WO2024059010A1 - Composés pour le traitement du cancer - Google Patents

Composés pour le traitement du cancer Download PDF

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WO2024059010A1
WO2024059010A1 PCT/US2023/032420 US2023032420W WO2024059010A1 WO 2024059010 A1 WO2024059010 A1 WO 2024059010A1 US 2023032420 W US2023032420 W US 2023032420W WO 2024059010 A1 WO2024059010 A1 WO 2024059010A1
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compound
cancer
alkyl
subject
substituted
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PCT/US2023/032420
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Advait Nagle
Nicholas Simon Stock
Wojciech Piotr SWIDERSKI
Evan Nathaniel Feinberg
Ben SKLAROFF
Brandon REINUS
Indrawan MCALPINE
Martin INDARTE
Christopher P. BURKE
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Genesis Therapeutics, Inc.
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Publication of WO2024059010A1 publication Critical patent/WO2024059010A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • 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.
  • Cyclin-dependent kinases 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.
  • 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.
  • 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.
  • cyclin A 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.
  • Some embodiments provide a compound of Formula (A), or a pharmaceutically acceptable salt thereof, wherein:
  • 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;
  • R c is hydrogen or C1-C6 alkyl
  • n is 0, 1, or 2
  • each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl
  • R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl.
  • Some embodiments provide a compound of Formula (A- 1), or a pharmaceutically acceptable salt thereof, wherein:
  • 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;
  • R c is hydrogen or C1-C6 alkyl
  • m is 0, 1, or 2
  • n is 0, 1, or 2
  • each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl
  • R 2 is optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 5-6 membered heterocyclyl.
  • Some embodiments provide a pharmaceutical composition
  • 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.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • tautomer 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.
  • tautomeric forms The following are examples of included tautomeric forms:
  • 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.
  • halogen refers to one of the halogens, group 17 of the periodic table.
  • the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine or chlorine.
  • 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.
  • alkylene refers to an alkyl group, as defined herein, which is a biradical and is connected to two other moieties.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • a haloalkoxy can be -OR, wherein R is a Cl -4 alkyl substituted by 1, 2 or 3 halogens.
  • 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.
  • 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.
  • the non-aromatic ring can be a cycloalkyl group, as defined herein.
  • 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.
  • 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.
  • 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.
  • heterocyclyl refers to a saturated or partially unsaturated 3-12 membered hydrocarbon monocyclic or bicyclic ring system, that is not aromatic, having at least one heteroatom within the ring selected from N, O and S.
  • bicyclic 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.
  • 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.
  • hydroxyl refers to an -OH moiety.
  • cyano refers to a -CN moiety
  • nitro refers to an -NO2 moiety.
  • azido refers to an -N3 moiety.
  • isocyanate refers to a -NCO moiety.
  • thiocyanate refers to a -CNS moiety.
  • isothiocyanate refers to an -NCS moiety.
  • acyl refers to an alkyl group, connected as a substituent, via an oxo group. Examples include, but are not limited to, acetyl.
  • S-sulfonamido 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).
  • R’ and R” are both alkyl.
  • R’ and R” are both hydrogen.
  • N-sulfonamido 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).
  • sulfenyl 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).
  • sulfonyl refers to an “SO 2 R” group in which R can be the same as defined with respect to sulfenyl.
  • 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.
  • heteroaryl(alkyl) refers to a heteroaryl group connected, as a substituent, an alkylene group.
  • heterocyclyl(alkyl) refers to a heterocyclyl group connected, as a substituent, via an alkylene group.
  • amino refers to a -NH2 group.
  • mono-substituted amine 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.
  • di-substituted amine 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.
  • an asterisk depicts the point of attachment of an atom or moiety to the indicated atom or group in the remainder of the molecule.
  • 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, azid
  • the compounds of Formula (A) include pharmaceutically acceptable salts thereof.
  • 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).
  • 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.
  • 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.
  • Ki values are shown in Table 3.
  • a “CDK2 inhibitor” as defined herein includes any compound exhibiting CDK2 inhibition activity.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • regulatory agency refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country.
  • a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
  • FDA U.S. Food and Drug Administration
  • CDK2-associated cancer 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.
  • a CDK-associated cancer is characterized by amplification or overexpression of CDK2.
  • a CDK-associated cancer is characterized by amplification or overexpression of cyclin A2 (CCNA2), cyclin El (CCNE1), and/or cyclin E2 (CCNE2).
  • a CDK-associated cancer is characterized by amplification or overexpression of cyclin El (CCNE1) and/or cyclin E2 (CCNE2).
  • a CDK-associated cancer is characterized by amplification or overexpression of cyclin A2 (CCNA2).
