WO2023241627A1 - Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation - Google Patents

Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation Download PDF

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WO2023241627A1
WO2023241627A1 PCT/CN2023/100207 CN2023100207W WO2023241627A1 WO 2023241627 A1 WO2023241627 A1 WO 2023241627A1 CN 2023100207 W CN2023100207 W CN 2023100207W WO 2023241627 A1 WO2023241627 A1 WO 2023241627A1
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alkyl
heterocycloalkyl
cycloalkyl
heteroaryl
aryl
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Xiao DING
Feng Ren
Jianyu Xu
Yingtao LIU
Jianping Wu
Xiaosong Liu
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Insilico Medicine Ip Limited
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems

Definitions

  • the disclosure relates to compounds that function as dual inhibitors of cyclic dependent kinase 8 and/or 19 (CDK8/19) and methods of use.
  • Cyclin-dependent kinase 8 ( “CDK8” ) and its paralog, CDK19, collectively termed “Mediator Kinase, ” are cyclin-dependent kinases that have been implicated as key rheostats in cellular homeostasis and developmental programming.
  • CDK8 and CDK19 are incorporated, in a mutually exclusive manner, as part of a 4-protein complex called the Mediator kinase module. This module reversibly associates with the Mediator, a 26 subunit protein complex that regulates RNA Polymerase II mediated gene expression.
  • the Mediator kinases have been implicated in diverse process such as developmental signaling, metabolic homeostasis and in innate immunity.
  • dysregulation of Mediator kinase module proteins including CDK8/19, has been implicated in the development of different human diseases, and in particular for oncological purposes.
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration, intravenous administration, or subcutaneous administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a dispersion, a solution, or an emulsion.
  • a method of inhibiting cyclic dependent kinase 8 and/or 19 (CDK8/19) activity in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.
  • a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.
  • the cancer is leukemia, acute myeloid leukemia (AML) , chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) , non-Hodgkin lymphoma (NHL) , Hodgkin lymphoma (HL) , or multiple myeloma (MM) .
  • the cancer is AML.
  • the cancer is a solid cancer.
  • the cancer is a prostate cancer, breast cancer, colon cancer, pancreatic cancer, skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, head and neck squamous cell carcinomas, melanoma.
  • the method further comprises administering a second therapeutic agent.
  • the second therapeutic agent is a chemotherapy, a targeted therapy, or an immune checkpoint inhibitor.
  • the second therapeutic agent is a CDK4/6 inhibitor, BCL-2 inhibitor, EGFR inhibitor, JAK1/2 inhibitor, anti-PD-L1 inhibitor or anti-PD1 inhibitor.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1 - 6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 - 10 alkyl.
  • the alkyl is a C 1 - 6 alkyl.
  • the alkyl is a C 1 - 5 alkyl.
  • the alkyl is a C 1 - 4 alkyl.
  • the alkyl is a C 1 - 3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2 - 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2 - 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -Oalkyl where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four carbon atoms (C 3 -C 4 fully saturated cycloalkyl or C 3 -C
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic fully saturated cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to five carbon atoms (C 2 -C 5 fully saturated heterocycloalkyl or C 2 -C 5
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a]pyridinyl, carbazolyl, cinnolinyl, be
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • an optionally substituted group may be un- substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating, ” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • a “disease or disorder associated with cyclic dependent kinase 8 and/or 19 (CDK8/19) ” or, alternatively, “acyclic dependent kinase 8 and/or 19 (CDK8/19) -mediated disease or disorder” means any disease or other deleterious condition in which cyclic dependent kinase 8 and/or 19 (CDK8/19) , or a mutant thereof, is known or suspected to play a role.
  • Described herein are compounds, or a pharmaceutically acceptable salt, or stereoisomer thereof useful in the treatment of a disease or disorder associated with cyclic dependent kinase 8 and/or 19 (CDK8/19) .
  • X 1 is -N-or -CR 2 -;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, or 4;
  • R Z2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 4 on different carbon taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, or 4;
  • R Z2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • X is -N-or -CR X -;
  • R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl;
  • Y is -NR Y1 -or -C (R Y2 ) 2 -;
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 4 on different carbon taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 - C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • the compound is a compound of Formula (Ia’) :
  • the compound is a compound of Formula (Ia) :
  • X 1 is -N-or -CR 2 -;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n 0, 1, 2, 3, or 4;
  • R Z2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 4 on different carbon taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • the compound is a compound of Formula (IVa) :
  • Z is -N-. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (IV) , or (IVa) , Z is -CR Z1 -.
  • R Z1 is hydrogen, halogen, -SF 5 , -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.
  • R Z1 is hydrogen, halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 hydroxyalkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (IV) , or (IVa) , R Z1 is hydrogen, -CN, or C 1 -C 6 hydroxyalkyl.
  • R Z1 is -CN or C 1 -C 6 hydroxyalkyl.
  • the compound is a compound of Formula (Ib’) :
  • the compound is a compound of Formula (Ib) :
  • the compound is a compound of Formula (IVb) :
  • R Z2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ib’) , (Ib) , (IV) , or (IVb) , R Z2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ib’) , (Ib) , (IV) , or (IVb) , R Z2 is C 1 -C 6 alkyl.
  • R 1 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , or (Ib) , R 1 is hydrogen or C 1 -C 6 alkyl.
  • R 1 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , or (Ib) , R 1 is C 1 -C 3 alkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , or (Ib) , R 1 is methyl.
  • R 1 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , or (Ib) , R 1 is C 1 -C 3 haloalkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , or (Ib) , R 1 is -CHF 2 .
  • X 1 is -N-. In some embodiments of a compound of Formula (I’) , (Ia’) , (Ib’) , (IV) , (IVa) , or (IVb) , X 1 is -CR 2 -.
  • R 2 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , R 2 is C 1 -C 6 alkyl.
  • Ring D is cycloalkyl or heterocycloalkyl.
  • Ring D is heterocycloalkyl. In some embodiments of a compound of Formula (I’) , (Ia’) , (Ib’) , (IV) , (IVa) , or (IVb) , Ring D is 5-to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (I’) , (Ia’) , (Ib’) , (IV) , (IVa) , or (IVb) , Ring D is 5-to 7-membered heterocycloalkyl.
  • Ring D is 5-to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I’) , (Ia’) , (Ib’) , (IV) , (IVa) , or (IVb) , Ring D is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I’) , (Ia’) , (Ib’) , (IV) , (IVa) , or (IVb) , Ring D is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I’) , (Ia’) , (Ib’) , (IV) , (IVa) , or (IVb) , is
  • a compound of Formula (I) or (Ia) or (Ib) is a single bond and X is -N-or -CR X -. In some embodiments of a compound of Formula (I) or (Ia) or (Ib) , is a single bond and X is -N-. In some embodiments of a compound of Formula (I) or (Ia) or (Ib) , is a single bond and X is -CR X -.
