WO2020177629A1 - Spiro-substituted pyrimidine-fused cyclic compound, preparation method therefor and medical use thereof - Google Patents

Spiro-substituted pyrimidine-fused cyclic compound, preparation method therefor and medical use thereof Download PDF

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Publication number
WO2020177629A1
WO2020177629A1 PCT/CN2020/077192 CN2020077192W WO2020177629A1 WO 2020177629 A1 WO2020177629 A1 WO 2020177629A1 CN 2020077192 W CN2020077192 W CN 2020077192W WO 2020177629 A1 WO2020177629 A1 WO 2020177629A1
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substituted
group
unsubstituted
membered
alkyl
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PCT/CN2020/077192
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French (fr)
Chinese (zh)
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周福生
赵金柱
彭灵
何宛
姜碧波
张磊涛
蔡礼健
杨华彬
胡刚
蓝小玲
郑彪
吕强
兰炯
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劲方医药科技(上海)有限公司
浙江劲方药业有限公司
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Publication of WO2020177629A1 publication Critical patent/WO2020177629A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to the technical field of medicine, in particular to a spirocyclic substituted pyrimidocyclic compound, its application as a selective inhibitor of KRAS gene mutation, and a pharmaceutical composition prepared therefrom.
  • Lung cancer is the cancer with the highest incidence in the world. It ranks first among all cancers in China. It is also the cancer with the highest incidence and mortality in China. According to data released by the American Cancer Society in 2016, about 1.8 million people suffer from lung cancer, of which nearly 80% are non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • RAS is a group of closely related monomeric globular proteins (21 kDa molecular weight), which have 188-189 amino acids and bind to guanosine diphosphate GDP or guanosine triphosphate GTP.
  • Members of the RAS subfamily include HRAS, KRAS, and NRAS.
  • RAS acts as a molecular switch. When RAS contains bound GDP, it is in a dormant or closed position and is "inactive". When cells are exposed to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. When it binds to GTP, RAS is “on” and can interact with other downstream target proteins and activate These proteins.
  • the RAS protein itself has a very low inherent ability to hydrolyze GTP and restore it to GDP (thus turning itself into a closed state).
  • the exogenous protein GTPase Activated Protein (GAP) is required to restore it to the closed state.
  • GAP GTPase Activated Protein
  • RAS radioactive protein
  • a mutation in any of the three main subtypes of the RAS (HRAS, NRAS or KRAS) gene can lead to human tumors. It has been reported that the KRAS gene has the highest mutation frequency among the RAS genes, and KRAS mutations are detected in 25-30% of tumors. In comparison, the rates of oncogenic mutations in NRAS and HRAS family members are much lower (8% and 3%, respectively).
  • the most common KRAS mutations are found in residues G12 and G13 and residue Q61 in the P loop.
  • the G12C mutation is a frequent mutation of the KRAS gene (mutation of glycine-12 to cysteine). This mutation has been found in about 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-related polyposis (familial colon cancer syndrome).
  • the present invention provides a spirocyclic substituted pyrimidocyclic compound, which, as a selective inhibitor of KRAS mutation, has the advantages of high activity, good selectivity, and low toxicity and side effects.
  • the present invention provides a spirocyclic substituted pyrimidocyclic compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof:
  • n 1;
  • B is a substituted or unsubstituted C 6-14 aryl group, or a substituted or unsubstituted C 5-14 heteroaryl group;
  • Z is N or CR 3 ;
  • R 1 and R 3 are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, substituted or unsubstituted C 2-8 alkenyl, A substituted or unsubstituted C 2-8 alkynyl group, or a substituted or unsubstituted C 3-20 cycloalkyl group;
  • L is a bond, CR 11 R 12 , O-(CR 11 R 12 ) t1 or NH-(CR 13 R 14 ) t2 ;
  • R 2 is halogen, hydroxyl, -SO 2 C 1-6 alkyl, substituted or unsubstituted C 3-20 heterocyclyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl group, or NR 21 R 22 ;
  • R 11 , R 12 , R 13 , and R 14 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or oxo;
  • R 21 and R 22 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)halo C 1-6 alkyl; or R 21 and R 22 and the connected nitrogen atom together form a substituted or unsubstituted C 3-20 heterocyclic group;
  • t1 and t2 are each independently 0, 1, 2, 3 or 4;
  • substituted means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the following S group: hydroxyl, halogen, nitro, oxygen Substitute, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl, -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -( CH 2 ) u -halo C 1-6 alkoxy, -(CH 2 ) u -halo C 1-6 alkyl, -(CH 2 ) u -C 3-6 monocyclic heterocyclic group, -( CH 2 ) u -5 or 6-membered monoheteroaryl, -(CH 2 ) u -C 3-8 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 Monocyclic cycloalkyl, -(CH 2 )
  • R 1 is hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 2- 4 Alkenyl, substituted or unsubstituted C 2-4 alkynyl, or substituted or unsubstituted C 3-6 cycloalkyl.
  • R 1 is hydrogen, halogen, or substituted or unsubstituted vinyl.
  • R 1 is chlorine or fluorine.
  • Z is N.
  • Z is CR 3 .
  • R 3 is hydrogen or halo.
  • R 3 is hydrogen or fluoro.
  • L is a bond
  • R 2 is NR 21 R 22 ; wherein R 21 and R 22 and the connected nitrogen atom together form a substituted or unsubstituted 3- to 6-membered saturated or partially unsaturated Monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11 membered spiro heterocyclic group; the "substituted” refers to a group 1, 2, 3, or 4 hydrogen atoms are each independently selected from the S group substituent.
  • L is CR 11 R 12 , O-(CR 11 R 12 ) t1 or NH-(CR 13 R 14 ) t2 ;
  • R 2 is halogen, hydroxyl, -SO 2 C 1- 6 alkyl, substituted or unsubstituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 To 11-membered spiro heterocyclyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl, or NR 21 R 22 ; wherein R 11 , R 12 , R 13 , R 14 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or ox
  • the present invention provides a spirocyclic substituted pyrimidocyclic compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof:
  • A is a substituted or unsubstituted C 6-14 aryl group, or a substituted or unsubstituted C 5-14 heteroaryl group;
  • W, R a is selected from the group consisting of a combination of:
  • W is N;
  • R a is hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, substituted or unsubstituted C 2-8 alkenyl group , Substituted or unsubstituted C 2-8 alkynyl, or substituted or unsubstituted C 3-20 cycloalkyl;
  • W is CR c ;
  • R a and R c are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, or substituted or unsubstituted C 3-20 cycloalkyl;
  • Q is a bond, CR a1 R b1 , O-(CR a1 R b1 ) q1 or NH-(CR c1 R d1 ) q2 ;
  • R b is halogen, hydroxy, -SO 2 C 1-6 alkyl, substituted or unsubstituted C 3-20 heterocyclyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl group, or NR a2 R b2 ;
  • R a1 , R b1 , R c1 , and R d1 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or oxo;
  • R a2 and R b2 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)halo C 1-6 alkyl; or Ra2 and R b2 together with the connected nitrogen atom to form a substituted or unsubstituted C 3-20 heterocyclic group;
  • q1 and q2 are each independently 0, 1, 2, 3 or 4;
  • substituted means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the following S group: hydroxyl, halogen, nitro, oxygen Substitute, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl, -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -( CH 2 ) u -halo C 1-6 alkoxy, -(CH 2 ) u -halo C 1-6 alkyl, -(CH 2 ) u -C 3-6 monocyclic heterocyclic group, -( CH 2 ) u -5 or 6-membered monoheteroaryl, -(CH 2 ) u -C 3-8 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 Monocyclic cycloalkyl, -(CH 2 )
  • R a is hydrogen or halogen.
  • R a is chloro or fluoro.
  • W is N.
  • W is CR c .
  • Rc is hydrogen or halogen
  • R c is hydrogen or fluorine.
  • Q is a bond
  • R b is NR a2 R b2 ; wherein R a2 and R b2 together with the connected nitrogen atom form a substituted or unsubstituted 3- to 6-membered saturated or partially unsaturated Monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11 membered spiro heterocyclic group; the "substituted” refers to a group 1, 2, 3, or 4 hydrogen atoms are each independently selected from the S group substituent.
  • Q is CR a1 R b1 , O-(CR a1 R b1 ) q1 or NH-(CR c1 R d1 ) q2 ;
  • R b is halogen, hydroxyl, -SO 2 C 1- 6 alkyl, substituted or unsubstituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 To 11-membered spiro heterocyclyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl, or NR a2 R b2 ; wherein R a1 , R b1 , R c1 , R d1 are the same or different, and are each independently hydrogen, halogen
  • the S group substituent is selected from the group consisting of: hydroxyl, halogen, nitro, oxo, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl, -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-3 alkoxy, -(CH 2 ) u -halo C 1-3 alkoxy, -(CH 2 ) u -halo Substitute C 1-3 alkyl, -(CH 2 ) u -C 3-6 monocyclic heterocyclic group, -(CH 2 ) u -5 or 6-membered monoheteroaryl group, -(CH 2 ) u -C 3 -6 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-6 monocyclic cycloalkyl, -(CH 2 ) u -O
  • the C 3-6 monocyclic heterocyclic group in the S group substituent is selected from: aziridine, ethylene oxide, azetidine, azetidine -2-one, oxetane, oxetan-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane , Dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2- Ketone, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine Azin-2-one,
  • the C 3-6 monocyclic cycloalkyl in the S group substituent is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, Cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1 ,3-Diketone.
  • the 5- or 6-membered monoheteroaryl group in the S group substituent is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole , 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1, 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyridine Azine.
  • the C 6-14 aryl group in B or A is a phenyl group, a naphthyl group, or a 9- or 10-membered aromatic condensate formed by condensing a phenyl group with a non-aromatic ring Bicyclic
  • said non-aromatic ring is 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, or 3 to 6 membered saturated or partially unsaturated monocyclic cycloalkyl, wherein said 3 to 6 membered saturated or Partially unsaturated monocyclic heterocyclic group is selected from: aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2- Ketone, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, di
  • the C 6-14 aryl group described in B or A is phenyl or naphthyl.
  • the C 5-14 heteroaryl group in B or A is a 5- or 6-membered monoheteroaryl group, wherein the 5- or 6-membered monoheteroaryl group is selected from: thiophene , Furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1, 3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1, 3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine; the 5- or 6-membered monoheteroaryl group is unsubstituted or is independently selected by 1, 2, 3 or 4
  • the C 5-14 heteroaryl group described in B or A is a 9- or 10-membered di-heteroaryl group formed by fusing a phenyl group with a 5- or 6-membered monoheteroaryl group, wherein The 5- or 6-membered monoheteroaryl group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4 -Triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxa Diazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine
  • the 9- or 10-membered bisheteroaryl group has a structure represented by formula (A) or formula (B):
  • ring C is a 5- or 6-membered monoheteroaryl group; wherein the 5- or 6-membered monoheteroaryl group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole , 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1, 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyridine
  • the 9- or 10-membered bisheteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the S group.
  • the C ring is selected from the following structures: among them Represents a pair of adjacent carbon atoms shared when fused with a phenyl group.
  • the 9- or 10-membered bis-heteroaryl group formed by the fusion of the phenyl group and the 5- or 6-membered monoheteroaryl group is selected from: benzoxazole, benzisoxazole, Benzimidazole, benzothiazole, benzoisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline , Suoline.
  • the 9- or 10-membered bis-heteroaryl group formed by the fusion of the phenyl group and the 5- or 6-membered monoheteroaryl group is selected from: benzo[d]isoxazole, 1H- Indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzene And [d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline.
  • the C 5-14 heteroaryl group described in B or A is an 8- to 10-membered group formed by condensing a 5 or 6-membered monoheteroaryl group with a 5 or 6-membered monoheteroaryl group.
  • Bi-heteroaryl wherein the 5- or 6-membered mono-heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole , 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1 , 2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine; the 8- to 10-membered double
  • the heteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
  • the 8- to 10-membered bis-heteroaryl group has a structure represented by formula (C) or formula (D):
  • ring D and ring E are 5- or 6-membered monoheteroaryl groups; wherein the 5- or 6-membered monoheteroaryl groups are selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole , Triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole , 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, Pyrimidine or pyrazine; the 8- to 10-membered biheteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from the S group.
  • D ring and E ring are selected from the following structures:
  • the 5- or 6-membered monoheteroaryl group is fused with a 5- or 6-membered monoheteroaryl group to form an 8- to 10-membered diheteroaryl group selected from: pyridopyrimidine, naphthalene Pyridine.
  • the 5- or 6-membered monoheteroaryl group is fused with a 5- or 6-membered monoheteroaryl group to form an 8- to 10-membered diheteroaryl group selected from: pyrido[3, 2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7- Naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine.
  • the 9- or 10-membered bisheteroaryl group is selected from the following structures:
  • the aforementioned 9- or 10-membered biheteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
  • the 8 to 10 diheteroaryl groups are selected from the following structures:
  • the above-mentioned 8- to 10-membered biheteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
  • the C 5-14 heteroaryl group described in B or A is an 8- to 10-membered bi-heteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl group with a non-aromatic ring
  • the non-aromatic ring is a 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, or a 3 to 6 membered saturated or partially unsaturated monocyclic cycloalkyl group, wherein the 5 or 6 membered monocyclic heterocyclic group
  • the group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5- Triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazol
  • -LR 2 in formula (I) and -QR b in formula (II) are independently selected from:
  • B and A are independently selected from the following structures:
  • Z 1e is NR 1e , O or S;
  • Z 1f is N or CR 1f ;
  • Z 1g is N or CR 1g ;
  • Z 1h is N or CR 1h ;
  • Z 1i is N or CR 1i ;
  • Z 2e is N or CR 2e ;
  • Z 2f is N or CR 2f ;
  • Z 2h is N or CR 2h ;
  • Z 2i is N or CR 2i ;
  • R 1e , R 1f , R 1g , R 1h , R 1i , R 1j , R 2e , R 2f , R 2g , R 2h , R 2i , and R 2j are each independently hydrogen, halogen, C 1-3 alkyl, -CONH 2 , -CONHC 1-3 alkyl, -CON (C 1-3 alkyl) 2 , cyanide Group, nitro, cyclopropyl, cyclobuty
  • B and A are independently selected from:
  • the C 3-20 heterocyclic group in R 2 or R b is a 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, a 6 to 10 membered saturated or partially unsaturated heterocyclic group Saturated condensed heterocyclic group, 7 to 11 membered spiro heterocyclic group, or 7 to 10 membered bridged heterocyclic group.
  • R 1, R 2, R 3, R a, R b, R c in a C 3-20 cycloalkyl said 3 to 8 membered monocyclic cycloalkyl or 6 To 10-membered bicyclic cycloalkyl.
  • the C 3-20 cycloalkyl group in R 2 or R b is a 3- to 8-membered monocyclic cycloalkyl group selected from: cyclopropyl, cyclobutyl, cyclopentan Group, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclobutanone, cyclobutane-1,2-dione, Cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione; the above 3- to 8-membered monocyclic cycloalkyl is unsubstituted or is 1, 2, 3 or 4 substituents each independently selected from group S are substituted.
  • the C 3-20 heterocyclic group formed by R 21 and R 22 and the connected nitrogen atom is a 3 to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group, 6 to 10-membered saturated or partially unsaturated nitrogen-containing fused heterocyclic group, or 7 to 11-membered nitrogen-containing spiro heterocyclic group.
  • the C 3-20 heterocyclic group formed by R a2 and R b2 and the connected nitrogen atom is a 3 to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group, 6 to 10-membered saturated or partially unsaturated nitrogen-containing fused heterocyclic group, or 7 to 11-membered nitrogen-containing spiro heterocyclic group.
  • the 3 to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group formed by R 21 and R 22 and the connected nitrogen atom, or R a2 and R b2 are connected with
  • the 3- to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group formed by the nitrogen atoms of is independently selected from the following structures:
  • the above-mentioned 3- to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
  • the present invention provides a spirocyclic substituted pyrimidocyclic compound represented by formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof:
  • Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5 or 6-membered monoheteroaryl group;
  • R a is C 2-4 alkenyl group; R c is a substituted or unsubstituted C 1-6 alkoxy; Q a is a bond or -O- (CH 2) s -; s is 0, 1 or 2; R b is a substituted or unsubstituted 3- to 6-membered monocyclic heterocyclic group or NR a0 R b0 ; R a0 and R b0 are each independently hydrogen or C 1-3 alkyl; the "substituted” refers to a group One, two, three, or four hydrogen atoms in the group are each independently substituted by substituents selected from the following: hydroxyl, halogen, amino, C 1-3 alkyl, C 1-3 alkoxy, NHCH 3 , N(CH 3 ) 2 .
  • R a is a vinyl or prop-1-en-1-yl.
  • R c is C 1-3 alkoxy, which C 1-3 alkoxy is optionally substituted with 1, 2 or 3 halogens.
  • R c is methoxy, ethoxy, trifluoroethoxy or difluoromethoxy.
  • R b is a 3- to 6-membered monocyclic heterocyclic group; the 3- to 6-membered monocyclic heterocyclic group is azetidine, tetrahydropyrrole, piperidine, piperazine Or morpholine; the 3- to 6-membered monocyclic heterocyclic group is optionally selected by 1, 2 or 3 independently selected from C 1-3 alkyl, C 1-3 alkoxy, NHCH 3 , N (CH 3 ) The substituent of 2 is substituted.
  • R b is N-methylpiperidine or N-methyltetrahydropyrrole.
  • Ar is phenyl, pyridyl or pyrazolyl; said phenyl, pyridyl and pyrazolyl are optionally selected from 1, 2, 3 or 4 each independently: Hydroxy, halogen, amino, C 1-3 alkyl, NHCH 3 , N(CH 3 ) 2 substituents are substituted.
  • Ar is selected from:
  • -Q a -R b is selected from:
  • the compound of formula (I) or formula (II) or formula (III) is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the present invention provides a pharmaceutical composition, which contains the aforementioned compound, a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable carrier” refers to any preparation or carrier medium representative that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or subject
  • sexual carriers include water, oil, vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine.
  • the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, and intramuscular , Intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or medication with the aid of an explanted reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present invention can be prepared into any orally acceptable formulations, including but not limited to tablets, capsules, aqueous solutions or suspensions. Carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added.
  • the diluents used in capsule formulations generally include lactose and dried corn starch.
  • Aqueous suspension formulations usually mix the active ingredients with suitable emulsifiers and suspending agents. If necessary, some sweeteners, fragrances or coloring agents can be added to the above oral preparations.
  • topical medication especially for the treatment of affected surfaces or organs that are easily reached by topical application, such as eye, skin or lower intestinal neurological diseases
  • the compound of the present invention can be prepared into different topical pharmaceutical preparations according to different affected surfaces or organs
  • the compound of the present invention can be formulated into a micronized suspension or solution.
  • the carrier used is isotonic sterile saline with a certain pH, which may or may not be added with preservatives such as Benzyl alkanolate chloride.
  • the compound can also be made into an ointment form such as petroleum jelly.
  • the compound of the present invention can be prepared into an appropriate ointment, lotion or cream formulation in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of sterile injection preparations, including sterile injection water or oil suspensions or sterile injection solutions.
  • Usable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution.
  • sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.
  • the present invention provides the above-mentioned spirocyclic substituted pyrimidocyclic compounds, pharmaceutically acceptable salts, stereoisomers, solvent compounds or prodrugs thereof in the preparation of drugs for the treatment and/or prevention of cancer the use of.
  • the present invention provides a method of treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of the aforementioned compound, its pharmaceutically acceptable salt, stereoisomer, or solvate Or a prodrug, or any combination of the above, or the step of administering the above-mentioned pharmaceutical composition.
  • the cancer is pancreatic ductal carcinoma, colorectal cancer, multiple myeloma, lung cancer, skin melanoma, endometrium-like carcinoma, uterine carcinosarcoma, thyroid cancer, acute myelogenous Leukemia, bladder urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung cancer, renal papillary Cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver cancer, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenal cortical carcinoma, prostate cancer, neuroblastoma, brain low-grade glial Tumor, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma,
  • the cancer is lung cancer, preferably non-small cell lung cancer.
  • the term "subject” refers to animals, especially mammals, preferably humans.
  • the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the amount of a given drug depends on many factors, such as the specific dosing regimen, the type of disease or condition and its severity, and the subject in need of treatment Or the uniqueness of the host (such as body weight), but, depending on the specific surrounding conditions, including, for example, the specific drug that has been used, the route of administration, the condition to be treated, and the subject or host to be treated, the dosage may be known in the art
  • the method is routinely decided.
  • the administered dose is typically in the range of 0.02-5000 mg/day, for example, about 1-1500 mg/day.
  • the required dose can conveniently be expressed as one dose, or simultaneous (or within a short period of time) or divided doses at appropriate intervals, such as two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the doctor's diagnosis.
  • the present invention provides the use of the above spirocyclic substituted pyrimidocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof in the preparation of KRAS mutation inhibitors, (Preferably, the KRAS mutation is KRAS G12C mutation).
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound.
  • Such salts include: acid addition salts formed with inorganic acids or organic acids, the inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; the organic acids such as acetic acid, propionic acid, Caproic acid, cyclopentapropionic acid, glycolic acid, pyruvic acid, trifluoroacetic acid, formic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid , Mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid,
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • solvent compound refers to a substance formed by combining the compound of the present invention with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include water, ethanol, acetic acid and the like.
  • the solvent compound includes a stoichiometric amount of solvent compound and a non-stoichiometric amount of solvent compound, and is preferably a hydrate.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • stereoisomer includes conformational isomers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, and any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above.
  • the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis isomer and trans isomer, and any combination thereof.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms.
  • C 1-10 alkyl refers to a straight or branched chain alkyl having 1 to 10 carbon atoms, more preferably a straight or branched chain having 1, 2, 3, 4, 5 or 6 carbon atoms Alkyl, ie, C 1-6 alkyl, more preferably C 1-4 alkyl, most preferably C 1-3 alkyl.
  • Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various Branched chain isomers and so on.
  • alkoxy refers to a group having the structure -O-alkyl, where the definition of alkyl is as described above.
  • C 1-10 alkoxy refers to an alkoxy group having 1 to 10 carbon atoms, preferably a C 1-6 alkoxy group, more preferably a C 1-4 alkoxy group, and more preferably a C 1- alkoxy. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy and the like.
  • alkenyl refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position in the chain
  • C 2-8 alkenyl refers to an alkyl group having 2 to
  • the alkenyl group having 8 carbon atoms and at least one carbon-carbon double bond is preferably an alkenyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds, that is, a C 2-6 alkenyl group. More preferred is an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds, that is, a C 2-4 alkenyl group.
  • Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, butadienyl and the like.
  • alkynyl refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any point in the chain
  • C 2-8 alkynyl refers to having 2 to
  • the alkynyl group having 8 carbon atoms and at least one carbon-carbon triple bond is preferably an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds, that is, a C 2-6 alkynyl group. More preferred is an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds, that is, a C 2-4 alkynyl group. Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • haloalkyl refers to an alkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above.
  • halogenated C 1-10 alkyl group refers to a halogenated alkyl group having 1 to 10 carbon atoms. It is preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-4 alkyl group, and more preferably a halogenated C 1-3 alkyl group.
  • Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • haloalkoxy refers to an alkoxy group substituted with one or more (eg, 1, 2, 3, 4, or 5) halogens, where the definition of alkoxy is as described above.
  • halogenated C 1-10 alkoxy group refers to a halogenated alkoxy group having 1 to 10 carbon atoms. It is preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-4 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
  • cycloalkyl and “cycloalkyl ring” are used interchangeably and refer to a saturated monocyclic or polycyclic fused cyclic hydrocarbon group.
  • C 3-20 cycloalkyl refers to a cycloalkyl group having 3 to 20 carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. Preferably, it is a C 3-12 cycloalkyl group.
  • the ring carbon atoms of the cycloalkyl group can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure.
  • C 3-8 monocyclic cycloalkyl and “C 3-8 cycloalkyl” refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 carbon atoms, preferably C 3-6 monocyclic cycloalkyl ( That is, C 3-6 cycloalkyl), more preferably C 3 , C 4 , C 5 or C 6 monocyclic cycloalkyl.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • spirocycloalkyl and “spirocycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by sharing one carbon atom (called a spiro atom) between two or more monocyclic rings. . According to the number of shared spiro atoms between rings, spirocycloalkyls are classified into single spirocycloalkyls, dispirocycloalkyls and polyspirocycloalkyls.
  • 5 to 20 membered spirocycloalkyl or "C 5-20 spirocycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, in which the monocyclic ring sharing spiro atoms is 3 to 8 members Monocyclic cycloalkyl ring.
  • fused cycloalkyl and “fused cycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing an adjacent pair of carbon atoms. According to the number of rings formed, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups.
  • the term “5 to 20 membered fused cycloalkyl” or “C 5-20 fused cycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the rings sharing adjacent pairs of carbon atoms are 3 to 8 Member monocyclic cycloalkyl ring.
  • it is 6 to 14 membered (C 6-14 ) fused cycloalkyl, more preferably 6 to 14 membered di-fused cycloalkyl, more preferably 7 to 10 membered (C 7-10 ) fused cycloalkyl, more preferably It is a 7 to 10 membered bi-fused cycloalkyl group.
  • fused cycloalkyl include but are not limited to:
  • the terms "5 to 20 membered bridged cycloalkyl” and “5 to 20 membered bridged cycloalkyl ring” refer to a polycyclic ring having 5 to 20 ring carbon atoms (C 5-20 ) Hydrocarbyl, in which any two rings share two carbon atoms that are not directly connected. It is preferably a 6 to 14-membered bridged cycloalkyl group, and more preferably a 7 to 10-membered bridged cycloalkyl group.
  • bridged cycloalkyl preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls.
  • bridged cycloalkyl include but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc.
  • the above-mentioned various types of cycloalkyl groups may be optionally substituted.
  • the substituents are preferably one or more substituent groups described in this application.
  • heterocyclyl and “heterocyclyl ring” are used interchangeably and refer to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group.
  • C 3-20 hetero “Cyclic group” or “3 to 20 membered heterocyclic group” refers to a saturated or partially unsaturated monocyclic or polycyclic condensed cyclic hydrocarbon group having 3 to 20 ring atoms, of which one or more (preferably 1, 2 , 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0 to 2), but do not include the ring part of -OO-, -OS- or -SS- , The remaining ring atoms are carbon.
  • the ring atom is a nitrogen atom, it may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • the ring carbon atoms of the heterocyclic group can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • the 3- to 20-membered heterocyclic group in the present invention includes monocyclic heterocyclic group, spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.
  • C 3-8 monocyclic heterocyclic group refers to having 3 to 8 Ring atoms, wherein 1, 2 or 3 ring atoms are saturated or partially unsaturated monocyclic cyclic hydrocarbon groups selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms.
  • It is preferably a 3- to 6-membered monocyclic heterocyclic group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms (ie C 3-6 monocyclic heterocyclic group or 3 to 6-membered saturated or partially non- Saturated monocyclic heterocyclic group). More preferably, it is a 5- or 6-membered monocyclic heterocyclic group having 5 or 6 ring atoms, 1 or 2 of which are heteroatoms.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents already defined herein).
  • the sulfur atom When the hetero atom is a sulfur atom, the sulfur atom may be optionally oxidized (ie S(O) m , m is an integer of 0 to 2).
  • the ring carbon atoms of the monocyclic heterocyclic group may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • monocyclic heterocyclic groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2 -Ketone, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3 -Dioxolane-2-one, oxazolidin-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholine-3-one
  • C 3-8 heterocycloalkyl and “3 to 8 membered heterocycloalkyl” refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 ring atoms, of which 1 or 2 ring atoms are heteroatoms. It is preferably a 3 to 6 membered heterocycloalkyl group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms.
  • heterocycloalkyl examples include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolane, Dioxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1- Dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazinyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1 ,4-Dioxanyl.
  • the two ring atoms connected to the above-mentioned monocyclic heterocyclyl ring, including CC and NC, can optionally be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclic ring, monoaryl ring, and 5 Or a 6-membered mono-heteroaryl ring such as cycloalkyl, heterocyclyl, aryl or heteroaryl fused to form a fused polycyclic ring, and 2 rings connected to a monocyclic heterocyclic group that forms a fused ring with other rings
  • the atom is preferably CC.
  • spiroheterocyclyl and “spiroheterocyclyl ring” refer to two or more saturated or partially unsaturated monocyclic rings that share one carbon atom (called a spiro atom).
  • Polycyclic cyclic hydrocarbon group where one or more (such as 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) p (where p is an integer from 0 to 2), and the remaining ring atoms Is carbon.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents already defined herein).
  • Each single ring can contain one or more double bonds, but no ring has a fully conjugated ⁇ electron system.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group.
  • the term "5 to 20 membered spiro heterocyclic group” refers to a spiro heterocyclic group having 5 to 20 ring atoms, wherein the monocyclic ring sharing the spiro atom is a 3 to 8 membered monocyclic heterocyclic ring.
  • It is preferably a 6 to 14-membered spiro heterocyclic group having 6 to 14 ring atoms, 1 or 2 of which are heteroatoms, and more preferably 7 to 11 ring atoms, of which 1 or 2 ring atoms are hetero Atomic 7 to 11 membered spiro heterocyclyl.
  • Specific examples of spiroheterocyclic groups include, but are not limited to:
  • fused heterocyclyl and “fused heterocyclyl ring” refer to a polycyclic ring formed by two or more saturated or partially unsaturated monocyclic rings sharing an adjacent pair of ring atoms A hydrocarbyl group in which one or more (such as 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) p (where p is an integer of 0 to 2), and the remaining ring atoms are carbon.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents already defined herein).
  • Each single ring can contain one or more double bonds, but no ring has a fully conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups.
  • the term "5 to 20 membered fused heterocyclic group” refers to a fused heterocyclic group having 5 to 20 ring atoms, wherein the rings sharing adjacent pairs of ring atoms are 3 to 8 membered monocyclic heterocyclyl rings, and the shared adjacent ring atoms It can be CC or NC.
  • a 6 to 10 membered fused heterocyclic group ie 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, more preferably 8 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms.
  • fused heterocyclic groups include but are not limited to:
  • the terms "5 to 20 membered heterocyclic ring” and “5 to 20 membered heterocyclic ring” refer to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms , Where any two rings share two atoms that are not directly connected, which can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system, one or more of the groups (such as 1, (2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon.
  • bridged heterocyclic group It is preferably a 6 to 14-membered bridged heterocyclic group, and more preferably a 7 to 10-membered bridged heterocyclic group. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Specific examples of bridged heterocyclic groups include, but are not limited to:
  • the above-mentioned various heterocyclic groups may be optionally substituted.
  • the substituents are preferably one or more of the substituent groups described in this application.
  • C 6-14 aryl As used herein, the terms "C 6-14 aryl”, “C 6-14 aryl ring” and “C 6-14 aryl ring” are used interchangeably and refer to all groups having 6 to 14 ring atoms. Carbon monocyclic, all-carbon polycyclic (ring and ring are connected by covalent bonds, non-fused) or all-carbon fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) group, at least one ring in the group is Aromatic, that is, it has a conjugated ⁇ -electron system. Preferably it is a C 6-10 aryl group.
  • C 6-14 aryl groups include monocyclic aryl groups, polycyclic aryl groups, and aromatic condensed polycyclic rings. Examples of monocyclic aryl groups include phenyl, and examples of polycyclic aryl groups include biphenyl and the like.
  • the aromatic fused polycyclic ring may be a polycyclic group formed by the fusion of a single aryl ring and one or more single aryl rings, Non-limiting examples thereof include naphthyl, anthracenyl and the like.
  • the aromatic fused polycyclic ring may also be a polycyclic group formed by the fusion of a single aryl ring (such as a phenyl group) with one or more non-aromatic rings, which is combined with the parent structure
  • the connected ring is aromatic or non-aromatic.
  • the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, and the ring carbon atoms of the monocyclic heterocyclic ring may be divided by 1 to 2 One oxo group is substituted to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the monocyclic cycloalkyl ring is The ring carbon atoms can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure).
  • the polycyclic group in which the above-mentioned single aryl ring is fused with one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or carbon atom, and the ring connected to the parent structure is a single aryl ring or non-aromatic ring.
  • a benzene ring is fused with a 5- or 6-membered monocyclic heterocyclic ring to form a 9- or 10-membered aromatic fused bicyclic ring, which means that two adjacent substituent groups on the phenyl group and the ring atoms to which they are connected form a Condensed 5- or 6-membered monocyclic heterocyclic ring, the 5- or 6-membered monocyclic heterocyclic ring is as defined above, and the formed 9- or 10-membered aromatic fused bicyclic ring can also be called 9 or 10-membered Phenyl heterocyclyl ring.
  • a benzene ring is fused with a 5- or 6-membered monocyclic cycloalkyl ring to form a 9- or 10-membered aromatic fused bicyclic ring, which means that two adjacent substituent groups on the phenyl group and the ring atoms to which they are connected form one Condensed 5- or 6-membered monocyclic cycloalkyl ring, the 5- or 6-membered monocyclic cycloalkyl ring is as defined above, and the formed 9- or 10-membered aromatic fused bicyclic ring can also be referred to as 9 or 10-membered Phenylcycloalkyl ring.
  • Non-limiting examples include:
  • the above-mentioned various aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the substituent groups described in this application.
  • heteroaryl As used herein, the terms “heteroaryl”, “heteroaryl ring” and “heteroaryl ring” are used interchangeably and refer to a single ring atom substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur.
  • the heteroaryl group has 6, 10 or 14 ⁇ electrons shared, and at least one ring in the group is aromatic.
  • C 5-14 heteroaryl and “5 to 14 membered heteroaryl” refer to heteroaryl groups having 5 to 14 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. It is preferably a 5- to 10-membered heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms.
  • the C 5-14 heteroaryl group may be a single heteroaryl group, a fused bicyclic heteroaryl group or a fused tricyclic heteroaryl group.
  • the term "5- or 6-membered monoheteroaryl group” refers to a monocyclic heteroaryl group having 5 or 6 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms.
  • Specific examples of single heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole , 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.
  • the term "8 to 10 membered diheteroaryl group” refers to a fused bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3, 4, or 5 ring atoms are heteroatoms .
  • the fused bicyclic heteroaryl group can be a bicyclic group (preferably 9) formed by the fusion of a single aryl ring (such as a phenyl) and a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring).
  • 10-membered bi-heteroaryl ring it can also be a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring) and a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring) A bicyclic group formed by fusion.
  • any two ring atoms connected to the above-mentioned single heteroaryl ring can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, single aryl ring, 5 or Cycloalkyl, heterocyclic, aryl or heteroaryl groups such as a 6-membered monoheteroaryl ring are fused to form a fused polycyclic ring.
  • the two ring atoms connected to the monoheteroaryl ring forming a fused ring with other rings are preferably CC, and include the following forms without limitation:
  • Non-limiting examples of 8- to 10-membered bisheteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, iso Quinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[ 4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-nap
  • the above-mentioned mono-heteroaryl group, or the double-heteroaryl group formed by the fusion of a benzene ring and a single heteroaryl ring, or the double-heteroaryl group formed by the fusion of a single heteroaryl ring and a single heteroaryl ring can pass through a nitrogen atom or carbon Atoms are connected to other groups or parent structures.
  • the ring connected to the parent structure is a mono-heteroaryl ring or a benzene ring. Specific examples thereof include but are not limited to:
  • the fused bicyclic heteroaryl group or fused tricyclic heteroaryl group may be a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring) and one or more A polycyclic group formed by the fusion of a non-aromatic ring, wherein the ring connected to the parent structure is a single heteroaryl ring or a non-aromatic ring.
  • the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, and the ring carbon atoms of the monocyclic heterocyclic ring may be divided by 1 to 2 One oxo group is substituted to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the monocyclic cycloalkyl ring is The ring carbon atoms can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure) and so on.
  • the polycyclic group formed by the condensation of the above-mentioned single heteroaryl ring with one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or carbon atom, and the ring connected to the parent structure is a single heteroaryl ring Or non-aromatic ring.
  • a 5- or 6-membered mono-heteroaryl ring is fused with a 5- or 6-membered monocyclic heterocyclic ring to form an 8- to 10-membered fused bicyclic heteroaryl group, which means that a 5- or 6-membered mono-heteroaryl group is Two adjacent substituent groups and the ring atoms to which they are connected form a fused 5- or 6-membered monocyclic heterocyclic ring.
  • the 5- or 6-membered monocyclic heterocyclic ring is defined as above, and the resulting 8 A to 10-membered fused bicyclic heteroaryl group can also be referred to as an 8- to 10-membered heteroaryl heterocyclyl ring.
  • a 5- or 6-membered mono-heteroaryl ring is fused with a 5- or 6-membered monocyclic cycloalkyl ring to form an 8- to 10-membered fused bicyclic heteroaryl group, which means that a 5- or 6-membered mono-heteroaryl group is Two adjacent substituent groups and the ring atoms to which they are connected form a fused 5- or 6-membered monocyclic cycloalkyl ring.
  • the 5- or 6-membered monocyclic cycloalkyl ring is as defined above, and the resulting 8 A to 10-membered fused bicyclic heteroaryl group can also be referred to as an 8- to 10-membered heteroaryl cycloalkyl ring.
  • Non-limiting examples include:
  • the above-mentioned various heteroaryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the substituent groups described in this application.
  • hydroxyl refers to -OH.
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CH(OH)CH 3 .
  • cyanomethyl refers to -CH 2 CN
  • cyanoethyl refers to -CH 2 CH 2 CN or -CHCNCH 3 .
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • benzyl as used herein means a -CH 2 used - benzene.
  • carboxylate group refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl).
  • acetyl refers to -COCH 3 .
  • substituted or “substituted” means that any one or more of the hydrogen atoms on a specific atom is replaced by a substituent, and may include deuterium and hydrogen variants, as long as the valence of the specific atom It is normal and the substituted compound is stable.
  • the oxo group substitution does not occur on the aromatic group.
  • optionally substituted or “optionally substituted” means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary based on chemically achievable.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • Step 2 2-Amino-3-fluoro-4-bromo-5-iodobenzoic acid (30.0g, 83.56mmol) and urea (50.1g, 835.6mmol) are heated to 200°C and stirred for 1 hour. The resulting solid is heated in hot water Grinding, filtering, and drying in an oven to obtain a brown solid as 7-bromo-8-fluoro-6-iodoquinazoline-2,4(1H,3H)-dione (60.0g).
  • ES-API: [M+H] + 385.1.
  • Step 3 7-bromo-8-fluoro-6-iodoquinazoline-2,4(1H,3H)-dione (60g, crude product, 156mmol) was added to phosphorus oxychloride (300mL), reaction solution 100 The reaction was stirred at °C for 16 hours, the phosphorus oxychloride was removed, and the residue was diluted with dichloromethane. The diluted solution was quenched with ice water below 10°C. The quenched reaction solution was adjusted to pH 6-7 with sodium bicarbonate. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the organic phase was removed in vacuo.
  • Step 1 2-Amino-3-fluoro-4-bromo-benzoic acid (10g, 42.7mmol) was dissolved in N,N-dimethylformamide (100mL), and N-chlorosuccinimide (6g, 44.9mmol) was added to the reaction solution, the reaction solution was reacted at 70°C for 18 hours; the reaction solution was cooled to room temperature, poured into ice brine (500mL), the precipitated solid was filtered with suction, washed with water (50mL), and dried to obtain The yellow solid is 2-amino-3-fluoro-4-bromo-5-chlorobenzoic acid (10.5 g, Y: 91.5%).
  • ES-API: [M+H] + 269.8.
  • Step 2 2-Amino-3-fluoro-4-bromo-5-chlorobenzoic acid (10.5g, 39.11mmol) and urea (23.5g, 392mmol) are heated to 200°C and react for 4 hours, and the solid obtained is rinsed in hot water 3 times, filtered and dried to obtain a brown solid as 7-bromo-8-fluoro-6-chloroquinazoline-2,4(1H,3H)-dione (11.4g, Y: 99.3%).
  • ES-API: [M+H] + 295.0.
  • Step 3 7-Bromo-8-fluoro-6-chloroquinazoline-2,4(1H,3H)-dione (11.4g, crude product, 38.8mmol) was added to phosphorus oxychloride (100mL), the reaction solution React at 100°C for 16 hours; the reaction solution is lowered to room temperature, the phosphorus oxychloride is removed under vacuum, the remainder is quenched with ice water at -10°C, the quenched reaction solution is adjusted to pH 6 with sodium bicarbonate and quenched The aqueous phase was extracted with dichloromethane (100mL x 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was vacuum desolventized, and column chromatography (petroleum ether/ethyl acetate: 1%) was used to obtain a yellow solid It is 7-bromo-2,4-dichloro-8-fluoro-6-chloroquinazoline (3.6g,
  • Step 1 2-Amino-3-fluoro-4-bromo-5-chlorobenzoic acid (14g, 52.1mmol) was dissolved in tetrahydrofuran (200mL), triphosgene (15.5g, 52.1mmol) was dissolved in tetrahydrofuran, 0°C After dropping, the reaction solution was heated to 50°C and reacted for 16 hours; the reaction solution was concentrated, the concentrate was diluted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate, brine, and water, and the organic phase was used Dry with anhydrous sodium sulfate and column chromatography (petroleum ether/ethyl acetate: 0-50%) to obtain a yellow solid as 6-chloro-7-bromo-8-fluoro-1H-benzo[d][1,3 ] Oxazine-2,4-dione (5g, Y: 32.6%).
  • ES-API: [M+H] + 29
  • Step 2 6-chloro-7-bromo-8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (5g, 0.691mmol), ethyl 2-cyanoacetate (2.3g, 20.1mmol) and triethylamine (3.43g, 34mmol) solution N,N-dimethylformamide (25mL), the reaction solution was stirred at 120°C for 16 hours, the reaction solution was cooled down, and the solvent was removed in vacuo.
  • Step 3 6-Chloro-7-bromo-8-fluoro-2,4-dihydroxyquinoline-3-carbonitrile (2g, 6.3mmol) is dissolved in acetonitrile (15mL), then phosphorus oxychloride (50mL) is added, The reaction solution was stirred and reacted at 90°C for 16 hours. The temperature of the reaction solution was lowered, the phosphorus oxychloride was removed in vacuum, the residue was poured into a mixed solvent of dichloromethane/triethylamine (300mL/30mL), the reaction solution was diluted with ethyl acetate, washed with water, the organic phase was dried and filtered, and the solvent was removed.
  • Step 1 Add 2-amino-4-bromo-5-chlorobenzoic acid (10.1g, 40.32mmol) and urea (24.2g, 403.2mmol) into a 250mL round-bottomed flask, and heat up to 200°C and stir for 2 hours. Cool down At 100° C., water (150 mL) was added to the reaction solution, stirred for 1 hour, filtered and dried to obtain 7-bromo-6-chloroquinazoline-2,4-diol (13 g, Y: crude product).
  • ES-API: [M+H] + 275.2/277.2.
  • Step 2 Add 6-chloro-7-bromoquinazoline-2,4-diol (13g, crude product, 40.32mmol) and phosphorus oxychloride (100mL) into a 250mL round bottom flask, and the reaction solution is heated to 105°C The reaction was stirred for 18 hours.
  • Step 2 Add 2-amino-5,6-dichloronicotinic acid (5.6g, 27mmol) and ultra-dry tetrahydrofuran (50mL) to a 100mL round bottom flask, add thionyl chloride (6.5mL) to it, and stir at room temperature After reacting for 20 hours, evaporate to dryness under vacuum, add tetrahydrofuran (20mL) twice to obtain a yellow solid product, add tetrahydrofuran (50mL) and ammonia water (24mL), stir at room temperature for 20 minutes, spin dry to obtain 2-amino-5, 6-Dichloronicotinamide (6.5g, Y: quantitative.).
  • ES-API: [M+H] + 205.9.
  • Example 1 1-(6-(6-Chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxy Synthesis of (phenyl)quinazolin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one
  • Step 1 Add 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300mg, 0.908mmol), 2,6-diazaspiro[3.3]heptane- to a 50mL round bottom flask Tert-butyl 2-carboxylate hemioxalate (243 mg, 0.999 mmol), 10 mL of tetrahydrofuran and DIPEA (353 mg, 2.731 mmol).
  • Step 2 Add 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.3]heptane into a 100mL round bottom flask Tert-Butyl 2-carboxylate (340mg, 0.691mmol), N,N-dimethylazacyclo-3-amine bishydrochloride (132mg, 0.763mmol), 20mL isopropanol and DIPEA (510mg, 3.946mmol) , The oil bath was heated to 105°C, stirred for 16 hours, cooled to room temperature, filtered, washed with isopropanol, and dried to obtain 6-(7-bromo-6-chloro-2-(3-(dimethylamino) Azetidine-1-yl)-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid ter
  • Step 3 Add 6-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazoline- to a 100mL round bottom flask 4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (250mg, 0.45mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (280mg, 1.796mmol) ), sodium carbonate (250mg, 2.359mmol), palladium tetrakistriphenylphosphorus (80mg, 0.069mmol), 15mL 1,4-dioxane and 3mL water, nitrogen replacement 3 times, the oil bath is heated to 110 °C, stirring Reacted for 16 hours, cooled to room temperature, added 30 mL of water, extracted twice with 30 mL of dichloromethane, dried the organic phase, concentrated, and column chromat
  • Step 4 Add 6-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-) into a 50mL round bottom flask 6-hydroxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (100mg, 0.17mmol), 5mL dichloromethane and 0.5mL Trifluoroacetic acid, stirred at room temperature for 5 hours, added 30 mL of dichloromethane, washed twice with 30 mL of saturated sodium bicarbonate, the aqueous phase was extracted with 30 mL of dichloromethane three times, combined the organic phases, dried and concentrated to obtain 2-(6-chloro -2-(3-(Dimethylamino)azetidin-1-yl)-8-fluoro-4-(2,6-diazaspir
  • Step 5 Add 2-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-4-(2,6- Diazaspiro[3.3]heptan-2-yl)quinazolin-7-yl)-3 fluorophenol (48mg, 0.099mmol), 5mL tetrahydrofuran, 3 drops of triethylamine, cool in an ice water bath, add 1 drop of acryloyl chloride, stirred for 10 minutes, added 20 mL of water, extracted twice with 20 mL of dichloromethane, dried the organic phase and concentrated, purified by preparative HPLC to obtain 1-(6-(6-chloro-2-(3-( ⁇ Methylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[ 3.3] Heptan-2-
  • Step 1 Dissolve compound 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (500mg, 1.51mmol) in 10mL of 1,4-dioxane, add triethylamine ( 0.63mL, 4.53mmol) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (342mg, 1.51mmol), reacted at 50°C for 0.5 hours. After the reaction was completed, 100 mL of ethyl acetate was added, followed by washing with 30 mL of 1M hydrochloric acid, 30 mL of saturated sodium bicarbonate solution and 30 mL of saturated brine.
