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WO2025060975A1 - Novel compounds as pkmyt1 inhibitors and use thereof - Google Patents

Novel compounds as pkmyt1 inhibitors and use thereof Download PDF

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Publication number
WO2025060975A1
WO2025060975A1 PCT/CN2024/119019 CN2024119019W WO2025060975A1 WO 2025060975 A1 WO2025060975 A1 WO 2025060975A1 CN 2024119019 W CN2024119019 W CN 2024119019W WO 2025060975 A1 WO2025060975 A1 WO 2025060975A1
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Prior art keywords
alkyl
heterocycloalkyl
cycloalkyl
compound
heteroaryl
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PCT/CN2024/119019
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French (fr)
Inventor
Xiao DING
Feng Ren
Chao Wang
Yazhou WANG
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • DNA is continuously subjected to both endogenous insults (e.g., stalled replication forks, reactive oxygen species) and exogenous insults (UV, ionizing radiation, chemical) that can lead to DNA damage.
  • endogenous insults e.g., stalled replication forks, reactive oxygen species
  • exogenous insults UV, ionizing radiation, chemical
  • WEE kinase family consists of three members: WEE1, PKMYT1, and the less important WEE1B.
  • PKMYT1 functions as negative regulators of the cell cycle by inhibiting the CDK1-cyclin B complex.
  • CDK1 a master regulator of the cell cycle, is essential for entry into mitosis, meaning that PKMYT1 might be expected to act as tumor suppressors by preventing CDK1 activation.
  • the concomitant inhibition of WEE1 and PKMYT1 leads to strong cytotoxic effects.
  • PKMYT1 is a promising target for anti-cancer therapy.
  • PKMYT1 has also been implicated in many cancer types, including gastric cancer, non-small-cell lung cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, and colorectal cancer, etc., in which overexpression of PKMYT1 generally correlates with poor prognosis and disease progression. Therefore, selective targeting PKMYT1 with small molecules provides new opportunities for cancer therapy.
  • novel compounds as PKMYT1 inhibitors Disclosed herein are novel compounds as PKMYT1 inhibitors. As a result, the compounds of the present disclosure are particularly useful in the modulation of PKMYT1 and thus in the treatment of PKMYT1-associated diseases and conditions.
  • the present disclosure provides a compound of Formula (V) , or a pharmaceutically acceptable salt thereof:
  • the present disclosure provides a compound of Formula (I) , or a pharmaceutically acceptable salt thereof:
  • the compound is of Formula (Ia) :
  • a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt thereof, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • a compound disclosed herein e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2
  • a pharmaceutically acceptable salt thereof, or stereoisomer thereof e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
  • the compound disclosed herein e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2
  • a pharmaceutically acceptable salt, or stereoisomer thereof e.g., a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
  • Also disclosed herein is a method of modulating PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
  • the compound disclosed herein e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2
  • a pharmaceutically acceptable salt, or stereoisomer thereof e.g., a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
  • Also disclosed herein is a method of inhibiting PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
  • the subject has cancer.
  • the cancer depends on the activity of PKMYT1.
  • the cancer overexpresses CCNE1.
  • the cancer has an inactivating mutation in the FBXW7 gene.
  • the cancer is a solid tumor.
  • the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, or uterine cancer.
  • compositions for treating a PKMYT1-associated disease or condition comprising the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2
  • Also disclosed herein is use of the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a PKMYT1-associated disease or condition, such as cancer.
  • a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2 or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a PKMYT1-associated disease or condition, such as cancer.
  • a kit for treating a PKMYT1-associated disease or condition such as cancer comprising the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein, a container, and optionally a package insert or label indicating treatment of said disease or condition.
  • the compound disclosed herein e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2
  • a pharmaceutically acceptable salt, or stereoisomer thereof e.g., a pharmaceutically acceptable salt, or stereoisomer thereof
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • C i -C j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1 -C 6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • Amino refers to the group -NR a R b , wherein R a and R b are independently selected from groups consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl or other suitable organic groups and each of which may be optionally substituted.
  • 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
  • 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 one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkylidenyl is a divalent group formed from alkanes by removal of two hydrogen atoms from the same carbon atom, the free valencies of which are part of a double bond attached to the rest part of the molecule. For example, in the compound below:
  • the alkylidenyl group is enclosed by the box which is indicated by the arrow.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • the group may be in either the cis or trans conformation, or alternatively, E or Z conformation about the double bond (s) , and should be understood to include both isomers.
  • 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 one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with one or more substituents, such as 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 one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Whenever it appears herein, a numerical range such as “C 1 -C 6 alkoxy” or “C 1-6 alkoxy” , 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 “alkoxy” where no numerical range is designated. In some embodiments, the alkoxy is a C 1-10 alkoxy. In some embodiments, the alkoxy is a C 1-6 alkoxy.
  • the alkoxy is a C 1-5 alkoxy. In some embodiments, the alkoxy is a C 1-4 alkoxy. In some embodiments, the alkyl is a C 1-3 alkoxy. In some embodiments, the alkyl is a C 1 - 2 alkoxy. In some embodiments, the alkyl is methoxy. 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.
  • 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 or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system, which may include fused (for example, fused with a cycloalkyl, heterocycloalkyl or heteroaryl 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 one or more substituents, such as 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 one or more substituents, such as halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more aminos. In some embodiments, the alkyl is substituted with one amino. In some embodiments, the alkyl is substituted with one, two, or three aminos. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (for example, fused with a heterocycloalkyl or another cycloalkyl ring) , spiro, or bridged ring systems.
  • the cycloalkyl is fully saturated.
  • the cycloalkyl is partially saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl) , from three to ten carbon atoms (C 3 -C 10 cycloalkyl) , from three to eight carbon atoms (C 3 -C 8 cycloalkyl) , from three to six carbon atoms (C 3 -C 6 cycloalkyl) , from three to five carbon atoms (C 3 -C 5 cycloalkyl or) , or three to four carbon atoms (C 3 -C 4 cycloalkyl) .
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with one or more substituents, such as 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 one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with one or more substituents, such as 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.
  • 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.
  • Heteroalkenyl refers to an alkenyl group in which one or more skeletal atoms of the alkenyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkenyl is attached to the rest of the molecule at a carbon atom of the heteroalkenyl.
  • a heteroalkenyl is a C 2 -C 6 heteroalkenyl wherein the heteroalkenyl is comprised of 2 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkenyl is attached to the rest of the molecule at a carbon atom of the heteroalkenyl.
  • a heteroalkenyl 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 heteroalkenyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkenyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkenyl is optionally substituted with halogen.
  • Heteroalkynyl refers to an alkynyl group in which one or more skeletal atoms of the alkynyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkynyl is attached to the rest of the molecule at a carbon atom of the heteroalkynyl.
  • a heteroalkynyl is a C 2 -C 6 heteroalkynyl wherein the heteroalkynyl is comprised of 2 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkynyl is attached to the rest of the molecule at a carbon atom of the heteroalkynyl.
  • heteroalkynyl are, for example, -C ⁇ COCH 3 , -C ⁇ COCH 2 CH 2 OCH 3 , -CH 2 CH 2 OC ⁇ COCH 3 , -C ⁇ C-NHCH 3 , or -C ⁇ C-N (CH 3 ) 2 .
  • a heteroalkynyl 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 heteroalkynyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkynyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkynyl 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 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur.
  • the heterocycloalkyl is fully saturated.
  • the heterocycloalkyl is partially saturated.
  • the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heterocycloalkyl comprises one to three nitrogens.
  • the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system, which may include fused (for example, fused with a cycloalkyl or another heterocycloalkyl ring) , 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 heterocycloalkyl) , from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl) , from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl) , from two to seven carbon atoms (C 2 -C 7 heterocycloalkyl) , from two to six carbon atoms (C 2 -C 6 heterocycloalkyl) , from two to five carbon atoms (C 2 -C 5 heterocycloalkyl) , or two to four carbon atoms (C 2 -C 4 heterocycloalkyl) .
  • 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.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • substituents such as 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 one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • 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 (for example fused with a cycloalkyl, heterocycloalkyl or aryl ring) 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,
  • heteroaryl also includes both tautomers such as hydroxyl pyridyl and pyridonyl, hydroxyl pyrimidinyl and pyrimidonyl, hydroxyl pyrazinyl and pyrazonyl, and hydroxyl triazinyl and triazonyl, or polycyclic system thereof.
  • a heteroaryl may be optionally substituted, for example, with one or more substituents, such as 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 one or more substituents, such as halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • cycloalkyl-alkyl or “alkyl-cycloalkyl” used interchangeably herein, whether as part of another term or used independently, refers to an alkyl group substituted with one cycloalkyl group on any carbon atom of the alkyl group or a cycloalkyl group substituted with one alkyl group on any carbon atom of the cycloalkyl group.
  • a cycloalkyl-alkyl may be bonded to the rest of a compound via the cycloalkyl moiety or alkyl moiety. Unless stated otherwise specifically in the specification, both the cycloalkyl moiety and alkyl moiety of a cycloalkyl-alkyl may be optionally substituted with one or more groups as described above.
  • heterocycloalkyl-alkyl or “alkyl-heterocycloalkyl” used interchangeably herein, whether as part of another term or used independently, refers to an alkyl group substituted with one heterocycloalkyl group on any carbon atom of the alkyl group or a heterocycloalkyl group substituted with one alkyl group on any carbon atom or heteroatom of the heterocycloalkyl group.
  • a heterocycloalkyl-alkyl may be bonded to the rest of a compound via the heterocycloalkyl moiety or alkyl moiety. Unless stated otherwise specifically in the specification, both the heterocycloalkyl moiety and alkyl moiety of a heterocycloalkyl-alkyl may be optionally substituted with one or more groups as described above.
  • arylalkyl or “alkylaryl” used interchangeably herein, whether as part of another term or used independently, refers to an alkyl group substituted with one aryl group on any carbon atom of the alkyl group or an aryl group substituted with one alkyl group on any carbon atom of the aryl group.
  • An arylalkyl may be bonded to the rest of a compound via the aryl moiety or alkyl moiety. Unless stated otherwise specifically in the specification, both the aryl moiety and alkyl moiety of an arylalkyl may be optionally substituted with one or more groups as described above.
  • heteroarylalkyl or “alkylheteroaryl” used interchangeably herein, whether as part of another term or used independently, refers to an alkyl group substituted with one heteroaryl group on any carbon atom of the alkyl group or an heteroaryl group substituted with one alkyl group on any carbon atom or heteroatom of the heteroaryl group.
  • a heteroarylalkyl may be bonded to the rest of a compound via the heteroaryl moiety or alkyl moiety. Unless stated otherwise specifically in the specification, both the heteroaryl moiety and alkyl moiety of a heteroarylalkyl may be optionally substituted with one or more groups as described above.
  • partially saturated or “partially unsaturated” refers to a radical that includes at least one double or triple bond, and is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • 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 substituents, 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 PKMYT1” or, alternatively, “a PKMYT1-mediated disease or disorder” means any disease or other deleterious condition in which PKMYT1, or a mutant thereof, is known or suspected to play a role.
  • Described herein are compounds, or pharmaceutically acceptable salts thereof useful in the modulation of PKMYT1 (e.g., inhibiting PKMYT1) and thus in the treatment of PKMYT1-associated diseases and conditions.
  • each of X, Y and Z is independently N or C;
  • each of is a single bond or double bond
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R Q is H, OH or NH 2 ;
  • R Q and R 1 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
  • R Q and R 7 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
  • each R A is independently halogen, cyano, oxo, -OR a , -SR a , -SO 2 R a , -N (R b ) 2 , -C (O) OR b , -C (O) N (R b ) 2 , -SO 2 N (R b ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl-alkyl, heterocyclo
  • R A taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
  • R 6 is oxo
  • each of R 1 and R 2 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
  • R 3 is hydrogen, halogen, cyano, -NO 2 , -OR a , -SR a , -N (R b ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R b ) 2 , alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
  • R 4 is hydrogen, halogen, cyano, -OR a , -SR a , -N (R b ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R b ) 2 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, whereinthe alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;
  • R 5 is -C (O) NH (R a ) , -C (O) R a , or -SO 2 R a ;
  • R 7 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -N (R b ) 2 , -C (O) R a , -C (O) OR b , -C (O) N (R b ) 2 , 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, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
  • each R is independently halogen, cyano, oxo, -OR a , -SR a , -SO 2 R a , -N (R b ) 2 , -C (O) N (R b ) 2 , -SO 2 N (R b ) 2 , alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R’ ;
  • each R’ is independently halogen, cyano, oxo, -OR a , -SR a , -SO 2 R a , -N (R b ) 2 , -C (O) N (R b ) 2 , -SO 2 N (R b ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R a is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R b is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n is an integer of 0-8.
  • Q is N. In some embodiments, is In some embodiments, is
  • Q is CR Q , and R Q and R 1 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R.
