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WO2023086417A1 - Compounds and methods of use thereof - Google Patents

Compounds and methods of use thereof Download PDF

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Publication number
WO2023086417A1
WO2023086417A1 PCT/US2022/049452 US2022049452W WO2023086417A1 WO 2023086417 A1 WO2023086417 A1 WO 2023086417A1 US 2022049452 W US2022049452 W US 2022049452W WO 2023086417 A1 WO2023086417 A1 WO 2023086417A1
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Prior art keywords
alkyl
compound
cycloalkyl
pharmaceutically acceptable
acceptable salt
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French (fr)
Inventor
Andrei W. Konradi
Chun-Hao Huang
Ko-Chuan LEE
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Algen Biotechnologies Inc
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Algen Biotechnologies Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Ring A is optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 10- membered heterocycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl
  • R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR 18 , C 1-4 alkyl, C 1-4 alkoxy,
  • Ring A is C 3-6 cycloalkyl or 3- to 10-membered heterocycloalkyl. [0005] In certain embodiments, Ring A is C 3-6 cycloalkyl. [0006] In certain embodiments, Ring A is selected from the group consisting of: [0007] In certain embodiments, Ring A is selected from the group consisting of:
  • Ring A is selected from the group consisting of: [0008] In certain embodiments, Ring A is selected from the group consisting of: [0009] In certain embodiments, Ring A is selected from the group consisting of: [0010] In certain embodiments, Ring A is selected from the group consisting of: . [0011] In certain embodiments, Ring A is selected from the group consisting of: [0012] In certain embodiments, Ring A is selected from the group consisting of: [0013] In certain embodiments, Ring A is [0014] In certain embodiments, Ring A is [0015] In certain embodiments, Ring A is . [0016] In certain embodiments, Ring A is .
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR 18 , –NR 16 R 17 , –C(O)NR 16 R 17 , – SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , C 1-6 alkyl, and C 1- 6haloalkyl.
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR 18 , –NR 16 R 17 , –C(O)NR 16 R 17 , – SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –NR 19 C(O)R 15 , and –NR 19 C(O)OR 15 .
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, halo, –OR 18 , and –NR 16 R 17 .
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or halo.
  • R 11 is halo, and R 8 , R 9 , R 12 , R 13 , and R 14 are each hydrogen.
  • R 11 is chloro, and R 8 , R 9 , R 12 , R 13 , and R 14 are each hydrogen.
  • R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl. [0024] In certain embodiments, R1 is Me. [0025] In certain embodiments, R1 is hydrogen.
  • R 2 and R 3 are each independently selected the group consisting of hydrogen, halo, –CN, –OR 18 , –SOR 15 , –SO 2 R 15 , –NR 16 R 17 , –C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , – C(O)R 18 , –C(O)OR 18 , –NR 19 C(O)R 18 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , –NR 19 SO 2 NR 16 R 17 , C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl.
  • R 2 and R 3 are each independently selected the group consisting of hydrogen, –CN, –OH, –OMe, –OEt, –NH 2 , –NHMe, –NMe 2 , Me, Et, n-Pr, i-Pr, –CF 3 , and cyclopropyl.
  • R 2 and R 3 are each independently selected the group consisting of hydrogen, Me, Et, n-Pr, and i-Pr.
  • R 2 and R 3 are the same.
  • R 2 and R 3 are each hydrogen.
  • R 4 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkoxy, optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, –OR 18 , –CN, –NR 16 R 17 , – C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –(C 1-4 alkyl)OC(O)(C 1-4 alkyl), –(C 1- 4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and – NR
  • R 4 is C 1-6 alkyl or C 1-6 alkoxy, optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, –OR 18 , –CN, –NR 16 R 17 , –C(O)NR 16 R 17 , – SO 2 NR 16 R 17 ,–C(O)OR 18 , –(C 1-4 alkyl)OC(O)(C 1-4 alkyl), –(C 1-4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 .
  • R 4’ and R 4’’ are both hydrogen.
  • R 4 is C 1-6 alkyl or C 1-6 alkoxy, optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, –OR 18 , –CN, –NR 16 R 17 , –C(O)NR 16 R 17 , – SO 2 NR 16 R 17 ,–C(O)OR 18 , –(C 1-4 alkyl)OC(O)(C 1-4 alkyl), –(C 1-4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 ; and R 4’ and R 4’’ are each hydrogen.
  • R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl. [0036] In certain embodiments, R 5 is Me. [0037] In certain embodiments, R 5 is hydrogen.
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, –(C 1-4 alkyl)C 3-6 cycloalkyl, –(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl), –(C 1-4 alkyl)C 6-10 aryl, and –(C 1-4 alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR 18 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, C 1-4 haloalkyl, –CN, and –NR 20 R 21 ; or R 6 and R 7 , along with the nitrogen atom to which they are attached, are taken together to form a 3- to 10-membered heterocycloalkyl optional
  • R 6 and R 7 are each independently hydrogen or –(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl); wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more substituents selected from halo, –OR 18 , –CN, and – NR 20 R 21 .
  • one of R 6 and R 7 is H and the other .
  • n is 0, 1, or 2.
  • n is 0.
  • the compound is a compound of Formula (II): Formula (II).
  • the compound is a compound of Formula (III): Formula (III). [0045] In certain embodiments, the compound is a compound of Formula (IV): Formula (IV). [0046] In certain embodiments, the compound is a compound of Formula (V): Formula (V). [0047] In certain embodiments, the compound is a compound of Formula (VI): Formula (VI). [0048] In certain embodiments, the compound is a compound of Formula (VII-A) or Formula (VII-B): or Formula (VII-A) Formula (VII-B).
  • the compound is a compound of Formula (VIII-A) or Formula (VIII-B): or Formula (VIII-A) Formula (VIII-B).
  • the compound is a compound of Formula (IX-A) or Formula (IX-B): or Formula (IX-A) Formula (IX-B).
  • the compound is a compound of Formula (X): Formula (X), wherein: R 22 , R 23 , R 24 , and R 25 are each independently selected from the group consisting of hydrogen, halo, –R 18 , –OR 18 , –CN, –NR 16 R 17 , –C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –(C 1- 4 alkyl)OC(O)(C 1-4 alkyl), –(C 1-4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , – NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 ; and R 26 is selected from the group consisting of halo, –R 18 , –OR 18 , –CN, –NR
  • R 22 , R 23 , R 24 , and R 25 are each independently selected from the group consisting of hydrogen, halo, –R 18 , and –OR 18 .
  • R 22 , R 23 , R 24 , and R 25 are each independently hydrogen or halo.
  • R 22 , R 23 , R 24 , and R 25 are each hydrogen.
  • R 26 is selected from the group consisting of –NR 16 R 17 , – NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 .
  • R 26 is selected from the group consisting of ––NH 2 , – NHC(O)OtBu, –NHSO 2 CH 3 , –NHSO 2 CF 3 , NH(CO)CH 3 –, , , , and –NHC(O)OCH 2 CF 3 .
  • the compound is a compound of Formula (XI): Formula (XI).
  • the compound is selected from the group consisting of:
  • a pharmaceutical composition comprising a compound disclosed herein, for example, a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein, and a pharmaceutically acceptable excipient.
  • a disease or disorder e.g., proliferative disease
  • methods of treating a disease or disorder comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition thereof described here.
  • a compound disclosed herein is for use in a method of treating a disease or disorder (e.g., a proliferative disease).
  • Such a compound is, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
  • the disease or disorder is a proliferative disease.
  • the proliferative disease is cancer.
  • the cancer is selected from leukemia, breast cancer, prostate cancer, ovarian cancer, colon cancer, cervical cancer, lung cancer, lymphoma, and liver cancer.
  • the cancer is liver cancer.
  • FIG.2 shows mean weight changes (relative to day 1) of BALB/c nude mice treated with vehicle and compounds. Error bars represent ⁇ SD. BID: oral administration twice (two times) a day. QD: oral administration once a day.
  • C x-y when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C 1-6 alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • the term –C x-y alkylene refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • alkylene may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • Alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups.
  • An alkyl group may contain from one to twelve carbon atoms (e.g., C 1-12 alkyl), such as one to eight carbon atoms (C 1-8 alkyl) or one to six carbon atoms (C 1-6 alkyl).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl.
  • An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein. [0072] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens.
  • haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.
  • Alkenyl refers to substituted or unsubstituted hydrocarbon groups, including straight- chain or branched-chain alkenyl groups containing at least one double bond.
  • An alkenyl group may contain from two to twelve carbon atoms (e.g., C 2-12 alkenyl).
  • alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein. [0074] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including straight- chain or branched-chain alkynyl groups containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C 2-12 alkynyl).
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein. [0075] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups which respectively have one or more skeletal chain atoms selected from an atom other than carbon.
  • Exemplary skeletal chain atoms selected from an atom other than carbon include, e.g., O, N, P, Si, S, or combinations thereof, wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain.
  • a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • heteroaryl refers to a 3- to 12-membered aromatic ring that comprises at least one heteroatom wherein each heteroatom may be independently selected from N, O, and S.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the heteroatom(s) in the heteroaryl may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyri
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are saturated or partially unsaturated.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom).
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms.
  • Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4- dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. [0079] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, or bicyclic 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) or bridged ring systems.
  • the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized.
  • the nitrogen atom may be optionally quaternized.
  • the heterocycloalkyl radical may be partially or fully saturated.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, 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, t
  • heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 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). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, a carbocycle, a hetero
  • substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants. [0082] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
  • Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the 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.
  • isotopic variations of the compounds of the present disclosure 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 certain 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.
  • Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art. [0086] “Isomers” are different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • Diastereoisomers or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form).
  • certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • the single enantiomers or diastereomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers.
  • Racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column.
  • HPLC high-pressure liquid chromatography
  • a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
  • certain small molecules include Z- and E- forms (or cis- and trans- forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds.
  • 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 excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • the term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • a “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the term “co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
  • antagonists are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein or enzyme. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.
  • a biological function e.g., activity, expression, binding, protein-protein interaction
  • Ring A is optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 10- membered heterocycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl
  • R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR 18 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalky
  • Ring A is optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl. In some embodiments, Ring A is optionally substituted C 3-6 cycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 6- to 10- membered heteroaryl. In some embodiments, Ring A is optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted 6- to 10- membered heteroaryl.
  • Ring A is optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C 6-10 aryl. In some embodiments, Ring A is optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C 6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl. In some embodiments, Ring A is optionally substituted C 3-6 cycloalkyl or optionally substituted 3- to 10- membered heterocycloalkyl. In some embodiments, Ring A is optionally substituted C 3- 6 cycloalkyl or optionally substituted C 6-10 aryl.
  • Ring A is optionally substituted C 3-6 cycloalkyl or optionally substituted 6- to 10-membered heteroaryl. In one embodiment, Ring A is optionally substituted C 3-6 cycloalkyl. In another embodiment, Ring A is optionally substituted 3- to 10-membered heterocycloalkyl. In yet another embodiment, Ring A is optionally substituted C 6-10 aryl. In yet another embodiment, Ring A is optionally substituted 6- to 10-membered heteroaryl. [0099] In some embodiments, Ring A is selected from the group consisting of: [0100] In some embodiments, Ring A is selected from the group consisting of: In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is .
  • Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . [0101] In some embodiments, Ring A is selected from the group consisting of optionally substituted optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl.
  • Ring A is selected from the group consisting of 1,2-cyclopropyl, 1,2-cyclobutyl, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, and 1,4-cyclohexyl.
  • Ring A is selected from the group consisting of trans-1,2- cyclopropyl, cis-1,2-cyclopropyl, trans-1,2-cyclobutyl, cis-1,2-cyclobutyl, trans-1,3-cyclobutyl, cis-1,3-cyclobutyl, trans-1,2-cyclopentyl, cis-1,2-cyclopentyl, trans-1,3-cyclopentyl, cis-1,3- cyclopentyl, trans-1,2-cyclohexyl, cis-1,2-cyclohexyl, trans-1,3-cyclohexyl, cis-1,3-cyclohexyl, trans-1,4-cyclohexyl, and cis-1,4-cyclohexyl.
  • Ring A is selected from the group consisting of trans-1,2-cyclopentyl, cis-1,2-cyclopentyl, trans-1,3-cyclopentyl, cis-1,3- cyclopentyl, trans-1,2-cyclohexyl, cis-1,2-cyclohexyl, trans-1,3-cyclohexyl, cis-1,3-cyclohexyl, trans-1,4-cyclohexyl, and cis-1,4-cyclohexyl.
  • Ring A is selected from the group consisting of trans-1,2-cyclohexyl, cis-1,2-cyclohexyl, trans-1,3-cyclohexyl, cis-1,3- cyclohexyl, trans-1,4-cyclohexyl, and cis-1,4-cyclohexyl. In some embodiments, Ring A is selected from the group consisting of trans-1,3-cyclohexyl, cis-1,3-cyclohexyl, trans-1,4- cyclohexyl, and cis-1,4-cyclohexyl.
  • Ring A is trans-1,4-cyclohexyl or cis-1,4-cyclohexyl. In one preferred embodiment, Ring A is trans-1,4-cyclohexyl. [0104] In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . [0105] In some embodiments, Ring A is selected from the group consisting of: [0106] In some embodiments, Ring A is selected from the group consisting of: .
  • Ring A is selected from the group consisting of: , [0108] In some embodiments, Ring A is selected from the group consisting of: . [0109] In some embodiments, Ring A is selected from the group consisting of: [0110] In some embodiments, Ring A is selected from the group consisting of: [0111] In some embodiments, Ring A is selected from the group consisting of: . In one embodiment, Ring A is . In another embodiment, Ring A is . In some embodiments, Ring A is selected from the group consisting of: . In one embodiment, Ring A is . In another embodiment, Ring A is . [0112] In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is .
  • Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is
  • Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is .
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR 18 , –SOR 15 , –SO 2 R 15 , –NR 16 R 17 , – C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , – NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , –NR 19 SO 2 NR 16 R 17 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 heteroalkyl, and C 1-6 haloalkyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR 18 , –NR 16 R 17 , –C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , – NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, halo, – CN, –OR 18 , –NR 16 R 17 , –C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –NR 19 C(O)R 15 , and –NR 19 C(O)OR 15 .
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR 18 , and –NR 16 R 17 .
  • R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or halo.
  • one of R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 is halo and the others are hydrogen.
  • R 8 , R 9 , R 12 , R 13 , and R 14 are each hydrogen, and R 11 is halo.
  • R 8 , R 9 , R 12 , R 13 , and R 14 are each hydrogen, and R 11 is chloro or fluoro. In one preferred embodiment, R 8 , R 9 , R 12 , R 13 , and R 14 are each hydrogen, and R 11 is chloro.
  • R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl. In some embodiments, R 1 is C 1-6 alkyl. In some embodiments, R 1 is C 1-6 haloalkyl. In some embodiments, R 1 is C 3-6 cycloalkyl.
  • R 1 is selected from hydrogen, Me, Et, n-Pr, i-Pr, –CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R 1 is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R 1 is selected from hydrogen, Me, Et, n-Pr, and i-Pr. In some embodiments, R 1 is selected from Me, Et, n-Pr, and i-Pr. In one preferred embodiment, R 1 is hydrogen. In another embodiment, R 1 is Me.
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR 18 , –SOR 15 , –SO 2 R 15 , –NR 16 R 17 , –C(O)NR 16 R 17 , – SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , – NR 19 SO 2 R 15 , –NR 19 SO 2 NR 16 R 17 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1- 6haloalkyl, C 3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 aryl, and 6- to 10- membered heteroaryl; wherein each alkyl, C 1-6 alkyl
  • R 2 and R 3 are each independently selected the group consisting of hydrogen, halo, –CN, – OR 18 , –SOR 15 , –SO 2 R 15 , –NR 16 R 17 , –C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , – NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , –NR 19 SO 2 NR 16 R 17 , C 1- 6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl.
  • R 2 and R 3 are each independently selected the group consisting of hydrogen, halo, –CN, –OH, –OMe, –OEt, –NH 2 , – NHMe, –NMe 2 , Me, Et, n-Pr, i-Pr, –CF 3 , and cyclopropyl.
  • R 2 and R 3 are each independently selected the group consisting of hydrogen, Me, Et, n-Pr, and i-Pr.
  • R 2 and R 3 are the same.
  • R 2 and R 3 are each independently hydrogen or Me.
  • R 2 and R 3 are each hydrogen.
  • R 4 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C 6-10 aryl, 6- to 10-membered heteroaryl, –O(C 1-4 alkyl)C 3-6 cycloalkyl, –O(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl), – O(C 1-4 alkyl)C 6-10 aryl, –O(C 1-4 alkyl)(6- to 10-membered heteroaryl), –O(C 1-4 alkyl)C(O)OR 18 , – O(C 1-4 alkyl)C(O)NR 19 SO 2 R 15 , –O(C 1-4 alkyl)
  • R 4 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkoxy, optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, –OR 18 , –CN, –NR 16 R 17 , – C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –(C 1-4 alkyl)OC(O)(C 1-4 alkyl), –(C 1- 4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and – NR
  • R 4 is C 1-6 alkyl or C 1-6 alkoxy, optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, –OR 18 , –CN, –NR 16 R 17 , –C(O)NR 16 R 17 , – SO 2 NR 16 R 17 ,–C(O)OR 18 , –(C 1-4 alkyl)OC(O)(C 1-4 alkyl), –(C 1-4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 .
  • R 4’ and R 4’’ are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3- 6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C 6-10 aryl, 6- to 10-membered heteroaryl, –O(C 1-4 alkyl)C 3-6 cycloalkyl, –O(C 1- 4 alkyl)(3- to 10-membered heterocycloalkyl), –O(C 1-4 alkyl)C 6-10 aryl, –O(C 1-4 alkyl)(6- to 10- membered heteroaryl), –O(C 1-4 alkyl)C(O)OR 18 , –O(C 1-4 alkyl)C(O)NR 19 SO 2 R
  • R 4’ and R 4’’ are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkyl, C 3- 6 cycloalkyl, C 3-6 cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C 6-10 aryl, 6- to 10-membered heteroaryl, –(C 1-4 alkyl)C 3-6 cycloalkyl, –(C 1- 4 alkyl)(3- to 10-membered heterocycloalkyl), –(C 1-4 alkyl)C 6-10 aryl, and –(C 1-4 alkyl)(6- to 10- membered heteroaryl).
