, 3H), 2.83-2.66 (m, 1H), 2.44-2.31 (m, 2H), 1.88-1.78 (m, 1H), 1.14 (d, J = 6.7 Hz, 3H).19F NMR (377 MHz, DMSO) δ -62.62, -120.86.

[0695] Example 19: Synthesis of (3S,5S)-5-{2-[(5-sulfamoylpyridin-3-yl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (Compound 132), (3S,5S)-5-{2-[(5- sulfamoylpyridin-3-yl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl] carbamate (Compound 133), and (3R,5R)-5-{2-[(5-sulfamoylpyridin-3-yl)aminoJpyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (Compound 134)

[0696] Step 1: Preparation of tert-butyl ((5-bromopyridin-3-yl)sulfonyl)carbamate:

[0697] A solution of 5-bromopyridine-3-sulfonamide (200 mg, 0.84 mmol, 1.00 equiv), di-tert-butyl dicarbonate (193.33 mg, 0.89 mmol, 1.05 equiv), DMAP (10.31 mg, 0.084 mmol, 0.10 equiv), Et3N (213.42 mg, 2.11 mmol, 2.5 equiv) in DCM (2 mL) = was stirred at room temperature for 1.5 h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA= (1: 1). The pure fraction was concentrated under reduced pressure to afford tert-butyl ((5-bromopyridin-3- yl)sulfonyl)carbamate (220 mg, 71.15%) as a white solid. LC-MS: (ES-H, m / z): [M-H+2]’ =337.0.1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.07 (d, J= 2.2 Hz, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.42 (t, J = 2.1 Hz, 1H), 1.32 (s, 9H). Step 2: Preparation of (3S,5S)-5-[2-({5-[(tert-butoxycarbonyl)aminosulfonyl]pyridin-3- y 1} amino) pyrimidin-5-yl] oxolan-3-yl N- [(2S)-butan-2-yl] carbamate:

[0698] A solution of tert-butyl ((5-bromopyridin-3-yl)sulfonyl)carbamate (31.86 mg, 0.09 mmol, 1.20 equiv), (3S,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (60 mg, 0.21 mmol, 1.00 equiv), EPhos Pd G4 (19.66 mg, 0.02 mmol, 0.10 equiv) and K2CO3(73.95 mg, 0.54 mmol, 2.50 equiv) in DMF (1 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 20% to 50% gradient in 20 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure to afford (3S,5S)-5-[2-({5-[(tert- butoxycarbonyl)aminosulfonyl]pyridin-3-yl}amino)pyrimidin-5-yl]oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (100 mg, 82.72%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=537.2.

[0699] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 10.35 (d, J= 2.0 Hz, 1H), 9.16 (t, J= 2.4 Hz, 1H), 8.79 (d, J= 2.8 Hz, 1H), 8.59 - 8.55 (m, 3H), 7.08 (d, J= 8.1 Hz, 1H), 5.19 (s, 1H), 4.83 (d, J= 9.6 Hz, 1H), 3.97 (dd, J= 10.7, 5.4 Hz, 1H), 3.86 - 3.80 (m, 1H), 3.39 (q, J= 6.9 Hz, 1H), 2.74 - 2.72 (m, 1H), 1.85 - 1.80 (m, 1H), 1.37 - 1.30 (m, 2H), 1.30 (s, 9H), 1.01 (t, J = 6.2 Hz, 3H), 0.80 - 0.76 (m, 3H).

[0700] Step 3: Preparation of (3S,5S)-5-{2-[(5-sulfamoylpyridin-3-yl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate:

[0701] A solution of (3S,5S)-5-[2-({5-[(tert-butoxycarbonyl)aminosulfonyl]pyridin-3- yl}amino)pyrimidin-5-yl]oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (100 mg, 0.19 mmol, 1.00 equiv) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 20% to 50% gradient in 15 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure and by lyophilization to afford (3S,5S)-5-{2-[(5-sulfamoylpyridin-3- yl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (55 mg, 67.28%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=437.1.1H NMR (400 MHz, DMSO-d6) δ 10.30-10.20 (m, 1H), 9.09-8.99 (m, 1H), 8.78-8.69 (m, 1H), 8.57 (s, 2H), 8.55 (d, J= 2.1 Hz, 1H), 7.60 (s, 2H), 7.14 - 7.02 (m, 1H), 5.28-5.15 (m, 1H), 4.90 - 4.78 (m, 1H), 4.06-3.87 (m, 1H), 3.87-3.77 (m, 1H), 3.44 - 3.35 (m, 1H), 2.80 - 2.67 (m, 1H), 1.85 - 1.79 (m, 1H), 1.44 - 1.29 (m, 2H), 1.02 (t, J = 6.2 Hz, 3H), 0.87 - 0.74 (m, 3H).

