CROSS-REFERENCE TO RELATED APPLICATIONS

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

TECHNICAL FIELD

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.

BACKGROUND

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.

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 El and Cyclin E2. Amplification or overexpression of cyclin El (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.

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 Sei. 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.

SUMMARY

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

R ¹ is -NR ^A R ^B , -C(=O)NR ^A R ^B , -OC(=O)NR ^A R ^B , an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each R ^A and R ^B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1-3 substituents independently selected from halogen, C ₁ -C ₆ alkyl, and C1-C6 alkoxy; -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; -(CH ₂ ) _a phenylene-(CH ₂ ) _b -; -(CH ₂ ) _a heteroarylene-(CH ₂ ) _b -; -(CH ₂ ) _a heterocyclylene-(CH ₂ ) _b -; and C2-C6 alkylene; a and b are independently 0, 1, or 2;

X ¹ is N or CR ^X1 ;

X ² is N or CR ^X2 ;

CR ^X1 and CR ^X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy;

Y is -NR ^C - *-C(=O)NR ^c (CR ^D R ^E ) _n - *-NR ^c C(=O)(CR ^D R ^E ) _n -, or -0- wherein * indicates the point of connection to the X ¹ -X ² ring;

R ^c is hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each R ^D and R ^E are independently hydrogen, fluoro, or C1-C6 alkyl; and

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

Some embodiments provide a compound of Formula (A- 1), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is -NR ^A R ^B , -C(=O)NR ^A R ^B , -OC(=O)NR ^A R ^B , or an optionally substituted 5-10 membered heteroaryl; each R ^A and R ^B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

X ¹ is N or CR ^X1 ;

X ² is N or CR ^X2 ;

CR ^X1 and CR ^X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C ₃ -C ₆ cycloalkyl, and C3-C6 cycloalkoxy;

Y is -NR ^C - *-C(=O)NR ^c (CR ^D R ^E ) _n - *-NR ^c C(=O)(CR ^D R ^E ) _n -, or -0- wherein * indicates the point of connection to the X ¹ -X ² ring;

R ^c is hydrogen or C1-C6 alkyl; m is 0, 1, or 2; n is 0, 1, or 2; each R ^D and R ^E are independently hydrogen, fluoro, or C1-C6 alkyl; and

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

DETAILED DESCRIPTION

Definitions

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.

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.

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.

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:

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.

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.

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.

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 (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), isopropylene (IUPAC: (methyl)ethylene) (-CH ₂ -CH(CH ₃ )-), and isobutylene (IUPAC: 2-(methyl)propylene) (-CH ₂ - CH(CH ₃ )-CH ₂ -). 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

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.

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.

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, trifluorom ethyl, 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, trichloropropyl, fluoropropyl, tri fluoropropyl.

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.

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 trihaloalkoxy). In some instances, a haloalkoxy can be -OR, wherein R is a Cl -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.

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.

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 an heteroatom independently selected from N, O, and S. Heteroaryl groups include rings where one or more groups are oxidized, such as a pyridone moiety. Nonlimiting examples of heteroaryl groups include pyridine, pyrimidine, pyrrole, imidazole, and indole.

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.

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 octahydropental en-2-yl.

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. In bicyclic ring systems, one ring can be aromatic. 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.

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

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

The term “nitro” refers to an -NO2 moiety.

The term “azido” refers to an -N3 moiety.

The term “isocyanate” group refers to a -NCO moiety. .

The term “thiocyanate” group refers to a -CNS moiety.

The term “isothiocyanate” group refers to an -NCS moiety.

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

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

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.

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.

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

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).

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).

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).

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).

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).

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).

The term “S-sulfonamido” group refers to a “-SO ₂ N(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.

The term “N-sulfonamido” group refers to a “RSO ₂ 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).

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).

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

The term “sulfonyl” group refers to an “SO ₂ R” group in which R can be the same as defined with respect to sulfenyl.

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.

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

The term “heterocyclyl(alkyl)” refers to a heterocyclyl group connected, as a substituent, via an alkylene group. The term “amino” refers to a -NH2 group.

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.

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.

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, 0- 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.

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). 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.

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 to ⁴ H, ² H, ³ H or mixtures thereof; when carbon is mentioned, it is understood to refer to ⁿ C, ¹² C, ¹³ C, ¹⁴ C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to ¹³ N, ¹⁴ N, ¹⁵ N or mixtures thereof; when oxygen is mentioned, it is understood to refer to ¹⁴ O, ¹⁵ O, ¹⁶ O, ¹⁷ O, ¹⁸ O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to ¹⁸ F, ¹⁹ F 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 ( ² H). 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.

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 3.

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.

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.

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.

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.

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.

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.

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). 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 El gene, a cyclin El 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 El (CCNE1), and/or cyclin E2 (CCNE2). In some embodiments, a CDK-associated cancer is characterized by amplification or overexpression of cyclin El (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 El (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.

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

An exemplary sequence of human Cyclin El is shown below:

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

An exemplary sequence of human Cyclin E2 is shown below:

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

An exemplary sequence of human Cyclin A2 is shown below:

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

Compounds of Formula (A)

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

R ¹ is -NR ^A R ^B , -C(=O)NR ^A R ^B , -OC(=O)NR ^A R ^B , an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each R ^A and R ^B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; or -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; a and b are independently 0, 1, or 2;

X ^I is N or CR ^X1 ;

X ² is N or CR ^X2 ;

CR ^X1 and CR ^X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy;

Y is -NR ^C - *-C(=O)NR ^c (CR ^D R ^E ) _n - *-NR ^c C(=O)(CR ^D R ^E ) _n -, or -O-, wherein * indicates the point of connection to the X ¹ -X ² ring;

R ^c is hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each R ^D and R ^E are independently hydrogen, fluoro, or C1-C6 alkyl; and

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

Provided herein are compounds of Formula (A-I), or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is -NR ^A R ^B , -C(=O)NR ^A R ^B , -OC(=O)NR ^A R ^B , or an optionally substituted 5-10 membered heteroaryl; each R ^A and R ^B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

X ¹ is N or CR ^X1 ;

X ² is N or CR ^X2 ; R ^X1 and R ^X2 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy;

Y is -NR ^C -, *-C(=O)NR ^c (CR ^D R ^E ) _n -, *-NR ^c C(=O)(CR ^D R ^E ) _n -, or -O-, wherein * indicates the point of connection to the X ² -X ² ring;

R ^c is hydrogen or C1-C6 alkyl; m is 0, 1, or 2; n is 0, 1, or 2; each R ^D and R ^E are independently hydrogen, fluoro, or C1-C6 alkyl; and

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

In some embodiments, R ¹ is -NR ^A R ^B

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

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

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

In some embodiments, R ^A and R ^B are the same. In some embodiments, R ^A and R ^B are each hydrogen.

In some embodiments, R ^A and R ^B are each unsubstituted C1-C6 alkyl. In some embodiments, R ^A and R ^B are each substituted C1-C6 alkyl.

In some embodiments, R ^A and R ^B are each unsubstituted C1-C6 haloalkyl. In some embodiments, R ^A and R ^B are each substituted C1-C6 haloalkyl.

In some embodiments, R ^A and R ^B are different.

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

In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is unsubstituted C1-C6 haloalkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is unsubstituted C1-C3 haloalkyl.

In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is substituted C1-C6 alkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is C1-C6 alkyl substituted with 1-5 halogen. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is C1-C4 alkyl substituted with 1-3 halogen.

In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is selected from the group consisting of

In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is substituted C1-C6 haloalkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is C1-C6 haloalkyl with 1-5 halogen. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is C1-C4 haloalkyl with 1-3 halogen.

In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is selected from the group consisting of:

In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is C3- C10 cycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is C3-C4 cycloalkyl optionally substituted with C1-C3 alkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is C3-C4 cycloalkyl substituted with C1-C3 alkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is

In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is unsubstituted C3-C10 cycloalkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is unsubstituted C3-C7 cycloalkyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, one of R ^A and R ^B is hydrogen, and the other of R ^A and R ^B is unsubstituted cyclopropyl.

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

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

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

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

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

In some embodiments, R ² is an optionally substituted 6 membered heteroaryl. In some embodiments, R ² is an unsubstituted 6 membered heteroaryl. In some embodiments, R ² is a substituted 6 membered heteroaryl. In some embodiments, the 6 membered heteroaryl of R ² is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

In some embodiments, R ² is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R ² is a substituted 9-10 membered heteroaryl. In some embodiments, R ² is an unsubstituted 9-10 membered heteroaryl. In some embodiments, the 9-10 membered heteroaryl of R ² is 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, R ² is an optionally substituted 5-9 membered heterocyclyl.

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

In some embodiments, R ² is an optionally substituted 5 membered heterocyclyl. In some embodiments, R ² is an unsubstituted 5 membered heterocyclyl. In some embodiments, R ² is a substituted 5 membered heterocyclyl. In some embodiments, the 5 membered heterocyclyl of R ² 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, R ² is an optionally substituted 6 membered heterocyclyl. In some embodiments, R ² is an unsubstituted 6 membered heterocyclyl. In some embodiments, R ² is a substituted 6 membered heterocyclyl. In some embodiments, the 6 membered heterocyclyl of R ² 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, oxadi azinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl. In some embodiments, R ² is piperidin- 4-yl.

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

In some embodiments, R ² is an optionally substituted phenyl. In some embodiments, R ² is an unsubstituted phenyl. In some embodiments, R ² is a substituted phenyl. In some embodiments, R ² is monosubstituted phenyl. In some embodiments, R ² is disubstituted phenyl.

In some embodiments, the R ² group is substituted with 1-3 substituents selected from the group consisting of -SO ₂ NH2, -F, cyano, -CFLOMe, -CO ₂ NH2, methyl, -CH ₂ OCF3, 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.

In some embodiments, the R ² group is substituted with an optionally substituted 5-10 membered heteroaryl. In some embodiments, the R ² group is substituted with an unsubstituted 5- 10 membered heteroaryl. In some embodiments, the R ² group is substituted with a substituted 5- 10 membered heteroaryl. In some embodiments, the R ² group 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.

In some embodiments, the R ² group is substituted with 1-3 substituents selected from the group consisting of -SO ₂ NH2, -F, -CFLOMe, and -CO ₂ NH2. In some embodiments, the R ² group is substituted with 1-3 substituents, where one is -(SO ₂ )NR’R”, wherein R’ and R” are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-9 membered heterocylyl, or optionally substituted 3-10 membered cycloalkyl.

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.

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.

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 ofR and R is unsubstituted Cl -C3 alkoxy.

In some embodiments, one of R and R is hydrogen, and the other of R and R is substituted Cl -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.

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. 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.

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 Cl -C 6 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.

In some embodiments, the R ² group is substituted with 1-3 substituents, where one is -(SO ₂ )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.

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.

In some embodiments, R’ is unsubstituted C1-C6 alkoxy. In some embodiments, R’ is unsubstituted C1-C3 alkoxy. In some embodiments, R’ is substituted C1-C6 alkoxy. In some embodiments, R’ is Cl- C6 alkoxy substituted with 1-5 halogen. In some embodiments, R’ is C1-C4 alkoxy substituted with 1-3 halogen.

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.

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.

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.

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.

In some embodiments, the R ² group is substituted with one -SO ₂ NH2 and one -F.

In some embodiments, the R ² group is substituted with one -SO ₂ NH2.

In some embodiments, the R ² group is substituted with one -(SCh)C3-C6 cycloalkyl. In v some embodiments, the R ² group is substituted with one .

In some embodiments, the R ² group is substituted with one -(SO ₂ )NHC3-C6 cycloalkyl

CF3. In some embodiments, the R ² group is substituted with one In some embodiments, the R ² group is substituted with one -(C=O)C1-C6 alkyl. In some embodiments, the R ² group is substituted with one -(C=O)CH ₃ .

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

In some embodiments, the R ² group is substituted with one -(C=0)NH2.

In some embodiments, the R ² group is substituted with one -NH(SO ₂ )C1-C6 alkyl. In some embodiments, the R ² group is substituted with one -NH(SO ₂ )C1-C3 alkyl. In some embodiments, the R group is substituted with one

In some embodiments, the R ² group is substituted with one -NH(SO ₂ )-optionally substituted C3-C8 cycloalkyl. In some embodiments, the R ² group is substituted with one - NH(SO ₂ )-optionally substituted C3-C6 cycloalkyl. In some embodiments, the R ² group is substituted with one -NH(SO ₂ )C3-C6 cycloalkyl. In some embodiments, the R ² group is substituted with one -NH(SO ₂ )-substituted C3-C6 cycloalkyl. In some embodiments, the R ² group is substituted with one -NH(SO ₂ )-halogen substituted C3-C6 cycloalkyl. In some embodiments, the R ² group is substituted with one -NH(SO ₂ )-fluoro-substituted C3-C6 cycloalkyl.

In some embodiments, the R ² group is substituted with one -(S(=NR ^L )(=O))C1-C6 alkyl, wherein R ^L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R ² group is substituted with one -(S(=NR ^L )(=O))C1-C3 alkyl, wherein R ^L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R ² group is substituted with one wherein R ^L is H or C1-C6 alkyl optionally substituted with hydroxyl.

In some embodiments, the R ² group is substituted with one -(S(=NR ^L )(=O))C1-C6 haloalkyl, wherein R ^L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R ² group is substituted with one -(S(=NR ^L )(=O))C1-C3 haloalkyl, wherein R ^L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R ² group is substituted with one wherein R ^L is H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, the R ² group is substituted with one -(S(=NR ^L )(=O))C3-C6 cycloalkyl. In some embodiments, the R ² group is substituted with one wherein R ^L is

H or C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R ^L is hydrogen. In some embodiments, R ^L is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments,

R ^L is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, R ^L is .

In some embodiments, R ^L is unsubstituted C1-C6 alkyl. In some embodiments, R ^L is methyl.

In some embodiments, the R ² group is substituted with one substituent selected from the group consisting of

In some embodiments, the R ² group is substituted with one -(SO ₂ )NR ^H R ^I , wherein R ^H and R ¹ are independently H and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, the R ² group is substituted with one -(SO ₂ )NR ^H R ^I , wherein one of R ^H and R ¹ is H and the other is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, the R ² group is substituted with one -(SO ₂ )NR ^H R ^I , wherein one of R ^H and R ¹ is H and the other is C1-C6 alkyl. In some embodiments, the R ² group is substituted with one - (SO ₂ )NR ^H R ^I , wherein one of R ^H and R ¹ is H and the other is C 1 -C6 alkyl substituted with hydroxyl.

In some embodiments, the R group is substituted with one i.e., R and R are each hydrogen.

In some embodiments, the R ² group is substituted with one selected from the group consisting of In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 2 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - substituted with 3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - substituted with 2 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - substituted with 1 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.

In some embodiments, X is unsubstituted -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b -.

In some embodiments, the -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - of X is -(CH ₂ ) _a C4-C6 cycloalkylene-(CH ₂ ) _b -.

In some embodiments, the -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - of X is cyclopentylene.

In some embodiments, X is -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl.

In some embodiments, X is -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 2 substituents independently selected from halogen and C1-C6 alkyl.

In some embodiments, X is -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 1 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, X is -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl.

In some embodiments, X is -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - substituted with 2 substituents independently selected from halogen and C1-C6 alkyl. In some embodiments, X is -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - substituted with 1 substituents independently selected from halogen and C1-C6 alkyl.

In some embodiments, X is unsubstituted -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b -.

In some embodiments, X is -(CH ₂ ) _a phenylene-(CH ₂ ) _b -.

In some embodiments, X is -(CH ₂ ) _a (4-8 membered heteroarylene)-(CH ₂ ) _b - In some embodiments, X is -(CH ₂ ) _a (4-8 membered heterocyclylene)-(CH ₂ ) _b -

In some embodiments, X is C2-C6 alkylene.

In some embodiments, X is C2-C4 alkylene.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, X is .A

In some embodiments, In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, when the ring member of the cycloalkylene of -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _a is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when the ring member of the cycloalkylene of -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _a is a stereocenter, the stereochemical configuration of the stereocenter is (S).

In some embodiments, when the ring member of the cycloalkylene of -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _b is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when the ring member of the cycloalkylene of -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _b is a stereocenter, the stereochemical configuration of the stereocenter is (S).

In some embodiments, when the ring member of the cycloalkenylene of -(CH ₂ ) _a C3-C8 cycloalkenylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _a is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when the ring member of the cycloalkenylene of -(CH ₂ ) _a C3-C8 cycloalkenylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _a is a stereocenter, the stereochemical configuration of the stereocenter is (S).

In some embodiments, when the ring member of the cycloalkenylene of -(CH ₂ ) _a C3-C8 cycloalkenylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _b is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when the ring member of the cycloalkenylene of -(CH ₂ ) _a C3-C8 cycloalkenylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _b is a stereocenter, the stereochemical configuration of the stereocenter is (S).

In some embodiments, when the ring member of the heterocyclylene of -(CH ₂ ) _a C3-C8 heterocyclylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _b is a stereocenter, the stereochemical configuration of the stereocenter is (R). In some embodiments, when the ring member of the heterocyclylene of -(CH ₂ ) _a C3-C8 heterocyclylene-(CH ₂ ) _b - that is connected to (CH ₂ ) _b is a stereocenter, the stereochemical configuration of the stereocenter is (S).

In some embodiments, a is 0 or 1. In some embodiments, a is 1 or 2. In some embodiments, a is 0 or 2. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, a is 2.

In some embodiments, b is 0 or 1. In some embodiments, b is 1 or 2. In some embodiments, b is 0 or 2. In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2.

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

In some embodiments, X ¹ is CR ^X1 .

In some embodiments, X ² is CR ^X2 . In some embodiments, R ^X1 is C1-C6 alkyl. In some embodiments, R ^X1 is methyl. In some embodiments, R ^X1 is C1-C6 alkoxy. In some embodiments, R ^X1 is methoxy. In some embodiments, R ^X1 is C1-C6 haloalkyl. In some embodiments, R ^X1 is trifluoromethyl. In some embodiments, R ^X1 is C1-C6 haloalkoxy. In some embodiments, wherein R ^X1 is trifluoromethoxy.

In some embodiments, R ^X1 is C3-C6 cycloalkyl. In some embodiments, R ^X1 is cyclopropyl. In some embodiments, R ^X1 is C3-C6 cycloalkoxy. In some embodiments, R ^X1 is cyclopropoxy. In some embodiments, R ^X1 is cyano. In some embodiments, R ^X1 is halogen. In some embodiments, R ^X1 is hydrogen.

In some embodiments, R ^X2 is C1-C6 alkyl. In some embodiments, R ^X2 is methyl. In some embodiments, R ^X2 is C1-C6 alkoxy. In some embodiments, R ^X2 is methoxy. In some embodiments, R ^X2 is C1-C6 haloalkyl. In some embodiments, R ^X2 is trifluoromethyl. In some embodiments, R ^X2 is C1-C6 haloalkoxy. In some embodiments, R ^X2 is trifluoromethoxy. In some embodiments, R ^X2 is C3-C6 cycloalkyl. In some embodiments, R ^X2 is cyclopropyl. In some embodiments, R ^X2 is C3-C6 cycloalkoxy. In some embodiments, R ^X2 is cyclopropoxy. In some embodiments, R ^X2 is cyano. In some embodiments, R ^X2 is halogen. In some embodiments, R ^X2 is hydrogen.

In some embodiments, X ¹ is N.

In some embodiments, X ² is N. In some embodiments, X ¹ is N and X ² is N.

In some embodiments, Y is *-C(=O)NR ^c (CR ^D R ^E ) _n - wherein * indicates the point of connection to the X'-X ² ring.

In some embodiments, Y is *-NR ^c C(=O)(CR ^D R ^E ) _n -, wherein * indicates the point of connection to the X'-X ² ring.

In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, each R ^D and R ^E are the same. In some embodiments, each R ^D and R ^E are the same except one of the R ^D and R ^E is different.

In some embodiments, each R ^D and R ^E is hydrogen.

In some embodiments, each R ^D and R ^E is fluoro.

In some embodiments, R ^D and R ^E is methyl.

In some embodiments, one of R ^D and R ^E is methyl or fluoro, and the remaining R ^D and R ^E are hydrogen.

In some embodiments, Y is -NR ^C -

In some embodiments, R ^c is C1-C6 alkyl.

In some embodiments, R ^c is methyl.

In some embodiments, R ^c is hydrogen.

In some embodiments, Y is -O-.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, m is 2.

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

In some embodiments, R ² is an optionally substituted 5 membered heteroaryl.

In some embodiments, R ² is an unsubstituted 5 membered heteroaryl.

In some embodiments, R ² is a substituted 5 membered heteroaryl.

In some embodiments, the 5 membered heteroaryl of R ² is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or 1,2,5-oxadiazolyl.

In some embodiments, R ² is an optionally substituted 6 membered heteroaryl.

In some embodiments, R ² is an unsubstituted 6 membered heteroaryl.

In some embodiments, R ² is a substituted 6 membered heteroaryl. In some embodiments, the 6 membered heteroaryl of R ² is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

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

In some embodiments, R ² is an optionally substituted 5 membered heterocyclyl.

In some embodiments, R ² is an unsubstituted 5 membered heterocyclyl.

In some embodiments, R ² is a substituted 5 membered heterocyclyl.

In some embodiments, the 5 membered heterocyclyl of R ² is 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.

In some embodiments, R ² is an optionally substituted 6 membered heterocyclyl.

In some embodiments, R ² is an unsubstituted 6 membered heterocyclyl.

In some embodiments, R ² is a substituted 6 membered heterocyclyl.

In some embodiments, the 6 membered heterocyclyl of R ² 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, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, and triazinanedionyl..

In some embodiments, R ² is an optionally substituted phenyl.

In some embodiments, R ² is an unsubstituted phenyl.

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

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.

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.

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

R ¹ is -NR ^A R ^B , -C(=O)NR ^A R ^B , -OC(=O)NR ^A R ^B , an optionally substituted 5-10 membered heteroaryloxy, or an optionally substituted 5-10 membered heteroaryl; each R ^A and R ^B are independently hydrogen, C1-C6 haloalkyl, optionally substituted Cl- C6 alkyl, or optionally substituted C3-C10 cycloalkyl;

X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; -(CH ₂ ) _a phenylene-(CH ₂ ) _b -; -(CH ₂ ) _a heteroarylene-(CH ₂ ) _b -; - (CH ₂ ) _a heterocyclylene-(CH ₂ ) _b -; and C2-C6 alkylene; a and b are independently 0, 1, or 2; ring A is an optionally substituted 6-membered heteroaryl other than pyridinyl and pyrimidinyl, or an optionally substituted 9-10 membered heteroaryl;

Y is -NR ^C - *-C(=O)NR ^c (CR ^D R ^E ) _n -, *-NR ^c C(=O)(CR ^D R ^E ) _n -, or -O-, wherein * indicates the point of connection to ring A;

R ^c is hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each R ^D and R ^E are independently hydrogen, fluoro, or C1-C6 alkyl; and R ² is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl.

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

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

In some embodiments, ring A is an optionally substituted 9-10 membered heteroaryl. In some embodiments, ring A is a substituted 9-10 membered heteroaryl. In some embodiments, ring A is an unsubstituted 9-10 membered heteroaryl. In some embodiments, the 9-10 membered heteroaryl is pyrido[2,3-d]pyrimidine, quinazoline, cinnoline, isoquinolin- l(2Z7)-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.

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

R ¹ is -NR ^A R ^B , -C(=O)NR ^A R ^B , -OC(=O)NR ^A R ^B , or an optionally substituted 5-10 membered heteroaryl; each R ^A and R ^B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; -(CH ₂ ) _a phenylene-(CH ₂ ) _b -; -(CH ₂ ) _a heteroarylene-(CH ₂ ) _b -; - (CH ₂ ) _a heterocyclylene-(CH ₂ ) _b -; and C2-C6 alkylene; a and b are independently 0, 1, or 2;

Y is -NR ^C -, *-C(=O)NR ^c (CR ^D R ^E ) _n - *-NR ^c C(=O)(CR ^D R ^E ) _n or -O-, wherein * indicates the point of connection to the pyrazinyl ring;

R ^c is hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each R ^D and R ^E are independently hydrogen, fluoro, or C1-C6 alkyl; and

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

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:

R ¹ is -NR ^A R ^B , -C(=O)NR ^A R ^B , -OC(=O)NR ^A R ^B , or an optionally substituted 5-10 membered heteroaryl; each R ^A and R ^B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; -(CH ₂ ) _a phenylene-(CH ₂ ) _b -; -(CH ₂ ) _a heteroarylene-(CH ₂ ) _b -; - (CH ₂ ) _a heterocyclylene-(CH ₂ ) _b -; and C2-C6 alkylene; a and b are independently 0, 1, or 2; Y is -NR ^C - *-C(=O)NR ^c (CR ^D R ^E ) _n - *-NR ^c C(=O)(CR ^D R ^E ) _n or -0- wherein * indicates the point of connection to the pyrazinonyl ring;

R ^c is hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each R ^D and R ^E are independently hydrogen, fluoro, or C1-C6 alkyl; and

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

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

R ¹ is -NR ^A R ^B , -C(=O)NR ^A R ^B , -OC(=O)NR ^A R ^B , or an optionally substituted 5-10 membered heteroaryl; each R ^A and R ^B are independently hydrogen, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl;

X is -(CH ₂ ) _a C3-C8 cycloalkylene-(CH ₂ ) _b - optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; -(CH ₂ ) _a C5-C8 cycloalkenylene-(CH ₂ ) _b - optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl; -(CH ₂ ) _a phenylene-(CH ₂ ) _b -; -(CH ₂ ) _a heteroarylene-(CH ₂ ) _b -; - (CH ₂ ) _a heterocyclylene-(CH ₂ ) _b -; and C2-C6 alkylene; a and b are independently 0, 1, or 2;

Y is -NR ^C -, *-C(=O)NR ^c (CR ^D R ^E ) _n -, *-NR ^c C(=O)(CR ^D R ^E ) _n -, or -O-, wherein * indicates the point of connection to the pyrrolo[l,2-a]pyrazine ring;

R ^c is hydrogen or C1-C6 alkyl; n is 0, 1, or 2; each R ^D and R ^E are independently hydrogen, fluoro, or C1-C6 alkyl; and

R ² is optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 5-6 membered heterocyclyl. In some embodiments, the compound of Formula (A) is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

Table 1 : Exemplary Compounds of Formula (A)

Methods of Treatment 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.