  • Step 2 The compound 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert Butyl ester (750mg, 1.44mmol) was dissolved in a mixed solution of 10mL dimethyl sulfoxide and 10mL 1,4-dioxane, and KF (830mg, 14.3mmol) and 1-methyl-4-piperidinol were added sequentially (330mg, 2.87mmol). The mixture was stirred at 120°C for 3 hours.
  • reaction solution was poured into 100 mL of ethyl acetate, and washed with 50 mL of saturated brine three times.
  • organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue.
  • Step 3 The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (250mg, 0.417mol), 5-methyl-1H-indazole-4-boronic acid (110mg, 0.626mol), tris(dibenzylidene Acetone) two palladium (38mg, 0.042mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (17mg, 0.042mol) and potassium phosphate (177mg, 0.834mol) dissolved in 5mL 1 , 4-Dioxane and 0.5 mL of water, and place the mixture in a microwave tube, bubbling with N 2 for 1 minute.
  • reaction solution After reacting at 120°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 10 mL of saturated brine three times, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Step 4 The compound 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin-4-yl)oxy )Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (200mg, 0.308mol) in methanol (3mL) is cooled to 0°C and slowly added HCl/dioxane solution (4M, 3mL, 12mmol). After the addition, return to room temperature and stir for 2 hours.
  • HCl/dioxane solution 4M, 3mL, 12mmol
  • Step 5 Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride crude product (200mg, 0.308mmol) in tetrahydrofuran (5mL) suspension 1 mL of saturated sodium bicarbonate aqueous solution was slowly added to the turbid solution. After the reaction solution was clear, acryloyl chloride (28 mg, 0.308 mol) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 6 The compound 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (55mg, 0.091mmol)
  • the compound is obtained by chiral resolution by SFC:
  • Step 1 The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.25mmol), 4-picoline-3-boronic acid pinacol ester (66mg, 0.3mmol), tris(dibenzylidene Acetone) two palladium (23mg, 0.025mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (10mg, 0.025mol) and potassium phosphate (106mg, 0.5mol) dissolved in 2mL 1 , 4-Dioxane and 0.2 mL of water, and place the mixture in a microwave tube, bubbling with N 2 for 1 minute.
  • reaction solution After reacting at 100°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 20 mL of saturated brine three times, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Step 2 The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)- 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (130mg, 0.213mmol) in methanol (2mL) was cooled to 0°C, and HCl/dioxane solution (4M, 2mL) , 8mmol). After the addition, return to room temperature and stir for 2 hours.
  • Step 3 Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridine- 3-yl)-4-(2,7-diazaspiro[3.5]non-7-yl)quinazoline hydrochloride (130mg, 0.213mmol) in tetrahydrofuran (5mL) suspension was slowly added 1mL saturated NaHCO 3 solution, the reaction solution after clarification, was added acryloyl chloride (0.017mL, 0,213mmol), stirred at room temperature for 0.5 hours.
  • Example 5 1-(7-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridin-3-yl)-6 -Vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one trifluoroacetate
  • Step 1 The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (300mg, 0.5mmol) was dissolved in 15mL tetrahydrofuran, and EtONa (0.5M/EtOH, 3mL, 1.5mmol) was added. The reaction solution was reacted at 60°C for 30 minutes under microwave irradiation. After the reaction was completed, it was quenched with 20 mL of water, and extracted three times with 50 mL of ethyl acetate.
  • Step 2 The compound 7-(7-bromo-6-chloro-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2 ,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg, 0.16mmol), 4-picoline-3-boronic acid pinacol ester (42mg, 0.192mol), tris(diethylene) Benzylacetone) two palladium (16mg, 0.018mmol), SPhos (8mg, 0.019mol) and potassium phosphate (68mg, 0.32mmol) dissolved in 1,4-dioxane (2mL) and water (0.2mL), and The mixture was placed in a microwave tube, and N 2 was bubbled in for 1 minute.
  • reaction solution After reacting at 100°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 20 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Step 3 The compound 7-(6-chloro-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridin-3-yl) Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg, 0.157mmol), vinyl boronic acid pinacol ester (29mg, 0.188mol), Tris(dibenzylideneacetone)dipalladium (15mg, 0.016mol), SPhos (7mg, 0.017mol) and potassium phosphate (67mg, 0.316mol) are dissolved in 1,4-dioxane (1.5mL) and water ( 0.15 mL), and put the mixture in a microwave tube, bubbling with N 2 for 1 minute.
  • reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 20 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Step 4 The compound 7-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridin-3-yl)-6-ethylene Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.238mmol) in methanol (3mL) was cooled to 0°C, and HCl was slowly added /Dioxane solution (4M, 3mL, 12mmol). After the addition, return to room temperature and stir for 2 hours.
  • Step 5 Under ice bath conditions, transfer the compound 8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridine-3- Yl)-4-(2,7-diazaspiro[3.5]non-7-yl)-6-vinylquinazoline hydrochloride (150mg, 0.238mmol) in tetrahydrofuran (5mL) suspension Slowly add 1 mL of saturated NaHCO 3 solution, after the reaction solution is clear, add acryloyl chloride (0.019 mL, 0.238 mmol), and stir at room temperature for 1 hour.
  • Example 6 1-(7-(7-(5-amino-2-chlorophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6 -Vinyl-quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 Combine 7-bromo-2,4-dichloro-8-fluoro-6-iodo-quinazoline (6g, 14.2mmoL) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid Tert-butyl ester (3.38g, 14.9mmoL) was dissolved in 1,4-dioxane (100mL), and triethylamine (2.87g, 28.4mmoL) was slowly added in an ice bath (0 ⁇ 5°C).
  • Step 2 Add 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (2g, 3.27mmoL), 1-methylpiperidin-4-ol (5.65g, 49.1mmoL), Cs 2 CO 3 (2.13g, 6.5mmoL) and KF (3.8mg, 65.4mmoL) were added to the dry In 1-4-dioxane/dimethyl sulfoxide (25mL/25mL), react in an oil bath at 120°C for 40 minutes.
  • Step 3 Add 7-(7-bromo-8-fluoro-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7- Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2.6g, 3.77mmoL) and sodium ethoxide (7.54mL, 1M ethanol solution) were added to dry 75mL tetrahydrofuran and reacted at 70°C in an oil bath for 50 minutes.
  • Step 4 Add 7-(7-bromo-8-ethoxy-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2, 7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.3g, 1.82mmoL), potassium ethylene trifluoroborate (266mg, 2.00mmoL), Pd(dppf)Cl 2 (133mg, 0.182mmoL) And potassium carbonate (502mg, 3.64mmoL) were added to 10mL 1,4-dioxane and 2mL water, and microwaved at 80°C for 50 minutes.
  • Step 5 Add 7-(7-bromo-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2 ,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (500mg, 0.81mmoL), (2-chloro-5-nitrophenyl)boronic acid (245mg, 1.22mmoL), Pd 2 (dba ) 3 (74mg, 0.081mmoL), 2-Biscyclohexylphosphine-2',6'-dimethoxybiphenyl Sphos (67mg, 0.162mmoL) and potassium phosphate (343mg, 1.62mmoL) were added to a 20mL microwave tube , And add 1mL water and 8mL 1,4-dioxane, nitrogen replacement for 1 minute, microwave heating at 120°C for 50 minutes.
  • Step 6 Add 7-(7-(2-chloro-5-nitrophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6-ethylene Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (393mg, 0.57mmoL) was added to 5mL of anhydrous methanol, under ice bath conditions, 4M HCl (1,4-dioxane solution, 5 mL) was slowly added dropwise, and the temperature was raised to room temperature to react for 2 hours.
  • Step 7 Add 7-(2-chloro-5-nitrophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7 -Diazaspiro[3.5]non-7-yl)-6-vinylquinazoline hydrochloride (310mg, 0.52mmoL), sodium bicarbonate (437mg, 5.2mmoL) were added to 5mL tetrahydrofuran and 3mL water, in Acrylic chloride (91 mg, 1.04 mmoL) was slowly added dropwise under ice bath conditions, and stirred for 10 minutes.
  • Step 8 The crude product 1-(7-(7-(2-chloro-5-nitrophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy) -6-Vinyl-quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (240mg, 0.37mmoL), iron powder (103 mg, 1.85 mmoL) and saturated ammonium chloride aqueous solution (3 mL, saturated aqueous solution) were added to 20 mL of absolute ethanol, and reacted in an oil bath at 60°C for 3 hours.
  • Example 7 1-(7-(6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-(1-methylpiperidin-4-yl) (Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg, 0.167mmol), 3-methyl-1H-pyrazole-4-boronic acid (42mg, 0.334mmol), tris(dibenzylidene Acetone) two palladium (15mg, 0.017mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (7mg, 0.017mol) and potassium phosphate (71mg, 0.334mol) dissolved in 1, 4-Dioxane (2 mL) and water (0.2 mL), and put the mixture in a microwave tube, bubbling with N 2 for 1 minute.
  • reaction solution After reacting at 120°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 20 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Step 2 The compound 7-(6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy Yl)quinazolin-4-yl))-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (15mg, 0.025mol) in methanol (2mL) is cooled to 0°C, Slowly add HCl/dioxane solution (4M, 2mL, 8mmol). After the addition, return to room temperature and stir for 2 hours.
  • Step 3 Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (15mg, 25umol) in tetrahydrofuran (2mL) suspension 0.2 mL of saturated NaHCO 3 solution was slowly added to the mixture. After the reaction solution was clear, acryloyl chloride (2.3 mg, 0.025 mol) was added, and the mixture was stirred at room temperature for 0.5 hours.
  • Example 8 1-(7-(6-Chloro-2-(2-(dimethylamino)ethoxy)-8-fluoro-7-(5-methyl-1H-indazol-4-yl )Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
  • Step 1 Add 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (245mg, 0.75mmol), triethylamine (224mg, 2.21mmol), 2,7-bis to a 100mL round bottom flask Azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (168mg, 0.75mmol) and 10mL dioxane. The temperature was raised to 50°C and reacted for 30 minutes, TLC detected the disappearance of the raw materials, and the reaction was stopped.
  • Step 2 Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane to a 100mL round bottom flask Crude tert-butyl 2-carboxylate (208mg, 0.40mmol), potassium fluoride (240mg, 4.1mmol), 2-(dimethylamino)-1-ol (80mg, 0.90mmol), 5mL anhydrous DMSO and 5mL dioxane. The temperature was raised to 120°C and reacted for 3 hours, TLC detected the disappearance of the raw materials, and the reaction was stopped.
  • Step 3 Add 7-(7-bromo-6-chloro-2-(2-(dimethylamino)ethoxy)-8-fluoroquinazolin-4-yl)-2 to the 10mL microwave reaction tube , 7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (115mg, 0.20mmol), (5-methyl-1H-indazol-4-yl)boronic acid (56mg, 0.31mmol), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (17mg, 0.04mmol), Pd 2 (dba) 3 (18mg, 0.02mmol), potassium phosphate (85mg, 0.40mmol), 3mL Dioxane and 0.3 mL water.
  • Step 4 Add 7-(6-chloro-2-(2-(dimethylamino)ethoxy)-8-fluoro-7-(5-methyl-1H-indazole-) to a 25mL round bottom flask 4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (22mg, 0.035mmol), 10mL dichloromethane and 2mL trifluoroacetic acid . Stir at room temperature for 1 hour, TLC detects the disappearance of the raw materials and stops the reaction.
  • Step 5 Add the 2-((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7 -Diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)-N,N-dimethyl-1-amine crude product 25mg, triethylamine (20mg, 0.20mmol ) And 10mL tetrahydrofuran. Stir in an ice-water bath for 10 minutes, slowly add acryloyl chloride (3.85 mg, 0.042 mmol) dropwise, and keep the reaction for 30 minutes. TLC detects the disappearance of the raw materials and stops the reaction.
  • Step 1 The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (30mg, 0.05mol), 2-fluoro-6-hydroxyphenylboronic acid (29mg, 0.25mmol), tetrakis(triphenylphosphine)palladium (29mg , 0.025 mol), sodium carbonate aqueous solution (1M, 1 mL) was dissolved in 1,4-dioxane (2 mL), and the mixture was placed in a microwave tube, and N 2 was bubbled in for 1 minute.
  • reaction solution After reacting at 120°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Step 2 The compound 7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)quinazole
  • a solution of tert-butyl nonane-2-carboxylate (50mg, 0.079mol) in methanol (2mL) is cooled to 0°C, and HCl/two is slowly added.
  • Oxane solution (4M, 2mL, 8mmol). After the addition, return to room temperature and stir for 2 hours.
  • Step 3 Under ice bath conditions, transfer the compound 2-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7 -Diazaspiro[3.5]nonane-7-yl)quinazolin-7-yl)-3 fluorophenol hydrochloride (50mg, 0.079mol) in tetrahydrofuran (2mL) suspension was slowly added 0.2mL saturated NaHCO 3 solution, the reaction solution after clarification, was added acryloyl chloride (7.15mg, 0.079mol), was stirred at room temperature for 0.5 hours.
  • Example 11 1-(7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-4-yl)quine Synthesis of oxazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 Add 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7- Diazaspiro[3.5]nonane-tert-butyl carboxylate (120mg, 0.2mmoL), (1H-pyrazol-4-yl)boronic acid (45mg, 0.4mmoL), Pd 2 (dba) 3 (18mg, 0.02mmoL) ), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (16mg, 0.04mmoL) and cesium carbonate ( 85mg, 0.4mmoL) was added to a 20mL microwave tube, 0.5mL water and 5mL dioxane were added, nitrogen replacement for 1 minute, microwave heating at 120°C for 50 minutes
  • Step 2 Add 7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-4-yl)quinazoline- 4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (32mg, 0.055mmoL) was added to 2mL of anhydrous methanol, and 4M HCl was slowly added dropwise under ice bath conditions (1,4-dioxane solution, 2mL), warm to room temperature and react for 2 hours.
  • Step 3 Add 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-4-yl)-4-(2,7 -Diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (30mg, 0.061mmoL) was added to 2mL tetrahydrofuran and 0.5mL water, under ice bath conditions, one after another dropwise addition of triethylamine (13mg , 0.122mmoL) and acryloyl chloride (8.0mg, 0.092mmoL), stir for 10 minutes.
  • triethylamine 13mg , 0.122mmoL
  • acryloyl chloride 8.0mg, 0.092mmoL
  • Step 1 Combine 2,4-dichloro-7-bromoquinazoline (500mg, 1.80mmol) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester in a 100mL three-necked flask (448mg, 2.00mmol) was suspended in 15mL of acetonitrile, and triethylamine (546mg, 5.40mmol) was added dropwise at 15-25°C. After dripping, the mixture was stirred at room temperature for 1 hour, and TLC monitored the completion of the reaction.
  • Step 2 Put 7-(7-bromo-2-chloroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.85mmol) into In a 50 mL three-necked flask, cesium carbonate (557 mg, 1.71 mmol) and 1-methyl-4-piperidinol (4.0 g, 34.7 mmol) were sequentially added, and stirred at 110°C for 2 hours. After cooling to room temperature, 15 mL of water was added to the mixture, extracted twice with 20 mL of ethyl acetate, and the organic phases were combined.
  • Step 3 Add 7-(7-bromo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non Alkyl-2-carboxylic acid tert-butyl ester (150mg, 0.27mmol) was put into a 25mL microwave tube, and 5-methyl-1H-indazole-4-boronic acid (86mg, 0.49mmol), tris(dibenzylidene acetone) ) Dipalladium (25mg, 0.027mmol), 2-Biscyclohexylphosphine-2',6'-dimethoxybiphenyl (23mg, 0.056mmol), potassium phosphate (116mg, 0.55mmol), dioxane 8mL and 1.5 mL of water was used to react in a microwave reactor at 115° C.
  • Step 4 Add 7-(7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl )-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (40mg, 0.067mmol) was dissolved in 2ml methanol, and 4.0mol/L hydrochloric acid dioxygen was added dropwise at 0-5°C 2 mL of the hexacyclic solution, and then the mixture was stirred at room temperature for 2 hours, and LCMS monitored the complete reaction of the raw materials. The solvent was removed by concentration under reduced pressure. The residue was used directly in the next reaction.
  • ES-API: [M+H] + 498.2.
  • Step 5 Add 3 mL of tetrahydrofuran and 0.3 mL of water to the crude product obtained by the above concentration, stir to dissolve, and add triethylamine (41 mg, 0.40 mmol) to adjust the pH to alkaline (7.5-9.0).
  • Acrylic chloride (8 mg, 0.088 mmol) was added dropwise at 0-5° C., stirred for 0.5 hour, 10 mL of water was added to the mixture, extracted twice with 10 mL of ethyl acetate, and the organic phases were combined.
  • Example 15 1-(7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-3-yl)quine Synthesis of oxazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
  • Step 1 Add compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl into a 5mL microwave tube )-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (70mg, 0.117mmol), 1H-pyrazole-3-boronic acid (21mg, 0.176mmol), 1,4-bis Oxane (3ml) and water (0.6mL), then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (9mg, 0.0117mmol) and cesium carbonate (76.3mg, 0.2134mmol), under nitrogen protection, microwave at 120°C for 1 hour, LC-MS monitored the formation of products, and the disappearance of raw materials.
  • Step 2 Add 7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazole-3-) to a 50mL round bottom flask Yl)quinazolin-4-yl)-2,7 diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (9mg, 0.015mmol) and dichloromethane (3mL), then add trifluoroacetic acid (0.5mL), react at room temperature for 5 hours, LC-MS monitors the disappearance of the raw materials, spin off the solvent to obtain the compound 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)- 7-(1H-pyrazol-3-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline (crude product 12mg, Y: 100%), proceed directly One step response.
  • Example 17 1-(6-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl )Oxy)quinazolin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one
  • Step 1 Combine 2,4-dichloro-7-bromo-8-fluoro-6-chloroquinazoline (600mg, 1.82mmol) and 2,6-diazaspiro[3.3]heptane- in a 100ml three-necked flask Tert-butyl 2-formate oxalate (530mg, 1.83mmol) was suspended in 10mL of acetonitrile, triethylamine (552mg, 5.45mmol) was added dropwise at 15 ⁇ 25°C, after dripping, stirred at room temperature for 2 hours, TLC monitored the reaction carry out.
  • the solvent was distilled off under reduced pressure, 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution were added to the obtained oily substance, and the layers were separated. The organic layer was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent.
  • Step 2 Add 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl Put the ester (200mg, 0.41mmol) into a 10mL microwave tube, add cesium carbonate (293mg, 0.89mmol) and 1-methyl-4-piperidinol (2.5g, 21.67mmol) in sequence, and use a microwave reactor at 110°C React for 60 minutes. After cooling to room temperature, 20 mL of water was added to the mixture, extracted twice with 20 L of dichloromethane, and the organic phases were combined.
  • Step 3 Add 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6- Diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (60mg, 0.10mmol) was put into a 10ml microwave tube, followed by 5-methyl-1H-indazole-4-boronic acid (33mg, 0.19mmol) , Tris(dibenzylideneacetone)dipalladium (10mg, 0.011mmo), 2-Biscyclohexylphosphine-2',6'-dimethoxybiphenyl (9mg, 0.021mmol), potassium phosphate (45mg, 0.21mmol) ), 4 mL of dioxane and 0.8 mL of water, reacted with a microwave reactor at 115°C for 50 minutes.
  • Step 4 Add 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy )Quinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (18mg, 0.029mmol) was dissolved in 1.5mL methanol at 0-5°C 1.5 mL of 4.0 mol/L dioxane hydrochloride solution was added dropwise, and then the mixture was stirred at room temperature for 1 hour, and LCMS monitored the completion of the raw material reaction. The solvent was removed by concentration under reduced pressure. The residue was used directly in the next reaction.
  • ES-API: [M+H] + 522.2.
  • Step 5 Add 2 mL of tetrahydrofuran and 0.3 mL of water to the crude product obtained by the above concentration, stir to dissolve, and add triethylamine (15 mg, 0.40 mmol) to adjust the pH to alkaline (7.5-9.0).
  • Example 18 1-(7-(7-((1H-pyrazol-4-yl)amino)-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy (Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one dicarboxylate
  • Step 1 The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (200mg, 0.334mmol), 4-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester (306mg, 1.67mmol), tris(diethylene Benzylacetone) two palladium (153mg, 0.167mmol), XPhos (80mg, 0.167mmol) and potassium phosphate (354mg, 1.67mmol) were dissolved in 5mL toluene, and the mixture was placed in a microwave tube, and N 2 was bubbled in 1 minute.
  • Step 2 The compound 7-(7-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)amino)-6-chloro-8-fluoro-2-(1-methylpiper (Pyridin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (150mg, 0.213mmol) in methanol (2mL) Cool to 0°C and slowly add HCl/dioxane solution (4M, 2mL, 8mmol). After the addition, return to room temperature and stir for 2 hours.
  • HCl/dioxane solution 4M, 2mL, 8mmol
  • Step 3 Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-N-(1H-pyrazole-4) obtained above -Yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-7-amine hydrochloride (150mg, 213umol) in tetrahydrofuran (2mL) suspension Slowly add 0.2 mL of saturated NaHCO 3 solution. After the reaction solution is clear, add acryloyl chloride (19.3 mg, 0.213 mmol) and stir for 0.5 hour.
  • Example 19 1-(7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)-6 -Vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 Add 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (1.5g, 3.55mmol), triethylamine (1.08g, 10.5mmol), into a 100mL round bottom flask, 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.767 g, 3.55 mmol) and 20 mL acetonitrile. The temperature was raised to 50°C and reacted for 1 hour, TLC detected the disappearance of the raw materials, and the reaction was stopped.
  • Step 2 Add 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane into a 100mL round bottom flask Crude tert-butyl -2-carboxylate (1.55g, 2.54mmol), potassium fluoride (1.55g, 26.7mmol), 1-methylpiperidin-4-ol (4.65g, 40.4mmol), 20mL anhydrous DMSO And 20mL dioxane. The temperature was raised to 120°C and reacted for 1 hour, TLC detected the disappearance of the raw materials, and the reaction was stopped.
  • Step 3 Add 7-(7-bromo-8-fluoro-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl into a 25mL microwave reaction tube )-2,7-diazaspiro[3.5]nonane-2 tert-butyl ester-carboxylic acid (690 mg, 1 mmol), 10 mg/mL C 2 H 5 ONa in tetrahydrofuran solution 7 ml (70 mg, 1.01 mmol) and 5 ml tetrahydrofuran. Place in a microwave reactor at 70°C for 45 minutes to stop the reaction.
  • Step 4 Add 7-(7-bromo-8-ethoxy-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazoline-4 to the 10mL microwave reaction tube -Yl)-2,7-diazaspiro[3.5]nonane-2 tert-butyl ester-formic acid (300mg, 0.42mmol), 4,4,5,5-tetramethyl-2-vinyl-1, 3,2-Dioxaborolane (129mg, 0.84mmol), Sphos (35mg, 0.08mmol), Pd 2 (dba) 3 (38mg, 0.04mmol), potassium phosphate (178mg, 0.84mmol), 3mL Dioxane and 0.3 mL water.
  • Step 5 Add 7-(7-bromo-8-ethoxy-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazoline-4 to the 5mL microwave reaction tube -Base)-2,7-diazaspiro[3.5]nonane-2 tert-butyl ester-formic acid (200mg, 0.325mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (101mg, 0.65mmol), Sphos (27 mg, 0.065 mmol), Pd 2 (dba) 3 (29 mg, 0.033 mmol), potassium phosphate (138 mg, 0.65 mmol), 3 mL dioxane and 0.3 mL water.
  • Step 6 Add 7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy group to a 25mL round bottom flask )-6-vinylquinazolin-4-yl)-2,7-tert-butyl diazaspiro[3.5]nonane-2-carboxylic acid methyl ester (60mg, 0.09mmol), 10mL of dichloromethane and 2mL trifluoroacetic acid. After stirring for 1 hour at room temperature, TLC detected the disappearance of the raw materials, and the reaction was stopped.
  • reaction solution was directly spin-dried to obtain 2-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]non -7-yl)-6-vinylquinazolin-7-yl)-3-fluorophenol crude product 75mg.
  • Step 7 Add the 2-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-di) obtained in the previous step into a 25mL round bottom flask Azaspiro[3.5]non-7-yl)-6-vinylquinazolin-7-yl)-3-fluorophenol crude 75mg, triethylamine (28mg, 0.27mmol) and 10mL tetrahydrofuran. Stir in an ice-water bath for 10 minutes, slowly add acryloyl chloride (10 mg, 0.11 mmol) dropwise, and keep warm and react for 30 minutes. TLC detects the disappearance of the raw materials and stops the reaction.
  • Step 1 Put 7-bromo 2,4,6-trichloro-8-fluoroquinazoline (4.0g, 12.12mmol) and 2,7-diazaspiro[3.5]nonane into a 250mL round bottom three-necked flask Tert-Butyl-2-carboxylate (2.82g, 12.48mmol) and 80mL of dioxane, triethylamine (3.67g, 36.36mmol) was added dropwise under ice bath, stirred at room temperature for 1 hour, TLC monitored the completion of the reaction. The solvent was distilled off under reduced pressure, and 80 mL of ethyl acetate and 80 mL of water were added to the resulting oily substance. The layers were separated.
  • Step 2 Put 7-(7-bromo-8-fluoro-6-chloro-2-chloro-4-quinoline)-2,7-diazaspiro[3.5]nonane-2 into a 50mL round bottom flask -Tert-butyl carboxylate (500mg, 0.96mmol), diisopropylethylamine (624mg, 4.83mmol) and 3-(dimethylamino)azetidine dihydrochloride (218mg, 1.26mmol), in Stir at 100°C for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, 20 mL of water was added to the mixture, and the mixture was extracted with 30 mL of ethyl acetate.
  • Step 3 Put 7-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazoline-4 into a 25ml microwave tube -Yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (340mg, 0.58mmol), 5-methyl-1H-indazole-4-boronic acid (185mg, 1.05mmol) ), tris(dibenzylideneacetone)dipalladium (53mg, 0.058mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (47mg, 0.114mmol), potassium phosphate (244mg, 1.15 mmol), 8 mL of dioxane and 1.5 mL of water were reacted in a microwave reactor at 115° C.
  • Step 4 Put 7-[7-(5-methyl-1H-indazol-4yl)-2-[(3-(dimethylamino)azetidinyl]-4 into a 50mL round bottom flask -Quinoline]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (80mg, 0.126mmol) and 2mL methanol, add 4.0mol/L hydrochloric acid dropwise at 0-5°C 2 mL of oxane solution, and then the mixture was stirred at room temperature for 1 hour, LCMS monitored the completion of the raw material reaction.
  • Step 5 Put the obtained 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-) into a 50mL round-bottom flask.
  • Diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)-N,N-dimethylazacyclo-3-amine (90mg, 0.16mmol), 3mL tetrahydrofuran and 0.3mL water , stir to dissolve, add triethylamine (64mg, 0.63mmol) to adjust the pH to alkaline (7.5-9.0).
  • Step 1 Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane into a 50mL round bottom flask Tert-butyl 2-carboxylate (200 mg, 0.385 mmol), potassium fluoride (224 mg, 3.86 mmol), N-methylpiperazine (46 mg, 0.46 mmol), and 10 mL DMSO. The temperature was raised to 120°C and reacted for 1 hour, TLC detected the disappearance of the raw materials, and the reaction was stopped.
  • Step 2 Add 7-(7-bromo-6-chloro-8-fluoro-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2 into a 10mL microwave reaction tube, Crude tert-butyl 7-diazaspiro[3.5]nonane-2-carboxylate (150mg, 0.257mmol), (5-methyl-1H-indazol-4-yl)boronic acid (54mg, 0.310mmol), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (32mg, 0.077mmol), Pd 2 (dba) 3 (35mg, 0.038mmol), potassium phosphate (110mg, 0.52mmol), 3mL Dioxane and 0.3 mL water.
  • Step 3 Add 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazine-1) into a 25mL round bottom flask -Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (60 mg, 0.09 mmol), 10 mL dichloromethane and 2 mL trifluoroacetic acid. After stirring at room temperature for 2 hours, TLC detected the disappearance of the raw materials, and the reaction was stopped.
  • Step 4 Add 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazine-) obtained in the previous step into a 25mL round bottom flask 1-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl) quinazoline crude 66mg, triethylamine (27mg, 0.27mmol) and 10mL tetrahydrofuran. Stir in an ice-water bath for 10 minutes, slowly add acryloyl chloride (9.8 mg, 0.108 mmol) dropwise, and keep the reaction warm for 30 minutes. TLC detects the disappearance of the raw materials and stops the reaction.
  • Step 1 Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane into a 50mL round bottom flask Tert-Butyl 2-carboxylate (200 mg, 0.385 mmol), potassium fluoride (224 mg, 3.86 mmol), N,N,-dimethylpiperidin-4-amine (67 mg, 0.46 mmol) and 10 mL DMSO. The temperature was raised to 120°C and reacted for 1 hour, TLC detected the disappearance of the raw materials, and the reaction was stopped.
  • Step 2 Add 7-(7-bromo-6-chloro-2-(4-(dimethylamino)piperidin-1-yl)-8-fluoroquinazolin-4-yl to 10mL microwave reaction tube )-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (120mg, 0.197mmol), (5-methyl-1H-indazol-4-yl)boronic acid (41mg, 0.236 mmol), 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (25mg, 0.06mmol), Pd 2 (dba) 3 (27mg, 0.03mmol), potassium phosphate (85mg, 0.4mmol) ), 3mL dioxane and 0.3mL water.
  • Step 3 Add 7-(6-chloro-2-(4-(dimethylamino)piperidin-1-yl)-8-fluoro-7-(5-methyl-1H-) to a 25mL round bottom flask Indazol-4-yl)quinazolin-4-yl-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (20mg, 0.03mmol), 10mL dichloromethane and 2mL three Fluoroacetic acid. Stir at room temperature for 1 hour, TLC detects the disappearance of the raw materials, and the reaction is stopped.
  • Step 4 Add 2-((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7) to a 25mL round bottom flask. -Diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)-N,N-dimethyl-1-amine crude product 26mg, triethylamine (10mg, 0.10mmol) And 10 mL of tetrahydrofuran. Stir in an ice-water bath for 10 minutes, slowly add acryloyl chloride (3.40 mg, 0.037 mmol) dropwise, and heat the reaction for 30 minutes. TLC detects the disappearance of the raw materials and stops the reaction.
  • Example 23 1-(7-(6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7-yl)-2-((1-methylpiperidin-4-yl )Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
  • Step 2 The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.25mmol), 6-methyl-7-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1H-indazole (100mg, 0.387mmol), tris(dibenzylideneacetone)dipalladium (25mg, 0.027mmol), 2-dicyclohexylphosphino- 2′,6′-Dimethoxybiphenyl (10mg, 0.024mol) and potassium phosphate (110mg, 0.518mol) were dissolved in 1,4-dioxane (2mL) and water (0.4mL), and the mixture Place it in a
  • reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Step 3 The compound 7-(6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7-yl)-2-(1-methylpiperidin-4-yl)oxy )Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg, 0.154mmol) in methanol (2mL) is cooled to 0°C slowly Add HCl/dioxane solution (4M, 2mL, 8mmol). After the addition, return to room temperature and stir for 2 hours.
  • Step 4 Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (100mg, 0.154mmol, 1eq) in tetrahydrofuran (2mL) 0.1 mL of Et 3 N was slowly added to the suspension. After the reaction solution was clear, acryloyl chloride (14 mg, 0.154 mmol, 1 eq) was added, and the mixture was stirred for 10 minutes.
  • Step 1 Combine 2,4-dichloro-7-bromo-8-fluoro-6-chloroquinazoline (4.0g, 12.12mmol) and 2,7-diazaspiro[3.5]nonane in a 100mL three-neck flask Tert-Butyl-2-carboxylate (2.82g, 12.48mmol) was dissolved in 80mL of dioxane, and triethylamine (3.67g, 36.36mmol) was added dropwise at 15 ⁇ 25°C, after dropping, stirring at room temperature for 1 hour , TLC monitors the completion of the reaction.
  • the solvent was distilled off under reduced pressure, and 80 mL of ethyl acetate and 80 mL of water were added to the resulting oily substance.
  • the layers were separated.
  • the organic layer was washed once with 20 mL of 1N brine solution, once with 20 mL of saturated sodium bicarbonate solution, and washed with 20 mL of saturated brine.
  • Step 2 Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Put the ester (300mg, 0.58mmol) into a 50mL three-necked flask, add cesium carbonate (375mg, 1.15mmol) and N-methyl-L-prolinol (2.0g, 17.3mmol) in sequence, and stir for 2 hours at 105°C. TLC monitors the complete reaction of the raw materials.
  • cesium carbonate 375mg, 1.15mmol
  • N-methyl-L-prolinol 2.0g, 17.3mmol
  • Step 3 Add (S)-7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) -2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (220mg, 0.37mmol) was put into a 25mL microwave tube, and 5-methyl-1H-indazole-4-boronic acid ( 116mg, 0.66mmol), Tris(dibenzylideneacetone) dipalladium (34mg, 0.037mmo), 2-Biscyclohexylphosphine-2',6'-dimethoxybiphenyl (31mg, 0.074mmol), potassium phosphate (157 mg, 0.74 mmol), 8 mL of dioxane and 1.5 mL of water were reacted in a microwave reactor at 115° C.
  • Step 4 Add 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidinyl- 2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (180mg, 0.27mmol) was dissolved in 5mL methanol, Add 5 mL of 4.0mol/L hydrochloric acid dioxane solution dropwise at 0-5°C, and then stir the mixture at room temperature for 1 hour. LCMS monitors the completion of the raw material reaction. Concentrate under reduced pressure to remove the solvent. The residue is used directly in the next step Reaction.
  • ES-API: [M+H] + 550.1.
  • Step 5 Add 6 mL of tetrahydrofuran and 1 mL of water to the crude product obtained by the above concentration, stir to dissolve, and add triethylamine (137 mg, 0.1.35 mmol) to adjust the pH to alkaline (7.5-9.0). Add acryloyl chloride (32 mg, 0.35 mmol) dropwise at 0-5° C., stir for 0.5 hour, add 15 mL of water and 15 mL of saturated sodium bicarbonate solution to the mixture, extract twice with 20 mL of dichloromethane, and combine the organic phases.
  • Step 6 The compound 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrole) Alkyl-2-yl)methoxy)quinazoline piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (50mg , 0.082mmol) preparation and resolution to obtain two chiral single isomers, Z24-1 (15.21mg, peak 1) and Z24-2 (8.53mg, peak 2).
  • Example 25 (S or R)-1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidine-4 -Yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
  • Step 1 Dissolve compound 7-bromo-2,4,6-trichloroquinazoline (2g, 6.4mmol) in 50mL of 1,4-dioxane, add Et 3 N (2.46mL, 19.2mmol) under stirring ) And 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.45g, 6.4mmol), reacted at 50°C for 0.5 hours. After the reaction is over, add 150 mL of ethyl acetate, and wash with 50 mL of 1M hydrochloric acid, 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated brine in sequence.
  • Step 2 The mixture 7-(7-bromo-2,6-dichloroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1g, 1.99mmol), 1-methyl-4-piperidinol (6.88g, 59.7mmol) and cesium carbonate (1.3g, 3.98mmol) were reacted at 120°C for 3 hours. After the reaction, the reaction solution was poured into 50 mL of water and extracted three times with 50 mL of ethyl acetate. The obtained organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue.
  • Step 3 The compound 7-(7-bromo-6-chloro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazepine Spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.689mmol), 5-methyl-1H-indazole-4-boronic acid (145mg, 0.826mol), three (dibenzylidene acetone) two Palladium (63mg, 0.069mol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (28mg, 0.069mol) and potassium phosphate (293mg, 1.38mmol) are dissolved in 1,4-di Oxane (10 mL) and water (1 mL), and put the mixture in a microwave tube, bubbling with N 2 for 1 minute.
  • 1,4-di Oxane 10 mL
  • reaction solution After reacting at 120°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 60 mL ethyl acetate and washed with 20 mL saturated brine three times, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.
  • Step 4 The compound 7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazole (Alkolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.633mmol) in methanol (4mL) was cooled to 0°C, and HCl/ Dioxane solution (4M, 4mL, 16mmol). After the addition, return to room temperature and stir for 2 hours.
  • Step 5 Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride crude product (400mg, 0.633mol) in tetrahydrofuran (4mL) suspension 0.4 mL of triethylamine was slowly added to the turbid solution. After the reaction solution was clear, acryloyl chloride (57 mg, 0.633 mol) was added and stirred at room temperature for 5 minutes.
  • Step 6 The compound 1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl) obtained above )Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (50mg, 0.085mol) chiral by SFC Resolve to get the compound (undefined configuration):
  • Example 26 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(tetrahydro-2H-pyran -4-yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-ene-1- Synthesis of ketones
  • Step 1 Add tetrahydropyrone (5.0g, 50mmol), 4-hydroxypiperidine (7.8g, 77mmol) and tetraisopropyl titanate (30mL, 101mmol) into a 250mL three-necked flask, and stir at 25°C overnight. Add 40 mL of methanol, cool the reaction solution to 0-5°C, add sodium borohydride (3.8g, 100mmol) in portions, control the temperature of the reaction solution to be ⁇ 15°C, and then stir at 0-5°C for 2 hours.
  • Step 2 Combine 2,4-dichloro-7-bromo-8-fluoro-6-chloroquinazoline (4.0g, 12.12mmol) and 2,7-diazaspiro[3.5]nonane in a 100mL three-neck flask Tert-Butyl-2-carboxylate (2.82g, 12.48mmol) was dissolved in 80mL of dioxane, and triethylamine (3.67g, 36.36mmol) was added dropwise at 15 ⁇ 25°C, after dropping, stirring at room temperature for 1 hour , TLC monitors the completion of the reaction.
  • the solvent was distilled off under reduced pressure, and 80 mL of ethyl acetate and 80 mL of water were added to the resulting oily substance.
  • the layers were separated.
  • the organic layer was washed once with 20 mL of 1N brine solution, once with 20 mL of saturated sodium bicarbonate solution, and washed with 20 mL of saturated brine.
  • Step 3 Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Put the ester (1.6g, 3.07mmol) into a 100mL three-necked flask, add cesium carbonate (3.0g, 9.23mmol) and 1-hydroxy-4-(morpholin-4-yl)-cyclohexane (1.26g, 6.80mmol) in sequence ), triethylenediamine (52mg, 0.46mmol) was stirred overnight at 60°C.
  • Step 4 Add 7-(7-bromo-6-chloro-8-fluoro-2-(((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)quine (Azolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (620mg, 0.93mmol) was put into a 25mL microwave tube, and 5-methyl-1H- Indazole-4-boronic acid (295mg, 1.67mmol), tris(dibenzylideneacetone) dipalladium (85mg, 0.093mmo), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (77mg , 0.186mmol), potassium phosphate (394mg, 1.86mmol), 9mL of dioxane and 2.0mL of water, reacted in a microwave reactor at 120°C for 70
  • Step 6 Add 10 mL of tetrahydrofuran and 1 mL of water to the residue obtained by the above concentration, stir to dissolve, and add triethylamine (281 mg, 2.77 mmol) to adjust the pH to alkaline (7.5-9.0). Add acryloyl chloride (65 mg, 0.72 mmol) dropwise at 0-5°C, stir for 1 hour, add 10 mL of water and 10 mL of saturated sodium bicarbonate solution to the mixture, extract twice with 30 mL of dichloromethane, and combine the organic phases.
  • Step 7 After chiral SFC resolution (column type: OD-H 100mm*4.6mm*5um; mobile phase: EtOH (ammonia water containing 1% methanol); flow rate 1.8mL/min; time 6min; column temperature 41.5°C) get
  • Example 28 1-(7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(5-methyl-1H-indazole-4 -Yl)pyrido[2,3-d]pyrimidinepiperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 Add 6,7-dichloropyrido[2,3-d]pyrimidine-2,4-diol (200mg, 0.86mmoL), (5-methyl-1H-indazol-4-yl)boronic acid (225mg, 1.29mmoL), Pd(PPh 4 ) 3 (99mg, 0.086mmoL) and K 2 CO 3 (238mg, 1.72mmoL) were added to a 20mL microwave reactor, and then 1,4-dioxane was added: H 2 O (8 mL: 1 mL), nitrogen replacement for 1 minute, microwave heating to 120° C., and reaction for 30 minutes.
  • Step 2 Combine 6-chloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4-diol (100mg, 0.306mmoL), oxygen Phosphorus chloride (5 mL) was stirred at 95°C for one hour. After it became a clear solution, diisopropylethylamine (4 mL) was slowly added dropwise, and the reaction was continued at 95°C for 5 hours.
  • Step 3 Add 2,4,6-trichloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine (100mg, 0.274mmoL), 2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (62mg, 0.274mmoL) was dissolved in dichloromethane, triethylamine (28mg, 0.274mmoL) was added dropwise and stirred at room temperature for 30 minutes.
  • Step 4 Add 7-(2,6-dichloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (20mg, 0.036mmoL), 3-(dimethylamino)azetidine dihydrochloride (8mg, 0.046mmoL) dissolved in two In methyl chloride, triethylamine (12mg, 0.12mmoL) was added dropwise and stirred at room temperature for 30 minutes.
  • Step 5 Add 7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(5-methyl-1H-indazol-4-yl) Pyrido[2,3-d]pyrimidine-3-piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (20mg, 0.032mmoL) was dissolved in Add 2 mL of trifluoroacetic acid dropwise to 2 mL of dichloromethane, and stir at room temperature for 2 hours.
  • Step 6 Add 1-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl) Pyrido[2,3-d]pyrimidin-2-yl)-N,N-dimethylazacyclo-3-amine (15mg, 0.029mmoL) was dissolved in 2mL tetrahydrofuran and 1mL water, and acryloyl chloride was added dropwise, Then add 5 drops of triethylamine, and stir for 5 minutes under ice-water bath.
  • Example 29 1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy) Synthesis of pyrido[2,3-d]pyrimidinepiperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 Add 7-(2,6-dichloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (see Z28 for synthesis method) (50mg, 0.09mmoL), 1-methylpiperidin-4-ol (212mg, 1.8mmoL), Cs 2 CO 3 (60mg, 0.18mmoL) and KF (52mg, 0.9mmoL) were added to dry 1-4-dioxane/dimethylsulfoxide (5mL/5mL), and reacted in an oil bath at 60°C for 1 hour.
  • Step 2 Add 7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)pyrido[ 2,3-d]pyrimidine-piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (30mg, 0.047mmoL) dissolved in 2mL dichloromethane , 2mL trifluoroacetic acid was added dropwise, and stirred at room temperature for 2 hours.
  • Step 3 Add 6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2, 7-diazaspiro[3.5]nonane-7-yl)pyrido[2,3-d]pyrimidine (22mg, 0.042mmoL) was dissolved in 2mL tetrahydrofuran and 1mL water, acryloyl chloride was added dropwise, and then triethyl 5 drops of amine, then stir for 5 minutes under ice-water bath.
  • Example 30 1-(2-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl )Oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-6-yl)prop-2-en-1-one
  • Step 1 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (500mg, 1.5mmol) was dissolved in dichloromethane/acetonitrile (5mL/5mL) and cooled to 0°C. Triethylamine (230 mg, 2.3 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (337 mg, 1.6 mmol) were added thereto, and the mixture was stirred at room temperature for 3 hours.
  • Step 2 2-(7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (227mg, 0.45mmol) dissolved in N,N-dimethylformamide/tetrahydrofuran (2mL/2mL), to which was added cesium carbonate (437mg, 1.3mmol), triethylenediamine (7.5mg, 0.07mmol) and 1 -Methylpiperidin-4-ol (155 mg, 1.3 mmol). The reaction solution was reacted at 45°C for 16 hours.
  • Step 3 2-(7-Bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-di Azaspiro[3.4]octane-6 tert-butyl-formic acid (156mg, 0.27mmol) was dissolved in 1,4-dioxane/water (2mL/0.5mL), and (5-methyl-1H- Indazol-4-yl)boronic acid (94mg, 0.53mmol), tris(dibenzylacetone)dipalladium (24mg, 0.03mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl ( 22mg, 0.05mmol), potassium phosphate (113mg, 0.53mmol).
  • Step 4 2-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy) Quinazolin-4-yl)tert-butyl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid ethyl ester (65mg, 0.1mmol) was dissolved in dichloromethane (0.5mL) and added Trifluoroacetic acid (0.5 mL), the reaction solution was stirred at room temperature for 1 hour, and the solvent was evaporated to remove 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(( 1-Methylpiperidin-4-yl)oxy)-4-(2,6-diazaspiro[3.4]octane-2-yl)quinazoline (brown solid, 55mg), used directly without purification In the next step reaction. ES
  • Step 5 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4- (2,6-diazaspiro[3.4]octane-2-yl)quinazoline (55mg, 0.1mmol) was dissolved in dichloromethane (1mL), the reaction solution was cooled to 0°C, and triethylamine (30mg , 0.3mmol) and acrylic anhydride (9mg, 0.07mmol), the reaction solution was reacted at 0°C for 1 hour, desolventized, and liquid phase separation was prepared to obtain 1-(2-(6-chloro-8-fluoro-7-(5-methyl) -1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4] Octane-6-yl)prop-2
  • Example 31 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(oxetan-3- (Yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (4.00g, 7.69mmol) was dissolved in DMF (40ml), cesium carbonate (6.25g, 19.2mmol), triethylenediamine (155mg, 1.38mmol) and 1-(oxbutacycloalkyl-3-yl) piper were added Pyridin-4-ol (1.45 g, 9.28 mmol). Under the protection of nitrogen, the reaction was stirred at room temperature for 4 hours.
  • Step 2 7-(7-bromo-6-chloro-8-fluoro-2-((1-(oxetan-3-yl)piperidin-4-yl)oxy)quinazoline-4- Yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was dissolved in dioxane/water (15mL/4mL), potassium phosphate (1.2g, 5.63mmol) was added, 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (78 mg, 0.18 mmol) and Pd 2 (dba) 3 (171 mg, 0.2 mmol).
  • Step 3 Add 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(oxetan-3-yl)piper (Pyridin-4-yl]oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (500mg, 0.7mmol) dissolved in dichloromethane (10mL), add trifluoroacetic acid (2mL). Stir the reaction at room temperature for 30 minutes.
  • Step 4 6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((1-(oxetan-3-yl)piperidine-4 -Yl)oxy]-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline (427mg, 0.72mmol) was dissolved in dichloromethane (10mL) and cooled to 0 Then add triethylamine (2mL) and acrylic anhydride (77mg, 0.61mmol) successively. Reaction at 0°C for 30 minutes.
  • Step 1 Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (3g, 5.77mmol) was dissolved in N,N-diisopropylethylamine (40mL), and 3-(hydroxymethyl)-1-methylpyrrolidone-2-one (893mg, 6.92mmol), carbonic acid Cesium (4.68g, 14.4mmol), 1,4-diazabicyclo[2.2.2]octane (116mg, 1.03mmol), under nitrogen protection, the reaction was stirred at room temperature for 3 hours.
