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WO2021093758A1 - Dérivé de pyrimido et son application en médecine - Google Patents

Dérivé de pyrimido et son application en médecine Download PDF

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Publication number
WO2021093758A1
WO2021093758A1 PCT/CN2020/128033 CN2020128033W WO2021093758A1 WO 2021093758 A1 WO2021093758 A1 WO 2021093758A1 CN 2020128033 W CN2020128033 W CN 2020128033W WO 2021093758 A1 WO2021093758 A1 WO 2021093758A1
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Prior art keywords
alkyl
cyano
alkoxy
ring
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/CN2020/128033
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English (en)
Chinese (zh)
Inventor
张晨
何平
魏琦
王健民
钱国飞
叶飞
唐平明
李瑶
严庞科
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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Priority to CN202080061791.2A priority Critical patent/CN114630832A/zh
Publication of WO2021093758A1 publication Critical patent/WO2021093758A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to compounds of general formula (I) or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, and intermediates and preparation methods thereof, and Application in the preparation of medicines for preventing or treating diseases related to KRAS G12C activity or expression.
  • the RAS protein is expressed by the RAS gene (Rat Sarcoma viral oncogene). It is an intracellular guanine nucleotide binding protein and belongs to GTPase (with weak hydrolytic activity). RAS protein exists in two different states: inactive GDP-bound state and active GTP-bound state.
  • the activated RAS protein conducts signal transduction by interacting with different downstream effectors, and has an impact on cell growth, differentiation, cytoskeleton, protein transportation and secretion.
  • the activation of RAS signal transduction is regulated by guanine nucleotide exchange factor (GEF, which can cause GDP-GTP exchange) or GTPase activation protein (GAP, which can cause the RAS protein to change from an activated state to an inactive state).
  • GEF guanine nucleotide exchange factor
  • GAP GTPase activation protein
  • Mutant RAS The protein can cause resistance to GAP and cause the RAS protein to be continuously activated, causing uncontrolled cell growth,
  • RAS gene mutations are a common type of gene mutation in cancer patients (Nat. Rev. Drug Discov. 2014, 13, 828-851). For example, RAS gene mutations account for 97.7 in pancreatic cancer, colorectal cancer, multiple myeloma, and NSLCL, respectively. %, 52.2%, 42.6% and 32.2%.
  • KARS gene (Kristen Rat Sarcoma viral oncogene) mutation is the most influential mutation among RAS mutations, accounting for 86% of all RAS mutations.
  • the most common way of KRAS gene activation is point mutation. 95% of KRAS mutations mainly occur at codon 12 and codon 13 of exon 2.
  • the most common form of mutation is KRAS G12C mutation (39%). KRAS G12V (18-21%) and KRAS G12D (17-18%) mutations.
  • KRAS mutant protein inhibitors Since the discovery of KRAS mutant proteins in cancer and the observation that inhibiting these mutant proteins can inhibit tumor proliferation, KRAS mutant protein inhibitors have received extensive attention. KRAS has long been considered a "non-drugable target": RAS has a high affinity for GTP/GDP (picomolar level), and the entire protein lacks other "ligand binding pockets” (Clin. Cancer Res. 2015, 21,1810–1818). In the KRAS G12C mutant protein, it was identified that a "binding pocket II" (Nature. 2013, 503, 548-551) appeared next to the GTP/GDP-RAS binding pocket, which can be used as a binding site for KRAS G12C mutant protein inhibitors.
  • One of the objectives of the present invention is to provide an inhibitor of KRAS G12C protein.
  • the present invention provides a compound capable of inhibiting KRAS G12C protein or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt.
  • the present invention also provides intermediates and preparation methods of the compound, and the preparation and prevention of the compound or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt Or the application in drugs for the treatment of diseases related to KRAS G12C activity or expression.
  • the present invention provides a compound of general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
  • R 1 is selected from
  • R 1a is selected from H, F, or C 1-4 alkyl, and the alkyl group is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) from H , F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 1a is selected from H, F, methyl, ethyl, propyl or isopropyl, and said methyl, ethyl, propyl or isopropyl is optionally further divided by 0 to 4 (E.g. 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy Replaced by
  • each of R 1b is independently selected from H, C 1-4 alkyl, or -(CH 2 ) p -3 to 6-membered heterocyclic ring, and the alkyl group or heterocyclic ring is optionally further divided by 0 to 4 (e.g.
  • heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S and N;
  • each R 1b is independently selected from H, methyl, ethyl, propyl, isopropyl, -CH 2 -4 membered nitrogen-containing heterocycle, -CH 2 -5 membered nitrogen-containing heterocycle, -CH 2 -6-membered nitrogen-containing heterocyclic ring, 4-membered nitrogen-containing heterocyclic ring, 5-membered nitrogen-containing heterocyclic ring or 6-membered nitrogen-containing heterocyclic ring, said methyl, ethyl, propyl, isopropyl or nitrogen-containing
  • the heterocycle is optionally further selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , 0 to 4 (e.g., 0, 1, 2, 3, or 4).