  • R X is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia) or (Ib) , R X is hydrogen.
  • a compound of Formula (I) or (Ia) or (Ib) is a double bond; and X is C.
  • Y is -NR Y1 -.
  • R Y1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) or (Ib) , R Y1 is hydrogen.
  • Y is -C (R Y2 ) 2 -.
  • each R Y2 is independently hydrogen, halogen, -OH, or C 1 -C 6 alkyl.
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 2 -C 6 alkynyl; wherein each alkyl and alkynyl is independently optionally substituted with one or more R.
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 2 -C 6 alkynyl; wherein each alkyl and alkynyl is independently optionally substituted with one or more R.
  • each R 4 is independently halogen, -OH, -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, or C 2 -C 6 alkynyl; wherein each alkyl and alkynyl is independently optionally substituted with one or more R.
  • each R 4 is independently C 1 -C 3 alkyl.
  • each R 4 is independently F, Cl, Br, I, -OH, NH 2 , methyl, ethynyl, -CH 2 OH, -CH 2 CH 2 OH, or -CH 2 CN.
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 4 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , each R 4 is independently halogen.
  • each R 4 is independently C 1 -C 6 alkyl.
  • two R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
  • two R 4 on the same carbon are taken together to form a cycloalkyl optionally substituted with one or more R.
  • two R 4 on the same carbon are taken together to form a heterocycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a cycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a heterocycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a aryl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a heteroaryl optionally substituted with one or more R.
  • m is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , m is 0, 1, or 2.
  • m is 0 or 1. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , m is 1 or 2.
  • m is 0. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , m is 1.
  • m is 2.
  • Ring A is cycloalkyl.
  • Ring A is 3-to 10-membered cycloalkyl.
  • Ring A is 3-to 8-membered cycloalkyl.
  • Ring A is 6-to 8-membered cycloalkyl.
  • Ring A is 3-to 6-membered cycloalkyl.
  • Ring A is cyclopentyl or cyclohexyl.
  • Ring A is heterocycloalkyl.
  • Ring A is 3-to 10-membered heterocycloalkyl.
  • Ring A is 3-to 10-membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring A is 3-to 8-membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring A is 6-to 8-membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring A is 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring A is piperidinyl or tetrahydropyranyl.
  • Ring A is piperidinyl.
  • Ring A is tetrahydropyranyl.
  • Ring A is phenyl.
  • Ring A is heteroaryl.
  • Ring A is 5-to 10-membered heteroaryl.
  • Ring A is 5-to 9-membered heteroaryl.
  • Ring A is 5-or 6-membered heteroaryl.
  • each R 3a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R 3a on the same atom are taken together to form an oxo.
  • n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , n is 0, 1, or 2.
  • n is 0 or 1. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , n is 1 or 2.
  • n is 0. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , n is 1.
  • n is 2. In some embodiments of a compound of Formula (I’) , (I) , (Ia’) , (Ia) , (Ib’) , (Ib) , (IV) , (IVa) , or (IVb) , n is 3.
  • Ring B is a 5-to 8-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 to 3 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
  • p 0, 1, 2, or 4;
  • X is -N-or -CR X -;
  • R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl;
  • Y is -NR Y1 -or -C (R Y2 ) 2 -;
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 4 on different carbon taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • Ring B is a 5-to 7-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 or 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring B is a 5-to 7-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring B is a 5-to 6-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring B is a 5-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring B is a 6-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring B is a 6-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 additional heteroatom selected from the group consisting of nitrogen and oxygen.
  • Ring B is a 6-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 additional heteroatom that is nitrogen.
  • the compound is a compound of Formula (IIa) :
  • R 1 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • R 1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , R 1 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , R 1 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , R 1 is -CHF 2 .
  • R Z1 is hydrogen, halogen, -SF 5 , -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.
  • R Z1 is hydrogen, halogen, -CN, or C 1 -C 6 alkyl.
  • R Z1 is -CN or C 1 -C 6 alkyl.
  • R Z1 is -CN. In some embodiments of a compound of Formula (II) or (IIa) , R Z1 is C 1 -C 6 alkyl.
  • a compound of Formula (II) or (IIa) is a single bond and X is -N-or -CR X -. In some embodiments of a compound of Formula (II) or (IIa) , is a single bond and X is -N-. In some embodiments of a compound of Formula (II) or (IIa) , is a single bond and X is -CR X -.
  • R X is hydrogen or halogen. In some embodiments of a compound of Formula (II) or (IIa) , R X is hydrogen.
  • a compound of Formula (II) or (IIa) is a double bond; and X is C.
  • Y is -NR Y1 -.
  • R Y1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , R Y1 is hydrogen.
  • Y is -C (R Y2 ) 2 -.
  • each R Y2 is independently hydrogen, halogen, -OH, or C 1 -C 6 alkyl.
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , each R 4 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , each R 4 is independently halogen. In some embodiments of a compound of Formula (II) or (IIa) , each R 4 is independently C 1 -C 6 alkyl.
  • two R 4 on the same carbon are taken together to form an oxo.
  • two R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
  • two R 4 on the same carbon are taken together to form a cycloalkyl optionally substituted with one or more R.
  • two R 4 on the same carbon are taken together to form a heterocycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a cycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a heterocycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a aryl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a heteroaryl optionally substituted with one or more R.
  • m is 0, 1, 2, or 3. In some embodiments of a compound of Formula (II) or (IIa) , m is 0, 1, or 2. In some embodiments of a compound of Formula (II) or (IIa) , m is 0 or 1. In some embodiments of a compound of Formula (II) or (IIa) , m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) , m is 0. In some embodiments of a compound of Formula (II) or (IIa) , m is 1. In some embodiments of a compound of Formula (II) or (IIa) , m is 2.
  • each R 5 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , each R 5 is independently halogen, -CN, -OH, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , each R 5 is independently halogen, -OH, or C 1 -C 6 alkyl.
  • each R 5 is independently -OH or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa) , each R 5 is independently -OH.
  • p is 0, 1, 2, or 3. In some embodiments of a compound of Formula (II) or (IIa) , p is 0, 1, or 2. In some embodiments of a compound of Formula (II) or (IIa) , p is 0 or 1. In some embodiments of a compound of Formula (II) or (IIa) , p is 0. In some embodiments of a compound of Formula (II) or (IIa) , p is 1. In some embodiments of a compound of Formula (II) or (IIa) , p is 2.