  • Step 2 7-(7-bromo-6-chloro-8-fluoro-2-((1-methyl-2-oxopyrrolidin-3-yl)methoxy)quinazolin-4-yl)- 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.20g, 1.96mmol) was dissolved in dioxane/water (15mL/4mL), and (5-methyl- 1H-indazol-4-yl)boronic acid (517mg, 2.94mmol), potassium phosphate (1.24g, 5.88mmol), tris(dibenzylideneacetone)dipalladium (183mg, 0.2mmol) and 2-dicyclohexylphosphine Benzyl-2',6'-dimethoxybiphenyl (82mg, 0.2mmol).
  • Step 3 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methyl-2-oxopyrrolidin-3-yl) )Methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (500mg, 0.75mmol) dissolved in dichloromethane (10mL) , Add trifluoroacetic acid (2mL). The reaction was stirred at room temperature for 30 minutes.
  • Step 4 3-(((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]non- 7-yl)quinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one (424mg, 0.75mmol) was dissolved in dichloromethane (10mL) and cooled to 0°C, Triethylamine (2mL) and acrylic anhydride (81mg, 0.64mmol) were added sequentially. The reaction was stirred at 0°C for 30 minutes. The reaction solution was extracted with ethyl acetate, washed with brine, and concentrated under reduced pressure.
  • Step 1 7-(7-bromo-6-iodo-8-methoxy-2-(((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2, 7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (4.7g, 6.69mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- Dioxaborolane (1.5g, 10.04mmol), sodium carbonate (1.4g, 13.38mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (400mg) , Added to the mixed solvent of dioxane (50mL) and water (5mL) in sequence, reacted at 40°C for 18 hours.
  • dioxane 50mL
  • water 5mL
  • Step 2 Add 7-(7-bromo-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (500mg, 0.85mmol) was dissolved in dioxane/water (5mL/1mL), and (2-fluoro-6-hydroxyphenyl ) Boric acid (264mg, 1.69mmol), potassium phosphate (538mg, 2.54mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (78mg, 0.17mmol) and tris(dibenzylidene) Acetone) Dipalladium (77 mg, 0.09 mmol).
  • Step 3 Add 7-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazole (Alkolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (315mg, 0.51mmol) was dissolved in dichloromethane (3mL), and trifluoroacetic acid (3mL ). The reaction was stirred at room temperature for 30 minutes.
  • Step 4 Add 3-fluoro-2-(8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane -7-yl)-6-vinylquinazolin-7-yl)phenol (264mg, 0.51mL) was dissolved in dichloromethane (3mL), triethylamine (3mL) was added, cooled to 0 degrees, acrylic acid was added Anhydride (54 mg, 0.43 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction solution was extracted with dichloromethane and concentrated under reduced pressure.
  • Example 34 1-(7-(6-chloro-8-fluoro-2-((((2S,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7 -(5-Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)propen-2-one
  • Step 1 Dissolve (2S, 4S)-1-tert-butyl-2-methyl-4-hydroxypyrrolidine-1,2-dicarboxylate (3.0g, 12.2mmoL) in 60mL THF and cool in an ice bath To 0°C, slowly add LiAlH 4 (3.8 g, 100 mmol) in batches, warm to room temperature, and stir overnight.
  • Step 2 Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.0g,1.92mmoL) and (3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-ol (630mg, 4.81mmoL) dissolved in 5mL DMF and 5mL THF mixture, add Triethylenediamine (96mg, 0.86mmoL) and Cs 2 CO 3 (1.57g, 4.81mmoL), heated to 50°C for 2 hours, cooled to room temperature, added 100ml ethyl acetate, washed with water (3x30ml), saturated brine Washed, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 7-(7-bromo-6-chloro-8-fluor
  • Step 3 Add 7-(7-bromo-6-chloro-8-fluoro-2-((((2S, 4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)quine Oxazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (360mg, 0.58mmoL), (5-methyl-1H-indazol-4-yl) Boric acid (204mg, 1.16mmoL), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl) Phen-2-yl)palladium(II) (42mg, 0.058mmoL), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (48mg, 0.117mmoL) and K
  • Step 4 Add 7-(6-chloro-8-fluoro-2-((((2S,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(5 -Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.225mmoL) dissolved in In 4ml of dichloromethane, slowly add 2ml of trifluoroacetic acid dropwise at room temperature.
  • Step 5 Add (3S,5S)-5-((((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-two Azaspiro[3.5]nonane-7-yl)quinazolin-2-yl-2-hydroxymethyl)-1-methylpyrrolidin-4-ol (120mg, 0.212mmol) dissolved in dichloromethane Under ice-water bath conditions, add triethylamine (64.2mg, 0.636mmol) and acrylic anhydride (21mg, 0.17mmol) dropwise, and stir under ice-bath conditions for 10 minutes.
  • Example 35 1-(7-(6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy ])-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)propan-2 -En-1-one synthesis
  • Step 1 Add 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.0g ,1.92mmoL) and (3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-ol (630mg, 4.81mmoL) dissolved in 5mL DMF and 5mL THF mixture, add triethylene Amine (96mg, 0.86mmoL) and Cs 2 CO 3 (1.57g, 4.81mmoL), heated to 50°C for 2 hours, cooled to room temperature, added 100ml ethyl acetate, washed with water (3x30ml), saturated brine, no Dried with sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 7-bromo-6-chloro-8-fluoro-2-(((3S)
  • Step 2 Add 7-bromo-6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy) Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (295mg, 0.48mmoL), chloro(2-dicyclohexylphosphino-2',6 '-Dimethoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (35mg, 0.048mmoL), 2-dicyclohexyl Phosphine-2′,6′-dimethoxybiphenyl (20mg, 0.048mmoL) and K 3 PO 4 (254mg, 1.2mmoL) were added to 1,4-dioxane (2mL) and water (0.3
  • Step 3 Add 6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy]-7-(5 -Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (127mg, 0.19mmoL) dissolved In 4ml of dichloromethane, at room temperature, slowly add 2ml of trifluoroacetic acid dropwise, after reaction for 2 hours, add 10ml of dichloromethane, and concentrate under reduced pressure to obtain (2S, 4S)-4-((6-chloro-8 -Fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl) (O
  • Step 4 Add (2S, 4S)-4-((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diaza Spiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)-1-methylpyrrolidin-2-yl)methanol (107mg, 0.19mmol) dissolved in dichloromethane, ice-water bath Under conditions, triethylamine (57mg, 0.57mmol) and acrylic anhydride (19mg, 0.15mmol) were added dropwise, and stirred for 10 minutes under ice bath conditions.
  • Example 36 1-(7-(6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy ])-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)propan-2 -En-1-one synthesis
  • Step 1 Dissolve (2S, 4R)-1-tert-butyl-2-methyl-4-hydroxypyrrolidine-1,2-dicarboxylate (5.0g, 20.4mmoL) in 60mL THF and cool in an ice bath To 0°C, slowly add LiAlH 4 (5.03 g, 132 mmol) in batches, warm to room temperature, and stir overnight.
  • Step 2 Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (1.58g, 12.01mmoL) and (3R,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-ol (2.5g, 4.81mmoL) were dissolved in a mixture of 20mL DMF and 20mL THF , Add triethylenediamine (270mg, 2.4mmoL) and Cs 2 CO 3 (3.9g, 12.01mmoL), heat to 50°C for 26 hours, cool to room temperature, add 100ml ethyl acetate, wash with water (3x30ml), saturated Washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 7-(7-bromo-6-chloro-8-
  • Step 3 Add 7-(7-bromo-6-chloro-8-fluoro-2-((((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)quine Oxazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (700mg, 1.14mmoL), (5-methyl-1H-indazol-4-yl) ) Boric acid (300mg, 1.71mmoL), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2'-amino-1,1'- Biphenyl-2-yl)palladium(II) (82mg, 0.11mmoL), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (93mg, 0.22mmoL) and K 3 PO 4
  • Step 4 Add 7-(6-chloro-8-fluoro-2-((((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(5 -Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (110mg, 0.165mmoL) dissolved In 4ml of dichloromethane, 2ml of trifluoroacetic acid was slowly added dropwise at room temperature.
  • Step 5 Add (3R,5S)-5-((((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-two Azaspiro[3.5]nonane-7-yl)quinazolin-2-yl-2-hydroxymethyl)-1-methylpyrrolidin-4-ol (120mg, 0.212mmol) dissolved in dichloromethane Under ice-water bath conditions, add triethylamine (64.2mg, 0.636mmol) and acrylic anhydride (21mg, 0.17mmol) dropwise, and stir under ice-bath conditions for 10 minutes.
  • Step 1 Add 6,7-dichloropyrido[2,3-d]pyrimidine-2,4-diol (1g, 4.31mmol), (2-fluoro-6-methoxybenzene) to a 25mL microwave reaction tube Base) Boric acid (1.1g, 6.46mmol), Pd(dppf)Cl 2 (457mg, 0.56mmol), K 2 CO 3 (1.189g, 8.62mmol), 14mL 1,4-dioxane, 2.5mL water, Under nitrogen replacement protection, react at 100°C for 1 hour.
  • Step 2 Add 6-chloro-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d]pyrimidine-2,4-diol (400mg, 1.24) to a 100mL round bottom flask mmol), 10 mL POCl 3 , and stirring at 80°C for 0.5 hour. Add 15 mL of toluene, add 10 mL of DIPEA dropwise, and stir at 80-90°C for 2 hours.
  • Step 3 Add 2,4,6-trichloro-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d]pyrimidine (50mg, 0.139mmol) into a 50mL round bottom flask , 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (31mg, 0.139mmol), 5mL 1,4-dioxane, TEA (42mg, 0.417mmol), reaction at room temperature 1 hour.
  • Step 4 Add 7-(2,6-dichloro-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d]pyrimidin-4-yl) into a 50mL round bottom flask -2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (76mg, 0.139mmol), N,N-dimethylazetidine-3-amine dihydrochloride ( 31 mg, 0.18 mmol), 5 mL of 1,4-dioxane, DIPEA (89 mg, 0.695 mmol), and react at 60°C for 2 hours.
  • Step 5 Add 7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(2-fluoro-6-methoxy) into a 50mL round bottom flask Phenyl)pyrido[2,3-d]pyrimidin-4-yl-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (30mg, 0.048mmol), 3mL methanol, 4M HCl/dioxane (3mL, 12mmol), react at room temperature for 1.5 hours.
  • Step 6 To the above 1-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)pyridine Add 3mL DCM, TEA (15mg, 0.15mmol) to the crude product of [2,3-d]pyrimidin-2-yl-N,N-dimethylazetidine-3-amine, and cool in an ice-water bath Acrylic anhydride (6mg, 0.048mmol) was added and reacted for 1 hour.
  • Step 7 To the above-(7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(2-fluoro-6-methoxyphenyl )Pyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one crude product was added with 5mL DCM, Place in an ice-salt bath, add 1M BBr 3 / DCM (0.5 mL, 0.5 mmol), and react at -10°C to 20°C for 2 hours.
  • Step 1 Methyl 2-bromo-6-methylbenzoate (7g, 31mmol), NBS (5.75g, 32.5mmol) and azobisisobutyronitrile (262mg, 1.6mmol) are added to carbon tetrachloride in one pot The solution (100 mL) was sealed and refluxed (85 degrees) overnight, cooled, filtered, and washed with petroleum ether to filter out the solid. The filtrate was concentrated, THF (80 mL), ammonia water (20 mL) were added, stirred at room temperature overnight, ethyl acetate (300 mL) was added, and washed with water (50 mL x 2).
  • Step 2 7-Bromoisoindolin-1-one (500mg, 2.4mmol), double pinacol borate (663mg, 2.61mmol), Pd(dppf)Cl 2 (88mg, 0.12mmol) and acetic acid Potassium (480mg, 4.8mmol) was added to dioxane (10mL), stirred at 90° under argon protection for 3 hours, and filtered after cooling. The filtrate was concentrated to obtain 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (black solid, 700mg, Y: 9%).
  • ES-API: [M+H] + 260.1.
  • Step 3 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.04g, 2mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (460mg, 4mmol), triethylenediamine (45mg, 0.4mmol) and cesium carbonate (2g, 6mmol) were added to In DMF (12mL), stir overnight at 50°C under argon protection.
  • Step 4 (S)-7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)- 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (300mg, 0.5mmol), 7-(4,4,5,5-tetramethyl-1,3,2-bis Oxyborolan-2-yl) isoindolin-1-one (194mg, 0.75mmol), Pd 2 (dba) 3 (46mg, 0.05mmol), 2-Dicyclohexylphosphino-2′,6′ -Dimethoxybiphenyl (41mg, 0.1mmol), Na 2 CO 3 (190mg, 1.8mmol) was added to a microwave tube (20mL) containing dioxane/water (4/1,5mL), microwave React at 90 degrees for 150 minutes, add EA (30 m
  • Step 5 7-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-oxo-2,3- Dihydro-1H-indene-tert-butyl)piperidin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg ,0.15mmol) was dissolved in a mixture of dioxane hydrochloride (4M) and methanol (2/2mL), stirred at room temperature for 1 hour and then spin-dried to obtain 7-(6-chloro-8-fluoro-2-((( S)-1-Methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-7-yl)-2 ,3-Di
  • Step 6 7-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[ 3.5]
  • Example 40 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(quinurea-3-oxy)quinazoline -4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (300mg, 0.576mmol), quininyl-3-ol (225mg, 1.73mmol), cesium carbonate (570mg, 1.73mmol) and 1,4-diazabicyclo[2.2.2]octane (15mg, 0.116 mmol) was added to dry tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL). The reaction solution was stirred at 60 degrees for 16 hours.
  • Step 2 7-(7-bromo-6-chloro-8-fluoro-2-(quinurea-3-oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non Tert-butyl alkane-2-carboxylate (352mg, 0.576mmol, crude product), (5-methyl-1H-indazol-4-yl)boronic acid (160mg, 0.864mmol), sodium carbonate (130mg, 1.16mmol), Tris(dibenzylideneacetone)dipalladium (30mg, 0.029mmol) and 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (29mg, 0.058mmol) add dioxane (2.0mL) In water (2.0 mL), replace with argon three to five times.
  • reaction solution was heated at 100 degrees in the microwave and stirred for 90 minutes.
  • the reaction was cooled to room temperature, filtered, and the filtrate was extracted three times with ethyl acetate (10.0 mL ⁇ 3), and the organic phases were combined.
  • the organic phase was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate.
  • Step 3 7-(6-chloro-8-fluoro-7-(4-methyl-1H-indazol-3-yl)-2-(quinurea-3-oxy)quinazolin-4-yl )-2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.23mmol) and dioxane hydrochloride (10.0mL) were added to methanol (10mL), reaction solution 25 The reaction time was 2 hours; the reaction solution was concentrated to obtain a yellow solid as 3-((6-chloro-8-fluoro-7-(5-methyl-1H-indolazol-4-yl)-4-(2,7- Diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)quinazolidine (127 mg, Y: 90%).
  • ES-API: [M+H] + 562.2.
  • Example 41 1-(7-(6-Chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-2-(3-(dimethylamino)azetidin Alk-1-yl)pyridyl(2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one synthesis
  • Step 1 Add 6,7-dichloropyrido[2,3-d]pyrimidine-2,4-diol (0.3g, 1.29mmoL), (3,5-dimethyl-1-tolyl-1H -Indazol-4-yl)boronic acid (0.53g, 1.55mmoL), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (93mg, 0.129mmoL), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (53mg, 0.129 mmoL) and K 3 PO 4 (820mg, 3.87mmoL) were added to the mixture of 1,4-dioxane (10mL) and water (1mL), replaced with nitrogen three times, heated to 110°C, stirred for 1.5 hours, and
  • Step 2 Add 6-chloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4-diol (70mg, 0.141mmoL) dissolved in 3ml of toluene, slowly dripped 3ml of phosphorus oxychloride and 3ml of diisopropylethylamine at room temperature, heated to 110°C for 2 hours, concentrated under reduced pressure, and obtained by column chromatography 2,4,6-Trichloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine (45mg, Y: 60 %).
  • ES-API: [M+H] + 532.0.
  • Step 3 Add 2,4,6-trichloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine (45mg , 0.084mmol) was dissolved in 3ml of dichloromethane, and triethylamine (26mg, 0.254mmol) was added dropwise under ice-water bath conditions. Add 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (57mg, 0.254mmol), and stir under ice bath for 10 minutes.
  • N,N-dimethylazetidine-3-amine (25.4 mg, 0.254 mmol) was added and reacted at 40° C. for 30 minutes.
  • Step 4 Add 7-(6-chloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)-2-(3-(dimethylamino)aza Cyclobutan-1-yl)pyridine[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (7mg, 0.009mmol) Dissolve in 3ml methanol, add 3ml 2M sodium hydroxide aqueous solution, heat at 80°C to react for 2h, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain 7-(6-chloro-7-(3,5-dimethyl Yl-1H-indazol-4-yl)-2-(3-(dimethylamino)azetidin-1-yl)pyridine[2,3-d]pyrimidin-4-yl)-2, 7-
  • Step 5 Add 7-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-2-(3-(dimethylamino)azetidine-1 -Yl)pyridine[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (5mg, crude product) dissolved in 2ml dichloromethane Add 1ml of trifluoroacetic acid and react at room temperature for 1h.
  • Step 6 Add 1-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7 -Yl)pyridyl[2,3-d]pyrimidin-2-yl)-N,N-dimethylazetidine-3-amine (6mg, crude product) was dissolved in 2ml of dichloromethane and added dropwise Triethylamine (20mg) and acryloyl chloride (2mg) were stirred under ice bath for 10 minutes.
  • Step 1 Add 6,7-dichloropyrido[2,3-d]pyrimidine-2,4-diol (0.3g, 1.29mmoL), (3-chloro-5-methyl-1H-indazole- 4-yl)boronic acid (325mg, 1.55mmoL), Pd(PPh 3 ) 4 (149mg, 0.129mmoL) and K 2 CO 3 (820mg, 3.87mmoL) were added to 1,4-dioxane (10mL) and water (1mL) in the mixed solution, replace with nitrogen for 3 times, heat to 110°C, stir for 1.5 hours, after the reaction is complete, cool to room temperature, filter, concentrate, add 100ml ethyl acetate, wash with water (3x50ml) and saturated brine in turn.
  • Step 2 Add 6-chloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4-diol (70mg, 0.165mmoL) was dissolved in 5ml of dichloromethane, p-toluenesulfonic acid (2.8mg, 0.0165) and THP (139mg, 1.65mmol) were slowly added dropwise at room temperature. After 16 hours of reaction at room temperature, it was concentrated under reduced pressure.
  • Step 3 Add 6-chloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrido(2, 3-d]Pyrimidine-2,4-diol (44mg, 0.099mmol) was dissolved in 3ml of toluene. At room temperature, slowly add 3ml of phosphorus oxychloride and 3ml of diisopropylethylamine, and heat to 110°C to react.
  • Step 4 Add 2,4,6-trichloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) Pyridine[2,3-d]pyrimidine (28mg, 0.058mmol) was dissolved in 3ml of dichloromethane, and triethylamine (26mg, 0.254mmol) was added dropwise under ice-water bath conditions. Add 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (57mg, 0.254mmol), and stir under ice bath for 10 minutes.
  • N,N-dimethylazetidine-3-amine (25.4 mg, 0.254 mmol) was added and reacted at 40° C. for 30 minutes.
  • Step 5 Add 7-(6-chloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2 -(3-(Dimethylamino)azetidin-1-yl)pyridine[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2 -Tert-butyl carboxylate (15mg, crude product) was dissolved in 2ml of dichloromethane, 2ml of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2h.
  • Step 6 Add 1-(6-chloro-7-(3-chloro-5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane- 7-yl)pyridyl[2,3-d]pyrimidin-2-yl)-N,N-dimethylazetidine-3-amine (8mg, crude product) was dissolved in 2ml of dichloromethane and dropped Add triethylamine (10mg) and acryloyl chloride (2mg), and stir for 10 minutes under ice bath conditions.
  • Example 43 1-(7-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((R)-4-methylmorpholine -3-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
  • Step 1 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2g, 3.8mmol), (R)-(4-methylmorpholin-3-yl)methanol (1g, 7.7mmol), 1,4-diazabicyclo[2.2.2]octane (86mg, A mixture of 0.77 mmol), cesium carbonate (2.5 g, 7.7 mmol) in N,N-dimethylformamide (1.5 mL) and tetrahydrofuran (1.5 mL) was placed in a microwave tube and reacted in a microwave at 120°C for 1 hour.
  • Step 2 Add (R)-7-(7-bromo-6-chloro-8-fluoro-2-((4-methylmorpholin-3-yl)methoxy)quinazole to the 10mL microwave reaction tube Lin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1g, 1.63mmol), (5-methyl-1H-indazol-4-yl) Boric acid (430mg, 2.45mmol), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (70mg, 0.17mmol), Chlorine (2-Dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (120mg, 0.17mmol), potassium phosphate (400mg, 1.
  • Step 3 To 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((((R)-4-methylmorpholine-3 -Yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.60mmol) in dichloromethane (5mL) Trifluoroacetic acid (2.5 mL) was added to the solution. Stirred at room temperature for 1 hour.
  • Step 4 The crude product (3R)-3-((((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl))-4-(2 , 7-diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)methyl)-4-methylmorpholine (350mg) was added dichloromethane (10mL), Triethylamine (300mg, 2.97mmol). After the solution is clear, slowly add acrylic anhydride (62 mg, 0.49 mmol) dropwise in an ice-water bath, and stir for 30 minutes.
  • Step 1 Add 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (1g, 2.37mmol), 2,7-diazaspiro[3.5]nonane to the round bottom flask Tert-Butyl-2-carboxylate (0.54 g, 2.37 mmol), triethylamine (0.48 g, 4.74 mmol) and 20 mL of dioxane. The reaction was stirred at 50°C for 30 minutes.
  • Step 2 Add 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane- to the round bottom flask Tert-Butyl 2-carboxylate (1.4g, 2.29mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (0.79g, 6.87mmol), triethylenediamine (0.025g, 0.23mmol) ), cesium carbonate (2.2 g, 6.87 mmol), 5 mL dry N,N-dimethylformamide and 10 mL dry tetrahydrofuran. The reaction was stirred at 25°C for 16 hours.
  • Step 3 Add (S)-7-(7-bromo-8-fluoro-6-iodo-2-((1-methylpyrrolidin-2-yl)methoxy)quinazoline to the round bottom flask -4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.8g, 1.16mmol), 1M sodium ethoxide in ethanol (1.8mL) and tetrahydrofuran (25mL ). The reaction was stirred at 60°C for 30 minutes. LC-MS detects that the reaction is complete. The reaction solution was quenched with 1M hydrochloric acid. Extract 3 times with ethyl acetate.
  • Step 4 Add (S)-7-(7-bromo-8-ethoxy-6-iodo-2-((1-methylpyrrolidin-2-yl)methoxy)quinazole to the reaction flask Lin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (250mg, 0.35mmol), potassium vinyl fluoroborate (75mg, 0.56mmol), Pd(dppf ) Cl 2 -DCM (28 mg, 0.035 mmol), potassium phosphate (223 mg, 1.05 mmol), 8 mL dioxane and 2 mL water.
  • Step 5 Add (S)-7-(7-bromo-8-ethoxy-2-((1-methylpyrrolidin-2-yl)methoxy)-6-vinylquine to the reaction flask (Azolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (90mg, 0.15mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (68mg , 0.44mmol), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2 -Base) palladium(II) (11mg, 0.015mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (6mg, 0.015mmol), potassium phosphate (93mg, 0.44m
  • Step 6 Add 7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((((S)-1-methylpyrrolidine-2- Yl)methoxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (80mg, 0.12mmol), 1mL methanol And 4M hydrogen chloride/dioxane solution (1mL). Stir at room temperature for 1 hour, LC-MS detected the completion of the reaction.
  • Step 7 Add 2-(8-ethoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7- Diazaspiro[3.5]nonane-7-yl)-6-vinylquinazolin-7-yl)-3-fluorophenol (67mg, 0.12mmol), 5mL dichloromethane and triethylamine (71mg, 0.7mmol). The reaction was cooled to 0°C, and a dichloromethane solution of acrylic anhydride (12mg, 0.1mmol, 0.5mL) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 10 minutes.
  • Example 45 1-(7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-(4-methylpiperazin-1-yl)-6-vinylquine Synthesis of oxazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
  • Step 1 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (2g, 3.27mmol), 1-methylpiperazine (654mg, 6.54mmol), cesium carbonate (3.18mg, 9.81mmol) was added to DMF (20mL), then triethylenediamine (73mg, 0.65mmol) , React at room temperature for 16 hours, pour the reaction solution into water for quenching, extract with ethyl acetate, and separate the crude product by column chromatography to obtain a yellow solid 7-(7-bromo-8-fluoro-6-iodo-2-(4-methylpiperidine) (Azin-1-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid ter
  • Step 2 7-(7-bromo-8-fluoro-6-iodo-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,7-diazaspiro[ 3.5]
  • Nonane-2-carboxylic acid tert-butyl ester (1.3g, 1.92mmol), dissolved in acetonitrile (10mL), add sodium ethoxide (130mg, 1.92mmol), after the addition, increase the temperature to 80 degrees and react for 2 hours, the reaction liquid drops Pour into water (20mL) at room temperature, extract with ethyl acetate (50mL x 2), the crude product 7-(7-bromo-8-ethoxy-6-iodo-2-(4-methylpiperazine-1- (Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was used directly in the next
  • Step 3 7-(7-bromo-8-ethoxy-6-iodo-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,7-diazepine Spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.4g, 1.5mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborole Cyclopentane (296mg, 1.92mmol), sodium carbonate (407mg, 3.0mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (140mg), were added to dioxane in sequence In the mixed solvent of ring (10 mL) and water (2 mL), replace with nitrogen three times and react at 35 degrees for 1 hour.
  • Step 4 7-(7-bromo-8-ethoxy-2-(4-methylpiperazin-1-yl)-6-vinylquinazolin-4-yl)-2,7-diazepine Heterosspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (600mg, 1.0mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (312mg, 2.0mmol), tripotassium phosphate (636mg, 3.0mmol) , Chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (72mg), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (82mg), added to dioxane (8mL) water
  • Step 5 7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-(4-methylpiperazin-1-yl)-6-vinylquinazoline-4 -Yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.2mmol), dissolved in dichloromethane (3mL), add trifluoroacetic acid (1mL) at room temperature React for 1 hour and concentrate to dry to obtain 2-(8-ethoxy-2-(4-methylpiperazin-1-yl)-4-(2,7-diazaspiro[3.5]nonane-7 -Yl)-6-vinylquinazolin-7-yl)-3-fluorophenol crude product (400mg, yield 100%), used directly in the next step.
  • Step 6 2-(8-Ethoxy-2-(4-methylpiperazin-1-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)-6 -Vinylquinazolin-7-yl)-3-fluorophenol crude product (400mg, 0.63mmol) and triethylamine (128mg, 1.28mmol), dissolved in dichloromethane (3mL), add acrylic acid after cooling to 0 degrees Anhydride (71mg, 0.57mmol), incubate at 0 degrees and react for 1 hour.
  • Examples 46-58 are prepared by referring to the synthesis method of Example 19 or 45 or the similar method of other examples above:
  • NCI-H358 is a human non-small cell lung cancer cell line with Kras G12C mutation, cultured in 10% FBS RPMI-1640 medium;
  • A549 is a human lung adenocarcinoma cell line with Kras G12S mutation, cultured in 10% FBS F-12K ⁇ .
  • the concentration is 1X, and the DMSO content is 0.1%.
  • DMSO was used as an experimental control (control), and 2% FBS medium was used as a blank control (blank). After adding the compound and culturing the cells for 5 days, add 25 ⁇ l of CellTiter-Glo working solution to each well, mix at 400rpm and incubate for 30 minutes.

Abstract

Disclosed are a spiro-substituted pyrimidine-fused cyclic compound represented by Formula I or Formula II and pharmaceutically acceptable salts, stereoisomers, solvent compounds or prodrugs thereof. The compound has a selective inhibitory effect on KRAS gene mutation. Also disclosed is a pharmaceutical composition containing the compound and an application thereof to the preparation of cancer drugs.

Description

螺环取代的嘧啶并环类化合物，其制法与医药上的用途Spirocyclic substituted pyrimido ring compound, its preparation method and medical use 技术领域Technical field
本发明涉及医药技术领域，特别涉及一种螺环取代的嘧啶并环类化合物，及其作为KRAS基因突变的选择性抑制剂的应用，以及由其制备的药物组合物。The present invention relates to the technical field of medicine, in particular to a spirocyclic substituted pyrimidocyclic compound, its application as a selective inhibitor of KRAS gene mutation, and a pharmaceutical composition prepared therefrom.
背景技术Background technique
肺癌是全球发病率最高的癌症，在中国肺癌发病率位居所有癌症中第一位，也是中国发病率和死亡率最高的癌症，根据2016年美国癌症协会公布的数据，世界上一年中约180万人罹患肺癌，其中接近80％的肺癌为非小细胞肺癌(NSCLC)。Lung cancer is the cancer with the highest incidence in the world. It ranks first among all cancers in China. It is also the cancer with the highest incidence and mortality in China. According to data released by the American Cancer Society in 2016, about 1.8 million people suffer from lung cancer, of which nearly 80% are non-small cell lung cancer (NSCLC).
RAS为一组紧密相关的单体球状蛋白质(21kDa分子量)，其具有188-189个氨基酸且与鸟苷二磷酸GDP或鸟苷三磷酸GTP结合。RAS亚家族成员包括HRAS、KRAS和NRAS。RAS起分子开关作用，当RAS含有所结合的GDP时，其处于休眠或关闭位置且“无活性”。当细胞暴露于某些促生长性刺激物时，RAS经诱导而使其所结合的GDP转化为GTP，当与GTP结合时，RAS“接通”且能够与其他下游标靶蛋白质相互作用并活化这些蛋白质。RAS蛋白自身使GTP水解而恢复为GDP(从而使其自身转换为关闭状态)的固有能力极低。需要外源性蛋白GTP酶活化蛋白(GAP)将其恢复为关闭状态，GAP与RAS相互作用极大地加速了GTP转化为GDP。RAS is a group of closely related monomeric globular proteins (21 kDa molecular weight), which have 188-189 amino acids and bind to guanosine diphosphate GDP or guanosine triphosphate GTP. Members of the RAS subfamily include HRAS, KRAS, and NRAS. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a dormant or closed position and is "inactive". When cells are exposed to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. When it binds to GTP, RAS is “on” and can interact with other downstream target proteins and activate These proteins. The RAS protein itself has a very low inherent ability to hydrolyze GTP and restore it to GDP (thus turning itself into a closed state). The exogenous protein GTPase Activated Protein (GAP) is required to restore it to the closed state. The interaction between GAP and RAS greatly accelerates the conversion of GTP to GDP.
RAS中的任何突变将影响RAS与GAP的相互作用，以及GTP转化为GDP的能力，这种突变将导致蛋白质活化时间的延长，从而延长细胞信号传导，继而导致细胞继续生长和***。由于这种信号传导引起细胞生长和***，因此过度活化的RAS信号传导最终可导致癌症。Any mutation in RAS will affect the interaction between RAS and GAP, as well as the ability of GTP to convert into GDP. This mutation will lead to prolonged protein activation time, thereby prolonging cell signal transduction, and then causing cells to continue to grow and divide. Since this signaling causes cell growth and division, over-activated RAS signaling can eventually lead to cancer.
在肺癌中，约32％的肺癌中确认有RAS基因的突变，RAS(HRAS、NRAS或KRAS)基因的三种主要亚型中的任意一个突变可导致人肿瘤的发生。有报道指出，在RAS基因中突变频率最高的为KRAS基因，在25-30％肿瘤中检测到KRAS突变。与之相比较，NRAS及HRAS家族成员中发生致癌性突变的比率低得多(分别为8％及3％)。最常见的KRAS突变发现于P环中的残基G12及G13上以及残基Q61上。G12C突变为KRAS基因的频繁突变(甘氨酸-12突变为半胱氨酸)。在约13％的癌症，约43％的肺癌及几乎100％的MYH相关息肉病(家族性结肠癌症候群)中已发现此突变。Among lung cancers, mutations in the RAS gene are confirmed in about 32% of lung cancers. A mutation in any of the three main subtypes of the RAS (HRAS, NRAS or KRAS) gene can lead to human tumors. It has been reported that the KRAS gene has the highest mutation frequency among the RAS genes, and KRAS mutations are detected in 25-30% of tumors. In comparison, the rates of oncogenic mutations in NRAS and HRAS family members are much lower (8% and 3%, respectively). The most common KRAS mutations are found in residues G12 and G13 and residue Q61 in the P loop. The G12C mutation is a frequent mutation of the KRAS gene (mutation of glycine-12 to cysteine). This mutation has been found in about 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-related polyposis (familial colon cancer syndrome).
因此开发选择性抑制KRAS突变的抑制剂是一个较好的方向，为了提高对KRAS突变抑制活性的同时降低对野生型KRAS的抑制活性，开发活性更高，选择性更好，毒性更低的新型RAS突变体选择性抑制剂具有重要的意义。Therefore, it is a better direction to develop inhibitors that selectively inhibit KRAS mutations. In order to increase the inhibitory activity against KRAS mutations while reducing the inhibitory activity against wild-type KRAS, develop new types with higher activity, better selectivity, and lower toxicity. Selective inhibitors of RAS mutants are of great significance.
发明内容Summary of the invention
本发明提供了一种螺环取代的嘧啶并环类化合物，其作为KRAS突变的选择性抑制剂，具有活性高，选择性好且毒副作用低等优点。The present invention provides a spirocyclic substituted pyrimidocyclic compound, which, as a selective inhibitor of KRAS mutation, has the advantages of high activity, good selectivity, and low toxicity and side effects.
在一个方面，本发明提供了一种式(I)所示的螺环取代的嘧啶并环类化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或其前药：In one aspect, the present invention provides a spirocyclic substituted pyrimidocyclic compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof:
Figure PCTCN2020077192-appb-000001
Figure PCTCN2020077192-appb-000001
式中，Where
m为1或2；n为1；m is 1 or 2; n is 1;
B为取代或未取代的C 6-14芳基、或取代或未取代的C 5-14杂芳基； B is a substituted or unsubstituted C 6-14 aryl group, or a substituted or unsubstituted C 5-14 heteroaryl group;
Z为N或CR 3； Z is N or CR 3 ;
R 1、R 3各自独立地为氢、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、或取代或未取代的C 3-20环烷基； R 1 and R 3 are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, substituted or unsubstituted C 2-8 alkenyl, A substituted or unsubstituted C 2-8 alkynyl group, or a substituted or unsubstituted C 3-20 cycloalkyl group;
L为一个键、CR 11R 12、O-(CR 11R 12) t1或NH-(CR 13R 14) t2； L is a bond, CR 11 R 12 , O-(CR 11 R 12 ) t1 or NH-(CR 13 R 14 ) t2 ;
R 2为卤素、羟基、-SO 2C 1-6烷基、取代或未取代的C 3-20杂环基、取代或未取代的C 3-20环烷基、取代或未取代的5或6元单杂芳基、或NR 21R 22； R 2 is halogen, hydroxyl, -SO 2 C 1-6 alkyl, substituted or unsubstituted C 3-20 heterocyclyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl group, or NR 21 R 22 ;
R 11、R 12、R 13、R 14相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、C 1-3烷基或氧代基； R 11 , R 12 , R 13 , and R 14 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or oxo;
R 21、R 22各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基、-C(O)卤代C 1-6烷基；或者R 21和R 22与相连的氮原子共同形成取代或未取代的C 3-20杂环基； R 21 and R 22 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)halo C 1-6 alkyl; or R 21 and R 22 and the connected nitrogen atom together form a substituted or unsubstituted C 3-20 heterocyclic group;
t1、t2各自独立地为0、1、2、3或4；t1 and t2 are each independently 0, 1, 2, 3 or 4;
上述基团中，所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自下述S组取代基所取代：羟基、卤素、硝基、氧代基、C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-C 3-6单环杂环基、-(CH 2) u-5或6元单杂芳基、-(CH 2) u-C 3-8单环环烷基、-(CH 2) u-O-(CH 2) v-C 3-8单环环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中所述C 3-6单环杂环基、5或6元单杂芳基任选地被1、2或3个选自卤素、氰基、C 1-3烷基、C 1-3烷氧基和C 3-6单环环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基。 In the above group, the "substituted" means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the following S group: hydroxyl, halogen, nitro, oxygen Substitute, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl, -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -( CH 2 ) u -halo C 1-6 alkoxy, -(CH 2 ) u -halo C 1-6 alkyl, -(CH 2 ) u -C 3-6 monocyclic heterocyclic group, -( CH 2 ) u -5 or 6-membered monoheteroaryl, -(CH 2 ) u -C 3-8 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 Monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 1-6 alkoxy, -(CH 2 ) u -O-(CH 2 ) v OH, -(CH 2 ) u -SO 2 C 1-6 alkyl, -(CH 2 ) u -NR a0 R b0 , -(CH 2 ) u -C(O)NR a0 R b0 , -(CH 2 ) u -C(O) C 1-6 alkyl, -C(O)OC 1-6 alkyl, NR a0 C(O)-(CH 2 ) u -NR a0 R b0 , NR a0 C(O)-(CH 2 ) u OH , NR a0 C(O)-halo C 1-6 alkyl; wherein the C 3-6 monocyclic heterocyclic group, 5 or 6-membered monoheteroaryl group is optionally selected from 1, 2 or 3 Substituent substitution of halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 monocyclic cycloalkyl; u and v are each independently 0, 1, 2, 3 or 4 ; R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
在本发明的一种实施方案中，R 1为氢、卤素、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基、取代或未取代的C 2-4烯基、取代或未取代的C 2-4炔基、或取代或未取代的C 3-6环烷基。 In one embodiment of the present invention, R 1 is hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 2- 4 Alkenyl, substituted or unsubstituted C 2-4 alkynyl, or substituted or unsubstituted C 3-6 cycloalkyl.
在本发明的一种实施方案中，R 1为氢、卤素或取代或未取代的乙烯基。 In one embodiment of the invention, R 1 is hydrogen, halogen, or substituted or unsubstituted vinyl.
在本发明的一种实施方案中，R 1为氯或氟。 In one embodiment of the invention, R 1 is chlorine or fluorine.
在本发明的一种实施方案中，Z为N。In one embodiment of the invention, Z is N.
在本发明的一种实施方案中，Z为CR 3。 In one embodiment of the invention, Z is CR 3 .
在本发明的一种实施方案中，R 3为氢或卤素。 In one embodiment of the present invention, R 3 is hydrogen or halo.
在本发明的一种实施方案中，R 3为氢或氟。 In one embodiment of the present invention, R 3 is hydrogen or fluoro.
在本发明的一种实施方案中，L为一个键；R 2为NR 21R 22；其中R 21和R 22与相连的氮原子共同形成取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。 In one embodiment of the present invention, L is a bond; R 2 is NR 21 R 22 ; wherein R 21 and R 22 and the connected nitrogen atom together form a substituted or unsubstituted 3- to 6-membered saturated or partially unsaturated Monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11 membered spiro heterocyclic group; the "substituted" refers to a group 1, 2, 3, or 4 hydrogen atoms are each independently selected from the S group substituent.
在本发明的一种实施方案中，L为CR 11R 12、O-(CR 11R 12) t1或NH-(CR 13R 14) t2；R 2为卤素、羟基、-SO 2C 1-6烷基、取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基、取代或未取代的C 3-8环烷基、取代或未取代的5或6元单杂芳基、或NR 21R 22；其中R 11、R 12、R 13、R 14相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、C 1-3烷基或氧代基；R 21、R 22各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基、-C(O)卤代C 1-6烷基；或者R 21和R 22与相连的氮原子共同形成取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基；t1、t2各自独立地为0、1、2、3或4；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。 In one embodiment of the present invention, L is CR 11 R 12 , O-(CR 11 R 12 ) t1 or NH-(CR 13 R 14 ) t2 ; R 2 is halogen, hydroxyl, -SO 2 C 1- 6 alkyl, substituted or unsubstituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 To 11-membered spiro heterocyclyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl, or NR 21 R 22 ; wherein R 11 , R 12 , R 13 , R 14 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or oxo; R 21 and R 22 are each independently hydrogen, substituted or not Substituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl, -C (O) C 1-6 alkyl, -C (O) halo C 1-6 alkyl; or R 21 and R 22 and the connected nitrogen atom together form a substituted or unsubstituted 3 to 6-membered saturated or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10-membered saturated or Partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11-membered spiro heterocyclic group; t1 and t2 are each independently 0, 1, 2, 3 or 4; the "substituted" refers to the group 1, 2, 3, or 4 hydrogen atoms are each independently selected from the S group substituent.
在另一个方面，本发明提供了一种式(II)所示的螺环取代的嘧啶并环类化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或其前药：In another aspect, the present invention provides a spirocyclic substituted pyrimidocyclic compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof:
Figure PCTCN2020077192-appb-000002
Figure PCTCN2020077192-appb-000002
式中，Where
A为取代或未取代的C 6-14芳基、或取代或未取代的C 5-14杂芳基； A is a substituted or unsubstituted C 6-14 aryl group, or a substituted or unsubstituted C 5-14 heteroaryl group;
W、R a为选自下组的组合： W, R a is selected from the group consisting of a combination of:
(i)W为N；R a为氢、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、或取代或未取代的C 3-20环烷基； (i) W is N; R a is hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, substituted or unsubstituted C 2-8 alkenyl group , Substituted or unsubstituted C 2-8 alkynyl, or substituted or unsubstituted C 3-20 cycloalkyl;
(ii)W为CR c；R a、R c各自独立地为氢、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、或取代或未取代的C 3-20环烷基； (ii) W is CR c ; R a and R c are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, or substituted or unsubstituted C 3-20 cycloalkyl;
Q为一个键、CR a1R b1、O-(CR a1R b1) q1或NH-(CR c1R d1) q2； Q is a bond, CR a1 R b1 , O-(CR a1 R b1 ) q1 or NH-(CR c1 R d1 ) q2 ;
R b为卤素、羟基、-SO 2C 1-6烷基、取代或未取代的C 3-20杂环基、取代或未取代的C 3-20 环烷基、取代或未取代的5或6元单杂芳基、或NR a2R b2； R b is halogen, hydroxy, -SO 2 C 1-6 alkyl, substituted or unsubstituted C 3-20 heterocyclyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl group, or NR a2 R b2 ;
R a1、R b1、R c1、R d1相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、C 1-3烷基或氧代基； R a1 , R b1 , R c1 , and R d1 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or oxo;
R a2、R b2各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基、-C(O)卤代C 1-6烷基；或者R a2和R b2与相连的氮原子共同形成取代或未取代的C 3-20杂环基； R a2 and R b2 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)halo C 1-6 alkyl; or Ra2 and R b2 together with the connected nitrogen atom to form a substituted or unsubstituted C 3-20 heterocyclic group;
q1、q2各自独立地为0、1、2、3或4；q1 and q2 are each independently 0, 1, 2, 3 or 4;
上述基团中，所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自下述S组取代基所取代：羟基、卤素、硝基、氧代基、C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-C 3-6单环杂环基、-(CH 2) u-5或6元单杂芳基、-(CH 2) u-C 3-8单环环烷基、-(CH 2) u-O-(CH 2) v-C 3-8单环环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中所述C 3-6单环杂环基、5或6元单杂芳基任选地被1、2或3个选自卤素、氰基、C 1-3烷基、C 1-3烷氧基和C 3-6单环环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基。 In the above group, the "substituted" means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the following S group: hydroxyl, halogen, nitro, oxygen Substitute, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl, -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -( CH 2 ) u -halo C 1-6 alkoxy, -(CH 2 ) u -halo C 1-6 alkyl, -(CH 2 ) u -C 3-6 monocyclic heterocyclic group, -( CH 2 ) u -5 or 6-membered monoheteroaryl, -(CH 2 ) u -C 3-8 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 Monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 1-6 alkoxy, -(CH 2 ) u -O-(CH 2 ) v OH, -(CH 2 ) u -SO 2 C 1-6 alkyl, -(CH 2 ) u -NR a0 R b0 , -(CH 2 ) u -C(O)NR a0 R b0 , -(CH 2 ) u -C(O) C 1-6 alkyl, -C(O)OC 1-6 alkyl, NR a0 C(O)-(CH 2 ) u -NR a0 R b0 , NR a0 C(O)-(CH 2 ) u OH , NR a0 C(O)-halo C 1-6 alkyl; wherein the C 3-6 monocyclic heterocyclic group, 5 or 6-membered monoheteroaryl group is optionally selected from 1, 2 or 3 Substituent substitution of halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 monocyclic cycloalkyl; u and v are each independently 0, 1, 2, 3 or 4 ; R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
在本发明的一种实施方案中，R a为氢或卤素。 In one embodiment of the present invention, R a is hydrogen or halogen.
在本发明的一种实施方案中，R a为氯或氟。 In one embodiment of the present invention, R a is chloro or fluoro.
在本发明的一种实施方案中，W为N。In one embodiment of the invention, W is N.
在本发明的一种实施方案中，W为CR c。 In one embodiment of the invention, W is CR c .
在本发明的一种实施方案中，R c为氢或卤素。 In one embodiment of the invention, Rc is hydrogen or halogen.
在本发明的一种实施方案中，R c为氢或氟。 In one embodiment of the invention, R c is hydrogen or fluorine.
在本发明的一种实施方案中，Q为一个键；R b为NR a2R b2；其中R a2和R b2与相连的氮原子共同形成取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。 In one embodiment of the present invention, Q is a bond; R b is NR a2 R b2 ; wherein R a2 and R b2 together with the connected nitrogen atom form a substituted or unsubstituted 3- to 6-membered saturated or partially unsaturated Monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11 membered spiro heterocyclic group; the "substituted" refers to a group 1, 2, 3, or 4 hydrogen atoms are each independently selected from the S group substituent.
在本发明的一种实施方案中，Q为CR a1R b1、O-(CR a1R b1) q1或NH-(CR c1R d1) q2；R b为卤素、羟基、-SO 2C 1-6烷基、取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基、取代或未取代的C 3-8环烷基、取代或未取代的5或6元单杂芳基、或NR a2R b2；其中R a1、R b1、R c1、R d1相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、C 1-3烷基或氧代基；R a2、R b2各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基、-C(O)卤代C 1-6烷基；或者R a2和R b2与相连的氮原子共同形成取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基；q1、q2各自独立地为0、1、2、3或4；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代 基所取代。 In one embodiment of the present invention, Q is CR a1 R b1 , O-(CR a1 R b1 ) q1 or NH-(CR c1 R d1 ) q2 ; R b is halogen, hydroxyl, -SO 2 C 1- 6 alkyl, substituted or unsubstituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 To 11-membered spiro heterocyclyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl, or NR a2 R b2 ; wherein R a1 , R b1 , R c1 , R d1 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or oxo; R a2 , R b2 are each independently hydrogen, substituted or not Substituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl, -C (O) C 1-6 alkyl, -C (O) halo C 1-6 alkyl; or R a2 and R b2 together with the connected nitrogen atom form a substituted or unsubstituted 3 to 6-membered saturated or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10-membered saturated or Partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11-membered spiro heterocyclic group; q1 and q2 are each independently 0, 1, 2, 3 or 4; the "substituted" refers to a group 1, 2, 3, or 4 hydrogen atoms are each independently selected from the S group substituent.
