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WO2025232877A1 - Inhibiteurs de kinases inductibles au sel (sik) - Google Patents

Inhibiteurs de kinases inductibles au sel (sik)

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Publication number
WO2025232877A1
WO2025232877A1 PCT/CN2025/093779 CN2025093779W WO2025232877A1 WO 2025232877 A1 WO2025232877 A1 WO 2025232877A1 CN 2025093779 W CN2025093779 W CN 2025093779W WO 2025232877 A1 WO2025232877 A1 WO 2025232877A1
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WIPO (PCT)
Prior art keywords
cycloalkyl
alkyl
heterocycloalkyl
heteroaryl
aryl
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Pending
Application number
PCT/CN2025/093779
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English (en)
Inventor
Xiao DING
Feng Gao
Tingting Liu
Feng Ren
Wei Zhu
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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Publication of WO2025232877A1 publication Critical patent/WO2025232877A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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

  • SIKs Salt-Inducible Kinases
  • SIK1 also referred as SNFI-Like Kinase (SNF1LK) or Myocardial Snfl-like Kinase (MSK)
  • SIK2 SNF1LK2 or KIAA0781
  • SIK3 SIK3
  • the SIKs play a number of roles in different cell types. They have been found to phosphorylate a number of substrates including CREB-responsive transcriptional co-activator (CRTC) proteins and histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes.
  • CRTC CREB-responsive transcriptional co-activator
  • HDAC histone de-acetylase
  • One of the roles of CRTC signaling relates to control the phenotype of macrophages, in particular polarization of macrophages through phosphorylation of CRTC3 as measured by decreased proinflammatory cytokine IL-12 secretion and concomitant increased pro-resolution cytokine IL-10 secretion.
  • SIK kinases Inhibition of SIK kinases has been demonstrated to result in the concomitant downregulation of pro-inflammatory and the induction of anti-inflammatory molecules. Therefore, the inhibition of the SIKs may result in the suppression of inflammation and the promotion of an immune tolerogenic, anti-inflammatory phenotype; these factors make the SIK family of kinases targets in disease intervention -diseases including inflammatory bowel disease, rheumatoid arthritis, psoriasis, vitiligo and other immune disorders.
  • SIK inhibitors compounds, or pharmaceutically acceptable salts, or stereoisomers thereof, that are SIK inhibitors, and more particularly SIK1, SIK2 and/or SIK3 inhibitors.
  • composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of inhibiting Salt-Inducible Kinase (SIK) activity in a subject in need thereof, comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need thereof.
  • SIK Salt-Inducible Kinase
  • the SIK is SIK1, SIK2, and/or SIK3. In some embodiments, the SIK is SIK1. In some embodiments, the SIK is SIK2. In some embodiments, the SIK is SIK3.
  • Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need 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.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2 - 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkylidenyl is alkenyl as defined above that is attached via the terminal divalent carbon.
  • the alkylidenyl group is enclosed by the box which is indicated by the arrow.
  • Alkoxy refers to a radical of the formula -Oalkyl where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -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.
  • heteroalkyl examples include, 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.
  • Heteroalkylene refers to a divalent heteroalkyl. Unless stated otherwise specifically in the specification, a heteroalkylene 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 heteroalkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the heteroalkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the heteroalkylene is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, di
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • a “disease or disorder associated with SIK” or, alternatively, “a SIK-mediated disease or disorder” means any disease or other deleterious condition in which SIK, or a mutant thereof, is known or suspected to play a role.
  • a “disease or disorder associated with SIK1, SIK2, and/or SIK3” or, alternatively, “a SIK1, SIK2, and/or SIK3-mediated disease or disorder” means any disease or other deleterious condition in which SIK1, SIK2, and/or SIK3, or a mutant thereof, is known or suspected to play a role.
  • a “disease or disorder associated with SIK1” or, alternatively, “a SIK1-mediated disease or disorder” means any disease or other deleterious condition in which SIK1, or a mutant thereof, is known or suspected to play a role.
  • a “disease or disorder associated with SIK2” or, alternatively, “a SIK2-mediated disease or disorder” means any disease or other deleterious condition in which SIK2, or a mutant thereof, is known or suspected to play a role.
  • a “disease or disorder associated with SIK3” or, alternatively, “a SIK3-mediated disease or disorder” means any disease or other deleterious condition in which SIK3, or a mutant thereof, is known or suspected to play a role.
  • Described herein are compounds, or pharmaceutically acceptable salts, or stereoisomers thereof useful in the treatment of a disease or disorder associated with SIK.
  • the compounds, or pharmaceutically acceptable salts, or stereoisomers thereof are useful in the treatment of a disease or disorder associated with SIK1, SIK2, or SIK3.
  • the compounds, or pharmaceutically acceptable salts, or stereoisomers thereof are useful in the treatment of a disease or disorder associated with SIK1.
  • the compounds, or pharmaceutically acceptable salts, or stereoisomers thereof are useful in the treatment of a disease or disorder associated with SIK2.