  • Z is -N-or -CR Z1 -;
  • Ring C is a 5-to 8-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 to 3 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; provided that Ring C is not piperidinyl;
  • p 0, 1, 2, or 4;
  • X is -N-or -CR X -;
  • R X is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl;
  • Y is -NR Y1 -or -C (R Y2 ) 2 -;
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
  • R 4 on different carbon taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • R 1 is hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) , R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) , R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) , R 1 is hydrogen or C 1 -C 6 alkyl.
  • R 1 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) , R 1 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) , R 1 is -CHF 2 .
  • Z is -N-. In some embodiments of a compound of Formula (III) , Z is -CR Z1 -.
  • R Z1 is hydrogen, halogen, -SF 5 , -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.
  • R Z1 is hydrogen, halogen, -CN, or C 1 -C 6 alkyl.
  • R Z1 is -CN or C 1 -C 6 alkyl.
  • R Z1 is -CN.
  • R Z1 is C 1 -C 6 alkyl.
  • a compound of Formula (III) is a single bond and X is -N-or -CR X -. In some embodiments of a compound of Formula (III) , is a single bond and X is -N-. In some embodiments of a compound of Formula (III) , is a single bond and X is -CR X -.
  • R X is hydrogen or halogen. In some embodiments of a compound of Formula (III) , R X is hydrogen.
  • a compound of Formula (III) is a double bond; and X is C.
  • Y is -NR Y1 -.
  • R Y1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) , R Y1 is hydrogen.
  • Y is -C (R Y2 ) 2 -.
  • each R Y2 is independently hydrogen, halogen, -OH, or C 1 -C 6 alkyl.
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) , each R 4 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) , each R 4 is independently halogen. In some embodiments of a compound of Formula (III) , each R 4 is independently C 1 -C 6 alkyl.
  • two R 4 on the same carbon are taken together to form an oxo.
  • two R 4 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
  • two R 4 on the same carbon are taken together to form a cycloalkyl optionally substituted with one or more R.
  • two R 4 on the same carbon are taken together to form a heterocycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a cycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a heterocycloalkyl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a aryl optionally substituted with one or more R.
  • two R 4 on different carbon are taken together to form a heteroaryl optionally substituted with one or more R.
  • m is 0, 1, 2, or 3. In some embodiments of a compound of Formula (III) , m is 0, 1, or 2. In some embodiments of a compound of Formula (III) , m is 0 or 1. In some embodiments of a compound of Formula (III) , m is 1 or 2. In some embodiments of a compound of Formula (III) , m is 0. In some embodiments of a compound of Formula (III) , m is 1. In some embodiments of a compound of Formula (III) , m is 2.
  • Ring C is a 5-to 7-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 to 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; provided that Ring C is not piperidinyl.
  • Ring C is a 5-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring C is a 7-membered heterocycloalkyl comprising 1 nitrogen atom and optionally 1 to 3 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring C is a 6-membered heterocycloalkyl comprising 1 nitrogen atom and 1 additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Ring C is a 6-membered heterocycloalkyl comprising 1 nitrogen atom and 1 additional heteroatom selected from the group consisting of nitrogen and oxygen.
  • each R 5 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) , each R 5 is independently halogen, -CN, -OH, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) , each R 5 is independently halogen, -OH, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) , each R 5 is independently -OH or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) , each R 5 is independently -OH.
  • p is 0, 1, 2, or 3. In some embodiments of a compound of Formula (III) , p is 0, 1, or 2. In some embodiments of a compound of Formula (III) , p is 0 or 1. In some embodiments of a compound of Formula (III) , p is 0. In some embodiments of a compound of Formula (III) , p is 1. In some embodiments of a compound of Formula (III) , p is 2.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, R c and R d are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, R c and R d are each hydrogen. In some embodiments of a compound disclosed herein, R c and R d are each independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -NH 2 , -NHC 1 -C 3 alkyl, -N (C 1 -C 3 alkyl) 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen or C 1 -C 3 alkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen or C 1 -C 3 alkyl.
  • one or more of R, R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 5a , R Z1 , R Z2 , R X , R Y1 , R Y2 , R a , R b , R c , and R d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 5a , R Z1 , R Z2 , R X , R Y1 , R Y2 , R a , R b , R c , and R d .
  • the abundance of deuterium in each of R, R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 5a , R Z1 , R Z2 , R X , R Y1 , R Y2 , R a , R b , R c , and R d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more 1 H of Ring A or Ring B or Ring C are replaced with one or more deuteriums.
  • the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof is one of the compounds in Table 1.
  • the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof is one of the compounds in Table 2.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Disclosed herein is method of modulating cyclic dependent kinase 8 and/or 19 (CDK8/19) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof.
  • a method of inhibiting cyclic dependent kinase 8 and/or 19 (CDK8/19) activity in a subject comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof.
  • provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition described herein.
  • the cancer is leukemia, acute myeloid leukemia (AML) , chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) , non-Hodgkin lymphoma (NHL) , Hodgkin lymphoma (HL) , or multiple myeloma (MM) .
  • the cancer is leukemia.
  • the cancer is acute myeloid leukemia (AML) .
  • the cancer is chronic myeloid leukemia.
  • the cancer is acute lymphoblastic leukemia (ALL) .
  • the cancer is non-Hodgkin lymphoma (NHL) .
  • the cancer is Hodgkin lymphoma (HL) .
  • the cancer is multiple myeloma (MM) .
  • the cancer is a solid cancer.
  • the cancer is a skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, pancreatic cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.
  • the cancer is a prostate cancer, breast cancer, colon cancer, pancreatic cancer, skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, head and neck squamous cell carcinomas, or melanoma.
  • the cancer is a prostate cancer, breast cancer, colon cancer, pancreatic cancer, head and neck squamous cell carcinomas, or melanoma.
  • the cancer is a prostate cancer.
  • the cancer is a breast cancer.
  • the cancer is a colon cancer. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a head and neck squamous cell carcinomas. In some embodiments, the cancer is a melanoma.
  • a method of treating an autoimmune disease or disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition described herein.
  • compositions containing the compound (s) described herein are administered for therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • the second therapeutic agent is a monoclonal antibody.
  • the monoclonal antibody is selected from edrecolomab, rituximab, gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, tositumomab, cetuximab, bevacizumab, and trastuzumab.
  • the second therapeutic agent is an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.
  • the immune checkpoint inhibitor is Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, or Cemiplimab.
  • the second therapeutic agent is chemotherapy (such as fulvestrant or cytarabine) target therapy or an immune checkpoint inhibitor.
  • the second therapeutic is fulvestrant or cytarabine.
  • the second therapeutic agent is a CDK4/6 inhibitor, BCL-2 inhibitor, EGFR inhibitor, JAK1/2 inhibitor, anti-PD-L1 inhibitor, or anti-PD1 inhibitor.