  • R 1c is selected from H, F, Cl, Br, I, cyano, CF 3 , C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy
  • 0 to 4 e.g. 0, 1, 2, 3 or 4
  • H, F, Cl, Br, I, oxo, OH, cyano, CF 3 COOH, NH 2 , -NH (C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
  • R 1a and any one of R 1b form a C 5-10 carbocyclic ring or 5 to 12 membered heterocyclic ring
  • the carbocyclic or heterocyclic ring is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -N (C 1-4 alkyl) 2 , C 1-4 Alkyl, C 1-4 alkoxy, C 3-10 carbocyclic or 5- to 12-membered heterocyclic group substituted by substituents, the heterocyclic group contains 1 to 4 (such as 1, 2, 3 Or 4) Heteroatoms selected from O, S, N;
  • each R 1d is independently selected from H or C 1-4 alkyl, and the alkyl group is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-4 Substituted by alkyl or C 1-4 alkoxy substituents;
  • ring A is selected from a 4- to 12-membered nitrogen-containing heterocyclic ring
  • the nitrogen-containing heterocyclic ring is selected from one of the following groups that are saturated or partially saturated: monocyclic, fused, bridged, or spirocyclic ring the nitrogen-containing heterocyclic ring, monocyclic, fused ring, bridged or spiro ring is optionally further substituted with 0-4 (e.g., 2, 3 or 4) R a;
  • ring A is selected from a 4- to 9-membered nitrogen-containing heterocyclic ring, and the nitrogen-containing heterocyclic ring is selected from one of the following structures that are saturated or partially saturated: monocyclic, fused, bridged, or spiro ring, so He said nitrogen-containing heterocycle optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) R a substituents;
  • each Ra is independently selected from H, oxo, F, Cl, Br, I, cyano, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkyl
  • the oxy group is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3, or 4) from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1 -4 substituted by alkyl or C 1-4 alkoxy substituents;
  • ring A is selected from unsubstituted or substituted When substituted, optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) R a substituents;
  • ring A is selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, cyano, OH, CF 3 , methyl, Ethyl, propyl, isopropyl or CH 2 CN substituents;
  • ring A is selected from
  • ring A is selected from
  • each Ra is independently selected from H, oxo, F, Cl, Br, I, cyano, C 1-4 alkyl or C 1-4 alkoxy, the alkyl or alkyl
  • the oxy group is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3, or 4) from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1 -4 substituted by alkyl or C 1-4 alkoxy substituents;
  • the carbocyclic or heterocyclic ring is a monocyclic ring, a bicyclic ring or Spiro ring
  • said carbocyclic, heterocyclic, monocyclic, fused ring or spiro ring is optionally further substituted with 0 to 5 (for example, 0 , 1 , 2, 3, 4 or 5) R 2, said hetero
  • the ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
  • Ring B is selected from non-aromatic 4- to 7-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N, X 1 is selected from N , Ring C and ring D together form a C 6-12 carbocyclic ring or 5 to 12 membered heterocyclic ring, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) From heteroatoms of O, S, and N, m1 is selected from 0, 1, 2, 3 or 4, m2, m3 are each independently selected from 0, 1, 2, 3 or 4, and m2+m3 ⁇ 5;
  • Ring B is selected from azetidine, azetidine, piperidine or imidazolidine
  • ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine
  • ring C is selected from C 4-6 carbocyclic ring, 4-6
  • the membered heterocyclic ring contains 1 to 3 (for example, 1, 2 or 3) heteroatoms selected from O, S, and N;
  • Ring B is selected from piperidine;
  • Q, M and the atoms directly connected to the two together form
  • Q, M and the atoms directly connected to the two together form Selected from
  • Q, M and the atoms directly connected to the two together form R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally further selected from 0 to 4 (e.g.
  • each R 2 is independently selected from R 2a , R 2b , R 2c , R 2d ;
  • heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
  • R 2a is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl, or 5 to 10 membered heteroaryl ,
  • the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl , Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -C 1-6 alkyl , C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl substituent Substituted, the heterocycloalkyl,
  • R 2a is selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthalene Group, thienyl, furanyl, pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (for example, 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I , OH, cyano, CF 3 , NH 2 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl substituents;
  • each of R 2b is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, or C 1-6 alkyl, and the alkyl group is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1 -4 alkyl), -N(C 1-4 alkyl) 2 , C 1-6 alkyl, C 2-6 alkynyl or C 1-6 alkoxy substituent;
  • each R 2b is independently selected from H, F, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally grouped by 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy Is substituted by the substituent;
  • each R 2b is independently selected from H, F, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally grouped by 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl;
  • R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy, or ethoxy.
  • Ethyl, methoxy or ethoxy is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3. Substituted by COOH, NH 2 , methyl or ethyl substituents;
  • R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 Cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or Heteroaryl groups are optionally further selected from 0 to 4 (e.g.
  • each R 2c is independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, or cyclopropyl.
  • Butyl, the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4)
  • R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , C 1-4 alkyl, or C 1-4 alkoxy, the The alkyl or alkoxy group is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , Substituted by COOH, NH 2 or C 1-6 alkyl substituents;
  • each of R 2d is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or Substituted by substituents of C 1-4 alkoxy;
  • each of R 2d is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl optionally further Substitution with 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl Substituted by
  • R 2A , R 2B or R 2C are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl Group or 5- to 10-membered heteroaryl group, the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally further divided by 0 to 4 (e.g. 0, 1, 2, 3 or 4 One) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2.
  • heterocycloalkyl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
  • X 3 is selected from bond, O, -OCH 2 -, -CH 2 O-, S or NR x ;
  • X 3 is selected from bond or O;
  • R x is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further substituted by 0, 1, 2, 3, or 4 Substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy; 0 to 4 ( (E.g. 0, 1, 2, 3, or 4)
  • R 3 is selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy,- N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -(CH 2 ) q -cyclopropane, -(CH 2 ) q -cyclobutane, -(CH 2 ) q -cyclopentane,- (CH 2 ) q -cyclohexane, -(CH 2 ) q -azetidine, -(CH 2 ) q -oxetane, -(CH 2 ) q -tetrahydrothiophene, -(CH 2 ) q -tetrahydrofuran, -(CH 2 ) q -tetrahydropyrrole, -(CH 2 ) q -phen
  • R 3 is selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, -(CH 2 ) q -tetrahydropyrrole, -(CH 2 ) q -aza Cyclobutane, -N(CH 3 ) 2 or -N(CH 2 CH 3 ) 2 , when substituted, optionally 0 to 4 (for example, 0, 1, 2, 3 or 4) are selected from H , F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1- 4 alkyl, -C 1-4 alkylene -OH, -(CH 2 )qC 3-6 carbocyclic ring, -(CH 2 )q-3 to 6-membered heterocyclic ring, C 3-6 cycloalkyl or C 1-4 alkoxy
  • each of R 3a is independently selected from H, C 1-4 alkyl, -C 1-4 alkyl, and 3 to 12-membered heterocyclic ring, and the alkyl group or heterocyclic ring is optionally further substituted by 0 To 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl ), -N(C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • R 3a is selected from H, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further divided by 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • the nitrogen-containing heterocyclic ring is optionally further divided by 0 to 4 (e.g., 0, 1 , 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1- 4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituents
  • the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O , S, N heteroatoms;
  • R 3b is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, or 3 to 12 membered heterocycle, and the alkyl, cycloalkyl or heterocycle is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkane Group), -N(C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic ring contains 1 to 4 (for example, 1, 2 , 3 or 4) heteroatoms selected from O, S, N;
  • R 3b is selected from H, methyl, ethyl, propyl, isopropyl, azetidine or oxetane, the methyl, ethyl, propyl, isopropyl Propyl, azetidine or oxetane is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 3 is selected from -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 ) 2 ,
  • X 3 -R 3 is selected from
  • R 4 is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 or C 1-6 alkyl, and the alkyl group is optionally further substituted by 0 To 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 Alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
  • each R 4 is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 or methyl;
  • n, p, q are each independently selected from 0, 1, 2, 3, or 4;
  • n is selected from 0;
  • m2 is selected from 0, 1, 2, or 3.
