WO2022152313A1 - Pyrimidine derivative and pharmaceutical application thereof - Google Patents

Pyrimidine derivative and pharmaceutical application thereof Download PDF

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Publication number
WO2022152313A1
WO2022152313A1 PCT/CN2022/072530 CN2022072530W WO2022152313A1 WO 2022152313 A1 WO2022152313 A1 WO 2022152313A1 CN 2022072530 W CN2022072530 W CN 2022072530W WO 2022152313 A1 WO2022152313 A1 WO 2022152313A1
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Prior art keywords
mixture
compound
pharmaceutically acceptable
stereoisomer
tautomer
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PCT/CN2022/072530
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French (fr)
Chinese (zh)
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张靖
魏用刚
尹杰
杨科
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成都百裕制药股份有限公司
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Publication of WO2022152313A1 publication Critical patent/WO2022152313A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • This application relates to pyrimidine derivatives and their use in medicine.
  • the RAS gene is one of the important human proto-oncogenes and plays a key role in regulating cell signal transduction and the occurrence and development of tumors; it is also the most frequently mutated oncogene in human cancers, and the RAS gene is present in about 30% of cancers. mutation.
  • the human RAS superprotein family contains three genes (KRAS, NRAS, and HRAS, respectively) that encode four proteins (KRAS-4A, KRAS-4B, NRAS, and HRAS).
  • KRAS is the most common subtype in the RAS family and the most easily mutated gene; 86% of RAS mutations are KRAS mutations, 86-96% of pancreatic cancer, 40-54% of colorectal cancer and 20-37% of KRAS gene mutations can be detected in lung cancers of 2000, and KRAS mutations are also found in cancers such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and breast cancer (Kessler et al., 2019).
  • KARS proteins belong to the small GTPase family of proteins. Under normal physiological conditions, KRAS proteins regulate signaling pathways by transitioning between inactive (binding to GDP) and activated (binding to GTP) states (Downward, 2003): when KRAS binds to guanosine diphosphate (GDP) Inactive state; active state can activate downstream signaling pathways when combined with guanosine triphosphate (GTP).
  • GDP guanosine diphosphate
  • GTP guanosine triphosphate
  • GEFs guanine nucleotide exchange factors
  • GAPs GTPase activating/accelerating proteins
  • KRAS has a stronger binding ability to GDP, so KRAS in cells is generally inactive; when KRAS is activated by binding to GTP, it can be promoted through multiple downstream signaling pathways such as MAPK, PI3K, and Ral-GEFs. Cell survival, proliferation and cytokine release, etc. (Liu et al., 2019).
  • KRAS When KRAS is mutated or its conformation changes, its GTP hydrolysis activity decreases, its binding stability to GDP increases, and its interaction with GAP is blocked, so that KRAS protein is in a long-term activated state, and by stimulating a large number of downstream cell signals, it continues to promote cell growth and growth. Divide, eventually leading to cancer. Current studies have shown that the most common mutation of KRAS is single-point mutations at codons 12, 13 and 61, of which codon 12 mutations account for about 82% of KRAS mutations.
  • KRAS mutant cells In addition to KRAS gene alterations that directly lead to tumorigenesis, KRAS mutant cells also have a wide range of effects on the microenvironment that causes tumor progression through paracrine action, which can promote the secretion of various cytokines, chemokines and growth factors to fibroblasts and immune cells. It also affects the tumor microenvironment, and can also remodel and reprogram stromal cells.
  • KRAS inhibitors have been carried out in recent decades, and it was generally believed that this target is difficult to be drugged. The main reasons are as follows: (1) The affinity of KRAS protein to guanosine phosphate (GDP or GTP) is as low as picomolar (pM) ), the concentration of guanosine phosphate in cells can reach the millimolar (mM) level, which makes it difficult for general drugs (analogs of guanosine phosphate) to compete with KRAS proteins (Waters & Der, 2018); (2) KRAS The guanosine phosphate binding site of the protein also lacks a region suitable for the binding of other small molecule compounds.
  • small-molecule compounds can inhibit tumors with KRAS-G12C mutation. Because the 12th codon of KRAS protein is close to the nucleoside binding domain and catalytic center of the protein, after cysteine mutation at this site, small molecule compounds can affect KRAS through irreversible covalent binding to cysteine The function of the protein, and the small molecule compound is more inclined to bind to the KRAS-GDP protein, which reduces the affinity of GTP to the protein (Lito, Solomon, Li, Hansen, & Rosen, 2016).
  • ARS-853 an early developed small-molecule compound targeting KRAS-G12C tumors, showed good activity in vitro and effectively inhibited the conversion of GDP and GTP, but lacked in vivo activity (Patricelli et al., 2016). Subsequently, the structure was further optimized to obtain ARS-1620, which showed good pharmacological activity against KRAS-G12C tumor cells in vitro and in vivo, but had no significant effect on other KRAS mutant cells (Janes et al., 2018). At present, a variety of KRAS inhibitor drugs have entered the stage of clinical research, but according to the data published so far, the clinical efficacy in tumor patients still needs to be further improved. Therefore, there is still a need to develop a new generation of efficient and safe KRAS-G12C mutation inhibitors to better meet clinical needs.
  • One of the objectives of one or more embodiments of the present application is to provide novel pyrimidine derivatives, pharmaceutical compositions thereof, and their preparation for KRAS G12C inhibitors.
  • One or more embodiments of the present application provide compounds of general formula (I) or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers thereof Isomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof:
  • R 1 is H, halogen or C 3-8 cycloalkyl
  • X is N or CR 3 ;
  • R 2 and R 3 are each independently H or halogen
  • Y is N or CR 4 ;
  • R 4 and R 5 are each independently H, hydroxy, halogen, amino, trifluoromethyl or C 1-6 alkyl;
  • R4 and R5 together with the carbon atom to which they are attached form a 4- or 5 -membered cycloalkyl or heterocycloalkyl containing 1 or 2 selected from N and O A heteroatom, the 4- or 5-membered cycloalkyl or heterocycloalkyl is optionally substituted with 1 or 2 C 1-6 alkyl groups;
  • n 1, 2, 3 or 4;
  • R 6 and R 7 are each independently C 1-6 alkyl or halogen
  • L is O or N atom
  • R 8 is C 3-8 cycloalkyl or C 3-8 heterocycloalkyl containing 1 to 4 heteroatoms selected from N and O, R 8 is optionally 1 or 2 C 1-6 alkyl substitutions;
  • n 0 or 1.
  • R 1 is selected from H, halogen or cyclopropyl
  • X is selected from N or CR 3 ;
  • R 2 and R 3 are each independently H or halogen
  • L is selected from O or N atoms
  • R 8 is selected from C 3-8 heterocycloalkyl containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from N or O, R 8 optionally substituted with 1 or 2 C 1-6 alkyl;
  • n 0 or 1.
  • the halogen is F.
  • the C 1-6 alkyl group is methyl
  • R1 is H.
  • R 2 is halogen
  • R3 is halogen
  • R 4 is halo or C 1-6 alkyl, and R 5 is hydroxy.
  • R4 and R5 are taken together with the carbon atom to which they are attached to form a 4- or 5 -membered heterocycloalkyl group containing 2 N heteroatoms, so The 4- or 5-membered heterocycloalkyl is optionally substituted with 1 C 1-6 alkyl.
  • m is 2.
  • L is O.
  • R8 is C5-6 heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, and R8 is optionally Substituted with 1 C 1-6 alkyl.
  • n is one.
  • One or more embodiments of the present application provide compounds or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or the same thereof A mixture, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, said compound being:
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the manufacture of a medicament for the treatment or prevention of cancer or tumor.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the preparation of a KRAS G12C inhibitor.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the manufacture of a composition for the treatment or prophylaxis of a disease associated with KRAS G12C.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a medicament.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of cancer or tumor.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a KRAS G12C inhibitor.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prophylaxis of a disease associated with KRAS G12C.
  • One or more embodiments of the present application provide a method of treating or preventing cancer or tumor comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, mesomer thereof , racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application .
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
  • One or more embodiments of the present application provide a method of treating or preventing a disease associated with KRAS G12C, comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, endoisomer thereof A racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or the present application Compositions.
  • One or more embodiments of the present application provide methods of inhibiting KRAS G12C, comprising administering to a subject in need thereof a compound of the present application, or a stereoisomer, tautomer, meso, racemic, or stereoisomer thereof Rotors, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application.
  • the disease associated with KRAS G12C is cancer or tumor.
  • the disease associated with KRAS G12C is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons 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 isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen 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.
  • isotopes of carbon include 12 C, 13 C
  • Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably 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 thereof; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.
  • Alkoxy refers to a group formed by substituting at least one carbon atom in an alkyl group with an oxygen atom.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy.
  • the definition of alkyl is the same as the definition of "alkyl" described above.
  • Alkenyl means a straight chain consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds Chain or branched unsaturated aliphatic hydrocarbon groups, preferably alkenyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-yl Alken-3-yl.
  • the alkenyl group may be optionally further substituted with one or more substituents.
  • Alkynyl means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
  • the alkynyl group may optionally be further substituted with one or more substituents.
  • Aryl means a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (eg, 5, 6, 7, 8) , 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be a bridged ring or a spiro ring, non-limiting implementation Examples include phenyl, naphthyl. The aryl group may optionally be further substituted with one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states.
  • N, S can be oxidized into various oxidation states.
  • Heteroaryl groups can be attached to heteroatoms or carbon atoms, and heteroaryl groups can be bridged or spirocyclic, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.