在本发明的一种实施方案中，所述S组取代基选自：羟基、卤素、硝基、氧代基、C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-3烷氧基、-(CH 2) u-卤代C 1-3烷氧基、-(CH 2) u-卤代C 1-3烷基、-(CH 2) u-C 3-6单环杂环基、-(CH 2) u-5或6元单杂芳基、-(CH 2) u-C 3-6单环环烷基、-(CH 2) u-O-(CH 2) v-C 3-6单环环烷基、-(CH 2) u-O-(CH 2) v-C 1-3烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-3烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-3烷基、-C(O)OC 1-3烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-3烷基；其中所述C 3-6单环杂环基、5或6元单杂芳基任选地被1、2或3个选自卤素、氰基、C 1-3烷基、C 1-3烷氧基和C 3-6单环环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基。 In one embodiment of the present invention, the S group substituent is selected from the group consisting of: hydroxyl, halogen, nitro, oxo, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl, -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-3 alkoxy, -(CH 2 ) u -halo C 1-3 alkoxy, -(CH 2 ) u -halo Substitute C 1-3 alkyl, -(CH 2 ) u -C 3-6 monocyclic heterocyclic group, -(CH 2 ) u -5 or 6-membered monoheteroaryl group, -(CH 2 ) u -C 3 -6 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-6 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 1 -3 Alkoxy, -(CH 2 ) u -O-(CH 2 ) v OH, -(CH 2 ) u -SO 2 C 1-3 alkyl, -(CH 2 ) u -NR a0 R b0 , -(CH 2 ) u -C(O)NR a0 R b0 , -(CH 2 ) u -C(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, NR a0 C( O)-(CH 2 ) u -NR a0 R b0 , NR a0 C(O)-(CH 2 ) u OH, NR a0 C(O)-halo C 1-3 alkyl; wherein the C 3- 6 -monocyclic heterocyclyl, 5- or 6-membered mono-heteroaryl is optionally selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and C 3- 6 Substituents of monocyclic cycloalkyl; u and v are each independently 0, 1, 2, 3, or 4; R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
在本发明的一种实施方案中，所述S组取代基中的C 3-6单环杂环基选自：氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、恶唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、恶唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-恶嗪烷、六氢嘧啶、1,4-二恶烷、四氢嘧啶-2(1H)-酮、1,4-二恶烷-2-酮、5,6-二氢-2H-吡喃-2-酮。 In one embodiment of the present invention, the C 3-6 monocyclic heterocyclic group in the S group substituent is selected from: aziridine, ethylene oxide, azetidine, azetidine -2-one, oxetane, oxetan-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane , Dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2- Ketone, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine Azin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1 ,1-Dioxide, Tetrahydropyran, 1,2-Dihydroazetidine, 1,2-Dihydrooxetadiene, 2,5-Dihydro-1H-pyrrole, 2 ,5-Dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-Dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2( 1H)-ketone, 1,4-dioxan-2-one, 5,6-dihydro-2H-pyran-2-one.
在本发明的一种实施方案中，所述S组取代基中的C 3-6单环环烷基选自：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环丁酮、环丁烷-1,2-二酮、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮。 In one embodiment of the present invention, the C 3-6 monocyclic cycloalkyl in the S group substituent is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, Cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1 ,3-Diketone.
在本发明的一种实施方案中，所述S组取代基中的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。In one embodiment of the present invention, the 5- or 6-membered monoheteroaryl group in the S group substituent is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole , 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1, 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyridine Azine.
在本发明的一种实施方案中，B或A中所述的C 6-14芳基为苯基、萘基、或为苯基与一个非芳香环稠合形成的9或10元芳香稠合双环，所述的非芳香环为3至6元饱和或部分不饱和单环杂环基、或3至6元饱和或部分不饱和单环环烷基，其中所述的3至6元饱和或部分不饱和单环杂环基选自：氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、恶唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、恶唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡 喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-恶嗪烷、六氢嘧啶、1,4-二恶烷、四氢嘧啶-2(1H)-酮、1,4-二恶烷-2-酮、5,6-二氢-2H-吡喃-2-酮；所述的3至6元饱和或部分不饱和单环环烷基选自：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环丁酮、环丁烷-1,2-二酮、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮；所述9或10元芳香稠合双环为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 In one embodiment of the present invention, the C 6-14 aryl group in B or A is a phenyl group, a naphthyl group, or a 9- or 10-membered aromatic condensate formed by condensing a phenyl group with a non-aromatic ring Bicyclic, said non-aromatic ring is 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, or 3 to 6 membered saturated or partially unsaturated monocyclic cycloalkyl, wherein said 3 to 6 membered saturated or Partially unsaturated monocyclic heterocyclic group is selected from: aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2- Ketone, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5 -Dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidin, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3- Dioxolane-2-one, oxazolidin-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholine-3-one, morpholine- 2-ketone, thiomorpholine-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydronitrogen Cyclobutadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3- Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6 -Tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxan-2-one, 5, 6-dihydro-2H-pyran-2-one; said 3- to 6-membered saturated or partially unsaturated monocyclic cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl , Cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexanone Hexane-1,3-dione; the 9- or 10-membered aromatic fused bicyclic ring is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
在本发明的一种实施方案中，B或A中所述的C 6-14芳基为苯基或萘基。 In one embodiment of the present invention, the C 6-14 aryl group described in B or A is phenyl or naphthyl.
在本发明的一种实施方案中，B或A中所述的C 5-14杂芳基为5或6元单杂芳基，其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述5或6元单杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 In one embodiment of the present invention, the C 5-14 heteroaryl group in B or A is a 5- or 6-membered monoheteroaryl group, wherein the 5- or 6-membered monoheteroaryl group is selected from: thiophene , Furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1, 3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1, 3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine; the 5- or 6-membered monoheteroaryl group is unsubstituted or is independently selected by 1, 2, 3 or 4 Substituted by substituents from the S group.
在本发明的一种实施方案中，B或A中所述的C 5-14杂芳基为苯基与5或6元单杂芳基稠合形成的9或10元双杂芳基，其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述9或10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 In one embodiment of the present invention, the C 5-14 heteroaryl group described in B or A is a 9- or 10-membered di-heteroaryl group formed by fusing a phenyl group with a 5- or 6-membered monoheteroaryl group, wherein The 5- or 6-membered monoheteroaryl group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4 -Triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxa Diazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine; the 9- or 10-membered bis-heteroaryl group is unsubstituted Or is substituted by 1, 2, 3 or 4 substituents each independently selected from the S group.
在本发明的一种实施方案中，所述9或10元双杂芳基为式(A)或式(B)所示结构：In one embodiment of the present invention, the 9- or 10-membered bisheteroaryl group has a structure represented by formula (A) or formula (B):
Figure PCTCN2020077192-appb-000003
Figure PCTCN2020077192-appb-000003
其中，C环为5或6元单杂芳基；其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述9或10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。Wherein, ring C is a 5- or 6-membered monoheteroaryl group; wherein the 5- or 6-membered monoheteroaryl group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole , 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1, 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyridine The 9- or 10-membered bisheteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the S group.
在本发明的一种实施方案中，C环选自如下的结构：
Figure PCTCN2020077192-appb-000004
Figure PCTCN2020077192-appb-000005
Figure PCTCN2020077192-appb-000006
其中
Figure PCTCN2020077192-appb-000007
代表与苯基稠合时共享的毗邻碳原子对。 In one embodiment of the invention, the C ring is selected from the following structures:
Figure PCTCN2020077192-appb-000004
Figure PCTCN2020077192-appb-000005
Figure PCTCN2020077192-appb-000006
among them
Figure PCTCN2020077192-appb-000007
Represents a pair of adjacent carbon atoms shared when fused with a phenyl group.
在本发明的一种实施方案中，所述的苯基与5或6元单杂芳基稠合形成的9或10元双杂芳基选自：苯并恶唑、苯并异恶唑、苯并咪唑、苯并噻唑、苯并异噻唑、苯并***、苯并呋喃、苯并噻吩、吲哚、吲唑、异吲哚、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉。In an embodiment of the present invention, the 9- or 10-membered bis-heteroaryl group formed by the fusion of the phenyl group and the 5- or 6-membered monoheteroaryl group is selected from: benzoxazole, benzisoxazole, Benzimidazole, benzothiazole, benzoisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline , Suoline.
在本发明的一种实施方案中，所述的苯基与5或6元单杂芳基稠合形成的9或10元双杂芳基选自：苯并[d]异恶唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]***、苯并[d]恶唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉。In an embodiment of the present invention, the 9- or 10-membered bis-heteroaryl group formed by the fusion of the phenyl group and the 5- or 6-membered monoheteroaryl group is selected from: benzo[d]isoxazole, 1H- Indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzene And [d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline.
在本发明的一种实施方案中，B或A中所述的C 5-14杂芳基为5或6元单杂芳基与5或6元单杂芳基稠合形成的8至10元双杂芳基，其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述8至10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 In one embodiment of the present invention, the C 5-14 heteroaryl group described in B or A is an 8- to 10-membered group formed by condensing a 5 or 6-membered monoheteroaryl group with a 5 or 6-membered monoheteroaryl group. Bi-heteroaryl, wherein the 5- or 6-membered mono-heteroaryl is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole , 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1 , 2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine; the 8- to 10-membered double The heteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
在本发明的一种实施方案中，所述8至10元双杂芳基为式(C)或式(D)所示结构：In one embodiment of the present invention, the 8- to 10-membered bis-heteroaryl group has a structure represented by formula (C) or formula (D):
Figure PCTCN2020077192-appb-000008
Figure PCTCN2020077192-appb-000008
其中，D环、E环为5或6元单杂芳基；其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述8至10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。Wherein, ring D and ring E are 5- or 6-membered monoheteroaryl groups; wherein the 5- or 6-membered monoheteroaryl groups are selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole , Triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole , 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, Pyrimidine or pyrazine; the 8- to 10-membered biheteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from the S group.
在本发明的一种实施方案中，D环、E环选自如下的结构：In one embodiment of the present invention, D ring and E ring are selected from the following structures:
Figure PCTCN2020077192-appb-000009
Figure PCTCN2020077192-appb-000010
其中
Figure PCTCN2020077192-appb-000011
代表与其他环稠合时共享的毗邻碳原子对。
Figure PCTCN2020077192-appb-000009
Figure PCTCN2020077192-appb-000010
among them
Figure PCTCN2020077192-appb-000011
Represents adjacent pairs of carbon atoms shared when fused with other rings.
在本发明的一种实施方案中，所述的5或6元单杂芳基与5或6元单杂芳基稠合形成的8至10元双杂芳基选自：吡啶并嘧啶、萘啶。In an embodiment of the present invention, the 5- or 6-membered monoheteroaryl group is fused with a 5- or 6-membered monoheteroaryl group to form an 8- to 10-membered diheteroaryl group selected from: pyridopyrimidine, naphthalene Pyridine.
在本发明的一种实施方案中，所述的5或6元单杂芳基与5或6元单杂芳基稠合形成的8至10元双杂芳基选自：吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶。In an embodiment of the present invention, the 5- or 6-membered monoheteroaryl group is fused with a 5- or 6-membered monoheteroaryl group to form an 8- to 10-membered diheteroaryl group selected from: pyrido[3, 2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7- Naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine.
在本发明的一种实施方案中，所述9或10元双杂芳基选自如下结构：In one embodiment of the present invention, the 9- or 10-membered bisheteroaryl group is selected from the following structures:
Figure PCTCN2020077192-appb-000012
Figure PCTCN2020077192-appb-000013
上述9或10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。
Figure PCTCN2020077192-appb-000012
Figure PCTCN2020077192-appb-000013
The aforementioned 9- or 10-membered biheteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
在本发明的一种实施方案中，所述8至10双杂芳基选自如下结构：In one embodiment of the present invention, the 8 to 10 diheteroaryl groups are selected from the following structures:
Figure PCTCN2020077192-appb-000014
Figure PCTCN2020077192-appb-000015
上述8至10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。
Figure PCTCN2020077192-appb-000014
Figure PCTCN2020077192-appb-000015
The above-mentioned 8- to 10-membered biheteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
在本发明的一种实施方案中，B或A中所述的C 5-14杂芳基为5或6元单杂芳基与一个非芳香环稠合形成的8至10元双杂芳基，所述的非芳香环为3至6元饱和或部分不饱和单环杂环基、或3至6元饱和或部分不饱和单环环烷基，其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述的3至6元饱和或部分不饱和单环杂环基选自：氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、恶唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、恶唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、 哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-恶嗪烷、六氢嘧啶、1,4-二恶烷、四氢嘧啶-2(1H)-酮、1,4-二恶烷-2-酮、5,6-二氢-2H-吡喃-2-酮；所述的3至6元饱和或部分不饱和单环环烷基选自：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环丁酮、环丁烷-1,2-二酮、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮；所述8至10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 In one embodiment of the present invention, the C 5-14 heteroaryl group described in B or A is an 8- to 10-membered bi-heteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl group with a non-aromatic ring , The non-aromatic ring is a 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, or a 3 to 6 membered saturated or partially unsaturated monocyclic cycloalkyl group, wherein the 5 or 6 membered monocyclic heterocyclic group The group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5- Triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole Diazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine; said 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group is selected from: aziridine , Ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidin-2-one, pyrrole Alkane-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine- 2,6-Dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidine-2 -Ketone, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one 1, 1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetadiene, 1,2-dihydrooxa Cyclobutadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro- 2H-pyran, 1,2,3,4-tetrahydropyran, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, six Hydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2(1H)-one, 1,4-dioxan-2-one, 5,6-dihydro-2H-pyran-2-one; The 3- to 6-membered saturated or partially unsaturated monocyclic cycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl , Cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione; the 8 to The 10-membered diheteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
在本发明的一种实施方案中，式(I)中的-L-R 2和式(II)中的-Q-R b独立选自： In one embodiment of the present invention, -LR 2 in formula (I) and -QR b in formula (II) are independently selected from:
Figure PCTCN2020077192-appb-000016
Figure PCTCN2020077192-appb-000016
Figure PCTCN2020077192-appb-000017
Figure PCTCN2020077192-appb-000017
Figure PCTCN2020077192-appb-000018
Figure PCTCN2020077192-appb-000018
Figure PCTCN2020077192-appb-000019
Figure PCTCN2020077192-appb-000019
Figure PCTCN2020077192-appb-000020
Figure PCTCN2020077192-appb-000020
在本发明的一种实施方案中，B和A独立选自如下结构：In one embodiment of the present invention, B and A are independently selected from the following structures:
Figure PCTCN2020077192-appb-000021
Figure PCTCN2020077192-appb-000021
其中Z 1e为NR 1e、O或S；Z 1f为N或CR 1f；Z 1g为N或CR 1g；Z 1h为N或CR 1h；Z 1i为N或CR 1i；Z 2e为N或CR 2e；Z 2f为N或CR 2f；Z 2h为N或CR 2h；Z 2i为N或CR 2i；R 1e、R 1f、R 1g、R 1h、R 1i、R 1j、R 2e、R 2f、R 2g、R 2h、R 2i、R 2j各自独立地为氢、卤素、C 1-3烷基、-CONH 2、-CONHC 1-3烷基、-CON(C 1-3烷基) 2、氰基、硝基、环丙基、环丁基、环戊基、环己基、羟基、乙酰基、羟甲基、羟乙基、羧基、NH 2、NHC 1-3烷基、N(C 1-3烷基) 2、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷氧基、C 2-4烯基、C 2-4炔基、-C(O)OC 1-3烷基、-CHO、-OC(O)C 1-3烷基、-SO 2C 1-3烷基、-SO 2-苯基或-CO-苯基。 Where Z 1e is NR 1e , O or S; Z 1f is N or CR 1f ; Z 1g is N or CR 1g ; Z 1h is N or CR 1h ; Z 1i is N or CR 1i ; Z 2e is N or CR 2e ; Z 2f is N or CR 2f ; Z 2h is N or CR 2h ; Z 2i is N or CR 2i ; R 1e , R 1f , R 1g , R 1h , R 1i , R 1j , R 2e , R 2f , R 2g , R 2h , R 2i , and R 2j are each independently hydrogen, halogen, C 1-3 alkyl, -CONH 2 , -CONHC 1-3 alkyl, -CON (C 1-3 alkyl) 2 , cyanide Group, nitro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxy, acetyl, hydroxymethyl, hydroxyethyl, carboxy, NH 2 , NHC 1-3 alkyl, N(C 1- 3 alkyl) 2 , halogenated C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -C (O ) OC 1-3 alkyl, -CHO, -OC(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 -phenyl or -CO-phenyl.
在本发明的一种实施方案中，B和A独立选自：In one embodiment of the invention, B and A are independently selected from:
Figure PCTCN2020077192-appb-000022
Figure PCTCN2020077192-appb-000022
Figure PCTCN2020077192-appb-000023
Figure PCTCN2020077192-appb-000023
Figure PCTCN2020077192-appb-000024
Figure PCTCN2020077192-appb-000024
在本发明的一种实施方案中，R 2或R b中所述的C 3-20杂环基为3至6元饱和或部分不饱和单环杂环基、6至10元饱和或部分不饱和稠杂环基、7至11元螺杂环基、或7至10元桥杂环基。 In one embodiment of the present invention, the C 3-20 heterocyclic group in R 2 or R b is a 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, a 6 to 10 membered saturated or partially unsaturated heterocyclic group Saturated condensed heterocyclic group, 7 to 11 membered spiro heterocyclic group, or 7 to 10 membered bridged heterocyclic group.
在本发明的一种实施方案中，R 1、R 2、R 3、R a、R b、R c中所述的C 3-20环烷基为3至8元单环环烷基或6至10元双环环烷基。 In one embodiment of the present invention, R 1, R 2, R 3, R a, R b, R c in a C 3-20 cycloalkyl said 3 to 8 membered monocyclic cycloalkyl or 6 To 10-membered bicyclic cycloalkyl.
在本发明的一种实施方案中，R 2或R b中所述的C 3-20环烷基为3至8元单环环烷基，选自：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基、环丁酮、环丁烷-1,2-二酮、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮；上述3至8元单环环烷基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 In one embodiment of the present invention, the C 3-20 cycloalkyl group in R 2 or R b is a 3- to 8-membered monocyclic cycloalkyl group selected from: cyclopropyl, cyclobutyl, cyclopentan Group, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclobutanone, cyclobutane-1,2-dione, Cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione; the above 3- to 8-membered monocyclic cycloalkyl is unsubstituted or is 1, 2, 3 or 4 substituents each independently selected from group S are substituted.
在本发明的一种实施方案中，R 21和R 22与相连的氮原子共同形成的C 3-20杂环基为3至6元饱和或部分不饱和含氮单环杂环基、6至10元饱和或部分不饱和含氮稠杂环基、或7至11元含氮螺杂环基。 In one embodiment of the present invention, the C 3-20 heterocyclic group formed by R 21 and R 22 and the connected nitrogen atom is a 3 to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group, 6 to 10-membered saturated or partially unsaturated nitrogen-containing fused heterocyclic group, or 7 to 11-membered nitrogen-containing spiro heterocyclic group.
在本发明的一种实施方案中，R a2和R b2与相连的氮原子共同形成的C 3-20杂环基为3至6元饱和或部分不饱和含氮单环杂环基、6至10元饱和或部分不饱和含氮稠杂环基、或7至11元含氮螺杂环基。 In one embodiment of the present invention, the C 3-20 heterocyclic group formed by R a2 and R b2 and the connected nitrogen atom is a 3 to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group, 6 to 10-membered saturated or partially unsaturated nitrogen-containing fused heterocyclic group, or 7 to 11-membered nitrogen-containing spiro heterocyclic group.
在本发明的一种实施方案中，所述R 21和R 22与相连的氮原子共同形成的3至6元饱和或部分不饱和含氮单环杂环基，或R a2和R b2与相连的氮原子共同形成的3至6元饱和或部分不饱和含氮单环杂环基独立选自如下结构： In one embodiment of the present invention, the 3 to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group formed by R 21 and R 22 and the connected nitrogen atom, or R a2 and R b2 are connected with The 3- to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group formed by the nitrogen atoms of is independently selected from the following structures:
Figure PCTCN2020077192-appb-000025
上述3 至6元饱和或部分不饱和含氮单环杂环基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。
Figure PCTCN2020077192-appb-000025
The above-mentioned 3- to 6-membered saturated or partially unsaturated nitrogen-containing monocyclic heterocyclic group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
在另一个方面，本发明提供了一种式(III)所示的螺环取代的嘧啶并环类化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或其前药：In another aspect, the present invention provides a spirocyclic substituted pyrimidocyclic compound represented by formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof:
Figure PCTCN2020077192-appb-000026
Figure PCTCN2020077192-appb-000026
式中，Ar为取代或未取代的苯基、或取代或未取代的5或6元单杂芳基；In the formula, Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5 or 6-membered monoheteroaryl group;
R a为C 2-4烯基；R c为取代或未取代的C 1-6烷氧基；Q a为一个键或-O-(CH 2) s-；s为0、1或2；R b为取代或未取代的3至6元单环杂环基或NR a0R b0；R a0、R b0各自独立地为氢或C 1-3烷基；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自下述的取代基所取代：羟基、卤素、氨基、C 1-3烷基、C 1-3烷氧基、NHCH 3、N(CH 3) 2。 R a is C 2-4 alkenyl group; R c is a substituted or unsubstituted C 1-6 alkoxy; Q a is a bond or -O- (CH 2) s -; s is 0, 1 or 2; R b is a substituted or unsubstituted 3- to 6-membered monocyclic heterocyclic group or NR a0 R b0 ; R a0 and R b0 are each independently hydrogen or C 1-3 alkyl; the "substituted" refers to a group One, two, three, or four hydrogen atoms in the group are each independently substituted by substituents selected from the following: hydroxyl, halogen, amino, C 1-3 alkyl, C 1-3 alkoxy, NHCH 3 , N(CH 3 ) 2 .
在本发明的一种实施方案中，R a为乙烯基或丙-1-烯-1-基。 In one embodiment of the present invention, R a is a vinyl or prop-1-en-1-yl.
在本发明的一种实施方案中，R c为C 1-3烷氧基，所述C 1-3烷氧基任选地被1、2或3个卤素取代。 In one embodiment of the present invention, R c is C 1-3 alkoxy, which C 1-3 alkoxy is optionally substituted with 1, 2 or 3 halogens.
在本发明的一种实施方案中，R c为甲氧基、乙氧基、三氟乙氧基或二氟甲氧基。 In one embodiment of the invention, R c is methoxy, ethoxy, trifluoroethoxy or difluoromethoxy.
在本发明的一种实施方案中，R b为3至6元单环杂环基；所述3至6元单环杂环基为氮杂环丁烷、四氢吡咯、哌啶、哌嗪或吗啉；所述3至6元单环杂环基任选地被1、2或3个各自独立选自C 1-3烷基、C 1-3烷氧基、NHCH 3、N(CH 3) 2的取代基取代。 In one embodiment of the present invention, R b is a 3- to 6-membered monocyclic heterocyclic group; the 3- to 6-membered monocyclic heterocyclic group is azetidine, tetrahydropyrrole, piperidine, piperazine Or morpholine; the 3- to 6-membered monocyclic heterocyclic group is optionally selected by 1, 2 or 3 independently selected from C 1-3 alkyl, C 1-3 alkoxy, NHCH 3 , N (CH 3 ) The substituent of 2 is substituted.
在本发明的一种实施方案中，R b为N-甲基哌啶或N-甲基四氢吡咯。 In one embodiment of the present invention, R b is N-methylpiperidine or N-methyltetrahydropyrrole.
在本发明的一种实施方案中，Ar为苯基、吡啶基或吡唑基；所述苯基、吡啶基和吡唑基任选地被1、2、3或4个各自独立选自：羟基、卤素、氨基、C 1-3烷基、NHCH 3、N(CH 3) 2取代基取代。 In one embodiment of the present invention, Ar is phenyl, pyridyl or pyrazolyl; said phenyl, pyridyl and pyrazolyl are optionally selected from 1, 2, 3 or 4 each independently: Hydroxy, halogen, amino, C 1-3 alkyl, NHCH 3 , N(CH 3 ) 2 substituents are substituted.
在本发明的一种实施方案中，Ar选自：In one embodiment of the present invention, Ar is selected from:
Figure PCTCN2020077192-appb-000027
Figure PCTCN2020077192-appb-000027
Figure PCTCN2020077192-appb-000028
Figure PCTCN2020077192-appb-000028
在本发明的一种实施方案中，-Q a-R b选自： In one embodiment of the present invention, -Q a -R b is selected from:
Figure PCTCN2020077192-appb-000029
Figure PCTCN2020077192-appb-000029
在本发明的一种实施方案中，式(I)或式(II)或式(III)化合物选自：In one embodiment of the invention, the compound of formula (I) or formula (II) or formula (III) is selected from:
Figure PCTCN2020077192-appb-000030
Figure PCTCN2020077192-appb-000030
在本发明的一种实施方案中，所述化合物选自：In one embodiment of the present invention, the compound is selected from:
Figure PCTCN2020077192-appb-000031
Figure PCTCN2020077192-appb-000031
Figure PCTCN2020077192-appb-000032
Figure PCTCN2020077192-appb-000032
在本发明的一种实施方案中，所述化合物选自：In one embodiment of the present invention, the compound is selected from:
Figure PCTCN2020077192-appb-000033
Figure PCTCN2020077192-appb-000033
在另一个方面，本发明提供了一种药物组合物，其含有前述的化合物、其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。In another aspect, the present invention provides a pharmaceutical composition, which contains the aforementioned compound, a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier.
如本文中所使用的，术语“药学可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质代表性的载体，包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。As used herein, the term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or subject Sexual carriers include water, oil, vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine.
在本发明的实施方案中，所述药物组合物可以以下的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入，或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。当口服用药时，本发明的化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要， 以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，可根据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式，当眼部局部施用时，本发明的化合物可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用，也可将化合物制成膏剂形式如凡士林膏。当皮肤局部施用时，本发明的化合物可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。本发明的化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。In an embodiment of the present invention, the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, and intramuscular , Intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or medication with the aid of an explanted reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred. When administered orally, the compounds of the present invention can be prepared into any orally acceptable formulations, including but not limited to tablets, capsules, aqueous solutions or suspensions. Carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added. The diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations usually mix the active ingredients with suitable emulsifiers and suspending agents. If necessary, some sweeteners, fragrances or coloring agents can be added to the above oral preparations. When topical medication, especially for the treatment of affected surfaces or organs that are easily reached by topical application, such as eye, skin or lower intestinal neurological diseases, the compound of the present invention can be prepared into different topical pharmaceutical preparations according to different affected surfaces or organs In the form of topical administration to the eye, the compound of the present invention can be formulated into a micronized suspension or solution. The carrier used is isotonic sterile saline with a certain pH, which may or may not be added with preservatives such as Benzyl alkanolate chloride. For ophthalmic use, the compound can also be made into an ointment form such as petroleum jelly. When applied topically to the skin, the compound of the present invention can be prepared into an appropriate ointment, lotion or cream formulation in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the present invention can also be administered in the form of sterile injection preparations, including sterile injection water or oil suspensions or sterile injection solutions. Usable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.
在另一个方面，本发明提供了上述螺环取代的嘧啶并环类化合物、其药学上可接受的盐、立体异构体、溶剂化合物或其前药在制备治疗和/或预防癌症的药物中的用途。In another aspect, the present invention provides the above-mentioned spirocyclic substituted pyrimidocyclic compounds, pharmaceutically acceptable salts, stereoisomers, solvent compounds or prodrugs thereof in the preparation of drugs for the treatment and/or prevention of cancer the use of.
在另一个方面，本发明提供了一种治疗癌症的方法，其包括向有此需要的受试者施用治疗有效量的前述的化合物、其药学上可接受的盐、立体异构体、溶剂化物或前药，或上述的任意组合，或施用上述的药物组合物的步骤。In another aspect, the present invention provides a method of treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of the aforementioned compound, its pharmaceutically acceptable salt, stereoisomer, or solvate Or a prodrug, or any combination of the above, or the step of administering the above-mentioned pharmaceutical composition.
在本发明的一种实施方案中，所述癌症为胰腺导管癌、结肠直肠癌、多发性骨髓瘤、肺癌、皮肤黑色素瘤、子宫体内膜样癌、子宫癌肉瘤、甲状腺癌、急性髓性白血病、膀胱尿路上皮癌、胃癌、***、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食管癌、慢性淋巴细胞白血病、肺鳞状细胞癌、小细胞肺癌、肾***状细胞癌、腺样囊性癌、嫌色细胞肾细胞癌、肝癌、乳腺***、宫颈鳞状细胞癌、卵巢浆液性腺癌、肾上腺皮质癌、***癌、神经母细胞瘤、脑低级别胶质瘤、胶质母细胞瘤、成神经管细胞瘤、食管鳞状细胞癌、肾透明细胞癌、骨肉瘤、卵巢小细胞癌、横纹肌样肿瘤、肉瘤、小肠神经内分泌肿瘤、T细胞幼淋巴细胞白血病。In one embodiment of the present invention, the cancer is pancreatic ductal carcinoma, colorectal cancer, multiple myeloma, lung cancer, skin melanoma, endometrium-like carcinoma, uterine carcinosarcoma, thyroid cancer, acute myelogenous Leukemia, bladder urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung cancer, renal papillary Cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver cancer, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenal cortical carcinoma, prostate cancer, neuroblastoma, brain low-grade glial Tumor, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestinal neuroendocrine tumor, T-cell young lymphocytic leukemia .
在本发明的一种实施方案中，所述癌症为肺癌，优选为非小细胞肺癌。In one embodiment of the present invention, the cancer is lung cancer, preferably non-small cell lung cancer.
如本文中所使用的，术语“受试者”是指动物，特别是哺乳动物，优选人。As used herein, the term "subject" refers to animals, especially mammals, preferably humans.
如本文中所使用的，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合 医师诊断而适当调节。As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. In the embodiments of the present invention, when a patient is treated according to the present invention, the amount of a given drug depends on many factors, such as the specific dosing regimen, the type of disease or condition and its severity, and the subject in need of treatment Or the uniqueness of the host (such as body weight), but, depending on the specific surrounding conditions, including, for example, the specific drug that has been used, the route of administration, the condition to be treated, and the subject or host to be treated, the dosage may be known in the art The method is routinely decided. Generally, in terms of doses used in adult therapy, the administered dose is typically in the range of 0.02-5000 mg/day, for example, about 1-1500 mg/day. The required dose can conveniently be expressed as one dose, or simultaneous (or within a short period of time) or divided doses at appropriate intervals, such as two, three, four or more divided doses per day. Those skilled in the art can understand that although the above-mentioned dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the doctor's diagnosis.
在另一个方面，本发明提供了上述螺环取代的嘧啶并环类化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或其前药在制备KRAS突变抑制剂中的用途，(优选地，所述KRAS突变为KRAS G12C突变)。In another aspect, the present invention provides the use of the above spirocyclic substituted pyrimidocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof in the preparation of KRAS mutation inhibitors, (Preferably, the KRAS mutation is KRAS G12C mutation).
如本文中所使用的，术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如盐酸，氢溴酸，硫酸，硝酸，磷酸等；所述的有机酸诸如乙酸，丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，三氟乙酸，甲酸，乳酸，丙二酸，琥珀酸，苹果酸，马来酸，富马酸，酒石酸，柠檬酸，苯甲酸，肉桂酸，扁桃酸，甲磺酸，乙磺酸，苯磺酸，萘磺酸，樟脑磺酸，葡庚糖酸，葡糖酸，谷氨酸，羟基萘甲酸，水杨酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺，二乙醇胺，三乙醇胺，N-甲基葡糖胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids or organic acids, the inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; the organic acids such as acetic acid, propionic acid, Caproic acid, cyclopentapropionic acid, glycolic acid, pyruvic acid, trifluoroacetic acid, formic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid , Mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, viscous Conic acid, etc.; or the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions, which form salts; or coordination compounds formed with organic bases, such as ethanolamine, two Ethanolamine, triethanolamine, N-methylglucamine, etc. The pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to salt forms, the compounds provided by the present invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
如本文中所使用的，术语“溶剂化合物”和“溶剂化物”是指本发明化合物与制药上可接受的溶剂结合形成的物质。制药上可接受的溶剂包括水，乙醇，乙酸等。溶剂化合物包括化学计算量的溶剂化合物和非化学计算量的溶剂化合物，优选为水合物。本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。As used herein, the terms "solvent compound" and "solvate" refer to a substance formed by combining the compound of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, acetic acid and the like. The solvent compound includes a stoichiometric amount of solvent compound and a non-stoichiometric amount of solvent compound, and is preferably a hydrate. Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
如本文中所使用的，术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，及其任何组合或任何混合物。例如单一对映异构体，单一非对映异构体或以上的混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, and any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above. When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis isomer and trans isomer, and any combination thereof.
如本文中所使用的，术语“烷基”指直链或支链饱和脂肪族烃基基团，其包含1到20个碳原子。术语“C 1-10烷基”指具有1到10个碳原子的直链或支链烷基，更优选是具有1、2、3、4、5或6个碳原子的直链或支链烷基，即C 1-6烷基，更优选是C 1-4烷基，最优选是C 1-3烷基。具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。 As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms. The term "C 1-10 alkyl" refers to a straight or branched chain alkyl having 1 to 10 carbon atoms, more preferably a straight or branched chain having 1, 2, 3, 4, 5 or 6 carbon atoms Alkyl, ie, C 1-6 alkyl, more preferably C 1-4 alkyl, most preferably C 1-3 alkyl. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various Branched chain isomers and so on.
如本文中所使用的，术语“烷氧基”指具有-O-烷基结构的基团，其中烷基的定义如上所述。术语“C 1-10烷氧基”指具有1到10个碳原子的烷氧基，优选是C 1-6烷氧基，更优选是C 1-4烷氧基，更优选是C 1-3烷氧基。具体实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、正戊氧基等。 As used herein, the term "alkoxy" refers to a group having the structure -O-alkyl, where the definition of alkyl is as described above. The term "C 1-10 alkoxy" refers to an alkoxy group having 1 to 10 carbon atoms, preferably a C 1-6 alkoxy group, more preferably a C 1-4 alkoxy group, and more preferably a C 1- alkoxy. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy and the like.
如本文中所使用的，术语“烯基”指在链的任何位点上具有一个或多个碳-碳双键的如上定义的烷基，术语“C 2-8烯基”指具有2到8个碳原子和至少一个碳-碳双键的烯基，优选为具有2到6个碳原子和1到2个碳-碳双键的烯基，即C 2-6烯基。更优选为具有2到4个碳原子和1到2个碳-碳双键的烯基，即C 2-4烯基。具体实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基、戊烯基、己烯基、丁间二烯基等。 As used herein, the term "alkenyl" refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position in the chain, and the term "C 2-8 alkenyl" refers to an alkyl group having 2 to The alkenyl group having 8 carbon atoms and at least one carbon-carbon double bond is preferably an alkenyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds, that is, a C 2-6 alkenyl group. More preferred is an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds, that is, a C 2-4 alkenyl group. Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, butadienyl and the like.
如本文中所使用的，术语“炔基”指在链的任何位点上具有一个或多个碳-碳三键的如上定义的烷基，术语“C 2-8炔基”指具有2到8个碳原子和至少一个碳-碳三键的炔基，优选为具有2到6个碳原子和1到2个碳-碳三键的炔基，即C 2-6炔基。更优选为具有2到4个碳原子和1到2个碳-碳三键的炔基，即C 2-4炔基。具体实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。 As used herein, the term "alkynyl" refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any point in the chain, and the term "C 2-8 alkynyl" refers to having 2 to The alkynyl group having 8 carbon atoms and at least one carbon-carbon triple bond is preferably an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds, that is, a C 2-6 alkynyl group. More preferred is an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds, that is, a C 2-4 alkynyl group. Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
如本文中所使用的，术语“卤素”指氟、氯、溴和碘。As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.
如本文中所使用的，术语“卤代烷基”指被一个或多个(如1、2、3、4或5个)卤素取代的烷基，其中烷基的定义如上所述。术语“卤代C 1-10烷基”指具有1到10个碳原子的卤代烷基。优选为卤代C 1-6烷基，更优选为卤代C 1-4烷基，更优选为卤代C 1-3烷基。具体实例包括但不限于一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。 As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above. The term "halogenated C 1-10 alkyl group" refers to a halogenated alkyl group having 1 to 10 carbon atoms. It is preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-4 alkyl group, and more preferably a halogenated C 1-3 alkyl group. Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
如本文中所使用的，术语“卤代烷氧基”指被一个或多个(如1、2、3、4或5个)卤素取代的烷氧基，其中烷氧基的定义如上所述。术语“卤代C 1-10烷氧基”指具有1到10个碳原子的卤代烷氧基。优选为卤代C 1-6烷氧基，更优选为卤代C 1-4烷氧基，更优选为卤代C 1-3烷氧基。具体实例包括但不限于三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。 As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more (eg, 1, 2, 3, 4, or 5) halogens, where the definition of alkoxy is as described above. The term "halogenated C 1-10 alkoxy group" refers to a halogenated alkoxy group having 1 to 10 carbon atoms. It is preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-4 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
如本文中所使用的，术语“环烷基”和“环烷基环”可互换使用，指饱和单环或多环稠合的环状烃基。术语“C 3-20环烷基”指具有3到20个碳原子的环烷基，包括单环环烷基、螺环烷基、稠环烷基和桥环烷基。优选为C 3-12环烷基。本发明中所述环烷基的环碳原子可任选地被1、2或3个氧代基取代形成环酮结构。术语“C 3-8单环环烷基”和“C 3-8环烷基”指具有3到8个碳原子的饱和单环环状烃基，优选为C 3-6单环环烷基(即C 3-6环烷基)，更优选为C 3、C 4、C 5或C 6单环环烷基。单环环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。 As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably and refer to a saturated monocyclic or polycyclic fused cyclic hydrocarbon group. The term "C 3-20 cycloalkyl" refers to a cycloalkyl group having 3 to 20 carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. Preferably, it is a C 3-12 cycloalkyl group. In the present invention, the ring carbon atoms of the cycloalkyl group can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure. The terms "C 3-8 monocyclic cycloalkyl" and "C 3-8 cycloalkyl" refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 carbon atoms, preferably C 3-6 monocyclic cycloalkyl ( That is, C 3-6 cycloalkyl), more preferably C 3 , C 4 , C 5 or C 6 monocyclic cycloalkyl. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
如本文中所使用的，术语“螺环烷基”和“螺环烷基环”指两个或两个以上的单环之间共用一个碳原子(称螺原子)形成的多环环状烃基。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基和多螺环烷基。术语“5到20元螺环烷基”或“C 5-20螺环烷基”指具有5到20个环碳原子的多环环状烃基，其中共用螺原子的单环为3到8元单环环烷基环。优选为6到14元(C 6-14)螺环烷基，更优选为6到14元单螺环烷基，更 优选为7到11元(C 7-11)螺环烷基，更优选为7到11元单螺环烷基，最优选为7元(4元单环环烷基环/4元单环环烷基环)、8元(4元单环环烷基环/5元单环环烷基环)、9元(4元单环环烷基环/6元单环环烷基环，5元单环环烷基环/5元单环环烷基环)、10元(5元单环环烷基环/6元单环环烷基环)或11元(6元单环环烷基环/6元单环环烷基环)单螺环烷基。螺环烷基的具体实例包括但不限于： As used herein, the terms "spirocycloalkyl" and "spirocycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed by sharing one carbon atom (called a spiro atom) between two or more monocyclic rings. . According to the number of shared spiro atoms between rings, spirocycloalkyls are classified into single spirocycloalkyls, dispirocycloalkyls and polyspirocycloalkyls. The term "5 to 20 membered spirocycloalkyl" or "C 5-20 spirocycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, in which the monocyclic ring sharing spiro atoms is 3 to 8 members Monocyclic cycloalkyl ring. It is preferably 6 to 14 membered (C 6-14 ) spirocycloalkyl, more preferably 6 to 14 membered monospirocycloalkyl, more preferably 7 to 11 membered (C 7-11 ) spirocycloalkyl, more preferably It is a 7- to 11-membered monospirocycloalkyl, most preferably 7-membered (4-membered monocyclic cycloalkyl ring/4-membered monocyclic cycloalkyl ring), 8-membered (4-membered monocyclic cycloalkyl ring/5-membered Monocyclic cycloalkyl ring), 9-membered (4-membered monocyclic cycloalkyl ring/6-membered monocyclic cycloalkyl ring, 5-membered monocyclic cycloalkyl ring/5-membered monocyclic cycloalkyl ring), 10-membered (5-membered monocyclic cycloalkyl ring/6-membered monocyclic cycloalkyl ring) or 11-membered (6-membered monocyclic cycloalkyl ring/6-membered monocyclic cycloalkyl ring) monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to:
Figure PCTCN2020077192-appb-000034
Figure PCTCN2020077192-appb-000034
如本文中所使用的，术语“稠环烷基”和“稠环烷基环”指两个或两个以上的单环通过共享毗邻的一对碳原子形成的多环环状烃基。根据形成环的数目可以分为双环、三环、四环或多环稠环烷基。术语“5到20元稠环烷基”或“C 5-20稠环烷基”指具有5到20个环碳原子的多环环状烃基，其中共享毗邻碳原子对的环为3到8元单环环烷基环。优选为6到14元(C 6-14)稠环烷基，更优选为6到14元双稠环烷基，更优选为7到10元(C 7-10)稠环烷基，更优选为7到10元双稠环烷基。最优选为8元(5元单环环烷基环与5元单环环烷基环稠合)、9元(5元单环环烷基环与6元单环环烷基环稠合)或10元(6元单环环烷基环与6元单环环烷基环稠合)双稠环烷基。稠环烷基的具体实例包括但不限于： As used herein, the terms "fused cycloalkyl" and "fused cycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing an adjacent pair of carbon atoms. According to the number of rings formed, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups. The term "5 to 20 membered fused cycloalkyl" or "C 5-20 fused cycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the rings sharing adjacent pairs of carbon atoms are 3 to 8 Member monocyclic cycloalkyl ring. Preferably it is 6 to 14 membered (C 6-14 ) fused cycloalkyl, more preferably 6 to 14 membered di-fused cycloalkyl, more preferably 7 to 10 membered (C 7-10 ) fused cycloalkyl, more preferably It is a 7 to 10 membered bi-fused cycloalkyl group. Most preferably 8-membered (5-membered monocyclic cycloalkyl ring fused with 5-membered monocyclic cycloalkyl ring), 9-membered (5-membered monocyclic cycloalkyl ring fused with 6-membered monocyclic cycloalkyl ring) Or 10-membered (6-membered monocyclic cycloalkyl ring fused with 6-membered monocyclic cycloalkyl ring) di-fused cycloalkyl. Specific examples of fused cycloalkyl include but are not limited to:
Figure PCTCN2020077192-appb-000035
Figure PCTCN2020077192-appb-000035
如本文中所使用的，术语“5到20元桥环烷基”和“5到20元桥环烷基环”指具有5到20个环碳原子(C 5-20)的多环环状烃基，其中任意两个环共用两个不直接连接的碳原子。优选为6到14元桥环烷基，更优选为7到10元桥环烷基。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环桥环烷基，更优选为双环或三环桥环烷基。桥环烷基的具体实例包括但不限于： As used herein, the terms "5 to 20 membered bridged cycloalkyl" and "5 to 20 membered bridged cycloalkyl ring" refer to a polycyclic ring having 5 to 20 ring carbon atoms (C 5-20 ) Hydrocarbyl, in which any two rings share two carbon atoms that are not directly connected. It is preferably a 6 to 14-membered bridged cycloalkyl group, and more preferably a 7 to 10-membered bridged cycloalkyl group. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls. Specific examples of bridged cycloalkyl include but are not limited to:
Figure PCTCN2020077192-appb-000036
Figure PCTCN2020077192-appb-000036
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基环，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。在本发明中，上述各类环烷基可以是任选取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl ring, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. In the present invention, the above-mentioned various types of cycloalkyl groups may be optionally substituted. When substituted, the substituents are preferably one or more substituent groups described in this application.
如本文中所使用的，术语“杂环基”和“杂环基环”可互换使用，指饱和或部分不饱和单环或多环稠合的环状烃基，术语“C 3-20杂环基”或“3到20元杂环基”指具有3到20个环原子的饱和或部分不饱和单环或多环稠合的环状烃基，其中一个或多个(优选为1、2、3 或4个)环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其中环原子为氮原子时，其可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。在本发明中所述杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。本发明所述的3到20元杂环基包括单环杂环基、螺杂环基、稠杂环基和桥杂环基。 As used herein, the terms "heterocyclyl" and "heterocyclyl ring" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group. The term "C 3-20 hetero "Cyclic group" or "3 to 20 membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic condensed cyclic hydrocarbon group having 3 to 20 ring atoms, of which one or more (preferably 1, 2 , 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0 to 2), but do not include the ring part of -OO-, -OS- or -SS- , The remaining ring atoms are carbon. Where the ring atom is a nitrogen atom, it may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein). In the present invention, the ring carbon atoms of the heterocyclic group can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. The 3- to 20-membered heterocyclic group in the present invention includes monocyclic heterocyclic group, spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.
