WO2021093758A1 - Pyrimido derivative and application thereof in medicine - Google Patents

Pyrimido derivative and application thereof in medicine 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
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PCT/CN2020/128033
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French (fr)
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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四川海思科制药有限公司
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Priority to CN202080061791.2A priority Critical patent/CN114630832A/en
Publication of WO2021093758A1 publication Critical patent/WO2021093758A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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.

Abstract

A compound represented by general formula (I), or a stereoisomer, deuterated product, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, an intermediate of the compound, and a preparation method for the compound, as well as an application in the preparation of a drug for preventing or treating diseases related to KRAS G12C activity or amount of expression.

Description

一种嘧啶并环衍生物及其在医药上的应用A kind of pyrimido ring derivative and its application in medicine 技术领域Technical field
本发明涉及通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，及其中间体和制备方法，以及在制备预防或治疗与KRAS G12C活性或表达量相关疾病的药物中的应用。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.
背景技术Background technique
RAS蛋白由RAS基因(Rat Sarcoma viral oncogene)表达，是细胞内鸟嘌呤核苷酸结合蛋白，属于GTP酶(水解活性较弱)。RAS蛋白存在于两种不同的状态：非活性的的GDP结合状态和活性的GTP结合状态。激活态的RAS蛋白通过与不同下游效应器相互作用进行信号传导，对细胞的生长、分化、细胞骨架、蛋白质运输和分泌等都具有影响。RAS信号传导的激活受鸟嘌呤核苷酸交换因子(GEF，可导致GDP-GTP交换)或者GTP酶活化蛋白(GAP，可导致RAS蛋白由活化态转变为失活态)的调节，突变型RAS蛋白可致对GAP的抵抗导致RAS蛋白处于持续激活状态，引起细胞不受控制的生长，最终发展为癌变组织(Molecular Cancer,2018,17:33)。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). Mutant RAS The protein can cause resistance to GAP and cause the RAS protein to be continuously activated, causing uncontrolled cell growth, and eventually developing into cancerous tissue (Molecular Cancer, 2018, 17: 33).
RAS基因突变是癌症患者中常见的基因突变类型(Nat.Rev.Drug Discov.2014,13,828-851)，例如RAS基因突变在胰腺癌、结直肠癌、多发性骨髓瘤及NSLCL中分别占到了97.7％，52.2％，42.6％及32.2％。KARS基因(Kristen Rat Sarcoma viral oncogene)突变是RAS突变中影响最大的突变，占到所有RAS突变的86％。KRAS基因被激活最常见的方式是点突变，95％的KRAS突变主要发生在2号外显子的第12号密码子和13号密码子上，常见的突变形式有KRAS G12C突变(39％)，KRAS G12V(18-21％)和KRAS G12D(17-18％)突变。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.
自发现癌症中的KRAS突变蛋白并且观察到抑制这些突变蛋白能抑制肿瘤增殖以来，KRAS突变蛋白抑制剂就受到了广泛关注。KRAS长期以来被认为是一个“不可成药靶点”：RAS对GTP/GDP具有很高的亲和力(皮摩尔级别)，整个蛋白也缺少其他的“配体结合口袋”(Clin.Cancer Res.2015,21,1810–1818)。在KRAS G12C突变蛋白中，鉴定发现紧邻GTP/GDP-RAS结合口袋处出现了一个“结合口袋II”(Nature.2013,503,548-551)，可以作为KRAS G12C突变蛋白抑制剂的结合位点。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.
发明内容Summary of the invention
本发明的目的之一在于提供一种KRAS G12C蛋白的抑制剂。One of the objectives of the present invention is to provide an inhibitor of KRAS G12C protein.
特别地，本发明提供了能够抑制KRAS G12C蛋白的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐。本发明还提供了所述化合 物的中间体和制备方法，以及所述化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐在制备预防或治疗与KRAS G12C活性或表达量相关疾病的药物中的应用。In particular, 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.
本发明提供通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中The present invention provides a compound of general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
Figure PCTCN2020128033-appb-000001
Figure PCTCN2020128033-appb-000001
在一些实施方案中，R 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2、
Figure PCTCN2020128033-appb-000002
-S(＝O) 2-C(R 1a)＝C(R 1b) 2或
Figure PCTCN2020128033-appb-000003
In some embodiments, R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ,
Figure PCTCN2020128033-appb-000002
-S(=O) 2 -C(R 1a )=C(R 1b ) 2 or
Figure PCTCN2020128033-appb-000003
在一些实施方案中，R 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2； In some embodiments, R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ;
在一些实施方案中，R 1选自
Figure PCTCN2020128033-appb-000004
Figure PCTCN2020128033-appb-000005
In some embodiments, R 1 is selected from
Figure PCTCN2020128033-appb-000004
Figure PCTCN2020128033-appb-000005
在一些实施方案中，R 1a各自独立地选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-NHC(＝O)R 1d，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, each R 1a is independently selected from H, F, Cl, Br, I, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, or -NHC(=O) R 1d , the alkyl group or alkoxy 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, Substituted by 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 ；
在一些实施方案中，R 1a选自H、F或C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 1a选自H、F、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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
在一些实施方案中，R 1b或R 1c各自独立地选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基、C 1-4烷氧基、-C(＝O)N(R 1d) 2、-(CH 2) p-N(C 1-4烷基) 2、-(CH 2) pNHC(＝O)-C 1-4烷基、-(CH 2) p-C 3-10碳环或-(CH 2) p-3至12元杂环，所述的烷基、烷氧基、杂环或碳环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-10碳环或5至12元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, R 1b or R 1c are each independently selected from H, F, Cl, Br, I, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, -C( ＝O)N(R 1d ) 2 , -(CH 2 ) p -N(C 1-4 alkyl) 2 , -(CH 2 ) p NHC(=O)-C 1-4 alkyl, -(CH 2 ) p -C 3-10 carbocyclic ring or -(CH 2 ) p -3 to 12 membered heterocyclic ring, said alkyl, alkoxy, heterocyclic or carbocyclic 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 3-10 carbocyclic or 5 to 12-membered heterocyclic substituents, the heterocyclic ring Containing 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
在一些实施方案中，R 1b各自独立地选自H、C 1-4烷基或-(CH 2) p-3至6元杂环，所述的烷基或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或3至6元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4)选自O、S、N的杂原子； In some embodiments, 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. 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, C 1-4 alkoxy, C 3-6 carbocyclic or 3- to 6-membered heterocyclic substituent substituted by The heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S and N;
在一些实施方案中，R 1b各自独立地选自H、甲基、乙基、丙基、异丙基、-CH 2-4元含氮杂环、-CH 2-5元含氮杂环、-CH 2-6元含氮杂环、4元含氮杂环、5元含氮杂环或6元含氮杂环，所述的甲基、乙基、丙基、异丙基或含氮杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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). -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituents;
在一些实施方案中，R 1c选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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 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 1-4 alkyl or C 1-4 alkoxy substituent;
在一些实施方案中，R 1a与任意一个R 1b形成C 5-10碳环或5至12元杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-10碳环基或5至12元杂环基的取代基所取代，所述的杂环基含有1至4个(例如1、2、3或4)选自O、S、N的杂原子； In some embodiments, R 1a and any one of R 1b form a C 5-10 carbocyclic ring or 5 to 12 membered heterocyclic ring, and 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;
在一些实施方案中，R 1d各自独立地选自H或C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，环A选自4至12元含氮杂环，所述的含氮杂环选自饱和或部分饱和的如下基团之一：单环、并环、桥环或螺环，所述的含氮杂环、单环、并环、桥环或螺环任选进一步被0至4个(例如0、1、2、3或4个)R a取代； In some embodiments, ring A is selected from a 4- to 12-membered nitrogen-containing heterocyclic ring, and 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;
在一些实施方案中，环A选自4至9元含氮杂环，所述的含氮杂环选自饱和或部分饱和如下结构之一：单环、并环、桥环或螺环，所述的含氮杂环任选进一步被0至4个(例如0、1、2、3或4个)R a取代基所取代； In some embodiments, 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;
在一些实施方案中，R a各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，环A选自未被取代的或者取代的
Figure PCTCN2020128033-appb-000006
Figure PCTCN2020128033-appb-000007
Figure PCTCN2020128033-appb-000008
当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)R a取代基所取代； In some embodiments, ring A is selected from unsubstituted or substituted
Figure PCTCN2020128033-appb-000006
Figure PCTCN2020128033-appb-000007
Figure PCTCN2020128033-appb-000008
When substituted, optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) R a substituents;
在一些实施方案中，环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2020128033-appb-000009
Figure PCTCN2020128033-appb-000010
当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、氰基、OH、CF 3、甲基、乙基、丙基、异丙基或CH 2CN的取代基所取代； In some embodiments, ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2020128033-appb-000009
Figure PCTCN2020128033-appb-000010
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;
在一些实施方案中，环A选自
Figure PCTCN2020128033-appb-000011
Figure PCTCN2020128033-appb-000012
In some embodiments, ring A is selected from
Figure PCTCN2020128033-appb-000011
Figure PCTCN2020128033-appb-000012
在一些实施方案中，环A选自
Figure PCTCN2020128033-appb-000013
Figure PCTCN2020128033-appb-000014
In some embodiments, ring A is selected from
Figure PCTCN2020128033-appb-000013
Figure PCTCN2020128033-appb-000014
在一些实施方案中，R a各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，Q、M和与二者直接相连接的原子一起形成C 3-12碳环或者3至12元的杂环，所述的碳环或者杂环为单环、并环或者螺环，所述的碳环、杂环、单环、并环或者螺环任选进一步被0至5(例如0、1、2、3、4或5)个R 2取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, Q, M and the atoms directly connected to the two together form a C 3-12 carbocyclic ring or a 3 to 12-membered heterocyclic ring, and 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;
在一些实施方案中，Q、M和与二者直接相连接的原子一起形成
Figure PCTCN2020128033-appb-000015
Figure PCTCN2020128033-appb-000016
环B选自非芳香4至7元杂环，所述的杂环含有1至4(例如1、2、3或4个)个选自O、S、N的杂原子，X 1选自N，环C和环D一起形成C 6-12碳环并环或5至12元杂环并环，所述的杂环并环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子，m1选自0、1、2、3或4，m2、m3各自独立地选自0、1、2、3或4，且m2+m3≤5； In some embodiments, Q, M and the atoms directly connected to the two together form
Figure PCTCN2020128033-appb-000015
Figure PCTCN2020128033-appb-000016
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;
在一些实施方案中，Q、M和与二者直接相连接的原子一起形成
Figure PCTCN2020128033-appb-000017
Figure PCTCN2020128033-appb-000018
环B选自氮杂环丁烷、氮杂环戊烷、哌啶或咪唑烷，环D选自苯环、吡啶、哒嗪或嘧啶；环C选自C 4-6碳环、4至6元杂环,所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, Q, M and the atoms directly connected to the two together form
Figure PCTCN2020128033-appb-000017
Figure PCTCN2020128033-appb-000018
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;
在一些实施方案中，Q、M和与二者直接相连接的原子一起形成
Figure PCTCN2020128033-appb-000019
环B选自哌啶； In some embodiments, Q, M and the atoms directly connected to the two together form
Figure PCTCN2020128033-appb-000019
Ring B is selected from piperidine;
在一些实施方案中，Q、M和与二者直接相连接的原子一起形成
Figure PCTCN2020128033-appb-000020
Figure PCTCN2020128033-appb-000021
In some embodiments, Q, M and the atoms directly connected to the two together form
Figure PCTCN2020128033-appb-000020
Figure PCTCN2020128033-appb-000021
在一些实施方案中，Q、M和与二者直接相连接的原子一起形成
Figure PCTCN2020128033-appb-000022
Figure PCTCN2020128033-appb-000023
选自
Figure PCTCN2020128033-appb-000024
Figure PCTCN2020128033-appb-000025
In some embodiments, Q, M and the atoms directly connected to the two together form
Figure PCTCN2020128033-appb-000022
Figure PCTCN2020128033-appb-000023
Selected from
Figure PCTCN2020128033-appb-000024
Figure PCTCN2020128033-appb-000025
在一些实施方案中，
Figure PCTCN2020128033-appb-000026
选自
Figure PCTCN2020128033-appb-000027
Figure PCTCN2020128033-appb-000028
In some embodiments,
Figure PCTCN2020128033-appb-000026
Selected from
Figure PCTCN2020128033-appb-000027
Figure PCTCN2020128033-appb-000028
在一些实施方案中，Q、M和与二者直接相连接的原子一起形成
Figure PCTCN2020128033-appb-000029
Figure PCTCN2020128033-appb-000030
G 1-G 2选自-CH 2CH 2-、-CH＝CH-、-C(＝O)-NH-、-C(＝O)-N(CH 3)-、-N(CH 3)-C(＝O)-或者-NH-C(＝O)-,m2选自0、1、2或3； In some embodiments, Q, M and the atoms directly connected to the two together form
Figure PCTCN2020128033-appb-000029
Figure PCTCN2020128033-appb-000030
G 1- G 2 is selected from -CH 2 CH 2 -, -CH=CH-, -C(=O)-NH-, -C(=O)-N(CH 3 )-, -N(CH 3 ) -C(=O)- or -NH-C(=O)-, m2 is selected from 0, 1, 2 or 3;
在一些实施方案中，Q、M和与二者直接相连接的原子一起形成
Figure PCTCN2020128033-appb-000031
Figure PCTCN2020128033-appb-000032
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基，所述的甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代，m2选自0、1、2或3； In some embodiments, Q, M and the atoms directly connected to the two together form
Figure PCTCN2020128033-appb-000031
Figure PCTCN2020128033-appb-000032
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 substituent substituted, m2 is selected from 0, 1, 2 or 3;
在一些实施方案中，R 2各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-3至8元杂环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个选自O、S、N的杂原子； In some embodiments, each R 2 is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, -C(=O)NR 2A R 2B , -NR 2AC (=O)R 2C , -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)-3 to 8-membered heterocycloalkane Group, -C(=O)-C 6-10 aryl, -C(=O)-5 to 10-membered heteroaryl, 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. 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(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , 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, C 6-10 aryl Substituted by a group or a substituent of a 5- to 10-membered heteroaryl group, the heterocycloalkyl group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
在一些实施方案中，R 2各自独立地选自R 2a、R 2b、R 2c、R 2d； In some embodiments, each R 2 is independently selected from R 2a , R 2b , R 2c , R 2d ;
在一些实施方案中，R 2a选自H、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-3至8元杂环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, R 2a is selected from H, COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)-3 to 8-membered heterocycloalkyl, -C(=O)-C 6-10 aryl, -C(=O ) -5 to 10 membered heteroaryl, 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, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl 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(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxyl substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, C 6-10 aryl or 5 to 10-membered heteroaryl substituents, the heterocycloalkane The radical or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
在一些实施方案中，R 2a选自H、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-4烷基、-C(＝O)-苯基、-C(＝O)-5至6元杂芳基、C 1-4烷基、C 3-6环烷基、3至8元杂环 烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, R 2a is selected from H, COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-4 alkyl, -C(=O)-phenyl, -C(=O)-5 to 6-membered heteroaryl, C 1-4 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) 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(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -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, C 6-10 aryl or 5 to 10-membered heteroaryl substituents, said The heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
在一些实施方案中，R 2a选自H或者取代的或者未被取代的如下基团之一：-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-CH 2CH 2CH 3、-C(＝O)-CH(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、-C(＝O)-苯基、-C(＝O)-吡啶、-C(＝O)-噻吩、-C(＝O)-呋喃、-C(＝O)-吡咯、甲基、乙基、异丙基、丙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、噻吩基、呋喃基、吡咯基、噻唑基、异噻唑基、噁唑基、异噁唑基、咪唑基、吡唑基、苯并咪唑基、苯并吡唑基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、C 1-4烷基、C 1-4烷氧基或C 2-4炔基的取代基所取代； In some embodiments, R 2a is selected from H or one of the following substituted or unsubstituted groups: -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH- CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O)-CH(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(= O)-pyridine, -C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzo Imidazolyl, benzopyrazolyl 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 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O )NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C( =0) NH-phenyl, -NHC(=O)-phenyl, C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl substituents;
在一些实施方案中，R 2a选自H或者取代的或者未被取代的如下基团之一：-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-CH 2CH 2CH 3、-C(＝O)-CH(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、-C(＝O)-苯基、-C(＝O)-吡啶、-C(＝O)-噻吩、-C(＝O)-呋喃、-C(＝O)-吡咯、甲基、乙基、异丙基、丙基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基或乙基的取代基所取代； In some embodiments, R 2a is selected from H or one of the following substituted or unsubstituted groups: -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH- CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O)-CH(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(= O)-pyridine, -C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl , 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 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(= O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C (=O) NH-phenyl, -NHC(=O)-phenyl, methyl or ethyl substituents;
在一些实施方案中，R 2a选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C 1-6烷基、C 2-6炔基、C 1-6烷氧基、C 3-6环 烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, 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 or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
在一些实施方案中，R 2a选自H或者取代的或者未被取代的如下基团之一：甲基、乙基、异丙基、丙基、环丙基、环丁基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、NH 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基或苯基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 2b各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH或C 1-6烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基或C 1-6烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 2b各自独立地选自H、F、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 2b各自独立地选自H、F、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 2c、R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、COOH、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, R 2c and R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , COOH, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)-C 6-10 Aryl, -C(=O)-5 to 10-membered heteroaryl, 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, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl 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(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , 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, C 6-10 aryl or 5 to 10 membered heteroaryl substituents Substitution, the heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
在一些实施方案中，R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6 炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, each R 2c is independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, -C(=O)NR 2A R 2B , -NR 2A C(= O) R 2C , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl 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) H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , 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, C 6-10 Substituted by an aryl group or a 5- to 10-membered heteroaryl group, the heterocycloalkyl group or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) selected from O, S, N Heteroatom
在一些实施方案中，R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、--C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代； In some embodiments, R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C (=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N (CH 3 ) 2 , --C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methyl Oxy or ethoxy, the methyl, ethyl, methoxy, ethoxy or phenyl 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 , C 1-4 alkyl, C 1-4 alkoxy substituents;
在一些实施方案中，R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； In some embodiments, R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C (=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N (CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy Group or ethoxy group, the methyl group, ethyl group, methoxy group, ethoxy group or phenyl group is optionally further selected from 0 to 4 (for example, 0, 1, 2, 3 or 4) from H, Substituted by F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl substituents;
在一些实施方案中，R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基或乙氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个1、2、3或4个选自O、S、N的杂原子； In some embodiments, 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. 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 Substituted by substituents of 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, said heterocycloalkyl Or the heteroaryl group contains 1 to 4 1, 2, 3 or 4 heteroatoms selected from O, S and N;
在一些实施方案中，R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基，所述的甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代； In some embodiments, 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) Substituted by H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl, and C 1-4 alkoxy substituents;
在一些实施方案中，R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2或C 1-6烷基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； In some embodiments, 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
在一些实施方案中，R 2A、R 2B或R 2C各自独立地选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基的取代基所取代，所述的杂环烷基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, 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. 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 The heterocycloalkyl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
在一些实施方案中，X 3选自键、O、-OCH 2-、-CH 2O-、S或NR x； In some embodiments, X 3 is selected from bond, O, -OCH 2 -, -CH 2 O-, S or NR x ;
在一些实施方案中，X 3选自键或O； In some embodiments, X 3 is selected from bond or O;
在一些实施方案中，R x选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代；0至4个(例如0、1、2、3或4个) In some embodiments, 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)
在一些实施方案中，R 3选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1- 6烷基、C 1-6烷氧基、N(R 3a) 2、-(CH 2) q-C(＝O)C 1-6烷基、-(CH 2) q-C(＝O)-3至12元杂环、-(CH 2) q-C(＝O)-C 3-10碳环、-(CH 2) q-C(＝O)-N(R 3a) 2、-(CH 2) q-N(R 3a)-C(＝O)R 3b、-(CH 2) q-3至12元杂环或-(CH 2) q-C 3-10碳环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2) q-C 3-10碳环、-(CH 2) q-3至12元杂环、C 3-6环烷基、C 1-4烷氧基、-N(C 1-4烷基)C(＝O)-3至12元杂 环或3至12元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, R 3 is selected from H, F, Cl, Br, I, OH, cyano, CF 3, COOH, NH 2 , C 1- 6 alkyl, C 1-6 alkoxy, N ( R 3a ) 2 , -(CH 2 ) q -C(=O)C 1-6 alkyl, -(CH 2 ) q -C(=O) -3 to 12-membered heterocyclic ring, -(CH 2 ) q -C(=O)-C 3-10 carbocyclic ring, -(CH 2 ) q -C(=O)-N(R 3a ) 2 , -(CH 2 ) q -N(R 3a )-C(= O) R 3b , -(CH 2 ) q -3 to 12-membered heterocyclic ring or -(CH 2 ) q -C 3-10 carbocyclic ring, said CH 2 , alkyl, alkoxy, carbocyclic or hetero The ring 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 ,- NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , C 1-4 alkyl, -C 1-4 alkylene-OH, -(CH 2 ) q -C 3- 10- carbon ring, -(CH 2 ) q -3 to 12-membered heterocycle, C 3-6 cycloalkyl, C 1-4 alkoxy, -N(C 1-4 alkyl)C(=O)- Substituted by a 3- to 12-membered heterocyclic ring or a substituent of a 3- to 12-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, and N ；
在一些实施方案中，R 3选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、-N(CH 3) 2、-N(CH 2CH 3) 2、-(CH 2) q-环丙烷、-(CH 2) q-环丁烷、-(CH 2) q-环戊烷、-(CH 2) q-环己烷、-(CH 2) q-氮杂环丁烷、-(CH 2) q-氧杂环丁烷、-(CH 2) q-四氢噻吩、-(CH 2) q-四氢呋喃、-(CH 2) q-四氢吡咯、-(CH 2) q-苯基、-(CH 2) q-萘基、-(CH 2) q-吡啶、-(CH 2) q-嘧啶、-(CH 2) q-吡嗪、-(CH 2) q-噻吩、-(CH 2) q-呋喃、-(CH 2) q-吡咯、-(CH 2) q-咪唑、-(CH 2) q-咪唑、-(CH 2) q-吡唑、-(CH 2) q-三氮唑、-(CH 2) q-四氮唑、-(CH 2) q-哌啶、-(CH 2) q-吗啉、-(CH 2) q-四氢吡喃、-(CH 2) q-吡咯双烷、-(CH 2) q-1,3-氧氮杂环庚烷、-(CH 2) q-2-氧杂-5-氮杂双环[2.2.1]庚烷、-(CH 2) q-哌嗪或-(CH 2) q-N(R 3a)-C(＝O)R 3b，当被取代时，任选被0、1、2、3或4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2) q-C 3-6碳环、-(CH 2) q-3至6元杂环、C 3-6环烷基、C 1-4烷氧基、-N(C 1-4烷基)C(＝O)-3至12元杂环或3至12元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, 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, -(CH 2 ) q -naphthyl, -(CH 2 ) q- pyridine, -(CH 2 ) q -pyrimidine, -(CH 2 ) q -pyrazine, -(CH 2 ) q -thiophene, -(CH 2 ) q -furan, -(CH 2 ) q -pyrrole, -(CH 2 ) q -imidazole , -(CH 2 ) q -imidazole, -(CH 2 ) q -pyrazole, -(CH 2 ) q -triazole, -(CH 2 ) q -tetrazolium, -(CH 2 ) q -piper Pyridine, -(CH 2 ) q -morpholine, -(CH 2 ) q -tetrahydropyran, -(CH 2 ) q -pyrrolidine, -(CH 2 ) q -1,3-oxazepine Heptane, -(CH 2 ) q -2-oxa-5-azabicyclo[2.2.1]heptane, -(CH 2 ) q -piperazine or -(CH 2 ) q -N(R 3a ) -C(=O)R 3b , when substituted, optionally 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 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -3 to 6-membered heterocyclic ring, C 3-6 cycloalkyl, C 1-4 alkoxy, -N (C 1-4 alkyl) C (=O) substituted by a substituent of a -3 to 12-membered heterocyclic ring or a 3 to 12-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 (for example, 1, 2, 3 or 4) selected from O, S , N heteroatoms;
在一些实施方案中，R 3选自H或者取代的或者未取代的如下基团之一：甲基、乙基、-(CH 2) q-四氢吡咯、-(CH 2) q-氮杂环丁烷、-N(CH 3) 2或-N(CH 2CH 3) 2，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2)q-C 3-6碳环、-(CH 2)q-3至6元杂环、C 3-6环烷基或C 1-4烷氧基，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, 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, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S and N;
在一些实施方案中，R 3a各自独立地选自H、C 1-4烷基、-C 1-4烷基-3至12元杂环，所述的烷基或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，R 3a选自H、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基取代基所取代； In some embodiments, 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;
在一些实施方案中，两个R 3a和与二者直接相连的氮原子一起形成4至8元含氮杂环，所述的含氮杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、 I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, two R 3a and the nitrogen atom directly connected to the two together form a 4- to 8-membered nitrogen-containing heterocyclic ring, and 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;
在一些实施方案中，R 3b选自H、C 1-6烷基、C 3-6环烷基或3至12元杂环，所述的烷基、环烷基或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，R 3b选自H、甲基、乙基、丙基、异丙基、氮杂环丁烷或氧杂环丁烷，所述的甲基、乙基、丙基、异丙基、氮杂环丁烷或氧杂环丁烷任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基取代基所取代； In some embodiments, 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;
在一些实施方案中，R 3选自-CH 2N(CH 3) 2、-CH 2N(CH 2CH 3) 2、-N(CH 2CH 3) 2、-N(CH 3) 2、
Figure PCTCN2020128033-appb-000033
Figure PCTCN2020128033-appb-000034
In some embodiments, 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 ,
Figure PCTCN2020128033-appb-000033
Figure PCTCN2020128033-appb-000034
在一些实施方案中，X 3-R 3选自
Figure PCTCN2020128033-appb-000035
Figure PCTCN2020128033-appb-000036
In some embodiments, X 3 -R 3 is selected from
Figure PCTCN2020128033-appb-000035
Figure PCTCN2020128033-appb-000036
在一些实施方案中，R 4各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3或C 1-6烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R 4各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3或甲基； In some embodiments, each R 4 is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 or methyl;
在一些实施方案中，n、p、q各自独立地选自0、1、2、3或4；In some embodiments, n, p, q are each independently selected from 0, 1, 2, 3, or 4;
在一些实施方案中，n选自0；In some embodiments, n is selected from 0;
在一些实施方案中，m2选自0、1、2或3。In some embodiments, m2 is selected from 0, 1, 2, or 3.
作为本发明的第一种实施方案，上述通式(I)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As a first embodiment of the present invention, the compound of the above general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
R 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2、
Figure PCTCN2020128033-appb-000037
-S(＝O) 2-C(R 1a)＝C(R 1b) 2或
Figure PCTCN2020128033-appb-000038
R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ,
Figure PCTCN2020128033-appb-000037
-S(=O) 2 -C(R 1a )=C(R 1b ) 2 or
Figure PCTCN2020128033-appb-000038
R 1a各自独立地选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-NHC(＝O)R 1d，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； R 1a is each independently selected from H, F, Cl, Br, I, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -NHC(=O)R 1d , said Alkyl or alkoxy 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 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , C 1-4 alkyl or C 1-4 alkoxy substituents;
R 1b或R 1c各自独立地选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基、C 1-4烷氧基、-C(＝O)N(R 1d) 2、-(CH 2) p-N(C 1-4烷基) 2、-(CH 2) pNHC(＝O)-C 1-4烷基、-(CH 2) p-C 3-10碳环或-(CH 2) p-3至12元杂环，所述的烷基、烷氧基、杂环或碳环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-10碳环或5至12元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； R 1b or R 1c are each independently selected from H, F, Cl, Br, I, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, -C(=O)N(R 1d ) 2 , -(CH 2 ) p -N(C 1-4 alkyl) 2 , -(CH 2 ) p NHC(=O)-C 1-4 alkyl, -(CH 2 ) p -C 3 -10 carbocyclic ring or -(CH 2 ) p -3 to 12 membered heterocyclic ring, said alkyl, alkoxy, heterocyclic or carbocyclic 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 , -NH (C 1-4 alkyl), -N (C 1-4 Alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-10 carbocyclic or 5 to 12-membered heterocyclic substituents, the heterocyclic ring contains 1 to 4 ( For example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;
作为选择，R 1a与任意一个R 1b形成C 5-10碳环或5至12元杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-10碳环基或5至12元杂环基的取代基所取代，所述的杂环基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； Alternatively, R 1a and any one of R 1b form a C 5-10 carbocyclic ring or a 5- to 12-membered heterocyclic ring, and 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各自独立地选自H或C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
环A选自4至12元含氮杂环，所述的含氮杂环选自饱和或部分饱和的如下基团之一：单环、并环、桥环或螺环，所述的含氮杂环、单环、并环、桥环或螺环任选进一步被0至4个(例如0、1、2、3或4个)R a取代； 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各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
Q、M和与二者直接相连接的原子一起形成C 3-12碳环或者3至12元的杂环，所述的碳环或者杂环为单环、并环或者螺环，所述的碳环、杂环、单环、并环或者螺环任选进一步被0至5个R 2取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； Q, M and the atoms directly connected to the two together form a C 3-12 carbocyclic ring or a 3 to 12-membered heterocyclic ring. 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;
R 2各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-3至8元杂环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； R 2 is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)-3 to 8-membered heterocycloalkyl, -C(= O) -C 6-10 aryl, -C (=O) -5 to 10-membered heteroaryl, 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. 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, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, -C(=O)NR 2A R 2B , -NR 2A C(=O ) Substituted by R 2C substituents, 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或R 2C各自独立地选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6- 10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基的取代基所取代，所述的杂环烷基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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, 2, 3, or 4) heteroatoms selected from O, S, and N;
X 3选自键、O、-OCH 2-、-CH 2O-、S或NR x； X 3 is selected from bond, O, -OCH 2 -, -CH 2 O-, S or NR x ;
R x选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 3选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-6烷基、C 1-6烷氧基、N(R 3a) 2、-(CH 2) q-C(＝O)C 1-6烷基、-(CH 2) q-C(＝O)-3至12元杂环、-(CH 2) q-C(＝O)-C 3-10碳环、-(CH 2) q-C(＝O)-N(R 3a) 2、-(CH 2) q-N(R 3a)-C(＝O)R 3b、-(CH 2) q-3至12元杂环或-(CH 2) q-C 3-10碳环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2) q-C 3-10碳环、-(CH 2) q-3至12元杂环、C 3-6环烷基、C 1-4烷氧基、-N(C 1-4烷基)C(＝O)-3至12元杂环或3至12元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； R 3 is selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, N(R 3a ) 2 ,- (CH 2 ) q -C(=O)C 1-6 alkyl, -(CH 2 ) q -C(=O)-3 to 12-membered heterocyclic ring, -(CH 2 ) q -C(=O) -C 3-10 carbocyclic ring, -(CH 2 ) q -C(=O)-N(R 3a ) 2 , -(CH 2 ) q -N(R 3a )-C(=O)R 3b ,- (CH 2 ) q -3 to 12-membered heterocyclic ring or -(CH 2 ) q -C 3-10 carbocyclic ring, said CH 2 , alkyl, alkoxy, carbocyclic 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, 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 ) q -C 3-10 carbocyclic ring, -( CH 2 ) q -3 to 12-membered heterocyclic ring, C 3-6 cycloalkyl, C 1-4 alkoxy, -N(C 1-4 alkyl)C(=O)-3 to 12-membered heterocyclic ring Or substituted by a substituent of a 3- to 12-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
R 3a各自独立地选自H、C 1-4烷基、-C 1-4烷基-3至12元杂环，所述的烷基或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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;
作为选择，两个R 3a和与二者直接相连的氮原子一起形成4至8元含氮杂环，所述的含氮杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； Alternatively, two R 3a and the nitrogen atom directly connected to the two together form a 4- to 8-membered nitrogen-containing heterocyclic ring, and 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选自H、C 1-6烷基、C 3-6环烷基或3至12元杂环，所述的烷基、环烷基或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3或C 1-6烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立地选自0、1、2、3或4。n, p, q are each independently selected from 0, 1, 2, 3, or 4.
作为本发明的第二种实施方案，下述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the second embodiment of the present invention, the compound of the following general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,among them
Figure PCTCN2020128033-appb-000039
Figure PCTCN2020128033-appb-000039
环B选自非芳香4至7元杂环，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子；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选自N； X 1 is selected from N;
R 2a选自H、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-3至8元杂环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； R 2a is selected from H, COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-6 alkyl, -C(=O) -C 3-6 cycloalkyl, -C(=O)-3 to 8-membered heterocycloalkyl, -C(=O)-C 6-10 aryl, -C(=O)-5 to 10-membered Heteroaryl, 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 , 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, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -C( =0)NR 2A R 2B , -NR 2A C(=O)R 2C , 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, C 6-10 aryl or 5 to 10 membered heteroaryl substituents, the heterocycloalkyl or heteroaryl contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;
R 2b各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH或C 1-6烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基或C 1-6烷氧基的取代基所取代； 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;
环C和环D一起形成C 6-12碳环并环或5至12元杂环并环，所述的杂环并环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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 2c、R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、COOH、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； R 2c and R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , COOH, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)-C 6-10 aryl, -C( =0)-5 to 10-membered heteroaryl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C 6-10 aryl Or a 5- to 10-membered heteroaryl group, the alkyl group, alkoxy 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) 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(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxyl Substituted by substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl substituents, the hetero Cycloalkyl or heteroaryl groups contain 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
R 2A、R 2B或R 2C各自独立地选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6- 10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基的取代基所取代，所述的杂环烷基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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, 2, 3, or 4) heteroatoms selected from O, S, and N;
m1选自0、1、2、3或4；m1 is selected from 0, 1, 2, 3 or 4;
m2、m3各自独立地选自0、1、2、3或4，且m2+m3≤5；m2 and m3 are each independently selected from 0, 1, 2, 3 or 4, and m2+m3≤5;
其余基团的定义与第一种实施方案相同。The definitions of the remaining groups are the same as in the first embodiment.
作为本发明的第三种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the third embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or its stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, among them
R 1c选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
环A选自4至9元含氮杂环，所述的含氮杂环选自饱和或部分饱和如下结构之一：单环、并环、桥环或螺环，所述的含氮杂环任选进一步被0至4个(例如0、1、2、3或4个)R a取代基所取代； 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各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
其余基团的定义与第二种实施方案相同。The definitions of the remaining groups are the same as in the second embodiment.
作为本发明的第四种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As a fourth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, among them
环A选自未被取代的或者取代的
Figure PCTCN2020128033-appb-000040
Figure PCTCN2020128033-appb-000041
Figure PCTCN2020128033-appb-000042
当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)R a取代基所取代； Ring A is selected from unsubstituted or substituted
Figure PCTCN2020128033-appb-000040
Figure PCTCN2020128033-appb-000041
Figure PCTCN2020128033-appb-000042
When substituted, optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) R a substituents;
R a各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
其余基团的定义与第三种实施方案相同。The definitions of the remaining groups are the same as in the third embodiment.
作为本发明的第五种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the fifth embodiment of the present invention, the compound of general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, among them
环B选自氮杂环丁烷、氮杂环戊烷或哌啶；Ring B is selected from azetidine, azetidine or piperidine;
或者环B选自咪唑烷；Or ring B is selected from imidazolidine;
R 2a选自H、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-4烷基、-C(＝O)-苯基、-C(＝O)-5至6元杂芳基、C 1-4烷基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； R 2a is selected from H, COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-4 alkyl, -C(=O) -Phenyl, -C(=O)-5 to 6-membered heteroaryl, C 1-4 alkyl, C 3-6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C 6-10 aryl 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 (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(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -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, C 6-10 aryl or 5 to 10 membered heteroaryl substituents, said heterocycloalkyl or Heteroaryl groups contain 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
环D选自苯环、吡啶、哒嗪或嘧啶；Ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine;
环C选自C 4-6碳环； Ring C is selected from C 4-6 carbocyclic ring;
或者环C选自4至6元杂环,所述的杂环含有1至3个选自O、S、N的杂原子；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 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, the alkane Group, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 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 , -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , 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, C 6-10 aryl or 5 to 10 Substituents of a membered heteroaryl group, 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或R 2C各自独立地选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6- 10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基的取代基所取代，所述的杂环烷基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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, 2, 3, or 4) heteroatoms selected from O, S, and N;
R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2或C 1-6烷基的取代基所取代； 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;
其余基团的定义与第二、三或四种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any of the second, third, or four embodiments.
作为本发明的第六种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the sixth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, among them
R 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2； R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ;
R 1a选自H、F或C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立地选自H、C 1-4烷基或-(CH 2) p-3至6元杂环，所述的烷基或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或3至6元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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;
其余基团的定义与第二、三、四或五种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any of the second, third, fourth or fifth embodiments.
作为本发明的第七种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As a seventh embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, among them
R 1a选自H、F、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立地选自H、甲基、乙基、丙基、异丙基、-CH 2-4元含氮杂环、-CH 2-5元含氮杂环、-CH 2-6元含氮杂环、4元含氮杂环、5元含氮杂环或6元含氮杂环，所述的甲基、乙基、丙基、异丙基或含氮杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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. 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 substituents;
X 3选自键或O； X 3 is selected from bond or O;
R 2a选自H或者取代的或者未被取代的如下基团之一：-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-CH 2CH 2CH 3、-C(＝O)-CH(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、-C(＝O)-苯基、-C(＝O)-吡啶、-C(＝O)-噻吩、-C(＝O)-呋喃、-C(＝O)-吡咯、甲基、乙基、异丙基、丙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、噻吩基、呋喃基、吡咯基、噻唑基、异噻唑基、噁唑基、异噁唑基、咪唑基、吡唑基、苯并咪唑基、苯并吡唑基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、- C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、C 1-4烷基、C 1-4烷氧基或C 2-4炔基的取代基所取代； R 2a is selected from H or one of the substituted or unsubstituted groups: -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC( ＝O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O) N(CH 2 CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O )-CH(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine,- C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyridine Azolyl or pyridyl, when substituted, is optionally 0 to 4 (for example, 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 ,-C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-benzene Substituted by the substituents of the group, -NHC(=O)-phenyl, C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl;
R 2b各自独立地选自H、F、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
环C和环D一起形成的并环选自
Figure PCTCN2020128033-appb-000043
The combined ring formed by ring C and ring D is selected from
Figure PCTCN2020128033-appb-000043
或者环C和环D一起形成的并环选自
Figure PCTCN2020128033-appb-000044
Figure PCTCN2020128033-appb-000045
Or the combined ring formed by ring C and ring D is selected from
Figure PCTCN2020128033-appb-000044
Figure PCTCN2020128033-appb-000045
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、--C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH- CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , --C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy , The methyl, ethyl, methoxy, ethoxy or phenyl 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 , C 1-4 alkyl, C 1-4 alkoxy substituents;
R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、-N(CH 3) 2、-N(CH 2CH 3) 2、-(CH 2) q-环丙烷、-(CH 2) q-环丁烷、-(CH 2) q-环戊烷、-(CH 2) q-环己烷、-(CH 2) q-氮杂环丁烷、-(CH 2) q-氧杂环丁烷、-(CH 2) q-四氢噻吩、-(CH 2) q-四氢呋喃、-(CH 2) q-四氢吡咯、-(CH 2) q-苯基、-(CH 2) q-萘基、-(CH 2) q-吡啶、-(CH 2) q-嘧啶、-(CH 2) q-吡嗪、-(CH 2) q-噻吩、-(CH 2) q-呋喃、-(CH 2) q-吡咯、-(CH 2) q-咪唑、-(CH 2) q-咪唑、-(CH 2) q-吡唑、-(CH 2) q-三氮唑、-(CH 2) q-四氮唑、-(CH 2) q-哌啶、-(CH 2) q-吗啉、-(CH 2) q-四氢吡喃、-(CH 2) q-吡咯双烷、-(CH 2) q-1,3-氧氮杂环庚烷、-(CH 2) q-2-氧杂-5-氮杂双环[2.2.1]庚烷、-(CH 2) q-哌嗪或-(CH 2) q-N(R 3a)-C(＝O)R 3b，当被取代时，任选被0至 4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2) q-C 3-6碳环、-(CH 2) q-3至6元杂环、C 3-6环烷基、C 1-4烷氧基、-N(C 1-4烷基)C(＝O)-3至12元杂环或3至12元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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, -(CH 2 ) q -naphthyl, -(CH 2 ) q- pyridine, -(CH 2 ) q -pyrimidine,- (CH 2 ) q -pyrazine, -(CH 2 ) q -thiophene, -(CH 2 ) q -furan, -(CH 2 ) q -pyrrole, -(CH 2 ) q -imidazole, -(CH 2 ) q -imidazole, -(CH 2 ) q -pyrazole, -(CH 2 ) q -triazole, -(CH 2 ) q -tetrazole, -(CH 2 ) q -piperidine, -(CH 2 ) q -morpholine, -(CH 2 ) q -tetrahydropyran, -(CH 2 ) q -pyrrolidine, -(CH 2 ) q -1,3-oxazepin, -(CH 2 ) q -2-oxa-5-azabicyclo[2.2.1]heptane, -(CH 2 ) q -piperazine or -(CH 2 ) q -N(R 3a )-C(=O) R 3b , when substituted, is 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 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -3 to 6-membered heterocyclic ring, C 3-6 cycloalkyl, C 1-4 alkoxy, -N (C 1-4 alkyl) C(=O) is substituted by a substituent of a 3 to 12 membered heterocyclic ring or a 3 to 12 membered heterocyclic ring, and the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) selected from O, S and N heteroatoms;
R 3a选自H、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基取代基所取代； 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选自H、甲基、乙基、丙基、异丙基、氮杂环丁烷或氧杂环丁烷，所述的甲基、乙基、丙基、异丙基、氮杂环丁烷或氧杂环丁烷任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基取代基所取代； 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各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3或甲基； R 4 is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 or methyl;
q选自0、1、2、3或4；q is selected from 0, 1, 2, 3 or 4;
其余基团的定义与第二、三、四、五或六种实施方案中任意一种相同。The definitions of the remaining groups are the same as any of the second, third, fourth, fifth or sixth embodiments.
作为本发明的第八种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As an eighth embodiment of the present invention, the compound of general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, among them
R 1选自
Figure PCTCN2020128033-appb-000046
Figure PCTCN2020128033-appb-000047
R 1 is selected from
Figure PCTCN2020128033-appb-000046
Figure PCTCN2020128033-appb-000047
环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2020128033-appb-000048
当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、氰基、OH、CF 3、甲基、乙基、丙基、异丙基或CH 2CN的取代基所取代； Ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2020128033-appb-000048
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;
环B选自哌啶；Ring B is selected from piperidine;
或者
Figure PCTCN2020128033-appb-000049
选自
Figure PCTCN2020128033-appb-000050
Figure PCTCN2020128033-appb-000051
or
Figure PCTCN2020128033-appb-000049
Selected from
Figure PCTCN2020128033-appb-000050
Figure PCTCN2020128033-appb-000051
R 2a选自H或者取代的或者未被取代的如下基团之一：-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-CH 2CH 2CH 3、-C(＝O)-CH(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、-C(＝O)-苯基、-C(＝O)-吡啶、-C(＝O)-噻吩、-C(＝O)-呋喃、-C(＝O)-吡咯、甲基、乙基、异丙基、丙基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基或乙基的取代基所取代； R 2a is selected from H or one of the substituted or unsubstituted groups: -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC( ＝O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O) N(CH 2 CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O )-CH(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine,- C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furanyl , Pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH- Substituted by phenyl, -NHC(=O)-phenyl, methyl or ethyl substituents;
R 2b各自独立地选自H、F、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； 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 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH- CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy, The methyl, ethyl, methoxy, ethoxy or phenyl 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 , methyl or ethyl substituents;
R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； 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选自H或者取代的或者未取代的如下基团之一：甲基、乙基、-(CH 2) q-四氢吡咯、-(CH 2) q-氮杂环丁烷、-N(CH 3) 2或-N(CH 2CH 3) 2，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2)q-C 3-6碳环、-(CH 2)q- 3至6元杂环、C 3-6环烷基或C 1-4烷氧基，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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 , The heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S and N;
其余基团的定义与第二、三、四、五、六或七种实施方案中任意一种相同。The definitions of the remaining groups are the same as any of the second, third, fourth, fifth, sixth, or seventh embodiments.