[0702] Step 4: Preparation of (3S,5S)-5-{2-[(5-sulfamoylpyridin-3-yl)amino]pyrimidin-5- yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate & (3R,5R)-5-{2-[(5-sulfamoylpyridin-3- yl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate:

[0703] The (3S,5S)-5-{2-[(5-sulfamoylpyridin-3-yl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2- yl]carbamate (50 mg) was purified by Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 25; Wave Length: 277 / 254 nm; RTl(min): 19.19; RT2(min): 24.93; Sample Solvent: ETOH: DCM=4: l(0.1%FA); Injection Volume: 1.2 mL; Number Of Runs: 7). The pure fraction was concentrated under reduced pressure and by lyophilization to afford (3S,5S)-5-{2-[(5-sulfamoylpyridin-3- yl)amino]pyrimidin-5-yl}oxolan-3-yl N-[(2S)-butan-2-yl]carbamate (9.8 mg, 19.46%) as a white solid and (3R,5R)-5-{2-[(5-sulfamoylpyridin-3-yl)amino]pyrimidin-5-yl}oxolan-3-yl N- [(2S)-butan-2-yl]carbamate (16.4 mg, 39.76 %) as a white solid.

[0704] Compound 133:

[0705] LC-MS: (ES+H, m / z): [M+H]+=437.1 .1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.08-8.99 (m, 1H), 8.78-8.69 (m, 1H), 8.61-8.47 (m, 3H), 7.60 (s, 2H), 7.10 (d, J= 8.4 Hz, 1H), 5.28-5.13 (m, 1H), 4.83 (t, J= 7.6 Hz, 1H), 4.01- 3.91 (m, 1H), 3.87-3.77 (m, 1H), 3.45-3.35 (m, 1H), 2.78 - 2.69 (m, 1H), 1.87 - 1.83 (m, 1H), 1.42 - 1.30 (m, 2H), 1.02 (d, J= 6.6 Hz, 2H), 0.78 (t, J= 7.4 Hz, 3H).

[0706] Compound 134:

[0707] LC-MS: (ES+H, m / z . [M+H]+=437.1.1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.04 (d, J= 2.5 Hz, 1H), 8.76-8.70 (m, 1H), 8.61 - 8.52 (m, 3H), 7.65-7.50 (m, 2H), 7.10 (d, J= 8.3 Hz, 1H), 5.27-2.15 (m, 1H), 4.83 (t, J = 7.6 Hz, 1H), 4.00-3.88 (m, 1H), 3.87-3.79 (m, 1H), 3.38 - 3.33 (m, 1H), 2.79 - 2.63 (m, 1H), 1.84 - 1.81 (m, 1H), 1.47 - 1.30 (m, 2H), 1.01 (d, J= 6.6 Hz, 2H), 0.82 (t, J= 7.4 Hz, 3H). Example 20: 5-(2-{[(1R,2R)-2-hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N- isopropylcarbamate (Compound 142), (3S,5S)-5-(2-{[(1R,2R)-2- hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (Compound 143), (3R,5R)-5-(2-{[(1R,2R)-2-hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N- isopropylcarbamate (Compound 144), (3R,5S)-5-(2-{[(lR,2R)-2- hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (Compound 145), and (3S,5R)-5-(2-{[(1R,2R)-2-hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N- isopropylcarbamates (Compound 146):

[0708] Step 1: Preparation of 5-(2-chloropyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate:

[0709] A solution of (3S,5S)-5-(2-aminopyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (400 mg, 1.502 mmol, 1 equiv) and ZnCh (409.40 mg, 3.004 mmol, 2 equiv) in concentrated HC1 (2 mL, 38%) was stirred at room temperature for 30 min under nitrogen atmosphere. To the above mixture was added Sodium nitrite (310.90 mg, 4.506 mmol, 3 equiv) in portions over 1 min at 0°C. The resulting mixture was stirred at room temperature for additional 2 h. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2CI2(3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (12: 1-10:1) to afford 5-(2- chloropyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (200 mg, 46.60%yield) as a brown solid.