  • Q is CR Q , and R Q and R 1 taken together with the atoms to which they are attached form a C 5-6 cycloalkyl, 5-to 6-membered heterocycloalkyl, phenyl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
  • Q is CR Q , and R Q and R 1 taken together with the atoms to which they are attached form a 5-to 6-membered heterocycloalkyl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
  • Q is CR Q , and R Q and R 1 taken together with the atoms to which they are attached form a pyrazolyl, wherein the pyrazolyl is optionally substituted with one or more R.
  • Q is CR Q , and R Q and R 7 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R.
  • Q is CR Q , and R Q and R 7 taken together with the atoms to which they are attached form a C 5-6 cycloalkyl, 5-to 6-membered heterocycloalkyl, phenyl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
  • Q is CR Q , and R Q and R 7 taken together with the atoms to which they are attached form a 5-to 6-membered heterocycloalkyl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
  • Q is CR Q , and R Q and R 7 taken together with the atoms to which they are attached form a pyrazolyl, wherein the pyrazolyl is optionally substituted with one or more R.
  • Q is CR Q
  • R Q is OH. In some embodiments, is In some embodiments, is
  • Q is CR Q
  • R Q is NH 2 . In some embodiments, is In some embodiments, is
  • R 7 is hydrogen or halogen. In some embodiments, R 7 is hydrogen or F. In some embodiments, R 7 is hydrogen.
  • each of X, Y and Z is independently N or C;
  • each of is a single bond or double bond
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R A taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
  • R 6 is oxo
  • each of R 1 and R 2 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
  • R 3 is hydrogen, halogen, cyano, -NO 2 , -OR a , -SR a , -N (R b ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R b ) 2 , alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
  • R 4 is hydrogen, halogen, cyano, -OR a , -SR a , -N (R b ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R b ) 2 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;
  • R 5 is -C (O) NH (R a ) , -C (O) R a , or -SO 2 R a ;
  • each R is independently halogen, cyano, oxo, -OR a , -SR a , -SO 2 R a , -N (R b ) 2 , -C (O) N (R b ) 2 , -SO 2 N (R b ) 2 , alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein the alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R’ ;
  • each R’ is independently halogen, cyano, oxo, -OR a , -SR a , -SO 2 R a , -N (R b ) 2 , -C (O) N (R b ) 2 , -SO 2 N (R b ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R a is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R b is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • n is an integer of 0-8.
  • X is C, Y is C and Z is C;
  • X is C, Y is C and Z is N;
  • X is N, Y is C and Z is C;
  • X is N, Y is C and Z is N;
  • X is C, Y is N and Z is C;
  • X is C, Y is N and Z is N;
  • X is N, Y is N and Z is C;
  • X is C, Y is C and Z is N;
  • X is N, Y is C and Z is N;
  • X is C, Y is N and Z is C;
  • X is N, Y is C and Z is C.
  • Ring A is heterocycloalkyl or heteroaryl. In some embodiments, Ring A is heterocycloalkyl or heteroaryl containing at least one N atom.
  • Ring A is 5-to 10-membered heterocycloalkyl, 5-to 9-membered heterocycloalkyl, 5-to 8-membered heterocycloalkyl, 6-to 8-membered heterocycloalkyl or 6-to 7-membered heterocycloalkyl. In some embodiments, Ring A is 10-membered heterocycloalkyl, 9-membered heterocycloalkyl, 8-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered heterocycloalkyl or 5-membered heterocycloalkyl.
  • Ring A is 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 6-to 8-membered heteroaryl or 6-to 7-membered heteroaryl. In some embodiments, Ring A is 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl or 5-membered heteroaryl.
  • Ring A is 6-membered heterocycloalkyl. In some embodiments, Ring A is 6-membered heteroaryl.
  • each of R A1 , R A2 and R A3 is independently hydrogen or independently selected from R A ;
  • R A1 and R A2 when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
  • R A1 and R A3 when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
  • R A2 and R A3 when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
  • each of R A1 , R A2 and R A3 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optional
  • R A1 and R A2 taken together with the atoms to which they are attached form a 5-to 6-membered heterocycloalkyl or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
  • R A2 and R A3 taken together with the atoms to which they are attached form a C 5-6 cycloalkyl, 5-to 6-membered heterocycloalkyl, C 6 aryl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
  • each R A is independently -OR a , hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more R. In some embodiments, one or more R A is C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl, each optionally substituted with one or more R.
  • one or more R A is C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl or C 2-3 alkenyl, each optionally substituted with one or more R. In some embodiments, one or more R A is C 6 alkenyl, C 5 alkenyl, C 4 alkenyl, C 3 alkenyl or C 2 alkenyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is C 2-6 alkynyl, C 2-5 alkynyl, C 2-4 alkynyl or C 2-3 alkynyl, each optionally substituted with one or more R. In some embodiments, one or more R A is C 6 alkynyl, C 5 alkynyl, C 4 alkynyl, C 3 alkynyl or C 2 alkynyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl, each optionally substituted with one or more R.
  • one or more R A is C 6 haloalkyl, C 5 haloalkyl, C 4 haloalkyl, C 3 haloalkyl, C 2 haloalkyl or C 1 haloalkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is C 1-6 hydroxyalkyl, C 1-5 hydroxyalkyl, C 1-4 hydroxyalkyl, C 1-3 hydroxyalkyl or C 1-2 hydroxyalkyl, each optionally substituted with one or more R. In some embodiments, one or more R A is C 6 hydroxyalkyl, C 5 hydroxyalkyl, C 4 hydroxyalkyl, C 3 hydroxyalkyl, C 2 hydroxyalkyl or C 1 hydroxyalkyl, each optionally substituted with one or more R.
  • one or more R A is C 1-6 aminoalkyl, C 1-5 aminoalkyl, C 1-4 aminoalkyl, C 1-3 aminoalkyl or C 1-2 aminoalkyl, each optionally substituted with one or more R. In some embodiments, one or more R A is C 6 aminoalkyl, C 5 aminoalkyl, C 4 aminoalkyl, C 3 aminoalkyl, C 2 aminoalkyl or C 1 aminoalkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is C 1-6 alkoxy, C 1-5 alkoxy, C 1-4 alkoxy, C 1-3 alkoxy, or C 1-2 alkoxy each optionally substituted with one or more R. In some embodiments, one or more R A is C 6 alkoxy, C 5 alkoxy, C 4 alkoxy, C 3 alkoxy, C 2 alkoxy or C 1 alkoxy, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is cycloalkyl-C 1-6 alkyl, cycloalkyl-C 1-5 alkyl, cycloalkyl-C 1-4 alkyl, cycloalkyl-C 1-3 alkyl or cycloalkyl-C 1-2 alkyl, each optionally substituted with one or more R.
  • one or more R A is cycloalkyl-C 6 alkyl, cycloalkyl-C 5 alkyl, cycloalkyl-C 4 alkyl, cycloalkyl-C 3 alkyl, cycloalkyl-C 2 alkyl or cycloalkyl-C 1 alkyl, each optionally substituted with one or more R.
  • one or more R A is C 3-10 cycloalkyl-C 1-6 alkyl, C 3-9 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-7 cycloalkyl-C 1-6 alkyl or C 3-6 cycloalkyl-C 1-6 alkyl, each optionally substituted with one or more R.
  • one or more R A is heterocycloalkyl-C 1-6 alkyl, heterocycloalkyl-C 1-5 alkyl, heterocycloalkyl-C 1-4 alkyl, heterocycloalkyl-C 1-3 alkyl or heterocycloalkyl-C 1-2 alkyl, each optionally substituted with one or more R.
  • one or more R A is heterocycloalkyl-C 6 alkyl, heterocycloalkyl-C 5 alkyl, heterocycloalkyl-C 4 alkyl, heterocycloalkyl-C 3 alkyl, heterocycloalkyl-C 2 alkyl or heterocycloalkyl-C 1 alkyl, each optionally substituted with one or more R.
  • one or more R A is 4-to 10-membered heterocycloalkyl-C 1-6 alkyl, 4-to 9-membered heterocycloalkyl-C 1-6 alkyl, 4-to 8-membered heterocycloalkyl-C 1-6 alkyl, 4-to 7-membered heterocycloalkyl-C 1-6 alkyl or 4-to 6-membered heterocycloalkyl-C 1-6 alkyl, each optionally substituted with one or more R.
  • one or more R A is 4-to 10-membered heterocycloalkyl-C 1 alkyl, 4-to 9-membered heterocycloalkyl-C 1 alkyl, 4-to 8-membered heterocycloalkyl-C 1 alkyl, 4-to 7-membered heterocycloalkyl-C 1 alkyl or 4-to 6-membered heterocycloalkyl-C 1 alkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is aryl-C 1-6 alkyl, aryl-C 1-5 alkyl, aryl-C 1-4 alkyl, aryl-C 1-3 alkyl or aryl-C 1-2 alkyl, each optionally substituted with one or more R.
  • one or more R A is aryl-C 6 alkyl, aryl-C 5 alkyl, aryl-C 4 alkyl, aryl-C 3 alkyl, aryl-C 2 alkyl or aryl-C 1 alkyl, each optionally substituted with one or more R.
  • one or more R A is C 6-12 aryl-C 1-6 alkyl, C 6-11 aryl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl, C 6-9 aryl-C 1-6 alkyl or C 6-8 aryl-C 1-6 alkyl, each optionally substituted with one or more R.
  • one or more R A is C 6-12 aryl-C 1 alkyl, C 6-11 aryl-C 1 alkyl, C 6-10 aryl-C 1 alkyl, C 6-9 aryl-C 1 alkyl or C 6-8 aryl-C 1 alkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is heteroaryl-C 1-6 alkyl, heteroaryl-C 1-5 alkyl, heteroaryl-C 1-4 alkyl, heteroaryl-C 1-3 alkyl or heteroaryl-C 1-2 alkyl, each optionally substituted with one or more R.
  • one or more R A is heteroaryl-C 6 alkyl, heteroaryl-C 5 alkyl, heteroaryl-C 4 alkyl, heteroaryl-C 3 alkyl, heteroaryl-C 2 alkyl or heteroaryl-C 1 alkyl, each optionally substituted with one or more R.
  • one or more R A is 5-to 10-membered heteroaryl-C 1-6 alkyl, 5-to 9-membered heteroaryl-C 1-6 alkyl, 5-to 8-membered heteroaryl-C 1-6 alkyl, 6-to 8-membered heteroaryl-C 1-6 alkyl or 6-to 7-membered heteroaryl-C 1-6 alkyl, each optionally substituted with one or more R.
  • one or more R A is 5-to 10-membered heteroaryl-C 1 alkyl, 5-to 9-membered heteroaryl-C 1 alkyl, 5-to 8-membered heteroaryl-C 1 alkyl, 6-to 8-membered heteroaryl-C 1 alkyl or 6-to 7-membered heteroaryl-C 1 alkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is C 3-10 cycloalkyl, C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl or C 3-5 cycloalkyl, each optionally substituted with one or more R.
  • one or more R A is C 10 cycloalkyl, C 9 cycloalkyl, C 8 cycloalkyl, C 7 cycloalkyl, C 6 cycloalkyl, C 5 cycloalkyl, C 4 cycloalkyl or C 3 cycloalkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is 4-to 10-membered heterocycloalkyl, 4-to 9-membered heterocycloalkyl, 4-to 8-membered heterocycloalkyl, 5-to 8-membered heterocycloalkyl, 5-to 8-membered heterocycloalkyl or 5-to 7-membered heterocycloalkyl, each optionally substituted with one or more R.
  • one or more R A is 10-membered heterocycloalkyl, 9-membered heterocycloalkyl, 8-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl or 4-membered heterocycloalkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 6-to 8-membered heteroaryl or 6-to 7-membered heteroaryl, each optionally substituted with one or more R.
  • one or more R A is 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl or 5-membered heteroaryl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • one or more R A is C 6-12 aryl, C 6-11 aryl, C 6-10 aryl, C 6-9 aryl or C 6-8 aryl, each optionally substituted with one or more R. In some embodiments, one or more R A is C 12 aryl, C 11 aryl, C 10 aryl, C 9 aryl, C 8 aryl, C 7 aryl or C 6 aryl, each optionally substituted with one or more (e.g., two, or three, etc) R.
  • R A is independently -OR a .
  • R a is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • R a is C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl.
  • R a is C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl.
  • R a is C 6 haloalkyl, C 5 haloalkyl, C 4 haloalkyl, C 3 haloalkyl, C 2 haloalkyl or C 1 haloalkyl.
  • one or more R A is -O-C 1-6 alkyl, -O-C 1-5 alkyl, -O-C 1-4 alkyl, -O-C 1-3 alkyl or -O-C 1-2 alkyl. In some embodiments, one or more R A is -O-C 6 alkyl, -O-C 5 alkyl, -O-C 4 alkyl, -O-C 3 alkyl, -O-C 2 alkyl or -O-C 1 alky.