  • the compounds, or pharmaceutically acceptable salts, or stereoisomers thereof are useful in the treatment of a disease or disorder associated with SIK3.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, or stereoisomer thereof: wherein: is a single bond or double bond;
  • X 1 is -N-, -N (R X1a ) -, -C (R X1b ) -, or -C (R X1c R X1d ) -;
  • X 2 is -N-, -N (R X2a ) -, -C (R X2b ) -, or -C (R X2c R X2d ) -;
  • X 3 is -N-, or -C-;
  • X 4 is -N-, or -C-;
  • X 5 is -N-, or -C-;
  • X 6 is -N-, or -C (R X6b ) -;
  • X 7 is -N-, or -C (R X7b )
  • a compound of Formula (I) is a heteroaryl.
  • X 1 is N and X 4 is N.
  • X 1 is N and X 5 is N.
  • X 1 is N and X 3 is N.
  • X 6 is -C (R X6b ) -
  • X 7 is -C (R X7b ) -
  • X 8 is -C (R X8b ) -
  • X 9 is -C (R X9b ) -.
  • X 6 is -C (R X6b ) -
  • X 7 is -C (R X7b ) -
  • X 8 is -C (R X8b ) -
  • X 9 is -C (R X9b ) -.
  • X 6 , X 7 , X 8 and X 9 when is then at least one of X 6 , X 7 , X 8 and X 9 is N.
  • X 6 when is then X 6 is -N-, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -and X 9 is -C (R X8b ) -, or X 6 is -C (R X6b ) -, X 7 is -N-, X 8 is -C (R X8b ) -and X 9 is -C (R X8b ) -, or X 6 is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -N-and X 9 is -C (R X8b ) -or X 6 is
  • At least one of X 6 , X 7 , X 8 and X 9 is N.
  • X 6 is -N-. In some embodiments, X 6 is -C (R X6b ) -. In some embodiments, R X6b is hydrogen. In some embodiments, R X6b is not hydrogen.
  • R X7b is -OR a or cycloalkyl.
  • X 6 is -C (R X6b ) -
  • X 7 is -C (R X7b ) -
  • X 8 is -C (R X8b ) -
  • X 9 is -C (R X9b ) -
  • R X7b is -O-C 1 -C 6 alkyl, -O-C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl.
  • R X7b is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -, and X 9 is -C (R X9b ) -, is then R X7b is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -, and X 9 is -C (R X9b ) -, is then R X7b is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -, and X 9 is -C (R X9b ) -, is then R X7b is -C (R X6b ) -, X 7
  • R x2b is not hydrogen.
  • R x2b is -NR c R d .
  • R x2b is NH 2 .
  • X 6 is -C (R X6b ) -
  • X 7 is -C (R X7b ) -
  • X 8 is -C (R X8b ) -
  • X 9 is -C (R X9b ) -
  • Y 2 is -CR Y2 -
  • R Y2 is -CN
  • one of Y 1 and Y 3 is N.
  • X 6 is -C (R X6b ) -
  • X 7 is -C (R X7b ) -
  • X 8 is -C (R X8b ) -
  • X 9 is -C (R X9b ) -
  • Y 1 and Y 3 is CH
  • Y 2 is -CR Y2 -
  • R Y2 is not -CN.
  • X 6 is -C (R X6b ) -
  • X 7 is -C (R X7b ) -
  • X 8 is -C (R X8b ) -
  • X 9 is -C (R X9b ) -
  • Y 1 is -CR Y1 -
  • Y 2 is -CR Y2 -
  • R Y2 is -CN
  • Y 3 is -CR Y3 -
  • a compound of Formula (I) is wherein at least one of X 6 , X 7 , X 8 and X 9 is N.
  • a compound of Formula (I) is wherein X 6 is -N-, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -and X 9 is -C (R X8b ) -.
  • a compound of Formula (I) is wherein X 6 is -C (R X6b ) -, X 7 is -N-, X 8 is -C (R X8b ) -and X 9 is -C (R X8b ) -.
  • a compound of Formula (I) is wherein X 6 is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -N-and X 9 is -C (R X8b ) -.
  • a compound of Formula (I) is wherein X 6 is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -and X 9 is -N-.
  • a compound of Formula (I) is wherein X 6 is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -, X 9 is -C (R X8b ) -and R X7b is -O-C 1 -C 6 alkyl, -O-C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl.
  • R X7b is
  • a compound of Formula (I) is wherein X 6 is -CH-, X 7 is -CH-, X 8 is -CH-, X 9 is -CH-and R X2b is not hydrogen.
  • a compound of Formula (I) is wherein X 6 is -CH-, X 7 is -CH-, X 8 is -CH-, X 9 is -CH-and R X2b is -NR c R d .
  • a compound of Formula (I) is wherein X 6 is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -, X 9 is -C (R X9b ) -, R X2b is hydrogen, Y 2 is -CR Y2 -, R Y2 is -CN and one of Y 1 and Y 3 is N.