  • Carbocyclyl or “carbocycle” refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for “aryl”; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) (membered) tricyclic ring system, which can be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclo
  • Heterocyclyl or “heterocycle” refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle, and when it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl” above; when When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (eg 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (eg 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
  • 1- to 10-membered eg 3, 4, 5, 6, 7, 8, 9, 10-membered
  • 4- to 12-membered eg 7, 8, 9, 10, 11, 12 membered
  • bicyclic ring or 10 to 15 membere
  • Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of “heterocyclyl” or “heterocycle” can be oxidized to various oxidation states; “heterocyclyl” or A “heterocycle” can be attached to a heteroatom or a carbon atom; a “heterocyclyl” or “heterocycle” can be a bridged ring or a spirocyclic ring.
  • heterocyclyl or “heterocycle” include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azazelyl, diazepine, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more
  • the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms.
  • Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl and the like. When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
  • heterocycloalkyl can be oxidized to various oxidation states; “heterocycloalkyl” can be attached to a heteroatom or carbon atom; “heterocycloalkyl” Alkyl” can be bridged or spiro.
  • heterocycloalkyl include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxetanyl Oxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
  • Halogens include F, Cl, Br and I.
  • “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
  • a “prodrug” refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
  • Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components.
  • a co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC assay was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6 mm, 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 specification used for TLC separation and purification products is 0.4mm -0.5mm.
  • reaction solution was concentrated under reduced pressure to obtain a crude product which was dissolved in tetrahydrofuran (200 mL), and triethylamine (88 g, 682 mmol) and 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane were slowly added dropwise at 0°C alkane (16.98 g, 75.0 mmol), and reacted at room temperature for 2 hours.
  • Water 200 mL
  • ethyl acetate 50 mL x 3
  • the organic phases were combined, concentrated, and separated by column chromatography to obtain 1c (yellow solid, 20 g, yield 56%).
  • compound 2 (white solid, 30 mg, yield 16%) was prepared under medium pressure.
  • compound 3 (white solid, 40 mg, yield 22%) was prepared under medium pressure.
  • compound 4 was prepared (white solid, 45 mg, yield 21%).
  • IC50 refers to the concentration of the compound at which the activity of KRAS is inhibited by 50%.
  • DMEM Dulbecco's modified eagle medium
  • FBS fetal bovine serum
  • NBT Nitrotetrazolium blue.
  • reaction temperature is room temperature
  • most suitable reaction temperature at room temperature is 20°C-30°C.
  • test compound was prepared into a 10 mM stock solution, doubling dilution (1:5) with growth medium, diluted 8-10 concentration gradients (initial concentration 10 ⁇ M), and added with 96 containing the upper layer of agarose-cells well (50 ⁇ L/well); set solvent control wells; each concentration was replicated twice, placed in a carbon dioxide incubator for 10-14 days.

Abstract

A pyrimidine derivative and a pharmaceutical application thereof. The structural formula of the pyrimidine derivative is as follows:

Description

嘧啶衍生物及其在医药上的应用Pyrimidine derivatives and their applications in medicine 技术领域technical field
本申请涉及嘧啶衍生物及其在医药上的应用。This application relates to pyrimidine derivatives and their use in medicine.
背景技术Background technique
RAS基因是人类重要的原癌基因之一，在调控细胞信号转导与肿瘤的发生发展中起着关键作用；也是人类癌症中最常出现突变的致癌基因，大约30％的癌症中存在RAS基因突变。人类RAS超蛋白家族含有三种基因(分别是KRAS、NRAS和HRAS)，编码四种蛋白(KRAS-4A、KRAS-4B、NRAS和HRAS)。其中KRAS是RAS家族中最常见的亚型，也是最容易突变的基因；RAS突变中有86％为KRAS突变，86-96％的胰腺癌、40-54％的结直肠癌和20-37％的肺癌中可以检测到KRAS基因突变，在胆管癌、***、膀胱癌、肝癌和乳腺癌等癌症中也出现KRAS突变(Kessler et al.,2019)。The RAS gene is one of the important human proto-oncogenes and plays a key role in regulating cell signal transduction and the occurrence and development of tumors; it is also the most frequently mutated oncogene in human cancers, and the RAS gene is present in about 30% of cancers. mutation. The human RAS superprotein family contains three genes (KRAS, NRAS, and HRAS, respectively) that encode four proteins (KRAS-4A, KRAS-4B, NRAS, and HRAS). Among them, KRAS is the most common subtype in the RAS family and the most easily mutated gene; 86% of RAS mutations are KRAS mutations, 86-96% of pancreatic cancer, 40-54% of colorectal cancer and 20-37% of KRAS gene mutations can be detected in lung cancers of 2000, and KRAS mutations are also found in cancers such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and breast cancer (Kessler et al., 2019).
KARS蛋白属于小GTP酶(small GTPase)蛋白家族。在正常生理状态下，KRAS蛋白通过在失活(结合GDP)和激活(结合GTP)状态之间转变实现对信号通路的调控(Downward,2003)：当KRAS与二磷酸鸟苷(GDP)结合时处于失活状态；当与三磷酸鸟苷(GTP)结合时处于激活状态可以激活下游信号通路。这两种状态之间的转换和平衡受到以下两类蛋白的调控：(1)鸟嘌呤核苷酸交换因子(guanine nucleotide exchange factors；GEF)，能促使KRAS与GTP的结合，提高GDP从KRAS中的解离效率，促进KRAS的激活；(2)GTP酶激活蛋白(GTPase activating/accelerating proteins；GAPs)，能提高KRAS蛋白本身相对较弱的GTPase活性，促使GTP水解为GDP，降低KRAS对下游信号通路的影响。生理条件下，KRAS与GDP有着更强的结合能力，因此细胞中的KRAS一般处于失活状态；当KRAS与GTP结合后被激活，可以通过MAPK、PI3K和Ral-GEFs等多条下游信号通路促进细胞生存、增殖和细胞因子释放等(Liu et al.,2019)。KARS proteins belong to the small GTPase family of proteins. Under normal physiological conditions, KRAS proteins regulate signaling pathways by transitioning between inactive (binding to GDP) and activated (binding to GTP) states (Downward, 2003): when KRAS binds to guanosine diphosphate (GDP) Inactive state; active state can activate downstream signaling pathways when combined with guanosine triphosphate (GTP). The transition and balance between these two states are regulated by the following two types of proteins: (1) guanine nucleotide exchange factors (GEFs), which can promote the binding of KRAS to GTP and increase GDP from KRAS (2) GTPase activating/accelerating proteins (GAPs), which can improve the relatively weak GTPase activity of KRAS protein itself, promote the hydrolysis of GTP to GDP, and reduce the effect of KRAS on downstream signals pathway effects. Under physiological conditions, KRAS has a stronger binding ability to GDP, so KRAS in cells is generally inactive; when KRAS is activated by binding to GTP, it can be promoted through multiple downstream signaling pathways such as MAPK, PI3K, and Ral-GEFs. Cell survival, proliferation and cytokine release, etc. (Liu et al., 2019).
当KRAS发生突变或者构象改变，它的GTP水解活性下降、与GDP结合稳定性增加、与GAP相互作用受阻，使得KRAS蛋白长期处于激活状态，通过刺激大量的下游细胞信号，持续促使细胞继续生长和***，最终导致癌症发生。目前研究表明，KRAS最常见的突变方式是在密码子的第12、13和61位发生的单点突变(single-point mutations)，其中第12位密码子突变约占KRAS突变的82％。体细胞中这些位点的错义突变会干扰KRAS本身的GTPase活性：如第12位(G12)突变通过干扰GAP蛋白结合和GTP水解来持续激活KRAS；第13位(G13)突变造成GAP结合能力降低；第61位(Q61)突变影响GTP水解中间态的稳定性(Ostrem & Shokat,2016)。除了KRAS基因改变直接导致肿瘤的发生外，KRAS突变细胞通过旁分泌作用对引起肿瘤恶化的微环境也影响广泛，可以促进分泌多种细胞因子、趋化因子和生长因子对纤维母细胞和免疫细胞等影响肿瘤微环境，也能对基质细胞进行改造和重编程。这些研究充分证实了KRAS基因可以作为重要的抗肿瘤药物靶点。When KRAS is mutated or its conformation changes, its GTP hydrolysis activity decreases, its binding stability to GDP increases, and its interaction with GAP is blocked, so that KRAS protein is in a long-term activated state, and by stimulating a large number of downstream cell signals, it continues to promote cell growth and growth. Divide, eventually leading to cancer. Current studies have shown that the most common mutation of KRAS is single-point mutations at codons 12, 13 and 61, of which codon 12 mutations account for about 82% of KRAS mutations. Missense mutations at these sites in somatic cells interfere with the GTPase activity of KRAS itself: for example, mutations at position 12 (G12) continue to activate KRAS by interfering with GAP protein binding and GTP hydrolysis; mutations at position 13 (G13) cause GAP binding ability Decreased; mutation at position 61 (Q61) affects the stability of the hydrolytic intermediate state of GTP (Ostrem & Shokat, 2016). In addition to KRAS gene alterations that directly lead to tumorigenesis, KRAS mutant cells also have a wide range of effects on the microenvironment that causes tumor progression through paracrine action, which can promote the secretion of various cytokines, chemokines and growth factors to fibroblasts and immune cells. It also affects the tumor microenvironment, and can also remodel and reprogram stromal cells. These studies fully confirmed that KRAS gene can be used as an important antitumor drug target.
