WO2025252075A1 - Nouveaux composés utilisés en tant qu'inhibiteurs de kinase inductible par un sel et leurs utilisations - Google Patents

Nouveaux composés utilisés en tant qu'inhibiteurs de kinase inductible par un sel et leurs utilisations

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Publication number
WO2025252075A1
WO2025252075A1 PCT/CN2025/098816 CN2025098816W WO2025252075A1 WO 2025252075 A1 WO2025252075 A1 WO 2025252075A1 CN 2025098816 W CN2025098816 W CN 2025098816W WO 2025252075 A1 WO2025252075 A1 WO 2025252075A1
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alkyl
cycloalkyl
heterocyclyl
compound
aryl
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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure relates to novel compounds or pharmaceutically acceptable salts thereof, which are useful as salt-inducible kinases (SIK) inhibitor.
  • the present disclosure further relates to pharmaceutical compositions comprising one or more of such compounds or pharmaceutically acceptable salts thereof as an active ingredient, and use of such compounds or pharmaceutically acceptable salts thereof in the treatment of diseases or disorders.
  • Adenosine monophosphate-activated protein kinases belong to the protein kinase family, which comprises salt-inducible kinases (SIKs) , a family of serine/threonine kinases widely expressed in the body, and involved in particular in cellular energy homeostasis.
  • SIKs salt-inducible kinases
  • SIK3 Three SIK isoforms have been identified, named SIK1 (also referred as SNFI-Like Kinase (SNF1LK) or Myocardial Snfl-like Kinase (MSK) )
  • SIK1LK also referred as SNFI-Like Kinase
  • MSK Myocardial Snfl-like Kinase
  • 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.
  • the present disclosure provides a compound of Formula (I) : or a pharmaceutically acceptable salt, or stereoisomer thereof, as disclosed herein.
  • the present disclosure provides a compound of Formula (I-1) , (I-2) or (I-3) : or a pharmaceutically acceptable salt, or stereoisomer thereof, as disclosed herein.
  • the present disclosure provides a compound of Formula (I-4) , (I-5) or (I-6) : or a pharmaceutically acceptable salt, or stereoisomer thereof, as disclosed herein.
  • a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I) , (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , 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 compound disclosed herein e.g., a compound of Formula (I) , (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , or a compound set forth in Table 1 or Table 2
  • a pharmaceutically acceptable salt, or stereoisomer thereof e.g., a compound set forth in Table 1 or Table 2
  • Also disclosed herein is a method of modulating (e.g., inhibiting) SIK in a subject, the method comprising administering to the subject the compound disclosed herein (e.g., a compound of Formula (I) , (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , 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 (I) , (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , or a compound set forth in Table 1 or Table 2
  • a pharmaceutically acceptable salt, or stereoisomer thereof e.g., 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 (I) , (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , 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 modulating (e.g., inhibiting) SIK in a subject.
  • a compound of Formula (I) e.g., a compound of Formula (I) , (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , or a compound set forth in Table 1 or Table 2
  • a pharmaceutically acceptable salt, or stereoisomer thereof e.g., 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 (I) , (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , (I-6) , 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 or preventing a disease or disorder in a subject in need thereof.
  • the disease or disorder is an SIK associated disease or disorder.
  • linking substituents are described.
  • the Markush variables listed for that group are understood to be linking groups which may connect to two or more other groups.
  • the “alkyl” represents a linking alkylene group.
  • the term “alkyl” may connect to one, two or three other group (s) , as required by Markush structures.
  • 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.
  • Cyano refers to -CN.
  • 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, heterocyclyl or other suitable organic groups and each of which may be optionally substituted.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon radical 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, heterocyclyl, 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.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, as defined above, e.g., hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, dihydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, and the like.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amino radicals, as defined above, e.g., aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, and the like.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon radical 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, heterocyclyl, 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 radical 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, heterocyclyl, 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 herein. 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, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, 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.
  • the polycyclic ring system may include fused (for example, an aromatic ring fused with a cycloalkyl ring) , bridged (for example, an aromatic ring fused with a bridged cycloalkyl ring) or spiro (for example, an aromatic ring fused with a spiro cycloalkyl ring) ring systems.
  • 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.
  • 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, heterocyclyl, 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.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (for example, fused with 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 (C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four carbon atoms (C 3 -C 4 fully saturated cycloalkyl or C 3 -C
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic 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, heterocyclyl, 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.
