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WO2025007859A1 - Substituted thiazole compounds as cdk2/4/6 inhibitors and methods of use thereof - Google Patents

Substituted thiazole compounds as cdk2/4/6 inhibitors and methods of use thereof Download PDF

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Publication number
WO2025007859A1
WO2025007859A1 PCT/CN2024/103156 CN2024103156W WO2025007859A1 WO 2025007859 A1 WO2025007859 A1 WO 2025007859A1 CN 2024103156 W CN2024103156 W CN 2024103156W WO 2025007859 A1 WO2025007859 A1 WO 2025007859A1
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alkyl
compound
cycloalkyl
heterocycloalkyl
heteroalkyl
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French (fr)
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Xiao DING
Jinxin LIU
Fanye MENG
Feng Ren
Yazhou WANG
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • 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

Definitions

  • Cyclin-dependent kinases are vital enzymes affecting the essential functions in eukaryotic cell division regulation and eukaryotic cell proliferation. Regulatory subunits (cyclins) active the catalytic units of CDK and are also important regulators of cell cycle progression. Furthermore, functions of cyclin/CDK heterodynes also include regulation of transcription, DNA repair, differentiation and apoptosis. Overexpression of CDK2 is associated with abnormal regulation of cell-cycle. Cyclin E, a regulatory cyclin for CDK2, is frequently overexpressed in cancer, and the amplification/overexpression of cyclin E has been associated with breast cancer.
  • the compound has a structure of Formula (II) , or a pharmaceutically acceptable salt thereof,
  • the compound has a structure of Formula (III) , or a pharmaceutically acceptable salt thereof,
  • described herein is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • described herein is a method of treating a cancer in a subject, the method comprising administering to a subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein
  • described herein is a method of modulating activity of a cyclin-dependent kinase (CDK) in a subject, the method comprising administering to a subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.
  • CDK cyclin-dependent kinase
  • described herein is a method of inhibiting activity of a cyclin-dependent kinase (CDK) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.
  • CDK cyclin-dependent kinase
  • described herein is a method of treating a disease or disorder associated with cyclin-dependent kinase (CDK) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.
  • the disease or disorder is cancer.
  • the cancer is a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin; a hematopoietic tumor of lymphoid lineage; a hematopoietic tumor of myeloid lineage; thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
  • the cancer is pRb+ breast cancer, or hormone receptor (HR) -positive (e.g., estrogen receptor positive (ER+) , progesterone receptor positive (PR+) , or ER+PR+) , HER2/neu-negative cancer.
  • HR hormone receptor
  • ER+ estrogen receptor positive
  • PR+ progesterone receptor positive
  • HER2/neu-negative cancer HER2/neu-negative cancer.
  • the cancer is advanced or metastatic or recurrent breast cancer.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1 - 6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • arylene refers to a bivalent aryl radical as described herein. An arylene can be bonded through the aryl at any suitable position. In some embodiments, when an arylene comprises an aryl fused with a cycloalkyl or heterocycloalkyl ring, the arylene is bonded at the aryl and the cycloalkyl, or the aryl and the heterocycloalkyl. In some embodiments, when an arylene comprises an aryl fused with a cycloalkyl or heterocycloalkyl ring, the arylene is bonded only at the aryl.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • cycloalkylene refers to a bivalent cycloalkyl radical as described herein.
  • a cycloalkylene when a cycloalkylene comprises a cycloalkyl fused with an aryl or a heteroaryl ring, the cycloalkylene is bonded at the cycloalkyl and the aryl, or the cycloalkyl and the heteroaryl. In some embodiments, when a cycloalkylene comprises a cycloalkyl fused with an aryl or a heteroaryl ring, the cycloalkylene is bonded only at the cycloalkyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • heterocycloalkylene refers to a bivalent heterocycloalkyl radical as described herein.
  • a heterocycloalkylene comprises a heterocycloalkyl fused with an aryl or a heteroaryl ring
  • the heterocycloalkylene is bonded at the heterocycloalkyl and the aryl, or the heterocycloalkyl and the heteroaryl.
  • the heterocycloalkylene when a heterocycloalkylene comprises a heterocycloalkyl fused with an aryl or a heteroaryl ring, the heterocycloalkylene is bonded only at the heterocycloalkyl.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzo
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • heteroarylene refers to a bivalent heteroaryl radical as described herein. In some embodiments, when a heteroarylene comprises a heteroaryl fused with a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded at the heteroaryl and the cycloalkyl, or the heteroaryl and the heterocycloalkyl. In some embodiments, when a heteroarylene comprises a heteroaryl fused with a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded only at the heteroaryl.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “prevent” or “preventing” as related to a disease or disorder can refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • treat, ” “treating” or “treatment, ” as used herein, can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • an “effective amount” or “therapeutically effective amount, ” as used herein refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.
  • an optionally substituted group can be un- substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9.
  • nested sub-ranges that extend from either end point of the range are specifically contemplated.
  • a nested sub-range of an exemplary range of 1 to 50 can comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
  • CDK2/4/6, or CDK2/4, or CDK2, or CDK4 selective inhibitor compounds are CDK2/4/6, or CDK2/4, or CDK2, or CDK4 selective inhibitor compounds.
  • the compounds represented by Formula (I) can have better kinase selectivity towards CDK2 or CDK4 or CDK2 and CDK4 and CDK6 over other cyclin-dependent kinases.
  • the disclosure provides a compound represented by Formula (I) , or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen, halogen, -NR c R d , C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R;
  • Y is a bond, -S-, -O-, -NR YN -, or -C (R Y ) 2 -;
  • R YN is hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
  • each R Y is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R Y are taken together to form an oxo;
  • X 1 is N or C
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • X 5 is N or C
  • X 6 is N or C
  • X 7 is O, S, N, NR 7N , CR 7 , or CR 7’ R 7 ;
  • X 8 is NR 8N , CR 8 , or CR 8’ R 8 ;
  • X 9 is O, S, N, NR 9N , CR 9 , or CR 9’ R 9 ;
  • each of R 2 , R 3 , and R 4 is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R;
  • each of R 7N and R 9N is independently hydrogen, -CN, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R;
  • each of R 7 and R 7’ is independently hydrogen, halogen, -CN, OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or
  • R 7 and R 7’ are taken together to form an oxo; or R 7 and R 7’ are taken together with the atom to which they are attached to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R;
  • each of R 9 and R 9’ is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or
  • R 9 and R 9’ are taken together to form an oxo; or R 9 and R 9’ are taken together with the atom to which they are attached to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R;
  • R 8’ is independently hydrogen, halogen, -CN, OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 8a ;
  • ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • the compound of Formula (I) has a structure of Formula (II) , or a pharmaceutically acceptable salt thereof,
  • the compound of Formula (I) has a structure of Formula (III) , or a pharmaceutically acceptable salt thereof,
  • ring A is heterocycloalkyl, aryl, heteroaryl, or C 4-12 cycloalkyl
  • Y is a bond, -S-, -O-, -NR YN -, or -C (R Y ) 2 -;
  • R YN is hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
  • each R Y is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl.
  • Y is a bond, -S-, -O-, -NR YN -, or -C (R Y ) 2 -.
  • Y is a bond.
  • Y is -S-or -O-.
  • Y is -S-.
  • Y is -O-.
  • Y is -NR YN -.
  • Y is -C (R Y ) 2 -.
  • Y is -C (R Y ) 2 -, wherein each R Y is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl.
  • R YN is hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R Y is hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl.
  • two R Y are taken together to form an oxo.
  • the compound of Formula (I) has a structure of Formula (IIa) , or a pharmaceutically acceptable salt thereof,
  • the compound of Formula (I) has a structure of Formula (IIIa) , or a pharmaceutically acceptable salt thereof,
  • X 1 is N or C. In some embodiments, X 1 is N. In some embodiments, X 1 is C. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X 2 is N or CR 2 . In some embodiments, X 2 is N. In some embodiments, X 2 is CR 2 .
  • X 3 is N or CR 3 . In some embodiments, X 3 is N. In some embodiments, X 3 is CR 3 . In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X 4 is N or CR 4 . In some embodiments, X 4 is N. In some embodiments, X 4 is CR 4 .
  • X 5 is N or C. In some embodiments, X 5 is N. In some embodiments, X 5 is C. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X 6 is N or C. In some embodiments, X 6 is N. In some embodiments, X 6 is C.
  • X 7 is O, S, N, NR 7N , CR 7 , or CR 7’ R 7 .
  • X 7 is O.
  • X 7 is S.
  • X 7 is N.
  • X 7 is NR 7N .
  • X 7 is CR 7 .
  • X 7 is CR 7’ R 7 .
  • X 8 is NR 8N , CR 8 , or CR 8’ R 8 . In some embodiments, X 8 is NR 8N . In some embodiments, X 8 is CR 8 . In some embodiments, X 8 is CR 8’ R 8 . In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X 9 is O, S, N, NR 9N , CR 9 , or CR 9’ R 9 . In some embodiments, X 9 is O.
  • X 9 is S. In some embodiments, X 9 is N. In some embodiments, X 9 is NR 9N . In some embodiments, X 9 is CR 9 . In some embodiments, X 9 is CR 9’ R 9 .
  • a compound of Formula (I) , (II) , or (IIa) is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is in some embodiments, is in some embodiments, is in some embodiments, is in some embodiments, is
  • a compound of Formula (I) , (III) , or (IIIa) is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is in some embodiments, is in some embodiments, is in some embodiments, is
  • R 1 is hydrogen, halogen, -NR c R d , C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R.
  • R 1 is hydrogen.
  • R 1 is halogen.
  • R 1 is -NR c R d .
  • R 1 is C 1-6 alkyl. In some embodiments, R 1 is C 1 -C 6 haloalkyl. In some embodiments, R 1 is C 1 -C 6 hydroxyalkyl. In some embodiments, R 1 is C 1 -C 6 aminoalkyl. In some embodiments, R 1 is C 1 -C 6 heteroalkyl.
  • R 2 is hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 2 . is hydrogen, halogen, -CN, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 2- 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 2 . is H, F, -CN, Cl, -CH 3 , -CHF 2 , or -C ⁇ CH.
  • R 2 is H.
  • R 2 is F.
  • R 2 is -CN.
  • R 2 is Cl.
  • R 2 is -CH 3 .
  • R 2 is -CHF 2 .
  • R 2 is -C ⁇ CH.
  • R 3 is hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 3 . is hydrogen, halogen, -CN, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 2- 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 3 . is H, F, -CN, Cl, -CH 3 , -CHF 2 , or -C ⁇ CH.
  • R 3 is H.
  • R 3 is F.
  • R 3 is -CN.
  • R 3 is Cl.
  • R 3 is -CH 3 .
  • R 3 is -CHF 2 .
  • R 3 is -C ⁇ CH.
  • R 4 is hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 4 . is hydrogen, halogen, -CN, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 2- 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 4 . is H, F, -CN, Cl, -CH 3 , -CHF 2 , or -C ⁇ CH.
  • R 4 is H.
  • R 4 is F.
  • R 4 is -CN.
  • R 4 is Cl.
  • R 4 is -CH 3 .
  • R 4 is -CHF 2 .
  • R 4 is -C ⁇ CH.
  • R 7 is hydrogen, halogen, -CN, OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 7 is hydrogen, halogen, C 1-6 alkyl, or cycloalkyl, wherein each of the alkyl and cycloalkyl is optionally substituted with one or more
  • R 7’ is hydrogen, halogen, -CN, OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 - C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 7’ is hydrogen, halogen, C 1-6 alkyl, or cycloalkyl, wherein each of the alkyl and cycloalkyl is optionally substituted with one
  • R 7’ is H, F, -CH 3 , or In some embodiments, R 7’ is H. In some embodiments, R 7’ is F. In some embodiments, R 7’ is -CH 3 . In some embodiments, R 7’ is
  • R 7 and R 7’ are taken together to form an oxo. In some embodiments, R 7 and R 7’ are taken together with the atom to which they are attached to form a cycloalkyl optionally substituted with one or more R.
  • R 7N is hydrogen, -CN, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 7N is hydrogen or C 1-6 alkyl, and wherein the alkyl is optionally substituted with one or more R In some embodiments, R 7N is hydrogen. In some embodiments, R 7N is C 1-6 alkyl. In some embodiments, R 7N is C 1- 6 alkyl, and wherein the alkyl is optionally substituted with one or more R.
  • R 9 is hydrogen, halogen, -CN, -OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 9 is hydrogen, halogen, C 1-6 alkyl, or cycloalkyl, wherein each of the alkyl and cycloalkyl is optionally substituted with one or
  • R 9’ is hydrogen, halogen, -CN, -OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 9’ is hydrogen, halogen, C 1-6 alkyl, or cycloalkyl, wherein each of the alkyl and cycloalkyl is optionally substituted with
  • R 9’ is H, F, -CH 3 , or In some embodiments, R 9’ is H. In some embodiments, R 9’ is F. In some embodiments, R 9’ is -CH 3 . In some embodiments, R 9’ is
  • R 9 and R 9’ are taken together to form an oxo. In some embodiments, R 9 and R 9’ are taken together with the atom to which they are attached to form a cycloalkyl optionally substituted with one or more R.
  • R 9N is hydrogen, -CN, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.
  • R 9N is hydrogen or C 1-6 alkyl, and wherein the alkyl is optionally substituted with one or more R In some embodiments, R 9N is hydrogen. In some embodiments, R 9N is C 1-6 alkyl. In some embodiments, R 9N is C 1- 6 alkyl, and wherein the alkyl is optionally substituted with one or more R.
  • R 8 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocycloalkyl, -C 1-6 heteroalkylene-cycloalkyl, -C 1-6 heteroalkylene-heterocycloalkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 heteroalkylene-aryl, or -C 1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, where
  • R 8 is C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, or -C 1-6 alkylene-heterocycloalkyl, wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more (e.g., 1-6) R 8a .
  • R 8 is In some embodiments, R 8 is heterocycloalkyl or cycloalkyl, wherein each of the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more (e.g., 1-6) R 8a . In some embodiments, R 8 is cycloalkyl, which is optionally substituted with one or more R 8a . In some embodiments, R 8 is a bicyclic cycloalkyl, which is optionally substituted with one or more R 8a . In some embodiments, R 8 is In some embodiments, R 8 is a 4-6 membered monocyclic cycloalkyl, which is optionally substituted with one or more R 8a .
  • R 8 is In some embodiments, R 8 is heterocycloalkyl, which is optionally substituted with one or more R 8a . In some embodiments, R 8 is heterocycloalkyl, which is optionally substituted with one or more R 8a . In some embodiments, R 8 is a bicyclic heterocycloalkyl, which is optionally substituted with one or more R 8a . In some embodiments, R 8 is a saturated ring. In some embodiments, R 8 is a partially saturated ring. In some embodiments, R 8 is In some embodiments, R 8 is a 4-6 membered monocyclic heterocycloalkyl, which is optionally substituted with one or more R 8a .