  • Step 4 9-Methyl-5, 6-dihydro-4H-pyrrolo [3, 2, 1-ij] quinoline-1-carboxylic acid
  • Step 5 N- (Tert-butyl) -9-methyl-5, 6-dihydro-4H-pyrrolo [3, 2, 1 -ij] quinoline-1-carboxamide
  • Step 6 9-Methyl-5, 6-dihydro-4H-pyrrolo [3, 2, 1-ij] quinoline-1-carbonitrile
  • Step 7 2-Chloro-9-methyl-5, 6-dihydro-4H-pyrrolo [3, 2, 1-ij] quinoline-1-carbonitrile
  • Step 4 Tert-butyl 4- (4-amino-5, 6-dibromo-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate
  • Step 4 8-Methyl-3, 4-dihydro-5-oxa-1, 2a-diazaacenaphthylen-2 (1H) -one
  • Step 5 2-Chloro-8-methyl-3, 4-dihydro-5-oxa-1, 2a-diazaacenaphthylene
  • Step 6 Tert-butyl 4- (8-methyl-3, 4-dihydro-5-oxa-1, 2a-diazaacenaphthylen-2-yl) piperazine-1-carboxylate
  • Step 7 Tert-butyl 4- (6, 7-dibromo-8-methyl-3, 4-dihydro-5-oxa-1, 2a-diazaacenaphthylen-2-yl) piperazine-1-carboxylate
  • Step 8 6, 7-Dibromo-8-methyl-2- (piperazin-1-yl) -3, 4-dihydro-5-oxa-1, 2a-diazaacenaphthylene
  • Step 1 Tert-butyl 4- (1-cyano-9-methyl-5, 6-dihydro-4H-pyrrolo [3, 2, 1-ij] quinolin-2-yl) piperazine-1-carboxylate
  • Step 2 7, 8-Dibromo-9-methyl-2- (piperazin-1-yl) -5, 6-dihydro-4H-pyrrolo [3, 2, 1-ij] quinoline-1-carbonitrile
  • Example 3 was synthesized by replacing tert-butyl piperazine-1-carboxylate with 1-methylpiperazine.
  • Step 1 tert-butyl 4- (1-cyano-9-methyl-5, 6-dihydro-4H-pyrrolo [3, 2, 1-ij] quinolin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate
  • Step 2 tert-butyl 4- (1-cyano-9-methyl-5, 6-dihydro-4H-pyrrolo [3, 2, 1-ij] quinolin-2-yl) piperidine-1-carboxylate
  • Step 3 7, 8-dibromo-9-methyl-2- (piperidin-4-yl) -5, 6-dihydro-4H-pyrrolo [3, 2, 1-ij] quinoline-1-carbonitrile
  • Step 4 tert-butyl 4- (3-cyano-4-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-indol-2-yl) piperazine-1-carboxylate
  • Step 5 5, 6-dibromo-4-methyl-2- (piperazin-1-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-indole-3-carbonitrile
  • Step 1 7-methyl-3, 4-dihydronaphthalen-1 (2H) -one oxime
  • Step 3 methyl 8-methyl-2, 3, 4, 5-tetrahydro-1H-benzo [b] azepine-1-carboxylate
  • Step 4 methyl 7-bromo-8-methyl-2, 3, 4, 5-tetrahydro-1H-benzo [b] azepine-1-carboxylate
  • Step 5 methyl 7-bromo-8-methyl-9-nitro-2, 3, 4, 5-tetrahydro-1H-benzo [b] azepine-1-carboxylate
  • Step 6 4-bromo-3-methyl-6, 7, 8, 9-tetrahydro-2, 9a-diazabenzo [cd] azulen-1 (2H) -one
  • Step 7 4-bromo-1-chloro-3-methyl-6, 7, 8, 9-tetrahydro-2, 9a-diazabenzo [cd] azulene
  • Step 8 tert-butyl 4- (4-bromo-3-methyl--6, 7, 8, 9-tetrahydro-2, 9a-diazabenzo [cd] azulen-1-yl) piperazine-1-carboxylate
  • Step 9 tert-butyl 4- (4, 5-dibromo-3-methyl-6, 7, 8, 9-tetrahydro-2, 9a-diazabenzo [cd] azulen-1-yl) piperazine-1-carboxylate
  • Step 10 4, 5-dibromo-3-methyl-1- (piperazin-1-yl) -6, 7, 8, 9-tetrahydro-2, 9a-diazabenzo [cd] azulene
  • Step 3 5, 6-dibromo-1- (3, 3-dimethylcyclopentyl) -4-methyl-2- (piperazin-1-yl) -1H-benzo [d] imidazole
  • Step 1 Intermediate 9.1: tert-butyl 4- (5, 6-dibromo-1-cyclopentyl-4-methyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate
  • Step 2 5, 6-dibromo-1-cyclopentyl-4-methyl-2- (piperazin-1-yl) -1H-benzo [d] imidazole
  • Step 2 5, 6-dibromo-1-cyclopentyl-7-methyl-2- (piperazin-1-yl) -1H-benzo [d] imidazole
  • Step 1 Intermediate 11.1: tert-butyl 4- (5, 6-dibromo-4-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate
  • Step 2 Example 11: 5, 6-dibromo-4-methyl-2- (piperazin-1-yl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole,
  • Example 11 (40 mg, 0.087 mmol, HCOOH salt) and a crude of Example 12.
  • the crude was re-purified by prep-HPLC to give Example 12 (10 mg, 0.022 mmol, 8.2%yield) .
  • Example 11 LC-MS (ESI+) : m/z 457.1, (M+H) + .
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 12 LC-MS (ESI+) : m/z 457.1, (M+H) + .
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 7.78 s, 1H
  • 4.54 -4.45 m, 1H
  • 4.14 m, 2H
  • 3.64 -3.57 m, 2H
  • 3.33 -3.21 m, 4H
  • 3.09 -3.01 m, 4H
  • 2.68 (s, 3H) 2.55 -2.45 (m, 2H) , 1.85 -1.75 (m, 2H) .
  • Step 1 tert-butyl 4- (5, 6-dibromo-1-cyclopentyl-4, 7-dimethyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate
  • Step 2 5, 6-dibromo-1-cyclopentyl-4, 7-dimethyl-2- (piperazin-1-yl) -1H-benzo [d] imidazole
  • Example 14 was synthesized by replacing intermediate 2 tert-butyl 4- (5, 6-dibromo-4-methyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate with intermediate 3 tert-butyl 4- (5, 6-dibromo-4, 7-dimethyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate.
  • the crude product was purified by prep-HPLC to give the title compound.
  • LC-MS (ESI+) m/z 471.0 (M+H) + .