  • R 4’ and R 4’’ are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkyl, – (C 1-4 alkyl)C 6-10 aryl, and –(C 1-4 alkyl)(6- to 10-membered heteroaryl).
  • R 4’ and R 4’’ are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, and C 1-6 haloalkyl.
  • R 4’ and R 4’’ are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 4’ and R 4’’ are each independently hydrogen or halo. In some embodiments, R 4’ and R 4’’ are the same. In one preferred embodiment, R 4’ and R 4’’ are each hydrogen.
  • R 4 is C 1-6 alkyl or C 1-6 alkoxy, optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, –OR 18 , –CN, –NR 16 R 17 , –C(O)NR 16 R 17 , – SO 2 NR 16 R 17 ,–C(O)OR 18 , –(C 1-4 alkyl)OC(O)(C 1-4 alkyl), –(C 1-4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 ; and R 4’ and R 4’’ are each hydrogen.
  • R 4 is C 1-6 alkoxy, optionally substituted with one or more substituents selected from C 1-4 alkyl, oxo, halo, –OR 18 , –CN, –NR 16 R 17 , –C(O)NR 16 R 17 , – SO 2 NR 16 R 17 ,–C(O)OR 18 , –(C 1-4 alkyl)OC(O)(C 1-4 alkyl), –(C 1-4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 ; and R 4’ and R 4’’ are each hydrogen.
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 3- 6 cycloalkyl. In some embodiments, R 5 is C 1-6 haloalkyl. In some embodiments, R 5 is C 3- 6 cycloalkyl. In some embodiments, R 5 is C 1-6 alkyl. In some embodiments, R 5 is hydrogen, Me, Et, n-Pr, or i-Pr. In some embodiments, R 5 is Me, Et, n-Pr, or i-Pr. In one preferred embodiment, R 5 is hydrogen. In another embodiment, R 5 is Me.
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, –(C 1-4 alkyl)C 3-6 cycloalkyl, –(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl), –(C 1-4 alkyl)C 6-10 aryl, and –(C 1-4 alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR 18 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, C 1-4 haloalkyl, –CN, and –NR 20 R 21 ; or R 6 and R 7 , along with the nitrogen atom to which they are attached, are taken together to form a 3- to 10-membered heterocycloalkyl optional
  • R 6 and R 7 are each independently hydrogen, C 1-4 alkyl, or ; each alkyl is independently optionally substituted with one or more substituents selected from halo, –OR 18 , –CN, and –NR 20 R 21 ; wherein R 31 and R 32 are each independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 heteroalkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl; each R 30 is independently selected from the group consisting of halo, –CN, –OR 18 , –NR 16 R 17 , –C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , – NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalky
  • each R 30 is independently selected from the group consisting of halo, –CN, –OR 18 , –NR 16 R 17 , –C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , – NR 19 C(O)R 15 , and –NR 19 C(O)OR 15 .
  • each R 30 is independently selected from the group consisting of halo, –CN, –OR 18 , and –NR 16 R 17 .
  • each R 30 is independently halo or –CN.
  • R 30 is halo or –CN and m is 1.
  • R 30 is–CN and m is 1.
  • R 31 and R 32 are each independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, and C 1-4 haloalkyl. In some embodiments, R 31 and R 32 are each independently hydrogen or halo. In some embodiments, R 31 and R 32 are each hydrogen.
  • Ring B is optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl.
  • Ring B is optionally substituted C 3-6 cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, Ring B is optionally substituted C 3-6 cycloalkyl. In some embodiments, Ring B is optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, Ring B is optionally substituted 6-membered heterocycloalkyl. In one embodiment, Ring B is optionally substituted tetrahydropyranyl. In one embodiment, Ring B is optionally substituted tetrahydro- 2H-pyranyl. In a specific embodiment, Ring B is optionally substituted tetrahydro-2H-pyran-4- yl.
  • Ring B is 4-cyanotetrahydro-2H-pyran-4-yl.
  • R 6 and R 7 are each independently hydrogen or –(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl); wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more substituents selected from halo, –OR 18 , –CN, and – NR 20 R 21 .
  • R 6 and R 7 are each independently hydrogen or –(C 1-4 alkyl)(3- to 10-membered heterocycloalkyl); wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more substituents selected from halo, –OR 18 , –CN, and – NR 20 R 21 .
  • one of R 6 and R 7 is hydrogen and the other is .
  • R 6 is hydrogen and R 7 is .
  • R 7 is hydrogen and R 6 is .
  • n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3.
  • n is 0, 1, or 2. In some embodiments, n is 0 or 1. 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. [0133] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.
  • the compound of Formula (I) is a compound of Formula (II): Formula (II); wherein Ring A, R 1 , R 4 , R 4’ , R 4’’ , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are as defined herein above.
  • the compound of Formula (I) is a compound of Formula (II’): Formula (II’).
  • the compound of Formula (I) is a compound of Formula (II’’): Formula (II’’).
  • the compound of Formula (I) is a compound of Formula (III): Formula (III); wherein Ring A, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are as defined herein above.
  • the compound of Formula (I) is a compound of Formula (III’): Formula (III’).
  • the compound of Formula (I) is a compound of Formula (III’’): Formula (III’’).
  • the compound of Formula (I) is a compound of Formula (IV): Formula (IV); wherein Ring A, R 1 , R 2 , R 3 , R 4 , R 4’ , R 4’’ , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are as defined herein above.
  • the compound of Formula (I) is a compound of Formula (IV’): Formula (IV’).
  • the compound of Formula (I) is a compound of Formula (V): Formula (V); wherein Ring A, R 1 , R 4 , R 4’ , R 4’’ , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are as defined herein above.
  • the compound of Formula (I) is a compound of Formula (V’): Formula (V’).
  • the compound of Formula (I) is a compound of Formula (VI): Formula (VI); wherein Ring A, R 1 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are as defined herein above.
  • the compound of Formula (I) is a compound of Formula (VI’): Formula (VI’).
  • the compound of Formula (I) is a compound of Formula (VII-A) or Formula (VII-B): or Formula (VII-A) Formula (VII-B); wherein R 1 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are as defined herein above.
  • the compound of Formula (I) is a compound of Formula (VII-A’) or Formula (VII-B’): or Formula (VII-A’) Formula (VII-B’); wherein R 4 , R 10 , and R 11 are as defined herein above.
  • the compound of Formula (I) is a compound of Formula (VIII-A) or Formula (VIII-B): or Formula (VIII-A) Formula (VIII-B); wherein R 4 , R 5 , and R 11 are as defined herein above.
  • the compound of Formula (I) is a compound of Formula (IX-A) or Formula (IX-B): or Formula (IX-A) Formula (IX-B); wherein R 4 is as defined herein above.
  • the compound of Formula (I) is a compound of Formula (X): Formula (X), wherein: R 22 , R 23 , R 24 , and R 25 are each independently selected from the group consisting of hydrogen, halo, –R 18 , –OR 18 , –CN, –NR 16 R 17 , –C(O)NR 16 R 17 , –SO 2 NR 16 R 17 , –C(O)R 18 , –C(O)OR 18 , –(C 1- 4 alkyl)OC(O)(C 1-4 alkyl), –(C 1-4 alkyl)OC(O)OR 18 , –NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , – NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 ; and R 26 is selected from the group consisting of halo, –R 18 ,
  • R 22 , R 23 , R 24 , and R 25 are each independently selected from the group consisting of hydrogen, halo, –R 18 , and –OR 18 .
  • R 22 , R 23 , R 24 , and R 25 are each independently hydrogen or halo.
  • R 22 , R 23 , R 24 , and R 25 are each hydrogen.
  • R 26 is selected from the group consisting of –NR 16 R 17 , – NR 19 C(O)R 15 , –NR 19 C(O)OR 15 , –NR 19 C(O)NR 16 R 17 , –NR 19 SO 2 R 15 , and –NR 19 SO 2 NR 16 R 17 .
  • R 26 is selected from the group consisting of –NH 2 , –NHC(O)OtBu, – NHSO 2 CH 3 , –NHSO 2 CF 3 , , –NH(CO)CH 3 –, , and –NHC(O)OCH 2 CF 3 .
  • the compound of Formula (I) is a compound of Formula (XI): Formula (XI); wherein , R 26 is as defined herein above.
  • the compound is selected from the group consisting of:
  • the compound i s . In another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is. In yet another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is . In yet another embodiment, the compound is l . In yet another embodiment, the compound is .
  • a disease or disorder e.g., proliferative disorder
  • methods for treating the proliferative disorder comprising administering to said subject a therapeutically effective amount of a compound having Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the method for treating the proliferative disorder comprises administering to said subject a CDK9 inhibitor disclosed herein.
  • the CDK9 inhibitor is a compound having Formula (I) as disclosed herein.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the disease or disorder is cancer.
  • the cancer is selected from leukemia, breast cancer, prostate cancer, ovarian cancer, colon cancer, cervical cancer, lung cancer, lymphoma, and liver cancer.
  • the cancer is leukemia.
  • the cancer is breast cancer.
  • the cancer is prostate cancer.
  • the cancer is ovarian cancer.
  • the cancer is colon cancer.
  • the cancer is cervical cancer.
  • the cancer is lung cancer.
  • the cancer is lymphoma.
  • the cancer is liver cancer.
  • the CDK9 inhibitors disclosed herein are highly targeted to the liver.
  • the CDK9 inhibitors disclosed herein have superior liver targeting as compared with known CDK9 inhibitors.
  • the CDK9 inhibitors disclosed herein e.g., compounds of Formula (I)
  • the CDK9 inhibitors disclosed herein accumulate in the liver while avoiding peripheral exposure to nearby tissues.
  • the CDK9 inhibitors disclosed herein have reduced peripheral exposure to nearby tissues as compared with known CDK9 inhibitors.
  • the CDK9 inhibitors disclosed herein e.g., compounds of Formula (I) have reduced toxicity as compared with known CDK9 inhibitors.
  • the present invention provides a method of treating a cancer condition, wherein the CDK9 inhibitors disclosed herein (e.g., compounds of Formula (I)) are effective in one or more method of inhibiting proliferation of cancer cells, inhibiting metastasis of cancer cells, reducing severity or incidence of symptoms associated with the presence of cancer cells, and promoting an immune response to tumor cells.
  • said method comprises administering to the cancer cells a therapeutically effective amount of a compound having Formula (I).
  • the compound having Formula (I) is a CDK9 inhibitor.
  • the administration takes place in vitro. In other embodiments, the administration takes place in vivo.
  • a therapeutically effective amount of a CDK9 inhibitor refers to an amount sufficient to effect the intended application, including but not limited to, disease treatment, as defined herein. Also contemplated in the subject methods is the use of a sub-therapeutic amount of a CDK9 inhibitor for treating an intended disease condition.
  • the amount of the CDK9 inhibitor (e.g., a compound of Formula (I)) administered may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • Measuring inhibition of biological effects of CDK9 can comprise performing an assay on a biological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to, blood samples (e.g.
  • a subject being treated with a CDK9 inhibitor may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject’s physiological response to treatment. For example, if inhibition of a biological effect of CDK9 degradation is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively.
  • the methods can further comprise continuing the therapy if the therapy is determined to be efficacious.
  • the methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound in the therapy if the therapy is determined to be efficacious.
  • the methods can comprise increasing the administered amount of a compound in the therapy if it is determined not to be efficacious. Alternatively, the methods can comprise stopping therapy if it is determined not to be efficacious. In some embodiments, treatment with a CDK9 inhibitor is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction.
  • the biological effect may be a change in any of a variety of physiological indicators.
  • a CDK9 inhibitor is a compound that inhibits one or more biological effects of CDK9. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.
  • the subject methods are useful for treating a disease condition associated with CDK9. Any disease condition that results directly or indirectly from an abnormal activity or expression level of CDK9 can be an intended disease condition.
  • the disease condition is a proliferative disorder, such as described herein, including but not limited to cancer.
  • the disease condition is cancer.
  • a role of CDK9 in tumorigenesis and tumor progression has been implicated in many human cancers. Consequently, agents that target CDK9 have therapeutic value.
  • the data presented in the Examples herein below demonstrate the anti-cancer effects of a CDK9 inhibitor. As such, the subject method is particularly useful for treating a proliferative disorder, such as a neoplastic condition.
  • the methods of administering a CDK9 inhibitor (e.g., a compound of Formula (I)) described herein are applied to the treatment of cancers of the blood, breast, prostate, ovaries, colon, cervix, lungs, lymph nodes, liver, or any combination thereof.
  • a compound provided herein is administered as a pure chemical.
  • a compound provided herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
  • Therapeutic Efficacy is measured based on effects of treating a proliferative disorder, such as cancer.
  • therapeutic efficacy of the treatment methods provided herein, with regard to the treatment of a proliferative disorder e.g.
  • cancer whether benign or malignant
  • Several parameters to be considered in the determination of therapeutic efficacy are discussed herein. The proper combination of parameters for a particular situation can be established by the clinician.
  • the progress of the methods for treating cancer e.g., reducing tumor size or eradicating cancerous cells
  • the primary efficacy parameter used to evaluate the treatment of cancer using the CDK9 inhibitors provided herein preferably is a reduction in the size of a tumor.
  • Tumor size can be figured using any suitable technique, such as measurement of dimensions, or estimation of tumor volume using available computer software, such as FreeFlight software developed at Wake Forest University that enables accurate estimation of tumor volume.
  • Tumor size can be determined by tumor visualization using, for example, CT, ultrasound, SPECT, spiral CT, MRI, photographs, and the like.
  • the presence of tumor tissue and tumor size can be determined by gross analysis of the tissue to be resected, and/or by pathological analysis of the resected tissue.
  • the growth of a tumor is stabilized (i.e., one or more tumors do not increase more than 1%, 5%, 10%, 15%, or 20% in size, and/or do not metastasize) as a result of the inventive method and compositions.
  • a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks.
  • a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months.
  • a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years.
  • the inventive method reduces the size of a tumor at least about 5% (e.g., at least about 10%, 15%, 20%, or 25%). More preferably, tumor size is reduced at least about 30% (e.g., at least about 35%, 40%, 45%, 50%, 55%, 60%, or 65%). Even more preferably, tumor size is reduced at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, or 95%). Most preferably, the tumor is completely eliminated, or reduced below a level of detection. In some embodiments, a subject remains tumor free (e.g.
  • the efficacy of the treatment methods provided herein in reducing tumor size can be determined by measuring the percentage of necrotic (i.e., dead) tissue of a surgically resected tumor following completion of the therapeutic period.
  • a treatment is therapeutically effective if the necrosis percentage of the resected tissue is greater than about 20% (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), more preferably about 90% or greater (e.g., about 90%, 95%, or 100%). Most preferably, the necrosis percentage of the resected tissue is 100%, that is, no tumor tissue is present or detectable.
  • the efficacy of the treatment methods provided herein can be determined by a number of secondary parameters.
  • secondary parameters include, but are not limited to, detection of new tumors, detection of tumor antigens or markers (e.g., CEA, PSA, or CA-125), biopsy, surgical downstaging (i.e., conversion of the surgical stage of a tumor from unresectable to resectable), PET scans, survival, disease progression-free survival, time to disease progression, quality of life assessments such as the Clinical Benefit Response Assessment, and the like, all of which can point to the overall progression (or regression) of cancer in a human.
  • Biopsy is particularly useful in detecting the eradication of cancerous cells within a tissue.
  • Radioimmunodetection is used to locate and stage tumors using serum levels of markers (antigens) produced by and/or associated with tumors (“tumor markers” or “tumor-associated antigens”), and can be useful as a pre-treatment diagnostic predicate, a post-treatment diagnostic indicator of recurrence, and a post-treatment indicator of therapeutic efficacy.
  • tumor markers or tumor-associated antigens that can be evaluated as indicators of therapeutic efficacy include, but are not limited to, carcinembryonic antigen (CEA), prostate-specific antigen (PSA), CA-125, CA19-9, ganglioside molecules (e.g., GM2, GD2, and GD3), MART-1, heat shock proteins (e.g., gp96), sialyl Tn (STn), tyrosinase, MUC-1, HER-2/neu, c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, and gp100.
  • CCA carcinembryonic antigen
  • PSA prostate-specific antigen
  • CA-125 CA19-9
  • CA19-9 ganglioside molecules
  • ganglioside molecules e.g., GM2, GD2, and GD3
  • MART-1 e.g., heat shock proteins (e.g., gp96), si
  • the treatment of cancer in a human patient in accordance with the treatment methods provided herein is evidenced by one or more of the following results: (a) the complete disappearance of a tumor (i.e., a complete response), (b) about a 25% to about a 50% reduction in the size of a tumor for at least four weeks after completion of the therapeutic period as compared to the size of the tumor before treatment, (c) at least about a 50% reduction in the size of a tumor for at least four weeks after completion of the therapeutic period as compared to the size of the tumor before the therapeutic period, and (d) at least a 2% decrease (e.g., about a 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% decrease) in a specific tumor-associated antigen level at about 4-12 weeks after completion of the therapeutic period as compared to
  • any decrease in the tumor- associated antigen level is evidence of treatment of a cancer in a patient by the treatment methods provided herein.
  • treatment can be evidenced by at least a 10% decrease in the CA19-9 tumor-associated antigen level at 4-12 weeks after completion of the therapeutic period as compared to the CA19-9 level before the therapeutic period.
  • treatment can be evidenced by at least a 10% decrease in the CEA tumor-associated antigen level at 4-12 weeks after completion of the therapeutic period as compared to the CEA level before the therapeutic period.
  • the therapeutic benefit of the treatment in accordance with the invention can be evidenced in terms of pain intensity, analgesic consumption, and/or the Karnofsky Performance Scale score.