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 El gene, a cyclin El 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 El gene, a cyclin El 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 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).

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).

In some embodiments, the subj ect has a tumor that is positive for a dysregulation of a cyclin El gene, a cyclin El 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 El gene, a cyclin El 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 El gene, a cyclin El 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).

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).

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 El gene, a cyclin El 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 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.

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

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 El gene, a cyclin El 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 El gene, a cyclin El 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 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 El gene, a cyclin El 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 El gene, a cyclin El 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 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.

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.

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. 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).

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

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.

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.

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

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

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

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

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

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.

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.

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.

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.

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.

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.

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).

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.

In some embodiments, the subject is a human.

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.

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.

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 El, 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).

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.

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.

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 IC ₅₀ value at least about 10-fold, about 25-fold, about 50-fold, about 100-fold, about 200-fold, about 300- fold, about 400-fold, about 500-fold, about 750-fold, about 1,000-fold, about 1,500-fold, or about 2,000-fold less than the IC ₅₀ value 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. 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 IC ₅₀ molar 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 IC ₅₀ molar 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 IC ₅₀ value 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 IC ₅₀ value 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 IC ₅₀ value 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 IC ₅₀ value 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 IC ₅₀ value 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 IC ₅₀ value 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 IC ₅₀ value 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 IC ₅₀ value 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 IC ₅₀ value 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 IC ₅₀ value 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.

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 El gene, a cyclin El 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.

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.

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 El gene, a cyclin El 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

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.

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 El gene, a cyclin El 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 El gene, a cyclin El 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.

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 El gene, a cyclin El protein, a cyclin E2 gene, a cyclin E2 protein, or expression or activity or level of any of the same (or any combination thereof).

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.

In some embodiments, an assay used to determine whether the subject has a dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin El, 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 El, and/or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin El, 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).

In some embodiments, dysregulation of a gene (e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin El, 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 El, and/or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin El, 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 El, and/or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin El, 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 El, and/or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin El, 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 El, and/or cyclin E2 gene), or a protein (e.g., a CDK2, cyclin A2, cyclin El, 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.

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.

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.

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.

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).

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.

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.

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).

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

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-lH-pyrazol-4-yl)-6-oxo-lH-pyrrolo[4,3,2- ef][2,3]benzodiazepin-8-yl]- cyclohexaneacetamide), PLX8394 ((3R)-N-[3-[5-(2-cyclopropylpyrimidin-5-yl)-lH-pyrrolo[2,3- b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidi ne-l-sulfonamide), PRN1371 (8-(3- (4-acryloylpiperazin-l-yl)propyl)-6-(2,6-dichloro-3,5-dimeth oxyphenyl)-2- (methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one), TG101209 (N-t-butyl-3-(5-methyl-2-(4-(4- methylpiperazin-l-yl)phenylamino)pyrimidin-4-ylamino) _b enzenesulfonamide), NMS- 1286937, NMS-088, INCB52793, PLX7486, PLX9486, and INCB40093.

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.

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 antiangiogenesis agents include enzastaurin, midostaurin, perifosine, teprenone (Selbex) and UCN 01, lenalidomide (Revlimid), pomalidomide (Pomalyst), squalamine (Evizon), and thalidomide (Thalomid).

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. 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.

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.

Methods of Inhibiting

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.

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.

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. 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.

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.

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.

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.

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. 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.

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.

Pharmaceutical Compositions and Kits

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.

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.

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.

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.

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.

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.

EXAMPLES

Preparation of Compounds

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.

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.

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

Step 1: Synthesis of 4-[(tert-biilyldimelhylsilyl)oxy|cyclohex-l-en-l-yl trifluoromethanesulfonate

To a stirred solution of 4-[(tert-butyldimethylsilyl)oxy]cyclohexan-l-one (2 g, 8.75 mmol, 1.00 equiv.) and LiHMDS (2 M in THF) (19.90 mL, 17.51 mmol, 2.00 equiv.) in THF (100 mL) was added l,l,l-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethane sulfonamide (6.3 g, 17.51 mmol, 2.00 equiv.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. 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 50 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4- [(tert-butyldimethylsilyl)oxy]cyclohex-l-en-l-yl trifluoromethanesulfonate as ayellow solid. The crude product was used in next step directly without further purification.

Step 2: Synthesis of 5-{4-[(tert-butyldimethylsilyl)oxy]cyclohex-l-en-l-yl}pyrimi din-2-amine

To a stirred solution of 4-[(tert-butyldimethylsilyl)oxy]cyclohex-l-en-l-yl trifluoromethanesulfonate (5 g, 13.87 mmol, 1.00 equiv.) and 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidin-2-amine (4.60 g, 20.80 mmol, 1.50 equiv.) in l,4-dioxane/H ₂ O = (4: 1) (20 mL) were added Pd(dppf)C12.CH ₂ C12 (2.26 g, 2.77 mmol, 0.2 equiv.) and K ₂ CO ₃ (5.75 g, 41.61 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (8: 1 to 6:1) to afford 5-{4-[(tert- butyldimethylsilyl)oxy]cyclohex-l-en-l-yl}pyrimidin-2-amine (1.6 g, 38 % over two steps) as a yellow solid. LC-MS: (ES+H, m/z) 306.1 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.22 (s, 2H), 6.52 (s, 2H), 5.83 (dd, J= 4.7, 2.8 Hz, 1H), 3.90 - 3.82 (m, 1H), 2.36 - 2.25 (m, 3H), 2.01 - 1.91 (m, 1H), 1.78 (d, J= 12.0 Hz, 1H), 1.55 - 1.30 (m, 1H), 0.80 (s, 9H).

Step 3: Synthesis of 5-((l s.4s)-4-((tert-butyldiinelhylsilyl)oxy)cyclohexyl)pyriniidin -2-amine

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

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

To a stirred solution of 5-[(1s,4s)-4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimi din-2- amine (200 mg, 0.65 mmol, 1.00 equiv.) and tert-butyl N-(4-bromo-3- fluorobenzenesulfonyl)carbamate (345.5 mg, 0.97 mmol, 1.50 equiv.) in t-BuOH (2 mL) were added EPhos Pd G4 (59.7 mg, 0.06 mmol, 0.10 equiv.) and K ₂ CO ₃ (269.6 mg, 1.95 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. 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 (3 x 5 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1 to 3: 1) to afford tert-butyl N-[3-fluoro-4-([5-[( 1s,4.s)- 4-[(tert-butyldimethylsilyl)oxy]cyclohexyl]pyrimidin-2-yl}am ino) _b enzenesulfonyl]carbamate (150 mg, 40 %) as a white solid. LC-MS: (ES+H, m/z) 581.3 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.75 (s, 1H), 9.44 (s, 1H), 8.35 (s, 1H), 8.32 - 8.26 (m, 1H), 7.95 (dd, J= 8.4, 6.8 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.61 - 7.55 (m, 2H), 4.01 - 3.95 (m, 2H), 1.93 (s, 2H), 1.63 - 1.51 (m, 5H), 1.26 (s, 4H), 1.24 (d, J= 22 Hz, 9H), 1.11 (t, J= 7.1 Hz, 2H), 0.84 (s, 9H).

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

A solution of tert-butyl N-[3-fluoro-4-({ 5-[( l.s,4.s)-4-[(tert- butyldimethylsilyl)oxy]cyclohexyl]pyrimidin-2-yl}amino) _b enzenesulfonyl]carbamate (150 mg, 0.25 mmol, 1.00 equiv.) in TBAF (4 mL) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. 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 (3 x 10 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (5: 1 to 2:1) to afford tert-butyl N-[3-fluoro-4-([5-[( l.s,4.s')-4-hydroxycyclohexyl]pyrimidin-2- yl}amino) _b enzenesulfonyl]carbamate (70 mg, 58 %) as a yellow solid. LC-MS: (ES+H, m/z) 467.1 [M+H] ⁺ ; ¹ HNMR (300 MHz, DMSO-d ₆ ) δ 11.62 (s, 1H), 9.47 (s, 1H), 8.43 (d, J= 15.8 Hz, 2H), 8.33 (d, J= 8.2 Hz, 1H), 7.66 - 7.57 (m, 2H), 4.38 (d, J= 3.7 Hz, 1H), 3.89 (s, 1H), 2.69 (s, 1H), 1.84 - 1.70 (m, 4H), 1.53 (d, J= 12.1 Hz, 4H), 1.32 (s, 9H).

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

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

Step 7: Synthesis of tert-butyl N-[3-fluoro-4-({5-[(1s,4s)-4-

[(propylcarbamoyl)oxy]cyclohexyl]pyrimidin-2-yl}amino)ben zenesulfonyl]carbamate

To a solution of (1s,4s)-4-[2-({4-[(tert-butoxycarbonyl)aminosulfonyl]-2- fluorophenyl}amino)pyrimidin-5-yl]cyclohexyl imidazole- 1 -carboxylate (112 mg, 0,20 mmol, 1.00 equiv.) in DCM (4 mL) were added propylamine (47.24 mg, 0.80 mmol, 4.00 equiv.) and DIEA (77.47 mg, 0.60 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 40 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase combi-flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (10 mmol/L NH ₄ HCO ₃ ), 30% to 50% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure to afford tert-butyl N-[3-fhioro-4-({5-[(1s,4s)-4- [(propylcarbamoyl)oxy]cyclohexyl]pyrimidin-2-yl}amino) _b enzenesulfonyl]carbamate (38 mg, 36 %) as a light yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.68 (s, 1H), 9.47 (s, 1H), 8.45 (d, J= 8.3 Hz, 2H), 8.29 (t, 7= 8.3 Hz, 1H), 7.70 - 7.57 (m, 2H), 7.06 (s, 1H), 4.81 - 4.80 (s, 1H), 2.95 (q, J= 6.6 Hz, 2H), 2.60 - 2.57 (m, 1H), 1.88 (d, J= 12.5 Hz, 2H), 1.62 - 1.58 (m, 6H), 1.43 (q, J= 7.3 Hz, 2H), 1.32 (s, 9H), 0.85 (t, J= 7.4 Hz, 3H).

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

To a solution of tert-butyl N-[3-fluoro-4-({5-[(lx,4x)-4- [(propylcarbamoyl)oxy]cyclohexyl]pyrimidin-2-yl}amino) _b enzenesulfonyl]carbamate (38 mg, 0.07 mmol, 1.00 equiv.) in HCOOH (2 mL) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3h at room temperature 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 dissolved in MeOH (3 mL) and neutralized to pH = 7 with NH3 H ₂ O. The mixture was purified by reversed- phase combi-flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water (10 mmol/L NH ₄ HCO ₃ ), 40% to 50% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure and lyophilized to afford (1s,4s)-4-{2- [(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclohexyl ZV-propylcarbamate (Compound 1, 19.4 mg, 62 %) as a white solid. LC-MS: (ES+H, m/z) 452.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.42 (s, 2H), 8.15 (t, J= 8.1 Hz, 1H), 7.61 - 7.58 (m, 2H), 7.35 (s, 2H), 7.03 - 7.01 (m, 1H), 4.80 - 4.78 (s, 1H), 2.99 - 2.91 (m, 2H), 2.57 - 2.52 (m, 1H), 1.85 (d, J= 13.0 Hz, 2H), 1.74 - 1.61 (m, 6H), 1.42 (q, J= 7.4 Hz, 2H), 0.84 (t, J= 7.5 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -121.81.

Example 2: Synthesis of (1RS,3SR)-3-(2-(imidazo| 1.2-/)|pyi idazin-6-ylainino)pyriinidin-5- yl)cyclopentyl ((ȣ)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 40)

Compound 40

Step 1: Synthesis of cyclopent-2-en-l-ol

To a solution of cyclopent-2-en-l-one (10 g, 121.80 mmol, 10.20 mL), tri chlorocerium (47.70 g, 193.53 mmol) in MeOH (80 mL) was added NaBH ₄ (5.10 g, 134.81 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min, and the reaction was allowed to warm to 20 °C for an additional 30 min. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (4.5 g, crude) as a white solid that required no further purification. ¹ HNMR (400 MHz, CDC1 ₃ ) δ 6.03 - 5.95 (m, 1H), 5.88 - 5.78 (m, 1H), 4.91 - 4.78 (m, 1H), 2.59 - 2.39 (m, 1H), 2.32 - 2.16 (m, 2H), 1.96 (s, 1H) 1.69 - 1.60 (m, 1H).

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

To a solution of tert-butyl N-(5-bromopyrimidin-2-yl)- N-tert-butoxycarbonyl-carbamate (2 g, 2.67 mmol) and cyclopent-2-en-l-ol (900 mg, 5.34 mmol) in DMF (40 mL) was added tetrabutylammonium chloride (743 mg, 2.67 mmol), Pd(OAc)2 (60 mg, 0.27 mmol) and KOAc (1.57 g, 8.02 mmol). The reaction mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction mixture was diluted with EtOAc (150 mL) and water (50 mL). The organic layer was washed with brine (30 mL x 5), dried over anhydrous Na ₂ SO ₄ , 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 (0.52 g, 23%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H), 8.58 (s, 2H), 3.38 - 3.35 (m, 1H), 2.61 - 2.50 (m, 1H), 2.41 - 2.22 (m, 4H), 1.96 - 1.87 (m, 1H), 1.45 (s, 9H).

Step 3: Synthesis of tert-butyl N-tert-butoxycarbonyl-/N-[5-(3-hydroxycyclopentyl)pyriniidin - 2-yl] carbamate To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-oxocyclopentyl)pyrimidin-2- yl]carbamate (12 g, 31.79 mmol) in THF (30 mL) was added LiBHEt ₃ (1 M, 51 mL) at -65 °C. The reaction mixture was stirred at -65 °C for 1 h. After the reaction was completed, the mixture was quenched by addition sat. aq. NaHCO ₃ (40 mL) at -65 °C, then the reaction was warmed up to room temperature, diluted with EtOAc (150 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , 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 (8 g, 66%) as yellow oil. LCMS (ESI) m/z: 380.2 [M+H] ⁺ .

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

To a solution of tert-butyl N-tertebutoxycarbonyl-N-[5-(3-hydroxycyclopentyl)pyrimidin-2 - yl]carbamate (9 g, 23.72 mmol) in DCM (50 mL) was added DMAP (580 mg, 4.74 mmol), pyridine (5.63 g, 71.16 mmol, 5.74 mL) and (4-nitrophenyl) carbonochloridate (7.17 g, 35.58 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition water (50 mL) at 0 °C, and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give rac -tert-butyl (tert-butoxycarbonyl)(5-((1R,3S )-3-(((4- nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbama te (cis isomers, absolute configuration arbitrarily assigned, 3.5 g, 27%) as a white solid. LCMS (ESI) m/z: 545.2 [M+H] ⁺ ; ¹ HNMR (400 MHz, CDC1 ₃ ) δ 8.71 (s, 2H), 8.30 (d, J= 9.2 Hz, 2H), 7.41 (d, J= 9.2 Hz, 2H), 5.40 - 5.34 (m, 1H), 3.17 - 3.32 (m, 1H), 2.80 - 2.68 (m, 1H), 2.33 - 2.18 (m, 2H), 2.16 - 2.04 (m, 1H), 2.01 - 1.87 (m, 2H), 1.49 (s, 18H). And rac-tert-butyl (tert-butoxycarbonyl)(5-((1R ,3R )-3-(((4- nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbama te (trans isomers not shown, absolute configuration arbitrarily assigned, 1.5 g, 12%) was obtained as a white solid. ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.66 (s, 2H), 8.30 (d, J= 9.2 Hz, 2H), 7.41 (d, J = 9.2 Hz, 2H), 5.40 - 5.34 (m, 1H), 3.51 - 3.37 (m, 1H), 2.58 - 2.31 (m, 3H), 2.12 - 1.98 (m, 2H), 2.81 - 1.70 (m, 1H), 1.49 (s, 18H).

Step 5: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((1RS,3SR)-3-((((A)-4,4,4- trifluorobutan-2-yl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl )carbamate To a solution of rac -tert-butyl (tert-butoxycarbonyl)(5-((1R,3S )-3-(('(4- nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbama te (2 g, 3.7 mmol) in dioxane (20 mL) was added DIEA (3.8 mL, 22.0 mmol) and (2S)-4,4,4-trifluorobutan-2-amine (1 g, 6.1 mmol, HC1 salt). The reaction mixture was stirred at 60 °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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (1.5 g, 87%) as a yellow solid. LCMS (ESI) m/z: 533.3 [M+H] ⁺ ; NMR (400 MHz, CDC1 ₃ ) δ 8.64 (s, 2H), 5.28 - 5.20 (m, 1H), 4.75 - 4.68 (m, 1H), 4.10 - 4.00 (m, 1H), 3.20 - 3.10 (m, 1H), 2.64 - 2.53 (m, 1H), 2.51 - 2.34 (m, 1H), 2.32 - 2.11 (m, 2H), 2.03 - 1.94 (m, 2H), 1.88 - 1.70 (m, 2H), 1.46 (s, 18H), 1.29 (d, J= 6.8 Hz, 3H).

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

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

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

A mixture of (1RS,3SR)-3-(2-aminopyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan- 2-yl)carbamate (54 mg, 150 μmol), 6-chloroimidazo[l,2-b]]pyridazine (34 mg, 225 μmol), BrettPhos Pd G3 (13 mg, 15 μmol), Brettphos (16 mg, 30 μmol) and CS ₂ CO ₃ (294 mg, 902 μmol) in dioxane (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 22% - 55% / 0.225% formic acid in water) to give Compound 40 (14 mg, 20%) as a white solid. LCMS (ESI) m/z: 450.1 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO- -d ₆ ) δ 10.29 (s, 1H), 8.52 - 8.41 (m, 2H), 8.05 - 8.00 (m, 2H), 7.90 - 7.85 (m, 1H), 7.63 (d, 0.8

Hz, 1H), 7.30 - 7.25 (m, 1H), 5.10 - 4.98 (m, 1H), 3.91 - 3.79 (m, 1H), 3.09 - 2.95 (m, 1H), 2.48 - 2.35 (m, 3H), 2.12 - 2.03 (m, 1H), 1.97 - 1.85 (m, 1H), 1.84 - 1.65 (m, 2H), 1.63 - 1.50 (m, 1H), 1.15 - 1.10 (d, J= 6.8 Hz, 3H).

Example 3: Synthesis of rel-(1R,3S )-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5- yl)cyclopentyl (l-methylcyclopropyl)carbamate (Compound 151) and reZ-(1R,3S )-3-(2-((4- sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate

(Compound 152)

Step 1: Synthesis of 3-iodocyclopent-2-en-l-one

To a stirred solution of (15.52 g, 61.16 mmol, 1.2 equiv) in MeCN (150 mL) was added PPI13 (16.04 g, 61.162 mmol, 1.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 2 h at room temperature. A mixture of 1,3-cyclopentanedione (5 g, 50.97 mmol, 1 equiv) in Et ₃ N (6.19 g, 61.162 mmol, 1.2 equiv) and MeCN (200 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1 - 3 :5) to afford 3-iodocyclopent-2-en-l-one (8 g, 75.46 %) as a white solid. LC-MS (ES+H, m/z) 209.0 [M+H] ⁺ .

Step 2: Synthesis of 3-iodocyclopent-2-en-l-ol

A mixture of 3-iodocyclopent-2-en-l-one (3.1 g, 14.90 mmol, 1 equiv) and NaBH ₄ (0.57 g, 14.90 mmol, 1.2 equiv) in EtOH (30 mL) was stirred for 1 h at 0 °C under nitrogen atmosphere. The reaction was monitored by H-NMR. The reaction was quenched by the addition of sat. NH ₄ CI (aq.) (20 mL) at 0 °C. The resulting mixture was extracted with CH ₂ CI ₂ (3 x 200 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 : 1 - 3 :5) to afford 3-iodocyclopent-2-en- l-ol (2.3 g, 73.5 %) as a colorless liquid. LC-MS: (ES+H, m/z) 192.9 [M-0H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.21 - 6.13 (m, 1H), 4.97 (d, J= 6.1 Hz, 1H), 4.55 - 4.47 (m, 1H), 2.74 - 2.61 (m, 1H), 2.49 - 2.42 (m, 1H), 2.24 - 2.12 (m, 1H), 1.65 - 1.56 (m, 1H) Step 3: Synthesis of 3-(2-aminopyrimidin-5-yl)cydopent-2-en-l-ol

A mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-a mine (1000 mg, 4.523 mmol, 1 equiv) and 3-iodocyclopent-2-en-l-ol (1140 mg, 5.42 mmol, 1.2 equiv), Pd(dppf)C12 (661.97 mg, 0.905 mmol, 0.2 equiv), K ₂ CO ₃ (1875 mg, 13.57 mmol, 3 equiv) in 1,4- dioxane (10 mL) and H ₂ O (1 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with CH ₂ CI ₂ (5 x 100 mL). After fdtration, the fdtrate 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 (10 mmol/L NH ₄ HCO ₃ ), 8 % to 16 % gradient in 10 min; detector, UV 254 nm. This resulted in 3-(2- aminopyrimidin-5-yl)cyclopent-2-en-l-ol (500 mg, 56,8 %) as a yellow solid. LC-MS: (ES+H, m/z) 178.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 2H), 6.76 (s, 2H), 6.14 - 6.10 (m, 1H), 4.81 - 4.70 (m, 2H), 2.77 - 2.64 (m, 1H), 2.48 - 2.37 (m, 1H), 2.31 - 2.17 (m, 1H), 1.71 - 1.57 (m, 1H).

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

To a solution of 3-(2-aminopyrimidin-5-yl)cyclopent-2-en-l-ol (2.8 g, 15.80 mmol, 1 equiv) in MeOH (50 mL) MeOH was added Pd/C (10 wt. %, 1.68 g) under nitrogen atmosphere in a 250 mL round-bottom flask. The mixture was stirred at room temperature for 2 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ + 0.1 % NH3.H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 1% B to 15% B in 10 min, 15% B; Wave Length: 254/220 nm; RTl(min): 7.92/8.82; Number Of Runs: 0), the resulting mixture was concentrated under reduced pressure to afford rac-(1R,3S )-3-(2- aminopyrimidin-5-yl)cyclopentan-l-ol (1.5 g, 53 %, absolute configuration was arbitrarily assigned) as a white solid. LC-MS: (ES+H, m/z) 180.3 [M+H]“; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 (s, 2H), 6.36 (s, 2H), 4.65 (d, J= 3.9 Hz, 1H), 4.24 - 4.13 (m, 1H), 2.86 - 2.72 (m, 1H), 2.29 - 2.17 (m, 1H), 1.95 -1.84 (m, 1H), 1.79 - 1.56 (m, 3H), 1.44 - 1.33 (m, 1H).

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

To a stirred solution of rac-(1R,3S )-3-(2-aminopyrimidin-5-yl)cyclopentan-l-ol (1.5 g, 8.369 mmol, 1 equiv) and DMAP (0.10 g, 0.837 mmol, 0.1 equiv) in DCM (20 mL) were added DIEA (3.25 g, 25.107 mmol, 3 equiv) and bis(4-nitrophenyl) carbonate (5.09 g, 16.738 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The resulting mixture 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, 25 % to 35 % gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in rac-(lA,3S)-3-(2-aminopyrimidin-5-yl)cyclopentyl (4- nitrophenyl) carbonate (2.2 g, 76 %) as a white solid. LC-MS: (ES+H, m/z) 345.2 [M+H] ⁺ ; ^r H NMR (400 MHz, DMSO-tfe) δ 8.36 - 8.28 (m, 2H), 8.17 (s, 2H), 7.62 - 7.54 (m, 2H), 6.44 (s, 2H), 5.27 - 5.17 (m, 1H), 3.00 - 2.86 (m, 1H), 2.61 - 2.53 (m, 1H), 2.10 - 1.93 (m, 3H), 1.85 - 1.60 (m, 2H).

Step 6: Synthesis of rac-(l/?,3^)-3-(2-aminopyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate

A solution of rac-(1R,3S )-3-(2-aminopyrimidin-5-yl)cyclopentyl (4-nitrophenyl) carbonate (1.2 g, 3.49 mmol, 1 equiv) in DMF (20 mL) was treated with 1 -methyl cy cl opropan-1- amine hydrochloride (0.56 g, 5.23 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere followed by the addition of DIEA (1.35 g, 10.46 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for 1.5 h at 60 °C under nitrogen atmosphere. 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 (3 x 10 mL), dried over anhydrous JXfeSCU. 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 (10 mmol/L NH ₄ HCO ₃ ), 30 % to 40 % gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in rac-(1R,3S )-3-(2-aminopyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate (860 mg, 89 %) as a white solid. LC-MS: (ES+H, m/z) 277.3 [M+H] ⁺ ; T1 NMR (400 MHz, DMSO-^e) δ 8.13 (s, 2H), 7.40 (s, 1H), 6.40 (s, 2H), 5.03 (d, J= 37.8 Hz, 1H), 2.85 (t, J= 9.1 Hz, 1H), 2.46 - 2.34 (m, 1H), 2.02 - 1.79 (m, 2H), 1.77 - 1.37 (m, 3H), 1.24 (s, 3H), 0.64 - 0.55 (m, 2H), 0.54 - 0.43 (m, 2H).