  • R 8 is In some embodiments, R 8 is-C 1-6 alkylene-heterocycloalkyl or -C 1-6 alkylene-cycloalkyl, wherein each of the alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R 8a . In some embodiments, R 8 is
  • R 8’ is independently hydrogen, halogen, -CN, OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 8a .
  • R 8’ is hydrogen, halogen, -CN, OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R 8a .
  • R 8N is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocycloalkyl, -C 1-6 heteroalkylene-cycloalkyl, -C 1-6 heteroalkylene-heterocycloalkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 heteroalkylene-aryl, or -C 1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, aryl, and
  • R 8N is C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, or -C 1- 6 alkylene-heterocycloalkyl, wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more (e.g., 1-6) R 8a .
  • R 8N is In some embodiments, R 8N is heterocycloalkyl or cycloalkyl, wherein each of the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R 8a . In some embodiments, R 8N is cycloalkyl, which is optionally substituted with one or more R 8a . In some embodiments, R 8N is a bicyclic cycloalkyl, which is optionally substituted with one or more R 8a . In some embodiments, R 8N is In some embodiments, R 8N is a 4-6 membered monocyclic cycloalkyl, which is optionally substituted with one or more R 8a . In some embodiments, R 8N is
  • R 8N is heterocycloalkyl, which is optionally substituted with one or more R 8a .
  • R 8N is a bicyclic heterocycloalkyl, which is optionally substituted with one or more R 8a .
  • R 8N is In some embodiments, R 8N is a 4-6 membered monocyclic heterocycloalkyl, which is optionally substituted with one or more R 8a .
  • R 8N is In some embodiments, R 8N is -C 1-6 alkylene-heterocycloalkyl or -C 1-6 alkylene-cycloalkyl, wherein each of the alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R 8a . In some embodiments, R 8N is
  • R 8a is independently selected from halogen, -OH, -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, ring A is cycloalkyl. In some embodiments, ring A is heterocycloalkyl. In some embodiments, ring A is aryl. In some embodiments, ring A is heteroaryl. In some embodiments, ring A is a bicyclic ring. In some embodiments, ring A is a 5-6 membered ring. In some embodiments, ring A is a 6 membered ring. In some embodiments, ring A is substituted at least at the para position.
  • Y 1 is N, C, or CR Y1 ;
  • Y 2 is O, S, N, NR Y2N , CR Y2 , or CR Y2 R Y2’ ;
  • Y 3 is O, S, N, NR Y3N , CR Y3 , or CR Y3 R Y3’ ;
  • Y 4 is O, NR Y4N , CR Y4 , or CR Y4 R Y4’ ;
  • Y 5 is O, S, N, NR Y5N , CR Y5 , or CR Y5 R Y5’ ;
  • Y 6 is O, S, N, NR Y6N , CR Y6 , or CR Y6 R Y6’ ;
  • each of R Y1 , R Y2 , R Y2’ , R Y3 , R Y3’ , R Y4 , R Y4’ , R Y5 , R Y5’ , R Y6 , and R Y6’ is independently selected from hydrogen and R 10 ;
  • Y 1 is N, C, or CR Y1 . In some embodiments, Y 1 is N. In some embodiments, Y 1 is C, or CR Y1 . In some embodiments, Y 1 is C.. In some embodiments, Y 1 is CR Y1 .
  • Y 2 is O, S, N, NR Y2N , CR Y2 , or CR Y2 R Y2’ .
  • Y 2 is N or NR Y2N .
  • Y 2 is CR Y2 or CR Y2 R Y2’ .
  • Y 2 is O.
  • Y 2 is S.
  • Y 2 is N.
  • Y 2 is NR Y2N .
  • Y 2 is CR Y2 .
  • Y 2 is CR Y2 R Y2’ .
  • Y 3 is O, S, N, NR Y3N , CR Y3 , or CR Y3 R Y3’ .
  • Y 3 is N or NR Y3N .
  • Y 3 is CR Y3 or CR Y3 R Y3’ .
  • Y 3 is O.
  • Y 3 is S.
  • Y 3 is N.
  • Y 3 is NR Y3N .
  • Y 3 is CR Y3 R Y3’ .
  • Y 4 is O, NR Y4N , CR Y4 , or CR Y4 R Y4’ . In some embodiments, Y 4 is O. In some embodiments, Y 4 is NR Y4N . In some embodiments, Y 4 is CR Y4 or CR Y4 R Y4’ . In some embodiments, Y 4 is CR Y4 . In some embodiments, Y 4 is CR Y4 R Y4’ .
  • Y 5 is O, S, N, NR Y5N , CR Y5 , or CR Y5 R Y5’ .
  • Y 5 is N or NR Y5N .
  • Y 5 is CR Y5 or CR Y5 R Y5’ .
  • Y 5 is O.
  • Y 5 is S.
  • Y 5 is N.
  • Y 5 is NR Y5N .
  • Y 5 is CR Y5 .
  • Y 5 is CR Y5 R Y5’ .
  • Y 6 is O, S, N, NR Y6N , CR Y6 , or CR Y6 R Y6’ .
  • Y 6 is N or NR Y6N .
  • Y 6 is CR Y6 or CR Y6 R Y6’ .
  • Y 6 is O.
  • Y 6 is S.
  • Y 6 is N.
  • Y 6 is NR Y6N .
  • Y 6 is CR Y6 .
  • Y 6 is CR Y6 R Y6’ .
  • each of R Y1 , R Y2 , R Y2’ , R Y3 , R Y3’ , R Y4 , R Y4’ , R Y5 , R Y5’ , R Y6 , and R Y6’ is independently selected from hydrogen and R 10 .
  • R Y1 , R Y2 , R Y2’ , R Y3 , R Y3’ , R Y5 , R Y5’ , R Y6 , and R Y6 are each hydrogen.
  • each of R Y1 , R Y2 , R Y2’ , R Y3 , R Y3’ , R Y4 , R Y4’ , R Y5 , R Y5’ , R Y6 , and R Y6’ are each R 10 .
  • R Y1 , R Y2 , R Y2’ , R Y3 , R Y3’ , R Y5 , R Y5’ , R Y6 , and R Y6 are each independently hydrogen, OH, or halogen.
  • n 1, 2, 3, 4, 5, or 6.
  • R 10 is taken together to form an oxo.
  • R 10 is halogen.
  • R a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, wherein each
  • R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • R c is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, where
  • R c is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more R. In some embodiments, R c is hydrogen. In some embodiments, R c is C 1 -C 6 alkyl.
  • R d is each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 - C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclo
  • R c is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • R d is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more R. In some embodiments, R d is hydrogen. In some embodiments, R d is C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • R is halogen. In some embodiments, R is C 1 -C 3 alkyl. In some embodiments, R is C 3 -C 6 cycloalkyl. In some embodiments, two R on the same atom form an oxo.
  • n is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.
  • Non-limiting examples of compounds described herein are compounds presented in Table 1, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from Table 1. Table 1. Exemplary Compounds of the Disclosure
  • bonds represented by solid wedge lines and dashed wedge lines are used to indicate absolute configuration of a chiral center; bonds represented by solid lines and dashed lines are used to indicate relative configuration of a chiral center; bond at a chiral center means the corresponding compound was racemic at this chiral center; bond at a chiral center means the corresponding compound was chiral pure, but the absolute configuration was not determined.
  • bonds represented by solid wedge lines and dashed wedge lines are used to indicate absolute configuration of a chiral center; bonds represented by solid lines and dashed lines are used to indicate relative configuration of a chiral center; bond at a chiral center means the corresponding compound was racemic at this chiral center; bond at a chiral center means the corresponding compound was chiral pure, but the absolute configuration was not determined.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium) , 2 H (deuterium) , and 3 H (tritium) .
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • the compounds described herein may be artificially enriched in one or more particular isotopes.
  • the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature.
  • the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • the compounds described herein are artificially enriched in one or more isotopes selected from 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 I.
  • the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound is deuterated in at least one position.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH
  • compositions containing the compound (s) described herein are administered for therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • CDKs Cyclin-dependent kinases
  • CDKs are heterodimeric of serine/threonine protein kinases involved in cell cycle and transcription (cell cycle CDK and transcriptional CDK) .
  • CDK functionality is determined by the specific interactions with regulatory proteins (cyclin) which form he heterodimeric complex, which are the regulators of the cellular processes (e.g., cell cycle progression and proliferation) .
  • Uncontrolled proliferation is synonymous with cancers which arises from problems in the cell cycle regulation.
  • CDK there are 20 CDK along with 29 cyclins as an estimate in the human proteome.
  • the CDKs generally associated with cell cycle regulation include CDK1, CDK2, CDK4 and CDK6.
  • the CDKs involved with transcription regulation include CDK7, CDK 8, CDK9 and CDK10.
  • Cyclin B/CDK1 , cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6, are vital regulators of cell cycle progression.
  • Overexpression of CDK2 has been related with abnormal regulation of cell-cycle.
  • the CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have been candidates in clinical trials for breast cancer and other cancers; and palbociclib and ribociclib have been approved for treatment of hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • the cyclin E/CDK2 complex has been studied as an important role in regulation of the G1/Stransition, histone biosynthesis and centrosome duplication. Cyclin E (regulatory cyclin for CDK2) is often amplified in cancer and the overexpression of Cyclin E2 (CCNE2) has been associated with endocrine resistance in breast cancer cells.
  • CDK2 has been shown to restore sensitivity to tamoxifen /CDK4 inhibitors in tamoxifen-resistant and CCNE2 overexpressing cells.
  • Cyclin E overexpression contributes to trastuzumab resistance in HER2+ breast cancer and known to play a role in basal-like and triple negative breast cancer (TNBC) , in addition to inflammatory breast cancer.
  • TNBC basal-like and triple negative breast cancer
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • the compounds described herein are used in a method of modulating cyclin-dependent kinase (CDK) in a subject.
  • the compounds described herein are used in a method of inhibiting cyclin-dependent kinase (CDK) in subject.
  • the compounds herein are used in a method of treating a disease or disorder associated with cyclin-dependent kinase (CDK) in a subject.
  • the compounds described herein are used in a method of treating a disease or disorder associated with modulation of cyclin-dependent kinase (CDK) in a subject.
  • a method for modulating, inhibiting, or treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein or a pharmaceutically acceptable salt thereof, in therapeutically effective amounts to said subject.
  • the CDK is CDK2. In some embodiments, the CDK is CDK4. In some embodiments, the CDK is CDK6.
  • the administration of the compounds can be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.01 -about 5000 mg per day, in some embodiments, about 1 –about 1500 mg per day.
  • the disclosure provides a method of modulating cyclin-dependent kinase (CDK) in a subject, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.
  • CDK cyclin-dependent kinase
  • the disclosure provides a method of inhibiting activity of cyclin-dependent kinase (CDK) in a subject, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.
  • CDK cyclin-dependent kinase
  • the disclosure provides a method of treating a disease or disorder associated with cyclin-dependent kinase (CDK) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein.
  • CDK cyclin-dependent kinase
  • the disease or a disorder is cancer.
  • the subject has a cancer.
  • the disclosure provides a method of treating a disease or disorder associated with modulation of CDK in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein.
  • the disease or disorder is cancer.
  • the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein.
  • the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein.
  • the cancer is leukemia, acute myeloid leukemia (AML) , chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) , non-Hodgkin lymphoma (NHL) , Hodgkin lymphoma (HL) , or multiple myeloma (MM) .
  • the cancer is a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin; a hematopoietic tumor of lymphoid lineage; a hematopoietic tumor of myeloid lineage; thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
  • a cancer to be treated by the methods of the present disclosure is breast cancer.
  • a cancer to be treated by the methods of treatment of the present disclosure is triple negative breast cancer (TNBC) .
  • the cancer is pRb+ breast cancer, or hormone receptor (HR) -positive (e.g., estrogen receptor positive (ER+) , progesterone receptor positive (PR+) , or ER+PR+) , HER2/neu-negative cancer.
  • the cancer is advanced or metastatic or recurrent breast cancer.
  • a patient or population of patients to be treated with a pharmaceutical composition of the present disclosure have a solid tumor.
  • a solid tumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma.
  • a solid tumor is breast cancer.
  • leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin’s disease, non-Hodgkin’s disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia,
  • leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic
  • cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.
  • the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein.
  • Example A3 -Synthesis of Compound 3 the title compound was prepared using Compound 3-4 and Compound 4-1 (which was synthesized according to step 1 in Example A3 -Synthesis of Compound 3) as substrates.
  • reaction mixture was filtered and purified by prep-HPLC (Gilson GX 281, Column: Pursuit XRs 10 C18, 19*250mm, 10 um; Mobile Phase A: 0.1%FA/H 2 O, B: ACN; flow rate: 25 mL/min; gradient: 17% ⁇ 17%; Retention Time: 6.8-7.0 min of 16 min) to afford the title compound.
  • Step 1 Preparation of compound 66-A/B
  • test compound was diluted with DMSO (Sigma, D4540) .
  • 40 nL of the diluted compound was transferred to 384-well plate (Greiner, 784075) using an Echo 655 (Beckman) .
  • a 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50mM Hepes, 10mM MgCl 2 , 0.01%Brij35, 2mM DTT) .
  • 2 ⁇ L of CDK1/CycA2 (4 nM, Proqinase, 0134-0054-1) solution was transferred to the 384-well plate, followed by a 10-minute incubation at 25°C after a 60-second centrifugation at 1000 rpm.
  • the reagent was centrifuged at 1000rpm for 60s and incubated at 25°C for 40 minutes.
  • the chemiluminescence (luminescence) signal was read using a multifunctional enzyme marker (BMG, PHERAstar FSX) .
  • test compound was diluted with DMSO (Sigma, D4540) .
  • 40 nL of the diluted compound was transferred to 384-well plate (Greiner, 784075) using an Echo 655 (Beckman) .
  • a 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50mM Hepes, 10mM MgCl 2 , 0.01%Brij35, 2mM DTT) .
  • 2 ⁇ L of CDK2/CycE1 (0.33 nM, Carna, 04-165) solution was transferred to the 384-well plate, followed by a 10-minute incubation at 25°C after a 60-second centrifugation at 1000 rpm.
  • the reagent was centrifuged at 1000rpm for 60s and incubated at 25°C for 40 minutes.
  • the chemiluminescence (luminescence) signal was read using a multifunctional enzyme marker (BMG, PHERAstar FSX) .
  • test compound was diluted with DMSO (Sigma, D4540) .
  • 40 nL of the diluted compound was transferred to 384-well plate (Greiner, 784075) using an Echo 655 (Beckman) .
  • a 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50mM Hepes, 10mM MgCl 2 , 0.01%Brij35, 2mM DTT) .
  • 2 ⁇ L of CDK4/CycD3 (31 nM, Proqinase, 0142-0373-1) solution was transferred to the 384-well plate, followed by a 10-minute incubation at 25°C after a 60-second centrifugation at 1000 rpm.
  • the reagent was centrifuged at 1000rpm for 60s and incubated at 25°C for 40 minutes.
  • the chemiluminescence (luminescence) signal was read using a multifunctional enzyme marker (BMG, PHERAstar FSX) .
  • test compound was diluted with DMSO (Sigma, D4540) .
  • 40 nL of the diluted compound was transferred to 384-well plate (Greiner, 784075) using an Echo 655 (Beckman) .
  • a 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50mM Hepes, 10mM MgCl 2 , 0.01%Brij35, 2mM DTT) .
  • 2 ⁇ L of CDK9/CycT1 (7 nM, Carna, 04-110) solution was transferred to the 384-well plate, followed by a 10-minute incubation at 25°C after a 60-second centrifugation at 1000 rpm.
  • the reagent was centrifuged at 1000rpm for 60s and incubated at 25°C for 40 minutes.
  • the chemiluminescence (luminescence) signal was read using a multifunctional enzyme marker (BMG, PHERAstar FSX) .
  • Table 3 presents corresponding biological data for CDK1, CDK2, CDK3, and CDK4 (nM) for the compounds presented in Table 1.

