WO2022253250A1 - Dégradation de la tyrosine kinase de bruton contenant un cycle fusionné ou un cycle spiro - Google Patents

Dégradation de la tyrosine kinase de bruton contenant un cycle fusionné ou un cycle spiro Download PDF

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WO2022253250A1
WO2022253250A1 PCT/CN2022/096512 CN2022096512W WO2022253250A1 WO 2022253250 A1 WO2022253250 A1 WO 2022253250A1 CN 2022096512 W CN2022096512 W CN 2022096512W WO 2022253250 A1 WO2022253250 A1 WO 2022253250A1
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compound
alkyl
reaction
membered
alternatively
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PCT/CN2022/096512
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English (en)
Chinese (zh)
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张寅生
任景
汪纪楠
杨晓骏
张晓平
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正大天晴药业集团股份有限公司
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Priority to CN202280037318.XA priority Critical patent/CN117377675A/zh
Publication of WO2022253250A1 publication Critical patent/WO2022253250A1/fr

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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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

  • the present application relates to a Bruton's tyrosine kinase degradation agent containing a ring or spiro ring, its preparation method, a pharmaceutical composition containing the degradation agent, and its use in treating BTK-related diseases.
  • BTK Bruton's tyrosine kinase
  • B cells distributed in the lymphatic system, hematopoietic and blood systems, and is a member of the non-receptor tyrosine kinase Tec family, which also includes TEC, ITK/TSK/EMT and BMX have high homology in structure.
  • BTK often has abnormal expression. Because it is mainly expressed in B cells and myeloid cells, BTK is a target with better targeting and safety.
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • E3 ubiquitin ligases These compounds can induce target proteins to be recognized by proteasomes in cells, causing degradation of target proteins, and can effectively Reduce the amount of target protein in the cell.
  • the application relates to a compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from -O- or -NHCO-;
  • each R is independently selected from halogen, -CN, C 1-4 alkoxy, or C 1-4 alkyl optionally substituted with one or more halogens;
  • each R 2 is independently selected from halogen or C 1-4 alkyl
  • n and n are independently selected from 0, 1, 2, or 3;
  • X is selected from CH or N;
  • X 1 , X 2 , or X 3 are independently selected from CH, C, or N;
  • the LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -;
  • Ak is selected from a bond or -C 1-12 alkyl-, one or more carbon atoms in the -C 1-12 alkyl- are optionally replaced by O or N atoms;
  • Ak 2 is selected from a bond or -C 1-6 alkyl-;
  • Cy 1 and Cy 2 are each independently selected from 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally substituted by one or more halogens;
  • R 3 is selected from hydrogen, halogen, amino, or C 1-4 alkyl.
  • the proviso is that the fragment not the following snippet:
  • the proviso is that the fragment not the following snippet:
  • X 4 is -CH 2 -, and other substituents are as defined above;
  • R is selected from halogen, amino, or C 1-4 alkyl, and other substituents are as defined above;
  • R is hydrogen
  • the LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -; and no The other substituents are as defined above.
  • L1 is selected from -O-. In some embodiments, L is selected from -NHCO-.
  • L is selected from -NHCO-, and other substituents are as defined above;
  • L is selected from -O-
  • each R is independently selected from fluoro, chloro, -CN, C alkoxy , or C optionally substituted with one or more F or chloro or bromo or iodo -3 alkyl.
  • each R is independently selected from fluoro, chloro, -CN, C 1-3 alkoxy, or C 1-3 alkyl optionally substituted with one or more F or chloro .
  • each R 1 is independently selected from fluoro, chloro, -CN, methoxy, ethoxy, or methyl optionally substituted with one or more F or chloro.
  • each R 1 is independently selected from fluoro, chloro, -CN, methoxy, or methyl optionally substituted with one or more F or chloro.
  • each R 1 is independently selected from chloro or -CF 3 .
  • each R 2 is independently selected from fluoro, chloro, bromo, iodo, or C 1-3 alkyl.
  • each R 2 is independently selected from fluoro, chloro, or C 1-3 alkyl.
  • each R 2 is independently selected from fluoro, chloro, methyl, or ethyl.
  • each R 2 is independently selected from fluoro, chloro, or methyl. In some embodiments, R is selected from fluoro.
  • n is selected from 0, 1, or 2. In some embodiments, m is selected from 0 or 1. In some embodiments, m is selected from zero.
  • n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1. In some embodiments, n is selected from zero.
  • X is selected from C or N. In some embodiments, X is selected from C or N. In some embodiments, X is selected from CH or N.