Step 7: Synthesis of rac-(1R,3‘V)-3-(2-((4-(A^-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclope ntyl (1- methylcyclopropyl)carbamate

To a stirred solution of rac-(lA,35)-3-(2-aminopyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate (150 mg, 0.543 mmol, 1 equiv) and /c ^; /7-butyl N-(4- bromobenzenesulfonyl)carbamate (218.99 mg, 0.652 mmol, 1.2 equiv) in LBuOH (5 mL) were added K ₂ CO ₃ (225.06 mg, 1.629 mmol, 3 equiv) and EPhos Pd G4 (49.86 mg, 0.054 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °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 (3 x 20 mL). 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 (10 mmol/L NH ₄ HCO ₃ ), 30% to 45% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to afford rac-(1R,3S )-3-(2-((4-(N- (tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)c yclopentyl (1- methylcyclopropyl)carbamate (100 mg, 35 %) as a white solid. LC-MS: (ES+H, m/z) 532.3 [M+H] ⁺ .

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

A solution of rac-(1R,3S )-3-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclope ntyl (1- methylcyclopropyl)carbamate (100 mg, 0.188 mmol, 1 equiv) in HC1 (gas) in 1,4-dioxane (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ +0.1%NH3.H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 40% B in 10 min, 40% B; Wave Length: 254/220 nm; RTl(min): 10; the resulting mixture was concentrated under reduced pressure by lyophilization to afford rac- (1R,3S )-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate (7.6 mg, 9.4 %) as a white solid. LC-MS: (ES+H, m/z) 432.1 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 8.57 - 8.42 (m, 2H), 7.95 - 7.88 (m, 2H), 7.71 (d, J= 8.5 Hz, 2H), 7.43 (s, 1H), 7.17 (s, 2H), 5.18 - 4.95 (m, 1H), 3.06 - 2.97 (m, 1H), 2.46 (d, J= 7.4 Hz, 1H), 2.11 - 1.98 (m, 1H), 1.96 - 1.85 (m, 1H), 1.81 - 1.64 (m, 2H), 1.61 - 1.50 (m, 1H), 1.27 - 1.24 (m, 3H), 0.61 (s, 2H), 0.49 (s, 2H).

Step 9: Synthesis of reZ-(1R,3S )-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cydopentyl (l-methylcyclopropyl)carbamate (Compound 151) and rel-(1R,3S )-3-(2-((4- sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate (Compound 152) The product (75 mg) was purified by Prep-CHIRAL-HPLC with the following conditions (Column: CHIRAL Cellulose-SB, 4.6*50mm 3um; Mobile Phase A: (MtBE: Hex=l : l)(0.1%DEA): IPA=50: 50; Flow rate: 1 mL/min; Gradient: 0% B to 0% B; Injection Volume: 5ul mL), the pure fractions were concentrated under reduced pressure by lyophilization to afford rel- ( 1 S, 3R ) -3 -(2-((4-sulfamoylphenyl)amino)pyrimidin-5 -yl)cy clopentyl ( 1 - methylcyclopropyl)carbamate (Compound 151, 27.6 mg, 45.3 %) as a white solid and rel-(1R,3S )- 3-{2-[(4-sulfamoylphenyl)amino]pyrimidin-5-yl}cyclopentyl N-( l -methylcyclopropyl (carbamate (Compound 152, 29.3 mg, 48.1 %) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 151 - LC-MS: (ES+H, m/z) 432.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 8.47 (s, 2H), 7.95 - 7.87 (m, 2H), 7.76 - 7.67 (m, 2H), 7.44 (s, 1H), 7.17 (s, 2H), 5.18 - 4.95 (m, 1H), 3.09 - 2.94 (m, 1H), 2.49 - 2.42 (m, 1H), 2.12 - 2.00 (m, 1H), 1.96 - 1.86 (m, 1H), 1.81 - 1.64 (m, 2H), 1.61 - 1.50 (m, 1H), 1.27 - 1.24 (m, 3H), 0.65 - 0.46 (m, 4H). Compound 152 - LC-MS: (ES+H, m/z) 432.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-7 ₆ ) δ 9.98 (s, 1H), 8.47 (s, 2H), 7.95 - 7.87 (m, 2H), 7.74 - 7.67 (m, 2H), 7.44 (s, 1H), 7.17 (s, 2H), 5.19 - 4.94 (m, 1H), 3.08 - 2.94 (m, 1H), 2.49 - 2.42 (m, 1H), 2.05 (d, 7= 10.6 Hz, 1H), 1.96 - 1.84 (m, 1H), 1.81 - 1.65 (m, 2H), 1.62 - 1.49 (m, 1H), 1.27 - 1.24 (m, 3H), 0.65 - 0.46 (m, 4H).

Example 4: Synthesis of rac-(1R,3S )-3-{2-[(l-sulfamoylpiperidin-4-yl)amino]pyrimidin-5- yl)cyclopentyl N-(l-methylcyclopropyl)carbamate (Compound 135) Step 1: Synthesis of rac-(H?,3^)-3-(2-chloropyrimidin-5-yl)cyclopentyl A-(l- methylcyclopropyl)carbamate

To a stirred solution of rac-(7A,35)-3-(2-aminopyrimidin-5-yl)cyclopentyl N-(1- methylcyclopropyl)carbamate (150 mg, 0.543 mmol, 1 equiv) and Z-BuNCh (167.93 mg, 1.629 mmol, 3 equiv) in DCM (2 mL) was added tetrabutylazanium chloride (452.57 mg, 1.629 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture 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 (10mmol/L NH ₄ HCO ₃ ), 30% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to afford rac-(1R,3S )-3-(2-chloropyrimidin-5- yl)cyclopentyl N-(l-methylcyclopropyl)carbamate (38 mg, 24 %) as a white solid. LC-MS: (ES+H, m/z) 296.2 [M+H] ⁺ .

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

To a stirred solution of rac-(1R,3S )-3-(2-chloropyrimidin-5-yl)cyclopentyl N-(1- methylcyclopropyl)carbamate (38 mg, 0.128 mmol, 1 equiv) and te/7-butyl 4-aminopiperidine-l- carboxylate (51.46 mg, 0.256 mmol, 2 equiv) in dioxane (2 mL) were added Pd-PEPPSI-IpentCl 2-methylpyridine (o-picoline (32.42 mg, 0.038 mmol, 0.3 equiv) and CS ₂ CO ₃ (125.58 mg, 0.384 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 120°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1: 1-1 :2) to afford rac- te/7-butyl 4-({5-[(1R,3S )-3-{[(l-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]pyrimid in-2- yl}amino)piperidine-l -carboxylate (50 mg, 85 %) as a white solid. LC-MS: (ES+H, m/z) 460.3 [M+H] ⁺ .

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

A solution of rac-fe/7-butyl 4-({5-[(1R,3S )-3-{[(l- methylcyclopropyl)carbamoyl]oxy}cyclopentyl]pyrimidin-2-yl}a mino)piperidine-l-carboxylate (50 mg, 0.109 mmol, 1 equiv) in HCOOH (3 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 8 with NH3 H ₂ O . The residue was purified by reversed-phase flash chromatography with the following conditions: column, C 18; mobile phase, MeCN in Water (10mmol/L NH ₄ HCO ₃ ), 30% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in rac-(1R,3S )-3-[2-(piperidin-4-ylamino)pyrimidin-5-yl]cyclopentyl N-(1- methylcyclopropyl)carbamate (30 mg, 77 %) as a white solid. LC-MS: (ES+H, m/z) 360.2 [M+H] ⁺ . Step 4: Synthesis of rac-(1R,3S )-3-{2-[(l-sulfamoylpiperidin-4-yl)amino]pyrimidin-5- yl}cyclopentyl N-( l-niethylcyclopropyl)carbaniate (Compound 135)

To a stirred solution of rac-(1R,3S )-3-[2-(piperidin-4-ylamino)pyrimidin-5-yl]cyclopentyl N-(l-methylcyclopropyl)carbamate (30 mg, 0.083 mmol, 1 equiv) and sulfamide (16.04 mg, 0.166 mmol, 2 equiv) in dioxane (1 mL) was added Et3N (25.34 mg, 0.249 mmol, 3 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: Mobile Phase A: Water (10mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ®; Flow rate: 60 mL/min mL/min; Gradient: 21% B to 33% B in 10 min; Wave Length: 254nm/220nm nm; RTl(min): 9.1. The resulting mixture was concentrated under reduced pressure and by lyophilization to afford rac-(1R ,3S)-3-{2-[(l-sulfamoylpiperidin- 4-yl)amino]pyrimidin-5-yl}cyclopentyl N-(l-methylcyclopropyl)carbamate (Compound 135, 16 mg, 44 %) as a white solid. LC-MS: (ES+H, m/z) 439.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (s, 2H), 7.40 (s, 1H), 6.97 (d, J= 7.7 Hz, 1H), 6.73 (s, 2H), 4.99 (s, 1H), 3.71 (d, J= 10.1 Hz, 1H), 3.43 (d, 11.9 Hz, 2H), 2.87 (s, 1H), 2.62 (t, ./ = 11.5 Hz, 2H), 2.41 (s, 1H), 2.07 - 1.84

(m, 4H), 1.73 - 1.43 (m, 5H), 1.24 (s, 3H), 0.60 (s, 2H), 0.48 (s, 2H).

Example 5: Synthesis of rac-(1R,3S )-3-(2-((l-((l-(trifluoromethyl)- 1H-pyrazol-4- yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2- yl)carbamate (Compound 302)

Compound 302

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

To a stirred mixture of piperidin-4-one hydrochloride (190.75 mg, 1.407 mmol, 1.1 equiv) and DIEA (330.58 mg, 2.558 mmol, 2 equiv) in THF (5 mL) was added 1- (trifluoromethyl)pyrazole-4-sulfonyl chloride (300 mg, 1.279 mmol, 1 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by H-NMR. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to afford l-[l-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-one (390 mg, crude) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.39 (q, J= 0.9 Hz, 1H), 3.42 - 3.33 (m, 4H), 2.49 - 2.44 (m, 4H).

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

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

Step 3: Synthesis of n/c-(l/?.3.S)-3-(2-((l-((l-(trinuoroinethyl)-lH-pyrazol-4- yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2- yl)carbamate (Compound 302)

To a stirred mixture of rac-(1R,3S )-3-(2-fluoropyrimidin-5-yl)cyclopentyl ((S)-4,4,4- trifluorobutan-2-yl)carbamate (80 mg, 0.239 mmol, 1 equiv) and DIEA (123.35 mg, 0.956 mmol, 4 equiv) in DMSO (3 mL) was added l-[l-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4- amine (142.33 mg, 0.478 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na ₂ SO ₄ . 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% NH ₄ HCO ₃ ), 30% to 60% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure and lyophilized to afford rac-(1R,3S )-3-(2-((l-((l-(trifluoromethyl)-lH-pyrazol-4-yl)sulfonyl)pi peridin-4- yl)amino)pyrimidin-5-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 302, 36 mg, 25 %) as a white solid. LC-MS: (ES+H, m/z) 614.2 [M+H] ⁺ ; NMR (400 MHz, DMSO- d ₆ ) 59.25 (s, 1H), 8.38 - 8.29 (m, 1H), 8.22 - 8.08 (m, 2H), 7.22 (d, J= 8.7 Hz, 1H), 7.03 (d, J= 7.7 Hz, 1H), 5.11 - 4.88 (m, 1H), 3.96 - 3.67 (m, 2H), 3.61 - 3.42 (m, 2H), 2.87 (p, J= 9.2 Hz, 1H), 2,73 - 2.57 (m, 2H), 2.48 - 2.28 (m, 3H), 2.03 - 1.81 (m, 4H), 1.80 - 1.68 (m, 1H), 1.67 - 1.41 (m, 4H), 1.13 (dd, J= 6.7, 1.9 Hz, 3H); ¹⁹ F NMR (377 MHz, DMSO) δ -59.50, -62.57.

Example 6: Synthesis of (l/?*,35*)-3-(2-((4-((5 ^,l! )-cyclopropanesulfonimidoyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate HC1 salt (Compound 580)

Step 1: Synthesis of rac-tert-butyl (terEbutoxycarbonyl)(5-((lJ?,35)-3-(((l- methylcyclopropyl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl)c arbamate

To a solution of 1-methylcyclopropanamine (2.3 g, 21.3 mmol) in dioxane (30 mL) and

TEA (4.45 mL, 31.9 mmol) was added rac-tert-butyl (tert-butoxycarbonyl)(5-((1R ,3A)-3-(((4- nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbama te (5.8 g, 10.7 mmol). The mixture was stirred at 25 °C for 5 h. The reaction mixture was quenched by addition water (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (4.2 g, 83%) as a white solid. LCMS (ESI) m/z: 477.4 [M+H] ⁺ .

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

To a solution of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,3S )-3-(((l- methylcyclopropyl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl)c arbamate (4.2 g, 8.8 mmol) in dioxane (10 mL) was added HCl/dioxane (30 mL, 4 M). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with MeOH (20 mL) and DCM (20 mL), adjust pH = 8 with sat. aq. NaHCCL, then stirred for 1 h. The solution was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (3.2 g, crude) as a white solid that required no further purification. LCMS (ESI) m/z: 277.2 [M+H] ⁺ ; ¹ HNMR (400 MHz, CDC1 ₃ ) δ 8.45 - 8.01 (m, 2H), 5.30 - 5.10 (m, 1H), 5.02 - 4.90 (m, 2H), 3.05 - 2.83 (m, 1H), 2.64 - 2.45 (m, 1H), 2.15 - 2.03 (m, 1H), 1.99 - 1.90 (m, 2H), 1.86 - 1.60 (m, 2H), 1.50 - 1.24 (m, 3H), 0.86 - 0.67 (m, 2H), 0.65 - 0.49 (m, 2H).

Step 3: Synthesis of rac-(lR,3S)-3-(2-((4-(N-(tert- butoxycarbonyl)cydopropanesulfonimidoyl)phenyl)amino)pyrimid in-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate

To a solution of rac-(lA,35)-3-(2-aminopyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate (1.1 g, 3.0 mmol) and K ₃ PO ₄ (3.13 g, 14.73 mmol) in dioxane (20 mL) was added tert-butyl N-[(4-bromo-3-fluoro-phenyl)-cyclopropyl-oxo- sulfanylidene]carbamate (1.7 g, 4.4 mmol), Brettphos (316 mg, 589 μmol), BrettPhos Pd G3 (267 mg, 294 μmol). The reaction mixture was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (1.1 g, 52%) as a white solid. LCMS (ESI) m/z: 574.3 [M+H] ⁺ .

Step 4: Synthesis of rel-(lR,3S)-3-(2-((4-(N-(tert- butoxycarbonyl)cyclopropanesulfonhnidoyl)-2-fluorophenyl)ami no)pyrimidin-5- yl)cyclopentyl (l-methylcyclopropyl)carbamate and rel-(lS,3R)-3-(2-((4-(N-(tert- butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)ami no)pyrimidin-5- yl)cyclopentyl (l-methylcyclopropyl)carbamate rac-(1R,3S )-3-(2-((4-(N-(tert-Butoxycarbonyl)cyclopropanesulfonimidoyl )-2- fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate (1.2 g, 1.7 mmol) was separated by using chiral SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um); Supercritical CO ₂ / z-PrOH+O.1% NEE’FhO = 40/60; 80 mL/min) to afford rel-(1R,3S )-3-(2-((4-(N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl )-2- fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate (397 mg, first peak and second peak) as a white solid and rel-(lS,3A)-3-(2-((4-(N-(fert- butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)ami no)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate (355 mg, third peak and fourth peak) as a white solid. Absolute configuration was arbitrarily assigned to each isomer. LCMS (ESI) m/z: 574.3 [M+H] ⁺ .

Step 5: Synthesis of (1R *,35*)-3-(2-((4-((l?)-N-(-tert- butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)ami no)pyrimidin-5- yl)cyclopentyl (l-methylcyclopropyl)carbamate and (1R*,35*)-3-(2-((4-((A)-N-(tert- butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)ami no)pyrimidin-5- yl)cyclopentyl (l-methylcyclopropyl)carbamate

(lA,3£)-3-(2-((4-(N-(fert-butoxycarbonyl)cyclopropanesul fonimidoyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (1-m ethyl cy cl opropyl)carbamate (397 mg, 692.0 μmol) was separated by using chiral SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10um); Supercritical CO ₂ / MeOH+O.1% NFL’FLO = 60/40; 150 mL/min) to afford (lA*,35*)-3-(2-((4-((R )-N-(tert-butoxycarbonyl)cyclopropanesulfonimidoyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate (147 mg, first peak) as a white solid and (1R *,35'*)-3-(2-((4-((S)-/V-(fert- butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)ami no)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate (119 mg, second peak) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. LCMS (ESI) m/z: 574.3 [M+H] ⁺ .

Step 6: Synthesis of (l/f*,35*)-3-(2-((4-((5)-cyclopropanesulfonimidoyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate HC1 salt (Compound 580) To a solution of (1R *, 35*)-3-(2-((4-((S)-N-(ferL butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)ami no)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate (147 mg, 255 μmol) in dioxane (5 mL) was added HCl/dioxane (5 mL, 4 M). The reaction was stirred at room temperature for 2 h. This mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 30% - 60% / 0.05% HC1 in water) to give Compound 580 (46 mg, 38%) as a white solid. Absolute configuration was arbitrarily assigned. LCMS (ESI) m/z: 474.1 [M+H] ⁺ ; NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 8.54 - 8.51 (m, 2H), 8.02 - 7.98 (m, 1H), 7.89 - 7.84 (m, 1H), 7.43 (s, 1H), 5.05 - 4.99 (m, 1H), 3.55 - 3.40 (m, 1H), 3.20 - 2.90 (m, 1H), 2.49 - 2.36 (m, 2H), 2.12 - 2.00 (m, 1H), 1.95 - 1.86 (m, 1H), 1.82 - 1.64 (m, 2H), 1.63 - 1.46 (m, 1H), 1.46 - 1.32 (m, 2H), 1.24 (s, 3H), 1.23 - 1.14 (m, 2H), 0.65 - 0.56 (m, 2H), 0.53 - 0.44 (m, 2H).

Example 7: Synthesis of rel-4-((5-((1R,3S )-3-((4-isopropyl-4 _J H-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 52) and rel-4-((5-

(( LS.3/?)-3-((4-isopropyl-4H-1.2.4-triazol-3-yl)oxy)cyclopenty l)pyrimidin-2- yl)amino)benzenesulfonamide (Compound 392)

Step 1: Synthesis of rac-tert-buty\ (5-((1R,3S )-3-((4-isopropyl-4LM,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate To a solution of rac-tert-butyl (5-((1R,3S )-3-hydroxycyclopentyl)pyrimidin-2- yl)carbamate (200 mg, 0.72 mmol) in DMF (8 mL) was added NaH (71 mg, 1.79 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then 4-isopropyl-3-methylsulfonyl-l,2,4- triazole (160 mg, 0.86 mmol) was added. The mixture was stirred at 40 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with sat. aq. NH4CI (3 mL), diluted with H ₂ O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% methanol in ethyl acetate) to give the title compound (100 mg, 36%) as yellow oil. LCMS (ESI) m/z: 389.2 [M+H] ⁺ .

Step 2: Synthesis of rac-5-((1R,3S )-3-((4-isopropyl-4H-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt

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

Step 3: Synthesis of rac-tert-butyl ((4-((5-((1R,3S )-3-((4-isopropyl-4H-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carb amate

To a solution of rac-5-((lA,3S)-3-((4-isopropyl-4H-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt (70.00 mg, 242 μmol), tert-butyl N-(4- bromophenyl)sulfonylcarbamate (122 mg, 364 μmol), and CS ₂ CO ₃ (476 mg, 1.46 mmol) in dioxane (3 mL) was added BrettPhos (13 mg, 24 μmol) and BrettPhos Pd G3 (22 mg, 24 μmol). The reaction was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (50 mg, 53%) as a yellow solid. LCMS (ESI) m/z: 544.2 [M+H] ⁺ .

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

Step 5: Synthesis of reZ-4-((5-((1R,3S )-3-((4-isopropyl-4H-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 52) and r<7-4-((5- (( LS.3/?)-3-((4-isopropyl-4H-1.2.4-triazol-3-yl)oxy)cyclopenly l)pyriniidin-2- yl)amino)benzenesulfonamide (Compound 392) rac-4-((5-((lA,3S)-3-((4-Isopropyl-4H-l,2,4-triazol-3-yl)oxy )cyclopentyl)pyrimidin-2- yl)amino) _b enzenesulfonamide (40 g, 90 μmol) was separated by using chiral SFC (DAICEL CEURALCEL OJ(250mm*30mm,10um); Supercritical CO ₂ / zPrOH+O.1% NH ₃ «H ₂ O =50/50; 60 mL/min) to afford rel-4-((5-((l A,35)-3-((4-isopropyl-4H-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino) _b enzenesulfonamide (Compound 52, 2.3 mg, first peak) as a white solid and rel-4-((5-((15,3A)-3-((4-isopropyl-4Z/-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino) _b enzenesulfonamide (Compound 392, 2.1 mg, last peak) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 52: LCMS (ESI) m/z: 444.2 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-t7 ₆ ) δ 10.02 (s, 1H), 8.50 (s, 2H), 8.25 (s, 1H), 7.91 (d, J= 8.8 Hz, 2H), 7.70 (d, J= 8.4 Hz, 2H), 7.16 (s, 2H), 5.37 - 5.29 (m, 1H), 4.23 - 4.13 (m, 1H), 3.19 - 3.09 (m, 1H), 2.70 - 2.60 (m, 1H), 2.17 - 1.93 (m, 3H), 1.92 - 1.78 (m, 2H), 1.33 (d, J= 6.8 Hz, 6H). Compound 392: LCMS (ESI) m/z: 444.2 [M+H] ⁺ ; Tl NMR (400 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.50 (s, 2H), 8.25 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.70 (d, J= 8.8 Hz, 2H), 7.16 (s, 2H), 5.37 - 5.29 (m, 1H), 4.23 - 4.13 (m, 1H), 3.19 - 3.10 (m, 1H), 2.71 - 2.62 (m, 1H), 2.17 - 1.94 (m, 3H), 1.93 - 1.79 (m, 2H), 1.33 (d, J= 6.8 Hz, 6H).

Example 8: Synthesis of /'<7-3-fluoro-4-(( 5-(( LS\3/?)-3-((4-( 1 -methylcy clopropyl)-4H- 1,2,4- triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesul fonamide (Compound 449)

Step 1: Synthesis of 4-( l-nielhylcyclopropyl)-4H-1.2.4-lri;izole-3-lhiol

To a solution of 1-isothiocyanato-l-methyl-cyclopropane (18 g, 159 mmol) in THF (200 mL) was added NaOH (3.6 g, 90 mmol), formic hydrazide (18.0 g, 299.7 mmol). The mixture was stirred at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was quenched by addition water (20 mL), and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% ethyl acetate in petroleum ether) to give the title compound (16 g, 64 %) as a white solid. Tl NMR (400 MHz, CDC1 ₃ ) δ 12.49 (s, 1H), 7.78 (s, 1H), 1.59 (s, 3H), 1.19 - 1.15 (m, 2H), 1.05 - 0.99 (m, 2H). Step 2: Synthesis of 4-( 1 -inethylcyclopropyl )-3-( met hylthio)-4H- 1 ,2,4-triazole To a solution of 4-(l-methylcyclopropyl)-4/7-l,2,4-triazole-3-thiol (16 g, 103.1 mmol) in acetone (100 mL) was added K ₂ CO ₃ (15.7 g, 113.4 mmol) and Mel (13.2 g, 92.8 mmol). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (50 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 100% ethyl acetate in petroleum ether) to give the title compound (15 g, 86 %) as a white solid. LCMS (ESI) m/z: 170.1 [M+H] ⁺ ; ¹ HNMR (400 MHZ, CDC1 ₃ ) δ 8.22 (s, 1H), 2.77 (s, 3H), 1.51 (s, 3H), 1.18 - 1.13 (m, 2H), 1.03 - 0.94 (m, 2H).

Step 3: Synthesis of 4-(l-methylcyclopropyl)-3-(methylsulfonyl)-4H-l,2,4-triazole

To a solution of 4-(l-methylcyclopropyl)-3-methylsulfanyl-l,2,4-triazole (14 g, 82.7 mmol) in DCM (100 mL) was added /w-CPBA (61.2 g, 301.3 mmol, 85% purity). The mixture was stirred at 25 °C for 16 h under a nitrogen atmosphere. The reaction was quenched by addition of 200 mL of sat. aq. Na2SCh, then extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 10% - 100% ethyl acetate in petroleum ether) to give the title compound (14 g, 69 %) as a white solid. LCMS (ESI) m/z: 202.1 [M+H] ⁺ ; Tl NMR (400 MHz, CDC1 ₃ ) δ 7.77 (s, 1H), 1.62 (s, 4H), 1.23 - 1.18 (m, 2H), 1.09 - 1.04 (m, 2H).