  • Heterocyclyl 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 heterocyclyl is fully saturated. In some embodiments, the heterocyclyl is partially unsaturated. In some embodiments, the heterocyclyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclyl comprises one to three nitrogens.
  • the heterocyclyl comprises one or two nitrogens. In some embodiments, the heterocyclyl comprises one nitrogen. In some embodiments, the heterocyclyl comprises one nitrogen and one oxygen.
  • the heterocyclyl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system.
  • the polycyclic ring system may include fused (for example, a heterocyclyl ring fused with a cycloalkyl or another heterocyclyl ring) , spiro, or bridged ring systems.
  • heterocyclyls include, but are not limited to, heterocyclyls having from two to fifteen carbon atoms (C 2 -C 15 heterocyclyl) , from two to ten carbon atoms (C 2 -C 10 heterocyclyl) , from two to eight carbon atoms (C 2 -C 8 heterocyclyl) , from two to seven carbon atoms (C 2 -C 7 heterocyclyl) , from two to six carbon atoms (C 2 -C 6 heterocyclyl) , from two to five carbon atoms (C 2 -C 5 heterocyclyl) , or two to four carbon atoms (C 2 -C 4 heterocyclyl) .
  • heterocyclyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, dihydrofuryl, 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, tetrahydr
  • heterocyclyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocyclyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocyclyl, the number of carbon atoms in the heterocyclyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocyclyl (i.e. skeletal atoms of the heterocyclyl ring) .
  • the heterocyclyl is a 3-to 8-membered fully saturated heterocyclyl.
  • the heterocyclyl is a 3-to 7-membered fully saturated heterocyclyl. In some embodiments, the heterocyclyl is a 3-to 6-membered fully saturated heterocyclyl. In some embodiments, the heterocyclyl is a 4-to 6-membered fully saturated heterocyclyl. In some embodiments, the heterocyclyl is a 5-to 6-membered fully saturated heterocyclyl.
  • a heterocyclyl 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, heterocyclyl, heteroaryl, and the like.
  • substituents such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like.
  • the heterocyclyl 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 heterocyclyl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heterocyclyl 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 or polycyclic (such as, bicyclic, tricyclic, or tetracyclic) ring system.
  • the polycyclic ring system may include fused (for example, a heteroaryl ring fused with a cycloalkyl, heterocyclyl or aryl ring, or an aryl ring fused with a heterocyclyl ring) , bridged (for example, an aryl or heteroaryl ring fused with a bridged cycloalkyl or heterocyclyl ring) or spiro (for example, an aryl ring fused with a spiro heterocyclyl ring, or an heteroaryl ring fused with a spiro cycloalkyl or spiro heterocyclyl ring) ring systems.
  • the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quarternized.
  • 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, dibenzofuranyl, dibenzothiophenyl, fur
  • 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, heterocyclyl, 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.
  • 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 , -CHFCHF 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.
  • Described herein are compounds, or pharmaceutically acceptable salts, or stereoisomer thereof useful as SIK inhibitors and in the treatment of diseases or disorders.
  • X 1 is N, X 2 is C and X 3 is C. In some embodiments, X 1 is C, X 2 is N and X 3 is C. In some embodiments, X 1 is C, X 2 is C and X 3 is N.
  • X 9 is C (R X9 ) . In some embodiments of Formula (I) , X 9 is N (R X9 ) . In some embodiments, R 1 together with R X9 form a linking moiety L connecting Ring A and Ring C.
  • the compound is of Formula (I-1) , (I-2) , or (I-3) ,
  • X 8 is C (R X8 ) . In some embodiments, X 8 is N (R X8 ) . In some embodiments, R 1 together with R X8 form a linking moiety L connecting Ring A and Ring C.
  • the compound is of Formula (I-4) , (I-5) , or (I-6) ,
  • X 5 is C (R X5 )
  • R X5 is hydrogen, halogen, cyano, -SR a or -OR a .
  • X 5 is CH.
  • X 3 is C (R X3 )
  • R X3 is hydrogen, halogen, cyano, -SR a or -OR a .
  • X 3 is CH.
  • R X8 is cyano
  • R X8 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 d . In some embodiments, R X8 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 d .
  • R X8 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 d .
  • R X8 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 R d .
  • R X8 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 d . In some embodiments, R X8 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 d .