  • the compound of the above general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt wherein
  • heterocyclic ring contains 1 to 4 ( For example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • R 1a and any one of R 1b form a C 5-10 carbocyclic ring or a 5- to 12-membered heterocyclic ring
  • the carbocyclic or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0, 1, 2, 3 Or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -N (C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-10 carbocyclic group or 5 to 12-membered heterocyclic group substituted by substituents
  • the heterocyclic group contains 1 to 4 (for example, 1, 2, 3 or 4 ) Heteroatoms selected from O, S, N;
  • R 1d are each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-4 alkyl or C 1- 4 substituted by substituents of alkoxy;
  • Ring A is selected from 4 to 12-membered nitrogen-containing heterocycles, and the nitrogen-containing heterocycles are selected from one of the following saturated or partially saturated groups: monocyclic, fused, bridged or spiro ring, and the nitrogen-containing heterocyclic, monocyclic, fused ring, bridged or spiro ring is optionally further substituted with 0-4 (e.g., 2, 3 or 4) R a;
  • R a is each independently selected from H, oxo, F, Cl, Br, I, cyano, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
  • the carbocyclic or heterocyclic ring is a monocyclic, fused ring or spirocyclic ring.
  • the carbocyclic, heterocyclic, monocyclic, fused ring or spiro ring is optionally further substituted with 0 to 5 R 2 , and the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O , S, N heteroatoms;
  • the heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
  • R 2A, R 2B or R 2C is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 8-membered heterocyclic group, C 6- 10 aryl group or 5 to 10 yuan Heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-6 Alkyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl substituents,
  • the heterocycloalkyl group contains 1 to 4 (for example, 1,
  • X 3 is selected from bond, O, -OCH 2 -, -CH 2 O-, S or NR x ;
  • R x is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally further divided by 0 to 4 (for example, 0, 1, 2, 3 or 4 ) Substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
  • R 3a is each independently selected from H, C 1-4 alkyl, -C 1-4 alkyl-3 to 12-membered heterocyclic ring, and the alkyl group or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0 , 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) Heteroatoms from O, S, N;
  • the nitrogen-containing heterocyclic ring is optionally further divided by 0 to 4 (for example, 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl ) 2 , substituted by a substituent of C 1-4 alkyl or C 1-4 alkoxy
  • the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O, S, N heteroatom;
  • R 3b is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or 3 to 12 membered heterocyclic ring, and the alkyl, cycloalkyl or heterocyclic ring is optionally further divided by 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N ( C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) Heteroatoms selected from O, S, N;
  • R 4 is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 or C 1-6 alkyl, and the alkyl group is optionally further divided by 0 to 4 (for example, 0 , 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , substituted by a substituent of C 1-4 alkyl or C 1-4 alkoxy;
  • n, p, q are each independently selected from 0, 1, 2, 3, or 4.
  • Ring B is selected from non-aromatic 4- to 7-membered heterocycles, said heterocycles containing 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, and N;
  • X 1 is selected from N;
  • the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H , F, Cl, Br
  • R 2b are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH or C 1-6 alkyl, and the alkyl group is optionally further divided by 0 to 4 ( For example, 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-6 alkyl, C 2-6 alkynyl or C 1-6 alkoxy substituent substituted;
  • Ring C and ring D together form a C 6-12 carbocyclic ring or 5 to 12 membered heterocyclic ring, and the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected from Heteroatoms of O, S, N;
  • R 2A, R 2B or R 2C is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 8-membered heterocyclic group, C 6- 10 aryl group or 5 to 10 yuan Heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-6 Alkyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl substituents,
  • the heterocycloalkyl group contains 1 to 4 (for example, 1,
  • n1 is selected from 0, 1, 2, 3 or 4;
  • n2 and m3 are each independently selected from 0, 1, 2, 3 or 4, and m2+m3 ⁇ 5;
  • R 1c is selected from H, F, Cl, Br, I, cyano, CF 3 , C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy is optionally further divided by 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkane Group), -N(C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;
  • Ring A is selected from 4 to 9-membered nitrogen-containing heterocycles, and the nitrogen-containing heterocycles are selected from one of the following structures that are saturated or partially saturated: monocyclic, fused, bridged or spiro ring, and the nitrogen-containing heterocyclic optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) R a substituents;
  • R a is each independently selected from H, oxo, F, Cl, Br, I, cyano, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
  • Ring A is selected from unsubstituted or substituted When substituted, optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) R a substituents;
  • R a is each independently selected from H, oxo, F, Cl, Br, I, cyano, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
  • Ring B is selected from azetidine, azetidine or piperidine;
  • Or ring B is selected from imidazolidine
  • Ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine;
  • Ring C is selected from C 4-6 carbocyclic ring
  • Or ring C is selected from a 4- to 6-membered heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
  • R 2A, R 2B or R 2C is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 8-membered heterocyclic group, C 6- 10 aryl group or 5 to 10 yuan Heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-6 Alkyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl substituents,
  • the heterocycloalkyl group contains 1 to 4 (for example, 1,
  • R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy
  • the group is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 or C Substituted by substituents of 1-6 alkyl;
  • R 1a is selected from H, F or C 1-4 alkyl, and the alkyl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br , I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 1b is each independently selected from H, C 1-4 alkyl or -(CH 2 ) p -3 to 6-membered heterocyclic ring, and the alkyl or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N ( C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 3 to 6-membered heterocyclic substituents, the heterocyclic ring contains 1 Up to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • R 1a is selected from H, F, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy;
  • R 1b are each independently selected from H, methyl, ethyl, propyl, isopropyl, -CH 2 -4 membered nitrogen-containing heterocyclic ring, -CH 2 -5 membered nitrogen-containing heterocyclic ring, -CH 2 -6 membered
  • a nitrogen-containing heterocyclic ring, a 4-membered nitrogen-containing heterocyclic ring, a 5-membered nitrogen-containing heterocyclic ring or a 6-membered nitrogen-containing heterocyclic ring, the methyl, ethyl, propyl, isopropyl or nitrogen-containing heterocyclic ring may optionally be further 0 to 4 (e.g.
