WO2023086417A1 - Composés et leurs procédés d'utilisation - Google Patents

Composés et leurs procédés d'utilisation 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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alkyl
compound
cycloalkyl
pharmaceutically acceptable
acceptable salt
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PCT/US2022/049452
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English (en)
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Andrei W. Konradi
Chun-Hao Huang
Ko-Chuan LEE
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Algen Biotechnologies, Inc.
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Publication of WO2023086417A1 publication Critical patent/WO2023086417A1/fr

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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

L'invention concerne des composés de formule (I) en tant qu'inhibiteurs de CDK9. L'invention concerne également des méthodes de traitement d'une maladie ou d'un trouble (par exemple, une maladie proliférative, telle que le cancer) chez un sujet en ayant besoin, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un inhibiteur de CDK9 selon l'invention (par exemple, un composé de formule (I)).
PCT/US2022/049452 2021-11-11 2022-11-09 Composés et leurs procédés d'utilisation WO2023086417A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012101062A1 (fr) * 2011-01-28 2012-08-02 Novartis Ag Composés bi-hétéroaryles substitués en tant qu'inhibiteurs de cdk9 et leurs utilisations
WO2021231892A1 (fr) * 2020-05-15 2021-11-18 Algen Biotechnologies, Inc. Compositions chimiques particulières et leurs procédés d'utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012101062A1 (fr) * 2011-01-28 2012-08-02 Novartis Ag Composés bi-hétéroaryles substitués en tant qu'inhibiteurs de cdk9 et leurs utilisations
WO2021231892A1 (fr) * 2020-05-15 2021-11-18 Algen Biotechnologies, Inc. Compositions chimiques particulières et leurs procédés d'utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY ANONYMOUS : "[2,4'-Bipyridine]-2',6-diamine, 3'-fluoro-N2'-[trans-4-[[(1R)-2-methoxy-1- methylethyl]amino]cyclohexyl]-N6-[(tetrahydro-2,2-dimethyl-2H-pyran-4- yl)methyl]-3-(trifluoromethyl)-, rel- (CA INDEX NAME) ", XP093067181, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "2H-Pyran-4-carbonitrile, 4-[[[5'-chloro-2'-[[4-[(2-methoxy-1- methylethyl)amino]cyclohexyl]amino][2,4'-bipyridin]-6- yl]amino]methyl]tetrahydro- (CA INDEX NAME)", XP093067179, retrieved from STN *
OLSON, C. M. ET AL.: "Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation", NATURE CHEMICAL BIOLOGY, vol. 14, no. 2, 2018, pages 163 - 170, XP055820762, DOI: 10.1038/nchembio.2538 *

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