  • a CDK-associated cancer is characterized by amplification or overexpression of cyclin El (CCNE1).
  • 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.
  • SEQ ID NO: 1 (UniProt Accession No. P24941)
  • 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;
  • R c is hydrogen or C1-C6 alkyl
  • n is 0, 1, or 2
  • each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl
  • R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl.
  • 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;
  • R c is hydrogen or C1-C6 alkyl
  • m is 0, 1, or 2
  • n is 0, 1, or 2
  • each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl
  • R 2 is optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 5-6 membered heterocyclyl.
  • R 1 is -NR A R B
  • R A and R B are independently hydrogen, optionally substituted Cl- C6 alkyl, C1-C6 haloalkyl, or optionally substituted C3-C10 cycloalkyl.
  • R A and R B are the same. In some embodiments, R A and R B are each hydrogen.
  • 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.
  • 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.
  • R A and R B are different.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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:
  • 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.
  • 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
  • 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.
  • 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.
  • 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).
  • 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.
  • the 5-10 membered heteroaryloxy of R 1 is substituted with .
  • the 5-10 membered heteroaryloxy of R 1 is substituted with .
  • R 1 is an unsubstituted 5-10 membered heteroaryl oxy.
  • the 5-10 membered heteroaryloxy of R 1 is a 5-6 membered heteroaryl oxy.
  • the 5-10 membered heteroaryloxy of R 1 is isothiazolyl, pyridyl, or 1,3,4-triazolyl.
  • 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.
  • 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.
  • 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.
  • R 2 is an optionally substituted 5-10 membered heteroaryl.
  • R 2 is an optionally substituted 5-6 membered heteroaryl.
  • 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.
  • 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.
  • 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.
  • R 2 is an optionally substituted 5-9 membered heterocyclyl.
  • R 2 is an optionally substituted 5-6 membered heterocyclyl.
  • 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.
  • 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, dioxolan
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • R’ is unsubstituted C1-C6 alkyl. In some embodiments, R’ is unsubstituted C1-C3 alkyl. In some embodiments, R’ is methyl, ethyl, or propyl.
  • 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.
  • 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.
  • R’ is C3-C10 cycloalkyl optionally substituted with C1-C6 alkyl.
  • R’ is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, R’ is C3-C6 cycloalkyl substituted with 1-3 halogen.
  • 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.
  • 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.
  • 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.
  • the R 2 group is substituted with one -SO 2 NH2 and one -F.
  • the R 2 group is substituted with one -SO 2 NH2.
  • the R 2 group is substituted with one -(SCh)C3-C6 cycloalkyl. In v some embodiments, the R 2 group is substituted with one .
  • the R 2 group is substituted with one -(SO 2 )NHC3-C6 cycloalkyl
  • 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
  • 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.
  • 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 .
  • R L is unsubstituted C1-C6 alkyl. In some embodiments, R L is methyl.
  • the R 2 group is substituted with one substituent selected from the group consisting of
  • 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.
  • the R group is substituted with one i.e., R and R are each hydrogen.
  • the R 2 group is substituted with one selected from the group consisting of
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • X is unsubstituted -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b -.
  • the -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b - of X is -(CH 2 ) a C4-C6 cycloalkylene-(CH 2 ) b -.
  • the -(CH 2 ) a C3-C8 cycloalkylene-(CH 2 ) b - of X is cyclopentylene.
  • 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.
  • X is -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b - optionally substituted with 2 substituents independently selected from halogen and C1-C6 alkyl.
  • 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.
  • 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.
  • X is unsubstituted -(CH 2 ) a C5-C8 cycloalkenylene-(CH 2 ) b -.
  • X is -(CH 2 ) a phenylene-(CH 2 ) b -.
  • 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 -
  • X is C2-C6 alkylene.
  • X is C2-C4 alkylene.
  • X is .A
  • the stereochemical configuration of the stereocenter is (R).
  • the stereochemical configuration of the stereocenter is (S).
  • the stereochemical configuration of the stereocenter is (R).
  • the stereochemical configuration of the stereocenter is (S).
  • the stereochemical configuration of the stereocenter is (R).
  • the stereochemical configuration of the stereocenter is (S).
  • the stereochemical configuration of the stereocenter is (R).
  • the stereochemical configuration of the stereocenter is (S).
  • the stereochemical configuration of the stereocenter is (R).
  • the stereochemical configuration of the stereocenter is (S).
  • 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.
  • 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.
  • 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.
  • X 1 is CR X1 .
  • X 2 is CR X2 .
  • 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.
  • 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.
  • 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.
  • 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.
  • X 1 is N.
  • X 2 is N. In some embodiments, X 1 is N and X 2 is N.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • 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.
  • each R D and R E is hydrogen.