  • the treatment of cancer in a human patient is evidenced by (a) at least a 50% decrease (e.g., at least a 60%, 70%, 80%, 90%, or 100% decrease) in pain intensity reported by a patient, such as for any consecutive four week period in the 12 weeks after completion of treatment, as compared to the pain intensity reported by the patient before treatment, (b) at least a 50% decrease (e.g., at least a 60%, 70%, 80%, 90%, or 100% decrease) in analgesic consumption reported by a patient, such as for any consecutive four week period in the 12 weeks after completion of treatment as compared to the analgesic consumption reported by the patient before treatment, and/or (c) at least a 20 point increase (e.g., at least a 30
  • a proliferative disorder e.g. cancer, whether benign or malignant
  • administration of a CDK9 inhibitor provides improved therapeutic efficacy. Improved efficacy may be measured using any method known in the art, including but not limited to those described herein.
  • the improved therapeutic efficacy is an improvement of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 1000% or more, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease-free survival).
  • an appropriate measure e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease-free survival.
  • Improved efficacy may also be expressed as fold improvement, such as at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100- fold, 1000-fold, 10000-fold or more, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease- free survival).
  • fold improvement such as at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100- fold, 1000-fold, 10000-fold or more, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease- free survival).
  • a disease or disorder e.g., a proliferative disease
  • a compound disclosed herein is for use in a method of treating a disease or disorder (e.g., a proliferative disease) in a subject in need thereof, such cancer.
  • a disease or disorder e.g., a proliferative disease
  • Such a compound is, for example, a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
  • compositions comprising a compound Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder (e.g., a proliferative disease) in a subject in need thereof.
  • a disease or disorder e.g., a proliferative disease
  • compositions comprising a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a composition of the present disclosure may be formulated in any suitable pharmaceutical formulation.
  • a pharmaceutical composition of the present disclosure typically contains an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants.
  • an active ingredient e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • pharmaceutically acceptable excipients or carriers including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants.
  • a composition of the present disclosure may be formulated in any suitable pharmaceutical formulation.
  • the pharmaceutical acceptable carriers or excipients are selected from water, alcohol, glycerol, chitosan
  • compositions may be provided in any suitable form, which may depend on the route of administration.
  • the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject.
  • the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and/or intraperitoneal administration.
  • the dosage form is formulated for oral administration.
  • the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder.
  • the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi- solid, or solid form.
  • an effective dosage may be in the range of about 0.001 to about 100 mg per kg body weight per day, in single or divided doses.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • an effective dosage may be provided in pulsed dosing (i.e., administration of the compound in consecutive days, followed by consecutive days of rest from administration).
  • the composition is provided in one or more unit doses.
  • the composition can be administered in 1, 2, 3, 4, 5, 6, 7, 14, 30, 60, or more doses. Such amount can be administered each day, for example in individual doses administered once, twice, or three or more times a day.
  • dosages stated herein on a per day basis should not be construed to require administration of the daily dose each and every day.
  • two or more daily dosage amounts can be administered at a lower frequency, e.g., as a depot injection or oral prodrug administered every second day to once a month or even longer.
  • a CDK9 inhibitor can be administered once a day, for example in the morning, in the evening or during the day.
  • the unit doses can be administered simultaneously or sequentially.
  • the composition can be administered for an extended treatment period.
  • the treatment period can be at least about one month, for example at least about 3 months, at least about 6 months or at least about 1 year. In some cases, administration can continue for substantially the remainder of the life of the subject.
  • the CDK9 inhibitor provided herein e.g., a compound of Formula (I)
  • the CDK9 inhibitor e.g., a compound of Formula (I)
  • the CDK9 inhibitor may be administered before or after the one or more second agents.
  • the CDK9 inhibitor e.g., a compound of Formula (I)
  • the one or more second agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising a CDK9 inhibitor and one or more second agents).
  • the combination treatment provided herein may be effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • composition for oral administration containing at least one compound of the present disclosure and a pharmaceutical excipient suitable for oral administration.
  • the composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid.
  • the composition further comprises a second agent.
  • the invention provides a solid pharmaceutical composition for oral administration containing: (i) a CDK9 inhibitor (e.g., a compound of Formula (I)); and (ii) a pharmaceutical excipient suitable for oral administration.
  • the composition further contains: (iii) a third agent or even a fourth agent.
  • each compound or agent is present in a therapeutically effective amount.
  • one or more compounds or agents is present in a sub-therapeutic amount, and the compounds or agents act synergistically to provide a therapeutically effective pharmaceutical composition.
  • compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs.
  • Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier.
  • the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro- crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations.
  • tablets can be coated by standard aqueous or nonaqueous techniques.
  • suitable fillers for use in the pharmaceutical composition and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the composition of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment.
  • Surfactant which can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for composition for non-oral use, e.g., composition for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti- foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • the base is a salt
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium. Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • Example 1 Synthesis of 4-(((2’-(((1R,4R)-4-aminocyclohexyl)amino)-5’-chloro-[2,4’- bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate 1) [0201] Step 1: Preparation of tetrahydro-4H-pyran-4,4-dicarbonitrile (INT-2) [0202] To a solution of 1-bromo-2-(2-bromoethoxy)ethane (INT-1, 20 g, 86.24 mmol) and propanedinitrile (6.27 g, 94.86 mmol) in DMF (30 mL) was added DBU (26.26 g, 172.48 mmol).
  • Step 2 Preparation of 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (INT-3)
  • INT-3 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile
  • Step 2 To a solution of tetrahydro-4H-pyran-4,4-dicarbonitrile (INT-2, 9.0 g, 66.10 mmol) in EtOH (270 mL) was added NaBH4 (7.50 g, 198.31 mmol) in portions. The reaction mixture was stirred at 20 °C for 4 hours, quenched by water (200 mL), and extracted with ethyl acetate (200 mL ⁇ 3).
  • Step 3 Preparation of 4-(((6-bromopyridin-2-yl)amino)methyl)tetrahydro-2H-pyran-4- carbonitrile (INT-4)
  • INT-3 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile
  • 2-bromo-6-fluoro-pyridine 7.72 g, 43.84 mmol
  • DMSO 80 mL
  • TEA 13.05 g, 128.94 mmol
  • reaction mixture was stirred at 130 °C for 18 hours, cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • the resulting residue was purified by silica gel chromatography (Biotage 20 g Silica Flash Column; 0-25% petroleum ether in ethyl acetate at 40 mL/min) to provide 4-(((6-bromopyridin-2- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (INT-4, 3.8 g, 18.35% yield) as a light green solid.
  • Step 4 Preparation of 4-(((5’-chloro-2’-fluoro-[2,4’-bipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (INT-5) [0208] To a solution of 4-(((6-bromopyridin-2-yl)amino)methyl)tetrahydro-2H-pyran-4- carbonitrile (INT-4, 3.8 g, 12.83 mmol), (5-chloro-2-fluoro-4-pyridyl)boronic acid (3.37 g, 19.25 mmol), and Pd(dppf)Cl2 (938.84 mg, 1.28 mmol) in DME (40 mL) was added Na2CO3 (2 M, 16.04 mL).
  • reaction mixture was sealed, stirred at 110 °C for 4 hrs under N 2 , cooled to ambient temperature, diluted with water (40 mL), and extracted with ethyl acetate (70 mL ⁇ 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • Step 5 Preparation of 4-(((2’-(((1R,4R)-4-aminocyclohexyl)amino)-5’-chloro-[2,4’- bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate 1)
  • the reaction mixture was stirred at 110 °C for 16 hours, diluted with water (40 mL), and extracted with ethyl acetate (100 mL ⁇ 3).
  • the combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • the resulting residue was dissolved in ethyl acetate(100 mL), added dropwise to HCl/dioxane (50 mL), filtered, and washed with ethyl acetate.
  • the resulting solid was dissolved in water (150 mL), basified with NaHCO 3 to pH 9, and extracted with ethyl acetate (100 mL ⁇ 3).
  • Example 3 Synthesis of 4-(((2'-(((1r,4r)-4-((2-(2- aminoethoxy)ethyl)amino)cyclohexyl)amino)-5'-chloro-[2,4'-bipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Compound 2) [0214] To a solution of Compound 1 (200 mg, 0.318 mmol) in 1,4-dioxane (2 mL) was added HCl/1,4-dioxane (4 M solution, 5.7 mL). The mixture was stirred at 25 °C for 1 hour, and then concentrated under reduced pressure.
  • Example 4 Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'-yl)amino)cyclohexyl)amino)ethoxy)ethyl)-1,1,1- trifluoromethanesulfonamide (Compound 3) [0216] A mixture of trifluoromethanesulfonyl chloride (57 mg) in anhydrous DCM (1 mL) was added Compound 2 (300 mg, 60% purity) and DIPEA (132 mg) at 0°C degassed and purged with N 2 for 3 times, then the mixture was stirred at 0°C for 30 minutes under N 2 atmosphere.
  • Example 7 Synthesis of N-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)cyclopropanesulfonamide (Compound 6) [0222] To a mixture of Compound 2 (80 mg, 0.151 mmol) in dichloromethane (3 mL) was added cyclopropanesulfonyl chloride (43 mg, 0.303 mmol) and DIPEA (59 mg, 0.454 mmol) at 0°C, then the mixture was stirred at 25°C for 12 h under N2 atmosphere.
  • Example 8 Synthesis of N-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)cyclopropanecarboxamide (Compound 7) [0224] To a mixture of cyclopropanecarboxylic acid (35 mg, 0.409 mmol) in pyridine (3 mL) were added Compound 2 (180 mg, 0.340 mmol) and EDCI (78 mg, 0.409 mmol) at 25°C, then the mixture was stirred at 25°C for 1 h under N 2 atmosphere.
  • Example 10 Synthesis of N-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran- 4-yl)methyl)amino)-[2,4'-bipyridin]-2'-yl)amino)cyclohexyl)amino)ethoxy)ethyl)-4- fluorobenzamide (Compound 9) [0228] To a solution of Compound 2 (200 mg, 0.246 mmol, 65% purity) in DMF (1 mL) were added DIPEA (95 mg, 0.74 mmol), HATU (112 mg, 0.295 mmol) and 4-fluorobenzoic acid (41 mg, 0.295 mmol).
  • Example 12 Synthesis of 2,2,2-trifluoroethyl (2-(2-(((1r,4r)-4-((5'-chloro-6-(((4- cyanotetrahydro-2H-pyran-4-yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)carbamate (Compound 11) [0233] To a solution of 2,2,2-trifluoroethanol (1.0 g, 10.00 mmol) in THF (20 mL) was added TEA (2.02 g, 19.99 mmol) and 4-nitrophenyl carbonochloridate (10A, 2.22 g, 11.00 mmol) at 0°C.
  • Example 16 Pharmacokinetic and Tissue Distribution Study [0242] All the procedures related to animal handling, care, and treatment were performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals were quarantined for 7 days before the study. The general health of the animals was evaluated by a veterinarian, and complete health checks were performed. Animals with abnormalities were excluded prior the study. Mice were maintained under specific pathogen-free conditions, and food and water were provided ad libitum.
  • IACUC Institutional Animal Care and Use Committee
  • Example 17 Tolerability and Safety Assessment Study [0245] Based on the body weight, BALB/c nude mice were randomly assigned to respective groups using a computer-generated randomization procedure. Body weights of all animals were measured daily. For routine monitoring, all study animals were monitored behavior such as mobility, food and water consumption, body weight, eye/hair matting and any other abnormal effect. Any mortality and/or abnormal clinical signs were recorded. If animals have lost significant body mass (emaciated, obvious body weight loss > 20%), the animals were euthanized.

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Abstract

Described herein are compounds of Formula (I) as CDK9 inhibitors. Also provided herein are methods of treating a disease or a disorder (e.g., a proliferative disease, such as cancer) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a CDK9 inhibitor provided herein (e.g., a compound of Formula (I)).

Description

COMPOUNDS AND METHODS OF USE THEREOF CROSS-REFERENCE [0001] This application claims benefit of U.S. Provisional Application No.63/278,247, filed on November 11, 2021, which is herein incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] Despite advances, treatment of cancer remains relatively difficult. Systemic treatments such as chemotherapies may be toxic and have negative side effects on patients. While CDK9 inhibitors have shown promise as small molecule cancer therapeutics, their potential utility has been limited by poor targeting to cancerous tissue and resulting peripheral exposure. Accordingly, there is a need for the development of CDK9 inhibitors as small molecule cancer therapeutics with improved targeting. SUMMARY OF THE INVENTION [0003] In one aspect, provided here in are compounds of Formula (I):
Figure imgf000003_0001
Formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is optionally substituted C3-6cycloalkyl, optionally substituted 3- to 10- membered heterocycloalkyl, optionally substituted C6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl; R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and – NR20R21; R2 and R3 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, – C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, – NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10- membered heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, – CN, and –NR20R21; R4 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –O(C1- 4alkyl)C3-6cycloalkyl, –O(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –O(C1- 4alkyl)C6-10aryl, –O(C1-4alkyl)(6- to 10-membered heteroaryl), –O(C1-4alkyl)C(O)OR18, – O(C1-4alkyl)C(O)NR19SO2R15, –O(C1-4alkyl)SO2 NR19C(O)R18, –O(C3-6cycloalkyl)C3- 6cycloalkyl, –O(C3-6cycloalkyl)(3- to 10-membered heterocycloalkyl), –O(C3- 6cycloalkyl)C6-10aryl, –O(C3-6cycloalkyl)(6- to 10-membered heteroaryl), –O(C3- 6cycloalkyl)C(O)OR18, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, –(C1-4alkyl)(6- to 10-membered heteroaryl), and –(C1-4alkyl)C(O)OR18; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, – C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and – NR19SO2NR16R17; and R4’ and R4’’ are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C3- 6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –O(C1-4alkyl)C3-6cycloalkyl, –O(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –O(C1-4alkyl)C6-10aryl, –O(C1- 4alkyl)(6- to 10-membered heteroaryl), –O(C1-4alkyl)C(O)OR18, –O(C1- 4alkyl)C(O)NR19SO2R15, –O(C1-4alkyl)SO2 NR19C(O)R18, –O(C3-6cycloalkyl)C3- 6cycloalkyl, –O(C3-6cycloalkyl)(3- to 10-membered heterocycloalkyl), –O(C3- 6cycloalkyl)C6-10aryl, –O(C3-6cycloalkyl)(6- to 10-membered heteroaryl), –O(C3- 6cycloalkyl)C(O)OR18, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1- 4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, – NR19SO2R15, and –NR19SO2NR16R17; R5 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and – NR20R21; R6 and R7 are each independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl, –(C1-4alkyl)C3-6cycloalkyl, – (C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1- 4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, – CN, and –NR20R21; or R6 and R7, along with the nitrogen atom to which they are attached, are taken together to form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, – NR19C(O)NR16R17, –NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C1-6heteroalkyl, and C1-6haloalkyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; each R10 is independently selected from the group consisting of halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, – NR19C(O)OR15, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10- membered heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; each R15 is independently selected from the group consisting of C1-4alkyl, C1- 4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10- membered heteroaryl; each R16 and R17 is independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4heteroalkyl, C1-4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl; or R16 and an R17 may be taken together along with the nitrogen atom to which they are attached to form a 3- to 10- membered heterocycloalkyl; each R18 is independently selected from the group consisting of hydrogen, C1- 4alkyl, C1-4heteroalkyl, C1-4haloalkyl, and C3-6cycloalkyl; each R19 is independently selected from the group consisting of hydrogen, C1- 4alkyl, C1-4heteroalkyl, C1-4haloalkyl, and C3-6cycloalkyl; each R20 and R21 is independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4heteroalkyl, C1-4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl; or R20 and R21 may be taken together along with the nitrogen atom to which they are attached to form a 3- to 10- membered heterocycloalkyl; and n is 0, 1, 2, 3, or 4. [0004] In certain embodiments, Ring A is C3-6cycloalkyl or 3- to 10-membered heterocycloalkyl. [0005] In certain embodiments, Ring A is C3-6cycloalkyl. [0006] In certain embodiments, Ring A is selected from the group consisting of:
Figure imgf000006_0001
[0007] In certain embodiments, Ring A is selected from the group consisting of:
Figure imgf000007_0001
[0008] In certain embodiments, Ring A is selected from the group consisting of:
Figure imgf000007_0002
[0009] In certain embodiments, Ring A is selected from the group consisting of:
Figure imgf000008_0001
[0010] In certain embodiments, Ring A is selected from the group consisting of:
Figure imgf000008_0002
. [0011] In certain embodiments, Ring A is selected from the group consisting of:
Figure imgf000008_0003
[0012] In certain embodiments, Ring A is selected from the group consisting of:
Figure imgf000008_0004
[0013] In certain embodiments, Ring A is
Figure imgf000008_0005
[0014] In certain embodiments, Ring A is
Figure imgf000008_0006
[0015] In certain embodiments, Ring A is
Figure imgf000008_0007
. [0016] In certain embodiments, Ring A is
Figure imgf000009_0001