  • X1 is selected from C
  • X2 is selected from N
  • X3 is selected from CH
  • X1 is selected from N
  • X2 is selected from C
  • X3 is selected from N.
  • X1 is selected from C
  • X2 is selected from N
  • X3 is selected from CH
  • X1 is selected from N
  • X2 is selected from C
  • X3 is selected from N.
  • Cy is selected from the group consisting of 7-12 membered spirobicycloalkyl, 7-12 membered heterospirobicycloalkyl, 6- 12-membered bicycloalkyl or 6-12-membered heterobicycloalkyl.
  • the heterospirobicycloalkyl or heterobicycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S. In some embodiments, the heterospirobicycloalkyl or heterobicycloalkyl contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heterospirobicycloalkyl or heterobicycloalkyl contains 1 or 2 N atoms, or 1 N atom and 1 O atom.
  • Cy is selected from
  • the LNK group is selected from -Ak 1 -, -Ak 2 -Cy 1 -Cy 2 -, or -Ak 2 -Cy 1 -;
  • Ak is selected from a bond or -C 1-12 alkyl-; or, Ak is selected from -C 1-12 alkyl-, one or more carbon atoms in the -C 1-12 alkyl- ( For example 1-5, preferably 1-3 carbon atoms) are optionally replaced by atoms selected from O or N;
  • Ak 2 is selected from a bond or -C 1-6 alkyl-; Or; Ak 2 is selected from -C 1-6 alkyl-;
  • Cy 1 and Cy 2 are each independently selected from a 3-12 membered cycloalkyl group or a 3-12 membered heterocycloalkyl group, the cycloalkyl group or heterocycloalkyl group being optionally substituted by one or more halogens.
  • the LNK group is selected from -Ak 1 -. In some embodiments, the LNK group is selected from -Ak 2 -Cy 1 -Cy 2 -. In some embodiments, the LNK group is selected from -Ak 2 -Cy 1 -.
  • Ak 1 is selected from a bond or -C 1-10 alkyl-, one or more carbon atoms in the -C 1-10 alkyl- are optionally replaced by O or N atoms. In some embodiments, Ak is selected from a bond or -C 1-10 alkyl-, 1-5, preferably 1-3 carbon atoms in the -C 1-10 alkyl- are optionally replaced by O Or N atom replacement.
  • Ak is selected from a bond, -C 1-9 alkyl-, -C 1-9 alkyl-O-, -C 1-9 alkyl-NH-, -C 1-5 alkyl -OC 1-5 alkyl-O-, -C 1-3 alkyl-OC 1-3 alkyl-OC 1-3 alkyl-O-, or -C 1-3 alkyl-OC 1-3 alkane The group -OC 1-3 alkyl-NH-.
  • Ak is selected from a bond, -C 1-3 alkyl-, -C 8-9 alkyl-, -C 2-8 alkyl-O-, -C 2-8 alkyl-NH -, -C 2-4 alkyl-OC 3-5 alkyl-O-, -C 1-2 alkyl-OC 1-2 alkyl-OC 1-2 alkyl-O-, or -C 1- 2Alkyl - OC1-2Alkyl - OC1-2Alkyl -NH-.
  • Ak 1 is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O- , -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-.
  • Ak 1 is selected from -C 1-10 alkyl-, and one or more carbon atoms in the -C 1-10 alkyl- are optionally replaced by O or N atoms.
  • Ak 1 is selected from -C 1-9 alkyl-, -C 1-9 alkyl-O-, -C 1-9 alkyl-NH-, -C 1-5 alkyl- OC 1-5 alkyl-O-, -C 1-3 alkyl-OC 1-3 alkyl-OC 1-3 alkyl-O-, or -C 1-3 alkyl-OC 1-3 alkyl -OC 1-3 alkyl-NH-.
  • Ak 1 is selected from -C 1-3 alkyl-, -C 8-9 alkyl-, -C 2-8 alkyl-O-, -C 2-8 alkyl-NH- , -C 2-4 Alkyl-OC 3-5 Alkyl-O-, -C 1-2 Alkyl-OC 1-2 Alkyl-OC 1-2 Alkyl-O-, or -C 1-2 Alkyl-OC 1-2 alkyl-OC 1-2 alkyl-NH-.
  • Ak 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH
  • Ak is selected from a bond or -C 1-4 alkyl-.
  • Ak is selected from a bond or -C 1-3 alkyl-.
  • Ak 2 is selected from a bond, -CH 2 -, or -(CH 2 ) 2 -. In some embodiments, Ak 2 is selected from a bond or -CH 2 -.