  • X 3 is selected from bond or O;
  • R 2b are each independently selected from H, F, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally selected from 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
  • the combined ring formed by ring C and ring D is selected from
  • R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally further divided by 0 to 4 ( For example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted by the substituents of the group;
  • R 3 is selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -(CH 2 ) q -cyclopropane, -(CH 2 ) q -cyclobutane, -(CH 2 ) q -cyclopentane, -(CH 2 ) q- Cyclohexane, -(CH 2 ) q -azetidine, -(CH 2 ) q -oxetane, -(CH 2 ) q -tetrahydrothiophene, -(CH 2 ) q -tetrahydrofuran, -(CH 2 ) q -tetrahydropyrrole, -(CH 2 ) q -phenyl,
  • R 3a is selected from H, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 3b is selected from H, methyl, ethyl, propyl, isopropyl, azetidine or oxetane, said methyl, ethyl, propyl, isopropyl, azacyclobutane Butane or oxetane is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C Substituted by 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 4 is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 or methyl;
  • q is selected from 0, 1, 2, 3 or 4;
  • R 1 is selected from
  • Ring A is selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, cyano, OH, CF 3 , methyl, Ethyl, propyl, isopropyl or CH 2 CN substituents;
  • Ring B is selected from piperidine;
  • R 2b are each independently selected from H, F, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally selected from 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl;
  • R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally further divided by 0 to 4 ( For example, 0, 1, 2, 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl;
  • R 3 is selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, -(CH 2 ) q -tetrahydropyrrole, -(CH 2 ) q -azetidine, -N (CH 3 ) 2 or -N(CH 2 CH 3 ) 2 , when substituted, optionally 0 to 4 (for example, 0, 1, 2, 3 or 4) selected from H, F, Cl, Br , I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-4 alkyl, -C 1-4 alkylene -OH, -(CH 2 )qC 3-6 carbocyclic ring, -(CH 2 )q- 3 to 6-membered heterocyclic ring, C 3-6 cycloalkyl or C 1-4 alkoxy ,
  • Ring A is selected from
  • X 3 is selected from O or bond
  • R 3 is selected from -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 ) 2 ,
  • n is selected from 0;
  • Ring A is selected from
  • X 3 -R 3 are selected from
  • n is selected from 0;
  • R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy or ethoxy, the methyl, ethyl, methoxy Group or ethoxy group is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , Substituted by methyl or ethyl substituents;
  • n is selected from 0;
  • n2 is selected from 0, 1, 2 or 3;
  • Ring A is selected from
  • X 3 is selected from O or bond
  • R 3 is selected from -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 ) 2 ,
  • n is selected from 0;
  • the compound of general formula (Ia) or (Ib) or its stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts among them
  • Ring A is selected from
  • X 3 -R 3 are selected from
  • the compound of the following general formula (Ia-1) or (Ib-1) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceuticals Acceptable salt of which
  • R 2a is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, said alkyl , Cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 (e.g.
  • heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
  • R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF2 3, C 1-6 alkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C 6-10 aryl or 5 to 10-membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further 0 to 4 (e.g.
  • heterocycloalkyl or heteroaryl group contains 1 Up to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;
  • n2 is selected from 0, 1, 2 or 3;
  • the compound of general formula (Ia-1) or (Ib-1) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically Acceptable salt where
  • R 1 is selected from
  • R 2a is selected from H or one of the following substituted or unsubstituted groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furan Group, pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , NH 2 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl substituents;
  • R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy substituents;
  • Ring A is selected from
  • X 3 -R 3 are selected from
  • n is selected from 0.
  • each group is the same as any one of the second, third, fourth, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen embodiments of the present invention.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein the compound is selected from one of the following structures:
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • R 1a is selected from H, F or C 1-4 alkyl, and the alkyl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br , I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 1b is each independently selected from H or C 1-4 alkyl, and the alkyl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3, or 4) from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-4 alkyl or C Substituents of 1-4 alkoxy are substituted.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • R 1a is selected from H, F or C 1-4 alkyl, and the alkyl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br , I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 1b is each independently selected from H, C 1-4 alkyl or -(CH 2 ) p -3 to 6-membered heterocyclic ring, and the alkyl or heterocyclic ring is optionally further divided by 0 to 4 (for example, 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N ( C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 3 to 6-membered heterocyclic substituents, the heterocyclic ring contains 1 Up to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, N.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, (Ic-1) or (Ic-2) or co-crystals,
  • R 1a is selected from H, F or C 1-4 alkyl, and the alkyl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br , I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 1b is each independently selected from H, C 1-4 alkyl or -(CH 2 ) p -4 to 6-membered nitrogen-containing heterocyclic ring, and the alkyl group or nitrogen-containing heterocyclic ring is optionally further divided by 0 to 4 (E.g.
  • heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ic-1) or (Ic-2) or their stereoisomers, deuterated products, solvates, pro Drugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • R 1a is selected from H, F, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy;
  • R 1b is each independently selected from H, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further substituted by 0 to 4 (e.g. 0, 1 , 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituent.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ic-1) or (Ic-2) or their stereoisomers, deuterated products, solvates, pro Drugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • R 1a is selected from H, F, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy;
  • R 1b are each independently selected from H, methyl, ethyl, propyl, isopropyl, -CH 2 -4 membered nitrogen-containing heterocyclic ring, -CH 2 -5 membered nitrogen-containing heterocyclic ring, -CH 2 -6 membered Nitrogen-containing heterocyclic ring, 4-membered nitrogen-containing heterocyclic ring, 5-membered nitrogen-containing heterocyclic ring or 6-membered nitrogen-containing heterocyclic ring, said methyl, ethyl, propyl, isopropyl or nitrogen-containing heterocyclic ring may be further 0 to 4 (e.g.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • R 1 is selected from
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • Ring A is selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, cyano, OH, CF 3 , methyl, Ethyl, propyl, isopropyl or CH 2 CN substituents.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • Ring A is selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, cyano, OH, CF 3 , methyl, Ethyl, propyl, isopropyl or CH 2 CN substituents.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • Ring A is selected from one of the following unsubstituted or substituted structures: When substituted, optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) R a take-substituted;
  • R a is each independently selected from H, oxo, F, Cl, Br, I, cyano, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy is optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C Substituents of 1-4 alkoxy are substituted.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • Ring A is selected from
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • R 3 is selected from one of the following substituted or unsubstituted groups: H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -(CH 2 ) q -cyclopropane, -(CH 2 ) q -cyclobutane, -(CH 2 ) q -cyclopentane, -(CH 2 ) q- Cyclohexane, -(CH 2 ) q -azetidine, -(CH 2 ) q -oxetane, -(CH 2 ) q -tetrahydrothiophene, -(CH 2 ) q -tetrahydrofuran, -(CH 2 ) q -tetrahydropyrrole, -(CH 2 ) q -phenyl,
  • R 3a is selected from H, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further divided by 0 to 4 (e.g., 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • R 3b is selected from H, methyl, ethyl, propyl, isopropyl, azetidine or oxetane, said methyl, ethyl, propyl, isopropyl, azacyclobutane Butane or oxetane is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C Substituted by 1-4 alkyl or C 1-4 alkoxy substituents.
  • R 3 is selected from one of the following substituted or unsubstituted groups: H, methyl, ethyl , -(CH 2 ) q -tetrahydropyrrole, -(CH 2 ) q -azetidine, -N(CH 3 ) 2 or -N(CH 2 CH 3 ) 2 , when substituted, optional 0 to 4 (e.g.
  • heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected Heteroatoms from O, S, N.
  • Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their Stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts,
  • R 3 is selected from -CH 2 N(CH 3 ) 2 , -CH 2 N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 ) 2 ,
  • Some embodiments of the present invention relate to compounds of general formula (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or their stereoisomers , Deuteride, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, X 3 -R 3 are selected from
  • ring B is selected from nitrogen Etidine, azolidine or piperidine.