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Abstract

The disclosure provides for small molecules inhibitory compounds of CDK2/4/6 and compositions comprising the same. The disclosure further provides methods for targeting CDK2/4/6 and methods of treating diseases or disorders related to CDK2/4/6, such as cancer.

Description

SUBSTITUTED THIAZOLE COMPOUNDS AS CDK2/4/6 INHIBITORS AND METHODS OF USE THEREOF
CROSS-REFERENCE
This patent application claims the benefit of International Application No. PCT/CN2023/105592, filed July 03, 2023; which is incorporated herein by reference in its entirety.
BACKGROUND
Cyclin-dependent kinases (CDKs) are vital enzymes affecting the essential functions in eukaryotic cell division regulation and eukaryotic cell proliferation. Regulatory subunits (cyclins) active the catalytic units of CDK and are also important regulators of cell cycle progression. Furthermore, functions of cyclin/CDK heterodynes also include regulation of transcription, DNA repair, differentiation and apoptosis. Overexpression of CDK2 is associated with abnormal regulation of cell-cycle. Cyclin E, a regulatory cyclin for CDK2, is frequently overexpressed in cancer, and the amplification/overexpression of cyclin E has been associated with breast cancer.
SUMMARY
The present disclosure addresses the above need and provides additional advantages as well.
In one aspect, described herein is a compound having the structure of Formula (I) , or a salt thereof,
In some embodiments, the compound has a structure of Formula (II) , or a pharmaceutically acceptable salt thereof,
In some embodiments, the compound has a structure of Formula (III) , or a pharmaceutically acceptable salt thereof,
In one aspect, described herein is a compound having the structure of Formula (IIa) , or a pharmaceutically acceptable salt thereof,
In one aspect, described herein is a compound having the structure of Formula (IIIa) , or a pharmaceutically acceptable salt thereof,
In one aspect, described herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
In one aspect, described herein is a method of treating a cancer in a subject, the method comprising administering to a subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein
In one aspect, described herein is a method of modulating activity of a cyclin-dependent kinase (CDK) in a subject, the method comprising administering to a subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.
In one aspect, described herein is a method of inhibiting activity of a cyclin-dependent kinase (CDK) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein.
In one aspect, described herein is a method of treating a disease or disorder associated with cyclin-dependent kinase (CDK) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein. In some embodiments, the disease or disorder is cancer.
In some embodiments, the cancer is a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin; a hematopoietic tumor of lymphoid lineage; a hematopoietic tumor of myeloid lineage; thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi's sarcoma. In some embodiments, the cancer is pRb+ breast cancer, or hormone receptor (HR) -positive (e.g., estrogen receptor positive (ER+) , progesterone receptor positive (PR+) , or ER+PR+) , HER2/neu-negative cancer. In some embodiments, the cancer is advanced or metastatic or recurrent breast cancer.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
DETAILED DESCRIPTION
While various embodiments of the disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions can occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein can be employed.
A. Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference.
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the disclosed technology may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.  Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
The terms below, as used herein, have the following meanings, unless indicated otherwise:
“oxo” refers to =O.
“Carboxyl” refers to -COOH.
“Cyano” refers to -CN.
“Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl” , means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double  bond (s) , and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2) , 1-propenyl (-CH2CH=CH2) , isopropenyl [-C (CH3) =CH2] , butenyl, 1, 3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl” , means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
“Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl” , means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
“Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
“Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl) . Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. As used herein, “arylene” refers to a bivalent aryl radical as described herein. An arylene can be bonded through the aryl at any suitable position. In some embodiments, when an arylene comprises an aryl fused with a cycloalkyl or heterocycloalkyl ring, the arylene is bonded at the aryl and the cycloalkyl, or the aryl and the heterocycloalkyl. In some embodiments, when an arylene comprises an aryl fused with a cycloalkyl or heterocycloalkyl ring, the arylene is bonded only at the aryl.
“Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl) , from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl) , from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl) , from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl) , from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl) , or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl) . In some embodiments, the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a  cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. As used herein, “cycloalkylene” refers to a bivalent cycloalkyl radical as described herein. In some embodiments, when a cycloalkylene comprises a cycloalkyl fused with an aryl or a heteroaryl ring, the cycloalkylene is bonded at the cycloalkyl and the aryl, or the cycloalkyl and the heteroaryl. In some embodiments, when a cycloalkylene comprises a cycloalkyl fused with an aryl or a heteroaryl ring, the cycloalkylene is bonded only at the cycloalkyl.
“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH (CH3) OCH3, -CH2NHCH3, -CH2N (CH3) 2, -CH2CH2NHCH3, or -CH2CH2N (CH3) 2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen,  methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“Heterocycloalkyl” refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl) , from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl) , or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl) . Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) . In some embodiments, the heterocycloalkyl is a 3-to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered fully saturated  heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
As used herein, “heterocycloalkylene” refers to a bivalent heterocycloalkyl radical as described herein. In some embodiments, when a heterocycloalkylene comprises a heterocycloalkyl fused with an aryl or a heteroaryl ring, the heterocycloalkylene is bonded at the heterocycloalkyl and the aryl, or the heterocycloalkyl and the heteroaryl. In some embodiments, when a heterocycloalkylene comprises a heterocycloalkyl fused with an aryl or a heteroaryl ring, the heterocycloalkylene is bonded only at the heterocycloalkyl.
“Heteroaryl” refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,  benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl) . Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. As used herein, “heteroarylene” refers to a bivalent heteroaryl radical as described herein. In some embodiments, when a heteroarylene comprises a heteroaryl fused with a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded at the heteroaryl and the cycloalkyl, or the heteroaryl and the heterocycloalkyl. In some embodiments, when a heteroarylene comprises a heteroaryl fused with a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded only at the heteroaryl.
The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3) , fully substituted (e.g., -CF2CF3) , mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc. ) . It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
As used in the specification and claims, the singular form “a” , “an” and “the” includes plural references unless the context clearly dictates otherwise.
The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric  acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder can refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
The terms “treat, ” “treating” or “treatment, ” as used herein, can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
The terms “effective amount” or “therapeutically effective amount, ” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.
The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group can be un- substituted (e.g., -CH2CH3) , fully substituted (e.g., -CF2CF3) , mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc. ) .
As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal.
Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 can comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
B. Compounds of the disclosure
In one aspect, disclosed herein are CDK2/4/6, or CDK2/4, or CDK2, or CDK4 selective inhibitor compounds. The compounds represented by Formula (I) can have better kinase selectivity towards CDK2 or CDK4 or CDK2 and CDK4 and CDK6 over other cyclin-dependent kinases.
In one aspect, the disclosure provides a compound represented by Formula (I) , or a pharmaceutically acceptable salt thereof:
wherein,
is
R1 is hydrogen, halogen, -NRcRd, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R; Y is a bond, -S-, -O-, -NRYN-, or -C (RY) 2-;
RYN is hydrogen, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
each RY is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl; or two RY are taken together to form an oxo;
is a single bond or a double bond;
X1 is N or C;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4;
X5 is N or C;
X6 is N or C;
X7 is O, S, N, NR7N, CR7, or CR7’ R7;
X8 is NR8N, CR8, or CR8’ R8;
X9 is O, S, N, NR9N, CR9, or CR9’ R9;
each of R2, R3, and R4 is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R;
each of R7N and R9N is independently hydrogen, -CN, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R;
each of R7 and R7’ is independently hydrogen, halogen, -CN, OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or
R7 and R7’ are taken together to form an oxo; or R7 and R7’ are taken together with the atom to which they are attached to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R;
each of R9 and R9’ is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or
R9 and R9’ are taken together to form an oxo; or R9 and R9’ are taken together with the atom to which they are attached to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R;
R8 is selected from halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1- 6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1- 6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R8a;
R8N is selected from -CN, -NO2, -OC (=O) Ra, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1- 6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R8a;
R8’ is independently hydrogen, halogen, -CN, OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R8a;
each R8a is independently selected from halogen, -CN, -NO2, -OH, oxo, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R10 is independently selected from halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -P (=O) RcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl,  heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a; or two R10 are taken together to form an oxo;
each R10a is independently selected from halogen, -CN, -NO2, -OH, oxo, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
n is 0, 1, 2, 3, 4, 5 or 6;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl;
or two R on the same atom form an oxo.
In some embodiments, the compound of Formula (I) has a structure of Formula (II) , or a pharmaceutically acceptable salt thereof,
In some embodiments, the compound of Formula (I) has a structure of Formula (III) , or a pharmaceutically acceptable salt thereof,
In some embodiments of a compound of Formula (III) , or a pharmaceutically acceptable salt thereof,
wherein
ring A is heterocycloalkyl, aryl, heteroaryl, or C4-12 cycloalkyl;
Y is a bond, -S-, -O-, -NRYN-, or -C (RY) 2-;
RYN is hydrogen, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
each RY is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl.
In some embodiments of a compound of Formula (I) , (II) , or (III) , Y is a bond, -S-, -O-, -NRYN-, or -C (RY) 2-. In some embodiments, Y is a bond. In some embodiments, Y is -S-or -O-. In some embodiments, Y is -S-. In some embodiments, Y is -O-. In some embodiments, Y is -NRYN-. In some embodiments, Y is -C (RY) 2-. In some embodiments, Y is -C (RY) 2-, wherein each RY is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl.
In some embodiments of a compound of Formula (I) , (II) , or (III) , RYN is hydrogen, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments, RY is hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6  alkynyl, cycloalkyl, or heterocycloalkyl. In some embodiments, two RY are taken together to form an oxo.
In some embodiments, the compound of Formula (I) has a structure of Formula (IIa) , or a pharmaceutically acceptable salt thereof,
In some embodiments, the compound of Formula (I) has a structure of Formula (IIIa) , or a pharmaceutically acceptable salt thereof,
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X1 is N or C. In some embodiments, X1 is N. In some embodiments, X1 is C. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X2 is N or CR2. In some embodiments, X2 is N. In some embodiments, X2 is CR2. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X3 is N or CR3. In some embodiments, X3 is N. In some embodiments, X3 is CR3. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X4 is N or CR4. In some embodiments, X4 is N. In some embodiments, X4 is CR4. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X5 is N or C. In some embodiments, X5 is N. In some embodiments, X5 is C. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X6 is N or C. In some embodiments, X6 is N. In some embodiments, X6 is C. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X7 is O, S, N, NR7N, CR7, or CR7’ R7. In some embodiments, X7 is O. In some embodiments, X7 is S. In some embodiments, X7 is N. In some embodiments, X7 is NR7N. In some embodiments, X7 is CR7. In some embodiments, X7 is CR7’ R7. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X8 is NR8N, CR8, or CR8’ R8. In some embodiments, X8 is NR8N. In some embodiments, X8 is CR8. In some embodiments, X8 is CR8’ R8. In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , X9 is O, S, N, NR9N, CR9, or CR9’ R9. In some embodiments, X9 is O. In some  embodiments, X9 is S. In some embodiments, X9 is N. In some embodiments, X9 is NR9N. In some embodiments, X9 is CR9. In some embodiments, X9 is CR9’ R9.