[0710] LC-MS: (ES+H, m / z) [M+H]+= 286.0 Step 2; Preparation of 5-(2-{[(1R,2R)-2-hydroxycyclohexyl]amino}pyrimidin-5- yl)oxolan-3-yl N-isopropylcarbamate (Compound 142):

[0711] A solution of 5-(2-chloropyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (200 mg, 0.700 mmol, 1 equiv), (lR,2R)-2-aminocyclohexan-l-ol (96.74 mg, 0.840 mmol, 1.2 equiv), dicaesium(l+) carbonate (684.18 mg, 2.100 mmol, 3 equiv) and Pd-PEPPSI-IPentCl 2- methylpyridine (o-picoline) (58.81 mg, 0.070 mmol, 0.1 equiv) in 1,4-dioxane (4 mL) was stirred at 100°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4After fdtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep- HPLC with the following conditions (Column: YMC-Actus Triart C18 EXRS 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 23% B to 30% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.42). The pure fraction was concentrated under reduced pressure and lyophilization to afford 5-(2- {[(1R,2R)-2-hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (65 mg, 25.48%yield) as a white solid. LC-MS: (ES+H, m / z) [M+H]+= 365.2. NMR (400 MHz, DMSO-d6) δ 8.24 (s, 2H), 7.17 (d, J= 7.8 Hz, 1H), 6.86 (dd, J = 7.6, 1.7 Hz, 1H), 5.28-5.10 (m, 1H), 4.83-4.53 (m, 2H), 4.22-3.85 (m, 1H), 3.80-3.65 (m, 1H), 3.65-3.48 (m, 2H), 3.39-3.36 (m, 1H), 2.71-2.62 (m, 1H), 2.25-2.03 (m, 1H), 1.98-1.83 (m, 2H), 1.77-1.58 (m, 2H), 1.29-1.11 (m, 4H), 1.10-0.94 (m, 6H).

[0712] Step 3: Preparation of (3S,5S)-5-(2-{[(1R,2R)-2- hydroxycyclohexyl] amino} pyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (Compound 143), (3R,5R)-5-(2-{[(1R,2R)-2-hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N- isopropylcarbamate (Compound 144), (3R,5S)-5-(2-{[(1R,2R)-2- hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (Compound 145) , and (3S,5R)-5-(2-{[(1R,2R)-2-hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamates (Compound 146)

[0713] The 5-(2-{[(lA,2A)-2-hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N- isopropylcarbamate was purified by Chiral-HPLC with the following conditions (Column: CHIRALPAK IA, 3*25 cm, 5 μm; Mobile Phase A: MTBE: DCM=1 : l(10mMNH3), Mobile Phase B: MeOH— HPLC; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 240 / 250 nm; RTl(min): 8.6; RT2(min): 10.7; RT2(min): 13.2; Sample Solvent: MEOH: DCM=6: 1; Injection Volume: 1 mL; Number Of Runs: 6). The pure fraction was concentrated under reduced pressure and lyophilization to afford (3S,5S)-5-(2-{[(1R,2R)-2- hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (12.0 mg, 20.00% yield, 95.0% purity) as a white solid, (3R,5S)-5-(2-{[(1R,2R)-2- hydroxycyclohexyl]amino}pyrimidin-5-yl)oxolan-3-yl N-isopropylcarbamate (8.6 mg, 14.33%yield, 95.7%purity) as a white solid.

[0714] The resulting mixture was purified by Chiral-HPLC with the following conditions (Column: CHIRALPAK IE, 3*25 cm, 5 μm; Mobile Phase A: MTBE: DCM~ 1 : l(10mMNH3), Mobile Phase B: MeOH— HPLC; Flow rate: 40 mL / min; Gradient: isocratic 50; Wave Length: 240 / 250 nm; RTl(min): 11.2; RT2(min): 15.5; Sample Solvent: MeOH— HPLC; Injection Volume: 0.7 mL; Number Of Runs: 5). The pure fraction was concentrated under reduced pressure...