研究KRAS抑制剂已经开展了近几十年，之前普遍认为该靶点难以成药，主要原因有以下两点：(1)KRAS蛋白与磷酸鸟苷(GDP或GTP)的亲和力低至皮摩尔(pM)，细胞中磷酸鸟苷的浓度可以达到毫摩尔(mM)级别，这使得一般药物(磷酸鸟苷的类似物)难以与KRAS蛋白进行竞争性结合(Waters & Der,2018)；(2)KRAS蛋白的磷酸鸟苷结合部位也缺乏适合其他小分子化合物结合的区域。最新研究发现，与野生型KRAS蛋白相比，小分子化合物可以针对具有KRAS-G12C突变的肿瘤有抑制作用。因为KRAS蛋白的第12位密码子靠近该蛋白的核苷结合域和催化中心，该位点发生半胱氨酸突变后，小分子化合物可以通过与半胱氨酸不可逆的共价结合来影响KRAS蛋白的功能，同时小分子化合物更倾 向于与KRAS-GDP蛋白结合，降低了GTP与蛋白的亲和力(Lito,Solomon,Li,Hansen,& Rosen,2016)。Research on KRAS inhibitors has been carried out in recent decades, and it was generally believed that this target is difficult to be drugged. The main reasons are as follows: (1) The affinity of KRAS protein to guanosine phosphate (GDP or GTP) is as low as picomolar (pM) ), the concentration of guanosine phosphate in cells can reach the millimolar (mM) level, which makes it difficult for general drugs (analogs of guanosine phosphate) to compete with KRAS proteins (Waters & Der, 2018); (2) KRAS The guanosine phosphate binding site of the protein also lacks a region suitable for the binding of other small molecule compounds. The latest study found that, compared with wild-type KRAS protein, small-molecule compounds can inhibit tumors with KRAS-G12C mutation. Because the 12th codon of KRAS protein is close to the nucleoside binding domain and catalytic center of the protein, after cysteine mutation at this site, small molecule compounds can affect KRAS through irreversible covalent binding to cysteine The function of the protein, and the small molecule compound is more inclined to bind to the KRAS-GDP protein, which reduces the affinity of GTP to the protein (Lito, Solomon, Li, Hansen, & Rosen, 2016).
早期研发的针对KRAS-G12C肿瘤的小分子化合物ARS-853在体外表现出良好的活性，有效抑制了GDP与GTP转换，但是缺乏体内活性(Patricelli et al.,2016)。随后进一步优化结构得到ARS-1620，在体内外均表现出对KRAS-G12C肿瘤细胞良好的药理活性，而对其他KRAS基因突变细胞无明显影响(Janes et al.,2018)。目前已有多种KRAS抑制剂药物进入了临床研究的阶段，但根据目前公布的数据，在肿瘤患者中的临床药效仍有待进一步提高。因此，目前仍需要开发新一代高效、安全的KRAS-G12C突变抑制剂，以更好的满足临床需求。ARS-853, an early developed small-molecule compound targeting KRAS-G12C tumors, showed good activity in vitro and effectively inhibited the conversion of GDP and GTP, but lacked in vivo activity (Patricelli et al., 2016). Subsequently, the structure was further optimized to obtain ARS-1620, which showed good pharmacological activity against KRAS-G12C tumor cells in vitro and in vivo, but had no significant effect on other KRAS mutant cells (Janes et al., 2018). At present, a variety of KRAS inhibitor drugs have entered the stage of clinical research, but according to the data published so far, the clinical efficacy in tumor patients still needs to be further improved. Therefore, there is still a need to develop a new generation of efficient and safe KRAS-G12C mutation inhibitors to better meet clinical needs.
发明内容SUMMARY OF THE INVENTION
本申请的一个或多个实施方案的目的之一在于提供新型嘧啶衍生物、其药物组合物以及其在制备KRAS G12C抑制剂。One of the objectives of one or more embodiments of the present application is to provide novel pyrimidine derivatives, pharmaceutical compositions thereof, and their preparation for KRAS G12C inhibitors.
本申请的一个或多个实施方案提供了通式(I)的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐：One or more embodiments of the present application provide compounds of general formula (I) or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers thereof Isomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof:
Figure PCTCN2022072530-appb-000001
Figure PCTCN2022072530-appb-000001
其中in
R 1为H、卤素或C 3-8环烷基； R 1 is H, halogen or C 3-8 cycloalkyl;
X为N或CR 3； X is N or CR 3 ;
R 2、R 3各自独立地为H或卤素； R 2 and R 3 are each independently H or halogen;
C环为
Figure PCTCN2022072530-appb-000002
C ring is
Figure PCTCN2022072530-appb-000002
Y为N或CR 4； Y is N or CR 4 ;
R 4、R 5各自独立地为H、羟基、卤素、氨基、三氟甲基或C 1-6烷基； R 4 and R 5 are each independently H, hydroxy, halogen, amino, trifluoromethyl or C 1-6 alkyl;
或者R 4与R 5与其相连的碳原子一起形成4元或5元的环烷基或杂环烷基，所述4元或5元杂环烷基包含1或2个选自N和O的杂原子，所述4元或5元的环烷基或杂环烷基任选地被1或2个C 1-6烷基取代； Or R4 and R5 together with the carbon atom to which they are attached form a 4- or 5 -membered cycloalkyl or heterocycloalkyl containing 1 or 2 selected from N and O A heteroatom, the 4- or 5-membered cycloalkyl or heterocycloalkyl is optionally substituted with 1 or 2 C 1-6 alkyl groups;
m为1、2、3或4；m is 1, 2, 3 or 4;
R 6、R 7各自独立地为C 1-6烷基或卤素； R 6 and R 7 are each independently C 1-6 alkyl or halogen;
L为O或N原子；L is O or N atom;
R 8为C 3-8环烷基或C 3-8杂环烷基，所述C 3-8杂环烷基包含1至4个选自N和O的杂 原子，R 8任选地被1或2个C 1-6烷基取代； R 8 is C 3-8 cycloalkyl or C 3-8 heterocycloalkyl containing 1 to 4 heteroatoms selected from N and O, R 8 is optionally 1 or 2 C 1-6 alkyl substitutions;
n为0或1。n is 0 or 1.
在一个或多个实施方案中，其中：In one or more embodiments, wherein:
R 1选自H、卤素或环丙基； R 1 is selected from H, halogen or cyclopropyl;
X选自N或CR 3； X is selected from N or CR 3 ;
R 2、R 3各自独立地为H或卤素； R 2 and R 3 are each independently H or halogen;
C环为
Figure PCTCN2022072530-appb-000003
C ring is
Figure PCTCN2022072530-appb-000003
L选自O或N原子；L is selected from O or N atoms;
R 8选自C 3-8杂环烷基，所述C 3-8杂环烷基包含1至4个(例如1、2、3或4个)选自N或O的杂原子，R 8任选地被1或2个C 1-6烷基取代； R 8 is selected from C 3-8 heterocycloalkyl containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from N or O, R 8 optionally substituted with 1 or 2 C 1-6 alkyl;
n为0或1。n is 0 or 1.
在一个或多个实施方案中，所述卤素为F。In one or more embodiments, the halogen is F.
在一个或多个实施方案中，所述C 1-6烷基为甲基。 In one or more embodiments, the C 1-6 alkyl group is methyl.
在一个或多个实施方案中，R 1为H。 In one or more embodiments, R1 is H.
在一个或多个实施方案中，R 2为卤素。 In one or more embodiments, R 2 is halogen.
在一个或多个实施方案中，R 3为卤素。 In one or more embodiments, R3 is halogen.
在一个或多个实施方案中，R 4为卤素或C 1-6烷基，R 5为羟基。 In one or more embodiments, R 4 is halo or C 1-6 alkyl, and R 5 is hydroxy.
在一个或多个实施方案中，R 4与R 5与其相连的碳原子一起形成4元或5元杂环烷基，所述4元或5元杂环烷基包含2个N杂原子，所述4元或5元杂环烷基任选地被1个C 1-6烷基取代。 In one or more embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a 4- or 5 -membered heterocycloalkyl group containing 2 N heteroatoms, so The 4- or 5-membered heterocycloalkyl is optionally substituted with 1 C 1-6 alkyl.
在一个或多个实施方案中，m为2。In one or more embodiments, m is 2.
在一个或多个实施方案中，L为O。In one or more embodiments, L is O.
在一个或多个实施方案中，R 8为C 5-6杂环烷基，所述C 5-6杂环烷基包含1或2个选自N和O的杂原子，R 8任选地被1个C 1-6烷基取代。 In one or more embodiments, R8 is C5-6 heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, and R8 is optionally Substituted with 1 C 1-6 alkyl.
在一个或多个实施方案中，n为1。In one or more embodiments, n is one.
本申请的一个或多个实施方案提供了化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，所述化合物为：One or more embodiments of the present application provide compounds or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or the same thereof A mixture, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, said compound being:
Figure PCTCN2022072530-appb-000004
Figure PCTCN2022072530-appb-000004
Figure PCTCN2022072530-appb-000005
Figure PCTCN2022072530-appb-000005
本申请的一个或多个实施方案提供了药物组合物，其包含：One or more embodiments of the present application provide pharmaceutical compositions comprising:
(1)本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐；(1) The compound of the present application or its stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or solvent thereof compounds, metabolites, co-crystals, prodrugs or pharmaceutically acceptable salts;
(2)任选的一种或者多种其他活性成分；以及(2) optionally one or more other active ingredients; and
(3)药学上可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.
本申请的一个或多个实施方案提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物在制备用于治疗或预防癌症或肿瘤的药物中的用途。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the manufacture of a medicament for the treatment or prevention of cancer or tumor.
在一个或多个实施方式中，所述癌症为胰腺癌、结直肠癌、肺癌、胆管癌、***、膀胱癌、肝癌或乳腺癌。In one or more embodiments, the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
本申请的一个或多个实施方案提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物在制备KRAS G12C抑制剂 中的用途。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the preparation of a KRAS G12C inhibitor.