如本文中所使用的，术语“C 3-8单环杂环基”、“3到8元单环杂环基”和“3到8元单环杂环基环”指具有3到8个环原子，其中1、2或3个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。优选为具有3到6个环原子，其中1或2个环原子为杂原子的3到6元单环杂环基(即C 3-6单环杂环基或3至6元饱和或部分不饱和单环杂环基)。更优选为具有5或6个环原子，其中1或2个环原子为杂原子的5或6元单环杂环基。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。当杂原子为硫原子时，硫原子可以为任选地被氧化(即S(O) m，m是整数0至2)。所述单环杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。单环杂环基的具体实例包括但不限于氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、恶唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、恶唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-恶嗪烷、六氢嘧啶、1,4-二恶烷、四氢嘧啶-2(1H)-酮、1,4-二恶烷-2-酮、5,6-二氢-2H-吡喃-2-酮、5,6-二氢嘧啶-4(3H)-酮、3,4-二氢吡啶-2(1H)-酮、5,6-二氢吡啶-2(1H)-酮、5,6-二氢嘧啶-4(1H)-酮、嘧啶-4(3H)-酮、嘧啶-4(1H)-酮、4,5-二氢-1H-咪唑、2,3-二氢-1H-咪唑、2,3-二氢恶唑、1,3-二氧杂环戊烯、2,3-二氢噻吩、2,5-二氢噻吩、3,4-二氢-2H-1,4-恶嗪、3,4-二氢-2H-1,4-噻嗪1,1-二氧化物、1,2,3,4-四氢吡嗪、1,3-二氢-2H-吡咯-2-酮、1,5-二氢-2H-吡咯-2-酮、1H-吡咯-2,5-二酮、呋喃-2(3H)-酮、呋喃-2(5H)-酮、1,3-二氧杂环戊烯-2-酮、恶唑-2(3H)-酮、1,3-二氢-2H-咪唑-2-酮、呋喃-2,5-二酮、3,6-二氢吡啶-2(1H)-酮、吡啶-2,6-(1H，3H)-二酮、5,6-二氢-2H-吡喃-2-酮、3,6-二氢-2H-吡喃-2-酮、3,4-二氢-2H-1,3-恶嗪、3,6-二氢-2H-1,3-恶嗪、1,2,3,4-四氢嘧啶等。术语“C 3-8杂环烷基”和“3到8元杂环烷基”指具有3到8个环原子，其中1或2个环原子为杂原子的饱和单环环状烃基。优选为具有3到6个环原子，其中1或2个环原子为杂原子的3到6元杂环烷基。杂环烷基具体实例包括但不限于氮丙环基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、恶唑烷基、1,3-二氧戊环基、二氧六环基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、硫代吗啉-1,1-二氧化物基、四氢吡喃基、1,4-氧氮杂环庚烷基、1,3-氧氮杂环庚烷基、1,3-恶嗪烷基、六氢嘧啶基、1,4-二恶烷基。 As used herein, the terms "C 3-8 monocyclic heterocyclic group", "3 to 8 membered monocyclic heterocyclic group" and "3 to 8 membered monocyclic heterocyclic ring" refer to having 3 to 8 Ring atoms, wherein 1, 2 or 3 ring atoms are saturated or partially unsaturated monocyclic cyclic hydrocarbon groups selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms. It is preferably a 3- to 6-membered monocyclic heterocyclic group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms (ie C 3-6 monocyclic heterocyclic group or 3 to 6-membered saturated or partially non- Saturated monocyclic heterocyclic group). More preferably, it is a 5- or 6-membered monocyclic heterocyclic group having 5 or 6 ring atoms, 1 or 2 of which are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents already defined herein). When the hetero atom is a sulfur atom, the sulfur atom may be optionally oxidized (ie S(O) m , m is an integer of 0 to 2). The ring carbon atoms of the monocyclic heterocyclic group may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Specific examples of monocyclic heterocyclic groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2 -Ketone, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3 -Dioxolane-2-one, oxazolidin-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholine-3-one, morpholine -2-one, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydro Azetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3 -Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxan-2-one, 5 ,6-Dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridine-2(1H)-one, 5,6-di Hydropyridine-2(1H)-one, 5,6-dihydropyrimidine-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro- 1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene , 3,4-Dihydro-2H-1,4-oxazine, 3,4-Dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydro Pyrazine, 1,3-dihydro-2H-pyrrole-2-one, 1,5-dihydro-2H-pyrrole-2-one, 1H-pyrrole-2,5-dione, furan-2(3H) -Ketone, furan-2(5H)-one, 1,3-dioxol-2-one, oxazole-2(3H)-one, 1,3-dihydro-2H-imidazole-2- Ketone, furan-2,5-dione, 3,6-dihydropyridine-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H- Pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1, 3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc. The terms "C 3-8 heterocycloalkyl" and "3 to 8 membered heterocycloalkyl" refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 ring atoms, of which 1 or 2 ring atoms are heteroatoms. It is preferably a 3 to 6 membered heterocycloalkyl group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms. Specific examples of heterocycloalkyl include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolane, Dioxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1- Dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazinyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1 ,4-Dioxanyl.
上述单环杂环基环上相连的2个环原子，包括C-C、N-C均可任选地与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环，与其他环形成稠合环的单环杂环基上相连的2个环原子优选地为C-C。The two ring atoms connected to the above-mentioned monocyclic heterocyclyl ring, including CC and NC, can optionally be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclic ring, monoaryl ring, and 5 Or a 6-membered mono-heteroaryl ring such as cycloalkyl, heterocyclyl, aryl or heteroaryl fused to form a fused polycyclic ring, and 2 rings connected to a monocyclic heterocyclic group that forms a fused ring with other rings The atom is preferably CC.
如本文中所使用的，术语“螺杂环基”和“螺杂环基环”指两个或两个以上的饱和或部分不饱和单环之间共用一个碳原子(称螺原子)形成的多环环状烃基，其中一个或多个(如1、2或3个)环原子为选自氮、氧或S(O) p(其中p是整数0至2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。术语“5到20元螺杂环基”指具有5到20个环原子的螺杂环基，其中共用螺原子的单环为3到8元单环杂环基环。优选为具有6到14个环原子，其中1或2个环原子为杂原子的6到14元螺杂环基，更优选为具有7到11个环原子，其中1或2个环原子为杂原子的7至11元螺杂环基。最优选为7元(4元单环杂环基环/4元单环杂环基环)、8元(4元单环杂环基环/5元单环杂环基环)、9元(4元单环杂环基环/6元单环杂环基环，5元单环杂环基环/5元单环杂环基环)、10元(5元单环杂环基环/6元单环杂环基环)或11元(6元单环杂环基环/6元单环杂环基环)单螺杂环基。螺杂环基的具体实例包括但不限于：
Figure PCTCN2020077192-appb-000037
As used herein, the terms "spiroheterocyclyl" and "spiroheterocyclyl ring" refer to two or more saturated or partially unsaturated monocyclic rings that share one carbon atom (called a spiro atom). Polycyclic cyclic hydrocarbon group, where one or more (such as 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) p (where p is an integer from 0 to 2), and the remaining ring atoms Is carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents already defined herein). Each single ring can contain one or more double bonds, but no ring has a fully conjugated π electron system. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group. The term "5 to 20 membered spiro heterocyclic group" refers to a spiro heterocyclic group having 5 to 20 ring atoms, wherein the monocyclic ring sharing the spiro atom is a 3 to 8 membered monocyclic heterocyclic ring. It is preferably a 6 to 14-membered spiro heterocyclic group having 6 to 14 ring atoms, 1 or 2 of which are heteroatoms, and more preferably 7 to 11 ring atoms, of which 1 or 2 ring atoms are hetero Atomic 7 to 11 membered spiro heterocyclyl. Most preferably 7-membered (4-membered monocyclic heterocyclyl ring/4-membered monocyclic heterocyclic ring), 8-membered (4-membered monocyclic heterocyclic ring/5-membered monocyclic heterocyclic ring), 9-membered ( 4-membered monocyclic heterocyclic ring/6-membered monocyclic heterocyclic ring, 5-membered monocyclic heterocyclic ring/5-membered monocyclic heterocyclic ring), 10-membered (5-membered monocyclic heterocyclic ring/6 Single-membered monocyclic heterocyclic ring) or 11-membered (6-membered monocyclic heterocyclic ring/6-membered monocyclic heterocyclic ring) monospiro heterocyclic group. Specific examples of spiroheterocyclic groups include, but are not limited to:
Figure PCTCN2020077192-appb-000037
Figure PCTCN2020077192-appb-000038
Figure PCTCN2020077192-appb-000038
如本文中所使用的，术语“稠杂环基”和“稠杂环基环”指两个或两个以上的饱和或部分不饱和单环通过共享毗邻的一对环原子形成的多环环状烃基，其中一个或多个(如1、2 或3个)环原子为选自氮、氧或S(O) p(其中p是整数0至2)的杂原子，其余环原子为碳。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。每个单环中可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基。术语“5到20元稠杂环基”指具有5到20个环原子的稠杂环基，其中共享毗邻环原子对的环为3到8元单环杂环基环，共享的毗邻环原子对可以是C-C或N-C。优选为具有6到14个环原子，其中1或2个环原子为杂原子的6到14元稠杂环基，更优选为具有6到10个环原子，其中1或2个环原子为杂原子的6至10元稠杂环基(即6至10元饱和或部分不饱和稠杂环基)，更优选为具有8到10个环原子，其中1或2个环原子为杂原子的8到10元稠杂环基。最优选为8元(5元单环杂环基环与5元单环杂环基环稠合)、9元(5元单环杂环基环与6元单环杂环基环稠合)或10元(6元单环杂环基环与6元单环杂环基环稠合)双环稠杂环基。稠杂环基的具体实例包括但不限于：
Figure PCTCN2020077192-appb-000039
Figure PCTCN2020077192-appb-000040
As used herein, the terms "fused heterocyclyl" and "fused heterocyclyl ring" refer to a polycyclic ring formed by two or more saturated or partially unsaturated monocyclic rings sharing an adjacent pair of ring atoms A hydrocarbyl group in which one or more (such as 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) p (where p is an integer of 0 to 2), and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents already defined herein). Each single ring can contain one or more double bonds, but no ring has a fully conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups. The term "5 to 20 membered fused heterocyclic group" refers to a fused heterocyclic group having 5 to 20 ring atoms, wherein the rings sharing adjacent pairs of ring atoms are 3 to 8 membered monocyclic heterocyclyl rings, and the shared adjacent ring atoms It can be CC or NC. It is preferably a 6 to 14-membered fused heterocyclic group having 6 to 14 ring atoms, 1 or 2 of which are heteroatoms, and more preferably 6 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms. A 6 to 10 membered fused heterocyclic group (ie 6 to 10 membered saturated or partially unsaturated fused heterocyclic group), more preferably 8 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms. To 10-membered fused heterocyclic group. Most preferably 8-membered (5-membered monocyclic heterocyclic ring and 5-membered monocyclic heterocyclic ring fused), 9-membered (5-membered monocyclic heterocyclic ring and 6-membered monocyclic heterocyclic ring fused) Or 10-membered (6-membered monocyclic heterocyclic ring and 6-membered monocyclic heterocyclic ring fused) bicyclic fused heterocyclic group. Specific examples of fused heterocyclic groups include but are not limited to:
Figure PCTCN2020077192-appb-000039
Figure PCTCN2020077192-appb-000040
如本文中所使用的，术语“5到20元桥杂环基”和“5到20元桥杂环基环”指具有5到20个环原子的饱和或部分不饱和多环杂环基团，其中任意两个环共用两个不直接连接的原子，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，基团中的一个或多个(如1、2或3个)环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6到14元桥杂环基，更优选为7到10元桥杂环基。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的具体实例包括但不限于： As used herein, the terms "5 to 20 membered heterocyclic ring" and "5 to 20 membered heterocyclic ring" refer to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms , Where any two rings share two atoms that are not directly connected, which can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, one or more of the groups (such as 1, (2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably a 6 to 14-membered bridged heterocyclic group, and more preferably a 7 to 10-membered bridged heterocyclic group. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Specific examples of bridged heterocyclic groups include, but are not limited to:
Figure PCTCN2020077192-appb-000041
Figure PCTCN2020077192-appb-000041
在本发明中，上述各类杂环基可以是任选取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。In the present invention, the above-mentioned various heterocyclic groups may be optionally substituted. When substituted, the substituents are preferably one or more of the substituent groups described in this application.
如本文中所使用的，术语“C 6-14芳基”，“C 6-14芳基环”和“C 6-14芳环”可互换使用，指具有6到14个环原子的全碳单环，全碳多环(环与环通过共价键连接，非稠合)或全碳稠合多环(也就是共享毗邻碳原子对的环)基团，基团中至少一个环为芳香性的，即具有共轭的π电子体系。优选为C 6-10芳基。本发明中C 6-14芳基包括单环芳基、多环芳基和芳香稠合多环，其中单环芳基的实例包括苯基，多环芳基的实例包括联苯基等。 As used herein, the terms "C 6-14 aryl", "C 6-14 aryl ring" and "C 6-14 aryl ring" are used interchangeably and refer to all groups having 6 to 14 ring atoms. Carbon monocyclic, all-carbon polycyclic (ring and ring are connected by covalent bonds, non-fused) or all-carbon fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) group, at least one ring in the group is Aromatic, that is, it has a conjugated π-electron system. Preferably it is a C 6-10 aryl group. In the present invention, C 6-14 aryl groups include monocyclic aryl groups, polycyclic aryl groups, and aromatic condensed polycyclic rings. Examples of monocyclic aryl groups include phenyl, and examples of polycyclic aryl groups include biphenyl and the like.
本发明中，C 6-14芳基为芳香稠合多环时，所述的芳香稠合多环可以为单芳基环与一个或多个单芳基环稠合形成的多环基团，其非限制性实例包括萘基，蒽基等。 In the present invention, when the C 6-14 aryl group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring may be a polycyclic group formed by the fusion of a single aryl ring and one or more single aryl rings, Non-limiting examples thereof include naphthyl, anthracenyl and the like.
在本发明的一些实施方案中，所述的芳香稠合多环也可以为单芳基环(如苯基)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为芳香环或非芳香环。所述非芳香环包括但不限于3到6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)，3到6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)。上述单芳基环与一个或多个非芳香环稠合的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单芳基环或非芳香环。In some embodiments of the present invention, the aromatic fused polycyclic ring may also be a polycyclic group formed by the fusion of a single aryl ring (such as a phenyl group) with one or more non-aromatic rings, which is combined with the parent structure The connected ring is aromatic or non-aromatic. The non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, and the ring carbon atoms of the monocyclic heterocyclic ring may be divided by 1 to 2 One oxo group is substituted to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the monocyclic cycloalkyl ring is The ring carbon atoms can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure). The polycyclic group in which the above-mentioned single aryl ring is fused with one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or carbon atom, and the ring connected to the parent structure is a single aryl ring or non-aromatic ring.
在本文中，苯环与一个5或6元单环杂环基环稠合形成9或10元芳香稠合双环即指由苯基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环杂环基环，所述5或6元单环杂环基环如上文中所定义，所形成的9或10元芳香稠合双环也可以称为9或10元苯基杂环基环。In this article, a benzene ring is fused with a 5- or 6-membered monocyclic heterocyclic ring to form a 9- or 10-membered aromatic fused bicyclic ring, which means that two adjacent substituent groups on the phenyl group and the ring atoms to which they are connected form a Condensed 5- or 6-membered monocyclic heterocyclic ring, the 5- or 6-membered monocyclic heterocyclic ring is as defined above, and the formed 9- or 10-membered aromatic fused bicyclic ring can also be called 9 or 10-membered Phenyl heterocyclyl ring.
在本文中，苯环与一个5或6元单环环烷基环稠合形成9或10元芳香稠合双环即指由苯基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环环烷基环，所述5或6元单环环烷基环如上文中所定义，所形成的9或10元芳香稠合双环也可称为9或10元苯基环烷基环。其非限制性实例包括：In this article, a benzene ring is fused with a 5- or 6-membered monocyclic cycloalkyl ring to form a 9- or 10-membered aromatic fused bicyclic ring, which means that two adjacent substituent groups on the phenyl group and the ring atoms to which they are connected form one Condensed 5- or 6-membered monocyclic cycloalkyl ring, the 5- or 6-membered monocyclic cycloalkyl ring is as defined above, and the formed 9- or 10-membered aromatic fused bicyclic ring can also be referred to as 9 or 10-membered Phenylcycloalkyl ring. Non-limiting examples include:
Figure PCTCN2020077192-appb-000042
Figure PCTCN2020077192-appb-000042
在本发明中，上述各类芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。In the present invention, the above-mentioned various aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the substituent groups described in this application.
如本文中所使用的，术语“杂芳基”，“杂芳基环”和“杂芳环”可互换使用，指环原子被至少一个独立选自氮、氧或硫的杂原子取代的单环或稠合多环(即共享毗邻环原子对，共享的毗邻环原子对可以是C-C或N-C。)基团，其中氮和硫原子可任选地被氧化，氮原子可任选地被季铵化。所述杂芳基具有共享的6，10或14个π电子，基团中至少一个环是芳族的。术语“C 5-14杂芳基”和“5到14元杂芳基”指具有5到14个环原子，其中1、2、3或4个环原子为杂原子的杂芳基。优选为具有5到10个环原子，其中1、2、3或4个环原子为杂原子的5到10元杂芳基。本发明中C 5-14杂芳基可以为单杂芳基、稠合双环杂芳基或稠合三环杂芳基。 As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaryl ring" are used interchangeably and refer to a single ring atom substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur. Ring or fused polycyclic (ie sharing adjacent pairs of ring atoms, the shared adjacent pairs of ring atoms may be CC or NC.) groups, wherein nitrogen and sulfur atoms can be optionally oxidized, and nitrogen atoms can be optionally quaternized Ammonium. The heteroaryl group has 6, 10 or 14 π electrons shared, and at least one ring in the group is aromatic. The terms "C 5-14 heteroaryl" and "5 to 14 membered heteroaryl" refer to heteroaryl groups having 5 to 14 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. It is preferably a 5- to 10-membered heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. In the present invention, the C 5-14 heteroaryl group may be a single heteroaryl group, a fused bicyclic heteroaryl group or a fused tricyclic heteroaryl group.
如本文中所使用的，术语“5或6元单杂芳基”指具有5或6个环原子，其中1、2或3个环原子为杂原子的单环杂芳基。单杂芳基的具体实例包括但不限于噻吩、呋喃、噻唑、 异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪等。As used herein, the term "5- or 6-membered monoheteroaryl group" refers to a monocyclic heteroaryl group having 5 or 6 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms. Specific examples of single heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole , 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.
如本文中所使用的，术语“8至10元双杂芳基”指具有8到10个环原子，其中1、2、3、4或5个环原子为杂原子的稠合双环杂芳基。所述稠合双环杂芳基既可以是单芳基环(如苯基)与单杂芳基环(优选为5或6元单杂芳基环)稠合形成的双环基团(优选为9或10元双杂芳基环)，也可以是单杂芳基环(优选为5或6元单杂芳基环)与单杂芳基环(优选为5或6元单杂芳基环)稠合形成的双环基团。As used herein, the term "8 to 10 membered diheteroaryl group" refers to a fused bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3, 4, or 5 ring atoms are heteroatoms . The fused bicyclic heteroaryl group can be a bicyclic group (preferably 9) formed by the fusion of a single aryl ring (such as a phenyl) and a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring). Or 10-membered bi-heteroaryl ring), it can also be a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring) and a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring) A bicyclic group formed by fusion.
上述单杂芳基环上任意相连的2个环原子，包括C-C、N-C、N-N均可与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环。与其他环形成稠合环的单杂芳基环上相连的2个环原子优选地为C-C，非限制性地包括如下形式：
Figure PCTCN2020077192-appb-000043
Any two ring atoms connected to the above-mentioned single heteroaryl ring, including CC, NC, NN, can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, single aryl ring, 5 or Cycloalkyl, heterocyclic, aryl or heteroaryl groups such as a 6-membered monoheteroaryl ring are fused to form a fused polycyclic ring. The two ring atoms connected to the monoheteroaryl ring forming a fused ring with other rings are preferably CC, and include the following forms without limitation:
Figure PCTCN2020077192-appb-000043
Figure PCTCN2020077192-appb-000044
Figure PCTCN2020077192-appb-000044
8至10元双杂芳基的非限制性实例包括：苯并[d]异恶唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]***、苯并[d]恶唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、吡唑并[1,5-a]嘧啶、咪唑并[1,2-b]哒嗪等。Non-limiting examples of 8- to 10-membered bisheteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, iso Quinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[ 4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo [1,2-b] Pyridazine and others.
上述单杂芳基，或苯环与单杂芳基环稠合形成的双杂芳基，或单杂芳基环与单杂芳基环稠合形成的双杂芳基可通过氮原子或碳原子与其他基团或母体结构连接。当为双杂芳基时，与母体结构连接的环为单杂芳基环或苯环，其具体实例包括但不限于：The above-mentioned mono-heteroaryl group, or the double-heteroaryl group formed by the fusion of a benzene ring and a single heteroaryl ring, or the double-heteroaryl group formed by the fusion of a single heteroaryl ring and a single heteroaryl ring can pass through a nitrogen atom or carbon Atoms are connected to other groups or parent structures. When it is a bi-heteroaryl group, the ring connected to the parent structure is a mono-heteroaryl ring or a benzene ring. Specific examples thereof include but are not limited to:
Figure PCTCN2020077192-appb-000045
Figure PCTCN2020077192-appb-000045
Figure PCTCN2020077192-appb-000046
Figure PCTCN2020077192-appb-000046
在本发明的一些实施方案中，所述的稠合双环杂芳基或稠合三环杂芳基可以是单杂芳基环(优选为5或6元单杂芳基环)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为单杂芳基环或非芳香环。所述非芳香环包括但不限于3到6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)，3到6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)等。上述单杂芳基环与一个或多个非芳香环稠合形成的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单杂芳基环或非芳香环。In some embodiments of the present invention, the fused bicyclic heteroaryl group or fused tricyclic heteroaryl group may be a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring) and one or more A polycyclic group formed by the fusion of a non-aromatic ring, wherein the ring connected to the parent structure is a single heteroaryl ring or a non-aromatic ring. The non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, and the ring carbon atoms of the monocyclic heterocyclic ring may be divided by 1 to 2 One oxo group is substituted to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the monocyclic cycloalkyl ring is The ring carbon atoms can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure) and so on. The polycyclic group formed by the condensation of the above-mentioned single heteroaryl ring with one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or carbon atom, and the ring connected to the parent structure is a single heteroaryl ring Or non-aromatic ring.
在本文中，5或6元单杂芳基环与一个5或6元单环杂环基环稠合形成8至10元稠合双环杂芳基即指由5或6元单杂芳基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环杂环基环，所述5或6元单环杂环基环如上文中所定义，所形成的8至10元稠合双环杂芳基也可以称为8至10元杂芳基杂环基环。In this context, a 5- or 6-membered mono-heteroaryl ring is fused with a 5- or 6-membered monocyclic heterocyclic ring to form an 8- to 10-membered fused bicyclic heteroaryl group, which means that a 5- or 6-membered mono-heteroaryl group is Two adjacent substituent groups and the ring atoms to which they are connected form a fused 5- or 6-membered monocyclic heterocyclic ring. The 5- or 6-membered monocyclic heterocyclic ring is defined as above, and the resulting 8 A to 10-membered fused bicyclic heteroaryl group can also be referred to as an 8- to 10-membered heteroaryl heterocyclyl ring.
在本文中，5或6元单杂芳基环与一个5或6元单环环烷基环稠合形成8至10元稠合双环杂芳基即指由5或6元单杂芳基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环环烷基环，所述5或6元单环环烷基环如上文中所定义，所形成的8至10元稠合双环杂芳基也可以称为8至10元杂芳基环烷基环。其非限制性实例包括：In this article, a 5- or 6-membered mono-heteroaryl ring is fused with a 5- or 6-membered monocyclic cycloalkyl ring to form an 8- to 10-membered fused bicyclic heteroaryl group, which means that a 5- or 6-membered mono-heteroaryl group is Two adjacent substituent groups and the ring atoms to which they are connected form a fused 5- or 6-membered monocyclic cycloalkyl ring. The 5- or 6-membered monocyclic cycloalkyl ring is as defined above, and the resulting 8 A to 10-membered fused bicyclic heteroaryl group can also be referred to as an 8- to 10-membered heteroaryl cycloalkyl ring. Non-limiting examples include:
Figure PCTCN2020077192-appb-000047
Figure PCTCN2020077192-appb-000047
Figure PCTCN2020077192-appb-000048
Figure PCTCN2020077192-appb-000048
Figure PCTCN2020077192-appb-000049
Figure PCTCN2020077192-appb-000049
在本发明中，上述各类杂芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。In the present invention, the above-mentioned various heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the substituent groups described in this application.
如本文中所使用的，术语“羟基”指-OH。As used herein, the term "hydroxyl" refers to -OH.
如本文中所使用的，术语“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CH(OH)CH 3。 As used herein, the term "hydroxymethyl" refers to -CH 2 OH, and "hydroxyethyl" refers to -CH 2 CH 2 OH or -CH(OH)CH 3 .
如本文中所使用的，术语“氰基甲基”指-CH 2CN，“氰基乙基”指-CH 2CH 2CN或-CHCNCH 3。 As used herein, the term "cyanomethyl" refers to -CH 2 CN, and "cyanoethyl" refers to -CH 2 CH 2 CN or -CHCNCH 3 .
如本文中所使用的，术语“氨基”指-NH 2。 As used herein, the term "amino" refers to -NH 2 .
如本文中所使用的，术语“氰基”指-CN。As used herein, the term "cyano" refers to -CN.
如本文中所使用的，术语“硝基”指-NO 2。 As used herein, the term "nitro" refers to -NO 2 .
如本文中所使用的，术语“苄基”指-CH 2-苯。 The term "benzyl" as used herein means a -CH 2 used - benzene.
如本文中所使用的，术语“氧代基”指＝O。As used herein, the term "oxo" refers to =0.
如本文中所使用的，术语“羧基”指-C(O)OH。As used herein, the term "carboxy" refers to -C(O)OH.
如本文中所使用的，术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)。As used herein, the term "carboxylate group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl).
如本文中所使用的，术语“乙酰基”指-COCH 3。 As used herein, the term "acetyl" refers to -COCH 3 .
如本文中所使用的，术语“取代”或“取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代基(即＝O)时，意味着两个氢原子被取代。氧代基取代不会发生在芳香基上。术语“任选取代”或“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。As used herein, the term "substituted" or "substituted" means that any one or more of the hydrogen atoms on a specific atom is replaced by a substituent, and may include deuterium and hydrogen variants, as long as the valence of the specific atom It is normal and the substituted compound is stable. When the substituent is an oxo group (ie =0), it means that two hydrogen atoms are replaced. The oxo group substitution does not occur on the aromatic group. The term "optionally substituted" or "optionally substituted" means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary based on chemically achievable.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
具体实施方式detailed description
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The present invention will be described in detail through the following examples, but it is not meant to limit the present invention in any way. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. It will be obvious. If specific conditions are not indicated in the examples, it shall be carried out in accordance with the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used without the manufacturer's indication are all conventional products that are commercially available.
制备例1：7-溴-2,4-二氯-8-氟-6-碘喹唑啉的合成Preparation Example 1: Synthesis of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline
Figure PCTCN2020077192-appb-000050
Figure PCTCN2020077192-appb-000050
步骤一：2-氨基-3-氟-4-溴苯甲酸(40g,171mmol)溶于N,N-二甲基甲酰胺(400mL),N-碘代丁二酰亚胺(40.4g,179mmol)加至反应液中，反应液于70℃搅拌反应18小时；反应液冷却至室温，倾入冰盐水中，析出的固体抽滤，所得固体用冰水洗涤，放入烘箱干燥，得到棕色固体为2-氨基-3-氟-4-溴-5-碘苯甲酸(58.0g,Y:94.3％)。ES-API:[M+H] +＝360.0。 Step 1: 2-Amino-3-fluoro-4-bromobenzoic acid (40g, 171mmol) dissolved in N,N-dimethylformamide (400mL), N-iodosuccinimide (40.4g, 179mmol) ) Was added to the reaction solution, and the reaction solution was stirred at 70°C for 18 hours; the reaction solution was cooled to room temperature, poured into ice brine, the precipitated solid was suction filtered, the obtained solid was washed with ice water, and dried in an oven to obtain a brown solid It is 2-amino-3-fluoro-4-bromo-5-iodobenzoic acid (58.0 g, Y: 94.3%). ES-API: [M+H] + = 360.0.
步骤二：2-氨基-3-氟-4-溴-5-碘苯甲酸(30.0g,83.56mmol)及尿素(50.1g,835.6mmol)加热至200℃搅拌反应1小时，所得固体在热水中研磨，过滤，放入烘箱干燥，得到棕色固体为7-溴-8-氟-6-碘喹唑啉-2,4(1H,3H)-二酮(60.0g)。ES-API:[M+H] +＝385.1。 Step 2: 2-Amino-3-fluoro-4-bromo-5-iodobenzoic acid (30.0g, 83.56mmol) and urea (50.1g, 835.6mmol) are heated to 200°C and stirred for 1 hour. The resulting solid is heated in hot water Grinding, filtering, and drying in an oven to obtain a brown solid as 7-bromo-8-fluoro-6-iodoquinazoline-2,4(1H,3H)-dione (60.0g). ES-API: [M+H] + =385.1.
步骤三：7-溴-8-氟-6-碘喹唑啉-2,4(1H,3H)-二酮(60g,粗品，156mmol)加入到三氯氧磷(300mL)中，反应液100℃搅拌反应16小时，将三氯氧磷脱除，剩余物加入二氯甲烷稀释，稀释液在10℃以下用冰水淬灭，淬灭的反应液用碳酸氢钠调节pH值至6-7，有机相分出后用盐水洗涤，无水硫酸镁干燥，过滤，有机相真空脱溶，柱层析(石油醚/乙酸乙酯： 1％)，得到黄色固体为7-溴-2,4-二氯-8-氟-6-碘喹唑啉(8.7g,Y:24.7％)。ES-API:[M+H] +＝421.1。 1H NMR(400MHz,DMSO-d 6)δ8.64(d,J＝1.6Hz,1H)。 Step 3: 7-bromo-8-fluoro-6-iodoquinazoline-2,4(1H,3H)-dione (60g, crude product, 156mmol) was added to phosphorus oxychloride (300mL), reaction solution 100 The reaction was stirred at ℃ for 16 hours, the phosphorus oxychloride was removed, and the residue was diluted with dichloromethane. The diluted solution was quenched with ice water below 10℃. The quenched reaction solution was adjusted to pH 6-7 with sodium bicarbonate. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the organic phase was removed in vacuo. The column chromatography (petroleum ether/ethyl acetate: 1%) gave a yellow solid of 7-bromo-2,4 -Dichloro-8-fluoro-6-iodoquinazoline (8.7 g, Y: 24.7%). ES-API: [M+H] + = 421.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (d, J = 1.6 Hz, 1H).
制备例2：7-溴-2,4-二氯-8-氟-6-氯喹唑啉的合成Preparation Example 2: Synthesis of 7-bromo-2,4-dichloro-8-fluoro-6-chloroquinazoline
Figure PCTCN2020077192-appb-000051
Figure PCTCN2020077192-appb-000051
步骤一：2-氨基-3-氟-4-溴-苯甲酸(10g,42.7mmol)溶于N,N-二甲基甲酰胺(100mL),室温下将N-氯代丁二酰亚胺(6g,44.9mmol)加至反应液中，反应液于70℃反应18小时；反应液降至室温，倾入冰盐水(500mL)中，析出的固体抽滤后用水(50mL)洗涤，干燥得到黄色固体为2-氨基-3-氟-4-溴-5-氯苯甲酸(10.5g,Y:91.5％)。ES-API:[M+H] +＝269.8。 Step 1: 2-Amino-3-fluoro-4-bromo-benzoic acid (10g, 42.7mmol) was dissolved in N,N-dimethylformamide (100mL), and N-chlorosuccinimide (6g, 44.9mmol) was added to the reaction solution, the reaction solution was reacted at 70°C for 18 hours; the reaction solution was cooled to room temperature, poured into ice brine (500mL), the precipitated solid was filtered with suction, washed with water (50mL), and dried to obtain The yellow solid is 2-amino-3-fluoro-4-bromo-5-chlorobenzoic acid (10.5 g, Y: 91.5%). ES-API: [M+H] + = 269.8.
步骤二：2-氨基-3-氟-4-溴-5-氯苯甲酸(10.5g,39.11mmol)及尿素(23.5g,392mmol)加热至200℃反应4小时，所得固体在热水淋洗3次，过滤，干燥，得到棕色固体为7-溴-8-氟-6-氯喹唑啉-2,4(1H,3H)-二酮(11.4g,Y:99.3％)。ES-API:[M+H] +＝295.0。 Step 2: 2-Amino-3-fluoro-4-bromo-5-chlorobenzoic acid (10.5g, 39.11mmol) and urea (23.5g, 392mmol) are heated to 200°C and react for 4 hours, and the solid obtained is rinsed in hot water 3 times, filtered and dried to obtain a brown solid as 7-bromo-8-fluoro-6-chloroquinazoline-2,4(1H,3H)-dione (11.4g, Y: 99.3%). ES-API: [M+H] + = 295.0.
步骤三：7-溴-8-氟-6-氯喹唑啉-2,4(1H,3H)-二酮(11.4g,粗品，38.8mmol)加入到三氯氧磷(100mL)中，反应液100℃反应16小时；反应液降至室温，真空将三氯氧磷脱除，剩余物于-10℃用冰水淬灭，淬灭的反应液用碳酸氢钠调节pH值至6，淬灭的水相用二氯甲烷(100mL x 4)萃取，合并有机相，无水硫酸钠干燥，过滤，有机相真空脱溶，柱层析(石油醚/乙酸乙酯：1％)，得到黄色固体为7-溴-2，4-二氯-8-氟-6-氯喹唑啉(3.6g,Y:28.1％)。ES-API:[M+H] +＝330.7。 1H NMR(400MHz,CDCl 3)δ8.21(d,J＝2.0Hz,1H). Step 3: 7-Bromo-8-fluoro-6-chloroquinazoline-2,4(1H,3H)-dione (11.4g, crude product, 38.8mmol) was added to phosphorus oxychloride (100mL), the reaction solution React at 100°C for 16 hours; the reaction solution is lowered to room temperature, the phosphorus oxychloride is removed under vacuum, the remainder is quenched with ice water at -10°C, the quenched reaction solution is adjusted to pH 6 with sodium bicarbonate and quenched The aqueous phase was extracted with dichloromethane (100mL x 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was vacuum desolventized, and column chromatography (petroleum ether/ethyl acetate: 1%) was used to obtain a yellow solid It is 7-bromo-2,4-dichloro-8-fluoro-6-chloroquinazoline (3.6g, Y: 28.1%). ES-API: [M+H] + =330.7. 1 H NMR (400MHz, CDCl 3 ) δ 8.21 (d, J = 2.0 Hz, 1H).
制备例3：2,4,6-三氯-7-溴-8-氟喹啉-3-腈的合成Preparation Example 3: Synthesis of 2,4,6-trichloro-7-bromo-8-fluoroquinoline-3-carbonitrile
Figure PCTCN2020077192-appb-000052
Figure PCTCN2020077192-appb-000052
步骤一：2-氨基-3-氟-4-溴-5-氯苯甲酸(14g,52.1mmol)溶于四氢呋喃(200mL)中，三光气(15.5g,52.1mmol)溶于四氢呋喃中，0℃下滴加至反应液中，滴毕，反应液加热至50℃反应16小时；反应液浓缩，浓缩物用乙酸乙酯稀释，有机相用饱和碳酸氢钠、盐水、水依次洗涤，有机相用无水硫酸钠干燥，柱层析(石油醚/乙酸乙酯：0～50％)，得到黄色固体为6-氯-7-溴-8-氟-1H-苯并[d][1,3]恶嗪-2,4-二酮(5g,Y:32.6％)。ES-API:[M+H] +＝295。 Step 1: 2-Amino-3-fluoro-4-bromo-5-chlorobenzoic acid (14g, 52.1mmol) was dissolved in tetrahydrofuran (200mL), triphosgene (15.5g, 52.1mmol) was dissolved in tetrahydrofuran, 0℃ After dropping, the reaction solution was heated to 50°C and reacted for 16 hours; the reaction solution was concentrated, the concentrate was diluted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate, brine, and water, and the organic phase was used Dry with anhydrous sodium sulfate and column chromatography (petroleum ether/ethyl acetate: 0-50%) to obtain a yellow solid as 6-chloro-7-bromo-8-fluoro-1H-benzo[d][1,3 ] Oxazine-2,4-dione (5g, Y: 32.6%). ES-API: [M+H] + =295.
步骤二：6-氯-7-溴-8-氟-1H-苯并[d][1,3]恶嗪-2,4-二酮(5g,0.691mmol)，2-氰基乙酸乙酯(2.3g,20.1mmol)及三乙胺(3.43g,34mmol)溶液N,N-二甲基甲酰胺(25mL)，反应液于120℃搅拌反应16小时，反应液降温，真空脱除溶剂，剩余物柱层析(甲醇/二氯甲烷：0～5％)，得到棕色固体为6-氯-7-溴-8-氟-2,4-二羟基喹啉-3-腈(2g,Y:37.1％)。ES-API:[M+H] +＝318。 Step 2: 6-chloro-7-bromo-8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (5g, 0.691mmol), ethyl 2-cyanoacetate (2.3g, 20.1mmol) and triethylamine (3.43g, 34mmol) solution N,N-dimethylformamide (25mL), the reaction solution was stirred at 120°C for 16 hours, the reaction solution was cooled down, and the solvent was removed in vacuo. The residue was column chromatographed (methanol/dichloromethane: 0～5%) to obtain a brown solid as 6-chloro-7-bromo-8-fluoro-2,4-dihydroxyquinoline-3-carbonitrile (2g, Y : 37.1%). ES-API: [M+H] + =318.
步骤三：6-氯-7-溴-8-氟-2,4-二羟基喹啉-3-腈(2g,6.3mmol)溶于乙腈(15mL)，然后加入三氯氧磷(50mL)，反应液90℃搅拌反应16小时。反应液降温，真空脱除三氯氧磷，剩余物倾入二氯甲烷/三乙胺(300mL/30mL)的混合溶剂中，反应液用乙酸乙酯稀释，水洗，有机相干燥过滤，脱溶，剩余物柱层析(石油醚/乙酸乙酯：0～10％)，得到棕色固体为2,4,6-三氯-7-溴-8-氟喹啉-3-腈(1.0g,Y:44.8％)。ES-API:[M+H] +＝354.9。 1H NMR(400MHz,氯仿 -d3)δ8.22(s,1H). Step 3: 6-Chloro-7-bromo-8-fluoro-2,4-dihydroxyquinoline-3-carbonitrile (2g, 6.3mmol) is dissolved in acetonitrile (15mL), then phosphorus oxychloride (50mL) is added, The reaction solution was stirred and reacted at 90°C for 16 hours. The temperature of the reaction solution was lowered, the phosphorus oxychloride was removed in vacuum, the residue was poured into a mixed solvent of dichloromethane/triethylamine (300mL/30mL), the reaction solution was diluted with ethyl acetate, washed with water, the organic phase was dried and filtered, and the solvent was removed. , The residue was column chromatographed (petroleum ether/ethyl acetate: 0-10%) to obtain a brown solid as 2,4,6-trichloro-7-bromo-8-fluoroquinoline-3-carbonitrile (1.0g, Y: 44.8%). ES-API: [M+H] + =354.9. 1 H NMR (400MHz, chloroform-d3) δ8.22(s, 1H).
制备例4：2,4,6-三氯-7-溴喹唑啉的合成Preparation Example 4: Synthesis of 2,4,6-trichloro-7-bromoquinazoline
Figure PCTCN2020077192-appb-000053
Figure PCTCN2020077192-appb-000053
步骤一：向250mL圆底烧瓶中加入2-氨基-4-溴-5-氯苯甲酸(10.1g,40.32mmol)和尿素(24.2g,403.2mmol)，升温至200℃搅拌反应2小时.降温至100℃，向反应液中加入水(150mL)，搅拌1小时，过滤干燥得到7-溴-6-氯喹唑啉-2,4-二醇(13g,Y:粗品)。ES-API:[M+H] +＝275.2/277.2。 Step 1: Add 2-amino-4-bromo-5-chlorobenzoic acid (10.1g, 40.32mmol) and urea (24.2g, 403.2mmol) into a 250mL round-bottomed flask, and heat up to 200℃ and stir for 2 hours. Cool down At 100° C., water (150 mL) was added to the reaction solution, stirred for 1 hour, filtered and dried to obtain 7-bromo-6-chloroquinazoline-2,4-diol (13 g, Y: crude product). ES-API: [M+H] + = 275.2/277.2.
步骤二：向250mL圆底烧瓶中加入6-氯-7-溴喹唑啉-2,4-二醇(13g,粗品，40.32mmol)，三氯氧磷(100mL)，反应液升温至105℃搅拌反应18小时。旋掉大部分三氯氧磷后，剩余物倾入水中(500mL)，乙酸乙酯萃取(100mL x 3)，合并有机相，水洗，盐水洗，干燥旋干，柱层析(石油醚/乙酸乙酯：10％)，得到2,4,6-三氯-7-溴喹唑啉(800mg,Y:6.4％)。ES-API:[M+H] +＝314.9。 1H NMR(400MHz,丙酮-d 6)δ8.50(s,1H),8.44(s,1H)。 Step 2: Add 6-chloro-7-bromoquinazoline-2,4-diol (13g, crude product, 40.32mmol) and phosphorus oxychloride (100mL) into a 250mL round bottom flask, and the reaction solution is heated to 105°C The reaction was stirred for 18 hours. After spinning off most of the phosphorus oxychloride, the residue was poured into water (500mL), extracted with ethyl acetate (100mL x 3), combined the organic phases, washed with water, washed with brine, dried and spin-dried, column chromatography (petroleum ether/acetic acid Ethyl ester: 10%) to obtain 2,4,6-trichloro-7-bromoquinazoline (800 mg, Y: 6.4%). ES-API: [M+H] + =314.9. 1 H NMR (400MHz, acetone-d 6 ) δ 8.50 (s, 1H), 8.44 (s, 1H).
制备例5：6,7-二氯吡啶[2,3-d]嘧啶-2,4-二醇的合成Preparation Example 5: Synthesis of 6,7-dichloropyridine[2,3-d]pyrimidine-2,4-diol
Figure PCTCN2020077192-appb-000054
Figure PCTCN2020077192-appb-000054
步骤一：向100mL圆底烧瓶中加入2-氨基-6-氯烟酸(5.0g,28.9mmol),N-氯代琥珀酰亚胺(4.1g,30.4mmol)和N,N-二甲基甲酰胺(50mL)，升温至70℃反应18小时。反应液冷却至室温，倾入冰盐水(300mL)中，过滤，滤饼水洗，干燥得到白色固体为2-氨基-5,6-二氯烟酸(5.6g,Y:93.3％)。ES-API:[M+H] +＝206.9。 Step 1: Add 2-amino-6-chloronicotinic acid (5.0g, 28.9mmol), N-chlorosuccinimide (4.1g, 30.4mmol) and N,N-dimethyl into a 100mL round bottom flask Formamide (50 mL) was heated to 70°C and reacted for 18 hours. The reaction solution was cooled to room temperature, poured into ice brine (300 mL), filtered, the filter cake was washed with water, and dried to obtain a white solid of 2-amino-5,6-dichloronicotinic acid (5.6 g, Y: 93.3%). ES-API: [M+H] + = 206.9.
步骤二：向100mL圆底烧瓶中加入2-氨基-5,6-二氯烟酸(5.6g,27mmol)，超干四氢呋喃(50mL)，向其中加入氯化亚砜(6.5mL)，室温搅拌反应20小时，真空旋蒸至干，加入四氢呋喃(20mL)带两次，所得黄色固体产品，加入四氢呋喃(50mL)和氨水(24mL),室温搅拌反应20分钟，旋干得到2-氨基-5,6-二氯烟酰胺(6.5g,Y:定量.)。ES-API:[M+H] +＝205.9。 Step 2: Add 2-amino-5,6-dichloronicotinic acid (5.6g, 27mmol) and ultra-dry tetrahydrofuran (50mL) to a 100mL round bottom flask, add thionyl chloride (6.5mL) to it, and stir at room temperature After reacting for 20 hours, evaporate to dryness under vacuum, add tetrahydrofuran (20mL) twice to obtain a yellow solid product, add tetrahydrofuran (50mL) and ammonia water (24mL), stir at room temperature for 20 minutes, spin dry to obtain 2-amino-5, 6-Dichloronicotinamide (6.5g, Y: quantitative.). ES-API: [M+H] + = 205.9.
步骤三：向250mL圆底烧瓶中，加入2-氨基-5,6-二氯烟酰胺(6.5g,27mmol),甲苯(60mL)和草酰氯(3.4mL)，反应液升温至110℃搅拌反应1小时。冷却至室温，过滤，甲苯(5mL)冲洗滤饼，真空干燥，所得粗品溶于水(100mL)，用乙酸乙酯(50mL)萃取6次，合并有机相，干燥浓缩后得到6,7-二氯吡啶[2,3-d]嘧啶-2,4-二醇(2.5g,Y:39.9％)。ES-API:[M+H] +＝231.9。 1H NMR(400MHz,DMSO-d 6)δ12.02(s,1H),11.66(s,1H),8.36(s,1H). Step 3: Into a 250mL round bottom flask, add 2-amino-5,6-dichloronicotinamide (6.5g, 27mmol), toluene (60mL) and oxalyl chloride (3.4mL), and the reaction solution was heated to 110°C and stirred for reaction 1 hour. Cool to room temperature, filter, rinse the filter cake with toluene (5 mL), and dry in vacuo. The resulting crude product is dissolved in water (100 mL), extracted with ethyl acetate (50 mL) 6 times, and the organic phases are combined. Chloropyridine [2,3-d]pyrimidine-2,4-diol (2.5 g, Y: 39.9%). ES-API: [M+H] + = 231.9. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.02 (s, 1H), 11.66 (s, 1H), 8.36 (s, 1H).
实施例1：1-(6-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟-7-(2-氟-6-羟基苯基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮的合成Example 1: 1-(6-(6-Chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxy Synthesis of (phenyl)quinazolin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000055
Figure PCTCN2020077192-appb-000055
步骤一：向50mL圆底烧瓶中加入7-溴-2,4,6-三氯-8-氟喹唑啉(300mg,0.908mmol)，2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯半草酸盐(243mg,0.999mmol)，10mL四氢呋喃和DIPEA(353mg,2.731mmol)。室温搅拌反应1小时，向反应液中加入30mL水，用30mL二氯甲烷萃取2次，有机相干燥后浓缩，残留物用甲醇打浆过滤，得到6-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(390mg,Y:87.2％)。ES-API:[M+H] +＝492.7。 Step 1: Add 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (300mg, 0.908mmol), 2,6-diazaspiro[3.3]heptane- to a 50mL round bottom flask Tert-butyl 2-carboxylate hemioxalate (243 mg, 0.999 mmol), 10 mL of tetrahydrofuran and DIPEA (353 mg, 2.731 mmol). The reaction was stirred at room temperature for 1 hour, 30 mL of water was added to the reaction solution, extracted twice with 30 mL of dichloromethane, the organic phase was dried and concentrated, and the residue was slurried and filtered with methanol to obtain 6-(7-bromo-2,6-dichloro -8-Fluoroquinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (390 mg, Y: 87.2%). ES-API: [M+H] + =492.7.
步骤二：向100mL圆底烧瓶中加入6-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(340mg,0.691mmol)，N，N-二甲基氮杂环-3-胺双盐酸盐(132mg,0.763mmol)，20mL异丙醇和DIPEA(510mg,3.946mmol)，油浴升温至105℃，搅拌反应16小时，冷却至室温，过滤，异丙醇冲洗滤饼，干燥得到6-(7-溴-6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(320mg,Y:83.3％)。ES-API:[M+H] +＝556.9。 Step 2: Add 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.3]heptane into a 100mL round bottom flask Tert-Butyl 2-carboxylate (340mg, 0.691mmol), N,N-dimethylazacyclo-3-amine bishydrochloride (132mg, 0.763mmol), 20mL isopropanol and DIPEA (510mg, 3.946mmol) , The oil bath was heated to 105°C, stirred for 16 hours, cooled to room temperature, filtered, washed with isopropanol, and dried to obtain 6-(7-bromo-6-chloro-2-(3-(dimethylamino) Azetidine-1-yl)-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (320mg, Y: 83.3 %). ES-API: [M+H] + =556.9.