作为本发明的第九种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As a ninth embodiment of the present invention, the compound of general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, among them
环A选自
Figure PCTCN2020128033-appb-000052
Figure PCTCN2020128033-appb-000053
Ring A is selected from
Figure PCTCN2020128033-appb-000052
Figure PCTCN2020128033-appb-000053
X 3选自O或键； X 3 is selected from O or bond;
R 3选自-CH 2N(CH 3) 2、-CH 2N(CH 2CH 3) 2、-N(CH 2CH 3) 2、-N(CH 3) 2、
Figure PCTCN2020128033-appb-000054
Figure PCTCN2020128033-appb-000055
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 ,
Figure PCTCN2020128033-appb-000054
Figure PCTCN2020128033-appb-000055
n选自0；n is selected from 0;
其余基团的定义与第二、三、四、五、六、七或八种实施方案中任意一种相同。The definitions of the remaining groups are the same as any of the second, third, fourth, fifth, sixth, seventh, or eight embodiments.
作为本发明的第十种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As a tenth embodiment of the present invention, the compound of the above general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, among them
环A选自
Figure PCTCN2020128033-appb-000056
Ring A is selected from
Figure PCTCN2020128033-appb-000056
X 3-R 3选自 X 3 -R 3 are selected from
Figure PCTCN2020128033-appb-000057
Figure PCTCN2020128033-appb-000057
n选自0；n is selected from 0;
其余基团的定义与第二、三、四、五、六、七、八或九种实施方案中任意一种相同。The definitions of the remaining groups are the same as any of the second, third, fourth, five, six, seven, eight, or ninth embodiments.
作为本发明的第十一种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the eleventh embodiment of the present invention, the compound of general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof ,among them
Figure PCTCN2020128033-appb-000058
选自
Figure PCTCN2020128033-appb-000059
Figure PCTCN2020128033-appb-000060
Figure PCTCN2020128033-appb-000058
Selected from
Figure PCTCN2020128033-appb-000059
Figure PCTCN2020128033-appb-000060
Figure PCTCN2020128033-appb-000061
选自
Figure PCTCN2020128033-appb-000062
Figure PCTCN2020128033-appb-000063
Figure PCTCN2020128033-appb-000061
Selected from
Figure PCTCN2020128033-appb-000062
Figure PCTCN2020128033-appb-000063
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基或乙氧基任选进一步被0至4个(例如0、1、2、3或 4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； 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选自0；n is selected from 0;
m2选自0、1、2或3；m2 is selected from 0, 1, 2 or 3;
其余基团的定义与第二、三、四、五、六、七、八、九或十种实施方案中任意一种相同。The definitions of the remaining groups are the same as any of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.
作为本发明的第十二种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the twelfth embodiment of the present invention, the compound of general formula (Ia) or (Ib) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof ,among them
环A选自
Figure PCTCN2020128033-appb-000064
Figure PCTCN2020128033-appb-000065
Ring A is selected from
Figure PCTCN2020128033-appb-000064
Figure PCTCN2020128033-appb-000065
X 3选自O或键； X 3 is selected from O or bond;
R 3选自-CH 2N(CH 3) 2、-CH 2N(CH 2CH 3) 2、-N(CH 2CH 3) 2、-N(CH 3) 2、
Figure PCTCN2020128033-appb-000066
Figure PCTCN2020128033-appb-000067
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 ,
Figure PCTCN2020128033-appb-000066
Figure PCTCN2020128033-appb-000067
n选自0；n is selected from 0;
其余基团的定义与第十一种实施方案相同。The definitions of the remaining groups are the same as in the eleventh embodiment.
作为本发明的第十三种实施方案，上述通式(Ia)或(Ib)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the thirteenth embodiment of the present invention, the compound of general formula (Ia) or (Ib) or its stereoisomers, deuteriums, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts ,among them
环A选自
Figure PCTCN2020128033-appb-000068
Ring A is selected from
Figure PCTCN2020128033-appb-000068
X 3-R 3选自
Figure PCTCN2020128033-appb-000069
Figure PCTCN2020128033-appb-000070
X 3 -R 3 are selected from
Figure PCTCN2020128033-appb-000069
Figure PCTCN2020128033-appb-000070
其余基团的定义与第十二种实施方案相同。The definitions of the remaining groups are the same as in the twelfth embodiment.
作为本发明的第十四种实施方案，下述通式(Ia-1)或(Ib-1)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the fourteenth embodiment of the present invention, 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
Figure PCTCN2020128033-appb-000071
Figure PCTCN2020128033-appb-000071
G 1-G 2选自-CH 2CH 2-、-CH＝CH-、-C(＝O)-NH-、-C(＝O)-N(CH 3)-、-N(CH 3)-C(＝O)-或者-NH-C(＝O)-； G 1- G 2 is selected from -CH 2 CH 2 -, -CH=CH-, -C(=O)-NH-, -C(=O)-N(CH 3 )-, -N(CH 3 ) -C(=O)- or -NH-C(=O)-;
R 2a选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C 1-6烷基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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. 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 alkyne Group, C 1-6 alkoxy, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, C 6-10 aryl or 5 to 10-membered heteroaryl substituents, said The heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N;
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、C 1-6烷基、C 1-6烷氧基、C 3- 6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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. 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, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl substituents, the heterocycloalkyl or heteroaryl group contains 1 Up to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N;
m2选自0、1、2或3；m2 is selected from 0, 1, 2 or 3;
其余基团的定义与第二、三、四、五、六、七或八种实施方案中任意一种相同。The definitions of the remaining groups are the same as any of the second, third, fourth, fifth, sixth, seventh, or eight embodiments.
作为本发明的第十五种实施方案，上述通式(Ia-1)或(Ib-1)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the fifteenth embodiment of the present invention, 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选自
Figure PCTCN2020128033-appb-000072
Figure PCTCN2020128033-appb-000073
R 1 is selected from
Figure PCTCN2020128033-appb-000072
Figure PCTCN2020128033-appb-000073
R 2a选自H或者取代的或者未被取代的如下基团之一：甲基、乙基、异丙基、丙基、环丙基、环丁基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、NH 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基或苯基的取代基所取代； 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各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基，所述的甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代； 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;
环A选自
Figure PCTCN2020128033-appb-000074
Ring A is selected from
Figure PCTCN2020128033-appb-000074
X 3-R 3选自
Figure PCTCN2020128033-appb-000075
Figure PCTCN2020128033-appb-000076
X 3 -R 3 are selected from
Figure PCTCN2020128033-appb-000075
Figure PCTCN2020128033-appb-000076
n选自0。n is selected from 0.
作为本发明的第十六种实施方案，下述通式(Ic-1)和(Ic-2)化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中As the sixteenth embodiment of the present invention, the following general formula (Ic-1) and (Ic-2) compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceuticals Acceptable salt, of which
Figure PCTCN2020128033-appb-000077
Figure PCTCN2020128033-appb-000077
各个基团的定义与本发明第二、三、四、五、六、七、八、九、十、十一、十二、十三、十四或十五种实施方案中任意一种相同。The definition of 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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中该化合物选自如下结构之一：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:
Figure PCTCN2020128033-appb-000078
Figure PCTCN2020128033-appb-000078
Figure PCTCN2020128033-appb-000079
Figure PCTCN2020128033-appb-000079
Figure PCTCN2020128033-appb-000080
Figure PCTCN2020128033-appb-000080
Figure PCTCN2020128033-appb-000081
Figure PCTCN2020128033-appb-000081
Figure PCTCN2020128033-appb-000082
Figure PCTCN2020128033-appb-000082
Figure PCTCN2020128033-appb-000083
Figure PCTCN2020128033-appb-000083
Figure PCTCN2020128033-appb-000084
Figure PCTCN2020128033-appb-000084
Figure PCTCN2020128033-appb-000085
Figure PCTCN2020128033-appb-000085
Figure PCTCN2020128033-appb-000086
Figure PCTCN2020128033-appb-000086
Figure PCTCN2020128033-appb-000087
Figure PCTCN2020128033-appb-000087
Figure PCTCN2020128033-appb-000088
Figure PCTCN2020128033-appb-000088
Figure PCTCN2020128033-appb-000089
Figure PCTCN2020128033-appb-000089
Figure PCTCN2020128033-appb-000090
Figure PCTCN2020128033-appb-000090
Figure PCTCN2020128033-appb-000091
Figure PCTCN2020128033-appb-000091
Figure PCTCN2020128033-appb-000092
Figure PCTCN2020128033-appb-000092
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自-C(＝O)-C(R 1a)＝C(R 1b) 2； R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ;
R 1a选自H、F或C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立地选自H或C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自-C(＝O)-C(R 1a)＝C(R 1b) 2； R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ;
R 1a选自H、F或C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立地选自H、C 1-4烷基或-(CH 2) p-3至6元杂环，所述的烷基或杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或3至6元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子。 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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐、(Ic-1)或(Ic-2)或共晶，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 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2； R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ;
R 1a选自H、F或C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立地选自H、C 1-4烷基或-(CH 2) p-4至6元含氮杂环，所述的烷基或含氮杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、 氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或3至6元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子。 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. 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, said The heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2； R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ;
R 1a选自H、F、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立地选自H、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2； R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ;
R 1a选自H、F、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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各自独立地选自H、甲基、乙基、丙基、异丙基、-CH 2-4元含氮杂环、-CH 2-5元含氮杂环、-CH 2-6元含氮杂环、4元含氮杂环、5元含氮杂环或6元含氮杂环，所述的甲基、乙基、丙基、异丙基或含氮杂环任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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. 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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自
Figure PCTCN2020128033-appb-000093
Figure PCTCN2020128033-appb-000094
R 1 is selected from
Figure PCTCN2020128033-appb-000093
Figure PCTCN2020128033-appb-000094
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2020128033-appb-000095
当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、氰基、OH、CF 3、甲基、乙基、丙基、异丙基或CH 2CN的取代基所取代。 Ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2020128033-appb-000095
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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
环A选自取代的或者未取代的如下基团之一：
Figure PCTCN2020128033-appb-000096
Figure PCTCN2020128033-appb-000097
当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、氰基、OH、CF 3、甲基、乙基、丙基、异丙基或CH 2CN的取代基所取代。 Ring A is selected from one of the following substituted or unsubstituted groups:
Figure PCTCN2020128033-appb-000096
Figure PCTCN2020128033-appb-000097
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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
环A选自未被取代的或者取代的如下结构之一：
Figure PCTCN2020128033-appb-000098
Figure PCTCN2020128033-appb-000099
Figure PCTCN2020128033-appb-000100
当被取代时，任选进一步被0至4个(例如0、1、2、3或4个)R a取取代； Ring A is selected from one of the following unsubstituted or substituted structures:
Figure PCTCN2020128033-appb-000098
Figure PCTCN2020128033-appb-000099
Figure PCTCN2020128033-appb-000100
When substituted, optionally further substituted with 0 to 4 (e.g. 2, 3 or 4) R a take-substituted;
R a各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
环A选自
Figure PCTCN2020128033-appb-000101
Figure PCTCN2020128033-appb-000102
Ring A is selected from
Figure PCTCN2020128033-appb-000101
Figure PCTCN2020128033-appb-000102
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自取代的或者未取代的如下基团之一：H、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、-N(CH 3) 2、-N(CH 2CH 3) 2、-(CH 2) q-环丙烷、-(CH 2) q-环丁烷、-(CH 2) q-环戊烷、-(CH 2) q-环己烷、-(CH 2) q-氮杂环丁烷、-(CH 2) q-氧杂环丁烷、-(CH 2) q-四氢噻吩、-(CH 2) q-四氢呋喃、-(CH 2) q-四氢吡咯、-(CH 2) q-苯基、-(CH 2) q-萘基、-(CH 2) q-吡啶、-(CH 2) q-嘧啶、-(CH 2) q-吡嗪、-(CH 2) q-噻吩、-(CH 2) q-呋喃、-(CH 2) q-吡咯、-(CH 2) q-咪唑、-(CH 2) q-咪唑、-(CH 2) q-吡唑、-(CH 2) q-三氮唑、-(CH 2) q-四氮唑、-(CH 2) q-哌啶、-(CH 2) q-吗啉、-(CH 2) q-四氢吡喃、-(CH 2) q-吡咯双烷、-(CH 2) q-1,3-氧氮杂环庚烷、-(CH 2) q-2-氧杂-5-氮杂双环[2.2.1]庚烷、-(CH 2) q-哌嗪或-(CH 2) q-N(R 3a)-C(＝O)R 3b，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2) q-C 3-6碳环、-(CH 2) q-3至6元杂环、C 3-6环烷基、C 1-4烷氧基、-N(C 1-4烷基)C(＝O)-3至12元杂环或3至12元杂环的取代基所取代，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； 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, -(CH 2 ) q -naphthyl, -(CH 2 ) q- pyridine, -(CH 2 ) q -pyrimidine,- (CH 2 ) q -pyrazine, -(CH 2 ) q -thiophene, -(CH 2 ) q -furan, -(CH 2 ) q -pyrrole, -(CH 2 ) q -imidazole, -(CH 2 ) q -imidazole, -(CH 2 ) q -pyrazole, -(CH 2 ) q -triazole, -(CH 2 ) q -tetrazole, -(CH 2 ) q -piperidine, -(CH 2 ) q -morpholine, -(CH 2 ) q -tetrahydropyran, -(CH 2 ) q -pyrrolidine, -(CH 2 ) q -1,3-oxazepin, -(CH 2 ) q -2-oxa-5-azabicyclo[2.2.1]heptane, -(CH 2 ) q -piperazine or -(CH 2 ) q -N(R 3a )-C(=O) R 3b , when substituted, is 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 ) q -C 3-6 carbocyclic ring, -(CH 2 ) q -3 to 6-membered heterocyclic ring, C 3-6 cycloalkyl, C 1-4 alkoxy, -N (C 1-4 alkyl) C(=O) is substituted by a substituent of a -3 to 12-membered heterocyclic ring or a 3 to 12-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 (for example, 1, 2, 3 or 4) selected from O, S and N heteroatoms;
R 3a选自H、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基取代基所取代； 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选自H、甲基、乙基、丙基、异丙基、氮杂环丁烷或氧杂环丁烷，所述的甲基、乙基、丙基、异丙基、氮杂环丁烷或氧杂环丁烷任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基取代基所取代。 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.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，R 3选自取代的或者未取代的如下基团之一：H、甲基、乙基、-(CH 2) q-四氢吡咯、-(CH 2) q-氮杂环丁烷、-N(CH 3) 2或-N(CH 2CH 3) 2，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2)q-C 3-6碳环、-(CH 2)q-3至6元杂环、C 3-6环烷基或C 1-4烷氧基，所述的杂环含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子。 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, 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. 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 group, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3 or 4) selected Heteroatoms from O, S, N.
本发明的一些实施例涉及通式(I)、(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自-CH 2N(CH 3) 2、-CH 2N(CH 2CH 3) 2、-N(CH 2CH 3) 2、-N(CH 3) 2、
Figure PCTCN2020128033-appb-000103
Figure PCTCN2020128033-appb-000104
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 ,
Figure PCTCN2020128033-appb-000103
Figure PCTCN2020128033-appb-000104
本发明的一些实施例涉及通式(Ia)、(Ib)、(Ia-1)、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，X 3-R 3选自
Figure PCTCN2020128033-appb-000105
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
Figure PCTCN2020128033-appb-000105
本发明的一些实施例涉及通式(Ia)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，环B选自氮杂环丁烷、氮杂环戊烷或哌啶。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 nitrogen Etidine, azolidine or piperidine.
本发明的一些实施例涉及通式(Ia)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
环B选自咪唑烷。Ring B is selected from imidazolidine.
本发明的一些实施例涉及通式(Ia)或(Ia-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自H、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-4烷基、-C(＝O)-3至8元杂环烷基、-C(＝O)-苯基、-C(＝O)-5至6元杂芳基、C 1-4烷基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C 1-6烷基、C 2-6炔基、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子； R 2a is selected from H, COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-4 alkyl, -C(=O) -3 to 8-membered heterocycloalkyl, -C(=O)-phenyl, -C(=O)-5 to 6-membered heteroaryl, C 1-4 alkyl, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl 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 1-6 alkyl, C 2-6 alkynyl, -C(=O)NR 2A R 2B , -NR 2A C(=O) R 2C , C 1-6 alkoxy, hydroxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered hetero Substituents of an aryl group, 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或R 2C各自独立地选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6- 10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、 COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基的取代基所取代，所述的杂环烷基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子。 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, 2, 3, or 4) heteroatoms selected from O, S, and N.
本发明的一些实施例涉及通式(Ia)或(Ia-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自取代的或者未被取代的如下基团之一：H、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、--C(＝O)N(CH 2CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-CH 2CH 2CH 3、-C(＝O)-CH(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、-C(＝O)-苯基、-C(＝O)-吡啶、-C(＝O)-噻吩、-C(＝O)-呋喃、-C(＝O)-吡咯、甲基、乙基、异丙基、丙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、噻吩基、呋喃基、吡咯基、噻唑基、异噻唑基、噁唑基、异噁唑基、咪唑基、吡唑基、苯并咪唑基、苯并吡唑基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、C 1-4烷基、C 1-4烷氧基或C 2-4炔基的取代基所取代。 R 2a is selected from one of the following substituted or unsubstituted groups: H, -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC( ＝O)-CH 3 , -C(＝O)NH-CH 2 CH 3 , -NHC(＝O)CH 2 CH 3 , -C(＝O)N(CH 3 ) 2 , --C(＝O )N(CH 2 CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(= O)-CH(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine, -C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentan Group, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzo Pyrazolyl 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 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH- Substituted by a substituent of phenyl, -NHC(=O)-phenyl, C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl.
本发明的一些实施例涉及通式(Ia)或(Ia-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自取代的或者未被取代的如下基团之一：H、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-CH 2CH 2CH 3、-C(＝O)-CH(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、-C(＝O)-苯基、-C(＝O)-吡啶、-C(＝O)-噻吩、-C(＝O)-呋喃、-C(＝O)-吡咯、甲基、乙基、异丙基、丙基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基或乙基的取代基所取代。 R 2a is selected from one of the following substituted or unsubstituted groups: H, -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC( ＝O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O) N(CH 2 CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O )-CH(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine,- C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furanyl , Pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl Or substituted by ethyl substituents.
本发明的一些实施例涉及通式(Ia)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
Figure PCTCN2020128033-appb-000106
选自
Figure PCTCN2020128033-appb-000107
Figure PCTCN2020128033-appb-000108
Figure PCTCN2020128033-appb-000106
Selected from
Figure PCTCN2020128033-appb-000107
Figure PCTCN2020128033-appb-000108
本发明的一些实施例涉及通式(Ib)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
Figure PCTCN2020128033-appb-000109
选自
Figure PCTCN2020128033-appb-000110
Figure PCTCN2020128033-appb-000111
Figure PCTCN2020128033-appb-000109
Selected from
Figure PCTCN2020128033-appb-000110
Figure PCTCN2020128033-appb-000111
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基或乙氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； 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;
m2选自0、1、2或3。m2 is selected from 0, 1, 2 or 3.
本发明的一些实施例涉及通式(Ia)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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各自独立地选自H、F、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代。 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.
本发明的一些实施例涉及通式(Ib)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
环D选自苯环、吡啶、哒嗪或嘧啶；Ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine;
环C选自C 4-6碳环或4至6元杂环,所述的杂环含有1至3个选自O、S、N的杂原子。 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.
本发明的一些实施例涉及通式(Ib)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
环C和环D一起形成的并环选自
Figure PCTCN2020128033-appb-000112
The combined ring formed by ring C and ring D is selected from
Figure PCTCN2020128033-appb-000112
本发明的一些实施例涉及通式(Ib)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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,
环C和环D一起形成的并环选自
Figure PCTCN2020128033-appb-000113
Figure PCTCN2020128033-appb-000114
The combined ring formed by ring C and ring D is selected from
Figure PCTCN2020128033-appb-000113
Figure PCTCN2020128033-appb-000114
本发明的一些实施例涉及通式(Ib)或(Ib-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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 ,
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子。 R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, the alkane Group, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 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 , -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , 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, C 6-10 aryl or 5 to 10 Substituents of a membered heteroaryl group are substituted, and the heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.
本发明的一些实施例涉及通式(Ib)或(Ib-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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 ,
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取 代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子。 R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, the alkane Group, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 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 , -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , 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, C 6-10 aryl or 5 to 10 Substituents of a membered heteroaryl group are substituted, and the heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.
本发明的一些实施例涉及通式(Ib)或(Ib-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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 ,
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH- CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy, The methyl, ethyl, methoxy, ethoxy or phenyl 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 alkyl, C 1-4 alkoxy substituent substituted;
本发明的一些实施例涉及通式(Ib)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2或C 1-6烷基的取代基所取代。 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.
本发明的一些实施例涉及通式(Ib)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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.
本发明的一些实施例涉及通式(Ib)或(Ib-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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 ,
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH- CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy, The methyl, ethyl, methoxy, ethoxy or phenyl 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 , methyl or ethyl substituents;
本发明的一些实施例涉及通式(Ib)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代。 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.
本发明的一些实施例涉及通式(Ib-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，G 1-G 2选自-CH 2CH 2-、-CH＝CH-、-C(＝O)-NH-、-C(＝O)-N(CH 3)-、-N(CH 3)-C(＝O)-或者-NH-C(＝O)-。 Some embodiments of the present invention relate to the compound of general formula (Ib-1) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, G 1- G 2 is selected from -CH 2 CH 2 -, -CH=CH-, -C(=O)-NH-, -C(=O)-N(CH 3 )-, -N(CH 3 )-C( =0)-or -NH-C(=O)-.
本发明的一些实施例涉及通式(Ia-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C 1-6烷基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子。 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. 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 Substituted by substituents of 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 , The heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, and N.
本发明的一些实施例涉及通式(Ia-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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选自取代的或者未被取代的如下基团之一：H、甲基、乙基、异丙基、丙基、环丙基、环丁基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基或苯基的取代基所取代。 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.
本发明的一些实施例涉及通式(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、C 1-6烷基、C 1-6烷氧基、C 3- 6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个(例如1、2、3或4个)选自O、S、N的杂原子。 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. 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, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl substituents, the heterocycloalkyl or heteroaryl group contains 1 Up to 4 (for example, 1, 2, 3, or 4) heteroatoms selected from O, S, N.
本发明的一些实施例涉及通式(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，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各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基，所述的甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选进一步被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代。 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.
本发明的一些实施例涉及通式(Ia)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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:
环A选自
Figure PCTCN2020128033-appb-000115
环B为哌啶；n为0；m1为0； Ring A is selected from
Figure PCTCN2020128033-appb-000115
Ring B is piperidine; n is 0; m1 is 0;
R 1选自
Figure PCTCN2020128033-appb-000116
R 1 is selected from
Figure PCTCN2020128033-appb-000116
R 2a选自取代的或者未被取代的如下基团之一：-C(＝O)-C 1-4烷基、苯基、萘基、吡啶基，当被取代时，任选被0至4个(例如0、1、2、3或4个)选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基、苯基或-C(＝O)NH-苯基的取代基所取代； R 2a is selected from one of the following substituted or unsubstituted groups: -C(=O)-C 1-4 alkyl, phenyl, naphthyl, pyridyl, and when substituted, it is optionally 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy, ethoxy, ring Substituted by propyl, cyclobutyl, phenyl or -C(=O)NH-phenyl substituents;
R 3选自
Figure PCTCN2020128033-appb-000117
X 3为键或O。 R 3 is selected from
Figure PCTCN2020128033-appb-000117
X 3 is a key or O.
本发明的一些实施例涉及通式(Ia)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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:
环A选自
Figure PCTCN2020128033-appb-000118
环B选自氮杂环丁烷或氮杂环戊烷； Ring A is selected from
Figure PCTCN2020128033-appb-000118
Ring B is selected from azetidine or azetidine;
n为0；m1为0，1或2；n is 0; m1 is 0, 1 or 2;
R 1选自
Figure PCTCN2020128033-appb-000119
R 1 is selected from
Figure PCTCN2020128033-appb-000119
R 2a选自取代的或者未被取代的苯基或萘基，当被取代时，所述苯基或萘基任选被0至4个(例如0、1、2、3或4个)选自F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基、乙氧基的取代基所取代； R 2a is selected from substituted or unsubstituted phenyl or naphthyl. When substituted, the phenyl or naphthyl is optionally selected from 0 to 4 (for example, 0, 1, 2, 3, or 4). Substituted by F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy, and ethoxy substituents;
R 2b为oxo； R 2b is oxo;
R 3选自
Figure PCTCN2020128033-appb-000120
X 3为O。 R 3 is selected from
Figure PCTCN2020128033-appb-000120
X 3 is O.
本发明的一些实施例涉及通式(Ib)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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:
环A选自
Figure PCTCN2020128033-appb-000121
Ring A is selected from
Figure PCTCN2020128033-appb-000121
环C和环D一起形成的并环选自
Figure PCTCN2020128033-appb-000122
The combined ring formed by ring C and ring D is selected from
Figure PCTCN2020128033-appb-000122
n为0；m2为1；m3为0；n is 0; m2 is 1; m3 is 0;
R 1选自
Figure PCTCN2020128033-appb-000123
R 1 is selected from
Figure PCTCN2020128033-appb-000123
R 2c各自独立地选自F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基或乙氧基； R 2c are each independently selected from F, Cl, Br, I, OH, cyano, CF 3 , methyl, ethyl, methoxy or ethoxy;
R 3选自
Figure PCTCN2020128033-appb-000124
X 3为O。 R 3 is selected from
Figure PCTCN2020128033-appb-000124
X 3 is O.
本发明的一些实施例涉及通式(Ia-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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:
环A选自
Figure PCTCN2020128033-appb-000125
n为0； Ring A is selected from
Figure PCTCN2020128033-appb-000125
n is 0;
R 2a为H或苯基，所述苯基任选被1、2、3或4个选自F、Cl、Br、I、OH、氰基、CF 3、NH 2、甲基、乙基、甲氧基、乙氧基的取代基取代； 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选自
Figure PCTCN2020128033-appb-000126
X 3为O。 R 3 is selected from
Figure PCTCN2020128033-appb-000126
X 3 is O.
本发明的一些实施例涉及通式(Ic-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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:
环A选自
Figure PCTCN2020128033-appb-000127
Figure PCTCN2020128033-appb-000128
Ring A is selected from
Figure PCTCN2020128033-appb-000127
Figure PCTCN2020128033-appb-000128
R 1选自
Figure PCTCN2020128033-appb-000129
Figure PCTCN2020128033-appb-000130
R 1 is selected from
Figure PCTCN2020128033-appb-000129
Figure PCTCN2020128033-appb-000130
R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代；m2选自0、1、2或3； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH-phenyl, methyl, ethyl, methoxy or ethoxy, The methyl, ethyl, methoxy, ethoxy or phenyl group is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2. Substituted by C 1-4 alkyl and C 1-4 alkoxy substituents; m2 is selected from 0, 1, 2 or 3;
R 3选自
Figure PCTCN2020128033-appb-000131
X 3为O。 R 3 is selected from
Figure PCTCN2020128033-appb-000131
X 3 is O.
本发明的一些实施例涉及通式(Ib-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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:
环A选自
Figure PCTCN2020128033-appb-000132
n为0；m2为0； Ring A is selected from
Figure PCTCN2020128033-appb-000132
n is 0; m2 is 0;
R 3选自
Figure PCTCN2020128033-appb-000133
X 3为O； R 3 is selected from
Figure PCTCN2020128033-appb-000133
X 3 is O;
G 1-G 2为NH-C(＝O)-或-C(＝O)-NH。 G 1 -G 2 are NH-C(=O)- or -C(=O)-NH.
本发明的一些实施例涉及通式(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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,
环A选自
Figure PCTCN2020128033-appb-000134
m2为0； Ring A is selected from
Figure PCTCN2020128033-appb-000134
m2 is 0;
R 3选自
Figure PCTCN2020128033-appb-000135
X 3为O。 R 3 is selected from
Figure PCTCN2020128033-appb-000135
X 3 is O.
本发明的一些实施例涉及通式(Ia-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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:
环A选自
Figure PCTCN2020128033-appb-000136
n为0；R 2a为苯基； Ring A is selected from
Figure PCTCN2020128033-appb-000136
n is 0; R 2a is phenyl;
R 3选自
Figure PCTCN2020128033-appb-000137
X 3为O。 R 3 is selected from
Figure PCTCN2020128033-appb-000137
X 3 is O.
本发明的一些实施例涉及通式(Ib-1)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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:
环A选自
Figure PCTCN2020128033-appb-000138
n为0；m2为0； Ring A is selected from
Figure PCTCN2020128033-appb-000138
n is 0; m2 is 0;
R 3选自
Figure PCTCN2020128033-appb-000139
X 3为O； R 3 is selected from
Figure PCTCN2020128033-appb-000139
X 3 is O;
G 1-G 2为NH-C(＝O)-。 G 1 -G 2 are NH-C(=O)-.
本发明的一些实施例涉及通式(Ic-1)或(Ic-2)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，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,
环A选自
Figure PCTCN2020128033-appb-000140
m2为0； Ring A is selected from
Figure PCTCN2020128033-appb-000140
m2 is 0;
R 3选自
Figure PCTCN2020128033-appb-000141
X 3为O。 R 3 is selected from
Figure PCTCN2020128033-appb-000141
X 3 is O.
本发明涉及一种药物组合物，包括本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，以及药学上可接受的载体。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.
本发明涉及一种本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐在用于制备预防或治疗与KRAS G12C活性或表达量相关疾病的药物中的应用，优选用于制备肿瘤药物中的应用。所述的肿瘤优选血液学癌症、胰脏癌、MYH相关息肉病、结肠直肠癌、非小细胞肺癌或小细胞肺癌。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.
本文所述反应中使用的化合物是根据本领域技术人员已知的有机合成技术制备的，起始于市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的，供应商包括：泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。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.
本领域的参考书和专著，详细介绍了可用于制备本文所述化合物的反应物的合成，或提供了描述该制备方法的文章以供参考。这些参考书和专著包括：“Synthetic Organic Chemistry”,John Wiley&Sons,Inc.,New York；S.R.Sandler et al.,“Organic Functional Group Preparations,”2nd Ed.,Academic Press,New York,1983；H.O.House,“Modern Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972；T.L.Gilchrist,“Heterocyclic Chemistry”,2nd Ed.,John Wiley&Sons,New York,1992；J.March,“Advanced Organic Chemistry:Reactions,Mechanisms and Structure”,4th Ed.,Wiley-Interscience,New York,1992；Fuhrhop,J.and Penzlin G.“Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN:3-527-29074-5；Hoffman,R.V.“Organic Chemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19- 509618-5；Larock,R.C.“Comprehensive Organic Transformations:A Guide to Functional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4；March,J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4th Edition(1992)John Wiley&Sons,ISBN:0-471-60180-2；Otera,J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1；Patai,S.“Patai’s 1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9；Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0；Stowell,J.C.,“Intermediate Organic Chemistry”2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2；“Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8volumes；“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55volumes；and“Chemistry of Functional Groups”John Wiley&Sons,in 73volumes.Reference 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. March, "Advanced Organic Chemistry" :Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley&Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley&Sons, ISBN:0 -471-60180-2; Otera,J. (editor) "Modern Carbonyl Chemis try" (2000) Wiley-VCH, ISBN:3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN:0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley&Sons, ISBN: 3-527-29645-X, in 8volumes; "Organic Reactions" (1942-2000) John; Wiandley&Sons, ins over 55 "Chemistry of Functional Groups" John Wiley&Sons, in 73volumes.
通过美国化学会化学文摘社制备的已知化学物质的索引，可以选择性地识别特定和类似的反应物，这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备，其中许多标准化学供应工厂(例如，上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,Verlag Helvetica Chimica Acta,Zurich,2002.Specific and similar reactants can be selectively identified through the index of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society. These indexes are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis plants, where many standard chemical supply plants (for example, those listed above) provide custom synthesis services. The reference for preparing and selecting medicinal salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.
R 1、R 2a、R 2b、R 2c、R 2d、R 3、R 4、环A、环B、环C、环D、X 1、X 3或m1、m2、m3、n的定义与上述通式(Ia)和(Ib)化合物相同； 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选自C 1-6烷基； R 5 is selected from C 1-6 alkyl;
R 6选自离去基团，优选F、Cl、Br、I、三氟甲磺酸酯基、甲磺酸酯基、对甲苯磺酸酯基或苯磺酸酯基；PG和R 7选自氨基保护基； 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;
合成方法一：Synthesis method one:
Figure PCTCN2020128033-appb-000142
Figure PCTCN2020128033-appb-000142
通式(Ia-1)化合物在碱的作用下与含有双离去基团的化合物反应得到通式(Ia-2)化合物；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);
通式(Ia-2)化合物在脱出羰基和乙二醇保护基后得到通式(Ia-3)化合物；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;
通式(Ia-3)化合物在碱的作用下与碳酸二酯基化合物反应得到通式(Ia-4)化合物；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);
通式(Ia-4)化合物在碱的作用下与S-甲基异硫脲硫酸盐反应、或者通式(Ia-4)化合物先与硫脲反应然后在碱的作用下与甲基化试剂反应得到通式(Ia-5)化合物；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);
通式(Ia-5)化合物在碱的作用下与三氟甲磺酸酐反应、或者通式(Ib-5)化合物通过氯代反应得到通式(Ia-6)化合物；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);
通式(Ia-6)化合物通过取代反应得到通式(Ia-7)化合物；The compound of general formula (Ia-6) can obtain the compound of general formula (Ia-7) through substitution reaction;
通式(Ia-7)化合物通过氧化反应得到通式(Ia-8)化合物；The compound of general formula (Ia-7) is oxidized to obtain the compound of general formula (Ia-8);
通式(Ia-8)化合物通过取代反应得到通式(Ia-9)化合物；The compound of general formula (Ia-8) can obtain the compound of general formula (Ia-9) through substitution reaction;
通式(Ia-9)化合物脱出R 7后得到通式(Ia-10)化合物； After removing R 7 from the compound of general formula (Ia-9), a compound of general formula (Ia-10) is obtained;
通式(Ia-10)化合物通过偶联、取代或缩合反应通式(Ib-11)化合物；The compound of general formula (Ia-10) reacts with the compound of general formula (Ib-11) through coupling, substitution or condensation reaction;
通式(Ia-11)化合物通过脱掉氨基保护基团得到通式(Ib-12)化合物；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);
通式(Ib-10)化合物通过取代反应或者缩合反应得通式(Ia)化合物。The compound of general formula (Ib-10) can obtain the compound of general formula (Ia) through substitution reaction or condensation reaction.
合成方法二：Synthesis method two:
Figure PCTCN2020128033-appb-000143
Figure PCTCN2020128033-appb-000143
通式(Ib-a)化合物在碱的作用下与含有双离去基团的化合物反应得到通式(Ib-2)化合物；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);
通式(Ib-2)化合物在脱出羰基和乙二醇保护基后得到通式(Ib-3)化合物；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;
通式(Ib-3)化合物在碱的作用下与碳酸二酯基化合物反应得到通式(Ib-4)化合物；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);
通式(Ib-4)化合物在碱的作用下与S-甲基异硫脲硫酸盐反应、或者通式(Ib-4)化合物先与硫脲反应然后在碱的作用下与甲基化试剂反应得到通式(Ib-5)化合物；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);
通式(Ib-5)化合物在碱的作用下与三氟甲磺酸酐反应、或者通式(Ib-5)化合物通过氯代反应得到通式(Ib-6)化合物；The compound of general formula (Ib-5) is reacted with trifluoromethanesulfonic anhydride under the action of a base, or the compound of general formula (Ib-5) is chlorinated to obtain the compound of general formula (Ib-6);
通式(Ib-6)化合物通过取代反应得到通式(Ib-7)化合物；The compound of general formula (Ib-6) can obtain the compound of general formula (Ib-7) through substitution reaction;
通式(Ib-7)化合物通过氧化反应得到通式(Ib-8)化合物；The compound of general formula (Ib-7) is oxidized to obtain the compound of general formula (Ib-8);
通式(Ib-8)化合物通过取代反应得到通式(Ib-9)化合物；The compound of general formula (Ib-8) can obtain the compound of general formula (Ib-9) through substitution reaction;
通式(Ib-9)化合物通过脱掉氨基保护基团得到通式(Ib-10)化合物；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);
通式(Ib-10)化合物通过取代反应或者缩合反应得通式(Ib)化合物。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.
合成方法三：Synthesis method three:
Figure PCTCN2020128033-appb-000144
Figure PCTCN2020128033-appb-000144
通式(Ib-1a)化合物经Danheiser-Stork反应得到通式(Ib-1b)化合物；The compound of general formula (Ib-1a) is subjected to Danheiser-Stork reaction to obtain the compound of general formula (Ib-1b);
通式(Ib-1b)化合物在酸催化下脱出甲基得到通式(Ib-1c)化合物；The compound of general formula (Ib-1b) is demethylated under acid catalysis to obtain the compound of general formula (Ib-1c);
通式(Ib-1c)化合物在有机胺催化下得到通式(Ib-1d)化合物；Compounds of general formula (Ib-1c) are catalyzed by organic amines to obtain compounds of general formula (Ib-1d);
通式(Ib-1d)化合物在碱的作用下引入离去基团例如OTf，卤素等得到通式(Ib-1e)化合物；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);
通式(Ib-1e)化合物在金属催化剂的作用下加氢得到通式(Ib-1f)化合物；Compounds of general formula (Ib-1e) are hydrogenated under the action of a metal catalyst to obtain compounds of general formula (Ib-1f);
合成方法四：Synthesis method four:
Figure PCTCN2020128033-appb-000145
Figure PCTCN2020128033-appb-000145
通式(Ib-1g)化合物经取代反应得到通式(Ib-1h)化合物；Compounds of general formula (Ib-1g) are substituted to obtain compounds of general formula (Ib-1h);
通式(Ib-1h)化合物金属催化剂作用下，加氢得到通式(Ib-1i)化合物；Under the action of the metal catalyst of the compound of the general formula (Ib-1h), the compound of the general formula (Ib-1i) is obtained by hydrogenation;
通式(Ib-1i)化合物在酸催化下得到通式(Ib-1f)化合物；Compounds of general formula (Ib-1i) are catalyzed by acid to obtain compounds of general formula (Ib-1f);
合成方法五：Synthesis method five:
Figure PCTCN2020128033-appb-000146
Figure PCTCN2020128033-appb-000146
通式(Ib-1f)化合物在碱的作用下与碳酸二酯基化合物或者氰基碳酸酯基化合物反应得到通式(Ib-1j)化合物；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);
通式(Ib-1j)化合物与氨作用的得到通式(Ib-1k)化合物；The compound of general formula (Ib-1j) is reacted with ammonia to obtain the compound of general formula (Ib-1k);
通式(Ib-1k)化合物与苯甲酰异硫氰酸酯反应得到通式(Ib-1l)化合物；The compound of general formula (Ib-1k) is reacted with benzoyl isothiocyanate to obtain the compound of general formula (Ib-1l);
通式(Ib-1l)化合物在碱性条件下关环得到通式(Ib-1m)化合物；或者通式(Ib-1j)化合物与硫脲反应得到通式(Ib-1m)化合物；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);
通式(Ib-1m)化合物在碱性作用下与甲基化试剂反应得到通式(Ib-1n)化合物；或者通式(Ib-1j)化合物在碱的作用下与S-甲基异硫脲硫酸盐反应得到通式(Ib-1n)化合物；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);
通式(Ib-1n)化合物在碱的作用下与三氟甲磺酸酐反应、或者通式(Ib-1n)化合物通过氯代反应得到通式(Ib-1o)化合物；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);
通式(Ib-1o)化合物通过取代反应得到通式(Ib-1p)化合物；The compound of general formula (Ib-1o) can obtain the compound of general formula (Ib-1p) through substitution reaction;
通式(Ib-1p)化合物通过氧化反应得到通式(Ib-1q)化合物(q＝1或2)；The compound of general formula (Ib-1p) is oxidized to obtain the compound of general formula (Ib-1q) (q=1 or 2);
通式(Ib-1q)化合物通过取代反应得到通式(Ib-1r)化合物；The compound of general formula (Ib-1q) can obtain the compound of general formula (Ib-1r) through substitution reaction;
通式(Ib-1r)化合物通过脱掉氨基保护基团得到通式(Ib-1s)化合物；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);
通式(Ib-1s)化合物通过取代反应或者缩合反应得通式(Ib-1)化合物。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.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 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.
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；所述的烷基可以任选进一步被0至6个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、C 1-6烷基、C 1-6羟基烷基、C 1-6烷氧基、3至8元碳环基、3至8元杂环基、3至8元碳环基氧基、3至8元杂环基氧基、羧基或者羧酸酯基的取代基所取代，本文中出现的烷基，其定义与本定义一致。 "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 a substituent. The definition of the alkyl group appearing in this text is consistent with this definition.
“亚烷基”是指直链和支链的二价饱和烃基，包括-(CH 2) v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等；所述的亚烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的亚烷基，其定义与本定义一致。 "Alkylene" refers to straight and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v- (v is an integer from 1 to 10). Examples of 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.
“环烷基”是指一价饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的环烷基，其定义如上所述。"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.
“炔基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基、1,3-丁二炔、1,3-戊二炔、1,4-戊二炔和1,4-己二炔等；所述的炔基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的炔基，其定义与本定义一致。"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, examples of 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-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1- Octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, 1,3-butadiyne, 1,3-pentadiyne, 1,4-pentadiyne and 1,4-hexadiyne, etc.; the alkynyl group may optionally be further selected from 0 to 5 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano , Amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carbocyclic oxy, heterocyclic oxy, carboxy or carboxylate The substituents are substituted. The definition of the alkynyl group appearing in this document is consistent with this definition.
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷氧基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的烷氧基，其定义与本定义一致。"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.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环或萘环。所述的碳环可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的碳环或碳环基，其定义与本定义一致。"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 carbocyclic ring may optionally be further selected from 0 to 5 F, Cl, Br, I, =0, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkyne Group, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituent. The definition of carbocyclic or carbocyclic group appearing in this text is consistent with this definition.