  • one or more R A is -O-C 1-6 haloalkyl, -O-C 1-5 haloalkyl, -O-C 1-4 haloalkyl, -O-C 1-3 haloalkyl or -O-C 1-2 haloalkyl. In some embodiments, one or more R A is -O-C 6 haloalkyl, -O-C 5 haloalkyl, -O-C 4 haloalkyl, -O-C 3 haloalkyl, -O-C 2 haloalkyl or -O-C 1 haloalkyl.
  • each R is independently halogen, hydroxyl, cyano, alkyl, oxo, or alkylidenyl, wherein the alkyl, and alkylidenyl are independently optionally substituted with one or more R’ .
  • each R is independently -F, hydroxyl, cyano, -CH 3 or oxo.
  • each R is alkylidenyl, wherein the alkylidenyl is independently optionally substituted with halogen, -OR a , or 5-to 6-membered heterocycloalkyl.
  • each R A is independently -CH 3 , -CH 2 CH 3 , -CF 3 , -CH 2 F, -CHF 2 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -OCH 3 , -OCF 3 , -OCH 2 F, -OCHF 2 , -OCH 2 CH 3 , -OCH 2 CF 3 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH 2 CH 2 F,
  • R 1 is alkyl optionally substituted with one or more R.
  • R 1 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more R.
  • R 1 is C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl, each optionally substituted with one or more R.
  • R 1 is -CH 3 .
  • R 2 is alkyl optionally substituted with one or more R.
  • R 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more R.
  • R 2 is C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl, each optionally substituted with one or more R.
  • R 2 is -CH 3 .
  • R 3 is hydrogen or halogen. In some embodiments, R 3 is hydrogen or -F.
  • R 4 is -N (R b ) 2 .
  • each R b is independently hydrogen or alkyl.
  • each R b is independently hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • each R b is hydrogen.
  • R 4 is -NH 2 .
  • R 5 is -C (O) NH (R a ) .
  • R a is hydrogen or alkyl.
  • R a is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • R a is hydrogen.
  • R 5 is -C (O) NH 2 .
  • n is 0, 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, n is 0, 1, 2, 3, 4 or 5. In some embodiments, n is 0, 1 or 2.
  • the compound provided herein is of Formula (Ia) :
  • Ring A, X, Y, Z, R 1 to R 6 , R A , and n are as defined herein.
  • one or more of R, R 1 , R 2 , R 3 , R 4 , R 5 , R A , R a and R b 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 4 , R 5 , R A , R a and R b .
  • the abundance of deuterium in each of R, R 1 , R 2 , R 3 , R 4 , R 5 , R A , R a and R b 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 are replaced with one or more deuteriums.
  • the present disclosure provides a compound selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium) , 2 H (deuterium) , and 3 H (tritium) .
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • the compounds described herein may be artificially enriched in one or more particular isotopes.
  • the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature.
  • the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • the compounds described herein are artificially enriched in one or more isotopes selected from 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 I.
  • the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound is deuterated in at least one position.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • each hydrogen atom of the compounds disclosed herein is independently 1 H, 2 H (D) or 3 H (T) .
  • one or more hydrogen atom of the compounds disclosed herein is 2 H (deuterium, or D) .
  • deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • 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 by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • the present disclosure is directed to a method of treating a PKMYT1-associated disease or condition in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the compound of Formula (V) , (I) or (Ia) or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof as provided herein, owning to the PKMYT1 inhibitory activity of the compound of the present disclosure.
  • the compounds of the present disclosure are selective PKMYT1 inhibitors.
  • the term “subject in need thereof” is a subject having a PKMYT1-associated disease or condition, or a subject having an increased risk of developing PKMYT1-associated disease or condition relative to the population at large.
  • the subject is a warm-blooded animal.
  • the warm-blooded animal is a mammal.
  • the warm-blooded animal is a human.
  • PKMYT1 has been implicated as a potentially important cancer target as it is essential in many cancer cells. Overexpression of PKMYT1 has been observed in various cancers including, for example, hepatocellular carcinoma as well as clear-cell renal-cell carcinoma. PKMyt1 downregulation has a minor role in unperturbed cells but has a more prominent role in cells exposed to DNA damage. Additionally, cells that exhibit high levels of replication stress in addition to defective G1 checkpoint regulation may be particularly sensitive to loss of PKMYT1 function, as these cells will be prone to entering mitosis prematurely with compromised genomic material leading to mitotic catastrophe.
  • Inhibitors of PKMYT1, a regulator of G2-M transition, has been found to be particularly useful in the treatment of tumors (e.g., cancers) harboring CCNE1-amplification or FBXW7 loss-of-function mutations using a synthetic lethal therapeutic strategy.
  • Cancers harboring CCNE1-amplification may include, e.g., uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, and endometrial cancer, etc.
  • Cancers harboring FBXW7 loss-of-function may include, e.g., uterine cancer, colorectal cancer, breast cancer, lung cancer, and esophageal cancer, etc.
  • PKMYT1 has been implicated in non-small-cell lung cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, etc.
  • the PKMYT1-associated disease or condition is tumor, and particularly, advanced solid tumor.
  • the PKMYT1-associated disease or condition is selected from the group consisting of uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer (e.g., non-small-cell lung cancer) , endometrial cancer, colorectal cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, etc.
  • the method of treating a PKMYT1-associated disease or condition as described herein may be used as a monotherapy.
  • monotherapy refers to the administration of a single active or therapeutic compound to a subject in need thereof.
  • monotherapy will involve administration of a therapeutically effective amount of one of the compounds of the present disclosure or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, to a subject in need of such treatment.
  • the method of treating a PKMYT1-associated disease or condition described herein may involve, in addition to administration of the compound of Formula (V) , (I) or (Ia) , combination therapy of one or more additional therapeutic agent (s) , for example, a second therapeutic agent which is an anti-cancer agent.
  • additional therapeutical agents may include an additional PKMYT1 inhibitor.
  • one or more additional therapeutic agent may be selected from the group consisting of: a cytotoxic agent; an antimetabolite; an alkylating agent; an anthracycline; an antibiotic; an anti-mitotic agent; a hormone therapy; a signal transduction inhibitor; a gene expression modulator; an apoptosis inducer; an angiogenesis inhibitor; an immunotherapy agent; a DNA damage repair inhibitor; or a combination thereof.
  • the present disclosure provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
  • the present disclosure provided a method of modulating PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
  • the present disclosure provided a method of inhibiting PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
  • the subject has cancer.
  • the cancer depends on the activity of PKMYT1.
  • the cancer overexpresses CCNE1.
  • the cancer has an inactivating mutation in the FBXW7 gene.
  • the cancer is a solid tumor.
  • the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, or uterine cancer.
  • the present disclosure provided a pharmaceutical composition for treating a PKMYT1-associated disease or condition, comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provided use of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for treating cancer.
  • kits for treating cancer comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein, a container, and optionally a package insert or label indicating treatment of said disease or condition.
  • 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.
  • 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 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.
  • non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and/or by making routine modifications of reaction conditions.
  • persons skilled in the art will also understand that individual steps described herein or in the separate batches of a compound may be combined.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure, but rather is specified by the claims appended hereto.
  • Compound 2 was prepared from compound 2-2 (1.50 g, 6.576 mmol) in a similar fashion with the synthesis of Compound 1, the isomer was separated by SFC.
  • LCMS 367.3 [M+H] + .
  • Compound 3-6 was obtained by SFC separation of racemic compound 3-5.
  • LCMS 324.2 [M+H] + .
  • Test compound serial dilution was performed by Echo, and the final concentrations vary from 10 ⁇ M to 0.5 nM. This was filled by the addition of 5 ⁇ L /well of Enzyme solution to the assay plate containing the test compound. The plate was centrifuged at 1000 rpm for 1 minute, and incubate 15 minutes at 25 °C. Then 5 ⁇ L /well of tracer solution (Tracer 178) was added to initiate the reaction, and incubate for 60 minutes at 25 °C. Next 5 ⁇ L GST-Tb was added into the assay plate, the plate was centrifuged at 1000 rpm for 1 minute, and incubate for 15 minutes at 25 °C. The assay plate was read on Envision.
  • Test compound serial dilution is performed by Echo, and the final concentrations vary from 10 ⁇ M to 0.5 nM. This was filled by the addition of 5 ⁇ L /well of Enzyme solution to the assay plate containing the test compound. The plate was centrifuged at 1000 rpm for 1 minute, and incubate 15 minutes at 25 °C. Then 5 ⁇ L /well of substrate solution was added to initiate the reaction, and incubate for 60 minutes at 25 °C. Next 10 ⁇ L kinase detection reagent was added into the assay plate, the plate was centrifuged at 1000 rpm for 1 minute, and incubate for 60 minutes at 25 °C. The assay plate was read on Envision for US LUM as RLU.
  • Example 2.1 and Example 2.2 The data for Example 2.1 and Example 2.2 is shown in Table 3, wherein “A” stands for IC 50 less than or equal to 10 nM; “B” stands for IC 50 larger than 10 nM but less than or equal to 50 nM; “C” stands for IC 50 larger than 50 nM but less than or equal to 500 nM; “D” stands for IC 50 larger than 500 nM but less than or equal to 5000 nM; “E” stands for IC 50 larger than 5000 nM; and “NT” stands for not tested.

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Abstract

Disclosed are compounds or pharmaceutically acceptable salts, stereoisomer, or isotopic variant thereof useful as PKMYT1 inhibitors, pharmaceutical compositions comprising the same, and use thereof in the treatment of PKMYT1-associated diseases or conditions such as cancer.

Description

NOVEL COMPOUNDS AS PKMYT1 INHIBITORS AND USE THEREOF
CROSS-REFERENCE
This patent application claims the benefit of International Application No. PCT/CN2023/119295, filed September 18, 2023; which is incorporated herein by reference in its entirety.
BACKGROUND
DNA is continuously subjected to both endogenous insults (e.g., stalled replication forks, reactive oxygen species) and exogenous insults (UV, ionizing radiation, chemical) that can lead to DNA damage. As a result, cells have established sophisticated mechanisms to counteract these deleterious events that would otherwise compromise genomic integrity and lead to genomic instability diseases such as tumor. To maintain genomic integrity, two checkpoints of cell cycle allow for efficient repair of DNA damages, one of which is the WEE kinase family. The WEE kinase family consists of three members: WEE1, PKMYT1, and the less important WEE1B. PKMYT1 functions as negative regulators of the cell cycle by inhibiting the CDK1-cyclin B complex. CDK1, a master regulator of the cell cycle, is essential for entry into mitosis, meaning that PKMYT1 might be expected to act as tumor suppressors by preventing CDK1 activation. Studies showed that loss of PKMYT1 interferes with the G2-M checkpoint, driving cells into mitosis prematurely, which results in the accumulation of genetic lesions from unrepaired DNA damage, ultimately leading to apoptosis or mitotic catastrophe. However, the concomitant inhibition of WEE1 and PKMYT1 leads to strong cytotoxic effects. Thus, PKMYT1 is a promising target for anti-cancer therapy. Moreover, PKMYT1 has also been implicated in many cancer types, including gastric cancer, non-small-cell lung cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, and colorectal cancer, etc., in which overexpression of PKMYT1 generally correlates with poor prognosis and disease progression. Therefore, selective targeting PKMYT1 with small molecules provides new opportunities for cancer therapy.
SUMMARY
Disclosed herein are novel compounds as PKMYT1 inhibitors. As a result, the compounds of the present disclosure are particularly useful in the modulation of PKMYT1 and thus in the treatment of PKMYT1-associated diseases and conditions.
In one aspect, the present disclosure provides a compound of Formula (V) , or a pharmaceutically acceptable salt thereof:
as disclosed herein.
In one aspect, the present disclosure provides a compound of Formula (I) , or a pharmaceutically acceptable salt thereof:
as disclosed herein.
In some embodiments of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, the compound is of Formula (Ia) :
as disclosed herein.
Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt thereof, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
Also disclosed herein is a method of modulating PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
Also disclosed herein is a method of inhibiting PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein. In some embodiments, the subject has cancer. In some embodiments, the cancer depends on the activity of PKMYT1. In some embodiments, the cancer overexpresses CCNE1. In some embodiments, the cancer has an inactivating mutation in the FBXW7 gene. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal  cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, or uterine cancer.
Also disclosed herein is a pharmaceutical composition for treating a PKMYT1-associated disease or condition, comprising the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
Also disclosed herein is use of the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a PKMYT1-associated disease or condition, such as cancer.
A kit for treating a PKMYT1-associated disease or condition such as cancer, comprising the compound disclosed herein (e.g., a compound of Formula (V) , (I) , (Ia) or a compound set forth in Table 1 or Table 2) , or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein, a container, and optionally a package insert or label indicating treatment of said disease or condition.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION
Definitions
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be  combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
The terms below, as used herein, have the following meanings, unless indicated otherwise.
Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2nd Edition, University Science Books, Sausalito, 2006; Smith and March March’s Advanced Organic Chemistry, 6th Edition, John Wiley &Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th Edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference.