  • each R D and R E is fluoro.
  • R D and R E is methyl.
  • one of R D and R E is methyl or fluoro, and the remaining R D and R E are hydrogen.
  • Y is -NR C -
  • R c is C1-C6 alkyl.
  • R c is methyl
  • R c is hydrogen
  • Y is -O-.
  • m is 0.
  • m is 1.
  • n is 2.
  • R 2 is an optionally substituted 5-6 membered heteroaryl.
  • R 2 is an optionally substituted 5 membered heteroaryl.
  • R 2 is an unsubstituted 5 membered heteroaryl.
  • R 2 is a substituted 5 membered heteroaryl.
  • the 5 membered heteroaryl of R 2 is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or 1,2,5-oxadiazolyl.
  • R 2 is an optionally substituted 6 membered heteroaryl.
  • R 2 is an unsubstituted 6 membered heteroaryl.
  • R 2 is a substituted 6 membered heteroaryl.
  • the 6 membered heteroaryl of R 2 is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
  • R 2 is an optionally substituted 5-6 membered heterocyclyl.
  • R 2 is an optionally substituted 5 membered heterocyclyl.
  • R 2 is an unsubstituted 5 membered heterocyclyl.
  • R 2 is a substituted 5 membered heterocyclyl.
  • 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, dioxolanon
  • R 2 is an optionally substituted 6 membered heterocyclyl.
  • R 2 is an unsubstituted 6 membered heterocyclyl.
  • R 2 is a substituted 6 membered heterocyclyl.
  • 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, piperazinetri
  • R 2 is an optionally substituted phenyl.
  • R 2 is an unsubstituted phenyl.
  • R 2 is a substituted phenyl. In some embodiments, R 2 is a monosubstituted phenyl. In some embodiments, R 2 is a disubstituted phenyl.
  • the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a compound of Formula (AA): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a compound of Formula (AA1): or a pharmaceutically acceptable salt thereof.
  • 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
  • R c is hydrogen or C1-C6 alkyl
  • n is 0, 1, or 2
  • each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl
  • R 2 is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 5-9 membered heterocyclyl.
  • 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).
  • 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.
  • 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.
  • 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.
  • the 9-10 membered heteroaryl is pyrrolo[l,2-a]pyrazine.
  • 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;
  • R c is hydrogen or C1-C6 alkyl
  • n is 0, 1, or 2
  • each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl
  • R 2 is optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 5-6 membered heterocyclyl.
  • R c is hydrogen or C1-C6 alkyl
  • n is 0, 1, or 2
  • each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl
  • R 2 is optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 5-6 membered heterocyclyl.
  • 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;
  • R c is hydrogen or C1-C6 alkyl
  • n is 0, 1, or 2
  • each R D and R E are independently hydrogen, fluoro, or C1-C6 alkyl
  • R 2 is optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 5-6 membered heterocyclyl.
  • the compound of Formula (A) is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
  • 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.
  • a method of treating cancer e.g., a CDK2-associated cancer
  • 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.
  • 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).
  • a CDK2-associated-associated cancer e.g., as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit.
  • 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).
  • 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).
  • a CDK2-associated-associated cancer e.g., as determined using a regulatory agency -approved, e.g., FDA-approved, assay or kit.
  • 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).
  • 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).
  • 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).
  • a regulatory agency -approved e.g., FDA-approved, kit or assay.
  • 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).
  • a regulatory agency-approved e.g., FDA-approved, kit or assay.
  • 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).
  • a regulatory agency-approved e.g., FDA-approved, kit or assay.
  • 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).
  • a regulatory agency-approved e.g., FDA-approved, kit or assay.
  • 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).
  • 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.
  • a dysregulation results in aberrations in the cell cycle.
  • the subject is suspected of having a CDK2-associated-associated cancer.
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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.
  • the subject has a cancer resistant to one or more previous therapies, for example, resistance to CDK4/CDK6 inhibition.
  • 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.
  • the cancer e.g., CDK2-associated cancer
  • 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
  • the cancer e.g., CDK2-associated cancer
  • the cancer is a solid tumor.
  • the cancer e.g., CDK2-associated cancer
  • pediatric tumors e.g., neuroblastoma
  • the cancer e.g., CDK2-associated cancer
  • a brain tumor e.g., glioblastoma
  • the cancer e.g., CDK2-associated cancer
  • the cancer is sarcoma.
  • the cancer e.g., CDK2-associated 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
  • brain cancer e.g., cholangiocarcinoma
  • the cancer e.g., CDK2-associated cancer
  • the 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.
  • the cancer e.g., CDK2-associated cancer
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and stomach cancer.
  • the cancer e.g., CDK2-associated cancer
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, and colorectal cancer.