Step 4: Synthesis of rac-tert-butyl (5-(( 1R,3S )-3-((4-( 1 -met hylcyclopropyl )-4H- 1.2.4-t riazol- 3-yl)oxy)cydopentyl)pyrimidin-2-yl)carbamate

To a solution of rac-tert-butyl (5-((1R,3S )-3-hydroxycyclopentyl)pyrimidin-2- yl)carbamate (0.5 g, 1.8 mmol) in DMF (10 mL) was added NaH (214 mg, 5.4 mmol, 60% purity) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min, then 4-(l- methylcyclopropyl)-3-(methylsulfonyl)-4rt-l,2,4-triazole (721 mg, 3.6 mmol) was added at 0 °C for 5 min, then the mixture was heated to 40 °C for 16 h. After cooling to room temperature, the reaction mixture was quenched by addition sat. aq. Ammonium chloride (10 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (solvent gradient: 5% - 10% MeOH in DCM) to afford the title compound (0.4 g, 55%) as white solid. LCMS (ESI) m/z: 401.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.55 (s, 2H), 7.86 (s, 1H), 7.47 (s, 1H), 5.59 - 5.52 (m, 1H), 3.23 - 3.09 (m, 1H), 2.87 - 2.75 (m, 1H), 2.34 - 2.20 (m, 2H), 2.17 - 2.05 (m, 1H), 2.03 - 1.81 (m, 2H), 1.56 (s, 9H), 1.48 (s, 3H), 1.11 - 1.02 (m, 2H), 0.99 - 0.90 (m, 2H).

Step 5: Synthesis of rac-5-((H?,3*S)-(3-((4-(l-methylcyclopropyl)-4H-l,2,4-triazo l-3- yl)oxy)cyclopentyl)pyrimidin-2-amine

To a solution of rac-Zc/V-butyl (5-((1R,3S )-3-((4-(l-methylcyclopropyl)-4H-l,2,4-triazol- 3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (0.3 g, 749 μmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo. The residue was diluted with MeOH (20 mL) and DCM (20 mL), adjust pH = 8 with sat. aq. NaHCCL, then stirred for 1 h, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to afford the title compound (0.2 g. crude) as yellow oil that required no further purification. LCMS (ESI) m/z: 301.2 [M+H] ⁺ .

Step 6: Synthesis of rac-tert-butyl ((3-fluoro-4-((5-((l R ,35)-3-((4-( l-melhylcyclopropyl)-4H- l,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phen yl)sulfonyl)carbamate

A mixture of rac-5-((1R,3S )-(3-((4-(l-methylcyclopropyl)-4Z7-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-amine (150 mg, 499 μmol), ferLbutyl N-(4-bromo-3-fluoro- phenyl)sulfonylcarbamate (265 mg, 749 μmol), BrettPhos Pd G3 (45 mg, 49 μmol), Brettphos (54 mg, 99 μmol) and CS ₂ CO ₃ (976 mg, 3.0 mmol) in dioxane (8 mL) was degassed and purged with a nitrogen atmosphere three times, and then the mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 3% - 5% methanol in ethyl acetate) to give the title compound (120 mg, 41%) as a yellow oil. LCMS (ESI) m/z: 574.1 [M+H] ⁺ .

Step 7: Synthesis of rel-tert-buty\ ((3-fluoro-4-((5-(( 1R,3*S)-3-((4-( l-nielhylcyclopropyl)-4H- l,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phen yl)sulfonyl)carbamate & rel- tert-butyl ((3-nuoi o-4-((5-((LS.3/?)-3-((4-(l-niethylcyclopi opyl)-4H-L2.4-triazol-3- yl)oxy)cyclopentyl)pyriimdin-2-yl)amino)phenyl)sulfonyl)carb amate rac-tert-Butyl ((3-fluoro-4-((5-((lJ?,35)-3-((4-(l-methylcyclopropyl)-4Z/-l ,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carb amate (120 mg, 209 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK AS(250mm*30mm,10um); Supercritical C0 ₂ /EtOH+O.1% NHs’HzO = 55/45; 80 mL/min) to afford rel-fe/7-butyl ((3-fluoro-4-((5- ((1R,3S )-3-((4-(l-methylcyclopropyl)-4H-l,2,4-triazol-3-yl)oxy)cycl opentyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)carbamate (50 mg, first peak) as a colorless oil and /'c7-tert-butyl ((3- fluoro-4-((5-((15',3R )-3-((4-(l-methylcyclopropyl)-47Z-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carb amate (50 mg, second peak) as a colorless oil. Absolute configuration was arbitrarily assigned to each enantiomer.

Step 8: Synthesis of reZ-3-fluoro-4-((5-(( l*S',3R )-3-((4-( l-nielhylcyclopropyl)-4H-1.2.4-lriazol- 3-yl)oxy)cyclopentyl)pyrimidiu-2-yl)amino)benzenesulfonamide (Compound 449)

A solution of /'c7-/<77-butyl ((3-fluoro-4-((5-((15,3J?)-3-((4-(l-methylcyclopropyl)-4Zf- l,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phen yl)sulfonyl)carbaamate (130 mg, 227 μmol) in HCl/dioxane (5 mL, 4 M) was stirred at 25 °C for 1 h. And then the reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 36 - 60% / 0.05% HC1 in water) to give the HC1 salt compound. The HC1 salt compound was diluted with MeOH (5 mL) and added Amberlystl5, then the mixture was stirred at 25 °C for 1 h, filtered and concentrated under reduced pressure to give Compound 449 (40 mg, 96%) as a white solid. LCMS (ESI) m/z: 474.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-tA) δ 8.50 (s, 2H), 8.17 (s, 1H), 8.16 - 8.12 (m, 1H), 7.61 - 7.59 (m, 2H), 5.37 - 5.31 (m, 1H), 3.21 - 3.10 (m, 1H), 2.70 - 2.60 (m, 1H), 2.21 - 2.10 (m, 1H), 2.08 - 1.99 (m, 2H), 1.94 - 1.85 (m, 1H), 1.85 - 1.77 (m, 1H), 1.39 (s, 3H), 1.05 - 1.01 (m, 2H), 0.90 - 0.84 (m, 2H).

Example 9: Synthesis of reZ-3-fluoro-4-((5-((15,3f?)-3-((4-(l-methylcyclopropyl)-5-p ropyl- 4H-l,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)b enzenesulfonamide

(Compound 480) and reZ-3-fluoro-4-((5-((H?,3^)-3-((4-(l-methylcyclopropyl)-5-pr opyl-4EZ- l,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benz enesulfonamide (Compound 551)

Step 1: Synthesis of 2-butyryl-/V-(l-methylcydopropyl)hydrazine-l-carbothioamide

To a solution of I -isothiocy an ato-1 -methyl -cyclopropane (3 g, 26.5 mmol) in THF (20 mL) was added butanehydrazide (4.06 g, 39.8 mmol). The mixture was stirred at 60 °C for 16 h. The reaction was concentrated in vacuo to afford the title compound (5.5 g, crude) as a yellow solid that required no further purification. LCMS (ESI) m/z: 215.9 [M+H] ⁺ .

Step 2: Synthesis of 4-( l-melhylcyclopropyl)-5-propyl-4H-1.2.4-lriazole-3-lhiol

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

Step 3: Synthesis of /i7-3-nuoro-4-((5-(( l.S',3/?)-3-((4-( l-niethylcyclopropyl)-5-propyl-4H- l,2,4-triazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benz enesulfonamide (Compound 480) and rel-3-fluoro-4-((5-((l /?.3.S)-3-((4-(l-inethylcyclopropyl)-5-propyl-4H-1.2.4-triaz ol- 3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)henzenesulfonamide (Compound 551) rel-3-fluoro-4-((5-((15,3A)-3-((4-(l-methylcyclopropyl)-5-pr opyl-4H-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino) _b enzenesulfonamide (Compound 480) and rel-3- fluoro-4-((5-((1R,3S )-3-((4-(l-methylcyclopropyl)-5-propyl-4/7-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino) _b enzenesulfonamide (Compound 551) were prepared in a manner analogous to Compound 449, using 4-(l-methylcyclopropyl)-5-propyl-4H-l,2,4- triazole-3 -thiol in place of 4-(l-methylcyclopropyl)-4/7-l,2,4-triazole-3-thiol as well as any appropriate modifications. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 449: LCMS (ESI) m/z: 516.1 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.50 (s, 2H), 8.21 - 8.10 (m, 1H), 7.64 - 7.56 (m, 2H), 7.36 (s, 2H), 5.34 - 5.25 (m, 1H), 3.23 - 3.10 (m, 1H), 2.66 - 2.58 (m, 3H), 2.20 - 2.08 (m, 1H), 2.06 - 1.99 (m, 2H), 1.92 - 1.78 (m, 2H), 1.77 - 1.68 (m, 2H), 1.33 (s, 3H), 1.04 - 1.00 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H), 0.94 - 0.88 (m, 2H). Compound 551: LCMS (ESI) m/z: 516.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.50 (s, 2H), 8.19 - 8.10 (m, 1H), 7.64 - 7.56 (m, 2H), 7.36 (s, 2H), 5.35 - 5.25 (m, 1H), 3.23 - 3.10 (m, 1H), 2.68 - 2.58 (m, 3H), 2.20 - 2.07 (m, 1H), 2.07 - 1.97 (m, 2H), 1.92 - 1.77 (m, 2H), 1.77 - 1.68 (m, 2H), 1.33 (s, 3H), 1.05 - 1.00 (m, 2H), 0.98 (t, J= 7.6 Hz, 3H), 0.94 - 0.89 (m, 2H).

Example 10: Synthesis of reZ-4-((5-((15,3^)-3-((4-cyclopropylisothiazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 574)

Compound 574

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

To a solution of 4-cyclopropylisothiazol-3-ol (555 mg, 3.93 mmol) and K ₂ CO ₃ (1.09 g, 7.87 mmol) in DMF (10 mL) was added rac-(1R ,3R )-3-(2-(fo'5(fcrt- butoxycarbonyl)amino)pyrimidin-5-yl)cyclopentyl methanesulfonate (1.5 g, 2.62 mmol). The reaction was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 100% ethyl acetate in petroleum ether) to give the title compound (1.1 g, 66%) as a white solid. LCMS (ESI) m/z: 503.2 [M+H] ⁺ .

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

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

Step 3: Synthesis of rac-tert-butyl ((4-((5-((1R,3S )-3-((4-cyclopropylisothiazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carb amate

To a solution of rac-5-((1R,3S )-3-((4-cyclopropylisothiazol-3- yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt (100 mg, 330 μmol) and tert-butyl N-(4- bromophenyl)sulfonylcarbamate (133 mg, 396 μmol) in dioxane (5 mL) was added BrettPhos (18 mg, 33 μmol), BrettPhos Pd G3 (30 mg, 33 μmol) and K3PO4 (351 mg, 1.65 mmol). The reaction mixture was stirred at 80 °C for 0.5 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous TsfeSCh, filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% methanol in ethyl acetate) to afford the title compound (100 mg, 54%) as a yellow oil. LCMS (ESI) m/z: 558.2 [M+H] ⁺ .

Step 4: Synthesis of reZ-tert-butyl ((4-((5-((l/?,3*V)-3-((4-cyclopropylisothiazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carb amate & reZ-tert-butyl ((4-((5- ((15,3^)-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)py rimidin-2- yl)amino)phenyl)sulfonyl)carbamate rac-tert-Butyl ((4-((5-((1R ,3S)-3-((4-cyclopropylisothiazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carb amate (256 mg, 466 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK IF (250mm*30mm,10um); Supercritical CO ₂ / Heptane-EtOH + 0.1% NH^FFO = 40/60; 80 ml/min) to afford rel-tert-butyl ((4-((5- ((1R,3S )-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin -2- yl)amino)phenyl)sulfonyl)carbamate (70 mg, first peak) and rc7-te/7-butyl ((4-((5-((15,3A)-3-((4- cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)am ino)phenyl)sulfonyl)carbamate (85 mg, second peak), both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. LCMS (ESI) m/z: 558.1 [M+H] ⁺ .

Step 5: Synthesis of rel-4-((5-((15',3^)-3-((4-cyclopropylisothiazol-3- yl)oxy)cydopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 574)

To a solution of /c/V-butyl N-[4-[[5-[( LS'.3/?)-3-(4-cyclopropylisothiazol-3- yl)oxycyclopentyl]pyrimidin-2-yl]amino]phenyl]sulfonylcarbam ate (85 mg, 152 μmol) in DCM (3 mL) added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. This mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 52% - 82% 10.05% NFE’EEO + 10 mM NH ₄ HCO ₃ in water) to give Compound 574 (20 mg, 35 %) as a white solid. LCMS (ESI) m/z: 458.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-t/r,) 5 9.99 (s, 1H), 8.52 (s, 2H), 8.29 (s, 1H), 7.90 (d, J= 8.0 Hz, 2H), 7.70 (d, J= 8.0 Hz, 2H), 7.15 (s, 2H), 5.43 - 5.32 (m, 1H), 3.20 - 3.11 (m, 1H), 2.69 - 2.58 (m, 1H), 2.17 - 1.95 (m, 3H), 1.87 - 1.68 (m, 3H), 0.93 - 0.84 (m, 2H), 0.69 - 0.64 (m, 2H).

Example 11: Synthesis of rac-3-fluoro-4-((5-((H?,3^)-3-((4-(prop-l-en-2-yl)pyridin-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 55) Step 1: Synthesis of rac-tert-butyl (5-((H?,3^)-3-((4-bromopyridin-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)(tert-butoxycarbonyl)carba mate

A solution of 4-brom opyri din-3 -ol (75 mg, 0.4 mmol), K ₂ CO ₃ (119 mg, 0.9 mmol) and rac-(lA,3A)-3-(2-(/>A(tertebutoxycarbonyl)amino)pyrimidin -5-yl)cyclopentyl methanesulfonate (237 mg, 0.5 mmol) in DMF (2 mL) was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 100% ethyl acetate in petroleum ether) to give the title compound (90 mg, 36%) as a white solid. LCMS (ESI) m/z: 537.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCI3) δ 8.76 (s, 2H), 8.25 (s, 1H), 8.06 (d, J= 5.2 Hz, 1H), 7.52 (d, J= 5.2 Hz, 1H), 5.10 (s, 1H), 3.30 - 3.18 (m, 1H), 2.80 - 2.70 (m, 1H), 2.30 - 2.20 (m, 2H), 2.10 - 2.06 (m, 1H), 2.03 - 1.96 (m, 2H), 1.46 (s, 18H).

Step 2: Synthesis of rac-5-((U?,3^)-3-((4-(prop-l-en-2-yl)pyridin-3- yl)oxy)cyclopentyl)pyrimidin-2-amine

A solution of rac-tert-butyl (5-((1R,3S )-3-((4-bromopyridin-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)(tert-butoxycarbonyl)carba mate (50 mg, 93 μmol), K ₂ CO ₃ (40 mg, 0.3 mmol), Pd(dppf)C12*CH ₂ C12 (2 mg, 2 μmol) and 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (31 mg, 0.2 mmol) in dioxane (0.8 mL) and H ₂ O (0.2 mL) was stirred at 130 °C for 16 h. under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% MeOH in DCM) to give the title compound (14 mg, 49%) as colorless oil. LCMS (ESI) m/z: 297.1[M+H] ⁺ . Step 3: Synthesis of rac-tert-butyl ((3-fluoro-4-((5-((l/?,3‘V)-3-((4-(prop-l-en-2-yl)pyridin- 3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carb amate

To a solution of rac-5-((1R,3S )-3-((4-(prop-l-en-2-yl)pyridin-3- yl)oxy)cyclopentyl)pyrimidin-2-amine (13 mg, 44 μmol) and tert-butyl N-(4-bromo-3-fluoro- phenyl)sulfonylcarbamate (47 mg, 0.14 mmol) in dioxane (2 mL) was added BrettPhos Pd G3 (8 mg, 9 μmol), BrettPhos (5 mg, 9 μmol) and CS ₂ CO ₃ (86 mg, 0.26 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 5 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous TsfeSCh, filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% methanol in ethyl acetate) to afford the title compound (14 mg, 31%) as yellow oil. LCMS (ESI) m/z: 570.1[M+H] ⁺ .

Step 4: Synthesis of rac-3-fluoro-4-((5-((H?,3^)-3-((4-(prop-l-en-2-yl)pyridin-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 55)

To a solution of rac-tert-butyl ((3-fluoro-4-((5-((1R,3S )-3-((4-(prop-l-en-2-yl)pyridin-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carb amate (14 mg, 25 μmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 44% - 74% I 0.05% NBE’HzO +10mM NH ₄ HCO ₃ in water) to give Compound 55 (2 mg, 16%) as a white solid. LCMS (ESI) m/z: 470.2 [M+H] ⁺ ; NMR (400 MHz, CDCI3) δ 8.90 - 8.80 (m, 1H), 8.44 (s, 2H), 8.30 - 8.17 (m, 2H), 7.76 - 7.71 (m, 1H), 7.70 - 7.65 (m, 1H), 7.59 - 7.51 (m, 1H), 7.23 - 7.18 (m, 1H), 5.34 - 5.26 (m, 2H), 5.09 - 4.99 (m, 1H), 4.87 - 4.81 (m, 2H), 3.23 - 3.04 (m, 1H), 2.83 - 2.65 (m, 1H), 2.25 - 2.18 (m, 2H), 2.15 (s, 3H), 2.12 - 2.01 (m, 1H), 1.97 - 1.90 (m, 2H).

Example 12: Synthesis of (H?5,3*Vl?)-3-(5-chloro-6-((4-sulfamoylphenyl)amino)pyridin- 3- yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 353)

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

A mixture of tert-butyl N-(5-bromo-3-chloro-2-pyridyl)-N-tert-butoxycarbonyl-carbama te (4 g, 9.8 mmol), cyclopent-2-en-l-ol (1.65 g, 19.62 mmol), Pd(OAc)2 (220 mg, 981 μmol), TBAC (2.73 g, 9.8 mmol) and KOAc (2.89 g, 29.4 mmol) in DMF (15 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (2 g, 49 %) as a lightyellow oil. LCMS (ESI) m/z: 433.1 [M+Na] ⁺ .

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

To a mixture of fert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[3-oxocyclopentyl]-2- pyridyl]carbamate (2 g, 4.9 mmol) in THF (40 mL) was added LiBHEts (1 M, 7.30 mL) at -65 °C under N2 atmosphere. The reaction was stirred at same time for 1 h. The reaction mixture was quenched by addition sat. aq. NaHCO ₃ (50 mL) at -65 °C, extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 70% EtOAc in petroleum ether) to give the title compound (1 g, 49 %) as a yellow solid. LCMS (ESI) m/z: 435.1 [M+Na] ⁺ .

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

To a solution of tert-butyl /V-tert-butoxycarbonyl-N-[3-chloro-5-[( l/f3,S)-3- hydroxycyclopentyl]-2-pyridyl]carbamate (1 g, 2.42 mmol) and DMAP (30 mg, 242 μmol), pyridine (0.6 mL, 7.3 mmol) in DCM (15 mL) was added (4-nitrophenyl) carb onochlori date (976 mg, 4.8 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition sat. aq. NaHCCL (10 mL) at 25 °C, extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (1.1 g, 78%) as a brown solid. LCMS (ESI) m/z: 600.1 [M+Na] ⁺ .

Step 4 - Synthesis of tert-butyl (tert-butoxycarbonyl)(3-chloro-5-(3-((((A)-4,4,4- trifluorobutan-2-yl)carbamoyl)oxy)cyclopentyl)pyridin-2-yl)c arbamate

To a mixture of [3-[6-[bis(tert-butoxycarbonyl)amino]-5-chloro-3-pyridyl]cyc lopentyl] (4-nitrophenyl) carbonate (1.1 g, 1.90 mmol) and (S)-4,4,4-trifluorobutan-2-amine(467 mg, 2.85 mmol, HC1 salt) in THF (15 mL) was added DIPEA (1 mL, 5.7 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition water (10 mL) at 25 °C, extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 60% EtOAc in petroleum ether) to give the title compound (1.05 g, 97 %) as a brown solid. LCMS (ESI) m/z: 588.2 [M+Na]“.

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

To a mixture of tert-butyl N-tert-butoxycarbonyl- N-[3-chloro-5-[3-[[(lS)-3,3,3-trifluoro- l-methyl-propyl]carbamoyloxy]cyclopentyl]-2-pyridyl]carbamat e (1.05 g, 1.86 mmol) in DCM (10 mL) was added TFA (3 mL, 40.32 mmol) at 25 °C under N2 atmosphere. The reaction mixture was stirred at 25 °C for 1 h. This reaction was concentrated in vacuo give the title compound (0.69 g, crude, TFA salt) as yellow oil that required no further purification. LCMS (ESI) m/z: 366.0 [M+H] ⁺ .

Step 6 - Synthesis of 3-(6-((4-( \-(tert-buloxycarbonyl)sulfainoyl)phenyl)amino)-5- chloropyridin-3-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate

To a mixture of 3-(6-amino-5-chloropyridin-3-yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2- yl)carbamate (0.5 g, 1.37 mmol) and tert-butyl N-(4-bromophenyl)sulfonylcarbamate (919 mg, 2.7 mmol) in dioxane (10 mL) was added BrettPhos Pd G3 (124 mg, 137 μmol), Brettphos (147 mg, 273 μmol), CS ₂ CO ₃ (1.34 g, 4.1 mmol) at 25 °C under N2 atmosphere. The reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , 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 (120 mg, 14%) as a white solid. LCMS (ESI) m/z 621.2 (M+H ⁺ ).

Step 7 - Synthesis of (1RS,3SR)-3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl) amino)- 5-chloropyridin-3-yl)cyclopentyl ((*£)-4,4,4-trifluorobutan-2-yl)carbamate and (lRS,3RS)-3- (6-((4-(/V-(teH-butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chl oropyridin-3-yl)cyclopentyl ((*£)-4,4,4-trifluorobutan-2-yl)carbamate

3-(6-((4-(N-(ferLbutoxycarbonyl)sulfamoyl)phenyl)amino)-5 -chloropyridin-3- yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (0.12 g, 193 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ(250mm*30mm,10um); Supercritical CO ₂ / EtOH+0.1% NEh’EEO = 75/25; 60 mL/min)) to afford (1 RS,3SR)-3-(6-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)-5-chloropyridin-3-yl) cyclopentyl ((S)-4,4,4- trifluorobutan-2-yl)carbamate (cis isomers, 25 mg, mixture of first peak and second peak) as a white solid and (lA5,3A5)-3-(6-((4-(N-(/erLbutoxycarbonyl)sulfamoyl)phenyl)a mino)-5- chl oropyri din-3 -yl)cy cl opentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (trans isomers, 20 mg, mixture of third peak and fourth peak) as a white solid.

Step 8: Synthesis of (1RS,3SR )-3-(5-chloro-6-((4-sulfamoylphenyl)amino)pyridin-3- yl)cyclopentyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 353)

To a solution of (1RS,3SR)-3-(6-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl) amino)-5- chl oropyri din-3 -yl)cy cl opentyl ((.S')-4, 4, 4-tri fl uorobutan-2-yl (carbarn ate (25 mg, 40 μmol) in dioxane (2 mL) was added HCl/dioxane (2 mL, 4 M) at 25 °C under N2 atmosphere. The mixture was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 35% - 63% 10.05% HC1 in water) to give Compound 353 (7.2 mg, 34 %) as a white solid. LCMS (ESI) m/z: 521.0 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO--d ₆ ) δ 8.72 (s, 1H), 8.10 (s, 1H), 7.85 - 7.79 (m, 3H), 7.72 - 7.66 (m, 2H), 7.37 - 7.04 (m, 3H), 5.15 - 5.07 (m, 1H), 3.91 - 3.78 (m, 1H), 3.31 - 3.10 (m, 1H), 2.44 - 2.32 (m, 2H), 2.27 - 2.17 (m, 1H), 2.15 - 2.07 (m, 1H), 2.06 - 1.97 (m, 1H), 1.94 - 1.83 (m, 1H), 1.72 - 1.49 (m, 2H), 1.13 (d, J= 6A Hz, 3H). Example 13: Synthesis of (1RS,4RS )-4-(2-((4-sulfamoylphenyl)aniino)pyrimidin-5- yl)cyclopent-2-en-l-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 412)

Step 1: Synthesis of rac-tert-butv\ (tert-butoxycarbonyl)(5-((17f,470-4-((tert- butyldiphenylsilyl)oxy)cyclopent-2-en-l-yl)pyrimidin-2-yl)ca rbamate

A mixture of tert-butyl N-(5-bromopyrimidin-2-yl)-A-tert-butoxycarbonyl-carbamate (3 g, 8.0 mmol), tert-butyl-cyclopent-3-en-l-yloxy-diphenyl-silane (3.9 g, 12.0 mmol), Pd(OAc)2 (180 mg, 802 μmol), KOAc (1.57 g, 16.0 mmol) and PPhs (420 mg, 1.60 mmol) in DMF (20 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at 140 °C for 1 h under N2 atmosphere in microwave reactor. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (1 g, 20 %) as a white solid. LCMS (ESI) m/z: 616.3 [M+H] ⁺ ; ¹ HNMR (400 MHz, CDC1 ₃ ) δ 8.44 (s, 2H), 7.70 - 7.67 (m, 4H), 7.44 - 7.38 (m, 6H), 5.93 - 5.86 (m, 2H), 5.10 - 5.05 (m, 1H), 4.17 - 4.13 (m, 1H), 2.46 - 2.37 (m, 1H), 1.92 - 1.84 (m, 1H), 1.45 (s, 18H), 1.08 (s, 9H).