“杂环基”或“杂环”是指包含1至3个选自N、O或S的杂原子的、取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，优选3至8元杂环基，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的杂环基，其定义与本定义一致。"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. Cyclobutyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxanyl, azepanyl, pyridyl, furanyl, thienyl, pyridine Pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiol, Dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl , Pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]12 Alkyl, azaadamantyl and oxaspiro[3.3]heptanyl. The heterocyclic group may optionally be further selected from 0 to 5 F, Cl, Br, I, =0, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, Alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituents are substituted. The definition of heterocyclic group appearing in this text is consistent with this definition.
“螺环”是指取代的或未取代的单环之间共用一个碳原子(称螺原子)的5至20元多环基团，其可以包含0至5个双键，且可以含有0至5个选自N、O或S(＝O)n的杂原子。优选为6至14元，进一步优选为6至12元，更优选6至10元，其非限定性实例包括：
Figure PCTCN2020128033-appb-000147
Figure PCTCN2020128033-appb-000148
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-Ra、-O-(CH 2) m-C(＝O)-Ra、-(CH 2) m-C(＝O)-NRbRc、-(CH 2) mS(＝O)nRa、-(CH 2) m-烯基-Ra、ORd或-(CH 2) m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基 团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的螺环，其定义与本定义一致。 "Spiro ring" refers to a 5- to 20-membered polycyclic group sharing one carbon atom (called a spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds, and may contain 0 to 5 heteroatoms selected from N, O or S(=O)n. It is preferably 6 to 14 yuan, more preferably 6 to 12 yuan, more preferably 6 to 10 yuan, non-limiting examples thereof include:
Figure PCTCN2020128033-appb-000147
Figure PCTCN2020128033-appb-000148
When substituted, the substituent may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano Group, isocyano group, aryl group, heteroaryl group, heterocyclic group, bridged ring group, spiro ring group, hydroxyalkyl group, =0, carbonyl group, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-Ra, -O-(CH 2 ) m -C(=O)-Ra, -(CH 2 ) m -C(=O)-NRbRc, -(CH 2 ) m S(=O)nRa, -(CH 2 ) m -alkenyl-Ra, ORd or -(CH 2 ) m -alkynyl-Ra (where m and n are 0, 1 or 2), arylthio, Groups such as thiocarbonyl, silyl or -NRbRc, where Rb and Rc are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , Sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc can form a five- or six-membered cycloalkyl or heterocyclic group. 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.
“并环”是指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的多环基团，其中一个或多个环可以含有0个或多个双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个选自N、S(＝O)n或O的杂原子。优选为5至20元，进一步优选为5至14元，更有选5至12元，再进一步优选5至10元。非限定性实例包括：
Figure PCTCN2020128033-appb-000149
Figure PCTCN2020128033-appb-000150
Figure PCTCN2020128033-appb-000151
"Polycyclic ring" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain 0 or more double bonds, and may be The substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms selected from N, S(=O)n or O. It is preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more preferably 5 to 12 yuan, and still more preferably 5 to 10 yuan. Non-limiting examples include:
Figure PCTCN2020128033-appb-000149
Figure PCTCN2020128033-appb-000150
Figure PCTCN2020128033-appb-000151
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-Ra、-O-(CH 2) m-C(＝O)-Ra、-(CH 2) m-C(＝O)-NRbRc、-(CH 2) mS(＝O)nRa、-(CH 2) m-烯基-Ra、ORd或-(CH 2) m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的并环，其定义与本定义一致。 When substituted, the substituent may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano Group, isocyano group, aryl group, heteroaryl group, heterocyclic group, bridged ring group, spiro ring group, hydroxyalkyl group, =0, carbonyl group, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-Ra, -O-(CH 2 ) m -C(=O)-Ra, -(CH 2 ) m -C(=O)-NRbRc, -(CH 2 ) m S(=O)nRa, -(CH 2 ) m -alkenyl-Ra, ORd or -(CH 2 ) m -alkynyl-Ra (where m and n are 0, 1 or 2), arylthio, Groups such as thiocarbonyl, silyl or -NRbRc, where Rb and Rc are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , Sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc can form a five- or six-membered cycloalkyl or heterocyclic group. 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.
“桥环”是指任意两个环共用2个不直接连接的原子的多环基团，可以含有0个或多个双键，且可以是取代的或未取代的，桥环体系中的任意环可以含0至5个选自N、S(＝O)n或O杂原子或基团(其中n为1、1、2)。环原子包含5至20个原子，优选为5至14个原子，进一步优选5至12个，再进一步优选5至10个。非限定性实例包括
Figure PCTCN2020128033-appb-000152
Figure PCTCN2020128033-appb-000153
和金刚烷。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-Ra、-O-(CH 2) m-C(＝O)-Ra、-(CH 2) m-C(＝O)-NRbRc、-(CH 2) mS(＝O)nRa、-(CH 2) m-烯基-Ra、ORd或-(CH 2) m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的桥环，其定义与本定义一致。 "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 may contain 0 to 5 heteroatoms or groups selected from N, S(=O)n or O (where n is 1, 1, 2). 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
Figure PCTCN2020128033-appb-000152
Figure PCTCN2020128033-appb-000153
And adamantane. When substituted, the substituent may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano Group, isocyano group, aryl group, heteroaryl group, heterocyclic group, bridged ring group, spiro ring group, hydroxyalkyl group, =0, carbonyl group, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-Ra, -O-(CH 2 ) m -C(=O)-Ra, -(CH 2 ) m -C(=O)-NRbRc, -(CH 2 ) m S(=O)nRa, -(CH 2 ) m -alkenyl-Ra, ORd or -(CH 2 ) m -alkynyl-Ra (where m and n are 0, 1 or 2), arylthio, Groups such as thiocarbonyl, silyl or -NRbRc, where Rb and Rc are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , Sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc can form a five- or six-membered cycloalkyl or heterocyclic group. 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.
“杂单环”是指单环体系的“杂环基”或“杂环”，本文中出现的杂单环，其定义与本定义一致。"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.
“杂并环”是指含有杂原子的“并环”。本文中出现的杂并环，其定义与本定义一致。"Heterocyclic ring" refers to a "polycyclic ring" containing heteroatoms. The definition of the heterocyclic ring appearing in this article is consistent with this definition.
“杂螺环”是指含有杂原子的“螺环”。本文中出现的杂螺环，其定义与本定义一致。"Heterospiro ring" refers to a "spiro ring" containing heteroatoms. The definition of heterospiro ring appearing in this article is consistent with this definition.
“杂桥环”是指含有杂原子的“桥环”。本文中出现的杂桥环，其定义与本定义一致。"Heterobridged ring" refers to a "bridged ring" containing heteroatoms. The definition of the heterobridging ring appearing in this article is consistent with this definition.
“芳基”或“芳环”是指具有单环或稠合环的一价芳香族烃基，通常有6至10个碳原子，且可以是取代的或未取代的。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-Ra、-O-(CH 2) m-C(＝O)-Ra、-(CH 2) m-C(＝O)-NRbRc、-(CH 2) mS(＝O)nRa、-(CH 2) m-烯基-Ra、ORd或-(CH 2) m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基。Ra与Rd各自独立选自芳基、杂 芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的芳基或芳环，其定义与本定义一致。 "Aryl" or "aromatic ring" refers to a monovalent aromatic hydrocarbon group having a single ring or a condensed ring, usually having 6 to 10 carbon atoms, and may be substituted or unsubstituted. When substituted, the substituent may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano Group, isocyano group, aryl group, heteroaryl group, heterocyclic group, bridged ring group, spiro ring group, hydroxyalkyl group, =0, carbonyl group, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-Ra, -O-(CH 2 ) m -C(=O)-Ra, -(CH 2 ) m -C(=O)-NRbRc, -(CH 2 ) m S(=O)nRa, -(CH 2 ) m -alkenyl-Ra, ORd or -(CH 2 ) m -alkynyl-Ra (where m and n are 0, 1 or 2), arylthio, Groups such as thiocarbonyl, silyl or -NRbRc, where Rb and Rc are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , Sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc can form a five- or six-membered cycloalkyl or heterocyclic group. 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 aryl or aromatic ring appearing in this text is consistent with this definition.
“杂芳基”是指取代或未取代的5至15元芳香环，且含有1至5个选自N、O或S(＝O)n杂原子或基团，优选5至10元杂芳香环，进一步优选5至6元。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并吡唑、哌叮基、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含
Figure PCTCN2020128033-appb-000154
"Heteroaryl" refers to a substituted or unsubstituted 5- to 15-membered aromatic ring and contains 1 to 5 heteroatoms or groups selected from N, O or S(=O)n, preferably 5- to 10-membered heteroaromatic The ring is more preferably 5 to 6 members. Non-limiting examples of 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
Figure PCTCN2020128033-appb-000154
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-Ra、-O-(CH 2) m-C(＝O)-Ra、-(CH 2) m-C(＝O)-NRbRc、-(CH 2) mS(＝O)nRa、-(CH 2) m-烯基-Ra、ORd或-(CH 2) m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。本文中出现的杂芳基，其定义与本定义一致。 When substituted, the substituent may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano Group, isocyano group, aryl group, heteroaryl group, heterocyclic group, bridged ring group, spiro ring group, hydroxyalkyl group, =0, carbonyl group, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-Ra, -O-(CH 2 ) m -C(=O)-Ra, -(CH 2 ) m -C(=O)-NRbRc, -(CH 2 ) m S(=O)nRa, -(CH 2 ) m -alkenyl-Ra, ORd or -(CH 2 ) m -alkynyl-Ra (where m and n are 0, 1 or 2), arylthio, Groups such as thiocarbonyl, silyl or -NRbRc, where Rb and Rc are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , Sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc can form a five- or six-membered cycloalkyl or heterocyclic group. 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.
“含有1至4个选自O、S、N的杂原子”是指含有1、2、3或4个选自O、S、N的杂原子。本文中，“所述的杂环含有1至4个选自O、S、N的杂原子”意指该表述所位于的段落中的所有杂环各自独立地含有1、2、3或4个选自O、S、N的杂原子。"Containing 1 to 4 heteroatoms selected from O, S, and N" means containing 1, 2, 3, or 4 heteroatoms selected from O, S, and N. As used herein, "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.
“0至X个取代基所取代”是指被0、1、2、3…X个取代基所取代，X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选进一步被0至4个选自H或F的取代基所取代”是指杂桥环任选进一步被0、1、2、3或4个选自H或F的取代基所取代。"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. For example, "substituted by 0 to 4 substituents" means substituted by 0, 1, 2, 3 or 4 substituents. For example, "substituted by 0 to 5 substituents" means substituted by 0, 1, 2, 3, 4 or 5 substituents. For example, "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.
X-Y元的环(X选自小于Y大于等于3的整数，Y选自4至12之间的任意整数)包括了X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元 或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。“4至9元含氮杂环”是指4元、5元、6元、7元、8元或9元的含氮杂环。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. For example, "4-7 membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "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. The "4- to 9-membered nitrogen-containing heterocyclic ring" refers to a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered nitrogen-containing heterocyclic ring.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"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.
“药物组合物”是指一种或多种本发明所述或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体。“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"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.
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药可被割裂形成游离的氨基或者羧基。"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. When the prodrug of the present invention is administered to a mammalian individual, the prodrug can be cleaved to form free amino or carboxyl groups.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"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. 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.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers arising from the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"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. For example, "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. Happening.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance  300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) 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);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；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;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;
Boc：叔丁氧基羰基；Ts：对甲苯磺酰基；Cbz：苄氧羰基；TMS：三甲基硅基；Boc: tert-butoxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl;
实施例1Example 1
2-[(S)-1-丙烯酰基-4-[2'-[[(S)-1-甲基吡咯烷-2-基]甲氧基]-1,3,5',8'-四氢-6'H-螺[茚-2,7'-喹唑啉]-4'-基]哌嗪-2-基]乙腈；2,2,2-三氟乙酸盐(化合物1)；2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'- Tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetate (Compound 1) ；
2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid.2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'-tetrahydro-6'H- spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid.
Figure PCTCN2020128033-appb-000155
Figure PCTCN2020128033-appb-000155
Figure PCTCN2020128033-appb-000156
Figure PCTCN2020128033-appb-000156
第一步：1,3-二氢二螺[茚-2,3'-环己烷-1',2”-[1,3]二氧戊环]-4'-酮(1a)；The first step: 1,3-dihydrodispiro[indene-2,3'-cyclohexane-1',2"-[1,3]dioxolane]-4'-one (1a);
1,3-dihydrodispiro[indene-2,3'-cyclohexane-1',2”-[1,3]dioxolan]-4'-one.1,3-dihydrodispiro[indene-2,3'-cyclohexane-1',2”-[1,3]dioxolan]-4'-one.
Figure PCTCN2020128033-appb-000157
Figure PCTCN2020128033-appb-000157
将1,4-环己二酮单乙二醇缩酮(8g，51.3mmol)溶于干燥的叔丁醇(130mL)中，氮气保护，加入叔丁醇钾固体(12.8g，113.7mmol)。室温下搅拌30min后加入1，2-二(溴甲基)苯(13.5g，51.2mmol)，加毕，保持室温反应过夜。TLC监控反应完全后，加入100mL冰水淬灭反应，用100mL二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物1a，无色粘稠状液体(3g，收率：22.7％)。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%).
MS m/z(ESI):259.3[M+H] + MS m/z(ESI): 259.3[M+H] +
第二步：1,3-二氢二螺[茚-2,1'-环己烷-3',2”-[1,3]二氧戊烷](1b)；The second step: 1,3-dihydrodispiro[indene-2,1'-cyclohexane-3',2"-[1,3]dioxolane](1b);
1,3-dihydrodispiro[indene-2,1'-cyclohexane-3',2”-[1,3]dioxolane].1,3-dihydrodispiro[indene-2,1'-cyclohexane-3',2”-[1,3]dioxolane].
Figure PCTCN2020128033-appb-000158
Figure PCTCN2020128033-appb-000158
将化合物1a(1g，3.87mmol)溶于10mL一缩二乙二醇中，加入2mL水合肼，体系升至80℃反应1h，后用微波加热至200℃反应30min。TLC监控反应结束，加入15mL 水稀释，用20mL二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物1b，无色粘稠状液体(0.7g，收率：77％)。Compound 1a (1 g, 3.87 mmol) was dissolved in 10 mL of diethylene glycol, and 2 mL of hydrazine hydrate was added. The system was heated to 80°C for 1 hour, and then heated to 200°C for 30 minutes by microwave. TLC monitored the completion of the reaction, diluted with 15 mL of water, extracted three times with 20 mL of dichloromethane, combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1b was obtained as a colorless viscous liquid (0.7 g, yield: 77%).
MS m/z(ESI):245.3[M+H] + MS m/z(ESI): 245.3[M+H] +
第三步：1',3'-二氢螺[环己烷-1,2'-茚]-3-酮(1c)；The third step: 1',3'-dihydrospiro[cyclohexane-1,2'-indene]-3-one (1c);
1',3'-dihydrospiro[cyclohexane-1,2'-inden]-3-one.1',3'-dihydrospiro[cyclohexane-1,2'-inden]-3-one.
Figure PCTCN2020128033-appb-000159
Figure PCTCN2020128033-appb-000159
将化合物1b(2.5g，10.23mmol)溶于10mL四氢呋喃溶液中，于室温下滴加6N盐酸20mL，滴加完全后，室温下反应4h。TLC监控反应完全后，加入15mL水稀释，用20mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物1c，白色固体(1.8g，收率：87.8％)。Compound 1b (2.5 g, 10.23 mmol) was dissolved in 10 mL of tetrahydrofuran solution, and 20 mL of 6N hydrochloric acid was added dropwise at room temperature. After the addition was complete, the reaction was carried out at room temperature for 4 hours. After TLC monitoring the completion of the reaction, it was diluted with 15 mL of water, extracted three times with 20 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1c was obtained as a white solid (1.8 g, yield: 87.8%).
MS m/z(ESI):201.3[M+H] + MS m/z(ESI): 201.3[M+H] +
第四步：3-氧代-1'，3'-二氢螺[环己烷-1,2'-茚]-4-羧酸甲酯(1d)；The fourth step: 3-oxo-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-4-carboxylic acid methyl ester (1d);
methyl 3-oxo-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-4-carboxylate.methyl 3-oxo-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-4-carboxylate.
Figure PCTCN2020128033-appb-000160
Figure PCTCN2020128033-appb-000160
将氢化钠(0.4g，10.0mmol)悬浮于15mL干燥的四氢呋喃中，氮气保护，加入碳酸二甲酯(2.1mL，25.0mmol)，加毕，体系加热至80℃搅拌30min。然后滴加化合物1c(1.0g，5.0mmol)的四氢呋喃溶液(8mL)，滴加完后保持80℃继续反应2h。TLC监控反应完成后，冷却至室温，垫硅藻土过滤，滤液加入20mL冰水稀释，用30mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物1d，白色固体(0.8g，收率：62％)。Sodium hydride (0.4g, 10.0mmol) was suspended in 15mL of dry tetrahydrofuran, protected by nitrogen, dimethyl carbonate (2.1mL, 25.0mmol) was added, after the addition, the system was heated to 80°C and stirred for 30min. Then, a tetrahydrofuran solution (8 mL) of compound 1c (1.0 g, 5.0 mmol) was added dropwise, and after the addition, the reaction was continued at 80° C. for 2 hours. After the reaction was monitored by TLC, it was cooled to room temperature and filtered through a pad of Celite. 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%).
MS m/z(ESI):259.1[M+H] + MS m/z(ESI): 259.1[M+H] +
第五步：2'-(甲硫基)-1,3,5'，8'-四氢-6'H-螺[茚-2,7'-喹唑啉]-4'-醇(1e)；The fifth step: 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-alcohol (1e );
2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-ol.2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-ol.
Figure PCTCN2020128033-appb-000161
Figure PCTCN2020128033-appb-000161
将化合物1d(0.2g，0.78mmol)溶于1mL四氢呋喃中，加入S-甲基异硫脲硫酸盐(335mg，1.17mmol)，后于室温下滴加氢氧化钾(359mg，6.4mmoL)的水溶液(2mL)。滴加完毕后保持室温反应过夜。待反应完成后，加入10mL水稀释，用1N盐酸调节pH至9-10 左右，然后用20mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物1e，白色固体(34mg，收率：14.6％)。Compound 1d (0.2g, 0.78mmol) was dissolved in 1mL of tetrahydrofuran, S-methylisothiourea sulfate (335mg, 1.17mmol) was added, and then potassium hydroxide (359mg, 6.4mmoL) aqueous solution was added dropwise at room temperature (2mL). After the addition is complete, keep the reaction at room temperature overnight. After the reaction is completed, add 10 mL of water to dilute, adjust the pH to about 9-10 with 1N hydrochloric acid, then extract three times with 20 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. After column chromatography, the target product 1e was obtained as a white solid (34 mg, yield: 14.6%).
Ms m/z(ESI):299.4[M+H] + Ms m/z(ESI):299.4[M+H] +
第六步：2'-(甲硫基)-1,3,5'，8'-四氢-6'H-螺[茚-2,7'-喹唑啉]-4'-三氟甲磺酸酯(1f)；The sixth step: 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-trifluoromethane Sulfonate (1f);
2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate
Figure PCTCN2020128033-appb-000162
Figure PCTCN2020128033-appb-000162
将化合物1e(34mg，0.114mmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(0.08mL，0.456mmol)，冰浴下加入三氟甲磺酸酐(64.3mg，0.228mmol)，冰浴下搅拌1h。待反应完全后加入15mL二氯甲烷稀释，后用10mL水洗涤反应液，再用10mL饱和碳酸氢钠水溶液洗涤反应液，有机层用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物1f，白色固体(30mg，收率：61％)。Compound 1e (34mg, 0.114mmol) was dissolved in 5mL of dichloromethane, N,N-diisopropylethylamine (0.08mL, 0.456mmol) was added, and trifluoromethanesulfonic anhydride (64.3mg, 0.228 mmol), stirring under ice bath for 1 h. After the reaction was completed, 15 mL of dichloromethane was added to dilute, and then the reaction solution was washed with 10 mL of water, and then washed with 10 mL of saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, the target product 1f was obtained as a white solid (30 mg, yield: 61%).
MS m/z(ESI):431.5[M+H] + MS m/z(ESI): 431.5[M+H] +
第七步：(S)-2-(氰甲基)-4-(2'-(甲硫基)-1,3,5'，8'-四氢-6'H-螺[茚-2,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(1g)；The seventh step: (S)-2-(cyanomethyl)-4-(2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2 ,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (1g);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylatetert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin] -4'-yl)piperazine-1-carboxylate
Figure PCTCN2020128033-appb-000163
Figure PCTCN2020128033-appb-000163
将化合物1f(30mg，0.07mmol)溶于3mL N,N-二甲基乙酰胺中，加入(S)-2-(哌嗪-2-基)乙腈(9.6mg，0.08mmol)和二异丙基乙胺(54mg，0.42mmol)，室温搅拌3h。TLC监控反应完全后，向体系中加入二碳酸二叔丁酯(46mg，0.21mmol)，加毕，反应室温过夜。加入20mL乙酸乙酯稀释，用10mL水洗有机相三次，有机相用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物1g，白色固体(40mg，收率：100％)。Compound 1f (30mg, 0.07mmol) was dissolved in 3mL N,N-dimethylacetamide, and (S)-2-(piperazin-2-yl)acetonitrile (9.6mg, 0.08mmol) and diisopropyl were added Ethylamine (54mg, 0.42mmol), stirred at room temperature for 3h. After the completion of the reaction monitored by TLC, di-tert-butyl dicarbonate (46 mg, 0.21 mmol) was added to the system, after the addition, the reaction was carried out at room temperature overnight. Add 20 mL of ethyl acetate to dilute, wash the organic phase three times with 10 mL of water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. After column chromatography, 1 g of the target product was obtained as a white solid (40 mg, yield: 100%).
MS m/z(ESI):506.7[M+H] + MS m/z(ESI): 506.7[M+H] +
第八步：(S)-2-(氰甲基)-4-(2'-(甲基磺酰基)-1,3,5'，8'-四氢-6'H-螺[茚-2,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(1h)；The eighth step: (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-1,3,5',8'-tetrahydro-6'H-spiro[indene- 2,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (1h);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylatetert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin] -4'-yl)piperazine-1-carboxylate
Figure PCTCN2020128033-appb-000164
Figure PCTCN2020128033-appb-000164
将化合物1g(40mg，0.079mmol)溶于2mL四氢呋喃中，室温下加入间氯过氧苯甲酸(27mg，0.16mmol)，室温搅拌2h。加入5mL饱和硫代硫酸钠水溶液，搅拌20min，加入15mL乙酸乙酯萃取，有机层用10mL饱和碳酸氢钠水溶液洗涤，减压浓缩，得到目标化合物1h粗品，黄色固体48mg，直接用于下一步。Compound 1g (40mg, 0.079mmol) was dissolved in 2mL of tetrahydrofuran, m-chloroperoxybenzoic acid (27mg, 0.16mmol) was added at room temperature, and stirred at room temperature for 2h. 5mL saturated sodium thiosulfate aqueous solution was added, stirred for 20min, 15mL ethyl acetate was added for extraction, the organic layer was washed with 10mL saturated sodium bicarbonate aqueous solution, and concentrated under reduced pressure to obtain the target compound 1h crude product, yellow solid 48mg, which was used directly in the next step.
MS m/z(ESI):538.7[M+H] + MS m/z(ESI): 538.7[M+H] +
第九步：(S)-2-(氰基甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲氧基)-1,3,5'，8'-四氢-6'H-螺[茚-2,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(1i)；The ninth step: (S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3, 5',8'-Tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (1i);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylatetert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6' H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate
Figure PCTCN2020128033-appb-000165
Figure PCTCN2020128033-appb-000165
将化合物1h粗品(48mg，0.089mmol)和(S)-(1-甲基吡咯烷-2-基)甲醇(22mg，0.19mmol)溶于2mL甲苯中，冰浴下加入叔丁醇钠(14mg，0.14mmol)，冰浴下搅拌1h。加入5mL水淬灭反应，加入10mL乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物1i，白色固体(46mg，收率：95％)。The crude compound 1h (48mg, 0.089mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (22mg, 0.19mmol) were dissolved in 2mL of toluene, and sodium tert-butoxide (14mg , 0.14mmol), stirred under ice bath for 1h. The reaction was quenched by adding 5 mL of water, 10 mL of ethyl acetate was added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1i was obtained as a white solid (46 mg, yield: 95%).
MS m/z(ESI):573.6[M+H] + MS m/z(ESI): 573.6[M+H] +
第十步：2-((S)-4-(2'-((((S)-1-甲基吡咯烷-2-基]甲氧基])-1,3,5'，8'-四氢-6'H-螺[2,7'-喹唑啉]-4'-基)哌嗪-2-基)乙腈(1j)；The tenth step: 2-((S)-4-(2'-((((S)-1-methylpyrrolidin-2-yl]methoxy])-1,3,5',8' -Tetrahydro-6'H-spiro[2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (1j);
2-((S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile2-((S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6'H-spiro[indene- 2,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2020128033-appb-000166
Figure PCTCN2020128033-appb-000166
将化合物1i(46mg，0.08mmol)溶于3mL二氯甲烷中，加入0.5mL三氟乙酸，于室温下搅拌2h。待反应完成后，加入5mL水稀释，然后用10mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩，得到目标化合物1j粗品，黄色固体40mg，直接用于下一步。Compound 1i (46 mg, 0.08 mmol) was dissolved in 3 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with 5 mL of water, and then extracted three times with 10 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude target compound 1j, 40 mg of yellow solid, which was directly used in the next step.
MS m/z(ESI):473.6[M+H] + MS m/z(ESI): 473.6[M+H] +
第十一步：2-[(S)-1-丙烯酰基-4-[2'-[[(S)-1-甲基吡咯烷-2-基]甲氧基]-1,3,5',8'-四氢-6'H-螺[茚-2,7'-喹唑啉]-4'-基]哌嗪-2-基]乙腈；2,2,2-三氟乙酸盐(化合物1)；The eleventh step: 2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5 ',8'-Tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid Salt (Compound 1);
2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid.2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'-tetrahydro-6'H- spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid.
Figure PCTCN2020128033-appb-000167
Figure PCTCN2020128033-appb-000167
将化合物1j粗品(46mg，0.097mmol)溶于5mL二氯甲烷中，加入三乙胺(49mg，0.49mmol)，冰浴下计入烯丙酰氯(8mg，0.092mmol)，冰浴下搅拌30min。加入5mL冰水淬灭反应，然后用10mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩，送液相酸性制备(流动相体系：乙腈/0.1％TFA水)得到目标化合物1，白色固体(23mg，收率：45％)。The crude compound 1j (46 mg, 0.097 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (49 mg, 0.49 mmol) was added, acryloyl chloride (8 mg, 0.092 mmol) was added under ice bath, and the mixture was stirred under ice bath for 30 min. The reaction was quenched by adding 5 mL of ice water, and then extracted three times with 10 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and sent to the liquid phase for acid preparation (mobile phase system: acetonitrile/0.1% TFA water) to obtain Target compound 1, white solid (23 mg, yield: 45%).
1H NMR(400MHz,CD 3OD)δ7.21–7.08(m,4H),6.90–6.70(m,1H),6.29(d,1H),5.84(d,1H),4.69(dd,1H),4.60(d,1H),4.41(d,1H),4.20–4.03(m,1H),3.96–3.83(m,1H),3.78–3.41(m,4H),3.26–3.14(m,1H),3.06–2.93(m,6H),2.89–2.81(m,3H),2.80(d,1H),2.75(s,2H),2.44–2.32(m,1H),2.22–1.97(m,4H),1.94–1.85(m,2H),1.35–1.25(m,2H). 1 H NMR (400MHz, CD 3 OD) δ7.21-7.08(m,4H), 6.90-6.70(m,1H), 6.29(d,1H), 5.84(d,1H), 4.69(dd,1H) , 4.60(d,1H), 4.41(d,1H), 4.20-4.03(m,1H), 3.96-3.83(m,1H), 3.78-3.41(m,4H), 3.26-3.14(m,1H) ,3.06–2.93(m,6H), 2.89–2.81(m,3H), 2.80(d,1H), 2.75(s,2H), 2.44–2.32(m,1H), 2.22–1.97(m,4H) ,1.94-1.85(m,2H),1.35-1.25(m,2H).
Ms m/z(ESI):527.6[M+H] + Ms m/z(ESI): 527.6[M+H] +
实施例2Example 2
2-[((2S)-4-[2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]-2'-氧-螺环[6,8-二氢-5H-喹唑啉-7,3'-二氢吲哚]-4-基]哌嗪-2-基]乙腈；2,2,2-三氟乙酸(化合物2)；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);
2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3' -indoline]-4-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid
Figure PCTCN2020128033-appb-000168
Figure PCTCN2020128033-appb-000168
第一步：3-(2-氨基苯基)环己-2-烯-1-酮(2a)The first step: 3-(2-aminophenyl)cyclohex-2-en-1-one (2a)
3-(2-aminophenyl)cyclohex-2-en-1-one3-(2-aminophenyl)cyclohex-2-en-1-one
Figure PCTCN2020128033-appb-000169
Figure PCTCN2020128033-appb-000169
将2-碘苯胺(44g,200.9mmol)，三(邻甲基苯基)磷(6.11g,20.09mmol),醋酸钯(2.26g,10.04mmol)，环己烯酮(21.24g,221.0mmol)和三乙胺(40.66g,401.8mmol)溶于1220mL乙腈，氮气氛围下加热至85℃回流反应40小时。TLC监测反应完全后，将反应液冷至室温，减压浓缩除去乙腈，加入800mL乙酸乙酯稀释，加入300mL水洗涤，搅拌静置分层， 水相用乙酸乙酯400mL x 2萃取，合并有机相，用500mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品柱层析纯化得目标产物2a,黄褐色固体(11.2g,收率：29.8％)。Combine 2-iodoaniline (44g, 200.9mmol), tris(o-methylphenyl)phosphorus (6.11g, 20.09mmol), palladium acetate (2.26g, 10.04mmol), cyclohexenone (21.24g, 221.0mmol) And triethylamine (40.66g, 401.8mmol) was dissolved in 1220mL of acetonitrile, and heated to 85°C under nitrogen atmosphere and refluxed for 40 hours. After the completion of the reaction monitored by TLC, 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%).
MS m/z(ESI):188.1[M+H] + MS m/z(ESI): 188.1[M+H] +
第二步：螺[环己烷-3,3'-二氢吲哚]-1,2'-二酮(2b)Step 2: Spiro[cyclohexane-3,3'-indoline]-1,2'-dione (2b)
spiro[cyclohexane-3,3'-indoline]-1,2'-dionespiro[cyclohexane-3,3'-indoline]-1,2'-dione
Figure PCTCN2020128033-appb-000170
Figure PCTCN2020128033-appb-000170
将三光气(9.51g,32.0mmol)用二氯甲烷(200mL)溶解于500mL单口圆底烧瓶中，将化合物2a(3g,16.0mmol)用二氯甲烷(100mL)溶解后滴加入到反应中，滴加完毕后将二氯甲烷(100mL)稀释的三乙胺(9.73g,96.1mmol)溶液滴加入到反应中，室温搅拌3小时。减压浓缩除去二氯甲烷，残余物加入200mL乙醚搅拌10分钟，抽滤，滤饼用100mL乙醚洗涤。将滤液减压浓缩后得到的残余物用100mL四氢呋喃溶解于1L容量的三口圆底烧瓶中，加入叔丁醇(1.19g,16.0mmol)，氮气氛围下降温至-78℃搅拌十分钟。将无水氯化锂(5.43g,128.2mmol)与二碘化钐-四氢呋喃溶液(40mmol,400mL,0.1M)的混合溶液于室温搅拌10分钟后滴加入到反应中，保持-78℃搅拌半小时。TLC显示原料消耗完全，加入200mL饱和氯化铵水溶液淬灭，升温至室温，加入乙酸乙酯(3x 300mL)萃取，合并有机相，饱和食盐水洗涤,无水硫酸钠干燥有机相，过滤，减压浓缩得到的残留物硅胶柱层析纯化得2b,棕色固体(2.34g,收率：67.8％)。Dissolve triphosgene (9.51g, 32.0mmol) with dichloromethane (200mL) in a 500mL single-neck round bottom flask, dissolve compound 2a (3g, 16.0mmol) with dichloromethane (100mL) and add dropwise to the reaction, After the addition was completed, a solution of triethylamine (9.73 g, 96.1 mmol) diluted with dichloromethane (100 mL) was added dropwise to the reaction, and the mixture was stirred at room temperature for 3 hours. 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. The mixed solution of anhydrous lithium chloride (5.43g, 128.2mmol) and samarium diiodide-tetrahydrofuran solution (40mmol, 400mL, 0.1M) was stirred at room temperature for 10 minutes and then added dropwise to the reaction, and kept at -78℃ and stirred for half hour. TLC showed that the raw materials were consumed completely. Add 200mL saturated ammonium chloride aqueous solution to quench, warm to room temperature, add ethyl acetate (3x 300mL) for extraction, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, reduce The residue obtained by pressure concentration was purified by silica gel column chromatography to obtain 2b, a brown solid (2.34 g, yield: 67.8%).
MS m/z(ESI):216.2[M+H] + MS m/z(ESI): 216.2[M+H] +
第三步：2,2'-二氧杂螺[环己烷-4,3'-二氢吲哚]-1-羧酸乙酯(2c)The third step: 2,2'-dioxaspiro[cyclohexane-4,3'-indoline]-1-carboxylic acid ethyl ester (2c)
ethyl 2,2'-dioxospiro[cyclohexane-4,3'-indoline]-1-carboxylateethyl 2,2'-dioxospiro[cyclohexane-4,3'-indoline]-1-carboxylate
Figure PCTCN2020128033-appb-000171
Figure PCTCN2020128033-appb-000171
将化合物2b(2.34g,10.9mmol)用四氢呋喃(200mL)溶解于500mL三口圆底烧瓶中，氮气氛围下冷却至-78℃，量取LiHMDS(22mL，1M in THF)滴加入到反应瓶中，搅拌十分钟，将3mL四氢呋喃稀释的氰基甲酸乙酯(1.4g,14.1mmol)缓慢滴加入到反应中，-78℃ 反应半小时后升温至室温反应2小时。加入50mL饱和氯化铵水溶液淬灭反应，加入100mL水，加入乙酸乙酯(3x 80mL)萃取，合并有机相，用饱和食盐水洗涤,无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品柱层析纯化得2c,淡黄色固体(1.22g,收率：38.4％)。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 reaction was quenched by adding 50mL saturated aqueous ammonium chloride solution, 100mL water was added, ethyl acetate (3x 80mL) was added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product, crude product Purified by column chromatography, 2c was obtained as a pale yellow solid (1.22 g, yield: 38.4%).
MS m/z(ESI):288.2[M+H] + MS m/z(ESI): 288.2[M+H] +
第四步：4-羟基-2-硫烷基-螺[6,8-二氢-5H-喹唑啉-7,3'-二氢吲哚]-2'-酮(2d)；The fourth step: 4-hydroxy-2-sulfanyl-spiro[6,8-dihydro-5H-quinazolin-7,3'-indoline]-2'-one (2d);
4-hydroxy-2-sulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one4-hydroxy-2-sulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one
Figure PCTCN2020128033-appb-000172
Figure PCTCN2020128033-appb-000172
将化合物2c(1.22g,4.25mmol)用甲醇(25mL)溶解于单口圆底烧瓶中，依次称取甲醇钠(1.38g,25.48mmol)和硫脲(970mg,12.74mmol)并加入到反应瓶中。加热至60℃反应5小时，LC-MS显示原料消耗完全。减压浓缩大部分甲醇，残余物加入35mL水溶解，加入25mL甲基叔丁基醚洗涤，水相加入2N稀盐酸调节pH＝3-4,大量固体析出，抽滤，滤饼加入水洗涤。滤饼加入8mL乙醇打浆过夜，抽滤，滤饼干燥得2d,白色固体(0.358g,收率：28.2％)。Compound 2c (1.22g, 4.25mmol) was dissolved in a single-necked round bottom flask with methanol (25mL), and sodium methoxide (1.38g, 25.48mmol) and thiourea (970mg, 12.74mmol) were weighed out and added to the reaction flask. . The reaction was heated to 60°C for 5 hours, and LC-MS showed that the raw material was consumed completely. Most of the methanol was concentrated under reduced pressure, the residue was dissolved by adding 35 mL of water, and 25 mL of methyl tert-butyl ether was added to wash, the aqueous phase was added with 2N dilute hydrochloric acid to adjust pH=3-4, a lot of solids were precipitated, filtered by suction, and the filter cake was washed with water. The filter cake was slurried overnight with 8 mL of ethanol, filtered with suction, and the filter cake was dried to obtain a white solid (0.358 g, yield: 28.2%) for 2 days.
MS m/z(ESI):298.1[M-H] - MS m/z(ESI): 298.1[MH] -
第五步：4-羟基-2-甲基硫烷基-螺[6,8-二氢-5H-喹唑啉-7,3'-二氢吲哚]-2'-酮(2e)；The fifth step: 4-hydroxy-2-methylsulfanyl-spiro[6,8-dihydro-5H-quinazolin-7,3'-indoline]-2'-one (2e);
4-hydroxy-2-methylsulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one.4-hydroxy-2-methylsulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one.
Figure PCTCN2020128033-appb-000173
Figure PCTCN2020128033-appb-000173
将化合物2d(0.1g,0.334mmol)用甲醇(15mL)溶解于单口圆底烧瓶中，加入碳酸钾(0.185g,1.34mmol)搅拌半小时，加入碘甲烷(0.05g,0.334mmol)搅拌1小时，LC-MS显示原料未消耗完全，继续加入碘甲烷(0.05g,0.334mmol)搅拌1小时，LC-MS显示原料几乎消耗完全。减压浓缩除去甲醇，加入20mL水溶解，加入2N稀盐酸调节pH＝3-4，有白色固体析出，加入3x 80mL混合溶剂(二氯甲烷/甲醇(v/v)＝10/1)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得2e,黄白色固体(120mg,收率：100％)。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. Concentrate under reduced pressure to remove methanol, add 20mL of water to dissolve, add 2N dilute hydrochloric acid to adjust pH=3-4, white solids are precipitated, add 3x 80mL mixed solvent (dichloromethane/methanol (v/v)=10/1) for extraction, The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2e, a yellow-white solid (120 mg, yield: 100%).
Ms m/z(ESI):314.1[M+H] + Ms m/z(ESI):314.1[M+H] +
第六步：(2-甲基硫烷基-2'-氧-螺[6,8-二氢-5H-喹唑啉-7,3'-二氢吲哚]-4-基)三氟甲磺酸酯(2f)；The sixth step: (2-methylsulfanyl-2'-oxy-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)trifluoro Mesylate (2f);
(2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)trifluoromethanesulfonate(2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)trifluoromethanesulfonate
Figure PCTCN2020128033-appb-000174
Figure PCTCN2020128033-appb-000174
将化合物2e(0.12g,0.383mmol)用二氯甲烷(20mL)溶解于单口圆底烧瓶中，加入三乙胺(0.117g,1.15mmol)，氮气氛围下用冰水浴降温，内温降至5-10℃，用2mL二氯甲烷稀释的三氟甲磺酸酐(0.162g，0.574mmol)加入反应中，反应十分钟，TLC监测原料未消耗完全，补加三氟甲磺酸酐(0.05g,0.191mmol)，继续反应十分钟，TLC监测原料消耗完全。加入20mL饱和碳酸氢钠水溶液淬灭，搅拌静置分层，水相用二氯甲烷(20mL x 2)萃取,合并有机相，用饱和食盐水30mL洗涤，无水硫酸钠干燥，过滤，减压浓缩得2f,棕黑色固体(170mg,收率：100％)。粗品直接用于下一步。Compound 2e (0.12g, 0.383mmol) was dissolved in a single-necked round bottom flask with dichloromethane (20mL), triethylamine (0.117g, 1.15mmol) was added, and the temperature was lowered with an ice water bath under a nitrogen atmosphere, and the internal temperature dropped to 5 At -10°C, trifluoromethanesulfonic anhydride (0.162g, 0.574mmol) diluted with 2mL of dichloromethane was added to the reaction for ten minutes. TLC monitored that the raw materials were not consumed completely. Add trifluoromethanesulfonic anhydride (0.05g, 0.191) mmol), continue the reaction for ten minutes, and TLC monitors that the raw material is consumed completely. Add 20mL saturated sodium bicarbonate aqueous solution to quench, stir and stand to separate the layers, the aqueous phase is extracted with dichloromethane (20mL x 2), the organic phases are combined, washed with saturated brine 30mL, dried with anhydrous sodium sulfate, filtered, and decompressed Concentrated to obtain 2f, brown-black solid (170 mg, yield: 100%). The crude product was used directly in the next step.
MS m/z(ESI):446.1[M+H] + MS m/z(ESI): 446.1[M+H] +
第七步：(2S)-2-(氰甲基)-4-(2-甲基硫烷基-2'-氧代螺基[6,8-二氢-5H-喹唑啉-7,3'-二氢吲哚]-4-基)哌嗪-1-甲酸叔丁酯(2g)；The seventh step: (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxospiro[6,8-dihydro-5H-quinazoline-7, 3'-Indole]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (2g);
tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine-1-carboxylatetert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine -1-carboxylate
Figure PCTCN2020128033-appb-000175
Figure PCTCN2020128033-appb-000175
将化合物2f(0.17g,0.383mmol)用N,N-二甲基乙酰胺(15mL)溶解于单口圆底烧瓶中，加入N,N-二异丙基乙胺(0.21g,1.62mmol)和(S)-2-(哌嗪-2-基)乙腈盐酸盐(0.152g,0.81mmol),室温反应半小时，TLC监测原料消耗完全，加入碳酸二叔丁酯(240mg,1.08mmol),室温搅拌16h。加入45mL水淬灭，加入二氯甲烷(30mL x 4)萃取，合并有机相， 饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品硅胶柱层析纯化得2g,棕色固体(0.13g,收率：65％)Compound 2f (0.17g, 0.383mmol) was dissolved in a single-necked round bottom flask with N,N-dimethylacetamide (15mL), and N,N-diisopropylethylamine (0.21g, 1.62mmol) and (S)-2-(piperazin-2-yl)acetonitrile hydrochloride (0.152g, 0.81mmol), react at room temperature for half an hour, TLC monitors the complete consumption of raw materials, add di-tert-butyl carbonate (240mg, 1.08mmol), Stir at room temperature for 16h. Add 45mL water for quenching, add dichloromethane (30mL x 4) for extraction, combine the organic phases, wash the organic phases with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography to obtain 2g , Brown solid (0.13g, yield: 65%)
MS m/z(ESI):521.3[M+H] + MS m/z(ESI): 521.3[M+H] +
第八步：(2S)-2-(氰甲基)-4-(2-甲基亚磺酰基-2'-氧代螺基[6,8-二氢-5H-喹唑啉-7,3'-二氢吲哚]-4-基)哌嗪-1-甲酸叔丁基酯(2h)；The eighth step: (2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxospiro[6,8-dihydro-5H-quinazoline-7, 3'-Indole]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (2h);
tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine-1-carboxylatetert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine -1-carboxylate
Figure PCTCN2020128033-appb-000176
Figure PCTCN2020128033-appb-000176
将化合物2g(0.13g,0.250mmol)用20mL四氢呋喃溶解于单口圆底烧瓶中，称取间氯过氧苯甲酸(87mg,0.499mmol)加入到反应瓶中，室温搅拌1小时，取样TLC显示原料消耗完全。可以后处理。加入20mL饱和硫代硫酸钠水溶液淬灭反应，搅拌半小时，加入乙酸乙酯(20mL x 3)萃取，合并有机相，用饱和碳酸氢钠水溶液(30mL x 3)洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得2f粗品，淡黄色固体(0.134g,收率：100％)，粗品直接用于下一步。Dissolve 2g (0.13g, 0.250mmol) of compound with 20mL of tetrahydrofuran in a single-necked round bottom flask, weigh m-chloroperoxybenzoic acid (87mg, 0.499mmol) into the reaction flask, stir at room temperature for 1 hour, sampling TLC shows the raw material Consume completely. Can be post-processed. Add 20mL saturated sodium thiosulfate aqueous solution to quench the reaction, stir for half an hour, add ethyl acetate (20mL x 3) for extraction, combine the organic phases, wash with saturated sodium bicarbonate aqueous solution (30mL x 3), and saturated brine. It was dried with aqueous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2f crude product as a pale yellow solid (0.134 g, yield: 100%), and the crude product was directly used in the next step.