  • the cancer e.g., CDK2-associated cancer
  • the cancer is colorectal cancer.
  • the cancer e.g., CDK2-associated cancer
  • the cancer is selected from the group consisting of breast cancer and ovarian cancer.
  • the cancer e.g., CDK2-associated cancer
  • the cancer is ovarian cancer.
  • the cancer e.g., CDK2-associated cancer
  • the cancer is breast cancer.
  • the cancer e.g., CDK2-associated cancer
  • the cancer is a breast cancer selected from the group consisting of: estrogen receptor (ER)-positive/hormone receptor (HR)- positive breast cancer, HER2-negative breast cancer; ER-positive/HR-positive breast cancer, HER2 -positive breast cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer.
  • the cancer e.g., CDK2-associated cancer
  • the 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.
  • the breast cancer is advanced breast cancer, metastatic breast cancer, or fully resected breast cancer.
  • resection 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.
  • the cancer e.g., CDK2-associated cancer
  • the cancer is a cancer that has been resected.
  • the cancer e.g., CDK2-associated cancer
  • 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).
  • 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.
  • the cancer e.g., CDK2-associated cancer
  • the cancer e.g., CDK2-associated cancer
  • 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).
  • ALL acute lymphocytic leukemia
  • AML acute myelocytic leukemia
  • CML chronic myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • B cell CLL e.g., hairy cell leukemia
  • CLL chronic neutrophilic leukemia
  • CML chronic myelomonocytic leukemia
  • 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), immunoblast
  • 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).
  • DLCL diffuse large cell lymphoma
  • DLBCL diffuse large B cell lymphoma
  • GCB germinal center B cell-like
  • ABSC activated B-cell like
  • 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.
  • CCL cutaneous T cell lymphoma
  • 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).
  • PV polycythemia vera
  • ET essential thrombocytosis
  • AAM agnogenic myeloid metaplasia
  • MF myelofibrosis
  • HES hypereosinophilic syndrome
  • the cancer e.g., CDK2-associated cancer
  • the 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.
  • 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
  • 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.
  • 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.
  • 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.
  • the method further includes obtaining a sample from the subject (e.g., a biopsy sample).
  • An assay can be any appropriate assay.
  • 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.
  • the compound of Formula (A), or a pharmaceutically acceptable salt thereof is a selective CDK2 inhibitor.
  • 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.
  • 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).
  • the compound of Formula (A), or a pharmaceutically acceptable salt thereof inhibits CDK2 activity while sparing CDK1 activity
  • 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 embodiment
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • the method further includes obtaining a sample from the subject (e.g., a biopsy sample).
  • An assay can be any appropriate assay.
  • 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).
  • sequencing e.g., pyrosequencing or next generation sequencing
  • immunohistochemistry e.g., enzyme-linked immunosorbent assay
  • FISH fluorescence in situ hybridization
  • 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.
  • 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.
  • 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.
  • 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.
  • the mammalian cell is a mammalian cancer cell.
  • the mammalian cancer cell is a mammalian CDK2-associated cancer cell.
  • 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.
  • 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
  • a protein e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 protein
  • 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).
  • 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).
  • the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject.
  • 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).
  • dysregulation of a gene e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 gene
  • a protein e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 protein
  • a liquid biopsy 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).
  • a gene e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 gene
  • a protein e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 protein
  • 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).
  • a gene e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 gene
  • a protein e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 protein
  • 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.
  • a gene e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 gene
  • a protein e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 protein
  • 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.
  • a liquid biopsy can be used to detect circulating tumor cells (CTCs).
  • CTCs circulating tumor cells
  • a liquid biopsy can be used to detect cell-free DNA.
  • cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells.
  • Analysis of ctDNA 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).
  • a gene e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 gene
  • a protein e.g., a CDK2, cyclin A2, cyclin El, and/or cyclin E2 protein
  • compositions provided herein may be, for example, surgery, radiotherapy, and additional therapeutic agents such as those described herein.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound of Formula (A), or a pharmaceutically acceptable salt thereof can be used after administration of an additional therapeutic agent or additional therapy.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a chemotherapeutic agent e.g., a CDK4/CDK6 inhibitor such as palbociclib, ribociclib, or abemaciclib
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy.
  • a subject is CDK2 inhibitor naive.
  • the subject is naive to treatment with a selective CDK2 inhibitor.
  • a subject is not CDK2 inhibitor naive (i.e., the subject has been previously administered one or more CDK2 inhibitors).
  • a subject is CDK4/CDK6 inhibitor naive.
  • the subject is naive to treatment with a selective CDK4/CDK6 inhibitor.