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In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R1 is hydrogen, halogen, -NRcRd, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R. In some embodiments, R1 is hydrogen. In some embodiments, R1 is halogen. In some embodiments, R1 is -NRcRd. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is C1-C6haloalkyl. In some embodiments, R1 is C1-C6hydroxyalkyl. In some embodiments, R1 is C1-C6aminoalkyl. In some embodiments, R1 is C1-C6heteroalkyl.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R2 is hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein  each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R2. is hydrogen, halogen, -CN, C1-6 alkyl, C1-C6haloalkyl, C2- 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R2. is H, F, -CN, Cl, -CH3, -CHF2, or -C≡CH. In some embodiments, R2 is H. In some embodiments, R2 is F. In some embodiments, R2 is -CN. In some embodiments, R2 is Cl. In some embodiments, R2 is -CH3. In some embodiments, R2 is -CHF2. In some embodiments, R2 is -C≡CH.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R3 is hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R3. is hydrogen, halogen, -CN, C1-6 alkyl, C1-C6haloalkyl, C2- 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R3. is H, F, -CN, Cl, -CH3, -CHF2, or -C≡CH. In some embodiments, R3 is H. In some embodiments, R3 is F. In some embodiments, R3 is -CN. In some embodiments, R3 is Cl. In some embodiments, R3 is -CH3. In some embodiments, R3 is -CHF2. In some embodiments, R3 is -C≡CH.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R4 is hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R4. is hydrogen, halogen, -CN, C1-6 alkyl, C1-C6haloalkyl, C2- 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R4. is H, F, -CN, Cl, -CH3, -CHF2, or -C≡CH. In some embodiments, R4 is H. In some embodiments, R4 is F. In some embodiments, R4 is -CN. In some embodiments, R4 is Cl. In some embodiments, R4 is -CH3. In some embodiments, R4 is -CHF2. In some embodiments, R4 is -C≡CH.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R7 is hydrogen, halogen, -CN, OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.In some embodiments, R7 is hydrogen, halogen, C1-6 alkyl, or cycloalkyl, wherein each of the alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments, R7 is H, F, -CH3, orIn some embodiments, R7 is H. In some embodiments, R7 is F. In some embodiments, R7 is -CH3. In some embodiments, R7 is
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R7’ is hydrogen, halogen, -CN, OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.In some embodiments, R7’ is hydrogen, halogen, C1-6 alkyl, or cycloalkyl, wherein each of the alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments, R7’ is H, F, -CH3, or In some embodiments, R7’ is H. In some embodiments, R7’ is F. In some embodiments, R7’ is -CH3. In some embodiments, R7’ is
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R7 and R7’ are taken together to form an oxo. In some embodiments, R7 and R7’ are taken together with the atom to which they are attached to form a cycloalkyl optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R7N is hydrogen, -CN, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R7N is hydrogen or C1-6 alkyl, and wherein the alkyl is optionally substituted with one or more R In some embodiments, R7N is hydrogen. In some embodiments, R7N is C1-6 alkyl. In some embodiments, R7N is C1- 6 alkyl, and wherein the alkyl is optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R9 is hydrogen, halogen, -CN, -OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.In some embodiments, R9 is hydrogen, halogen, C1-6 alkyl, or cycloalkyl, wherein each of the alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments, R9 is H, F, -CH3, orIn some embodiments, R9 is H. In some embodiments, R9 is F. In some embodiments, R9 is -CH3. In some embodiments, R9 is
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R9’ is hydrogen, halogen, -CN, -OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R.In some embodiments, R9’ is hydrogen, halogen, C1-6 alkyl, or cycloalkyl, wherein each of the alkyl and cycloalkyl is optionally substituted with one or more R. In some embodiments, R9’ is H, F, -CH3, or In some embodiments, R9’ is H. In some embodiments, R9’ is F. In some embodiments, R9’ is -CH3. In some embodiments, R9’ is
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R9 and R9’ are taken together to form an oxo. In some embodiments, R9 and R9’ are taken together with the atom to which they are attached to form a cycloalkyl optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R9N is hydrogen, -CN, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments, R9N is hydrogen or C1-6 alkyl, and wherein the alkyl is optionally substituted with one or more R In some embodiments, R9N is hydrogen. In some embodiments, R9N is C1-6 alkyl. In some embodiments, R9N is C1- 6 alkyl, and wherein the alkyl is optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R8 is selected from halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R8a. In some embodiments, R8 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, or -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R8a. In some embodiments, R8 is C1-C6hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, or -C1-6 alkylene-heterocycloalkyl, wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more (e.g., 1-6) R8a. In some embodiments, R8 isIn some embodiments, R8 is heterocycloalkyl or cycloalkyl, wherein each of the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more (e.g., 1-6) R8a. In some embodiments, R8 is cycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8 is a bicyclic cycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8 isIn some embodiments, R8 is a 4-6 membered monocyclic cycloalkyl, which is optionally substituted with one or more R8a. In some  embodiments, R8 is In some embodiments, R8 is heterocycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8 is heterocycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8 is a bicyclic heterocycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8 is a saturated ring. In some embodiments, R8 is a partially saturated ring. In some embodiments, R8 is In some embodiments, R8 is a 4-6 membered monocyclic heterocycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8 is In some embodiments, R8 is-C1-6 alkylene-heterocycloalkyl or -C1-6 alkylene-cycloalkyl, wherein each of the alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R8a. In some embodiments, R8 is
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R8’ is independently hydrogen, halogen, -CN, OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R8a. In some embodiments, R8’ is hydrogen, halogen, -CN, OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R8a.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R8N is selected from -CN, -NO2, -OC (=O) Ra, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R8a. In some embodiments, R8N is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, or -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more (e.g., 1-6) R8a. In some embodiments, R8N is C1-C6hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, or -C1- 6 alkylene-heterocycloalkyl, wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more (e.g., 1-6) R8a. In some embodiments, R8N isIn some embodiments, R8N is heterocycloalkyl or cycloalkyl, wherein each of the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R8a. In some embodiments, R8N is cycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8N is a bicyclic cycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8N isIn some embodiments, R8N is a 4-6 membered monocyclic cycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8N is
In some embodiments, R8N is heterocycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8N is a bicyclic heterocycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8N isIn some embodiments, R8N is a 4-6 membered monocyclic heterocycloalkyl, which is optionally substituted with one or more R8a. In some embodiments, R8N is In some embodiments, R8N is -C1-6 alkylene-heterocycloalkyl or -C1-6 alkylene-cycloalkyl, wherein each of the alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R8a. In some embodiments, R8N is
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R8a is selected from halogen, -CN, -NO2, -OH, oxo, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, - NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, R8a is independently selected from halogen, -OH, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, ring A is cycloalkyl. In some embodiments, ring A is heterocycloalkyl. In some embodiments, ring A is aryl. In some embodiments, ring A is heteroaryl. In some embodiments, ring A is a bicyclic ring. In some embodiments, ring A is a 5-6 membered ring. In some embodiments, ring A is a 6 membered ring. In some embodiments, ring A is substituted at least at the para position.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , is
Y1 is N, C, or CRY1;
Y2 is O, S, N, NRY2N, CRY2, or CRY2RY2’;
Y3 is O, S, N, NRY3N, CRY3, or CRY3RY3’;
Y4 is O, NRY4N, CRY4, or CRY4RY4’;
Y5 is O, S, N, NRY5N, CRY5, or CRY5RY5’;
Y6 is O, S, N, NRY6N, CRY6, or CRY6RY6’;
each of RY1, RY2, RY2’, RY3, RY3’, RY4, RY4’, RY5, RY5’, RY6, and RY6’ is independently selected from hydrogen and R10;
each of RY2N, RY3N, aRY4N, RY5N, and RY6N is independently selected from -CN, -NO2, -OC (=O) Ra, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1- 6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl,  cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Y1 is N, C, or CRY1. In some embodiments, Y1 is N. In some embodiments, Y1 is C, or CRY1. In some embodiments, Y1 is C.. In some embodiments, Y1 is CRY1.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Y2 is O, S, N, NRY2N, CRY2, or CRY2RY2’. In some embodiments, Y2 is N or NRY2N. In some embodiments, Y2 is CRY2 or CRY2RY2’. In some embodiments, Y2 is O. In some embodiments, Y2 is S. In some embodiments, Y2 is N. In some embodiments, Y2 is NRY2N. In some embodiments, Y2 is CRY2. In some embodiments, Y2 is CRY2RY2’.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Y3 is O, S, N, NRY3N, CRY3, or CRY3RY3’. In some embodiments, Y3 is N or NRY3N. In some embodiments, Y3 is CRY3 or CRY3RY3’. In some embodiments, Y3 is O. In some embodiments, Y3 is S. In some embodiments, Y3 is N. In some embodiments, Y3 is NRY3N. In some embodiments, Y3 is CRY3. In some embodiments, Y3 is CRY3RY3’.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Y4 is O, NRY4N, CRY4, or CRY4RY4’. In some embodiments, Y4 is O. In some embodiments, Y4 is NRY4N. In some embodiments, Y4 is CRY4 or CRY4RY4’. In some embodiments, Y4 is CRY4. In some embodiments, Y4 is CRY4RY4’.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Y5 is O, S, N, NRY5N, CRY5, or CRY5RY5’. In some embodiments, Y5 is N or NRY5N. In some embodiments, Y5 is CRY5 or CRY5RY5’. In some embodiments, Y5 is O. In some embodiments, Y5 is S. In some embodiments, Y5 is N. In some embodiments, Y5 is NRY5N. In some embodiments, Y5 is CRY5. In some embodiments, Y5 is CRY5RY5’.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Y6 is O, S, N, NRY6N, CRY6, or CRY6RY6’. In some embodiments, Y6 is N or NRY6N. In some embodiments, Y6 is CRY6 or CRY6RY6’. In some embodiments, Y6 is O. In some embodiments, Y6 is S. In some embodiments, Y6 is N. In some embodiments, Y6 is NRY6N. In some embodiments, Y6 is CRY6. In some embodiments, Y6 is CRY6RY6’.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , each of RY1, RY2, RY2’, RY3, RY3’, RY4, RY4’, RY5, RY5’, RY6, and RY6’ is independently selected from hydrogen and R10.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , RY1, RY2, RY2’, RY3, RY3’, RY5, RY5’, RY6, and RY6 are each hydrogen. In some embodiments, each of RY1, RY2, RY2’, RY3, RY3’, RY4, RY4’, RY5, RY5’, RY6, and RY6’ are each R10. In some embodiments, RY1, RY2, RY2’, RY3, RY3’, RY5, RY5’, RY6, and RY6 are each independently hydrogen, OH, or halogen.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , RY4 and RY4’ are each independently hydrogen, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -C (=O) Ra, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl,  aryl, and heteroaryl is independently optionally substituted with one or more R10a. In some embodiments, RY4’ is hydrogen. In some embodiments, RY4 is -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -C (=O) Ra, C1-C6alkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a. In some embodiments, RY4N is -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -C (=O) Ra, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) ,  wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments, is
In some embodiments, isIn some embodiments, isIn some embodiments, isIn  some embodiments, isIn some embodiments, is
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , RY2N, RY3N, RY4N, RY5N, and RY6N is independently selected from -CN, -NO2, -OC (=O) Ra, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a. In some embodiments, RY2N, RY3N, RY4N, RY5N, and RY6N is independently selected from -S (=O) Ra or -S (=O) 2Ra. In some embodiments, RY4N is -S (=O) Ra or -S (=O) 2Ra. In some embodiments, RY4N is -S (=O) Ra. In some embodiments, RY4N is -S (=O) 2Ra. In some embodiments, RY4N is -S (=O) 2NRcRd.
In some embodiments, RY4N is -S (=O) 2CH3 , -CH2CH2S (=O) 2CH3, -S (=O) 2CHF2, -S (=O) 2CH (CH3) 2, -S (=O) 2CH2CH2OH, -S (=O) (=NH) CH3, or -S (=O) 2NHCH3, 
In some embodiments, RY4N is -S (=O) 2CH3 , -S (=O) 2CHF2, -S (=O) 2CH (CH3) 2,  In some embodiments, RY4N is -S (=O) 2CH3 or
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R10 is independently selected from halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -P (=O) RcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a. In some embodiments, two R10 are taken together to form an oxo. In some embodiments, R10 is independently selected from halogen, -OH, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -C (=O) Ra, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a. In some embodiments, R10 is halogen. In some embodiments, R10 is F. In some embodiments, R10 is F or OH. In some embodiments, R10 is -OH. In some embodiments, R10 is -S (=O) 2Ra, -S (=O) 2NRcRd, or -S (=O) (=NRb) Rb. In some embodiments, at least one R10 is -S (=O) 2Ra, -S (=O) 2NRcRd, or -S (=O) (=NRb) Rb. In some embodiments, R10 is -S (=O) 2Ra. In some embodiments, R10 is -S (=O) 2NRcRd. In some embodiments, R10 is -S (=O) (=NRb) Rb. In some embodiments, R10 is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more R10a. In some embodiments, R10 is heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R10a. In some embodiments, at least one R10 is -S (=O) 2CH3, -S (=O) 2CH (CH3) 2,  -S (=O) 2NH2, or -S (=O) 2NHCH3. In some embodiments, at least one R10 is In some embodiments, R10 is -S (=O) 2CH3. In some embodiments, R10 is -S (=O) 2CH (CH3) 2.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R10a is selected from halogen, -CN, -NO2, -OH, oxo, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Ra is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, Ra is C1-C6alkyl.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, Rb is C1-C6alkyl. In some embodiments, Rb is hydrogen.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Rc is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, Rc is hydrogen or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more R. In some embodiments, Rc is hydrogen. In some embodiments, Rc is C1-C6alkyl.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Rd is each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1- C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, Rc is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, Rd is hydrogen or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more R. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C6alkyl.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , R is halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl. In some embodiments, R is halogen. In some embodiments, R is C1-C3alkyl. In some embodiments, R is C3-C6cycloalkyl. In some embodiments, two R on the same atom form an oxo.
In some embodiments of a compound of Formula (I) , (II) , (III) , (IIa) , or (IIIa) , n is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.
Non-limiting examples of compounds described herein, are compounds presented in Table 1, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from Table 1. Table 1. Exemplary Compounds of the Disclosure