  • a compound of Formula (I) is wherein X 6 is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -, X 9 is -C (R X9b ) -, R X2b is hydrogen, Y 2 is -CR Y2 -, R Y2 is -CN, Y 1 is -CR Y1 -, Y 3 is -CR Y3 -and one of R Y1 and R Y3 is not hydrogen.
  • a compound of Formula (I) is wherein X 6 is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -, X 9 is -C (R X9b ) -, R X2b is hydrogen, Y 1 is CH, Y 3 is CH, Y 2 is -CR Y2 -, and R Y2 is not -CN.
  • a compound of Formula (I) is wherein X 6 is -C (R X6b ) -, X 7 is -C (R X7b ) -, X 8 is -C (R X8b ) -, X 9 is -C (R X9b ) -, R X2b is hydrogen, Y 1 is CH, Y 3 is CH, Y 2 is -CR Y2 -, R Y2 is -CN, and Ring A is partially saturated cycloalkyl, fused cycloalkyl, partially saturated heterocycloalkyl or fused heterocycloalkyl.
  • R X6b is hydrogen.
  • R X8b is hydrogen, halogen, C 1 -C 6 alkyl, -OR a , -NR c R d , C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocycloalkyl, wherein each alkyl cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R X8b is hydrogen, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , or-OCH 3 .
  • R X9b is -CN or -OR a .
  • R X9b is -CN, or -OCH 3 .
  • R X6b and R X7b together with the intervening atoms form a C 3 -C 6 cycloalkyl, 3-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R.
  • R X6b and R X7b together with the intervening atoms form a C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, or 6-membered heterocyclyl, wherein each cycloalkyl and heterocyclyl is independently optionally substituted with one or more R.
  • R X7b and R X8b together with the intervening atoms form a C 3 -C 6 cycloalkyl, 3-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R.
  • R X7b and R X8b together with the intervening atoms form a C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, or 6-membered heterocyclyl, wherein each cycloalkyl and heterocyclyl is independently optionally substituted with one or more R.
  • R X8b and R X9b together with the intervening atoms form a C 3 -C 6 cycloalkyl, 3-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R.
  • R X7b and R X8b together with the intervening atoms form a C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, or 6-membered heterocyclyl, wherein each cycloalkyl and heterocyclyl is independently optionally substituted with one or more R.
  • Ring B is cycloalkyl, heterocyclyl, aryl or heteroaryl, each R B is independently R, m2 is 0, 1, 2, or 3.
  • Ring B is C 3 -C 6 cycloalkyl (e.g., C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl or C 6 cycloalkyl, etc) or 3-to 6-membered heterocyclyl (e.g., 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, or 6-membered heterocyclyl, etc) .
  • Y 1 is -N-. In some embodiments, Y 1 is -CR Y1 -. In some embodiments, R Y1 is hydrogen.
  • Y 3 is -N-. In some embodiments, Y 3 is -CR Y3 -. In some embodiments, R Y3 is hydrogen.
  • R Y2 is -CN.
  • the compound is of Formula (Ia) :
  • the compound is of Formula (Ib) :
  • the compound is of Formula (Ic) :
  • the compound is of Formula (Id) :
  • the compound is of Formula (Ie) :
  • the compound is of Formula (Ie’) or (Ie”) :
  • the compound is of Formula (If) :
  • the compound is of Formula (If-1) : wherein R x2b is not hydrogen; or at least one of Y 1 and Y 3 is N; or when Y 2 is -CR Y2 -, then R Y2 is not -CN.
  • the compound is of Formula (Ig) :
  • the compound is of Formula (I-1) or (I-2) : wherein Ring B is cycloalkyl, heterocyclyl, aryl or heteroaryl, each R B is independently R, m2 is 0, 1, 2, or 3.
  • Ring B is cycloalkyl or heterocyclyl.
  • Ring B is C 3 -C 6 cycloalkyl (e.g., C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl or C 6 cycloalkyl, etc) or 3-to 6-membered heterocyclyl (e.g., 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, or 6-membered heterocyclyl, etc) .
  • the compound is of Formula (I-3) or (I-4) :
  • the compound is of Formula (I-5) or (I-6) : wherein Y 1 is N; or Y 3 is N; or Y 1 is -CR Y1 -, R Y1 is not hydrogen, or Y 3 is -CR Y3 -, R Y3 is not hydrogen.
  • L 1 is a bond, -NR 6 -, -O-, -S-, - [C (R 5 ) 2 ] n -, -O- [C (R 5 ) 2 ] n -, - [C (R 5 ) 2 ] n -O-, or -S- [C (R 5 ) 2 ] n -, or - [C (R 5 ) 2 ] n -S-.
  • L 1 is a bond, -O- [C (R 5 ) 2 ] n -, - [C (R 5 ) 2 ] n -O-, or -S- [C (R 5 ) 2 ] n -, or - [C (R 5 ) 2 ] n -S-.
  • L 1 is a bond.
  • L 1 is -O- [C (R 5 ) 2 ] n -, or - [C (R 5 ) 2 ] n -O-.
  • L is -S- [C (R 5 ) 2 ] n -, or - [C (R 5 ) 2 ] n -S-.