  • a subject is not CDK4/CDK6 inhibitor naive (i.e., the subject has been previously administered one or more CDK4/CDK6 inhibitors).
  • 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.
  • kinase inhibitors e.g., receptor tyrosine kinase-targeted therapeutic agents such as EGFR, HER2, MEK, RAF, or KRAS inhibitors
  • cytotoxic chemotherapeutics e.g., angiogenesis inhibitors, and radiotherapy.
  • the additional therapeutic agent is an epidermal growth factor receptor typrosine kinase inhibitor (EGFR).
  • EGFR inhibitors can include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), necitumumab (Portrazza), neratinib (Nerlynx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).
  • the additional therapeutic agent is a HER2 inhibitor.
  • HER2 inhibitors include trastuzumab and pertuzumab.
  • 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, pexi
  • the additional therapeutic agent is a cytotoxic chemotherapeutic.
  • 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.
  • the additional therapeutic agent is an angiogenesis inhibitor, for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKC ⁇ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors.
  • angiogenesis inhibitor for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKC ⁇ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors.
  • 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.
  • sunitinib Sunitinib
  • bevacizumab Avastin
  • axitinib SU-14813
  • AG-13958 vatalanib
  • antiangiogenesis agents include enzastaurin, midostaurin, perifosine, teprenone (Selbex) and UCN 01, lenalidomide (Revlimid), pomalidomide (Pomalyst), squalamine (Evizon), and thalidomide (Thalomid).
  • 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 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.
  • a CDK4/CDK6 inhibitor such as palbociclib, ribociclib, or abemaciclib
  • an endocrine therapy such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen
  • 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.
  • a CDK4/CDK6 inhibitor such as palbociclib, ribociclib, or abemaciclib
  • an endocrine therapy such as fulvestrant, toremifene, anastrozole, exemestane, letrozole, and tamoxifen
  • tumorigenesis may vary between different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types.
  • 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.
  • 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 thereof.
  • the cancer is a CDK2-associated cancer.
  • 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.
  • 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.
  • methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a CDK2-associated cancer 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.
  • 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.
  • additional tumor e.g., a solid tumor
  • 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.
  • a method for inhibiting CDK2 activity in a mammalian cell comprising contacting the mammalian cell with a compound of Formula (A).
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo.
  • the mammalian cell is a mammalian cancer cell.
  • the mammalian cancer cell is any cancer as described herein.
  • the mammalian cancer cell is a CDK2-associated mammalian cancer cell.
  • the amount of the compound of Formula (A) is a therapeutically effective amount.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “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).
  • the amount of the compound of Formula (A) is a therapeutically effective amount.
  • compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • 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.
  • compositions which contain, as the active ingredient, a compound of Formula (A) or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition prepared using a compound of Formula (A) or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Step 1 Synthesis of 4-[(tert-biilyldimelhylsilyl)oxy
  • Step 2 Synthesis of 5- ⁇ 4-[(tert-butyldimethylsilyl)oxy]cyclohex-l-en-l-yl ⁇ pyrimidin-2-amine
  • Step 3 Synthesis of 5-((l s.4s)-4-((tert-butyldiinelhylsilyl)oxy)cyclohexyl)pyriniidin-2-amine
  • Step 4 Synthesis of tert-butyl N-[3-fluoro-4-( ⁇ 5-[(1s,4s)-4-[(tert- butyldimethylsilyl)oxy]cyclohexyl] pyrimidin-2-yl ⁇ amino)benzenesulfonyl]carbamate
  • 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.
  • Step 5 Synthesis of tert-butyl N-[3-fluoro-4-( ⁇ 5-[(1s,4s)-4-hydroxycyclohexyl]pyriniidin-2- yl)amino) benzenesulfonyl]carbamate
  • Step 6 Synthesis of (1s,4s)-4-[2-( ⁇ 4-[(tert-butoxycarbonyl)aminosulfonyl]-2- fluorophenyl ⁇ amino) pyrimidin-5-yl]cyclohexyl)imidazole-l-carboxylate
  • Step 7 Synthesis of tert-butyl N-[3-fluoro-4-( ⁇ 5-[(1s,4s)-4-
  • Step 8 Synthesis of (1s,4s)-4- ⁇ 2-[(2-fluoro-4-sulfamoylphenyl)amino]pyrimidin-5- yl)cyclohexyl N-propylcarbamate (Compound 1)
  • Step 1 Synthesis of cyclopent-2-en-l-ol
  • Step 2 Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[5-(3-oxocyclopentyl)pyrimidin-2- yl)carbamate
  • Step 3 Synthesis of tert-butyl N-tert-butoxycarbonyl-/N-[5-(3-hydroxycyclopentyl)pyriniidin- 2-yl] carbamate
  • 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.