  • Step 2 4, 7-dimethyl-1-phenyl-1, 3-dihydro-2H-benzo [d] imidazol-2-one
  • Example 15 was synthesized by replacing 4, 7-dimethyl-1, 3-dihydro-2H-benzo [d] imidazol-2-one with 4, 7-dimethyl-1-phenyl-1, 3-dihydro-2H-benzo [d] imidazol-2-one.
  • the crude product was purified by prep-HPLC to give the title compound.
  • LC-MS (ESI+) m/z 463.2 (M+H) + .
  • Step 1 tert-butyl 4- (5, 6-dibromo-4-methyl-1-phenyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate
  • Step 2 5, 6-dibromo-4-methyl-1-phenyl-2- (piperazin-1-yl) -1H-benzo [d] imidazole
  • Step 2 4, 5-dibromo-3-methyl-N- (4- (1-methyl-1H-pyrazol-5-yl) phenyl) -2-nitroaniline
  • Step 3 4, 5-dibromo-3-methyl-N1- (4- (1-methyl-1H-pyrazol-5-yl) phenyl) benzene-1, 2-diamine
  • Example 17 was synthesized by replacing 6-methyl-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-5-amine with 4, 5-dibromo-3-methyl-N1- (4- (1-methyl-1H-pyrazol-5-yl) phenyl) benzene-1, 2-diamine. There was no bromination step for Example 17. The crude product was purified by prep-HPLC to give the title compound. LC-MS (ESI+) : m/z 529.1 (M+H) + .
  • Example 18 was synthesized by replacing 4- (1-methyl-1H-pyrazol-5-yl) aniline with 1-methyl-1H-indazol-5-amine. The crude product was purified by prep-HPLC to give the title compound. LC-MS (ESI+) : m/z 503.1 (M+H) + .
  • Example 19 and Example 20 were synthesized by replacing tetrahydro-2H-pyran-4-yl methanesulfonate with 1- (1-methyl-1H-pyrazol-3-yl) piperidin-4-yl methanesulfonate.
  • Example 21 and Example 22 were synthesized by replacing 1- (1-methyl-1H-pyrazol-3-yl) piperidin-4-ol with cyclopropyl (4-hydroxypiperidin-1-yl) methanone.
  • Example 23 and Example 24 were synthesized by replacing 1- (1-methyl-1H-pyrazol-3-yl) piperidin-4-ol with 1- ( (1s, 4s) -4-hydroxycyclohexyl) pyrrolidin-2-one.
  • Example 25 and Example 26 were synthesized by replacing cyclopropanecarbonyl chloride with acetyl chloride.
  • Example 27 and Example 28 were synthesized by replacing tetrahydro-2H-pyran-4-yl methanesulfonate with 1-(methylsulfonyl) piperidin-4-yl methanesulfonate.
  • Example 30 and Example 31 were synthesized by replacing tetrahydro-2H-pyran-4-yl methanesulfonate with trans-4-hydroxycyclohexyl methanesulfonate.
  • Example 32 and Example 33 were synthesized by replacing trans-cyclohexane-1, 4-diol with cis-cyclohexane-1, 4-diol.
  • Step 1 To a mixture of 5, 6-dibromo-2-chloro-1H-benzo [d] imidazole (50.00 g, 161.08 mmol) , Cs 2 CO 3 (157.10 g, 483.35 mmol) and tetrabutylammonium iodide (17.80 g, 48.24 mmol) in NMP (500 mL) was added tetrahydropyran-4-ylmethanesulfonate (87.10 g, 483.38 mmol) at 20 °C. After addition, the mixture was stirred at 130 °C for 4 hrs.
  • Step 2 To a solution of 5, 6-dibromo-2-chloro-1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (5.00 g, 12.67 mmol) in THF (50 mL) was added lithium 2, 2, 6, 6-tetramethyl piperidine (25.35 mL, 25.14 mmol) dropwise at -78 °C over 1 hr. After addition, the mixture was stirred at -78 °C for 1 hr, and then DMF (1.95 mL, 25.99 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 hr under N 2 .
  • Step 3 To a solution of 5, 6-dibromo-2-chloro-1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-carbaldehyde (7.70 g, 18.22 mmol) in DCM (100 mL) was added DAST (12 mL, 91.19 mmol) at 0 °C. After addition, the mixture was stirred at 50 °C for 2 hrs under N 2 . After cooling to 20 °C, the resulting mixture was quenched with water (500 mL) and extracted with DCM (300 mL ⁇ 2) .
  • Step 1 To a solution of 5, 6-dibromo-2-chloro-4-nitro-1H-benzo [d] imidazole (5.00 g, 14.07 mmol) and DIEA (5.50 g, 42.57 mmol) in NMP (20 mL) was added tert-butyl (S) -3-methylpiperazine-1-carboxylate (2.80 g, 13.98 mmol) at 20 °C. After addition, the reaction mixture was stirred at 150 °C for 6 hrs under N 2 . After cooling to 20 °C. The reaction solution was poured into ice water (100 mL) and extracted with EtOAc (100 mL ⁇ 3) .
  • Step 2 To a solution of tert-butyl (S) -4- (5, 6-dibromo-4-nitro-1H-benzo [d] imidazol-2-yl) -3-methylpiperazine-1-carboxylate (3.00 g, 5.78 mmol) and NH 4 Cl (3.10 g, 57.94 mmol) in EtOH (50 mL) and water (10 mL) was added Fe (3.20 g, 57.94 mmol) at 20 °C. After addition, the reaction mixture was stirred at 50 °C for 2 hrs. After cooling to 20 °C. The reaction mixture was filtered and concentrated to dryness under reduced pressure to afford the desired product.
  • Step 3 To a solution of tert-butyl (S) -4- (4-amino-5, 6-dibromo-1H-benzo [d] imidazol-2-yl) -3-methylpiperazine-1-carboxylate (2.70 g, 5.52 mmol) and TsOH (2.80 g, 16.28 mmol) in MeCN (100 mL) and water (20 mL) was added sodium nitrite (0.80 g, 11.59 mmol) in portions at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 30 min. Then potassium iodide (2.30 g, 13.86 mmol) was added at 0 °C.
  • Step 4 To a solution of tert-butyl (S) -4- (5, 6-dibromo-4-iodo-1H-benzo [d] imidazol-2-yl) -3-methylpiperazine-1-carboxylate (2.70 g, 4.50 mmol) , Na 2 CO 3 (1.40 g, 13.21 mmol) and potassium vinyltrifluoroborate (1.20 g, 8.96 mmol) in 1, 4-dioxane (50 mL) and water (10 mL) was added Pd (dppf) Cl 2 (0.30 g, 0.41 mmol) .