  • Ak 2 is selected from -C 1-4 alkyl-.
  • Ak 2 is selected from -C 1-3 alkyl-.
  • Ak 2 is selected from -CH 2 -, or -(CH 2 ) 2 -. In other embodiments, Ak 2 is selected from -CH 2 -.
  • Cy 1 and Cy 2 are independently selected from 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
  • Cy 1 and Cy 2 are independently selected from 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
  • Cy 1 and Cy 2 are independently selected from 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
  • Cy 1 and Cy 2 are independently selected from 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally replaced by one or more a halogen substitution.
  • Cy 1 and Cy 2 are each independently selected from 4-6 membered heterocycloalkyl optionally substituted by one or more halogens.
  • the heterocycloalkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S. In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O. In some embodiments, the heterocycloalkyl group contains 1 or 2 N atoms.
  • Cy 1 and Cy 2 are each independently selected from 3-7 membered (eg 4-6 membered) containing 1-3 (eg 1-2) heteroatoms selected from N or O or S atoms. ) heterocycloalkyl group, preferably a 4-6 membered heterocycloalkyl group containing 1-2 N atoms.
  • Cy 1 and Cy 2 are each independently selected from azetidinyl, pyrrolidinyl, piperidine ring group, piperazine ring group or azabicyclo[3.1.0]hexyl group, so The azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azabicyclo[3.1.0]hexyl groups are optionally substituted by one or more halogens.
  • Cy 1 is selected from azetidinyl, pyrrolidinyl, piperidine ring, piperazine ring or azabicyclo[3.1.0]hexyl, the azetidine
  • the radical, pyrrolidinyl, piperidinecyclyl, piperazinecyclyl or azabicyclo[3.1.0]hexyl is optionally substituted with one or more halogens.
  • Cy 1 is selected from
  • Cy 2 is selected from azetidinyl, pyrrolidinyl, or piperidinecyclyl.
  • Cy 2 is selected from azetidinyl. In some embodiments, Cy 2 is selected from
  • Cy 1 and Cy 2 are independently selected from said Optionally substituted with one or more halogens.
  • Cy 1 and Cy 2 are independently selected from
  • -Ak 2 -Cy 1 -Cy 2 - is selected from
  • -Ak 2 -Cy 1 -Cy 2 - is selected from
  • -Ak 2 -Cy 1 - is selected from
  • -Ak 2 -Cy 1 - is selected from
  • LNK is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-,
  • LNK is selected from -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, - (CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-,
  • LNK is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 9 -, -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 5 O-, -(CH 2 ) 8 O-, -(CH 2 ) 4 NH-, -(CH 2 ) 8 NH-, -(CH 2 ) 2 O(CH 2 ) 5 O-, -(CH 2 ) 2 O(CH 2 ) 3 O-, -(CH 2 ) 3 O(CH 2 ) 3 O-, -(CH 2 ) 4 O-(CH 2 ) 4 O-, -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 O-, or -(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH-.
  • LNK is
  • R 3 is selected from hydrogen, halogen, amino, or C 1-3 alkyl.
  • R is selected from hydrogen, fluoro, chloro, bromo, iodo, or amino.
  • R is selected from hydrogen, fluoro, chloro, bromo, or amino.
  • R is selected from hydrogen, fluoro, or amino.
  • the "one or more” is selected from one, two, three, four, five or six. In some embodiments, the “one or more” is selected from one, two, or three. In some embodiments, the “one or more” is selected from one, or two.
  • the present application encompasses the above-defined variables and embodiments thereof, and any combination thereof.
  • the present application also relates to compounds of formula II or formula II-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
  • L 1 , R 1 , R 2 , m, n, X, X 1 , X 2 , X 3 , X 4 , LNK, R 3 are as defined above;
  • X 5 is selected from CH, CH 2 or N.
  • the present application also relates to compounds of formula III, formula IV or formula III-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
  • R 1 , R 2 , m, n, X, X 4 , LNK, R 3 are as defined above.
  • the present application also relates to compounds of formula V, formula VI, formula VII, formula VIII, formula V-1 or formula VI-1, stereoisomers thereof or pharmaceutically acceptable salts thereof,
  • R 1 , R 2 , m, n, X, X 4 , Ak 2 , Cy 1 , Cy 2 and R 3 are as defined above.
  • the aforementioned -Ak 2 -Cy 1 - is selected from -CH 2 -Cy 1 -.