Step 2: Synthesis of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,4/?)-4-hydroxycyclopent-2- en-l-yl)pyrimidin-2-yl)carbamate

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

Step 3: Synthesis of rac-tert-butyl (ri77-buloxycarbonyl)(5-((l/?.4/?)-4-(((4- nitrophenoxy)carbonyl)oxy)cyclopent-2-en-l-yl)pyrimidin-2-yl )carbamate

To a solution of rac-te/7-butyl (tert-butoxycarbonyl)(5-((1R ,4R )-4-hydroxycyclopent-2- en-l-yl)pyrimidin-2-yl)carbamate (530 mg, 1.4 mmol), pyridine (333 mg, 4.2 mmol) and DMAP (34 mg, 280 μmol) in DCM (10 mL) was added (4-nitrophenyl) carbonochloridate (424 mg, 2.1 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition sat. aq. NaHCCf (10 mL) at 25 °C, extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% ethyl acetate in petroleum ether) to give the title compound (700 mg, 92 %) as colorless oil. LCMS (ESI) m/z: 543.1 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((l/iy,41t5)-4-((((S)-4,4,4- trifluorobutan-2-yl)carbamoyl)oxy)cyclopent-2-en-l-yl)pyrimi din-2-yl)carbamate

To a solution of rac-fert-butyl (tert-butoxycarbonyl)(5-((lA,4A)-4-(((4- nitrophenoxy)carbonyl)oxy)cyclopent-2-en-l-yl)pyrimidin-2-yl )carbamate (700 mg, 1.3 mmol), (S)-4,4,4-trifluorobutan-2-amine (316 mg, 1.9 mmol, HC1 salt) in THF (10 mL) was added TEA (540 μL, 3.9 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition sat. aq. NaHCCL (10 mL) at 25 °C, extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% ethyl acetate in petroleum ether) to give the title compound (600 mg, 88 %) as a yellow solid. LCMS (ESI) m/z: 531.2 [M+H] ⁺ .

Step 5: Synthesis of (1RS,4RS )-4-(2-aniinopyrimidin-5-yl)cyclopent-2-en-l-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate

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

Step 6: Synthesis of (1RS,4RS )-4-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopent-2- en-l-yl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 412)

A mixture of (1RS,4RS)-4-(2-aminopyrimidin-5-yl)cyclopent-2-en-l-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate (0.15 g, 454 μmol), tert-butyl N-(4- bromophenyl)sulfonylcarbamate (305 mg, 908 μmol), CS ₂ CO ₃ (296 mg, 908 μmol) in dioxane (5 mL) was added Brettphos (24 mg, 45 μmol), CS ₂ CO ₃ (296 mg, 908 μmol) and BrettPhos Pd G3 (41 mg, 45 μmol), then the mixture was stirred at 100 °C for 3 h under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 0 - 35% / 0.04% HC1 in water) to give Compound 412 (2.1 mg) as a yellow solid. LCMS (ESI) m/z: 486.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.18 (s, 2H), 10.05 (s, 1H), 8.70 (s, 4H), 8.39 (s, 2H), 7.82 - 8.01 (m, 7H), 7.65 - 7.77 (m, 7H), 7.30 (d, 8.8 Hz, 3H), 7.12 - 7.23 (m, 6H), 6.33 (brs, 2H), 6.18 - 6.14 (m, 1H),

6.05 - 6.00 (m, 1H), 5.74 - 5.67 (m, 1H), 5.35 - 5.25 (m, 2H), 4.09 - 4.01 (m, 1H), 3.82 - 3.90 (m, 3H), 3.00 - 3.08 (m, 2H), 2.84 - 2.93 (m, 2H), 2.62 - 2.73 (m, 3H), 2.34 - 2.42 (m, 6H), 2.06 - 2.25 (m, 2H), 1.05 - 1.18 (m, 11H).

Example 14: Synthesis of (1s,3s)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl) amino)pyrimidin-5-yl)cyclobutyl(l-methylcyclopropyl)carbamat e (Compound 2) and (lr,3r)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino )pyrimidin-5-yl)cyclobutyl (1- methylcyclopropyl)carbamate (Compound 3)

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

To a solution of (2-aminopyrimidin-5-yl) _b oronic acid (3.0 g, 21.6 mmol) in dioxane (100 mL) was added N-[(3-benzyloxycyclobutylidene)amino]-4-methyl-benzenesulfon amide (14.2 g, 43.2 mmol, prepared according to the procedure in WO 2021/155320, which is incorporated by reference herein in its entirety) and CS ₂ CO ₃ (14.1 g, 43.2 mmol). The mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was filtrated, the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (3.5 g, crude), which was further purified by reverse phase chromatography (acetonitrile 17 - 47% 1 0.225% formic acid in water) to give the title compound (1.3 g, 24%) as a yellow solid. LCMS (ESI) m/z: 256.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 - 8.08 (m, 2H), 7.47 - 7.14 (m, 5H), 6.47 (s, 2H), 4.42 - 4.36 (m, 2H), 4.28 - 4.18 (m, 1H), 4.02 - 3.90 (m, 0.6H), 3.45 - 3.27 (m, 1H), 2.85 - 2.75 (m, 0.4H), 2.61 - 2.48 (m, 1H), 2.42 - 2.23 (m, 2H), 1.98 - 1.86 (m, 1H).

Step 2: Synthesis of 4-((5-(3-(benzyloxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluor o-/V- isopropylbenzenesulfonamide

To a solution of 5-(3-benzyloxycyclobutyl)pyrimidin-2-amine (0.4 g, 1.33 mmol) and 4- bromo-3-fluoro-N-isopropyl-benzenesulfonamide (786 mg, 2.65 mmol) in dioxane (10 mL) was added CS ₂ CO ₃ (1.30 g, 3.98 mmol), BrettPhos (71 mg, 132 μmol) and BrettPhos Pd G3 (120 mg, 132 μmol). The mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (0.6 g, 96%) as a yellow oil. LCMS (ESI) m/z: 471.1 [M+H] ⁺ . Tl NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.56 - 8.36 (m, 2H), 8.28 - 8.15 (m, 1H), 7.63 - 7.51 (m, 3H), 7.40 - 7.31 (m, 4H), 7.31 - 7.24 (m, 1H), 4.46 - 4.38 (m, 2H), 4.29 - 4.26 (m, 0.6 H), 3.58 - 3.39 (m, 1H), 3.29 - 3.21 (m, 2H), 3.00 - 2.85 (m, 0.4 H), 2.69 - 2.54 (m, 1H), 2.45 - 2.35 (m, 2H), 0.99 - 0.93 (m, 6H).

Step 3: Synthesis of 3-fluoro-4-((5-(3-hydroxycyclobutyl)pyrimidin-2-yl)amino)-/V - isopropylbenzenesulfonamide

To a solution of 4-((5-(3-(benzyloxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluor o-A- isopropylbenzenesulfonamide (0.55 g, 1.17 mmol) in DCM (4 mL) was added BCI ₃ (1 M, 11.69 mL) slowly at -78 °C. After addition, the mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with NH ₃ /MeOH (1 M, 5 mL), and then concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (0.42 g, 95%) as a colorless oil. LCMS (ESI) m/z: 381.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 6 9.46 - 9.29 (m, 1H), 8.55 - 8.37 (m, 2H), 8.29 - 8.16 (m, 1H), 7.69

- 7.39 (m, 3H), 5.13 (s, 1H), 4.35 - 4.21 (m, 0.6H), 3.48 - 3.35 (m, 1H), 3.26 - 3.21 (m, 1H), 2.90

- 2.78 (m, 0.4H), 2.68 - 2.53 (m, 1H), 2.38 - 2.25 (m, 2H), 1.97 - 1.80 (m, 1H), 0.96 (d, J= 6.4 Hz, 6 H).

Step 4: Synthesis of 3-(2-((2-fluoro-4-(/V-isopropylsulfamoyl)phenyl)aniino)pyrin iidin-5- yl)cyclobutyl (4-nitrophenyl) carbonate

To a solution of 3-fluoro-4-((5-(3-hydroxycyclobutyl)pyrimidin-2-yl)amino)-A- isopropylbenzenesulfonamide (0.37 g, 0.97 mmol) in DCM (20 mL) was added DMAP (24 mg, 0.19 mmol) and pyridine (230 mg, 2.92 mmol). Then (4-nitrophenyl) carbonochloridate (392 mg, 1.95 mmol) was added slowly. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with water (20 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na ₂ SO ₄ , 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 (0.43 g, 81%) as a white solid. LCMS (ESI) m/z: 546.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.58 - 8.49 (m, 2H), 8.35 - 8.30 (m, 2H), 8.27 - 8.18 (m, 1H), 7.64 - 7.53 (m, 5H), 5.33 - 4.91 (m, 1H), 3.78 - 3.63 (m, 0.6H),

3.30 - 3.21 (m, 1H), 3.20 - 3.03 (m, 0.4H), 2.87 - 2.76 (m, 1H), 2.68 - 2.62 (m, 2H), 2.42 - 2.29 (m, 1H), 0.96 (d, J= 6.4 Hz, 6 H).

Step 5: Synthesis of (1s,3s)-3-(2-((2-fluoro-4-(N- isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cydobutyl (1- methylcyclopropyl)carbamate (Compound 2) and (lr,3r)-3-(2-((2-fluoro-4-(/V- isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl (1- methylcyclopropyl)carbamate (Compound 3)

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

Example 15: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-((l-isopropyl-lH-l,2,4-triazol-3- yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 367)

Step 1: Synthesis of tert-butyl (5-(( l s,3s)-3-(( 1 -isopropyl-1 H- 1.2.4-triazol-3- yl)oxy)cyclobutyl)pyrimidin-2-yl)carbamate

To a solution of tert-butyl (5-((1s,3s)-3-hydroxycyclobutyl)pyrimidin-2-yl)carbamate (453 mg, 1.71 mmol) in DMF (8 mL) was added NaH (150 mg, 3.82 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then l-isopropyl-3-nitro-l,2,4-triazole (400 mg, 2.56 mmol, prepared according to the procedure in Chem Hete Compounds., 2005, 41, 861) was added. The mixture was stirred at 65 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with sat. aq. NH4CI (3 mL), diluted with H ₂ O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (106 mg, 17%) as yellow oil. LCMS (ESI) m/z: 375.2 [M+H] ⁺ .

Step 2: Synthesis of 5-( (I s.3s)-3-((l -iso propyl- 1H- 1.2.4-t riazol-3- yl)oxy)cydobutyl)pyrimidin-2-amine

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

To a solution of 5-((1s,3s)-3-((l-isopropyl-lrt-l,2,4-triazol-3- yl)oxy)cyclobutyl)pyrimidin-2-amine (75 mg, 273 μmol), tert-butyl N-(4-bromo-3-fluoro- phenyl)sulfonylcarbamate (145 mg, 410 μmol) and CS ₂ CO ₃ (267 mg, 820 μmol) in dioxane (3 mL) was added BrettPhos (15 mg, 27 μmol) and BrettPhos Pd G3 (25 mg, 27 μmol). The reaction was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (98 mg, 65%) as a yellow solid. LCMS (ESI) m/z: 548.2 [M+H] ⁺ .

Step 4: Synthesis of 3-fl uoro-4-( (5-((l v.3v)-3-(( 1 -iso propyl- 1H- 1.2.4-1 riazol-3- yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 367)

A solution of tert-butyl ((3-fluoro-4-((5-((l.s,3s)-3-(( l-isopropyl- lrt- l,2,4-triazol-3- yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carba mate (98 mg, 179 μmol) in HCl/dioxane (2 mL, 4M) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 25% - 55% / 0.225% formic acid in water) to give Compound 367 (68 mg, 85%) as a white solid. LCMS (ESI) m/z: 448.0 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.48 (s, 2H), 8.20 (s, 1H), 8.19

- 8.12 (m, 1H), 7,63 - 7.57 (m, 2H), 7.36 (s, 2H), 4.96 - 4.85 (m, 1H), 4.45 - 4.35 (m, 1H), 3.13

- 3.01 (m, 1H), 2.86 - 2.75 (m, 2H), 2.25 - 2.14 (m, 2H), 1.39 (d, J= 6.4 Hz, 6H).

Example 16: Synthesis of (3-nnoro-4-((5-(( ls.3,s)-3-((4-( 1 -met hylcy clopropyl )-4H- 1.2.4- triazol-3-yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)phenyl)dime thylphosphine oxide

(Compound 523)

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

To a solution of l-bromo-2-fluoro-4-iodo-benzene (1 g, 3.32 mmol) and methylphosphonoylmethane (350 mg, 4.49 mmol) in THF (15 mL) and dioxane (15 mL) was added Pd2(dba)s (152 mg, 166 μmol), Xantphos (192 mg, 332 μmol) and TEA (4.63 mL, 33.23 mmol). The reaction was stirred at 60 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and brine (30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , 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 (220 mg, 26%) as a white solid. LCMS (ESI) m/z: 251.1 [M+H] ⁺ .

Step 2: Synthesis of (3-fluoro-4-((5-( ( l,s.,3s)-3-((4-( 1 -met hylcyclopropy l)-4H- 1.2.4-t riazol-3- yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)phenyl)dimethylphosph ine oxide (Compound 523)

To a solution of 5-((1s,3s)-3-((4-(l-methylcyclopropyl)-4#-l,2,4-triazol-3- yl)oxy)cyclobutyl)pyrimidin-2-amine (30 mg, 104.77 μmol) and CS ₂ CO ₃ (204 mg, 629 μmol) in dioxane (2 mL) was added l-bromo-4-dimethylphosphoryl-2-fluoro-benzene (42 mg, 168 μmol), BrettPhos (8 mg, 16 μmol) and BrettPhos Pd G3 (14 mg, 16 μmol). The reaction mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 20% - 50% / 0.225% formic acid in water) to give Compound 523 (10 mg, 21%) as a white solid. LCMS (ESI) m/z: 457.0 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.47 (s, 2H), 8.19 (s, 1H), 8.03 - 8.10 (m, 1H), 7.50 - 7.63 (m, 2H), 5.03 - 5.14 (m, 1H), 3.05 - 3.17 (m, 1H), 2.84 - 2.93 (m, 2H), 2.21 - 2.33 (m, 2H), 1.65 (d, J= 13.2 Hz, 6H), 1.42 (s, 3H), 1.03 - 1.09 (m, 2H), 0.85 - 0.90 (m, 2H). Example 17: Synthesis of 4-((5-((1s,3s)-3-((5-(l-aminocyclobutyl)thiazol-2- yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfo namide HC1 salt (Compound 368)

Compound 368

Step 1: Synthesis of N-cyclobutylidene-2-methylpropane-2-sulfinamide

To a solution of 5-bromo-2-methylsulfanyl-thiazole (500 mg, 2.38 mmol, prepared according to the procedure in WO2022105771) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 1.05 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min. Then N-cyclobutylidene-2- methyl-propane-2-sulfmamide (454 mg, 2.62 mmol) in THF (1 mL) was added to the reaction mixture and stirred at -78 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with sat. aq. NH4CI (3 mL), diluted with H ₂ O (20 mL), and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (200 mg, 27%) as a yellow solid. LCMS (ESI) m/z: 305.2 [M+H] ⁺ . Step 2: Synthesis of 2-methyl-N-(l-(2-(methylsulfonyl)thiazol-5-yl)cyclobutyl)pro pane-2- sulfinamide

To a mixture of 2-methyl-N-(l-(2-(methylthio)thiazol-5-yl)cyclobutyl)propane -2- sulfinamide (150 mg, 0.49 mmol) in MeCN (3 mL) and H ₂ O (1 mL) was added oxone (332 mg, 1.97 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water (10 mL), then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (110 mg, crude) as yellow oil that required no further purification.

Step 3: Synthesis of tert-butyl (5-((1s,3s)-3-((5-(l-((tert- bntylsulfinyl)amino)cyclobutyl)thiazol-2-yl)oxy)cyclobutyl)p yriniidin-2-yl)carbamate

To a solution of tert-butyl (5-( -3-hydroxycyclobutyl)pyrimidin-2-yl)carbamate (90 mg, 0.34 mmol) in DMF (5 mL) was added NaH (41 mg, 1.02 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then 2-methyl-N-[l-(2-methylsulfonylthiazol-5- yl)cyclobutyl]propane-2-sulfinamide (110 mg, 0.34 mmol) was added. The mixture was stirred at 40 °C for 16 h under a nitrogen atmosphere. The reaction was quenched with sat. aq. NH4CI (3 mL), diluted with H ₂ O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (40 mg, 28%) as yellow oil. LCMS (ESI) m/z: 522.3 [M+H] ⁺ .

Step 4: N-(l-(2-((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutoxy)thiazo l-5-yl)cyclobutyl)-2- methylpropane-2-sulfinamide

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

Step 5: tert-butyl ((4-((5-((1s,3s)-3-((5-(l-((tert-butylsulfinyl)amino)cyclobu tyl)thiazol-2- yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfo nyl)carbamate

To a solution of N-(l-(2-((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutoxy)thiazo l-5- yl)cyclobutyl)-2-methylpropane-2-sulfinamide (30 mg, 71 μmol), tert-butyl ((4-bromo-3- fluorophenyl)sulfonyl)carbamate (50 mg, 142 μmol) and CS ₂ CO ₃ (186 mg, 569 μmol) in dioxane (3 mL) was added BrettPhos (10 mg, 19 μmol) and BrettPhos Pd G3 (9 mg, 9 μmol). The reaction was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (30 mg, 46%) as a yellow solid. LCMS (ESI) m/z: 695.3 [M+H] ⁺ .

Step 6: 4-((5-((1s,3s)-3-((5-(l-aminocyclobutyl)thiazol-2-yl)oxy)cyc lobutyl)pyrimidin-2- yl)amino)-3-fluorobenzenesulfonamide (Compound 368)

To a solution of ferLbutyl ((4-((5-( -3-((5-(l-((ferLbutylsulfmyl)amino)cyclobutyl)thiazol- 2 -yl)oxy)cy cl obutyl)pyrimidin-2-yl)amino)-3 -fluorop henyl)sulfonyl)carbamate (30 mg, 43 μmol) in HCl/di oxane (4 mL, 4 M) was stirred at room temperature for 2 h. This mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 15% - 45% I 0.04% HC1 in water) to give Compound 368 (10.4 mg, 62%) as a white solid. LCMS (ESI) m/z: 513.2 [M+Na] ⁺ . Tl NMR (400 MHz, DMSO-t7 ₆ ) δ 9.45 (s, 1H), 8.85 (s, 3H), 8.50 (s, 2H), 8.13 - 8.09 (m, 1H), 7.67 - 7.54 (m, 2H), 7.39 (s, 2H), 5.23 - 5.08 (m, 1H), 3.18 - 3.04 (m, 1H), 2.88 - 2.85 (m, 2H), 2.66 - 2.59 (m, 2H), 2.48 - 2.41 (m, 2H), 2.37 - 2.21 (m, 2H), 2.07 - 1.97 (m, 1H), 1.90 - 1.77 (m, 1H).

Example 18: Synthesis of (1s,3^)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino ) pyrimidin-5-yl)cyclobutyl (l-methylcyclopropyl)carbamate (Compound 4) and (lr,35)-3-(2- ((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5- yl)cyclobutyl (1- methylcyclopropyl) carbamate (Compound 5)

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

To a mixture of 3-(benzyloxymethyl) cyclobutanone (5 g, 26.28 mmol) in MeOH (50 mL) was added 4-methylbenzenesulfonohydrazide (4.89 g, 26.28 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated in vacuo to give the title compound (8.4 g, crude) as a white solid that required no further purification. LCMS (ESI) m/z: 359.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDC1 ₃ ) 37.87 - 7.60 (m, 2H), 7.50 - 7.29 (m, 7H), 4.59 - 4.47 (m, 2H), 3.65 - 3.40 (m, 2H), 319 - 3.05 (m, 1H), 3.01 - 2.90 (m, 1H), 2.89 - 2.79 (m, 1H), 2.74 - 2.64 (m, 1H), 2.62 - 2.53 (m, 1H), 2.43 (s, 3H).

Step 2: Synthesis of 5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine

To a mixture of (2-aminopyrimidin-5-yl) _b oronic acid (3.85 g, 27.72 mmol) in dioxane (150 mL) was added N-[[3-(benzyloxymethyl)cyclobutylidene]amino]-4-methyl-benze nesulfonamide (19.80 g, 55.24 mmol) and CszCCh (13.51 g, 40.52 mmol). The mixture was stirred at 105 °C for 16 h. After cooling to room temperature, the reaction mixture was filtrated, the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (3.5 g, crude). The crude product was further purified by reverse phase chromatography (acetonitrile 25 - 55% 10.225% formic in water) to give the title compound (1.75 g, 22%) as a yellow solid. LCMS (ESI) m/z: 270.1 [M+H] ⁺ . *H NMR (400 MHz, CDC1 ₃ ) 6 8.23 - 8.15 (m, 2H), 7.39 - 7.26 (m, 5H), 5.11 (s, 2H), 4.60 - 4.51 (m, 2H), 3.64 - 3.59 (m, 1H), 3.50 - 3.20 (m, 2H), 2.71 - 2.56 (m, 1H), 2.52 - 2.41 (m, 1H), 2.30 - 2.15 (m, 2H), 1.95 - 1.84 (m, 1H).

Step 3: Synthesis of tert-butyl ((4-((5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2- yl)amino)-3-fluorophenyl)sulfonyl)carbamate To a solution of 5-[3-(benzyloxymethyl)cyclobutyl]pyrimidin-2-amine (1.3 g, 4.83 mmol) in dioxane (40 mL) was added tert-butyl N-(4-bromo-3-fluoro-phenyl)sulfonylcarbamate (2.22 g, 6.27 mmol), CS ₂ CO ₃ (4.72 g, 14.48 mmol), BrettPhos (259 mg, 482.66 μmol) and BrettPhos Pd G3 (437.53 mg, 482.66 μmol). The reaction was stirred at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, EtOAc (50 mL) was added, then adjusted to pH = 7 by progressively adding aq. HC1 (0.5 M). And the mixture was washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 40% EtOAc in petroleum ether) to give the title compound (1.9 g, 72%) as a brown solid. LCMS (ESI) m/z: 543.2 [M+H] ⁺ .

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

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

Step 5: Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)aniino)pyriniidin-5- yl)cyclobutyl)methyl (4-nitrophenyl) carbonate

To a solution of 3-fluoro-4-[[5-[3-(hydroxymethyl)cyclobutyl]pyrimidin-2- yl]amino]benzenesulfonamide (130 mg, 368.92 μmol) in DCM (5 mL) was added (4-nitrophenyl) carb onochlori date (148.72 mg, 737.83 μmol), DMAP (45 mg, 368.92 μmol) and pyridine (87.54 mg, 1.11 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (30 mL), then washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous IXfeSCU, filtered and concentrated in vacuo. The residue was purified by prep-TLC (5% MeOH in DCM) to give the title compound (82 mg, 43%) as a white solid. LCMS (ESI) m/z: 518.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-tL) 6 9.43 - 9.38 (m, 1H), 8.52 - 8.45 (m, 2H), 8.35 - 8.29 (m, 2H), 8.15 (t, J= 8.4 Hz, 1H), 7.63 - 7.55 (m, 4H), 7.37 (s, 2H), 4.47 - 4.25 (m, 2H), 3.64 - 3.38 (m, 1H), 2.77 - 2.67 (m, 1H), 2.47 - 2.36 (m, 1H), 2.35 - 2.30 (m, 1H), 2.28 - 2.24 (m, 1H), 2.05 - 1.91 (m, 1H).

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

To a solution of [3-[2-(2-fluoro-4-sulfamoyl-anilino)pyrimidin-5-yl]cyclobuty l]methyl (4- nitrophenyl) carbonate (50 mg, 96.62 μmol) in THF (4 mL) was added (2S)-4,4,4-trifluorobutan- 2-amine (47.41 mg, 289.86 μmol, HC1 salt) and EtsN (29.33 mg, 289.86 μmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (20 mL), then washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by prep-TLC (5% MeOH in DCM) to give the title compound (36 mg, 74%) as a white solid. LCMS (ESI) m/z: 506.1 [M+H] ⁺ . Step 7: Synthesis of ((1s,31f)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin- 5- yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 4) and ((lr,3^)-3- (2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobu tyl)methyl (S)-4,4 ₉ 4- trifluorobutan-2-yl)carbamate (Compound 5)

The mixture of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5- yl)cyclobutyl)methyl (S)-(4,4,4-trifluorobutan-2-yl)carbamate (36 mg, 71.22 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL AS (250mm*30mm,5um); Supercritical CO ₂ 1 EtOH + 0.1% NEL’ELO = 60/40; 100 ml/min) to afford ((1s,3R )-3-(2-((2-fluoro-4- sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2- yl)carbamate (Compound 4, 8.82 mg, first peak) as a white solid. LC-MS: (ES+H, m/z) δ06.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-t/s) δ 9.37 (s, 1H), 8.45 (s, 2H), 8.15 (t, J = 8.2 Hz, 1H), 7.66 - 7.55 (m, 2H), 7.36 (s, 2H), 7.30 (d, J = 8.4 Hz, 1H), 4.07 - 3.91 (m, 2H), 3.89 - 3.79 (m, 1H), 3.28 - 3.27 (m, 1H), 2.66 - 2.61 (m,lH), 2.46 - 2.27 (m, 4H), 1.89 (q, J= 10.3 Hz, 2H), 1.14 (d, J= 6.7 Hz, 3H); ¹⁹ F NMR (377 MHz, DMSO) δ -121.67, -62.54. And ((lr,3S)-3-(2-((2-fhioro- 4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2- yl)carbamate (Compound 5, 18.10 mg, second peak) as white solid. LC-MS: (ES+H, m/z) δ06.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.48 (s, 2H), 8.17 (t, J= 8.1 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.37 (s, 2H), 7.30 (d, J= 8.4 Hz, 1H), 4.19 - 4.06 (m, 2H), 3.93 - 3.81 (m, 1H), 3.59-3.51 (m, 1H), 2.62 - 2.54 (m, 1H), 2.47 - 2.33 (m, 2H), 2.31 - 2.20 (m, 2H), 2.20 - 2.06 (m, 2H), 1.15 (d, J= 6.7 Hz, 3H); ¹⁹ F NMR (377 MHz, DMSO) δ -121.79, -62.55. Example 19: Synthesis of 4-((5-((1s,3s)-3-(((4-(trifluoromethyl)isothiazol-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino) _b enzenesulfonamide HC1 salt (Compound 586)

Step 1: Synthesis of 3-(benzyloxy)isothiazole

To a solution of isothiazol-3-one (5 g, 49 mmol) in DMF (50 mL) was added K ₂ CO ₃ (13.67 g, 98.9 mmol) and BnBr (10.15 g, 59.3 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 16 h. The reaction was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was washed with water (20 mL x 5), dried over anhydrous Na ₂ SO ₄ , fdtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% ethyl acetate in petroleum ether) to give the title compound (6.7 g, 71%) as yellow oil. LCMS (ESI) m/z: 191.8 [M+H] ⁺ .