  • n is 0, 1, 2, 3, or 4.
  • n is 1, 2 or 3.
  • n is 1 or 2.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • each R 5 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R 5 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) ; wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R 5 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R 5 is independently hydrogen, halogen, or C 1 -C 6 alkyl is independently optionally substituted with one or more R.
  • each R 5 is hydrogen.
  • each R 5 is independently hydrogen, or C 1 -C 6 alkyl.
  • two R 5 on adjacent carbons are taken together to form a double bond.
  • two R 5 on different atoms are taken together to form a cycloalkyl optionally substituted with one or more R. In some embodiments, two R 5 on different atoms are taken together to form a C 3-6 cycloalkyl optionally substituted with one or more R. In some embodiments, two R 5 on the same carbon are taken together to form a cycloalkyl optionally substituted with one or more R. In some embodiments, two R 5 on the same carbon are taken together to form a C 3-6 cycloalkyl optionally substituted with one or more R. In some embodiments, two R 5 on different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • R 6 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, R 6 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 6 is hydrogen.
  • L 1 is - [C (R 5 ) 2 ] 2 -.
  • L 1 is -CH 2 -, -CH (CH 3 ) CH 2 -, -C (CH 3 ) 2 CH 2 -, -CH 2 CH (CH 3 ) -, -CH 2 CH 2 CH 2 -, -CH (CH 3 ) CH 2 CH 2 -, -CH 2 CH (CH 3 ) CH 2 -, -CH 2 CH (CH 3 ) CH 2 -, -CH 2 CH 2 CH (CH 3 ) -, or -CH 2 CH 2 CH 2 CH 2 -.
  • L 1 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -.
  • L 1 is -CH (CH 3 ) CH 2 -, -CH 2 CH (CH 3 ) -, -CH (CH 3 ) CH 2 CH 2 -, -CH 2 CH (CH 3 ) CH 2 -, or -CH 2 CH 2 CH (CH 3 ) -.
  • L 1 is -CH 2 -or -CH 2 CH 2 -.
  • L 1 is -CH 2 CH 2 -.
  • L 1 is -CH 2 -.
  • L 1 is -O-C (R 5 ) 2 -, -O- [C (R 5 ) 2 ] 2 -or -O- [C (R 5 ) 2 ] 3 -.
  • L 1 is -O-CH 2 CH 2 CH 2 -.
  • L 1 is -O-CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 -, or -O-CH 2 -.
  • L 1 is -O-CH 2 -.
  • L 1 is -S-C (R 5 ) 2 -, -S- [C (R 5 ) 2 ] 2 -or -S- [C (R 5 ) 2 ] 3 -.
  • L 1 is -S-CH 2 CH 2 CH 2 -.
  • L 1 is -S-CH 2 CH 2 CH 2 -, -S-CH 2 CH 2 -, or -S-CH 2 -.
  • L 1 is -S-CH 2 -.
  • the Right end of L 1 is attaching to Ring A.
  • L 1 is a bond.
  • L 2 a bond, -O-, -S-, -NR L2 -or -CR L2 R L2’ -.
  • L 2 is a bond, -O-, -S-, or -NR L2 -.
  • L 2 is -O-, or -S-.
  • L 2 is -O-.
  • L 2 is -S-.
  • each R L2 and R L2’ is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R L2 and R L2’ is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.
  • each R L2 and R L2’ is independently is hydrogen, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.
  • R 1 is -SF 5 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, wherein each alkyl, alkenyl, or alkynyl is independently optionally substituted with one or more R.
  • R 1 is -SF 5 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • R 1 is -SF 5 , or C 1 -C 6 alkyl.
  • R 1 is C 1 -C 3 alkyl.
  • R 1 is methyl.
  • Y 1 is -N-. In some embodiments, Y 1 is -CR Y1 -.
  • R Y1 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • R Y1 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments, R Y1 is hydrogen.
  • Y 3 is -N-. In some embodiments, Y 3 is -CR Y3 -.
  • R Y3 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • R Y3 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, wherein each alkyl is independently optionally substituted with one or more R. In some embodiments, R Y3 is hydrogen.
  • Y 2 is -N-. In some embodiments, Y 2 is -CR Y2 -.
  • R Y2 is heteroaryl, wherein heteroaryl is independently optionally substituted with one or more R.
  • R Y2 is 5-to 12 membered heteroaryl, wherein heteroaryl is independently optionally substituted with one or more R.
  • R Y2 is 5-to 6 membered heteroaryl, wherein heteroaryl is independently optionally substituted with one or more R.
  • R Y2 is 5 membered heteroaryl, wherein heteroaryl is independently optionally substituted with one or more R.