  • Step 4 Synthesis of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,3S )-3-(((4- nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate
  • 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
  • a solution of rac -tert-butyl (tert-butoxycarbonyl)(5-((1R,3S )-3-(('(4- nitrophenoxy)carbonyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate (2 g, 3.7 mmol) in dioxane (20 mL) was added DIEA (3.8 mL, 22.0 mmol) and (2S)-4,4,4-trifluorobutan-2-amine (1 g, 6.1 mmol, 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.
  • Step 6 Synthesis of (1RS,3SR)-3-(2-aminopyrimidin-5-yl)cyclopentyl ((S)-4,4,4- trifluorobutan-2-yl)carbamate
  • 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)
  • 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
  • Step 4 Synthesis of rac-(1R,3S )-3-(2-aminopyrimidin-5-yl)cyclopentan-l-ol
  • 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.
  • Step 5 Synthesis of rac-(1R,3S )-3-(2-aminopyrimidin-5-yl)cyclopentyl (4-nitrophenyl) carbonate
  • Step 6 Synthesis of rac-(l/?,3 ⁇ )-3-(2-aminopyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate
  • Step 7 Synthesis of rac-(1R,3‘V)-3-(2-((4-(A ⁇ -(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate
  • Step 8 Synthesis of rac-(1R,3S )-3-(2-((4-sulfamoylphenyl)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate
  • 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.
  • 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)
  • Step 2 Synthesis of rac-terZ-butyl 4-( ⁇ 5-[(1R,3S )-3- ⁇ [(l- methylcyclopropyl)carbamoyl]oxy ⁇ cyclopentyl]pyrimidin-2-yl ⁇ amino)piperidine-l- carboxylate
  • Step 3 Synthesis of rac-(1R ,3‘V)-3-[2-(piperidin-4-ylamino)pyrimidin-5-yl]cyclopentyl ⁇ -( 1 - methylcyclopropyl)carbamate
  • Step 4 Synthesis of rac-(1R,3S )-3- ⁇ 2-[(l-sulfamoylpiperidin-4-yl)amino]pyrimidin-5- yl ⁇ cyclopentyl N-( l-niethylcyclopropyl)carbaniate (Compound 135)
  • Step 1 Synthesis of l-[l-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-one
  • Step 2 Synthesis of l-[l-(trifluoromethyl)pyrazol-4-ylsulfonyl]piperidin-4-amine
  • 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)
  • Step 1 Synthesis of rac-tert-butyl (terEbutoxycarbonyl)(5-((lJ?,35)-3-(((l- methylcyclopropyl)carbamoyl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate
  • Step 2 Synthesis of rac-(1R,3S )-3-(2-aminopyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate
  • Step 3 Synthesis of rac-(lR,3S)-3-(2-((4-(N-(tert- butoxycarbonyl)cydopropanesulfonimidoyl)phenyl)amino)pyrimidin-5-yl)cyclopentyl (1- methylcyclopropyl)carbamate
  • 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)amino)pyrimidin-5- yl)cyclopentyl (l-methylcyclopropyl)carbamate and rel-(lS,3R)-3-(2-((4-(N-(tert- butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)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-methylcyclo
  • Step 5 Synthesis of (1R *,35*)-3-(2-((4-((l?)-N-(-tert- butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5- yl)cyclopentyl (l-methylcyclopropyl)carbamate and (1R*,35*)-3-(2-((4-((A)-N-(tert- butoxycarbonyl)cyclopropanesulfonimidoyl)-2-fluorophenyl)amino)pyrimidin-5- yl)cyclopentyl (l-methylcyclopropyl)carbamate
  • 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)amino)pyrimidin-5-yl)cyclopentyl (l-methylcyclopropyl)carbamate (147 mg, 255 ⁇ mol) in dioxane (5 mL) was added HCl/dioxane (5 mL, 4 M).
  • 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
  • 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.
  • 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
  • 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)carbamate
  • 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
  • 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)cyclopenlyl)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 ⁇ mol) was separated by using chir
  • Step 1 Synthesis of 4-( l-nielhylcyclopropyl)-4H-1.2.4-lri;izole-3-lhiol
  • Step 2 Synthesis of 4-( 1 -inethylcyclopropyl )-3-( met hylthio)-4H- 1 ,2,4-triazole
  • acetone 100 mL
  • K 2 CO 3 15.7 g, 113.4 mmol
  • Mel 13.2 g, 92.8 mmol
  • 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.