本申请的一个或多个实施方案提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物在制备用于治疗或预防与KRAS G12C相关的疾病中的用途。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the manufacture of a composition for the treatment or prophylaxis of a disease associated with KRAS G12C.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物，其作为药物。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a medicament.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物，其用于治疗或预防癌症或肿瘤。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of cancer or tumor.
在一个或多个实施方式中，所述癌症为胰腺癌、结直肠癌、肺癌、胆管癌、***、膀胱癌、肝癌或乳腺癌。In one or more embodiments, the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物，其作为KRAS G12C抑制剂。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a KRAS G12C inhibitor.
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物，其用于治疗或预防与KRAS G12C相关的疾病。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prophylaxis of a disease associated with KRAS G12C.
本申请的一个或多个实施方式提供了治疗或预防癌症或肿瘤的方法，其包括向有此需要的对象给予本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物。One or more embodiments of the present application provide a method of treating or preventing cancer or tumor comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, mesomer thereof , racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application .
在一个或多个实施方式中，所述癌症为胰腺癌、结直肠癌、肺癌、胆管癌、***、膀胱癌、肝癌或乳腺癌。In one or more embodiments, the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
本申请的一个或多个实施方式提供了治疗或预防与KRAS G12C相关的疾病的方法，其包括向有此需要的对象给予本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物。One or more embodiments of the present application provide a method of treating or preventing a disease associated with KRAS G12C, comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, endoisomer thereof A racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or the present application Compositions.
本申请的一个或多个实施方式提供了抑制KRAS G12C的方法，其包括向有此需要的对象给予本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物。One or more embodiments of the present application provide methods of inhibiting KRAS G12C, comprising administering to a subject in need thereof a compound of the present application, or a stereoisomer, tautomer, meso, racemic, or stereoisomer thereof Rotors, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application.
在一个或多个实施方式中，所述与KRAS G12C相关的疾病为癌症或肿瘤。In one or more embodiments, the disease associated with KRAS G12C is cancer or tumor.
在一个或多个实施方式中，所述与KRAS G12C相关的疾病为胰腺癌、结直肠癌、肺癌、胆管癌、***、膀胱癌、肝癌或乳腺癌。In one or more embodiments, the disease associated with KRAS G12C is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
发明详述Detailed description of the invention
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, 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, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons 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 isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen 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(例如1、2、3、4、5、6、7、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；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。"Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably 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 thereof; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。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。所述的烷基定义与上文所述的“烷基”定义相同。"Alkoxy" refers to a group formed by substituting at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy. The definition of alkyl is the same as the definition of "alkyl" described above.
“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基，更优选2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。"Alkenyl" means a straight chain consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds Chain or branched unsaturated aliphatic hydrocarbon groups, preferably alkenyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-yl Alken-3-yl. The alkenyl group may be optionally further substituted with one or more substituents.
“炔基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基，更优选2至8个碳原子的炔基，进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被一至多个取代基所取代。"Alkynyl" means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group may optionally be further substituted with one or more substituents.
“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。"Aryl" means a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (eg, 5, 6, 7, 8) , 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be a bridged ring or a spiro ring, non-limiting implementation Examples include phenyl, naphthyl. The aryl group may optionally be further substituted with one or more substituents.
“杂芳基”是指取代的或未取代的芳香环，其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子，优选5至8元杂芳基，杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂芳基可以连接在杂原子或者碳原子上，杂芳基可以是桥环或者螺环，非限制性实施例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states. Heteroaryl groups can be attached to heteroatoms or carbon atoms, and heteroaryl groups can be bridged or spirocyclic, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时，其定义与上文“芳基”的定义相同；当为非芳香环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，可以是桥环或者螺环，非限制性实施例 包括环丙基、环丁基、环戊基、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、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、
Figure PCTCN2022072530-appb-000006
所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。 "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for "aryl"; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) (membered) tricyclic ring system, which can be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cyclohexyl Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,
Figure PCTCN2022072530-appb-000006
Said "carbocyclyl" or "carbocycle" is optionally further substituted with one or more substituents.
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环，当为芳香性杂环时，其定义与上文“杂芳基”定义相同；当为非芳香性杂环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子或者碳原子上；“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、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、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、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、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、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”或“杂环”可以任选进一步被1个或者多个取代基所取代。"Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle, and when it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above; when When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (eg 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (eg 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or A "heterocycle" can be attached to a heteroatom or a carbon atom; a "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azazelyl, diazepine, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuran base, dithiopenyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzene Imidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline, 2H-pyranyl, 4H-pyranyl , Dioxanyl, 1,3-dioxopentyl, pyrazolinyl, dithianyl, dithiazolinyl, dihydrothienyl, pyrazolidine, imidazolinyl, imidazolidinyl, 1,2,3,4-Tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-Indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl Alkyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. Said "heterocyclyl" or "heterocycle" may be optionally further substituted with one or more substituents.
“环烷基”是指饱和的环烃基，其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多环体系，环碳原子优选3至10个碳原子，进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时，可以任选进一步被1个或者多个取代基所取代。"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more In the ring system, the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl and the like. When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.
“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1、2或3个选自N、O或S的杂原子，优选3至8元杂环基。“杂环烷基”的环中选择性取代的1、2或3个N、S可被氧化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”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、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、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、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。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. Optionally substituted 1, 2 or 3 N, S in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be attached to a heteroatom or carbon atom; "heterocycloalkyl" Alkyl" can be bridged or spiro. Non-limiting examples of "heterocycloalkyl" include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxetanyl Oxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时，可以选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C 1-6烷基氨基、＝O、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-NR q4R q5、＝NR q6、-C(＝O)OC 1-6烷基、-OC(＝O)C 1-6烷基、-C(＝O)NR q4R q5、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-C(＝O)OC 6-10芳基、-OC(＝O)C 6-10芳基、-OC(＝O)C 5-10杂芳基、-C(＝O)OC 5-10杂芳基、-OC(＝O)C 3-8杂环烷基、-C(＝O)OC 3-8杂环烷基、-OC(＝O)C 3-8环烷基、-C(＝O)OC 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 2-6烯基或者-NHC(＝O)C 2-6炔基的取代基所取代，且其中所述的取代基C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8杂环烷基或者-NHC(＝O)C 3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、-NR q4R q5或者＝O的取代基所取代；R q1选自C 1-6烷基、C 1-6烷氧基或者C 6-10芳基；R q2、R q3选自H或者C 1-6烷基；其中，R q4、R q5选自H、C 1-6烷基、-NH(C＝NR q1)NR q2R q3、-S(＝O) 2NR q2R q3、-C(＝O)R q1或者-C(＝O)NR q2R q3，其中所述的C 1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 5-10杂芳基、C 3-8环烷基或者C 3-8杂环烷基的取代基所取代；或者R q4与R q5及N原子形成一个3至8元杂环，所述杂环可以含有1个或者多个选自N、O或者S的杂原子。 When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", " When "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it may be further selected by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, - C(=O)OC 6-10 aryl, -OC(=O)C 6-10 aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl Aryl, -OC(=O)C 3-8 heterocycloalkyl, -C(=O)OC 3-8 heterocycloalkyl, -OC(=O)C 3-8 cycloalkyl, -C( =O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 hetero Aryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 2-6 alkenyl or -NHC(=O ) C 2-6 alkynyl substituents, and wherein the substituents C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 aryl, -NHC(=O) C 5-10 heteroaryl, -NHC(=O)C 3-8 heterocycloalkyl or -NHC(=O) C 3-8 cycloalkyl is optionally further selected from 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or a substituent of =O; R q1 is selected from C 1-6 alkyl, C 1-6 Alkoxy or C 6-10 aryl; R q2 and R q3 are selected from H or C 1-6 alkyl; wherein, R q4 and R q5 are selected from H, C 1-6 alkyl, -NH (C= NR q1 ) NR q2 R q3 , -S(=O) 2 NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 , wherein said C 1-6 alkyl Optionally further selected by one or more selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl R q4 , R q5 and N atom form a 3- to 8 - membered heterocycle, the heterocycle may contain 1 or a plurality of heteroatoms selected from N, O or S.
卤素包括F、Cl、Br和I。Halogens include F, Cl, Br and I.
“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 "a pharmaceutically acceptable salt thereof" means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药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、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
“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。"Carrier" refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
“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，前药被割裂形成游离的氨基或者羧基。A "prodrug" refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are 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 a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
“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 resulting from 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，“任选地被烷 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 "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not occur what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group Happening.
具体实施方式Detailed ways
以下实施例详细说明本申请的技术方案，但本申请的保护范围包括但是不限于此。The following examples illustrate the technical solutions of the present application in detail, but the protection scope of the present application includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)和/或质谱(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-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS).
MS的测定用Agilent 6120B(ESI)和Agilent 6120B(APCI))。Agilent 6120B (ESI) and Agilent 6120B (APCI) were used for MS determination.
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)。The HPLC assay was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM).
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 specification used for TLC 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.
实施例1Example 1
SC和RCSC and RC
1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬-2-基)丙-2-烯-1-酮化合物1-1和化合物1-21-(7-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl )Methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one compound 1-1 and compound 1-2
1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4 -yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2022072530-appb-000007
Figure PCTCN2022072530-appb-000007
Figure PCTCN2022072530-appb-000008
Figure PCTCN2022072530-appb-000008
第一步first step
7-溴-6-氯-8-氟喹唑啉-2,4(1H,3H)-二酮1b7-Bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione 1b
7-bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione7-bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione
在500mL的圆底烧瓶中，加入1a(20g，74.5mmol)和尿素(54g，894mmol)，氮气保护下200℃反应6小时，反应完加入蒸馏水(200mL)搅拌0.5小时，过滤得到1b(棕色固体，20g，收率92％)。In a 500mL round-bottomed flask, add 1a (20g, 74.5mmol) and urea (54g, 894mmol), react at 200°C for 6 hours under nitrogen protection, add distilled water (200mL) and stir for 0.5 hours after the reaction, and filter to obtain 1b (brown solid) , 20g, yield 92%).