. [0017] In certain embodiments, R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, – SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, C1-6alkyl, and C1- 6haloalkyl. [0018] In certain embodiments, R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, – SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, and –NR19C(O)OR15. [0019] In certain embodiments, R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –OR18, and –NR16R17. [0020] In certain embodiments, R8, R9, R11, R12, R13, and R14 are each independently hydrogen or halo. [0021] In certain embodiments, R11 is halo, and R8, R9, R12, R13, and R14 are each hydrogen. [0022] In certain embodiments, R11 is chloro, and R8, R9, R12, R13, and R14 are each hydrogen. [0023] In certain embodiments, R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. [0024] In certain embodiments, R1 is Me. [0025] In certain embodiments, R1 is hydrogen. [0026] In certain embodiments, R2 and R3 are each independently selected the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, – C(O)R18, –C(O)OR18, –NR19C(O)R18, –NR19C(O)NR16R17, –NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. [0027] In certain embodiments, R2 and R3 are each independently selected the group consisting of hydrogen, –CN, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, Me, Et, n-Pr, i-Pr, –CF3, and cyclopropyl. [0028] In certain embodiments, R2 and R3 are each independently selected the group consisting of hydrogen, Me, Et, n-Pr, and i-Pr. [0029] In certain embodiments, R2 and R3 are the same. [0030] In certain embodiments, R2 and R3 are each hydrogen. [0031] In certain embodiments, R4 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and C3-6cycloalkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, – C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1- 4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and – NR19SO2NR16R17. [0032] In certain embodiments, R4 is C1-6alkyl or C1-6alkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17,–C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. [0033] In certain embodiments, R4’ and R4’’ are both hydrogen. [0034] In certain embodiments, R4 is C1-6alkyl or C1-6alkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17,–C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17; and R4’ and R4’’ are each hydrogen. [0035] In certain embodiments, R5 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. [0036] In certain embodiments, R5 is Me. [0037] In certain embodiments, R5 is hydrogen. [0038] In certain embodiments, R6 and R7 are each independently selected from the group consisting of hydrogen, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; or R6 and R7, along with the nitrogen atom to which they are attached, are taken together to form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21. [0039] In certain embodiments, R6 and R7 are each independently hydrogen or –(C1-4alkyl)(3- to 10-membered heterocycloalkyl); wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more substituents selected from halo, –OR18, –CN, and – NR20R21. [0040] In certain embodiments, one of R6 and R7 is H and the other
Figure imgf000010_0001
. [0041] In certain embodiments, n is 0, 1, or 2. [0042] In certain embodiments, n is 0. [0043] In certain embodiments, the compound is a compound of Formula (II):
Figure imgf000011_0001
Formula (II). [0044] In certain embodiments, the compound is a compound of Formula (III):
Figure imgf000011_0002
Formula (III). [0045] In certain embodiments, the compound is a compound of Formula (IV):
Figure imgf000011_0003
Formula (IV). [0046] In certain embodiments, the compound is a compound of Formula (V):
Figure imgf000011_0004
Formula (V). [0047] In certain embodiments, the compound is a compound of Formula (VI):
Figure imgf000012_0001
Formula (VI). [0048] In certain embodiments, the compound is a compound of Formula (VII-A) or Formula (VII-B): or
Figure imgf000012_0003
Figure imgf000012_0002
Formula (VII-A) Formula (VII-B). [0049] In certain embodiments, the compound is a compound of Formula (VIII-A) or Formula (VIII-B): or
Figure imgf000012_0005
Figure imgf000012_0004
Formula (VIII-A) Formula (VIII-B). [0050] In certain embodiments, the compound is a compound of Formula (IX-A) or Formula (IX-B):
Figure imgf000012_0006
or
Figure imgf000012_0007
Formula (IX-A) Formula (IX-B). [0051] In certain embodiments, the compound is a compound of Formula (X):
Figure imgf000013_0001
Formula (X), wherein: R22, R23, R24, and R25 are each independently selected from the group consisting of hydrogen, halo, –R18, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1- 4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, – NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17; and R26 is selected from the group consisting of halo, –R18, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. [0052] In certain embodiments, R22, R23, R24, and R25 are each independently selected from the group consisting of hydrogen, halo, –R18, and –OR18. [0053] In certain embodiments, R22, R23, R24, and R25 are each independently hydrogen or halo. [0054] In certain embodiments, R22, R23, R24, and R25 are each hydrogen. [0055] In certain embodiments, R26 is selected from the group consisting of –NR16R17, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. [0056] In certain embodiments, R26 is selected from the group consisting of ––NH2, – NHC(O)OtBu, –NHSO2CH3, –NHSO2CF3,
Figure imgf000013_0002
NH(CO)CH3–,
Figure imgf000013_0003
, , , and –NHC(O)OCH2CF3. [0057] In certain embodiments, the compound is a compound of Formula (XI):
Figure imgf000013_0004
Formula (XI). [0058] In certain embodiments, the compound is selected from the group consisting of:
Figure imgf000014_0001
Figure imgf000015_0001
[0059] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, for example, a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein, and a pharmaceutically acceptable excipient. [0060] In a further aspect, provided herein are methods of treating a disease or disorder (e.g., proliferative disease) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt described herein, or the pharmaceutical composition thereof described here. Thus, a compound disclosed herein is for use in a method of treating a disease or disorder (e.g., a proliferative disease). Such a compound is, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein. [0061] In certain embodiments, the disease or disorder is a proliferative disease. [0062] In certain embodiments, the proliferative disease is cancer. [0063] In certain embodiments, the cancer is selected from leukemia, breast cancer, prostate cancer, ovarian cancer, colon cancer, cervical cancer, lung cancer, lymphoma, and liver cancer. [0064] In certain embodiments, the cancer is liver cancer. BRIEF DESCRIPTION OF THE DRAWINGS [0065] FIG.1 shows ratio of compound concentrations in liver versus blood in CD-1 mice following a single oral administration dose of 5 mg/kg compound suspension. Samples were collected at 2 hours (n = 3 for each compound). Collected liver and blood samples were analyzed using a LC-MS/MS method to quantify compound concentrations. [0066] FIG.2 shows mean weight changes (relative to day 1) of BALB/c nude mice treated with vehicle and compounds. Error bars represent ± SD. BID: oral administration twice (two times) a day. QD: oral administration once a day. Mice treated with 10 mg/kg NVP-2 QD lost significant body mass (body weight loss > 20%) on day 7. INCORPORATION BY REFERENCE [0067] 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. DETAILED DESCRIPTION OF THE INVENTION Definitions [0068] 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. [0069] As used herein, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. [0070] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term –Cx-yalkylene– refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example –C1-6alkylene– may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. [0071] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl), such as one to eight carbon atoms (C1-8 alkyl) or one to six carbon atoms (C1-6 alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein. [0072] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. [0073] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including straight- chain or branched-chain alkenyl groups containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein. [0074] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including straight- chain or branched-chain alkynyl groups containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein. [0075] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups which respectively have one or more skeletal chain atoms selected from an atom other than carbon. Exemplary skeletal chain atoms selected from an atom other than carbon include, e.g., O, N, P, Si, S, or combinations thereof, wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein. [0076] “Aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. [0077] “Heteroaryl” refers to a 3- to 12-membered aromatic ring that comprises at least one heteroatom wherein each heteroatom may be independently selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a- octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5- c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted by one or more substituents such as those substituents described herein. [0078] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4- dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. [0079] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic 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) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, 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. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 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). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted. [0080] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, a heterocycloalkyl, an aromatic and heteroaromatic moiety. [0081] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants. [0082] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. [0083] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution. [0084] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. [0085] The 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 certain 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. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art. [0086] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined. [0087] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well. [0088] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used. [0089] When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration. In addition, such certain small molecules include Z- and E- forms (or cis- and trans- forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds. Where certain small molecules described herein exist in various tautomeric forms, the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule. [0090] 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. [0091] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. [0092] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. [0093] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. [0094] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. [0095] The term “co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present. [0096] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein or enzyme. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor. Compounds [0097] In one aspect, provided herein are compounds of Formula (I):
Figure imgf000025_0001
Formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is optionally substituted C3-6cycloalkyl, optionally substituted 3- to 10- membered heterocycloalkyl, optionally substituted C6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl; R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and – NR20R21; R2 and R3 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, – C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, – NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10- membered heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, – CN, and –NR20R21; R4 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –O(C1- 4alkyl)C3-6cycloalkyl, –O(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –O(C1- 4alkyl)C6-10aryl, –O(C1-4alkyl)(6- to 10-membered heteroaryl), –O(C1-4alkyl)C(O)OR18, – O(C1-4alkyl)C(O)NR19SO2R15, –O(C1-4alkyl)SO2 NR19C(O)R18, –O(C3-6cycloalkyl)C3- 6cycloalkyl, –O(C3-6cycloalkyl)(3- to 10-membered heterocycloalkyl), –O(C3- 6cycloalkyl)C6-10aryl, –O(C3-6cycloalkyl)(6- to 10-membered heteroaryl), –O(C3- 6cycloalkyl)C(O)OR18, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, –(C1-4alkyl)(6- to 10-membered heteroaryl), and –(C1-4alkyl)C(O)OR18; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, – C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and – NR19SO2NR16R17; and R4’ and R4’’ are each independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C3- 6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –O(C1-4alkyl)C3-6cycloalkyl, –O(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –O(C1-4alkyl)C6-10aryl, –O(C1- 4alkyl)(6- to 10-membered heteroaryl), –O(C1-4alkyl)C(O)OR18, –O(C1- 4alkyl)C(O)NR19SO2R15, –O(C1-4alkyl)SO2 NR19C(O)R18, –O(C3-6cycloalkyl)C3- 6cycloalkyl, –O(C3-6cycloalkyl)(3- to 10-membered heterocycloalkyl), –O(C3- 6cycloalkyl)C6-10aryl, –O(C3-6cycloalkyl)(6- to 10-membered heteroaryl), –O(C3- 6cycloalkyl)C(O)OR18, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1- 4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, – NR19SO2R15, and –NR19SO2NR16R17; R5 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and – NR20R21; R6 and R7 are each independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl, –(C1-4alkyl)C3-6cycloalkyl, – (C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1- 4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, – CN, and –NR20R21; or R6 and R7, along with the nitrogen atom to which they are attached, are taken together to form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, – NR19C(O)NR16R17, –NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C1-6heteroalkyl, and C1-6haloalkyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; each R10 is independently selected from the group consisting of halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, – NR19C(O)OR15, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10- membered heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; each R15 is independently selected from the group consisting of C1-4alkyl, C1- 4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10- membered heteroaryl; each R16 and R17 is independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4heteroalkyl, C1-4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl; or R16 and an R17 may be taken together along with the nitrogen atom to which they are attached to form a 3- to 10- membered heterocycloalkyl; each R18 is independently selected from the group consisting of hydrogen, C1- 4alkyl, C1-4heteroalkyl, C1-4haloalkyl, and C3-6cycloalkyl; each R19 is independently selected from the group consisting of hydrogen, C1- 4alkyl, C1-4heteroalkyl, C1-4haloalkyl, and C3-6cycloalkyl; each R20 and R21 is independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4heteroalkyl, C1-4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl; or R20 and R21 may be taken together along with the nitrogen atom to which they are attached to form a 3- to 10- membered heterocycloalkyl; and n is 0, 1, 2, 3, or 4. [0098] In some embodiments, Ring A is optionally substituted C3-6cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl. In some embodiments, Ring A is optionally substituted C3-6cycloalkyl, optionally substituted C6-10 aryl, or optionally substituted 6- to 10- membered heteroaryl. In some embodiments, Ring A is optionally substituted C3-6cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted 6- to 10- membered heteroaryl. In some embodiments, Ring A is optionally substituted C3-6cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C6-10 aryl. In some embodiments, Ring A is optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl. In some embodiments, Ring A is optionally substituted C3-6cycloalkyl or optionally substituted 3- to 10- membered heterocycloalkyl. In some embodiments, Ring A is optionally substituted C3- 6cycloalkyl or optionally substituted C6-10 aryl. In some embodiments, Ring A is optionally substituted C3-6cycloalkyl or optionally substituted 6- to 10-membered heteroaryl. In one embodiment, Ring A is optionally substituted C3-6cycloalkyl. In another embodiment, Ring A is optionally substituted 3- to 10-membered heterocycloalkyl. In yet another embodiment, Ring A is optionally substituted C6-10 aryl. In yet another embodiment, Ring A is optionally substituted 6- to 10-membered heteroaryl. [0099] In some embodiments, Ring A is selected from the group consisting of:
Figure imgf000028_0001
[0100] In some embodiments, Ring A is selected from the group consisting of: In
Figure imgf000029_0001
some embodiments, Ring A is
Figure imgf000029_0002
. In some embodiments, Ring A is
Figure imgf000029_0003
. In some embodiments, Ring A is
Figure imgf000029_0004
. In some embodiments, Ring A is
Figure imgf000029_0007
. In some embodiments, Ring A is
Figure imgf000029_0005
. In some embodiments, Ring A is
Figure imgf000029_0008
. In some embodiments, Ring A is
Figure imgf000029_0006
. In some embodiments, Ring A is
Figure imgf000029_0009
. [0101] In some embodiments, Ring A is selected from the group consisting of optionally substituted optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl. [0102] In some embodiments, Ring A is selected from the group consisting of 1,2-cyclopropyl, 1,2-cyclobutyl, 1,3-cyclobutyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, and 1,4-cyclohexyl. [0103] In some embodiments, Ring A is selected from the group consisting of trans-1,2- cyclopropyl, cis-1,2-cyclopropyl, trans-1,2-cyclobutyl, cis-1,2-cyclobutyl, trans-1,3-cyclobutyl, cis-1,3-cyclobutyl, trans-1,2-cyclopentyl, cis-1,2-cyclopentyl, trans-1,3-cyclopentyl, cis-1,3- cyclopentyl, trans-1,2-cyclohexyl, cis-1,2-cyclohexyl, trans-1,3-cyclohexyl, cis-1,3-cyclohexyl, trans-1,4-cyclohexyl, and cis-1,4-cyclohexyl. In some embodiments, Ring A is selected from the group consisting of trans-1,2-cyclopentyl, cis-1,2-cyclopentyl, trans-1,3-cyclopentyl, cis-1,3- cyclopentyl, trans-1,2-cyclohexyl, cis-1,2-cyclohexyl, trans-1,3-cyclohexyl, cis-1,3-cyclohexyl, trans-1,4-cyclohexyl, and cis-1,4-cyclohexyl. In some embodiments, Ring A is selected from the group consisting of trans-1,2-cyclohexyl, cis-1,2-cyclohexyl, trans-1,3-cyclohexyl, cis-1,3- cyclohexyl, trans-1,4-cyclohexyl, and cis-1,4-cyclohexyl. In some embodiments, Ring A is selected from the group consisting of trans-1,3-cyclohexyl, cis-1,3-cyclohexyl, trans-1,4- cyclohexyl, and cis-1,4-cyclohexyl. In some embodiments, Ring A is trans-1,4-cyclohexyl or cis-1,4-cyclohexyl. In one preferred embodiment, Ring A is trans-1,4-cyclohexyl. [0104] In some embodiments, Ring A is
Figure imgf000030_0001
. In some embodiments, Ring A is
Figure imgf000030_0002
. In some embodiments, Ring A is
Figure imgf000030_0003
. In some embodiments, Ring A is
Figure imgf000030_0004
. In some embodiments, Ring A is
Figure imgf000030_0005
. In some embodiments, Ring A is
Figure imgf000030_0007
. In some embodiments, Ring A is
Figure imgf000030_0006
. In some embodiments, Ring A is
Figure imgf000030_0008
. [0105] In some embodiments, Ring A is selected from the group consisting of:
Figure imgf000030_0009
Figure imgf000031_0001
[0106] In some embodiments, Ring A is selected from the group consisting of:
Figure imgf000031_0002