  • Step 5 To a solution of tert-butyl (S) -4- (5, 6-dibromo-4-vinyl-1H-benzo [d] imidazol-2-yl) -3-methylpiperazine-1-carboxylate (1.70 g, 3.41 mmol) , Cs 2 CO 3 (4.40 g, 13.51 mmol) and tetrabutylammonium iodide (0.50 g, 1.36 mmol) in NMP (20 mL) was added tetrahydro-2H-pyran-4-yl methanesulfonate (2.40 g, 13.32 mmol) at 20 °C.
  • Step 6 To a solution of tert-butyl (S) -4- (5, 6-dibromo-1- (tetrahydro-2H-pyran-4-yl) -4-vinyl-1H-benzo [d] imidazol-2-yl) -3-methylpiperazine-1-carboxylate (200.0 mg, 0.34 mmol) in THF (5 mL) and water (5 mL) was added NaIO 4 (218.7 mg, 1.03 mmol) and potassium osmate dihydrate (8.7 mg, 0.03 mmol) at 0 °C. After addition, the mixture was stirred at 20 °C for 2 hrs.
  • Step 7 To a solution of tert-butyl (S) -4- (5, 6-dibromo-4-formyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) -3-methylpiperazine-1-carboxylate (200.0 mg, 0.34 mmol) in DCM (5 mL) was added DAST (0.22 mL, 1.70 mmol) dropwise at 0 °C. After addition, the mixture was stirred at 50 °C for 2 hrs under N 2 . After cooling to 20 °C, the reaction solution was poured into ice water (50 mL) and extracted with DCM (50 mL ⁇ 2) .
  • Step 8 To a solution of tert-butyl (S) -4- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) -3-methylpiperazine-1-carboxylate (150.0 mg, 0.21 mmol) in EtOAc (3 mL) was added HCl/1, 4-dioxane (3 mL, 4 M) , the mixture was stirred at 20 °C for 4 hrs under N 2 .
  • example 35 was synthesized by replacing tert-butyl (S) -3-methylpiperazine-1-carboxylate with tert-butyl (R) -3-methylpiperazine-1-carboxylate.
  • example 36 was synthesized by replacing tert-butyl (S) -3-methylpiperazine-1-carboxylate with tert-butyl (R) -2-methylpiperazine-1-carboxylate.
  • the crude was purified by prep-HPLC (Column: YMC-ACTUS Prep OBD C18 20 ⁇ 250 mm ⁇ 5 ⁇ m; Mobile phase: from 30%to 50%MeCN in water [0.1%NH 4 OH] ; Wavelength: 220 nm; Flow rate: 20 mL/min, 20 min) to afford the desired product example 36.
  • example 37 was synthesized by replacing tert-butyl (S) -3-methylpiperazine-1-carboxylate with tert-butyl (S) -2-methylpiperazine-1-carboxylate.
  • the crude was purified by prep-HPLC (Column: Waters Xbridge Prep OBD C18 20 ⁇ 250 mm ⁇ 5 ⁇ m; Mobile phase: from 40%to 60%MeCN in water [0.1%NH 4 OH] ; Wavelength: 220 nm; Flow rate: 20 mL/min, 20 min) to afford example 37.
  • Step 1 To a solution of 5, 6-dibromo-2-chloro-4-nitro-1H-benzo [d] imidazole (5.00 g, 14.07 mmol) and DIEA (5.50 g, 42.21 mmol) in NMP (50 mL) was added tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate (6.10 g, 28.10 mmol) at 20 °C. After addition, the mixture was stirred at 150 °C for 6 hrs under N 2 . After cooling to 20 °C. The reaction solution was poured into ice water (200 mL) and extracted with EtOAc (100 ⁇ 3 mL) .
  • Step 2 To a solution of tert-butyl (R) -4- (5, 6-dibromo-4-nitro-1H-benzo [d] imidazol-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (4.80 g, 8.97 mmol) and NH 4 Cl (4.80 g, 89.69 mmol) in EtOH (50 mL) and water (10 mL) was added Fe (5.0 g, 89.69 mmol) . After addition, the mixture was stirred at 50 °C for 2 hr. After cooling to 20 °C. The mixture was filtered and the filter cake was washed with EtOH (50 mL ⁇ 3) .
  • Step 3 To a solution of tert-butyl (R) -4- (4-amino-5, 6-dibromo-1H-benzo [d] imidazol-2-yl) -3-(hydroxymethyl) piperazine-1-carboxylate (4.00 g, 7.92 mmol) and TsOH (4.10 g, 23.75 mmol) in MeCN (100 mL) and water (20 mL) was added sodium nitrite (1.10 g, 15.84 mmol) at 0 °C, the reaction mixture was stirred at 0 °C for 1 hr. Then potassium iodide (3.30 g, 19.79 mmol) was added at 0 °C.
  • Step 4 To a solution of tert-butyl (R) -4- (5, 6-dibromo-4-iodo-1H-benzo [d] imidazol-2-yl) -3-(hydroxymethyl) piperazine-1-carboxylate (2.50 g, 4.06 mmol) , Na 2 CO 3 (1.30 g, 12.17 mmol) and potassium vinyltrifluoroborate (1.40 g, 10.14 mmol) in 1, 4-dioxane (50 mL) and water (10 mL) was added Pd (dppf) Cl 2 (0.30 g, 0.41 mmol) .
  • Step 5 To a solution of tert-butyl (R) -4- (5, 6-dibromo-4-vinyl-1H-benzo [d] imidazol-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (500.0 mg, 0.97 mmol) , Cs 2 CO 3 (1262.7 mg, 3.87 mmol) and tetrabutylammonium iodide (148.0 mg, 0.39 mmol) in NMP (10 mL) was added tetrahydro-2H-pyran-4-ylmethanesulfonate (698.2 mg, 3.87 mmol) . After addition, the mixture was stirred at 130 °C for 12 hrs under N 2 .
  • Step 6 To a solution of tert-butyl (R) -4- (5, 6-dibromo-1- (tetrahydro-2H-pyran-4-yl) -4-vinyl-1H-benzo [d] imidazol-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (220.0 mg, 0.37 mmol) and 1H-imidazole (99.7 mg, 1.47 mmol) in DCM (6 mL) was added TBSCl (121.5 mg, 0.81 mmol) at 0 °C. After addition, the reaction was stirred at 20 °C for 1 hr.
  • Step 7 To a solution of tert-butyl (R) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -4- (5, 6-dibromo-1- (tetrahydro-2H-pyran-4-yl) -4-vinyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (100.0 mg, 0.14 mmol) in THF (3 mL) and water (3 mL) was added NaIO 4 (89.4 mg, 0.42 mmol) and potassium osmate dihydrate (5.2 mg, 0.014 mmol) at 0 °C. After addition, the reaction was stirred at 20 °C for 4 hrs.
  • Step 8 To a solution of tert-butyl (R) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -4- (5, 6-dibromo-4-formyl-1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (70.0 mg, 0.098 mmol) in DCM (10 mL) was added DAST (78.7 mg, 0.49 mmol) dropwise at 0 °C After addition, the mixture was stirred at 50 °C for 2 hrs under N 2 .