  • Some embodiments of the present invention relate to the compound of general formula (Ia) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • Ring B is selected from imidazolidine.
  • Some embodiments of the present invention relate to the compound of general formula (Ia) or (Ia-1) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,
  • R 2A, R 2B or R 2C is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 8-membered heterocyclic group, C 6- 10 aryl group or 5 to 10 yuan Heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-6 Alkyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl substituents,
  • the heterocycloalkyl group contains 1 to 4 (for example, 1,
  • Some embodiments of the present invention relate to the compound of general formula (Ia) or (Ia-1) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,
  • Some embodiments of the present invention relate to the compound of general formula (Ia) or (Ia-1) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,
  • Some embodiments of the present invention relate to the compound of general formula (Ia) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • Some embodiments of the present invention relate to the compound of general formula (Ib) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy or ethoxy, the methyl, ethyl, methoxy Group or ethoxy group is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , Substituted by methyl or ethyl substituents;
  • n2 is selected from 0, 1, 2 or 3.
  • Some embodiments of the present invention relate to the compound of general formula (Ia) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • R 2b are each independently selected from H, F, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally selected from 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituted by a substituent selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl.
  • Some embodiments of the present invention relate to the compound of general formula (Ib) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • Ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine;
  • Ring C is selected from C 4-6 carbocyclic ring or 4 to 6 membered heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N.
  • Some embodiments of the present invention relate to the compound of general formula (Ib) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • the combined ring formed by ring C and ring D is selected from
  • Some embodiments of the present invention relate to the compound of general formula (Ib) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • the combined ring formed by ring C and ring D is selected from
  • Some embodiments of the present invention relate to compounds of general formula (Ib) or (Ib-1) or their stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,
  • Some embodiments of the present invention relate to compounds of general formula (Ib) or (Ib-1) or their stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,
  • Some embodiments of the present invention relate to compounds of general formula (Ib) or (Ib-1) or their stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,
  • Some embodiments of the present invention relate to the compound of general formula (Ib) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy
  • the group is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 or C Substituents of 1-6 alkyl are substituted.
  • Some embodiments of the present invention relate to the compound of general formula (Ib) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally further divided by 0 to 4 ( For example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituents of the group are substituted.
  • Some embodiments of the present invention relate to compounds of general formula (Ib) or (Ib-1) or their stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,
  • Some embodiments of the present invention relate to the compound of general formula (Ib) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , methyl or ethyl, and the methyl or ethyl is optionally further divided by 0 to 4 ( For example, 0, 1, 2, 3, or 4) is substituted with a substituent selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl.
  • Some embodiments of the present invention relate to the compound of general formula (Ia-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • R 2a is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, said alkyl , Alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 (e.g.
  • heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.
  • Some embodiments of the present invention relate to the compound of general formula (Ia-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
  • R 2a is selected from one of the following substituted or unsubstituted groups: H, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furan Group, pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (for example 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl substituents.
  • Some embodiments of the present invention relate to compounds of general formula (Ib-1), (Ic-1) or (Ic-2) or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, co- Crystals or pharmaceutically acceptable salts,
  • R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF2 3, C 1-6 alkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C 6-10 aryl or 5 to 10-membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further 0 to 4 (e.g.
  • heterocycloalkyl or heteroaryl group contains 1 Up to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, N.
  • Some embodiments of the present invention relate to compounds of general formula (Ib-1), (Ic-1) or (Ic-2) or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, co- Crystals or pharmaceutically acceptable salts,
  • R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl is optionally further selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy substituents.
  • Some embodiments of the present invention relate to the compound of general formula (Ia) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from Ring B is piperidine; n is 0; m1 is 0;
  • R 1 is selected from
  • R 3 is selected from X 3 is a key or O.
  • Some embodiments of the present invention relate to the compound of general formula (Ia) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from Ring B is selected from azetidine or azetidine;
  • R 1 is selected from
  • R 2a is selected from substituted or unsubstituted phenyl or naphthyl.
  • the phenyl or naphthyl is optionally selected from 0 to 4 (for example, 0, 1, 2, 3, or 4).
  • R 2b is oxo
  • R 3 is selected from X 3 is O.
  • Some embodiments of the present invention relate to the compound of general formula (Ib) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from
  • the combined ring formed by ring C and ring D is selected from
  • R 1 is selected from
  • R 2c are each independently selected from F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy or ethoxy;
  • R 3 is selected from X 3 is O.
  • Some embodiments of the present invention relate to the compound of general formula (Ia-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from n is 0;
  • R 2a is H or phenyl, and the phenyl is optionally selected from F, Cl, Br, I, OH, cyano, CF 3 , NH 2 , methyl, ethyl, Substituent substitution of methoxy and ethoxy;
  • R 3 is selected from X 3 is O.
  • Some embodiments of the present invention relate to the compound of the general formula (Ic-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from
  • R 1 is selected from
  • R 3 is selected from X 3 is O.
  • Some embodiments of the present invention relate to the compound of the general formula (Ib-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from n is 0; m2 is 0;
  • R 3 is selected from X 3 is O;
  • Some embodiments of the present invention relate to the compound of general formula (Ic-2) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein,
  • Ring A is selected from m2 is 0;
  • R 3 is selected from X 3 is O.
  • Some embodiments of the present invention relate to the compound of general formula (Ia-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from n is 0; R 2a is phenyl;
  • R 3 is selected from X 3 is O.
  • Some embodiments of the present invention relate to the compound of the general formula (Ib-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
  • Ring A is selected from n is 0; m2 is 0;
  • R 3 is selected from X 3 is O;
  • Some embodiments of the present invention relate to compounds described by general formula (Ic-1) or (Ic-2) or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable Of salt, of which,
  • Ring A is selected from m2 is 0;
  • R 3 is selected from X 3 is O.
  • the present invention relates to a pharmaceutical composition, including the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, and pharmaceutically acceptable a.
  • the present invention relates to a compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts for use in the preparation of prevention or treatment and KRAS G12C activity Or the application in drugs for expression-related diseases, preferably in the preparation of tumor drugs.
  • the tumor is preferably hematological cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, non-small cell lung cancer or small cell lung cancer.
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in chemical literature. "Commercially available chemicals” are obtained from formal commercial sources. Suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Medicine Stone, WuXi AppTec, and Bailingwei Technology, etc. the company.
  • references books and monographs in this field detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing the preparation methods for reference.
  • These reference books and monographs include: “Synthetic Organic Chemistry”, John Wiley&Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; HOHouse, "Modern Synthetic Reactions", 2nd Ed., WABenjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, “Heterocyclic Chemistry", 2nd Ed., John Wiley&Sons, New York, 1992; J.