. [0107] In some embodiments, Ring A is selected from the group consisting of:
Figure imgf000031_0003
, [0108] In some embodiments, Ring A is selected from the group consisting of:
Figure imgf000031_0004
. [0109] In some embodiments, Ring A is selected from the group consisting of:
Figure imgf000031_0005
[0110] In some embodiments, Ring A is selected from the group consisting of:
Figure imgf000032_0001
[0111] In some embodiments, Ring A is selected from the group consisting of: . In one embodiment, Ring A is
Figure imgf000032_0003
. In
Figure imgf000032_0002
another embodiment, Ring A is
Figure imgf000032_0004
. In some embodiments, Ring A is selected from the group consisting of:
Figure imgf000032_0005
. In one embodiment, Ring A is
Figure imgf000032_0006
. In another embodiment, Ring A is
Figure imgf000032_0007
. [0112] In some embodiments, Ring A is
Figure imgf000032_0008
. In some embodiments, Ring A is
Figure imgf000032_0009
. In some embodiments, Ring A is
Figure imgf000032_0014
. In some embodiments, Ring A is
Figure imgf000032_0010
. In some embodiments, Ring A is
Figure imgf000032_0015
. In some embodiments, Ring A is
Figure imgf000032_0011
. In some embodiments, Ring A is
Figure imgf000032_0016
. In some embodiments, Ring A is
Figure imgf000032_0012
. In some embodiments, Ring A is
Figure imgf000032_0017
. In some embodiments, Ring A is
Figure imgf000032_0013
. In some embodiments, Ring A is
Figure imgf000032_0018
. In some embodiments, Ring A is
Figure imgf000033_0001
. In some embodiments, Ring A is
Figure imgf000033_0002
. In some embodiments, Ring A is
Figure imgf000033_0003
. In some embodiments, Ring A is
Figure imgf000033_0004
. In some embodiments, Ring A is
Figure imgf000033_0005
. In some embodiments, Ring A is
Figure imgf000033_0006
. In some embodiments, Ring A is
Figure imgf000033_0007
. In some embodiments, Ring A is
Figure imgf000033_0008
. In some embodiments, Ring A is
Figure imgf000033_0009
. In some embodiments, Ring A is
Figure imgf000033_0013
. In some embodiments, Ring A is
Figure imgf000033_0010
. In some embodiments, Ring A is
Figure imgf000033_0014
. In some embodiments, Ring A is
Figure imgf000033_0011
. In some embodiments, Ring A is
Figure imgf000033_0015
. In some embodiments, Ring A is
Figure imgf000033_0012
. In some embodiments, Ring A is
Figure imgf000033_0016
. In some embodiments, Ring A is . In some embodiments,
Figure imgf000033_0018
Figure imgf000033_0017
Ring A is . In some embodiments, Ring A is
Figure imgf000034_0001
. In some embodiments, Ring A is
Figure imgf000034_0002
. In some embodiments, Ring A is
Figure imgf000034_0003
. [0113] In some embodiments, R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, – C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, – NR19C(O)NR16R17, –NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1- 6heteroalkyl, and C1-6haloalkyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21. In some embodiments, R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, – CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, and –NR19C(O)OR15. In some embodiments, R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, and –NR16R17. In some embodiments, R8, R9, R11, R12, R13, and R14 are each independently hydrogen or halo. In some embodiments, one of R8, R9, R11, R12, R13, and R14 is halo and the others are hydrogen. In one embodiment, R8, R9, R12, R13, and R14 are each hydrogen, and R11 is halo. In another embodiment, R8, R9, R12, R13, and R14 are each hydrogen, and R11 is chloro or fluoro. In one preferred embodiment, R8, R9, R12, R13, and R14 are each hydrogen, and R11 is chloro. [0114] In some embodiments, R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R1 is C1-6alkyl. In some embodiments, R1 is C1-6haloalkyl. In some embodiments, R1 is C3-6cycloalkyl. In some embodiments, R1 is selected from hydrogen, Me, Et, n-Pr, i-Pr, –CF3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R1 is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R1 is selected from hydrogen, Me, Et, n-Pr, and i-Pr. In some embodiments, R1 is selected from Me, Et, n-Pr, and i-Pr. In one preferred embodiment, R1 is hydrogen. In another embodiment, R1 is Me. [0115] In some embodiments, R2 and R3 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, – SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, – NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10- membered heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21. [0116] R2 and R3 are each independently selected the group consisting of hydrogen, halo, –CN, – OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, –NR19SO2NR16R17, C1- 6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R2 and R3 are each independently selected the group consisting of hydrogen, halo, –CN, –OH, –OMe, –OEt, –NH2, – NHMe, –NMe2, Me, Et, n-Pr, i-Pr, –CF3, and cyclopropyl. In some embodiments, R2 and R3 are each independently selected the group consisting of hydrogen, Me, Et, n-Pr, and i-Pr. In some embodiments, R2 and R3 are the same. In some embodiments, R2 and R3 are each independently hydrogen or Me. In some embodiments, R2 and R3 are each hydrogen. [0117] In some embodiments, R4 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –O(C1-4alkyl)C3-6cycloalkyl, –O(C1-4alkyl)(3- to 10-membered heterocycloalkyl), – O(C1-4alkyl)C6-10aryl, –O(C1-4alkyl)(6- to 10-membered heteroaryl), –O(C1-4alkyl)C(O)OR18, – O(C1-4alkyl)C(O)NR19SO2R15, –O(C1-4alkyl)SO2 NR19C(O)R18, –O(C3-6cycloalkyl)C3- 6cycloalkyl, –O(C3-6cycloalkyl)(3- to 10-membered heterocycloalkyl), –O(C3-6cycloalkyl)C6- 10aryl, –O(C3-6cycloalkyl)(6- to 10-membered heteroaryl), –O(C3-6cycloalkyl)C(O)OR18, –(C1- 4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, – (C1-4alkyl)(6- to 10-membered heteroaryl), and –(C1-4alkyl)C(O)OR18; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. [0118] In some embodiments, R4 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and C3-6cycloalkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, – C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1- 4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and – NR19SO2NR16R17. [0119] In some embodiments, R4 is C1-6alkyl or C1-6alkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17,–C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. [0120] In some embodiments, R4’ and R4’’ are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C3-6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –O(C1-4alkyl)C3-6cycloalkyl, –O(C1- 4alkyl)(3- to 10-membered heterocycloalkyl), –O(C1-4alkyl)C6-10aryl, –O(C1-4alkyl)(6- to 10- membered heteroaryl), –O(C1-4alkyl)C(O)OR18, –O(C1-4alkyl)C(O)NR19SO2R15, –O(C1- 4alkyl)SO2 NR19C(O)R18, –O(C3-6cycloalkyl)C3-6cycloalkyl, –O(C3-6cycloalkyl)(3- to 10- membered heterocycloalkyl), –O(C3-6cycloalkyl)C6-10aryl, –O(C3-6cycloalkyl)(6- to 10- membered heteroaryl), –O(C3-6cycloalkyl)C(O)OR18, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, – OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1- 4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, – NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. [0121] In some embodiments, R4’ and R4’’ are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C3-6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –(C1-4alkyl)C3-6cycloalkyl, –(C1- 4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10- membered heteroaryl). In some embodiments, R4’ and R4’’ are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, – (C1-4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10-membered heteroaryl). In some embodiments, R4’ and R4’’ are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4’ and R4’’ are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R4’ and R4’’ are each independently hydrogen or halo. In some embodiments, R4’ and R4’’ are the same. In one preferred embodiment, R4’ and R4’’ are each hydrogen. [0122] In some embodiments, R4 is C1-6alkyl or C1-6alkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17,–C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17; and R4’ and R4’’ are each hydrogen. In some embodiments, R4 is C1-6alkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17,–C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17; and R4’ and R4’’ are each hydrogen. [0123] In some embodiments, R5 is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, and C3- 6cycloalkyl. In some embodiments, R5 is C1-6haloalkyl. In some embodiments, R5 is C3- 6cycloalkyl. In some embodiments, R5 is C1-6alkyl. In some embodiments, R5 is hydrogen, Me, Et, n-Pr, or i-Pr. In some embodiments, R5 is Me, Et, n-Pr, or i-Pr. In one preferred embodiment, R5 is hydrogen. In another embodiment, R5 is Me. [0124] In some embodiments, R6 and R7 are each independently selected from the group consisting of hydrogen, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; or R6 and R7, along with the nitrogen atom to which they are attached, are taken together to form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and – NR20R21. [0125] In some embodiments, R6 and R7 are each independently hydrogen, C1-4alkyl, or
Figure imgf000037_0001
; each alkyl is independently optionally substituted with one or more substituents selected from halo, –OR18, –CN, and –NR20R21; wherein R31 and R32 are each independently selected from the group consisting of hydrogen, halo, C1-4alkyl, C1-4heteroalkyl, C1-4haloalkyl, and C3-6cycloalkyl; each R30 is independently selected from the group consisting of halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents selected from oxo, halo, – OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; m is 0, 1, 2, 3, or 4. [0126] In some embodiments, each R30 is independently selected from the group consisting of halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, – NR19C(O)R15, and –NR19C(O)OR15. In some embodiments, each R30 is independently selected from the group consisting of halo, –CN, –OR18, and –NR16R17. In some embodiments, each R30 is independently halo or –CN. In one embodiment, R30 is halo or –CN and m is 1. In another embodiment, R30 is–CN and m is 1. [0127] In some embodiments, R31 and R32 are each independently selected from the group consisting of hydrogen, halo, C1-4alkyl, and C1-4haloalkyl. In some embodiments, R31 and R32 are each independently hydrogen or halo. In some embodiments, R31 and R32 are each hydrogen. [0128] In some embodiments, Ring B is optionally substituted C3-6cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl. In some embodiments, Ring B is optionally substituted C3-6cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, Ring B is optionally substituted C3-6cycloalkyl. In some embodiments, Ring B is optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, Ring B is optionally substituted 6-membered heterocycloalkyl. In one embodiment, Ring B is optionally substituted tetrahydropyranyl. In one embodiment, Ring B is optionally substituted tetrahydro- 2H-pyranyl. In a specific embodiment, Ring B is optionally substituted tetrahydro-2H-pyran-4- yl. In another specific embodiment, Ring B is 4-cyanotetrahydro-2H-pyran-4-yl. [0129] In some embodiments, R6 and R7 are each independently hydrogen or –(C1-4alkyl)(3- to 10-membered heterocycloalkyl); wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more substituents selected from halo, –OR18, –CN, and – NR20R21. [0130] In some embodiments, R6 and R7 are each independently hydrogen or –(C1-4alkyl)(3- to 10-membered heterocycloalkyl); wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more substituents selected from halo, –OR18, –CN, and – NR20R21. [0131] In some embodiments, one of R6 and R7 is hydrogen and the other is
Figure imgf000039_0001
. In some embodiments, R6 is hydrogen and R7 is
Figure imgf000039_0002
. In some embodiments, R7 is hydrogen and R6 is
Figure imgf000039_0003
. [0132] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. 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. [0133] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [0134] In some embodiments, the compound of Formula (I) is a compound of Formula (II):
Figure imgf000039_0004
Formula (II); wherein Ring A, R1, R4, R4’, R4’’, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are as defined herein above. [0135] In some embodiments, the compound of Formula (I) is a compound of Formula (II’):
Figure imgf000039_0005
Formula (II’). [0136] In some embodiments, the compound of Formula (I) is a compound of Formula (II’’):
Figure imgf000040_0001
Formula (II’’). [0137] In some embodiments, the compound of Formula (I) is a compound of Formula (III):
Figure imgf000040_0002
Formula (III); wherein Ring A, R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are as defined herein above. [0138] In some embodiments, the compound of Formula (I) is a compound of Formula (III’):
Figure imgf000040_0003
Formula (III’). [0139] In some embodiments, the compound of Formula (I) is a compound of Formula (III’’):
Figure imgf000040_0004
Formula (III’’). [0140] In some embodiments, the compound of Formula (I) is a compound of Formula (IV):
Figure imgf000041_0001
Formula (IV); wherein Ring A, R1, R2, R3, R4, R4’, R4’’, R5, R8, R9, R10, R11, R12, R13, and R14 are as defined herein above. [0141] In some embodiments, the compound of Formula (I) is a compound of Formula (IV’):
Figure imgf000041_0002
Formula (IV’). [0142] In some embodiments, the compound of Formula (I) is a compound of Formula (V):
Figure imgf000041_0003
Formula (V); wherein Ring A, R1, R4, R4’, R4’’, R5, R8, R9, R10, R11, R12, R13, and R14 are as defined herein above. [0143] some embodiments, the compound of Formula (I) is a compound of Formula (V’):
Figure imgf000041_0004
Formula (V’). [0144] In some embodiments, the compound of Formula (I) is a compound of Formula (VI):
Figure imgf000042_0001
Formula (VI); wherein Ring A, R1, R4, R5, R8, R9, R10, R11, R12, R13, and R14 are as defined herein above. [0145] In some embodiments, the compound of Formula (I) is a compound of Formula (VI’):
Figure imgf000042_0002
Formula (VI’). [0146] In some embodiments, the compound of Formula (I) is a compound of Formula (VII-A) or Formula (VII-B):
Figure imgf000042_0003
or
Figure imgf000042_0004
Formula (VII-A) Formula (VII-B); wherein R1, R4, R5, R8, R9, R10, R11, R12, R13, and R14 are as defined herein above. [0147] In some embodiments, the compound of Formula (I) is a compound of Formula (VII-A’) or Formula (VII-B’):
Figure imgf000043_0001
or
Figure imgf000043_0002
Formula (VII-A’) Formula (VII-B’); wherein R4, R10, and R11 are as defined herein above. [0148] In some embodiments, the compound of Formula (I) is a compound of Formula (VIII-A) or Formula (VIII-B):
Figure imgf000043_0003
or
Figure imgf000043_0004
Formula (VIII-A) Formula (VIII-B); wherein R4, R5, and R11 are as defined herein above. [0149] In some embodiments, the compound of Formula (I) is a compound of Formula (IX-A) or Formula (IX-B):
Figure imgf000043_0005
or
Figure imgf000043_0006
Formula (IX-A) Formula (IX-B); wherein R4 is as defined herein above. [0150] In some embodiments, the compound of Formula (I) is a compound of Formula (X):
Figure imgf000043_0007
Formula (X), wherein: R22, R23, R24, and R25 are each independently selected from the group consisting of hydrogen, halo, –R18, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1- 4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, – NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17; and R26 is selected from the group consisting of halo, –R18, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. [0151] In certain embodiments, R22, R23, R24, and R25 are each independently selected from the group consisting of hydrogen, halo, –R18, and –OR18. In certain embodiments, R22, R23, R24, and R25 are each independently hydrogen or halo. R22, R23, R24, and R25 are each hydrogen. [0152] In certain embodiments, R26 is selected from the group consisting of –NR16R17, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. In certain embodiments, R26 is selected from the group consisting of –NH2, –NHC(O)OtBu, – NHSO2CH3, –NHSO2CF3,
Figure imgf000044_0001
, –NH(CO)CH3–,
Figure imgf000044_0002
, and –NHC(O)OCH2CF3. [0153] In some embodiments, the compound of Formula (I) is a compound of Formula (XI):
Figure imgf000044_0003
Formula (XI); wherein , R26 is as defined herein above. [0154] In some embodiments, the compound is selected from the group consisting of:
Figure imgf000044_0004
.
Figure imgf000045_0001
[0155] In one embodiment, the compound i
Figure imgf000046_0006
s . In another embodiment, the compound is
Figure imgf000046_0005
. In yet another embodiment, the compound is
Figure imgf000046_0004
. In yet another embodiment, the compound is
Figure imgf000046_0003
. In yet another embodiment, the compound is
Figure imgf000046_0002
. In yet another embodiment, the compound is. In yet another embodiment, the compound is
Figure imgf000046_0001
. In yet another embodiment, the compound is
Figure imgf000047_0001
. In yet another embodiment, the compound is
Figure imgf000047_0002
. In yet another embodiment, the compound is
Figure imgf000047_0003
. In yet another embodiment, the compound is
Figure imgf000047_0004
. In yet another embodiment, the compound is l
Figure imgf000047_0005
. In yet another embodiment, the compound is
Figure imgf000047_0006