Unless explained otherwise, in the present disclosure, bonds represented by solid wedge lines and dashed wedge linesare used to indicate absolute configuration of a chiral center; bonds represented by solid linesand dashed linesare used to indicate relative configuration of a chiral center; bondat a chiral center means the corresponding compound was racemic at this chiral center; bondat a chiral center means the corresponding compound was chiral pure, but the absolute configuration was not determined.
Additional non-limiting examples of compounds described herein, are compounds presented in Table 2, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from Table 2.
Table 2. Exemplary Compounds of the Disclosure





Unless explained otherwise, in the present disclosure, bonds represented by solid wedge lines and dashed wedge linesare used to indicate absolute configuration of a chiral center; bonds represented by solid linesand dashed linesare used to indicate relative configuration of a chiral center; bondat a chiral center means the corresponding compound was racemic at this chiral center; bondat a chiral center means the corresponding compound was chiral pure, but the absolute configuration was not determined.
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E) , and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc. ) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.  In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
Isotopically enriched compounds
Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 1H (protium) , 2H (deuterium) , and 3H (tritium) . Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H) , tritium (3H) , iodine-125 (125I) or carbon-14 (14C) . In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 131I, and 125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms.
The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods  disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.
Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4’ -methylenebis- (3-hydroxy-2-ene-1 -carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+ (C1-4 alkyl) 4, and the like.
Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
Tautomers
In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH
Dosing
In certain embodiments, the compositions containing the compound (s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.
Routes of Administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
Pharmaceutical Compositions/Formulations
The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999) , herein incorporated by reference for such disclosure.
Methods of Treatment
Cyclin-dependent kinases (CDKs) play important roles in regulating cell division and proliferation. CDKs are heterodimeric of serine/threonine protein kinases involved in cell cycle and transcription (cell cycle CDK and transcriptional CDK) . CDK’s functionality is determined by the specific interactions with regulatory proteins (cyclin) which form he heterodimeric complex, which are the regulators of the cellular processes (e.g., cell cycle progression and proliferation) . Uncontrolled proliferation is synonymous with cancers which arises from problems in the cell cycle regulation.
There are 20 CDK along with 29 cyclins as an estimate in the human proteome. The CDKs generally associated with cell cycle regulation include CDK1, CDK2, CDK4 and CDK6. The CDKs involved with transcription regulation include CDK7, CDK 8, CDK9 and CDK10. Cyclin B/CDK1 , cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6, are vital regulators of cell cycle progression. Overexpression of CDK2 has been related with abnormal regulation of cell-cycle. The CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have been candidates in clinical trials for breast cancer and other cancers; and palbociclib and ribociclib have been approved for treatment of hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer. The cyclin E/CDK2 complex has been studied as an important role in regulation of the G1/Stransition, histone biosynthesis and centrosome duplication. Cyclin E (regulatory cyclin for CDK2) is often amplified in cancer and the overexpression of Cyclin E2 (CCNE2) has been associated with endocrine resistance in breast cancer cells. The inhibition of CDK2 has been shown to restore sensitivity to tamoxifen /CDK4 inhibitors in tamoxifen-resistant and CCNE2 overexpressing cells. Also, Cyclin E overexpression contributes to trastuzumab resistance in HER2+ breast cancer and  known to play a role in basal-like and triple negative breast cancer (TNBC) , in addition to inflammatory breast cancer.
The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In some embodiments, the compounds described herein are used in a method of modulating cyclin-dependent kinase (CDK) in a subject. In some embodiments, the compounds described herein are used in a method of inhibiting cyclin-dependent kinase (CDK) in subject. In some embodiments, the compounds herein are used in a method of treating a disease or disorder associated with cyclin-dependent kinase (CDK) in a subject. In some embodiments, the compounds described herein are used in a method of treating a disease or disorder associated with modulation of cyclin-dependent kinase (CDK) in a subject. In addition, a method for modulating, inhibiting, or treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein or a pharmaceutically acceptable salt thereof, in therapeutically effective amounts to said subject.
In some embodiments, the CDK is CDK2. In some embodiments, the CDK is CDK4. In some embodiments, the CDK is CDK6.
In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds can be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.01 -about 5000 mg per day, in some embodiments, about 1 –about 1500 mg per day.
In one aspect, the disclosure provides a method of modulating cyclin-dependent kinase (CDK) in a subject, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.
In one aspect, the disclosure provides a method of inhibiting activity of cyclin-dependent kinase (CDK) in a subject, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.
In one aspect, the disclosure provides a method of treating a disease or disorder associated with cyclin-dependent kinase (CDK) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein. In some embodiments, the disease or a disorder is cancer. In some embodiments, the subject has a cancer.
In one aspect, the disclosure provides a method of treating a disease or disorder associated with modulation of CDK in a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein. In some embodiments, the disease or disorder is cancer.
In one aspect, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein.
In one aspect, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein. In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML) , chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) , non-Hodgkin lymphoma (NHL) , Hodgkin lymphoma (HL) , or multiple myeloma (MM) .
In some embodiments, the cancer is a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin; a hematopoietic tumor of lymphoid lineage; a hematopoietic tumor of myeloid lineage; thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi's sarcoma. In some embodiments, a cancer to be treated by the methods of the present disclosure is breast cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is triple negative breast cancer (TNBC) . In some embodiments, the cancer is pRb+ breast cancer, or hormone receptor (HR) -positive (e.g., estrogen receptor positive (ER+) , progesterone receptor positive (PR+) , or ER+PR+) , HER2/neu-negative cancer. In some embodiments, the cancer is advanced or metastatic or recurrent breast cancer.
In some embodiments, a patient or population of patients to be treated with a pharmaceutical composition of the present disclosure have a solid tumor. In some embodiments, a solid tumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, a solid tumor is breast cancer..
Specific examples of cancers that can be prevented and/or treated in accordance with present disclosure include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma;
neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin’s disease, non-Hodgkin’s disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom’s macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget’s disease of bone, osteosarcoma, chondrosarcoma, Ewing’s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma) , fibrosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget’s disease (including juvenile Paget’s disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytoma and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing’s disease, prolactin-secreting tumor, acromegaly, and diabetes insipidus; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and ciliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid) , ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; colorectal cancer, KRAS mutated colorectal cancer; colon carcinoma; rectal cancers; liver cancers such as but not limited to  hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to papillary, nodular, and diffuse; lung cancers such as KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma) , adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical) , spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor) , prostate cancers such as but not limited to, androgen-independent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/or ureter) ; renal carcinoma; Wilms’ tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.
In one aspect, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of described herein.
EXAMPLES
The following examples are offered to illustrate, but not to limit the claimed disclosure. The following examples further illustrate the disclosure but, of course, should not be construed as in any way limiting its scope.
The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.
The compounds and salts described herein can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either  commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the synthesis schemes below, the steps in some cases can be performed in a different order than the order shown below. Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.
Examples
Example A1: Synthesis of Intermediate 1
Step 1: Preparation of Int 1-1
To a solution of 1- (methylsulfonyl) piperidin-4-amine (2.98 g, 16.72 mmol) and 2-chlorothiazole (2.00 g, 16.72 mmol) in Dioxane (100 mL) was added Ruphos (1.56 g, 3.34 mmol) , Pd2 (dba) 3 (1.53 g, 1.67 mmol) and Cs2CO3 (16.34 g, 50.16 mmol) . The resulting mixture was stirred under nitrogen atmosphere at 100 ℃ for 3 h. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, ethyl acetate/petroleum ether = 100/1 to 3/1) to afford Int 1-1 (2.4 g, 54.9%yield, 82%purity) . LCMS: 262.1 [M+H] +;
Step 2: Preparation of Intermediate 1
To a solution of Int 1-1 (500 mg, 1.91 mmol) in AcOH (10 mL) was added Br2 (457 mg, 1.91 mmol) , the resulting mixture was stirred under nitrogen atmosphere at 25 ℃ for 15 min. The mixture was concentrated under reduced pressure to give a residue, whose pH was adjusted to 7 by NaHCO3 (aq. ) . Then the reaction was quenched by the addition of H2O (30 mL) . The resulting mixture was extracted with EA (10 mL × 3) , the combined organic layers was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, ethyl acetate/petroleum ether = 50/1 to 10/1) to afford the title compound (300 mg) . LCMS: 340.0/342.0 [M+H] +;
Example A2: Synthesis of Intermediate 2
According to the procedure in Example A1, the Intermediate 2 was synthesized with (3S, 4R) -4-aminotetrahydro-2H-pyran-3-ol as the substrate. LCMS: 279.1/281.1 [M+H] +;
Example A3: Synthesis of Compound 1
Step 1: Preparation of Compound 1-1
To a solution 3-bromobenzene-1, 2-diamine (10 g, 53.46 mmol) in DCM (15 ml) was added CDI (17.33 g, 106.92 mmol) , then the solution was stirred at 50 ℃ for overnight. Upon completion, the reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL × 3) . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude product.
Step 2: Preparation of Compound 1-2
A solution of Compound 1-1 (9 g, 42.25 mmol) in POCl3 (30 mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with NaHCO3 (aq, 20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography (PE/EA = 50/1 to 10/1) to afford Compound 1-2 (1.5 g, 15.3%yield) . LCMS: 230.9/232.9 [M+H] +;
Step 3: Preparation of Compound 1-3
To a solution of Compound 1-2 (1 g, 4.31 mmol) in MeSO3H (15 mL) was added (R) -3-fluoropyrrolidine (1.08 g, 8.62 mmol) . The resulting mixture was stirred at 150℃ for 0.5 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography (PE/EA = 50/1 to 3/1) to afford Compound 1-3 (800 mg, 65.3%yield) . LCMS: 284.0/286.0 [M+H] +;
Step 4: Preparation of Compound 1-4
To a solution of Compound 1-3 (100 mg, 0.35 mmol) in 1, 4-dioxane (10 mL) was added Pd(dppf) Cl2 (52 mg, 0.07 mmol) , KOAc (103 mg, 1.05 mmol) , B2PIN2 (1.08 g, 8.62 mmol) and K2CO3 (145 mg, 1.05 mmol) , the solution was stirred at 100℃ for overnight. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography (PE/EA = 50/1 to 1/1) to afford
Compound 1-4. LCMS: 250.1 [M+H] +;
Step 5: Preparation of Compound 1
To a solution of Compound 1-4 (87.5 mg, 0.35 mmol) in dioxane/H2O (6 ml/3 ml) was added Intermediate 1 (60 mg, 0.29 mmol) , Pd (dppf) Cl2 (42.40 mg, 0.058 mmol) and K2CO3 (120 mg, 0.87  mmol) . The solution was stirred at 90 ℃ for overnight. The reaction mixture was filtered, quenched with water (20 mL) and extracted with EA (20 mL × 3) . The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which was purified by prep-HPLC to afford Compound 1. LCMS: 465.3 [M+H] +; 1H NMR (400 MHz, Methanol-d4) δ 7.73 (s, 1H) , 7.09 (dd, J = 7.5, 1.3 Hz, 1H) , 7.02 (dd, J = 7.7, 1.3 Hz, 1H) , 6.99 –6.93 (m, 1H) , 5.50 –5.30 (m, 1H) , 3.95 –3.61 (m, 7H) , 2.93 (td, J = 11.8, 2.7 Hz, 2H) , 2.83 (s, 3H) , 2.39 –2.26 (m, 2H) , 2.22 –2.11 (m, 2H) , 1.68 –1.53 (m, 2H) .
According to a similar procedure of Compound 1, the following compounds were prepared using the corresponding substrates.
Example A4: Synthesis of Compound 3
Step 1: Preparation of Compound 3-1
To a solution of 5- (1-methylpiperidin-4-yl) pyridin-2-amine (400 mg, 2.091 mmol) in HBr (6 mL, 0.136 mmol) was added Br2 (0.5 mL, 9.105 mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 15 min. After addition of NaNO2 (400 mg, 5.797 mmol) in H2O (20 mL) , the mixture was stirred at 0 ℃for 20 min. The mixture was adjusted to pH = 9 with aqueous NaHCO3, partitioned between EtOAc (50 mL) and H2O (50 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1) to afford Compound 3-1 (160 mg, 29.99%) . LCMS: 255.0 [M+H] +;
Step 2: Preparation of Compound 3-3
To a solution of tert-butyl (5-bromothiazol-2-yl) carbamate (758.2 mg, 2.72 mmol) and Compound 3-2 (850 mg, 2.47 mmol, which was prepared according to step 1 to step 4 in Example 1 -Synthesis of Compound 1) in dioxane (13 mL) and H2O (2.60 mL) were added K2CO3 (682.5 mg, 4.94 mmol) and Pd (dtbpf) Cl2 (161.44 mg, 0.25 mmol) . The reaction was stirred at 80 ℃ for 30 min. The mixture was partitioned between EtOAc (50 mL) and H2O (50 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1) to afford Compound 3-3 (208 mg, 20.23%) . LCMS: 417.2 [M+H] +;
Step 3: Preparation of Compound 3-4
To a solution of Compound 3-3 (310 mg, 0.744 mmol) in DCM (5 mL) were added TFA (4 mL, 0.744 mmol) , and the reaction was stirred at r. t. for 2 hr. The mixture was adjusted to pH 9 with a. q. NaHCO3, and extracted with solvent DCM/MeOH=10: 1 (100 mL × 5) . The combined organic phase was washed with water and saturated NaCl solution, dried by Na2SO4, filtered and concentrated to afford Compound 3-4 (200 mg, 84.93%) . LCMS: 317.0 [M+H] +;
Step 4: Preparation of Compound 3
To a solution of Compound 3-4 (110 mg, 0.348 mmol) in dioxane (3 mL) was added Compound 3-1 (88.71 mg, 0.348 mmol) , Cs2CO3 (226.77 mg, 0.696 mmol) , Xantphos (40.27 mg, 0.070 mmol) and Pd2 (dba) 3 (31.87 mg, 0.035 mmol) . The reaction was stirred at 90 ℃ for overnight under N2. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give the title compound. LCMS: 491.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H) , 9.38 (s, 1H) , 8.24 (d, J = 2.2 Hz, 1H) , 7.96 (s, 1H) , 7.64 (dd, J = 8.6, 2.3 Hz, 1H) , 7.18 –7.14 (m, 3H) , 7.13 –7.09 (m, 1H) , 3.83 –3.46 (m, 5H) , 3.15 –3.02 (m, 2H) , 2.87 –2.78 (m, 4H) , 2.08 –1.94 (m, 5H) , 1.90 –1.77 (m, 2H) , 1.40 (s, 3H) .
Example A5: Synthesis of Compound 4
According to a similar procedure of Example A3 -Synthesis of Compound 3, the title compound was prepared using Compound 3-4 and Compound 4-1 (which was synthesized according to step 1 in Example A3 -Synthesis of Compound 3) as substrates. LCMS: 534.0 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H) , 8.26 (d, J = 2.3 Hz, 1H) , 7.97 (s, 1H) , 7.67 (dd, J = 8.8, 2.6 Hz, 1H) , 7.23 –7.10 (m, 4H) , 5.00 (s, 1H) , 3.75 (t, J = 7.0 Hz, 2H) , 3.69 –3.36 (m, 4H) , 2.78 –2.43 (m, 1H) , 2.43 –2.33 (m, 2H) , 2.23 (s, 6H) , 2.11 –1.94 (m, 2H) , 1.97 (t, J = 7.3 Hz, 2H) , 1.39 (s, 3H) .
Example A6: Synthesis of Compound 6
Step 1: Preparation of Compound 6-1
To a solution of cyclopentane-1, 3-diol (5 g, 48.972 mmol) in Pyridine (25 mL) and DCM (50 mL) was added a solution of TsCl (7.5 g, 39.177 mmol) in DCM (50 mL) dropwise at 0 ℃. The solution was stirred at 25 ℃ for 2 h. The solution was diluted with dichloromethane (100 mL) and water (100 mL) . The organic layer was washed with 2 N hydrochloric acid (100 mL × 2) , brine (50 mL × 2) , dried over sodium sulfate, filtered, and concentrated in vacuo to afford Compound 6-1 (9.5 g, 75.7%) . LCMS: 279.1 [M+Na] +;
Step 2: Preparation of Compound 6-2
To a solution of Compound 6-1 (7.5 g, 29.263 mmol) and 4-bromo-2H-indazole (4.8 g, 24.385 mmol) in DMF (50 mL) was added Cs2CO3 (19.1 g, 58.526 mmol) . The mixture was stirred at 90 ℃ for 16 h under N2. The reaction was quenched by addition of water (500 mL) at 20 ℃, then the mixture was extracted with Ethyl acetate (50 mL × 3) . The combined organic layers were washed with brine (50 mL ×2) , dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (ISCO; 80 g SepaFlash Silica Flash Column, Eluent of 0-50%Ethyl acetate/Petroleum ether gradient at 40 mL/min) to afford Compound 6-2 (1.3 g, 15.8 %) . LCMS: 281.1/283.1 [M+H] +;
Step 3: Preparation of Compound 6-3
To a solution of oxalyl dichloride (0.59 mL, 6.935 mmol) in dichloromethane (10 mL) was added DMSO (0.49 mL, 6.935 mmol) dropwise over a period of 10 min at -78° C under N2. A solution of Compound 6-2 (1.3 g, 4.623 mmol) in dichloromethane (20 mL) was added and the resulting solution was stirred at -78° C for 45 min. Then DIEA (3.83 mL, 23.115 mmol) was added over 5 min. The resulting mixture was stirred at -78° C for 25 min and at room temperature for another 30 min. The reaction was quenched by the addition of aqueous NH4Cl (100 mL) . The organic layer was separated, and washed with brine (50 mL × 2) , dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 0-50%Ethyl acetate/Petroleum ether gradient at 35 mL/min) to afford
Compound 6-3 (816 mg, 63.2%) . LCMS: 279.0/281.0 [M+H] +;
Step 4: Preparation of Compound 6-4
To a solution of Compound 6-3 (816 mg, 2.924 mmol) in THF (20 mL) was added Methylmagnesium bromide (8.77 mL, 8.771 mmol) dropwise at -60 ℃. The solution was stirred at room temperature for 2 h under N2. The reaction mixture was quenched by saturated NH4C1 solution (20 mL) at 0℃, and diluted with EtOAc (100 mL) . The organic phase was separated, washed with brine 100 mL (50 mL × 2) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column chromatography to afford Compound 6-4 (216 mg, 25.0%) . LCMS: 295.1/297.1 [M+H] +;
Step 5: Preparation of Compound 6-5
To a solution of Compound 6-4 (216 mg, 0.732 mmol) , B2Pin2 (438.6 mg, 1.728 mmol) and KOAc (464.5 mg, 1.829 mmol) in DMSO (5 mL) was added Pd (dppf) Cl2 (107 mg, 0.146 mmol) . The reaction mixture was stirred at 90℃ for 18 h under N2. The resulting mixture was cooled and diluted with ethyl acetate (50 mL) . The organic layer was washed with water (50 mL × 3) and brine (50 mL) , dried over Na2SO4 and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography to afford Compound 6-5. LCMS: 343.2 [M+H] +;
Step 6: Preparation of Compound 6
To a solution of Compound 6-5 (128 mg, 0.374 mmol) and Intermediate 1 (151.2 mg, 0.444 mmol) in dioxane (3 mL) and H2O (1 mL) was added K2CO3 (103 mg, 0.748 mmol) and Pd (dppf) Cl2 (54.7 mg, 0.075 mmol) . The reaction mixture was stirred at 85℃ for 16 h under N2. The reaction mixture was diluted with dichloromethane (50 mL) . The separated organic layer was washed with water (30mL) and saturated brine (50 mL) , concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford the title compound. LCMS: 476.2 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H) , 7.92 (d, J = 7.2 Hz, 1H) , 7.60 (s, 1H) , 7.46 (d, J = 8.6 Hz, 1H) , 7.20 (dd, J =8.6, 7.0 Hz, 1H) , 6.96 (d, J = 6.9 Hz, 1H) , 5.18 –5.06 (m, 1H) , 5.03 (s, 1H) , 3.79 –3.68 (m, 1H) , 3.55 –3.47 (m, 2H) , 2.97 –2.90 (m, 2H) , 2.89 (s, 3H) , 2.34 –2.25 (m, 3H) , 2.22 –2.15 (m, 1H) , 2.12 –2.03 (m, 2H) , 1.93 –1.85 (m, 1H) , 1.71 –1.62 (m, 1H) , 1.62 –1.51 (m, 2H) , 1.32 (s, 3H) .
According to a similar procedure of Compound 6, the following compounds were prepared using the corresponding substrates.