At various places in the present disclosure, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
When any variable (e.g., Ri) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ri moieties, then the group may optionally be substituted with up to two Ri moieties and Ri at each occurrence is selected independently from the definition of Ri. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
As used herein, the term “Ci-Cj” indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i. For examples, C1-C6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four  carbon atoms, five carbon atoms and six carbon atoms. In some embodiments, the term “C1-12” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
“Oxo” refers to =O.
“Amino” , whether as part of another term or used independently, refers to the group -NRaRb, wherein Ra and Rb are independently selected from groups consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl or other suitable organic groups and each of which may be optionally substituted.
“Hydroxy” or “hydroxyl” , whether as part of another term or used independently, refers to -OH.
“Alkyl” , whether as part of another term or used independently, refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl” , means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
“Alkylidenyl” is a divalent group formed from alkanes by removal of two hydrogen atoms from the same carbon atom, the free valencies of which are part of a double bond attached to the rest part of the molecule. For example, in the compound below:
the alkylidenyl group is enclosed by the box which is indicated by the arrow.
“Alkenyl” , whether as part of another term or used independently, refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation, or alternatively, E or Z conformation about the double bond (s) , and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2) , 1-propenyl (-CH2CH=CH2) , isopropenyl [-C (CH3) =CH2] , butenyl, 1, 3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl” , means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
“Alkynyl” , whether as part of another term or used independently, refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” or “C2-6alkynyl” , means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
“Alkoxy” , whether as part of another term or used independently, refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Whenever it appears herein, a numerical range  such as “C1-C6 alkoxy” or “C1-6alkoxy” , 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 “alkoxy” where no numerical range is designated. In some embodiments, the alkoxy is a C1-10alkoxy. In some embodiments, the alkoxy is a C1-6alkoxy. In some embodiments, the alkoxy is a C1-5alkoxy. In some embodiments, the alkoxy is a C1-4alkoxy. In some embodiments, the alkyl is a C1-3alkoxy. In some embodiments, the alkyl is a C1-2alkoxy. In some embodiments, the alkyl is methoxy. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
“Aryl” , whether as part of another term or used independently, 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 or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system, which may include fused (for example, fused with a cycloalkyl, heterocycloalkyl or heteroaryl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl) . Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more substituents, such as halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
“Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more aminos. In some embodiments, the alkyl is substituted with one amino. In some embodiments, the alkyl is substituted with one, two, or three aminos. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
“Cycloalkyl” , whether as part of another term or used independently, refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (for example,  fused with a heterocycloalkyl or another cycloalkyl ring) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. In some embodiments, the cycloalkyl is partially saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl) , from three to ten carbon atoms (C3-C10 cycloalkyl) , from three to eight carbon atoms (C3-C8 cycloalkyl) , from three to six carbon atoms (C3-C6 cycloalkyl) , from three to five carbon atoms (C3-C5 cycloalkyl or) , or three to four carbon atoms (C3-C4 cycloalkyl) . Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, 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.
“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl  are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH (CH3) OCH3, -CH2NHCH3, -CH2N (CH3) 2, -CH2CH2NHCH3, or -CH2CH2N (CH3) 2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“Heteroalkenyl” refers to an alkenyl group in which one or more skeletal atoms of the alkenyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkenyl is attached to the rest of the molecule at a carbon atom of the heteroalkenyl. In one aspect, a heteroalkenyl is a C2-C6 heteroalkenyl wherein the heteroalkenyl is comprised of 2 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkenyl is attached to the rest of the molecule at a carbon atom of the heteroalkenyl. Examples of such heteroalkenyl are, for example, -CH=CHOCH3, -CH=CHOCH2CH2OCH3, -CH2CH2OCH=CHOCH3, -C (=CH2) OCH3, -CH=NCH3, -CH2N=CH2, -CH=CHNHCH3, or -CH=CHN (CH3) 2. Unless stated otherwise specifically in the specification, a heteroalkenyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkenyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkenyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkenyl is optionally substituted with halogen.
“Heteroalkynyl” refers to an alkynyl group in which one or more skeletal atoms of the alkynyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkynyl is attached to the rest of the molecule at a carbon atom of the heteroalkynyl. In one aspect, a heteroalkynyl is a C2-C6 heteroalkynyl wherein the heteroalkynyl is comprised of 2 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkynyl is attached to the rest of the molecule at a carbon atom of the heteroalkynyl. Examples of such heteroalkynyl are, for example, -C≡COCH3, -C≡COCH2CH2OCH3, -CH2CH2OC≡COCH3, -C≡C-NHCH3, or -C≡C-N (CH3) 2. Unless stated otherwise specifically in the specification, a heteroalkynyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkynyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkynyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkynyl is optionally substituted with halogen.
“Heterocycloalkyl” , whether as part of another term or used independently, refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from 1 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 is partially saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system, which may include fused (for example, fused with a cycloalkyl or another heterocycloalkyl ring) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl) , from two to ten carbon atoms (C2-C10 heterocycloalkyl) , from two to eight carbon atoms (C2-C8 heterocycloalkyl) , from two to seven carbon atoms (C2-C7 heterocycloalkyl) , from two to six carbon atoms (C2-C6 heterocycloalkyl) , from two to five carbon atoms (C2-C5 heterocycloalkyl) , or two to four carbon atoms (C2-C4 heterocycloalkyl) . Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) . In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl. In some embodiments, 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. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
“Heteroaryl” , whether as part of another term or used independently, refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (for example fused with a cycloalkyl, heterocycloalkyl or aryl ring) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, 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, dibenzofuranyl, dibenzothiophenyl, furanyl, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl) . It should be appreciated that any ring system satisfying Hückel’s Rule is considered as aromatic ring. Therefore, “heteroaryl” also includes both tautomers such as hydroxyl pyridyl and  pyridonyl, hydroxyl pyrimidinyl and pyrimidonyl, hydroxyl pyrazinyl and pyrazonyl, and hydroxyl triazinyl and triazonyl, or polycyclic system thereof. Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with one or more substituents, such as halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
The term “cycloalkyl-alkyl” or “alkyl-cycloalkyl” used interchangeably herein, whether as part of another term or used independently, refers to an alkyl group substituted with one cycloalkyl group on any carbon atom of the alkyl group or a cycloalkyl group substituted with one alkyl group on any carbon atom of the cycloalkyl group. A cycloalkyl-alkyl may be bonded to the rest of a compound via the cycloalkyl moiety or alkyl moiety. Unless stated otherwise specifically in the specification, both the cycloalkyl moiety and alkyl moiety of a cycloalkyl-alkyl may be optionally substituted with one or more groups as described above.
The term “heterocycloalkyl-alkyl” or “alkyl-heterocycloalkyl” used interchangeably herein, whether as part of another term or used independently, refers to an alkyl group substituted with one heterocycloalkyl group on any carbon atom of the alkyl group or a heterocycloalkyl group substituted with one alkyl group on any carbon atom or heteroatom of the heterocycloalkyl group. A heterocycloalkyl-alkyl may be bonded to the rest of a compound via the heterocycloalkyl moiety or alkyl moiety. Unless stated otherwise specifically in the specification, both the heterocycloalkyl moiety and alkyl moiety of a heterocycloalkyl-alkyl may be optionally substituted with one or more groups as described above.
The term “arylalkyl” or “alkylaryl” used interchangeably herein, whether as part of another term or used independently, refers to an alkyl group substituted with one aryl group on any carbon atom of the alkyl group or an aryl group substituted with one alkyl group on any carbon atom of the aryl group. An arylalkyl may be bonded to the rest of a compound via the aryl moiety or alkyl moiety. Unless stated otherwise specifically in the specification, both the aryl moiety and alkyl moiety of an arylalkyl may be optionally substituted with one or more groups as described above.
The term “heteroarylalkyl” or “alkylheteroaryl” used interchangeably herein, whether as part of another term or used independently, refers to an alkyl group substituted with one heteroaryl group on any carbon atom of the alkyl group or an heteroaryl group substituted with one alkyl group on any carbon atom or heteroatom of the heteroaryl group. A heteroarylalkyl may be bonded to the rest of a compound via the heteroaryl moiety or alkyl moiety. Unless stated otherwise specifically in the specification, both the heteroaryl moiety and alkyl moiety of a heteroarylalkyl may be optionally substituted with one or more groups as described above.
The term “partially saturated” or “partially unsaturated” refers to a radical that includes at least one double or triple bond, and is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
When two atoms are directly connected via one bond (e.g., a single bond, double bond or triple bond) , then these two atoms are “adjacent” to each other. When two atoms are connected via one or more other atoms and two or more bonds (e.g., a single bond, double bond or triple bond) , then these two atoms are not adjacent or “non-adjacent” to each other. For example, in the following hexane, Carbon Atom 1 and Carbon Atom 2 or Carbon Atom 1 and Carbon Atom 6 are “adjacent” atoms; whereas Carbon Atom 1 and Carbon Atom 3, Carbon Atom 1 and Carbon Atom 4 or Carbon Atom 1 and Carbon Atom 5 are “non-adjacent” atoms.
Hexane with carbon atom numbers indicated
The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3) , fully substituted (e.g., -CF2CF3) , mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc. ) . It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1, 000 daltons, and more typically, up to about 500 daltons.
The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four substituents, 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.
The terms “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.
As used herein, a “disease or disorder associated with PKMYT1” or, alternatively, “a PKMYT1-mediated disease or disorder” means any disease or other deleterious condition in which PKMYT1, or a mutant thereof, is known or suspected to play a role.
Compounds
Described herein are compounds, or pharmaceutically acceptable salts thereof useful in the modulation of PKMYT1 (e.g., inhibiting PKMYT1) and thus in the treatment of PKMYT1-associated diseases and conditions.
In one aspect, provided herein is a compound of Formula (V) :
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y and Z is independently N or C;
each ofis a single bond or double bond;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Q is N or CRQ;
RQ is H, OH or NH2;
or RQ and R1 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
or RQ and R7 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
each RA is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) ORb, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
or two adjacent RA taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
R6 is oxo;
each of R1 and R2 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl,  alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
R3 is hydrogen, halogen, cyano, -NO2, -ORa, -SRa, -N (Rb) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Rb) 2, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
R4 is hydrogen, halogen, cyano, -ORa, -SRa, -N (Rb) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Rb) 2, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, whereinthe alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;
R5 is -C (O) NH (Ra) , -C (O) Ra, or -SO2Ra;
R7 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -N (Rb) 2, -C (O) Ra, -C (O) ORb, -C (O) N (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
each R is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R’ ;
each R’ is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Ra is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Rb is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two Rb taken together with the atom to which they are attached form a heterocycloalkyl; and
n is an integer of 0-8.
In some embodiments, Q is N. In some embodiments, isIn some embodiments, is
In some embodiments, Q is CRQ, and RQ and R1 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R. In some embodiments, Q is CRQ, and RQ and R1 taken together with the atoms to which they are attached form a C5-6 cycloalkyl, 5-to 6-membered heterocycloalkyl, phenyl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R. In some embodiments, Q is CRQ, and RQ and R1 taken together with the atoms to which they are attached form a 5-to 6-membered heterocycloalkyl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R. In some embodiments, Q is CRQ, and RQ and R1 taken together with the atoms to which they are attached form a pyrazolyl, wherein the pyrazolyl is optionally substituted with one or more R. In some embodiments, is In some embodiments, is In some embodiments, is
In some embodiments, Q is CRQ, and RQ and R7 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R. In some embodiments, Q is CRQ, and RQ and R7 taken together with the atoms to which they are attached form a C5-6 cycloalkyl, 5-to 6-membered heterocycloalkyl, phenyl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R. In some embodiments, Q is CRQ, and RQ and R7 taken together with the atoms to which they are attached form a 5-to 6-membered heterocycloalkyl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R. In some embodiments, Q is CRQ, and RQ and R7 taken together with the atoms to which they are attached form a pyrazolyl, wherein the pyrazolyl is optionally substituted with one or more R. In  some embodiments, isIn some embodiments, is
In some embodiments, Q is CRQ, and RQ is OH. In some embodiments, is In some embodiments, is
In some embodiments, Q is CRQ, and RQ is NH2. In some embodiments, is In some embodiments, is
In some embodiments, R7 is hydrogen or halogen. In some embodiments, R7 is hydrogen or F. In some embodiments, R7 is hydrogen.
In one aspect, provided herein is a compound of Formula (I) :
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y and Z is independently N or C;
each of is a single bond or double bond;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each RA is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) ORb, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
or two adjacent RA taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
R6 is oxo;
each of R1 and R2 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
R3 is hydrogen, halogen, cyano, -NO2, -ORa, -SRa, -N (Rb) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Rb) 2, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
R4 is hydrogen, halogen, cyano, -ORa, -SRa, -N (Rb) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Rb) 2, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;
R5 is -C (O) NH (Ra) , -C (O) Ra, or -SO2Ra;
each R is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein the alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R’ ;
each R’ is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Ra is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each Rb is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two Rb taken together with the atom to which they are attached form a heterocycloalkyl; and
n is an integer of 0-8.