步骤三：向100mL圆底烧瓶中加入6-(7-溴-6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(250mg,0.45mmol)，(2-氟-6-羟基苯基)硼酸(280mg,1.796mmol)，碳酸钠(250mg,2.359mmol)，四三苯基磷钯(80mg,0.069mmol)，15mL 1,4-二氧六环和3mL水，氮气置换3次，油浴升温至110℃，搅拌反应16小时，冷却至室温，加入30mL水，用30mL二氯甲烷萃取2次，有机相干燥后浓缩，柱层析(甲醇/二氯甲烷：0～10％)，得到6-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟-7-(2-氟-6-羟基苯基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(100mg,Y:30.6％)。ES-API:[M+H] +＝587.0。 Step 3: Add 6-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazoline- to a 100mL round bottom flask 4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (250mg, 0.45mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (280mg, 1.796mmol) ), sodium carbonate (250mg, 2.359mmol), palladium tetrakistriphenylphosphorus (80mg, 0.069mmol), 15mL 1,4-dioxane and 3mL water, nitrogen replacement 3 times, the oil bath is heated to 110 ℃, stirring Reacted for 16 hours, cooled to room temperature, added 30 mL of water, extracted twice with 30 mL of dichloromethane, dried the organic phase, concentrated, and column chromatography (methanol/dichloromethane: 0-10%) to obtain 6-(6-chloro -2-(3-(Dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2 ,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (100mg, Y: 30.6%). ES-API: [M+H] + = 587.0.
步骤四：向50mL圆底烧瓶中加入6-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟-7-(2-氟-6-羟基苯基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(100mg,0.17mmol)，5mL二氯甲烷和0.5mL三氟乙酸，室温搅拌反应5小时，加入30mL二氯甲烷，用30mL饱和碳酸氢钠洗2次，水相用30mL二氯甲烷萃取3次，合并有机相，干燥浓缩得到2-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟-4-(2,6-二氮杂螺[3.3]庚烷-2-基)喹唑啉-7-基)-3氟苯酚(48mg,57.8％)。ES-API:[M+H] +＝487.0。 Step 4: Add 6-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-) into a 50mL round bottom flask 6-hydroxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (100mg, 0.17mmol), 5mL dichloromethane and 0.5mL Trifluoroacetic acid, stirred at room temperature for 5 hours, added 30 mL of dichloromethane, washed twice with 30 mL of saturated sodium bicarbonate, the aqueous phase was extracted with 30 mL of dichloromethane three times, combined the organic phases, dried and concentrated to obtain 2-(6-chloro -2-(3-(Dimethylamino)azetidin-1-yl)-8-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)quinazole Lin-7-yl)-3 fluorophenol (48 mg, 57.8%). ES-API: [M+H] + =487.0.
步骤五：向50mL圆底烧瓶中加入2-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟 -4-(2,6-二氮杂螺[3.3]庚烷-2-基)喹唑啉-7-基)-3氟苯酚(48mg,0.099mmol)，5mL四氢呋喃，3滴三乙胺，置于冰水浴下冷却，加入1滴丙烯酰氯，搅拌反应10分钟，加入20mL水，用20mL二氯甲烷萃取2次，有机相干燥后浓缩，制备HPLC纯化得到1-(6-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟-7-(2-氟-6-羟基苯基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮(6.6mg,Y:12.5％)。ES-API:[M+H] +＝541.0。 Step 5: Add 2-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-4-(2,6- Diazaspiro[3.3]heptan-2-yl)quinazolin-7-yl)-3 fluorophenol (48mg, 0.099mmol), 5mL tetrahydrofuran, 3 drops of triethylamine, cool in an ice water bath, add 1 drop of acryloyl chloride, stirred for 10 minutes, added 20 mL of water, extracted twice with 20 mL of dichloromethane, dried the organic phase and concentrated, purified by preparative HPLC to obtain 1-(6-(6-chloro-2-(3-(二Methylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[ 3.3] Heptan-2-yl)prop-2-en-1-one (6.6 mg, Y: 12.5%). ES-API: [M+H] + = 541.0.
实施例2：(S或R)-1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 2: (S or R)-1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methyl (Piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000056
Figure PCTCN2020077192-appb-000056
步骤一：将化合物7-溴-2,4,6-三氯-8-氟喹唑啉(500mg,1.51mmol)溶于10mL的1,4-二氧六环，搅拌下加入三乙胺(0.63mL,4.53mmol)和2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(342mg,1.51mmol)，50℃反应0.5小时。反应结束后，加入100mL的乙酸乙酯，依次用30mL 1M的盐酸，30mL的饱和碳酸氢钠溶液和30mL的饱和食盐水洗涤。得到的有机相用无水硫酸钠干燥，过滤，浓缩得到黄色固体7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(750mg,Y：95％)。ES-API:[M+H] +＝519.0，521.0。 Step 1: Dissolve compound 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (500mg, 1.51mmol) in 10mL of 1,4-dioxane, add triethylamine ( 0.63mL, 4.53mmol) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (342mg, 1.51mmol), reacted at 50°C for 0.5 hours. After the reaction was completed, 100 mL of ethyl acetate was added, followed by washing with 30 mL of 1M hydrochloric acid, 30 mL of saturated sodium bicarbonate solution and 30 mL of saturated brine. The obtained organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazepine Spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (750 mg, Y: 95%). ES-API: [M+H] + = 519.0, 521.0.
步骤二：将化合物7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(750mg,1.44mmol)溶于10mL二甲亚砜和10mL 1,4-二氧六环的混合溶液中，依次加入KF(830mg,14.3mmol)和1-甲基-4-哌啶醇(330mg,2.87mmol)。混合物在120℃下搅拌3小时。反应结束后，将反应液倒入100mL乙酸乙酯中，并用50mL的饱和食盐水洗涤三遍。得到的有机相用无水硫酸钠干燥，过滤浓缩得到残留物。残留物用柱色谱(DCM:MeOH(1％Et 3N)＝300:1 to 100:1)纯化,得到淡黄色固体7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(550mg,Y：64％)。ES-API:[M+H] +＝598.0，600.0。 Step 2: The compound 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert Butyl ester (750mg, 1.44mmol) was dissolved in a mixed solution of 10mL dimethyl sulfoxide and 10mL 1,4-dioxane, and KF (830mg, 14.3mmol) and 1-methyl-4-piperidinol were added sequentially (330mg, 2.87mmol). The mixture was stirred at 120°C for 3 hours. After the reaction, the reaction solution was poured into 100 mL of ethyl acetate, and washed with 50 mL of saturated brine three times. The obtained organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (DCM:MeOH(1%Et 3 N)=300:1 to 100:1) to obtain a pale yellow solid 7-(7-bromo-6-chloro-8-fluoro-2-(( 1-Methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (550mg, Y: 64% ). ES-API: [M+H] + =598.0, 600.0.
步骤三：将化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(250mg,0.417mol)，5-甲基-1H-吲唑-4-硼酸(110mg,0.626mol),三(二亚苄基丙酮)二钯(38mg,0.042mmol)，2-二环己基膦基-2′,6′-二甲氧基联苯(17mg,0.042mol)和磷酸钾(177mg,0.834mol)溶于5mL 1,4-二氧六环和0.5mL水，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下120℃反应1小时后，反应液过滤，溶于30mL乙酸乙酯中并用10mL饱和食盐水洗涤三遍，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用层析板(DCM:MeOH＝10:1)纯化，得到黄色固体的7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷 -2-甲酸叔丁酯(200mg)。ES-API:[M+H] +＝650.2。 Step 3: The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (250mg, 0.417mol), 5-methyl-1H-indazole-4-boronic acid (110mg, 0.626mol), tris(dibenzylidene Acetone) two palladium (38mg, 0.042mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (17mg, 0.042mol) and potassium phosphate (177mg, 0.834mol) dissolved in 5mL 1 , 4-Dioxane and 0.5 mL of water, and place the mixture in a microwave tube, bubbling with N 2 for 1 minute. After reacting at 120°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 10 mL of saturated brine three times, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified with a chromatography plate (DCM:MeOH=10:1) to obtain 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl) as a yellow solid )-2-(1-Methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (200mg ). ES-API: [M+H] + =650.2.
步骤四：将化合物7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(200mg,0.308mol)的甲醇(3mL)的溶液冷却至0℃，缓慢加入HCl/二氧六环溶液(4M,3mL,12mmol)。加完后回到室温，并搅拌2小时。反应结束后，反应液减压浓缩，得到黄色固体的6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐粗品(200mg)。Step 4: The compound 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin-4-yl)oxy )Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (200mg, 0.308mol) in methanol (3mL) is cooled to 0℃ and slowly added HCl/dioxane solution (4M, 3mL, 12mmol). After the addition, return to room temperature and stir for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidine) as a yellow solid -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride crude product (200 mg).
步骤五：在冰浴条件下，往上述得到的化合物6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐粗品(200mg,0.308mmol)的四氢呋喃(5mL)的悬浊液中缓慢加入1mL的饱和碳酸氢钠水溶液，反应液澄清后，加入丙烯酰氯(28mg,0.308mol)，室温搅拌1小时。反应液用无水硫酸钠干燥，过滤浓缩，得到的残留物用prep-HPLC制备得到白色固体1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(60mg,P:100％，Y：32.2％)。ES-API:[M+H] +＝:604.2。 Step 5: Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride crude product (200mg, 0.308mmol) in tetrahydrofuran (5mL) suspension 1 mL of saturated sodium bicarbonate aqueous solution was slowly added to the turbid solution. After the reaction solution was clear, acryloyl chloride (28 mg, 0.308 mol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was dried with anhydrous sodium sulfate, filtered and concentrated, and the residue obtained was prepared by prep-HPLC to obtain a white solid 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazole) -4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl ) Pro-2-en-1-one (60 mg, P: 100%, Y: 32.2%). ES-API: [M+H] + =: 604.2.
步骤六：将上述得到的化合物1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(55mg,0.091mmol)用SFC手性拆分得到化合物：Step 6: The compound 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (55mg, 0.091mmol) The compound is obtained by chiral resolution by SFC:
(S)-1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(16.66mg,纯度：99％，ee值：100％)。ES-API:[M+H] +＝:604.2。 1H NMR(400MHz,CD 3OD,ppm)7.92(d,J＝1.4Hz,1H),7.55(d,J＝8.6Hz,1H),7.51(s,1H),7.39(d,J＝8.7Hz,1H),6.37(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,2.1Hz,1H),5.73(dd,J＝10.2,2.1Hz,1H),5.17(s,1H),4.11(s,2H),3.91–3.80(m,6H),2.74(s,2H),2.38(s,2H),2.28(s,3H),2.19(s,3H),2.08(s,2H),2.04–1.98(m,4H),1.89(m,2H)。 (S)-1-(7-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl )Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (16.66mg, purity: 99%, ee Value: 100%). ES-API: [M+H] + =: 604.2. 1 H NMR (400MHz, CD 3 OD, ppm) 7.92 (d, J = 1.4 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 7.39 (d, J = 8.7 Hz, 1H), 6.37 (dd, J = 17.0, 10.2 Hz, 1H), 6.25 (dd, J = 17.0, 2.1 Hz, 1H), 5.73 (dd, J = 10.2, 2.1 Hz, 1H), 5.17 (s ,1H), 4.11(s, 2H), 3.91--3.80(m, 6H), 2.74(s, 2H), 2.38(s, 2H), 2.28(s, 3H), 2.19(s, 3H), 2.08( s, 2H), 2.04-1.98 (m, 4H), 1.89 (m, 2H).
(R)-1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(15.61mg,纯度：97％，ee值：97％)。ES-API:[M+H] +＝:604.2。 1H NMR(400MHz,CD 3OD,ppm)7.92(d,J＝1.2Hz,1H),7.55(d,J＝8.7Hz,1H),7.51(s,1H),7.39(d,J＝8.6Hz,1H),6.37(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,2.0Hz,1H),5.73(dd,J＝10.2,2.0Hz,1H),5.18(s,1H),4.11(s,2H),3.93–3.78(m,6H),2.75(s,2H),2.39(s,2H),2.29(s,3H),2.19(s,3H),2.08(s,2H),2.04–1.99(m,4H),1.89(m,2H)。 (R)-1-(7-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl )Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (15.61mg, purity: 97%, ee Value: 97%). ES-API: [M+H] + =: 604.2. 1 H NMR (400MHz, CD 3 OD, ppm) 7.92 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 7.39 (d, J = 8.6 Hz, 1H), 6.37 (dd, J = 17.0, 10.2 Hz, 1H), 6.25 (dd, J = 17.0, 2.0 Hz, 1H), 5.73 (dd, J = 10.2, 2.0 Hz, 1H), 5.18 (s ,1H),4.11(s,2H),3.93-3.78(m,6H),2.75(s,2H),2.39(s,2H),2.29(s,3H),2.19(s,3H),2.08( s, 2H), 2.04-1.99 (m, 4H), 1.89 (m, 2H).
实施例4：1-(7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2基)丙-2-烯-1-酮的合成Example 4: 1-(7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridin-3-yl) Synthesis of quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000057
Figure PCTCN2020077192-appb-000057
步骤一：将化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮 杂螺[3.5]壬烷-2-甲酸叔丁酯(150mg,0.25mmol)，4-甲基吡啶-3-硼酸频哪醇酯(66mg,0.3mmol)，三(二亚苄基丙酮)二钯(23mg,0.025mmol)，2-二环己基膦基-2′,6′-二甲氧基联苯(10mg,0.025mol)和磷酸钾(106mg,0.5mol)溶于2mL 1,4-二氧六环和0.2mL水，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下100℃反应1小时后，反应液过滤，溶于30mL乙酸乙酯中并用20mL饱和食盐水洗涤三遍，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用层析板(DCM:MeOH＝10:1)纯化，得到黄色固体的7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(130mg)。ES-API:[M+H] +＝611.2。 Step 1: The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.25mmol), 4-picoline-3-boronic acid pinacol ester (66mg, 0.3mmol), tris(dibenzylidene Acetone) two palladium (23mg, 0.025mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (10mg, 0.025mol) and potassium phosphate (106mg, 0.5mol) dissolved in 2mL 1 , 4-Dioxane and 0.2 mL of water, and place the mixture in a microwave tube, bubbling with N 2 for 1 minute. After reacting at 100°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 20 mL of saturated brine three times, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified with a chromatography plate (DCM:MeOH=10:1) to obtain 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidine-4) as a yellow solid -Yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (130 mg). ES-API: [M+H] + = 611.2.
步骤二：将上述得到的化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(130mg,0.213mmol)的甲醇(2mL)溶液冷却至0℃，缓慢加入HCl/二氧六环溶液(4M,2mL,8mmol)。加完后回到室温，并搅拌2小时。反应结束后，加入20mL的乙酸乙酯，减压浓缩，得到黄色固体的6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)-4-(2,7-二氮杂螺[3.5]壬-7-基)喹唑啉盐酸盐(130mg)。ES-API:[M+H] +＝511.1。 Step 2: The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)- 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (130mg, 0.213mmol) in methanol (2mL) was cooled to 0℃, and HCl/dioxane solution (4M, 2mL) , 8mmol). After the addition, return to room temperature and stir for 2 hours. After the reaction, 20 mL of ethyl acetate was added and concentrated under reduced pressure to obtain 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(4 -Methylpyridin-3-yl)-4-(2,7-diazaspiro[3.5]non-7-yl)quinazoline hydrochloride (130 mg). ES-API: [M+H] + = 511.1.
步骤三：在冰浴条件下，往上述得到的化合物6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)-4-(2,7-二氮杂螺[3.5]壬-7-基)喹唑啉盐酸盐(130mg,0.213mmol)的四氢呋喃(5mL)的悬浊液中缓慢加入1mL的饱和NaHCO 3溶液，反应液澄清后，加入丙烯酰氯(0.017mL，0,213mmol)，室温搅拌0.5小时。反应液用二氯甲烷萃取，浓缩后得到的化合物用prep-HPLC制备，得到白色固体1-(7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2基)丙-2-烯-1-酮(25.5mg,P:99％，Y：21％)。ES-API:[M+H] +＝565.2。 1H NMR(400MHz,DMSO-d6,ppm):8.53(d,J＝5.6Hz,1H),8.37(s,1H),7.84(s,1H),7.43(d,J＝5.2Hz,1H),6.30(dd,J＝17.2,10.4Hz,1H),6.08(d,J＝17.2Hz,1H),5.65(d,J＝10.8Hz,1H),4.98(m,1H),3.99(s,2H),3.70(s,6H),2.60(s,2H),2.14(s,3H),2.12(s,1H),2.09(s,4H),1.95(m,2H),1.89(m,4H),1.68(m,2H)。 Step 3: Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridine- 3-yl)-4-(2,7-diazaspiro[3.5]non-7-yl)quinazoline hydrochloride (130mg, 0.213mmol) in tetrahydrofuran (5mL) suspension was slowly added 1mL saturated NaHCO 3 solution, the reaction solution after clarification, was added acryloyl chloride (0.017mL, 0,213mmol), stirred at room temperature for 0.5 hours. The reaction solution was extracted with dichloromethane, and the compound obtained after concentration was prepared by prep-HPLC to obtain a white solid 1-(7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl) )Oxy)-7-(4-methylpyridin-3-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2yl)prop-2-ene- 1-ketone (25.5 mg, P: 99%, Y: 21%). ES-API: [M+H] + = 565.2. 1 H NMR (400MHz, DMSO-d6, ppm): 8.53(d,J=5.6Hz,1H), 8.37(s,1H), 7.84(s,1H), 7.43(d,J=5.2Hz,1H) ,6.30(dd,J＝17.2,10.4Hz,1H),6.08(d,J＝17.2Hz,1H), 5.65(d,J＝10.8Hz,1H), 4.98(m,1H),3.99(s, 2H), 3.70(s, 6H), 2.60(s, 2H), 2.14(s, 3H), 2.12(s, 1H), 2.09(s, 4H), 1.95(m, 2H), 1.89(m, 4H ), 1.68 (m, 2H).
实施例5：1-(7-(8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮三氟乙酸盐的合成Example 5: 1-(7-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridin-3-yl)-6 -Vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one trifluoroacetate
Figure PCTCN2020077192-appb-000058
Figure PCTCN2020077192-appb-000058
步骤一：将化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮 杂螺[3.5]壬烷-2-甲酸叔丁酯(300mg，0.5mmol)溶于15mL四氢呋喃，并加入EtONa(0.5M/EtOH，3mL,1.5mmol)。反应液在微波照射下60℃反应30分钟。反应结束后用20mL的水淬灭，50mL乙酸乙酯萃取三遍，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用硅胶柱(DCM:MeOH＝200:1到100:1)纯化，得到白色固体的7-(7-溴-6-氯-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(200mg)。ES-API:[M+H] +＝624.0，626.0。 Step 1: The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (300mg, 0.5mmol) was dissolved in 15mL tetrahydrofuran, and EtONa (0.5M/EtOH, 3mL, 1.5mmol) was added. The reaction solution was reacted at 60°C for 30 minutes under microwave irradiation. After the reaction was completed, it was quenched with 20 mL of water, and extracted three times with 50 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified with a silica gel column (DCM:MeOH=200:1 to 100:1) to obtain 7-(7-bromo-6-chloro-8-ethoxy-2-((1-methyl) as a white solid Piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (200 mg). ES-API: [M+H] + = 624.0, 626.0.
步骤二：将化合物7-(7-溴-6-氯-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(100mg，0.16mmol)，4-甲基吡啶-3-硼酸频哪醇酯(42mg，0.192mol)，三(二亚苄基丙酮)二钯(16mg，0.018mmol)，SPhos(8mg，0.019mol)和磷酸钾(68mg，0.32mmol)溶于1,4-二氧六环(2mL)和水(0.2mL)，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下100℃反应1小时后，反应液过滤，溶于30mL乙酸乙酯中并用20mL饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用层析板(DCM:MeOH＝10:1)纯化，得到黄色固体的7-(6-氯-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(100mg)。ES-API:[M+H] +＝637.3。 Step 2: The compound 7-(7-bromo-6-chloro-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2 ,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg, 0.16mmol), 4-picoline-3-boronic acid pinacol ester (42mg, 0.192mol), tris(diethylene) Benzylacetone) two palladium (16mg, 0.018mmol), SPhos (8mg, 0.019mol) and potassium phosphate (68mg, 0.32mmol) dissolved in 1,4-dioxane (2mL) and water (0.2mL), and The mixture was placed in a microwave tube, and N 2 was bubbled in for 1 minute. After reacting at 100°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 20 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified with a chromatography plate (DCM:MeOH=10:1) to obtain 7-(6-chloro-8-ethoxy-2-((1-methylpiperidin-4-yl) as a yellow solid )Oxy)-7-(4-methylpyridin-3-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg) . ES-API: [M+H] + = 637.3.
步骤三：将化合物7-(6-氯-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(100mg，0.157mmol)，乙烯基硼酸频哪醇酯(29mg，0.188mol)，三(二亚苄基丙酮)二钯(15mg，0.016mol)，SPhos(7mg，0.017mol)和磷酸钾(67mg，0.316mol)溶于1,4-二氧六环(1.5mL)和水(0.15mL)，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下150℃反应1.5小时后，反应液过滤，溶于30mL乙酸乙酯中并用20mL饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用层析板(DCM:MeOH＝10:1)纯化，得到黄色固体的7-(8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(90mg)。ES-API:[M+H] +＝629.3。 Step 3: The compound 7-(6-chloro-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridin-3-yl) Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg, 0.157mmol), vinyl boronic acid pinacol ester (29mg, 0.188mol), Tris(dibenzylideneacetone)dipalladium (15mg, 0.016mol), SPhos (7mg, 0.017mol) and potassium phosphate (67mg, 0.316mol) are dissolved in 1,4-dioxane (1.5mL) and water ( 0.15 mL), and put the mixture in a microwave tube, bubbling with N 2 for 1 minute. After reacting at 150°C under microwave for 1.5 hours, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 20 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified with a chromatography plate (DCM:MeOH=10:1) to obtain 7-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy) as a yellow solid -7-(4-methylpyridin-3-yl)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (90mg ). ES-API: [M+H] + =629.3.
步骤四：将化合物7-(8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(150mg，0.238mmol)的甲醇(3mL)溶液冷却至0℃，缓慢加入HCl/二氧六环溶液(4M,3mL,12mmol)。加完后回到室温，并搅拌2小时。反应结束后，加入20mL的乙酸乙酯，减压浓缩得到黄色固体的8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)-4-(2,7-二氮杂螺[3.5]壬-7-基)-6-乙烯基喹唑啉盐酸盐(150mg)。ES-API:[M+H] +＝529.2。 Step 4: The compound 7-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridin-3-yl)-6-ethylene Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.238mmol) in methanol (3mL) was cooled to 0℃, and HCl was slowly added /Dioxane solution (4M, 3mL, 12mmol). After the addition, return to room temperature and stir for 2 hours. After the reaction, 20 mL of ethyl acetate was added, and concentrated under reduced pressure to obtain 8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methyl) as a yellow solid Pyridin-3-yl)-4-(2,7-diazaspiro[3.5]non-7-yl)-6-vinylquinazoline hydrochloride (150 mg). ES-API: [M+H] + =529.2.
步骤五：在冰浴条件下，往上述得到的化合物8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)-4-(2,7-二氮杂螺[3.5]壬-7-基)-6-乙烯基喹唑啉盐酸盐(150mg，0.238mmol)的四氢呋喃(5mL)的悬浊液中缓慢加入1mL的饱和NaHCO 3溶液，反应液澄清后，加入丙烯酰氯(0.019mL,0.238mmol)，室温搅拌1小时。反应液用二氯甲烷萃取，浓缩后得到的化合物用prep-HPLC(TFA)制备，得到白色固体1-(7-(8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-7-(4-甲基吡啶-3-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬-2-基)丙-2-烯-1-酮三氟乙酸盐(7.3mg，P:96％，Y:4％)。ES-API:[M+H] +＝583.3。 1H NMR(400MHz, DMSO-d6,ppm)8.71(d,J＝5.4Hz,1H),8.55(s,1H),7.89(s,1H),7.75(d,J＝5.6Hz,1H),6.29(ddd,J＝28.4,17.2,10.6Hz,2H),6.12(dd,J＝17.0,2.0Hz,1H),5.71(dd,J＝18.8,14.8Hz,2H),5.23(d,J＝11.2Hz,1H),5.14(s,1H),4.15(d,J＝7.2Hz,1H),4.03(s,3H),3.76(s,6H),3.53(d,J＝11.6Hz,1H),3.37(d,J＝10.8Hz,1H),3.18(s,2H),2.90–2.75(m,3H),2.36(d,J＝12.0Hz,1H),2.24(d,J＝8.8Hz,1H),2.13(s,4H),1.95(s,5H),0.97(dt,J＝11.6,7.2Hz,3H)。 Step 5: Under ice bath conditions, transfer the compound 8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-7-(4-methylpyridine-3- Yl)-4-(2,7-diazaspiro[3.5]non-7-yl)-6-vinylquinazoline hydrochloride (150mg, 0.238mmol) in tetrahydrofuran (5mL) suspension Slowly add 1 mL of saturated NaHCO 3 solution, after the reaction solution is clear, add acryloyl chloride (0.019 mL, 0.238 mmol), and stir at room temperature for 1 hour. The reaction solution was extracted with dichloromethane, and the compound obtained after concentration was prepared with prep-HPLC (TFA) to obtain white solid 1-(7-(8-ethoxy-2-((1-methylpiperidine-4- Yl)oxy)-7-(4-methylpyridin-3-yl)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl) Prop-2-en-1-one trifluoroacetate (7.3 mg, P: 96%, Y: 4%). ES-API: [M+H] + = 583.3. 1 H NMR (400MHz, DMSO-d6, ppm) 8.71 (d, J = 5.4 Hz, 1H), 8.55 (s, 1H), 7.89 (s, 1H), 7.75 (d, J = 5.6 Hz, 1H), 6.29 (ddd, J = 28.4, 17.2, 10.6 Hz, 2H), 6.12 (dd, J = 17.0, 2.0 Hz, 1H), 5.71 (dd, J = 18.8, 14.8 Hz, 2H), 5.23 (d, J = 11.2Hz, 1H), 5.14 (s, 1H), 4.15 (d, J = 7.2 Hz, 1H), 4.03 (s, 3H), 3.76 (s, 6H), 3.53 (d, J = 11.6 Hz, 1H) , 3.37 (d, J = 10.8 Hz, 1H), 3.18 (s, 2H), 2.90-2.75 (m, 3H), 2.36 (d, J = 12.0 Hz, 1H), 2.24 (d, J = 8.8 Hz, 1H), 2.13 (s, 4H), 1.95 (s, 5H), 0.97 (dt, J=11.6, 7.2 Hz, 3H).
实施例6：1-(7-(7-(5-氨基-2-氯苯基)-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基-喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 6: 1-(7-(7-(5-amino-2-chlorophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6 -Vinyl-quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000059
Figure PCTCN2020077192-appb-000059
步骤一：将7-溴-2,4-二氯-8-氟-6-碘-喹唑啉(6g，14.2mmoL)和2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(3.38g，14.9mmoL)溶解在1,4-二氧六环(100mL)中，在冰浴(0～5℃)条件下，缓慢加入三乙胺(2.87g，28.4mmoL)，室温搅拌3h，浓缩，反应液加入50mL水中，用乙酸乙酯萃取(50mL×2),合并有机相，减压浓缩,得到粗品7-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(8.0g，Y92％)。ES-API:[M+H] +＝611.0。 Step 1: Combine 7-bromo-2,4-dichloro-8-fluoro-6-iodo-quinazoline (6g, 14.2mmoL) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid Tert-butyl ester (3.38g, 14.9mmoL) was dissolved in 1,4-dioxane (100mL), and triethylamine (2.87g, 28.4mmoL) was slowly added in an ice bath (0～5℃). Stir at room temperature for 3 hours, concentrate, add the reaction solution to 50 mL of water, extract with ethyl acetate (50 mL×2), combine the organic phases, and concentrate under reduced pressure to obtain crude 7-(7-bromo-2-chloro-8-fluoro-6- Iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (8.0 g, Y92%). ES-API: [M+H] + = 611.0.
步骤二：将7-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(2g，3.27mmoL)、1-甲基哌啶-4-醇(5.65g，49.1mmoL)、Cs 2CO 3(2.13g，6.5mmoL)和KF(3.8mg，65.4mmoL)加入到干燥的1-4-二氧六环/二甲亚砜(25mL/25mL)中，油浴120℃反应40分钟。冷却室温，反应液加入100mL水中，用乙酸乙酯萃取3次,合并有机相，减压浓缩,柱层析(甲醇/二氯甲烷：0～10％)，得到7-(7-溴-8-氟-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(1.47g，Y65％)。ES-API:[M+H] +＝690.1。 Step 2: Add 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (2g, 3.27mmoL), 1-methylpiperidin-4-ol (5.65g, 49.1mmoL), Cs 2 CO 3 (2.13g, 6.5mmoL) and KF (3.8mg, 65.4mmoL) were added to the dry In 1-4-dioxane/dimethyl sulfoxide (25mL/25mL), react in an oil bath at 120°C for 40 minutes. After cooling to room temperature, the reaction solution was added to 100 mL of water, extracted 3 times with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and column chromatography (methanol/dichloromethane: 0-10%) was used to obtain 7-(7-bromo-8). -Fluoro-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2- Tert-Butyl formate (1.47 g, Y65%). ES-API: [M+H] + =690.1.
步骤三：将7-(7-溴-8-氟-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(2.6g，3.77mmoL)和乙醇钠(7.54mL,1M乙醇溶液)加入到干燥的75mL 四氢呋喃，油浴70℃反应50分钟。冷却室温，反应液加入100mL水中，用乙酸乙酯萃取3次,合并有机相，减压浓缩,柱层析(甲醇/二氯甲烷：0～10％)，得到7-(7-溴-8-乙氧基-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(1.30g，Y48％)。ES-API:[M+H] +＝716.0。 Step 3: Add 7-(7-bromo-8-fluoro-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7- Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2.6g, 3.77mmoL) and sodium ethoxide (7.54mL, 1M ethanol solution) were added to dry 75mL tetrahydrofuran and reacted at 70°C in an oil bath for 50 minutes. After cooling to room temperature, the reaction solution was added to 100 mL of water, extracted 3 times with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and column chromatography (methanol/dichloromethane: 0-10%) was used to obtain 7-(7-bromo-8). -Ethoxy-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane- Tert-Butyl 2-formate (1.30 g, Y48%). ES-API: [M+H] + = 716.0.
步骤四：将7-(7-溴-8-乙氧基-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(1.3g，1.82mmoL)、乙烯三氟硼酸钾(266mg，2.00mmoL)、Pd(dppf)Cl 2(133mg，0.182mmoL)和碳酸钾(502mg，3.64mmoL)加入到10mL 1,4-二氧六环和2mL水中，微波80℃反应50分钟。冷却室温，反应液加入50mL水中，用乙酸乙酯萃取3次,合并有机相，干燥后减压浓缩,柱层析(甲醇/二氯甲烷：0～10％)，得到7-(7-溴-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(840mg，Y75％)。ES-API:[M+H] +＝616.3。 Step 4: Add 7-(7-bromo-8-ethoxy-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2, 7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.3g, 1.82mmoL), potassium ethylene trifluoroborate (266mg, 2.00mmoL), Pd(dppf)Cl 2 (133mg, 0.182mmoL) And potassium carbonate (502mg, 3.64mmoL) were added to 10mL 1,4-dioxane and 2mL water, and microwaved at 80°C for 50 minutes. After cooling to room temperature, the reaction solution was added to 50 mL of water, extracted 3 times with ethyl acetate, the organic phases were combined, dried and concentrated under reduced pressure, and column chromatography (methanol/dichloromethane: 0-10%) was used to obtain 7-(7-bromo -8-Ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5] Tert-Butyl Nonane-2-carboxylate (840 mg, Y75%). ES-API: [M+H] + = 616.3.
步骤五：将7-(7-溴-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(500mg，0.81mmoL)、(2-氯-5-硝基苯基)硼酸(245mg，1.22mmoL)、Pd 2(dba) 3(74mg，0.081mmoL)、2-双环己基膦-2',6'-二甲氧基联苯Sphos(67mg，0.162mmoL)和磷酸钾(343mg，1.62mmoL)加入到20mL的微波管中，并加入1mL水和8mL1,4-二氧六环，氮气置换1分钟，微波加热120℃反应50分钟。TLC检测反应完全，倒入水中，乙酸乙酯10萃取，无水硫酸钠干燥，浓缩，经柱层析(甲醇/二氯甲烷：0～10％)纯化得到7-(7-(2-氯-5-硝基苯基)-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(393mg，Y70％)。ES-API:[M+H] +＝693.3 Step 5: Add 7-(7-bromo-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2 ,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (500mg, 0.81mmoL), (2-chloro-5-nitrophenyl)boronic acid (245mg, 1.22mmoL), Pd 2 (dba ) 3 (74mg, 0.081mmoL), 2-Biscyclohexylphosphine-2',6'-dimethoxybiphenyl Sphos (67mg, 0.162mmoL) and potassium phosphate (343mg, 1.62mmoL) were added to a 20mL microwave tube , And add 1mL water and 8mL 1,4-dioxane, nitrogen replacement for 1 minute, microwave heating at 120°C for 50 minutes. TLC detects that the reaction is complete, poured into water, extracted with ethyl acetate 10, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(7-(2-chloro -5-nitrophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (393 mg, Y70%). ES-API: [M+H] + ＝693.3
步骤六：将7-(7-(2-氯-5-硝基苯基)-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(393mg，0.57mmoL)加入到5mL无水甲醇中，在冰浴条件下，缓慢滴加4M HCl(1,4-二氧六环溶液，5mL)，升至室温反应2小时。反应结束后，减压浓缩，得到7-(2-氯-5-硝基苯基)-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬-7-基)-6-乙烯基喹唑啉盐酸盐(310mg，Y95％)。ES-API:[M+H] +＝593.3。 Step 6: Add 7-(7-(2-chloro-5-nitrophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6-ethylene Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (393mg, 0.57mmoL) was added to 5mL of anhydrous methanol, under ice bath conditions, 4M HCl (1,4-dioxane solution, 5 mL) was slowly added dropwise, and the temperature was raised to room temperature to react for 2 hours. After the reaction, it was concentrated under reduced pressure to obtain 7-(2-chloro-5-nitrophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4 -(2,7-diazaspiro[3.5]non-7-yl)-6-vinylquinazoline hydrochloride (310 mg, Y95%). ES-API: [M+H] + =593.3.
步骤七：将7-(2-氯-5-硝基苯基)-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬-7-基)-6-乙烯基喹唑啉盐酸盐(310mg，0.52mmoL)、碳酸氢钠(437mg，5.2mmoL)加入到5mL四氢呋喃和3mL水中，在冰浴条件下再缓慢滴加丙烯酰氯(91mg，1.04mmoL)，搅拌10分钟。二氯甲烷萃取，用无水硫酸钠干燥有机层，减压浓缩，得到粗品1-(7-(7-(2-氯-5-硝基苯基)-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基-喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬-2-基)丙-2-烯-1-酮(280mg,Y78％粗品)。ES-API:[M+H] +＝647.3。 Step 7: Add 7-(2-chloro-5-nitrophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7 -Diazaspiro[3.5]non-7-yl)-6-vinylquinazoline hydrochloride (310mg, 0.52mmoL), sodium bicarbonate (437mg, 5.2mmoL) were added to 5mL tetrahydrofuran and 3mL water, in Acrylic chloride (91 mg, 1.04 mmoL) was slowly added dropwise under ice bath conditions, and stirred for 10 minutes. Extracted with dichloromethane, dried the organic layer with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 1-(7-(7-(2-chloro-5-nitrophenyl)-8-ethoxy-2-( (1-Methylpiperidin-4-yl)oxy)-6-vinyl-quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)propan-2 -En-1-one (280 mg, Y78% crude product). ES-API: [M+H] + =647.3.
步骤八：将粗品1-(7-(7-(2-氯-5-硝基苯基)-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基-喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬-2-基)丙-2-烯-1-酮(240mg，0.37mmoL)、铁粉(103mg，1.85mmoL)和饱和氯化铵水溶液(3mL,饱和水溶液)加入到20mL无水乙醇中，油浴60℃反应3小时。反应完全，趁热硅藻土过滤，减压浓缩，经制备HPLC纯化，得到1-(7-(7-(5-氨基-2-氯苯基)-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基-喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬-2-基)丙-2-烯-1-酮(16.5mg,Y7％)。ES-API:[M+H] +＝617.3。1H NMR(400MHz,DMSO-d 6)δ7.77(s,1H),7.12(d,J＝8.6Hz,1H),6.57(dd,J＝8.6,2.7Hz,1H),6.36(d,J＝ 2.7Hz,1H),6.34-6.28(m,1H),6.27-6.21(m,1H),6.08(dd,J＝17.0,2.3Hz,1H),5.69-5.64(m,1H),5.63(d,J＝1.9Hz,1H),5.26(s,2H),5.13(d,J＝11.2Hz,1H),4.93(m,1H),4.08(q,J＝7.0,2H),4.02-3.94(m,2H),3.70(s,2H),3.67-3.62(m,2H),3.29-3.24(m,2H),2.66(m,2H),2.15(s,3H),2.09-1.95(m,4H),1.94-1.82(m,4H),1.73-1.60(m,2H),1.07(t,J＝7.0Hz,3H)。 Step 8: The crude product 1-(7-(7-(2-chloro-5-nitrophenyl)-8-ethoxy-2-((1-methylpiperidin-4-yl)oxy) -6-Vinyl-quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (240mg, 0.37mmoL), iron powder (103 mg, 1.85 mmoL) and saturated ammonium chloride aqueous solution (3 mL, saturated aqueous solution) were added to 20 mL of absolute ethanol, and reacted in an oil bath at 60°C for 3 hours. After the reaction was complete, filtered while hot Celite, concentrated under reduced pressure, and purified by preparative HPLC to obtain 1-(7-(7-(5-amino-2-chlorophenyl)-8-ethoxy-2-(( 1-methylpiperidin-4-yl)oxy)-6-vinyl-quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)propan-2- En-1-one (16.5mg, Y7%). ES-API: [M+H] + ＝617.3. 1H NMR (400MHz, DMSO-d 6 )δ7.77(s,1H), 7.12(d,J=8.6Hz,1H), 6.57(dd,J= 8.6,2.7Hz,1H), 6.36(d,J=2.7Hz,1H),6.34-6.28(m,1H),6.27-6.21(m,1H),6.08(dd,J=17.0,2.3Hz,1H ), 5.69-5.64 (m, 1H), 5.63 (d, J = 1.9 Hz, 1H), 5.26 (s, 2H), 5.13 (d, J = 11.2 Hz, 1H), 4.93 (m, 1H), 4.08 (q,J=7.0,2H),4.02-3.94(m,2H),3.70(s,2H),3.67-3.62(m,2H),3.29-3.24(m,2H),2.66(m,2H) , 2.15 (s, 3H), 2.09-1.95 (m, 4H), 1.94-1.82 (m, 4H), 1.73-1.60 (m, 2H), 1.07 (t, J = 7.0 Hz, 3H).
实施例7：1-(7-(6-氯-8-氟-7-(3-甲基-1H-吡唑-4-基)-2–(1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 7: 1-(7-(6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-(1-methylpiperidin-4-yl) (Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000060
Figure PCTCN2020077192-appb-000060
步骤一：将化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(100mg,0.167mmol)，3-甲基-1H-吡唑-4-硼酸(42mg,0.334mmol),三(二亚苄基丙酮)二钯(15mg,0.017mmol)，2-二环己基膦基-2′,6′-二甲氧基联苯(7mg,0.017mol)和磷酸钾(71mg,0.334mol)溶于1,4-二氧六环(2mL)和水(0.2mL)，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下120℃反应1小时后，反应液过滤，溶于30mL乙酸乙酯中并用20mL饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用层析板(DCM:MeOH＝10:1)纯化，得到白色固体的7-(6-氯-8-氟-7-(3-甲基-1H-吡唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基))-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(15mg)。ES-API:[M+H] +＝600.0。 Step 1: The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg, 0.167mmol), 3-methyl-1H-pyrazole-4-boronic acid (42mg, 0.334mmol), tris(dibenzylidene Acetone) two palladium (15mg, 0.017mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (7mg, 0.017mol) and potassium phosphate (71mg, 0.334mol) dissolved in 1, 4-Dioxane (2 mL) and water (0.2 mL), and put the mixture in a microwave tube, bubbling with N 2 for 1 minute. After reacting at 120°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with 20 mL of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified with a chromatography plate (DCM:MeOH=10:1) to obtain 7-(6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl) as a white solid )-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl))-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (15mg). ES-API: [M+H] + = 600.0.
步骤二：将化合物7-(6-氯-8-氟-7-(3-甲基-1H-吡唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基))-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(15mg,0.025mol)的甲醇(2mL)的溶液冷却至0℃，缓慢加入HCl/二氧六环溶液(4M,2mL,8mmol)。加完后回到室温，并搅拌2小时。反应结束后，加入20mL的乙酸乙酯，减压浓缩得到黄色固体的6-氯-8-氟-7-(3-甲基-1H-吡唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐(15mg)。ES-API:[M+H] +＝500.0。 Step 2: The compound 7-(6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy Yl)quinazolin-4-yl))-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (15mg, 0.025mol) in methanol (2mL) is cooled to 0°C, Slowly add HCl/dioxane solution (4M, 2mL, 8mmol). After the addition, return to room temperature and stir for 2 hours. After the reaction, 20 mL of ethyl acetate was added, and concentrated under reduced pressure to obtain 6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-((1- Methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (15 mg). ES-API: [M+H] + =500.0.
步骤三：在冰浴条件下，往上述得到的化合物6-氯-8-氟-7-(3-甲基-1H-吡唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐(15mg,25umol)的四氢呋喃(2mL)的悬浊液中缓慢加入0.2mL的饱和NaHCO 3溶液，反应液澄清后，加入丙烯酰氯(2.3mg,0.025mol)，室温搅拌0.5小时。反应液用二氯甲烷萃取，浓缩后得到的残留物用硅胶层析板纯化(DCM:MeOH＝10:1)，得到白色固体1-(7-(6-氯-8-氟-7-(3-甲基-1H-吡唑-4-基)-2–(1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(2.2mg,纯度:90％，Y：15.6％)。ES-API:[M+H] +＝554.2。 1H NMR(400MHz,DMSO-d 6,ppm)7.76(s,1H),7.20–7.11(m,1H),6.73–6.46(m,1H),6.37–6.23(m,1H),6.09(s,1H),5.66(s,1H),5.28(s,1H),3.97(s,2H),3.69(s,6H),2.29(s,3H),2.10(s,3H),2.01–1.91(m,4H),1.87(s,4H),1.72(s,2H),1.45–1.35(m,2H). Step 3: Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (15mg, 25umol) in tetrahydrofuran (2mL) suspension 0.2 mL of saturated NaHCO 3 solution was slowly added to the mixture. After the reaction solution was clear, acryloyl chloride (2.3 mg, 0.025 mol) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was extracted with dichloromethane, and the residue obtained after concentration was purified by silica gel chromatography (DCM:MeOH=10:1) to obtain a white solid 1-(7-(6-chloro-8-fluoro-7-( 3-Methyl-1H-pyrazol-4-yl)-2-(1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[ 3.5] Nonane-2-yl)prop-2-en-1-one (2.2 mg, purity: 90%, Y: 15.6%). ES-API: [M+H] + = 554.2. 1 H NMR (400MHz, DMSO-d 6 , ppm) 7.76 (s, 1H), 7.20-7.11 (m, 1H), 6.73-6.46 (m, 1H), 6.37-6.23 (m, 1H), 6.09 (s ,1H), 5.66(s, 1H), 5.28(s, 1H), 3.97(s, 2H), 3.69(s, 6H), 2.29(s, 3H), 2.10(s, 3H), 2.01-1.91( m, 4H), 1.87 (s, 4H), 1.72 (s, 2H), 1.45-1.35 (m, 2H).
实施例8：1-(7-(6-氯-2-(2-(二甲基氨基)乙氧基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7--二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 8: 1-(7-(6-Chloro-2-(2-(dimethylamino)ethoxy)-8-fluoro-7-(5-methyl-1H-indazol-4-yl )Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000061
Figure PCTCN2020077192-appb-000061
步骤一：向100mL圆底烧瓶中加入7-溴2,4,6-三氯-8-氟喹唑啉(245mg,0.75mmol)、三乙胺(224mg,2.21mmol)、2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(168mg,0.75mmol)和10mL二氧六环。升温至50℃反应30分钟，TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，得到7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯粗品440mg。ES-API:[M+H] +＝518.9。 Step 1: Add 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (245mg, 0.75mmol), triethylamine (224mg, 2.21mmol), 2,7-bis to a 100mL round bottom flask Azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (168mg, 0.75mmol) and 10mL dioxane. The temperature was raised to 50°C and reacted for 30 minutes, TLC detected the disappearance of the raw materials, and the reaction was stopped. 30 mL of water was added to the reaction solution, extracted with 30 mL of ethyl acetate 3 times, the organic phase was dried and concentrated to obtain 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)- 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester crude product 440mg. ES-API: [M+H] + =518.9.
步骤二：向100mL圆底烧瓶中加入7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯粗品(208mg,0.40mmol)、氟化钾(240mg,4.1mmol)、2-(二甲基氨基)乙-1-醇(80mg,0.90mmol)、5mL无水DMSO和5mL二氧六环。升温至120℃反应3小时，TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到7-(7-溴-6-氯-2-(2-(二甲基氨基)乙氧基)-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(187mg,Y:81.7％)。ES-API:[M+H] +＝572.0。 Step 2: Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane to a 100mL round bottom flask Crude tert-butyl 2-carboxylate (208mg, 0.40mmol), potassium fluoride (240mg, 4.1mmol), 2-(dimethylamino)-1-ol (80mg, 0.90mmol), 5mL anhydrous DMSO and 5mL dioxane. The temperature was raised to 120°C and reacted for 3 hours, TLC detected the disappearance of the raw materials, and the reaction was stopped. Add 30 mL of water to the reaction solution, extract 3 times with 30 mL of ethyl acetate, dry the organic phase and concentrate, and separate and purify by chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(7-bromo-6) -Chloro-2-(2-(dimethylamino)ethoxy)-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert Butyl ester (187 mg, Y: 81.7%). ES-API: [M+H] + = 572.0.