  • Step 9 To a solution of tert-butyl (R) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -4- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (40.0 mg, 0.054 mmol) in THF (3 mL) was added TBAF (17.0 mg, 0.065 mmol) at 0 °CAfter addition, the mixture was stirred at 20 °C for 1 hr under N 2 .
  • Step 10 To a solution of tert-butyl (R) -4- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (25.0 mg, 0.04 mmol) in EtOAc (4 mL) was added HCl/1, 4-dioxane (2 mL, 4 M) at 0 °C. After addition, the mixture was stirred at 20 °C for 4 hrs under N 2 .
  • example 39 was synthesized by replacing tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate with tert-butyl (S) -3- (hydroxymethyl) piperazine-1-carboxylate.
  • the crude was purified by prep-HPLC (Column: YMC-ACTUS Prep OBD C18 20 ⁇ 250 mm ⁇ 5 ⁇ m; Mobile phase: from 20%to 50%MeCN in water [0.1%NH 4 OH] ; Wavelength: 220 nm; Flow rate: 20 mL/min, 20 min) to afford example 39.
  • example 40 was synthesized by replacing tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate with tert-butyl (R) -2- (hydroxymethyl) piperazine-1-carboxylate.
  • the crude was purified by prep-HPLC (Column: Waters Xbridge Prep OBD C18 20 ⁇ 250 mm ⁇ 10 ⁇ m; Mobile phase: from 20%to 40%MeCN in water [0.1%NH 4 OH] ; Wavelength: 220 nm; Flow rate: 20 mL/min, 20 min) to afford example 40.
  • example 41 was synthesized by replacing tert-butyl (S) -3-methylpiperazine-1-carboxylate with tert-butyl (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate.
  • the crude was purified by prep-HPLC (Column: YMC-ACTUS Prep OBD C18 20 ⁇ 250 mm ⁇ 5 ⁇ m; Mobile phase: from 50%to 70%MeCN in water [0.1%NH 4 OH] ; Wavelength: 220 nm; Flow rate: 20 mL/min, 20 min) to afford the desired product example 41.
  • Step 1 To a solution of 5, 6-dibromo-2-chloro-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (1.00 g, 2.25 mmol) and DIEA (1.12 mL, 6.97 mmol) in NMP (10 mL) was added tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate (1.50 g, 6.93 mmol) . After addition, the reaction mixture was stirred at 150 °C for 10 hrs under N 2 .
  • Step 2 To a solution of tert-butyl (R) -4- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (400.0 mg, 0.64 mmol) in DCM (5 mL) was added Dess-Martin periodinane (543.5 mg, 1.28 mmol) . After addition, the reaction mixture was stirred at 20 °C for 8 hrs. The suspension was filtered. The filter cake was washed with DCM (20 mL ⁇ 3) .
  • Step 3 To a solution of tert-butyl (R) -4- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) -3-formylpiperazine-1-carboxylate (200.0 mg, 0.32 mmol) in MeOH (4 mL) were added dimethyl (1-diazo-2-oxopropyl) phosphonate (123.5 mg, 0.64 mmol) and K 2 CO 3 (88.8 mg, 0.64 mmol) at 0 °C. After addition, the mixture was stirred at 20 °C for 10 hrs.
  • Step 4 To a solution of tert-butyl (S) -4- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) -3-ethynylpiperazine-1-carboxylate (140.0 mg, 0.23 mmol) in EtOAc (4 mL) was added HCl/1, 4-dioxane (3 mL, 4 M) . After addition, the mixture was stirred at 20 °Cfor 4 hrs under N 2 .
  • example 43 was synthesized by replacing tetrahydro-2H-pyran-4-yl methanesulfonate with (3-endo) -8-oxabicyclo [3.2.1] octan-3-yl methanesulfonate.
  • the crude was purified by prep-HPLC (Column: YMC-ACTUS Prep OBD C18 20 ⁇ 250 mm ⁇ 5 ⁇ m; Mobile phase: from 30%to 60%MeCN in water [0.1%NH 4 OH] ; Wavelength: 220 nm; Flow rate: 20 mL/min, 20 min) to afford the desired product example 43.
  • example 44 was synthesized by replacing tert-butyl (S) -3-methylpiperazine-1-carboxylate with tert-butyl piperazine-1-carboxylate.
  • Step 1 To a solution of 5, 6-dibromo-2-chloro-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (500.0 mg, 1.13 mmol) and DIEA (436.0 mg, 3.38 mmol) in NMP (1 mL) was added tert-butyl (S) -3- (cyanomethyl) piperazine-1-carboxylate (1267.2 mg, 5.62 mmol) . After addition, the mixture was stirred at 150 °C for 6 hrs under N 2 .
  • Step 2 To a solution of tert-butyl (S) -3- (cyanomethyl) -4- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (160.0 mg, 0.25 mmol) in EtOAc (2 mL) was added HCl/1, 4-dioxane (2 mL, 4 M) . After addition, the mixture was stirred at 20 °C for 4 hrs under N 2 .
  • Step 1 To a mixture of tert-butyl 4- (5, 6-dibromo-4-vinyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (100.0 mg, 0.21 mmol) , Cs 2 CO 3 (268.5 mg, 0.83 mmol) and tetrabutylammonium iodide (22.8 mg, 0.06 mmol) in NMP (2 mL) was added 1, 1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (376.2 mg, 1.65 mmol) at 20 °C. After addition, the mixture was stirred at 130 °C for 4 hrs.
  • Step 2 To a solution of tert-butyl 4- (5, 6-dibromo-1- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -4-vinyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (100.0 mg, 0.16 mmol) in THF (10 mL) and water (10 mL) were added NaIO 4 (103.3 mg, 0.49 mmol) and potassium osmate dihydrate (4.1 mg, 0.02 mmol) at 0 °C. After addition, the reaction was stirred at 20 °C for 2 hrs.
  • Step 3 To a solution of tert-butyl 4- (5, 6-dibromo-1- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -4-formyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (90.0 mg, 0.15 mmol) in DCM (10 mL) was added DAST (0.10 mL, 0.73 mmol) dropwise at 0 °C. After addition, the mixture was stirred at 50 °C for 2 hrs under N 2 . After cooling to 20 °C, the reaction solution was poured into ice water (50 mL) and extracted with DCM (50 mL ⁇ 2) .
  • Step 4 To a solution of tert-butyl 4- (5, 6-dibromo-4- (difluoromethyl) -1- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (20.0 mg, 0.03 mmol) in EtOAc (2 mL) was added HCl/1, 4-dioxane (3 mL, 4 M) dropwise at 0 °C. After addition, the mixture was stirred at 20 °C for 1 hr.