MS m/z(ESI):537.3[M+H] + MS m/z(ESI): 537.3[M+H] +
第九步：(2S)-2-(氰甲基)-4-[2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]-2`-氧代螺[6,8-二氢-5H-喹唑啉-7,3`-二氢吲哚]-4-基]哌嗪-1-甲酸叔丁酯(2i)；The ninth step: (2S)-2-(cyanomethyl)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxospiro [6,8-Dihydro-5H-quinazoline-7,3`-indoline]-4-yl]piperazine-1-carboxylic acid tert-butyl ester (2i);
tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline]-4-yl]piperazine-1-carboxylatetert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H- quinazoline-7,3`-indoline]-4-yl]piperazine-1-carboxylate
Figure PCTCN2020128033-appb-000177
Figure PCTCN2020128033-appb-000177
将化合物2h(0.134g，0.250mmoL)用干燥四氢呋喃(15mL)溶解于单口圆底烧瓶中，加入N-甲基-L-脯氨醇(87mg,0.749mmol)，氮气氛围下，用冰水浴降温，内温降至5-10℃，加入叔丁醇钠(48mg,0.499mmol)，在此温度反应十分钟，TLC显示原料消耗完全。 加入10mL饱和碳酸氢钠水溶液淬灭，用20mL x 3混合溶剂(二氯甲烷/甲醇(v/v)＝10/1)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品硅胶柱层析纯化得2h,淡黄色固体(108mg,收率：73.6％)。Compound 2h (0.134g, 0.250mmoL) was dissolved in a single-necked round bottom flask with dry tetrahydrofuran (15mL), and N-methyl-L-prolinol (87mg, 0.749mmol) was added, and the temperature was cooled with an ice-water bath under a nitrogen atmosphere. , The internal temperature was lowered to 5-10°C, sodium tert-butoxide (48mg, 0.499mmol) was added and reacted at this temperature for ten minutes. TLC showed that the raw material was consumed completely. Add 10mL saturated sodium bicarbonate aqueous solution to quench, use 20mL x 3 mixed solvent (dichloromethane/methanol (v/v)=10/1), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product , The crude product was purified by silica gel column chromatography to obtain a pale yellow solid (108mg, yield: 73.6%) for 2h.
MS m/z(ESI):588.3[M+H] + MS m/z(ESI): 588.3[M+H] +
第十步：2-[((2S)-4-[2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]-2'-氧-螺环[6,8-二氢-5H-喹唑啉-7,3'-二氢吲哚]-4-基]哌嗪-2-基]乙腈(2i)；The tenth 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 (2i);
2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2-yl]acetonitrile2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3' -indoline]-4-yl]piperazin-2-yl]acetonitrile
Figure PCTCN2020128033-appb-000178
Figure PCTCN2020128033-appb-000178
将化合物2h(0.108g,0.184mmol)用二氯甲烷(5mL)溶解于单口圆底烧瓶中，加入2.5mL三氟醋酸，室温搅拌一小时，取样，TLC和LC-MS。MS显示有产品生成，TLC显示原料消耗完全。减压浓缩得2i粗品，黄色固体(89mg，收率：99％)，粗品直接用于下一步。Compound 2h (0.108 g, 0.184 mmol) was dissolved in a single-necked round bottom flask with dichloromethane (5 mL), 2.5 mL of trifluoroacetic acid was added, stirred at room temperature for one hour, sampled, TLC and LC-MS. MS shows that there is product generation, and TLC shows that the raw materials are completely consumed. Concentrated under reduced pressure to obtain 2i crude product, a yellow solid (89mg, yield: 99%), and the crude product was directly used in the next step.
MS m/z(ESI):488.3[M+H] + MS m/z(ESI): 488.3[M+H] +
第十一步：2-[((2S)-4-[2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]-2'-氧-螺环[6,8-二氢-5H-喹唑啉-7,3'-二氢吲哚]-4-基]哌嗪-2-基]乙腈；2,2,2-三氟乙酸(化合物2)；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);
2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline]- 4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid
Figure PCTCN2020128033-appb-000179
Figure PCTCN2020128033-appb-000179
将化合物2i(0.089g,0.182mmol)用30mL二氯甲烷溶解于单口圆底烧瓶中，加入N,N-二异丙基乙胺(0.2g,1.46mmol),氮气氛围下，用冰水浴降温，内温降至5-10℃，将2mL二氯甲烷稀释的烯丙酰氯(0.016g,0.182mmol),注射加入到反应中，在此温度反应10分钟，TLC监测原料反应完全。加入15mL饱和碳酸氢钠水溶液淬灭，搅拌静置分层，用 二氯甲烷(20mL x 2)萃取，合并有机相，饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品送制备液相(酸性制备，流动相体系：乙腈/0.1％TFA水)得到目标化合物2，白色固体(25mg，收率：26％)。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. Add 15mL saturated sodium bicarbonate aqueous solution to quench, stir and stand to separate the layers, extract with dichloromethane (20mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The crude product, the crude product is sent to the preparation liquid phase (acidic preparation, mobile phase system: acetonitrile/0.1% TFA water) to obtain the target compound 2, a white solid (25 mg, yield: 26%).
1H NMR(400MHz,CD 3OD)δ7.27(t,1H),7.22–7.13(m,1H),7.07–6.94(m,2H),6.90–6.70(m,1H),6.30(d,1H),5.84(d,1H),5.10–4.78(m,2H),4.73–4.62(m,1H),4.60–4.46(m,1H),4.40–4.04(m,2H),4.01–3.35(m,5H),3.30-3.19(m,1H),3.17–2.84(m,9H),2.49–2.34(m,1H),2.28–1.85(m,5H). 1 H NMR(400MHz,CD 3 OD)δ7.27(t,1H), 7.22-7.13(m,1H), 7.07-6.94(m,2H), 6.90-6.70(m,1H), 6.30(d, 1H), 5.84(d, 1H), 5.10--4.78(m, 2H), 4.73--4.62(m, 1H), 4.60--4.46(m, 1H), 4.40--4.04(m, 2H), 4.01--3.35( m,5H), 3.30-3.19(m,1H), 3.17-2.84(m,9H), 2.49-2.34(m,1H), 2.28-1.85(m,5H).
Ms m/z(ESI):542.3[M-CF 3COOH+H] + Ms m/z(ESI): 542.3[M-CF 3 COOH+H] +
实施例3Example 3
2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]甲氧基]-2'-氧代-1'-苯基-螺[6,8-二氢-5H-喹唑啉]-7,4'-吡咯烷]-4-基]-1-丙-2-烯酰基-哌嗪-2-基]乙腈(化合物3)；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);
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.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.
Figure PCTCN2020128033-appb-000180
Figure PCTCN2020128033-appb-000180
第一步：3-[叔丁基(二甲基)甲硅烷基]氧基环己醇(3a)；The first step: 3-[tert-butyl(dimethyl)silyl]oxycyclohexanol (3a);
3-[tert-butyl(dimethyl)silyl]oxycyclohexanol.3-[tert-butyl(dimethyl)silyl]oxycyclohexanol.
Figure PCTCN2020128033-appb-000181
Figure PCTCN2020128033-appb-000181
将化合物1,3-环己二醇(5g,43.04mmol)溶于30mL N,N-二甲基甲酰胺中，依次加入咪唑(4.40g,64.50mmol)和叔丁基二甲基氯硅烷(6.49g,43.04mmol)，室温搅拌4h。加入50mL甲基叔丁基醚和50mL水，萃取分液，有机层用饱和食盐水洗涤(40mL x 3)，有机层减压浓缩后硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/10-1/3)得化合物3a，淡黄色油状物(4g，收率：40％)。The compound 1,3-cyclohexanediol (5g, 43.04mmol) was dissolved in 30mL N,N-dimethylformamide, and imidazole (4.40g, 64.50mmol) and tert-butyldimethylchlorosilane ( 6.49g, 43.04mmol), stirred at room temperature for 4h. Add 50mL methyl tert-butyl ether and 50mL water, extract and separate the layers, wash the organic layer with saturated brine (40mL x 3), concentrate the organic layer under reduced pressure and purify it by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether) (v/v)=1/10-1/3) Compound 3a was obtained as a pale yellow oil (4g, yield: 40%).
Ms m/z(ESI):231.3[M+H] + Ms m/z(ESI):231.3[M+H] +
第二步：3-[叔丁基(二甲基)甲硅烷基]氧基环己酮(3b)；The second step: 3-[tert-butyl(dimethyl)silyl]oxycyclohexanone (3b);
3-[tert-butyl(dimethyl)silyl]oxycyclohexanone.3-[tert-butyl(dimethyl)silyl]oxycyclohexanone.
Figure PCTCN2020128033-appb-000182
Figure PCTCN2020128033-appb-000182
将化合物3a(2.7g,11.74mmol)溶于20mL二氯甲烷中，加入戴斯马丁氧化剂(5g,11.79mmol)，室温下搅拌反应1h。加入20mL饱和硫代硫酸钠和20mL饱和碳酸氢钠水溶液，室温搅拌20min，分液，有机层减压浓缩后，硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/10-1/3)得化合物3b，浅黄色油状物(2g，收率：75％)。Compound 3a (2.7 g, 11.74 mmol) was dissolved in 20 mL of dichloromethane, and Dess Martin oxidant (5 g, 11.79 mmol) was added, and the reaction was stirred at room temperature for 1 h. Add 20mL saturated sodium thiosulfate and 20mL saturated sodium bicarbonate aqueous solution, stir at room temperature for 20min, separate the layers, after the organic layer is concentrated under reduced pressure, purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) = 1/10-1/3) to obtain compound 3b as a pale yellow oil (2g, yield: 75%).
1HNMR(400MHz,CDCl 3)δ4.21-4.10(m,1H),2.56-2.48(m,1H),2.42-2.34(m,1H),2.34-2.22(m,2H),2.12-2.00(m,1H),1.93-1.85(m,1H),1.78-1.62(m,2H),0.87(s,9H),0.05(s,6H). 1 HNMR (400MHz, CDCl 3 ) δ 4.21-4.10 (m, 1H), 2.56-2.48 (m, 1H), 2.42-2.34 (m, 1H), 2.34-2.22 (m, 2H), 2.12-2.00 ( m, 1H), 1.93-1.85 (m, 1H), 1.78-1.62 (m, 2H), 0.87 (s, 9H), 0.05 (s, 6H).
Ms m/z(ESI):229.3[M+H] + Ms m/z(ESI): 229.3[M+H] +
第三步：2-[3-[3-[叔丁基(二甲基)甲硅烷基]氧基环己叉]乙酸乙酯(3c)；The third step: 2-[3-[3-[tert-butyl(dimethyl)silyl]oxycyclohexylidene] ethyl acetate (3c);
ethyl 2-[3-[tert-butyl(dimethyl)silyl]oxycyclohexylidene]acetate.ethyl 2-[3-[tert-butyl(dimethyl)silyl]oxycyclohexylidene]acetate.
Figure PCTCN2020128033-appb-000183
Figure PCTCN2020128033-appb-000183
将氢化钠(2.05g,85.38mmol)加入到100mL的四氢呋喃中，冰浴下缓慢滴入磷酰基乙酸三乙酯(21.69g,96.76mmol)，滴毕，冰浴下搅拌30min后加入3b(13g,56.92mmol)，冰浴下搅拌30min。加入30mL饱和氯化铵水溶液和100mL水淬灭，加入100mL甲基叔丁基醚萃取，有机层用100mL饱和食盐水洗涤，减压干燥后，硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/20-1/6)得化合物3c，淡黄色油状物(13g，收率：76％)。Sodium hydride (2.05g, 85.38mmol) was added to 100mL of tetrahydrofuran, and triethyl phosphonoacetate (21.69g, 96.76mmol) was slowly added dropwise under ice bath. After the dripping was completed, stirred under ice bath for 30min and then added 3b(13g , 56.92mmol), stirred for 30min under ice bath. It was quenched by adding 30 mL of saturated aqueous ammonium chloride solution and 100 mL of water, adding 100 mL of methyl tert-butyl ether for extraction, and the organic layer was washed with 100 mL of saturated brine, dried under reduced pressure, and purified by silica gel column chromatography (mobile phase: ethyl acetate/ Petroleum ether (v/v) = 1/20-1/6) to obtain compound 3c as a pale yellow oil (13 g, yield: 76%).
Ms m/z(ESI):299.3[M+H] + Ms m/z(ESI): 299.3[M+H] +
第四步：2-[3-羟基-1-(硝基甲基)环己基]乙酸乙酯(3d)；The fourth step: ethyl 2-[3-hydroxy-1-(nitromethyl)cyclohexyl]acetate (3d);
ethyl 2-[3-hydroxy-1-(nitromethyl)cyclohexyl]acetate.ethyl 2-[3-hydroxy-1-(nitromethyl)cyclohexyl]acetate.
Figure PCTCN2020128033-appb-000184
Figure PCTCN2020128033-appb-000184
将化合物3c(0.5g,1.7mmol)溶于10mL四氢呋喃中，依次加入硝基甲烷(0.31g,5.0mmol)和四丁基氟化铵(1.1g,4.2mmol)，升温回流搅拌过夜。加入20mL水和20mL甲基叔丁基醚萃取，有机层减压浓缩后，残留物硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/10-1/2)得化合物3d，淡黄色油状物(0.35g，收率：85％)。Compound 3c (0.5 g, 1.7 mmol) was dissolved in 10 mL of tetrahydrofuran, and nitromethane (0.31 g, 5.0 mmol) and tetrabutylammonium fluoride (1.1 g, 4.2 mmol) were added in sequence, and the temperature was heated to reflux and stirred overnight. Add 20mL water and 20mL methyl tert-butyl ether for extraction, and after the organic layer is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) = 1/10-1/2 ) Compound 3d was obtained as a pale yellow oil (0.35 g, yield: 85%).
Ms m/z(ESI):246.3[M+H] + Ms m/z(ESI):246.3[M+H] +
第五步：7-羟基-2-氮杂螺[4.5]癸烷-3-酮(3e)；The fifth step: 7-hydroxy-2-azaspiro[4.5]decane-3-one (3e);
7-hydroxy-2-azaspiro[4.5]decan-3-one.7-hydroxy-2-azaspiro[4.5]decan-3-one.
Figure PCTCN2020128033-appb-000185
Figure PCTCN2020128033-appb-000185
将化合物3d(0.35g,1.4mmol)溶于10mL甲醇中，加入雷尼镍(0.1g,≤50μm,分散在水中)和碳酸钾(19mg,0.14mmol)，于氢气(1atm)下搅拌过夜。过滤，滤液减压浓缩，残留物硅胶柱层析纯化(流动相：二氯甲烷/甲醇(v/v)＝100/1-10/1)得化合物3e，白色固体(0.16g，收率：66％)。Compound 3d (0.35g, 1.4mmol) was dissolved in 10mL methanol, Raney nickel (0.1g, ≤50μm, dispersed in water) and potassium carbonate (19mg, 0.14mmol) were added, and stirred overnight under hydrogen (1atm). After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v)=100/1-10/1) to obtain compound 3e, a white solid (0.16g, yield: 66%).
1H NMR(400MHz,CD 3OD)δ3.68-3.58(m,1H),3.21-3.14(m,2H),2.26-2.13(m,2H),1.94-1.84(m,2H),1.78-1.68(m,1H),1.65-1.56(m,1H),1.48-1.20(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 3.68-3.58 (m, 1H), 3.21-3.14 (m, 2H), 2.26-2.13 (m, 2H), 1.94-1.84 (m, 2H), 1.78- 1.68 (m, 1H), 1.65-1.56 (m, 1H), 1.48-1.20 (m, 4H).
Ms m/z(ESI):170.2[M+H] + Ms m/z(ESI): 170.2[M+H] +
第六步：7-[叔丁基(二甲基)甲硅烷基]氧基-2-氮杂螺[4.5]癸烷-3-酮(3f)；The sixth step: 7-[tert-butyl(dimethyl)silyl]oxy-2-azaspiro[4.5]decane-3-one (3f);
7-[tert-butyl(dimethyl)silyl]oxy-2-azaspiro[4.5]decan-3-one.7-[tert-butyl(dimethyl)silyl]oxy-2-azaspiro[4.5]decan-3-one.
Figure PCTCN2020128033-appb-000186
Figure PCTCN2020128033-appb-000186
将化合物3e(0.16g,0.95mmol)溶于10mL二氯甲烷中，依次加入咪唑(0.13g,1.90mmol)和叔丁基二甲基氯硅烷(0.17g,1.10mmol)，室温搅拌3h。加入10mL的水溶液洗涤有机层，有机层减压浓缩，残留物硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/5-1/0)得化合物3f，白色固体(0.17g，收率：63％)。Compound 3e (0.16g, 0.95mmol) was dissolved in 10mL of dichloromethane, imidazole (0.13g, 1.90mmol) and tert-butyldimethylchlorosilane (0.17g, 1.10mmol) were added in sequence, and stirred at room temperature for 3h. 10mL of aqueous solution was added to wash the organic layer, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v)=1/5-1/0) to obtain compound 3f, white Solid (0.17 g, yield: 63%).
Ms m/z(ESI):284.3[M+H] + Ms m/z(ESI):284.3[M+H] +
第七步：7-[叔丁基(二甲基)甲硅烷基]氧基-2-苯基-2-氮杂螺[4.5]癸烷-3-酮(3g)；The seventh step: 7-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-2-azaspiro[4.5]decane-3-one (3g);
7-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-2-azaspiro[4.5]decan-3-one.7-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-2-azaspiro[4.5]decan-3-one.
Figure PCTCN2020128033-appb-000187
Figure PCTCN2020128033-appb-000187
将化合物3f(0.13g,0.46mmol)和碘苯(0.14g,0.69mmol)溶于10mL甲苯中，依次加入碳酸铯(0.30g,0.92mmol)、反式1,2-环己二胺(5.2mg,0.046mmol)和碘化亚铜(4.4mg,0.023mmol)，氮气保护下升温至110℃搅拌过夜。冷却至室温，加入10mL乙酸乙酯和20mL氨水萃取，有机层用无水硫酸钠干燥后，残留物硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/20-1/5)得化合物3g，白色固体(0.1g，收率：61％)。Compound 3f (0.13g, 0.46mmol) and iodobenzene (0.14g, 0.69mmol) were dissolved in 10mL of toluene, and cesium carbonate (0.30g, 0.92mmol), trans 1,2-cyclohexanediamine (5.2 mg, 0.046mmol) and cuprous iodide (4.4mg, 0.023mmol), heated to 110°C under the protection of nitrogen and stirred overnight. After cooling to room temperature, adding 10 mL ethyl acetate and 20 mL ammonia for extraction, the organic layer was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) = 1/20 -1/5) Compound 3g was obtained as a white solid (0.1g, yield: 61%).
1HNMR(400MHz,CDCl 3)δ7.59(d,2H),7.38-7.32(m,2H),7.16-7.10(m,1H),3.93-3.85(m,1H),3.83-3.64(m,2H),2.51-2.36(m,2H),1.82-1.74(m,2H),1.70-1.40(m,6H),0.90(s,9H),0.06(d,6H). 1 HNMR (400MHz, CDCl 3 ) δ 7.59 (d, 2H), 7.38-7.32 (m, 2H), 7.16-7.10 (m, 1H), 3.93-3.85 (m, 1H), 3.83-3.64 (m, 2H), 2.51-2.36 (m, 2H), 1.82-1.74 (m, 2H), 1.70-1.40 (m, 6H), 0.90 (s, 9H), 0.06 (d, 6H).
Ms m/z(ESI):360.3[M+H] + Ms m/z(ESI): 360.3[M+H] +
第八步：7-羟基-2-苯基-2-氮杂螺[4.5]癸烷-3-酮(3h)；The eighth step: 7-hydroxy-2-phenyl-2-azaspiro[4.5]decane-3-one (3h);
7-hydroxy-2-phenyl-2-azaspiro[4.5]decan-3-one.7-hydroxy-2-phenyl-2-azaspiro[4.5]decan-3-one.
Figure PCTCN2020128033-appb-000188
Figure PCTCN2020128033-appb-000188
将化合物3g(1g,2.78mmol)溶于10mL的四氢呋喃中，加入四丁基氟化铵(1.45g,5.56mmol)，升温至60℃搅拌2h。加入20mL水和20mL乙酸乙酯萃取，有机层减压浓缩后直接用于下一步。Compound 3g (1g, 2.78mmol) was dissolved in 10mL of tetrahydrofuran, tetrabutylammonium fluoride (1.45g, 5.56mmol) was added, and the temperature was raised to 60°C and stirred for 2h. 20 mL of water and 20 mL of ethyl acetate were added for extraction, and the organic layer was concentrated under reduced pressure and used directly in the next step.
Ms m/z(ESI):246.2[M+H] + Ms m/z(ESI):246.2[M+H] +
第九步：2-苯基-2-氮杂螺[4.5]癸烷-3,7-二酮(3i)；The ninth step: 2-phenyl-2-azaspiro[4.5]decane-3,7-dione (3i);
2-phenyl-2-azaspiro[4.5]decane-3,7-dione.2-phenyl-2-azaspiro[4.5]decane-3,7-dione.
Figure PCTCN2020128033-appb-000189
Figure PCTCN2020128033-appb-000189
将化合物3h(0.7g,2.85mmol)溶于20mL二氯甲烷中，加入戴斯马丁氧化剂(1.21g,2.85mmol)，室温下搅拌反应1h。加入20mL饱和硫代硫酸钠和20mL饱和碳酸氢钠水溶液，室温搅拌20min，分液，有机层减压浓缩后，残留物硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/10-1/1)得化合物3i，白色固体(0.6g，收率：86％)。Compound 3h (0.7 g, 2.85 mmol) was dissolved in 20 mL of dichloromethane, Dess Martin oxidant (1.21 g, 2.85 mmol) was added, and the reaction was stirred at room temperature for 1 h. Add 20mL saturated sodium thiosulfate and 20mL saturated sodium bicarbonate aqueous solution, stir at room temperature for 20min, separate the layers, after the organic layer is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) )=1/10-1/1) to obtain compound 3i as a white solid (0.6 g, yield: 86%).
Ms m/z(ESI):244.2[M+H] + Ms m/z(ESI):244.2[M+H] +
第十步：3,7-二氧代-2-苯基-2-氮杂螺[4.5]癸烷-8-羧酸乙酯(3k)；The tenth step: 3,7-dioxo-2-phenyl-2-azaspiro[4.5]decane-8-carboxylic acid ethyl ester (3k);
ethyl 3,7-dioxo-2-phenyl-2-azaspiro[4.5]decane-8-carboxylate.ethyl 3,7-dioxo-2-phenyl-2-azaspiro[4.5]decane-8-carboxylate.
Figure PCTCN2020128033-appb-000190
Figure PCTCN2020128033-appb-000190
将化合物3i(0.4g,1.64mmol)，碳酸(2,3,4,5,6-五氟苯基)乙酯(3j,合成参考Org.Lett.2013,15,2,370-373)(0.42g,1.64mmol)，二异丙基乙胺(0.64g,4.95mmol)和4-二甲氨基吡啶(0.06g,0.493mmol)混合在一50mL的单口瓶中，加入20mL二氯甲烷，氮气保护下加入溴化镁乙醚络合物(1.06g,4.11mmol)，于氮气保护下室温搅拌3h。加入20mL 5％的盐酸水溶液和20mL二氯甲烷溶液萃取，有机层用无水硫酸钠干燥后，减压浓缩，残留物硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/5-1/1)得化合物3k，浅黄色油状物(0.4g，收率：77％)。Compound 3i (0.4g, 1.64mmol), (2,3,4,5,6-pentafluorophenyl) ethyl carbonate (3j, synthesis reference Org.Lett.2013,15,2,370-373) (0.42g , 1.64mmol), diisopropylethylamine (0.64g, 4.95mmol) and 4-dimethylaminopyridine (0.06g, 0.493mmol) mixed in a 50mL single-necked flask, add 20mL dichloromethane, under nitrogen protection Magnesium bromide ether complex (1.06g, 4.11mmol) was added and stirred at room temperature for 3h under nitrogen protection. Add 20mL 5% aqueous hydrochloric acid and 20mL dichloromethane solution for extraction, the organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) )=1/5-1/1) Compound 3k was obtained as a pale yellow oil (0.4g, yield: 77%).
Ms m/z(ESI):316.2[M+H] + Ms m/z(ESI):316.2[M+H] +
第十一步：2-甲基硫烷基-1'-苯基-螺基[3,5,6,8-四氢喹唑啉-7,4'-吡咯烷]-2',4-二酮(3l)；The eleventh step: 2-methylsulfanyl-1'-phenyl-spiro[3,5,6,8-tetrahydroquinazoline-7,4'-pyrrolidine]-2',4- Dione (3l);
2-methylsulfanyl-1'-phenyl-spiro[3,5,6,8-tetrahydroquinazoline-7,4'-pyrrolidine]-2',4-dione.2-methylsulfanyl-1'-phenyl-spiro[3,5,6,8-tetrahydroquinazoline-7,4'-pyrrolidine]-2',4-dione.
Figure PCTCN2020128033-appb-000191
Figure PCTCN2020128033-appb-000191
将化合物3k(0.36g,1.14mmol)和S-甲基异硫脲硫酸盐(0.32g,1.71mmol)溶于5mL的乙腈中，加入5mL水和碳酸钾(0.32g,2.30mmol)，升温至60℃搅拌3h。用0.5N的稀盐酸调节pH＝5～6,过滤，滤饼用20mL 50％的乙腈水溶液和20mL水依次洗涤。滤饼减压干燥后，得化合物3l，白色固体(0.18g，收率：46％)，直接用于下一步。Dissolve compound 3k (0.36g, 1.14mmol) and S-methyl isothiourea sulfate (0.32g, 1.71mmol) in 5mL of acetonitrile, add 5mL of water and potassium carbonate (0.32g, 2.30mmol), and heat to Stir at 60°C for 3h. Adjust pH=5-6 with 0.5N dilute hydrochloric acid, filter, and wash the filter cake with 20 mL of 50% acetonitrile aqueous solution and 20 mL of water in turn. After the filter cake was dried under reduced pressure, compound 3l was obtained as a white solid (0.18 g, yield: 46%), which was directly used in the next step.
Ms m/z(ESI):342.2[M+H] + Ms m/z(ESI):342.2[M+H] +
第十二步：(2-甲基硫烷基-2'-氧代-1'-苯基-螺[6,8-二氢-5H-喹唑啉-7,4'-吡咯烷]-4-基)三氟甲磺酸酯(3m)；The twelfth step: (2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]- 4-yl) triflate (3m);
(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)trifluoromethanesulfonate.(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)trifluoromethanesulfonate.
将化合物3l(0.17g,0.50mmol)溶于10mL二氯甲烷中，加入三乙胺(0.10g,1.0mmol)，冰浴下加入三氟甲磺酸酐(0.21g,0.75mmol)，冰浴下搅拌1h。用10mL水洗涤反应液， 再用10mL饱和碳酸氢钠水溶液洗涤反应液，有机层减压浓缩后，残留物硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/20-1/5)得化合物3m，黄色固体(0.17g，收率：72％)。Dissolve compound 3l (0.17g, 0.50mmol) in 10mL of dichloromethane, add triethylamine (0.10g, 1.0mmol), add trifluoromethanesulfonic anhydride (0.21g, 0.75mmol) under ice bath Stir for 1h. The reaction solution was washed with 10 mL of water, and then washed with 10 mL of saturated sodium bicarbonate aqueous solution. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) = 1 /20-1/5) Compound 3m was obtained as a yellow solid (0.17 g, yield: 72%).
Ms m/z(ESI):474.1[M+H] + Ms m/z(ESI):474.1[M+H] +
第十三步：叔丁基(2S)-2-(氰甲基)-4-(2-甲基硫烷基-2'-氧代-1'-苯基-螺[6,8-二氢-5H-喹唑啉-7,4'-吡咯烷]-4-基)哌嗪-1-羧酸酯(3n)；The thirteenth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-di Hydrogen-5H-quinazoline-7,4'-pyrrolidin]-4-yl)piperazine-1-carboxylate (3n);
tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)piperazine-1-carboxylate.tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]- 4-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000192
Figure PCTCN2020128033-appb-000192
将化合物3m(0.17g,0.36mmol)溶于10mL N,N-二甲基甲酰胺中，加入二异丙基乙胺(0.28g,2.17mmol)和2-[(2S)-哌嗪-2-基]乙腈二盐酸盐(0.071g,0.36mmol)，室温搅拌1h后加入二碳酸二叔丁酯(0.24g,1.10mmol)，继续搅拌5h。加入20mL水和20mL乙酸乙酯萃取，有机层减压浓缩后，残留物硅胶柱层析纯化(流动相：乙酸乙酯/石油醚(v/v)＝1/10-1/2)得化合物3n，白色固体(0.14g，收率：71％)。Dissolve compound 3m (0.17g, 0.36mmol) in 10mL N,N-dimethylformamide, add diisopropylethylamine (0.28g, 2.17mmol) and 2-[(2S)-piperazine-2 -Yl]acetonitrile dihydrochloride (0.071g, 0.36mmol), stirred at room temperature for 1h, then added di-tert-butyl dicarbonate (0.24g, 1.10mmol), and continued stirring for 5h. Add 20 mL of water and 20 mL of ethyl acetate for extraction. After the organic layer is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) = 1/10-1/2) to obtain the compound 3n, white solid (0.14 g, yield: 71%).
Ms m/z(ESI):549.3[M+H] + Ms m/z(ESI): 549.3[M+H] +
第十四步：叔丁基(2S)-2-(氰甲基)-4-(2-甲基亚磺酰基-2'-氧代-1'-苯基-螺[6,8-二氢-5H-喹唑啉-7,4'-吡咯烷]-4-基)哌嗪-1-羧酸酯(3o)；The fourteenth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-1'-phenyl-spiro[6,8-di Hydrogen-5H-quinazoline-7,4'-pyrrolidin]-4-yl)piperazine-1-carboxylate (3o);
tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)piperazine-1-carboxylate.tert-butyl(2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]- 4-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000193
Figure PCTCN2020128033-appb-000193
将化合物3n(0.13g,0.24mmol)溶于10mL四氢呋喃中，加入间氯过氧苯甲酸(0.082g,0.47mmol)，室温搅拌2h。加入10mL饱和硫代硫酸钠水溶液，搅拌20min，加入20 mL乙酸乙酯萃取，有机层用10mL饱和碳酸氢钠水溶液洗涤，减压浓缩得化合物3o，直接用于下一步。Compound 3n (0.13 g, 0.24 mmol) was dissolved in 10 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (0.082 g, 0.47 mmol) was added, and the mixture was stirred at room temperature for 2 h. Add 10 mL of saturated sodium thiosulfate aqueous solution, stir for 20 min, add 20 mL of ethyl acetate for extraction, and wash the organic layer with 10 mL of saturated sodium bicarbonate aqueous solution, and concentrate under reduced pressure to obtain compound 3o, which is used directly in the next step.
Ms m/z(ESI):565.3[M+H] + Ms m/z(ESI):565.3[M+H] +
第十五步：叔丁基(2S)-2-(氰甲基)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]甲氧基]-2'-氧代-1'-苯基-螺[6,8-二氢-5H-喹唑啉-7,4'-吡咯烷]-4-基]哌嗪-1-甲酸酯(3p)；The fifteenth step: tert-butyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'- Oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazine-1-carboxylate (3p);
tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazine-1-carboxylate.tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8 -dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000194
Figure PCTCN2020128033-appb-000194
将化合物3o(0.15g,0.27mmol)和(S)-(1-甲基吡咯烷-2-基)甲醇(0.092g,0.80mmol)溶于10mL四氢呋喃中，冰浴下加入叔丁醇钠(0.051g,0.53mmol)，冰浴下搅拌1h。加入10mL水淬灭反应，加入20mL乙酸乙酯萃取，有机层减压浓缩，残留物硅胶柱层析纯化(流动相：二氯甲烷/甲醇(v/v)＝50/1-10/1)得化合物3p，白色固体(0.11g，收率：67％)。Compound 3o (0.15g, 0.27mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (0.092g, 0.80mmol) were dissolved in 10mL of tetrahydrofuran, and sodium tert-butoxide ( 0.051g, 0.53mmol), stirred under ice bath for 1h. The reaction was quenched by adding 10 mL of water, 20 mL of ethyl acetate was added for extraction, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v)=50/1-10/1) Compound 3p was obtained as a white solid (0.11 g, yield: 67%).
Ms m/z(ESI):616.3[M+H] + Ms m/z(ESI):616.3[M+H] +
第十六步：2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]甲氧基]-2'-氧代-1'-苯基-螺[6,8-二氢-5H-喹唑啉]-7,4'-吡咯烷]-4-基]哌嗪-2-基]乙腈；2,2,2-三氟乙酸盐(3q)；The sixteenth step: 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]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetate (3q);
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]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid.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]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid.
Figure PCTCN2020128033-appb-000195
Figure PCTCN2020128033-appb-000195
将化合物3p(0.11g,0.18mmol)溶于4mL二氯甲烷中，加入4mL三氟乙酸，室温搅拌2h。减压除去溶剂得到化合物3q，直接用于下一步。Compound 3p (0.11 g, 0.18 mmol) was dissolved in 4 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to obtain compound 3q, which was used directly in the next step.
Ms m/z(ESI):516.4[M+H] + Ms m/z(ESI):516.4[M+H] +
第十七步：2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]甲氧基]-2'-氧代-1'-苯基-螺[6,8-二氢-5H-喹唑啉]-7,4'-吡咯烷]-4-基]-1-丙-2-烯酰基-哌嗪-2-基]乙腈(化合物3)；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);
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.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.
Figure PCTCN2020128033-appb-000196
Figure PCTCN2020128033-appb-000196
将化合物3p(0.13g,0.17mmol)溶于5mL二氯甲烷中，加入三乙胺(0.053g,0.52mmol)，冰浴下加入烯丙酰氯(16mg,0.17mmol)，冰浴下搅拌30min。加入10mL饱和碳酸氢钠水溶液淬灭，有机层减压浓缩后，残留物硅胶柱层析纯化(流动相：二氯甲烷/甲醇(v/v)＝30/1-8/1)得化合物3，白色固体(0.06g，收率：60％)。Compound 3p (0.13g, 0.17mmol) was dissolved in 5mL of dichloromethane, triethylamine (0.053g, 0.52mmol) was added, acryloyl chloride (16mg, 0.17mmol) was added under ice bath, and stirred under ice bath for 30min. It was quenched by adding 10 mL saturated aqueous sodium bicarbonate solution, and the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v)=30/1-8/1) to obtain compound 3. , White solid (0.06g, yield: 60%).
1H NMR(400MHz,CDCl 3)δ7.59(t,2H),7.40-7.32(m,2H),7.19-7.10(m,1H),6.65-6.50(m,1H),6.43-6.33(m,1H),5.86-5.77(m,1H),5.16-4.33(m,2H),4.25-3.94(m,3H),3.93-3.45(m,4H),3.42-3.26(m,1H),3.24-3.11(m,1H),3.11-2.98(m,1H),2.98-2.87(m,2H),2.85-2.59(m,6H),2.58-2.45(m,4H),2.41-2.29(m,1H),2.13-1.93(m,2H),1.92-1.70(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.59 (t, 2H), 7.40-7.32 (m, 2H), 7.19-7.10 (m, 1H), 6.65-6.50 (m, 1H), 6.43-6.33 (m ,1H),5.86-5.77(m,1H),5.16-4.33(m,2H),4.25-3.94(m,3H),3.93-3.45(m,4H),3.42-3.26(m,1H), 3.24 -3.11(m,1H),3.11-2.98(m,1H),2.98-2.87(m,2H),2.85-2.59(m,6H),2.58-2.45(m,4H),2.41-2.29(m, 1H), 2.13-1.93 (m, 2H), 1.92-1.70 (m, 4H).
Ms m/z(ESI):570.4[M+H] + Ms m/z(ESI): 570.4[M+H] +
实施例4Example 4
2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]亚甲氧基]杂环[6,8-二氢-5H-喹唑啉-7,1'-茚满]-4-基]-1-丙基-2-烯酰-哌嗪-2-基]乙腈(化合物4)；2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methyleneoxy]heterocycle[6,8-dihydro-5H-quinazoline- 7,1'-Indan]-4-yl]-1-propyl-2-enoyl-piperazin-2-yl]acetonitrile (Compound 4);
2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4- yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile
Figure PCTCN2020128033-appb-000197
Figure PCTCN2020128033-appb-000197
Figure PCTCN2020128033-appb-000198
Figure PCTCN2020128033-appb-000198
第一步：2-(3,5-二甲氧基苯基)乙-1-醇(4a)；The first step: 2-(3,5-dimethoxyphenyl)ethan-1-ol (4a);
2-(3,5-dimethoxyphenyl)ethan-1-ol.2-(3,5-dimethoxyphenyl)ethan-1-ol.
Figure PCTCN2020128033-appb-000199
Figure PCTCN2020128033-appb-000199
将(3，5-二甲氧基苯基)乙酸(1.07g，5.48mmol)的THF(10mL)溶液，于室温下滴加到四氢铝锂(312mg，8.22mmol)在THF(35mL)中的悬浮液中。保持室温反应一小时，待原料反应完全后，将反应冷却至0℃，并通过缓慢加入1mL水将过量的四氢铝锂淬灭。然后将混合物倒入1N HCl水溶液中，用乙酸乙酯(50mL)萃取3次，合并有机相，有机相用饱和食盐水洗涤，经无水硫酸镁干燥，并减压浓缩，得到无色液体粗产品(4a)直接用于下一步(0.9g，收率：90％)。A solution of (3,5-dimethoxyphenyl)acetic acid (1.07g, 5.48mmol) in THF (10mL) was added dropwise to lithium tetrahydroaluminum (312mg, 8.22mmol) in THF (35mL) at room temperature In the suspension. The reaction was maintained at room temperature for one hour. After the reaction of the raw materials was completed, the reaction was cooled to 0° C., and the excess lithium aluminum tetrahydrogen was quenched by slowly adding 1 mL of water. Then the mixture was poured into 1N HCl aqueous solution, extracted with ethyl acetate (50 mL) 3 times, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a colorless crude liquid The product (4a) was directly used in the next step (0.9g, yield: 90%).
第二步：1-(2-溴乙基)-3,5-二甲氧基苯(4b)；The second step: 1-(2-bromoethyl)-3,5-dimethoxybenzene (4b);
1-(2-bromoethyl)-3,5-dimethoxybenzene.1-(2-bromoethyl)-3,5-dimethoxybenzene.
Figure PCTCN2020128033-appb-000200
Figure PCTCN2020128033-appb-000200
将化合物4a溶于二氯甲烷(11mL)中，并加入CBr 4(2.00g，6.03mmol)。然后将体系冷却至0℃，并缓慢添加Ph 3P(1.58g，6.03mmol)。体系自动升至室温并搅拌30分钟，待原料反应完全后，将溶液倒入20mL水中，用乙酸乙酯50mL萃取3次，合并有机相，有机相用饱和食盐水洗涤，并用无水硫酸镁干燥，再减压浓缩。将浓缩后的混合物置于-20℃条件下析出白色固体，用混合溶剂(冷正己烷：乙醚＝7:1)溶解混合物后，过滤，继续用混合溶剂(冷正己烷：乙醚＝7:1)洗涤滤饼两次，滤液旋干，柱层析得到澄清油状物化合物4b(1.18g，收率：88％)。 Compound 4a was dissolved in dichloromethane (11 mL), and CBr 4 (2.00 g, 6.03 mmol) was added. Then the system was cooled to 0°C, and Ph 3 P (1.58 g, 6.03 mmol) was slowly added. The system was automatically warmed to room temperature and stirred for 30 minutes. After the reaction of the raw materials was completed, the solution was poured into 20 mL of water, extracted with 50 mL of ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate , And then concentrated under reduced pressure. Place the concentrated mixture at -20°C to precipitate a white solid. After dissolving the mixture with a mixed solvent (cold n-hexane: ether = 7:1), filter and continue to use the mixed solvent (cold n-hexane: ether = 7:1) ) The filter cake was washed twice, the filtrate was spin-dried, and column chromatography was used to obtain a clear oily compound 4b (1.18 g, yield: 88%).
MS m/z(ESI):245.1[M+H] + MS m/z(ESI): 245.1[M+H] +
第三步：3-(3,5-二甲氧基苯乙基)环己-2-烯-1-酮(4c)；The third step: 3-(3,5-dimethoxyphenethyl)cyclohex-2-en-1-one (4c);
3-(3,5-dimethoxyphenethyl)cyclohex-2-en-1-one.3-(3,5-dimethoxyphenethyl)cyclohex-2-en-1-one.
Figure PCTCN2020128033-appb-000201
Figure PCTCN2020128033-appb-000201
在干燥氮气保护下，将镁屑(228mg，8.65mmol)置于50mL的三口烧瓶中，缓慢滴加约1/4的化合物4b(424mg，1.73mmol)的THF(0.5mL)溶液。加入一粒碘，并对烧瓶加热使得碘单质的颜色褪去，继续缓慢滴加化合物4b的THF溶液，使得反应体系保持微沸。滴加完毕后，体系于室温下继续反应1h。并在0℃下滴加到3-乙氧基-2-环己烯酮(107mg，0.763mmol)的THF(1.5mL)溶液中。体系于室温下搅拌2h，并在0℃下加入1N HCl水溶液(10mL)淬灭反应。然后在室温下再搅拌30分钟后，将混合物用EA(20mL×3)萃取。将合并的萃取液干燥并在减压下浓缩。经柱层析纯化(EtOAc/己烷，1∶4)，得到无色油状化合物4c(89mg，收率：45％)。Under the protection of dry nitrogen, 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 system was stirred at room temperature for 2h, and the reaction was quenched by adding 1N HCl aqueous solution (10 mL) at 0°C. Then, after stirring for another 30 minutes at room temperature, the mixture was extracted with EA (20 mL×3). The combined extracts were dried and concentrated under reduced pressure. Purification by column chromatography (EtOAc/hexane, 1:4) gave compound 4c (89 mg, yield: 45%) as a colorless oil.