LC-MS m/z(ESI)＝292.90[M+1]。LC-MS m/z (ESI) = 292.90 [M+1].
第二步second step
7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮螺环[3.5]壬烷-2-羧酸叔丁酯1c7-(7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester 1c
tert-butyl 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylatetert-butyl 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
将1b(20g，68.2mmol)溶解在N,N-二甲基甲酰胺(200mL)中，在0℃氮气保护下缓慢滴加二氯亚砜(50mL，682mmol)，滴加完毕后100℃反应6小时。将反应液减压浓缩，得到粗品用四氢呋喃(200mL)溶解，0℃下缓慢滴加三乙胺(88g，682mmol)和2-叔丁氧羰基-2,7-二氮杂螺[3.5]壬烷(16.98g，75.0mmol)，室温反应2小时。加入水(200mL),乙酸乙酯(50mL x 3)萃取，合并有机相，浓缩，柱层析分离得到1c(黄色固体，20g，收率56％)。1b (20 g, 68.2 mmol) was dissolved in N,N-dimethylformamide (200 mL), and thionyl chloride (50 mL, 682 mmol) was slowly added dropwise at 0 °C under nitrogen protection, and the reaction was performed at 100 °C after the dropwise addition. 6 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product which was dissolved in tetrahydrofuran (200 mL), and triethylamine (88 g, 682 mmol) and 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane were slowly added dropwise at 0°C alkane (16.98 g, 75.0 mmol), and reacted at room temperature for 2 hours. Water (200 mL) was added, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, concentrated, and separated by column chromatography to obtain 1c (yellow solid, 20 g, yield 56%).
1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),3.77-3.69(m,8H),1.76-1.72(m,4H),1.39(s,9H)。 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 3.77-3.69 (m, 8H), 1.76-1.72 (m, 4H), 1.39 (s, 9H).
LC-MS m/z(ESI)＝519.00[M+1]。LC-MS m/z (ESI) = 519.00 [M+1].
第三步third step
叔丁基-7-(7-溴-6-氯-8-氟-2-((1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸盐1dtert-Butyl-7-(7-bromo-6-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl )-2,7-diazaspiro[3.5]nonane-2-carboxylate 1d
tert-butyl 7-(7-bromo-6-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy) quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylatetert-butyl 7-(7-bromo-6-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5] nonane-2-carboxylate
将1c(20g，38.5mmol)和(1-(吡咯烷-1-基甲基)环丙基)甲醇(15.8g，100mmol)置于50mL圆底烧瓶中，80℃反应8小时，反应完用硅胶柱层析得到1d(黄色固体，14.7g，收率60％)。1c (20g, 38.5mmol) and (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol (15.8g, 100mmol) were placed in a 50mL round-bottom flask, and reacted at 80°C for 8 hours. Silica gel column chromatography gave 1d (yellow solid, 14.7 g, yield 60%).
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),4.28(s,2H),3.78-3.63(m,10H),3.27-3.19(m,2H),3.12-3.02(m,2H),2.04-1.96(m,2H),1.89-1.83(m,6H),1.39(s,9H),0.83-0.81(m,2H)，0.79-0.77(m,2H)。 1 H NMR(400MHz, DMSO-d6)δ7.88(s,1H),4.28(s,2H),3.78-3.63(m,10H),3.27-3.19(m,2H),3.12-3.02(m, 2H), 2.04-1.96 (m, 2H), 1.89-1.83 (m, 6H), 1.39 (s, 9H), 0.83-0.81 (m, 2H), 0.79-0.77 (m, 2H).
LC-MS m/z(ESI)＝638.20[M+1]。LC-MS m/z (ESI) = 638.20 [M+1].
第四步the fourth step
叔丁基-7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(((1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-yl)-2,7-二氮杂螺[3.5]壬烷-2-羧酸酯1etert-Butyl-7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((1-(pyrrolidin-1-ylmethyl) Cyclopropyl)methoxy)quinazoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate 1e
tert-butyl 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-基)-2,7-diazaspiro[3.5]nonane-2-carboxylatetert-butyl 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4 -base)-2,7-diazaspiro[3.5]nonane-2-carboxylate
将1d(1.7g，2.66mmol)，(5-甲基-1H-吲唑-4-基)硼酸(937mg，5.3mmol)，三(二亚苄-BASE丙酮)二钯(488mg，0.53mmol)，2-二环己基膦-2’,6’-二甲氧基-联苯(437mg，1.06mmol)，磷酸三钾(2.3g，10.6mmol)溶解在1,4-二氧六环(16mL)和蒸馏水(4mL)中，氮气氛围下110℃反应8小时，浓缩反应液，中压制备得到1e(白色固体，600mg，收率33％)。1d (1.7 g, 2.66 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (937 mg, 5.3 mmol), tris(dibenzylidene-BASE acetone)dipalladium (488 mg, 0.53 mmol) , 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl (437 mg, 1.06 mmol), tripotassium phosphate (2.3 g, 10.6 mmol) was dissolved in 1,4-dioxane (16 mL ) and distilled water (4 mL), react at 110° C. for 8 hours under nitrogen atmosphere, concentrate the reaction solution, and prepare 1e (white solid, 600 mg, yield 33%) under medium pressure.
1H NMR(400MHz,DMSO-d6)δ13.13(s,1H),7.89(s,1H),7.56(d,1H),7.54(s,1H),7.36(d,1H),4.22(s,2H),4.03(s,2H),3.85-3.62(m,6H),2.44-2.36(m,6H),2.13(s,3H),2.00-1.85(m,4H),1.62-1.59(m,4H),1.38(s,9H),0.61-0.58(m,2H),0.41-0.38(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ13.13(s,1H),7.89(s,1H),7.56(d,1H),7.54(s,1H),7.36(d,1H),4.22(s ,2H),4.03(s,2H),3.85-3.62(m,6H),2.44-2.36(m,6H),2.13(s,3H),2.00-1.85(m,4H),1.62-1.59(m , 4H), 1.38(s, 9H), 0.61-0.58(m, 2H), 0.41-0.38(m, 2H).
LC-MS m/z(ESI)＝690.30[M+1]。LC-MS m/z (ESI) = 690.30 [M+1].
第五步the fifth step
6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)-4-(2,7-二氮螺环[3.5]壬基-7-基)喹唑啉1f6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)- 4-(2,7-Diazaspiro[3.5]nonyl-7-yl)quinazoline 1f
6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazoline6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-4-(2,7-diazaspiro [3.5]nonan-7-yl)quinazoline
将1e(600mg，0.87mmol)溶解于二氯甲烷(6mL)中，冰水浴下缓慢滴加三氟乙酸(1.5mL)，滴加完反应0.5小时。加入碳酸氢钠(1.65g)搅拌10min，过滤，收集滤液减压浓缩得到1f(黄色固体，500mg，收率97％)。1e (600 mg, 0.87 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was slowly added dropwise under an ice-water bath, and the reaction was completed dropwise for 0.5 hour. Sodium bicarbonate (1.65 g) was added, stirred for 10 min, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 1f (yellow solid, 500 mg, yield 97%).
LC-MS m/z(ESI)＝590.30[M+1]。LC-MS m/z (ESI) = 590.30 [M+1].
第六步Step 6
1-(7-(-氯-8-氟-7-(-甲基-1H-吲唑-4-基)2-(-(咯烷-1-基甲基)丙基)氧基)唑啉-4-基)2,7-二氮螺环[3.5]壬-2-基)-2-烯-1-酮化合物11-(7-(-Chloro-8-fluoro-7-(-methyl-1H-indazol-4-yl)2-(-(rolidin-1-ylmethyl)propyl)oxy)azole Linn-4-yl)2,7-diazaspiro[3.5]non-2-yl)-2-en-1-one compound 1
1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4 -yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
将1f(160mg，0.27mmol)，丙烯酸(23mg，0.33mmol)，N,N-二异丙基乙胺(175mg，1.35mmol)溶解于N,N-二甲基甲酰胺(2mL)中，冰水浴下缓慢加入1-丙基磷酸酐(129mg，0.4mmol)，室温过夜。反应液浓缩后用中压制备得到化合物1(白色固体，40mg，收率23％)。1f (160 mg, 0.27 mmol), acrylic acid (23 mg, 0.33 mmol), N,N-diisopropylethylamine (175 mg, 1.35 mmol) were dissolved in N,N-dimethylformamide (2 mL) on ice 1-Propylphosphoric anhydride (129 mg, 0.4 mmol) was slowly added under a water bath, overnight at room temperature. The reaction solution was concentrated and prepared under medium pressure to obtain compound 1 (white solid, 40 mg, yield 23%).
LC-MS m/z(ESI)＝644.30[M+1]。LC-MS m/z (ESI) = 644.30 [M+1].
第七步Step 7
化合物1(40mg)通过SFC拆分得到化合物1-1(白色固体，19mg，收率48％，RT＝1.757min，ee＝99.9％)和化合物1-2(白色固体，19mg，收率48％，RT＝2.613min，ee ＝99.9％)。手性HPLC(AS)流动相:正己烷/乙醇＝95/5；时间＝5min；柱温:35℃；流速:1.5mL/min；检测器信号通道:[email protected]；二极管阵列检测器起止波长:200～400nm。Compound 1 (40 mg) was resolved by SFC to obtain compound 1-1 (white solid, 19 mg, yield 48%, RT=1.757 min, ee=99.9%) and compound 1-2 (white solid, 19 mg, yield 48%) , RT=2.613min, ee=99.9%). Chiral HPLC (AS) mobile phase: n-hexane/ethanol=95/5; time=5min; column temperature: 35℃; flow rate: 1.5mL/min; detector signal channel: [email protected]; start and end of diode array detector Wavelength: 200～400nm.