  • R Y2 is 6 membered heteroaryl, wherein heteroaryl is independently optionally substituted with one or more R. In some embodiments, R Y2 is In some embodiments, R Y2 is In some embodiments, R Y2 is In some embodiments, R Y2 is In some embodiments, R Y2 is In some embodiments, R Y2 is in some embodiments, R Y2 is 6 membered heteroaryl, wherein heteroaryl is independently optionally substituted with one or more R. In some embodiments, R Y2 is In some embodiments, R Y2 is In some embodiments, R Y2 is In some embodiments, R Y2 is 6 membered heteroaryl, wherein heteroaryl is independently optionally substituted with one or more R. In some embodiments, R Y2 is In some embodiments, R Y2 is In some embodiments, R Y2 is In some embodiments, R Y2 is 6 membered heteroaryl, wherein heteroaryl is independently optionally substituted with one or more R
  • X 2 is -N-, -N (R X2a ) -, -C (R X2b ) -, or -C (R X2c R X2d ) -.
  • X 2 is -N-, or-C (R X2b ) -.
  • X 2 is -N-.
  • X 2 is-C (R X2b ) -.
  • R X2b is -OR a , -NR c R d , -C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • R X2b is -NR c R d .
  • R X2b is NH 2 .
  • X 1 is -N-, -N (R X1a ) -, -C (R X1b ) -, or -C (R X1c R X1d ) -. In some embodiments, X 1 is -N-, or -C (R X1b ) -.
  • R X1b is hydrogen. In some embodiments, R X1b is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • R 2 is-NR c R d .
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 5-to 6-membered heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen or C 1 -C 6 alkyl, wherein alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen or C 1 -C 3 alkyl, wherein alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen.
  • R c is C 1 -C 6 alkyl and R d is hydrogen. In some embodiments, R c and R d are each independently C 1 -C 3 alkyl, wherein alkyl is independently optionally substituted with one or more R. In some embodiments, R 2 is -NH 2 , -NHCH 3 , or N (CH 3 ) 2 .
  • Ring A is cycloalkyl, or heterocycloalkyl. In some embodiments, Ring A is cycloalkyl. In some embodiments, Ring A is C 3 -C 12 cycloalkyl. In some embodiments, Ring A is C 5 -C 6 mono-cyclic cycloalkyl. In some embodiments, Ring A is C 5 mono-cyclic cycloalkyl. In some embodiments, Ring A is C 5 fully saturated mono-cyclic cycloalkyl.
  • Ring A is In some embodiments, Ring A is C 5 partially saturated mono-cyclic cycloalkyl. In some embodiments, Ring A is In some embodiments, Ring A is C 6 mono-cyclic cycloalkyl. In some embodiments, Ring A is C 6 -C 12 bi-cyclic cycloalkyl. In some embodiments, Ring A is C 6 -C 12 fused cycloalkyl. In some embodiments, Ring A is C 6 -C 9 fused cycloalkyl. In some embodiments, Ring A is [3, 5] -fused cycloalkyl, [4, 5] -fused cycloalkyl, or [5, 5] -fused cycloalkyl.
  • Ring A is In some embodiments, Ring A is C 6 -C 12 bridged cycloalkyl. In some embodiments, Ring A is C 6 -C 12 spiro cycloalkyl. In some embodiments, Ring A is fully saturated cycloalkyl. In some embodiments, Ring A is partially saturated cycloalkyl. In some embodiments, Ring A is 3-to 12 membered heterocycloalkyl. In some embodiments, Ring A is 5 to 6-membered mono-cyclic heterocycloalkyl. In some embodiments, Ring A is 5-membered mono-cyclic heterocycloalkyl. In some embodiments, Ring A is In some embodiments, Ring A is 6-membered mono-cyclic heterocycloalkyl.
  • Ring A is 6-to 12 membered bi-cyclic heterocycloalkyl. In some embodiments, Ring A is 6-to 12 membered fused heterocycloalkyl. In some embodiments, Ring A is 6-to 10 membered fused heterocycloalkyl. In some embodiments, Ring A is [3, 5] -fused heterocycloalkyl, [4, 5] -fused heterocycloalkyl, or [5, 5] -fused heterocycloalkyl. In some embodiments, Ring A is In some embodiments, Ring A is 6-to 12 membered bridged heterocycloalkyl. In some embodiments, Ring A is 6-to 12 membered spiro heterocycloalkyl. In some embodiments, Ring A is fully saturated heterocycloalkyl. In some embodiments, Ring A is partially saturated heterocycloalkyl.
  • each R A is independently halogen, 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, C 2 -C 6 alkylidenyl, C 3 -C 6 cycloalkyl, 3-to 6-membered heterocycloalkyl; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R A1 .
  • each R A is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-to 6-membered heterocycloalkyl; wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R A1 .
  • each R A is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 3 -C 6 cycloalkyl; wherein each alkyl, alkenyl and cycloalkyl is independently optionally substituted with one or more R A1 .
  • each of R AA1 , R AA2 , R AB1 , R AB2 , R AC1 , R AC2 , R AD1 and R AD2 is independently hydrogen and R A , each of T 1 , T 2 , T 3 and T 4 is -O-, -S-, -Se-or -NR c R d -, or R AA1 and R AA2 , R AA1 and R AB1 , R AB1 and R AB2 , R AB1 and R AC1 , R AC1 and R AC2 , R AC1 and R AD1 , R AD1 and R AD2 together with the intervening atom (s) form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl, heterocyclyl,
  • R AA1 and R AA2 together with the intervening atom (s) form a C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclylwherein each C 3 -C 6 cycloalkyl and 3 to 6-membered heterocyclyl is independently optionally substituted with one or more R.