MS m/z(ESI):261.1[M+H] + MS m/z(ESI): 261.1[M+H] +
第四步：3-(3,5-二羟基苯乙基)环己-2-烯-1-酮(4d)；The fourth step: 3-(3,5-dihydroxyphenethyl)cyclohex-2-en-1-one (4d);
3-(3,5-dihydroxyphenethyl)cyclohex-2-en-1-one.3-(3,5-dihydroxyphenethyl)cyclohex-2-en-1-one.
Figure PCTCN2020128033-appb-000202
Figure PCTCN2020128033-appb-000202
将4c(2.5g，9.6mmol)溶于DCM(100mL)中，冷却至-78℃。然后缓慢滴加BBr 3(1N的CH 2Cl 2溶液，24mL，24mmol)。滴加完毕后，体系自动升至室温反应6h。待反应完成后，体系于-78℃下，加入冰水淬灭反应，后用EA(100mL)萃取3次。合并有机相，有机相用饱和食盐水洗涤，并用无水硫酸镁干燥，再减压浓缩。通过柱层析得到白色固体4d(1.3g，收率：58％)。 4c (2.5g, 9.6mmol) was dissolved in DCM (100mL) and cooled to -78°C. Then BBr 3 (1N CH 2 Cl 2 solution, 24 mL, 24 mmol) was slowly added dropwise. After the addition is complete, the system automatically rises to room temperature and reacts for 6 hours. After the reaction was completed, the system was quenched with ice water at -78°C, and then extracted 3 times with EA (100 mL). The organic phases were combined, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A white solid 4d (1.3 g, yield: 58%) was obtained by column chromatography.
MS m/z(ESI):233.1[M+H] + MS m/z(ESI): 233.1[M+H] +
第五步：5′，7′-二羟基-2′，3′-二氢螺[环己烷-1，1′-茚基]-3-酮(4e)；The fifth step: 5',7'-dihydroxy-2',3'-dihydrospiro[cyclohexane-1,1'-indenyl]-3-one (4e);
5',7'-dihydroxy-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.5',7'-dihydroxy-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.
Figure PCTCN2020128033-appb-000203
Figure PCTCN2020128033-appb-000203
向搅拌的4d(19.4mg，83.5μmol)的苯(0.8mL)溶液中加入催化剂cat.(A:B＝1:1,24.4mg，83.5μmol)，对溴苯酚(14.4mg，83.5μmol)和H 2O(1.5μL，83μmol)。在65℃下搅拌10h后，将混合物用1N HCl水溶液(3mL)淬灭，并用EtOAc(5mL×3)萃取。将合并的萃取液干燥并在减压下浓缩。通过柱色谱法纯化，得到白色固体4e(15mg，收率：77％)。 To the stirred 4d (19.4mg, 83.5μmol) benzene (0.8mL) solution was added the catalyst cat. (A:B=1:1,24.4mg, 83.5μmol), p-bromophenol (14.4mg, 83.5μmol) and H 2 O (1.5 μL, 83 μmol). After stirring at 65°C for 10 h, the mixture was quenched with 1 N aqueous HCl (3 mL) and extracted with EtOAc (5 mL×3). The combined extracts were dried and concentrated under reduced pressure. Purified by column chromatography, a white solid 4e (15 mg, yield: 77%) was obtained.
MS m/z(ESI):233.1[M+H] + MS m/z(ESI): 233.1[M+H] +
第六步：3-氧代-2'，3'-二氢螺[环己烷-1,1'-茚]-5'，7'-二基双(三氟甲磺酸酯)(4f)；The sixth step: 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-5',7'-diylbis(trifluoromethanesulfonate) (4f );
3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-5',7'-diyl bis(trifluoromethanesulfonate).3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-5',7'-diyl bis(trifluoromethanesulfonate).
Figure PCTCN2020128033-appb-000204
Figure PCTCN2020128033-appb-000204
将化合物4e(0.35g，1.51mmol)溶于15mL二氯甲烷中，加入N,N-二异丙基乙胺(1.5mL，9.05mmol)，冰浴下加入三氟甲磺酸酐(0.76mL，4.53mmol)，冰浴下搅拌1h。待反应完全后加入15mL二氯甲烷稀释，加入5mL水洗涤淬灭反应，再用10mL饱和碳酸氢 钠水溶液洗涤反应液，有机层用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物4f，无色液体(0.37g，收率：50％)。Compound 4e (0.35g, 1.51mmol) was dissolved in 15mL of dichloromethane, N,N-diisopropylethylamine (1.5mL, 9.05mmol) was added, and trifluoromethanesulfonic anhydride (0.76mL, 4.53mmol), stirring under ice bath for 1h. After the reaction was completed, 15 mL of dichloromethane was added to dilute, 5 mL of water was added to wash and quench the reaction, and then the reaction solution was washed with 10 mL of saturated sodium bicarbonate aqueous solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 4f was obtained as a colorless liquid (0.37 g, yield: 50%).
MS m/z(ESI):497.0[M+H] + MS m/z(ESI): 497.0[M+H] +
第七步：2’，3'-二氢螺[环己烷-1,1'-茚]-3-酮(4g)；The seventh step: 2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-one (4g);
(2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.(2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.
Figure PCTCN2020128033-appb-000205
Figure PCTCN2020128033-appb-000205
将4f(0.1g，0.2mmol)溶于DMF(5mL)中，于冰浴下依次加入Pd(OAc) 2(4.4mg，0.02mmol)，dppe(1,2-双(二苯基膦)乙烷，cas:1663-45-2，16.4mg，0.04mmol)，Et 3N(110μL，0.8mmol)和甲酸(30μL，0.8mmol)。氮气置换气三次后加热至60℃下搅拌1小时，后用饱和NH 4Cl水溶液(30mL)淬灭，并用EtOAc(10mL×3)萃取。合并有机相，有机相用饱和食盐水洗涤，并用无水硫酸镁干燥，再减压浓缩。通过柱层析得到白色固体4g(22mg，收率：55％)。 Dissolve 4f (0.1g, 0.2mmol) in DMF (5mL), add Pd(OAc) 2 (4.4mg, 0.02mmol), dppe(1,2-bis(diphenylphosphine) ethyl Alkane, cas: 1663-45-2, 16.4 mg, 0.04 mmol), Et 3 N (110 μL, 0.8 mmol) and formic acid (30 μL, 0.8 mmol). After replacing the gas with nitrogen three times, it was heated to 60°C and stirred for 1 hour, then quenched with saturated aqueous NH 4 Cl (30 mL), and extracted with EtOAc (10 mL×3). The organic phases were combined, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A white solid 4g (22mg, yield: 55%) was obtained by column chromatography.
MS m/z(ESI):201.3[M+H] + MS m/z(ESI): 201.3[M+H] +
第八步：3-氧代-2'，3'-二氢螺[环己烷-1,1'-茚]-4-羧酸甲酯(4h)；The eighth step: 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylic acid methyl ester (4h);
methyl-3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.methyl-3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.
Figure PCTCN2020128033-appb-000206
Figure PCTCN2020128033-appb-000206
将氢化钠(0.1g，4.0mmol)悬浮于10mL干燥的四氢呋喃中，氮气保护，加入碳酸二甲酯(0.9g，10.0mmol)，加毕，体系加热至80℃搅拌30min。然后滴加化合物4g(0.4g，2.0mmol)的四氢呋喃溶液(8mL)，滴加完后保持80℃继续反应2h。TLC监控反应完成后，冷却至室温，垫硅藻土过滤，滤液加入20mL冰水稀释，用30mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到产物4h，粘稠液体(0.4g，收率：80％)。Sodium hydride (0.1g, 4.0mmol) was suspended in 10mL of dry tetrahydrofuran, protected by nitrogen, dimethyl carbonate (0.9g, 10.0mmol) was added, after the addition, the system was heated to 80°C and stirred for 30min. Then a tetrahydrofuran solution (8 mL) of 4 g (0.4 g, 2.0 mmol) of compound was added dropwise, and the reaction was continued at 80° C. for 2 hours after the addition was completed. After the reaction was monitored by TLC, it was cooled to room temperature and filtered through a pad of Celite. 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 product was obtained for 4h, viscous liquid (0.4g, yield: 80%).
MS m/z(ESI):259.1[M+H] + MS m/z(ESI): 259.1[M+H] +
第九步：2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-醇(4i)；The ninth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-alcohol (4i );
2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.
Figure PCTCN2020128033-appb-000207
Figure PCTCN2020128033-appb-000207
将化合物4h(0.4g，2.0mmol)溶于1mL四氢呋喃中，加入S-甲基异硫脲硫酸盐(858mg，3.0mmol)，后于室温下滴加氢氧化钾(897mg，16mmol)的水溶液(5mL)。滴加完毕后保持室温反应过夜。待反应完成后，加入10mL水稀释，用1N盐酸调节pH至9-10左右，然后用20mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物4i，白色固体(0.1g，收率：20％)。Compound 4h (0.4g, 2.0mmol) was dissolved in 1mL of tetrahydrofuran, S-methylisothiourea sulfate (858mg, 3.0mmol) was added, and then potassium hydroxide (897mg, 16mmol) in water was added dropwise at room temperature ( 5mL). After the addition is complete, keep the reaction at room temperature overnight. After the reaction is completed, add 10 mL of water to dilute, adjust the pH to about 9-10 with 1N hydrochloric acid, then extract three times with 20 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. After column chromatography, the target product 4i was obtained as a white solid (0.1 g, yield: 20%).
Ms m/z(ESI):299.4[M+H] + Ms m/z(ESI):299.4[M+H] +
第十步：2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-三氟甲磺酸酯(4j)；The tenth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethane Sulfonate (4j);
2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.
Figure PCTCN2020128033-appb-000208
Figure PCTCN2020128033-appb-000208
将化合物4i(100mg，0.3mmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(0.5g，1.2mmol)，冰浴下加入三氟甲磺酸酐(169.2mg，0.6mmol)，冰浴下搅拌1h。待反应完全后加入15mL二氯甲烷稀释，加入5mL水洗涤淬灭反应，再用10mL饱和碳酸氢钠水溶液洗涤反应液，有机层用无水硫酸钠干燥，减压浓缩。柱层析后得到产物4j，白色固体(80mg，收率：61％)。Compound 4i (100mg, 0.3mmol) was dissolved in 5mL of dichloromethane, N,N-diisopropylethylamine (0.5g, 1.2mmol) was added, and trifluoromethanesulfonic anhydride (169.2mg, 0.6 mmol), stirring under ice bath for 1h. After the reaction was completed, 15 mL of dichloromethane was added to dilute, 5 mL of water was added to wash and quench the reaction, and then the reaction solution was washed with 10 mL of saturated sodium bicarbonate aqueous solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the product 4j was obtained as a white solid (80 mg, yield: 61%).
MS m/z(ESI):431.5[M+H] + MS m/z(ESI): 431.5[M+H] +
第十一步：(S)-2-(氰甲基)-4-(2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(4k)；The eleventh step: (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene- 1,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (4k);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin] -4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000209
Figure PCTCN2020128033-appb-000209
将化合物4j(80mg，0.18mmol)溶于3mL N,N-二甲基乙酰胺中，加入(S)-2-(哌嗪-2-基)乙腈(40mg，0.2mmol)和二异丙基乙胺(139mg，1.08mmol)，室温搅拌1h。TLC监控反应完全后，向体系中加入二碳酸二叔丁酯(118mg，0.54mmol)，加毕，反应室温过夜。加入20mL乙酸乙酯稀释，用10mL水洗有机相三次，有机相用无水硫酸钠干燥，减压浓缩。柱层析后得到产物4k，白色固体(90mg，收率：100％)。Dissolve compound 4j (80mg, 0.18mmol) in 3mL N,N-dimethylacetamide, add (S)-2-(piperazin-2-yl)acetonitrile (40mg, 0.2mmol) and diisopropyl Ethylamine (139mg, 1.08mmol) was stirred at room temperature for 1h. After the completion of the reaction monitored by TLC, di-tert-butyl dicarbonate (118 mg, 0.54 mmol) was added to the system, after the addition, the reaction was carried out at room temperature overnight. Add 20 mL of ethyl acetate to dilute, wash the organic phase three times with 10 mL of water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. After column chromatography, the product 4k was obtained as a white solid (90 mg, yield: 100%).
MS m/z(ESI):506.7[M+H] + MS m/z(ESI): 506.7[M+H] +
第十二步：(S)-2-(氰甲基)-4-(2'-(甲基磺酰基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(4l)；The twelfth step: (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene -1,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (4l);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin] -4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000210
Figure PCTCN2020128033-appb-000210
将化合物4k(90mg，0.178mmol)溶于2mL四氢呋喃中，室温下加入间氯过氧苯甲酸(61mg，0.356mmol)，室温搅拌2h。加入5mL饱和硫代硫酸钠水溶液，搅拌20min，加入15mL乙酸乙酯萃取，有机层用10mL饱和碳酸氢钠水溶液洗涤3次，有机相干燥，减压浓缩，得到化合物4l粗品，黄色固体90mg，直接用于下一步。Compound 4k (90 mg, 0.178 mmol) was dissolved in 2 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (61 mg, 0.356 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 h. 5mL saturated sodium thiosulfate aqueous solution was added, stirred for 20min, 15mL ethyl acetate was added for extraction, the organic layer was washed 3 times with 10mL saturated sodium bicarbonate aqueous solution, the organic phase was dried and concentrated under reduced pressure to obtain compound 4l crude product, yellow solid 90mg, directly Used in the next step.
MS m/z(ESI):538.7[M+H] + MS m/z(ESI): 538.7[M+H] +
第十三步：(S)-2-(氰甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(4m)；The thirteenth step: (S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3, 5',8'-Tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (4m);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6' H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000211
Figure PCTCN2020128033-appb-000211
将化合物4l粗品(90mg，0.167mmol)和(S)-(1-甲基吡咯烷-2-基)甲醇(38mg，0.335mmol)溶于2mL甲苯中，冰浴下加入叔丁醇钠(14mg，0.14mmol)，冰浴下搅拌1h。加入5mL水淬灭反应，加入10mL乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到产物4m，白色固体(78mg，收率：80％)。The crude compound 4l (90mg, 0.167mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (38mg, 0.335mmol) were dissolved in 2mL of toluene, and sodium tert-butoxide (14mg , 0.14mmol), stirred under ice bath for 1h. The reaction was quenched by adding 5 mL of water, 10 mL of ethyl acetate was added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the product 4m was obtained as a white solid (78mg, yield: 80%).
MS m/z(ESI):573.6[M+H] + MS m/z(ESI): 573.6[M+H] +
第十四步：2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]亚甲氧基]杂环[6,8-二氢-5H-喹唑啉-7,1'-茚满]-4-基]-哌嗪-2-基]乙腈(4n)；The fourteenth step: 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methyleneoxy] heterocycle [6,8-dihydro-5H -Quinazoline-7,1'-indan]-4-yl]-piperazin-2-yl]acetonitrile (4n);
2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4- yl]piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000212
Figure PCTCN2020128033-appb-000212
将化合物4m(78mg，0.136mmol)溶于3mL二氯甲烷中，加入0.5mL三氟乙酸，于室温下搅拌2h。待反应完成后，加入5mL水稀释，滴加饱和碳酸氢钠调节pH到碱性，然后用10mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩，得到化合物4n粗品，黄色固体63mg，直接用于下一步。Compound 4m (78 mg, 0.136 mmol) was dissolved in 3 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is completed, add 5 mL of water to dilute, add dropwise saturated sodium bicarbonate to adjust the pH to alkaline, then extract three times with 10 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude compound 4n , Yellow solid 63mg, used directly in the next step.
MS m/z(ESI):473.6[M+H] + MS m/z(ESI): 473.6[M+H] +
第十五步：The fifteenth step:
2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]亚甲氧基]杂环[6,8-二氢-5H-喹唑啉-7,1'-茚满]-4-基]-1-丙基-2-烯酰-哌嗪-2-基]乙腈(化合物4)2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methyleneoxy]heterocycle[6,8-dihydro-5H-quinazoline- 7,1'-Indan]-4-yl]-1-propyl-2-enoyl-piperazin-2-yl)acetonitrile (Compound 4)
2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4- yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile
Figure PCTCN2020128033-appb-000213
Figure PCTCN2020128033-appb-000213
将化合物4n粗品(63mg，0.133mmol)溶于5mL二氯甲烷中，加入三乙胺(40mg，0.4mmol)，冰浴下计入烯丙酰氯(12mg，0.13mmol)，冰浴下搅拌30min。加入5mL冰水淬灭反应，然后用10mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩，经制备TLC纯化得到化合物4(8mg，收率：10％)。手性HPLC积分面积 T 8.2min:积分面积 T 11.6min(63:37) The crude compound 4n (63 mg, 0.133 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (40 mg, 0.4 mmol) was added, acryloyl chloride (12 mg, 0.13 mmol) was added under ice bath, and the mixture was stirred under ice bath for 30 min. The reaction was quenched by adding 5 mL of ice water, and then extracted three times with 10 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC to obtain compound 4 (8 mg, yield: 10%). Chiral HPLC integral area T 8.2min : integral area T 11.6min (63:37)
Ms m/z(ESI):527.6[M+H] + Ms m/z(ESI): 527.6[M+H] +
手性HPLC分析方法：Chiral HPLC analysis method:
样品溶于正己烷/异丙醇(90:10)中，The sample is dissolved in n-hexane/isopropanol (90:10),
仪器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6×250mm,5μmInstrument: Shimadzu LC-20AT; Chiral column: CHIRALPAK AD-H, 4.6×250mm, 5μm
流动相：正己烷(含0.1％二乙胺)-异丙醇(80:20)；流速：1mL/minMobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (80:20); flow rate: 1mL/min
柱温：35℃；检测波长：210nm；进样量：20μLColumn temperature: 35℃; detection wavelength: 210nm; injection volume: 20μL
实施例4-1和4-2：Examples 4-1 and 4-2:
2-((2S)-1-丙烯酰基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-2-基)乙腈–异构体4-1和异构体4-22-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'- Tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile-isomer 4-1 and isomer 4-2
2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile–isomer 4-1and isomer 4-2.2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile--isomer 4-1 and isomer 4-2.
Figure PCTCN2020128033-appb-000214
Figure PCTCN2020128033-appb-000214
第一步：3-氧代-2'，3'-二氢螺[环己烷-1,1'-茚]-4-羧酸乙酯(4o)；The first step: 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylic acid ethyl ester (4o);
ethyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.ethyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.
Figure PCTCN2020128033-appb-000215
Figure PCTCN2020128033-appb-000215
-78℃氮气保护下，将化合物4g(0.37g，1.84mmol,参照化合物4合成路线中间体4g的合成)悬浮于30mL干燥的四氢呋喃中，缓慢滴加LiHMDS的四氢呋喃溶液(2.77mL,1mol/L，2.77mmol)，保持-78℃搅拌30min后，将氰基甲酸乙酯(0.3g，2.77mmol)的四氢呋喃溶液(8mL)缓慢滴入反应液中，滴加完后反应液缓慢升至室温反应4h。TLC监控反应完成后，冷却至0℃，滴加100mL冰水淬灭反应。乙酸乙酯100mL萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩得到化合物4o，黄色粘稠液体(0.54g粗品)。无需纯化直接用于下一步反应。Under nitrogen protection at -78℃, 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. After the completion of the reaction monitored by TLC, it was cooled to 0°C, and 100 mL of ice water was added dropwise to quench the reaction. It was extracted three times with 100 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4o, a yellow viscous liquid (0.54 g crude product). It is directly used in the next reaction without purification.
MS m/z(ESI):273.1[M+H] + MS m/z(ESI): 273.1[M+H] +
第二步：3-氨基-2'，3'-二氢螺[环己烷-1,1'-茚]-3-烯-4-羧酸乙酯(4p)；The second step: 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (4p);
ethyl 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.ethyl 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.
Figure PCTCN2020128033-appb-000216
Figure PCTCN2020128033-appb-000216
将粗品化合物4o溶于20mL乙醇中，加入醋酸铵(0.7g，9.2mmol)室温反应12h，TLC监控反应完成后，减压旋干溶剂，加入100mL乙酸乙酯稀释，然后用10mL水洗三次，有机相用无水硫酸钠干燥，减压浓缩得到化合物4p，黄色粘稠液体(0.49g粗品)，无需纯化直接用于下一步反应。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.
MS m/z(ESI):272.2[M+H] + MS m/z(ESI): 272.2[M+H] +
第三步：3-(3-苯甲酰基硫脲基)-2'，3'-二氢螺[环己烷-1,1'-茚]-3-烯-4-羧酸乙酯(4q)；The third step: 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester ( 4q);
ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.
Figure PCTCN2020128033-appb-000217
Figure PCTCN2020128033-appb-000217
将粗品化合物4p溶于50mL丙酮中，加入苯甲酰基异硫氰酸酯氢化钠(0.37mL，2.76mmol)，氮气保护下加热至80℃，反应1h。TLC监控反应完成后，冷却至室温，减压浓缩。柱层析(PE：EA＝3:1)后得到目标产物4q，黄色粘稠液体(0.43g，三步收率：53％)。The crude compound 4p was dissolved in 50 mL of acetone, sodium hydride benzoyl isothiocyanate (0.37 mL, 2.76 mmol) was added, and the mixture was heated to 80° C. under the protection of nitrogen, and reacted for 1 h. After the completion of the reaction monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure. After column chromatography (PE:EA=3:1), the target product 4q was obtained as a yellow viscous liquid (0.43g, three-step yield: 53%).
MS m/z(ESI):435.2[M+H] + MS m/z(ESI): 435.2[M+H] +
第四步：2'-巯基-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-醇(4r)；The fourth step: 2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-ol (4r);
2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.
Figure PCTCN2020128033-appb-000218
Figure PCTCN2020128033-appb-000218
将化合物4q(0.43g，0.99mmol)溶于15mL乙醇中，加入氢氧化钾(0.17g，3.0mmol)，体系加热至80℃搅拌1h。TLC监控反应完成后，冷却至室温，减压浓缩除去溶剂至2mL左右。滴加1N稀盐酸至不再有白色固体析出(pH＝2)，过滤，滤饼用水洗两次，收集滤饼得到目标产物4r，白色固体(0.28g，收率：99％)。Compound 4q (0.43 g, 0.99 mmol) was dissolved in 15 mL of ethanol, potassium hydroxide (0.17 g, 3.0 mmol) was added, and the system was heated to 80° C. and stirred for 1 h. After the completion of the reaction monitored by TLC, it was cooled to room temperature, and concentrated under reduced pressure to remove the solvent to about 2 mL. 1N dilute hydrochloric acid was added dropwise until no white solid precipitated (pH=2), filtered, the filter cake was washed twice with water, and the filter cake was collected to obtain the target product 4r, a white solid (0.28 g, yield: 99%).
MS m/z(ESI):285.4[M+H] + MS m/z(ESI): 285.4[M+H] +
第五步：2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-醇(4i)；The fifth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-alcohol (4i );
2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.
Figure PCTCN2020128033-appb-000219
Figure PCTCN2020128033-appb-000219
将化合物4r(0.28g，0.99mmol)溶于氢氧化钾(0.17g，3.0mmoL)的水溶液中，再加入2mL甲醇使不溶物溶解。于室温下滴加碘甲烷(184mg，1.3mmoL)，保持室温反应2h。TLC监控反应完成后，滴加1N稀盐酸至不再有白色固体析出(pH＝2)，过滤，滤饼用水洗两次，收集滤饼得到目标产物4i，白色固体(0.2g，收率：68％)。Compound 4r (0.28g, 0.99mmol) was dissolved in an aqueous solution of potassium hydroxide (0.17g, 3.0mmoL), and then 2mL of methanol was added to dissolve the insoluble matter. Add iodomethane (184mg, 1.3mmoL) dropwise at room temperature, and react at room temperature for 2h. After the reaction was monitored by TLC, 1N dilute hydrochloric acid was added dropwise until no white solid was precipitated (pH=2), filtered, the filter cake was washed twice with water, and the filter cake was collected to obtain the target product 4i, a white solid (0.2g, yield: 68%).
Ms m/z(ESI):299.4[M+H] + Ms m/z(ESI):299.4[M+H] +
第六步：2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-三氟甲磺酸酯(4j)；The sixth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethane Sulfonate (4j);
2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.
Figure PCTCN2020128033-appb-000220
Figure PCTCN2020128033-appb-000220
将化合物4i(200mg，0.67mmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(1.0g，1.2mmol)，冰浴下加入三氟甲磺酸酐(378mg，1.35mmol)，冰浴下搅拌1h。待反应完全后加入30mL二氯甲烷稀释，加入5mL水洗涤淬灭反应，再用10mL饱和碳酸氢钠水溶液洗涤反应液，有机层用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物4j，白色固体(256mg，收率：89％)。Compound 4i (200mg, 0.67mmol) was dissolved in 5mL of dichloromethane, N,N-diisopropylethylamine (1.0g, 1.2mmol) was added, and trifluoromethanesulfonic anhydride (378mg, 1.35mmol) was added under ice bath ), stirring under ice bath for 1h. After the reaction was completed, 30 mL of dichloromethane was added to dilute, 5 mL of water was added to wash and quench the reaction, and then the reaction solution was washed with 10 mL of saturated sodium bicarbonate aqueous solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 4j was obtained as a white solid (256 mg, yield: 89%).
MS m/z(ESI):431.5[M+H] + MS m/z(ESI): 431.5[M+H] +
第七步：(S)-2-(氰甲基)-4-(2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(4k)；The seventh step: (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1 ,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (4k);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin] -4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000221
Figure PCTCN2020128033-appb-000221
将化合物4j(256mg，0.6mmol)溶于3mL N,N-二甲基乙酰胺中，加入(S)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(202mg，0.9mmol)和二异丙基乙胺(0.4mL，2.4mmol)，室温搅拌12h。TLC监控反应完全后，加入50mL乙酸乙酯稀释，用10mL水洗有机相三次，有机相用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物4k，白色固体(330mg，收率：99％)。Compound 4j (256mg, 0.6mmol) was dissolved in 3mL N,N-dimethylacetamide, and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (202mg, 0.9 mmol) and diisopropylethylamine (0.4 mL, 2.4 mmol) and stirred at room temperature for 12 h. After the completion of the reaction monitored by TLC, 50 mL of ethyl acetate was added to dilute, the organic phase was washed three times with 10 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 4k was obtained as a white solid (330 mg, yield: 99%).
MS m/z(ESI):506.7[M+H] + MS m/z(ESI): 506.7[M+H] +
第八步：(S)-2-(氰甲基)-4-(2'-(甲基磺酰基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(4l)；The eighth step: (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene- 1,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (4l);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin] -4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000222
Figure PCTCN2020128033-appb-000222
将化合物4k(330mg，0.65mmol)溶于15mL四氢呋喃中，室温下加入间氯过氧苯甲酸(449mg，2.6mmol)，室温搅拌2h。加入10mL饱和硫代硫酸钠水溶液，搅拌20min，加入50mL乙酸乙酯萃取，有机层用10mL饱和碳酸氢钠水溶液洗涤3次，有机相干燥，减压浓缩，柱层析后得到目标产物4l，白色固体(300mg，收率：93％)。Compound 4k (330 mg, 0.65 mmol) was dissolved in 15 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (449 mg, 2.6 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 h. Add 10 mL of saturated sodium thiosulfate aqueous solution, stir for 20 min, add 50 mL of ethyl acetate for extraction, and wash the organic layer 3 times with 10 mL of saturated sodium bicarbonate aqueous solution, dry the organic phase, concentrate under reduced pressure, and obtain 4l of the target product after column chromatography, white Solid (300 mg, yield: 93%).
MS m/z(ESI):538.7[M+H] + MS m/z(ESI): 538.7[M+H] +
第九步：(S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(4m)；The ninth step: (S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5' ,8'-Tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (4m);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6' H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000223
Figure PCTCN2020128033-appb-000223
将化合物4l(300mg，0.56mmol)和(S)-(1-甲基吡咯烷-2-基)甲醇(128mg，1.1mmol)溶于10mL甲苯中，冰浴下加入叔丁醇钠(81mg，0.84mmol)，冰浴下搅拌1h。加入5mL水淬灭反应，加入50mL乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物4m，白色固体(292mg，收率：91％)。Compound 4l (300mg, 0.56mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (128mg, 1.1mmol) were dissolved in 10mL of toluene, and sodium tert-butoxide (81mg, 0.84mmol), stirring under ice bath for 1h. The reaction was quenched by adding 5 mL of water, 50 mL of ethyl acetate was added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 4m was obtained as a white solid (292 mg, yield: 91%).
MS m/z(ESI):573.6[M+H] + MS m/z(ESI): 573.6[M+H] +
第十步：2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-2-基)乙腈(化合物4n)；The tenth step: 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetra Hydrogen-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (compound 4n);
2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene- 1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2020128033-appb-000224
Figure PCTCN2020128033-appb-000224
将化合物4m(292mg，0.51mmol)溶于15mL二氯甲烷中，加入5mL三氟乙酸，于室温下搅拌2h。待反应完成后，加入5mL水稀释，滴加饱和碳酸氢钠调节pH到碱性，然后用30mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩，得到目标化合物4n粗品，黄色固体350mg，直接用于下一步。Compound 4m (292 mg, 0.51 mmol) was dissolved in 15 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is complete, add 5 mL of water to dilute, add dropwise saturated sodium bicarbonate to adjust the pH to alkaline, then extract three times with 30 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the target compound 4n The crude product, 350 mg of yellow solid, was used directly in the next step.
MS m/z(ESI):473.6[M+H] + MS m/z(ESI): 473.6[M+H] +
第十一步：2-((2S)-1-丙烯酰基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-2-基)乙腈-异构体4-1和异构体4-2The eleventh step: 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5 ',8'-Tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile-isomer 4-1 and isomer 4-2
2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile–isomer 4-1and isomer 4-2.2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile--isomer 4-1 and isomer 4-2.
Figure PCTCN2020128033-appb-000225
Figure PCTCN2020128033-appb-000225
将化合物4n粗品(350mg)溶于20mL二氯甲烷中，加入三乙胺(258mg，2.55mmol)，冰浴下滴加入烯丙酰氯(46mg，0.51mmol)，冰浴下搅拌30min。加入5mL冰水淬灭反应，然后用30mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标化合物4(216mg，收率：81％，手性HPLC积分面积 T 8.2min：积分面积 T 11.6min＝65：35，分析方法参照实施例4)。化合物4经SFC制备分离纯化后得到4-1(60mg,SFC制备保留时间为4.5min；手性HPLC保留时间为8.2min)和4-2(31mg，SFC制备保留时间为3.9min，手性HPLC保留时间为11.6min). The crude compound 4n (350 mg) was dissolved in 20 mL of dichloromethane, triethylamine (258 mg, 2.55 mmol) was added, acryloyl chloride (46 mg, 0.51 mmol) was added dropwise under ice bath, and the mixture was stirred under ice bath for 30 min. The reaction was quenched by adding 5 mL of ice water, and then extracted three times with 30 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 4 was obtained (216 mg, yield: 81%, chiral HPLC integral area T 8.2 min : integral area T 11.6 min = 65: 35, the analysis method refers to Example 4). 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).
SFC制备分离条件：仪器:MGⅡpreparative SFCSFC preparation and separation conditions: Instrument: MGⅡpreparative SFC
柱子:ChiralCel OJ,250×30mm I.D.,5μm流动相:A为CO 2，B为乙醇(含0.1％氨水)，30％B洗脱。流速:60mL/min；柱温:38℃；检测波长:220nm经制备分离后，合并相同保留时间的组分，减压浓缩得化合物4-1和4-2。 Column: ChiralCel OJ, 250×30mm ID, 5μm mobile phase: A is CO 2 , B is ethanol (containing 0.1% ammonia), 30% B elution. Flow rate: 60 mL/min; column temperature: 38° C.; detection wavelength: 220 nm. After preparation and separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 4-1 and 4-2.
化合物4-1:Compound 4-1:
LCMS:m/z(ESI):527.3[M+H] + LCMS: m/z(ESI): 527.3[M+H] +
1H NMR(400MHz,CD 3COOD)δ7.30–7.11(m,4H),6.91–6.67(m,1H),6.37(d,1H),5.87(d,1H),5.16–5.02(m,1H),4.97–4.80(m,2H),4.72–4.57(m,1H),4.56–4.43(m,1H),4.24–4.07(m,1H),4.06–3.53(m,5H),3.51–3.16(m,2H),3.13–2.77(m,10H),2.48–2.34(m,1H),2.26–2.05(m,6H),1.91–1.79(m,1H). 1 H NMR (400MHz, CD 3 COOD) δ 7.30-7.11 (m, 4H), 6.91-6.67 (m, 1H), 6.37 (d, 1H), 5.87 (d, 1H), 5.16-5.02 (m, 1H), 4.97--4.80(m,2H), 4.72--4.57(m,1H), 4.56--4.43(m,1H), 4.24--4.07(m,1H), 4.06--3.53(m,5H), 3.51-- 3.16 (m, 2H), 3.13-2.77 (m, 10H), 2.48-2.34 (m, 1H), 2.26-2.05 (m, 6H), 1.91-1.79 (m, 1H).
化合物4-2:Compound 4-2:
LCMS:m/z(ESI):527.3[M+H] + LCMS: m/z(ESI): 527.3[M+H] +
1H NMR(400MHz,CD 3OD)δ7.27–7.19(m,1H),7.19–7.08(m,2H),7.08–7.01(m,1H),6.94–6.72(m,1H),6.28(d,1H),5.82(d,1H),5.15–5.00(m,1H),4.63–4.46(m,1H),4.43–4.28(m,2H),4.18–3.92(m,3H),3.68–3.49(m,1H),3.26–3.19(m,1H),3.16–2.73(m,9H),2.72–2.60(m,1H),2.54(s,3H),2.47–2.37(m,1H),2.17–1.94(m,4H),1.89–1.66(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.27--7.19 (m, 1H), 7.19-7.08 (m, 2H), 7.08-7.01 (m, 1H), 6.94-6.72 (m, 1H), 6.28 ( d, 1H), 5.82 (d, 1H), 5.15 - 5.00 (m, 1H), 4.63 - 4.46 (m, 1H), 4.43 - 4.28 (m, 2H), 4.18 - 3.92 (m, 3H), 3.68 - 3.49(m,1H), 3.26–3.19(m,1H), 3.16–2.73(m,9H), 2.72–2.60(m,1H), 2.54(s,3H), 2.47–2.37(m,1H), 2.17–1.94(m,4H), 1.89–1.66(m,4H).
2'，3'-二氢螺环[环己烷-1,1'-茚]-3-酮(中间体1)2',3'-Dihydrospiro[cyclohexane-1,1'-indene]-3-one (Intermediate 1)
Figure PCTCN2020128033-appb-000226
Figure PCTCN2020128033-appb-000226
第一步：2-溴-1-环丙烯-1-酮(中间体1B)The first step: 2-bromo-1-cyclopropene-1-one (Intermediate 1B)
2-bromo-1-cyclopropylethan-1-one2-bromo-1-cyclopropylethan-1-one
Figure PCTCN2020128033-appb-000227
Figure PCTCN2020128033-appb-000227
将原料甲基环丙酮(8.4g,0.1mol)溶解在60mL甲醇中，置于0℃搅拌溶解，再向体系中缓慢滴加溴素(5.0mL，90mmol)，溴素滴加完毕后，继续在此温度下搅拌直至反应体系变为无色透明。反应结束后，向反应中加入三乙胺直至体系PH为中性，再将反应液甲醇减压蒸馏除去，得到三乙胺氢溴酸盐固体以及油状产物的混合物，该混合物用石油醚洗涤过滤，将液体部分旋蒸抽干后得到无色油状产物(中间体1B)(16.0g，产率97％)。Dissolve the raw material methyl cycloacetone (8.4g, 0.1mol) in 60mL of methanol, place it at 0℃ and stir to dissolve, and then slowly add bromine (5.0mL, 90mmol) to the system dropwise. After the bromine addition is complete, continue Stir at this temperature until the reaction system becomes colorless and transparent. After the reaction, triethylamine was added to the reaction until the pH of the system was neutral, and then the methanol of the reaction solution was distilled off under reduced pressure to obtain a mixture of triethylamine hydrobromide solid and oily product, which was washed and filtered with petroleum ether After evaporating the liquid part to dryness, a colorless oily product (Intermediate 1B) (16.0 g, yield 97%) was obtained.
第二步：1,5-二溴戊烷-2-酮(中间体1C)Step 2: 1,5-Dibromopentane-2-one (Intermediate 1C)
1,5-dibromopentan-2-one1,5-dibromopentan-2-one
Figure PCTCN2020128033-appb-000228
Figure PCTCN2020128033-appb-000228
将底物中间体1B(16.0g,98mmol)加入到50mL氢溴酸水溶液(v/v＝48％)中，再将反应液置于50℃搅拌2小时，反应结束后，向反应液中加入200mL石油醚，再加入适量的冰块，直至白色固体析出，过滤干燥得到白色固体产物(中间体1C)(18g，75％)。The substrate intermediate 1B (16.0g, 98mmol) was added to 50mL of hydrobromic acid aqueous solution (v/v=48%), and the reaction solution was placed at 50°C and stirred for 2 hours. After the reaction was completed, added to the reaction solution 200 mL of petroleum ether, and then add an appropriate amount of ice cubes until a white solid precipitates, and filter and dry to obtain a white solid product (Intermediate 1C) (18 g, 75%).
第三步：2-(溴甲基)-2-(3-溴丙基)-1,3-二氧环烷(中间体1D)The third step: 2-(bromomethyl)-2-(3-bromopropyl)-1,3-dioxane (Intermediate 1D)
2-(bromomethyl)-2-(3-bromopropyl)-1,3-dioxolane2-(bromomethyl)-2-(3-bromopropyl)-1,3-dioxolane
Figure PCTCN2020128033-appb-000229
Figure PCTCN2020128033-appb-000229
将底物中间体1C(14.0g,57.6mmol)与乙二醇(21.4g,0.35mol)以及对甲苯磺酸(1.1g,5.8mmol)加入到150mL的甲苯中，再将体系置于120℃加热回流分水。反应至分水器中没有新增水，且甲苯清澈时，反应即结束，冷却至室温，减压浓缩，残余物经硅胶色谱分离得到黄色油状物中间体1D(11.7g，产率70％)。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℃ 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%) .
1H NMR(400MHz,CDCl 3)δ4.09–4.04(m,2H),4.03–3.98(m,2H),3.43(t,2H),3.37(s,2H),2.02–1.96(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ 4.09-4.04 (m, 2H), 4.03-3.98 (m, 2H), 3.43 (t, 2H), 3.37 (s, 2H), 2.02-1.96 (m, 4H) ).
第四步：双螺环[茚-1,1'-环己烷-3'，2'-[1,3]二氧环烷](中间体1E)Step 4: Bispiro [indene-1,1'-cyclohexane-3',2'-[1,3]dioxane] (Intermediate 1E)
dispiro[indene-1,1'-cyclohexane-3',2”-[1,3]dioxolane]dispiro[indene-1,1'-cyclohexane-3',2”-[1,3]dioxolane]
Figure PCTCN2020128033-appb-000230
Figure PCTCN2020128033-appb-000230
将茚(4.87g,42.0mmol)加入到80mL的THF中，置于0℃搅拌溶解后，向体系中缓慢滴加LiHMDS(42mL,42.0mmol,1M in hexane),滴加完毕后，反应置于此温度下继续搅拌30min。在0℃下，将此反应液用转移针头缓慢滴加到中间体1D(10.0g,35.0mmol)的THF(80mL)的溶液中，滴加完毕后，反应置于0℃搅拌1小时。再向体系中缓慢滴加LiHMDS(42mL,42.0mmol,1M in hexane),滴加完毕后，将反应温度缓慢上升至室温并搅拌过夜。反应即结束，冷却至0℃，将反应液加入到NH 4Cl的饱和水溶液中淬灭，用乙酸乙酯萃取，有机相干燥过滤后直接旋干，硅胶色谱分离得到白色固体中间体1E(4.1g，产率48％)。 Add indene (4.87g, 42.0mmol) to 80mL of THF, place it at 0°C and stir to dissolve, slowly drop LiHMDS (42mL, 42.0mmol, 1M in hexane) into the system, after the addition is complete, the reaction is placed Continue stirring at this temperature for 30 minutes. At 0°C, the reaction solution was slowly added dropwise to a solution of Intermediate 1D (10.0 g, 35.0 mmol) in THF (80 mL) with a transfer needle. After the addition was completed, the reaction was placed at 0°C and stirred for 1 hour. Then LiHMDS (42mL, 42.0mmol, 1M in hexane) was slowly added dropwise to the system. After the addition was completed, the reaction temperature was slowly raised to room temperature and stirred overnight. The reaction was over, cooled to 0°C, the reaction solution was added to a saturated aqueous solution of NH 4 Cl for quenching, extracted with ethyl acetate, the organic phase was dried and filtered, and then spin-dried directly. Silica gel chromatography to obtain a white solid intermediate 1E (4.1 g, yield 48%).
第五步：2,3-二氢双螺环[茚-1,1'-环己烷-3'，2'-[1,3]二氧环烷](中间体1F)Step 5: 2,3-Dihydrobispiro [indene-1,1'-cyclohexane-3', 2'-[1,3]dioxane] (Intermediate 1F)
2,3-dihydrodispiro[indene-1,1'-cyclohexane-3',2”-[1,3]dioxolane]2,3-dihydrodispiro[indene-1,1'-cyclohexane-3',2”-[1,3]dioxolane]
Figure PCTCN2020128033-appb-000231
Figure PCTCN2020128033-appb-000231
将中间体1E(4.0g,16.5mmol)溶解到50mL甲醇中，加入400mg Pd/C(10％ wt)反应用氢气球保护，置于室温搅拌3小时。反应即结束，用硅藻土过滤，滤液旋干再使用硅胶色谱柱分离得到无色油状物产物中间体1F(3.7g，产率92％)。 Intermediate 1E (4.0 g, 16.5 mmol) was dissolved in 50 mL of methanol, 400 mg Pd/C (10% wt ) was added, and the reaction was protected with a hydrogen balloon, and the mixture was stirred at room temperature for 3 hours. The reaction was completed immediately, filtered with celite, and the filtrate was spin-dried and separated by a silica gel column to obtain a colorless oily product Intermediate 1F (3.7 g, yield 92%).
第六步：2'，3'-二氢螺环[环己烷-1,1'-茚]-3-酮(中间体1)The sixth step: 2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-one (Intermediate 1)
2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one
Figure PCTCN2020128033-appb-000232
Figure PCTCN2020128033-appb-000232
将中间体1F(3.7g,15.1mmol)溶解到10mL的THF中，再向体系中加入6N的盐酸甲醇溶液(20mL)，反应置于室温搅拌1小时。反应结束后，减压浓缩，残余物加水50mL，乙酸乙酯萃取(50mL×3)，饱和NaHCO 3水溶液洗涤，有机相干燥过滤后直接旋干经硅胶色谱柱分离得到白色固体中间体1(2.8g，产率94％)。 Intermediate 1F (3.7 g, 15.1 mmol) was dissolved in 10 mL of THF, and 6N hydrochloric acid methanol solution (20 mL) was added to the system, and the reaction was stirred at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure, add 50 mL of water to the residue, extract with ethyl acetate (50 mL×3), wash with saturated aqueous NaHCO 3 solution, dry and filter the organic phase, spin dry, and separate by silica gel chromatography to obtain a white solid intermediate 1 (2.8 g, yield 94%).