化合物1-1Compound 1-1
1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),7.90(s,1H),7.58(d,1H),7.55(s,1H),7.38(d,1H),6.35(dd,1H),6.12(dd,1H),5.69(dd,1H),4.24(s,2H),4.04(s,2H),3.87-3.64(m,6H),2.46-2.38(m,6H),2.16(s,3H),2.02-1.85(m,4H),1.64-1.62(m,4H),0.62-0.59(m,2H),0.43-0.40(m,2H)。 1 H NMR (400MHz, DMSO-d6)δ13.16(s,1H), 7.90(s,1H), 7.58(d,1H), 7.55(s,1H), 7.38(d,1H), 6.35(dd ,1H),6.12(dd,1H),5.69(dd,1H),4.24(s,2H),4.04(s,2H),3.87-3.64(m,6H),2.46-2.38(m,6H), 2.16(s, 3H), 2.02-1.85(m, 4H), 1.64-1.62(m, 4H), 0.62-0.59(m, 2H), 0.43-0.40(m, 2H).
LC-MS m/z(ESI)＝644.30[M+1]。LC-MS m/z (ESI) = 644.30 [M+1].
化合物1-2Compound 1-2
1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),7.91(s,1H),7.58(d,1H),7.55(s,1H),7.38(d,1H),6.36(dd,1H),6.12(dd,1H),5.70(dd,1H),4.24(s,2H),4.05(s,2H),3.87-3.64(m,6H),2.46-2.38(m,6H),2.16(s,3H),2.02-1.85(m,4H),1.64-1.62(m,4H),0.62-0.59(m,2H),0.43-0.40(m,2H)。 1 H NMR (400MHz, DMSO-d6)δ13.16(s,1H), 7.91(s,1H), 7.58(d,1H), 7.55(s,1H), 7.38(d,1H), 6.36(dd ,1H),6.12(dd,1H),5.70(dd,1H),4.24(s,2H),4.05(s,2H),3.87-3.64(m,6H),2.46-2.38(m,6H), 2.16(s, 3H), 2.02-1.85(m, 4H), 1.64-1.62(m, 4H), 0.62-0.59(m, 2H), 0.43-0.40(m, 2H).
LC-MS m/z(ESI)＝644.30[M+1]。LC-MS m/z (ESI) = 644.30 [M+1].
实施例2Example 2
Sc和RcSc and Rc
1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬基-2-基)-2-环丙基-2-烯-1-酮化合物2-1和化合物2-21-(7-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl )Methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)-2-cyclopropyl-2-en-1-one compound 2-1 and compound 2-2
1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2，7-diazaspiro[3.5]nonan-2-yl)-2-cyclopropylprop-2-en-1-one1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4 -yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-cyclopropylprop-2-en-1-one
Figure PCTCN2022072530-appb-000009
Figure PCTCN2022072530-appb-000009
按照化合物1的合成方法，中压制备得到化合物2(白色固体，30mg，收率16％)。According to the synthesis method of compound 1, compound 2 (white solid, 30 mg, yield 16%) was prepared under medium pressure.
LC-MS m/z(ESI)＝684.30[M+1]。LC-MS m/z (ESI) = 684.30 [M+1].
化合物2(36mg)通过SFC拆分得到化合物2-1(白色固体，18mg，收率50％，RT＝1.836min，ee＝99.9％)和化合物2-2(白色固体，18mg，收率50％，RT＝2.582min，ee＝99.9％)。手性HPLC(AS)流动相:正己烷/乙醇＝95/5；时间＝5min；柱温:35℃；流速:1.5mL/min；检测器信号通道:[email protected]；二极管阵列检测器起止波长:200～400nm。Compound 2 (36 mg) was resolved by SFC to obtain compound 2-1 (white solid, 18 mg, yield 50%, RT=1.836 min, ee=99.9%) and compound 2-2 (white solid, 18 mg, yield 50%) , RT=2.582min, ee=99.9%). Chiral HPLC (AS) mobile phase: n-hexane/ethanol=95/5; time=5min; column temperature: 35℃; flow rate: 1.5mL/min; detector signal channel: [email protected]; start and end of diode array detector Wavelength: 200～400nm.
化合物2-1Compound 2-1
1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),7.89(s,1H),7.58(d,1H),7.56(s,1H),7.39(d,1H),5.23(s,1H),5.18(s,1H),4.24(s,2H),3.98(s,2H),3.75-3.73(m,6H),2.43-2.39(m,6H),2.16(s,3H),2.00-1.89(m,4H),1.64-1.62(m,4H),1.60-1.57(m,1H),0.75-0.73(m,2H),0.60-0.59(m,2H),0.56-0.54(m,2H),0.43-0.41(m,2H)。 1 H NMR(600MHz,DMSO-d6)δ13.18(s,1H),7.89(s,1H),7.58(d,1H),7.56(s,1H),7.39(d,1H),5.23(s ,1H),5.18(s,1H),4.24(s,2H),3.98(s,2H),3.75-3.73(m,6H),2.43-2.39(m,6H),2.16(s,3H), 2.00-1.89(m, 4H), 1.64-1.62(m, 4H), 1.60-1.57(m, 1H), 0.75-0.73(m, 2H), 0.60-0.59(m, 2H), 0.56-0.54(m , 2H), 0.43-0.41 (m, 2H).
LC-MS m/z(ESI)＝684.30[M+1]。LC-MS m/z (ESI) = 684.30 [M+1].
化合物2-2Compound 2-2
1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),7.88(s,1H),7.58(d,1H),7.57(s,1H),7.39(d,1H),5.23(s,1H),5.19(s,1H),4.24(s,2H),3.99(s,2H),3.75-3.73(m,6H),2.43-2.39(m,6H),2.15(s,3H),2.01-1.90(m,4H),1.64-1.62(m,4H),1.61-1.58(m,1H),0.74-0.72(m,2H),0.60-0.59(m,2H),0.56-0.54(m,2H),0.43-0.41(m,2H)。 1 H NMR(600MHz,DMSO-d6)δ13.18(s,1H),7.88(s,1H),7.58(d,1H),7.57(s,1H),7.39(d,1H),5.23(s ,1H),5.19(s,1H),4.24(s,2H),3.99(s,2H),3.75-3.73(m,6H),2.43-2.39(m,6H),2.15(s,3H), 2.01-1.90(m,4H),1.64-1.62(m,4H),1.61-1.58(m,1H),0.74-0.72(m,2H),0.60-0.59(m,2H),0.56-0.54(m , 2H), 0.43-0.41 (m, 2H).
LC-MS m/z(ESI)＝684.30[M+1]。LC-MS m/z (ESI) = 684.30 [M+1].
实施例3Example 3
Sc和RcSc and Rc
1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬-2-基)-2-氟丙-2-烯-1-酮化合物3-1和化合物3-21-(7-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl )Methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)-2-fluoroprop-2-en-1-one compound 3-1 and compound 3-2
1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-fluoroprop-2-en-1-one1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4 -yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-fluoroprop-2-en-1-one
Figure PCTCN2022072530-appb-000010
Figure PCTCN2022072530-appb-000010
按照化合物1的合成方法，中压制备得到化合物3(白色固体，40mg，收率22％)。According to the synthesis method of compound 1, compound 3 (white solid, 40 mg, yield 22%) was prepared under medium pressure.
LC-MS m/z(ESI)＝662.30[M+1]。LC-MS m/z (ESI) = 662.30 [M+1].
化合物3(40mg)通过SFC拆分得到化合物3-1(白色固体，20mg，收率50％，RT＝1.796min，ee＝99.9％)和化合物3-2(白色固体，19mg，收率48％，RT＝2.589min，ee＝99.9％)。手性HPLC(AS)流动相:正己烷/乙醇＝95/5；时间＝5min；柱温:35℃；流速:1.5mL/min；检测器信号通道:[email protected]；二极管阵列检测器起止波长:200～400nm。Compound 3 (40 mg) was resolved by SFC to obtain compound 3-1 (white solid, 20 mg, yield 50%, RT=1.796 min, ee=99.9%) and compound 3-2 (white solid, 19 mg, yield 48%) , RT=2.589min, ee=99.9%). Chiral HPLC (AS) mobile phase: n-hexane/ethanol=95/5; time=5min; column temperature: 35℃; flow rate: 1.5mL/min; detector signal channel: [email protected]; start and end of diode array detector Wavelength: 200～400nm.
化合物3-1Compound 3-1
1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),7.90(s,1H),7.60(d,1H),7.57(s,1H),7.41(d,1H),5.16(dd,1H),5.10(dd,1H),4.26(s,2H),4.05(s,2H),3.88-3.64(m,6H),2.49-2.40(m,6H),2.18(s,3H),2.06-1.89(m,4H),1.65-1.63(m,4H),0.66-0.63(m,2H),0.43-0.40(m,2H)。 1 H NMR (600MHz, DMSO-d6)δ13.18(s,1H), 7.90(s,1H), 7.60(d,1H), 7.57(s,1H), 7.41(d,1H), 5.16(dd ,1H),5.10(dd,1H),4.26(s,2H),4.05(s,2H),3.88-3.64(m,6H),2.49-2.40(m,6H),2.18(s,3H), 2.06-1.89 (m, 4H), 1.65-1.63 (m, 4H), 0.66-0.63 (m, 2H), 0.43-0.40 (m, 2H).
LC-MS m/z(ESI)＝662.30[M+1]。LC-MS m/z (ESI) = 662.30 [M+1].