Claims

WHAT IS CLAIMED IS:

1. A compound of F ormula (A),or a pharmaceutically acceptable salt thereof, wherein:R1is -NRARB, -C(=O)NRARB, -OC(=O)NRARB, an optionally substituted 5-10 membered heteroaryl oxy, or an optionally substituted 5-10 membered heteroaryl; each RAand RBare independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;Ring A is a 4-8 membered heterocyclyl; each Rxis independently halogen, C1-C6 alkyl, or C1-C6 alkoxy; m is 0, 1, or 2;X1is N or CRX1;X2is N or CRX2;CRX1and CRX2are 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 -NRC-, *-C(=O)NRc(CRDRE)n-, *-NRcC(=O)(CRDRE)n-, or -O-, wherein * indicates the point of connection to the Xx-X2ring;Rcis hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each RDand REare independently hydrogen, fluoro, or C1-C6 alkyl; andR2is phenyl optionally substituted with 1-4 independently selected R3, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R3, C3-C10 cycloalkyl optionally substituted with 1-4 independently selected R3, or 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3; each R3is independently selected from halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -NR3AR3B, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 haloalkoxy, optionally substituted C3-C6 cycloalkyl, optionallysubstituted C3-C6 cycloalkoxy, -C(=O)NR3AR3B, -NR3AC(=O)R3B, -C(=O)R3C, -(SO2)NR3AR3B, - -(SO2)R3C, optionally substituted 5-9 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;R3Aand R3Bare independently selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;R3Cis optionally substituted alkyl, optionally substituted 5-9 membered heterocyclyl, optionally substituted C1-C6 alkoxy, or optionally substituted 5-10 membered heteroaryl.

2. The compound of Claim 1, wherein R1is -NRARB.

3. The compound of Claim 1, wherein R1is -C(=O)NRARB.

4. The compound of Claim 1, wherein R1is -OC(=O)NRARB.

5. The compound of any one of Claims 1-4, wherein RAand RBare each independently hydrogen, C1-C6 haloalkyl, unsubstituted C1-C6 alkyl, or unsubstituted C3-C10 cycloalkyl.

6. The compound of any one of Claims 1-5, wherein RAand RBare the same.

7. The compound of any one of Claims 1-6, wherein RAand RBare each hydrogen.

8. The compound of any one of Claims 1-6, wherein RAand RBare each unsubstitutedC1-C6 alkyl.

9. The compound of any one of Claims 1-5, wherein RAand RBare different.

10. The compound of any one of Claims 1-5 and 9, wherein one of RAand RBis hydrogen, and the other of RAand RBis substituted C1-C6 alkyl.

11. The compound of any one of Claims 1-5 and 9, wherein one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted C1-C6 alkyl.

12. The compound of any one of Claims 1-5 and 9, wherein one of RAand RBis hydrogen, and the other of RAand RBis C1-C6 haloalkyl.

13. The compound of any one of Claims 1-5 and 9, wherein one of RAand RBis hydrogen, and the other of RAand RBis C2-C4 haloalkyl.

14. The compound of any one of Claims 1-5 and 9, wherein one of RAand RBis hydrogen, and the other of RAand RBis unsubstituted C3-C10 cycloalkyl.

15. The compound of any one of Claims 1-5 and 9, wherein one of RAand RBis hydrogen, and the other of RAand RBis substituted C3-C10 cycloalkyl.

16. The compound of Claim 1, wherein R1is an optionally substituted 5-10 membered heteroaryloxy.

17. The compound of any one of Claims 1 and 16, wherein R1is a substituted 5-10 membered heteroaryloxy.

18. The compound of any one of Claims 1 and 16, wherein R1is an unsubstituted 5-10 membered heteroaryloxy.

19. The compound of any one of Claims 1 and 16-18, wherein the 5-10 membered heteroaryloxy of R1is a 5-6 membered heteroaryloxy.

20. The compound of any one of Claims 1 and 16-19, wherein the 5-10 membered heteroaryloxy of R1is isothiazolyloxy, pyridyloxy, or 1,3,4-triazolyloxy.

21. The compound of Claim 1, wherein R1is an optionally substituted 5-10 membered heteroaryl.

22. The compound of any one of Claims 1 and 21, wherein R1is an unsubstituted 5-10 membered heteroaryl.

23. The compound of any one of Claims 1 and 21, wherein R1is a substituted 5-10 membered heteroaryl.

24. The compound of any one of Claims 1-23, wherein R2is phenyl optionally substituted with 1-4 independently selected R3.