  • the present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:
  • the present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:
  • the pharmaceutically acceptable salts include salts formed with inorganic acids, salts formed with organic acids, or salts formed with acidic amino acids.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the present application relates to a method for preventing or treating BTK-related diseases in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomer or Its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the present application relates to the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of medicines for preventing or treating BTK-related diseases.
  • the present application relates to the use of the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in preventing or treating BTK-related diseases.
  • the present application relates to the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition for preventing or treating BTK-related diseases.
  • the above-mentioned BTK-related diseases are selected from autoimmune diseases, inflammatory diseases or cancers.
  • the present application relates to a BTK degradation agent, including the above-mentioned compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the present application relates to the above-mentioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preparing a BTK degradation agent.
  • the compounds of the present application have a degradative effect on BTK (such as OCI-LY10 cells); in vitro cell proliferation inhibitory activity; for example, for OCI-LY10 cells and TMD8-BTK (C481S) cells; compared with the kinase EGFR and TEC, it has BTK (WT) and BTK (C481S) kinase selective inhibitory activity; stable in vitro liver microsome metabolism, especially human and mouse liver microsomes; excellent in vivo pharmacokinetic data (for example, for mice); good in vivo efficacy (for example, for TMD-8 mouse subcutaneous transplanted tumor); the degradation kinetics of BTK protein in TMD8 cells is good, such as the degradation rate is high, and the degradation rate gradually increases with time.
  • BTK such as OCI-LY10 cells
  • in vitro cell proliferation inhibitory activity for example, for OCI-LY10 cells and TMD8-BTK (C481S) cells
  • WT BTK
  • C481S
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • Optionally substituted means substituted or unsubstituted, for example, the ethyl group is "optionally” substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (eg CHFCH 2 F, CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • C mn herein is that moiety has an integer number of carbon atoms in the given range mn.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • variable e.g, R
  • R any variable
  • its definition is independent at each occurrence. For example, if a group contains 2 R, each R has independent options.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to a -OH group.
  • amino refers to a -NH2 group.
  • alkyl refers to a hydrocarbon group with the general formula C n H 2n+1 , such as C 1 - 10 , C 1 - 6 , C 1 - 4 alkyl.
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n - butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion ie, alkyl group of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
  • alkoxy refers to -O-alkyl, such as -OC 1 -10 alkyl, -OC 1 -6 alkyl, -OC 1 -4 alkyl.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • alkenyl include, but are not limited to, C 2-10 , C 2-6 , C 2-5 alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl , 1,3-butadienyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond.
  • alkynyl include, but are not limited to, C 2-10 , C 2-6 , C 2-5 alkynyl, such as ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, Adamantyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged (eg, fused) or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 7 membered ring, a 3 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen or a 3 to 5 membered ring.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl
  • 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazin
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or multiple fused rings comprising 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.
  • Structural units Indicates a heteroaryl system, the linkage
  • X 1 , X 2 , and X 3 in this application they are represented as single bonds or double bonds, so that the above-mentioned structural units are heteroaryl systems, and will not violate the rules of valence bond connection, for example, it can be
  • Groups or structural fragments in this application such as LNK, Cy, Ak 1 , Cy 1 , Cy 2 , -Ak 2 -Cy 1 -Cy 2 -, -Ak 2 -Cy 1 - and specific options thereof can optionally be used
  • the reading order from left to right is correspondingly connected to the left group and the right group of the group or fragment in the general formula, for example, when Cy is selected from According to the reading order from left to right, the left side of Cy and the fragment corresponding to the left side in the general formula Link, right and right fragments connected, the resulting fragments are
  • groups or structural fragments in this application such as LNK, Cy, Ak 1 , Cy 1 , Cy 2 , -Ak 2 -Cy 1 -Cy 2 -, -Ak 2 -Cy 1 - and their specific options can be Using the reading order from right to left, they are respectively connected to the left side group and the right side group of the group or fragment in the general formula, for example, when Cy
  • treating means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including: preventing a disease or disease state from occurring in a mammal, especially when the when the mammalian mammal is susceptible to the disease state but has not been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. .
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • parameter values should be understood as being modified by the term "about”.
  • the term “about” indicates an error value exists, for example, it means a variation within ⁇ 5%, such as ⁇ 1% or ⁇ 0.1%, of a certain value.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some of the bonding electrons.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotopically labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (ie3H ) and carbon-14 (ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • deuterium substitution may be partial or complete, partial deuterium substitution meaning at least one hydrogen is replaced by at least one deuterium.
  • Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administering a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and then processing the mixture into granules to obtain tablets or The core of the icing.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • the daily dose is administered in a dose of 0.01 to 200 mg/kg body weight, in single or divided doses.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalents well known to those skilled in the art Alternatives, preferred implementations include but are not limited to the examples of this application.
  • the compound of formula I of the present application can be prepared by those skilled in the art of organic synthesis through the following routes:
  • the compound of general formula (1-1) obtains the compound of general formula (1-2) through nucleophilic substitution reaction or Guangyan reaction, then obtains the compound of general formula (1-3) by coupling reaction, obtains general formula ( 1-4) compound, the corresponding compound of general formula (1-5) is obtained by nucleophilic substitution reaction or reductive amination, if the reaction site of the compound of general formula (1-5) has an amino protecting group, first remove the amino protecting group and then The compound of general formula I is obtained by nucleophilic substitution reaction, coupling reaction or reductive amination.
  • the preparation of a longer chain can be obtained by repeating the fourth step and removing the amino protecting group.
  • the compound of general formula (2-2) is reacted with the compound of general formula (1-4) to obtain the compound of general formula (2-3) through reductive amination or nucleophilic substitution reaction, and then the compound of general formula I is obtained through ring closure reaction.
  • the compound of the general formula (3-1) obtains the compound of the general formula (3-2) through a nucleophilic substitution reaction or the Mitsunobu reaction, and then removes the protecting group to obtain a compound of the general formula (3-3).
  • chemical reaction or coupling reaction to obtain the corresponding compound of general formula (3-4) if there is an amino protecting group at the reaction site of the compound of general formula (3-4), first remove the amino protecting group and then pass nucleophilic substitution reaction, reductive amination or The coupling reaction gives the compound of general formula I.
  • the preparation of a longer chain can be obtained by repeating the third step and removing the amino protecting group.
  • X6 is selected from halogen
  • X7 is selected from H, and other substituents are as defined above;
  • the compound of general formula (4-1) obtains the compound of general formula (4-2) through nucleophilic substitution reaction or coupling reaction, then obtains the compound of general formula (4-3) through oxidation reaction, and the compound of general formula (4-3) and The compound of general formula (3-3) is obtained by reductive amination to the compound of general formula I.
  • HATU stands for 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DMF stands for N,N-di Methylformamide
  • DCM represents dichloromethane
  • NBS represents N-bromosuccinimide
  • EA represents ethyl acetate
  • DMSO represents dimethyl sulfoxide
  • Boc represents tert-butoxycarbonyl
  • PdCl 2 (dppf) ⁇ CH 2 Cl 2 stands for [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex
  • PE stands for petroleum ether
  • THF stands for tetrahydrofuran
  • AIBN stands for azobisisobutyronitrile
  • MeOH represents methanol
  • AcOH represents acetic acid
  • NMP represents methylpyrrolidone
  • IBX represents 2-iodano
  • intermediate 1u (267mg), DMF (2mL), 1j (450mg) and triethylamine (398mg) were sequentially added, and the mixture was reacted at 60°C for 1h under the protection of N 2 .
  • the reaction liquid was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EA/CH 3 OH/NH 4 OH) to obtain 0.283 g of intermediate 1v.
  • intermediate 2a (20.93g), DMSO (50mL), intermediate 2b (10g), slowly drop the solution of potassium hydroxide (8.09g) in H 2 O (2mL)
  • the reaction solution was stirred at 0° C. for 10 min, then transferred to room temperature and stirred for 6 h.
  • Water (200 mL) was added to the reaction solution to quench it.
  • the organic phase was separated, washed with 200 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 30 g of intermediate 2c.
  • intermediate 3a Into a one-necked flask, intermediate 3a (5 g), triethylamine (4.50 g) and DCM (30 mL) were sequentially added. The temperature was lowered to about 0°C, p-toluenesulfonyl chloride (6.52 g) was slowly added, and the mixture was reacted overnight at room temperature under the protection of N 2 . After the reaction, DCM (100 mL) and water (200 mL) were added to the reaction solution.
  • the intermediate 1t (2g) was dissolved in N,N-dimethylformamide (20mL), and then 1,5-dibromopentane (5.95g) and cesium carbonate (6.02g) were added, React at room temperature for 2 hours. After the reaction was complete, ethyl acetate (200 mL) and water (200 mL) were added to the system. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 2), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off from the filtrate under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 7b (1.5 g).
  • silica gel column chromatography eluent: dichloromethane/methanol
  • Embodiment 8 the synthesis of compound 8
  • intermediate 8a (1021mg), DMF (20mL), potassium carbonate (546mg) and intermediate 1t (500mg) were added sequentially, and the mixture was reacted at 80°C for 16.5h.