化合物3-2Compound 3-2
1H NMR(600MHz,DMSO-d6)δ13.18(s,1H),7.91(s,1H),7.60(d,1H),7.58(s,1H),7.40(d,1H),5.17(dd,1H),5.09(dd,1H),4.26(s,2H),4.06(s,2H),3.88-3.64(m,6H),2.50-2.41(m,6H),2.17(s,3H),2.06-1.89(m,4H),1.66-1.64(m,4H),0.66-0.63(m,2H),0.44-0.41(m,2H)。 1 H NMR (600MHz, DMSO-d6)δ13.18(s,1H), 7.91(s,1H), 7.60(d,1H), 7.58(s,1H), 7.40(d,1H), 5.17(dd ,1H),5.09(dd,1H),4.26(s,2H),4.06(s,2H),3.88-3.64(m,6H),2.50-2.41(m,6H),2.17(s,3H), 2.06-1.89 (m, 4H), 1.66-1.64 (m, 4H), 0.66-0.63 (m, 2H), 0.44-0.41 (m, 2H).
LC-MS m/z(ESI)＝662.30[M+1]。LC-MS m/z (ESI) = 662.30 [M+1].
实施例4Example 4
1-(7-(6-氯-8-氟-7-(1-甲基-1H-吲唑-4-基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬-2-基)丙-2-烯-1-酮化合物41-(7-(6-Chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one compound 4
1-(7-(6-chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one1-(7-(6-chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4 -yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2022072530-appb-000011
Figure PCTCN2022072530-appb-000011
第一步first step
叔丁基7-(6-氯-8-氟-7-(1-甲基-1H-吲唑-4-基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬-2-羧酸酯4atert-Butyl 7-(6-Chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-carboxylate 4a
tert-butyl 7-(6-chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylatetert-butyl 7-(6-chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4 -yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
参照1e的合成方法，得到4a(黄色固体，250mg，收率23％)。Referring to the synthesis method of 1e, 4a (yellow solid, 250 mg, yield 23%) was obtained.
1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.71(s,1H),7.58(d,1H),7.52(t,1H),7.43(d,1H),4.28(s,2H),4.14(s,3H),4.08(s,2H),3.86-3.62(m,6H),2.50-2.40(m,6H),2.07-1.90(m,4H),1.68-1.65(m,4H),1.39(s,9H),0.64-0.61(m,2H),0.43-0.40(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.71(s,1H),7.58(d,1H),7.52(t,1H),7.43(d,1H),4.28(s ,2H),4.14(s,3H),4.08(s,2H),3.86-3.62(m,6H),2.50-2.40(m,6H),2.07-1.90(m,4H),1.68-1.65(m , 4H), 1.39 (s, 9H), 0.64-0.61 (m, 2H), 0.43-0.40 (m, 2H).
LC-MS m/z(ESI)＝690.30[M+1]。LC-MS m/z (ESI) = 690.30 [M+1].
第二步second step
6-氯-8-氟-7-(1-甲基-1H-吲唑-4-基)-2-((1-(吡咯烷-1-基甲基)环丙基)甲氧基)-4-(2,7-二氮螺环[3.5]壬基-7-基)喹唑啉4b6-Chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy) -4-(2,7-diazaspiro[3.5]nonyl-7-yl)quinazoline 4b
6-chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazoline6-chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-4-(2,7-diazaspiro [3.5]nonan-7-yl)quinazoline
按照1f的合成方法，制备得到4b(黄色固体，200mg，收率94％)。According to the synthesis method of 1f, 4b was prepared (yellow solid, 200 mg, yield 94%).
LC-MS m/z(ESI)＝590.30[M+1]。LC-MS m/z (ESI) = 590.30 [M+1].
第三步third step
1-(7-(6-氯-8-氟-7-(1-甲基-1H-吲唑-4-基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬-2-基)丙-2-烯-1-酮化合物41-(7-(6-Chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl )methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one compound 4
1-(7-(6-chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one1-(7-(6-chloro-8-fluoro-7-(1-methyl-1H-indazol-4-yl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4 -yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
按照化合物1的合成方法，制备得到化合物4(白色固体，45mg，收率21％)。According to the synthesis method of compound 1, compound 4 was prepared (white solid, 45 mg, yield 21%).
1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.61(s,1H),7.55(d,1H),7.51(t,1H),7.40(d,1H),6.38(dd,1H),6.10(dd,1H),5.69(dd,1H),4.25(s,2H),4.10(s,3H),4.06(s,2H), 3.85-3.61(m,6H),2.48-2.39(m,6H),2.05-1.88(m,4H),1.65-1.63(m,4H),0.63-0.60(m,2H),0.43-0.40(m,2H)。 1 H NMR (400MHz, DMSO-d6)δ7.89(s,1H), 7.61(s,1H), 7.55(d,1H), 7.51(t,1H), 7.40(d,1H), 6.38(dd ,1H),6.10(dd,1H),5.69(dd,1H),4.25(s,2H),4.10(s,3H),4.06(s,2H), 3.85-3.61(m,6H),2.48- 2.39 (m, 6H), 2.05-1.88 (m, 4H), 1.65-1.63 (m, 4H), 0.63-0.60 (m, 2H), 0.43-0.40 (m, 2H).
LC-MS m/z(ESI)＝644.30[M+1]。LC-MS m/z (ESI) = 644.30 [M+1].
实施例5Example 5
1-(7-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬基-2-基)丙-2-烯-1-酮化合物51-(7-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy ) quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one compound 5
1-(7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one1-(7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)- 2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2022072530-appb-000012
Figure PCTCN2022072530-appb-000012
第一步first step
叔丁基7-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬-2-羧酸酯5atert-Butyl 7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy )quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-carboxylate 5a
tert-butyl 7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-(pyrrolidin-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylatetert-butyl 7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-(pyrrolidin-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2, 7-diazaspiro[3.5]nonane-2-carboxylate
按照1e的合成方法，制备得到5a(黄色固体，200mg，19％)。Following the synthetic method of 1e, 5a was prepared (yellow solid, 200 mg, 19%).
1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),7.79(s,1H),7.48-7.44(m,1H),7.22-7.18(m,1H),6.95-6.93(m,1H),4.25(s,2H),4.05(s,2H),3.86-3.44(m,6H),2.50-2.39(m,6H),2.05-1.17(m,4H),1.66-1.62(m,4H),1.38(s,9H),0.66-0.62(m,2H),0.44-0.40(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ9.20(s,1H),7.79(s,1H),7.48-7.44(m,1H),7.22-7.18(m,1H),6.95-6.93(m, 1H), 4.25(s, 2H), 4.05(s, 2H), 3.86-3.44(m, 6H), 2.50-2.39(m, 6H), 2.05-1.17(m, 4H), 1.66-1.62(m, 4H), 1.38 (s, 9H), 0.66-0.62 (m, 2H), 0.44-0.40 (m, 2H).
LC-MS m/z(ESI)＝670.30[M+1]。LC-MS m/z (ESI) = 670.30 [M+1].
第二步second step
2-(6-氯-8-氟-2-((1-(吡咯烷-1-基甲基)环丙基)甲氧基)-4-(2,7-二氮螺环[3.5]壬-7-基)喹唑啉-7-基)-3-氟苯酚5b2-(6-Chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-4-(2,7-diazaspiro[3.5] Non-7-yl)quinazolin-7-yl)-3-fluorophenol 5b
2-(6-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-7-yl)-3-fluorophenol2-(6-chloro-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)-4-(2,7-diazaspiro[3.5]nonan-7-yl)quinazolin-7- yl)-3-fluorophenol
按照1f的合成方法，制备得到5b(黄色固体，160mg，95％)。Following the synthesis of 1f, 5b was prepared (yellow solid, 160 mg, 95%).
LC-MS m/z(ESI)＝570.30[M+1]。LC-MS m/z (ESI) = 570.30 [M+1].
第三步third step
1-(7-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-(1-(吡咯烷-1-基甲基)环丙基)甲氧基)喹唑啉-4- 基)-2,7-二氮螺环[3.5]壬基-2-基)丙-2-烯-1-酮化合物51-(7-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy ) quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one compound 5
1-(7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one1-(7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)quinazolin-4-yl)- 2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
按照化合物1的合成方法，制备得到化合物5(白色固体，30mg，17％)。According to the synthesis method of compound 1, compound 5 (white solid, 30 mg, 17%) was prepared.
1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),7.93(s,1H),7.48-7.45(m,1H),7.32(dd,1H),6.97-6.93(m,1H),6.39(dd,1H),6.17(dd,1H),5.68(dd,1H),4.27(s,2H),4.08(s,2H),3.88-3.40(m,6H),2.51-2.40(m,6H),2.09-1.21(m,4H),1.68-1.64(m,4H),0.67-0.63(m,2H),0.45-0.41(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ9.21(s,1H),7.93(s,1H),7.48-7.45(m,1H),7.32(dd,1H),6.97-6.93(m,1H) ,6.39(dd,1H),6.17(dd,1H),5.68(dd,1H),4.27(s,2H),4.08(s,2H),3.88-3.40(m,6H),2.51-2.40(m , 6H), 2.09-1.21 (m, 4H), 1.68-1.64 (m, 4H), 0.67-0.63 (m, 2H), 0.45-0.41 (m, 2H).
LC-MS m/z(ESI)＝624.30[M+1]。LC-MS m/z (ESI) = 624.30 [M+1].
IC 50：是指KRAS的活性受到50％抑制时化合物的浓度。 IC50 : refers to the concentration of the compound at which the activity of KRAS is inhibited by 50%.