  • R AA1 and R AB1 together with the intervening atom (s) form a C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, phenyl or 5 to 6-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, phenyl and 5 to 6-membered heteroaryl is independently optionally substituted with one or more R.
  • R AB1 and R AB2 together with the intervening atom (s) form a C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl, wherein each C 3 -C 6 cycloalkylor 3 to 6-membered heterocyclyl is independently optionally substituted with one or more R.
  • R AB1 and R AC1 together with the intervening atom (s) form a C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, phenyl or 5 to 6-membered heteroaryl, wherein each C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl phenyl and 5 to 6-membered heteroaryl is independently optionally substituted with one or more R.
  • R AC1 and R AC2 together with the intervening atom (s) form a C 3 -C 6 cycloalkyl, or 3 to 6-membered heterocyclyl, , wherein each C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl is independently optionally substituted with one or more R.
  • R AC1 and R AD1 together with the intervening atom (s) form a C 3 -C 6 cycloalkyl, 3 to 6-heterocyclyl, phenyl or 5 to 6-membered , wherein each C 3 -C 6 cycloalkyl, 3 to 6-membered heterocyclyl, phenyl and 5 to 6-membered heteroaryl is independently optionally substituted with one or more R.
  • R AD1 and R AD2 together with the intervening atom (s) form a C 3 -C 6 cycloalkyl or 3 to 6-membered heterocyclyl, aryl or heteroaryl, wherein each C 3 -C 6 cycloalkyl and 3 to 6-membered heterocyclyl is independently optionally substituted with one or more R.
  • each of T 1 , T 2 , T 3 and T 4 is -O-, -S-, -Se-, -NH 2 -, -NH (CH 3 ) -or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • each R a is independently cycloalkyl or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkylene (cycloalkyl) , or C 1 -C 6 alkylene (heterocycloalkyl) , wherein each alkyl, alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each alkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R c and R d are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, R c and R d are each hydrogen. In some embodiments of a compound disclosed herein, R c and R d are each independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo.
  • one or more of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , L 1 , L 2 , Y 1 , Y 2 , Y 3 , R A , R B , R, R 1 , R 2 , R a , R b , R c , and R d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , L 1 , L 2 , Y 1 , Y 2 , Y 3 , R A , R B , R, R 1 , R 2 , R a , R b , R c , and R d .
  • the abundance of deuterium in each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , L 1 , L 2 , Y 1 , Y 2 , Y 3 , R A , R B , R, R 1 , R 2 , R a , R b , R c , and R d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more 1 H of Ring A and Ring B are replaced with one or more deuteriums.
  • the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof is one of the compounds in Table 1. TABLE 1
  • the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof is one of the compounds in Table 2.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • 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 carbon14 ( 14 C) .
  • the compounds described herein are artificially enriched in one or more isotopes selected from 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 I.
  • the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound is deuterated in at least one position.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • 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 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 a or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Tautomers
  • 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.
  • SIK Salt-Inducible Kinase
  • SIK Salt-Inducible Kinase
  • the SIK is SIK1, SIK2, and/or SIK3.
  • provided herein are methods for treating diseases or disorders selected from the group consisting of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and abnormal angiogenesis associated diseases, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition described herein.
  • the disease or disorder is an inflammatory disease.
  • the inflammatory disease is rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g., asthma) , chronic obstructive pulmonary disease (COPD) , or inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis) .
  • the disease or disorder is an autoinflammatory disease.
  • the autoinflammatory disease is Cryopyrin-Associated Periodic Syndromes (CAPS) , Familial Mediterranean Fever (FMF) , tumor necrosis factor receptor-associated periodic syndrome (TRAPS) , Behcet’s disease, Systemic-onset Juvenile Idiopathic Arthritis (SJIA) , or Still’s disease.
  • the disease or disorder is an autoimmune diseases.
  • the autoimmune disease is COPD, asthma, bronchitis, systemic lupus erythematosus (SLE) , cutaneous lupus erythematosus (CLE) , lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g., Crohn’s disease and ulcerative colitis) , atherosclerosis, or amyotrophic lateral sclerosis.
  • COPD chronic lupus erythematosus
  • SLE systemic lupus erythematosus
  • the disease or disorder is a proliferative disease.
  • the proliferative disease is cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis.
  • the disease or disorder is a fibrotic disease.
  • the fibrotic disease is idiopathic pulmonary fibrosis (IPF) , Dupuytren’s disease, nonalcoholic steatohepatitis (NASH) , systemic sclerosis, renal fibrosis, or cutaneous fibrosis.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue, or solid organ alio-or xenografts of e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea, or esophagus, or graft-versus-host diseases.
  • transplantation rejection refers to acute or chronic rejection of cells, tissue, or solid organ alio-or xenografts of e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea, or esophagus, or graft-versus-host diseases.