LCMS:m/z(ESI):201.2[M+H] + LCMS: m/z(ESI): 201.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.24–7.02(m,4H),2.96–2.76(m,2H),2.55–2.24(m,4H),2.11–1.64(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.24-7.02(m,4H), 2.96-2.76(m,2H), 2.55-2.24(m,4H), 2.11-1.64(m,4H).
实施例5Example 5
2-[(2S)-4-[2-[[((2S，4R)-4-氟-1-甲基-吡咯烷-2-基]甲氧基]螺[6,8-二氢-5H-喹唑啉-7，1'-茚满]-4-基]-1-丙-2-烯酰基-哌嗪-2-基]乙腈(化合物5)；2-[(2S)-4-[2-[[(((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro- 5H-quinazoline-7,1'-indan]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (compound 5);
2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7, 1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000233
Figure PCTCN2020128033-appb-000233
第一步：3-氧代-2'，3'-二氢螺[环己烷-1,1'-茚]-4-羧酸乙酯(5b)；The first step: 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylic acid ethyl ester (5b);
ethyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.ethyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.
Figure PCTCN2020128033-appb-000234
Figure PCTCN2020128033-appb-000234
将中间体1(8.0g，40mmol)悬浮于150mL干燥的四氢呋喃中，氮气保护降温至-78℃，缓慢滴加LiHMDS的四氢呋喃溶液(60mL,1mol/L，60mmol)，加毕，体系保持-78℃搅拌30min。然后滴加氰基甲酸乙酯(5.9g，60mmol)的四氢呋喃溶液(20mL)，滴加完后体系自动升至室温反应。TLC监控反应完成后，冷却至0℃，滴加100mL冰水淬灭反应。然后用乙酸乙酯150mL萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩得到化合物5b，黄色粘稠液体(11.5g粗品)，无需纯化直接用于下一步反应。Intermediate 1 (8.0g, 40mmol) was suspended in 150mL of dry tetrahydrofuran, the temperature was reduced to -78℃ under nitrogen protection, and LiHMDS's tetrahydrofuran solution (60mL, 1mol/L, 60mmol) was slowly added dropwise. After the addition, the system remained at -78. Stir at °C for 30 min. Then a tetrahydrofuran solution (20 mL) of ethyl cyanoformate (5.9 g, 60 mmol) was added dropwise, and the system was automatically warmed to room temperature for reaction after the addition was completed. After the completion of the reaction monitored by TLC, it was cooled to 0°C, and 100 mL of ice water was added dropwise to quench the reaction. Then it was extracted three times with 150 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5b, a yellow viscous liquid (11.5 g crude product), which was directly used in the next reaction without purification.
MS m/z(ESI):273.1[M+H] + MS m/z(ESI): 273.1[M+H] +
第二步：3-氨基-2'，3'-二氢螺[环己烷-1,1'-茚]-3-烯-4-羧酸乙酯(5c)；The second step: 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (5c);
ethyl 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.ethyl 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.
Figure PCTCN2020128033-appb-000235
Figure PCTCN2020128033-appb-000235
将粗品化合物5b溶于200mL乙醇中，加入醋酸铵(23.1g，300mmol)室温反应12h，TLC监控反应完成后，减压旋干溶剂，加入100mL乙酸乙酯稀释，然后用30mL水洗三次，有机相用无水硫酸钠干燥，减压浓缩得到化合物5c，黄色粘稠液体(10.7g粗品)，无需纯化直接用于下一步反应。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.
MS m/z(ESI):272.2[M+H] + MS m/z(ESI): 272.2[M+H] +
第三步：3-(3-苯甲酰基硫脲基)-2'，3'-二氢螺[环己烷-1,1'-茚]-3-烯-4-羧酸乙酯(5d)；The third step: 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester ( 5d);
ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.
Figure PCTCN2020128033-appb-000236
Figure PCTCN2020128033-appb-000236
将粗品化合物5c溶于100mL丙酮中，加入苯甲酰基异硫氰酸酯(12.1mL，90mmol)，氮气保护下加热至80℃，反应1h。TLC监控反应完成后，冷却至室温，减压浓缩。柱层析(PE：EA＝3:1)后得到目标产物5d，黄色粘稠液体(12g，三步收率：69％)。The crude compound 5c was dissolved in 100 mL of acetone, benzoyl isothiocyanate (12.1 mL, 90 mmol) was added, and the mixture was heated to 80° C. under nitrogen protection and reacted for 1 h. After the completion of the reaction monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure. After column chromatography (PE:EA=3:1), the target product 5d was obtained as a yellow viscous liquid (12g, three-step yield: 69%).
MS m/z(ESI):435.2[M+H] + MS m/z(ESI): 435.2[M+H] +
第四步：2'-巯基-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-醇(5e)；The fourth step: 2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-ol (5e);
2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.
Figure PCTCN2020128033-appb-000237
Figure PCTCN2020128033-appb-000237
将化合物5d(12g，27.6mmol)溶于150mL乙醇中，加入氢氧化钾(4.6g，82.8mmol)，体系加热至80℃搅拌1h。TLC监控反应完成后，冷却至室温，减压浓缩除去溶剂至20mL左右。滴加1N HCl水溶液至不再有白色固体析出(PH＝2)，过滤，滤饼用水洗两次，收集滤饼得到目标产物5e，白色固体(6.0g，收率：70.5％)。Compound 5d (12 g, 27.6 mmol) was dissolved in 150 mL of ethanol, potassium hydroxide (4.6 g, 82.8 mmol) was added, and the system was heated to 80° C. and stirred for 1 h. After the reaction was monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent to about 20 mL. 1N HCl aqueous solution was added dropwise until no white solid precipitated (PH=2), filtered, the filter cake was washed twice with water, and the filter cake was collected to obtain the target product 5e, a white solid (6.0 g, yield: 70.5%).
MS m/z(ESI):285.4[M+H] + MS m/z(ESI): 285.4[M+H] +
第五步：2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-醇(5f)；The fifth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-alcohol (5f );
2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.
Figure PCTCN2020128033-appb-000238
Figure PCTCN2020128033-appb-000238
将化合物5e(6.0g，21.1mmol)溶于氢氧化钾(3.6g，63.4mmoL)的水(100mL)溶液中，再加入2mL甲醇使不溶物溶解。于室温下滴加碘甲烷(3.9g，27.4mmoL)，保持室温反应2h。TLC监控反应完成后，滴加1N HCl至不再有白色固体析出(PH＝2)，过滤，滤饼用水洗两次，收集滤饼得到目标产物5f，白色固体(4.1g，收率：65％)。Compound 5e (6.0 g, 21.1 mmol) was dissolved in a water (100 mL) solution of potassium hydroxide (3.6 g, 63.4 mmoL), and 2 mL of methanol was added to dissolve the insoluble matter. Add iodomethane (3.9g, 27.4mmoL) dropwise at room temperature, and react at room temperature for 2h. After the reaction was monitored by TLC, 1N HCl was added dropwise until no white solid precipitated (PH=2), filtered, the filter cake was washed twice with water, and the filter cake was collected to obtain the target product 5f, a white solid (4.1g, yield: 65 %).
MS m/z(ESI):299.4[M+H] + MS m/z(ESI): 299.4[M+H] +
第六步：2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-三氟甲磺酸酯(5g)；The sixth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethane Sulfonate (5g);
2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.
Figure PCTCN2020128033-appb-000239
Figure PCTCN2020128033-appb-000239
将化合物5f(1.7g，5.7mmol)溶于300mL二氯甲烷中，加入N,N-二异丙基乙胺(4.4g，34.2mmol)，冰浴下加入三氟甲磺酸酐(4.83g，17.1mmol)，冰浴下搅拌1h。待反应完全后，加入30mL水洗涤淬灭反应，再用20mL饱和碳酸氢钠水溶液洗涤反应液，有机层 用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物5g，白色固体(2.42g，收率：99％)。Compound 5f (1.7g, 5.7mmol) was dissolved in 300mL of dichloromethane, N,N-diisopropylethylamine (4.4g, 34.2mmol) was added, and trifluoromethanesulfonic anhydride (4.83g, 17.1mmol), stirring under ice bath for 1h. After the reaction was completed, 30 mL of water was added to wash and quench the reaction, and then the reaction solution was washed with 20 mL of saturated sodium bicarbonate aqueous solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, 5 g of the target product was obtained as a white solid (2.42 g, yield: 99%).
MS m/z(ESI):431.5[M+H] + MS m/z(ESI): 431.5[M+H] +
第七步：(S)-2-(氰甲基)-4-(2'-(甲硫基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(5h)；The seventh step: (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1 ,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (5h);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin] -4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000240
Figure PCTCN2020128033-appb-000240
将化合物5g(2.42g，5.6mmol)溶于30mL N,N-二甲基乙酰胺中，加入(S)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯(1.9g，8.4mmol)和二异丙基乙胺(3.67mL，22.4mmol)，室温搅拌12h。TLC监控反应完全后，加入150mL乙酸乙酯稀释，用30mL水洗有机相三次，有机相用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物5h，白色固体(2.73g，收率：96％)。Dissolve compound 5g (2.42g, 5.6mmol) in 30mL N,N-dimethylacetamide, add (S)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (1.9g , 8.4mmol) and diisopropylethylamine (3.67mL, 22.4mmol), stirred at room temperature for 12h. After the completion of the reaction monitored by TLC, 150 mL of ethyl acetate was added to dilute, the organic phase was washed three times with 30 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product was obtained for 5h as a white solid (2.73g, yield: 96%).
MS m/z(ESI):506.7[M+H] + MS m/z(ESI): 506.7[M+H] +
第八步：(S)-2-(氰甲基)-4-(2'-(甲基磺酰基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(5i)；The eighth step: (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene- 1,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (5i);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin] -4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000241
Figure PCTCN2020128033-appb-000241
将化合物5h(2.73g，5.4mmol)溶于100mL四氢呋喃中，室温下加入间氯过氧苯甲酸(2.8g，16.2mmol)，室温搅拌2h。加入20mL饱和硫代硫酸钠水溶液，搅拌20min，减压除去大部分溶剂后，加入100mL乙酸乙酯稀释，有机层用30mL饱和碳酸氢钠水溶液洗涤3次，有机相干燥，减压浓缩，柱层析后得到目标产物5i，白色固体(2.54g，收率：87％)。Compound 5h (2.73 g, 5.4 mmol) was dissolved in 100 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (2.8 g, 16.2 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. Add 20mL saturated sodium thiosulfate aqueous solution, stir for 20min, after removing most of the solvent under reduced pressure, add 100mL ethyl acetate to dilute, the organic layer is washed 3 times with 30mL saturated sodium bicarbonate aqueous solution, the organic phase is dried, concentrated under reduced pressure, column layer After analysis, the target product 5i was obtained as a white solid (2.54 g, yield: 87%).
MS m/z(ESI):538.7[M+H] + MS m/z(ESI): 538.7[M+H] +
第九步：(2S)-2-(氰基甲基)-4-[2-[[((2S，4R)-4-氟-1-甲基-吡咯烷基-2-基]甲氧基]螺[6,8-二氢-5H-喹唑啉-7,1'-茚满]-4-基]哌嗪-1-甲酸叔丁酯(5j)；The ninth step: (2S)-2-(cyanomethyl)-4-[2-[[((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy Yl]spiro[6,8-dihydro-5H-quinazoline-7,1'-indan]-4-yl]piperazine-1-carboxylic acid tert-butyl ester (5j);
tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazine-1-carboxylate.tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro- 5H-quinazoline-7,1'-indane]-4-yl]piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000242
Figure PCTCN2020128033-appb-000242
将化合物5i(950mg，1.77mmol)和(1-甲基-4-氟代吡咯烷-2-基)甲醇(471mg，3.54mmol)溶于40mL甲苯中，冰浴下加入叔丁醇钠(255mg，2.66mmol)，冰浴下搅拌1h。加入15mL水淬灭反应，加入100mL乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物5j，白色固体(1.0g，收率：96％)。Compound 5i (950mg, 1.77mmol) and (1-methyl-4-fluoropyrrolidin-2-yl)methanol (471mg, 3.54mmol) were dissolved in 40mL of toluene, and sodium tert-butoxide (255mg , 2.66mmol), stirred under ice bath for 1h. The reaction was quenched by adding 15 mL of water, 100 mL of ethyl acetate was added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 5j was obtained as a white solid (1.0 g, yield: 96%).
MS m/z(ESI):591.3[M+H] + MS m/z(ESI): 591.3[M+H] +
第十步：2-[(2S)-4-[2-[[((2S，4R)-4-氟-1-甲基-吡咯烷-2-基]甲氧基]螺[6,8-二氢-5H-喹唑啉-7，1'-茚满]-4-基]哌嗪-2-基]乙腈(5k)；The tenth step: 2-[(2S)-4-[2-[[((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8 -Dihydro-5H-quinazoline-7,1'-indan]-4-yl]piperazin-2-yl]acetonitrile (5k);
2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7, 1'-indane]-4-yl]piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000243
Figure PCTCN2020128033-appb-000243
将化合物5j(1.0g，1.7mmol)溶于20mL二氯甲烷中，加入5mL三氟乙酸，于室温下搅拌2h。待反应完成后，减压旋干溶剂，再加入100mL二氯甲烷稀释，滴加饱和碳酸氢钠调节PH到碱性，然后用100mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩，得到目标化合物5k粗品，黄色固体1.2g，直接用于下一步。Compound 5j (1.0 g, 1.7 mmol) was dissolved in 20 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is completed, the solvent is spin-dried under reduced pressure, then diluted with 100 mL of dichloromethane, saturated sodium bicarbonate is added dropwise to adjust the pH to alkaline, and then extracted three times with 100 mL of dichloromethane, the organic phases are combined, and dried with anhydrous sodium sulfate , Concentrated under reduced pressure to obtain the target compound 5k crude product, 1.2 g of yellow solid, which was directly used in the next step.
MS m/z(ESI):491.3[M+H] + MS m/z(ESI): 491.3[M+H] +
第十一步：2-[(2S)-4-[2-[[((2S，4R)-4-氟-1-甲基-吡咯烷-2-基]甲氧基]螺[6,8-二氢-5H-喹唑啉-7，1'-茚满]-4-基]-1-丙-2-烯酰基-哌嗪-2-基]乙腈(化合物5)；The eleventh step: 2-[(2S)-4-[2-[[((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6, 8-Dihydro-5H-quinazoline-7,1'-indan]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (compound 5);
2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7, 1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000244
Figure PCTCN2020128033-appb-000244
将化合物5k粗品(0.6g，1.23mmol)溶于50mL二氯甲烷中，加入三乙胺(0.85mL，6.1mmol)，冰浴下计入烯丙酰氯(111mg，1.23mmol)，冰浴下搅拌30min。加入5mL冰水淬灭反应，然后用50mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标化合物5，白色固体(254mg，两步收率：55％)。化合物5经SFC制备分离纯化后得到异构体5-1(95mg,SFC制备保留时间为1.23min；手性HPLC保留时间为12.78min)和异构体5-2(100mg，SFC制备保留时间为1.47min，手性HPLC保留时间为18.30min).Dissolve the crude compound 5k (0.6g, 1.23mmol) in 50mL of dichloromethane, add triethylamine (0.85mL, 6.1mmol), add acryloyl chloride (111mg, 1.23mmol) under ice bath, and stir under ice bath 30min. The reaction was quenched by adding 5 mL of ice water, and then extracted three times with 50 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 5 was obtained as a white solid (254 mg, two-step yield: 55%). 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).
手性HPLC分析方法：Chiral HPLC analysis method:
样品溶于正己烷/异丙醇(90:10)中，The sample is dissolved in n-hexane/isopropanol (90:10),
仪器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6×250mm,5μmInstrument: Shimadzu LC-20AT; Chiral column: CHIRALPAK AD-H, 4.6×250mm, 5μm
流动相：正己烷(含0.1％二乙胺)-异丙醇(80:20)；流速：1mL/minMobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (80:20); flow rate: 1mL/min
柱温：35℃；检测波长：210nm；进样量：50μLColumn temperature: 35℃; detection wavelength: 210nm; injection volume: 50μL
SFC制备分离条件：仪器:MGⅡpreparative SFC柱子:ChiralPak AD,250×30mm I.D.,10μmSFC preparation and separation conditions: instrument: MGⅡpreparative SFC column: ChiralPak AD, 250×30mm I.D., 10μm
流动相:A为CO 2，B为乙醇(含0.1％氨水)，30％B洗脱。 Mobile phase: A is CO 2 , B is ethanol (containing 0.1% ammonia water), 30% B is eluted.
流速:70mL/min；柱温:38℃；检测波长:220nmFlow rate: 70mL/min; column temperature: 38℃; detection wavelength: 220nm
经制备分离后，合并相同保留时间的组分，减压浓缩得化合物5-1和5-2。After preparation and separation, the components with the same retention time are combined and concentrated under reduced pressure to obtain compounds 5-1 and 5-2.
异构体5-1Isomer 5-1
1H NMR(400MHz,CD 3OD)δ7.30–7.03(m,4H),6.93–6.71(m,1H),6.27(d,1H),5.82(d,1H),5.26–4.99(m,2H),4.43–4.30(m,2H),4.21–3.96(m,3H),3.76–3.58(m,1H),3.57–3.42(m,2H),3.42–3.36(m,1H),3.18–3.03(m,2H),3.02–2.90(m,3H),2.90–2.77(m,3H),2.77–2.48(m,5H),2.33–2.18(m,1H),2.13–1.86(m,4H),1.85–1.75(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 7.30-7.03 (m, 4H), 6.93-6.71 (m, 1H), 6.27 (d, 1H), 5.82 (d, 1H), 5.26-4.99 (m, 2H), 4.43--4.30 (m, 2H), 4.21--3.96 (m, 3H), 3.76--3.58 (m, 1H), 3.57--3.42 (m, 2H), 3.42--3.36 (m, 1H), 3.18-- 3.03 (m, 2H), 3.02-2.90 (m, 3H), 2.90-2.77 (m, 3H), 2.77-2.48 (m, 5H), 2.33-2.18 (m, 1H), 2.13-1.86 (m, 4H) ), 1.85-1.75 (m, 1H).
19F NMR(376MHz,CD 3OD)δ-169.68. 19 F NMR (376MHz, CD 3 OD) δ-169.68.
Ms m/z(ESI):545.3[M+H] + Ms m/z(ESI): 545.3[M+H] +
异构体5-2Isomer 5-2
1H NMR(400MHz,CD 3OD)δ7.26–7.19(m,1H),7.19–7.09(m,2H),7.09–7.02(m,1H),6.94–6.72(m,1H),6.28(d,1H),5.82(d,1H),5.28–5.00(m,2H),4.44–4.31(m,2H),4.21–3.93(m,3H),3.67–3.43(m,2H),3.28–3.20(m,1H),3.19–3.08(m,2H),3.07–2.86(m,4H),2.85–2.62(m,5H),2.55(s,3H),2.35–2.21(m,1H),2.10–1.88(m,4H),1.82–1.72(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 7.26–7.19 (m, 1H), 7.19–7.09 (m, 2H), 7.09–7.02 (m, 1H), 6.94–6.72 (m, 1H), 6.28 ( d,1H), 5.82(d,1H), 5.28--5.00(m,2H), 4.44--4.31(m,2H), 4.21-3.93(m,3H), 3.67--3.43(m,2H), 3.28-- 3.20(m,1H),3.19-3.08(m,2H),3.07-2.86(m,4H), 2.85-2.62(m,5H),2.55(s,3H),2.35-2.21(m,1H), 2.10–1.88(m,4H), 1.82–1.72(m,1H).
19F NMR(376MHz,CD 3OD)δ-169.73. 19 F NMR (376MHz, CD 3 OD) δ-169.73.
Ms m/z(ESI):545.3[M+H] + Ms m/z(ESI): 545.3[M+H] +
实施例6Example 6
2-[(2S)-4-[2-[[((2S，4R)-4-氟-1-甲基-吡咯烷-2-基]甲氧基]螺[6,8-二氢-5H-喹唑啉-7，1'-茚满]-4-基]-1-(2-氟丙-2-烯酰基)哌嗪-2-基]乙腈(化合物6)；2-[(2S)-4-[2-[[(((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro- 5H-quinazoline-7,1'-indan]-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (compound 6);
2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7, 1'-indane]-4-yl)-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000245
Figure PCTCN2020128033-appb-000245
将化合物5k粗品(0.6g，1.23mmol)和2-氟丙烯酸(166mg，1.85mmol)溶于30mLN,N-二甲基甲酰胺中，加入二异丙基乙胺(793mg，6.15mmol)，室温下加入O-(7-氮杂苯并三唑-1-基)-N,N,N'；-四甲基脲六氟磷酸盐(701mg，1.85mmol)，反应3h。待原料反应完全后加入100mL乙酸乙酯稀释反应，然后用30mL水洗有机相三次，有机相用无水硫酸钠干燥，减压浓缩。柱层析后得到目标化合物6，白色固体(334mg，收率：two steps 70％)。化合物6经SFC制备分离纯化后得到异构体6-1(100mg,SFC制备保留时间为1.07min；手性HPLC保留时间为11.46min)和异构体6-2(150mg，SFC制备保留时间为1.29min，手性HPLC保留时间为19.75min).The crude compound 5k (0.6g, 1.23mmol) and 2-fluoroacrylic acid (166mg, 1.85mmol) were dissolved in 30mL of N,N-dimethylformamide, and diisopropylethylamine (793mg, 6.15mmol) was added at room temperature. Add O-(7-azabenzotriazol-1-yl)-N,N,N';-tetramethylurea hexafluorophosphate (701mg, 1.85mmol), and react for 3h. After the reaction of the raw materials was completed, 100 mL of ethyl acetate was added to dilute the reaction, and then the organic phase was washed three times with 30 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 6 was obtained as a white solid (334 mg, yield: two steps 70%). Compound 6 was separated and purified by SFC preparation to obtain isomer 6-1 (100mg, SFC preparation retention time is 1.07min; chiral HPLC retention time is 11.46min) and isomer 6-2 (150mg, SFC preparation retention time is 1.29min, chiral HPLC retention time is 19.75min).
手性HPLC分析方法：Chiral HPLC analysis method:
样品溶于正己烷/异丙醇(90:10)中，The sample is dissolved in n-hexane/isopropanol (90:10),
仪器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6×250mm,5μmInstrument: Shimadzu LC-20AT; Chiral column: CHIRALPAK AD-H, 4.6×250mm, 5μm
流动相：正己烷(含0.1％二乙胺)-异丙醇(80:20)；流速：1mL/minMobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (80:20); flow rate: 1mL/min
柱温：35℃；检测波长：210nm；进样量：50μLColumn temperature: 35℃; detection wavelength: 210nm; injection volume: 50μL
SFC制备分离条件：仪器:MGⅡpreparative SFC柱子:ChiralPak AD,250×30mm I.D.,10μmSFC preparation and separation conditions: instrument: MGⅡpreparative SFC column: ChiralPak AD, 250×30mm I.D., 10μm
流动相:A为CO 2，B为乙醇(含0.1％氨水)，30％B洗脱。 Mobile phase: A is CO 2 , B is ethanol (containing 0.1% ammonia water), 30% B is eluted.
流速:70mL/min；柱温:38℃；检测波长:220nmFlow rate: 70mL/min; column temperature: 38℃; detection wavelength: 220nm
经制备分离后，合并相同保留时间的组分，减压浓缩得化合物6-1和6-2。After preparation and separation, the components with the same retention time are combined and concentrated under reduced pressure to obtain compounds 6-1 and 6-2.
异构体6-1Isomer 6-1
1H NMR(400MHz,CD 3OD)δ7.06–7.02(m,4H),5.42–5.04(m,3H),5.02–4.85(m,1H),4.44–4.30(m,2H),4.20–3.98(m,3H),3.75–3.57(m,1H),3.56–3.42(m,1H),3.42–3.34(m,1H),3.17–2.76(m,9H),2.76–2.64(m,2H),2.52(s,3H),2.33–2.18(m,1H),2.12–1.85(m,4H),1.85–1.74(m,1H). 1 H NMR (400MHz, CD 3 OD) δ7.06--7.02 (m, 4H), 5.42-5.04 (m, 3H), 5.02--4.85 (m, 1H), 4.44-4.30 (m, 2H), 4.20- 3.98 (m, 3H), 3.75 - 3.57 (m, 1H), 3.56 - 3.42 (m, 1H), 3.42 - 3.34 (m, 1H), 3.17 - 2.76 (m, 9H), 2.76 - 2.64 (m, 2H) ), 2.52 (s, 3H), 2.33-2.18 (m, 1H), 2.12-1.85 (m, 4H), 1.85-1.74 (m, 1H).
19F NMR(376MHz,CD 3OD)δ-105.10,-169.66. 19 F NMR (376MHz, CD 3 OD) δ-105.10, -169.66.
Ms m/z(ESI):563.3[M+H] + Ms m/z(ESI):563.3[M+H] +
异构体6-2Isomer 6-2
1H NMR(400MHz,CD 3OD)δ7.26–7.20(m,1H),7.19–7.09(m,2H),7.09–7.02(m,1H),5.42–5.05(m,3H),4.99–4.84(m,1H),4.43–4.31(m,2H),4.22–3.93(m,3H),3.63–3.42(m,2H),3.28–3.11(m,3H),3.10–3.01(m,2H),3.01–2.85(m,2H),2.85–2.72(m,3H),2.71–2.57(m,2H),2.53(s,3H),2.34–2.16(m,1H),2.11–1.85(m,4H),1.85–1.71(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 7.26 - 7.20 (m, 1H), 7.19 - 7.09 (m, 2H), 7.09 - 7.02 (m, 1H), 5.42 - 5.05 (m, 3H), 4.99 - 4.84 (m, 1H), 4.43 - 4.31 (m, 2H), 4.22 - 3.93 (m, 3H), 3.63 - 3.42 (m, 2H), 3.28 - 3.11 (m, 3H), 3.10 - 3.01 (m, 2H) ), 3.01–2.85(m,2H), 2.85–2.72(m,3H), 2.71–2.57(m,2H), 2.53(s,3H), 2.34–2.16(m,1H), 2.11–1.85(m ,4H),1.85-1.71(m,1H).
19F NMR(376MHz,CD 3OD)δ-105.06,-169.64. 19 F NMR (376MHz, CD 3 OD) δ-105.06, -169.64.
Ms m/z(ESI):563.3[M+H] + Ms m/z(ESI):563.3[M+H] +
实施例7Example 7
2-[(2S)-1-(2-氟丙-2-烯酰基)-4-[2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]螺[6,8-二氢-5H-喹唑啉-7,1'-茚满]-4-基]哌嗪-2-基]乙腈(化合物7)；2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[ 6,8-Dihydro-5H-quinazoline-7,1'-indan]-4-yl]piperazin-2-yl]acetonitrile (compound 7);
2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H- quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000246
Figure PCTCN2020128033-appb-000246
Figure PCTCN2020128033-appb-000247
Figure PCTCN2020128033-appb-000247
第一步：(S)-2-(氰甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-甲酸叔丁酯(7a)；The first step: (S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5 Tert-butyl',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (7a);
tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6' H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.
Figure PCTCN2020128033-appb-000248
Figure PCTCN2020128033-appb-000248
将化合物5i(1.6g，3.0mmol)和(1-甲基吡咯烷-2-基)甲醇(686mg，6.0mmol)溶于60mL甲苯中，冰浴下加入叔丁醇钠(432mg，4.5mmol)，冰浴下搅拌1h。加入20mL水淬灭反应，加入1000mL乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩。柱层析后得到目标产物7a，白色固体(1.54g，收率：90％)。Compound 5i (1.6g, 3.0mmol) and (1-methylpyrrolidin-2-yl)methanol (686mg, 6.0mmol) were dissolved in 60mL of toluene, and sodium tert-butoxide (432mg, 4.5mmol) was added under ice bath. , Stir under ice bath for 1h. The reaction was quenched by adding 20 mL of water, and then extracted three times by adding 1000 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 7a was obtained as a white solid (1.54 g, yield: 90%).
MS m/z(ESI):573.6[M+H] + MS m/z(ESI): 573.6[M+H] +
第二步：2-((S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5'，8'-四氢-6'H-螺[茚-1,7'-喹唑啉]-4'-基)哌嗪-2-基)乙腈(7b)；The second step: 2-((S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetra Hydrogen-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (7b);
2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4- yl]piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000249
Figure PCTCN2020128033-appb-000249
将化合物7a(1.54g，2.7mmol)溶于25mL二氯甲烷中，加入5mL三氟乙酸，于室温下搅拌2h。待反应完成后，减压旋干溶剂，再加入100mL二氯甲烷稀释，滴加饱和碳 酸氢钠调节PH到碱性，然后用100mL二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，减压浓缩，得到目标化合物7b粗品，黄色固体1.5g，直接用于下一步。Compound 7a (1.54 g, 2.7 mmol) was dissolved in 25 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is completed, the solvent is spin-dried under reduced pressure, then diluted with 100 mL of dichloromethane, saturated sodium bicarbonate is added dropwise to adjust the pH to alkaline, and then extracted three times with 100 mL of dichloromethane, the organic phases are combined, and dried with anhydrous sodium sulfate , Concentrated under reduced pressure to obtain crude target compound 7b, 1.5 g of yellow solid, which was directly used in the next step.
MS m/z(ESI):473.6[M+H] + MS m/z(ESI): 473.6[M+H] +
第三步：2-[(2S)-1-(2-氟丙-2-烯酰基)-4-[2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]螺[6,8-二氢-5H-喹唑啉-7,1'-茚满]-4-基]哌嗪-2-基]乙腈(化合物7)；The third step: 2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methoxy Yl]spiro[6,8-dihydro-5H-quinazolin-7,1'-indan]-4-yl]piperazin-2-yl]acetonitrile (compound 7);
2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H- quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000250
Figure PCTCN2020128033-appb-000250
将化合物7b粗品(0.46g，0.97mmol)和2-氟丙烯酸(132mg，1.46mmol)溶于30mLN,N-二甲基甲酰胺中，加入二异丙基乙胺(626mg，4.85mmol)，室温下加入O-(7-氮杂苯并三唑-1-基)-N,N,N'；-四甲基脲六氟磷酸盐(555mg，1.46mmol)，反应3h。待原料反应完全后加入100mL乙酸乙酯稀释反应，然后用30mL水洗有机相三次，有机相用无水硫酸钠干燥，减压浓缩。柱层析后得到目标化合物7，白色固体(330mg，两步收率：72％)。化合物7经SFC制备分离纯化后得到异构体7-1(95mg,SFC制备保留时间为1.07min；手性HPLC保留时间为7.69min)和异构体7-2(60mg，SFC制备保留时间为1.26min，手性HPLC保留时间为13.65min).The crude compound 7b (0.46g, 0.97mmol) and 2-fluoroacrylic acid (132mg, 1.46mmol) were dissolved in 30mL N,N-dimethylformamide, and diisopropylethylamine (626mg, 4.85mmol) was added at room temperature. Add O-(7-azabenzotriazol-1-yl)-N,N,N';-tetramethylurea hexafluorophosphate (555mg, 1.46mmol) and react for 3h. After the reaction of the raw materials was completed, 100 mL of ethyl acetate was added to dilute the reaction, and then the organic phase was washed three times with 30 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 7 was obtained as a white solid (330 mg, two-step yield: 72%). Compound 7 was separated and purified by SFC preparation to obtain isomer 7-1 (95mg, retention time of SFC preparation is 1.07min; chiral HPLC retention time is 7.69min) and isomer 7-2 (60mg, retention time of SFC preparation is 1.26min, chiral HPLC retention time is 13.65min).
手性HPLC分析方法：Chiral HPLC analysis method:
样品溶于正己烷/异丙醇(90:10)中，The sample is dissolved in n-hexane/isopropanol (90:10),
仪器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6×250mm,5μmInstrument: Shimadzu LC-20AT; Chiral column: CHIRALPAK AD-H, 4.6×250mm, 5μm
流动相：正己烷(含0.1％二乙胺)-异丙醇(80:20)；流速：1mL/minMobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (80:20); flow rate: 1mL/min
柱温：35℃；检测波长：210nm；进样量：50μLColumn temperature: 35℃; detection wavelength: 210nm; injection volume: 50μL
SFC制备分离条件：SFC preparation and separation conditions:
仪器:MGⅡpreparative SFC柱子:ChiralPak AD,250×30mm I.D.,10μm；流动相:A为CO 2，B为乙醇(含0.1％氨水)，30％B洗脱。 Instrument: MGⅡpreparative SFC column: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A is CO 2 , B is ethanol (containing 0.1% ammonia), 30% B elution.
流速:70mL/min；柱温:38℃；检测波长:220nmFlow rate: 70mL/min; column temperature: 38℃; detection wavelength: 220nm
经制备分离后，合并相同保留时间的组分，减压浓缩得化合物7-1和7-2。After preparation and separation, the components with the same retention time are combined and concentrated under reduced pressure to obtain compounds 7-1 and 7-2.
异构体7-1Isomer 7-1
1H NMR(400MHz,CD 3OD)δ7.26–7.06(m,4H),5.41–5.22(m,2H),5.02–4.84(m,1H),4.43–4.25(m,2H),4.21–3.99(m,3H),3.75–3.52(m,1H),3.44–3.33(m,1H),3.17–3.00(m,3H),2.99–2.90(m,3H),2.89–2.65(m,5H),2.51(s,3H),2.37(dd,1H),2.16–1.96(m,4H),1.88–1.76(m,3H),1.76–1.64(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 7.26--7.06 (m, 4H), 5.41--5.22 (m, 2H), 5.02--4.84 (m, 1H), 4.43--4.25 (m, 2H), 4.21-- 3.99 (m, 3H), 3.75 - 3.52 (m, 1H), 3.44 - 3.33 (m, 1H), 3.17 - 3.00 (m, 3H), 2.99 - 2.90 (m, 3H), 2.89 - 2.65 (m, 5H) ), 2.51 (s, 3H), 2.37 (dd, 1H), 2.16-1.96 (m, 4H), 1.88-1.76 (m, 3H), 1.76-1.64 (m, 1H).
19F NMR(376MHz,CD 3OD)δ-105.11. 19 F NMR (376MHz, CD 3 OD) δ-105.11.
Ms m/z(ESI):545.3[M+H] + Ms m/z(ESI): 545.3[M+H] +
异构体7-2Isomer 7-2
1H NMR(400MHz,CD 3OD)δ7.26–7.19(m,1H),7.19–7.08(m,2H),7.09–7.01(m,1H),5.42–5.19(m,2H),5.01–4.84(m,1H),4.42–4.25(m,2H),4.23–3.91(m,3H),3.67–3.38(m,1H),3.27–3.01(m,5H),3.01–2.85(m,2H),2.85–2.60(m,5H),2.50(s,3H),2.36(dd,1H),2.15–1.94(m,4H),1.89–1.64(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.26 - 7.19 (m, 1H), 7.19 - 7.08 (m, 2H), 7.09 - 7.01 (m, 1H), 5.42 - 5.19 (m, 2H), 5.01 - 4.84 (m, 1H), 4.42 - 4.25 (m, 2H), 4.23 - 3.91 (m, 3H), 3.67 - 3.38 (m, 1H), 3.27 - 3.01 (m, 5H), 3.01 - 2.85 (m, 2H) ), 2.85-2.60(m,5H), 2.50(s,3H), 2.36(dd,1H), 2.15-1.94(m,4H), 1.89-1.64(m,4H).
19F NMR(376MHz,CD 3OD)δ-105.06. 19 F NMR (376MHz, CD 3 OD) δ-105.06.
Ms m/z(ESI):545.3[M+H] + Ms m/z(ESI): 545.3[M+H] +
实施例8Example 8
2-[((2S)-1-[(E)-4-(二甲基氨基)丁-2-烯酰基]-4-[2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]螺][6，8-二氢-5H-喹唑啉-7,1'-茚满]-4-基]哌嗪-2-基]乙腈(化合物8)；2-[((2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[2-[[((2S)-1-methylpyrrolidine- 2-yl]methoxy]spiro][6,8-dihydro-5H-quinazolin-7,1'-indan]-4-yl]piperazin-2-yl]acetonitrile (compound 8);
2-[(2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.2-[(2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6 ,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.
Figure PCTCN2020128033-appb-000251
Figure PCTCN2020128033-appb-000251
将化合物7b粗品(0.4g，0.85mmol)和反式-4-二甲基胺基巴豆酸盐酸盐(211mg，1.28mmol)溶于30mL N,N-二甲基甲酰胺中，加入二异丙基乙胺(548mg，4.25mmol)，室温下加入O-(7-氮杂苯并三唑-1-基)-N,N,N'；-四甲基脲六氟磷酸盐(486mg，1.28mmol)，反应3h。待原料反应完全后加入100mL乙酸乙酯稀释反应，然后用30mL水洗有机相三次，有机相用无水硫酸钠干燥，减压浓缩。柱层析后得到目标化合物8，白色固体(100mg，收率：23％)。化合物8经SFC制备分离纯化后得到异构体8-1(36mg,SFC制备保留时间 为5.57min；手性HPLC保留时间为11.6min)和异构体8-2(25mg，SFC制备保留时间为6.08min，手性HPLC保留时间为14.9min).The crude compound 7b (0.4g, 0.85mmol) and trans-4-dimethylamino crotonic acid hydrochloride (211mg, 1.28mmol) were dissolved in 30mL N,N-dimethylformamide, and the diisopropyl ether was added. Propyl ethylamine (548mg, 4.25mmol), add O-(7-azabenzotriazol-1-yl)-N,N,N';-tetramethylurea hexafluorophosphate (486mg, 1.28mmol), react for 3h. After the reaction of the raw materials was completed, 100 mL of ethyl acetate was added to dilute the reaction, and then the organic phase was washed three times with 30 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, target compound 8 was obtained as a white solid (100 mg, yield: 23%). Compound 8 was separated and purified by SFC preparation to obtain Isomer 8-1 (36mg, SFC preparation retention time is 5.57min; Chiral HPLC retention time is 11.6min) and Isomer 8-2 (25mg, SFC preparation retention time is 6.08min, chiral HPLC retention time is 14.9min).
手性HPLC分析方法：Chiral HPLC analysis method:
样品溶于正己烷/异丙醇(90:10)中，The sample is dissolved in n-hexane/isopropanol (90:10),
仪器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6×250mm,5μmInstrument: Shimadzu LC-20AT; Chiral column: CHIRALPAK AD-H, 4.6×250mm, 5μm
流动相：正己烷(含0.1％二乙胺)-乙醇(80:20)；流速：1mL/minMobile phase: n-hexane (containing 0.1% diethylamine)-ethanol (80:20); flow rate: 1mL/min
柱温：35℃；检测波长：210nm；进样量：50μLColumn temperature: 35℃; detection wavelength: 210nm; injection volume: 50μL
SFC制备分离条件：仪器:MGⅡpreparative SFC；柱子:ChiralCel OD,250×30mm I.D.,5μmSFC preparation and separation conditions: instrument: MGⅡpreparative SFC; column: ChiralCel OD, 250×30mm I.D., 5μm
流动相:A为CO 2，B为乙醇(含0.1％氨水)，30％B洗脱。 Mobile phase: A is CO 2 , B is ethanol (containing 0.1% ammonia water), 30% B is eluted.
流速:70mL/min；柱温:38℃；检测波长:220nmFlow rate: 70mL/min; column temperature: 38℃; detection wavelength: 220nm
经制备分离后，合并相同保留时间的组分，减压浓缩得化合物8-1和8-2。After preparation and separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 8-1 and 8-2.
异构体8-1Isomer 8-1
1H NMR(400MHz,CD 3OD)δ7.26–7.19(m,1H),7.19–7.05(m,3H),6.91–6.59(m,2H),5.12–4.97(m,1H),4.60–4.46(m,1H),4.43–4.28(m,2H),4.19–3.99(m,3H),3.76–3.60(m,1H),3.44–3.35(m,1H),3.23–3.16(m,2H),3.16–3.06(m,2H),3.00–2.76(m,7H),2.76–2.67(m,1H),2.53(s,3H),2.48–2.34(m,1H),2.30(s,6H),2.16–1.97(m,4H),1.90–1.65(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.26--7.19 (m, 1H), 7.19--7.05 (m, 3H), 6.91--6.59 (m, 2H), 5.12--4.97 (m, 1H), 4.60-- 4.46 (m, 1H), 4.43 - 4.28 (m, 2H), 4.19 - 3.99 (m, 3H), 3.76 - 3.60 (m, 1H), 3.44 - 3.35 (m, 1H), 3.23 - 3.16 (m, 2H) ), 3.16–3.06(m,2H), 3.00–2.76(m,7H), 2.76–2.67(m,1H), 2.53(s,3H), 2.48–2.34(m,1H), 2.30(s,6H) ), 2.16–1.97(m,4H), 1.90–1.65(m,4H).
Ms m/z(ESI):584.3[M+H] + Ms m/z(ESI):584.3[M+H] +
异构体8-2Isomer 8-2
1H NMR(400MHz,CD 3OD)δ7.27–7.19(m,1H),7.19–7.08(m,2H),7.08–7.01(m,1H),6.89–6.79(m,1H),6.79–6.58(m,1H),5.16–4.98(m,1H),4.61–4.45(m,1H),4.42–4.26(m,2H),4.19–3.92(m,3H),3.66–3.50(m,1H),3.26–3.06(m,5H),3.06–2.86(m,4H),2.85–2.74(m,3H),2.71–2.61(m,1H),2.51(s,3H),2.42–2.33(m,1H),2.29(s,6H),2.15–1.95(m,4H),1.87–1.65(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.27--7.19 (m, 1H), 7.19-7.08 (m, 2H), 7.08-7.01 (m, 1H), 6.89--6.79 (m, 1H), 6.79- 6.58(m,1H), 5.16–4.98(m,1H), 4.61–4.45(m,1H), 4.42–4.26(m,2H), 4.19–3.92(m,3H), 3.66–3.50(m,1H) ), 3.26-3.06 (m, 5H), 3.06-2.86 (m, 4H), 2.85-2.74 (m, 3H), 2.71-2.61 (m, 1H), 2.51 (s, 3H), 2.42-2.33 (m ,1H), 2.29(s,6H), 2.15-1.95(m,4H), 1.87-1.65(m,4H).
Ms m/z(ESI):584.3[M+H] + Ms m/z(ESI):584.3[M+H] +
实施例9：Example 9:
2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-基)哌嗪-2-基)乙腈的光学纯异构体(化合物9-1和化合物9-2)2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6 Optically pure isomers of'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (compound 9-1 and compound 9-2)
2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile；isomer 9-1 and isomer 9-22-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene- 1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile; isomer 9-1 and isomer 9-2
Figure PCTCN2020128033-appb-000252
Figure PCTCN2020128033-appb-000252
第一步：螺环[环己烷-1,1'-茚]-3-酮(9F)Step 1: Spiro[cyclohexane-1,1'-indene]-3-one (9F)
spiro[cyclohexane-1,1'-inden]-3-onespiro[cyclohexane-1,1'-inden]-3-one
Figure PCTCN2020128033-appb-000253
Figure PCTCN2020128033-appb-000253
将中间体1E(3.0g,12.4mmol)溶解到THF(10.0mL)中，再向体系中加入6N的盐酸(20.0mL)，反应置于室温搅拌1h。反应结束后，将反应液直接旋干，再用乙酸乙酯萃取，饱和NaHCO 3水溶液洗涤，有机相干燥过滤后直接旋干经硅胶色谱柱分离得到产物9F，无油状物(2.5g，产率98％)。 Intermediate 1E (3.0 g, 12.4 mmol) was dissolved in THF (10.0 mL), 6N hydrochloric acid (20.0 mL) was added to the system, and the reaction was stirred at room temperature for 1 h. After the reaction, the reaction solution was directly spin-dried, and then extracted with ethyl acetate, washed with saturated NaHCO 3 aqueous solution, the organic phase was dried and filtered, and then spin-dried directly to separate by silica gel column to obtain the product 9F, oil-free (2.5g, yield) 98%).