DMEM：Dulbecco's modified eagle培养基；DMEM: Dulbecco's modified eagle medium;
FBS：胎牛血清；FBS: fetal bovine serum;
NBT：硝基四氮唑蓝。NBT: Nitrotetrazolium blue.
实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为20℃-30℃。There is no special description in the examples, the reaction temperature is room temperature, and the most suitable reaction temperature at room temperature is 20°C-30°C.
生物学试验biological test
软琼脂凝胶克隆形成试验Soft agar gel colony formation assay
(1)底层高浓度琼脂糖凝胶层：将高浓度琼脂糖凝胶铺板于96孔板中(50μL/孔)。(1) Bottom layer of high-concentration agarose gel: Plate the high-concentration agarose gel in a 96-well plate (50 μL/well).
(2)上层低浓度琼脂糖凝胶层：将低浓度的琼脂糖和含细胞的培养基按1:1混合后铺于底层琼脂糖凝胶层上(100μL/孔；所用细胞为NCI-H358和MiaPaca细胞，细胞量为10000细胞/孔)；冷却凝固后置于37℃培养过夜。(2) Upper low-concentration agarose gel layer: Mix low-concentration agarose and cell-containing medium at 1:1 and spread on the bottom agarose gel layer (100 μL/well; the cells used are NCI-H358 and MiaPaca cells, the cell amount was 10,000 cells/well); after cooling and solidification, it was placed at 37°C and cultured overnight.
(3)将受试化合物配制成10mM母液，用生长培养基进行倍比稀释(1:5)，稀释8-10个浓度梯度(起始浓度10μM)，加入含有上层琼脂凝胶-细胞的96孔中(50μL/孔)；设置溶剂对照孔；每个浓度2个重复，置于二氧化碳培养箱培养10-14天。(3) The test compound was prepared into a 10 mM stock solution, doubling dilution (1:5) with growth medium, diluted 8-10 concentration gradients (initial concentration 10 μM), and added with 96 containing the upper layer of agarose-cells well (50 μL/well); set solvent control wells; each concentration was replicated twice, placed in a carbon dioxide incubator for 10-14 days.
(4)第7天更换一次含待选化合物的培养基，观察细胞克隆生长情况。(4) On the 7th day, the medium containing the compound to be selected was replaced, and the growth of cell clones was observed.
(5)培养结束后，用NBT对细胞进行染色，计算克隆形成数量，GraphPad Prism 8软件拟合IC 50值。 (5) After the culture, the cells were stained with NBT, the number of clones was calculated, and the IC 50 value was fitted by GraphPad Prism 8 software.
化合物compound H358细胞IC 50(μM) H358 cells IC50 (μM)
化合物1-1Compound 1-1 0.00780.0078
化合物3-1Compound 3-1 0.08940.0894
化合物5Compound 5 <0.4<0.4
结果表明，本发明化合物对KRAS突变肿瘤细胞具有良好的抑制效果。The results show that the compounds of the present invention have a good inhibitory effect on KRAS mutant tumor cells.
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。The specification of the present invention describes the specific embodiments in detail. Those skilled in the art should realize that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention Under the premise, by carrying out several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (18)

  1. 通式(I)的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐：A compound of general formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a solvent thereof Compounds, metabolites, co-crystals, prodrugs or pharmaceutically acceptable salts:
    Figure PCTCN2022072530-appb-100001
    Figure PCTCN2022072530-appb-100001
    其中in
    R 1为H、卤素或C 3-8环烷基； R 1 is H, halogen or C 3-8 cycloalkyl;
    X为N或CR 3； X is N or CR 3 ;
    R 2、R 3各自独立地为H或卤素； R 2 and R 3 are each independently H or halogen;
    C环为
    Figure PCTCN2022072530-appb-100002
    C ring is
    Figure PCTCN2022072530-appb-100002
    Y为N或CR 4； Y is N or CR 4 ;
    R 4、R 5各自独立地为H、羟基、卤素、氨基、三氟甲基或C 1-6烷基； R 4 and R 5 are each independently H, hydroxy, halogen, amino, trifluoromethyl or C 1-6 alkyl;
    或者R 4与R 5与其相连的碳原子一起形成4元或5元的环烷基或杂环烷基，所述4元或5元杂环烷基包含1或2个选自N和O的杂原子，所述4元或5元的环烷基或杂环烷基任选地被1或2个C 1-6烷基取代； Or R4 and R5 together with the carbon atom to which they are attached form a 4- or 5 -membered cycloalkyl or heterocycloalkyl containing 1 or 2 selected from N and O A heteroatom, the 4- or 5-membered cycloalkyl or heterocycloalkyl is optionally substituted with 1 or 2 C 1-6 alkyl groups;
    m为1、2、3或4；m is 1, 2, 3 or 4;
    R 6、R 7各自独立地为C 1-6烷基或卤素； R 6 and R 7 are each independently C 1-6 alkyl or halogen;
    L为O或N原子；L is O or N atom;
    R 8为C 3-8环烷基或C 3-8杂环烷基，所述C 3-8杂环烷基包含1至4个选自N和O的杂原子，R 8任选地被1或2个C 1-6烷基取代； R 8 is C 3-8 cycloalkyl or C 3-8 heterocycloalkyl containing 1 to 4 heteroatoms selected from N and O, R 8 is optionally 1 or 2 C 1-6 alkyl substitutions;
    n为0或1。n is 0 or 1.
  2. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof Solvates, metabolites, co-crystals, prodrugs or pharmaceutically acceptable salts, wherein
    R 1选自H、卤素或环丙基； R 1 is selected from H, halogen or cyclopropyl;
    X选自N或CR 3； X is selected from N or CR 3 ;
    R 2、R 3各自独立地为H或卤素； R 2 and R 3 are each independently H or halogen;
    C环为
    Figure PCTCN2022072530-appb-100003
    C ring is
    Figure PCTCN2022072530-appb-100003
    L选自O或N原子；L is selected from O or N atoms;
    R 8选自C 3-8杂环烷基，所述C 3-8杂环烷基包含1至4个选自N或O的杂原子，R 8任选地被1或2个C 1-6烷基取代； R 8 is selected from C 3-8 heterocycloalkyl containing 1 to 4 heteroatoms selected from N or O, R 8 is optionally surrounded by 1 or 2 C 1- 6 alkyl substitution;
    n为0或1。n is 0 or 1.
  3. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中所述卤素为F。The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt wherein the halogen is F.
  4. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中所述C 1-6烷基为甲基。 The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein said C1-6 alkyl is methyl.
  5. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中R 1为H。 The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co - crystal, prodrug or pharmaceutically acceptable salt, wherein R1 is H.
  6. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中R 2为卤素。 The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co - crystal, prodrug or pharmaceutically acceptable salt, wherein R2 is halogen.
  7. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中R 3为卤素。 The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein R3 is halogen.
  8. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中R 4为卤素或C 1-6烷基，R 5为羟基。 The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein R 4 is halogen or C 1-6 alkyl, and R 5 is hydroxy.
  9. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中R 4与R 5与其相连的碳原子一起形成4元或5元杂环烷基，所述4元或5元杂环烷基包含2个N杂原子，所述4元或5元杂环烷基任选地被1个C 1-6烷基取代。 The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein R 4 and R 5 together form a 4- or 5-membered heterocycloalkyl with the carbon atom to which it is attached, the 4- or 5-membered heterocycloalkyl Cycloalkyl contains 2 N heteroatoms, the 4- or 5-membered heterocycloalkyl is optionally substituted with 1 C1-6 alkyl.
  10. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中m为2。The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein m is 2.
  11. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋 体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中L为O。The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein L is O.
  12. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中R 8为C 5-6杂环烷基，所述C 5-6杂环烷基包含1或2个选自N和O的杂原子，R 8任选地被1个C 1-6烷基取代。 The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein R 8 is a C 5-6 heterocycloalkyl containing 1 or 2 selected from N and a heteroatom of O, R8 is optionally substituted with 1 C1-6 alkyl.
  13. 如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中n为1。The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein n is 1.
  14. 化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，所述化合物为：Compounds or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co- crystals, prodrugs or pharmaceutically acceptable salts, the compounds are:
    Figure PCTCN2022072530-appb-100004
    Figure PCTCN2022072530-appb-100005
    Figure PCTCN2022072530-appb-100004
    Figure PCTCN2022072530-appb-100005
  15. 药物组合物，其包含：A pharmaceutical composition comprising:
    (1)权利要求1-14中任一项所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐；(1) The compound of any one of claims 1 to 14, or a stereoisomer, tautomer, meso, racemate, enantiomer, or diastereomer thereof body, or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof;
    (2)任选的一种或者多种其他活性成分；以及(2) optionally one or more other active ingredients; and
    (3)药学上可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.
  16. 权利要求1-14中任一项所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者权利要求15所述的组合物在制备用于治疗或预防癌症或肿瘤的药物中的用途；优选地，所述癌症为胰腺癌、结直肠癌、肺癌、胆管癌、***、膀胱癌、肝癌或乳腺癌。The compound of any one of claims 1-14, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or the use of the composition of claim 15 in the manufacture of a medicament for the treatment or prevention of cancer or tumor; preferably Typically, the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer or breast cancer.
  17. 权利要求1-14中任一项所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者权利要求15所述的组合物在制备KRAS G12C抑制剂中的用途。The compound of any one of claims 1-14, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of the composition of claim 15 in the preparation of a KRAS G12C inhibitor.
  18. 权利要求1-14中任一项所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者权利要求15所述的组合物在制备用于治疗或预防与KRAS G12C相关的疾病中的用途。The compound of any one of claims 1-14, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of the composition of claim 15 in the manufacture of a composition for the treatment or prophylaxis of a disease associated with KRAS G12C.
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