Step 2: Synthesis of 3-(benzyloxy)-4-bromoisothiazole

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

Step 3: Synthesis of 3-(benzyloxy)-4-iodoisothiazole

To a mixture of 3-benzyloxy-4-bromo-isothiazole (1 g, 3.7 mmol) in THF (10 mL) was added chloro(isopropyl)magnesium (2 M, 2.8 mL) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min, then I2 (1.41 g, 5.5 mmol) in THF (10 mL) was added dropwise at 0 °C and stirred for 1 h. The resulting mixture was quenched with sat. aq. ISfeSCb (10 mL) and diluted with ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% ethyl acetate in petroleum ether) to give the title compound (1 g, 90%) as yellow oil. LCMS (ESI) m/z: 317.8 [M+H] ⁺ .

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

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

A solution of 3-benzyloxy-4-(trifluoromethyl)isothiazole (0.33 g, 1.3 mmol) in aq. HC1 (2.12 mL, 12 M) was stirred at 50 °C for 5 h. After cooling to room temperature, the reaction mixture was dilute with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% ethyl acetate in petroleum ether) to give the title compound (190 mg, 88%) as a white solid. ¹ HNMR (400 MHz, DMSO-^) δ 12.57 (s, 1H), 9.44 (s, 1H). LCMS (ESI) m/z: 169.8 [M+H] ⁺ .

Step 6: Synthesis of 5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine

To a mixture of (2-aminopyrimidin-5-yl) _b oronic acid (3.85 g, 27.72 mmol) in dioxane (150 mL) was added N-[[3-(benzyloxymethyl)cyclobutylidene]amino]-4-methyl-benze nesulfonamide (19.80 g, 55,24 mmol) and CS ₂ CO ₃ (13.51 g, 40.52 mmol). The mixture was stirred at 105 °C for 16 h. After cooling to room temperature, the reaction was filtrated and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (3.5 g, crude). The crude product was further purified by reverse phase chromatography (acetonitrile 25% - 55% / 0.225% formic in water) to give the title compound (1.75 g, 22%) as a yellow solid. LCMS (ESI) m/z: 270.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ 8.23 - 8.15 (m, 2H), 7.39 - 7.26 (m, 5H), 5.11 (s, 2H), 4.60 - 4.51 (m, 2H), 3.64 - 3.59 (m, 1H), 3.50 - 3.20 (m, 2H), 2.71 - 2.56 (m, 1H), 2.52 - 2.41 (m, 1H), 2.30 - 2.15 (m, 2H), 1.95 - 1.84 (m, 1H). Step 7: Synthesis of 5-((1s,3s)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine and 5- ((lr,3r)-3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine trans-5-(3-

((benzyloxy)methyl)cydobutyl)pyrimidin-2-ainine:

The mixture of 5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (300 g, 1.12 mol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*50mm,10um); Supercritical CO ₂ / EtOH + 0.1% NEE’EhO = 60/40; 220 ml/min) to afford 5-((1s,3s)-3- ((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (125 g, first peak, cis isomer) and 5-((lr,3r)- 3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2-amine (130 g, second peak, trans isomer) both as white solid. First peak (cA-isomer): LCMS (ESI) m/z: 270.0 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO- d ₆ ) 6 8.12 (s, 2 H), 7.29 - 7.37 (m, 5 H), 6.43 (s, 2 H), 4.46 (s, 2 H), 3.41 (d, J= 6.0 Hz, 2 H), 3.09 - 3.20 (m, 1 H), 2.50 - 2.40 (m, 1 H), 2.24 - 2.34 (m, 2 H), 1.75 - 1.85 (m, 2 H). Second peak (/rms-i sorrier): LCMS (ESI) m/z: 270.0 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 2 H), 7.31 - 7.38 (m, 5 H), 6.43 (s, 2 H), 4.50 (s, 2 H), 3.55 (d, J = 7.2 Hz, 2 H), 3.29 - 3.41 (m, 2 H), 2.06 - 2.16 (m, 4 H).

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

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

Step 9: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((1s,3s)-3-(((tert- butoxycarbonyl)oxy)methyl)cydobntyl)pyrimidin-2-yl)carbaniat e

To a solution of ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl)methanol (4 g, 22.3 mmol) in THF (50 mL) was added DMAP (545 mg, 4.5 mmol) and BOC2O (24.4 g, 112 mmol). The mixture was stirred at 40 °C for 16 h. The reaction was concentrated in vacuo to give the title compound (10 g, crude) as a white solid. LCMS (ESI) m/z: 480.1 [M+H] ⁺ .

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

A mixture of tert-butyl (/c'/7-butoxycarbonyl)(5-((l.s',3.s)-3-(((tert- butoxycarbonyl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamat e (18 g, 37.5 mmol) and NaOH (7.1 g, 17.75 mmol) in EtOH (100 mL) and H ₂ O (10 mL) was stirred at 20 °C for 12 h. The residue was poured into water (10 mL), extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried with anhydrous ISfeSCU, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 100% ethyl acetate in petroleum ether) to give the title compound (9 g, 85%) as a white solid. LCMS (ESI) m/z: 280.0 [M+H] ⁺ . TlNMR (400 MHz, DMSO-d ₆ ) δ 8.43 (s, 2H), 3.38 (d, J= 5.6 Hz, 2H), 3.28 - 3.24 (m, 1H), 2.43 - 2.36 (m, 1H), 2.34 - 2.27 (m, 2H), 1.90 - 1.81 (m, 2H), 1.44 (s, 9H).

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

A mixture of tert-butyl (5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2- yl)carbamate 1 (1 g, 5.6 mmol), tert-butyl N-(4-bromophenyl)sulfonylcarbamate (3.75 g, 11.2 mmol), BrettPhos Pd G3 (506 mg, 558 μmol), Brettphos (300 mg, 558 μmol) and CS ₂ CO ₃ (5.45 g, 16.7 mmol) in dioxane (20 mL) was degassed and purged with N2 three times. Then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 2% MeOH in DCM) to give the title compound (1.21 mg, 39%) as a white solid. LCMS (ESI) m/z: 435.2 [M+H] ⁺ .

Step 12: Synthesis of ((ls,3s)-3-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cydobut yl)methyl methanesulfonate

To a solution of tert-butyl ((4-((5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)carbamate (1.21 g, 2.1 mmol) in DCM (30 mL) was added TEA (0.87 mL, 6.3 mmol) and MsCl (0.26 g, 2.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The residue was poured into ice-water (50 mL), stirred for 2 min, and extracted with DCM (50 mL). The organic layer was washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (1 g, crude) as yellow oil that required no further purification. LCMS (ESI) m/z: 513.2 [M+H ⁺ ], Step 13: Synthesis of tert-butyl ((4-((5-((1s,3s)-3-(((4-(trifluoromethyl)isothiazol-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfony l)carbamate

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

Step 14: Synthesis of 4-((5-((1s,3s)-3-(((4-(trifluoromethyl)isothiazol-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino) _b enzenesulfonamide HC1 salt (Compound 586)

A solution of tert-butyl ((4-((5-(( l.s',3.s)-3-(((4-(trifluorornethyl)isothiazol-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfony l)carbamate (0.16 g, 273 μmol) in HCl/dioxane (5 mL, 4 M) was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 50% - 80% I HC1 in water) to give Compound 586 (25 mg, 17%) as a white solid. LCMS (ESI) m/z: 486.0 [M+H]“; ¹ H NMR (400 MHz, DMSO-t/e) δ 10.03 (s, 1H), 9.57 (s, 1H), 8.50 (s, 2H), 7.91 (d, J= 8.4 Hz, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7.16 (s, 2H), 4.46 - 4.39 (m, 2H), 3.47 - 3.27 (m, 1H), 2.90 - 2.70 (m, 1H), 2.46 - 2.34 (m, 2H), 2.13 - 1.99 (m, 2H).

Example 20: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-((5-(l-methylpyrrolidin-2-yl)-2- oxopyridin-1 (2H)-yl)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfon amide HC1 salt

(Compound 469)

Step 1: Synthesis of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-((5-(l-methylpyrrolidin-2-yl)-2- oxopyridin-l(2H)-yl)methyl)cyclobutyl)pyrimidin-2-yl)amino)p henyl)sulfonyl)carbamate

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

Step 2: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-((5-(l-methylpyrrolidin-2-yl)-2-ox opyridin-

I (2J/)-yl)methyl)cyclobutyl)pyrimidin-2-yl)amino)benzenesulfo namide HC1 salt

(Compound 469)

A solution of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-((5-(l-methylpyrrolidin-2-yl)-2- oxopyridin- 1 (2rt)-yl)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfo nyl)carbamate (7 mg,

I I μmol) in HCl/dioxane (5 mL, 4 M) was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo to give Compound 469 (3 mg, 32%) as a white solid. LCMS (ESI) m/z: 513.1 [M+H] ⁺ ; TlNMR (400 MHz, DMSO-d ₆ ) δ 11.08 - 10.93 (m, 1H), 9.41 (s, 1H), 8.46 (s, 2H), 8.17 - 8.10 (m, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 9.6, 2.4 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.38 (s, 2H), 6.46 (d, J= 9.2 Hz, 1H), 4.13 - 4.06 (m, 1H), 3.98 (d, J= 7.2 Hz, 2H), 3.69 - 3.60 (m, 3H), 3.31 - 3.23 (m, 1H), 3.13 - 3.04 (m, 1H), 2.75 - 2.66 (m, 1H), 2.59 (d, J= 4.8 Hz, 2H), 2.37 - 2.28 (m, 3H), 2.18 - 2.12 (m, 1H), 2.12 - 2.04 (m, 2H), 2.02 - 1.94 (m, 2H). Example 21: Synthesis of 3-fluoro-A ^/ -((1s,3s) ^_ 3-hydroxy-3-(trifluoromethyl)cyclobutyl)-4- ((5-((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclo butyl)pyrimidin-2- yl)amino)benzenesulfonamide (Compound 571)

Compound 571

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

To a solution of tert-butyl (5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2- yl)carbamate (0.5 g, 1.79 mmol) in DMF (5 mL) was addedNaH (358 mg, 8.95 mmol, 60% purity) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 30 min. Then 3-chloro-4- isopropyl-pyridazine (560 mg, 3.58 mmol, prepared according to the procedure in WO2022/174031) was added at 0 °C. The mixture was heated to 40 °C for 16 h. The reaction was quenched by addition MeOH (10 mL) at 0 °C. The solution was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EE (30% ethanol in ethyl ether) in petroleum ether) to give the title compound (0.26 g, 36%) as yellow oil. LCMS (ESI) m/z: 400.1 [M+H] ⁺ .

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

Step 3 - Synthesis of 3-fluoro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl) -4-((5- ((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobuty l)pyrimidin-2- yl)amino)benzenesulfonamide (Compound 571)

A mixture of 5-( -3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimi din- 2-amine (170 mg, 567 μmol), 4-bromo-3-fluoro-N-[3 -hydroxy-3 - (trifluoromethyl)cyclobutyl]benzenesulfonamide (334 mg, 851 μmol), BrettPhos (30 mg, 56 μmol), BrettPhos Pd G3 (51 mg, 56 μmol) and K3PO4 (482 mg, 2.27 mmol) in dioxane (5 mL) was degassed and purged with N2 3 times. And then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), washed with aq. HC1 (0.5 M, 20 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 51% - 81% I 0.05% NH ₃ -H ₂ O + 10 mM NH ₄ HCO ₃ in water) to give Compound 571 (0.2 mg, 80%) as a white solid. LCMS (ESI) m/z: 611.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 8.77 (d, J= 4.8 Hz, 1H), 8.50 (s, 2H), 8.32 - 8.26 (m, 1H), 8.12 (s, 1H), 7.61 - 7.55 (m, 2H), 7.44 (d, J= 4.8 Hz, 1H), 6.60 (s, 1H), 4.47 (d, 6.0 Hz, 2H), 3.47 - 3.35 (m, 1H), 3.10 - 3.01 (m, 1H), 2.89 - 2.78

(m, 1H), 2.56 - 2.52 (m, 1H), 2.49 - 2.41 (m, 4H), 2.14 - 1.96 (m, 4H), 1.18 (d, J= 6.8 Hz, 6H).

Example 22: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino) _b enzenesulfonamide (Compound 495)

Compound 495

Step 1: Synthesis of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfony l)carbamate

To a stirring solution of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3- (hydroxymethyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfon yl)carbamate (0.3 g, 663 μmol) in DMF (5 mL) was added NaH (132 mg, 3.31 mmol, 60% purity) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 30 min. Then 3-chloro-4-isopropyl-pyridazine (156 mg, 994 μmol, prepared according to the procedure in WO2022/174031) was added at 0 °C. The mixture was heated to 40 °C for 16 h. The reaction was quenched by addition MeOH (10 mL) at 0 °C. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography [solvent gradient: 0 - 20% (ethyl acetate/EtOH = 3: 1) in petroleum ether] to afford the title compound (0.35 g, 92 %) as yellow oil. LCMS (ESI) m/z: 573.0 [M+H] ⁺ .

Step 2: Synthesis of 3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino) _b enzenesulfonamide (Compound 495)

To a solution of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfony l)carbamate (0.3 g, 524 μmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 2 h. The solution was concentrated in vacuo. The crude residue was dissolved in MeOH (2 mL). The solution was adjusted pH to 10 with aq. NaOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 29% - 59% / 0.225% formic acid in water) to give Compound 495 (0.1 g, 40 %) as a white solid. LCMS(ESI) m/z: 473.1 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.78 (d, J= 4.4 Hz, 1H), 8.47 (s, 2H), 8.17 - 8.11 (m, 1H), 7.63 - 7.57 (m, 2H), 7.44 (d, ./ = 4.8 Hz, 1H), 7.36 (s, 2H), 4.47 (d, J= 6.0 Hz, 2H), 3.47 - 3.36 (m, 1H), 3.12 - 2.99 (m, 1H), 2.90 - 2.75 (m, 1H), 2.49 - 2.41 (m, 2H), 2.15 - 2.02 (m, 2H), 1.19 (d, J= 6.8 Hz, 6H). Example 23: Synthesis of 4-((5-((1s,3s)-3-(((l-(l-(aminomethyl)cyclopropyl)-lZ7-l,2,3 - triazol-4-yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-f luorobenzenesulfonamide (Compound 504)

Step 1: Synthesis of 1-azidocyclopropane-l-carboxamide A mixture of N-diazosulfamoyl fluoride (4.5 g, 36.0 mmol), 1- aminocyclopropanecarboxamide (4 g, 40 mmol) in DMF (5 mL) and H ₂ O (8 mL) was added NaHCCh (16.8 g, 200 mmol). Then the mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was dissolved in ethyl acetate (100 mL), washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (4.5 g, crude) as yellow oil that required no further purification. Step 2: Synthesis of l-(4-ethoxy-lH-l,2,3-triazol-l-yl)cyclopropane-l-carboxamide

A mixture of 1 -azidocyclopropanecarboxamide (1.2 g, 9.52 mmol), ethynoxyethane (1.33 g, 9.52 mmol) in DMF (5 mL) was added sodium (2A)-2-[(lS)-l,2-dihydroxyethyl]-4-hydroxy-5- oxo-2H-furan-3-olate (754 mg, 3.8 mmol) and copper sulfate (1.52 g, 9.5 mmol). Then the mixture was stirred at 110 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL), washed with brine (50 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% ethyl acetate in petroleum ether) to give the title compound (1.08 g, 58%) as yellow oil.

Step 3: Synthesis of l-(4-elhoxy-lH-L2.3-ti iazol-l-yl)cyclopropane-l-carbonitrile

A mixture of l-(4-ethoxytriazol-l-yl)cyclopropanecarboxamide (1.08 g, 5.50 mmol), 2,4,6-trichloro-l,3,5-triazine (2.23 g, 12.1 mmol) in DMF (20 mL) was stirred at 25 °C for 2 h under N2 atmosphere. The reaction was quenched with water (30 ml). The solution was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% ethyl acetate in petroleum ether) to give the title compound (0.5 g, 51%) as ayellow solid. ¹ HNMR (400 MHz, DMSO-tfc) δ 8.05 (s, 1H), 4.15 - 4.10 (m, 2H), 2.06 - 1.98 (m, 2H), 1.97 - 1.88 (m, 2H), 1.32 (t, J= 8.0 Hz, 3H).

Step 4: Synthesis of (l-(4-ethoxy-lH-l,2,3-triazol-l-yl)cyclopropyl)methanamine

To a solution of l-(4-ethoxytriazol-l-yl)cyclopropanecarbonitrile (0.3 g, 1.7 mmol) and NiCh’O^O (1.20 g, 5,05 mmol) in MeOH (5 mL) was added NaBH4 (0.24 g, 6.34 mmol). The mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction was poured into water (20 ml), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous TsfeSCL, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (150 mg, 49%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (s, 1H), 4.13 - 4.05 (m, 2H), 2.88 (s, 2H), 1.30 (t, J= 7.2 Hz, 4H), 1.16 - 1.12 (m, 2H), 1.09 - 1.06 (m, 2H).

Step 5: Synthesis of l-( l-(aniinonielhyl)cyclopropyl)-lH-1.2.3-lriazol-4-ol

A mixture of [l-(4-ethoxytriazol-l-yl)cyclopropyl]methanamine (150 mg, 823 μmol) and HBr in AcOH (5 mL, 30.4 mmol, 33% purity) was stirred at 100 °C for 16 h under N2 atmosphere. The mixture was poured into water (20 ml), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (120 mg, 95%) as a yellow solid.

Step 6: Synthesis of tert-butyl ((l-(4-((tert-butoxycarbonyl)oxy)-lH-l,2,3-triazol-l- yl)cyclopropyl)methyl)carbamate

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

Step 7: Synthesis of tert-butyl (( 1 -(4-hydroxy- 1 H- 1.2.3-t riazol- 1 - yl)cyclopropyl)methyl)carbamate

A mixture of tert-butyl ((l-(4-((tert-butoxycarbonyl)oxy)-17/-l,2,3-triazol-l- yl)cyclopropyl)methyl)carbamate (180 mg, 508 μmol) and NaOH (61 mg, 1.52 mmol) in EtOH (1 mL) and H ₂ O (0.2 mL) was stirred at 25 °C for 2 h. The reaction was concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (120 mg, 93%) as a yellow solid. LCMS (ESI) m/z: 255.1 [M+H] ⁺ ; *H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 7.26 (s, 1H), 7.10 - 7.01 (m, 1H), 3.31 (s, 2H), 1.34 (s, 9H), 1.17 - 1.11 (m, 2H), 1.11 - 1.04 (m, 2H).

Step 8: Synthesis of tert-butyl ((4-((5-((1s,3s)-3-(((l-(l-(((tert- butoxycarbonyl)amino)methyl)cyclopropyl)-LH-l,2,3-triazol-4- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluoropheny l)sulfonyl)carbamate

A mixture of tert-butyl ((l-(4-hydroxy-17/-l,2,3-triazol-l- yl)cyclopropyl)methyl)carbamate (17 mg, 68 μmol), ((1s,3s)-3-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)-2-fluorophenyl)amino)pyrimidin-5-y l)cyclobutyl)methyl methanesulfonate (30 mg, 57 μmol) and K ₂ CO ₃ (23 mg, 169 μmol) in DMF (2 mL) was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL), washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 40% - 80% 10.225% formic acid in water) to give the title compound (20 mg, 25%) as a brown solid. LCMS (ESI) m/z: 689.3 [M+H] ⁺ .

Step 9: Synthesis of 4-((5-((1s,3s)-3-(((l-(l-(aminomethyl)cyclopropyl)-lH-l,2,3- triazol-4- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorobenze nesulfonamide (Compound 504)

A mixture of tert-butyl ((4-((5-(( l ,s,3.s)-3-((( l -(1 -(((tert- butoxycarbonyl)amino)methyl)cyclopropyl)-l rt- l .2.3-triazol-4- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)-3-fluoropheny l)sulfonyl)carbamate (20 mg, 14 μmol) in HCl/di oxane (2 mL, 4 M) was stirred at 25 °C for 16 h. The reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 10% - 40% / 0.04% HC1 in water) to give Compound 504 (5.87 mg, 86%) as a white solid. LCMS (ESI) m/z: 489.0 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO- s) δ 9.45 (s, 1H), 8.48 (s, 2H), 8.30 (s, 3H), 8.17 - 8.09 (m, 1H), 7.85 (s, 1H), 7.57 - 7.64 (m, 2H), 7.40 (s, 2H), 4.09 (d, J= 6.0 Hz, 2H), 3.35 - 3.42 (m, 1H), 3.28 - 3.34 (m, 2H), 2.67 - 2.78 (m, 1H), 2.39 - 2.47 (m, 2H), 1.91 - 2.03 (m, 2H), 1.36 (s, 4H).

Example 24: Synthesis of ((1s,31?)-3-(2-((l-((LH-l,2,3-triazol-l-yl)methyl)-lH-indazo l-6- yl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((5)-4,4,4-trifluorobutan-2-yl)carbamate

Step 1: Synthesis of (6-bromo-LH-indazol-l-yl)methanol

A mixture of 6-bromo-lH-indazole (2 g, 10.15 mmol), aq. HCHO (7.6 mL, 101.51 mmol, 37% purity) in EtOH (7 mL) was degassed and purged with N2 three times. The reaction was stirred at 50 °C for 16 h. After cooling to room temperature, the reaction was quenched by addition sat. aq. NH4CI (5 mL) at 0 °C, then diluted with H ₂ O (15 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na ₂ SO ₄ , fdtered 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 (2.1 g, 91%) as a white solid. ¹ H NMR (400 MHz, CDC1 ₃ ) δ 8.06 - 7.98 (m, 1H), 7.85 - 7.74 (m, 1H), 7.61 (d, J= 8.4 Hz, 1H), 7.38 - 7.30 (m, 1H), 5.93 - 5.78 (m, 2H).

Step 2: Synthesis of 6-bromo-l-(chloromethyl)-l H-indazole

A mixture of (6-bromoindazol-l-yl) methanol (500 mg, 2.20 mmol) in SOCI ₂ (0.5 mL) was degassed and purged with N2 three times. Then the mixture was stirred at 0 °C for 30 min. The reaction was quenched by addition sat. aq. NH4CI (5 mL) at 0 °C, then diluted with H ₂ O (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous JSfeSCL, 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 (0.5 g, 9%) as yellow oil.

Step 3: Synthesis of l-((LH-l,2,3-triazol-l-yl)methyl)-6-bromo-L£/-indazole

A mixture of 1 H-tri azole (0.1 mL, 1.88 mmol), LBuOK (317 mg, 2.82 mmol) in THF (5 mL) was degassed and purged with N2 three times. After the mixture was stirring at 25 °C for 30 min, 6-bromo-l-(chloromethyl)indazole (462 mg, 1.88 mmol) was added and then the mixture was stirred for 30 min under N2 atmosphere. The reaction was quenched with water (30 ml). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na ₂ SO ₄ , 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 (0.18 g, 34%) as a yellow solid.

Step 4: Synthesis of ((1s,3^)-3-(2-((l-((l/f-l,2,3-triazol-l-yl)methyl)-lH-indazo l-6- yl)amino)pyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (Compound 524)

To a solution of 6-bromo-l -(triazol- l-ylmethyl)indazole (63 mg, 226 μmol), ((1s,3R )-3-(2- aminopyrimidin-5-yl)cyclobutyl)methyl ((S)-4,4,4-trifluorobutan-2-yl)carbamate (50 mg, 150 μmol) and CS ₂ CO ₃ (294 mg, 903 μmol) in dioxane (2 mL) were added Brettphos (8 mg, 15 μmol) and BrettPhos Pd G3 (14 mg, 15 μmol). The mixture was stirred at 100 °C for 12 h under N2 atmosphere. The reaction was diluted with ethyl acetate (10 mL), washed with aq. HC1 (0.5 M, 5 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , fdtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (acetonitrile 23% - 63% / 0.025% formic acid in water) to give Compound 524 (12.57 mg, 16%) as a white solid. LCMS (ESI) m/z: 530.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 8.56 (s, 1H), 8.50 (s, 2H), 8.25 (d, J= 0.8 Hz, 1H), 8.04 (s, 1H), 7.74 (s, 1H), 7.62 (d, J= 8.8 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.95 (s, 2H), 3.99 (d, J= 5.6 Hz, 2H), 3.90 - 3.80 (m, 1H), 3.39 - 3.35 (m, 1H), 2.60 - 2.54 (m, 1H), 2.42 - 2.32 (m, 4H), 1.97 - 1.88 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H).