  • the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and EA (200 mL) and water (200 mL) were added to the residue.
  • EA 200 mL
  • water 200 mL
  • the organic phase was separated, washed with 100 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, then purified by reverse phase column chromatography (H 2 O/CH 3 CN) to obtain 0.220 g of intermediate Body 8b.
  • intermediate 9b (642mg), intermediate 1j (600mg), potassium carbonate (383mg) and DMF (10mL) successively, under N2 protection, oil bath to 50 °C for 2 hours, the reaction is complete, the reaction Add water (100mL) to the solution, extract with DCM-MeOH (20:1) (50mL ⁇ 2), combine organic layers, wash with water (50mL ⁇ 1), and saturated brine (50mL ⁇ 1), dry the extract, filter, After the filtrate was rotary evaporated, the residue was purified by silica gel column chromatography (DCM-MeOH) to obtain the target compound 9c (302 mg).
  • DCM-MeOH silica gel column chromatography
  • the intermediate 11c (2 g) and allyl benzyl ether (0.807 g) were dissolved in dioxane (20 mL), and tetrakis(triphenylphosphine) palladium (1.16 g) and carbonic acid Potassium (1.38g), under the protection of N 2 , the mixture was heated to 100°C for 16 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 11d (1.5 g).
  • the intermediate 11d (1g) was dissolved in methanol (10mL), and then Pd/C (0.1g, 0.094mmol) was added, and the reaction solution was first replaced with nitrogen for 2-3 times, and then replaced with hydrogen for 2 -3 times, stirred at 50°C for 17 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, and rinsed with methanol solvent (50 mL). The filtrate was evaporated to remove the solvent under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain the target intermediate 11e (400 mg).
  • the intermediate 11e (300 mg) was dissolved in dichloromethane (5 mL), and Dess Martin oxidant (1.053 g) was added, and reacted at room temperature for 1 hour. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL ⁇ 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and no purification was required. The solvent was evaporated under reduced pressure to obtain intermediate 11f (300 mg).
  • intermediate 11f 250 mg
  • intermediate 1j 352 mg
  • sodium cyanoborohydride 131 mg
  • acetic acid 1 drop
  • dichloromethane 50 mL
  • water 50 mL
  • intermediate 15c (2.20g), iron powder (1.655g), ammonium chloride (3.17g), ethanol (50mL) and water (5mL) in sequence, and heat at 80°C for 2 hours under the protection of N2 , the reaction was complete, the iron powder residue was filtered off, the filter cake was washed with methanol and DCM-MeOH (10:1) successively, the filtrate and washings were combined, and spin-dried to obtain the target object 15d (1.85g).
  • intermediate 15g (550mg), acetone (100mL) and sodium iodide (5110mg) in sequence, under the protection of N2 , heat at 100°C to react overnight, the reaction is complete, and the residue after the reaction liquid is rotary evaporated is used EA (30mL ⁇ 2) was extracted, the organic layers were combined and washed with saturated brine (50mL ⁇ 1), the organic layer extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 15h (782mg).
  • intermediate 16c (280mg), acetonitrile (25mL) and IBX (494mg) successively, under the protection of N2 , react at 80°C for 2.5 hours, the reaction is complete, filter, and obtain intermediate 16d (610mg ).
  • intermediate 17h (1.8g), intermediate 1b (1.636g), potassium carbonate (1.500g), H2O (3mL), 1,4-dioxane (15mL) and PdCl2 to the reaction flask in sequence (dppf) ⁇ CH 2 Cl 2 (0.265 g), replaced by N 2 three times, then the mixture was heated to 85° C. for 2 h, and the heating was stopped. 200 mL of water was added to the reaction liquid, and then extracted twice with 100 mL of DCM. The combined organic layers were washed twice with 100 mL of saturated sodium chloride solution. After washing, it was dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 17i (1.109 g).
  • reaction solution was cooled to room temperature, 200 mL of ethyl acetate and 300 mL of water were added, the organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried with anhydrous sodium sulfate, filtered, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate Body 18b (5.039 g).
  • intermediate 18b (5g), intermediate 1b (6.90g), potassium carbonate (5.07g) and PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.998g) in the reaction flask, add solvent water (6mL) and 1 , 4-dioxane (30mL), under the protection of N 2 , the mixture was heated to 80°C for 14h.
  • the reaction solution was cooled to room temperature, 100mL EA and 100mL water were added, the organic phase was separated, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain the intermediate 18c (5.0 g).