  • 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
  • Step 5 Synthesis of rac-5-((H?,3*S)-(3-((4-(l-methylcyclopropyl)-4H-l,2,4-triazol-3- yl)oxy)cyclopentyl)pyrimidin-2-amine
  • 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)phenyl)sulfonyl)carbamate
  • 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)phenyl)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)carbamate rac-tert-Butyl ((3-fluoro-4-((5-((lJ?,35)-3-((4-(l-
  • 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)
  • Step 1 Synthesis of 2-butyryl-/V-(l-methylcydopropyl)hydrazine-l-carbothioamide
  • Step 2 Synthesis of 4-( l-melhylcyclopropyl)-5-propyl-4H-1.2.4-lriazole-3-lhiol
  • 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)benzenesulfonamide (Compound 480) and rel-3-fluoro-4-((5-((l /?.3.S)-3-((4-(l-inethylcyclopropyl)-5-propyl-4H-1.2.4-triazol- 3-yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)henzenesulfonamide (Compound 551) rel-3-fluoro-4-((5-((15,3A)-3-((4-(l-methylcyclopropyl)-5-propyl-4H-l,2,4-triazol
  • Step 1 Synthesis of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,3S )-3-((4- cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2-yl)carbamate
  • Step 2 Synthesis of rac-5-((1R,3S )-3-((4-cyclopropylisothiazol-3- yl)oxy)cyclopentyl)pyrimidin-2-amine TFA salt
  • Step 3 Synthesis of rac-tert-butyl ((4-((5-((1R,3S )-3-((4-cyclopropylisothiazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate
  • 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)carbamate & reZ-tert-butyl ((4-((5- ((15,3 ⁇ )-3-((4-cyclopropylisothiazol-3-yl)oxy)cyclopentyl)pyrimidin-2- yl)amino)phenyl)sulfonyl)carbamate rac-tert-Butyl ((4-((5-((1R ,3S)-3-((4-cyclopropylisothiazol-3- yl)oxy)cyclopentyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate
  • Step 5 Synthesis of rel-4-((5-((15',3 ⁇ )-3-((4-cyclopropylisothiazol-3- yl)oxy)cydopentyl)pyrimidin-2-yl)amino)benzenesulfonamide (Compound 574)
  • 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)carbamate
  • Step 2 Synthesis of rac-5-((U?,3 ⁇ )-3-((4-(prop-l-en-2-yl)pyridin-3- yl)oxy)cyclopentyl)pyrimidin-2-amine
  • 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)carbamate
  • 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)
  • Step 1 Synthesis of tert-butyl N-tert-butoxycar bonyl-V- [3-chloro-5- [(1R)-3-oxocyclopentyl]- 2-pyridyl]carbamate
  • Step 2 Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-5-[3-hydroxycyclopentyl]- 2-pyridyl]carbamate
  • 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)carbamate
  • 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
  • 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.
  • 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-chloropyridin-3-yl)cyclopentyl ((*£)-4,4,4-trifluorobutan-2-yl)carbamate
  • 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)
  • Step 1 Synthesis of rac-tert-butv ⁇ (tert-butoxycarbonyl)(5-((17f,470-4-((tert- butyldiphenylsilyl)oxy)cyclopent-2-en-l-yl)pyrimidin-2-yl)carbamate
  • 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.
  • Step 2 Synthesis of rac-tert-butyl (tert-butoxycarbonyl)(5-((1R,4/?)-4-hydroxycyclopent-2- en-l-yl)pyrimidin-2-yl)carbamate
  • 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
  • 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)pyrimidin-2-yl)carbamate
  • Step 5 Synthesis of (1RS,4RS )-4-(2-aniinopyrimidin-5-yl)cyclopent-2-en-l-yl ((S)-4,4,4- trifluorobutan-2-yl)carbamate
  • 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)
  • Example 14 Synthesis of (1s,3s)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl) amino)pyrimidin-5-yl)cyclobutyl(l-methylcyclopropyl)carbamate (Compound 2) and (lr,3r)-3-(2-((2-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)pyrimidin-5-yl)cyclobutyl (1- methylcyclopropyl)carbamate (Compound 3)
  • Step 2 Synthesis of 4-((5-(3-(benzyloxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluoro-/V- isopropylbenzenesulfonamide
  • Step 3 Synthesis of 3-fluoro-4-((5-(3-hydroxycyclobutyl)pyrimidin-2-yl)amino)-/V- isopropylbenzenesulfonamide
  • Step 4 Synthesis of 3-(2-((2-fluoro-4-(/V-isopropylsulfamoyl)phenyl)aniino)pyriniidin-5- yl)cyclobutyl (4-nitrophenyl) carbonate
  • 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)
  • 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
  • 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
  • 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)carbamate
  • 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)
  • 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)dimethylphosphine oxide
  • 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)dimethylphosphine oxide (Compound 523)
  • Step 3 Synthesis of tert-butyl (5-((1s,3s)-3-((5-(l-((tert- bntylsulfinyl)amino)cyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyriniidin-2-yl)carbamate
  • Step 4 N-(l-(2-((1s,3s)-3-(2-aminopyrimidin-5-yl)cyclobutoxy)thiazol-5-yl)cyclobutyl)-2- methylpropane-2-sulfinamide
  • Step 5 tert-butyl ((4-((5-((1s,3s)-3-((5-(l-((tert-butylsulfinyl)amino)cyclobutyl)thiazol-2- yl)oxy)cyclobutyl)pyrimidin-2-yl)amino)-3-fluorophenyl)sulfonyl)carbamate
  • Step 6 4-((5-((1s,3s)-3-((5-(l-aminocyclobutyl)thiazol-2-yl)oxy)cyclobutyl)pyrimidin-2- yl)amino)-3-fluorobenzenesulfonamide (Compound 368)
  • 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
  • Step 3 Synthesis of tert-butyl ((4-((5-(3-((benzyloxy)methyl)cyclobutyl)pyrimidin-2- yl)amino)-3-fluorophenyl)sulfonyl)carbamate
  • 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 ⁇ mol
  • BrettPhos Pd G3 (437.53 mg, 482.66 ⁇ mol).