Example 25: Synthesis of 5-((l s,3v)-3-(((4-isopropyl-4H-1.2.4-triazol-3- yl)oxy)methyl)cyclobutyl)-N-(l-(methylsulfonyl)piperidin-4-y l)pyrimidin-2-amine

(Compound 477)

Compound 477

Step 1: Synthesis of tert-butyl (5-((1s,3s)-3-(((4-isopropyl-4/M,2,4-triazol-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate

To a solution of C7.s-/t77-butyl A ^f -[5-[3-(hydroxyrnethyl)cyclobutyl]pyrimidin-2- yl]carbamate (200 mg, 716 μmol) in DMF (6 mL) was added NaH (63 mg, 1.6 mmol, 60% purity) at 0 °C and stirred at 0 °C for 1 h. Then 4-isopropyl-3-methylsulfonyl-l,2,4-triazole (271 mg, 1.43 mmol ) was added. The mixture was stirred at 40 °C for 72 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with sat. aq. NH4CI (3 mL), diluted with H ₂ O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo, The residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in EtOAc) to give the title compound (172 mg, 53%) as yellow oil. LCMS (ESI) m/z: 389.1 [M+H] ⁺ .

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

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

Step 3: Synthesis of 5-((1s,3s)-3-(((4-isopropyl-4H-l,2,4-triazol-3-yl)oxy)methyl )cyclobutyl)- N-(l-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine (Compound 477)

To a stirring solution of 5-((1s,3s)-3-(((4-isopropyl-4#-l,2,4-triazol-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-amine (90 mg, 312 μmol) in DMF (5 mL) was added 1- methylsulfonylpiperidin-4-one (276 mg, 1.6 mmol ) and TFA (0.25 mL, 3.12 mmol ) at 25°C. The mixture was stirred at 25°C for 2 h. Then NaBH(OAc)3 (661 mg, 3.1 mmol) was added. The mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction was quenched with sat.aq. NaHCCL (3 mL), diluted with H ₂ O (20 mL), and then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 20% - 50% 10.225% formic acid in water) to give Compound 477 (2.06 mg, 1.5%) as a white solid. LCMS (ESI) m/z: 450.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- t/ ₆ ) δ 8.20 - 8.23 (m, 3H), 7.05 (d, J= 8.0 Hz, 1H), 4.37 - 4.32 (m, 2H), 4.25 - 4.16 (m, 1H), 3.86 - 3.76 (m, 1H), 3.55 - 3.47 (m, 1H), 3.51 (d, J= 11.6 Hz, 2H), 3.28 - 3.19 (m, 2H), 2.92 - 2.81 (m, 5H), 2.77 - 2.67 (m, 1H), 2.43 - 2.31 (m, 2H), 1.96 - 1.89 (m, 3H), 1.59 - 1.46 (m, 2H), 1.34 (d, J = 6.8 Hz, 6H).

Example 26: Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5- yl)cyclobutyl)methyl-6?2 (A)-(4,4,4-trifluorobutan-2-yl)carbamate (Compound 321)

Step 1: Synthesis of (5,8-dioxaspiro[3.4]octan-2-yl)methan-<Z2-ol

To a stirred solution of methyl 5,8-dioxaspiro[3.4]octane-2-carboxylate (4 g, 23.23 mmol, 1 equiv) in Methanol-t/ (20 mL) was added Sodium borodeuteride (2.92 g, 69.69 mmol, 3 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with CHCL:IPA (1 : 1) (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. This resulted in (5,8-dioxaspiro[3.4]octan-2-yl)methan-fl?2- ol (3.3 g, crude) as a yellow oil. LC-MS: (ES+H, m/z) 147.1 [M +H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.60 (s, 1H), 3.85 - 3.70 (m, 4H), 2.25 - 2.16 (m, 2H), 2.10 - 2.00 (m, 1H), 2.00 - 1.91 (m, 2H).

Step 2: Synthesis of 2-((benzyloxy)methyl-rf2)-5,8-dioxaspiro[3.4]octane

A solution of NaH (0.64 g, 26.7 mmol, 1.3 equiv) in THF (20 mL) was treated with (5,8- dioxaspiro[3.4]octan-2-yl)methan-<i2-ol (3 g, 20.5 mmol, 1 equiv) for 30 min at 0 °C under nitrogen atmosphere followed by the addition of BnBr (3.69 g, 21.5 mmol, 1.05 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water/ice at 0 °C. The resulting mixture was extracted with CHCL:IPA (3:1) (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ . 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 % NH ₄ HCO ₃ ), 30% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in 2-((benzyloxy)methyl-t/2)-5,8- dioxaspiro[3.4]octane (3 g, 58 %) as a yellow oil. LC-MS: (ES+H, m/z) 237.0 [M +H] ⁺ ; ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 7.41 - 7.20 (m, 5H), 4.46 (s, 2H), 3.83 - 3.71 (m, 4H), 2.35 - 2.17 (m, 3H), 2.03 - 1.91 (m, 2H).

Step 3: Synthesis of 3-((benzyloxy)methyl-<Z2)cyclobutan-l-one

A solution of 2-((benzyloxy)methyl-t/2)-5,8-dioxaspiro[3.4]octane (3 g, 12.69 mmol, 1 equiv) in HC1 (2 mL) and H ₂ O (12 mL) was stirred for 1.5 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with CHCI3 IPA (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, 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, 40% to 60% gradient in 10 min; detector, UV 200 nm. This resulted in 3-((benzyloxy)methyl-6?2)cyclobutan-l-one (2 g, 78 %) as a light yellow oil. LC-MS: (ES+H, m/z) 193.1 [M +H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.45 - 7.21 (m, 5H), 4.51 (s, 2H), 3.14 - 3.03 (m, 2H), 2.86 - 2.74 (m, 2H), 2.80 - 2.60 (m, 1H).

Step 4 and 5: Synthesis of 5-(3-((benzyloxy)methyl-<Z2)cyclobutyl)pyrimidin-2-amine To a stirred solution of 3-((benzyloxy)methyl-fi?2)cyclobutan-l-one (2 g, 10.40 mmol, 1 equiv) in MeOH (20 mL) was added tosyl hydrazide (2.03 g, 10.92 mmol, 1.05 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 20 min at RT under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (2.5 g) was used in the next step directly without further purification.

To a stirred solution of N-(3 -((benzyloxy )m ethyl -tAlcy cl obutylidene)-4- methylbenzenesulfonohydrazide (2.5 g, 6.93 mmol, 1 equiv) and 2-aminopyrimidin-5-ylboronic acid (1.45 g, 10.40 mmol, 1.5 equiv) in 1,4-dioxane (30 mL) was added CS ₂ CO ₃ (1.44 g, 10.40 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 110 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ . 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% NH ₄ HCO ₃ ), 40% to 60% gradient in 18 min; detector, UV 254 nm. This resulted in 5-(3-((benzyloxy)methyl-d?2)cyclobutyl)pyrimidin-2-amine (330 mg, 14 %) as ayellow oil. LC-MS: (ES+H, m/z) 272.1 [M +H] ⁺ ; ¹ HNMR(400 MHz, DMSO- t/ ₆ ) δ 8.14 (d, J= 17.5 Hz, 2H), 7.34 (dd, J = 5.6, 2.6 Hz, 5H), 6.40 (s, 2H), 4.51 (d, J= 1.9 Hz, 2H), 3.20 - 3.05 (m, 1H), 2.84 - 2.74 (m, 1H), 2.35 - 2.23 (m, 1H), 2.16 - 2.07 (m, 2H), 1.87 -1.77 (m, 1H).

Step 6: Synthesis of (3-(2-aminopyrimidin-5-yl)cydobutyl)methan-J2-ol

A solution of 5-(3-((benzyloxy)methyl-t/2)cyclobutyl)pyrimidin-2-amine (300 mg, 1.10 mmol, 1 equiv) and methanesulfonic acid (3.19 g, 33.18 mmol, 30 equiv) in DCM (1 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with CH ₂ C12:MeOH (5: 1 - 1 :1) to afford (3-(2- aminopyrimidin-5-yl)cyclobutyl)methan-cZ2-ol (130 mg, 62 %) as a yellow oil. LC-MS: (ES+H, m/z) 182.1 [M +H] ⁺ .

Step 7: Synthesis of (3-(2-aminopyrimidin-5-yl)cydobutyl)methyl-J2 (4-nitrophenyl) carbonate To a stirred solution of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methan-t/2-ol (130 mg, 0.71 mmol, 1 equiv) and bis(4-nitrophenyl) carbonate (262 mg, 0.86 mmol, 1.2 equiv) in DCM (3 mL) were added DIEA (278 mg, 2.15 mmol, 3 equiv) and DMAP (18 mg, 0.14 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. 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 Na ₂ SO ₄ . After filtration, 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, 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (3-(2-aminopyrimidin-5- yl)cyclobutyl)methyl-t/2 (4-nitrophenyl) carbonate (150 mg, 54.34%) as a yellow solid. LC-MS: (ES+H, m/z) 347.1 [M +H] ⁺ .

Step 8: Synthesis of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl-J2 (S)-(4,4,4- trifluorobutan-2-yl)carbamate

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

Step 9: Synthesis of (3-(2-((4-(/V-(tert-butoxycarbonyl)sulfamoyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-</2 (A)-(4,4,4-trifluorobutan-2- yl)carbamate

To a stirred solution of (3-(2-aminopyrimidin-5-yl)cyclobutyl)methyl-<72 (S)-(4,4,4- trifluorobutan-2-yl)carbamate (100 mg, 0.29 mmol, 1 equiv) and /c ^; /7-butyl N-(4-bromo-3- fluorobenzenesulfonyl)carbamate (74.16 mg, 0.20 mmol, 0.7 equiv) in 1,4-dioxane (5 mL) were added Pd2(dba)3 (54.78 mg, 0.06 mmol, 0.2 equiv), CS ₂ CO ₃ (292.36 mg, 0.89 mmol, 3 equiv) and XantPhos (34.61 mg, 0.06 mmol, 0.2 equiv) in portions at room temperature. The resulting mixture was stirred for 3 h at 90 °C under nitrogen atmosphere. 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 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous ISfeSCU. 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, 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (3-(2-((4-(N-(fert-butoxycarbonyl)sulfamoyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-6/2 (S)-(4,4,4-trifluorobutan-2- yl)carbamate (120 mg, 59 %) as a yellow solid. LC-MS: (ES+H, m/z) δ08.0 [M +H] ⁺ .

Step 10: Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5- yl)cyclobutyl)methyl-<Z2 (A)-(4,4,4-trifluorobutan-2-yl)carbamate (Compound 321)

A solution of (3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl)methyl-t/2 (S)-(4,4,4-trifluorobutan-2- yl)carbamate (120 mg, 0.19 mmol, 1 equiv) in formic acid (3 mL) was stirred for 30 min at 50 °C under nitrogen atmosphere. 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, 30% to 50% gradient in 10 min; detector, UV 254 nm. The pure fraction was concentrated under reduced pressure and lyophilization to afford (3-(2- ((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclobutyl )methyl-t/2 (S)-(4,4,4- trifluorobutan-2-yl)carbamate (Compound 321, 75 mg, 71 %) as a white solid. LC-MS: (ES+H, m/z) δ08.0 [M +H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (s, 1H), 8,46 (d, J = 12.0 Hz, 2H), 8.20 - 8.12 (m,lH), 7.64 - 7.56 (m, 2H), 7.32 (d, J= 32.9 Hz, 3H), 3.90 - 3.78 (m, 1H), 3.62 - 3.28 (m, 1H), 2.55 (s, 1H), 2.47 - 2.30 (m, 3H), 2.29 - 2.18 (m, 1H), 2.16 (d, J= 11.3 Hz, 1H), 1.90 (q, J= 10.2 Hz, 1H), 1.14 (dd, J= 6.8, 3.2 Hz, 3H); ¹⁹ F NMR (376 MHz, DMSO) δ -62.55, -121.72.

Example 27: Synthesis of ((1s,3«)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin- 5- yl)cydobutyl-3-d)methyl-</2 (3,3-difluoro-l-methylcyclobutyl)carbamate (Compound 332) Step 1: Synthesis of 3-(hydroxymethyl-J2)cyclobutan-l-J-l-ol

A mixture of methyl 3-oxocyclobutanecarboxylate (10 g, 78.1 mmol) in THF (200 mL) was added LiAlD4 (5 g, 108.7 mmol) at 0 °C. Then the reaction was degassed and purged with N2 gas 3 times, and then the mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction was quenched with H ₂ O (5 mL), aq. NaOH (15%, 5 mL) and H ₂ O (15 mL), diluted with ethyl acetate (300 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give 3- (hydroxymethyl-t72)cyclobutan-l-t7-l-ol (7.6 g, crude) as colorless oil that required no further purification. ¹ HNMR (400 MHz, DMS(M>) δ 4.85 (s, lH), 4.37 (s, 1H), 2.17 - 2.09 (m, 2H), 1.78 - 1.67 (m, 1H), 1.52 - 1.43 (m, 2H). Step 2: Synthesis of 3-(((tert-butyldiphenylsilyl)oxy)methyl-tZ2)cyclobutan-l-J-l -ol

A mixture of 3-(hydroxymethyl-t/2)cyclobutan-l-fif-l-ol (7.6 g, 72.3 mmol) in DCM (150 mL) was added DMAP (883 mg, 7.2 mmol), TEA (20 mL, 144.6 mmol) and TBDPSC1 (16.7 mL, 65.1 mmol) at 0 °C, then the mixture was stirred at 0 °C for 2 h. The reaction was diluted with DCM (100 mL) and H ₂ O (25 mL). The organic layer was washed with brine (50 mL x 2), dried over anhydrous Na ₂ SO ₄ , fdtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give 3-(((tert-butyldiphenylsilyl)oxy)methyl-t/2)cyclobutan-l-t7- l-ol (13.4 g, 54%) as a white oil.

Step 3: Synthesis of tert-butyl (5-(3-(((tert-butyldiphenylsilyl)oxy)methyl-rf2)cyclobutyl-l - J)pyrimidin-2-yl)carbamate

To a mixture of 3-(((tertebutyldiphenylsilyl)oxy)methyl-<72)cyclobutan-l- <7-l-ol (6 g, 17.5 mmol), 5,7-di-tert-butyl-3-phenylbenzo[<7]oxazol-3-ium tetrafluoroborate (6.9 g, 17.5 mmol) in t- BuOMe (120 mL) was added pyridine (1.4 mL, 17.5 mmol). The reaction was stirred for 5 min. The mixture was filtered and filter liquor was added to a solution of tert-butyl N-(5- bromopyrimidin-2-yl)carbamate (3.19 g, 11.6 mmol), NiBr2(dtbbpy) (283.5 mg, 582 μmol), quinuclidine (1.94 g, 17.5 mmol), Ir(ppy)2(dtbbpy)PFe (159.6 mg, 174 μmol) in DMA (120 mL) under N2 atmosphere. The mixture was stirred and irradiated under blue LED at room temperature for 16 h. EtOAc (400 mL) was added to dilute the mixture, and the mixture was washed with brine (100 mL x 3). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 40% EtOAc in petroleum ether) to give tert-butyl (5-(3-(((tert-butyldiphenylsilyl)oxy)methyl- t/2)cyclobutyl-l-t7)pyrimidin-2-yl)carbamate (2.9 g, 48%) as a colorless oil. LCMS (ESI) m/z: 521.3 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl (5-(3-(hydroxymethyl-rf2)cyclobutyl-l-d)pyriniidin-2- yl)carbamate

To a solution of tert-butyl (5-(3-(((tert-butyldiphenylsilyl)oxy)methyl-tZ2)cyclobutyl-l - t7)pyrimidin-2-yl)carbamate (2.5 g, 3.8 mmol) in THF (50 mL) was added TBAF (19.2 mL, 1 M). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc (200 mL) and washed with brine (50 mL x 3). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% ethyl acetate in petroleum ether) to give /crt-butyl (5-(3-(hydroxymethyl- t/2)cyclobutyl-l-t/)pyrimidin-2-yl)carbamate (800 mg, 66%) as a white solid. LCMS (ESI) m/z: 283.2 [M+H] ⁺ .

Step 5: Synthesis of tert-butyl (5-(3-((((4-nitrophenoxy)carbonyl)oxy)methyl-rf2)cyclobutyl- l- J)pyrimidin-2-yl)carbamate

To a solution of tert-butyl (5-(3-(hydroxymethyl-c/2)cyclobutyl- l-c/)pyrirnidin-2- yl)carbamate (1 g, 3.5 mmol) and pyridine (0.1 mL, 10.6 mmol) in DCM (50 mL) was added (4- nitrophenyl) carbonochloridate (1.07 g, 5.3 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was washed with brine (50 mL x 3). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give tert-butyl (5-(3-((((4- nitrophenoxy)carbonyl)oxy)methyl-<f2)cyclobutyl-l-<7)p yrimidin-2-yl)carbamate (660 mg, 37%) as a white solid. LCMS (ESI) m/z: 392.2 [M-56+H] ⁺ .

Step 6: Synthesis of tert-butyl (5-(3-((((3,3-difluoro-l- methylcyclobutyl)carbamoyl)oxy)methyl-J2)cyclobutyl-l-</) pyi'iniidin-2-yl)carbaniate

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

Step 7: Synthesis of ((1s,3s)-3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyc lobutyl-3- i/)methyl-(/2 (3,3-difluoro-l-methylcyclobutyl)carbamate and ((lr.3r)-3-(2-((tert- butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-6r)niethyl- rf2 (3,3-difluoro-l- methylcyclobutyl)carbamate tert-Butyl (5-(3-((((3,3-difluoro-l-methylcyclobutyl)carbamoyl)oxy)meth yl- t/2)cyclobutyl-l-t7)pyrimidin-2-yl)carbamate (710 mg, 1.7 mmol) was separated by using chiral SFC (column: DAICEL CHIRALCEL OD (250mm*30mm,10um); Supercritical CO ₂ I EtOH +0.1% NHs’HzO = 85/15; 60 mL/min) to afford ((H,35)-3-(2-((tert- butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3-tZ)methyl-t Z2 (3, 3 -difluoro- 1- methylcyclobutyl)carbamate (181 mg, first peak, cis isomer, desired) as a white solid and ((lr,3r)- 3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl-3 -t7)methyl-t/2 (3, 3 -difluoro- 1- methylcyclobutyl)carbamate (260 mg, second peak, trans isomer) as a white solid. LCMS (ESI) m/z: 430.3 [M+H] ⁺ ; TlNMR (400 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 8.51 (s, 2H), 7.70 (s, 1H), 2.90 - 2.79 (m, 2H), 2.60 - 2.55 (m, 3H), 2.35 - 2.32 (m, 2H), 1.95 - 1.84 (m, 2H), 1.46 (s, 9H), 1.40 (s, 3H).

Step 8: Synthesis of ((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutyl-3-J)niethyl-< ;/2 (3,3- difluoro-l-methylcyclobutyl)carbamate

To a solution of ( -3-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)cyclobutyl- 3- <7)methyl-<72 (3,3-difluoro-l-methylcyclobutyl)carbamate (180 mg, 419 μmol) inDCM (6 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 2 h. This mixture was concentrated in vacuo to give ( -3-(2-aminopyrimidin-5-yl)cyclobutyl-3-£/)methyl-fi?2 (3,3- difluoro-l-methylcyclobutyl)carbamate (160 mg, crude) as a white solid that required no further purification. LCMS (ESI) m/z: 330.2 [M+H] ⁺ .

Step 9: Synthesis of ((1s,3s)-3-(2-((4-(/V-(tert-butoxycarbonyl)sulfanioyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl-3-J)methyl-< Z2 (3,3-difluoro-l- methylcyclobutyl)carbamate

A mixture of ( -3-(2-aminopyrimidin-5-yl)cyclobutyl-3-i7)methyl-6/2 (3, 3 -difluoro- 1- methylcyclobutyl)carbamate (80 mg, 243 μmol) and K3PO4 (309 mg, 1.5 mmol) in dioxane (6 mL) was added tert-butyl N-(4-bromo-3-fluoro-phenyl)sulfonylcarbamate (258 mg, 729 μmol), Brettphos (26 mg, 49 μmol), BrettPhos Pd G3 (44 mg, 49 μmol) was degassed and purged with N2 three times. Then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. After cooling to room temperature, EtOAc (10 mL) was added, and the mixture was washed with HC1 (0.5 M, 10 mL) and brine (10 mL x 3). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by prep-TLC (solvent gradient: 0 - 20% MeOH in DCM) to give ( -3-(2-((4-(N-(tert-butoxycarbonyl)sulfamoyl)-2- fluorophenyl)amino)pyrimidin-5-yl)cyclobutyl-3-</)methyl- 6/2 (3, 3 -difluoro- 1- methylcyclobutyl)carbamate (80 mg, 41%) as a white solid. LCMS (ESI) m/z: 603.3 [M+H] ⁺ . Step 10: Synthesis of ((1s,3s)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5 - yl)cyclobutyl-3-J)methyl-J2 (3,3-difluoro-l-methylcyclobutyl)carbamate

To a solution of ((1s,3s)-3-(2-((4-(N-(ferLbutoxycarbonyl)sulfamoyl)-2- Huorophenyl)amino)pyrimidin-5-yl)cyclobutyl-3-t7)methyl-t72 (3, 3 -difluoro- 1- methylcyclobutyl)carbamate (80 mg, 100 iimol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo. The crude residue was dissolved in MeOH (2 mL), adjusted pH to 10 with aq. NaOH (2 M), and then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 36% - 68% I 0.225% formic acid in water) to give Compound 332 (26 mg, 51%) as a white solid. LCMS (ESI) m/z: 502.9 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 9.33 (s, 1H), 8.45 (s, 2H), 8.18 - 8.10 (m, 1H), 7.74 - 7.65 (m, 1H), 7.62 - 7.58 (m, 2H), 7.36 (s, 2H), 2.92 - 2.77 (m, 2H), 2.61 - 2.52 (m, 3H), 2.37 - 2.31 (m, 2H), 1.97 - 1.82 (m, 2H), 1.39 (s, 3H).

Example 28: Synthesis of ((1s,3s)-3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5 - yl)cyclobutyl-3-d)methyl-<Z2 (3,3-difluoro-l-methylcyclobutyl)carbamate (Compound 172)

Compound 172

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

To a solution of tert-butyl N-terZ-butoxycarbonyl-N-[5-(3-oxocyclopentyl)pyrazin-2- yl]carbamate (720 mg, 1.91 mmol) in THF (10 mL) was added LiBHEts (1 M, 2.7 mL) at -65 °C. The reaction mixture was stirred at -65 °C for 1 h. The reaction mixture was quenched by addition sat. aq. NaHCO ₃ (50 mL) at -65 °C, extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous ISfeSCU, filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 70% EtOAc in petroleum ether) to give the title compound (400 mg, 55%) as a white solid. LCMS (ESI) m/z: 380.2 [M+H ⁺ ],

Step 2: Synthesis of |3-|5-|/v’s(te/7-butoxycarbonyl)aniino|pyrazin-2-yl|cyclop entyl] (4- nitrophenyl) carbonate

To a solution of tert-butyl N--tertb-utoxycarbonyl-N-[5-(3-hydroxycyclopentyl)pyrazin-2- yl]carbamate (340 mg, 896 μmol) in DCM (30 mL) was added DMAP (22 mg, 179 μmol), pyridine (212 mg, 2.69 mmol) and (4-nitrophenyl) carbonochloridate (361 mg, 1.79 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition sat. aq. NaHCCL (20 mL) at 25 °C, extracted with DCM (100 mL). The organic layer was washed with brine (100 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (370 mg, 75%) as a white solid. LCMS (ESI) m/z: 545.2 [M+H ⁺ ],

Step 3: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-(3-

((isopropylcarbamoyl)oxy)cyclopentyl)pyrazin-2-yl)carbama te

To a solution of [3-[5-[to(tert-butoxycarbonyl)amino]pyrazin-2-yl]cyclopentyl ] (4- nitrophenyl) carbonate (370 mg, 679 μmol) and propan-2-amine (201 mg, 3.40 mmol) in THF (4 mL) was added DIPEA (264 mg, 2.04 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition water (10 mL) at 25 °C, extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 70% EtOAc in petroleum ether) to give the title compound (300 mg, 95%) as a white solid. LCMS (ESI) m/z: 465.3 [M+H ⁺ ],

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

To a solution of tert-butyl N-te/7-butoxycarbonyl-N-[5-[3- (isopropylcarbamoyloxy)cyclopentyl]pyrazin-2-yl]carbamate (200 mg, 430 μmol) in DCM (3 mL) was added TFA (1 mL, 13.44 mmol). The reaction mixture was stirred at 25 °C for 1 h. This reaction was concentrated in vacuo to give the title compound (0.11 g, crude, TFA salt) as a yellow oil that required no further purification. LCMS (ESI) m/z: 265.2 [M+H ⁺ ],

Step 5: Synthesis of 3-(5-((4-(/V-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyr azin-2- yl)cyclopentyl isopropylcarbamate

To a solution of tert-butyl N-(4-broinophenyl)sulfonylcarbamate (954 mg, 2.84 mmol) and [3-(5-aminopyrazin-2-yl)cyclopentyl] N-isopropylcarbamate (250 mg, 946 μmol) in dioxane (4 mL) was added CS ₂ CO ₃ (2.47 g, 7.57 mmol), BrettPhos Pd G3 (85 mg, 94 μmol) and Brettphos (50 mg, 94 μmol). The reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , 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 (70 mg, 14%) as a white solid. LCMS (ESI) m/z 520.2 [M+H ⁺ ],

Step 6: Synthesis of rel-(lS,3R)-3-(5-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopent yl isopropylcarbamate and reZ-(1R,3S )-3-(5-((4-(/V-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)p yrazin-2- yl)cyclopentyl isopropylcarbamate rac-3-(5-((4-(N-(tert-Butoxycarbonyl)sulfamoyl)phenyl)amino) pyrazin-2-yl)cyclopentyl isopropylcarbamate was separated by using chiral SFC (DAICEL CHIRALPAK AS(250mm*30mm,10um); Supercritical CO ₂ / EtOH+0.1% NEL’ELO =30/70; 60 mL/min)) to afford rel-(15,3A)-3-(5-((4-(N-(tert-butoxycarbonyl)sulfamoyl)pheny l)amino)pyrazin-2- yl)cyclopentyl isopropylcarbamate (10 mg, first peak) as a white solid and re7-(1R,3S )-3-(5-((4- (N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl) cyclopentyl isopropylcarbamate (10 mg, second peak) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer.