步骤三：向10mL微波反应管中加入7-(7-溴-6-氯-2-(2-(二甲基氨基)乙氧基)-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(115mg,0.20mmol)、(5-甲基-1H-吲唑-4-基)硼酸(56mg,0.31mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯(17mg,0.04mmol)，Pd 2(dba) 3(18mg,0.02mmol)，磷酸钾(85mg,0.40mmol)，3mL二氧六环和0.3mL水。置于微波反应器中120℃反应1小时，停止反应。向反应液中加入10mL水，用10mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到7-(6-氯-2-(2-(二甲基氨基)乙氧基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(22mg,Y:17.5％)。ES-API:[M+H] +＝624.3。 Step 3: Add 7-(7-bromo-6-chloro-2-(2-(dimethylamino)ethoxy)-8-fluoroquinazolin-4-yl)-2 to the 10mL microwave reaction tube , 7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (115mg, 0.20mmol), (5-methyl-1H-indazol-4-yl)boronic acid (56mg, 0.31mmol), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (17mg, 0.04mmol), Pd 2 (dba) 3 (18mg, 0.02mmol), potassium phosphate (85mg, 0.40mmol), 3mL Dioxane and 0.3 mL water. Place in a microwave reactor at 120°C for 1 hour to stop the reaction. Add 10 mL of water to the reaction solution, extract 3 times with 10 mL of ethyl acetate, dry the organic phase and concentrate, and separate and purify by chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(6-chloro-2 -(2-(Dimethylamino)ethoxy)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-di Azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (22 mg, Y: 17.5%). ES-API: [M+H] + = 624.3.
步骤四：向25mL圆底烧瓶中加入7-(6-氯-2-(2-(二甲基氨基)乙氧基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(22mg,0.035mmol)、10mL二氯甲烷和2mL三氟乙酸。室温搅拌1小时，TLC检测原料消失，停止反应。反应液直接旋干，得到2-((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基基)氧基)-N，N-二甲基-1-胺粗品25mg。ES-API:[M+H] +＝524.2。 Step 4: Add 7-(6-chloro-2-(2-(dimethylamino)ethoxy)-8-fluoro-7-(5-methyl-1H-indazole-) to a 25mL round bottom flask 4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (22mg, 0.035mmol), 10mL dichloromethane and 2mL trifluoroacetic acid . Stir at room temperature for 1 hour, TLC detects the disappearance of the raw materials and stops the reaction. The reaction solution was directly spin-dried to obtain 2-((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5 ]Nonane-7-yl)quinazolin-2-yl)oxy)-N,N-dimethyl-1-amine crude product 25mg. ES-API: [M+H] + =524.2.
步骤五：向25mL圆底烧瓶中加入上步得到的2-((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基基)氧基)-N，N-二甲基-1-胺粗品25mg,三乙胺(20mg,0.20mmol)和10mL四氢呋喃。冰水浴中搅拌10分钟，缓慢滴加丙烯酰氯(3.85mg, 0.042mmol)，保温反应30分钟。TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取2次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到1-(7-(6-氯-2-(2-(二甲基氨基)乙氧基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7--二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(7mg,Y:34.7％)。ES-API:[M+H] +＝578.0。 1H NMR(400MHz,DMSO-d 6)δ13.13(s,1H),7.87(s,1H),7.54(d,J＝8.6Hz,2H),7.34(d,J＝8.3Hz,1H),6.31(dd,J＝17.1,10.3Hz,1H),6.08(dd,J＝16.9,2.2Hz,1H),5.64(dd,J＝10.3,2.2Hz,1H),4.38(t,J＝5.8Hz,2H),3.71(s,8H),2.58(t,J＝5.8Hz,2H),2.16(s,6H),2.12(s,3H),1.98–1.86(m,4H)。 Step 5: Add the 2-((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7 -Diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)-N,N-dimethyl-1-amine crude product 25mg, triethylamine (20mg, 0.20mmol ) And 10mL tetrahydrofuran. Stir in an ice-water bath for 10 minutes, slowly add acryloyl chloride (3.85 mg, 0.042 mmol) dropwise, and keep the reaction for 30 minutes. TLC detects the disappearance of the raw materials and stops the reaction. 30 mL of water was added to the reaction solution, extracted twice with 30 mL of ethyl acetate, the organic phase was dried and concentrated, and separated and purified by chromatography (methanol/dichloromethane: 0-10%) to obtain 1-(7-(6- Chloro-2-(2-(dimethylamino)ethoxy)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2, 7-Diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (7mg, Y: 34.7%). ES-API: [M+H] + = 578.0. 1 H NMR (400MHz, DMSO-d 6 ) δ 13.13 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.3 Hz, 1H) ,6.31(dd,J＝17.1,10.3Hz,1H), 6.08(dd,J＝16.9,2.2Hz,1H), 5.64(dd,J＝10.3,2.2Hz,1H), 4.38(t,J＝5.8 Hz, 2H), 3.71 (s, 8H), 2.58 (t, J = 5.8 Hz, 2H), 2.16 (s, 6H), 2.12 (s, 3H), 1.98-1.86 (m, 4H).
实施例9：1-(7-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 9: 1-(7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy) Synthesis of quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000062
Figure PCTCN2020077192-appb-000062
步骤一：将化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(30mg,0.05mol)，2-氟-6-羟基苯硼酸(29mg,0.25mmol),四(三苯基膦)钯(29mg,0.025mol)，碳酸钠水溶液(1M,1mL)溶于1,4-二氧六环(2mL)，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下120℃反应1小时后，反应液过滤，溶于30mL乙酸乙酯中并用饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用层析板(DCM:MeOH＝10:1)纯化，得到白色固体的7-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(15mg)。ES-API:[M+H] +＝630.1。 Step 1: The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (30mg, 0.05mol), 2-fluoro-6-hydroxyphenylboronic acid (29mg, 0.25mmol), tetrakis(triphenylphosphine)palladium (29mg , 0.025 mol), sodium carbonate aqueous solution (1M, 1 mL) was dissolved in 1,4-dioxane (2 mL), and the mixture was placed in a microwave tube, and N 2 was bubbled in for 1 minute. After reacting at 120°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified with a chromatography plate (DCM:MeOH=10:1) to obtain 7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2- as a white solid ((1-Methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (15 mg). ES-API: [M+H] + =630.1.
步骤二：将化合物7-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(50mg,0.079mol)的甲醇(2mL)的溶液冷却至0℃，缓慢加入HCl/二氧六环溶液(4M,2mL,8mmol)。加完后回到室温，并搅拌2小时。反应结束后，加入30mL的乙酸乙酯，减压浓缩得到黄色固体的2-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-7-基)-3氟苯酚盐酸盐(50mg)。Step 2: The compound 7-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)quinazole A solution of tert-butyl nonane-2-carboxylate (50mg, 0.079mol) in methanol (2mL) is cooled to 0℃, and HCl/two is slowly added. Oxane solution (4M, 2mL, 8mmol). After the addition, return to room temperature and stir for 2 hours. After the reaction, 30 mL of ethyl acetate was added and concentrated under reduced pressure to obtain 2-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-4- as a yellow solid (2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-7-yl)-3fluorophenol hydrochloride (50 mg).
步骤三：在冰浴条件下，往上述得到的化合物2-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-7-基)-3氟苯酚盐酸盐(50mg,0.079mol)的四氢呋喃(2mL)的悬浊液中缓慢加入0.2mL的饱和NaHCO 3溶液，反应液澄清后，加入丙烯酰氯(7.15mg,0.079mol)，室温搅拌0.5小时。反应液用二氯甲烷萃取，浓缩后得到的残留物用层析板(DCM:MeOH＝10:1)纯化，得到白色固体1-(7-(6-氯-8-氟-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(2.9mg,纯度:92％，Y：6％)。ES-API:[M+H] +＝584.1。 1H NMR(400MHz,DMSO-d6,ppm)7.80(s,1H),7.31(dd,J＝15.6,8.4Hz,1H),6.83(d,J＝8.4Hz,1H),6.76(t,J＝8.8Hz,1H),6.30(dd,J＝16.8,10.4Hz,1H),6.13–6.03(m,1H),5.64(d,J＝12.4Hz,1H),5.28(s,1H),5.13(s,1H),3.98(s,2H),3.70(s,6H),2.10(s,3H),1.88(s,8H),1.22(s,4H)。 Step 3: Under ice bath conditions, transfer the compound 2-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7 -Diazaspiro[3.5]nonane-7-yl)quinazolin-7-yl)-3 fluorophenol hydrochloride (50mg, 0.079mol) in tetrahydrofuran (2mL) suspension was slowly added 0.2mL saturated NaHCO 3 solution, the reaction solution after clarification, was added acryloyl chloride (7.15mg, 0.079mol), was stirred at room temperature for 0.5 hours. The reaction solution was extracted with dichloromethane, and the residue obtained after concentration was purified with a chromatography plate (DCM:MeOH=10:1) to obtain a white solid 1-(7-(6-chloro-8-fluoro-7-(2 -Fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane -2-yl)prop-2-en-1-one (2.9 mg, purity: 92%, Y: 6%). ES-API: [M+H] + =584.1. 1 H NMR (400MHz, DMSO-d6, ppm) 7.80 (s, 1H), 7.31 (dd, J = 15.6, 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.76 (t, J =8.8Hz,1H),6.30(dd,J=16.8,10.4Hz,1H),6.13-6.03(m,1H),5.64(d,J=12.4Hz,1H),5.28(s,1H),5.13 (s, 1H), 3.98 (s, 2H), 3.70 (s, 6H), 2.10 (s, 3H), 1.88 (s, 8H), 1.22 (s, 4H).
实施例11：1-(7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-4-基)喹唑啉-4-基)-2,7—二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 11: 1-(7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-4-yl)quine Synthesis of oxazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000063
Figure PCTCN2020077192-appb-000063
步骤一：将7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-甲酸叔丁酯(120mg,0.2mmoL)、(1H-吡唑-4-基)硼酸(45mg,0.4mmoL)、Pd 2(dba) 3(18mg,0.02mmoL)、2-双环己基膦-2’,6’-二甲氧基联苯2-二环己基膦基-2′,6′-二甲氧基联苯(16mg,0.04mmoL)和碳酸铯(85mg,0.4mmoL)加入到20mL的微波管中，并加入0.5mL水和5mL二氧六环，氮气置换1分钟，微波加热120℃反应50分钟。TLC检测反应完全，倒入水中，乙酸乙酯10萃取，无水硫酸钠干燥，旋除溶剂，经柱层析纯化的目标产物(32mg,Y28％)。ES-API:[M+H] +＝586.3。 Step 1: Add 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7- Diazaspiro[3.5]nonane-tert-butyl carboxylate (120mg, 0.2mmoL), (1H-pyrazol-4-yl)boronic acid (45mg, 0.4mmoL), Pd 2 (dba) 3 (18mg, 0.02mmoL) ), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (16mg, 0.04mmoL) and cesium carbonate ( 85mg, 0.4mmoL) was added to a 20mL microwave tube, 0.5mL water and 5mL dioxane were added, nitrogen replacement for 1 minute, microwave heating at 120°C for 50 minutes. TLC detects that the reaction is complete, pour into water, extract with 10 ethyl acetate, dry with anhydrous sodium sulfate, spin off the solvent, and purify the target product (32mg, Y28%) by column chromatography. ES-API: [M+H] + = 586.3.
步骤二：将7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(32mg,0.055mmoL)加入到2mL无水甲醇中，在冰浴条件下，缓慢滴加4M HCl(1,4-二氧六环溶液，2mL)，升至室温反应2小时。反应结束后，减压浓缩，得到6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐(30mg,Y95％)。ES-API:[M+H] +＝486.2。 Step 2: Add 7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-4-yl)quinazoline- 4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (32mg, 0.055mmoL) was added to 2mL of anhydrous methanol, and 4M HCl was slowly added dropwise under ice bath conditions (1,4-dioxane solution, 2mL), warm to room temperature and react for 2 hours. After the reaction, it was concentrated under reduced pressure to obtain 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-4-yl)-4 -(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (30mg, Y95%). ES-API: [M+H] + =486.2.
步骤三：将6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐(30mg,0.061mmoL)加入到2mL四氢呋喃和0.5mL水中，在冰浴条件下，先后滴加三乙胺(13mg,0.122mmoL)和丙烯酰氯(8.0mg,0.092mmoL)，搅拌10分钟。反应结束后，加入1mL甲醇淬灭，室温减压浓缩，经过制备HPLC纯化，得到1-(7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-4-基)喹唑啉-4-基)-2,7—二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(2.8mg,Y2.5％)。ES-API:[M+H] +＝540.1。 Step 3: Add 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-4-yl)-4-(2,7 -Diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (30mg, 0.061mmoL) was added to 2mL tetrahydrofuran and 0.5mL water, under ice bath conditions, one after another dropwise addition of triethylamine (13mg , 0.122mmoL) and acryloyl chloride (8.0mg, 0.092mmoL), stir for 10 minutes. After the reaction, it was quenched by adding 1 mL of methanol, concentrated under reduced pressure at room temperature, and purified by preparative HPLC to obtain 1-(7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)) Oxy)-7-(1H-pyrazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-ene-1 -Ketone (2.8mg, Y2.5%). ES-API: [M+H] + =540.1.
实施例14：1-(7-(7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 14: 1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazoline- Synthesis of 4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000064
Figure PCTCN2020077192-appb-000064
步骤一：在100mL三口瓶中将2,4-二氯-7-溴喹唑啉(500mg,1.80mmol)和2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(448mg,2.00mmol)悬浮于15mL乙腈中，在15～25℃下滴加三乙 胺(546mg,5.40mmol)，滴毕，室温搅拌1小时，TLC监测反应完成。减压蒸馏除去溶剂，在所得油状物中加入15mL乙酸乙酯和15mL水，分层，有机层用饱和食盐水10mL洗涤，用无水硫酸钠干燥，减压浓缩除去溶剂，得到7-(7-溴-2-氯喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯800mg,粗品直接用于下一步反应。ES-API:[M+H] +＝467.1。 Step 1: Combine 2,4-dichloro-7-bromoquinazoline (500mg, 1.80mmol) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester in a 100mL three-necked flask (448mg, 2.00mmol) was suspended in 15mL of acetonitrile, and triethylamine (546mg, 5.40mmol) was added dropwise at 15-25°C. After dripping, the mixture was stirred at room temperature for 1 hour, and TLC monitored the completion of the reaction. The solvent was distilled off under reduced pressure, and 15 mL of ethyl acetate and 15 mL of water were added to the resulting oily substance. The layers were separated. The organic layer was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 7-(7 -Bromo-2-chloroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester 800mg, the crude product was directly used in the next reaction. ES-API: [M+H] + =467.1.
步骤二：将7-(7-溴-2-氯喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(400mg,0.85mmol)投入50mL三口瓶中，依次加入碳酸铯(557mg,1.71mmol)和1-甲基-4-哌啶醇(4.0g,34.7mmol)，在110℃下搅拌2小时。冷却至室温后，在混合物中加入水15mL,用乙酸乙酯20mL萃取两次，合并有机相。用15mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1－10：1纯化，得到7-(7-溴-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(390mg,0.71mmol)，收率为83％。ES-API:[M+H] +＝546.2。 1H NMR(400MHz，CDCl 3)：δ7.82(1H，m)，7.57(1H，m)，7.30(1H，m)，5.10(1H，m)，3.70(4H，s)，3.59(4H，t)，2.80(2H，m)，2.30(3H，s)，1.91(4H，m)，1.80(2H，m)，1.40(9H，s)，1.23(4H，m)。 Step 2: Put 7-(7-bromo-2-chloroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.85mmol) into In a 50 mL three-necked flask, cesium carbonate (557 mg, 1.71 mmol) and 1-methyl-4-piperidinol (4.0 g, 34.7 mmol) were sequentially added, and stirred at 110°C for 2 hours. After cooling to room temperature, 15 mL of water was added to the mixture, extracted twice with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1-10:1) to obtain 7-(7-bromo-2-((1-methylpiperidin-4-yl)oxy)quine (Azolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (390mg, 0.71mmol), the yield was 83%. ES-API: [M+H ] + = 546.2. 1 H NMR (400MHz, CDCl 3 ): δ 7.82 (1H, m), 7.57 (1H, m), 7.30 (1H, m), 5.10 (1H, m), 3.70 (4H, s) ), 3.59 (4H, t), 2.80 (2H, m), 2.30 (3H, s), 1.91 (4H, m), 1.80 (2H, m), 1.40 (9H, s), 1.23 (4H, m) .
步骤三：将7-(7-溴-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(150mg,0.27mmol)投入25mL微波管中，依次加入5-甲基-1H-吲唑-4-硼酸(86mg,0.49mmol)，三(二亚苄基丙酮)二钯(25mg,0.027mmol)，2-双环己基膦-2',6'-二甲氧基联苯(23mg,0.056mmol)，磷酸钾(116mg,0.55mmol)，二氧六环8mL和水1.5mL,用微波反应器于115℃下反应45分钟，冷却至室温后，在混合物中加入水15mL，用乙酸乙酯20mL萃取两次，合并有机相。用15mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1→10：1纯化，得到7-(7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(85mg,0.14mmol)，收率为51％。ES-API:[M+H] +＝598.2。 Step 3: Add 7-(7-bromo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non Alkyl-2-carboxylic acid tert-butyl ester (150mg, 0.27mmol) was put into a 25mL microwave tube, and 5-methyl-1H-indazole-4-boronic acid (86mg, 0.49mmol), tris(dibenzylidene acetone) ) Dipalladium (25mg, 0.027mmol), 2-Biscyclohexylphosphine-2',6'-dimethoxybiphenyl (23mg, 0.056mmol), potassium phosphate (116mg, 0.55mmol), dioxane 8mL and 1.5 mL of water was used to react in a microwave reactor at 115° C. for 45 minutes. After cooling to room temperature, 15 mL of water was added to the mixture, extracted twice with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane: methanol=100:1→10:1 to obtain 7-(7-(5-methyl-1H-indazol-4-yl)-2-((1 -Methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (85mg, 0.14mmol), The yield was 51%. ES-API: [M+H] + =598.2.
步骤四：将7-(7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(40mg,0.067mmol)溶解在2ml甲醇中，在0-5℃下滴加4.0mol/L盐酸二氧六环溶液2mL，接下来将混合物在室温下搅拌2小时，LCMS监测原料反应完全。减压浓缩除去溶剂。将残渣直接用于下一步反应。ES-API:[M+H] +＝498.2。 Step 4: Add 7-(7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl )-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (40mg, 0.067mmol) was dissolved in 2ml methanol, and 4.0mol/L hydrochloric acid dioxygen was added dropwise at 0-5℃ 2 mL of the hexacyclic solution, and then the mixture was stirred at room temperature for 2 hours, and LCMS monitored the complete reaction of the raw materials. The solvent was removed by concentration under reduced pressure. The residue was used directly in the next reaction. ES-API: [M+H] + =498.2.
步骤五：在上述浓缩所得到的粗品中加入3mL四氢呋喃和0.3mL水，搅拌溶解，加入三乙胺(41mg,0.40mmol)调节pH至碱性(7.5-9.0)。在0-5℃下滴加丙烯酰氯(8mg,0.088mmol)，搅拌0.5小时，在混合物中加入水10mL，用乙酸乙酯10mL萃取两次，合并有机相。用10mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂，将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1-10：1纯化，得到1-(7-(7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(8.0mg,0.0049mmol)，收率为21.6％。ES-API:[M+H] +＝552.3。 1H NMR(400MHz,DMSO-d 6)δ13.14(s,1H),δ7.86(d,J＝8.4Hz,1H),7.57–7.46(m,3H),7.48(s,1H),7.34(d,J＝8.6Hz,1H),6.35(dd,J＝17.0,10.3Hz,1H),6.12(dd,J＝17.0,2.3Hz,1H),5.69(dd,J＝10.3,2.3Hz,1H),5.07-4.96(m,1H),4.04(s,2H),3.74(s,2H),3.75-3.69(m,4H),2.74-2.63(m,2H),2.19-2.14(m,2H),2.21(s,3H),2.16(s,3H),2.02-1.92(m,6H),1.77-1.65(m,2H)。 Step 5: Add 3 mL of tetrahydrofuran and 0.3 mL of water to the crude product obtained by the above concentration, stir to dissolve, and add triethylamine (41 mg, 0.40 mmol) to adjust the pH to alkaline (7.5-9.0). Acrylic chloride (8 mg, 0.088 mmol) was added dropwise at 0-5° C., stirred for 0.5 hour, 10 mL of water was added to the mixture, extracted twice with 10 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1-10:1) to obtain 1-(7 -(7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (8.0mg, 0.0049mmol), the yield was 21.6%. ES-API: [M+H] + =552.3 。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.14 (s, 1H), δ 7.86 (d, J = 8.4 Hz, 1H), 7.57-7.46 (m, 3H), 7.48 (s, 1H) ,7.34(d,J＝8.6Hz,1H),6.35(dd,J＝17.0,10.3Hz,1H),6.12(dd,J＝17.0,2.3Hz,1H),5.69(dd,J＝10.3,2.3 Hz,1H),5.07-4.96(m,1H),4.04(s,2H),3.74(s,2H),3.75-3.69(m,4H),2.74-2.63(m,2H),2.19-2.14( m, 2H), 2.21 (s, 3H), 2.16 (s, 3H), 2.02-1.92 (m, 6H), 1.77-1.65 (m, 2H).
实施例15：1-(7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-3-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 15: 1-(7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-3-yl)quine Synthesis of oxazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000065
Figure PCTCN2020077192-appb-000065
步骤一：向5mL微波管中加入化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(70mg,0.117mmol)、1H-吡唑-3-硼酸(21mg,0.176mmol)、1,4-二氧六环(3ml)和水(0.6mL)，后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(9mg,0.0117mmol)和碳酸铯(76.3mg,0.2134mmol)，氮气保护，微波120℃反应1小时，LC-MS监测产物生成，原料消失，向反应液中加入10mL水，用10ml乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，旋干溶剂，后薄层色谱法分离(展开剂二氯甲烷：甲醇＝10:1)，得到7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-3-基)喹唑啉-4-基)-2,7二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(9mg,Y:13％)。ES-API:[M+H] +＝586.1。 Step 1: Add compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl into a 5mL microwave tube )-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (70mg, 0.117mmol), 1H-pyrazole-3-boronic acid (21mg, 0.176mmol), 1,4-bis Oxane (3ml) and water (0.6mL), then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (9mg, 0.0117mmol) and cesium carbonate (76.3mg, 0.2134mmol), under nitrogen protection, microwave at 120°C for 1 hour, LC-MS monitored the formation of products, and the disappearance of raw materials. Add 10 mL of water to the reaction solution and extract three times with 10 mL of ethyl acetate. Combine the organic phases and dry with anhydrous sodium sulfate. The solvent was spin-dried, and then separated by thin-layer chromatography (developing solvent dichloromethane: methanol = 10:1) to obtain 7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl) )Oxy)-7-(1H-pyrazol-3-yl)quinazolin-4-yl)-2,7 diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (9mg, Y : 13%). ES-API: [M+H] + =586.1.
步骤二：向50mL圆底烧瓶中加入7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-3-基)喹唑啉-4-基)-2,7二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(9mg,0.015mmol)和二氯甲烷(3mL)，后加入三氟乙酸(0.5mL)，室温反应5小时，LC-MS监测原料消失，旋干溶剂，得到化合物6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-3-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉(粗品12mg,Y:100％)，直接进行下一步反应。ES-API:[M+H] +＝486.1。 Step 2: Add 7-(6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazole-3-) to a 50mL round bottom flask Yl)quinazolin-4-yl)-2,7 diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (9mg, 0.015mmol) and dichloromethane (3mL), then add trifluoroacetic acid (0.5mL), react at room temperature for 5 hours, LC-MS monitors the disappearance of the raw materials, spin off the solvent to obtain the compound 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)- 7-(1H-pyrazol-3-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline (crude product 12mg, Y: 100%), proceed directly One step response. ES-API: [M+H] + =486.1.
步骤三：向50mL圆底烧瓶中加入化合物6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-3-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉(12mg,0.024mmol)、三乙胺(7.5mg,0.075mmol)和四氢呋喃(3mL)，后于冰水浴下，慢慢滴加丙烯酰氯(2mg,0.025mmol)的四氢呋喃(0.5mL)溶液，冰水浴下反应5分钟，TLC(展开剂二氯甲烷：甲醇＝15:1)监测原料消失，反应完成。加10mL水洗，10mL乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，旋干溶剂，制备液相分离，得化合物1-(7-(6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-7-(1H-吡唑-3-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(2.0mg,Y：15％)。ES-API:[M+H] +＝540.1。 Step 3: Add the compound 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-3-yl) into a 50mL round bottom flask -4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline (12mg, 0.024mmol), triethylamine (7.5mg, 0.075mmol) and tetrahydrofuran (3mL), followed by Under ice-water bath, slowly add acryloyl chloride (2mg, 0.025mmol) in tetrahydrofuran (0.5mL) solution, react for 5 minutes under ice-water bath, TLC (developing solvent dichloromethane: methanol = 15:1) monitors the disappearance of raw materials, and react carry out. Wash with 10 mL of water, extract three times with 10 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, spin off the solvent, and prepare liquid separation to obtain compound 1-(7-(6-chloro-8-fluoro-2-(( 1-methylpiperidin-4-yl)oxy)-7-(1H-pyrazol-3-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane- 2-yl)prop-2-en-1-one (2.0 mg, Y: 15%). ES-API: [M+H] + =540.1.
实施例17：1-(6-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮的合成Example 17: 1-(6-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl )Oxy)quinazolin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000066
Figure PCTCN2020077192-appb-000066
步骤一：在100ml三口瓶中将2,4-二氯-7-溴-8-氟-6-氯喹唑啉(600mg,1.82mmol)和2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯草酸盐(530mg,1.83mmol)悬浮于10mL乙腈中，在15～25℃下滴加三乙胺(552mg,5.45mmol)，滴毕，室温搅拌2小时，TLC监测反应完成。减压蒸馏除去溶剂，在所得油状物中加入15mL二氯甲烷和10mL饱和碳酸氢钠溶液，分层，有机层用饱和食盐水10mL洗涤，用无水硫酸钠干燥，减压浓缩除去溶剂，将残渣用硅胶柱色谱法(石油醚：乙酸乙酯＝3：1)纯化，得到6-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(390mg,0.79mmol)，收率为55％，直接用于下一步反应。ES-API:[M+H] +＝491。 Step 1: Combine 2,4-dichloro-7-bromo-8-fluoro-6-chloroquinazoline (600mg, 1.82mmol) and 2,6-diazaspiro[3.3]heptane- in a 100ml three-necked flask Tert-butyl 2-formate oxalate (530mg, 1.83mmol) was suspended in 10mL of acetonitrile, triethylamine (552mg, 5.45mmol) was added dropwise at 15～25℃, after dripping, stirred at room temperature for 2 hours, TLC monitored the reaction carry out. The solvent was distilled off under reduced pressure, 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution were added to the obtained oily substance, and the layers were separated. The organic layer was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to obtain 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6 -Diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (390mg, 0.79mmol), yield 55%, directly used in the next reaction. ES-API: [M+H] + =491.
步骤二：将6-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(200mg,0.41mmol)投入10mL微波管中，依次加入碳酸铯(293mg,0.89mmol)和1-甲基-4-哌啶醇(2.5g,21.67mmol)，用微波反应器于110℃下反应60分钟。冷却至室温后，在混合物中加入水20mL，用二氯甲烷20L萃取两次，合并有机相。用15ml饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1→10：1纯化，得到6-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(67mg,0.12mmol)，收率为29％。ES-API:[M+H] +＝570.1。 Step 2: Add 6-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl Put the ester (200mg, 0.41mmol) into a 10mL microwave tube, add cesium carbonate (293mg, 0.89mmol) and 1-methyl-4-piperidinol (2.5g, 21.67mmol) in sequence, and use a microwave reactor at 110℃ React for 60 minutes. After cooling to room temperature, 20 mL of water was added to the mixture, extracted twice with 20 L of dichloromethane, and the organic phases were combined. The organic phase was washed with 15 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane: methanol=100:1→10:1 to obtain 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidine- 4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (67 mg, 0.12 mmol), the yield was 29%. ES-API: [M+H] + = 570.1.
步骤三：将6-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(60mg,0.10mmol)投入10ml微波管中，依次加入5-甲基-1H-吲唑-4-硼酸(33mg,0.19mmol)，三(二亚苄基丙酮)二钯(10mg,0.011mmo)，2-双环己基膦-2',6'-二甲氧基联苯(9mg,0.021mmol)，磷酸钾(45mg,0.21mmol)，二氧六环4mL和水0.8mL，用微波反应器于115℃下反应50分钟，冷却至室温后，在混合物中加入水15mL，用二氯甲烷15mL萃取两次，合并有机相。用15mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1→10：1)纯化，得到6-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(18mg,0.029mmol)，收率为27％。ES-API:[M+H] +＝622.2。 Step 3: Add 6-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6- Diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (60mg, 0.10mmol) was put into a 10ml microwave tube, followed by 5-methyl-1H-indazole-4-boronic acid (33mg, 0.19mmol) , Tris(dibenzylideneacetone)dipalladium (10mg, 0.011mmo), 2-Biscyclohexylphosphine-2',6'-dimethoxybiphenyl (9mg, 0.021mmol), potassium phosphate (45mg, 0.21mmol) ), 4 mL of dioxane and 0.8 mL of water, reacted with a microwave reactor at 115°C for 50 minutes. After cooling to room temperature, 15 mL of water was added to the mixture, extracted twice with 15 mL of dichloromethane, and the organic phases were combined. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1→10:1) to obtain 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazole-4) -Yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert Butyl ester (18mg, 0.029mmol), the yield was 27%. ES-API: [M+H] + =622.2.
步骤四：将6-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(18mg,0.029mmol)溶解在1.5mL甲醇中，在0-5℃下滴加4.0mol/L盐酸二氧六环溶液1.5mL，接下来将混合物在室温下搅拌1小时，LCMS监测原料反应完全。减压浓缩除去溶剂。将残渣直接用于下一步反应。ES-API:[M+H] +＝522.2。 Step 4: Add 6-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy )Quinazolin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (18mg, 0.029mmol) was dissolved in 1.5mL methanol at 0-5℃ 1.5 mL of 4.0 mol/L dioxane hydrochloride solution was added dropwise, and then the mixture was stirred at room temperature for 1 hour, and LCMS monitored the completion of the raw material reaction. The solvent was removed by concentration under reduced pressure. The residue was used directly in the next reaction. ES-API: [M+H] + =522.2.
步骤五：在上述浓缩所得到的粗品中加入2mL四氢呋喃和0.3mL水，搅拌溶解，加入三乙胺(15mg,0.40mmol)调节pH至碱性(7.5-9.0)。在0-5℃下滴加丙烯酰氯(5mg,0.043mmol)，搅拌0.5小时，在混合物中加入甲醇2mL，过滤，减压浓缩除去溶剂，将残渣用制备液相法制备，得到1-(6-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮(2.0mg,0.0034mmol)，收率为12％。ES-API:[M+H] +＝576.3。 Step 5: Add 2 mL of tetrahydrofuran and 0.3 mL of water to the crude product obtained by the above concentration, stir to dissolve, and add triethylamine (15 mg, 0.40 mmol) to adjust the pH to alkaline (7.5-9.0). Add acryloyl chloride (5 mg, 0.043 mmol) dropwise at 0-5°C, stir for 0.5 hour, add 2 mL of methanol to the mixture, filter, concentrate under reduced pressure to remove the solvent, and prepare the residue by preparative liquid phase method to obtain 1-(6 -(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazoline- 4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one (2.0 mg, 0.0034 mmol), the yield was 12%. ES-API: [M+H] + = 576.3.
实施例18：1-(7-(7-((1H-吡唑-4-基)氨基)-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮二甲酸盐的合成Example 18: 1-(7-(7-((1H-pyrazol-4-yl)amino)-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy (Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one dicarboxylate
Figure PCTCN2020077192-appb-000067
Figure PCTCN2020077192-appb-000067
步骤一：将化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(200mg,0.334mmol)，4-氨基-1H-吡唑-1-甲酸叔丁酯(306mg,1.67mmol),三(二亚苄基丙酮)二钯(153mg,0.167mmol)，XPhos(80mg,0.167mmol)和磷酸钾(354mg,1.67mmol)溶于5mL甲苯，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下120℃反应2小时后，反应液过滤，减压浓缩得到残留物。得到的残留物用层析板(DCM:MeOH＝10:1)纯化，得到黄色油状物7-(7-((1-(叔丁氧基羰基)-1H-吡唑-4-基)氨基)-6-氯-8-氟-2-(1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(100mg)。ES-API:[M+H] +＝701.1。 Step 1: The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (200mg, 0.334mmol), 4-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester (306mg, 1.67mmol), tris(diethylene Benzylacetone) two palladium (153mg, 0.167mmol), XPhos (80mg, 0.167mmol) and potassium phosphate (354mg, 1.67mmol) were dissolved in 5mL toluene, and the mixture was placed in a microwave tube, and N 2 was bubbled in 1 minute. After reacting at 120°C under microwave for 2 hours, the reaction solution was filtered and concentrated under reduced pressure to obtain a residue. The obtained residue was purified with a chromatography plate (DCM:MeOH=10:1) to obtain 7-(7-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)amino )-6-chloro-8-fluoro-2-(1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane- Tert-Butyl 2-formate (100 mg). ES-API: [M+H] + =701.1.
步骤二：将化合物7-(7-((1-(叔丁氧基羰基)-1H-吡唑-4-基)氨基)-6-氯-8-氟-2-(1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(150mg,0.213mmol)的甲醇(2mL)溶液冷却至0℃，缓慢加入HCl/二氧六环溶液(4M,2mL,8mmol)。加完后回到室温，并搅拌2小时。反应结束后，加入20mL的乙酸乙酯，减压浓缩得到黄色固体的6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-N-(1H-吡唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-7-胺盐酸盐(150mg)。ES-API:[M+H] +＝501.0。 Step 2: The compound 7-(7-((1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)amino)-6-chloro-8-fluoro-2-(1-methylpiper (Pyridin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (150mg, 0.213mmol) in methanol (2mL) Cool to 0°C and slowly add HCl/dioxane solution (4M, 2mL, 8mmol). After the addition, return to room temperature and stir for 2 hours. After the reaction, 20 mL of ethyl acetate was added and concentrated under reduced pressure to obtain 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-N-(1H- Pyrazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-7-amine hydrochloride (150 mg). ES-API: [M+H] + =501.0.
步骤三：在冰浴条件下，往上述得到的化合物6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)-N-(1H-吡唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-7-胺盐酸盐(150mg,213umol)的四氢呋喃(2mL)的悬浊液中缓慢加入0.2mL的饱和NaHCO 3溶液，反应液澄清后，加入丙烯酰氯(19.3mg,0.213mmol)，搅拌0.5小时。反应液用二氯甲烷萃取，浓缩后得到的残留物用prep-HPLC(HCOOH)纯化，得到的白色固体1-(7-(7-((1H-吡唑-4-基)氨基)-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮二甲酸盐(2mg,P:86％，Y：1％)。ES-API:[M+H] +＝555.2。 1H NMR(400MHz,DMSO-d 6,ppm)12.51(s,1H),7.63(s,1H),7.46(s,3H),6.33(dd,J＝17.0,10.3Hz,1H),6.11(dd,J＝17.0,2.2Hz,1H),5.68(dd,J＝10.3,2.2Hz,1H),4.99–4.87(m,1H),4.00(s,2H),3.72(s,2H),3.61(s,4H),2.65(d,J＝20.6Hz,2H),2.17(s,3H),2.11(d,J＝9.1Hz,2H),1.97(d,J＝9.6Hz,2H),1.88(s,4H),1.71–1.61(m,2H)。 Step 3: Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-N-(1H-pyrazole-4) obtained above -Yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-7-amine hydrochloride (150mg, 213umol) in tetrahydrofuran (2mL) suspension Slowly add 0.2 mL of saturated NaHCO 3 solution. After the reaction solution is clear, add acryloyl chloride (19.3 mg, 0.213 mmol) and stir for 0.5 hour. The reaction solution was extracted with dichloromethane, and the residue obtained after concentration was purified by prep-HPLC (HCOOH) to obtain a white solid 1-(7-(7-((1H-pyrazol-4-yl)amino)-6 -Chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2- Yl)prop-2-en-1-one dicarboxylate (2mg, P: 86%, Y: 1%). ES-API: [M+H] + = 555.2. 1 H NMR (400MHz, DMSO-d 6 , ppm) 12.51 (s, 1H), 7.63 (s, 1H), 7.46 (s, 3H), 6.33 (dd, J = 17.0, 10.3 Hz, 1H), 6.11 ( dd,J=17.0,2.2Hz,1H),5.68(dd,J=10.3,2.2Hz,1H),4.99–4.87(m,1H),4.00(s,2H),3.72(s,2H),3.61 (s, 4H), 2.65 (d, J = 20.6 Hz, 2H), 2.17 (s, 3H), 2.11 (d, J = 9.1 Hz, 2H), 1.97 (d, J = 9.6 Hz, 2H), 1.88 (s, 4H), 1.71–1.61 (m, 2H).
实施例19：1-(7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 19: 1-(7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)-6 -Vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000068
Figure PCTCN2020077192-appb-000068
步骤一：向100mL圆底烧瓶中加入7-溴-2,4-二氯-8-氟-6-碘喹唑啉(1.5g，3.55mmol)、三乙胺(1.08g，10.5mmol)、2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.767g，3.55mmol)和20mL乙腈。升温至50℃反应1小时，TLC检测原料消失，停止反应。向反应液中加入50mL水，用50mL乙酸乙酯萃取3次，有机相干燥后浓缩，得到7-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯粗品2g。ES-API:[M+H] +＝610.8。 Step 1: Add 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (1.5g, 3.55mmol), triethylamine (1.08g, 10.5mmol), into a 100mL round bottom flask, 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.767 g, 3.55 mmol) and 20 mL acetonitrile. The temperature was raised to 50°C and reacted for 1 hour, TLC detected the disappearance of the raw materials, and the reaction was stopped. Add 50 mL of water to the reaction solution, extract 3 times with 50 mL of ethyl acetate, dry the organic phase and concentrate to obtain 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl) -2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester crude product 2g. ES-API: [M+H] + = 610.8.
步骤二：向100mL圆底烧瓶中加入7-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯粗品(1.55g，2.54mmol)、氟化钾(1.55g，26.7mmol)、1-甲基哌啶-4-醇(4.65g，40.4mmol)、20mL无水DMSO和20mL二氧六环。升温至120℃反应1小时，TLC检测原料消失，停止反应。向反应液中加入50mL水，用50mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到7-(7-溴-8-氟-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2叔丁酯-甲酸(1.4g，Y:78.7％)。ES-API:[M+H] +＝689.8。 Step 2: Add 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane into a 100mL round bottom flask Crude tert-butyl -2-carboxylate (1.55g, 2.54mmol), potassium fluoride (1.55g, 26.7mmol), 1-methylpiperidin-4-ol (4.65g, 40.4mmol), 20mL anhydrous DMSO And 20mL dioxane. The temperature was raised to 120°C and reacted for 1 hour, TLC detected the disappearance of the raw materials, and the reaction was stopped. Add 50 mL of water to the reaction solution, extract 3 times with 50 mL of ethyl acetate, dry the organic phase and concentrate, and separate and purify by chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(7-bromo-8) -Fluoro-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2 tert Butyl ester-formic acid (1.4 g, Y: 78.7%). ES-API: [M+H] + =689.8.
步骤三：向25mL微波反应管中加入7-(7-溴-8-氟-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2叔丁酯-甲酸(690mg，1mmol)、10mg/mL C 2H 5ONa的四氢呋喃溶液7ml(70mg，1.01mmol)和5ml四氢呋喃。置于微波反应器中70℃反应45分钟，停止反应。向反应液中加入20mL水，用20mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到7-(7-溴-8-乙氧基-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-叔丁酯-甲酸(300mg，Y:42.0％)。ES-API:[M+H] +＝716.2。 Step 3: Add 7-(7-bromo-8-fluoro-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl into a 25mL microwave reaction tube )-2,7-diazaspiro[3.5]nonane-2 tert-butyl ester-carboxylic acid (690 mg, 1 mmol), 10 mg/mL C 2 H 5 ONa in tetrahydrofuran solution 7 ml (70 mg, 1.01 mmol) and 5 ml tetrahydrofuran. Place in a microwave reactor at 70°C for 45 minutes to stop the reaction. 20 mL of water was added to the reaction solution, extracted with 20 mL of ethyl acetate 3 times, the organic phase was dried and concentrated, and separated and purified by chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(7-bromo-8) -Ethoxy-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane- 2-tert-Butyl carboxylic acid (300 mg, Y: 42.0%). ES-API: [M+H] + = 716.2.
步骤四：向10mL微波反应管中加入7-(7-溴-8-乙氧基-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2叔丁酯-甲酸(300mg，0.42mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼杂环戊烷(129mg，0.84mmol)、Sphos(35mg，0.08mmol)，Pd 2(dba) 3(38mg，0.04mmol)，磷酸钾(178mg，0.84mmol)，3mL二氧六环和0.3mL水。置于微波反应器中100℃反应1小时，停止反应。向反应液中加入20mL水，用20mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到7-(7- 溴-8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-叔丁酯羧酸(200mg，Y:77.4％)。ES-API:[M+H] +＝616.2。 Step 4: Add 7-(7-bromo-8-ethoxy-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazoline-4 to the 10mL microwave reaction tube -Yl)-2,7-diazaspiro[3.5]nonane-2 tert-butyl ester-formic acid (300mg, 0.42mmol), 4,4,5,5-tetramethyl-2-vinyl-1, 3,2-Dioxaborolane (129mg, 0.84mmol), Sphos (35mg, 0.08mmol), Pd 2 (dba) 3 (38mg, 0.04mmol), potassium phosphate (178mg, 0.84mmol), 3mL Dioxane and 0.3 mL water. Place in a microwave reactor at 100°C for 1 hour to stop the reaction. 20 mL of water was added to the reaction solution, extracted with 20 mL of ethyl acetate 3 times, the organic phase was dried and concentrated, and separated and purified by chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(7-bromo-8) -Ethoxy-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane -2-tert-butyl carboxylic acid (200 mg, Y: 77.4%). ES-API: [M+H] + = 616.2.
步骤五：向5mL微波反应管中加入7-(7-溴-8-乙氧基-6-碘-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2叔丁酯-甲酸(200mg，0.325mmol)、(2-氟-6-羟基苯基)硼酸(101mg，0.65mmol)、Sphos(27mg，0.065mmol)，Pd 2(dba) 3(29mg，0.033mmol)，磷酸钾(138mg，0.65mmol)，3mL二氧六环和0.3mL水。置于微波反应器中120℃反应1小时，停止反应。向反应液中加入10mL水，用10mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-叔丁酯二氮杂螺[3.5]壬烷-2-羧酸甲酯(60mg，Y:27.7％)。ES-API:[M+H] +＝648.3。 Step 5: Add 7-(7-bromo-8-ethoxy-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazoline-4 to the 5mL microwave reaction tube -Base)-2,7-diazaspiro[3.5]nonane-2 tert-butyl ester-formic acid (200mg, 0.325mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (101mg, 0.65mmol), Sphos (27 mg, 0.065 mmol), Pd 2 (dba) 3 (29 mg, 0.033 mmol), potassium phosphate (138 mg, 0.65 mmol), 3 mL dioxane and 0.3 mL water. Place in a microwave reactor at 120°C for 1 hour to stop the reaction. Add 10 mL of water to the reaction solution, extract 3 times with 10 mL of ethyl acetate, dry the organic phase and concentrate, and separate and purify by chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(8-ethoxy) -7-(2-Fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2,7 -Tert-butyl diazaspiro[3.5]nonane-2-carboxylic acid methyl ester (60 mg, Y: 27.7%). ES-API: [M+H] + =648.3.
步骤六：向25mL圆底烧瓶中加入7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-叔丁酯二氮杂螺[3.5]壬烷-2-羧酸甲酯(60mg，0.09mmol)、10mL二氯甲烷和2mL三氟乙酸。室温搅拌1小时，TLC检测原料消失，停止反应。反应液直接旋干，得到2-(8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬-7-基)-6-乙烯基喹唑啉-7-基)-3-氟苯酚粗品75mg。Step 6: Add 7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy group to a 25mL round bottom flask )-6-vinylquinazolin-4-yl)-2,7-tert-butyl diazaspiro[3.5]nonane-2-carboxylic acid methyl ester (60mg, 0.09mmol), 10mL of dichloromethane and 2mL trifluoroacetic acid. After stirring for 1 hour at room temperature, TLC detected the disappearance of the raw materials, and the reaction was stopped. The reaction solution was directly spin-dried to obtain 2-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]non -7-yl)-6-vinylquinazolin-7-yl)-3-fluorophenol crude product 75mg.
步骤七：向25mL圆底烧瓶中加入上步得到的2-(8-乙氧基-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬-7-基)-6-乙烯基喹唑啉-7-基)-3-氟苯酚粗品75mg，三乙胺(28mg，0.27mmol)和10mL四氢呋喃。冰水浴中搅拌10分钟，缓慢滴加丙烯酰氯(10mg，0.11mmol)，保温反应30分钟。TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取2次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到1-(7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬-2-基)丙-2-烯-1-酮(6.5mg，Y:13.3％)。ES-API:[M+H] +＝602.2。 Step 7: Add the 2-(8-ethoxy-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-di) obtained in the previous step into a 25mL round bottom flask Azaspiro[3.5]non-7-yl)-6-vinylquinazolin-7-yl)-3-fluorophenol crude 75mg, triethylamine (28mg, 0.27mmol) and 10mL tetrahydrofuran. Stir in an ice-water bath for 10 minutes, slowly add acryloyl chloride (10 mg, 0.11 mmol) dropwise, and keep warm and react for 30 minutes. TLC detects the disappearance of the raw materials and stops the reaction. 30mL of water was added to the reaction solution, extracted twice with 30mL of ethyl acetate, the organic phase was dried and concentrated, and then separated and purified by chromatography (methanol/dichloromethane: 0-10%) to obtain 1-(7-(8- Ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)- 2,7-Diazaspiro[3.5]non-2-yl)prop-2-en-1-one (6.5 mg, Y: 13.3%). ES-API: [M+H] + = 602.2.