25. The compound of any one of Claims 1-24, wherein R2is phenyl substituted with 1- 4 independently selected R3.

26. The compound of any one of Claims 1-24, wherein R2is an unsubstituted phenyl.

27. The compound of any one of Claims 1-23, wherein R2is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R3.

28. The compound of any one of Claims 1-23 or 27, wherein R2is 5-10 membered heteroaryl substituted with 1-4 independently selected R3.

29. The compound of any one of Claims 1-23 or 27, wherein R2is an unsubstituted 5- 10 membered heteroaryl.

30. The compound of any one of Claims 1-23 or 27-28, wherein R2is 5-6 membered heteroaryl optionally substituted with 1-4 independently selected R3.

31. The compound of any one of Claims 1-23 or 27-28, wherein R2is 5 membered heteroaryl optionally substituted with 1-4 independently selected R3.

32. The compound of any one of Claims 1 -23 or 27, wherein R2is an unsubstituted 5 membered heteroaryl.

33. The compound of any one of Claims 1-23 or 27, wherein R2is a substituted 5 membered heteroaryl substituted with 1-4 independently selected R3.

34. The compound of any one of Claims 1-33, wherein the 5 membered heteroaryl of R2is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or 1,2,5-oxadiazolyl.

35. The compound of any one of Claims 1-23 or 27, wherein R2is 6 membered heteroaryl optionally substituted with 1-4 independently selected R3.

36. The compound of any one of Claims 1-23 or 35, wherein R2is an unsubstituted 6 membered heteroaryl.

37. The compound of any one of Claims 1-23 or 35, wherein R2is 6 membered heteroaryl substituted with 1-4 independently selected R3.

38. The compound of any one of Claims 1-23 or 35-37, wherein the 6 membered heteroaryl of R2is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

39. The compound of any one of Claims 1-23, wherein R2is 5-9 membered heterocyclyl optionally substituted with 1-4 independently selected R3.

40. The compound of any one of Claims 1-23 or 39, wherein R2is 5-9 membered heterocyclyl substituted with 1-4 independently selected R3.

41. The compound of any one of Claims 1-23 or 39, wherein R2is an unsubstituted 5- 9 membered heterocyclyl.

42. The compound of any one of Claims 1-23 or 39, wherein R2is 5-6 membered heterocyclyl optionally substituted with 1-4 independently selected R3.

43. The compound of any one of Claims 1-23 or 42, wherein R2is 5 membered heterocyclyl optionally substituted with 1-4 independently selected R3.

44. The compound of any one of Claims 1-23 or 42-43, wherein R2is an unsubstituted 5 membered heterocyclyl.

45. The compound of any one of Claims 1-23 or 42-44, wherein R2is 5 membered heterocyclyl substituted with 1-4 independently selected R3.

46. The compound of any one of Claims 1-23 or 42-45, wherein the 5 membered heterocyclyl of R2is seleted from the group consisting of pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl,pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydantionyl, thiohydantionyl, imidazolidinonyl, oxazolidinonyl, thiazolidinonyl, oxathiol anonyl, dioxolanonyl, dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanethionyl, oxazolidinethionyl, imidazolidinethionyl, and isothiazolidinonyl.

47. The compound of any one of Claims 1-23 or 42, wherein R2is 6 membered heterocyclyl optionally substituted with 1-4 independently selected R3.

48. The compound of any one of Claims 1-23 or 47, wherein R2is an unsubstituted 6 membered heterocyclyl.

49. The compound of any one of Claims 1-23 or 47, wherein R2is 6 membered heterocyclyl optionally substituted with 1-4 independently selected R3.

50. The compound of any one of Claims 1-23 or 47-49, wherein the 6 membered heterocyclyl of R2is selected from the group consisting of piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidindione, tetrahydropyridazinonyl, triazinanonyl, oxadiazinanonyl, di oxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl.

51. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with 1-3 independently selected R3selected from the group consisting of -SO2NH2, -F, cyano, -CFFOMe, -CO2NH2, methyl, -CH2OCF3, pyrazolyl optionally substituted with 1-2 methyl, pyrazolyl optionally substituted with 1-2 substituents selected from methyl and isopropoxymethyl, 1,2,4-triazolyl optionally substituted with 1-2 methyl, and tetrazolyl optionally substituted with 1-2 methyl.

52. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-51, wherein the R2group is substituted with 1-3 independently selected R3selected from the group consisting of -SO2NH2, -F, -CFFOMe, and -CO2NH2.

53. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one -(SO2)C3-C6 cycloalkyl.

54. The compound of any one of claims 1-25, 27-28, 29-31 , 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one -(SO2)NH-C3-C6 cycloalkyl optionally substituted with 1-3 substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, andC1-C6 haloalkyl.

55. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one -(SO2)NRHR1, wherein RHand R1are independently H and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

56. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, 49-50, or 54, wherein the R2group is substituted with one -(SO2)NRHRI, wherein one of RHand R1is H and the other is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

57. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, 49-50, or 54, wherein the R2group is substituted with one -(SO2)NRHRI, wherein one of RHand R1is H and the other is C1-C6 alkyl.

58. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, 49-50, or 54, wherein the R2group is substituted with one -(SO2)NRHRI, wherein one of RHand R1is H and the other is C1-C6 alkyl substituted with hydroxyl.

59. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one selected from the group consisting of60. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one -(C=O)C1-C6 alkyl or -(C=O)C3-C6 cycloalkyl.

61. The compound of any one of claims 1-25, 27-28, 29-31 , 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one -NH(SO2)C1-C3 alkyl.

62. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one -(S(=NRL)(=O))C1-C6 alkyl, wherein RLis H or C1-C6 alkyl optionally substituted with hydroxyl.

63. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one -(S(=NRL)(=O))C1-C3 haloalkyl, wherein RLis H or C1-C6 alkyl optionally substituted with hydroxyl.

64. The compound of any one of claims 1-25, 27-28, 29-31, 33-35, 37-40, 42-43, 45- 47, or 49-50, wherein the R2group is substituted with one -(S(=NRL)(=O))C3-C6 cycloalkyl.

65. The compound of any one of claims 51-64, wherein each H on the substituted R2group is independently deuterium.

66. The compound of any one of claims 1-65, wherein Ring A is a 4 membered heterocyclyl.

67. The compound of any one of claims 1-65, wherein Ring A is a 5-6 membered heterocyclyl.

68. The compound of any one of claims 1-65, wherein Ring A is 5 membered heterocyclyl.

69. The compound of any one of claims 1-65, wherein Ring A is 6 membered heterocyclyl.

70. The compound of any one of claims 1-65, wherein Ring A is a 7-8 membered heterocyclyl.

71. The compound of any one of Claims 1-70, wherein X1is CRX1.

72. The compound of any one of Claims 1-71, wherein X2is CRX2.

73. The compound of any one of Claims 1-72, wherein RX1is C1-C6 alkyl.

74. The compound of any one of Claims 1-73, wherein RX1is methyl.

75. The compound of any one of Claims 1-74, wherein RX1is C1-C6 alkoxy76. The compound of any one of Claims 1-72 or 75, wherein RX1is methoxy.

77. The compound of any one of Claims 1-72, wherein RX1is C1-C6 haloalkyl.

78. The compound of any one of Claims 1-72 or 77, wherein RX1is trifluoromethyl.

79. The compound of any one of Claims 1 -72, wherein RX1is C1-C6 haloalkoxy.

80. The compound of any one of Claims 1-72 or 79, wherein RX1is trifluoromethoxy.

81. The compound of any one of Claims 1-72, wherein RX1is C3-C6 cycloalkyl.

82. The compound of any one of Claims 1-72 or 81, wherein RX1is cyclopropyl.

83. The compound of any one of Claims 1-72, wherein RX1is C3-C6 cycloalkoxy.

84. The compound of any one of Claims 1-72 or 83, wherein RX1is cyclopropoxy.

85. The compound of any one of Claims 1-72, wherein RX1is cyano.

86. The compound of any one of Claims 1-72, wherein RX1is halogen.

87. The compound of any one of Claims 1-72, wherein RX1is hydrogen.

88. The compound of any one of Claims 1-87, wherein RX2is C1-C6 alkyl.

89. The compound of any one of Claims 1-88, wherein RX2is methyl.

90. The compound of any one of Claims 1-87, wherein RX2is C1-C6 alkoxy91. The compound of any one of Claims 1-87 or 90, wherein RX2is methoxy.