Step 7: Synthesis of rel-(1R,3S )-3-(5-((4-sulfamoylphenyl)amino)pyrazin-2-yl)cyclopentyl isopropylcarbamate (Compound 172)

To a stirring solution of rel-(1R,3S )-3-(5-((4-(N-(fert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopent yl isopropylcarbamate (0.01 g, second peak on SFC) in DCM (3 mL) was added TFA (1 mL, 13.44 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 aq. NaOH (2 M), then adjusted pH to 6 with formic acid. The residue was purified by reverse phase chromatography (acetonitrile 20% - 50% / 0.225% formic acid in water) to give Compound 172 (5 mg, second peak on SFC) as a white solid. Absolute configuration was arbitrarily assigned. LCMS (ESI) m/z 420.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.81 (d, J= 9.2 Hz, 2H), 7.72 (d, J= 8.8 Hz, 2H), 7.17 (s, 2H), 6.97 (d, J= 7.2 Hz, 1H), 5.08 - 5.00 (m, 1H), 3.65 - 3.52 (m, 1H), 3.22 - 3.11 (m, 1H), 2.45 - 2.35 (m, 1H), 1.99 - 1.90 (m, 2H), 1.88 - 1.72 (m, 3H), 1.03 (d, J= 6.Q Hz, 6H).

Example 29: Synthesis of ((l^,3*V)-3-(5-((4-sulfamoylphenyl)amino)pyrazin-2- yl)cyclopentyl)carbamate (Compound 179)

Compound 179

Step 1: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-(3-

((isopropoxycarbonyl)amino)cyclopentyl)pyrazin-2-yl)carba mate

To a solution of tert-butyl N-[5-(3-aminocyclopentyl)pyrazin-2-yl]-N-tert- butoxycarbonyl-carbamate (100 mg, 264 μmol) in DCM (3 mL) was added EbN (80 mg, 792 μmol) and isopropyl carb onochlori date (32 mg, 264 μmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition sat. aq. NaHCCh (10 mL) at 25 °C, extracted with DCM (100 mL). The organic layer was washed with brine (30 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30 % EtOAc in petroleum ether) to give the title compound (50 mg, 78%) as a brown solid. LCMS (ESI) m/z: 365.3 [M-Boc+H] ⁺ .

Step 2: Synthesis of isopropyl (3-(5-aminopyrazin-2-yl)cyclopentyl)carbamate

To a mixture of ferLbutyl N-ferLbutoxycarbonyl-N-[5-[3- (isopropoxycarbonylamino)cyclopentyl]pyrazin-2-yl]carbamate (50 mg, 108 μmol) in DCM (3 mL) was added TFA (0.5 mL). The reaction mixture was stirred at 25 °C for 1 h. This reaction was quenched by addition aq. K ₂ CO ₃ (5 mL), and then extracted with EtOAc (30 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 100% EtOAc in petroleum ether) to give the title compound (26 mg, 91%) as a white solid. LCMS (ESI) m/z: 265.2 [M+H] ⁺ .

Step 3: Synthesis of isopropyl (3-(5-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopent yl)carbaniate

A mixture of isopropyl N-[3-(5-aminopyrazin-2-yl)cyclopentyl]carbamate (26 mg, 98 μmol), tert-butyl N-(4-bromophenyl)sulfonyl carbarn ate (49 mg, 147 μmol), BrettPhos Pd G3 (9 mg, 10 μmol), BrettPhos (6 mg, 10 μmol) and CS ₂ CO ₃ (96 mg, 295 μmol) in dioxane (3 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL), washed with aq. HC1 (0.5 M, 10 mL). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 100% EtOAc in petroleum ether) to give the title compound (40 mg, 78%) as a white solid. LCMS (ESI) m/z: 520.1 [M+H ⁺ ],

Step 4: Synthesis of reLisopropyl ((lR,3S)-3-(5-((^-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopent yl)carbamate and rel- isopropyl ((15,3A)-3-(5-((4-(A^-(tert-butoxycarbonyl)sulfamoyl)phenyl) amino)pyrazin-2- yl)cyclopentyl)carbamate and rel-isopropyl ((l/?.3/?)-3-(5-((4-( V-(t<7t- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopent yl)carbamate and rel- isopropyl ((15,3^)-3-(5-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)a mino)pyrazin-2- yl)cyclopentyl)carbamate

Isopropyl (3-(5-((4-(;N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)py razin-2- yl)cyclopentyl)carbamate (0.12 g, 193 μmol) was separated by using chiral SFC (Phenom enex Lux Cellulose-4 250*30mm*5um; Supercritical CO ₂ / MeOH+0.1% NEfi^ELO =45/55; 60 mL/min)) to afford isopropyl ((lA,35)-3-(5-((4-(N-(tert-butoxycarbonyl)sulfamoyl)phenyl)a mino)pyrazin- 2-yl)cyclopentyl)carbamate (16 mg, first peak) as a white solid and isopropyl ((15,35)-3-(5-((4- (N-(tert-butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl) cyclopentyl)carbamate (36 mg, second peak) as a white solid and isopropyl ((lA,3A)-3-(5-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopent yl)carbamate (13 mg, third peak) as a white solid and isopropyl ((lS,3A)-3-(5-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopent yl)carbamate (36 mg, fourth peak) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer.

Step 5: Synthesis of rel-isopropyl (( l/L3S)-3-(5-((4-sulfainoylphenyl)aniino)pyrazin-2- yl)cyclopentyl)carbamate (Compound 179)

To a solution of rel-isopropyl ((1R,3S )-3-(5-((4-(N-(fert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrazin-2-yl)cyclopent yl)carbamate (10 mg, 19 μmol, first peak on SFC) in DCM (3 mL) was added TFA (1 mL, 13.44 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 aq. NaOH (2 M), then adjusted pH to 6 with formic acid. The residue was purified by reverse phase chromatography (acetonitrile 35% - 65% / 0.225% formic acid in water) to give Compound 179 (4.73 mg, second peak on SFC) as a white solid. Absolute configuration was arbitrarily assigned. LCMS (ESI) m/z: 420.2 [M+H] ⁺ ; ¹ H NMR. (400 MHz, DMSO-afc) δ 9.82 (s, 1H), 8,26 (s, 1H), 8.10 (s, 1H), 7.81 (d, J= 8.8 Hz, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7.21 - 7.11 (m, 3H), 4.80 - 4.69 (m, 1H), 4.00 - 3.86 (m, 1H), 3.21 - 3.10 (m, 1H), 2.26 - 2.15 (m, 1H), 2.00 - 1.88 (m, 2H), 1.85 - 1.73 (m, 1H), 1.70 - 1.55 (m, 2H), 1.16 (d, J= 6.4 Hz, 6H).

Analytical data of compounds is shown in Table 2 below. The compounds in Table 2 were prepared using procedures analogous to those disclosed above with appropriate modifications within the purview of one skilled in the art.

Table 2. Compounds of Formula (A)

Biochemical Assays

CDKl/Cyclin Bl Mobility Shift Assay 10 nL of 2000X compound in 100 % DMSO is added to a 384-well polypropylene assay plate. 15 μL of 1.3X CDK1/B1 and 1.3X fluorescent substrate (Wild-type, full length CDK1 in complex with wildtype, full length CyclinBl : Cama Cat# 04-102 and FL-Peptide 29: PerkinElmer Cat# 760429) diluted in kinase buffer (5 O mMHepes, 0.01% Brij-35, 10 mMMgCI ₂ , 1 mMEGTA, 0.05% BSA, and 2 mM DTT) is added to the plates on top of the compound, mixed, and preincubated for 30 minutes at room temperature. The fluorescently labeled peptide substrate is phosphorylated by CDK1/B1 upon ATP hydrolysis. Following the incubation, 5 μL of 4X ATP diluted in kinase buffer is added to the plate to initiate the reaction. Following the 30-minute incubation, the reaction is stopped by adding 75 μL of stopping buffer containing 0.5 M EDTA.

The assay plate is then read on a Lab Chip EZ Reader which separates the fluorescently labeled substrate and product peptides through a mobility difference. The phosphorylation of the substrate imparts a negative charge, which allows differences in separation as both are pulled through the microfluidic chip. The ratio of substrate and product values are used to generate percent conversion. These raw percent conversion values are normalized to calculate percent inhibition, which are fit to a four-parameter logistic curve and IC ₅₀ values are calculated. IC ₅₀ values are converted to Ki using substrate, Kmapp values, and the Cheng-Prusoff equation.

CDK9/CyclinTl Mobility Shift Assay

10 nL of 2000X compound in 100 % DMSO is added to a 384-well polypropylene assay plate. 15 μL of 1.3X CDK9/T1 and 1.3X fluorescent substrate (Wild-type, full length CDK9 in complex with wildtype, CyclinTl (1-259): Biortus Cat# BP480/792/691 and FL-Peptide 34: PerkinElmer Cat# 760643) diluted in kinase buffer (50 mM Hepes, 0.01% Brij-35, 10 mM MgCI ₂ , 1 mM EGTA, 0.05% BSA, and 2 mM DTT) is added to the plates on top of the compound, mixed, and pre-incubated for 30 minutes at room temperature. The fluorescently labeled peptide substrate is phosphorylated by CDK9/T1 upon ATP hydrolysis. Following the incubation, 5 μL of 4X ATP diluted in kinase buffer is added to the plate to initiate the reaction. Following the 30-minute incubation, the reaction is stopped by adding 75 μL of stopping buffer containing 0.5 M EDTA.

The assay plate is then read on a Lab Chip EZ Reader which separates the fluorescently labeled substrate and product peptides through a mobility difference. The phosphorylation of the substrate imparts a negative charge, which allows differences in separation as both are pulled through the microfluidic chip. The ratio of substrate and product values are used to generate percent conversion. These raw percent conversion values are normalized to calculate percent inhibition, which are fit to a four-parameter logistic curve and IC ₅₀ values are calculated. IC ₅₀ values are converted to Ki using substrate, Kmapp values, and the Cheng-Prusoff equation.

CDK2/Cyclin A2 Mobility Shift Assay

10 nL of 2000X compound in 100 % DMSO is added to a 384-well polypropylene assay plate. 15 μL of 1.3X CDK2/A2 and 1.3X fluorescent substrate (Wild-type, full length CDK2 in complex with wildtype, full length CyclinA2: Cama Cat# 04-103 and FL-Peptide 18: PerkinElmer Cat#760362) diluted in kinase buffer (50 mMHepes, 0.01% Brij-35, 10 mMMgC12, 1 mMEGTA, 0.05% BSA, and 2 mM DTT) is added to the plates on top of the compound, mixed, and preincubated for 30 minutes at room temperature. The fluorescently labeled peptide substrate is phosphorylated by CDK2/A2 upon ATP hydrolysis. Following the incubation, 5 μL of 4X ATP diluted in kinase buffer is added to the plate to initiate the reaction. Following the 30-minute incubation, the reaction is stopped by adding 75 μL of stopping buffer containing 0.5 M EDTA.

The assay plate is then read on a Lab Chip EZ Reader which separates the fluorescently labeled substrate and product peptides through a mobility difference. The phosphorylation of the substrate imparts a negative charge, which allows differences in separation as both are pulled through the microfluidic chip. The ratio of substrate and product values are used to generate percent conversion. These raw percent conversion values are normalized to calculate percent inhibition, which are fit to a four-parameter logistic curve and IC ₅₀ values are calculated. IC ₅₀ values are converted to Ki through using substrate and K _m ^app values, and the Cheng-Prusoff equation.

CDK6/Cyclin D3 Mobility Shift Assay

10 nL of 2000X compound in 100 % DMSO is added to a 384-well polypropylene assay plate. 15 μL of 1.3X CDK6/D3 and 1.3X fluorescent substrate (Wild-type, full length CDK6 in complex with wildtype, full length CyclinD3 : Cama Cat# 04-107 and FL-Peptide 34: PerkinElmer Cat# 760643) diluted in kinase buffer (50 mM Hepes, 0.01% Brij-35, 10 mMMgC12, 1 mMEGTA, 0.05 % BSA, and 2 mM DTT) is added to the plates on top of the compound, mixed, and preincubated for 30 minutes at room temperature. The fluorescently labeled peptide substrate is phosphorylated by CDK6/D3 upon ATP hydrolysis. Following the incubation, 5 μL of 4X ATP diluted in kinase buffer is added to the plate to initiate the reaction. Following the 30-minute incubation, the reaction is stopped by adding 75 μL of stopping buffer containing 0.5 M EDTA. The assay plate is then read on a Lab Chip EZ Reader which separates the fluorescently labeled substrate and product peptides through a mobility difference. The phosphorylation of the substrate imparts a negative charge, which allows differences in separation as both are pulled through the microfluidic chip. The ratio of substrate and product values are used to generate percent conversion. These raw percent conversion values are normalized to calculate percent inhibition, which are fit to a four-parameter logistic curve and IC ₅₀ values are calculated. IC ₅₀ values are converted to Ki through using substrate and K _m ^app values, and the Cheng-Prusoff equation.

Table A lists the following. CDK2/CCNA2 Caliper 10xKm Ki: Average Ki (A < 0.1 nM; 0.1 nM < B <1 nM; 1 nM <

C < 10 nM; 10 nM < D < 100 nM)

CDK1/CCNB1 Caliper Ki (A < 1 nM; 1 nM < B <10 nM; 10 nM < C < 100 nM; 100 nM < D < 500 nM; F > 500 nM)

CDK6/CCND3 Caliper Ki: Average Ki (A < 1 nM; 1 nM < B <10 nM; 10 nM < C < 100 nM; 100 nM < D < 500 nM; F > 500 nM)

CDK9/CyclinTl Caliper Ki: Average Ki (A < 1 nM; 1 nM < B <10 nM; 10 nM < C < 100 nM; 100 nM < D < 500 nM; F > 500 nM)

ND = not determined

Table A. Biological Activity of Selected Compounds

NanoBRET Target Engagement Assays

CDK2/A2-NanoLuc and CDKl/A2-NanoLuc stably transduced cells were seeded at 5,000 cells per well in a 384-well white, tissue-culture treated plate with 10Ong/mL doxycycline in FluorBRITE DMEM media and incubated at 37°C, 5% CO ₂ . After 3 days, cells were pre-treated with 700nM of K-10 Tracer (Promega N2642) for 5 minutes. Then, cells were treated with compound for 2hrs at 37°C, 5% CO ₂ . NanoLuc Complete Substrate plus Inhibitor Solution (Promega) were added according to manufacturer’s instructions and incubated for 2-3 minutes at room temperature. Donor emission wavelength (460nm) and acceptor emission wavelength (610nm) were measured on a Synergy Neo2 reader (BioTek). milliBRET ratios were calculated for each sample by dividing the acceptor emission value by the donor emission value and multiplied by 1000. Dose response curves were generated using a four-parameter logistics equation and OC50 was calculated.

CyQUANT Anti-proliferation Assay

Ovcar3 cells were seeded at 3,000 cells per well in growth media in a 96-well tissue culture treated plate and allowed to adhere overnight at 37°C, 5% CO ₂ . The next day, cells were treated with compound for 6 days (144hrs) at 37°C, 5% CO ₂ . CyQUANT™ Direct Cell Proliferation Assay (Invitrogen C35011) was performed by following the manufacturer’s protocol. Direct cell counts of fluorescently labeled cells were measured on the Celigo (Nexcelom). Dose response curves were generated using a four-parameter logistics equation and IC ₅₀ was calculated. CDK2/CyclinA2 ChEF Assay

16 nL of 1000X compound in 100% DMSO is added to a 384-well low volume, black assay plate. 12 μL of 1.3X CDK2/CyclinA2 (Wild-type, full length CDK2 in complex with wildtype, full length CyclinA2: Cama Cat# 04-103 diluted in assay buffer (54 mM Hepes, 0.012% Brij-35, 10 mM MgC12, 0.55 mM EGTA, 1% Glycerol, 0.02% BSA, and 1.2 mM DTT) is added to the plates on top of the compound and pre-incubated for 30 minutes at room temperature. Following the incubation, 4 uL of 4X Sox-chromophore (CSox) labeled peptide substrate (AQT0297, AssayQuant) & ATP diluted in assay buffer is added to the plate to initiate the reaction. The assay is incubated at room temperature for 90 min after initiation. The CSox peptide substrate is phosphorylated by CDK2/A2 upon ATP hydrolysis.

The fluorescent intensity measurement of the assay plate is read on a microplate reader once the assay is initiated and again at the completion of the assay. Phosphorylation of the CSox- based peptide substrate sensor results in an immediate increase in fluorescence. These raw fluorescence intensity values are normalized to calculate percent inhibition, which are fit to a four- parameter logistic curve and IC ₅₀ values are calculated. IC ₅₀ values are converted to Ki using substrate, KM ^aPP values, and the Cheng-Prusoff equation.

CDK6/CyclinD3 ChEF Assay

16 nL of 1000X compound in 100% DMSO is added to a 384-well low volume, black assay plate. 12 μL of 1.3X CDK6/CyclinD3 (Wild-type, full length CDK6 in complex with wildtype, full length CyclinD3: Carna Cat# 04-107) diluted in assay buffer (54 mM Hepes, 0.012% Brij-35, 10 mM MgC12, 0.55 mM EGTA, 1% Glycerol, 0.02% BSA, and 1.2 mM DTT) is added to the plates on top of the compound and pre-incubated for 30 minutes at room temperature. Following the incubation, 4 uL of 4X Sox-chromophore (CSox) labeled peptide substrate (AQT0258, AssayQuant) & ATP diluted in assay buffer is added to the plate to initiate the reaction. The assay is incubated at room temperature for 300 min after initiation. The CSox peptide substrate is phosphorylated by CDK6/D3 upon ATP hydrolysis.

The fluorescent intensity measurement of the assay plate is read on a microplate reader once the assay is initiated and again at the completion of the assay. Phosphorylation of the CSox- based peptide substrate sensor results in an immediate increase in fluorescence. These raw fluorescence intensity values are normalized to calculate percent inhibition, which are fit to a four- parameter logistic curve and IC ₅₀ values are calculated. IC ₅₀ values are converted to Ki using substrate, KM ^aPP values, and the Cheng-Prusoff equation

CDKl/CyclinBl ChEF Assay

16 nL of 1000X compound in 100% DMSO is added to a 384-well low volume, black assay plate. 12 μL of 1.3X CDKl/CyclinBl (Wild-type, full length CDK1 in complex with wildtype, full length CyclinBl : Carna Cat# 04-102) diluted in assay buffer (54 mM Hepes, 0.012% Brij-35, 10 mM MgC12, 0.55 mM EGTA, 1% Glycerol, 0.02% BSA, and 1.2 mM DTT) is added to the plates on top of the compound and pre-incubated for 30 minutes at room temperature. Following the incubation, 4 uL of 4X Sox-chromophore (CSox) labeled peptide substrate (AQT0297, AssayQuant) & ATP diluted in assay buffer is added to the plate to initiate the reaction. The assay is incubated at room temperature for 120 min after initiation. The CSox peptide substrate is phosphorylated by CDK1/B1 upon ATP hydrolysis.

The fluorescent intensity measurement of the assay plate is read on a microplate reader once the assay is initiated and again at the completion of the assay. Phosphorylation of the CSox- based peptide substrate sensor results in an immediate increase in fluorescence. These raw fluorescence intensity values are normalized to calculate percent inhibition, which are fit to a four- parameter logistic curve and IC ₅₀ values are calculated. IC ₅₀ values are converted to Ki using substrate, KM ^aPP values, and the Cheng-Prusoff equation.

CDK9/CyclinTl ChEF Assay

16 nL of 1000X compound in 100% DMSO is added to a 384-well low volume, black assay plate. 12 μL of 1.3X CDK9/CyclinTl (Wild-type, full length CDK9 in complex with wildtype, CyclinTl (1-259): Biortus Cat# BP480/792/691) diluted in assay buffer (54 mM Hepes, 0.012% Brij-35, 10 mM MgC12, 0.55 mM EGTA, 1% Glycerol, 0.02% BSA, and 1.2 mM DTT) is added to the plates on top of the compound and pre-incubated for 30 minutes at room temperature. Following the incubation, 4 μL of 4X Sox-chromophore (CSox) labeled peptide substrate (AQT0449, AssayQuant) & ATP diluted in assay buffer is added to the plate to initiate the reaction. The assay is incubated at room temperature for 180 min after initiation. The CSox peptide substrate is phosphorylated by CDK9/T1 upon ATP hydrolysis.

The fluorescent intensity measurement of the assay plate is read on a microplate reader once the assay is initiated and again at the completion of the assay. Phosphorylation of the CSox- based peptide substrate sensor results in an immediate increase in fluorescence. These raw fluorescence intensity values are normalized to calculate percent inhibition, which are fit to a four- parameter logistic curve and IC ₅₀ values are calculated. IC ₅₀ values are converted to Ki using substrate, KM ^aPP values, and the Cheng-Prusoff equation.

CDK4/CyclinDl ChEF Assay

16 nL of 1000X compound in 100% DMSO is added to a 384-well low volume, black assay plate. 12 uL of 1.3X CDK4/CyclinDl (Wild-type, full length CDK4 in complex with wildtype, CyclinDl : ThermoFisher Cat# PR8064A) diluted in assay buffer (54 mM Hepes, 0.012% Brij-35, 10 mM MgC12, 0.55 mM EGTA, 1% Glycerol, 0.02% BSA, and 1.2 mM DTT) is added to the plates on top of the compound and pre-incubated for 30 minutes at room temperature. Following the incubation, 4 uL of 4X Sox-chromophore (CSox) labeled peptide substrate (AQT0258, AssayQuant) & ATP diluted in assay buffer is added to the plate to initiate the reaction. The assay is incubated at room temperature for 150 min after initiation. The CSox peptide substrate is phosphorylated by CDK4/D1 upon ATP hydrolysis.

The fluorescent intensity measurement of the assay plate is read on a microplate reader once the assay is initiated and again at the completion of the assay. Phosphorylation of the CSox-based peptide substrate sensor results in an immediate increase in fluorescence. These raw fluorescence intensity values are normalized to calculate percent inhibition, which are fit to a four- parameter logistic curve and IC50 values are calculated. IC ₅₀ values are converted to Ki using substrate, KM ^aPP values, and the Cheng-Prusoff equation.

Table B lists the following.

CDK2/CCNA2 AQT10xKm Ki: Average Ki (A < 0.1 nM; 0.1 nM < B <1 nM; 1 nM < C

< 10 nM; 10 nM < D < 100 nM)

CDK1/CCNB1 AQT10xKm Ki: Average Ki (A < 1 nM; 1 nM < B <10 nM; 10 nM < C < 100 nM; 100 nM < D < 500 nM; F > 500 nM)

CDK4/CCNB1 AQT10xKm Ki: Average Ki (A < 1 nM; 1 nM < B <10 nM; 10 nM < C < 100 nM; 100 nM < D < 500 nM; F > 500 nM)

CDK6/CCND3 AQT10xKm Ki: Average Ki (A < 1 nM; 1 nM < B <10 nM; 10 nM < C < 100 nM; 100 nM < D < 500 nM; F > 500 nM)

CDK9/CyclinTl AQT10xKm Ki: Average Ki (A < 1 nM; 1 nM < B <10 nM; 10 nM < C

< 100 nM; 100 nM < D < 500 nM; F > 500 nM)

CDK2-A2 MCF7 NanoBret EC ₅₀ 700nM: Average EC ₅₀ (A < 1 nM; 1 nM < B <100 nM; 100 nM < C < 500 nM; 500 nM < D < 1000 nM; F > 1000 nM)

CDK2-A2 MCF7 NanoBret EC ₅₀ _7OOnM: CDKl-A2 Fold Selectivity (A >75 ; 75 <B <50 ; 50 < C < 25; D < 25)

OVCAR3 CyQuant Proliferation IC ₅₀ : Average IC ₅₀ (A < 1 nM; 1 nM < B <10 nM; 10 nM

< C < 100 nM; 100 nM < D < 500 nM; F > 500 nM)

ND = not determined

Table B, Biological Activity of Selected Compounds