. Methods of Use [0156] In one aspect, provided herein are methods for treating a disease or disorder (e.g., proliferative disorder) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound having Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the method for treating the proliferative disorder comprises administering to said subject a CDK9 inhibitor disclosed herein. In some embodiments, the CDK9 inhibitor is a compound having Formula (I) as disclosed herein. [0157] In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [0158] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is selected from leukemia, breast cancer, prostate cancer, ovarian cancer, colon cancer, cervical cancer, lung cancer, lymphoma, and liver cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is liver cancer. [0159] In some embodiments, the CDK9 inhibitors disclosed herein (e.g., compounds of Formula (I)) are highly targeted to the liver. In some embodiments, the CDK9 inhibitors disclosed herein (e.g., compounds of Formula (I)) have superior liver targeting as compared with known CDK9 inhibitors. In some embodiments, the CDK9 inhibitors disclosed herein (e.g., compounds of Formula (I)) accumulate in the liver while avoiding peripheral exposure to nearby tissues. In some embodiments, the CDK9 inhibitors disclosed herein have reduced peripheral exposure to nearby tissues as compared with known CDK9 inhibitors. In some embodiments, the CDK9 inhibitors disclosed herein (e.g., compounds of Formula (I)) have reduced toxicity as compared with known CDK9 inhibitors. [0160] In a further embodiment, the present invention provides a method of treating a cancer condition, wherein the CDK9 inhibitors disclosed herein (e.g., compounds of Formula (I)) are effective in one or more method of inhibiting proliferation of cancer cells, inhibiting metastasis of cancer cells, reducing severity or incidence of symptoms associated with the presence of cancer cells, and promoting an immune response to tumor cells. In some embodiments, said method comprises administering to the cancer cells a therapeutically effective amount of a compound having Formula (I). In some embodiments, the compound having Formula (I) is a CDK9 inhibitor. In some embodiments, the administration takes place in vitro. In other embodiments, the administration takes place in vivo. [0161] As used herein, a therapeutically effective amount of a CDK9 inhibitor (e.g., a compound of Formula (I)) refers to an amount sufficient to effect the intended application, including but not limited to, disease treatment, as defined herein. Also contemplated in the subject methods is the use of a sub-therapeutic amount of a CDK9 inhibitor for treating an intended disease condition. [0162] The amount of the CDK9 inhibitor (e.g., a compound of Formula (I)) administered may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. [0163] Measuring inhibition of biological effects of CDK9 can comprise performing an assay on a biological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to, blood samples (e.g. blood plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples. [0164] A subject being treated with a CDK9 inhibitor (e.g., a compound of Formula (I)) may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject’s physiological response to treatment. For example, if inhibition of a biological effect of CDK9 degradation is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively. The methods can further comprise continuing the therapy if the therapy is determined to be efficacious. The methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound in the therapy if the therapy is determined to be efficacious. The methods can comprise increasing the administered amount of a compound in the therapy if it is determined not to be efficacious. Alternatively, the methods can comprise stopping therapy if it is determined not to be efficacious. In some embodiments, treatment with a CDK9 inhibitor is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction. The biological effect may be a change in any of a variety of physiological indicators. [0165] In general, a CDK9 inhibitor is a compound that inhibits one or more biological effects of CDK9. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more. [0166] In some other embodiments, the subject methods are useful for treating a disease condition associated with CDK9. Any disease condition that results directly or indirectly from an abnormal activity or expression level of CDK9 can be an intended disease condition. In some embodiments, the disease condition is a proliferative disorder, such as described herein, including but not limited to cancer. In some embodiments, the disease condition is cancer. A role of CDK9 in tumorigenesis and tumor progression has been implicated in many human cancers. Consequently, agents that target CDK9 have therapeutic value. [0167] The data presented in the Examples herein below demonstrate the anti-cancer effects of a CDK9 inhibitor. As such, the subject method is particularly useful for treating a proliferative disorder, such as a neoplastic condition. [0168] In some embodiments, the methods of administering a CDK9 inhibitor (e.g., a compound of Formula (I)) described herein are applied to the treatment of cancers of the blood, breast, prostate, ovaries, colon, cervix, lungs, lymph nodes, liver, or any combination thereof. [0169] In some embodiments, a compound provided herein is administered as a pure chemical. In other embodiments, a compound provided herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Therapeutic Efficacy [0170] In some embodiments, the therapeutic efficacy is measured based on effects of treating a proliferative disorder, such as cancer. In general, therapeutic efficacy of the treatment methods provided herein, with regard to the treatment of a proliferative disorder (e.g. cancer, whether benign or malignant), may be measured by the degree to which the methods and compositions promote inhibition of tumor cell proliferation, the inhibition of tumor vascularization, the eradication of tumor cells, the reduction in the rate of growth of a tumor, and/or a reduction in the size of at least one tumor. Several parameters to be considered in the determination of therapeutic efficacy are discussed herein. The proper combination of parameters for a particular situation can be established by the clinician. The progress of the methods for treating cancer (e.g., reducing tumor size or eradicating cancerous cells) can be ascertained using any suitable method, such as those methods currently used in the clinic to track tumor size and cancer progress. The primary efficacy parameter used to evaluate the treatment of cancer using the CDK9 inhibitors provided herein (e.g., a compound of Formula (I)) preferably is a reduction in the size of a tumor. Tumor size can be figured using any suitable technique, such as measurement of dimensions, or estimation of tumor volume using available computer software, such as FreeFlight software developed at Wake Forest University that enables accurate estimation of tumor volume. Tumor size can be determined by tumor visualization using, for example, CT, ultrasound, SPECT, spiral CT, MRI, photographs, and the like. In embodiments where a tumor is surgically resected after completion of the therapeutic period, the presence of tumor tissue and tumor size can be determined by gross analysis of the tissue to be resected, and/or by pathological analysis of the resected tissue. [0171] In some embodiments, the growth of a tumor is stabilized (i.e., one or more tumors do not increase more than 1%, 5%, 10%, 15%, or 20% in size, and/or do not metastasize) as a result of the inventive method and compositions. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years. Preferably, the inventive method reduces the size of a tumor at least about 5% (e.g., at least about 10%, 15%, 20%, or 25%). More preferably, tumor size is reduced at least about 30% (e.g., at least about 35%, 40%, 45%, 50%, 55%, 60%, or 65%). Even more preferably, tumor size is reduced at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, or 95%). Most preferably, the tumor is completely eliminated, or reduced below a level of detection. In some embodiments, a subject remains tumor free (e.g. in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks following treatment. In some embodiments, a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months following treatment. In some embodiments, a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years after treatment. [0172] In some embodiments, the efficacy of the treatment methods provided herein in reducing tumor size can be determined by measuring the percentage of necrotic (i.e., dead) tissue of a surgically resected tumor following completion of the therapeutic period. In some further embodiments, a treatment is therapeutically effective if the necrosis percentage of the resected tissue is greater than about 20% (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), more preferably about 90% or greater (e.g., about 90%, 95%, or 100%). Most preferably, the necrosis percentage of the resected tissue is 100%, that is, no tumor tissue is present or detectable. [0173] The efficacy of the treatment methods provided herein can be determined by a number of secondary parameters. Examples of secondary parameters include, but are not limited to, detection of new tumors, detection of tumor antigens or markers (e.g., CEA, PSA, or CA-125), biopsy, surgical downstaging (i.e., conversion of the surgical stage of a tumor from unresectable to resectable), PET scans, survival, disease progression-free survival, time to disease progression, quality of life assessments such as the Clinical Benefit Response Assessment, and the like, all of which can point to the overall progression (or regression) of cancer in a human. Biopsy is particularly useful in detecting the eradication of cancerous cells within a tissue. Radioimmunodetection (RAID) is used to locate and stage tumors using serum levels of markers (antigens) produced by and/or associated with tumors (“tumor markers” or “tumor-associated antigens”), and can be useful as a pre-treatment diagnostic predicate, a post-treatment diagnostic indicator of recurrence, and a post-treatment indicator of therapeutic efficacy. Examples of tumor markers or tumor-associated antigens that can be evaluated as indicators of therapeutic efficacy include, but are not limited to, carcinembryonic antigen (CEA), prostate-specific antigen (PSA), CA-125, CA19-9, ganglioside molecules (e.g., GM2, GD2, and GD3), MART-1, heat shock proteins (e.g., gp96), sialyl Tn (STn), tyrosinase, MUC-1, HER-2/neu, c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, and gp100. Other tumor-associated antigens are known in the art. RAID technology in combination with endoscopic detection systems also can efficiently distinguish small tumors from surrounding tissue (see, for example, U.S. Pat. No.4,932,412). [0174] In additional desirable embodiments, the treatment of cancer in a human patient in accordance with the treatment methods provided herein is evidenced by one or more of the following results: (a) the complete disappearance of a tumor (i.e., a complete response), (b) about a 25% to about a 50% reduction in the size of a tumor for at least four weeks after completion of the therapeutic period as compared to the size of the tumor before treatment, (c) at least about a 50% reduction in the size of a tumor for at least four weeks after completion of the therapeutic period as compared to the size of the tumor before the therapeutic period, and (d) at least a 2% decrease (e.g., about a 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% decrease) in a specific tumor-associated antigen level at about 4-12 weeks after completion of the therapeutic period as compared to the tumor-associated antigen level before the therapeutic period. While at least a 2% decrease in a tumor-associated antigen level is preferred, any decrease in the tumor- associated antigen level is evidence of treatment of a cancer in a patient by the treatment methods provided herein. For example, with respect to unresectable, locally advanced pancreatic cancer, treatment can be evidenced by at least a 10% decrease in the CA19-9 tumor-associated antigen level at 4-12 weeks after completion of the therapeutic period as compared to the CA19-9 level before the therapeutic period. Similarly, with respect to locally advanced rectal cancer, treatment can be evidenced by at least a 10% decrease in the CEA tumor-associated antigen level at 4-12 weeks after completion of the therapeutic period as compared to the CEA level before the therapeutic period. [0175] With respect to quality of life assessments, such as the Clinical Benefit Response Criteria, the therapeutic benefit of the treatment in accordance with the invention can be evidenced in terms of pain intensity, analgesic consumption, and/or the Karnofsky Performance Scale score. The treatment of cancer in a human patient alternatively, or in addition, is evidenced by (a) at least a 50% decrease (e.g., at least a 60%, 70%, 80%, 90%, or 100% decrease) in pain intensity reported by a patient, such as for any consecutive four week period in the 12 weeks after completion of treatment, as compared to the pain intensity reported by the patient before treatment, (b) at least a 50% decrease (e.g., at least a 60%, 70%, 80%, 90%, or 100% decrease) in analgesic consumption reported by a patient, such as for any consecutive four week period in the 12 weeks after completion of treatment as compared to the analgesic consumption reported by the patient before treatment, and/or (c) at least a 20 point increase (e.g., at least a 30 point, 50 point, 70 point, or 90 point increase) in the Karnofsky Performance Scale score reported by a patient, such as for any consecutive four week period in the 12 weeks after completion of the therapeutic period as compared to the Karnofsky Performance Scale score reported by the patient before the therapeutic period. [0176] The treatment of a proliferative disorder (e.g. cancer, whether benign or malignant) in a human patient desirably is evidenced by one or more (in any combination) of the foregoing results, although alternative or additional results of the referenced tests and/or other tests can evidence treatment efficacy. [0177] In some embodiments, administration of a CDK9 inhibitor provides improved therapeutic efficacy. Improved efficacy may be measured using any method known in the art, including but not limited to those described herein. In some embodiments, the improved therapeutic efficacy is an improvement of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 1000% or more, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease-free survival). Improved efficacy may also be expressed as fold improvement, such as at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100- fold, 1000-fold, 10000-fold or more, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease- free survival). [0178] In another aspect, provided herein are uses of a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII- A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof as described herein, in the preparation of a medicament for treating a disease or disorder (e.g., a proliferative disease) in a subject in need thereof. [0179] In another aspect, a compound disclosed herein is for use in a method of treating a disease or disorder (e.g., a proliferative disease) in a subject in need thereof, such cancer. Such a compound is, for example, a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein. [0180] In another aspect, provided herein are pharmaceutical compositions comprising a compound Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder (e.g., a proliferative disease) in a subject in need thereof. Pharmaceutical compositions [0181] In another aspect, provided herein are pharmaceutical compositions comprising a compound of Formula (I), (II), (II’), (II’’), (III), (III’), (III’’), (IV), (IV’), (V), (V’), (VI), (VI’), (VII-A), (VII-B), (VII-A’), (VII-B’), (VIII-A), (VIII-B), (IX-A), (IX-B), (X), or (XI), as disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0182] A composition of the present disclosure may be formulated in any suitable pharmaceutical formulation. A pharmaceutical composition of the present disclosure typically contains an active ingredient (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants. A composition of the present disclosure may be formulated in any suitable pharmaceutical formulation. In some embodiments, the pharmaceutical acceptable carriers or excipients are selected from water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, and dimethyl sulfoxide (DMSO). [0183] Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and/or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In some embodiments, the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi- solid, or solid form. [0184] The amount of each compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage may be in the range of about 0.001 to about 100 mg per kg body weight per day, in single or divided doses. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day. In some embodiments, an effective dosage may be provided in pulsed dosing (i.e., administration of the compound in consecutive days, followed by consecutive days of rest from administration). [0185] In some embodiments, the composition is provided in one or more unit doses. For example, the composition can be administered in 1, 2, 3, 4, 5, 6, 7, 14, 30, 60, or more doses. Such amount can be administered each day, for example in individual doses administered once, twice, or three or more times a day. However, dosages stated herein on a per day basis should not be construed to require administration of the daily dose each and every day. For example, if one of the agents is provided in a suitably slow-release form, two or more daily dosage amounts can be administered at a lower frequency, e.g., as a depot injection or oral prodrug administered every second day to once a month or even longer. Most typically and conveniently for the subject, a CDK9 inhibitor can be administered once a day, for example in the morning, in the evening or during the day. [0186] The unit doses can be administered simultaneously or sequentially. The composition can be administered for an extended treatment period. Illustratively, the treatment period can be at least about one month, for example at least about 3 months, at least about 6 months or at least about 1 year. In some cases, administration can continue for substantially the remainder of the life of the subject. [0187] In some embodiments, the CDK9 inhibitor provided herein (e.g., a compound of Formula (I)) can be administered as part of a therapeutic regimen that comprises administering one or more second agents (e.g.1, 2, 3, 4, 5, or more second agents), either simultaneously or sequentially with the CDK9 inhibitor (e.g., a compound of Formula (I)). When administered sequentially, the CDK9 inhibitor (e.g., a compound of Formula (I)) may be administered before or after the one or more second agents. When administered simultaneously, the CDK9 inhibitor (e.g., a compound of Formula (I)) and the one or more second agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising a CDK9 inhibitor and one or more second agents). [0188] The combination treatment provided herein may be effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the agent selected, the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. Pharmaceutical composition for oral administration [0189] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing at least one compound of the present disclosure and a pharmaceutical excipient suitable for oral administration. The composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent. [0190] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) a CDK9 inhibitor (e.g., a compound of Formula (I)); and (ii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iii) a third agent or even a fourth agent. In some embodiments, each compound or agent is present in a therapeutically effective amount. In other embodiments, one or more compounds or agents is present in a sub-therapeutic amount, and the compounds or agents act synergistically to provide a therapeutically effective pharmaceutical composition. [0191] Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier. In general, the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0192] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the composition for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro- crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. [0193] Examples of suitable fillers for use in the pharmaceutical composition and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. [0194] Disintegrants may be used in the composition of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. A sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. [0195] Surfactant which can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed. [0196] In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for composition for non-oral use, e.g., composition for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion. [0197] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti- foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. [0198] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium. Suitable acids are pharmaceutically acceptable organic or inorganic acids. EXAMPLES I. Chemical Synthesis [0199] Solvents, reagents and starting materials were purchased from commercial vendors and used without further purification unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using literature procedures or the present disclosure. Abbreviations [0200] The following abbreviations are used in the Examples and other parts of the description: AcOH = acetic acid DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DCE = 1,2-dichloroethane, DCM = dichloromethane, DIPEA = N,N-diisopropylethylamine, DME = dimethoxyethane, DMF = dimethylformamide, DMSO = dimethyl sulfoxide, EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EtOAc = ethyl acetate, EtOH = ethanol, HATU = (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HPLC = high-performance liquid chromatography, SFC = supercritical fluid chromatography, TEA = triethylamine, TFA = trifluoroacetic acid, and THF = tetrahydrofuran.