  • R X8 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 d . In some embodiments, R X8 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 R d .
  • R X8 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 d . In some embodiments, R X8 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 R d .
  • R X8 is C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 cycloalkyl, each optionally substituted with one or more R d . In some embodiments, R X8 is C 6 cycloalkyl, C 5 cycloalkyl, C 4 cycloalkyl or C 3 cycloalkyl, each optionally substituted with one or more R d .
  • R X8 is 3-to 6-membered heterocyclyl, 3-to 5-membered heterocyclyl or 3-to 4-membered heterocyclyl, each optionally substituted with one or more R d .
  • R X8 is 6-membered heterocyclyl, 5-membered heterocyclyl, 4-membered heterocyclyl or 3-membered heterocyclyl, each optionally substituted with one or more R d .
  • R X8 is C 6-12 aryl, C 6-11 aryl, C 6-10 aryl, C 6-9 aryl, C 6-8 aryl or C 6-7 aryl, each optionally substituted with one or more R d .
  • R X8 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 R d .
  • R X8 is 5-to 12-membered heteroaryl, 5-to 11-membered heteroaryl, 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 5-to 7-membered heteroaryl or 5-to 6-membered heteroaryl, each optionally substituted with one or more R d .
  • R X8 is 12-membered heteroaryl, 11-membered heteroaryl, 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 R d .
  • each of R b and R c is independently hydrogen or alkyl.
  • each of R b and R c is independently hydrogen or C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alky.
  • each of R b and R c is independently hydrogen, C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alky.
  • each R d is independently halogen or hydroxy.
  • R X9 is hydrogen, halogen, cyano, -S (C 1-6 alkyl) , -S (C 1-5 alkyl) , -S (C 1-4 alkyl) , -S (C 1-3 alkyl) , -S(C 1-2 alkyl) , -O (C 1-6 alkyl) , -O (C 1-5 alkyl) , -O (C 1-4 alkyl) , -O (C 1-3 alkyl) , -O (C 1-2 alkyl) , C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • R X9 is hydrogen, halogen, -SCH 3 , -OCH 3 or -CH 3 .
  • each of R X6 and R X7 is independently hydrogen, halogen, cyano, -S (C 1-6 alkyl) , -S (C 1-5 alkyl) , -S (C 1-4 alkyl) , -S (C 1-3 alkyl) , -S (C 1-2 alkyl) , -O (C 1-6 alkyl) , -O (C 1-5 alkyl) , -O (C 1-4 alkyl) , -O (C 1-3 alkyl) , -O (C 1-2 alkyl) , C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • each of R X6 and R X7 is independently hydrogen, halogen, -SCH 3 , -OCH 3 or -CH 3 .
  • R X10 is hydrogen, halogen, cyano, -S (C 1-6 alkyl) , -S (C 1-5 alkyl) , -S (C 1-4 alkyl) , -S (C 1-3 alkyl) , -S (C 1-2 alkyl) , -O (C 1-6 alkyl) , -O (C 1-5 alkyl) , -O (C 1-4 alkyl) , -O (C 1-3 alkyl) , -O (C 1-2 alkyl) , C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • R X10 is hydrogen, halogen, -SCH 3 , -OCH 3 or -CH 3 .
  • R 2 is hydrogen, halogen, hydroxy, cyano, -OR a1 , -N (R b1 ) 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, wherein the alkyl, haloalkyl and hydroxyalkyl are optionally substituted with one or more R d1 .
  • R 2 is In some embodiments of Formula (I) , (I-1) , (I-2) , (I-3) , (I-4) , (I-5) , or (I-6) , R 2 is In some embodiments, Ring D is a cycloalkyl, heterocyclyl, aryl or heteroaryl, each R 3 is independently R d1 , and n is any integer of 0-6.
  • Ring D is C 3-12 cycloalkyl, C 3-11 cycloalkyl, C 3-10 cycloalkyl, C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 cycloalkyl.
  • Ring D is C 12 cycloalkyl, C 11 cycloalkyl, 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.
  • Ring D is 3-to 12-membered heterocyclyl, 3-to 11-membered heterocyclyl, 3-to 10-membered heterocyclyl, 3-to 9-membered heterocyclyl, 3-to 8-membered heterocyclyl, 3-to 7-membered heterocyclyl, 3-to 6-membered heterocyclyl, 3-to 5-membered heterocyclyl or 3-to 4-membered heterocyclyl.