  • R 1 , R 2a , R 2b , R 2c , R 2d , R 3 , R 4 , ring A, ring B, ring C, ring D, X 1 , X 3 or m1, m2, m3, n are defined as above
  • the compounds of general formula (Ia) and (Ib) are the same;
  • R 5 is selected from C 1-6 alkyl
  • R 6 is selected from leaving groups, preferably F, Cl, Br, I, triflate, mesylate, p-toluenesulfonate or benzenesulfonate; PG and R 7 are selected From amino protecting group;
  • the compound of general formula (Ia-1) reacts with a compound containing a double leaving group under the action of a base to obtain a compound of general formula (Ia-2);
  • the compound of the general formula (Ia-2) can obtain the compound of the general formula (Ia-3) after removing the carbonyl group and the ethylene glycol protecting group;
  • the compound of general formula (Ia-3) reacts with a carbonic acid diester-based compound under the action of a base to obtain a compound of general formula (Ia-4);
  • the compound of general formula (Ia-4) reacts with S-methyl isothiourea sulfate under the action of a base, or the compound of general formula (Ia-4) first reacts with thiourea and then reacts with a methylating reagent under the action of a base The reaction obtains a compound of general formula (Ia-5);
  • the compound of the general formula (Ia-5) is reacted with trifluoromethanesulfonic anhydride under the action of a base, or the compound of the general formula (Ib-5) is chlorinated to obtain the compound of the general formula (Ia-6);
  • the compound of general formula (Ia-6) can obtain the compound of general formula (Ia-7) through substitution reaction;
  • the compound of general formula (Ia-8) can obtain the compound of general formula (Ia-9) through substitution reaction;
  • the compound of general formula (Ia-10) reacts with the compound of general formula (Ib-11) through coupling, substitution or condensation reaction;
  • the compound of the general formula (Ia-11) is obtained by removing the amino protecting group to obtain the compound of the general formula (Ib-12);
  • the compound of general formula (Ib-10) can obtain the compound of general formula (Ia) through substitution reaction or condensation reaction.
  • the compound of general formula (Ib-a) reacts with a compound containing a double leaving group under the action of a base to obtain a compound of general formula (Ib-2);
  • the compound of general formula (Ib-2) can obtain the compound of general formula (Ib-3) after removing the carbonyl group and the ethylene glycol protecting group;
  • the compound of general formula (Ib-3) reacts with a carbonic acid diester-based compound under the action of a base to obtain a compound of general formula (Ib-4);
  • the compound of general formula (Ib-4) reacts with S-methyl isothiourea sulfate under the action of a base, or the compound of general formula (Ib-4) first reacts with thiourea and then reacts with a methylating reagent under the action of a base The reaction obtains the compound of general formula (Ib-5);
  • the compound of general formula (Ib-6) can obtain the compound of general formula (Ib-7) through substitution reaction;
  • the compound of general formula (Ib-8) can obtain the compound of general formula (Ib-9) through substitution reaction;
  • the compound of the general formula (Ib-9) is obtained by removing the amino protecting group to obtain the compound of the general formula (Ib-10);
  • the compound of the general formula (Ib-10) can obtain the compound of the general formula (Ib) through a substitution reaction or a condensation reaction.
  • the compound of general formula (Ib-1a) is subjected to Danheiser-Stork reaction to obtain the compound of general formula (Ib-1b);
  • the compound of general formula (Ib-1b) is demethylated under acid catalysis to obtain the compound of general formula (Ib-1c);
  • the compound of general formula (Ib-1d) introduces a leaving group such as OTf, halogen, etc. under the action of a base to obtain a compound of general formula (Ib-1e);
  • the compound of general formula (Ib-1f) reacts with a carbonic acid diester-based compound or a cyanocarbonate-based compound under the action of a base to obtain a compound of general formula (Ib-1j);
  • the compound of the general formula (Ib-1l) is ring-closed under basic conditions to obtain the compound of the general formula (Ib-1m); or the compound of the general formula (Ib-1j) is reacted with thiourea to obtain the compound of the general formula (Ib-1m);
  • the compound of general formula (Ib-1m) reacts with a methylating reagent under the action of alkali to obtain the compound of general formula (Ib-1n); or the compound of general formula (Ib-1j) reacts with S-methyl isosulfide under the action of a base. Urea sulfate reaction yields a compound of general formula (Ib-1n);
  • the compound of general formula (Ib-1n) reacts with trifluoromethanesulfonic anhydride under the action of a base, or the compound of general formula (Ib-1n) undergoes chlorination to obtain the compound of general formula (Ib-1o);
  • the compound of general formula (Ib-1o) can obtain the compound of general formula (Ib-1p) through substitution reaction;
  • the compound of general formula (Ib-1q) can obtain the compound of general formula (Ib-1r) through substitution reaction;
  • the compound of the general formula (Ib-1r) is obtained by removing the amino protecting group to obtain the compound of the general formula (Ib-1s);
  • the compound of the general formula (Ib-1s) can obtain the compound of the general formula (Ib-1) through a substitution reaction or a condensation reaction.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , Hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and more preferably It is an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And various branched chain isomers; the alkyl group may optionally be further selected from 0 to 6 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, Amido, alkenyl, alkynyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 8 membered carbocyclic group, 3 to 8 membered heterocyclic group, 3 to An 8-membered carbocyclyloxy group, a 3- to 8-membered heterocyclyloxy group, a carboxyl group or a carboxylate group is substituted by
  • Alkylene refers to straight and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v- (v is an integer from 1 to 10).
  • alkylene include, but are not limited to, methylene, methylene, and Ethyl, propylene and butylene, etc.; the alkylene group may optionally be further selected from 0 to 5 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkyl Amino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituent substituted .
  • the definition of the alkylene group appearing in this text is consistent with this definition.
  • Cycloalkyl refers to a monovalent saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • the cycloalkyl group can optionally be further selected from 0 to 5 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituted by substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate.
  • the definition of the cycloalkyl group appearing herein is as described above.
  • Alkynyl refers to a linear and branched monovalent unsaturated hydrocarbon group, which has at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain
  • alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butanyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl Group, 1-methyl
  • Alkoxy refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyl Oxy and cyclobutoxy.
  • the alkoxy group may optionally be further selected from 0 to 5 F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituted by substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate.
  • the definition of the alkoxy group appearing in this document is consistent with this definition.
  • Carbocyclic group or “carbocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring.
  • the aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10- to 15-membered tricyclic ring system, the aromatic or non-aromatic ring is optionally monocyclic, bridged or spiro ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, or naphthalene ring.
  • the definition of carbocyclic or carbocyclic group appearing in this text is consistent with this definition.
  • Heterocyclic group or “heterocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, aromatic ring or
  • the non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, preferably a 3- to 8-membered heterocyclic group.
  • the optionally substituted N and S in the heterocyclic ring can be Is oxidized into various oxidation states.
  • the heterocyclic group can be connected to a hetero atom or a carbon atom, and the heterocyclic group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include oxirane ethyl, aziridinyl, oxetanyl, and aza.