Example A7: Synthesis of Compound 10
Step 1: Preparation of Compound 10-1
According to the previous procedures, compound 10-1 was synthesized with tert-butyl 3-hydroxypyrrolidine-1-carboxylate as the starting substrate. LCMS: 547.3 [M+H] +;
Step 2: Preparation of compound 10-2
To a solution of Compound 10-1 (400.0 mg, 0.732 mmol) in dioxane (4 mL) was added HCl-dioxane (4 mL) . The mixture was stirred at r. t for 1 hrs. The reaction mixture was concentrated under reduced pressure to Compound 10-2; LCMS: 447.1 [M+H] +;
Step 2: Preparation of compound 10
To a solution of Compound 10-2 (300 mg, 0.672 mmol) , HCOH (0.04 mL, 1.343 mmol) , AcOH (0.19 mL, 3.359 mmol) in dichloromethane (8 mL) and MeOH (4 mL) was added STAB (708.4 mg, 3.359 mmol) . The reaction was stirred at r. t for 1 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by prep-HPLC (Waters 2767/Qda, Column: Pursuit XRs C18, 19.5*250mm, 10 um; Mobile Phase A: 0.1%FA/H2O, B: ACN; flow rate: 20ml/min; gradient: 20%～30%; Retention Time: 8-8.8min of 17 min) to afford Compound 10.LCMS: 461.2 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.7 (s, 1H) , 7.9 (d, J = 7.2 Hz, 1H) , 7.6 (s, 1H) , 7.5 (d, J = 8.6 Hz, 1H) , 7.2 (dd, J = 8.6, 7.0 Hz, 1H) , 7.0 (d, J = 6.9 Hz, 1H) , 5.3 –5.1 (m, 1H) , 3.8 –3.7 (m, 1H) , 3.5 –3.5 (m, 2H) , 3.0 –2.9 (m, 2H) , 2.9 –2.9 (m, 2H) , 2.9 (s, 3H) , 2.9 –2.8 (m, 1H) , 2.6 –2.6 (m, 1H) , 2.5 –2.4 (m, 1H) , 2.3 (s, 3H) , 2.3 –2.2 (m, 1H) , 2.1 –2.0 (m, 2H) , 1.6 –1.5 (m, 2H) .
According to a similar procedure of Compound 10, the following compounds were prepared using the corresponding substrates.



Example A8: Synthesis of Compound 17
Step 1: Preparation of compound 17-1
To a solution of Compound 6-3 (600 mg, 2.150 mmol) in DCM (15 mL) was added DAST (0.85 mL, 6.449 mmol) at 0℃ under N2. The mixture was stirred at r. t under N2 for 1 h. The reaction mixture was partitioned between H2O (30 mL) and Ethyl acetate (90 mL) . The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 40 g SepaFlash@Silica Flash Column, Eluent  of 0-30%Ethyl acetate/Petroleum ether gradient @50 mL/min) to afford Compound 17-1. LCMS: 301.0/303.0 [M+H] +; 1HNMR: (400 MHz, DMSO) δ 8.52 (d, J = 0.8 Hz, 1H) , 7.71 –7.60 (m, 1H) , 7.29 (d, J = 7.1 Hz, 1H) , 7.18 (dd, J = 8.6, 7.2 Hz, 1H) , 5.33 (p, J = 7.5 Hz, 1H) , 2.93 –2.69 (m, 2H) , 2.49 –2.36 (m, 2H) , 2.36 –2.14 (m, 2H) ;
Step 2: Preparation of the title compound
The title compound was synthesized according to a similar previous procedure with compound 17-1 as the substrate. LCMS: 464.2 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.8 (s, 1H) , 8.0 (d, J = 7.2 Hz, 1H) , 7.6 (s, 1H) , 7.5 (d, J = 8.8 Hz, 1H) , 7.3 –7.2 (m, 1H) , 7.0 (d, J = 6.8 Hz, 1H) , 5.3 (t, J = 7.7 Hz, 1H) , 3.8 –3.7 (m, 1H) , 3.5 –3.5 (m, 2H) , 3.2 –3.2 (m, 1H) , 3.0 –2.8 (m, 8H) , 2.5 –2.4 (m, 2H) , 2.1 –2.0 (m, 2H) , 1.6 –1.5 (m, 2H) .
According to a similar procedure of Compound 10, the following compounds were prepared using the corresponding substrates.
Example A9: Synthesis of Compound 19
Step 1: Preparation of compound 19-1
To a solution of 4-bromo-2H-indazole (3.00 g, 15.2 mmol) in DMF (60 mL) were added potassium carbonate (6.31 g, 45.7 mmol) and methyl cyclopent-1-ene-1-carboxylate (4.80 g, 38.1 mmol) . The reaction was stirred at room temperature for 16 hrs under the protection of N2. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 3) . The combined organic phase was washed with brine (200 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford compound 19-1. LCMS: 323.0/325.0 [M+H] +;
Step 2: Preparation of compound 19-2
To a solution of Compound 19-1 (1.50 g, 4.64 mmol) in tetrahydrofuran (50 mL) was added magnesium monobromide methanide (13.5 mL, 0.278 mmol) dropwise at 0 ℃. The reaction mixture was stirred at room temperature overnight under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3) . The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give the residue. The  residue was purified by flash silica gel chromatography to afford Compound 19-2. LCMS: 323.2/325.2 [M+H] +;
Step 3: Preparation of the title compound
The title compound was synthesized according to a similar previous procedure with compound 19-2 as the substrate. LCMS: 504.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H) , 7.94 –7.91 (m, 1H) , 7.63 (s, 1H) , 7.46 (d, J = 8.4 Hz, 1H) , 7.19 –7.15 (m, 1H) , 6.94 (d, J = 7.2 Hz, 1H) , 5.05 –5.04 (m, 1H) , 3.74 –3.73 (m, 1H) , 3.51 (d, J = 11.6 Hz, 3H) , 2.97 –2.89 (m, 6H) , 2.08 (d, J = 10.8 Hz, 3H) , 1.95 (s, 3H) , 1.68 –1.66 (m, 2H) , 1.57 –1.55 (m, 2H) , 1.05 (s, 3H) , 0.94 (s, 3H) .
Example A10: Synthesis of Compound 22
Step 1: Preparation of compound 22-1
To a solution of 4-bromo-2H-indazole (5 g, 25.381 mmol) , and 2, 2-dimethyloxirane (9.1 g, 126.904 mmol) in dioxane (100 mL) was added Cs2CO3 (16.5 g, 50.761 mmol) . The mixture was stirred at 90℃ for 2 h under N2. The mixture was diluted with water (300 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (300 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 22-1. LCMS: 269.1/270.8 [M+H] +;
Step 2: Preparation of the title compound
The title compound was synthesized according to a similar previous procedure with compound 22-1 as the substrate. LCMS: 450.1 [M+H] +; 1H NMR (400 MHz, DMSO) δ 8.58 (s, 1H) , 7.92 (d, J = 7.3 Hz, 1H) , 7.56 (s, 1H) , 7.48 (d, J = 8.6 Hz, 1H) , 7.20 (dd, J = 8.6, 7.0 Hz, 1H) , 6.99 (d, J = 6.8 Hz, 1H) , 4.85 (s, 1H) , 4.36 (s, 2H) , 3.81 –3.67 (m, 1H) , 3.51 (d, J = 12.3 Hz, 2H) , 2.94 (dd, J = 16.7, 6.0 Hz, 2H) , 2.89 (s, 3H) , 2.16 –1.97 (m, 2H) , 1.56 (td, J = 13.8, 4.0 Hz, 2H) , 1.12 (s, 6H) .
According to a similar procedure of Compound 22, the following compounds were prepared using the corresponding substrates.

Example A11: Synthesis of Compound 39
To a solution of 39-1 (20 mg, 0.040 mmol, which was synthesized according to the previous procedures) and 2-bromoethan-1-ol (7.5 mg, 0.060 mmol) in DMF (1 mL) was added K2CO3 (16.7 mg, 0.121 mmol) and potassium iodide (0.7 mg, 0.004 mmol) . The mixture was stirred at 65 ℃ for 12 hrs. The reaction mixture was filtered and purified by prep-HPLC (Gilson GX 281, Column: Pursuit XRs 10 C18, 19*250mm, 10 um; Mobile Phase A: 0.1%FA/H2O, B: ACN; flow rate: 25 mL/min; gradient: 17%～17%; Retention Time: 6.8-7.0 min of 16 min) to afford the title compound. LCMS: 505.3 [M+H] +; 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1H) , 8.00 (s, 1H) , 7.71 (d, J = 8.5 Hz, 1H) , 7.64 (s, 1H) , 7.47 (s, 1H) , 7.32 (d, J = 8.5 Hz, 1H) , 4.59 (t, J = 14.3 Hz, 1H) , 3.87 (t, J = 5.4 Hz, 2H) , 3.80 –3.66 (m, 3H) , 3.60 (d, J = 11.9 Hz, 2H) , 3.15 –2.92 (m, 6H) , 2.87 (s, 3H) , 2.49 (dd, J = 22.2, 11.1 Hz, 2H) , 2.19 (s, 4H) , 1.73 –1.54 (m, 2H) .
According to a similar procedure of Compound 39, the following compounds were prepared using the corresponding substrates.
Example A12: Synthesis of Compound 43
Step 1: Preparation of compound 43-1
To a solution of 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1, 5-a] pyridine (550 mg, 2.25 mmol) in 1, 4-dioxane and H2O (5 mL /1 mL) were added 5-bromo-N- (1- (methylsulfonyl) piperidin-4-yl) thiazol-2-amine (767 mg, 2.25 mmol) , Pd (dppf) Cl2 (330 mg, 0.451 mmol) and Cs2CO3 (2.20 g, 6.76 mmol) . The reaction was stirred at 100 ℃ for 16 hrs under nitrogen atmosphere. After being cooled to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (200 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give the residue. The crude was purified by flash silica gel chromatography to afford Compound 43-1. LCMS: 378.1 [M+H] +;
Step 2: Preparation of compound 43-2
To a solution of Compound 43-1 (350 mg, 0.927 mmol) in DMF (3 mL) was added POCl3 (426 mg, 2.78 mmol) . The mixture was stirred at room temperature overnight. The mixture was quenched with H2O (0.1 mL) . The resulting mixture was purified by reversed-phase HPLC (0.1%TFA) to afford
Compound 43-2. LCMS: 405.9 [M+H] +;
Step 3: Preparation of the title compound
To a solution of Compound 43-2 (100 mg, 0.247 mmol) in MeOH/DCE (1 mL/1 mL) were added AcOH (6 drop) , formaldehyde (75 mg, 0.740 mmol) and TiO (iPr) 4 (140 mg, 0.493 mmol) . The mixture was stirred at room temperature overnight. After that, STAB (155 mg, 0.740 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was purified by prep-HPLC (Waters 3767/Column: SunFire Sunfire C18, 19*250mm, 10 um; Mobile Phase A: 0.1%FA/H2O, B: ACN ; flow rate: 20ml/min; gradient: 30-31%. Retention Time: 8.5-9.5 min of 20 min) to afford the title compound. LCMS: 513.2 [M+Na] +; 1H NMR (400 MHz, MeOD) δ 8.49 (d, J = 7.2 Hz, 1H) , 8.09 (s, 1H) , 7.72 (s, 1H) , 7.60 (s, 1H) , 7.21 (d, J = 7.2 Hz, 1H) , 4.56 –4.54 (m, 2H) , 3.82 –3.81 (M, 1H) , 3.76 –3.67 (m, 2H) , 3.61 –3.60 (m, 1H) , 3.43 –3.42 (m, 1H) , 3.23 –3.22 (m, 1H) , 3.17 –3.16 (m, 1H) , 3.01 –2.91 (m, 2H) , 2.86 (s, 3H) , 2.28 –2.02 (m, 4H) , 1.75 –1.56 (m, 2H) , 1.43 (s, 3H) .
Example A13: Synthesis of Compound 76
Step 1: Preparation of compound 76-1
To a solution of 2-amino-4-bromo-3-methylbenzoic acid (25 g, 108.648 mmol) , iodomethane (46.3 g, 325.945 mmol) in DMF (50 mL) was added Cs2CO3 (70.8 g, 217.297 mmol) . The reaction mixture was stirred at r. t for 16 h under N2. The mixture was diluted with water (300 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 76-1 (15.7 g, 59.2%) . LCMS: 244.09 /245.9 [M+H] +;
Step 2: Preparation of compound 76-2
To a solution of methyl Compound 76-1 (15.7 g, 64.318 mmol) in HOAc (80 mL) was added sodium nitrite (4.9 g, 70.750 mmol) and H2O (8 mL) at 0℃. The reaction was stirred at r. t for 1 h under N2.The mixture was adjusted to pH 9 with a. q. NaHCO3. The mixture was diluted with water (300 mL) and extracted with ethyl acetate. The crude product was triturated with Ethyl acetate/Petroleum ether =10%at r. t for 20 min to afford Compound 76-2 (7.6 g, 46.3%) . LCMS: 255.0/257.0 [M+H] +;
Step 3: Preparation of compound 76-3
To a solution of Compound 76-2 (7.4 g, 29.008 mmol) in DCM (50 mL) was added SEMCl (10.29 mL, 58.016 mmol) and DIEA (9.61 mL, 58.016 mmol) . The reaction was stirred at r. t for 16 h under N2. The mixture was diluted with water (200 mL) and extracted with Dichloromethane. The combined organic phase was washed with brine (200 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 76-3; LCMS: 384.9/386.9 [M+H] +;
Step 4: Preparation of compound 76-4
To a solution of Compound 76-3 (3.7 g, 9.603 mmol) in THF (15 mL) was added LiAlH4 (2.30 mL, 5.762 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min under N2. The mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 76-4. LCMS: 357.3/359.0 [M +H] +;
Step 5: Preparation of compound 76-5
To a solution of Compound 76-4 (2.0 g, 5.598 mmol) in DCM (100 mL) was added manganese dioxide (4.9 g, 55.980 mmol) . The reaction mixture was stirred at r. t for 16 h under N2. After completion  of reaction, the reaction was filtered. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Compound 76-5. LCMS: 355.3/357.0 [M+H] +;
Step 6: Preparation of compound 76-6
To a solution of Compound 76-5 (2 g, 5.629 mmol) in DCM (30 mL) was added DAST (3.12 mL, 23.642 mmol) at 0℃. The reaction mixture was stirred at r. t for 16 h under N2. The mixture was diluted with water (50 mL) and extracted with Dichloromethane. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 76-6. LCMS: 377.0/379.0 [M+H] +;
Step 7: Preparation of compound 76-7
To a solution of Compound 76-6 (1.3 g, 3.446 mmol) in DCM (10 mL) was added TFA (5 mL, 0.318 mmol) . The reaction mixture was stirred at r. t for 2 h. The combined organic layers were concentrated under reduced pressure to afford Compound 76-7. LCMS: 246.9/248.9 [M+H] +;
Step 8: Preparation of the title compound
The title compound was synthesized according to the previous procedures with Compound 76-7 as the substrate. LCMS: 526.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.9 (s, 1H) , 8.1 (d, J = 7.2 Hz, 1H) , 7.7 (s, 1H) , 7.5 –7.1 (m, 2H) , 7.0 (d, J = 7.2 Hz, 1H) , 5.2 –5.1 (m, 1H) , 5.0 (s, 1H) , 3.8 –3.7 (m, 1H) , 3.6 –3.5 (m, 2H) , 2.9 (t, J = 10.4 Hz, 2H) , 2.9 (s, 3H) , 2.4 –2.2 (m, 3H) , 2.2 (dd, J = 13.3, 5.5 Hz, 1H) , 2.1 –2.0 (m, 2H) , 1.9 –1.9 (m, 1H) , 1.7 –1.6 (m, 1H) , 1.6 –1.5 (m, 2H) , 1.3 (s, 3H) .
According to a similar procedure of Compound 76, the following compounds were prepared using the corresponding substrates.
Example A14: Synthesis of Compound 108
Step 1: Preparation of compound 108-1
To a solution of 4-bromo-2-fluoro-1-methoxybenzene (60 g, 293 mmol) in THF (500 ml) was added LDA (219 ml, 439 mmol) drop wise at -78℃ under N2 atmosphere and the mixture was stirred at -78℃ for 0.5 hr. DMF (45.3 ml, 585 mmol) was added to the mixture dropwise at -78℃ and the resulting mixture was stirred at room temperature for 1 h under N2 atmosphere. The mixture was quenched with saturated aq. NH4Cl solution (500 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude product was triturated with PE at 35℃ for 20 min to give Compound 108-1 (60 g, 87 %yield) . 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H) , 7.56 (dd, J = 8.9, 1.8 Hz, 1H) , 7.42 (t, J = 8.8 Hz, 1H) , 3.89 (s, 3H) .
Step 2: Preparation of compound 108-2
A mixture of Compound 108-1 (50 g, 213 mmol) in N2H4. H2O (500 ml, 213 mmol) was stirred at 100℃ for 16 h under N2. The mixture was diluted with water (1000 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 108-2 (35 g, 72.5 %yield) . LCMS: 227.0/229.0 [M+H] +;
Step 3: Preparation of compound 108-3
Compound 108-3 was synthesized according to the previous procedure. LCMS: 311.0/313.0 [M+H] +.
Step 4: Preparation of compound 108-4
To a solution of Compound 108-3 (2.70 g, 8.68 mmol) in DCM (20 ml) at 0 ℃ was added a solution of BBr3 (6.21 ml, 69.4 mmol) . The reaction mixture was stirred at 0℃for 30 min under N2. The mixture was diluted with water (100 mL) and extracted with Dichloromethane. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 108-4. Step 5: Preparation of compound 108-5
To a solution of Compound 108-4 (600 mg, 2.019 mmol) , Cs2CO3 (1974 mg, 6.06 mmol) in DMF (20 ml) was added CF2ClCOONa (924 mg, 6.06 mmol) . The reaction mixture was stirred at 100℃for 2h under N2. The mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 108-5. LCMS: 347.16/349.0 [M+H] +.
Step 6: Preparation of the title compound
The title compound was synthesized according to previous procedures. LCMS: 605.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.8 (s, 1H) , 8.8 (d, J = 4.0 Hz, 1H) , 8.1 (td, J = 7.8, 1.6 Hz, 1H) , 7.9 (d, J = 7.9 Hz, 1H) , 7.9 (d, J = 7.1 Hz, 1H) , 7.8 –7.7 (m, 2H) , 7.5 (s, 1H) , 7.5 (t, J = 74.6 Hz, 1H) , 7.0 –6.8 (m, 2H) , 5.1 (p, J = 7.7 Hz, 1H) , 5.0 (s, 1H) , 3.7 –3.6 (m, 2H) , 2.9 (t, J = 10.4 Hz, 2H) , 2.3 (ddt, J =  15.9, 8.1, 3.4 Hz, 1H) , 2.3 –2.3 (m, 2H) , 2.2 (dd, J = 13.9, 5.8 Hz, 1H) , 2.1 –2.0 (m, 2H) , 1.9 –1.9 (m, 1H) , 1.7 –1.6 (m, 1H) , 1.5 (qd, J = 10.7, 3.6 Hz, 2H) , 1.3 (s, 3H) .
According to a similar procedure of Compound 108, the following compounds were prepared using the corresponding substrates.
Example A15: Synthesis of Compound 116
Step 1: Preparation of compound 116-1
To a solution of tert-butyl 6-amino-2-azaspiro [3.3] heptane-2-carboxylate (5.0 g, 23.552 mmol) , 2-chlorothiazole (2.8 g, 23.552 mmol) , Cs2CO3 (15.3 g, 47.103 mmol) in dioxane (50 mL) was added Pd2 (dba) 3 (1.1 g, 1.178 mmol) and RuPhos (1.1 g, 2.355 mmol) . The reaction mixture was stirred at 100℃ for 16 h under N2. The mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 116-1 (3.9 g, 13.202 mmol, 56.1%) . LCMS: 296.1 [M+H] +;
Step 2: Preparation of compound 116-2
TFA (20 mL) was added dropwise to a solution of Compound 116-1 (3800 mg, 12.864 mmol) in DCM (30 mL) at 0℃ and the reaction mixture was stirred at rt for 2 hours. The mixture was concentrated to afford Compound 116-2 (2.5 g, 12.801 mmol, 99.5%, crude) which was used in the next reaction step without further purification.
Step 3: Preparation of compound 116-3
To a solution of Compound 116-2 (3700 mg, 18.945 mmol) and TEA (10.5 mL, 75.781 mmol) in DCM (50 mL) was added MsCl (1.6 mL, 20.840 mmol) over a period of 20 min at 0℃ under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with water (100 mL) and extracted with Dichloromethane. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford Compound 116-3. LCMS: 274.0 [M+H] +;
Step 4: Preparation of the title compound
The title compound was synthesized according to the previous procedures. LCMS: 488.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H) , 8.13 (d, J = 6.6 Hz, 1H) , 7.60 (s, 1H) , 7.46 (d, J = 8.6 Hz, 1H) , 7.22 –7.16 (m, 1H) , 6.97 (d, J = 6.9 Hz, 1H) , 5.17 –5.08 (m, 1H) , 5.03 (s, 1H) , 4.02 (dt, J = 14.6, 7.3 Hz, 1H) , 3.94 (s, 2H) , 3.83 (d, J = 6.6 Hz, 2H) , 2.97 (s, 3H) , 2.68 –2.60 (m, 2H) , 2.31 (ddd, J = 23.1, 11.4, 6.6 Hz, 3H) , 2.21 –2.13 (m, 3H) , 1.91 (d, J = 8.7 Hz, 1H) , 1.72 –1.61 (m, 1H) , 1.32 (s, 3H) .
According to a similar procedure of Compound 116, the following compounds were prepared using the corresponding substrates.