  • intermediate 20a 25g
  • NBS 29.6g
  • azobisisobutyronitrile 6.83g
  • carbon tetrachloride 200mL
  • intermediate 21a (12.8g), NBS (13.13g), azobisisobutyronitrile (3.03g) and carbon tetrachloride (130mL) in sequence, and heat to 85°C under N2 protection 4.5 hours. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was washed with water (150mL ⁇ 2), and saturated brine (150mL ⁇ 1), the organic layer was stirred and dried with anhydrous sodium sulfate, and then suction filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 21b ( 19.27g).
  • Embodiment 23 the synthesis of compound 23
  • intermediate 25b (1.198g), intermediate 15d (1.5g), acetic acid (0.270g) and methanol (30mL) successively, add sodium cyanoborohydride (1.131g), under N 2 protection, The reaction was stirred overnight at room temperature. After the reaction, add saturated sodium bicarbonate solution (30mL) and saturated sodium chloride solution (30mL) to the reaction solution, extract with EA (70mL ⁇ 2), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and filter , concentrated, and subjected to silica gel column chromatography to obtain 1.876 g of intermediate 25c.
  • intermediate 26b (1.9g), DCM (100mL) and dess-martin oxidant (4.49g) successively, under the protection of N 2 , stir at room temperature for 1.5 hours, the reaction is complete, and the reaction solution is watered (50mL ⁇ 2) After washing, the organic layer was washed with saturated brine (100 mL ⁇ 1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 26c (3.67 g).
  • intermediate 27b (0.72g), DCM (30mL) and Dess Martin oxidant (1.691g) in turn, under N2 protection, stir at room temperature for 1.5 hours, the reaction is complete, the reaction solution is water (50mL ⁇ 2) After washing, the organic layer was washed with saturated brine (100 mL ⁇ 1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 27c (1.405 g).
  • compound 28d (868 mg) and compound 1j (500 mg) were dissolved in methanol (5 mL), sodium cyanoborohydride (147 mg) was added, 1 drop of acetic acid was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system.
  • intermediate 29c (1.4g), bromoacetaldehyde diethyl acetal (2.418g), N,N-diisopropylethylamine (2.64g) and DMSO (10mL) to the reaction flask, under N 2 protection, The mixture was heated to 80°C for 6h. The reaction solution was cooled to room temperature, and DCM (100 mL) and water (100 mL) were added. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain intermediate 29d (0.495 g).
  • compound 30d (352 mg) and compound 1j (500 mg) were dissolved in methanol (5 mL), then sodium cyanoborohydride (147 mg) was added, and 1 drop of acetic acid was added, and reacted at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system.
  • compound 31b (1.300 g) was dissolved in N-methylpyrrolidone (10 mL), and (1R, 5S, 6R)-3-azabicyclo[3.1.0]hexane-6-methanol ( 0.5g) and N,N-diisopropylethylamine (1.713g), heated to 80°C for 9 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, and the solvent was evaporated. The crude product was separated by silica gel column chromatography (eluent: dichloromethane/methanol) to obtain intermediate 31c (1.21g).
  • intermediate 31c (550mg), DCM (20mL) and dess-martin oxidant (1193mg) successively, under N protection, react at room temperature for 2 hours, the reaction is complete, after adding water in the reaction solution, use DCM-MeOH ( 20:1, 50mL ⁇ 2) extraction, the organic layers were combined and washed with saturated brine (50mL ⁇ 1), the extract was dried and filtered, and the filtrate was rotary evaporated to dryness to obtain intermediate 31d (555mg).
  • DCM-MeOH 20:1, 50mL ⁇ 2
  • intermediate 33c (0.36g), intermediate 13b (0.080g), N,N-diisopropylethylamine (0.075g) and DMSO (6mL) to the reaction flask in sequence, and heat the mixture to 80°C for 5h . After cooling to room temperature, 100 mL of DCM and 100 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain compound 33 (0.052 g).
  • compound 33c 200mg
  • compound 31b 115mg
  • dimethyl sulfoxide 5mL
  • N,N-diisopropylethylamine 230mg
  • the temperature was raised to 90°C for reaction 4 Hour.
  • the reaction solution was cooled to room temperature, and the crude product was purified by reverse phase (eluent: water/acetonitrile) to obtain compound 34 (70 mg).