  • the definition of heterocyclic group appearing in this text is consistent with this definition.
  • Ra and Rd are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a double ring group.
  • the definition of the spiro ring appearing in this article is consistent with this definition.
  • Non-limiting examples include:
  • Ra and Rd are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a double ring group.
  • the definition of the union appearing in this article is consistent with this definition.
  • Bridged ring refers to a polycyclic group in which any two rings share 2 atoms that are not directly connected. It can contain 0 or more double bonds, and can be substituted or unsubstituted. Any of the bridged ring systems
  • the ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12, and still more preferably 5 to 10 atoms.
  • Non-limiting examples include And adamantane.
  • Ra and Rd are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a double ring group.
  • the definition of bridge ring appearing in this article is consistent with this definition.
  • Heteromonocyclic ring refers to the “heterocyclic group” or “heterocyclic ring” of a monocyclic ring system. The definition of heteromonocyclic ring appearing in this text is consistent with this definition.
  • Heterocyclic ring refers to a "polycyclic ring” containing heteroatoms. The definition of the heterocyclic ring appearing in this article is consistent with this definition.
  • Heterospiro ring refers to a “spiro ring” containing heteroatoms. The definition of heterospiro ring appearing in this article is consistent with this definition.
  • Heterobridged ring refers to a “bridged ring” containing heteroatoms.
  • the definition of the heterobridging ring appearing in this article is consistent with this definition.
  • Ra and Rd are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a double ring group.
  • aryl or aromatic ring appearing in this text is consistent with this definition.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzopyrazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include
  • Ra and Rd are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group, or a double ring group.
  • the definition of heteroaryl groups appearing in this text is consistent with this definition.
  • Consing 1 to 4 heteroatoms selected from O, S, and N means containing 1, 2, 3, or 4 heteroatoms selected from O, S, and N.
  • the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N means that all heterocycles in the paragraph where the expression is located independently contain 1, 2, 3, or 4 heteroatoms. Heteroatoms selected from O, S, and N.
  • Substituted by 0 to X substituents means substituted by 0, 1, 2, 3...X substituents, and X is selected from any integer between 1 and 10.
  • substituted by 0 to 4 substituents means substituted by 0, 1, 2, 3 or 4 substituents.
  • substituted by 0 to 5 substituents means substituted by 0, 1, 2, 3, 4 or 5 substituents.
  • hetero-bridged ring is optionally further substituted with 0 to 4 substituents selected from H or F” means that the hetero-bridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F Substituted by the group.
  • XY-membered ring (X is selected from an integer less than Y and greater than or equal to 3, Y is selected from any integer between 4 and 12) including X+1, X+2, X+3, X+4.... Y-membered ring.
  • the ring includes heterocyclic ring, carbocyclic ring, aromatic ring, aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, heterocyclic ring, heterospiro ring or heterobridged ring.
  • “4-7 membered heteromonocyclic ring” refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring
  • “5-10 membered heterocyclic ring” refers to a 5-membered, 6-membered, 7-membered, or 8-membered ring.
  • 9-membered or 10-membered heterocyclic ring refers to a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered nitrogen-containing heterocyclic ring.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and that the free acid is combined with a non-toxic inorganic base or An organic base is a salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to one or more of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts and other chemical components formed
  • the mixture of "other chemical components” refers to a pharmaceutically acceptable carrier.
  • Carrier refers to a material that does not produce significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.
  • Prodrug refers to a compound of the present invention that can be transformed into a biologically active compound by metabolism in the body.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian individual, the prodrug can be cleaved to form free amino or carboxyl groups.
  • Co-crystal refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF co-crystal former
  • the pure state of API and CCF are both at room temperature. Solid, and there is a fixed stoichiometric ratio between the components.
  • a eutectic is a multi-component crystal, which includes both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.
  • Stepoisomers refer to isomers arising from the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Optional or “optionally” or “selective” or “selectively” means that the event or condition described later can but does not necessarily occur, and the description includes the situation in which the event or condition occurs and its failures. What happened.
  • heterocyclic group optionally substituted by an alkyl group means that the alkyl group may but does not necessarily exist.
  • the description includes the case where the heterocyclic group is substituted by an alkyl group, and the heterocyclic group is not substituted by an alkyl group.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • NMR is measured by (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetometers, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), internal standard It is tetramethylsilane (TMS);
  • HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the size used for thin layer chromatography separation and purification products is 0.4mm. -0.5mm;
  • Boc tert-butoxycarbonyl
  • Ts p-toluenesulfonyl
  • Cbz benzyloxycarbonyl
  • TMS trimethylsilyl
  • 1,4-Cyclohexanedione monoethylene ketal (8g, 51.3mmol) was dissolved in dry tert-butanol (130mL), protected by nitrogen, and potassium tert-butoxide solid (12.8g, 113.7mmol) was added. After stirring for 30 min at room temperature, 1,2-bis(bromomethyl)benzene (13.5g, 51.2mmol) was added, after the addition, the reaction was kept at room temperature overnight. After the completion of the reaction was monitored by TLC, the reaction was quenched by adding 100 mL of ice water, extracted three times with 100 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1a was obtained as a colorless viscous liquid (3 g, yield: 22.7%).
  • the filtrate was diluted with 20 mL of ice water, extracted three times with 30 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1d was obtained as a white solid (0.8 g, yield: 62%).
  • the sixth step 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-trifluoromethane Sulfonate (1f);
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, diluted by adding 800 mL of ethyl acetate, washed with 300 mL of water, stirred and left to stand for separation, the aqueous phase was extracted with 400 mL of ethyl acetate, and the organics were combined. The phase was washed with 500 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product 2a, a yellow-brown solid (11.2 g, yield: 29.8%).
  • the dichloromethane was removed by concentration under reduced pressure, and the residue was added with 200 mL of ether and stirred for 10 minutes, filtered with suction, and the filter cake was washed with 100 mL of ether.
  • the residue obtained after the filtrate was concentrated under reduced pressure was dissolved in 100 mL of tetrahydrofuran in a 1 L three-necked round bottom flask, tert-butanol (1.19 g, 16.0 mmol) was added, and the temperature was lowered to -78 °C under nitrogen atmosphere and the mixture was stirred for ten minutes.
  • Dissolve compound 2b (2.34g, 10.9mmol) with tetrahydrofuran (200mL) in a 500mL three-necked round bottom flask, cool to -78°C under nitrogen atmosphere, measure LiHMDS (22mL, 1M in THF) and add dropwise to the reaction flask. After stirring for ten minutes, 3 mL of ethyl cyanoformate (1.4 g, 14.1 mmol) diluted with tetrahydrofuran was slowly added dropwise to the reaction. After reacting for half an hour at -78° C., the temperature was raised to room temperature for 2 hours.