92. The compound of any one of Claims 1-87, wherein RX2is C1-C6 haloalkyl.

93. The compound of any one of Claims 1-87 or 92, wherein RX2is trifluoromethyl.

94. The compound of any one of Claims 1-87, wherein RX2is C1-C6 haloalkoxy.

95. The compound of any one of Claims 1-87 or 94, wherein RX2is trifluoromethoxy.

96. The compound of any one of Claims 1-87, wherein RX2is C3-C6 cycloalkyl.

97. The compound of any one of Claims 1-87 or 96, wherein RX2is cyclopropyl.

98. The compound of any one of Claims 1-87, wherein RX2is C3-C6 cycloalkoxy.

99. The compound of any one of Claims 1-87 or 98, wherein RX2is cyclopropoxy.

100. The compound of any one of Claims 1-87, wherein RX2is cyano.

101. The compound of any one of Claims 1-87, wherein RX2is halogen.

102. The compound of any one of Claims 1-87, wherein RX2is hydrogen.

103. The compound of any one of Claims 1-70 or 88-102, wherein X1is N.

104. The compound of any one of Claims 1-87 or 103, wherein X2is N.

105. The compound of any one of Claims 1-104, wherein Y is *-C(=O)NRc(CRDRE)n- , wherein * indicates the point of connection to the X1-X2ring.

106. The compound of any one of Claims 1-104, wherein Y is * NRcC(=O)(CRDRE)n , wherein * indicates the point of connection to the X1-X2ring.

107. The compound of any one of Claims 1-106, wherein n is 0.

108. The compound of any one of Claims 1 -106, wherein n is i .

109. The compound of any one of Claims 1-106, wherein n is 2.

110. The compound of any one of Claims 1-109, wherein each RDand REare the same.

111. The compound of any one of Claims 1-109, wherein each RDand REare the same except one of the RDand REis different.

112. The compound of any one of Claims 1-109, wherein each RDand REis hydrogen.

113. The compound of any one of Claims 1-109, wherein each RDand REis fluoro.

114. The compound of any one of Claims 1-109, wherein each RDand REis methyl.

115. The compound of any one of Claims 1-109, wherein one of RDand REis methyl or fluoro, and the remaining RDand REare hydrogen.

116. The compound of any one of Claims 1-104, wherein Y is -NRC-117. The compound of any one of Claims 1-116, wherein Rcis C1-C6 alkyl.

118. The compound of any one of Claims 1-117, wherein Rcis methyl.

119. The compound of any one of Claims 1-117, wherein Rcis hydrogen.

120. The compound of any one of Claims 1-104, wherein Y is -O-.

121. The compound of Claim 1, wherein the compound of Formula (A) is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

122. A pharmaceutical composition comprising a compound of any one of Claims 1- 121, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

123. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-121 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 122.

124. A method for treating a cancer in a subject in need thereof, comprising:(a) identifying the cancer as being a CDK2-associated cancer; and(b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-121 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 122.

125. The method of Claim 124, wherein the step of identifying the cancer in the subject as a CDK2-associated cancer includes performing an assay to detect dysregulation in a CDK2 gene, a CDK2 protein, or expression or activity or level of any of the same in a sample from thesubject.

126. The method of Claim 124, wherein the step of identifying the cancer in the subject as a CDK2-associated cancer includes performing an assay to detect dysregulation in a cyclin A2 gene, a cyclin A2 protein, or expression or activity or level of any of the same in a sample from the subject.

127. The method of Claim 124, wherein the step of identifying the cancer in the subject as a CDK2-associated cancer includes performing an assay to detect dysregulation in a cyclin E1 gene, a cyclin E1 protein, or expression or activity or level of any of the same in a sample from the subject.

128. The method of Claim 124, wherein the step of identifying the cancer in the subject as a CDK2-associated cancer includes performing an assay to detect dysregulation in a cyclin E2 gene, a cyclin E2 protein, or expression or activity or level of any of the same in a sample from the subject.

129. The method of any one of Claims 124-128, further comprising obtaining a sample from the subject.

130. The method of Claim 129, wherein the sample is a biopsy sample.

131. The method of any one of Claims 124-130 wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

132. The method of Claim 131, wherein the sequencing is pyrosequencing or next generation sequencing.

133. A method for treating a cancer in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-121 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 122; wherein the subject has been identified as having a CDK2-associated cancer.