Example 1: Synthesis of 4-(((2’-(((1R,4R)-4-aminocyclohexyl)amino)-5’-chloro-[2,4’- bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate 1)
Figure imgf000060_0001
[0201] Step 1: Preparation of tetrahydro-4H-pyran-4,4-dicarbonitrile (INT-2)
Figure imgf000060_0002
[0202] To a solution of 1-bromo-2-(2-bromoethoxy)ethane (INT-1, 20 g, 86.24 mmol) and propanedinitrile (6.27 g, 94.86 mmol) in DMF (30 mL) was added DBU (26.26 g, 172.48 mmol). The reaction mixture was stirred at 85 °C for 3 hours, cooled to ambient temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide tetrahydro-4H-pyran-4,4-dicarbonitrile (INT-2, 12.61 g, crude) as a brown solid. The crude product was used directly in the next step without further purification.1H NMR (400 MHz, methanol-d4) δ = 3.86-3.77 (m, 4H), 2.32-2.21 (m, 4H). [0203] Step 2: Preparation of 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (INT-3)
Figure imgf000060_0003
[0204] To a solution of tetrahydro-4H-pyran-4,4-dicarbonitrile (INT-2, 9.0 g, 66.10 mmol) in EtOH (270 mL) was added NaBH4 (7.50 g, 198.31 mmol) in portions. The reaction mixture was stirred at 20 °C for 4 hours, quenched by water (200 mL), and extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide 4-(aminomethyl)tetrahydro-2H- pyran-4-carbonitrile (INT-3, 7.23 g, 78% yield) as a brown oil. The crude product was used directly in the next step without further purification. [0205] Step 3: Preparation of 4-(((6-bromopyridin-2-yl)amino)methyl)tetrahydro-2H-pyran-4- carbonitrile (INT-4)
Figure imgf000061_0001
[0206] To a solution of 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (INT-3, 7.23 g, 51.58 mmol) and 2-bromo-6-fluoro-pyridine (7.72 g, 43.84 mmol) in DMSO (80 mL) was added TEA (13.05 g, 128.94 mmol). The reaction mixture was stirred at 130 °C for 18 hours, cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Biotage 20 g Silica Flash Column; 0-25% petroleum ether in ethyl acetate at 40 mL/min) to provide 4-(((6-bromopyridin-2- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (INT-4, 3.8 g, 18.35% yield) as a light green solid. MS (ESI) m/z = 296.1 [M+H]+. [0207] Step 4: Preparation of 4-(((5’-chloro-2’-fluoro-[2,4’-bipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (INT-5)
Figure imgf000061_0002
[0208] To a solution of 4-(((6-bromopyridin-2-yl)amino)methyl)tetrahydro-2H-pyran-4- carbonitrile (INT-4, 3.8 g, 12.83 mmol), (5-chloro-2-fluoro-4-pyridyl)boronic acid (3.37 g, 19.25 mmol), and Pd(dppf)Cl2 (938.84 mg, 1.28 mmol) in DME (40 mL) was added Na2CO3 (2 M, 16.04 mL). The reaction mixture was sealed, stirred at 110 °C for 4 hrs under N2 , cooled to ambient temperature, diluted with water (40 mL), and extracted with ethyl acetate (70 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Biotage 40 g Silica Flash Column; 20-26 % petroleum ether in ethyl acetate at 80 mL/min) to provide 4-(((5’-chloro-2’-fluoro-[2,4’-bipyridin]-6-yl)amino)methyl)tetrahydro- 2H-pyran-4-carbonitrile (INT-5, 3.6 g, 73% yield) as a yellow oil. MS (ESI) m/z = 347.1 [M+H]+. [0209] Step 5: Preparation of 4-(((2’-(((1R,4R)-4-aminocyclohexyl)amino)-5’-chloro-[2,4’- bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate 1)
Figure imgf000062_0001
[0210] To a solution of 4-(((5’-chloro-2’-fluoro-[2,4’-bipyridin]-6-yl)amino)methyl)tetrahydro- 2H-pyran-4-carbonitrile (INT-5, 4.33 g, 12.49 mmol) and cyclohexane-1,4-diamine (2.14 g, 18.73 mmol) in DMSO (50 mL) was added TEA (2.53 g, 24.97 mmol). The reaction mixture was stirred at 110 °C for 16 hours, diluted with water (40 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate(100 mL), added dropwise to HCl/dioxane (50 mL), filtered, and washed with ethyl acetate. The resulting solid was dissolved in water (150 mL), basified with NaHCO3 to pH 9, and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide 4- (((2’-(((1R,4R)-4-aminocyclohexyl)amino)-5’-chloro-[2,4’-bipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate 1, 4.1 g, 61.11% yield) as a brown solid. MS (ESI) m/z = 441.3 [M+H]+. Example 2: Synthesis of tert-butyl (2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H- pyran-4-yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)carbamate (Compound 1)
Figure imgf000063_0001
[0211] A solution of DMSO (1.75 g, 22.41 mmol) in anhydrous DCM (10 mL) was added dropwise over a period of 1 hour to a solution of (COCl)2 (1.42 g, 11.21 mmol) in DCM (10 mL) at -60°C under N2. The mixture was stirred for 30 min, and a solution of tert-butyl N-[2-(2- hydroxyethoxy)ethyl]carbamate (1A, 1 g, 4.87 mmol) in DCM (10 mL) was then added dropwise over 30 minutes. After stirring for 30 minutes, to this mixture was added dropwise a solution of triethylamine (4.44 g, 43.85 mmol) in dichloromethane (10 mL) over 30 minutes. The whole mixture was allowed to be stirred at room temperature for 12 hours. The solvent was then evaporated and the crude material was diluted with ethyl acetate (30 mL) and washed with water (10 mL). The organic phase was dried over Na2SO4 and concentrated over vacuum to afford compound 1B (0.98 g, 4.82 mmol, 99% yield) as yellow oil which was used in next step without any further purification. [0212] A mixture of Intermediate 1 (1.6 g, 3.63 mmol), compound 1B (884.90 mg, 4.35 mmol), NaBH(OAc)3 (1.54 g, 7.26 mmol), AcOH (654 mg, 10.89 mmol) in 1,2-dichloroethane (30 mL) was degassed and purged with N2 for 3 times, then the mixture was stirred at 20°C for 6 hours under N2 atmosphere. The mixture was quenched by addition H2O (50 mL) at 25 °C, and then diluted with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: C18-6100*30 mm*5 um; mobile phase: [water (FA)-ACN]; B%: 17%-47%, 15min) to afford Compound 1 (62.9 mg, 3% yield) as a yellow solid. LCMS: tR = 1.230 min in 5-95AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z =628.5[M+H]+. [0213] Compound 1: 1H NMR (400 MHz, Methanol-d4): δ = 8.66-8.45 (m, 1H), 8.05-7.87 (m, 1H), 7.57-7.41 (m, 1H), 6.88-6.78 (m, 1H), 6.69 (s, 1H), 6.65-6.59 (m, 1H), 4.02-3.91 (m, 2H), 3.76-3.51 (m, 9H), 3.29-3.24 (m, 2H), 3.21-3.11 (m, 2H), 3.08-2.97 (m, 1H), 2.26- 2.10 (m, 4H), 1.93-1.85 (m, 2H), 1.82-1.72 (m, 2H), 1.59-1.31 (m, 13H). Example 3: Synthesis of 4-(((2'-(((1r,4r)-4-((2-(2- aminoethoxy)ethyl)amino)cyclohexyl)amino)-5'-chloro-[2,4'-bipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Compound 2)
Figure imgf000064_0001
[0214] To a solution of Compound 1 (200 mg, 0.318 mmol) in 1,4-dioxane (2 mL) was added HCl/1,4-dioxane (4 M solution, 5.7 mL). The mixture was stirred at 25 °C for 1 hour, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: C18-6100*30mm*5um;mobile phase: [water(FA)-ACN]; B%: 4%-34%, 15min) to afford Compound 2 (57.5 mg, 34% yield) as a yellow solid. LCMS: tR = 0.732 min 10- 80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 528.5 [M+H]+. [0215] Compound 2: 1H NMR (400 MHz, Methanol-d4): δ = 8.58-8.45 (m, 2H), 8.02-7.91 (m, 1H), 7.54-7.42 (m, 1H), 6.85-6.80 (m, 1H), 6.71-6.67 (m, 1H), 6.64-6.60 (m, 1H), 4.01-3.89 (m, 2H), 3.61 (d, J = 2.0 Hz, 9H), 3.28-3.20 (m, 2H), 3.19-3.05 (m, 3H), 2.29-2.14 (m, 4H), 1.94- 1.84 (m, 2H), 1.83-1.70 (m, 2H), 1.65-1.50 (m, 2H), 1.42-1.28 (m, 2H). Example 4: Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'-yl)amino)cyclohexyl)amino)ethoxy)ethyl)-1,1,1- trifluoromethanesulfonamide (Compound 3)
Figure imgf000064_0002
[0216] A mixture of trifluoromethanesulfonyl chloride (57 mg) in anhydrous DCM (1 mL) was added Compound 2 (300 mg, 60% purity) and DIPEA (132 mg) at 0°C degassed and purged with N2 for 3 times, then the mixture was stirred at 0°C for 30 minutes under N2 atmosphere. The mixture was quenched by addition H2O (5 mL) at 25°C, and then diluted with H2O (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xtimate C18100*30 mm*10 um; mobile phase: [water(FA)-ACN]; B%: 20%-40%, 10 min) to afford Compound 3 (37 mg, 16% yield) as a white solid. LCMS: tR = 1.208 min 5-95AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 660.4 [M+H]+. [0217] Compound 3: 1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 2 H), 8.05-8.01 (m, 1H), 7.53 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.67 (s, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.07 (brs, 1H), 4.02-3.97 (m, 2H), 3.77-3.61 (m, 9H), 3.46 (t, J = 4.4 Hz, 2H), 3.22 (d, J = 4.0 Hz, 3H), 2.32-2.22 (m, 4H), 1.95-1.74 (m, 7H), 1.35 (d, J = 12.0 Hz, 3H). Example 5: Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)methanesulfonamide (Compound 4)
Figure imgf000065_0001
[0218] To a mixture of methanesulfonyl chloride (31 mg, 0.27 mmol) in DCM (2 mL) was Compound 2 (200 mg, 0.246 mmol, 65% purity) and DIPEA (95 mg, 0.74 mmol) at 25°C, then the mixture was stirred at 0°C for 30 minutes under N2 atmosphere. The mixture was quenched by H2O (50 mL) at 25 °C, then diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C1875*30 mm*3 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 10 min) to afford Compound 4 (63.8 mg, 43% yield) as a white solid. LCMS: tR = 2.318 min in 10-80CD_4min_Pos_220&254_Shimadzu.lcm, MS (ESI) m/z = 666.4 [M+H]+. [0219] Compound 4: 1H NMR (400 MHz, Methanol-d4): δ = 8.01-7.89 (m, 1H), 7.55-7.41 (m, 1H), 6.89-6.80 (m, 1H), 6.70-6.66 (m, 1H), 6.64-6.58 (m, 1H), 4.01-3.91 (m, 2H), 3.77-3.71 (m, 2H), 3.68-3.55 (m, 7H), 3.28-3.22 (m, 2H), 2.99 (s, 3H), 2.86-2.80 (m, 2H), 2.57-2.46 (m, 1H), 2.16-2.00 (m, 4H), 1.93-1.86 (m, 2H), 1.82-1.73 (m, 2H), 1.36-1.25 (m, 4H). Example 6: Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'-yl)amino)cyclohexyl)amino)ethoxy)ethyl)acetamide (Compound 5)
Figure imgf000066_0001
[0220] To a solution of Compound 2 (200 mg, 0.38 mmol) in DMF (2 mL) were added DIPEA (98 mg, 0.76 mmol ), HATU (173 mg, 0.45 mmol) and AcOH (27 mg, 0.45 mmol). The mixture was stirred at 25°C for 1 hour. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18-6100*30 mm*5 um; mobile phase: [water (0.05% NH3.H2O+10 mM NH4HCO3)-ACN]; B%: 17%-36%, 15 min) to afford Compound 5 (30.2 mg, 14% yield) as a white solid. LCMS: tR = 0.821 min 10- 80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 570.5 [M+H]+. [0221] Compound 5: 1H NMR (400 MHz, Methanol-d4): δ = 7.96 (s, 1H), 7.50 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.0 Hz, 1H), 6.70 (s, 1H), 6.63 (d, J = 7.9 Hz, 1H), 3.97 (d, J = 11.5 Hz, 2H), 3.78-3.73 (m, 2H), 3.70-3.52 (m, 7H), 3.37 (s, 2H), 2.82 (s, 2H), 2.53 (s, 1H), 2.18-2.00 (m, 5H), 1.98-1.89 (m, 4H), 1.83-1.74 (m, 2H), 1.31 (s, 4H). Example 7: Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)cyclopropanesulfonamide (Compound 6)
Figure imgf000066_0002
[0222] To a mixture of Compound 2 (80 mg, 0.151 mmol) in dichloromethane (3 mL) was added cyclopropanesulfonyl chloride (43 mg, 0.303 mmol) and DIPEA (59 mg, 0.454 mmol) at 0°C, then the mixture was stirred at 25°C for 12 h under N2 atmosphere. The mixture was quenched by H2O (5 mL) at 25 °C, then diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: C18-6100*30 mm*5 um; mobile phase: [water (FA)-ACN]; B%: 16%-46%, 15min) to afford Compound 6 (49.2 mg, 0.078 mmol, 51% yield) as a white solid. LCMS: tR = 1.252 min in 5-95AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z =632.3[M+H]+. [0223] Compound 6: 1H NMR (400 MHz, CDCl3): δ = 8.31-8.27 (m, 1H), 8.08-8.06 (m, 1H), 7.55-7.50 (m, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.61-6.56 (m, 1H), 6.52 (d, J = 8.4 Hz, 1H), 4.99-4.84 (m, 2H), 4.00 (dd, J = 12.4, 2.4 Hz, 2H), 3.89-3.84 (m, 2H), 3.80-3.75 (m, 2H), 3.75-3.69 (m, 2H), 3.68-3.58 (m, 4H), 3.37 (t, J = 4.8 Hz, 2H), 3.22-3.16 (m, 2H), 3.15-3.06 (m, 1H), 3.15-3.04 (m, 2H), 2.52 (ddd, J = 12.8, 8.0, 4.8 Hz, 3H), 2.34-2.22 (m, 5H), 1.97-1.89 (m, 2H), 1.86-1.71 (m, 5H), 1.38-1.24 (m, 2H), 1.20-1.14 (m, 2H), 1.03-0.95 (m, 2H). Example 8: Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)cyclopropanecarboxamide (Compound 7)
Figure imgf000067_0001
[0224] To a mixture of cyclopropanecarboxylic acid (35 mg, 0.409 mmol) in pyridine (3 mL) were added Compound 2 (180 mg, 0.340 mmol) and EDCI (78 mg, 0.409 mmol) at 25°C, then the mixture was stirred at 25°C for 1 h under N2 atmosphere. The mixture was quenched by H2O (5 mL) at 25 °C, then diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18-6100*30 mm*5 um; mobile phase: [water (0.05% NH3.H2O + 10mM NH4HCO3)-ACN]; B%: 20%-50%, 9 min) to afford Compound 7 (36.3 mg, 18% yield) as a white solid. LCMS: tR = 1.004 min 10-80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 596.5 [M+H]+. [0225] Compound 7: 1H NMR (400 MHz, CDCl3): δ = 8.56-8.47 (m, 1H), 8.12-8.05 (m, 1H), 7.76-7.64 (m, 1H), 7.54-7.48 (m, 1H), 6.99-6.93 (m, 1H), 6.60-6.54 (m, 1H), 6.54-6.49 (m, 1H), 4.96-4.86 (m, 1H), 4.73-4.43 (m, 1H), 3.99 (dd, J = 12.4, 2.4 Hz, 2H), 3.77 (d, J = 6.4 Hz, 4H), 3.74-3.68 (m, 4H), 3.67 (s, 2H), 3.60-3.56 (m, 2H), 3.46 (d, J = 4.0 Hz, 2H), 3.19-3.09 (m, 2H), 3.06-2.94 (m, 1H), 2.33-2.16 (m, 4H), 1.96-1.88 (m, 2H), 1.80-1.70 (m, 3H), 1.64-1.57 (m, 1H), 1.36-1.19 (m, 2H), 0.99-0.90 (m, 2H), 0.78-0.63 (m, 2H). Example 9: Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran-4- yl)methyl)amino)-[2,4'-bipyridin]-2'-yl)amino)cyclohexyl)amino)ethoxy)ethyl)-4- fluorobenzenesulfonamide (Compound 8)
Figure imgf000068_0001
[0226] To a mixture of 4-fluorobenzenesulfonyl chloride (121 mg) in DCM (10 mL) was added Compound 2 (300 mg) and DIPEA (220 mg) at 0°C. The mixture was stirred at 25°C for 2 hours under N2 atmosphere, then quenched by addition H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~8% methanol/dichloromethane gradient at 70 mL/min). The resultant crude product was further purified by preparative HPLC (column: C18-6100*30 mm*5 um; mobile phase: [water(FA)- ACN]; B%: 14%-48%, 15 min) to afford Compound 8 (54 mg, 13% yield) as a white solid. LCMS: tR = 1.222 min 10-80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 686.5 [M+H]+. [0227] Compound 8: 1H NMR (400 MHz, Methanol-d4): δ = 7.96 (s, 1H), 7.50 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.70 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 3.97 (d, J = 11.6 (m, 5H), 1.98-1.89 (m, 4H), 1.83-1.74 (m, 2H), 1.31 (s, 4H). Example 10: Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran- 4-yl)methyl)amino)-[2,4'-bipyridin]-2'-yl)amino)cyclohexyl)amino)ethoxy)ethyl)-4- fluorobenzamide (Compound 9)
Figure imgf000069_0001
[0228] To a solution of Compound 2 (200 mg, 0.246 mmol, 65% purity) in DMF (1 mL) were added DIPEA (95 mg, 0.74 mmol), HATU (112 mg, 0.295 mmol) and 4-fluorobenzoic acid (41 mg, 0.295 mmol). The mixture was stirred at 25°C for 1 hour, then quenched by H2O (5 mL) at 25°C, diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: C18-6100*30 mm*5 um; mobile phase: [water(FA)-ACN]; B%: 16%-46%, 15 min) to afford Compound 9 (52.7 mg, 33% yield) as a white solid. LCMS: tR = 1.219 min 10-80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 650.5 [M+H]+. [0229] Compound 9: 1H NMR (400 MHz, Methanol-d4): δ = 8.55-8.47 (m, 1H), 8.00-7.95 (m, 1H), 7.94-7.86 (m, 2H), 7.53-7.46 (m, 1H), 7.26-7.16 (m, 2H), 6.86-6.81 (m, 1H), 6.72-6.67 (m, 1H), 6.65-6.60 (m, 1H), 4.01-3.90 (m, 2H), 3.80-3.60 (m, 11H), 3.27-3.22 (m, 2H), 3.18-3.07 (m, 1H), 2.24-2.13 (m, 4H), 1.92-1.85 (m, 2H), 1.82-1.71 (m, 2H), 1.63-1.50 (m, 2H), 1.40-1.27 (m, 2H). Example 11: Synthesis of cyclopropyl (2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro- 2H-pyran-4-yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)carbamate (Compound 10)
Figure imgf000070_0001
[0230] To a mixture of cyclopropanol (500 mg, 8.61 mmol) and (4-nitrophenyl) carbonochloridate (10A, 1.5 g, 7.44 mmol) in DCM (10 mL) was added pyridine (735 mg, 9.30 mmol, 1.08 eq) in one portion at 0°C under N2 atmosphere. The mixture was stirred at 25°C for 16 hours, then diluted with DCM (10 mL), washed with HCl (1 N aqueous, 30 mL) and saturated NaHCO3 solution (30 mL). The aqueous phase was extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% of ethyl acetate in petroleum ether) to give compound 10B (1.9 g, 8.51 mmol, 98.89% yield) as yellow oil.1H NMR (400 MHz, CDCl3): δ = 8.36-8.24 (m, 2H), 7.48-7.33 (m, 2H), 4.29 (tt, J = 6.0, 3.2 Hz, 1H), 0.95-0.88 (m, 2H), 0.88-0.81 (m, 2H). [0231] To a mixture of Compound 2 (120 mg, 0.227 mmol) and compound 10B (60.9 mg, 0.273 mmol) in DCM (5.0 mL) was added DIEA (147 mg, 1.14 mmol) in one portion at 0°C under N2 atmosphere. The mixture was stirred at 0°C for 2 hours and then the reaction mixture was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC (column: Phenomenex C1875*30mm*3um; mobile phase: [water (FA)-MeCN]; B%: 5%-45%, 28 min) to afford Compound 10 (82.8 mg, 98.08% purity, 0.133 mmol, 58.38% yield) as a white solid. LCMS: tR = 1.138 min 10-80AB_4 min_220&254_Shimadzu.lcm, MS (ESI) m/z = 612.5 [M+H]+. [0232] Compound 10: 1H NMR (400 MHz, Methanol-d4): δ = 7.99 (s, 1H), 7.50 (dd, J = 8.4, 7.2 Hz, 1H), 6.84 (dd, J = 7.2, 0.8 Hz, 1H), 6.70 (s, 1H), 6.63 (dd, J = 8.4, 0.8 Hz, 1H), 4.03-3.93 (m, 3H), 3.76 (s, 5H), 3.75-3.71 (m, 3H), 3.67 (dd, J = 11.6, 2.0 Hz, 2H), 3.60-3.55 (m, 2H), 3.23 (d, J = 5.2 Hz, 2H), 3.18-3.07 (m, 1H), 2.22 (d, J = 9.6 Hz, 4H), 1.88 (s, 2H), 1.82-1.73 (m, 2H), 1.64- 1.52 (m, 2H), 1.43-1.31 (m, 2H), 0.64 (s, 3H). Example 12: Synthesis of 2,2,2-trifluoroethyl (2-(2-(((1r,4r)-4-((5'-chloro-6-(((4- cyanotetrahydro-2H-pyran-4-yl)methyl)amino)-[2,4'-bipyridin]-2'- yl)amino)cyclohexyl)amino)ethoxy)ethyl)carbamate (Compound 11)
Figure imgf000071_0001
[0233] To a solution of 2,2,2-trifluoroethanol (1.0 g, 10.00 mmol) in THF (20 mL) was added TEA (2.02 g, 19.99 mmol) and 4-nitrophenyl carbonochloridate (10A, 2.22 g, 11.00 mmol) at 0°C. The mixture was stirred at 25°C for 12 hours, then diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated over vacuum. The residue was purified by flash column chromatography on silica gel (gradient 0 ~ 30% ethyl acetate in petroleum ether) to afford compound 11A (1.43 g, 54% yield) as light yellow oil. [0234] To a solution of Compound 2 (300 mg, 0.34 mmol) in acetonitrile (12 mL) were added DIPEA (308 mg, 2.39 mmol) and compound 11A (99 mg, 0.37 mmol). The mixture was stirred at 25°C for 12 hours, then concentrated over vacuum. The residue was purified by preparative HPLC (Column: Xtimate C18150*40mm*10um; water (water (0.225% FA))-MeCN; B% from 15 to 45; Gradient time: 10 min; Flow rate: 25 mL/min) to afford Compound 11 (72.3 mg, 99% purity, 31% yield) as light yellow gum. LCMS: tR = 1.287 min in 10-80 AB_4 min_220&254_Shimadzu.lcm, MS (ESI) m/z = 654.5 [M+H]+. [0235] Compound 11: 1H NMR (400 MHz, Method-d4): δ = 8.46 (s, 1H), 7.97 (s, 1H), 7.51- 7.47 (m, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.69 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 4.57 (m, 2H), 3.94 (m, 2H), 3.75-3.58 (m, 9H), 3.38-3.36 (m, 2H), 3.25-3.08 (m, 3H), 2.21 (d, J = 10.4 Hz, 4H), 1.90-1.87 (m, 2H), 1.80-1.75 (m, 2H), 1.65-1.57 (m, 2H), 1.37-1.34 (m, 2H). Example 13: Synthesis of N-(2-(2-(((1r,4r)-4-((5'-chloro-6-(((4-cyanotetrahydro-2H-pyran- 4-yl)methyl)amino)-[2,4'-bipyridin]-2'-yl)amino)cyclohexyl)amino)ethoxy)ethyl)-4- (trifluoromethyl)benzenesulfonamide (Compound 12)
Figure imgf000072_0001