In some embodiments,
X is C, Y is C and Z is C;
X is C, Y is C and Z is N;
X is N, Y is C and Z is C;
X is N, Y is C and Z is N;
X is C, Y is N and Z is C;
X is C, Y is N and Z is N;
X is N, Y is N and Z is C; or
X is N, Y is N and Z is N.
In some embodiments,
X is C, Y is C and Z is N;
X is N, Y is C and Z is N;
X is C, Y is N and Z is C; or
X is N, Y is C and Z is C.
In some embodiments, is
In some embodiments, Ring A is heterocycloalkyl or heteroaryl. In some embodiments, Ring A is heterocycloalkyl or heteroaryl containing at least one N atom.
In some embodiments, Ring A is 5-to 10-membered heterocycloalkyl, 5-to 9-membered heterocycloalkyl, 5-to 8-membered heterocycloalkyl, 6-to 8-membered heterocycloalkyl or 6-to 7-membered heterocycloalkyl. In some embodiments, Ring A is 10-membered heterocycloalkyl, 9-membered heterocycloalkyl, 8-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered heterocycloalkyl or 5-membered heterocycloalkyl. In some embodiments, Ring A is 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 6-to 8-membered heteroaryl or 6-to 7-membered heteroaryl. In some embodiments, Ring A is 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl or 5-membered heteroaryl.
In some embodiments, Ring A is 6-membered heterocycloalkyl. In some embodiments, Ring A is 6-membered heteroaryl.
In some embodiments, is wherein
each of RA1, RA2 and RA3 is independently hydrogen or independently selected from RA;
or RA1 and RA2 , when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
or RA1 and RA3, when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
or RA2 and RA3 , when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
or two RA2 taken together with the same atom to which they are attached form a cycloalkyl, or heterocycloalkyl, each optionally substituted with one or more R;
or two RA3 taken together with the same atom to which they are attached form a cycloalkyl, or heterocycloalkyl, each optionally substituted with one or more R.
In some embodiments, each of RA1, RA2 and RA3 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R.
In some embodiments, RA1 and RA2 taken together with the atoms to which they are attached form a 5-to 6-membered heterocycloalkyl or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
In some embodiments, RA2 and RA3 taken together with the atoms to which they are attached form a C5-6 cycloalkyl, 5-to 6-membered heterocycloalkyl, C6aryl, or 5-to 6-membered heteroaryl, each optionally substituted with one or more R.
In some embodiments, each RA is independently -ORa, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl, each optionally substituted with one or more R.
In some embodiments, one or more RA is C2-6 alkenyl, C2-5 alkenyl, C2-4 alkenyl or C2-3 alkenyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C6 alkenyl, C5 alkenyl, C4 alkenyl, C3 alkenyl or C2 alkenyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is C2-6 alkynyl, C2-5 alkynyl, C2-4 alkynyl or C2-3 alkynyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C6 alkynyl, C5 alkynyl, C4 alkynyl, C3 alkynyl or C2 alkynyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is C1-6 haloalkyl, C1-5 haloalkyl, C1-4 haloalkyl, C1-3 haloalkyl or C1-2 haloalkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl or C1 haloalkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is C1-6 hydroxyalkyl, C1-5 hydroxyalkyl, C1-4 hydroxyalkyl, C1-3 hydroxyalkyl or C1-2 hydroxyalkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C6 hydroxyalkyl, C5 hydroxyalkyl, C4 hydroxyalkyl, C3 hydroxyalkyl, C2 hydroxyalkyl or C1 hydroxyalkyl, each optionally substituted with one or more R.
In some embodiments, one or more RA is C1-6 aminoalkyl, C1-5 aminoalkyl, C1-4 aminoalkyl, C1-3 aminoalkyl or C1-2 aminoalkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C6 aminoalkyl, C5 aminoalkyl, C4 aminoalkyl, C3 aminoalkyl, C2 aminoalkyl or C1 aminoalkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is C1-6alkoxy, C1-5alkoxy, C1-4alkoxy, C1-3alkoxy, or C1-2alkoxy each optionally substituted with one or more R. In some embodiments, one or more RA is C6alkoxy, C5 alkoxy, C4alkoxy, C3alkoxy, C2alkoxy or C1alkoxy, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is cycloalkyl-C1-6 alkyl, cycloalkyl-C1-5 alkyl, cycloalkyl-C1-4 alkyl, cycloalkyl-C1-3 alkyl or cycloalkyl-C1-2 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is cycloalkyl-C6 alkyl, cycloalkyl-C5 alkyl, cycloalkyl-C4 alkyl, cycloalkyl-C3 alkyl, cycloalkyl-C2 alkyl or cycloalkyl-C1 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C3-10 cycloalkyl-C1-6 alkyl, C3-9 cycloalkyl-C1-6 alkyl, C3-8 cycloalkyl-C1-6 alkyl, C3-7 cycloalkyl-C1-6 alkyl or C3-6 cycloalkyl-C1-6 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C3-10 cycloalkyl-C1 alkyl, C3-9 cycloalkyl-C1 alkyl, C3-8 cycloalkyl-C1 alkyl, C3-7 cycloalkyl-C1 alkyl or C3-6 cycloalkyl-C1 alkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is heterocycloalkyl-C1-6 alkyl, heterocycloalkyl-C1-5 alkyl, heterocycloalkyl-C1-4 alkyl, heterocycloalkyl-C1-3 alkyl or heterocycloalkyl-C1-2 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is heterocycloalkyl-C6 alkyl, heterocycloalkyl-C5 alkyl, heterocycloalkyl-C4 alkyl, heterocycloalkyl-C3 alkyl, heterocycloalkyl-C2 alkyl or heterocycloalkyl-C1 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is 4-to 10-membered heterocycloalkyl-C1-6 alkyl, 4-to 9-membered heterocycloalkyl-C1-6 alkyl, 4-to 8-membered heterocycloalkyl-C1-6 alkyl, 4-to 7-membered heterocycloalkyl-C1-6 alkyl or 4-to 6-membered heterocycloalkyl-C1-6 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is 4-to 10-membered heterocycloalkyl-C1 alkyl, 4-to 9-membered heterocycloalkyl-C1 alkyl, 4-to 8-membered heterocycloalkyl-C1 alkyl, 4-to 7-membered heterocycloalkyl-C1 alkyl or 4-to 6-membered heterocycloalkyl-C1 alkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is aryl-C1-6 alkyl, aryl-C1-5 alkyl, aryl-C1-4 alkyl, aryl-C1-3 alkyl or aryl-C1-2 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is aryl-C6 alkyl, aryl-C5 alkyl, aryl-C4 alkyl, aryl-C3 alkyl, aryl-C2 alkyl or aryl-C1 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C6-12 aryl-C1-6 alkyl, C6-11 aryl-C1-6 alkyl, C6-10 aryl-C1-6 alkyl, C6-9 aryl-C1-6 alkyl or C6-8 aryl-C1-6 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C6-12 aryl-C1 alkyl, C6-11 aryl-C1 alkyl, C6-10 aryl-C1 alkyl, C6-9 aryl-C1 alkyl or C6-8 aryl-C1 alkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is heteroaryl-C1-6 alkyl, heteroaryl-C1-5 alkyl, heteroaryl-C1-4 alkyl, heteroaryl-C1-3 alkyl or heteroaryl-C1-2 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is heteroaryl-C6 alkyl, heteroaryl-C5 alkyl, heteroaryl-C4 alkyl, heteroaryl-C3 alkyl, heteroaryl-C2 alkyl or heteroaryl-C1 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is 5-to 10-membered heteroaryl-C1-6 alkyl, 5-to 9-membered heteroaryl-C1-6 alkyl, 5-to 8-membered heteroaryl-C1-6 alkyl, 6-to 8-membered heteroaryl-C1-6 alkyl or 6-to 7-membered heteroaryl-C1-6 alkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is 5-to 10-membered heteroaryl-C1 alkyl, 5-to 9-membered heteroaryl-C1 alkyl, 5-to 8-membered heteroaryl-C1 alkyl, 6-to 8-membered heteroaryl-C1 alkyl or 6-to 7-membered heteroaryl-C1 alkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is C3-10 cycloalkyl, C3-9 cycloalkyl, C3-8 cycloalkyl, C3-7 cycloalkyl, C3-6 cycloalkyl or C3-5 cycloalkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is C10 cycloalkyl, C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl or C3 cycloalkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is 4-to 10-membered heterocycloalkyl, 4-to 9-membered heterocycloalkyl, 4-to 8-membered heterocycloalkyl, 5-to 8-membered heterocycloalkyl, 5-to 8-membered heterocycloalkyl or 5-to 7-membered heterocycloalkyl, each optionally substituted with one or more R. In some embodiments, one or more RA is 10-membered heterocycloalkyl, 9-membered heterocycloalkyl, 8-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl or 4-membered heterocycloalkyl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 6-to 8-membered heteroaryl or 6-to 7-membered heteroaryl, each optionally substituted with one or more R. In some embodiments, one or more RA is 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl or 5-membered heteroaryl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is C6-12 aryl, C6-11 aryl, C6-10 aryl, C6-9 aryl or C6-8 aryl, each optionally substituted with one or more R. In some embodiments, one or more RA is C12 aryl, C11 aryl, C10 aryl, C9 aryl, C8 aryl, C7 aryl or C6 aryl, each optionally substituted with one or more (e.g., two, or three, etc) R.
In some embodiments, one or more RA is independently -ORa. In some embodiments, Ra is C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, Ra is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl. In some embodiments, Ra is C1-6 haloalkyl, C1-5 haloalkyl, C1-4 haloalkyl, C1-3 haloalkyl or C1-2 haloalkyl. In some embodiments, Ra is C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl or C1 haloalkyl.
In some embodiments, one or more RA is -O-C1-6 alkyl, -O-C1-5 alkyl, -O-C1-4 alkyl, -O-C1-3 alkyl or -O-C1-2 alkyl. In some embodiments, one or more RA is -O-C6 alkyl, -O-C5 alkyl, -O-C4 alkyl, -O-C3 alkyl, -O-C2 alkyl or -O-C1 alky.
In some embodiments, one or more RA is -O-C1-6 haloalkyl, -O-C1-5 haloalkyl, -O-C1-4 haloalkyl, -O-C1-3 haloalkyl or -O-C1-2 haloalkyl. In some embodiments, one or more RA is -O-C6 haloalkyl, -O-C5 haloalkyl, -O-C4 haloalkyl, -O-C3 haloalkyl, -O-C2 haloalkyl or -O-C1 haloalkyl.
In some embodiments, each R is independently halogen, hydroxyl, cyano, alkyl, oxo, or alkylidenyl, wherein the alkyl, and alkylidenyl are independently optionally substituted with one or more R’ . In some embodiments, each R is independently -F, hydroxyl, cyano, -CH3 or oxo. In some embodiments, each R is alkylidenyl, wherein the alkylidenyl is independently optionally substituted with halogen, -ORa, or 5-to 6-membered heterocycloalkyl.
In some embodiments, each RA is independently -CH3, -CH2CH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -OCH3, -OCF3, -OCH2F, -OCHF2, -OCH2CH3, -OCH2CF3, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, 
In some embodiments, R1 is alkyl optionally substituted with one or more R. In some embodiments, R1 is C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl, each optionally substituted with one or more R. In some embodiments, R1 is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl, each optionally substituted with one or more R.
In some embodiments, R1 is -CH3.
In some embodiments, R2 is alkyl optionally substituted with one or more R. In some embodiments, R2 is C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl, each optionally substituted with one or more R. In some embodiments, R2 is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl, each optionally substituted with one or more R.
In some embodiments, R2 is -CH3.
In some embodiments, R3 is hydrogen or halogen. In some embodiments, R3 is hydrogen or -F.
In some embodiments, R4 is -N (Rb) 2. In some embodiments, each Rb is independently hydrogen or alkyl. In some embodiments, each Rb is independently hydrogen, C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, each Rb is hydrogen. In some embodiments, R4 is -NH2.
In some embodiments, R5 is -C (O) NH (Ra) . In some embodiments, Ra is hydrogen or alkyl. In some embodiments, Ra is hydrogen, C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, Ra is hydrogen. In some embodiments, R5 is -C (O) NH2.
In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, n is 0, 1, 2, 3, 4 or 5. In some embodiments, n is 0, 1 or 2.
In some embodiments, the compound provided herein is of Formula (Ia) :
wherein Ring A, X, Y, Z, R1 to R6, RA, and n are as defined herein.
In some embodiments of a compound disclosed herein, one or more of R, R1, R2, R3, R4, R5, RA, Ra and Rb groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
In some embodiments of a compound disclosed herein, one or more 1H are replaced with one or more deuteriums in one or more of the following groups R, R1, R2, R3, R4, R5, RA, Ra and Rb.
In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R, R1, R2, R3, R4, R5, RA, Ra and Rb is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
In some embodiments of a compound disclosed herein, one or more 1H of Ring A are replaced with one or more deuteriums.
Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
In some embodiments, the present disclosure provides a compound selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
TABLE 1 Exemplary Compounds

In some embodiments, the present disclosure provides a compound selected from any one of the compounds in Table 2, or a pharmaceutically acceptable salt thereof.
TABLE 2 Exemplary Compounds




In some embodiments, the compound disclosed herein is not
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds  presented herein include all cis, trans, syn, anti, entgegen (E) , and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc. ) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
Isotopically enriched compounds
Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 1H (protium) , 2H (deuterium) , and 3H (tritium) . Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H) , tritium (3H) , iodine-125 (125I) or carbon-14 (14C) . In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 131I, and 125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. In some embodiments, each hydrogen atom of the compounds disclosed herein is independently 1H, 2H (D) or 3H (T) . In some embodiments, one or more hydrogen atom of the compounds disclosed herein is 2H (deuterium, or D) .
The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.
Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4’ -methylenebis- (3-hydroxy-2-ene-1 -carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, and their pharmaceutically acceptable acid addition salts.
In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+ (C1-4 alkyl) 4, and the like.
Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
Tautomers
In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
Method of Treatment
In a further aspect, the present disclosure is directed to a method of treating a PKMYT1-associated disease or condition in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the compound of Formula (V) , (I) or (Ia) or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof as provided herein, owning to the PKMYT1 inhibitory activity of the compound of the present disclosure. In some embodiments, the compounds of the present disclosure are selective PKMYT1 inhibitors.
As used herein, the term “subject in need thereof” is a subject having a PKMYT1-associated disease or condition, or a subject having an increased risk of developing PKMYT1-associated disease or condition relative to the population at large. In some embodiments, the subject is a warm-blooded animal. In some embodiments, the warm-blooded animal is a mammal. In some embodiments, the warm-blooded animal is a human.
PKMYT1 has been implicated as a potentially important cancer target as it is essential in many cancer cells. Overexpression of PKMYT1 has been observed in various cancers including, for example, hepatocellular carcinoma as well as clear-cell renal-cell carcinoma. PKMyt1 downregulation has a minor role in unperturbed cells but has a more prominent role in cells exposed to DNA damage. Additionally, cells that exhibit high levels of replication stress in addition to defective G1 checkpoint regulation may be particularly sensitive to loss of PKMYT1 function, as these cells will be prone to entering mitosis prematurely with compromised genomic material leading to mitotic catastrophe. Inhibitors of PKMYT1, a regulator of G2-M transition, has been found to be particularly useful in the treatment of tumors (e.g., cancers) harboring CCNE1-amplification or FBXW7 loss-of-function mutations using a synthetic lethal therapeutic strategy. Cancers harboring CCNE1-amplification may include, e.g., uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, and endometrial cancer, etc. Cancers harboring FBXW7 loss-of-function may include, e.g., uterine cancer, colorectal cancer, breast cancer, lung cancer, and esophageal cancer, etc. Moreover, PKMYT1 has been implicated in non-small-cell lung cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, etc.
In some embodiments, the PKMYT1-associated disease or condition is tumor, and particularly, advanced solid tumor. In some embodiments, the PKMYT1-associated disease or  condition is selected from the group consisting of uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer (e.g., non-small-cell lung cancer) , endometrial cancer, colorectal cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, etc.
The method of treating a PKMYT1-associated disease or condition as described herein may be used as a monotherapy. As used herein, the term “monotherapy” refers to the administration of a single active or therapeutic compound to a subject in need thereof. In some embodiments, monotherapy will involve administration of a therapeutically effective amount of one of the compounds of the present disclosure or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, to a subject in need of such treatment.
Depending upon the particular disease or condition to be treated, the method of treating a PKMYT1-associated disease or condition described herein may involve, in addition to administration of the compound of Formula (V) , (I) or (Ia) , combination therapy of one or more additional therapeutic agent (s) , for example, a second therapeutic agent which is an anti-cancer agent. In some embodiments, non-limiting examples of the additional therapeutical agents may include an additional PKMYT1 inhibitor. In some embodiments, one or more additional therapeutic agent (s) may be selected from the group consisting of: a cytotoxic agent; an antimetabolite; an alkylating agent; an anthracycline; an antibiotic; an anti-mitotic agent; a hormone therapy; a signal transduction inhibitor; a gene expression modulator; an apoptosis inducer; an angiogenesis inhibitor; an immunotherapy agent; a DNA damage repair inhibitor; or a combination thereof.
In a further aspect, the present disclosure provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
In a further aspect, the present disclosure provided a method of modulating PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
In a further aspect, the present disclosure provided a method of inhibiting PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.
In some embodiments, the subject has cancer. In some embodiments, the cancer depends on the activity of PKMYT1. In some embodiments, the cancer overexpresses CCNE1. In some embodiments, the cancer has an inactivating mutation in the FBXW7 gene. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, or uterine cancer.
In a further aspect, the present disclosure provided a pharmaceutical composition for treating a PKMYT1-associated disease or condition, comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In a further aspect, the present disclosure provided use of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for treating cancer.
In a further aspect, the present disclosure provided a kit for treating cancer, comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein, a container, and optionally a package insert or label indicating treatment of said disease or condition.
Dosing
In some embodiments, the compositions containing the compound (s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
Routes of Administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
In some embodiments, 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. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, 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.
Pharmaceutical Compositions/Formulations
The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999) , herein incorporated by reference for such disclosure.
Examples
For the purpose of illustration, the following examples are included. The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. However, it is to be understood that these examples do not limit the present disclosure and are only meant to suggest a method of practicing the present disclosure. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are deemed to be within the scope of the present disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and/or by making routine modifications of reaction conditions. Besides, persons skilled in the art will also understand that individual steps described herein or in the separate batches of a compound may be combined. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure, but rather is specified by the claims appended hereto.
Example 1: Synthesis of Exemplary Compounds
Example 1.1:
Step 1: Preparation of Compound 1-2
To a solution of compound 1-1 (3.70 g, 19.68 mmol) in THF (10 mL) were added TBAF (78.7 mL, 78.72 mmol) and CH3I (2.45 mL, 39.36 mmol) . The mixture was stirred at 60 ℃ for 16 h. The mixture was cooled to rt, diluted with EA (100 mL) , washed with water (100 mL) . The organic layer was dried over Na2SO4, filtered and concentrated, and purified by silica gel column to give compound 1-2 (3.50 g, 88.0%) . LCMS: 204.0 [M+H] +; 1H NMR (400 MHz, CDCl3) : δ 6.72 (d, J = 4.0 Hz, 1H) , 6.23 (s, 1H) , 3.48 (s, 3H) , 2.34 (s, 3H) .
Step 2: Preparation of Compound 1-3
To a solution of compound 1-2 (1.0 g, 4.949 mmol) in DMF (10 mL) was added NCS (726.96 mg, 5.444 mmol) . The mixture was stirred at 45 ℃ for 16 h. The reaction mixture was diluted with EA (100 mL) , and washed with brine (100 mL × 3) . The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column to give compound 1-3 (1.00 g, 85.4%) . LCMS: 237.9 [M+H] +.
Step 3: Preparation of Compound 1-5
To a solution of compound 1-3 (500 mg, 2.114 mmol) in dioxane (10 mL) were added compound 1-4 (352 mg, 2.326 mmol) , XantPhos Pd G3 (240.6 mg, 0.254 mmol) , and Cs2CO3 (2.07 g, 6.343 mmol) , and the mixture was stirred at 110 ℃ for 16 h and cooled to rt. The mixture was diluted with EA (100 mL) and water (30 mL) . The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford compound 1-5 (230 mg, 35.5%) . LCMS: 307.1 [M+H] +.
Step 4: Preparation of Compound 1-7
To a solution of compound 1-6 (75.79 mg, 1.147 mmol) in DMF (3 mL) was added NaH (46 mg, 1.147 mmol) at 0 ℃. The mixture was stirred for 0.5 h. Then CuI (4.9 mg, 0.026 mmol) ,  methyl [ (1S, 2S) -2- (methylamino) cyclohexyl] amine (7.42 mg, 0.052 mmol) , and compound 1-5 (160 mg, 0.522 mmol) were added. The mixture was stirred at 150 ℃ for 1 h under microwave. The mixture was quenched with water (10 mL) and extracted with EA (10 mL) . The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-TLC to afford compound 1-7. LCMS: 337.1 [M+H] +.
Step 5: Preparation of Compound 1-8
A mixture of compound 1-7 (50 mg, 0.149 mmol) in H2SO4 (2 mL) was stirred at 15 ℃ for 0.5 h. The mixture was quenched with ice-water (15 mL) , basified to pH～8 with 2 M NaOH. The mixture was extracted with DCM (20 mL × 3) . The organic layers were combined dried over Na2SO4, concentrated to dryness. The residue was purified by prep-TLC to afford compound 1-8. LCMS: 355.1 [M+H] +.
Step 6: Preparation of Compound 1
To a solution of compound 1-8 (90 mg, 0.277 mmol) in DCM (1 mL) was added BBr3 (0.3 μL, 0.027 mmol) . The mixture was stirred at 15 ℃ for 2 h. The reaction was quenched with MeOH (1mL) . The mixture was concentrated and purified by prep-HPLC to afford Compound 1. LCMS: 341.0 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 10.33 (s, 1H) , 9.63 (s, 1H) , 7.09 (t, J = 7.8 Hz, 1H) , 6.94 (d, J = 8.2 Hz, 1H) , 6.64 (s, 1H) , 6.45 (s, 1H) , 6.27 (s, 1H) , 5.67 (s, 1H) , 3.49 (s, 3H) , 2.30 (s, 3H) , 1.78 (s, 3H) , 1.69 (s, 3H) .
Example 1.2
Step 1: Preparation of Compound 2-2
To a solution of compound 1-1 (2.50 g, 13.296 mmol) in toluene (50 mL) were added compound 2-1 (2.28 g, 26.593 mmol) , Cu (OAc) 2 (2.42 g, 13.296 mmol) , pyridine (5.35 mL, 66.482 mmol) , and KHMDS (13.3 mL, 13.296 mmol) , and the reaction was stirred at 100 ℃ under O2 overnight. The mixture was cooled to rt, diluted with DCM and water. The organic layer was separated, dried, filtered, and concentrated. The residue was purified using silica gel column chromatography to afford compound 2-2 (1.70 g, 56.1%) . LCMS: 230.1 [M+H] +.
Step 2: Preparation of Compound 2
Compound 2 was prepared from compound 2-2 (1.50 g, 6.576 mmol) in a similar fashion with the synthesis of Compound 1, the isomer was separated by SFC. Instrument: Waters SFC 150; Column: 250*25 mm 10 μm; Condition: 45%MeOH (+0.1%7.0mol/L  ammonia in MeOH) with 55%CO2; Flow rate: 80 mL/min; RT = 2.671 min (the other enantiomer RT = 4.589 min) . LCMS: 367.3 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 10.26 (s, 1H) , 9.63 (s, 1H) , 7.09 (d, J = 8.2 Hz, 1H) , 6.93 (d, J = 8.2 Hz, 1H) , 6.63 (s, 1H) , 6.42 (s, 2H) , 5.61 (s, 1H) , 2.95–2.79 (m, 1H) , 2.38 (s, 3H) , 1.78 (s, 3H) , 1.69 (s, 3H) , 1.17–1.12 (m, 2H) , 0.85–0.81 (m, 2H) .
Example 1.3
Step 1: Preparation of Compound 3-2
To a solution of compound 3-1 (50 g, 306.748 mmol) in THF (2 L) was added LDA (245.40 mL, 490.798 mmol) at -78 ℃. The mixture was stirred at -78 ℃ for 0.5 h. Then I2 (217.7 g, 490.798 mmol) in THF (500 mL) was added and stirred at -78 ℃ for 1 h. The reaction was quenched by NH4Cl (sat. aq, 2 L) under ice-bath, which was extracted with EA (2 L × 3) . The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 3-2 (25 g, 28.2%) . 1H NMR (400 MHz, DMSO-d6) : δ 2.54 (s, 3H) .
Step 2: Preparation of Compound 3-3
To a solution of compound 3-2 (38 g, 131.533 mmol) , compound 1-4 (19.9 g, 131.533 mmol) in THF (1.5 L) was added LiHMDS (1.0 M, 263.07 mL) at 0 ℃ under N2. The mixture was stirred at 0 ℃ for 1 h. The mixture quenched by NH4Cl (sat. aq, 1 L) under ice-bath, which was extracted with EA (500 mL × 3) . Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 3-3 (11.5 g, 21.7%) . LCMS: 404.0 [M+H] +.
1H NMR (400 MHz, CDCl3) : δ 7.08 (d, J = 8.4 Hz, 1H) , 6.81–6.77 (m, 2H) , 3.84 (s, 3H) , 2.36 (s, 3H) , 2.13 (s, 3H) , 2.06 (s, 3H) .