  • the fourth step 4-hydroxy-2-sulfanyl-spiro[6,8-dihydro-5H-quinazolin-7,3'-indoline]-2'-one (2d);
  • the fifth step 4-hydroxy-2-methylsulfanyl-spiro[6,8-dihydro-5H-quinazolin-7,3'-indoline]-2'-one (2e);
  • Dissolve compound 2d (0.1g, 0.334mmol) with methanol (15mL) in a single-necked round bottom flask, add potassium carbonate (0.185g, 1.34mmol) and stir for half an hour, add iodomethane (0.05g, 0.334mmol) and stir for 1 hour , LC-MS showed that the raw material was not completely consumed, and continued to add methyl iodide (0.05 g, 0.334 mmol) and stirred for 1 hour. LC-MS showed that the raw material was almost completely consumed.
  • the sixth step (2-methylsulfanyl-2'-oxy-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)trifluoro Mesylate (2f);
  • the eleventh step 2-[((2S)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxy-spiro[6 ,8-Dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid (compound 2);
  • Dissolve compound 2i (0.089g, 0.182mmol) with 30mL of dichloromethane in a single-necked round bottom flask, add N,N-diisopropylethylamine (0.2g, 1.46mmol), and cool down with an ice-water bath under a nitrogen atmosphere , The internal temperature was lowered to 5-10°C, and 2 mL of dichloromethane diluted acryloyl chloride (0.016 g, 0.182 mmol) was injected into the reaction, and the reaction was carried out at this temperature for 10 minutes. TLC monitored the complete reaction of the raw materials.
  • the first step 3-[tert-butyl(dimethyl)silyl]oxycyclohexanol (3a);
  • the sixth step 7-[tert-butyl(dimethyl)silyl]oxy-2-azaspiro[4.5]decane-3-one (3f);
  • the seventh step 7-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-2-azaspiro[4.5]decane-3-one (3g);
  • the eighth step 7-hydroxy-2-phenyl-2-azaspiro[4.5]decane-3-one (3h);
  • the ninth step 2-phenyl-2-azaspiro[4.5]decane-3,7-dione (3i);
  • Step 17 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl -Spiro[6,8-dihydro-5H-quinazoline]-7,4'-pyrrolidine]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (compound 3);
  • magnesium chips (228 mg, 8.65 mmol) were placed in a 50 mL three-necked flask, and about 1/4 of compound 4b (424 mg, 1.73 mmol) in THF (0.5 mL) was slowly added dropwise. A pellet of iodine was added, and the flask was heated to make the color of the iodine element disappear, and the THF solution of compound 4b was slowly added dropwise to keep the reaction system slightly boiling. After the addition, the system continued to react for 1 hour at room temperature. It was added dropwise to a solution of 3-ethoxy-2-cyclohexenone (107 mg, 0.763 mmol) in THF (1.5 mL) at 0°C.
  • the ninth step 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-alcohol (4i );
  • the sample is dissolved in n-hexane/isopropanol (90:10),
  • compound 4g (0.37g, 1.84mmol, refer to the synthesis of compound 4 synthetic route intermediate 4g) was suspended in 30mL dry tetrahydrofuran, and LiHMDS tetrahydrofuran solution (2.77mL, 1mol/L) was slowly added dropwise. , 2.77mmol), and after stirring at -78°C for 30 min, slowly drip ethyl cyanoformate (0.3g, 2.77mmol) in tetrahydrofuran (8mL) into the reaction solution, and after the addition, the reaction solution was slowly raised to room temperature for reaction 4h.
  • the crude compound 4o was dissolved in 20 mL of ethanol, and ammonium acetate (0.7 g, 9.2 mmol) was added to react at room temperature for 12 hours. After the reaction was monitored by TLC, the solvent was spin-dried under reduced pressure, diluted with 100 mL of ethyl acetate, and then washed three times with 10 mL of water. The phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 4p as a yellow viscous liquid (0.49 g crude product), which was directly used in the next reaction without purification.
  • Compound 4 was separated and purified by SFC preparation to obtain 4-1 (60 mg, SFC preparation retention time is 4.5 min; chiral HPLC retention time is 8.2 min) and 4-2 (31 mg, SFC preparation retention time is 3.9 min, chiral HPLC The retention time is 11.6min).
  • the substrate intermediate 1C (14.0g, 57.6mmol), ethylene glycol (21.4g, 0.35mol) and p-toluenesulfonic acid (1.1g, 5.8mmol) were added to 150mL of toluene, and the system was placed at 120°C Heat to reflux to separate water.
  • the reaction is complete when there is no new water in the water trap and the toluene is clear, the reaction is finished, cooled to room temperature, concentrated under reduced pressure, and the residue is separated by silica gel chromatography to obtain a yellow oily intermediate 1D (11.7g, yield 70%) .
  • Step 4 Bispiro [indene-1,1'-cyclohexane-3',2'-[1,3]dioxane] (Intermediate 1E)
  • Step 5 2,3-Dihydrobispiro [indene-1,1'-cyclohexane-3', 2'-[1,3]dioxane] (Intermediate 1F)
  • the crude compound 5b was dissolved in 200 mL of ethanol, and ammonium acetate (23.1 g, 300 mmol) was added to react at room temperature for 12 h. After the reaction was monitored by TLC, the solvent was spin-dried under reduced pressure, diluted with 100 mL of ethyl acetate, and then washed three times with 30 mL of water. It was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 5c, a yellow viscous liquid (10.7 g crude product), which was directly used in the next reaction without purification.
  • the sixth step 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethane Sulfonate (5g);
  • Compound 5 was separated and purified by SFC preparation to obtain isomer 5-1 (95mg, retention time of SFC preparation is 1.23min; chiral HPLC retention time is 12.78min) and isomer 5-2 (100mg, retention time of SFC preparation is 1.47min, chiral HPLC retention time is 18.30min).
  • the sample is dissolved in n-hexane/isopropanol (90:10),
  • Mobile phase A is CO 2 , B is ethanol (containing 0.1% ammonia water), 30% B is eluted.
  • the sample is dissolved in n-hexane/isopropanol (90:10),
  • Mobile phase A is CO 2 , B is ethanol (containing 0.1% ammonia water), 30% B is eluted.

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Abstract

L'invention concerne un composé représenté par la formule générale (I), ou un stéréoisomère, un produit deutéré, un solvate, un promédicament, un métabolite, un co-cristal ou un sel pharmaceutiquement acceptable de celui-ci, un intermédiaire du composé, et un procédé de préparation du composé, ainsi qu'une application dans la préparation d'un médicament pour la prévention ou le traitement de maladies associées à l'activité ou à la quantité d'expression de KRAS G12C.
PCT/CN2020/128033 2019-11-15 2020-11-11 Dérivé de pyrimido et son application en médecine Ceased WO2021093758A1 (fr)

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