  • Ring D is 12-membered heterocyclyl, 11-membered heterocyclyl, 10-membered heterocyclyl, 9-membered heterocyclyl, 8-membered heterocyclyl, 7-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heterocyclyl, 4-membered heterocyclyl or 3-membered heterocyclyl.
  • Ring D is C 6-12 aryl, C 6-11 aryl, C 6-10 aryl, C 6-9 aryl, C 6-8 aryl or C 6-7 aryl. In some embodiments, Ring D is C 12 aryl, C 11 aryl, C 10 aryl, C 9 aryl, C 8 aryl, C 7 aryl or C 6 aryl.
  • Ring D is 5-to 12-membered heteroaryl, 5-to 11-membered heteroaryl, 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 5-to 7-membered heteroaryl or 5-to 6-membered heteroaryl.
  • Ring D is 12-membered heteroaryl, 11-membered heteroaryl, 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl or 5-membered heteroaryl.
  • Ring D is selected from pyridazinyl, pyridyl, pyrimidinyl, triazinyl, tetrazinyl, dihydropyrrolopyridazinyl, dihydropyranopyridazinyl, thiadiazolyl, pyrazolyl, pyrrolidinyl, pyridinonyl, pyrimidinonyl, pyrrolidinonyl, isothiazolidinyl dioxide or piperidinyl.
  • Ring D is selected from the group consisting of: wherein *indicates the connecting point to T.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently 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 y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently 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 y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently C 1-6 alkenyl, C 1- 5 alkenyl, C 1-4 alkenyl, C 1-3 alkenyl or C 1-2 alkenyl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently C 6 alkenyl, C 5 alkenyl, C 4 alkenyl, C 3 alkenyl, C 2 alkenyl or C 1 alkenyl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently C 1-6 alkynyl, C 1-5 alkynyl, C 1-4 alkynyl, C 1-3 alkynyl or C 1-2 alkynyl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently C 6 alkynyl, C 5 alkynyl, C 4 alkynyl, C 3 alkynyl, C 2 alkynyl or C 1 alkynyl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently C 3-12 cycloalkyl, C 3-11 cycloalkyl, C 3-10 cycloalkyl, C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 cycloalkyl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently C 12 cycloalkyl, C 11 cycloalkyl, 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 R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently 3-to 12-membered heterocyclyl, 3-to 11-membered heterocyclyl, 3-to 10-membered heterocyclyl, 3-to 9-membered heterocyclyl, 3-to 8-membered heterocyclyl, 3-to 7-membered heterocyclyl, 3-to 6-membered heterocyclyl, 3-to 5-membered heterocyclyl or 3-to 4-membered heterocyclyl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently 12-membered heterocyclyl, 11-membered heterocyclyl, 10-membered heterocyclyl, 9-membered heterocyclyl, 8-membered heterocyclyl, 7-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heterocyclyl, 4-membered heterocyclyl or 3-membered heterocyclyl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently C 6-12 aryl, C 6-11 aryl, C 6-10 aryl, C 6-9 aryl, C 6-8 aryl or C 6-7 aryl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently 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 R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently 5-to 12-membered heteroaryl, 5-to 11-membered heteroaryl, 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 5-to 7-membered heteroaryl or 5-to 6-membered heteroaryl, each optionally substituted with one or more R y .
  • one or more of L 11 , L 12 , L 13 , L 14 , and L 15 is independently 12-membered heteroaryl, 11-membered heteroaryl, 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 R y .
  • each R L is independently hydrogen or C 1-6 alkyl (e.g., C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, such as C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl) .
  • C 1-6 alkyl e.g., C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, such as C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl
  • each R y is independently cyano, alkyl or haloalkyl.
  • each R y is independently cyano, C 1-6 alkyl (e.g., C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, such as C 6 alkyl, C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl or C 1 alkyl) or C 1-6 haloalkyl (e.g., C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl such as C 1-2 haloalkyl, or C 6 haloalkyl, C 5 haloalkyl, C 4 haloalkyl, C 3 haloalkyl, C 2 haloalkyl or C 1 haloalkyl) .
  • C 1-6 alkyl e.g., C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, such as C 6 alkyl, C 5
  • 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 embodiments, 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.
  • 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.
  • 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.
  • 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 several 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.