  • Step 1 To a solution of 5, 6-dibromo-2-chloro-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (20.0 mg, 0.045 mmol) and DIEA (0.02 mL, 0.135 mmol) in NMP (2 mL) was added tert-butyl piperidin-4-ylcarbamate (27.0 mg, 0.135 mmol) . After addition, the mixture was stirred at 130 °C for 4 hrs under N 2 . After cooling to 20 °C, The reaction solution was poured into ice water (20 mL) and extracted with EtOAc (10 mL ⁇ 3) .
  • Step 2 To a solution of tert-butyl (1- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) piperidin-4-yl) carbamate (50.0 mg, 0.082 mmol) in EtOAc (1 mL) was added HCl/1, 4-dioxane (2 mL, 4 M) . After addition, the mixture was stirred at 20 °C for 2 hrs under N 2 .
  • Step 1 To a solution of 5, 6-dibromo-2-chloro-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (35.0 mg, 0.08 mmol) in NMP (2 mL) were added DIEA (0.01 mL, 0.08 mmol) and tert-butyl (R) -pyrrolidin-3-ylcarbamate (14.7 mg, 0.08 mmol) at 20 °C. After addition, the mixture was stirred at 130 °C for 2 hrs.
  • Step 2 To a solution of tert-butyl (R) - (1- (5, 6-dibromo-7- (difluoromethyl) -3- (tetrahydro-2H-pyran-4-yl) -3H-imidazo [4, 5-b] pyridin-2-yl) pyrrolidin-3-yl) carbamate (13.0 mg, 0.02 mmol) in EtOAc (2 mL) was added HCl/1, 4-dioxane (1 mL, 4 M) dropwise at 0 °C. After addition, the mixture was stirred at 25 °C for 30 mins.
  • Step 1 To a solution of 5, 6-dibromo-2-chloro-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (20.0 mg, 0.05 mmol) in NMP (1 mL) were added DIEA (0.01 mL, 0.05 mmol) and tert-butyl (S) -pyrrolidin-3-ylcarbamate (8.4 mg, 0.05 mmol) at 25 °C. After addition, the mixture was stirred at 130 °C for 2 hrs.
  • Step 2 To a solution of tert-butyl (S) - (1- (5, 6-dibromo-4- (difluoromethyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-2-yl) pyrrolidin-3-yl) carbamate (11.0 mg, 0.02 mmol) in EtOAc (1 mL) was added HCl/1, 4-dioxane (1 mL, 4 M) dropwise at 0 °C. After addition, the mixture was stirred at 25 °C for 30 mins.
  • Step 1 To a solution of tert-butyl 4- (5, 6-dibromo-4-vinyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (500.0 mg, 1.03 mmol) , Cs 2 CO 3 (1671.1 mg, 5.14 mmol) and tetrabutylammonium iodide (37.9 mg, 0.10 mmol) in NMP (7 mL) was added tetrahydro-2H-thiopyran-4-yl methanesulfonate (1009.4 mg, 5.14 mmol) at 20 °C. After addition, the mixture was stirred at 130 °Cfor 10 hrs under N 2 .
  • Step 2 To a solution of tert-butyl 4- (5, 6-dibromo-1- (tetrahydro-2H-thiopyran-4-yl) -4-vinyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (330.0 mg, 0.56 mmol) in DCM (5 mL) were added PhI (OAc) 2 (401.3 mg, 1.24 mmol) and ammonium carbamate (153.8 mg, 1.97 mmol) . After addition, the reaction was stirred at 20 °C for 12 hrs under N 2 . The reaction solution was poured into water (10 mL) and extracted with DCM (20 mL ⁇ 3) .
  • Step 3 To a solution of tert-butyl 4- (5, 6-dibromo-1- (1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl) -4-vinyl-1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (195.0 mg, 0.32 mmol) in THF (5 mL) and H 2 O (5 mL) were added NaIO 4 (269.1 mg, 1.26 mmol) and potassium osmate dihydrate (11.2 mg, 0.032 mmol) at 0 °C. After addition, the reaction mixture was stirred at 20 °C for 2 hrs.
  • Step 4 To a solution of tert-butyl 4- (5, 6-dibromo-4-formyl-1- (1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl) -1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (180.0 mg, 0.29 mmol) in DCM (5 mL) was added DAST (234.2 mg, 1.45 mmol) dropwise at 0 °C. After addition, the mixture was stirred at 50 °C for 2 hrs under N 2 . After cooling to 20 °C, the reaction solution was poured into water (20 mL) and extracted with DCM (30 mL ⁇ 3) .
  • Step 5 To a solution of tert-butyl4- (5, 6-dibromo-4- (difluoromethyl) -1- (1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl) -1H-benzo [d] imidazol-2-yl) piperazine-1-carboxylate (20.0 mg, 0.031 mmol) in EtOAc (2 mL) was added HCl/1, 4-dioxane (2 mL, 4 M) at 0 °C. After addition, the mixture was stirred at 20 °C for 2 hr.
  • Compound IC 50 were determined against CDK8.
  • Compound serial dilution is performed by Echo, and the final concentrations vary from 1 ⁇ M to 0.017 nM. This was filled by the addition of 5 ⁇ L /well of Enzyme &antibodies mixture to the assay plate containing the compound. The plate was centrifuged at 1000 rpm about 15 seconds, and incubate 15 minutes at 23 °C. Then 5 ⁇ L /well of tracer solution was added to initiate the reaction. Next the plate was centrifuged at 1000 rpm for about 15 seconds and a film seal was used to cover the assay plate. This was followed by incubation for 90 min at 23 °C.
  • the assay plate was analyzed on Envision.
  • Compound IC 50 were determined against CDK19 in a similar manner to CDK8.
  • Example A2 KG-1 cell viability test by CellTiter-Glo assay
  • Compound IC 50 were determined against KG-1.
  • KG-1 cells were cultured and maintained in IMDM +20%FBS media. Count the cell numbers with Vi-cell XR and adjust cells to appropriate density.
  • the compounds were dissolved in DMSO of 10 mM stock solution.
  • the start working concentration (0.2 mM) was prepared with DMSO.
  • Staurosporine was prepared in DMSO at working concentration.
  • the CellTiter-Glo substrate should go into solution easily in less than one minute.
  • Example A3 MV-4-11 cell viability test by CellTiter-Glo assay
  • the compounds were dissolved in DMSO of 10 mM stock solution.
  • the starting working concentration (2 mM) were prepared with DMSO.
  • the CellTiter-Glo substrate should go into solution easily in less than one minute.

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Abstract

L'invention concerne des composés et des procédés de modulation ou d'inhibition de CDK8/19.
PCT/CN2023/100207 2022-06-15 2023-06-14 Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation WO2023241627A1 (fr)

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