第二步：3-羟基螺环[环己烷-1,1'-茚]-3-烯-4-羧酸乙酯(9G)Step 2: 3-Hydroxyspirocyclo[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9G)
ethyl 3-hydroxyspiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylateethyl 3-hydroxyspiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate
Figure PCTCN2020128033-appb-000254
Figure PCTCN2020128033-appb-000254
将螺环[环己烷-1,1'-茚]-3-酮(9F)(2.3g,11.6mmol)溶解到THF(80.0mL)中，-70℃下搅拌降温，再向体系中缓慢滴加LiHMDS(14mL,14.0mmol)，反应置于此温度下继续搅拌1h后,向反应中缓慢滴加氰基甲酸乙酯(1.38g,14.0mmol)，滴加完毕后，反应缓慢升温至室温后再搅拌30m in。反应结束后，将反应液降温到0℃，用饱和氯化铵水溶液淬灭反应，再用乙酸乙酯萃取，有机相干燥过滤后直接旋干，经硅胶色谱柱分离得到产物9G，无油状物(2.3g，产率73％)。Dissolve spiro[cyclohexane-1,1'-indene]-3-one (9F) (2.3g, 11.6mmol) in THF (80.0mL), stir and cool down at -70℃, and then slowly add to the system LiHMDS (14mL, 14.0mmol) was added dropwise. After the reaction was kept at this temperature and stirring continued for 1h, ethyl cyanoformate (1.38g, 14.0mmol) was slowly added dropwise to the reaction. After the addition was completed, the reaction was slowly warmed to room temperature Then stir for 30m in. After the reaction, the reaction solution was cooled to 0°C, quenched with saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate. The organic phase was dried and filtered and was directly spin-dried. The product 9G was separated by silica gel chromatography column without oil. (2.3g, yield 73%).
第三步：3-氨基螺[1,1'-茚]-3-烯-4-羧酸乙酯(9H)The third step: 3-aminospiro[1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9H)
ethyl 3-aminospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylateethyl 3-aminospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate
Figure PCTCN2020128033-appb-000255
Figure PCTCN2020128033-appb-000255
将3-羟基螺环[环己烷-1,1'-茚]-3-烯-4-羧酸乙酯(9G)(2.3g,8.4mmol)和乙酸铵(2.2g,29mmol)溶解到乙醇(80.0mL)中，置于90℃搅拌回流2小时。反应结束后，将反应液直接旋干，经硅胶色谱柱分离得到产物9H，无油状物(2.15g，产率95％)。Dissolve 3-hydroxyspirocyclo[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9G) (2.3g, 8.4mmol) and ammonium acetate (2.2g, 29mmol) to In ethanol (80.0 mL), the mixture was placed at 90°C with stirring and refluxed for 2 hours. After the completion of the reaction, the reaction solution was directly spin-dried, and separated by silica gel chromatography to obtain the product 9H without oil (2.15 g, yield 95%).
第四步：3-(3-苯甲酰硫脲基)螺环[环己烷-1,1'-茚]-3-烯-4-羧酸乙酯(9I)The fourth step: 3-(3-benzoylthioureido) spiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9I)
ethyl 3-(3-benzoylthioureido)spiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylateethyl 3-(3-benzoylthioureido)spiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate
Figure PCTCN2020128033-appb-000256
Figure PCTCN2020128033-appb-000256
将3-氨基螺[1,1'-茚]-3-烯-4-羧酸乙酯(9H)(2.1g,8.0mmol),苯甲酰基异硫氰酸酯(1.9g,12.0mmol)加入到丙酮(50.0mL)中搅拌均匀，再置于60℃搅拌回流1h.反应结束后，将反应液冷却至室温，反应液直接减压旋蒸，经硅胶柱纯化得到产物9I,白色固体(2.8g,产率81％)。Combine 3-aminospiro[1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9H) (2.1g, 8.0mmol), benzoyl isothiocyanate (1.9g, 12.0mmol) Add it to acetone (50.0mL) and stir evenly, and then place it at 60°C and stir under reflux for 1h. After the reaction is over, the reaction solution is cooled to room temperature, the reaction solution is directly evaporated under reduced pressure and purified by silica gel column to obtain the product 9I, a white solid ( 2.8g, yield 81%).
第五步：2'-巯基-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-醇(9J)The fifth step: 2'-mercapto-5',8'-dihydro-6'H-spirocyclo[indene-1,7'-quinazoline]-4'-alcohol (9J)
2'-mercapto-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol2'-mercapto-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol
Figure PCTCN2020128033-appb-000257
Figure PCTCN2020128033-appb-000257
将3-(3-苯甲酰硫脲基)螺环[环己烷-1,1'-茚]-3-烯-4-羧酸乙酯(9I)(2.8g,6.5mmol)和KOH(1.1g,19.5mmol)溶解到乙醇(50.0mL)中，置于90℃搅拌回流30min。反应结束后，将反应液冷却至室温，再用2N盐酸中和至大量白色固体析出，将固体过滤，得到滤饼减压干燥得到产物9J。白色固体(1.3g，产率74％)。Combine 3-(3-benzoylthioureido) spiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9I) (2.8g, 6.5mmol) and KOH (1.1g, 19.5mmol) was dissolved in ethanol (50.0mL) and placed at 90°C under reflux with stirring for 30min. After the completion of the reaction, the reaction solution was cooled to room temperature, and then neutralized with 2N hydrochloric acid until a large amount of white solid precipitated, and the solid was filtered to obtain a filter cake and dry under reduced pressure to obtain the product 9J. White solid (1.3g, yield 74%).
第六步：2'-(甲硫基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-醇(9K)The sixth step: 2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazoline]-4'-alcohol (9K)
2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol
Figure PCTCN2020128033-appb-000258
Figure PCTCN2020128033-appb-000258
将2'-巯基-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-醇(9J)(1.3g,4.6mmol)和KOH(1.0g,18mmol)溶解到THF(10mL)-H 2O(40.0mL)的混合溶剂中，置于室温搅拌均匀后，再置于冰浴中，向反应液中滴加MeI(930mg,6.4mmol),滴加完毕后，继续再该温度下搅拌1h。反应结束后，向反应液加2N盐酸中和至pH＝7，再赢乙酸乙酯萃取，有机相用无水硫酸钠干燥后过滤，旋干，再用硅胶柱纯化得到产物9K，白色固体(1.3g，产率95％)。 Combine 2'-mercapto-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazoline]-4'-alcohol (9J) (1.3g, 4.6mmol) and KOH (1.0g, 18mmol) was dissolved in a mixed solvent of THF (10mL)-H 2 O (40.0mL), placed at room temperature and stirred evenly, then placed in an ice bath, and MeI (930mg, 6.4 mmol), after the addition is complete, continue to stir at this temperature for 1 h. After the reaction, add 2N hydrochloric acid to the reaction solution to neutralize to pH=7, and then extract with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, spin-dried, and purified with a silica gel column to obtain the product 9K, a white solid ( 1.3g, yield 95%).
第七步：2'-(甲硫基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-三氟甲基磺酸酯(9L)The seventh step: 2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethanesulfonic acid Ester (9L)
2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate
Figure PCTCN2020128033-appb-000259
Figure PCTCN2020128033-appb-000259
将2'-(甲硫基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-醇(9K)(1.3g,4.5mmol)和DIPEA(1.5g,11.6mmol)溶解到DCM(50.0mL)中，置于-20℃搅拌10min,再向反应中缓慢滴加Tf 2O(1.9g,6.7mmol),反应继续在该温度下搅拌10min。反应结束后，用碳酸氢钠 水溶液淬灭反应，再用DCM萃取，有机相用无水硫酸钠干燥后过滤，旋干，再用硅胶柱纯化得到产物9L，无色油状物(1.7g，产率88％)。 The 2'-(methylthio)-5',8'-dihydro-6'H-spirocyclo[indene-1,7'-quinazoline]-4'-alcohol (9K) (1.3g, 4.5 mmol) and DIPEA (1.5g, 11.6mmol) were dissolved in DCM (50.0mL), placed at -20°C and stirred for 10 min, and then slowly added Tf 2 O (1.9g, 6.7mmol) to the reaction. The reaction continued at this point. Stir at temperature for 10 min. After the reaction, the reaction was quenched with aqueous sodium bicarbonate solution, and then extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and purified with a silica gel column to obtain 9L of the product as a colorless oil (1.7g, product). Rate 88%).
第八步：叔丁基(2S)-2-(氰基甲基)-4-(2'-(甲硫醇)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-羧酸酯的光学纯异构体(9M-1和9M-2)The eighth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(methyl mercaptan)-5',8'-dihydro-6'H-spiro[indene- Optically pure isomers of 1,7'-quinazoline)-4'-yl)piperazine-1-carboxylate (9M-1 and 9M-2)
tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate；isomer 9M-1 and isomer 9M-2tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate; isomer 9M-1 and isomer 9M-2
Figure PCTCN2020128033-appb-000260
Figure PCTCN2020128033-appb-000260
将2'-(甲硫基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-三氟甲基磺酸酯(9L)(1.7g,4.0mmol)和DIPEA(1.3g,10.0mmol)，以及叔丁基(S)-2-(氰基甲基)哌嗪-1-羧酸酯(1.1g,4.8mmol)溶解到DMA(20.0mL)中，置于室温搅拌1h。反应结束后，将反应液直接旋干，经硅胶柱纯化得到叔丁基(2S)-2-(氰基甲基)-4-(2'-(甲硫醇)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-羧酸酯(9M消旋体)白色固体(1.7g，产率88％)。2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethanesulfonate (9L ) (1.7g, 4.0mmol) and DIPEA (1.3g, 10.0mmol), and tert-butyl (S)-2-(cyanomethyl)piperazine-1-carboxylate (1.1g, 4.8mmol) dissolved Into DMA (20.0 mL), place at room temperature and stir for 1 h. After the reaction, the reaction solution was directly spin-dried and purified by silica gel column to obtain tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(methyl mercaptan)-5',8'- Dihydro-6'H-spirocyclo[indene-1,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (9M racemate) white solid (1.7g, yield 88 %).
9M消旋体经手性拆分(Preparative separation method:Instrument:MGⅡpreparative SFC(SFC-14),Column:ChiralCel OJ,250×30mm I.D.,5μm,Mobile phase:A for CO 2and B for Ethanol,Gradient:B 40％,Flow rate:50mL/min,Back pressure:100bar,Column temperature:38℃,Wavelength:220nm,Cycle time:～4.2min)后得到光学纯的异构体9M-1(860mg)和异构体9M-2(820mg)。 The 9M racemate was separated by chiral separation (Preparative separation method: Instrument: MGⅡpreparative SFC (SFC-14), Column: ChiralCel OJ, 250×30mm ID, 5μm, Mobile phase: A for CO 2 and B for Ethanol, Gradient: B 40%,Flow rate:50mL/min,Back pressure:100bar,Column temperature:38℃,Wavelength:220nm,Cycle time:～4.2min) to obtain optically pure isomer 9M-1 (860mg) and isomer 9M-2 (820mg).
第九步：叔丁基(2S)-2-(氰基甲基)-4-(2'-(甲基亚磺酰基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-羧酸酯的其中一个光学纯异构体(9N-1)The ninth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(methylsulfinyl)-5',8'-dihydro-6'H-spiro ring[ One of the optically pure isomers of indene-1,7'-quinazoline)-4'-yl)piperazine-1-carboxylate (9N-1)
tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(methylsulfinyl)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate；isomer 9N-1tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(methylsulfinyl)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate; isomer 9N-1
Figure PCTCN2020128033-appb-000261
Figure PCTCN2020128033-appb-000261
将9M-1(150mg,0.3mmol)溶解到DCM(6.0mL)中，置于0℃搅拌10min,再向体系中加入间氯过氧苯甲酸(62mg,0.36mmol),反应置于室温搅拌1h。反应结束后，向反应 液中添加硫代硫酸钠水溶液淬灭反应，再用DCM萃取，有机相用无水硫酸钠干燥后旋干，经硅胶柱纯化得到产物9N-1。白色固体(140mg，产率90％)。Dissolve 9M-1 (150mg, 0.3mmol) in DCM (6.0mL), place it at 0℃ and stir for 10min, then add m-chloroperoxybenzoic acid (62mg, 0.36mmol) to the system, and place the reaction at room temperature and stir for 1h . After the reaction, the reaction was quenched by adding sodium thiosulfate aqueous solution to the reaction solution, and then extracted with DCM, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column to obtain the product 9N-1. White solid (140 mg, 90% yield).
第十步：叔丁基(2S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-基)哌嗪-1-羧酸酯的其中一个光学纯异构体(9O-1)The tenth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5', One of the optically pure isomers of 8'-dihydro-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (9O-1 )
tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate；isomer 9O-1tert-butyl(2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[ indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate; isomer 9O-1
Figure PCTCN2020128033-appb-000262
Figure PCTCN2020128033-appb-000262
将底物9N-1(140mg,0.27mmol)和N-甲基-L-脯氨醇(46mg,0.4mmol)溶解到甲苯(6.0mL)中，置于0℃搅拌10min后，再向体系中添加叔丁醇钠(39mg,0.4mmol),继续在该温度下搅拌30min。反应结束后，向反应液中加入氯化铵水溶液淬灭，DCM萃取，有机相用无水硫酸钠干燥后过滤，旋干，经硅胶柱纯化得到产物9O-1。白色固体(140mg，产率91％)。The substrate 9N-1 (140mg, 0.27mmol) and N-methyl-L-prolinol (46mg, 0.4mmol) were dissolved in toluene (6.0mL), placed at 0℃ and stirred for 10 minutes, and then added to the system Sodium tert-butoxide (39mg, 0.4mmol) was added, and stirring was continued at this temperature for 30 min. After the reaction, the reaction solution was quenched by adding aqueous ammonium chloride solution, extracted with DCM, the organic phase was dried with anhydrous sodium sulfate, filtered, spin-dried, and purified by silica gel column to obtain the product 9O-1. White solid (140 mg, 91% yield).
第十一步：2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-基)哌嗪-2-基)乙腈的其中一个光学纯异构体(9P-1)The eleventh step: 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6 One of the optically pure isomers of'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (9P-1)
2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile；isomer 9P-12-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7' -quinazolin]-4'-yl)piperazin-2-yl)acetonitrile; isomer 9P-1
Figure PCTCN2020128033-appb-000263
Figure PCTCN2020128033-appb-000263
将底物9O-1(140mg,0.24mmol)溶解到DCM(6.0mL)中，再缓慢滴加三氟乙酸(1.0mL)置于室温搅拌30min。反应结束后，用碳酸钠水溶液淬灭反应并用DCM萃取，有机相用无水硫酸钠干燥后，过滤旋干得到产物9P-1。白色固体(120mg，产率106％)。The substrate 9O-1 (140 mg, 0.24 mmol) was dissolved in DCM (6.0 mL), and trifluoroacetic acid (1.0 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 30 min. After the reaction, the reaction was quenched with sodium carbonate aqueous solution and extracted with DCM, the organic phase was dried with anhydrous sodium sulfate, filtered and spin-dried to obtain the product 9P-1. White solid (120 mg, 106% yield).
第十二步：2-((2S)-1-丙烯酰-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5'，8'-二氢-6'H-螺环[茚-1,7'-喹唑啉]-4'-基)哌嗪-2-基)乙腈的光学纯异构体(化合物9-1和化合物9-2)The twelfth step: 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5', 8' -Dihydro-6'H-spirocyclo[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)optically pure isomers of acetonitrile (compound 9-1 and compound 9 -2)
2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene- 1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile
Figure PCTCN2020128033-appb-000264
Figure PCTCN2020128033-appb-000264
将底物9P-1(70mg,0.15mmol)以及三乙胺(46mg,0.45mmol)溶解到DCM(10.0mL)中，置于0℃搅拌10min,再缓慢滴加丙烯酰氯(20mg,0.23mmol),置于该温度下搅拌30min。反应结束后，用碳酸钠水溶液淬灭反应并用DCM萃取，有机相用无水硫酸钠干燥后，过滤旋干后送HPLC制备纯化(制备条件：仪器及制备柱：采用WATERS 2767制备液相，制备柱型号Xbridge C18,5μm,内径×长度＝19mm×250mm。流动相体系：乙腈/(含0.05％三氟乙酸)水。梯度洗脱：乙腈含量30％-75％，洗脱时间15min。)得到化合物9-1。白色固体(33mg，产率42％)。Dissolve the substrate 9P-1 (70mg, 0.15mmol) and triethylamine (46mg, 0.45mmol) in DCM (10.0mL), place at 0℃ and stir for 10min, then slowly add acryloyl chloride (20mg, 0.23mmol) dropwise , Stir at this temperature for 30min. After the reaction, the reaction was quenched with sodium carbonate aqueous solution and extracted with DCM. The organic phase was dried with anhydrous sodium sulfate, filtered and spin-dried, and then sent to HPLC preparation and purification (preparation conditions: instrument and preparation column: using WATERS 2767 to prepare the liquid phase, preparation Column model Xbridge C18, 5μm, inner diameter×length=19mm×250mm. Mobile phase system: acetonitrile/(containing 0.05% trifluoroacetic acid) water. Gradient elution: acetonitrile content 30%-75%, elution time 15min.) to obtain Compound 9-1. White solid (33 mg, yield 42%).
LCMS m/z＝525.3[M+1] + LCMS m/z=525.3[M+1] +
1H NMR(400MHz,CD 3OD)δ7.34(d,1H),7.29(d,1H),7.25(dt,1H),7.17(dt,1H),6.84(s,1H),6.80(d,1H),6.58(d,1H),6.28(d,1H),5.83(d,1H),5.10(s,1H),4.70–4.36(m,3H),4.23(d,1H),4.19–4.09(s,1H),4.06(d,1H),3.58(s,1H),3.37–3.31(m,1H),3.27–3.12(m,3H),3.09–3.01(m,2H),2.94(t,2H),2.72(s,3H),2.68(t,2H),2.25–2.15(m,1H),2.04–1.93(m,2H),1.93–1.89(m,1H),1.88–1.80(m,1H),1.80–1.71(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 7.34 (d, 1H), 7.29 (d, 1H), 7.25 (dt, 1H), 7.17 (dt, 1H), 6.84 (s, 1H), 6.80 (d ,1H), 6.58(d,1H), 6.28(d,1H), 5.83(d,1H), 5.10(s,1H), 4.70--4.36(m,3H), 4.23(d,1H), 4.19-- 4.09(s,1H),4.06(d,1H),3.58(s,1H), 3.37-3.31(m,1H), 3.27-3.12(m,3H), 3.09-3.01(m,2H), 2.94( t, 2H), 2.72 (s, 3H), 2.68 (t, 2H), 2.25-2.15 (m, 1H), 2.04-1.93 (m, 2H), 1.93-1.89 (m, 1H), 1.88-1.80 ( m,1H), 1.80-1.71(m,1H).
9M-2(150mg,0.3mmol)经过与9M-1到化合物9-1相同的合成路线方法得到化合物9-2。白色固体(28mg)。9M-2 (150mg, 0.3mmol) went through the same synthetic route method as 9M-1 to compound 9-1 to obtain compound 9-2. White solid (28 mg).
LCMS m/z＝525.3[M+1] + LCMS m/z=525.3[M+1] +
1H NMR(400MHz,CD 3OD)δ7.33(t,2H),7.24(dt,1H),7.19(dt,1H),6.81(d,2H),6.69(d,1H),6.28(d,1H),5.83(d,1H),5.05(s,1H),4.50–4.38(m,2H),4.16(d,2H),4.09(s,1H),3.72(s,1H),3.47(s,1H),3.29–3.24(m,1H),3.21–3.05(m,3H),3.02–2.86(m,4H),2.67(s, 3H),2.65–2.60(t,1H),2.54(d,1H),2.24–2.04(m,2H),1.96–1.93(m,1H),1.92–1.88(m,1H),1.85–1.75(m,1H),1.70–1.61(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 7.33 (t, 2H), 7.24 (dt, 1H), 7.19 (dt, 1H), 6.81 (d, 2H), 6.69 (d, 1H), 6.28 (d ,1H),5.83(d,1H),5.05(s,1H),4.50--4.38(m,2H),4.16(d,2H),4.09(s,1H),3.72(s,1H),3.47( s, 1H), 3.29--3.24 (m, 1H), 3.21 - 3.05 (m, 3H), 3.02 - 2.86 (m, 4H), 2.67 (s, 3H), 2.65 - 2.60 (t, 1H), 2.54 ( d, 1H), 2.24-2.04 (m, 2H), 1.96-1.93 (m, 1H), 1.92-1.88 (m, 1H), 1.85-1.75 (m, 1H), 1.70-1.61 (m, 1H).
实施例10Example 10
1-(7-(2'-((((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7-二氮杂螺[3.5]壬基-2-基)丙-2-烯-1-酮(化合物10)1-(7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro -5'H-spiro[indene-1,7'-quinazoline]-4'-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene-1 -Ketone (Compound 10)
1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[ indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020128033-appb-000265
Figure PCTCN2020128033-appb-000265
第一步:叔丁基7-(2'-(甲硫基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7二氮杂螺[3.5]壬烷-2-羧酸酯(10a)The first step: tert-butyl 7-(2'-(methylthio)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline]- 4'-yl)-2,7 diazaspiro[3.5]nonane-2-carboxylate (10a)
tert-butyl 7-(2'-(methylthio)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylatetert-butyl 7-(2'-(methylthio)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7 -diazaspiro[3.5]nonane-2-carboxylate
Figure PCTCN2020128033-appb-000266
Figure PCTCN2020128033-appb-000266
向化合物5f(2.1g,7.04mmol)中依次加入15mL DMF和二异丙基乙胺(2.73g,21.12mmol)，搅拌下加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(4.4g,8.45mmol)。加毕，待反应液澄清，加入2-叔丁氧羰基-2,7-二氮杂螺[3.5]壬烷(1.91g,8.45mmol)，升温至80℃搅拌2h。加入50mL乙酸乙酯稀释，用30mL水洗有机相三次，有机相用无水硫酸钠干燥，减压浓缩。硅胶柱层析得到目标产物叔丁基7-(2'-(甲硫基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7二氮杂螺[3.5]壬烷-2-羧酸酯(10a)，白色固体(2.7g，收率：75％)。Add 15mL DMF and diisopropylethylamine (2.73g, 21.12mmol) to compound 5f (2.1g, 7.04mmol) in sequence, and add 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluoride under stirring Phosphate (4.4 g, 8.45 mmol). After the addition, when the reaction solution is clear, add 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (1.91g, 8.45mmol), heat up to 80°C and stir for 2h. Add 50 mL of ethyl acetate to dilute, wash the organic phase three times with 30 mL of water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. Silica gel column chromatography to obtain the target product tert-butyl 7-(2'-(methylthio)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazole (Pholino]-4'-yl)-2,7diazaspiro[3.5]nonane-2-carboxylate (10a), white solid (2.7g, yield: 75%).
LCMS m/z＝507.2[M+H] +. LCMS m/z=507.2[M+H] + .
第二步：叔丁基7-(2'-(甲基磺酰基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7二氮杂螺[3.5]壬烷-2-羧酸酯(10b)The second step: tert-butyl 7-(2'-(methylsulfonyl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline] -4'-yl)-2,7 diazaspiro[3.5]nonane-2-carboxylate (10b)
tert-butyl 7-(2'-(methylsulfonyl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylatetert-butyl 7-(2'-(methylsulfonyl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7 -diazaspiro[3.5]nonane-2-carboxylate
Figure PCTCN2020128033-appb-000267
Figure PCTCN2020128033-appb-000267
将化合物10a(2.7g，5.33mmol)溶于20mL甲苯中，冰浴下加入间氯过氧苯甲酸(1.84g，10.66mmol)，升温至室温搅拌1h。加入20mL饱和硫代硫酸钠水溶液，搅拌40min，加入50mL乙酸乙酯，混合液用30mL饱和碳酸氢钠水溶液洗涤3次，有机相干燥，减压浓缩，得到目标产物叔丁基7-(2'-(甲基磺酰基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7二氮杂螺[3.5]壬烷-2-羧酸酯(10b)粗品(2.9g)，直接用于下一步。Compound 10a (2.7 g, 5.33 mmol) was dissolved in 20 mL of toluene, m-chloroperoxybenzoic acid (1.84 g, 10.66 mmol) was added under ice bath, and the temperature was raised to room temperature and stirred for 1 h. 20mL saturated sodium thiosulfate aqueous solution was added, stirred for 40min, 50mL ethyl acetate was added, the mixture was washed 3 times with 30mL saturated sodium bicarbonate aqueous solution, the organic phase was dried and concentrated under reduced pressure to obtain the target product tert-butyl 7-(2' -(Methylsulfonyl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline]-4'-yl)-2,7 diazide The crude product (2.9g) of heterospiro[3.5]nonane-2-carboxylate (10b) was used directly in the next step.
LCMS m/z＝539.2[M+H] + LCMS m/z=539.2[M+H] +
第三步：叔丁基7-(2'-((((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3,6',8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸酯(10c)The third step: tert-butyl 7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8 '-Tetrahydro-5'H-spiro[indene-1,7'-quinazoline]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (10c )
tert-butyl 7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylatetert-butyl 7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[ indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
Figure PCTCN2020128033-appb-000268
Figure PCTCN2020128033-appb-000268
将化合物10b(2.7g)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(2.67g，20.04mmol)溶于20mL甲苯中，冰浴下加入叔丁醇钠(1.44g，15.03mmol)，冰浴下搅拌1h。加入15mL水淬灭反应，加入20mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩。硅胶柱层析后得到目标产物叔丁基7-(2'-((((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3,6',8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸酯(10c)，白色固体(2.0g，两步收率：67％)。Compound 10b (2.7g) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (2.67g, 20.04mmol) were dissolved in 20mL of toluene, and tert-butyl was added under ice bath. Sodium alkoxide (1.44g, 15.03mmol), stirred under ice bath for 1h. The reaction was quenched by adding 15 mL of water, 20 mL of ethyl acetate was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After silica gel column chromatography, the target product tert-butyl 7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3, 6',8'-Tetrahydro-5'H-spiro[indene-1,7'-quinazoline]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxy Acid ester (10c), white solid (2.0 g, two-step yield: 67%).
LCMS m/z＝592.3[M+H] + LCMS m/z=592.3[M+H] +
第四步：2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-(基)甲氧基)-4'-(2,7-二氮杂螺[3.5]壬基-7-基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉](10d)The fourth step: 2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-(yl)methoxy)-4'-(2,7-diazaspiro[3.5 ]Nonyl-7-yl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline](10d)
2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4'-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline]2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4'-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3,6 ',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline]
Figure PCTCN2020128033-appb-000269
Figure PCTCN2020128033-appb-000269
将底物10d(2g,3.38mmol)溶解到DCM(10mL)中，再缓慢滴加三氟乙酸(5mL)置于室温搅拌30min。反应结束后，减压浓缩，残留物用10mL饱和碳酸氢钠水溶液碱化，并用DCM(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥后，过滤，减压浓缩得到产物2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-(基)甲氧基)-4'-(2,7-二氮杂螺[3.5]壬基-7-基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉](10d)粗品(2g)，直接用于下一步。The substrate 10d (2g, 3.38mmol) was dissolved in DCM (10mL), then trifluoroacetic acid (5mL) was slowly added dropwise, and the mixture was stirred at room temperature for 30min. After the reaction, it was concentrated under reduced pressure. The residue was basified with 10 mL saturated aqueous sodium bicarbonate solution and extracted with DCM (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product 2' -(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-(yl)methoxy)-4'-(2,7-diazaspiro[3.5]nonyl-7- Base)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline] (10d) crude product (2g), used directly in the next step.
第五步：1-(7-(2'-((((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7-二氮杂螺[3.5]壬基-2-基)丙-2-烯-1-酮(化合物10)The fifth step: 1-(7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6', 8 '-Tetrahydro-5'H-spiro[indene-1,7'-quinazoline]-4'-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -En-1-one (Compound 10)
1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[ indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020128033-appb-000270
Figure PCTCN2020128033-appb-000270
将底物9d(800mg,1.63mmol)以及二异丙基乙胺(0.63g,4.89mmol)溶解到DCM(10.0mL)中，置于0℃搅拌10min,再缓慢滴加丙烯酰氯(150mg,1.63mmol),置于该温度下搅拌30min。反应结束后，用20mL碳酸氢钠水溶液淬灭反应并用20mL DCM萃取，有机相用无水硫酸钠干燥后，减压浓缩，残留物硅胶柱层析得到1-(7-(2'-((((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3,6'，8'-四氢-5'H-螺[茚-1,7'-喹唑啉]-4'-基)-2,7-二氮杂螺[3.5]壬基-2-基)丙-2-烯-1-酮(化合物10)，白色固体(450mg,两步收率：61％)。The substrate 9d (800mg, 1.63mmol) and diisopropylethylamine (0.63g, 4.89mmol) were dissolved in DCM (10.0mL), placed at 0℃ and stirred for 10min, and then slowly added dropwise acryloyl chloride (150mg, 1.63 mmol), placed at this temperature and stirred for 30 min. After the reaction, the reaction was quenched with 20 mL of aqueous sodium bicarbonate solution and extracted with 20 mL of DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-(7-(2'-(( ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1, 7'-quinazoline]-4'-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one (compound 10), white solid (450mg , Two-step yield: 61%).
LCMS m/z＝546.2[M+H] + LCMS m/z=546.2[M+H] +
实施例11Example 11
2-氟-1-(7-(2'-((((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3,6'，8'-四氢-5'H-螺[吲哚-1,7'-喹唑啉]-4'-基)-2,7-二氮杂螺[3.5]壬基-2-基)丙-2-烯-1-酮(化合物11)2-Fluoro-1-(7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6', 8 '-Tetrahydro-5'H-spiro[indole-1,7'-quinazoline]-4'-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan- 2-en-1-one (Compound 11)
2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5' H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020128033-appb-000271
Figure PCTCN2020128033-appb-000271
第一步：2-氟-1-(7-(2'-((((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-2,3,6'，8'-四氢-5'H-螺[吲哚-1,7'-喹唑啉]-4'-基)-2,7-二氮杂螺[3.5]壬基-2-基)丙-2-烯-1-酮(化合物11)The first step: 2-fluoro-1-(7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3, 6',8'-Tetrahydro-5'H-spiro[indole-1,7'-quinazoline]-4'-yl)-2,7-diazaspiro[3.5]nonyl-2- Yl)prop-2-en-1-one (Compound 11)
2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5' H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020128033-appb-000272
Figure PCTCN2020128033-appb-000272
将化合物10d(0.65g，1.32mmol)和2-氟丙烯酸(140mg，1.58mmol)溶于10mLN,N-二甲基甲酰胺中，加入二异丙基乙胺(510mg，3.96mmol)，室温下加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(0.82g，1.58mmol)，反应1h。加入20mL水，析出大量固体，过滤，滤饼减压干燥，硅胶柱层析纯化得到2-氟-1-(7-(2'-((((2S，4R)-4- 氟-1-甲基吡咯烷-2-基)甲氧基)-2,3,6'，8'-四氢-5'H-螺[吲哚-1,7'-喹唑啉]-4'-基)-2,7-二氮杂螺[3.5]壬基-2-基)丙-2-烯-1-酮(化合物11)，白色固体(200mg,两步收率：32％)。Compound 10d (0.65g, 1.32mmol) and 2-fluoroacrylic acid (140mg, 1.58mmol) were dissolved in 10mL of N,N-dimethylformamide, and diisopropylethylamine (510mg, 3.96mmol) was added at room temperature. 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (0.82g, 1.58mmol) was added and reacted for 1h. 20mL of water was added to precipitate a large amount of solids, filtered, the filter cake was dried under reduced pressure, and purified by silica gel column chromatography to obtain 2-fluoro-1-(7-(2'-((((2S,4R)-4-fluoro-1- Methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indole-1,7'-quinazoline]-4'-yl )-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one (Compound 11), white solid (200mg, two-step yield: 32%).
LCMS m/z＝564.3[M+H] + LCMS m/z=564.3[M+H] +
参考实施例3的方法，选取相应的原料/中间体，制备得到化合物如下表格A中的化合物12、13、14、15、16、17、18。With reference to the method in Example 3, the corresponding raw materials/intermediates were selected to prepare the compounds 12, 13, 14, 15, 16, 17, and 18 in Table A below.
参考实施例1的方法，选取相应的原料/中间体，制备得到化合物如下表格A中的化合物20、21、22、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41。Refer to the method of Example 1, select the corresponding raw materials/intermediates, and prepare the compounds 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41.
参考实施例4至11的方法，选取相应的原料/中间体，制备得到化合物如下表格A中的化合物42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126。With reference to the methods in Examples 4 to 11, the corresponding raw materials/intermediates were selected to prepare the compounds 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, as shown in Table A below. 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126.
表A:化合物12-化合物126结构Table A: Structure of compound 12-compound 126
Figure PCTCN2020128033-appb-000273
Figure PCTCN2020128033-appb-000273
Figure PCTCN2020128033-appb-000274
Figure PCTCN2020128033-appb-000274
Figure PCTCN2020128033-appb-000275
Figure PCTCN2020128033-appb-000275
Figure PCTCN2020128033-appb-000276
Figure PCTCN2020128033-appb-000276
Figure PCTCN2020128033-appb-000277
Figure PCTCN2020128033-appb-000277
Figure PCTCN2020128033-appb-000278
Figure PCTCN2020128033-appb-000278
Figure PCTCN2020128033-appb-000279
Figure PCTCN2020128033-appb-000279
Figure PCTCN2020128033-appb-000280
Figure PCTCN2020128033-appb-000280
Figure PCTCN2020128033-appb-000281
Figure PCTCN2020128033-appb-000281
Figure PCTCN2020128033-appb-000282
Figure PCTCN2020128033-appb-000282
Figure PCTCN2020128033-appb-000283
Figure PCTCN2020128033-appb-000283
Figure PCTCN2020128033-appb-000284
Figure PCTCN2020128033-appb-000284
Figure PCTCN2020128033-appb-000285
Figure PCTCN2020128033-appb-000285
生物测试例Biological test case
方法1:NCI-H358细胞(人非小细胞肺癌细胞)购自于ATCC，培养于RPMI1640，10％FBS，37℃,5％CO2。第一天，收集处于指数生长期的NCI-H358细胞，用Vi-Cell XR细胞计数仪(Beckman Coulter，TACEL0030)进行活细胞计数。用培养基将细胞悬液调整到5000个/90μL。每孔加90μL细胞悬液于96-孔细胞培养板。第二天，化合物孵育。受试化合物起始浓度10μM，3倍稀释，9个浓度，每孔DMSO终浓度为0.1％。于37℃，5％CO 2孵箱中培养72小时。药物处理72小时后，每孔加入50μL(1/2培养体积)预先融化并平衡到室温的CTG溶液(promega，G7572)，用微孔板震荡器混匀2分钟，于室温放置10分钟后用Envision2104读板仪测定荧光信号值。 Method 1: NCI-H358 cells (human non-small cell lung cancer cells) were purchased from ATCC and cultured in RPMI1640, 10% FBS, 37°C, 5% CO2. On the first day, NCI-H358 cells in the exponential growth phase were collected, and viable cells were counted with a Vi-Cell XR cell counter (Beckman Coulter, TACEL0030). Adjust the cell suspension to 5000 cells/90μL with culture medium. Add 90 μL of cell suspension to each well on a 96-well cell culture plate. The next day, the compounds were incubated. The initial concentration of the test compound was 10 μM, 3 times dilution, 9 concentrations, and the final concentration of DMSO per well was 0.1%. Incubate for 72 hours in a 37°C, 5% CO 2 incubator. After 72 hours of drug treatment, add 50μL (1/2 culture volume) to each well of CTG solution (promega, G7572) which has been melted and equilibrated to room temperature, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes. Envision2104 plate reader measures the fluorescence signal value.
细胞存活率用公式(1)计算。其中V sample为药物处理组的读数，V vehicle control为溶剂对照组的平均值。应用GraphPad Prism 5.0软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC 50值。细胞最大抑制率(Max inh.％)化合物在某一浓度下，对细胞的最大抑制作用，用公式(2)计算 The cell survival rate is calculated using formula (1). V sample is the reading of the drug treatment group, and V vehicle control is the average value of the solvent control group. Using GraphPad Prism 5.0 software, a non-linear regression model was used to draw the S-type dose-survival rate curve and calculate the IC 50 value. Maximum cell inhibition rate (Max inh.%) The maximum inhibitory effect of the compound on cells at a certain concentration is calculated by formula (2)
V sample/V vehicle controlx100％    公式(1) V sample /V vehicle control x100% formula (1)
1-V sample/V vehicle controlx100％    公式(2) 1-V sample /V vehicle control x100% formula (2)
方法2:NCI-H358细胞购自于ATCC，培养基为RPMI1640+10％FBS，于37℃,5％CO 2孵箱中培养。第一天，收集处于指数生长期的NCI-H358细胞，用自动细胞分析仪(countstar)进行活细胞计数。用培养基将细胞悬液调整后铺板96孔细胞培养板，每孔1500个细胞。第二天，吸去培养基，每孔加入90μL新鲜培养基和10μL不同浓度化合物，每孔DMSO终浓度为0.1％。于37℃，5％CO 2孵箱中培养72小时。药物处理72小时后，每孔加入50μL预先融化并平衡到室温的CTG溶液(promega，G7572)，用微孔板震荡器混匀2分钟，于室温放置10分钟后用酶标仪(PHERAstar FSX)测定荧光信号值。 Method 2: NCI-H358 cells were purchased from ATCC, the medium was RPMI1640+10% FBS, and they were cultured in a 37°C, 5% CO 2 incubator. On the first day, NCI-H358 cells in the exponential growth phase were collected and counted viable cells with an automatic cell analyzer (countstar). After adjusting the cell suspension with culture medium, spread a 96-well cell culture plate with 1500 cells per well. On the second day, the medium was aspirated, and 90 μL of fresh medium and 10 μL of compounds of different concentrations were added to each well, and the final concentration of DMSO in each well was 0.1%. Incubate for 72 hours in a 37°C, 5% CO 2 incubator. After 72 hours of drug treatment, add 50μL of CTG solution (promega, G7572) pre-melted and equilibrated to room temperature to each well, mix with a microplate shaker for 2 minutes, and place at room temperature for 10 minutes, then use a microplate reader (PHERAstar FSX) Measure the fluorescence signal value.
细胞存活率用公式V sample/V vehicle control x100％计算。其中V sample为药物处理组的读数，V vehicle control为溶剂对照组的平均值。应用origen9.2软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC 50值。 The cell survival rate is calculated using the formula V sample /V vehicle control x100%. V sample is the reading of the drug treatment group, and V vehicle control is the average value of the solvent control group. Survival curves and IC50 values calculated IC - origen9.2 software application, dose-S plotted using non-linear regression model.
表1抑制NCI-H358细胞增殖的IC 50值 Table 1 IC 50 value of inhibiting the proliferation of NCI-H358 cells
序号Serial number 测试方法testing method 化合物编号Compound number IC 50(μM) IC 50 (μM)
11 方法1method 1 化合物1Compound 1 0.2790.279
22 方法2Method 2 化合物4Compound 4 0.0350.035
33 方法2Method 2 化合物4-1Compound 4-1 0.0240.024
44 方法2Method 2 化合物4-2Compound 4-2 1.2311.231
55 方法2Method 2 化合物5Compound 5 0.1170.117
66 方法2Method 2 化合物5-1Compound 5-1 0.0440.044
77 方法2Method 2 化合物5-2Compound 5-2 0.9680.968
88 方法2Method 2 化合物6-1Compound 6-1 0.4670.467
99 方法2Method 2 化合物6-2Compound 6-2 4.2444.244
1010 方法2Method 2 化合物7-1Compound 7-1 1.1331.133
1111 方法2Method 2 化合物8-1Compound 8-1 0.3750.375
1212 方法2Method 2 化合物8-2Compound 8-2 4.7024.702
1313 方法2Method 2 化合物9-1Compound 9-1 0.6050.605
1414 方法2Method 2 化合物9-2Compound 9-2 0.0550.055
结论：本发明实施例化合物具有良好的抑制NCI-H358细胞增殖作用，化合物1、4、4-1、4-2、5、5-1、5-2、6-1、6-2、7-1、8-1、8-2、9-1、9-2、10的IC 50小于5μM、化合物10的IC 50小于3μM。部分化合物的具体IC 50值见表1。 Conclusion: The compounds of the examples of the present invention have a good inhibitory effect on the proliferation of NCI-H358 cells. The IC 50 of -1, 8-1, 8-2, 9-1, 9-2, 10 is less than 5 μM, and the IC 50 of compound 10 is less than 3 μM. The specific IC 50 values of some compounds are shown in Table 1.
测试例2：KRAS G12C激酶抑制活性测试Test example 2: KRAS G12C kinase inhibitory activity test
激酶KRAS G12C(Sino,Cat.No 12259-H07E2)配制成2.5×的激酶溶液，底物及抗体混合液配制成2×的溶液(c-RAF：Pharmaron；SOS1：Pharmaron；GTP：Sigma，Cat.No G8877-25MG；MAb Anti 6HIS-d2：Cisbio，Cat.No 61HISDLB；MAb Anti GST-Eu：Cisbio，Cat.No 61GSTKLB)。在384孔板中加入1μL不同浓度的化合物，加入4μL 2.5×的激酶溶液，室温孵育60分钟。加入5μL 2×的底物及抗体混合液，室温孵育120分钟后，使用BioTek(Synergy 4)多功能酶标仪设置激发光为320nM，发射光为615nM和665nM，读615nm(Eu)和665nm(d2)的荧光信号。计算每孔的比值Ratio＝(665/615)×10000。运用Prism GraphPad 7.0软件计算IC 50值。抑制率计算公式见式1，其中
Figure PCTCN2020128033-appb-000286
10个阳性对照孔比值的平均值(10μM AMG510)，
Figure PCTCN2020128033-appb-000287
10个阴性对照孔比值的平均值(0.5％DMSO)。 Kinase KRAS G12C (Sino, Cat. No 12259-H07E2) was prepared as a 2.5× kinase solution, and the substrate and antibody mixture was prepared as a 2× solution (c-RAF: Pharmaron; SOS1: Pharmaron; GTP: Sigma, Cat. No G8877-25MG; MAb Anti 6HIS-d2: Cisbio, Cat. No 61HISDLB; MAb Anti GST-Eu: Cisbio, Cat. No 61GSTKLB). In a 384-well plate, add 1 μL of compounds of different concentrations, 4 μL of 2.5× kinase solution, and incubate at room temperature for 60 minutes. Add 5μL of 2× substrate and antibody mixture, incubate at room temperature for 120 minutes, use BioTek (Synergy 4) multifunctional microplate reader to set excitation light to 320nM, emission light to 615nM and 665nM, reading 615nm(Eu) and 665nm( d2) Fluorescence signal. Calculate the ratio of each hole Ratio=(665/615)×10000. Use Prism GraphPad 7.0 software to calculate IC 50 value. The calculation formula of the inhibition rate is shown in Equation 1, where
Figure PCTCN2020128033-appb-000286
The average value of the ratio of 10 positive control wells (10μM AMG510),
Figure PCTCN2020128033-appb-000287
The average of the ratio of 10 negative control wells (0.5% DMSO).