  • the disease or disorder involves impairment of cartilage turnover.
  • the disease involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy (complex regional pain syndrome or CRPS) , Tietze syndrome, costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica (Kashin–Beck disease) , Mseleni joint disease (MJD) , Handigodu syndrome, degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis.
  • the disease or disorder involves the treatment of congenital cartilage malformation.
  • congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, or metaphyseal chondrodysplasia.
  • the disease or disorder involves impairment of bone turnover.
  • diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget’s disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, or hypophosphatasia.
  • the disease or disorder is associated with hypersecretion of IL-6.
  • the disease associated with hypersecretion of IL-6 is Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma, or mesangial proliferative glomerulonephritis.
  • the disease or disorder is associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23.
  • the disease associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, or Crohn’s disease.
  • the disease or disorder is a respiratory disease.
  • the respiratory disease is asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia.
  • the disease or disorder is an endocrine and/or metabolic disease.
  • the endocrine and/or metabolic disease is hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU) , diabetes, hyperlipidemia, gout, or rickets.
  • PKU phenylketonuria
  • the disease or disorder is a cardiovascular disease.
  • the cardiovascular disease is arrhythmia (atrial or ventricular or both) , atherosclerosis and its sequelae, angina, cardiac rhythm disturbances, myocardial ischemia, myocardial infarction, cardiac or vascular aneurysm, vasculitis, stroke, peripheral obstructive arteriopathy of a limb, an organ, or a tissue, reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue, endotoxic, surgical, or traumatic shock, hypertension, valvular heart disease, heart failure, abnormal blood pressure, vasoconstriction (including that associated with migraines) , vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue.
  • the disease or disorder is a dermatological disease.
  • the dermatological disease is atopic dermatitis, bullous disorder, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren-Larsson syndrome, or urticaria.
  • the disease or disorder is an abnormal angiogenesis associated disease.
  • abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, or diabetic retinopathy.
  • the disease or disorder is an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, a fibrotic disease, transplantation rejection, a disease involving impairment of cartilage turnover, congenital cartilage malformation, a diseases involving impairment of bone turnover, a disease associated with hypersecretion of IL-6, a disease associated with hypersecretion of TNF ⁇ , interferons, IL-12 and/or IL-23, a respiratory disease, an endocrine and/or metabolic disease, a cardiovascular disease, a dermatological disease, or an abnormal angiogenesis associated disease.
  • the disease or disorder is cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is lung cancer, non-small cell lung cancer (NSCLC) , bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva) , Hodgkin’s disease, hepatocellular cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid or adrenal glands) , sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, hormone-refractory prostate cancer, bladder cancer, kidney cancer
  • the cancer is a liquid tumor cancer.
  • the cancer is a leukemia.
  • the leukemia is acute lymphocytic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , or chronic myelogenous leukemia (CML) .
  • ALL acute lymphocytic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • the cancer is a lymphoma.
  • the lymphoma is small lymphocytic lymphoma (SLL) , cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, or Waldenstrom macroglobulinemia.
  • SLL small lymphocytic lymphoma
  • 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. 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.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • Example 1A and Example 1B To a solution of EX1-4 (250 mg, 1.745 mmol) in THF (25 mL) was added t-BuOK (3.49 mL, 3.49 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 0.5 hr, followed by the addition of EX1-6 (200 mg, 0.698 mmol) . The resulting mixture was stirred at 0 °C for 1 hr. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) . The combined organic layer was dried over MgSO 4 , concentrated under reduced pressure, and purified by prep-HPLC, followed by the SFC separation to afford Example 1A and Example 1B.
  • Example 1A 1 H NMR (400 MHz, CD 3 OD) ⁇ 8.74 (s, 1H) , 7.89 (s, 1H) , 7.59 (s, 1H) , 6.97 –6.92 (m, 2H) , 4.07 (s, 3H) , 4.03 (s, 2H) , 3.98 (s, 3H) , 2.08 –1.90 (m, 2H) , 1.87 –1.71 (m, 3H) , 1.70 –1.57 (m, 2H) , 1.53 –1.43 (m, 1H) , 1.32 –1.28 (m, 1H) , 1.02 –0.92 (m, 3H) .
  • Example 2A (3.0 mg) & Example 2B (4.9 mg) were separated from EX2-9 via SFC.
  • Analytical condition Column: Chiralpak AD-3 100 ⁇ 4.6 mm I. D., 3 um; Mobile phase: 40%of iso-propanol (0.05%DEA) in CO 2 ; Flow rate: 2.8 mL/min; Column temp.: 35 °C; ABPR: 1500 psi.
  • Example 3A (1.16 mg) and Example 3B (2.03 mg) were separated from EX3-3 via SFC.
  • SFC analytic conditions Column: Chiralcel OX-3 100 ⁇ 4.6 mm I. D., 3 um; Mobile phase: A: CO 2 B: ethanol (0.05%DEA) ; Isocratic: 50%B; Flow rate: 2.8 mL/min; Column temp.: 40 °C; Back pressure: 100 bar.