Example A16: Synthesis of Compound 61
Step 1: Preparation of compound 61-1
To a solution of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (11.9 g, 51.9 mmol) in DMF (50 mL) were added 1H-benzo [d] [1, 2, 3] triazol-4-ol (5.3 g, 38.904 mmol) , 1- { [3-(dimethylamino) propyl] azanylidene} -N-ethylmethanimine hydrochloride (7.50 g, 38.9 mmol) , DIEA (10.0 g, 77.7 mmol) and (5-bromopyridin-2-yl) methanamine (4.85 g, 25.9 mmol) . The mixture was stirred at room temperature for 16 hrs. The mixture was diluted with water (200 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (200 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The crude was purified by flash silica gel chromatography to afford Compound 61-1 (6.00 g, 48.4%) . LCMS: 398.2/400.2 [M+H] +;
Step 2: Preparation of compound 61-2
A solution of Compound 61-1 (4.2 g, 10.55 mmol) in POCl3 (50 g) was stirred at 130 ℃ for 16 hrs. The mixture was concentrated in vacuum to give a residue. The residue was purified by reversed-phase chromatography to afford Compound 61-2 (2.30 g, 50.5%) . LCMS: 280.0/282.0 [M+H] +;
Step 3: Preparation of compound 61-3
To a solution of Compound 61-2 (1.4 g, 5.00 mmol) in DCM (36 mL) were added 4- (dimethylamino) pyridine (61.1 mg, 0.500 mmol) , triethylamine (2 mL, 15.0 mmol) and (2-methylprop-2-yl) oxidanecarboxylic anhydride (1.7 mL, 7.50 mmol) . The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate. The combined organic phase was washed with brine (100 mL) , dried over sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography to afford compound 61-3. LCMS: 380.0/382.0 [M+H] +;
Step 4: Preparation of the title compound
The title compound was synthesized according to the previous procedure with compound 61-3 as the substrate. LCMS: 475.3 [M+H] +; 1H NMR (400 MHz, Methanol-d4) δ 8.13 (s, 1H) , 7.55 (d, J = 9.3 Hz, 1H) , 7.43 (s, 1H) , 7.39 (s, 1H) , 7.02 (d, J = 9.3 Hz, 1H) , 3.79 –3.17 (m, 8H) , 3.02 –2.92 (m, 5H) , 2.87 (s, 3H) , 2.35 –2.10 (m, 6H) , 1.75 –1.50 (m, 2H) .
According to a similar procedure of Compound 61, the following compounds were prepared using the corresponding substrates.

Example A17: Synthesis of Compound 66-1/2
Step 1: Preparation of compound 66-A/B
5- (1- (2, 2-dimethylpiperidin-4-yl) -5-fluoro-1H-indazol-6-yl) -N- (1- (methylsulfonyl) piperidin-4-yl) thiazol-2-amine was synthesized according to the previous procedure as a racemic mixture. The racemic mixture was separated by SFC (Waters SFC 150, Column name: AD, Column size: 250 × 25 mm 10 μm; Mobile Phase A: Supercritical CO2, Mobile Phase B: MeOH (+0.1%7.0 mol/L Ammonia in ETOH) , A: B = 60: 40; 214 nm; Flow: 120 mL/min) to give Compound 66-A as the first effluent, Compound 66-B as the second effluent.
Compound 66-A: 1H NMR (400 MHz, Methanol-d4) δ 7.96 (s, 1H) , 7.72 (d, J = 6.0 Hz, 1H) , 7.56 (s, 1H) , 7.48 (d, J = 11.2 Hz, 1H) , 5.00 –4.91 (m, 1H) , 3.83 –3.68 (m, 3H) , 3.14 –2.95 (m, 4H) , 2.87 (s, 3H) , 2.24 –2.14 (m, 2H) , 2.07 –1.86 (m, 4H) , 1.70 –1.60 (m, 2H) , 1.36 (s, 3H) , 1.24 (s, 3H) .
Compound 66-B: 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H) , 7.83 (d, J = 6.0 Hz, 1H) , 7.60 (s, 1H) , 7.52 (d, J = 11.2 Hz, 1H) , 5.30 –5.13 (m, 1H) , 3.92 –3.64 (m, 3H) , 3.54 –3.38 (m, 2H) , 2.98 (t, J = 9.6 Hz, 2H) , 2.46 –2.15 (m, 6H) , 1.72 –1.64 (m, 2H) , 1.62 (s, 3H) , 1.50 (s, 3H) .
Step 2: Preparation of compound 66-1/2
The title compound was synthesized according to the previous procedure with compound 66-A and 66-B as the substrate respectively.
Compound 66-1: LCMS: 520.9 [M+H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H) , 8.03 (s, 1H) , 7.96 (d, J = 7.2 Hz, 1H) , 7.87 (d, J = 6.0 Hz, 1H) , 7.61 (s, 1H) , 5.07 –4.74 (m, 1H) , 3.85 –3.63 (m, 1H) , 3.55 –3.49 (m, 2H) , 3.00 –2.90 (m, 2H) , 2.89 (s, 3H) , 2.82 –2.74 (m, 2H) , 2.30 (s, 3H) , 2.12 –2.04 (m, 4H) , 1.98 –1.88 (m, 1H) , 1.83 –1.72 (m, 1H) , 1.61 –1.48 (m, 2H) , 1.17 (s, 6H) .
Compound 66-2: LCMS: 520.9 [M+H] +; 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H) , 8.00 (s, 1H) , 7.76 (d, J = 6.0 Hz, 1H) , 7.56 (s, 1H) , 7.50 (d, J = 11.2 Hz, 1H) , 5.11 –4.95 (m, 1H) , 3.81 –3.70  (m, 3H) , 3.27 –3.12 (m, 2H) , 2.97 (t, J = 10.4 Hz, 2H) , 2.87 (s, 3H) , 2.67 (s, 3H) , 2.47 –2.33 (m, 2H) , 2.22 –2.06 (m, 4H) , 1.70 –1.61 (m, 2H) , 1.46 (s, 3H) , 1.41 (s, 3H) .
According to a similar procedure of Compound 66, the following compounds were prepared using the corresponding substrates.
The SFC condition for compound 175&176: System: Waters SFC 80; column :
IC, 250 × 25 mm 10 μm; Mobile phase A: Supercritical CO2, Mobile phase B: MeOH (+0.1%7.0mol/l Ammonia in MeOH) ; Flow rate 70 mL/min; Gradient: isocratic 35%B; column Temperature (RT) ; Back pressure (bar) : 100 ; wave Length: 214 nm; RI1 (min) : 3.529, RI2 (min) : 4.204.
The SFC condition for compound 177&178: YMC-300; column : IE, 250 × 30 mm 10 μm; Mobile phase A: n-Hexane , Mobile phase B: EtOH (+0.1%7.0 mol/L Ammonia in MeOH) ; Flow rate 100 mL/min; Gradient: isocratic 30%B; column Temperature (RT) ; wave Length: 254 nm; RI1 (min) : 25.909, RI2 (min) : 29.837;
Example B. Biological Assays
CDK1/CycA2
The test compound was diluted with DMSO (Sigma, D4540) . 40 nL of the diluted compound was transferred to 384-well plate (Greiner, 784075) using an Echo 655 (Beckman) . A 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50mM Hepes, 10mM MgCl2, 0.01%Brij35, 2mM DTT) . 2 μL of CDK1/CycA2 (4 nM, Proqinase, 0134-0054-1) solution was transferred to the 384-well plate, followed by a 10-minute incubation at 25℃ after a 60-second centrifugation at 1000 rpm. 2 μL of the mixture containing 2× substrate (Histone H1: 0.1 mg /mL) and ATP (50 μM) in kinase reaction buffer was then added to each well, followed by a 60-second centrifugation and incubated for 60 minutes at 25℃. 4 μL of ADP-Glo Reagent (Promega , V9103) was added to each well of 384 reaction plate and incubated at 25℃. The reagent was centrifuged at 1000rpm for 60s and incubated at 25℃ for 40 minutes. 8 μL Detection Reagent (Promega , V9103) was added to each well of 384 reaction plate for incubation at 25℃. The reagent was centrifuged at 1000rpm for 60s and incubated at 25℃ for 40 minutes. The chemiluminescence (luminescence) signal was read using a multifunctional enzyme marker (BMG, PHERAstar FSX) .
CDK2/CycE1
The test compound was diluted with DMSO (Sigma, D4540) . 40 nL of the diluted compound was transferred to 384-well plate (Greiner, 784075) using an Echo 655 (Beckman) . A 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50mM Hepes, 10mM MgCl2, 0.01%Brij35, 2mM DTT) . 2 μL of CDK2/CycE1 (0.33 nM, Carna, 04-165) solution was transferred to the 384-well plate, followed by a 10-minute incubation at 25℃ after a 60-second centrifugation at 1000 rpm. 2 μL of the mixture containing 2× substrate (Histone H1: 0.1 mg /mL) and ATP (20 μM) in kinase reaction buffer was then added to each well, followed by a 60-second centrifugation and incubated for 60 minutes at 25℃. 4 μL of ADP-Glo Reagent (Promega , V9103) was added to each well of 384 reaction plate and incubated at 25℃. The reagent was centrifuged at 1000rpm for 60s and incubated at 25℃ for 40 minutes. 8 μL Detection Reagent (Promega , V9103) was added to each well of 384 reaction plate for incubation at 25℃. The reagent was centrifuged at 1000rpm for 60s and incubated at 25℃ for 40 minutes. The chemiluminescence (luminescence) signal was read using a multifunctional enzyme marker (BMG, PHERAstar FSX) .
CDK4/CycD3
The test compound was diluted with DMSO (Sigma, D4540) . 40 nL of the diluted compound was transferred to 384-well plate (Greiner, 784075) using an Echo 655 (Beckman) . A 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50mM Hepes, 10mM MgCl2, 0.01%Brij35, 2mM DTT) . 2 μL of CDK4/CycD3 (31 nM, Proqinase, 0142-0373-1) solution was transferred to the 384-well plate, followed by a 10-minute incubation at 25℃ after a 60-second centrifugation at 1000 rpm. 2 μL of the mixture containing 2× substrate (DYRK tide: 0.1 mg /mL) and ATP (100 μM) in kinase reaction buffer was then added to each well, followed by a 60-second centrifugation and incubated for 60 minutes at 25℃. 4 μL of ADP-Glo Reagent (Promega , V9103) was added to each well of 384 reaction plate and incubated at 25℃. The reagent was centrifuged at 1000rpm for 60s and incubated at 25℃ for  40 minutes. 8 μL Detection Reagent (Promega , V9103) was added to each well of 384 reaction plate for incubation at 25℃. The reagent was centrifuged at 1000rpm for 60s and incubated at 25℃ for 40 minutes. The chemiluminescence (luminescence) signal was read using a multifunctional enzyme marker (BMG, PHERAstar FSX) .
CDK9/CycT1
The test compound was diluted with DMSO (Sigma, D4540) . 40 nL of the diluted compound was transferred to 384-well plate (Greiner, 784075) using an Echo 655 (Beckman) . A 2x kinase solution was prepared by diluting 1x kinase reaction buffer (50mM Hepes, 10mM MgCl2, 0.01%Brij35, 2mM DTT) . 2 μL of CDK9/CycT1 (7 nM, Carna, 04-110) solution was transferred to the 384-well plate, followed by a 10-minute incubation at 25℃ after a 60-second centrifugation at 1000 rpm. 2 μL of the mixture containing 2× substrate (CDK tide: 0.1 mg /mL) and ATP (20 μM) in kinase reaction buffer was then added to each well, followed by a 60-second centrifugation and incubated for 60 minutes at 25℃. 4 μL of ADP-Glo Reagent (Promega , V9103) was added to each well of 384 reaction plate and incubated at 25℃. The reagent was centrifuged at 1000rpm for 60s and incubated at 25℃ for 40 minutes. 8 μL Detection Reagent (Promega , V9103) was added to each well of 384 reaction plate for incubation at 25℃. The reagent was centrifuged at 1000rpm for 60s and incubated at 25℃ for 40 minutes. The chemiluminescence (luminescence) signal was read using a multifunctional enzyme marker (BMG, PHERAstar FSX) .
Table 3 presents corresponding biological data for CDK1, CDK2, CDK3, and CDK4 (nM) for the compounds presented in Table 1.
Table 3:



IC50 (nM) :
0 < A ≤ 10 nM;
10< B ≤ 200 nM;
200 < C ≤ 1000 nM;
D > 1000 nM.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims (52)

  1. A compound having the structure of Formula (I) , or a pharmaceutically acceptable salt thereof,
    wherein,
    is
    R1 is hydrogen, halogen, -NRcRd, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R;
    Y is a bond, -S-, -O-, -NRYN-, or -C (RY) 2-;
    RYN is hydrogen, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
    each RY is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl; or two RY are taken together to form an oxo;
    is a single bond or a double bond;
    X1 is N or C;
    X2 is N or CR2;
    X3 is N or CR3;
    X4 is N or CR4;
    X5 is N or C;
    X6 is N or C;
    X7 is O, S, N, NR7N, CR7, or CR7’R7;
    X8 is NR8N, CR8, or CR8’R8;
    X9 is O, S, N, NR9N, CR9, or CR9’R9;
    each of R2, R3, and R4 is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl,  C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R;
    each of R7N and R9N is independently hydrogen, -CN, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R;
    each of R7 and R7’ is independently hydrogen, halogen, -CN, OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or
    heterocycloalkyl is optionally substituted with one or more R; or
    R7 and R7’ are taken together to form an oxo; or R7 and R7’ are taken together with the atom to which they are attached to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R;
    each of R9 and R9’ is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or
    R9 and R9’ are taken together to form an oxo; or R9 and R9’ are taken together with the atom to which they are attached to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R;
    R8 is selected from halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1- 6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1- 6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R8a;
    R8N is selected from -CN, -NO2, -OC (=O) Ra, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1-6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1- 6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R8a;
    R8’ is independently hydrogen, halogen, -CN, OH, -SF5, -SH, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R8a;
    each R8a is independently selected from halogen, -CN, -NO2, -OH, oxo, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each of R10 is independently selected from halogen, -CN, -NO2, -OH, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -P (=O) RcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a; or two R10 are taken together to form an oxo;
    each R10a is independently selected from halogen, -CN, -NO2, -OH, oxo, -ORa, -OC (=O) Ra, -OC (=O) ORb, -OC (=O) NRcRd, -SF5, -SH, -SRa, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -NRcRd, -NRbC (=O) NRcRd, -NRbC (=O) Ra, -NRbC (=O) ORb, -NRbS (=O) 2Ra, -N=S (=O) (Rb) 2, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    n is 0, 1, 2, 3, 4, 5 or 6;
    each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1- C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene (cycloalkyl) , C1-C6alkylene (heterocycloalkyl) , C1-C6alkylene (aryl) , or C1-C6alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
    or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
    each R is independently halogen, -CN, -OH, -SF5, -SH, -S (=O) C1-C3alkyl, -S (=O) 2C1-C3alkyl, -S (=O) 2NH2, -S (=O) 2NHC1-C3alkyl, -S (=O) 2N (C1-C3alkyl) 2, -S (=O) (=NC1-C3alkyl) (C1-C3alkyl) , -NH2, -NHC1-C3alkyl, -N (C1-C3alkyl) 2, -N=S (=O) (C1-C3alkyl) 2, -C (=O) C1-C3alkyl, -C (=O) OH, -C (=O) OC1-C3alkyl, -C (=O) NH2, -C (=O) NHC1-C3alkyl, -C (=O) N (C1-C3alkyl) 2, -P (=O) (C1-C3alkyl) 2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl;
    or two R on the same atom form an oxo.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (II) ,
  3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (III) ,
    wherein
    ring A is heterocycloalkyl, aryl, heteroaryl, or C4-12 cycloalkyl;
    Y is a bond, -S-, -O-, -NRYN-, or -C (RY) 2-;
    RYN is hydrogen, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl;
    each RY is independently hydrogen, halogen, -CN, -OH, -SF5, -SH, -NRcRd, -NO2, -ORa, -SRa, C1-6 alkyl, C1-6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl.
  4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (IIa) ,
  5. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (IIIa) ,
  6. The compound of any one of claims 1, 2, or 4, or a pharmaceutically acceptable salt thereof, whereinis
  7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, whereinis
  8. The compound of any one of claims 1, 3, or 5, or a pharmaceutically acceptable salt thereof, whereinis
  9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, whereinis
  10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R2 is H, F, -CN, Cl, -CH3, -CHF2, or -C≡CH.
  11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
  12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R3 is H, F, -CN, Cl, -CH3, -CHF2, or -C≡CH.
  13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.
  14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R4 is H, F, -CN, Cl, -CH3, -CHF2, or -C≡CH.
  15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.
  16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R7 is H, F, -CH3, or
  17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R7 is hydrogen.
  18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R7’ is H, F, CH3, or
  19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R7’ is hydrogen.
  20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R7 and R7’ are taken together to form an oxo, or R7 and R7’ are taken together with the atom to which they are attached to form a cycloalkyl optionally substituted with one or more R.
  21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R7N is hydrogen or C1-6 alkyl, and wherein the alkyl is optionally substituted with one or more R.
  22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R9 is H, F, -CH3, or
  23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R9 is hydrogen.
  24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R9’ is H, F, -CH3, or
  25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R9’ is hydrogen.
  26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R9 and R9’ are taken together to form an oxo, or R9 and R9’ are taken together with the atom to which they are attached to form a cycloalkyl optionally substituted with one or more R.
  27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R9N is hydrogen or C1-6 alkyl, wherein each of the alkyl is optionally substituted with one or more R.
  28. The compound of any one of claims 1-27, wherein R8 is heterocycloalkyl or cycloalkyl, wherein each of the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more (e.g., 1-6) R8a.
  29. The compound of any one of claims 1-28, wherein R8 is
  30. The compound of any one of claims 1-28, wherein R8 is
  31. The compound of any one of claims 1-28, wherein R8 is
  32. The compound of any one of claims 1-27, wherein R8’ is hydrogen, halogen, -CN, OH, -SF5, -SH, C1- 6 alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R8a.
  33. The compound of any one of claims 1-27, wherein R8N is heterocycloalkyl or cycloalkyl, wherein each of the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R8a.
  34. The compound of any one of claims 1-27, wherein R8N is a 4-6 membered monocyclic cycloalkyl, which is optionally substituted with one or more R8a.
  35. The compound of any one of claims 1-27, wherein R8N is
  36. The compound of any one of claims 1-27, wherein R8N is
  37. The compound of any one of claims 1-27, wherein R8N is
  38. The compound of any one of claims 1-37, wherein each R8a is independently selected from halogen, -OH, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, and heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, whereinis
    Y1 is N, C, or CRY1;
    Y2 is O, S, N, NRY2N, CRY2, or CRY2RY2’;
    Y3 is O, S, N, NRY3N, CRY3, or CRY3RY3’;
    Y4 is O, NRY4N, CRY4, or CRY4RY4’;
    Y5 is O, S, N, NRY5N, CRY5, or CRY5RY5’;
    Y6 is O, S, N, NRY6N, CRY6, or CRY6RY6’;
    each of RY1, RY2, RY2’, RY3, RY3’, RY4, RY4’, RY5, RY5’, RY6, and RY6’ is independently selected from hydrogen and R10;
    each of RY2N, RY3N, RY4N, RY5N, and RY6N is independently selected from -CN, -NO2, -OC (=O) Ra, -S (=O) Ra, -S (=O) 2Ra, -S (=O) 2NRcRd, -NRbS (=O) 2Ra, -C (=O) Ra, -C (=O) ORb, -C (=O) NRcRd, -P (=O) RcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-6 alkylene-cycloalkyl, -C1- 6 alkylene-heterocycloalkyl, -C1-6 heteroalkylene-cycloalkyl, -C1-6 heteroalkylene-heterocycloalkyl, -C1-6 alkylene-aryl, -C1-6 alkylene-heteroaryl, -C1-6 heteroalkylene-aryl, and -C1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a.
  40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, whereinis wherein n is 1, 2, 3, 4, 5, or 6.
  41. The compound of claim 39, or a pharmaceutically acceptable salt thereof, whereinis
  42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each R10 is independently selected from halogen, -OH, -S (=O) 2Ra, -S (=O) 2NRcRd, -S (=O) (=NRb) Rb, -C (=O) Ra, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R10a.
  43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein one or more R10 is F or OH.
  44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein at least one R10 -S (=O) 2Ra, -S (=O) 2NRcRd, or -S (=O) (=NRb) Rb.
  45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein at least one R10 is -S (=O) 2CH3, -S (=O) 2CH (CH3) 2, or -S (=O) 2NHCH3.
  46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein RY4N is -S (=O) 2CH3 , -CH2CH2S (=O) 2CH3, -S (=O) 2CHF2, -S (=O) 2CH (CH3) 2, -S (=O) 2CH2CH2OH, -S (=O) (=NH) CH3, or -S (=O) 2NHCH3, 
  47. A compound of Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.
  48. A pharmaceutical composition comprising a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  49. A method of treating a cancer comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.
  50. A method of treating a disease or disorder associated cyclin-dependent kinase (CDK) in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.
  51. The method of claim 50, wherein the disease or disorder is cancer.
  52. The method of claim 49 of 51, wherein the cancer is a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin; a hematopoietic tumor of lymphoid lineage; a hematopoietic tumor of myeloid lineage; thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum;keratoacanthoma;thyroid follicular cancer;or Kaposi's sarcoma.
PCT/CN2024/103156 2023-07-03 2024-07-02 Substituted thiazole compounds as cdk2/4/6 inhibitors and methods of use thereof Pending WO2025007859A1 (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075120A1 (en) * 1999-06-04 2000-12-14 Agouron Pharmaceuticals, Inc. Diaminothiazoles and their use for inhibiting protein kinases
WO2001072745A1 (en) * 2000-03-29 2001-10-04 Cyclacel Limited 2-substituted 4-heteroaryl-pyrimidines and their use in the treatmetn of proliferative disorders
WO2011058139A1 (en) * 2009-11-12 2011-05-19 Selvita Sp. Z O. O. A compound, a process for its preparation, a pharmaceutical composition, use of a compound, a method for modulating or regulating serine/threonine kinases and a serine/threonine kinases modulating agent
WO2019161224A1 (en) * 2018-02-15 2019-08-22 GiraFpharma LLC Heterocyclic compounds as kinase inhibitors
WO2022155941A1 (en) * 2021-01-25 2022-07-28 Qilu Regor Therapeutics Inc. Cdk2 inhibitors
WO2022236256A1 (en) * 2021-05-03 2022-11-10 Nuvation Bio Inc. Heterocyclic compounds as kinase inhibitors
WO2022236253A1 (en) * 2021-05-03 2022-11-10 Nuvation Bio Inc. Heterocyclic compounds as kinase inhibitors

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000075120A1 (en) * 1999-06-04 2000-12-14 Agouron Pharmaceuticals, Inc. Diaminothiazoles and their use for inhibiting protein kinases
WO2001072745A1 (en) * 2000-03-29 2001-10-04 Cyclacel Limited 2-substituted 4-heteroaryl-pyrimidines and their use in the treatmetn of proliferative disorders
WO2011058139A1 (en) * 2009-11-12 2011-05-19 Selvita Sp. Z O. O. A compound, a process for its preparation, a pharmaceutical composition, use of a compound, a method for modulating or regulating serine/threonine kinases and a serine/threonine kinases modulating agent
WO2019161224A1 (en) * 2018-02-15 2019-08-22 GiraFpharma LLC Heterocyclic compounds as kinase inhibitors
WO2022155941A1 (en) * 2021-01-25 2022-07-28 Qilu Regor Therapeutics Inc. Cdk2 inhibitors
WO2022236256A1 (en) * 2021-05-03 2022-11-10 Nuvation Bio Inc. Heterocyclic compounds as kinase inhibitors
WO2022236253A1 (en) * 2021-05-03 2022-11-10 Nuvation Bio Inc. Heterocyclic compounds as kinase inhibitors

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