  • SIK salt-inducible kinase
  • the disease or disorder is an SIK associated disease or disorder.
  • the SIK is SIK1, SIK2 and/or SIK3.
  • the disease or disorder is an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease (e.g., cancer) , 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.
  • a proliferative disease e.g., cancer
  • a fibrotic disease e.g., 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,
  • the disease or disorder is rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH) , primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD) , atherosclerosis, type 2 diabetes or glomerulonephritis.
  • NASH non-alcoholic steatohepatitis
  • IBD inflammatory bowel diseases
  • atherosclerosis type 2 diabetes or glomerulonephritis.
  • Also disclosed herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for modulating SIK, in a subject in need thereof.
  • Also disclosed herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting SIK, in a subject in need thereof.
  • Also disclosed herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a disease or disorder, in a subject in need thereof.
  • the disease or disorder is an SIK associated disease or disorder.
  • the SIK is SIK1, SIK2 and/or SIK3.
  • the disease or disorder is an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease (e.g., cancer) , 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.
  • a proliferative disease e.g., cancer
  • a fibrotic disease e.g., 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,
  • the disease or disorder is rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH) , primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD) , atherosclerosis, type 2 diabetes or glomerulonephritis.
  • NASH non-alcoholic steatohepatitis
  • IBD inflammatory bowel diseases
  • atherosclerosis type 2 diabetes or glomerulonephritis.
  • the disease or disorder is cancer, including but not limited to 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-refrac
  • compositions containing the compound (s) described herein are administered for therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • 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 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.
  • EX12-2 was prepared in a way similar as EX4-6.
  • LCMS [M+H] + 398.9, 400.9.
  • EX15-3 was prepared in a way similar as EX4-6. LCMS [M+H] + : 518.1.
  • 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.
  • SIK e.g., SIK1, SIK2 and/or SIK3 inhibitory activity.

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Abstract

L'invention concerne des inhibiteurs de kinase inductible par un sel (SIK) et des compositions pharmaceutiques comprenant lesdits composés. Les composés et compositions de l'invention sont utiles pour le traitement d'une maladie ou d'un trouble associé à la kinase SIK.
PCT/CN2025/098816 2024-06-04 2025-06-03 Nouveaux composés utilisés en tant qu'inhibiteurs de kinase inductible par un sel et leurs utilisations Pending WO2025252075A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014140313A1 (fr) * 2013-03-15 2014-09-18 Oncodesign S.A. Inhibiteurs macrocycliques de la kinase inductible par un sel
WO2022031928A1 (fr) * 2020-08-05 2022-02-10 The General Hospital Corporation Inhibiteurs de kinases inductibles par un sel
CN115197208A (zh) * 2021-04-01 2022-10-18 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
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
WO2023066204A1 (fr) * 2021-10-18 2023-04-27 上海美悦生物科技发展有限公司 Inhibiteur de sik, composition de celui-ci, son procédé de préparation et son utilisation
WO2023226976A1 (fr) * 2022-05-24 2023-11-30 上海美悦生物科技发展有限公司 Inhibiteur de sik et composition de celui-ci, son procédé de préparation et son utilisation
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

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014140313A1 (fr) * 2013-03-15 2014-09-18 Oncodesign S.A. Inhibiteurs macrocycliques de la kinase inductible par un sel
WO2022031928A1 (fr) * 2020-08-05 2022-02-10 The General Hospital Corporation Inhibiteurs de kinases inductibles par un sel
CN115197208A (zh) * 2021-04-01 2022-10-18 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
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
WO2023066204A1 (fr) * 2021-10-18 2023-04-27 上海美悦生物科技发展有限公司 Inhibiteur de sik, composition de celui-ci, son procédé de préparation et son utilisation
WO2023226976A1 (fr) * 2022-05-24 2023-11-30 上海美悦生物科技发展有限公司 Inhibiteur de sik et composition de celui-ci, son procédé de préparation et son utilisation
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SATO TADATOSHI, CHRISTIAN D. CASTRO ANDRADE , SUNG-HEE YOON , YINGSHE ZHAO , WILLIAM J. GREENLEE , PATRICIA C. WEBER , USHA VISWAN: "Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice", PNAS, vol. 119, no. 50, 13 December 2022 (2022-12-13), pages 1 - 9, XP093378390, DOI: 10.1073/pnas.2214396119 *

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