[0236] To a mixture of Compound 2 (220 mg, 0.42 mmol) in anhydrous DCM (10 mL) were added 4-(trifluoromethyl)benzenesulfonyl chloride (112 mg, 0.458 mmol) and DIPEA (215mg, 1.67 mmol) at 0°C, then the mixture was stirred at 25°C for 2 hours under N2 atmosphere. The mixture was quenched by H2O (5 mL) at 25 °C, diluted with H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18150*30 mm*5 um; mobile phase: [water (HCl)- MeCN]; B%: 15%-50%, 10 min) to afford Compound 12 (123.8 mg, 0.168 mmol, 40% yield) as a yellow solid. LCMS: tR = 1.666 min 10-80AB_4 min_220&254_Shimadzu.lcm, MS (ESI) m/z = 736.5 [M+H]+. [0237] Compound 12: 1H NMR (400 MHz, Methanol-d4): δ = 8.15 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.99-7.88 (m, 3H), 7.36-7.20 (m, 2H), 7.10 (d, J = 7.2 Hz, 1H), 3.99 (dd, J = 12.4, 3.2 Hz, 2H), 3.88-3.78 (m, 3H), 3.77-3.72 (m, 2H), 3.69-3.58 (m, 4H), 3.30-3.25 (m, 3H), 3.14 (t, J = 5.2 Hz, 2H), 2.29-2.25 (m, 4H), 1.99-1.97 (m, 2H), 1.84-1.58 (m, 6H). II. Biological Assays Example 14: CDK9 Biochemical Assay [0238] To each well of a 96-well plate was added 5x kinase assay buffer with 10 mM DTT (6 μL), 500 μM ATP (1 μL), 5x CDK substrate (10 μL), and water (8 μL).5 μL of compound were added to the test and positive control groups, while 5 μL of solvent was added to the blank groups.100 ng of CDK9/CyclinT in 20 μL water was added to the test and positive control groups, while 20 μL of 1x kinase assay buffer was added to the blank groups. The reaction mixtures were incubated at 30 °C for 45 minutes, and 50 μL of Kinase-Glo® Max was added to each well and the plates were shielded from light and incubated for 15 minutes at room temperature. Luminescence was measured on a microplate reader and IC50 values were calculated using Prism 9 software. [0239] The IC50 values obtained according to the above procedure are summarized in Table 1:
Figure imgf000073_0001
A < 2.50 nM; 2.50 nM ≤ B < 5.00 nM; 5.00 nM ≤ C < 10.00 nM; 10.00 nM < D Example 15: Cancer Cell Viability Assay [0240] Human liver cancer cell lines HepG2, Hep3B, Huh7, and SK-HEP-1 cells were rinsed and trypsinized with 0.25% trypsin (Corning #25-053-CI) in an incubator at 37 °C until detached. The cells were resuspended and seeded in 96-well plates to a density of 5,000 cells per well. Following cell adhesion, compounds were added to a final concentration of 2x dilution.72 hours following compound treatment, CellTiter-Glo® 2.0 was added to the well in a 2:1 ratio of media/CellTiter-Glo® 2.0. The plates were shielded from light, shaken for 2 minutes, and incubated for 10 minutes. Luminescence was measured on a microplate reader and EC50 values were calculated using Prism 9 software. [0241] The EC50 values obtained according to the above procedure are summarized in Table 2:
Figure imgf000073_0002
Figure imgf000074_0001
A: < 25 nM; 25 nM ≤ B < 100 nM; 100 nM ≤ C < 200 nM; 200 nM < D. Example 16: Pharmacokinetic and Tissue Distribution Study [0242] All the procedures related to animal handling, care, and treatment were performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals were quarantined for 7 days before the study. The general health of the animals was evaluated by a veterinarian, and complete health checks were performed. Animals with abnormalities were excluded prior the study. Mice were maintained under specific pathogen-free conditions, and food and water were provided ad libitum. [0243] For mice experiments, the liver and blood pharmacokinetics of compounds were analyzed in CD-1 mice following a single oral administration dose of 5 mg/kg compound suspension. Liver and blood samples for determination of compound concentration were obtained at 2 hours following administration of compounds (n = 3 for each compound). Collected liver and blood samples were analyzed using a LC-MS/MS method to quantify compound concentrations. The ratios of compound concentrations in liver versus blood in CD-1 mice are summarized in FIG.1. Data are presented as mean ± standard deviation. Statistical significance between groups was calculated by two-tailed Student’s t-test. Significance values are P < 0.05 (*) and P < 0.01 (**). [0244] The data in FIG.1 show that Compounds 1, 7, 8, and 12 have higher liver/blood ratios than NVP-2, demonstrating that these compounds have improved liver selectivity. Example 17: Tolerability and Safety Assessment Study [0245] Based on the body weight, BALB/c nude mice were randomly assigned to respective groups using a computer-generated randomization procedure. Body weights of all animals were measured daily. For routine monitoring, all study animals were monitored behavior such as mobility, food and water consumption, body weight, eye/hair matting and any other abnormal effect. Any mortality and/or abnormal clinical signs were recorded. If animals have lost significant body mass (emaciated, obvious body weight loss > 20%), the animals were euthanized. Mean weight changes (relative to day 1) of BALB/c nude mice treated with vehicle and compounds are summarized in FIG.2. The data in FIG.2 show that Compounds 1, 7, 8, and 12 display lower toxicity than NVP-2. [0246] While preferred embodiments of the present invention 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 will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I):
Figure imgf000076_0001
Formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ring A is optionally substituted C3-6cycloalkyl, optionally substituted 3- to 10- membered heterocycloalkyl, optionally substituted C6-10 aryl, or optionally substituted 6- to 10-membered heteroaryl; R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and – NR20R21; R2 and R3 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, – C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, – NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1- 6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10- membered heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, – CN, and –NR20R21; R4 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –O(C1- 4alkyl)C3-6cycloalkyl, –O(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –O(C1- 4alkyl)C6-10aryl, –O(C1-4alkyl)(6- to 10-membered heteroaryl), –O(C1-4alkyl)C(O)OR18, – O(C1-4alkyl)C(O)NR19SO2R15, –O(C1-4alkyl)SO2 NR19C(O)R18, –O(C3-6cycloalkyl)C3- 6cycloalkyl, –O(C3-6cycloalkyl)(3- to 10-membered heterocycloalkyl), –O(C3- 6cycloalkyl)C6-10aryl, –O(C3-6cycloalkyl)(6- to 10-membered heteroaryl), –O(C3- 6cycloalkyl)C(O)OR18, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, –(C1-4alkyl)(6- to 10-membered heteroaryl), and –(C1-4alkyl)C(O)OR18; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, – C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and – NR19SO2NR16R17; and R4’ and R4’’ are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C3- 6cycloalkoxy, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkoxy, C6-10 aryl, 6- to 10-membered heteroaryl, –O(C1-4alkyl)C3-6cycloalkyl, –O(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –O(C1-4alkyl)C6-10aryl, –O(C1- 4alkyl)(6- to 10-membered heteroaryl), –O(C1-4alkyl)C(O)OR18, –O(C1- 4alkyl)C(O)NR19SO2R15, –O(C1-4alkyl)SO2 NR19C(O)R18, –O(C3-6cycloalkyl)C3- 6cycloalkyl, –O(C3-6cycloalkyl)(3- to 10-membered heterocycloalkyl), –O(C3- 6cycloalkyl)C6-10aryl, –O(C3-6cycloalkyl)(6- to 10-membered heteroaryl), –O(C3- 6cycloalkyl)C(O)OR18, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1- 4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, – NR19SO2R15, and –NR19SO2NR16R17; R5 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and – NR20R21; R6 and R7 are each independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl, –(C1-4alkyl)C3-6cycloalkyl, – (C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1-4alkyl)C6-10aryl, and –(C1- 4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, – CN, and –NR20R21; or R6 and R7, along with the nitrogen atom to which they are attached, are taken together to form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, – NR19C(O)NR16R17, –NR19SO2R15, –NR19SO2NR16R17, C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C1-6heteroalkyl, and C1-6haloalkyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; each R10 is independently selected from the group consisting of halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –NR19C(O)R15, – NR19C(O)OR15, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10- membered heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; each R15 is independently selected from the group consisting of C1-4alkyl, C1- 4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 6- to 10- membered heteroaryl; each R16 and R17 is independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4heteroalkyl, C1-4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl; or R16 and an R17 may be taken together along with the nitrogen atom to which they are attached to form a 3- to 10- membered heterocycloalkyl; each R18 is independently selected from the group consisting of hydrogen, C1- 4alkyl, C1-4heteroalkyl, C1-4haloalkyl, and C3-6cycloalkyl; each R19 is independently selected from the group consisting of hydrogen, C1- 4alkyl, C1-4heteroalkyl, C1-4haloalkyl, and C3-6cycloalkyl; each R20 and R21 is independently selected from the group consisting of hydrogen, C1-4alkyl, C1-4heteroalkyl, C1-4haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, 6- to 10-membered heteroaryl; or R20 and R21 may be taken together along with the nitrogen atom to which they are attached to form a 3- to 10- membered heterocycloalkyl; and n is 0, 1, 2, 3, or 4. 2. The compound or pharmaceutically acceptable salt of claim 1, wherein Ring A is C3- 6cycloalkyl or 3- to 10-membered heterocycloalkyl. 3. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein Ring A is C3- 6cycloalkyl. 4. The compound or pharmaceutically acceptable salt of any one of claims 1 to 3, wherein Ring A is selected from the group consisting of:
Figure imgf000079_0001
5. The compound or pharmaceutically acceptable salt of any one of claims 1 to 4, wherein Ring A is selected from the group consisting of:
Figure imgf000079_0002
Figure imgf000080_0001
6. The compound or pharmaceutically acceptable salt of claim 5, wherein Ring A is selected from the group consisting of:
Figure imgf000080_0002
7. The compound or pharmaceutically acceptable salt of any one of claims 1 to 6, wherein Ring A is selected from the group consisting of:
Figure imgf000080_0003
, , 8. The compound or pharmaceutically acceptable salt of claim 7, wherein Ring A is selected from the group consisting of:
Figure imgf000081_0001
. 9. The compound or pharmaceutically acceptable salt of any one of claims 1 to 6, wherein Ring A is selected from the group consisting of:
Figure imgf000081_0002
10. The compound or pharmaceutically acceptable salt of claim 9, wherein Ring A is selected from the group consisting of:
Figure imgf000081_0003
11. The compound or pharmaceutically acceptable salt of any one of claims 1 to 6, wherein Ring A is
Figure imgf000081_0004
12. The compound or pharmaceutically acceptable salt of claim 11, wherein Ring A is
Figure imgf000081_0005
or . 13. The compound or pharmaceutically acceptable salt of any one of claims 1 to 6, wherein Ring A is
Figure imgf000081_0006
. 14. The compound or pharmaceutically acceptable salt of claim 13, wherein Ring A is
Figure imgf000081_0007
15. The compound or pharmaceutically acceptable salt of any one of claims 1 to 14, wherein R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, – C(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, C1-6alkyl, and C1-6haloalkyl. 16. The compound or pharmaceutically acceptable salt of any one of claims 1 to 15, wherein R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –CN, –OR18, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, – C(O)OR18, –NR19C(O)R15, and –NR19C(O)OR15. 17. The compound or pharmaceutically acceptable salt of any one of claims 1 to 16, wherein R8, R9, R11, R12, R13, and R14 are each independently selected from the group consisting of hydrogen, halo, –OR18, and –NR16R17. 18. The compound or pharmaceutically acceptable salt of any one of claims 1 to 17, wherein R8, R9, R11, R12, R13, and R14 are each independently hydrogen or halo. 19. The compound or pharmaceutically acceptable salt of any one of claims 1 to 18, wherein R11 is halo, and R8, R9, R12, R13, and R14 are each hydrogen. 20. The compound or pharmaceutically acceptable salt of any one of claims 1 to 19, wherein R11 is chloro, and R8, R9, R12, R13, and R14 are each hydrogen. 21. The compound or pharmaceutically acceptable salt of any one of claims 1 to 20, wherein R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, and C3- 6cycloalkyl. 22. The compound or pharmaceutically acceptable salt of any one of claims 1 to 21, wherein R1 is Me. 23. The compound or pharmaceutically acceptable salt of any one of claims 1 to 21, wherein R1 is hydrogen. 24. The compound or pharmaceutically acceptable salt of any one of claims 1 to 23, wherein R2 and R3 are each independently selected the group consisting of hydrogen, halo, –CN, – OR18, –SOR15, –SO2R15, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, – C(O)OR18, –NR19C(O)R18, –NR19C(O)NR16R17, –NR19SO2R15, –NR19SO2NR16R17, C1- 6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. 25. The compound or pharmaceutically acceptable salt of any one of claims 1 to 24, wherein R2 and R3 are each independently selected the group consisting of hydrogen, –CN, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, Me, Et, n-Pr, i-Pr, –CF3, and cyclopropyl. 26. The compound or pharmaceutically acceptable salt of any one of claims 1 to 25, wherein R2 and R3 are each independently selected the group consisting of hydrogen, Me, Et, n-Pr, and i-Pr.
27. The compound or pharmaceutically acceptable salt of any one of claims 24 to 26, wherein R2 and R3 are the same. 28. The compound or pharmaceutically acceptable salt of any one of claims 1 to 27, wherein R2 and R3 are each hydrogen. 29. The compound or pharmaceutically acceptable salt of any one of claims 1 to 28, wherein: R4 is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and C3-6cycloalkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, – C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1- 4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. 30. The compound or pharmaceutically acceptable salt of any one of claims 1 to 29, wherein: R4 is C1-6alkyl or C1-6alkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17,–C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and – NR19SO2NR16R17. 31. The compound or pharmaceutically acceptable salt of any one of claims 1 to 30, wherein R4’ and R4’’ are both hydrogen. 32. The compound or pharmaceutically acceptable salt of any one of claims 1 to 31, wherein: R4 is C1-6alkyl or C1-6alkoxy, optionally substituted with one or more substituents selected from C1-4alkyl, oxo, halo, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17,–C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and – NR19SO2NR16R17; and R4’ and R4’’ are each hydrogen. 33. The compound or pharmaceutically acceptable salt of any one of claims 1 to 32, wherein R5 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, and C3- 6cycloalkyl. 34. The compound or pharmaceutically acceptable salt of any one of claims 1 to 33, wherein R5 is Me. 35. The compound or pharmaceutically acceptable salt of any one of claims 1 to 33, wherein R5 is hydrogen. 36. The compound or pharmaceutically acceptable salt of any one of claims 1 to 35, wherein: R6 and R7 are each independently selected from the group consisting of hydrogen, –(C1-4alkyl)C3-6cycloalkyl, –(C1-4alkyl)(3- to 10-membered heterocycloalkyl), –(C1- 4alkyl)C6-10aryl, and –(C1-4alkyl)(6- to 10-membered heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1- 4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21; or R6 and R7, along with the nitrogen atom to which they are attached, are taken together to form a 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents selected from oxo, halo, –OR18, C1-4alkyl, C1-4alkoxy, C1-4heteroalkyl, C1-4haloalkyl, –CN, and –NR20R21. 37. The compound or pharmaceutically acceptable salt of any one of claims 1 to 36, wherein R6 and R7 are each independently hydrogen or –(C1-4alkyl)(3- to 10-membered heterocycloalkyl); wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more substituents selected from halo, –OR18, –CN, and –NR20R21. 38. The compound or pharmaceutically acceptable salt of any one of claims 1 to 37, wherein one of R6 and R7 is H and the other is
Figure imgf000084_0001
39. The compound or pharmaceutically acceptable salt of any one of claims 1 to 38, wherein n is 0, 1, or 2. 40. The compound or pharmaceutically acceptable salt of claim 39, wherein n is 0. 41. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (II):
Figure imgf000084_0002
Formula (II). 42. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (III):
Figure imgf000085_0001
Formula (III). 43. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (IV):
Figure imgf000085_0002
Formula (IV). 44. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (V):
Figure imgf000085_0003
Formula (V). 45. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (VI):
Figure imgf000085_0004
Formula (VI).
46. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (VII-A) or Formula (VII-B):
Figure imgf000086_0001
or
Figure imgf000086_0002
Formula (VII-A) Formula (VII-B). 47. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (VIII-A) or Formula (VIII-B):
Figure imgf000086_0003
or
Figure imgf000086_0004
Formula (VIII-A) Formula (VIII-B). 48. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (IX-A) or Formula (IX-B):
Figure imgf000086_0005
or
Figure imgf000086_0006
Formula (IX-A) Formula (IX-B). 49. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (X):
Figure imgf000087_0001
Formula (X), wherein: R22, R23, R24, and R25 are each independently selected from the group consisting of hydrogen, halo, –R18, –OR18, –CN, –NR16R17, –C(O)NR16R17, –SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1- 4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, –NR19C(O)R15, –NR19C(O)OR15, – NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17; and R26 is selected from the group consisting of halo, –R18, –OR18, –CN, –NR16R17, –C(O)NR16R17, – SO2NR16R17, –C(O)R18, –C(O)OR18, –(C1-4alkyl)OC(O)(C1-4alkyl), –(C1-4alkyl)OC(O)OR18, – NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. 50. The compound or pharmaceutically acceptable salt of claim 49, wherein R22, R23, R24, and R25 are each independently selected from the group consisting of hydrogen, halo, –R18, and –OR18. 51. The compound or pharmaceutically acceptable salt of claim 49 or 50, wherein R22, R23, R24, and R25 are each independently hydrogen or halo. 52. The compound or pharmaceutically acceptable salt of claim 49 or 51, wherein R22, R23, R24, and R25 are each hydrogen. 53. The compound or pharmaceutically acceptable salt of any one of claims 49 to 52, wherein R26 is selected from the group consisting of –NR16R17, –NR19C(O)R15, –NR19C(O)OR15, –NR19C(O)NR16R17, –NR19SO2R15, and –NR19SO2NR16R17. 54. The compound or pharmaceutically acceptable salt of any one of claims 49 to 53, wherein R26 is selected from the group consisting of –NH2, –NHC(O)OtBu, –NHSO2CH3, – NHSO2CF3, , –NH(CO)CH3–, ,
Figure imgf000087_0002
Figure imgf000087_0003
, and –NHC(O)OCH2CF3.
Figure imgf000087_0004
55. The compound or pharmaceutically acceptable salt of any one of claims 1 to 54, wherein the compound is a compound of Formula (XI):
Figure imgf000088_0001
Formula (XI). 56. The compound or pharmaceutically acceptable salt of any one of claims 1 to 55, wherein the compound is selected from the group consisting of:
Figure imgf000088_0002
Figure imgf000089_0001
57. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of claims 1 to 56, and a pharmaceutically acceptable excipient. 58. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1 to 56, or the pharmaceutical composition of claim 57. 59. The method of claim 58, wherein the disease or disorder is a proliferative disease. 60. The method of claim 59, wherein the proliferative disease is cancer. 61. The method of claim 60, wherein the cancer is selected from leukemia, breast cancer, prostate cancer, ovarian cancer, colon cancer, cervical cancer, lung cancer, lymphoma, and liver cancer. 62. The method of claim 60, wherein the cancer is liver cancer.
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