Figure PCTCN2020128033-appb-000288
Figure PCTCN2020128033-appb-000288
表2抑制KRAC G12C激酶的IC 50值 Table 2 IC 50 value of inhibiting KRAC G12C kinase
序号Serial number 化合物编号Compound number IC 50(μM) IC 50 (μM)
11 化合物4-1Compound 4-1 0.0410.041
22 化合物5-1Compound 5-1 0.0080.008
33 化合物6-1Compound 6-1 0.0500.050
44 化合物8-1Compound 8-1 0.0270.027
55 化合物9-2Compound 9-2 0.0100.010
结论：本发明实施例化合物具有良好的抑制KRAC G12C激酶活性作用。Conclusion: The compounds of the examples of the present invention have a good inhibitory effect on KRAC G12C kinase activity.
测试例3：人肝微粒CYP酶抑制测试Test Example 3: CYP Enzyme Inhibition Test of Human Liver Microparticles
孵育体系为200μL。先取20μL底物溶液于样品孔中，20μL空白磷酸盐缓冲液于空白对照孔中，随后加入2μL系列浓度的待测化合物工作液和阳性对照至相应样品孔中，于阴性对照和空白对照孔中加入2μL空白溶剂替代；于所有样品孔中加入158μL人肝微粒体工作液后置37℃水浴中预孵10min，之后加入20μL NADPH再生系统启动反应，在37℃水浴中继续孵育10min后，加入400μL含200ng/mL甲苯磺丁脲和拉贝洛尔的冰乙腈 溶液终止反应并沉淀蛋白，样品于4000rpm，4℃离心20min，取上清液200μL，加入100μL超纯水，涡漩混匀10min后，LC-MS/MS进样分析。The incubation system is 200μL. First take 20μL of the substrate solution in the sample wells, 20μL of blank phosphate buffer in the blank control wells, then add 2μL of the test compound working solution and the positive control in a series of concentrations to the corresponding sample wells, in the negative control and blank control wells Add 2μL of blank solvent instead; add 158μL of human liver microsomal working solution to all sample wells and pre-incubate in a 37°C water bath for 10 minutes, then add 20μL of NADPH regeneration system to start the reaction. After incubating in a 37°C water bath for 10 minutes, add 400μL The ice acetonitrile solution containing 200ng/mL tolbutamide and labetalol was used to terminate the reaction and precipitate the protein. The sample was centrifuged at 4000 rpm and 4°C for 20 minutes, 200 μL of the supernatant was taken, 100 μL of ultrapure water was added, and the mixture was vortexed for 10 minutes. , LC-MS/MS sample injection analysis.
表3抑制人肝微粒CYP酶的IC 50值 Table 3 The IC 50 value of inhibiting the CYP enzyme of human liver particles
Figure PCTCN2020128033-appb-000289
Figure PCTCN2020128033-appb-000289
J.Med.Chem.2020,63,13,6679–6693公开报道MRTX849结构为J. Med. Chem. 2020, 63, 13, 6679–6693 publicly reported that the structure of MRTX849 is
Figure PCTCN2020128033-appb-000290
Figure PCTCN2020128033-appb-000290
结论：本发明实施例化合物对人肝微粒主要代谢酶亚型无明显抑制(IC 50大于10μM)，且与MRTX849相比，对CYP2C9、CYP2C19、CYP2D6和CYP3A4-M亚型代谢酶的抑制作用明显降低。 Conclusion: The compounds of the examples of the present invention have no significant inhibition on the main metabolizing enzyme subtypes of human liver particles (IC 50 greater than 10 μM), and compared with MRTX849, they have obvious inhibitory effects on CYP2C9, CYP2C19, CYP2D6 and CYP3A4-M subtype metabolizing enzymes. reduce.
测试例4：hERG抑制测试Test case 4: hERG inhibition test
细胞外液配方(mM)：140NaCl,5KCl,1CaCl 2,1.25MgCl 2,10HEPES and 10Glucose，用NaOH调节pH至7.4。细胞内液配方(mM)：140KCl,1MgCl2,1CaCl2,10EGTA and 10HEPES，用KOH调节pH至7.2。 Extracellular fluid formula (mM): 140NaCl, 5KCl, 1CaCl 2 , 1.25MgCl 2 , 10HEPES and 10Glucose, adjust the pH to 7.4 with NaOH. Intracellular fluid formula (mM): 140KCl, 1MgCl2, 1CaCl2, 10EGTA and 10HEPES, adjust the pH to 7.2 with KOH.
稳定表达hERG的CHO细胞培养于直径35mm的细胞培养皿中，置于37℃，5％CO 2的培养箱培养，每48小时按1:5比例进行传代，培养基配方：90％F12(Invitrogen)，10％胎牛血清(Gibco)，100μg/mL G418(Invitrogen)和100μg/mL Hygromycin B(Invitrogen)。试验当天，吸走细胞培养液，用细胞外液淋洗一遍后加入0.25％Trypsin-EDTA(Invitrogen)溶液，在室温下消化3-5分钟。吸走消化液，用细胞外液重悬后将细胞转移到用于电生理记录的实验皿中备用。 CHO cells stably expressing hERG were cultured in a cell culture dish with a diameter of 35mm, placed in an incubator at 37°C and 5% CO 2 and subcultured at a ratio of 1:5 every 48 hours. Medium formula: 90% F12 (Invitrogen ), 10% fetal bovine serum (Gibco), 100 μg/mL G418 (Invitrogen) and 100 μg/mL Hygromycin B (Invitrogen). On the day of the test, aspirate the cell culture fluid, rinse with extracellular fluid, add 0.25% Trypsin-EDTA (Invitrogen) solution, and digest for 3-5 minutes at room temperature. Aspirate the digestion fluid, resuspend in extracellular fluid, and transfer the cells to a laboratory dish for electrophysiological recording for later use.
测试当天，将化合物DMSO母液用100％DMSO进行稀释，即取10μL的化合物母液加 入到20μL DMSO中，3倍稀连续释成中间浓度。然后再取10μL的化合物中间浓度加入到4990μL细胞外液中，500倍稀释得到需要测试的最终浓度：最高测试浓度为40μM，一次分别为40、13.33、4.44、1.48、0.49、0.16μM。阳性对照化合物cisapride准备：取150μM的cisapride DMSO母液10μL，加入到4990μL细胞外液中，500倍稀释得到需要测试的最终浓度300nM。最终测试浓度中的DMSO含量不超过0.2％，此浓度的DMSO对hERG钾通道没有影响。On the day of the test, the compound DMSO mother liquid was diluted with 100% DMSO, that is, 10 μL of the compound mother liquid was added to 20 μL DMSO, and the 3 times dilution was continuously released to an intermediate concentration. Then take 10 μL of the intermediate compound concentration and add it to 4990 μL of extracellular fluid, and dilute 500 times to obtain the final concentration that needs to be tested: the highest test concentration is 40 μM, and the first test concentration is 40, 13.33, 4.44, 1.48, 0.49, 0.16 μM, respectively. Positive control compound cisapride preparation: Take 10μL of 150μM cisapride DMSO mother solution, add it to 4990μL extracellular fluid, and dilute 500 times to obtain the final concentration of 300nM that needs to be tested. The DMSO content in the final test concentration does not exceed 0.2%, and this concentration of DMSO has no effect on the hERG potassium channel.
稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel, record the hERG potassium channel current using the whole-cell patch clamp technique at room temperature. Data analysis and processing adopts pClamp 10, GraphPad Prism 5 and Excel software. The inhibitory degree of different compound concentration on hERG potassium current (hERG tail current peak induced at -50mV) is calculated by the following formula:
Inhibition％＝[1–(I/Iο)]×100％Inhibition%=[1–(I/Iο)]×100%
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Iο分别表示在加药后和加药前hERG钾电流的幅度。Among them, Inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Iο represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.
化合物IC 50使用GraphPad Prism 5软件通过以下方程拟合计算得出： The compound IC 50 was calculated by the following equation fitting using GraphPad Prism 5 software:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。Among them, X is the Log value of the concentration of the test product, Y is the percentage of inhibition at the corresponding concentration, and Bottom and Top are the minimum and maximum percentages of inhibition, respectively.
表4化合物对hERG钾通道电流抑制的IC 50值 Table 4 The IC 50 value of compounds inhibiting hERG potassium channel current
化合物编号Compound number IC 50(μM) IC 50 (μM)
化合物4-1Compound 4-1 4.514.51
MRTX849MRTX849 1.601.60
结论：与MRTX849相比，本发明实施例化合物对hERG钾通道电流抑制作用明显降低。Conclusion: Compared with MRTX849, the compound of the examples of the present invention has a significantly reduced inhibitory effect on hERG potassium channel current.

Claims (21)

  1. 通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中The compound of general formula (I) or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
    Figure PCTCN2020128033-appb-100001
    Figure PCTCN2020128033-appb-100001
    R 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2、
    Figure PCTCN2020128033-appb-100002
    -S(＝O) 2-C(R 1a)＝C(R 1b) 2或
    Figure PCTCN2020128033-appb-100003
    R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ,
    Figure PCTCN2020128033-appb-100002
    -S(=O) 2 -C(R 1a )=C(R 1b ) 2 or
    Figure PCTCN2020128033-appb-100003
    R 1a各自独立地选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基、C 1-4烷氧基或-NHC(＝O)R 1d，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； R 1a is each independently selected from H, F, Cl, Br, I, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -NHC(=O)R 1d , said Alkyl or alkoxy is optionally further selected from 0 to 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 alkyl or C 1-4 alkoxy substituent substituted;
    R 1b或R 1c各自独立地选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基、C 1-4烷氧基、-C(＝O)N(R 1d) 2、-(CH 2) p-N(C 1-4烷基) 2、-(CH 2) pNHC(＝O)-C 1-4烷基、-(CH 2) p-C 3-10碳环或-(CH 2) p-3至12元杂环，所述的烷基、烷氧基、杂环或碳环任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-10碳环或5至12元杂环的取代基所取代，所述的杂环含有1至4个选自O、S、N的杂原子； R 1b or R 1c are each independently selected from H, F, Cl, Br, I, cyano, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, -C(=O)N(R 1d ) 2 , -(CH 2 ) p -N(C 1-4 alkyl) 2 , -(CH 2 ) p NHC(=O)-C 1-4 alkyl, -(CH 2 ) p -C 3 -10 carbocyclic ring or -(CH 2 ) p -3 to 12 membered heterocyclic ring, said alkyl, alkoxy, heterocyclic or carbocyclic ring is optionally further selected from 0 to 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 Substituted by 1-4 alkoxy, C 3-10 carbocyclic or 5 to 12-membered heterocyclic substituents, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S and N;
    作为选择，R 1a与任意一个R 1b形成C 5-10碳环或5至12元杂环，所述的碳环或杂环任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-10碳环基或5至12元杂环基的取代基所取代，所述的杂环基含有1至4个选自O、S、N的杂原子； Alternatively, R 1a and any one of R 1b form a C 5-10 carbocyclic ring or a 5- to 12-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 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 carbon A cyclic group or a substituent of a 5- to 12-membered heterocyclic group, said heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N;
    R 1d各自独立地选自H或C 1-4烷基，所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 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 substituent;
    环A选自4至12元含氮杂环，所述的含氮杂环选自饱和或部分饱和的如下基团之一：单环、并环、桥环或螺环，所述的含氮杂环、单环、并环、桥环或螺环任选进一步被0至4个R a取代； 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 R a;
    R a各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-6烷基或C 1-6烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 substituents selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
    Q、M和与二者直接相连接的原子一起形成C 3-12碳环或者3至12元的杂环，所述的碳环或者杂环为单环、并环或者螺环，所述的碳环、杂环、单环、并环或者螺环任选进一步0至5个R 2取代，所述的杂环含有1至4个选自O、S、N的杂原子； Q, M and the atoms directly connected to the two together form a C 3-12 carbocyclic ring or a 3 to 12-membered heterocyclic ring. 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 heteroatoms selected from O, S, and N;
    R 2各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-3至8元杂环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C的取代基所取代，所述的杂环烷基或杂芳基含有1至4个选自O、S、N的杂原子； R 2 is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)-3 to 8-membered heterocycloalkyl, -C(= O) -C 6-10 aryl, -C (=O) -5 to 10-membered heteroaryl, 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 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, C 1-6 alkoxy, hydroxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6-membered hetero Cycloalkyl, C 6-10 aryl or 5 to 10-membered heteroaryl, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C substituents, the hetero Cycloalkyl or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, and N;
    R 2A、R 2B或R 2C各自独立地选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6- 10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基的取代基所取代，所述的杂环烷基含有1至4个选自O、S、N的杂原子； 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, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, oxo, OH, cyanide Group, 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 contains 1 to 4 selected Heteroatoms from O, S, N;
    X 3选自键、O、-OCH 2-、-CH 2O-、S或NR x； X 3 is selected from bond, O, -OCH 2 -, -CH 2 O-, S or NR x ;
    R x选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； R x is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, the alkyl or cycloalkyl is optionally further selected from 0 to 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;
    R 3选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-6烷基、C 1-6烷氧基、N(R 3a) 2、-(CH 2) q-C(＝O)C 1-6烷基、-(CH 2) q-C(＝O)-3至12元杂环、-(CH 2) q-C(＝O)-C 3-10碳环、-(CH 2) q-C(＝O)-N(R 3a) 2、-(CH 2) q-N(R 3a)-C(＝O)R 3b、-(CH 2) q-3至12元杂环或-(CH 2) q-C 3-10碳 环，所述的CH 2、烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1- 4亚烷基-OH、-(CH 2) q-C 3-10碳环、-(CH 2) q-3至12元杂环、C 3-6环烷基、C 1-4烷氧基、-N(C 1-4烷基)C(＝O)-3至12元杂环或3至12元杂环的取代基所取代，所述的杂环含有1至4个选自O、S、N的杂原子； R 3 is selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, N(R 3a ) 2 ,- (CH 2 ) q -C(=O)C 1-6 alkyl, -(CH 2 ) q -C(=O)-3 to 12-membered heterocyclic ring, -(CH 2 ) q -C(=O) -C 3-10 carbocyclic ring, -(CH 2 ) q -C(=O)-N(R 3a ) 2 , -(CH 2 ) q -N(R 3a )-C(=O)R 3b ,- (CH 2 ) q -3 to 12-membered heterocyclic ring or -(CH 2 ) q -C 3-10 carbocyclic ring, said CH 2 , alkyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted by 0 Up to 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) q -C 3-10 carbocycle, - (CH 2) q -3 to 12-membered heterocyclyl, C 3-6 cycloalkyl, C 1-4 alkoxy, -N(C 1-4 alkyl)C(=O)-3 to 12-membered heterocyclic ring or 3 to 12-membered heterocyclic substituent, The heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N;
    R 3a各自独立地选自H、C 1-4烷基、-C 1-4烷基-3至12元杂环，所述的烷基或杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个选自O、S、N的杂原子； R 3a is each independently selected from H, C 1-4 alkyl, -C 1-4 alkyl-3 to 12-membered heterocycle, said alkyl or heterocycle is optionally further selected from 0 to 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 alkane substituted C 1-4 alkoxy group or a substituted group, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N heteroatoms;
    作为选择，两个R 3a和与二者直接相连的氮原子一起形成4至8元含氮杂环，所述的含氮杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个选自O、S、N的杂原子； Alternatively, two R 3a and the nitrogen atom directly connected to the two together form a 4- to 8-membered nitrogen-containing heterocyclic ring, and the nitrogen-containing heterocyclic ring is optionally further selected from 0 to 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 substituted by alkoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;
    R 3b选自H、C 1-6烷基、C 3-6环烷基或3至12元杂环，所述的烷基、环烷基或杂环任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的杂环含有1至4个选自O、S、N的杂原子； R 3b is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or 3 to 12 membered heterocyclic ring, said alkyl, cycloalkyl or heterocyclic ring is optionally further selected from 0 to 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, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;
    R 4各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3或C 1-6烷基，所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 selected from 0 to 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 substituted by alkyl or C 1-4 alkoxy substituents;
    n、p、q各自独立地选自0、1、2、3或4。n, p, q are each independently selected from 0, 1, 2, 3, or 4.
  2. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，所述化合物如通式(Ia)或(Ib)所示，The compound according to claim 1 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, wherein the compound has the formula (Ia) or ( As shown in Ib),
    Figure PCTCN2020128033-appb-100004
    Figure PCTCN2020128033-appb-100004
    通式(Ia)和(Ib)中R 1、R 4、R 3、X 3、环A和n的定义与权利要求1一致； The definitions of R 1 , R 4 , R 3 , X 3 , ring A and n in the general formulas (Ia) and (Ib) are consistent with claim 1;
    环B选自非芳香4至7元杂环，所述的杂环含有1至4个选自O、S、N的杂原子；Ring B is selected from non-aromatic 4- to 7-membered heterocycles, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, and N;
    X 1选自N； X 1 is selected from N;
    R 2a选自H、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-3至8元杂环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个选自O、S、N的杂原子； R 2a is selected from H, COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-6 alkyl, -C(=O) -C 3-6 cycloalkyl, -C(=O)-3 to 8-membered heterocycloalkyl, -C(=O)-C 6-10 aryl, -C(=O)-5 to 10-membered Heteroaryl, 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 , The alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally further selected from 0 to 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(=O)NR 2A R 2B , -NR 2A C( =0) R 2C , 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 members Heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl substituents, said heterocycloalkyl or heteroaryl containing 1 to 4 heterocyclic groups selected from O, S, N atom;
    R 2b各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH或C 1-6烷基，所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基或C 1-6烷氧基的取代基所取代； R 2b is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH or C 1-6 alkyl, and the alkyl is optionally further selected from 0 to 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 Substituted by 1-6 alkyl, C 2-6 alkynyl or C 1-6 alkoxy substituent;
    环C和环D一起形成C 6-12碳环并环或5至12元杂环并环，所述的杂环并环含有1至4个选自O、S、N的杂原子； Ring C and ring D together form a C 6-12 carbocyclic ring or 5 to 12 membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S and N;
    R 2c、R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、COOH、-C(＝O)-C 1-6烷基、-C(＝O)-C 3-6环烷基、-C(＝O)-C 6-10芳基、-C(＝O)-5至10元杂芳基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个选自O、S、N的杂原子； R 2c and R 2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , COOH, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 cycloalkyl, -C(=O)-C 6-10 aryl, -C( =0)-5 to 10-membered heteroaryl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C 6-10 aryl Or a 5- to 10-membered heteroaryl group, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 0 to 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(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , 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, C 6-10 aryl or 5 to 10 membered heteroaryl substituents, the heterocycloalkyl or heteroaryl group contains 1 to 4 selected Heteroatoms from O, S, N;
    R 2A、R 2B或R 2C各自独立地选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6- 10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、 3至6元杂环烷基的取代基所取代，所述的杂环烷基含有1至4个选自O、S、N的杂原子； 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, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, oxo, OH, cyanide Group, 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 contains 1 to 4 selected Heteroatoms from O, S, N;
    m1选自0、1、2、3或4；m1 is selected from 0, 1, 2, 3 or 4;
    m2、m3各自独立地选自0、1、2、3或4，且m2+m3≤5。m2 and m3 are each independently selected from 0, 1, 2, 3, or 4, and m2+m3≦5.
  3. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中The compound according to claim 2 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
    R 1c选自H、F、Cl、Br、I、氰基、CF 3、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 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;
    环A选自4至9元含氮杂环，所述的含氮杂环选自饱和或部分饱和如下结构之一：单环、并环、桥环或螺环，所述的含氮杂环任选进一步被0至4个R a取代基所取代； 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, and the nitrogen-containing heterocyclic ring optionally further substituted with 0-4 R a substituted;
    R a各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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 substituents selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy.
  4. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，The compound according to claim 3 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof,
    环A选自未被取代的或者取代的
    Figure PCTCN2020128033-appb-100005
    Figure PCTCN2020128033-appb-100006
    Figure PCTCN2020128033-appb-100007
    当被取代时，任选进一步被0至4个R a取代基所取代；     Ring A is selected from unsubstituted or substituted
    Figure PCTCN2020128033-appb-100005
    Figure PCTCN2020128033-appb-100006
    Figure PCTCN2020128033-appb-100007
    When substituted, optionally further substituted with 0-4 R a substituted;
    R a各自独立地选自H、oxo、F、Cl、Br、I、氰基、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 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 substituents selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy.
  5. 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，The compound according to claim 4 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
    环B选自氮杂环丁烷、氮杂环戊烷或哌啶；Ring B is selected from azetidine, azetidine or piperidine;
    或者环B选自咪唑烷；Or ring B is selected from imidazolidine;
    R 2a选自H、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C(＝O)-C 1-4烷基、-C(＝O)-苯基、-C(＝O)-5至6元杂芳基、C 1-4烷基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、-C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个选自O、S、N的杂原子； R 2a is selected from H, COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -C(=O)-C 1-4 alkyl, -C(=O) -Phenyl, -C(=O)-5 to 6-membered heteroaryl, C 1-4 alkyl, C 3-6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl group, the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally further selected from 0 to 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(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , -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, C 6-10 aryl or 5 to 10-membered heteroaryl substituents, said heterocycloalkyl or heteroaryl contains 1 to 4 selected from O, S , N heteroatoms;
    环D选自苯环、吡啶、哒嗪或嘧啶；Ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine;
    环C选自C 4-6碳环； Ring C is selected from C 4-6 carbocyclic ring;
    或者环C选自4至6元杂环,所述的杂环含有1至3个选自O、S、N的杂原子；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 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-C(＝O)NR 2AR 2B、-NR 2AC(＝O)R 2C、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个选自O、S、N的杂原子； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, the alkane Group, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -C(=O)NR 2A R 2B , -NR 2A C(=O)R 2C , C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, Substituents substituted by hydroxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, said The heterocycloalkyl or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;
    R 2A、R 2B或R 2C各自独立地选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6- 10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基的取代基所取代，所述的杂环烷基含有1至4个选自O、S、N的杂原子； 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, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, oxo, OH, cyanide Group, 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 contains 1 to 4 selected Heteroatoms from O, S, N;
    R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、C 1-4烷基或C 1-4烷氧基，所述的烷基或烷氧基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2或C 1-6烷基的取代基所取代。 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 substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 or C 1-6 alkyl.
  6. 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中The compound according to claim 5 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
    R 1选自-C(＝O)-C(R 1a)＝C(R 1b) 2； R 1 is selected from -C(=O)-C(R 1a )=C(R 1b ) 2 ;
    R 1a选自H、F或C 1-4烷基，所述的烷基任选进一步被0至4个选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； R 1a is selected from H, F or C 1-4 alkyl, and the alkyl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1 -4 substituted by alkyl or C 1-4 alkoxy substituents;
    R 1b各自独立地选自H、C 1-4烷基或-(CH 2) p-3至6元杂环，所述的烷基或杂环任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或3至6元杂环的取代基所取代，所述的杂环含有1至4个选自O、S、N的杂原子。 R 1b is each independently selected from H, C 1-4 alkyl or -(CH 2 ) p -3 to 6-membered heterocyclic ring, said alkyl or heterocyclic ring is optionally further selected from 0 to 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, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N .
  7. 根据权利要求6所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中The compound according to claim 6 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
    R 1a选自H、F、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基的取代基所取代； R 1a is selected from H, F, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further selected from 0 to 4 selected from H, F, Substituted by Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituents;
    R 1b各自独立地选自H、甲基、乙基、丙基、异丙基、-CH 2-4元含氮杂环、-CH 2-5元含氮杂环、-CH 2-6元含氮杂环、4元含氮杂环、5元含氮杂环或6元含氮杂环，所述的甲基、乙基、丙基、异丙基或含氮杂环任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 , COOH, NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkane Group) 2 , C 1-4 alkyl or C 1-4 alkoxy substituents;
    X 3选自键或O； X 3 is selected from bond or O;
    R 2a选自H或者取代的或者未被取代的如下基团之一：-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-CH 2CH 2CH 3、-C(＝O)-CH(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、-C(＝O)-苯基、-C(＝O)-吡啶、-C(＝O)-噻吩、-C(＝O)-呋喃、-C(＝O)-吡咯、甲基、乙基、异丙基、丙基、环丙基、环丁基、环戊基、环己基、苯基、萘基、噻吩基、呋喃基、吡咯基、噻唑基、异噻唑基、噁唑基、异噁唑基、咪唑基、吡唑基、苯并咪唑基、苯并吡唑基或吡啶基，当被取代时，任选被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、C 1-4烷基、C 1-4烷氧基或C 2-4炔基的取代基所取代； R 2a is selected from H or one of the substituted or unsubstituted groups: -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC( ＝O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O) N(CH 2 CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O )-CH(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine,- C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyridine Azolyl or pyridyl, when substituted, is optionally 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC( =O)H, -C(=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl substituents;
    R 2b各自独立地选自H、F、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents;
    环C和环D一起形成的并环选自
    Figure PCTCN2020128033-appb-100008
    The combined ring formed by ring C and ring D is selected from
    Figure PCTCN2020128033-appb-100008
    或者环C和环D一起形成的并环选自
    Figure PCTCN2020128033-appb-100009
    Figure PCTCN2020128033-appb-100010
    Or the combined ring formed by ring C and ring D is selected from
    Figure PCTCN2020128033-appb-100009
    Figure PCTCN2020128033-appb-100010
    R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、--C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH- CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , --C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy , The methyl, ethyl, methoxy, ethoxy or phenyl group is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, Substituted by NH 2 , C 1-4 alkyl, and C 1-4 alkoxy substituents;
    R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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 selected from 0 to 4 Substituted by substituents of H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
    R 3选自H或者取代的或者未取代的如下基团之一：甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、-N(CH 3) 2、-N(CH 2CH 3) 2、-(CH 2) q-环丙烷、-(CH 2) q-环丁烷、-(CH 2) q-环戊烷、-(CH 2) q-环己烷、-(CH 2) q-氮杂环丁烷、-(CH 2) q-氧杂环丁烷、-(CH 2) q-四氢噻吩、-(CH 2) q-四氢呋喃、-(CH 2) q-四氢吡咯、-(CH 2) q-苯基、-(CH 2) q-萘基、-(CH 2) q-吡啶、-(CH 2) q-嘧啶、-(CH 2) q-吡嗪、-(CH 2) q-噻吩、-(CH 2) q-呋喃、-(CH 2) q-吡咯、-(CH 2) q-咪唑、-(CH 2) q-咪唑、-(CH 2) q-吡唑、-(CH 2) q-三氮唑、-(CH 2) q-四氮唑、-(CH 2) q-哌啶、-(CH 2) q-吗啉、-(CH 2) q-四氢吡喃、-(CH 2) q-吡咯双烷、-(CH 2) q-1,3-氧氮杂环庚烷、-(CH 2) q-2-氧杂-5-氮杂双环[2.2.1]庚烷、-(CH 2) q-哌嗪或-(CH 2) q-N(R 3a)-C(＝O)R 3b，当被取代时，任选被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2) q-C 3-6碳环、-(CH 2) q-3至6元杂环、C 3-6环烷基、C 1-4烷氧基、-N(C 1-4烷基)C(＝O)-3至12元杂环或3至12元杂环的取代基所取代，所述的杂环含有1至4个选自O、S、N的杂原子； 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, -(CH 2 ) q -naphthyl, -(CH 2 ) q- pyridine, -(CH 2 ) q -pyrimidine,- (CH 2 ) q -pyrazine, -(CH 2 ) q -thiophene, -(CH 2 ) q -furan, -(CH 2 ) q -pyrrole, -(CH 2 ) q -imidazole, -(CH 2 ) q -imidazole, -(CH 2 ) q -pyrazole, -(CH 2 ) q -triazole, -(CH 2 ) q -tetrazole, -(CH 2 ) q -piperidine, -(CH 2 ) q -morpholine, -(CH 2 ) q -tetrahydropyran, -(CH 2 ) q -pyrrolidine, -(CH 2 ) q -1,3-oxazepin, -(CH 2 ) q -2-oxa-5-azabicyclo[2.2.1]heptane, -(CH 2 ) q -piperazine or -(CH 2 ) q -N(R 3a )-C(=O) R 3b , when substituted, is optionally 0 to 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, -C 1-4 alkylene-OH, -(CH 2 ) q -C 3-6 carbocyclic, -(CH 2 ) q -3 to 6-membered heterocycle, C 3-6 cycloalkyl, C 1-4 alkoxy, -N(C 1-4 alkyl)C(=O)-3 to 12-membered heterocycle or It is substituted by a substituent of a 3- to 12-membered heterocyclic ring, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, and N;
    R 3a选自H、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基取代基所取代； R 3a is selected from H, methyl, ethyl, propyl or isopropyl, and the methyl, ethyl, propyl or isopropyl is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy substituent substituted;
    R 3b选自H、甲基、乙基、丙基、异丙基、氮杂环丁烷或氧杂环丁烷，所述的甲基、乙基、丙基、异丙基、氮杂环丁烷或氧杂环丁烷任选进一步被0至4个选自H、F、Cl、Br、I、氰基、OH、CF 3、C 1-4烷基或C 1-4烷氧基取代基所取代； 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 selected from H, F, Cl, Br, I, cyano, OH, CF 3 , C 1-4 alkyl or C 1-4 alkoxy Substituent substituted;
    R 4各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3或甲基； R 4 is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF 3 or methyl;
    q选自0、1、2、3或4。q is selected from 0, 1, 2, 3, or 4.
  8. 根据权利要求7所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中The compound according to claim 7 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
    R 1选自
    Figure PCTCN2020128033-appb-100011
    Figure PCTCN2020128033-appb-100012
    R 1 is selected from
    Figure PCTCN2020128033-appb-100011
    Figure PCTCN2020128033-appb-100012
    环A选自取代的或者未取代的如下基团之一：
    Figure PCTCN2020128033-appb-100013
    当被取代时，任选被0至4个选自H、F、Cl、Br、I、oxo、氰基、OH、CF 3、甲基、乙基、丙基、异丙基或CH 2CN的取代基所取代；     Ring A is selected from one of the following substituted or unsubstituted groups:
    Figure PCTCN2020128033-appb-100013
    When substituted, it is optionally 0 to 4 selected from H, F, Cl, Br, I, oxo, cyano, OH, CF 3 , methyl, ethyl, propyl, isopropyl or CH 2 CN Is substituted by the substituent;
    环B选自哌啶；Ring B is selected from piperidine;
    或者
    Figure PCTCN2020128033-appb-100014
    选自
    Figure PCTCN2020128033-appb-100015
    Figure PCTCN2020128033-appb-100016
    or
    Figure PCTCN2020128033-appb-100014
    Selected from
    Figure PCTCN2020128033-appb-100015
    Figure PCTCN2020128033-appb-100016
    R 2a选自H或者取代的或者未被取代的如下基团之一：-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-CH 2CH 2CH 3、-C(＝O)-CH(CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、-C(＝O)-苯基、-C(＝O)-吡啶、-C(＝O)-噻吩、-C(＝O)-呋喃、-C(＝O)-吡咯、甲基、乙基、异丙基、丙基、苯基、萘基、噻 吩基、呋喃基、吡咯基或吡啶基，当被取代时，任选被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基或乙基的取代基所取代； R 2a is selected from H or one of the substituted or unsubstituted groups: -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH-CH 3 , -NHC( ＝O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O) N(CH 2 CH 3 ) 2 , -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O )-CH(CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine,- C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furanyl , Pyrrolyl or pyridyl, when substituted, optionally 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC (=O)H, -C(=O)NH-CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, Substituted by methyl or ethyl substituents;
    R 2b各自独立地选自H、F、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； 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 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl substituents;
    R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、-C(＝O)NH 2、-NHC(＝O)H、-C(＝O)NH-CH 3、-NHC(＝O)-CH 3、-C(＝O)NH-CH 2CH 3、-NHC(＝O)CH 2CH 3、-C(＝O)N(CH 3) 2、-C(＝O)N(CH 2CH 3) 2、-C(＝O)NH-苯基、-NHC(＝O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； R 2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF 3 , -C(=O)NH 2 , -NHC(=O)H, -C(=O)NH- CH 3 , -NHC(=O)-CH 3 , -C(=O)NH-CH 2 CH 3 , -NHC(=O)CH 2 CH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)N(CH 2 CH 3 ) 2 , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy, The methyl, ethyl, methoxy, ethoxy or phenyl group is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2. Substituted by methyl or ethyl substituents;
    R 2d各自独立地选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、甲基或乙基，所述的甲基或乙基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； 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 selected from 0 to 4 Substituted by H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl substituents;
    R 3选自H或者取代的或者未取代的如下基团之一：甲基、乙基、-(CH 2) q-四氢吡咯、-(CH 2) q-氮杂环丁烷、-N(CH 3) 2或-N(CH 2CH 3) 2，当被取代时，任选被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-4烷基、-C 1-4亚烷基-OH、-(CH 2)q-C 3-6碳环、-(CH 2)q-3至6元杂环、C 3-6环烷基或C 1-4烷氧基，所述的杂环含有1至4个选自O、S、N的杂原子。 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 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, said heterocyclic ring contains 1 to 4 selected from Heteroatoms of O, S and N.
  9. 根据权利要求8所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中The compound according to claim 8 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein
    环A选自
    Figure PCTCN2020128033-appb-100017
    Figure PCTCN2020128033-appb-100018
    Ring A is selected from
    Figure PCTCN2020128033-appb-100017
    Figure PCTCN2020128033-appb-100018
    X 3选自O或键； X 3 is selected from O or bond;
    R 3选自-CH 2N(CH 3) 2、-CH 2N(CH 2CH 3) 2、-N(CH 2CH 3) 2、-N(CH 3) 2、
    Figure PCTCN2020128033-appb-100019
    Figure PCTCN2020128033-appb-100020
    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 ,
    Figure PCTCN2020128033-appb-100019
    Figure PCTCN2020128033-appb-100020
    n选自0。n is selected from 0.
  10. 根据权利要求9所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，The compound according to claim 9 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
    环A选自
    Figure PCTCN2020128033-appb-100021
    Ring A is selected from
    Figure PCTCN2020128033-appb-100021
    X 3-R 3选自 X 3 -R 3 are selected from
    Figure PCTCN2020128033-appb-100022
    Figure PCTCN2020128033-appb-100022
    n选自0。n is selected from 0.
  11. 根据权利要求8所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，The compound according to claim 8 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
    Figure PCTCN2020128033-appb-100023
    选自
    Figure PCTCN2020128033-appb-100024
    Figure PCTCN2020128033-appb-100025
    Figure PCTCN2020128033-appb-100023
    Selected from
    Figure PCTCN2020128033-appb-100024
    Figure PCTCN2020128033-appb-100025
    Figure PCTCN2020128033-appb-100026
    选自
    Figure PCTCN2020128033-appb-100027
    Figure PCTCN2020128033-appb-100028
    Figure PCTCN2020128033-appb-100026
    Selected from
    Figure PCTCN2020128033-appb-100027
    Figure PCTCN2020128033-appb-100028
    R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基或乙氧基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、甲基或乙基的取代基所取代； 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 The group or ethoxy group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH, NH 2 , methyl or ethyl;
    n选自0；n is selected from 0;
    m2选自0、1、2或3。m2 is selected from 0, 1, 2 or 3.
  12. 根据权利要求11所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，The compound according to claim 11 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
    环A选自
    Figure PCTCN2020128033-appb-100029
    Figure PCTCN2020128033-appb-100030
    Ring A is selected from
    Figure PCTCN2020128033-appb-100029
    Figure PCTCN2020128033-appb-100030
    X 3选自O或键； X 3 is selected from O or bond;
    R 3选自-CH 2N(CH 3) 2、-CH 2N(CH 2CH 3) 2、-N(CH 2CH 3) 2、-N(CH 3) 2、
    Figure PCTCN2020128033-appb-100031
    Figure PCTCN2020128033-appb-100032
    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 ,
    Figure PCTCN2020128033-appb-100031
    Figure PCTCN2020128033-appb-100032
    n选自0。n is selected from 0.
  13. 根据权利要求12所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中，The compound according to claim 12 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein:
    环A选自
    Figure PCTCN2020128033-appb-100033
    Ring A is selected from
    Figure PCTCN2020128033-appb-100033
    X 3-R 3选自
    Figure PCTCN2020128033-appb-100034
    Figure PCTCN2020128033-appb-100035
    X 3 -R 3 are selected from
    Figure PCTCN2020128033-appb-100034
    Figure PCTCN2020128033-appb-100035
  14. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，所述化合物选自通式(Ia-1)或(Ib-1)所示的化合物，The compound according to claim 2 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, the compound selected from general formula (Ia-1) or The compound represented by (Ib-1),
    Figure PCTCN2020128033-appb-100036
    Figure PCTCN2020128033-appb-100036
    G 1-G 2选自-CH 2CH 2-、-CH＝CH-、-C(＝O)-NH-、-C(＝O)-N(CH 3)-、-N(CH 3)-C(＝O)-或者-NH-C(＝O)-； G 1- G 2 is selected from -CH 2 CH 2 -, -CH=CH-, -C(=O)-NH-, -C(=O)-N(CH 3 )-, -N(CH 3 ) -C(=O)- or -NH-C(=O)-;
    R 2a选自H、C 1-6烷基、C 3-6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-C 1-6烷基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个选自O、S、N的杂原子； 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 optionally further selected from 0 to 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, C 1-6 alkoxy, C 3- Substituents substituted by 6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl, said heterocycloalkyl or heteroaryl contains 1 to 4 Heteroatoms selected from O, S, N;
    R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、C 1-6烷基、C 1-6烷氧基、C 3- 6环烷基、3至8元杂环烷基、C 6-10芳基或5至10元杂芳基，所述的烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、oxo、OH、氰基、CF 3、COOH、NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、羟基取代的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基或5至10元杂芳基的取代基所取代，所述的杂环烷基或杂芳基含有1至4个选自O、S、N的杂原子； 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 group optionally further 0 to 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, C 1-6 alkoxy, hydroxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6-membered hetero Cycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl substituents, said heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N ；
    m2选自0、1、2或3。m2 is selected from 0, 1, 2 or 3.
  15. 根据权利要求14所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，The compound according to claim 14 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt,
    R 1选自
    Figure PCTCN2020128033-appb-100037
    Figure PCTCN2020128033-appb-100038
    R 1 is selected from
    Figure PCTCN2020128033-appb-100037
    Figure PCTCN2020128033-appb-100038
    R 2a选自H或者取代的或者未被取代的如下基团之一：甲基、乙基、异丙基、丙基、环丙基、环丁基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，当被取代时，任选被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、NH 2、甲基、乙基、甲氧基、乙氧基、环丙基、环丁基或苯基的取代基所取代； 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 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , NH 2 , methyl, ethyl, methyl Oxy, ethoxy, cyclopropyl, cyclobutyl or phenyl substituents;
    R 2c各自独立地选自H、F、Cl、Br、I、OH、氰基、CF 3、甲基、乙基、甲氧基、乙氧基、环丙基或环丁基，所述的甲基、乙基、甲氧基、乙氧基、环丙基或环丁基任选进一步被0至4个选自H、F、Cl、Br、I、OH、氰基、CF 3、COOH、NH 2、C 1-4烷基、C 1-4烷氧基取代基所取代； 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 selected from H, F, Cl, Br, I, OH, cyano, CF 3 , COOH , NH 2 , C 1-4 alkyl, C 1-4 alkoxy substituents;
    环A选自
    Figure PCTCN2020128033-appb-100039
    Figure PCTCN2020128033-appb-100040
    Ring A is selected from
    Figure PCTCN2020128033-appb-100039
    Figure PCTCN2020128033-appb-100040
    X 3-R 3选自
    Figure PCTCN2020128033-appb-100041
    Figure PCTCN2020128033-appb-100042
    X 3 -R 3 are selected from
    Figure PCTCN2020128033-appb-100041
    Figure PCTCN2020128033-appb-100042
    n选自0。n is selected from 0.
  16. 根据权利要求15所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，所述化合物选自通式(Ic-1)和(Ic-2)所示的化合物，The compound according to claim 15 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, the compound selected from the group consisting of general formula (Ic-1) and The compound represented by (Ic-2),
    Figure PCTCN2020128033-appb-100043
    Figure PCTCN2020128033-appb-100043
  17. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，其中所述化合物选自：The compound according to claim 1 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein the compound is selected from:
    Figure PCTCN2020128033-appb-100044
    Figure PCTCN2020128033-appb-100044
    Figure PCTCN2020128033-appb-100045
    Figure PCTCN2020128033-appb-100045
    Figure PCTCN2020128033-appb-100046
    Figure PCTCN2020128033-appb-100046
    Figure PCTCN2020128033-appb-100047
    Figure PCTCN2020128033-appb-100047
    Figure PCTCN2020128033-appb-100048
    Figure PCTCN2020128033-appb-100048
    Figure PCTCN2020128033-appb-100049
    Figure PCTCN2020128033-appb-100049
    Figure PCTCN2020128033-appb-100050
    Figure PCTCN2020128033-appb-100050
    Figure PCTCN2020128033-appb-100051
    Figure PCTCN2020128033-appb-100051
    Figure PCTCN2020128033-appb-100052
    Figure PCTCN2020128033-appb-100052
    Figure PCTCN2020128033-appb-100053
    Figure PCTCN2020128033-appb-100053
    Figure PCTCN2020128033-appb-100054
    Figure PCTCN2020128033-appb-100054
    Figure PCTCN2020128033-appb-100055
    Figure PCTCN2020128033-appb-100055
    Figure PCTCN2020128033-appb-100056
    Figure PCTCN2020128033-appb-100056
    Figure PCTCN2020128033-appb-100057
    Figure PCTCN2020128033-appb-100057
    Figure PCTCN2020128033-appb-100058
    Figure PCTCN2020128033-appb-100058
  18. 药物组合物，包括权利要求1-17任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐，以及药学上可接受的载体。A pharmaceutical composition comprising the compound of any one of claims 1-17 or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, and pharmaceutically acceptable salts thereof Accepted carrier.
  19. 根据权利要求1-17任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、共晶或药学上可接受的盐在用于制备预防或治疗与KRAS G12C活性或表达量相关疾病的药物中的应用。The compound according to any one of claims 1-17 or its stereoisomer, deuterium, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt is used in the preparation of prevention or treatment and KRAS Application in medicine for diseases related to G12C activity or expression.
  20. 根据权利要求19所述的应用，其特征在于，所述的疾病选自肿瘤。The use according to claim 19, wherein the disease is selected from tumors.
  21. 根据权利要求20所述的应用，其特征在于，所述的肿瘤选自血液学癌症、胰脏癌、MYH相关息肉病、结肠直肠癌、非小细胞肺癌或小细胞肺癌。The application according to claim 20, wherein the tumor is selected from the group consisting of hematological cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, non-small cell lung cancer or small cell lung cancer.
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