134. A method of treating a CDK2-associated cancer, comprising administering a therapeutically effective amount of a compound of any one of Claims 1-121 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 122, to a subject identified or diagnosed as having a CDK2-associated cancer.

135. A method for treating cancer in a subject in need thereof, comprising:(a) determining that the cancer is associated with a dysregulation of a CDK2 gene, a CDK2protein, or expression or activity or level of any of the same; and(b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-121 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 122.

136. The method of Claim 135, wherein the step of determining that the cancer in the subject is a CDK2-associated cancer includes performing an assay to detect dysregulation in a CDK2 gene, a CDK2 protein, or expression or activity or level of any of the same in a sample from the subject.

137. The method of Claim 135, wherein the step of determining that the cancer in the subject is a CDK2-associated cancer includes performing an assay to detect dysregulation in a cyclin A2 gene, a cyclin A2 protein, or expression or activity or level of any of the same in a sample from the subject.

138. The method of Claim 135, wherein the step of determining that the cancer in the subject is a CDK2-associated cancer includes performing an assay to detect dysregulation in a cyclin E1 gene, a cyclin E1 protein, or expression or activity or level of any of the same in a sample from the subject.

139. The method of Claim 135, wherein the step of determining that the cancer in the subject is a CDK2-associated cancer includes performing an assay to detect dysregulation in a cyclin E2 gene, a cyclin E2 protein, or expression or activity or level of any of the same in a sample from the subject.

140. The method of any one of Claims 135-139, further comprising obtaining a sample from the subject.

141. The method of Claim 140, wherein the sample is a biopsy sample.

142. The method of any one of Claims 136-141, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

143. The method of Claim 142, wherein the sequencing is pyrosequencing or next generation sequencing.

144. A method for inhibiting metastasis in a subject having a cancer in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-121 or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of Claim 122.

145. The method of any one of Claims 123-144, further comprising administering an additional therapy or therapeutic agent to the subject.

146. The method of Claim 145, wherein the additional therapy or therapeutic agent is selected from EGFR inhibitors, HER2 inhibitors, MEK inhibitors, RAF inhibitors, KRAS inhibitors, cytotoxic chemotherapeutics, angiogenesis inhibitors, and radiotherapy.

147. The method of any one of Claims 123-146, 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 stomach cancer.

148. The method of any one of Claims 123-147, 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 stomach cancer.

149. The method of any one of Claims 123-148, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, and colorectal cancer.

150. The method of any one of Claims 123-149, wherein the cancer is selected from the group consisting of breast cancer and ovarian cancer.

151. The method of any one of Claims 123-150, wherein the cancer is breast cancer.

152. The method of any one of Claims 123-151, 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 88cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer.

153. The method of any one of Claims 123-152, wherein the cancer is breast cancer selected from the group consisting of endocrine resistant breast cancer, trastuzumab-resistant breast cancer, and breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition.

154. The method of any one of Claims 123-153, wherein the cancer is ovarian cancer.

155. The method of any one of Claims 123-154, wherein the cancer is colorectal cancer.

156. A method for inhibiting mammalian cell proliferation, comprising contacting the mammalian cell with a compound of any one of Claims 1-135, or a pharmaceutically acceptablesalt thereof.

157. A method for inhibiting CDK2 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of any one of Claims 1-121, or a pharmaceutically acceptable salt thereof.

158. The method of Claim 156 or 157, wherein the contacting occurs in vivo.

159. The method of Claim 156 or 157, wherein the contacting occurs in vitro.

160. The method of any one of Claims 156-159, wherein the mammalian cell is a mammalian cancer cell.

161. The method of any one of Claims 156160, wherein the mammalian cell has dysregulation of a CDK2 gene, a CDK2 protein, or expression or activity or level of any of the same.

162. The method of any one of Claims 156-161, wherein the mammalian cell has dysregulation of a cyclin A2 gene, a cyclin A2 protein, or expression or activity or level of any of the same in a sample from the subject.

163. The method of any one of Claims 156-162, wherein the mammalian cell has dysregulation of a cyclin E1 gene, a cyclin E1 protein, or expression or activity or level of any of the same.

164. The method of any one of Claims 156-163, wherein the mammalian cell has dysregulation of a cyclin E2 gene, a cyclin E2 protein, or expression or activity or level of any of the same.

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