  • intermediate 35c (0.4g), intermediate 13b (0.054g), N,N-diisopropylethylamine (0.050g) and DMSO (6mL) to the reaction flask in sequence, and heat the mixture to 80°C for 5h . After cooling to room temperature, 100 mL of DCM and 100 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by silica gel column chromatography to obtain compound 35 (0.015 g).
  • intermediate 13b (1.0g), 3-hydroxymethylazetidine hydrochloride (0.534g), NMP (15mL) and N,N-diisopropylethylamine (1.863 g), under the protection of N 2 , heated at 80°C for 4 hours, the reaction was complete, and the residue was extracted with DCM-MeOH (10:1, 30mL ⁇ 3) after the reaction solution was rotary evaporated, and the organic layers were combined and washed with saturated brine (50mL ⁇ 3) 1) Washing, drying and filtering the extract, and rotary evaporation of the filtrate to obtain intermediate 36b (2.49g).
  • intermediate 36b (0.25g), DCM (10mL) and Dess Martin oxidant (0.911g) successively, under N protection, react at room temperature for 2 hours, the reaction is complete, and the reaction solution is washed with DCM-MeOH (20 :1, 30mL ⁇ 2) extraction, the organic layers were combined and washed with saturated brine (50mL ⁇ 1), the extract was dried and filtered, and the filtrate was rotary evaporated and dried to obtain intermediate 36c (400mg).
  • the S-configuration intermediate 37b-1 600 mg was the first peak
  • the R-configuration intermediate 37b-2 510 mg was the last peak.
  • compound 37c 300 mg
  • tert-butyl 3-oxazetidine-1-carboxylate 128 mg
  • sodium cyanoborohydride 62.8 mg
  • Embodiment 39 Preparation of compound 39
  • Embodiment 40 the synthesis of compound 40
  • Embodiment 41 Preparation of compound 41
  • compound 41c 300 mg
  • tert-butyl 3-oxazetidine-1-carboxylate 110 mg
  • sodium cyanoborohydride 53.9 mg
  • reaction flask Into the reaction flask, add intermediate 44c (120mg), intermediate 13b (63.8mg), DMSO (3mL) and N,N-diisopropylethylamine (124mg) in turn, under N 2 protection, react at 90°C 4 Hours, the reaction was complete, and the reaction solution was directly eluted with a C18 reverse-phase column (10nM ammonium acetate aqueous solution-acetonitrile), and the column liquid was combined, extracted with DCM-MeOH (10:1) and then evaporated to dryness to obtain the target object 44 (62mg ).
  • a C18 reverse-phase column 10nM ammonium acetate aqueous solution-acetonitrile
  • intermediate 46a (1.12g), tert-butyl-7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (0.89g), triphenyl Phosphorus (1.94g) and tetrahydrofuran (150mL) were cooled to 0°C, diisopropyl azodicarboxylate (2.24g) was added dropwise, and the addition was completed in about 15 minutes, and the temperature was raised to 25°C for 16 hours.
  • reaction solution was poured into 200 mL of purified water, ethyl acetate (200 mL) was added for extraction and layering, the organic phase was washed with saturated aqueous sodium chloride solution (100 mL), and the organic phase was concentrated to obtain a crude product, which was purified by a silica gel column (petroleum ether /ethyl acetate) to obtain intermediate 46b (5.26g).
  • Embodiment 47 the preparation of compound 47
  • intermediate 46c (170 mg), intermediate 36c (253 mg), DCM (30 mL) and glacial acetic acid (22.26 mg) were sequentially added, and the mixture was stirred at room temperature for 20 min under N 2 protection.
  • Sodium cyanoborohydride (69.9mg) was added to the reaction solution, and continued to stir at room temperature under N2 protection for 2 hours. The reaction was complete.
  • Step 1 Preparation of intermediates 51b-1 and 51b-2
  • Embodiment 53 Preparation of compound 53

Abstract

La présente invention concerne un agent de dégradation de la tyrosine kinase de Bruton (BTK) contenant un cycle fusionné ou un cycle spiro, son procédé de préparation, une composition pharmaceutique contenant le composé, et une utilisation de celui-ci dans la prévention ou le traitement de maladies associées à BTK.
PCT/CN2022/096512 2021-06-01 2022-06-01 Dégradation de la tyrosine kinase de bruton contenant un cycle fusionné ou un cycle spiro WO2022253250A1 (fr)

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WO2023072270A1 (fr) * 2021-10-29 2023-05-04 百极弘烨(南通)医药科技有限公司 Composé protac, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
US11897862B2 (en) 2022-03-17 2024-02-13 Gilead Sciences, Inc. IKAROS zinc finger family degraders and uses thereof

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