Step 3: Preparation of Compound 3-4
To a solution of compound 1-6 (245.7 mg, 3.717 mmol) in DME (15 mL) was added NaH (123.9 mg, 3.097 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 30 min. Then compound 3-3 (500 mg, 1.239 mmol) and XantPhos Pd G3 (176.2 mg, 0.186 mmol) were added. The mixture was stirred at 130 ℃ for 3 h under N2. The mixture was quenched by H2O (50 mL) , and extracted with EA (30 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford compound 3-4 (70.4 mg, 33.7%) . LCMS: 342.1 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 7.49 (s, 2H) , 7.26 (d, J = 8.4 Hz, 1H) , 7.12 (d, J = 8.4 Hz, 1H) , 3.85 (s, 3H) , 2.42 (s, 3H) , 1.80 (s, 3H) , 1.71 (s, 3H) .
Step 4: Preparation of Compound 3-5
To a solution of compound 3-4 (500 mg, 1.463 mmol) in AcOH (10 mL) was added NaOAc (959.7 mg, 11.704 mmol) . The mixture was stirred at 100 ℃ for 24 h. The reaction mixture was carefully added into ice-water (30 mL) while stirring, which was adjusted to pH～8 with NaOH (4 M in water) . The mixture was extracted with EA (30 mL × 3) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 3-5. LCMS: 324.0 [M+H] +.
Step 4: Preparation of Compound 3-6
Compound 3-6 was obtained by SFC separation of racemic compound 3-5. Instrument: Waters SFC150; Column: 250*25 mm 10 μm; Condition: 25%EtOH (+0.1%7.0 mol/L Ammonia in MeOH) with Supercritical CO2; Flow rate: 120 mL/min; RT = 1.654 min (the other enantiomer RT = 2.534 min) . LCMS: 324.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) : δ 12.10 (s, 1H) , 7.21 (d, J = 8.4 Hz, 1H) , 7.06 (d, J = 8.4 Hz, 1H) , 6.39 (s, 2H) , 3.83 (s, 3H) , 2.17 (s, 3H) , 1.82 (s, 3H) , 1.72 (s, 3H) .
Step 5: Preparation of Compound 3-7
To a solution of compound 3-6 (500 mg, 1.546 mmol) in ACN (10 mL) and Cs2CO3 (756 mg, 2.319 mmol) was added fluoroiodomethane (297 mg, 1.856 mmol) . The mixture was stirred at rt for 2 h. The mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 3-7. LCMS: 356.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 7.23 (d, J = 8.4 Hz, 1H) , 7.09 (d, J = 8.4 Hz, 1H) , 6.59 (s, 2H) , 6.17 (d, J = 52.0 Hz, 1H) , 3.84 (s, 3H) , 2.45 (s, 3H) , 1.84 (s, 3H) , 1.74 (s, 3H)
Step 6: Preparation of Compound 3
Compound 3 was synthesized from compound 3-7 (900 mg, 2.53 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 360.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.59 (s, 1H) , 9.14 (s, 1H) , 7.06 (d, J = 8.4 Hz, 1H) , 6.92 (d, J = 8.4 Hz, 1H) , 6.88 (s, 1H) , 6.54 (s, 2H) , 6.23 (d, J = 52.0 Hz, 2H) , 2.49 (s, 3H) , 1.80 (s, 3H) , 1.71 (s, 3H) .
Example 1.4
Step 1: Preparation of Compound 4-2
To a solution of compound 3-6 (70 mg, 0.216 mmol) and Cs2CO3 (141.0 mg, 0.433 mmol) in CH3CN (4 mL) was added MeI (46.1 mg, 0.325 mmol) . The mixture was stirred at rt for 2 h. The mixture was diluted with H2O (10 mL) and extracted with EA (10 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford compound 4-2 (50 mg, 68.5%) . LCMS: 338.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) : δ 7.22 (d, J = 8.4 Hz, 1H) , 7.07 (d, J = 8.4 Hz, 1H) , 6.44 (s, 2H) , 3.83 (s, 3H) , 3.47 (s, 3H) , 2.37 (s, 3H) , 1.82 (s, 3H) , 1.73 (s, 3H) .
Step 2: Preparation of Compound 4
Compound 4 was synthesized from compound 4-2 (40 mg, 0.119 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 342.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.54 (s, 1H) , 9.50 (s, 1H) , 7.05 (d, J = 8.4 Hz, 1H) , 6.90 (d, J = 8.4 Hz, 1H) , 6.75 (s, 1H) , 6.45 (s, 2H) , 3.52 (s, 3H) , 2.40 (s, 3H) , 1.78 (s, 3H) , 1.69 (s, 3H) .
Example 1.5
Step 1: Preparation of Compound 5-2
To a solution of compound 3-6 (150 mg, 0.464 mmol) in ACN (8 mL) were added compound 5-1 (129.2 mg, 0.557 mmol) and Cs2CO3 (181.3 mg, 0.557 mmol) . The mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 5-2 (90 mg, 47.9%) . LCMS: 406.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) : δ 7.22 (d, J = 8.4 Hz, 1H) , 7.08 (d, J = 8.4 Hz, 1H) , 6.59 (s, 2H) , 5.05 (q, J = 8.0 Hz, 2H) , 3.83 (s, 3H) , 2.43 (s, 3H) , 1.83 (s, 3H) , 1.74 (s, 3H) .
Step 2: Preparation of Compound 5
Compound 5 was synthesized from compound 5-2 (80 mg, 0.197 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 410.3 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.56 (s, 1H) , 9.16 (s, 1H) , 7.06 (d, J = 8.4 Hz, 1H) , 6.91 (d, J = 8.4 Hz, 1H) , 6.85 (s, 1H) , 6.55 (s, 2H) , 5.05 (q, J = 8.0 Hz, 2H) , 2.47 (s, 3H) , 1.79 (s, 3H) , 1.71 (s, 3H) .
Example 1.6
Step 1: Preparation of Compound 6-2
To a solution of compound 3-6 (150 mg, 0.464 mmol) in ACN (8 mL) were added compound 6-1 (119.2 mg, 0.557 mmol) and Cs2CO3 (181.3 mg, 0.557 mmol) . The mixture was stirred at rt for 2 h. The mixture was diluted with water (30 mL) , which was extracted with EA (30 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 6-2 (75 mg, 41.7%) . LCMS: 388.1 [M+H] +; 1H NMR (400 MHz, DMSO-d6) : δ 7.22 (d, J = 8.4 Hz, 1H) , 7.08 (d, J = 8.4 Hz, 1H) , 6.55 (s, 2H) , 6.50–6.20 (m, 1H) , 4.52–4.44 (m, 2H) , 3.84 (s, 3H) , 2.41 (s, 3H) , 1.83 (s, 3H) , 1.74 (s, 3H) .
Step 2: Preparation of Compound 6
Compound 6 was synthesized from compound 6-2 (65 mg, 0.168 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 392.2 [M+H] +; 1H NMR (400 MHz, DMSO-d6) : δ 9.62 (s, 1H) , 9.25 (s, 1H) , 7.06 (d, J = 8.4 Hz, 1H) , 6.91 (d, J = 8.4 Hz, 1H) , 6.85 (d, J =2.8 Hz, 1H) , 6.52 (s, 2H) , 6.40–6.24 (m, 1H) , 4.57–4.49 (m, 2H) , 2.45 (s, 3H) , 1.79 (s, 3H) , 1.70 (s, 3H) .
Example 1.7
Step 1: Preparation of Compound 7-2
To a solution of compound 3-6 (150 mg, 0.464 mmol) in DMF (5 mL) were added iodoethane (86.8 mg, 0.557 mmol) and Cs2CO3 (181.3 mg, 0.557 mmol) . The mixture was stirred at rt  for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3) . The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 7-2 (90 mg, 55.2%) . LCMS: 352.1 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 7.21 (d, J = 8.4 Hz, 1H) , 7.07 (d, J = 8.4 Hz, 1H) , 6.43 (s, 2H) , 4.06–4.01 (m, 2H) , 3.83 (s, 3H) , 2.41 (s, 3H) , 1.82 (s, 3H) , 1.73 (s, 3H) , 1.22 (t, J = 7.2 Hz, 3H) .
Step 2: Preparation of Compound 7
Compound 7 was synthesized from compound 7-2 (70 mg, 0.199 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 356.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.57 (s, 1H) , 9.49 (s, 1H) , 7.05 (d, J = 8.4 Hz, 1H) , 6.90 (d, J = 8.4 Hz, 1H) , 6.78 (d, J = 3.2 Hz, 1H) , 6.46 (s, 2H) , 4.08 (q, J = 8.0 Hz, 2H) , 2.45 (s, 3H) , 1.78 (s, 3H) , 1.69 (s, 3H) , 1.25 (t, J = 8.0 Hz, 3H) .
Example 1.8
Step 1: Preparation of Compound 8-2
To a solution of compound 3-6 (150 mg, 0.464 mmol) and compound 8-1 (112.2 mg, 0.928 mmol) in DMF (5 mL) was added Cs2CO3 (181.3 mg, 0.557 mmol) . The solution was stirred at rt for 3 h. The reaction mixture was diluted with water (20 mL) , which was extracted with EA (30 mL × 3) . The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 8-2 (70 mg, 41.5%) . LCMS: 364.0 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 7.24 (d, J = 8.4 Hz, 1H) , 7.07 (d, J = 8.4 Hz, 1H) , 6.48 (s, 2H) , 5.98–5.89 (m, 1H) , 5.18 (dd, J = 10.4, 0.8 Hz, 1H) , 5.11–4.94 (m, 1H) , 4.69 (d, J = 4.8 Hz, 2H) , 3.84 (s, 3H) , 2.36 (s, 3H) , 1.84 (s, 3H) , 1.74 (s, 3H) .
Step 2: Preparation of Compound 8
Compound 8 was synthesized from compound 8-2 (80 mg, 0.220 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 368.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.57 (s, 1H) , 9.42 (d, J = 3.2 Hz, 1H) , 7.05 (d, J = 8.4 Hz, 1H) , 6.91 (d, J = 8.4 Hz, 1H) , 6.80 (d, J = 3.2 Hz, 1H) , 6.49 (s, 2H) , 5.98–5.91 (m, 1H) , 5.19 (dd, J = 10.4, 1.2 Hz, 1H) , 5.00 (dd, J = 17.2, 1.2 Hz, 1H) , 4.73 (d, J = 5.2 Hz, 2H) , 2.40 (s, 3H) , 1.79 (s, 3H) , 1.70 (s, 3H) .
Example 1.9
Step 1: Preparation of Compound 9-1
A solution of compound 3-6 (150 mg, 0.464 mmol) in H2SO4 (5 mL) was stirred at 40 ℃for 1 h. The reaction mixture was carefully added into ice-water (20 mL) while stirring and adjusted to pH～8 with NaOH (4 M in water) . The mixture was extracted with DCM (30 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 9-1 (150 mg, 94.7%) . LCMS: 342.3 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 12.28 (s, 1H) , 9.46 (s, 1H) , 7.23 (d, J = 8.4 Hz, 1H) , 7.07 (d, J = 8.4 Hz, 1H) , 6.76 (s, 1H) , 6.41 (s, 2H) , 3.84 (s, 3H) , 2.21 (s, 3H) , 1.83 (s, 3H) , 1.73 (s, 3H) .
Step 2: Preparation of Compound 9-3
To a solution of compound 9-1 (150 mg, 0.439 mmol) and compound 9-2 (79.0 mg, 0.659 mmol) in DMF (1 mL) was added K2CO3 (182.2 mg, 1.318 mmol) . The solution was stirred at 50 ℃for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 9-3. LCMS: 381.3 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.14 (s, 1H) , 7.25 (d, J = 8.4 Hz, 1H) , 7.10 (d, J = 8.4 Hz, 1H) , 6.91 (s, 1H) , 6.61 (s, 2H) , 5.22 (s, 2H) , 3.85 (s, 3H) , 2.50 (s, 3H) , 1.85 (s, 3H) , 1.75 (s, 3H) .
Step 3: Preparation of Compound 9
Compound 9 was synthesized from compound 9-3 (60 mg, 0.158 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 367.0 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.58 (s, 1H) , 9.12 (s, 1H) , 7.06 (d, J = 8.4 Hz, 1H) , 6.92 (d, J = 8.4 Hz, 1H) , 6.85 (s, 1H) , 6.56 (s, 2H) , 5.20 (s, 2H) , 2.51 (s, 3H) , 1.79 (s, 3H) , 1.70 (s, 3H) .