  • Step 4 Synthesis of 3-fluoro-4-((5-(3-(hydroxymethyl)cyclobutyl)pyrimidin-2- yl)amino)benzenesulfonamide
  • Step 5 Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)aniino)pyriniidin-5- yl)cyclobutyl)methyl (4-nitrophenyl) carbonate
  • Step 6 Synthesis of (3-(2-((2-fluoro-4-sulfamoylphenyl)amino)pyrimidin-5- yl)cyclobutyl)methyl (5)-(4,4,4-trifluorobutan-2-yl)carbamate:
  • 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)cyclobutyl)methyl (S)-4,4 9 4- trifluorobutan-2-yl)carbamate (Compound 5)
  • 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).
  • 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-
  • Second peak (/rms-i sorrier): LCMS (ESI) m/z: 270.0 [M+H] + ; 1 HNMR (400 MHz, DMSO-d 6 ) ⁇ 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
  • Step 9 Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((1s,3s)-3-(((tert- butoxycarbonyl)oxy)methyl)cydobntyl)pyrimidin-2-yl)carbaniate
  • Step 10 Synthesis of tert-butyl (5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyrimidin-2- yl)carbamate
  • Step 11 Synthesis of tert-butyl ((4-((5-((1s,3s)-3-(hydroxymethyl)cyclobutyl)pyriniidin-2- yl)amino)phenyl)sulfonyl)carbamate
  • Step 12 Synthesis of ((ls,3s)-3-(2-((4-(N-(tert- butoxycarbonyl)sulfamoyl)phenyl)amino)pyrimidin-5-yl)cydobutyl)methyl methanesulfonate
  • 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)
  • 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)phenyl)sulfonyl)carbamate
  • Step 2 Synthesis of 3-fluoro-4-((5-((1s,3s)-3-((5-(l-methylpyrrolidin-2-yl)-2-oxopyridin-)
  • 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)cyclobutyl)pyrimidin-2- yl)amino)benzenesulfonamide (Compound 571)
  • Step 1 Synthesis of tert-butyl (5-((1s,3s)-3-(((4-isopropylpyridazin-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate
  • Step 2 Synthesis of 5-((1s,3s)-3-(((4-isopropylpyridazin-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-amine
  • tert-butyl 5-((1s,3s)-3-(((4-isopropylpyridazin-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)carbamate (0.25 g, 625 ⁇ mol) 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).
  • Step 3 Synthesis of 3-fluoro-N-((1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-4-((5- ((1s,3s)-3-(((4-isopropylpyridazin-3-yl)oxy)methyl)cyclobutyl)pyrimidin-2- yl)amino)benzenesulfonamide (Compound 571)
  • Step 1 Synthesis of tert-butyl ((3-fluoro-4-((5-((1s,3s)-3-(((4-isopropylpyridazin-3- yl)oxy)methyl)cyclobutyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)carbamate
  • 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)

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (A), tels que définis dans la description, et des sels pharmaceutiquement acceptables de ceux-ci, ainsi que des procédés de préparation de composés de formule (A), et des sels pharmaceutiquement acceptables de ceux-ci. La présente invention concerne également une composition pharmaceutique comprenant un composé de formule (A), et des sels pharmaceutiquement acceptables de celui-ci, ainsi que des méthodes d'utilisation des composés et des compositions pour le traitement de maladies, telles que le cancer.
PCT/US2023/032420 2022-09-13 2023-09-11 Composés pour le traitement du cancer WO2024059010A1 (fr)

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