  • Example 4A (24.7 mg) and Example 4B (26.87 mg) were separated from EX4-4 via SFC.
  • SFC analytic conditions Column: Chiralpak AD-3 100 ⁇ 4.6 mm I. D., 3 um; Mobile phase: 50%of methanol (0.05%DEA) in CO 2 ; Flow rate: 2.8 mL/min; Column temp.: 35 °C; ABPR: 1500 psi.
  • ADP-Glo reagents Added 5 ⁇ L ADP-Glo reagents. Centrifuged plate at 1000 g for 1 min, and incubated at room temperature for 60 min.
  • kinase detection reagents Added 10 ⁇ L kinase detection reagents. Centrifuged plate at 1000 g for 1 min, and incubated at room temperature for 60 min.
  • Signal Ave_PC The average for the positive controls across the plate. 1 ⁇ M HG-9-91-01 group as positive control.
  • Signal Ave_VC The average for the negative controls across the plate. DMSO group as negative control.

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Abstract

L'invention concerne des composés, des compositions et des procédés de modulation ou d'inhibition de SIK.
PCT/CN2025/093779 2024-05-10 2025-05-09 Inhibiteurs de kinases inductibles au sel (sik) Pending WO2025232877A1 (fr)

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CN112292129A (zh) * 2018-06-15 2021-01-29 加拉帕戈斯股份有限公司 用于治疗疾病的新化合物及其药物组合物
CN113924146A (zh) * 2019-05-29 2022-01-11 加拉帕戈斯股份有限公司 用于治疗疾病的新化合物及其药物组合物
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WO2024003209A1 (fr) * 2022-07-01 2024-01-04 F. Hoffmann-La Roche Ag Dérivés d'imidazo [4,5-c] pyridine en tant que modulateurs de sik pour le traitement de la polyarthrite rhumatoïde
WO2024062360A1 (fr) * 2022-09-21 2024-03-28 Pfizer Inc. Inhibiteurs hétérocycliques de sik
CN117843634A (zh) * 2022-05-24 2024-04-09 上海美悦生物科技发展有限公司 Sik抑制剂及其组合物、制备方法和用途
WO2024104441A1 (fr) * 2022-11-17 2024-05-23 Insilico Medicine Ip Limited Inhibiteurs de kinases inductibles par sel (sik) et leurs procédés d'utilisation
CN118684661A (zh) * 2023-03-21 2024-09-24 上海美悦生物科技发展有限公司 杂芳基类化合物及其药物组合物、制备方法和用途
CN119462647A (zh) * 2024-11-07 2025-02-18 杭州禹泓医药科技有限公司 芳联稠环类化合物、含其的药物组合物及其应用
CN119751443A (zh) * 2024-05-28 2025-04-04 杭州禹泓医药科技有限公司 含氮稠环化合物、包含该化合物的药物组合物及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112292129A (zh) * 2018-06-15 2021-01-29 加拉帕戈斯股份有限公司 用于治疗疾病的新化合物及其药物组合物
CN113924146A (zh) * 2019-05-29 2022-01-11 加拉帕戈斯股份有限公司 用于治疗疾病的新化合物及其药物组合物
CN116234549A (zh) * 2020-08-05 2023-06-06 总医院公司 盐诱导激酶抑制剂
CN115677690A (zh) * 2021-07-30 2023-02-03 江苏恒瑞医药股份有限公司 杂芳基类化合物、其制备方法及其在医药上的应用
CN117843634A (zh) * 2022-05-24 2024-04-09 上海美悦生物科技发展有限公司 Sik抑制剂及其组合物、制备方法和用途
WO2024003208A1 (fr) * 2022-07-01 2024-01-04 F. Hoffmann-La Roche Ag Dérivés d'imidazo[4,5-b]pyridine et de pyrazolo[1,5-a]pyrimidine utilisés en tant que modulateurs de sik pour le traitement de la polyarthrite rhumatoïde
WO2024003209A1 (fr) * 2022-07-01 2024-01-04 F. Hoffmann-La Roche Ag Dérivés d'imidazo [4,5-c] pyridine en tant que modulateurs de sik pour le traitement de la polyarthrite rhumatoïde
WO2024062360A1 (fr) * 2022-09-21 2024-03-28 Pfizer Inc. Inhibiteurs hétérocycliques de sik
WO2024104441A1 (fr) * 2022-11-17 2024-05-23 Insilico Medicine Ip Limited Inhibiteurs de kinases inductibles par sel (sik) et leurs procédés d'utilisation
CN118684661A (zh) * 2023-03-21 2024-09-24 上海美悦生物科技发展有限公司 杂芳基类化合物及其药物组合物、制备方法和用途
CN119751443A (zh) * 2024-05-28 2025-04-04 杭州禹泓医药科技有限公司 含氮稠环化合物、包含该化合物的药物组合物及其应用
CN119462647A (zh) * 2024-11-07 2025-02-18 杭州禹泓医药科技有限公司 芳联稠环类化合物、含其的药物组合物及其应用

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