Example 1.10
Step 1: Preparation of Compound 10-2
To a solution of compound 9-1 (100 mg, 0.293 mmol) in DMF (2 mL) were added compound 10-1 (61.6 mg, 0.322 mmol) and Cs2CO3 (286.5 mg, 0.879 mmol) . The mixture was stirred at rt under N2 for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 10-2 (90 mg, 81.0%) . LCMS: 380.0 [M+H] +; 1H NMR (400 MHz, DMSO-d6) : δ 9.31 (d, J = 2.8 Hz, 1H) , 7.24 (d, J = 8.4 Hz, 1H) , 7.09 (d, J = 8.4 Hz, 1H) , 6.85 (d, J = 2.8 Hz, 1H) , 6.56 (s, 2H) , 4.94 (d, J = 2.0 Hz, 2H) , 3.84 (s, 3H) , 3.38 (t, J = 2.0 Hz, 1H) , 2.52 (s, 3H) , 1.84 (s, 3H) , 1.74 (s, 3H) .
Step 2: Preparation of Compound 10
Compound 10 was synthesized from compound 10-2 (40 mg, 0.105 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 366.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.57 (s, 1H) , 9.31 (d, J = 2.8 Hz, 1H) , 7.06 (d, J = 8.4 Hz, 1H) , 6.91 (d, J = 8.4 Hz, 1H) , 6.83 (d, J = 2.8 Hz, 1H) , 6.51 (s, 2H) , 4.94 (d, J = 2.0 Hz, 2H) , 3.38 (t, J = 2.0 Hz, 1H) , 2.52 (s, 3H) , 1.79 (s, 3H) , 1.70 (s, 3H) .
Example 1.11
Step 1: Preparation of Compound 11-2
To a solution of compound 9-1 (135 mg, 0.395 mmol) in DMF (3 mL) was added compound 11-1 (86.3 mg, 0.474 mmol) and Cs2CO3 (154.4 mg, 0.474 mmol) . The mixture was stirred at rt under N2 for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 11-2 (90 mg, 57.5%) . LCMS: 396.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.49 (d, J = 3.2 Hz, 1H) , 7.24 (d, J = 8.4 Hz, 1H) , 7.08 (d, J = 8.4 Hz, 1H) , 6.78 (d, J = 3.2 Hz, 1H) , 6.51 (s, 2H) , 4.00 (d, J = 6.8 Hz, 2H) , 3.84 (s, 3H) , 2.48 (s, 3H) , 1.84 (s, 3H) , 1.74 (s, 3H) , 1.24–1.19 (m, 1H) , 0.57–0.37 (m, 4H) .
Step 2: Preparation of Compound 11
Compound 11 was synthesized from compound 11-2 (110 mg, 0.278 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 382.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.57 (s, 1H) , 9.48 (d, J = 3.2 Hz, 1H) , 7.05 (d, J = 8.4 Hz, 1H) , 6.91 (d, J = 8.4 Hz, 1H) , 6.76 (d, J = 3.2 Hz, 1H) , 6.47 (s, 2H) , 4.00 (d, J = 6.8 Hz, 2H) , 1.79 (s, 3H) , 1.70 (s, 3H) , 1.25–1.21 (m, 1H) , 0.65–0.35 (m, 4H) .
Example 1.12
Step 1: Preparation of Compound 12-2
A mixture of compound 9-1 (50 mg, 0.146 mmol) , compound 12-1 (38.4 mg, 0.161 mmol) , Cs2CO3 (143.1 mg, 0.439 mmol) in DMF (1 mL) was stirred at 50 ℃ for 3 h. The reaction mixture was diluted with water (10 mL) , which was extracted with EA (10 mL × 3) . The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-TLC to afford compound 12-2 (50 mg, 68.5%) . LCMS: 500.3 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.59 (s, 1H) , 7.37 (d, J = 8.4 Hz, 1H) , 7.22 (d, J = 8.4 Hz, 1H) , 6.92 (s, 1H) , 6.62 (s, 2H) , 4.32 (t, J = 4.8 Hz, 2H) , 4.04 (t, J = 4.8 Hz, 2H) , 3.98 (s, 3H) , 2.61 (s, 3H) , 1.97 (s, 3H) , 1.87 (s, 3H) , 0.88 (s, 9H) , 0.00 (s, 6H) .
Step 2: Preparation of Compound 12
Compound 12 was synthesized from compound 12-2 (50 mg, 0.100 mmol) in a similar fashion according to the procedure for Compound 1. LCMS: 372.2 [M+H] +.
1H NMR (400 MHz, DMSO-d6) : δ 9.54 (s, 1H) , 9.48 (s, 1H) , 7.05 (d, J = 8.4 Hz, 1H) , 6.90 (d, J = 8.4 Hz, 1H) , 6.75 (s, 1H) , 6.45 (s, 2H) , 4.96 (s, 1H) , 4.11 (t, J = 5.4 Hz, 2H) , 3.70 (t, J = 5.4 Hz, 2H) , 2.49 (s, 3H) , 1.79 (s, 3H) , 1.70 (s, 3H) .
Other compound disclosed herein can be synthesized with similar methods with modified conditions and different starting materials.
Example 2: Biological Assay
Example 2.1: PKMYT1 HTRF assay
Test compound serial dilution was performed by Echo, and the final concentrations vary from 10 μM to 0.5 nM. This was filled by the addition of 5 μL /well of Enzyme solution to the assay plate containing the test compound. The plate was centrifuged at 1000 rpm for 1 minute, and incubate 15 minutes at 25 ℃. Then 5 μL /well of tracer solution (Tracer 178) was added to initiate the reaction, and incubate for 60 minutes at 25 ℃. Next 5 μL GST-Tb was added into the assay plate, the plate was centrifuged at 1000 rpm for 1 minute, and incubate for 15 minutes at 25 ℃. The assay plate was read on Envision.
Example 2.2: WEE1 ADP-Glo assay
Test compound serial dilution is performed by Echo, and the final concentrations vary from 10 μM to 0.5 nM. This was filled by the addition of 5 μL /well of Enzyme solution to the assay plate containing the test compound. The plate was centrifuged at 1000 rpm for 1 minute, and incubate 15 minutes at 25 ℃. Then 5 μL /well of substrate solution was added to initiate the reaction, and incubate for 60 minutes at 25 ℃. Next 10 μL kinase detection reagent was added into the assay plate, the plate was centrifuged at 1000 rpm for 1 minute, and incubate for 60 minutes at 25 ℃. The assay plate was read on Envision for US LUM as RLU.
The data for Example 2.1 and Example 2.2 is shown in Table 3, wherein “A” stands for IC50 less than or equal to 10 nM; “B” stands for IC50 larger than 10 nM but less than or equal to 50 nM; “C” stands for IC50 larger than 50 nM but less than or equal to 500 nM; “D” stands for IC50 larger than 500 nM but less than or equal to 5000 nM; “E” stands for IC50 larger than 5000 nM; and “NT” stands for not tested.
TABLE 3
Other compounds of disclosed herein also show PKMYT1 inhibitory activity.

Claims (27)

  1. A compound of Formula (I) :
    or a pharmaceutically acceptable salt thereof, wherein:
    each of X, Y and Z is independently N or C;
    each ofis a single bond or double bond;
    Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    Q is N or CRQ;
    RQ is H, OH or NH2;
    or RQ and R1 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
    or RQ and R7 taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
    each RA is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) ORb, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
    or two adjacent RA taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
    R6 is oxo;
    each of R1 and R2 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
    R3 is hydrogen, halogen, cyano, -NO2, -ORa, -SRa, -N (Rb) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Rb) 2, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
    R4 is hydrogen, halogen, cyano, -ORa, -SRa, -N (Rb) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Rb) 2, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl,  heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl aare independently optionally substituted with one or more R;
    R5 is -C (O) NH (Ra) , -C (O) Ra, or -SO2Ra;
    R7 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -N (Rb) 2, -C (O) Ra, -C (O) ORb, -C (O) N (Rb) 2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
    each R is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R’;
    each R’ is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each Ra is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each Rb is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    or two Rb taken together with the atom to which they are attached form a heterocycloalkyl; and
    n is an integer of 0-8.
  2. A compound of Formula (I) :
    or a pharmaceutically acceptable salt thereof, wherein:
    each of X, Y and Z is independently N or C;
    each of is a single bond or double bond;
    Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each RA is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) ORb, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl,  hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
    or two adjacent RA taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R;
    R6 is oxo;
    each of R1 and R2 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R;
    R3 is hydrogen, halogen, cyano, -NO2, -ORa, -SRa, -N (Rb) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Rb) 2, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R;
    R4 is hydrogen, halogen, cyano, -ORa, -SRa, -N (Rb) 2, -C (O) Ra, -C (O) ORa, -C (O) N (Rb) 2, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R;
    R5 is -C (O) NH (Ra) , -C (O) Ra, or -SO2Ra;
    each R is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkylidenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more R’;
    each R’ is independently halogen, cyano, oxo, -ORa, -SRa, -SO2Ra, -N (Rb) 2, -C (O) N (Rb) 2, -SO2N (Rb) 2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each Ra is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    each Rb is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
    or two Rb taken together with the atom to which they are attached form a heterocycloalkyl; and
    n is an integer of 0-8.
  3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein
    X is C, Y is C and Z is N;
    X is N, Y is C and Z is N;
    X is C, Y is N and Z is C; or
    X is N, Y is C and Z is C.
  4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein
    is
  5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Ring A is heterocycloalkyl or heteroaryl.
  6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is 6-membered heterocycloalkyl or 6-membered heteroaryl.
  7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein
    is wherein
    each of RA1, RA2 and RA3 is independently hydrogen or independently selected from RA;
    or RA1 and RA2 , when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
    or RA1 and RA3, when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
    or RA2 and RA3, when adjacent to each other, taken together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted with one or more R;
    or two RA2 taken together with the same atom to which they are attached form a cycloalkyl, or heterocycloalkyl, each optionally substituted with one or more R;
    or two RA3 taken together with the same atom to which they are attached form a cycloalkyl, or heterocycloalkyl, each optionally substituted with one or more R.
  8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, each RA is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R.
  9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each RA is independently -ORa, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R.
  10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein each R is independently halogen, hydroxyl, cyano, alkyl, oxo, or alkylidenyl, wherein the alkyl and alkylidenyl are optionally substituted with one or more R’.
  11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein each RA is independently -CH3, -CH2CH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, -CH2CHF2, -OCH3, -OCF3, -OCH2F, -OCHF2, -OCH2CH3, -OCH2CF3, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, 
  12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R1 is alkyl optionally substituted with one or more R.
  13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R1 is -CH3.
  14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl optionally substituted with one or more R.
  15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R2 is -CH3.
  16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen or halogen.
  17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4 is -N (Rb) 2.
  18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein each Rb is hydrogen.
  19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R5 is -C (O) NH (Ra) .
  20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein Ra is hydrogen.
  21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ia) :
  22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any compound set forth in Table 1 or Table 2.
  23. A pharmaceutical composition comprising the compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  24. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the compound of any one of claims 1-22, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition of claim 23.
  25. A method of modulating PKMYT1 in a subject, the method comprising administering to the subject the compound of any one of claims 1-22, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition of claim 23.
  26. A method of inhibiting PKMYT1 in a subject, the method comprising administering to the subject the compound of any one of claims 1-22, or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition of claim 23.
  27. The method of claim 25 or 26, wherein the subject has cancer.
PCT/CN2024/119019 2023-09-18 2024-09-14 Novel compounds as pkmyt1 inhibitors and use thereof Pending WO2025060975A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022213204A1 (en) * 2021-04-07 2022-10-13 Repare Therapeutics Inc. Combination therapies including myt1 inhibitors
US20230122909A1 (en) * 2021-10-04 2023-04-20 Repare Therapeutics Inc. Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use
WO2023174329A1 (en) * 2022-03-15 2023-09-21 Insilico Medicine Ip Limited Heteroaromatic compounds as pkmyt1 inhibitors and use thereof
WO2023198199A1 (en) * 2022-04-15 2023-10-19 先声再明医药有限公司 Myt1 kinase inhibitor
CN117510503A (en) * 2022-08-03 2024-02-06 成都先导药物开发股份有限公司 A tyrosine-threonine kinase PKMYT1 inhibitor
WO2024109942A1 (en) * 2022-11-25 2024-05-30 上海齐鲁制药研究中心有限公司 Pkmyt1 inhibitor, preparation method therefor, and pharmaceutical composition and use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022213204A1 (en) * 2021-04-07 2022-10-13 Repare Therapeutics Inc. Combination therapies including myt1 inhibitors
US20230122909A1 (en) * 2021-10-04 2023-04-20 Repare Therapeutics Inc. Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use
WO2023174329A1 (en) * 2022-03-15 2023-09-21 Insilico Medicine Ip Limited Heteroaromatic compounds as pkmyt1 inhibitors and use thereof
WO2023198199A1 (en) * 2022-04-15 2023-10-19 先声再明医药有限公司 Myt1 kinase inhibitor
CN117510503A (en) * 2022-08-03 2024-02-06 成都先导药物开发股份有限公司 A tyrosine-threonine kinase PKMYT1 inhibitor
WO2024109942A1 (en) * 2022-11-25 2024-05-30 上海齐鲁制药研究中心有限公司 Pkmyt1 inhibitor, preparation method therefor, and pharmaceutical composition and use thereof

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