步骤八：经过手性SFC拆分(柱型：OZ-H 100mm*4.6mm*5um；流动相：甲醇:乙腈＝3:2(0.2％甲醇的氨水)；流速：1.8mL/min；时间＝4min；柱温41.5℃)得到化合物Z19-1。(9.77mg；峰2，保留时间2.58min)，白色固体。 1HNMR(400MHz,DMSO-d 6)7.80(s,1H),7.22-7.21(m,1H),6.74-6.65(m,2H),6.37-6.09(m,3H),5.70-5.66(m,2H),5.31-4.96(m,3H),4.11-4.09(m,2H),4.01(s,2H),3.73-3.50(m,8H),2.66-2.64(m,2H),2.17(s,3H),2.01-1.92(m,6H),1.70-1.67(m,2H),1.05(t,J＝7.2Hz,3H)。ES-API:[M+H] +＝601.7。和化合物Z19-2。(9.78mg；峰1，保留时间1.32min)，白色固体。 1HNMR(400MHz,DMSO-d 6)7.80(s,1H),7.22-7.21(m,1H),6.76-6.69(m,2H),6.35-6.10(m,3H),5.71-5.66(m,2H),5.31-4.95(m,3H),4.12-4.08(m,2H),4.01(s,2H),3.73-3.69(m,8H),2.66-2.64(m,2H),2.17(s,3H),2.00-1.92(m,6H),1.68-1.67(m,2H),1.05(t,J＝7.2Hz,3H)。ES-API:[M+H] +＝601.6。 Step 8: Resolution by chiral SFC (column type: OZ-H 100mm*4.6mm*5um; mobile phase: methanol: acetonitrile = 3:2 (0.2% methanol in ammonia); flow rate: 1.8 mL/min; time = 4min; column temperature 41.5°C) to obtain compound Z19-1. (9.77 mg; peak 2, retention time 2.58 min), white solid. 1 HNMR (400MHz, DMSO-d 6 ) 7.80 (s, 1H), 7.22-7.21 (m, 1H), 6.74-6.65 (m, 2H), 6.37-6.09 (m, 3H), 5.70-5.66 (m, 2H),5.31-4.96(m,3H),4.11-4.09(m,2H),4.01(s,2H),3.73-3.50(m,8H),2.66-2.64(m,2H),2.17(s, 3H), 2.01-1.92 (m, 6H), 1.70-1.67 (m, 2H), 1.05 (t, J=7.2 Hz, 3H). ES-API: [M+H] + =601.7. And compound Z19-2. (9.78 mg; peak 1, retention time 1.32 min), white solid. 1 HNMR (400MHz, DMSO-d 6 ) 7.80 (s, 1H), 7.22-7.21 (m, 1H), 6.76-6.69 (m, 2H), 6.35-6.10 (m, 3H), 5.71-5.66 (m, 2H),5.31-4.95(m,3H),4.12-4.08(m,2H),4.01(s,2H),3.73-3.69(m,8H),2.66-2.64(m,2H),2.17(s, 3H), 2.00-1.92 (m, 6H), 1.68-1.67 (m, 2H), 1.05 (t, J=7.2 Hz, 3H). ES-API: [M+H] + =601.6.
实施例20：1-(7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 20: 1-(7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(5-methyl-1H- Synthesis of indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000069
Figure PCTCN2020077192-appb-000069
步骤一：在250mL圆底三口瓶中投入7-溴2,4,6-三氯-8-氟喹唑啉(4.0g,12.12mmol)和2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(2.82g,12.48mmol)及80mL二氧六环，冰浴下滴加三乙胺(3.67g,36.36mmol)，室温搅拌1小时，TLC监测反应完成。减压蒸馏除去溶剂，在所得油状物中加入80mL乙酸乙酯和80mL水，分层，有机层用1N盐水水溶液20mL洗涤一次，饱和碳酸氢钠溶液20mL洗涤一次，饱和食盐水20mL洗涤，用无水硫酸钠干燥，减压浓缩除去溶剂，加入25mL乙腈和20mL水，搅拌1小时，过滤，于50℃鼓风烘箱烘干燥3小时，得到7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(5.3g,Y83.4％)，直接用于下一步反应。ES-API:[M+H] +＝519.1。 Step 1: Put 7-bromo 2,4,6-trichloro-8-fluoroquinazoline (4.0g, 12.12mmol) and 2,7-diazaspiro[3.5]nonane into a 250mL round bottom three-necked flask Tert-Butyl-2-carboxylate (2.82g, 12.48mmol) and 80mL of dioxane, triethylamine (3.67g, 36.36mmol) was added dropwise under ice bath, stirred at room temperature for 1 hour, TLC monitored the completion of the reaction. The solvent was distilled off under reduced pressure, and 80 mL of ethyl acetate and 80 mL of water were added to the resulting oily substance. The layers were separated. The organic layer was washed once with 20 mL of 1N brine solution, once with 20 mL of saturated sodium bicarbonate solution, and washed with 20 mL of saturated brine. Dry with water sodium sulfate, concentrate under reduced pressure to remove the solvent, add 25mL acetonitrile and 20mL water, stir for 1 hour, filter, and dry in a forced air oven at 50°C for 3 hours to obtain 7-(7-bromo-2,6-dichloro- 8-Fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (5.3g, Y83.4%) was directly used in the next reaction. ES-API: [M+H] + =519.1.
步骤二：在50mL圆底烧瓶中投入7-(7-溴-8-氟-6-氯-2-氯-4-喹啉)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(500mg,0.96mmol)，二异丙基乙胺(624mg,4.83mmol)和3-(二甲氨基)氮杂环丁烷二盐酸盐(218mg,1.26mmol)，在100℃下搅拌3小时。冷却至室温后，减压蒸馏除去溶剂，在混合物中加入水20mL，用乙酸乙酯30mL萃取，有机相用15mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂，由此得到7-(7-溴-6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(550mg,Y：98％)，粗品直接用于下一步反应。ES-API:[M+H] +＝583.3。 Step 2: Put 7-(7-bromo-8-fluoro-6-chloro-2-chloro-4-quinoline)-2,7-diazaspiro[3.5]nonane-2 into a 50mL round bottom flask -Tert-butyl carboxylate (500mg, 0.96mmol), diisopropylethylamine (624mg, 4.83mmol) and 3-(dimethylamino)azetidine dihydrochloride (218mg, 1.26mmol), in Stir at 100°C for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, 20 mL of water was added to the mixture, and the mixture was extracted with 30 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. This gives 7-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (550mg, Y: 98%), the crude product was directly used in the next reaction. ES-API: [M+H] + = 583.3.
步骤三：在25ml微波管中投入7-(7-溴-6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(340mg,0.58mmol)，5-甲基-1H-吲唑-4-硼酸(185mg,1.05mmol)，三(二亚苄基丙酮)二钯(53mg,0.058mmol)，2-双环己基膦-2',6'-二甲氧基联苯(47mg,0.114mmol)，磷酸钾(244mg,1.15mmol)，二氧六环8mL和水1.5mL，用微波反应器于115℃下反应50分钟，冷却至室温后，在混合物中加入水30mL，用乙酸乙酯25mL萃取两次，合并有机相。用20mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣柱层析(二氯甲烷：甲醇＝100：1－10：1)，得到7-[7-(5-甲基-1H-吲唑-4基)-2-[(3-(二甲氨基)氮杂环丁烷基]-4-喹唑啉]-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(290mg,Y：78％)。ES-API:[M+H] +＝635.3。 Step 3: Put 7-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazoline-4 into a 25ml microwave tube -Yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (340mg, 0.58mmol), 5-methyl-1H-indazole-4-boronic acid (185mg, 1.05mmol) ), tris(dibenzylideneacetone)dipalladium (53mg, 0.058mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (47mg, 0.114mmol), potassium phosphate (244mg, 1.15 mmol), 8 mL of dioxane and 1.5 mL of water were reacted in a microwave reactor at 115° C. for 50 minutes. After cooling to room temperature, 30 mL of water was added to the mixture, extracted twice with 25 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. Column chromatography of the residue (dichloromethane: methanol = 100:1-10:1) to obtain 7-[7-(5-methyl-1H-indazol-4yl)-2-[(3-(二Methylamino)azetidinyl]-4-quinazoline]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (290mg, Y: 78%). ES- API: [M+H] + = 635.3.
步骤四：在50mL圆底烧瓶中投入7-[7-(5-甲基-1H-吲唑-4基)-2-[(3-(二甲氨基)氮杂环丁烷基]-4-喹啉]-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(80mg,0.126mmol)和2mL甲醇，在0-5℃下滴加4.0mol/L盐酸二氧六环溶液2mL，接下来将混合物在室温下搅拌1小时，LCMS监测原料反应完全。减压浓缩除去溶剂，得到1-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基)-N，N-二甲基氮杂环-3-胺(90mg,Y：100％)。 ES-API:[M+H] +＝535.4。 Step 4: Put 7-[7-(5-methyl-1H-indazol-4yl)-2-[(3-(dimethylamino)azetidinyl]-4 into a 50mL round bottom flask -Quinoline]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (80mg, 0.126mmol) and 2mL methanol, add 4.0mol/L hydrochloric acid dropwise at 0-5℃ 2 mL of oxane solution, and then the mixture was stirred at room temperature for 1 hour, LCMS monitored the completion of the raw material reaction. Concentration under reduced pressure to remove the solvent to obtain 1-(6-chloro-8-fluoro-7-(5-methyl-1H) -Indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)-N,N-dimethylazacyclo- 3-amine (90 mg, Y: 100%). ES-API: [M+H] + =535.4.
步骤五：在50mL圆底烧瓶中投入上述浓缩所得到1-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基)-N，N-二甲基氮杂环-3-胺(90mg,0.16mmol)，3mL四氢呋喃和0.3mL水，搅拌溶解，加入三乙胺(64mg,0.63mmol)调节pH至碱性(7.5-9.0)。在0-5℃下滴加丙烯酰氯(15mg,0.16mmol)，搅拌0.5小时，在混合物中加入水10mL，用二氯甲烷15mL萃取两次，合并有机相。用10mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂，制备HPLC纯化得到1-(7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(9.0mg,Y：12％)。ES-API:[M+H] +＝589.5。 1H NMR(400MHz,CDCl 3)δ7.63(d,J＝1.6Hz,1H),7.58(s,1H),7.47(d,J＝8.5Hz,1H),7.34(d,J＝8.6Hz,1H),6.37(dd,J＝17.0,1.9Hz,1H),6.22(dd,J＝16.9,10.2Hz,1H),5.69(dd,J＝10.3,2.0Hz,1H),4.23(t,J＝8.2Hz,2H),4.08(d,J＝8.8Hz,2H),3.99(s,2H),3.89(s,2H),3.72–3.62(m,2H),3.65–3.50(m,2H),3.24(s,1H),2.25(s,6H),2.22(s,3H),2.00(t,J＝5.4Hz,4H)。 Step 5: Put the obtained 1-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-) into a 50mL round-bottom flask. Diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)-N,N-dimethylazacyclo-3-amine (90mg, 0.16mmol), 3mL tetrahydrofuran and 0.3mL water , Stir to dissolve, add triethylamine (64mg, 0.63mmol) to adjust the pH to alkaline (7.5-9.0). Add acryloyl chloride (15 mg, 0.16 mmol) dropwise at 0-5°C, stir for 0.5 hour, add 10 mL of water to the mixture, extract twice with 15 mL of dichloromethane, and combine the organic phases. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by preparative HPLC to obtain 1-(7-(6-chloro-2-(3-(dimethylamino)) nitrogen heterocycle Butane-1-yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]non Alk-2-yl)prop-2-en-1-one (9.0 mg, Y: 12%). ES-API: [M+H] + =589.5. 1 H NMR(400MHz, CDCl 3 )δ7.63(d,J=1.6Hz,1H), 7.58(s,1H), 7.47(d,J=8.5Hz,1H), 7.34(d,J=8.6Hz ,1H), 6.37(dd,J=17.0,1.9Hz,1H), 6.22(dd,J=16.9,10.2Hz,1H), 5.69(dd,J=10.3,2.0Hz,1H), 4.23(t, J = 8.2Hz, 2H), 4.08 (d, J = 8.8Hz, 2H), 3.99 (s, 2H), 3.89 (s, 2H), 3.72-3.62 (m, 2H), 3.65-3.50 (m, 2H ), 3.24 (s, 1H), 2.25 (s, 6H), 2.22 (s, 3H), 2.00 (t, J = 5.4 Hz, 4H).
实施例21：1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 21: 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazin-1-yl) Synthesis of quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000070
Figure PCTCN2020077192-appb-000070
步骤一：向50mL圆底烧瓶中加入7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(200mg,0.385mmol)、氟化钾(224mg,3.86mmol)、N-甲基哌嗪(46mg,0.46mmol)和10mL DMSO。升温至120℃反应1小时，TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，得到7-(7-溴-6-氯-8-氟-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯粗品(150mg,Y:67.0％)。ES-API:[M+H] +＝583.1。 Step 1: Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane into a 50mL round bottom flask Tert-butyl 2-carboxylate (200 mg, 0.385 mmol), potassium fluoride (224 mg, 3.86 mmol), N-methylpiperazine (46 mg, 0.46 mmol), and 10 mL DMSO. The temperature was raised to 120°C and reacted for 1 hour, TLC detected the disappearance of the raw materials, and the reaction was stopped. Add 30 mL of water to the reaction solution, extract 3 times with 30 mL of ethyl acetate, dry the organic phase and concentrate to obtain 7-(7-bromo-6-chloro-8-fluoro-2-(4-methylpiperazine-1) -Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl crude product (150 mg, Y: 67.0%). ES-API: [M+H] + =583.1.
步骤二：向10mL微波反应管中加入7-(7-溴-6-氯-8-氟-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯粗品(150mg,0.257mmol)、(5-甲基-1H-吲唑-4-基)硼酸(54mg,0.310mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯(32mg,0.077mmol)，Pd 2(dba) 3(35mg,0.038mmol)，磷酸钾(110mg,0.52mmol)，3mL二氧六环和0.3mL水。升温至120℃反应1.5小时，TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(60mg,Y:35.0％)。ES-API:[M+H] +＝635.3。 Step 2: Add 7-(7-bromo-6-chloro-8-fluoro-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2 into a 10mL microwave reaction tube, Crude tert-butyl 7-diazaspiro[3.5]nonane-2-carboxylate (150mg, 0.257mmol), (5-methyl-1H-indazol-4-yl)boronic acid (54mg, 0.310mmol), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (32mg, 0.077mmol), Pd 2 (dba) 3 (35mg, 0.038mmol), potassium phosphate (110mg, 0.52mmol), 3mL Dioxane and 0.3 mL water. The temperature was raised to 120°C and reacted for 1.5 hours, TLC detected the disappearance of the raw materials, and the reaction was stopped. Add 30 mL of water to the reaction solution, extract 3 times with 30 mL of ethyl acetate, dry the organic phase and concentrate, and separate and purify by chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(6-chloro-8) -Fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,7-diazide Heterosspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (60 mg, Y: 35.0%). ES-API: [M+H] + = 635.3.
步骤三：向25mL圆底烧瓶中加入7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(60mg,0.09mmol)、10mL二氯甲烷和2mL三氟乙酸。室温搅拌2小时，TLC检测原料消失，停止反应。反应液直接旋干，得到6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(4-甲基哌嗪-1-基)-4-(2,7-二氮杂螺[3.5]壬烷-7- 基)喹唑啉粗品66mg。ES-API:[M+H] +＝535.3。 Step 3: Add 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazine-1) into a 25mL round bottom flask -Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (60 mg, 0.09 mmol), 10 mL dichloromethane and 2 mL trifluoroacetic acid. After stirring at room temperature for 2 hours, TLC detected the disappearance of the raw materials, and the reaction was stopped. The reaction solution was directly spin-dried to obtain 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazin-1-yl)-4- (2,7-diazaspiro[3.5]nonane-7-yl)quinazoline crude product 66mg. ES-API: [M+H] + =535.3.
步骤四：向25mL圆底烧瓶中加入上步得到的6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(4-甲基哌嗪-1-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉粗品66mg,三乙胺(27mg,0.27mmol)和10mL四氢呋喃。冰水浴中搅拌10分钟，缓慢滴加丙烯酰氯(9.8mg,0.108mmol)，保温反应30分钟。TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(16mg,Y:30.0％)。ES-API:[M+H] +＝589.5。 1H NMR(400MHz,DMSO-d 6)δ13.10(s,1H),7.69(s,1H),7.52(d,J＝8.2Hz,2H),7.33(d,J＝8.7Hz,1H),6.31(dd,J＝16.9,10.2Hz,1H),6.08(dd,J＝17.0,2.1Hz,1H),5.65(dd,J＝10.2,2.2Hz,1H),3.99(s,2H),3.77(s,4H),3.71(s,2H),3.60(s,4H),2.36(s,4H),2.20(s,3H),2.12(s,3H),1.97–1.87(m,4H)。 Step 4: Add 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazine-) obtained in the previous step into a 25mL round bottom flask 1-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl) quinazoline crude 66mg, triethylamine (27mg, 0.27mmol) and 10mL tetrahydrofuran. Stir in an ice-water bath for 10 minutes, slowly add acryloyl chloride (9.8 mg, 0.108 mmol) dropwise, and keep the reaction warm for 30 minutes. TLC detects the disappearance of the raw materials and stops the reaction. 30mL of water was added to the reaction solution, extracted 3 times with 30mL of ethyl acetate, the organic phase was dried and concentrated, and separated and purified by chromatography (methanol/dichloromethane: 0-10%) to obtain 1-(7-(6- Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (16mg, Y: 30.0%). ES-API: [M+H] + =589.5. 1 H NMR (400MHz, DMSO-d 6 ) δ 13.10 (s, 1H), 7.69 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.7 Hz, 1H) ,6.31(dd,J=16.9,10.2Hz,1H), 6.08(dd,J=17.0,2.1Hz,1H), 5.65(dd,J=10.2,2.2Hz,1H), 3.99(s,2H), 3.77(s, 4H), 3.71(s, 2H), 3.60(s, 4H), 2.36(s, 4H), 2.20(s, 3H), 2.12(s, 3H), 1.97-1.87(m, 4H) .
实施例22：1-(7-(6-氯-2-(4-(二甲基氨基)哌啶-1-基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 22: 1-(7-(6-chloro-2-(4-(dimethylamino)piperidin-1-yl)-8-fluoro-7-(5-methyl-1H-indazole- Synthesis of 4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000071
Figure PCTCN2020077192-appb-000071
步骤一：向50mL圆底烧瓶中加入7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(200mg,0.385mmol)、氟化钾(224mg,3.86mmol)、N，N，-二甲基哌啶-4-胺(67mg,0.46mmol)和10mL DMSO。升温至120℃反应1小时，TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，得到7-(7-溴-6-氯-2-(4-(二甲基氨基)哌啶-1-基)-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯粗品240mg。ES-API:[M+H] +＝611.1。 Step 1: Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane into a 50mL round bottom flask Tert-Butyl 2-carboxylate (200 mg, 0.385 mmol), potassium fluoride (224 mg, 3.86 mmol), N,N,-dimethylpiperidin-4-amine (67 mg, 0.46 mmol) and 10 mL DMSO. The temperature was raised to 120°C and reacted for 1 hour, TLC detected the disappearance of the raw materials, and the reaction was stopped. Add 30 mL of water to the reaction solution, extract 3 times with 30 mL of ethyl acetate, dry the organic phase and concentrate to obtain 7-(7-bromo-6-chloro-2-(4-(dimethylamino)piperidine-1) -Yl)-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate crude product 240mg. ES-API: [M+H] + = 611.1.
步骤二：向10mL微波反应管中加入7-(7-溴-6-氯-2-(4-(二甲基氨基)哌啶-1-基)-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(120mg,0.197mmol)、(5-甲基-1H-吲唑-4-基)硼酸(41mg,0.236mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯(25mg,0.06mmol)，Pd 2(dba) 3(27mg,0.03mmol)，磷酸钾(85mg,0.4mmol)，3mL二氧六环和0.3mL水。升温至120℃反应1.5小时，TLC检测原料消失，停止反应。向反应液中加入10mL水，用10mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到7-(6-氯-2-(4-(二甲基氨基)哌啶-1-基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(20mg,Y:15.2％)。ES-API:[M+H] +＝663.3。 Step 2: Add 7-(7-bromo-6-chloro-2-(4-(dimethylamino)piperidin-1-yl)-8-fluoroquinazolin-4-yl to 10mL microwave reaction tube )-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (120mg, 0.197mmol), (5-methyl-1H-indazol-4-yl)boronic acid (41mg, 0.236 mmol), 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (25mg, 0.06mmol), Pd 2 (dba) 3 (27mg, 0.03mmol), potassium phosphate (85mg, 0.4mmol) ), 3mL dioxane and 0.3mL water. The temperature was raised to 120°C and reacted for 1.5 hours, TLC detected the disappearance of the raw materials, and the reaction was stopped. Add 10 mL of water to the reaction solution, extract 3 times with 10 mL of ethyl acetate, dry the organic phase and concentrate, and separate and purify by chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(6-chloro-2 -(4-(Dimethylamino)piperidin-1-yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (20mg, Y: 15.2%). ES-API: [M+H] + =663.3.
步骤三：向25mL圆底烧瓶中加入7-(6-氯-2-(4-(二甲基氨基)哌啶-1-基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(20mg,0.03mmol)、10mL二氯甲烷和2mL三氟乙酸。室温搅拌1小时，TLC检测原料消失，停止反应。反应液直接旋干，得到2-((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基)氧基)-N,N-二甲基-1-胺粗品26mg。ES-API:[M+H] +＝563.3。 Step 3: Add 7-(6-chloro-2-(4-(dimethylamino)piperidin-1-yl)-8-fluoro-7-(5-methyl-1H-) to a 25mL round bottom flask Indazol-4-yl)quinazolin-4-yl-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (20mg, 0.03mmol), 10mL dichloromethane and 2mL three Fluoroacetic acid. Stir at room temperature for 1 hour, TLC detects the disappearance of the raw materials, and the reaction is stopped. The reaction solution is directly spin-dried to obtain 2-((6-chloro-8-fluoro-7-(5-methyl-1H-indazole-4- Yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)-N,N-dimethyl-1-amine crude product 26mg. ES-API: [M+H] + = 563.3.
步骤四：向25mL圆底烧瓶中加入上步得到的2-((6-氯-8-氟-7-(5-甲基-1H-吲唑-4- 基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基)氧基)-N,N-二甲基-1-胺粗品26mg,三乙胺(10mg,0.10mmol)和10mL四氢呋喃。冰水浴中搅拌10分钟，缓慢滴加丙烯酰氯(3.40mg,0.037mmol)，保温反应30分钟。TLC检测原料消失，停止反应。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，层析板分离纯化(甲醇/二氯甲烷：0～10％)，得到1-(7-(6-氯-2-(4-(二甲基氨基)哌啶-1-基)-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(6mg,Y:32.5％)。ES-API:[M+H] +＝617.3。 Step 4: Add 2-((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7) to a 25mL round bottom flask. -Diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)-N,N-dimethyl-1-amine crude product 26mg, triethylamine (10mg, 0.10mmol) And 10 mL of tetrahydrofuran. Stir in an ice-water bath for 10 minutes, slowly add acryloyl chloride (3.40 mg, 0.037 mmol) dropwise, and heat the reaction for 30 minutes. TLC detects the disappearance of the raw materials and stops the reaction. 30mL of water was added to the reaction solution, extracted 3 times with 30mL of ethyl acetate, the organic phase was dried and concentrated, and separated and purified by chromatography (methanol/dichloromethane: 0-10%) to obtain 1-(7-(6- Chloro-2-(4-(dimethylamino)piperidin-1-yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl) -2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (6mg, Y: 32.5%). ES-API: [M+H] + = 617.3.
实施例23：1-(7-(6-氯-8-氟-7-(6-甲基-1H-吲唑-7-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 23: 1-(7-(6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7-yl)-2-((1-methylpiperidin-4-yl )Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000072
Figure PCTCN2020077192-appb-000072
步骤一：将化合物7-溴-6-甲基-1H-吲唑(400mg,1.9mmol)，联硼酸频那醇酯(1.44mg,5.7mmol)，醋酸钾(559mg,5.7mmol)，Pd(dppf)Cl 2.DCM(164mg,0.2mmol)的1,4-二氧六环(20mL)的溶液在氮气保护下，100℃反应24h。将反应液过滤，浓缩并用快速硅胶柱纯化得到500mg白色固体6-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吲唑。API:[M+H] +＝259.2。 Step 1: The compound 7-bromo-6-methyl-1H-indazole (400mg, 1.9mmol), pinacol diborate (1.44mg, 5.7mmol), potassium acetate (559mg, 5.7mmol), Pd( dppf) Cl 2 .DCM (164mg, 0.2mmol) in 1,4-dioxane (20mL) solution was reacted at 100°C for 24h under nitrogen protection. The reaction solution was filtered, concentrated and purified with a flash silica column to obtain 500 mg of white solid 6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Base)-1H-indazole. API: [M+H] + = 259.2.
步骤二：将化合物7-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(150mg,0.25mmol)，6-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吲唑(100mg,0.387mmol),三(二亚苄基丙酮)二钯(25mg,0.027mmol)，2-二环己基膦基-2′,6′-二甲氧基联苯(10mg,0.024mol)和磷酸钾(110mg,0.518mol)溶于1,4-二氧六环(2mL)和水(0.4mL)，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下120℃反应1h后，反应液过滤，溶于30mL乙酸乙酯中并用饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用快速硅胶柱(DCM:MeOH：0～10％)纯化，得到黄色油状的7-(6-氯-8-氟-7-(6-甲基-1H-吲唑-7-基)-2-(1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(100mg)。API:[M+H] +＝650.3。 Step 2: The compound 7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.25mmol), 6-methyl-7-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1H-indazole (100mg, 0.387mmol), tris(dibenzylideneacetone)dipalladium (25mg, 0.027mmol), 2-dicyclohexylphosphino- 2′,6′-Dimethoxybiphenyl (10mg, 0.024mol) and potassium phosphate (110mg, 0.518mol) were dissolved in 1,4-dioxane (2mL) and water (0.4mL), and the mixture Place it in a microwave tube and bubbling with N 2 for 1 minute. After reacting at 120°C under microwave for 1 h, the reaction solution was filtered, dissolved in 30 mL of ethyl acetate and washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by a flash silica gel column (DCM:MeOH:0～10%) to obtain 7-(6-chloro-8-fluoro-7-(6-methyl-1H-indazole-7- Yl)-2-(1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg). API: [M+H] + =650.3.
步骤三：将化合物7-(6-氯-8-氟-7-(6-甲基-1H-吲唑-7-基)-2-(1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(100mg,0.154mmol)的甲醇(2mL)的溶液冷却至0℃，缓慢加入HCl/二氧六环溶液(4M,2mL,8mmol)。加完后回到室温，并搅拌2小时。反应结束后，加入20mL的乙酸乙酯，减压浓缩得到黄色固体的6-氯-8-氟-7-(6-甲基-1H-吲唑-7-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐 (100mg)。Step 3: The compound 7-(6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7-yl)-2-(1-methylpiperidin-4-yl)oxy )Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg, 0.154mmol) in methanol (2mL) is cooled to 0℃ slowly Add HCl/dioxane solution (4M, 2mL, 8mmol). After the addition, return to room temperature and stir for 2 hours. After the reaction, 20 mL of ethyl acetate was added and concentrated under reduced pressure to obtain 6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7-yl)-2-((1- Methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (100 mg).
步骤四：在冰浴条件下，往上述得到的化合物6-氯-8-氟-7-(6-甲基-1H-吲唑-7-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐(100mg,0.154mmol，1eq)的四氢呋喃(2mL)的悬浊液中缓慢加入0.1mL的Et 3N，反应液澄清后，加入丙烯酰氯(14mg,0.154mmol，1eq)，搅拌10分钟。反应液浓缩后用prep-HPLC(碱性)制备得到10.12mg的白色固体1-(7-(6-氯-8-氟-7-(6-甲基-1H-吲唑-7-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(纯度88％，收率：10.8％)。ES-API:[M+H] +＝604.3。 1H NMR(400MHz,DMSO-d6,ppm)12.71(s,1H),8.08(s,1H),7.90(s,1H),7.77(d,J＝8.2Hz,1H),7.15(d,J＝8.3Hz,1H),6.35(dd,J＝17.0,10.2Hz,1H),6.12(dd,J＝16.9,2.3Hz,1H),5.69(dd,J＝10.3,2.3Hz,1H),5.03(s,1H),4.04(s,2H),3.76(s,6H),2.66(s,2H),2.19(s,3H),2.18(s,3H),2.13(s,2H),2.00(s,2H),1.95(s,4H),1.72(d,J＝7.8Hz,2H)。 Step 4: Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (100mg, 0.154mmol, 1eq) in tetrahydrofuran (2mL) 0.1 mL of Et 3 N was slowly added to the suspension. After the reaction solution was clear, acryloyl chloride (14 mg, 0.154 mmol, 1 eq) was added, and the mixture was stirred for 10 minutes. The reaction solution was concentrated and prepared by prep-HPLC (alkaline) to obtain 10.12 mg of white solid 1-(7-(6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7-yl)) -2-((1-Methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)propan-2- En-1-one (purity 88%, yield: 10.8%). ES-API: [M+H] + = 604.3. 1 H NMR (400MHz, DMSO-d6, ppm) 12.71 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.15 (d, J =8.3Hz,1H),6.35(dd,J=17.0,10.2Hz,1H), 6.12(dd,J=16.9,2.3Hz,1H), 5.69(dd,J=10.3,2.3Hz,1H),5.03 (s, 1H), 4.04(s, 2H), 3.76(s, 6H), 2.66(s, 2H), 2.19(s, 3H), 2.18(s, 3H), 2.13(s, 2H), 2.00( s, 2H), 1.95 (s, 4H), 1.72 (d, J=7.8 Hz, 2H).
实施例24：(R或S)1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 24: (R or S)1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1 -Methylpyrrolidin-2-yl)methoxy)quinazolinepiperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-ene-1 -Synthesis of ketones
Figure PCTCN2020077192-appb-000073
Figure PCTCN2020077192-appb-000073
步骤一：在100mL三口瓶中将2,4-二氯-7-溴-8-氟-6-氯喹唑啉(4.0g,12.12mmol)和2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(2.82g,12.48mmol)溶解于80mL二氧六环中，在15～25℃下滴加三乙胺(3.67g,36.36mmol)，滴毕，室温搅拌1小时，TLC监测反应完成。减压蒸馏除去溶剂，在所得油状物中加入80mL乙酸乙酯和80mL水，分层，有机层用1N盐水水溶液20mL洗涤一次，饱和碳酸氢钠溶液20mL洗涤一次，饱和食盐水20mL洗涤，用无水硫酸钠干燥，减压浓缩除去溶剂，加入25mL乙腈和20mL水，搅拌1小时，过滤，于50℃鼓风烘箱烘干燥3小时，得到7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯5.3g,粗品直接用于下一步反应。ES-API:[M+H] +＝519.1。 Step 1: Combine 2,4-dichloro-7-bromo-8-fluoro-6-chloroquinazoline (4.0g, 12.12mmol) and 2,7-diazaspiro[3.5]nonane in a 100mL three-neck flask Tert-Butyl-2-carboxylate (2.82g, 12.48mmol) was dissolved in 80mL of dioxane, and triethylamine (3.67g, 36.36mmol) was added dropwise at 15～25℃, after dropping, stirring at room temperature for 1 hour , TLC monitors the completion of the reaction. The solvent was distilled off under reduced pressure, and 80 mL of ethyl acetate and 80 mL of water were added to the resulting oily substance. The layers were separated. The organic layer was washed once with 20 mL of 1N brine solution, once with 20 mL of saturated sodium bicarbonate solution, and washed with 20 mL of saturated brine. Dry with water sodium sulfate, concentrate under reduced pressure to remove the solvent, add 25mL acetonitrile and 20mL water, stir for 1 hour, filter, and dry in a forced air oven at 50°C for 3 hours to obtain 7-(7-bromo-2,6-dichloro- 8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was 5.3g, and the crude product was directly used in the next reaction. ES-API: [M+H] + =519.1.
步骤二：将7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(300mg,0.58mmol)投入50mL三口瓶中，依次加入碳酸铯(375mg,1.15mmol)和N-甲基-L-脯氨醇(2.0g,17.3mmol)，在105℃下搅拌2小时，TLC监测原料反应完全。冷却至室温后，在混合物中加入水20mL，用乙酸乙酯30mL萃取，有机相用15mL饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1→10：1)纯化，得到(S)-7-(7-溴-6-氯-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(220mg,0.37mmol)，收率为63％。ES-API:[M+H] +＝598.2。 Step 2: Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Put the ester (300mg, 0.58mmol) into a 50mL three-necked flask, add cesium carbonate (375mg, 1.15mmol) and N-methyl-L-prolinol (2.0g, 17.3mmol) in sequence, and stir for 2 hours at 105°C. TLC monitors the complete reaction of the raw materials. After cooling to room temperature, 20 mL of water was added to the mixture, extracted with 30 mL of ethyl acetate, the organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1→10:1) to obtain (S)-7-(7-bromo-6-chloro-8-fluoro-2-((1- Methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (220mg, 0.37mmol), The yield was 63%. ES-API: [M+H] + =598.2.
步骤三：将(S)-7-(7-溴-6-氯-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮 杂螺[3.5]壬烷-2-羧酸叔丁酯(220mg,0.37mmol)投入25mL微波管中，依次加入5-甲基-1H-吲唑-4-硼酸(116mg,0.66mmol)，三(二亚苄基丙酮)二钯(34mg,0.037mmo)，2-双环己基膦-2',6'-二甲氧基联苯(31mg,0.074mmol)，磷酸钾(157mg,0.74mmol)，二氧六环8mL和水1.5mL，用微波反应器于115℃下反应70分钟，冷却至室温后，在混合物中加入水20mL，用乙酸乙酯30mL萃取相。用20mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1→10：1)纯化，得到7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((((S)-1-甲基吡咯烷基-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(110mg,0.17mmol)，收率为46％。ES-API:[M+H] +＝650.3。 Step 3: Add (S)-7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) -2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (220mg, 0.37mmol) was put into a 25mL microwave tube, and 5-methyl-1H-indazole-4-boronic acid ( 116mg, 0.66mmol), Tris(dibenzylideneacetone) dipalladium (34mg, 0.037mmo), 2-Biscyclohexylphosphine-2',6'-dimethoxybiphenyl (31mg, 0.074mmol), potassium phosphate (157 mg, 0.74 mmol), 8 mL of dioxane and 1.5 mL of water were reacted in a microwave reactor at 115° C. for 70 minutes. After cooling to room temperature, 20 mL of water was added to the mixture, and the phase was extracted with 30 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1→10:1) to obtain 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazole-4) -Yl)-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non Tert-butyl alkane-2-carboxylate (110 mg, 0.17 mmol), the yield was 46%. ES-API: [M+H] + =650.3.
步骤四：将7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((((S)-1-甲基吡咯烷基-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(180mg,0.27mmol)溶解在5mL甲醇中，在0-5℃下滴加4.0mol/L盐酸二氧六环溶液5mL，接下来将混合物在室温下搅拌1小时，LCMS监测原料反应完全。减压浓缩除去溶剂。将残渣直接用于下一步反应。ES-API:[M+H] +＝550.1。 Step 4: Add 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((((S)-1-methylpyrrolidinyl- 2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (180mg, 0.27mmol) was dissolved in 5mL methanol, Add 5 mL of 4.0mol/L hydrochloric acid dioxane solution dropwise at 0-5°C, and then stir the mixture at room temperature for 1 hour. LCMS monitors the completion of the raw material reaction. Concentrate under reduced pressure to remove the solvent. The residue is used directly in the next step Reaction. ES-API: [M+H] + =550.1.
步骤五：在上述浓缩所得到的粗品中加入6mL四氢呋喃和1mL水，搅拌溶解，加入三乙胺(137mg,0.1.35mmol)调节pH至碱性(7.5-9.0)。在0-5℃下滴加丙烯酰氯(32mg,0.35mmol)，搅拌0.5小时，在混合物中加入水15mL和饱和碳酸氢钠溶液15ml，用二氯甲烷20mL萃取两次，合并有机相。用20mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂，将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1→10：1)纯化，得到1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(50mg,0.082mmol)，收率为30％。ES-API:[M+H] +＝604.3。 Step 5: Add 6 mL of tetrahydrofuran and 1 mL of water to the crude product obtained by the above concentration, stir to dissolve, and add triethylamine (137 mg, 0.1.35 mmol) to adjust the pH to alkaline (7.5-9.0). Add acryloyl chloride (32 mg, 0.35 mmol) dropwise at 0-5° C., stir for 0.5 hour, add 15 mL of water and 15 mL of saturated sodium bicarbonate solution to the mixture, extract twice with 20 mL of dichloromethane, and combine the organic phases. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1→10:1) to obtain 1-( 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy Yl)quinazoline piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (50mg, 0.082mmol), the yield is 30%. ES-API: [M+H] + = 604.3.
步骤六：将化合物1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(50mg,0.082mmol)制备拆分得到两个手性单一异构体，分别为Z24-1(15.21mg,峰1)和Z24-2(8.53mg,峰2)。 1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.56(s,1H),7.51(d,J＝8.5Hz,1H),7.36(d,J＝8.5Hz,1H),6.37(dd,J＝17.0,1.9Hz,1H),6.21(dd,J＝17.0,10.3Hz,1H),5.70(dd,J＝10.3,1.9Hz,1H),4.00(s,2H),3.96-3.89(m,2H),3.85-3.75(m,2H),3.72-3.67(m,2H),3.3(d,2H)，2.65(s,2H),2.35-2.30(m,2H),2.22(s,3H),2.05(s,3H),2.18-2.10(m,3H),1.92(s,2H),1.87(s,2H)。 Step 6: The compound 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((S)-1-methylpyrrole) Alkyl-2-yl)methoxy)quinazoline piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (50mg , 0.082mmol) preparation and resolution to obtain two chiral single isomers, Z24-1 (15.21mg, peak 1) and Z24-2 (8.53mg, peak 2). 1 H NMR(400MHz,CDCl3)δ7.76(s,1H),7.56(s,1H),7.51(d,J=8.5Hz,1H), 7.36(d,J=8.5Hz,1H), 6.37( dd,J＝17.0,1.9Hz,1H), 6.21(dd,J＝17.0,10.3Hz,1H), 5.70(dd,J＝10.3,1.9Hz,1H), 4.00(s,2H),3.96-3.89 (m,2H),3.85-3.75(m,2H),3.72-3.67(m,2H),3.3(d,2H),2.65(s,2H),2.35-2.30(m,2H),2.22(s , 3H), 2.05 (s, 3H), 2.18-2.10 (m, 3H), 1.92 (s, 2H), 1.87 (s, 2H).
实施例25：(S或R)-1-(7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 25: (S or R)-1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidine-4 -Yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000074
Figure PCTCN2020077192-appb-000074
步骤一：将化合物7-溴-2,4,6-三氯喹唑啉(2g,6.4mmol)溶于50mL的1,4-二氧六环，搅拌下加入Et 3N(2.46mL,19.2mmol)和2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.45g,6.4mmol)，50℃反应0.5小时。反应结束后，加入150mL的乙酸乙酯，依次用50mL 1M的盐酸，50mL的饱和碳酸氢钠溶液和50mL的饱和食盐水洗涤。得到的有机相用无水硫酸钠干燥，过滤，浓缩得到黄色固体7-(7-溴-2,6-二氯喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(3g)。ES-API:[M+H] +＝501.1，503.0。 Step 1: Dissolve compound 7-bromo-2,4,6-trichloroquinazoline (2g, 6.4mmol) in 50mL of 1,4-dioxane, add Et 3 N (2.46mL, 19.2mmol) under stirring ) And 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.45g, 6.4mmol), reacted at 50°C for 0.5 hours. After the reaction is over, add 150 mL of ethyl acetate, and wash with 50 mL of 1M hydrochloric acid, 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated brine in sequence. The obtained organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 7-(7-bromo-2,6-dichloroquinazolin-4-yl)-2,7-diazaspiro[3.5]non Tert-Butyl alkane-2-carboxylate (3g). ES-API: [M+H] + =501.1, 503.0.
步骤二：将混合物7-(7-溴-2,6-二氯喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1g,1.99mmol)，1-甲基-4-哌啶醇(6.88g,59.7mmol)和碳酸铯(1.3g,3.98mmol)在120℃下反应3小时。反应结束后，将反应液倒入50mL水中，并用50mL乙酸乙酯萃取三遍。得到的有机相合并，无水硫酸钠干燥，过滤浓缩得到残留物。残留物用快速硅胶柱纯化得到白色固体7-(7-溴-6-氯-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(750mg,Y：65％)。ES-API:[M+H] +＝580.2，582.1。 Step 2: The mixture 7-(7-bromo-2,6-dichloroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1g, 1.99mmol), 1-methyl-4-piperidinol (6.88g, 59.7mmol) and cesium carbonate (1.3g, 3.98mmol) were reacted at 120°C for 3 hours. After the reaction, the reaction solution was poured into 50 mL of water and extracted three times with 50 mL of ethyl acetate. The obtained organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by a flash silica gel column to obtain a white solid 7-(7-bromo-6-chloro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2, 7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (750 mg, Y: 65%). ES-API: [M+H] + = 580.2, 582.1.
步骤三：将化合物7-(7-溴-6-氯-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(400mg,0.689mmol)，5-甲基-1H-吲唑-4-硼酸(145mg,0.826mol),三(二亚苄基丙酮)二钯(63mg,0.069mol)，2-二环己基膦基-2′,6′-二甲氧基联苯(28mg,0.069mol)和磷酸钾(293mg,1.38mmol)溶于1,4-二氧六环(10mL)和水(1mL)，并将混合物置于微波管中，通入N 2鼓泡1分钟。微波下120℃反应1h后，反应液过滤，溶于60mL乙酸乙酯中并用20mL饱和食盐水洗涤三遍，有机层用无水硫酸钠干燥，过滤，减压浓缩得到残留物。得到的残留物用快速硅胶柱(DCM:MeOH：0％～10％)纯化，得到黄色固体的7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯，(400mg,P:77％，Y：71％)。ES-API:[M+H] +＝632.3。 Step 3: The compound 7-(7-bromo-6-chloro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazepine Spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.689mmol), 5-methyl-1H-indazole-4-boronic acid (145mg, 0.826mol), three (dibenzylidene acetone) two Palladium (63mg, 0.069mol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (28mg, 0.069mol) and potassium phosphate (293mg, 1.38mmol) are dissolved in 1,4-di Oxane (10 mL) and water (1 mL), and put the mixture in a microwave tube, bubbling with N 2 for 1 minute. After reacting at 120°C under microwave for 1 hour, the reaction solution was filtered, dissolved in 60 mL ethyl acetate and washed with 20 mL saturated brine three times, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by a flash silica gel column (DCM:MeOH:0%-10%) to obtain 7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)- as a yellow solid 2-((1-Methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, ( 400mg, P: 77%, Y: 71%). ES-API: [M+H] + = 632.3.
步骤四：将化合物7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(400mg,0.633mmol)的甲醇(4mL)的溶液冷却至0℃，缓慢加入HCl/二氧六环溶液(4M,4mL,16mmol)。加完后回到室温，并搅拌2小时。反应结束后，反应液减压浓缩得到黄色固体的6-氯-8-氟-7-(3-甲基-1H-吡唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐(400mg)。Step 4: The compound 7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazole (Alkolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.633mmol) in methanol (4mL) was cooled to 0℃, and HCl/ Dioxane solution (4M, 4mL, 16mmol). After the addition, return to room temperature and stir for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain 6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-((1-methylpiperidine- 4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride (400 mg).
步骤五：在冰浴条件下，往上述得到的化合物6-氯-8-氟-7-(3-甲基-1H-吡唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉盐酸盐粗品(400mg,0.633mol)的四氢呋喃(4mL)的悬浊液中缓慢加入0.4mL的三乙胺，反应液澄清后，加入丙烯酰氯 (57mg,0.633mol)，室温搅拌5分钟。反应液过滤浓缩后得到的残留物用prep-HPLC制备得到白色固体1-(7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(50mg,P:100％，Y：13.5％)。ES-API:[M+H] +＝586.3。 Step 5: Under ice bath conditions, transfer the compound 6-chloro-8-fluoro-7-(3-methyl-1H-pyrazol-4-yl)-2-((1-methylpiperidine) obtained above -4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline hydrochloride crude product (400mg, 0.633mol) in tetrahydrofuran (4mL) suspension 0.4 mL of triethylamine was slowly added to the turbid solution. After the reaction solution was clear, acryloyl chloride (57 mg, 0.633 mol) was added and stirred at room temperature for 5 minutes. The residue obtained after the reaction solution was filtered and concentrated was prepared by prep-HPLC to obtain a white solid 1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1 -Methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one ( 50mg, P: 100%, Y: 13.5%). ES-API: [M+H] + = 586.3.
步骤六：将上述得到的化合物1-(7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(50mg,0.085mol)用SFC手性拆分得到化合物(构型不确定)：Step 6: The compound 1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl) obtained above )Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (50mg, 0.085mol) chiral by SFC Resolve to get the compound (undefined configuration):
(S)-1-(7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(25.56mg,纯度：100％，ee值：100％)。ES-API:[M+H] +＝586.2。 1H NMR(400MHz,DMSO-d 6,ppm)13.11(s,1H),8.01(s,1H),7.50(d,J＝8.4Hz,1H),7.45(d,J＝6.6Hz,2H),7.31(d,J＝8.6Hz,1H),6.31(dd,J＝17.0,10.3Hz,1H),6.09(dd,J＝17.1,2.1Hz,1H),5.71–5.60(m,1H),5.05(s,1H),4.00(s,2H),3.71(m,6H),2.84(s,2H),2.35(s,2H),2.12(s,3H),2.02(m,2H),1.92(s,3H),1.78(s,2H),1.19(m,4H). (S)-1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy) Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (25.56mg, purity: 100%, ee value: 100% ). ES-API: [M+H] + = 586.2. 1 H NMR (400MHz, DMSO-d 6 , ppm) 13.11 (s, 1H), 8.01 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 6.6 Hz, 2H) ,7.31(d,J＝8.6Hz,1H), 6.31(dd,J＝17.0,10.3Hz,1H), 6.09(dd,J＝17.1,2.1Hz,1H), 5.71–5.60(m,1H), 5.05 (s, 1H), 4.00 (s, 2H), 3.71 (m, 6H), 2.84 (s, 2H), 2.35 (s, 2H), 2.12 (s, 3H), 2.02 (m, 2H), 1.92 (s, 3H), 1.78 (s, 2H), 1.19 (m, 4H).
(R)-1-(7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(22.29mg,纯度：100％，ee值：100％)。ES-API:[M+H] +＝586.0。 1H NMR(400MHz,DMSO-d 6,ppm)13.11(s,1H),8.01(s,1H),7.50(d,J＝8.8Hz,1H),7.46(s,1H),7.44(s,1H),7.31(d,J＝8.5Hz,1H),6.31(dd,J＝17.0,10.3Hz,1H),6.09(dd,J＝17.0,2.3Hz,1H),5.65(dd,J＝10.3,2.2Hz,1H),5.03(s,1H),4.00(s,2H),3.71(m,6H),2.80(s,2H),2.29(s,2H),2.12(s,3H),2.02(m,2H),1.91(s,3H),1.75(bs,2H),1.19(m,4H). (R)-1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy) Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (22.29mg, purity: 100%, ee value: 100% ). ES-API: [M+H] + =586.0. 1 H NMR (400MHz, DMSO-d 6 , ppm) 13.11 (s, 1H), 8.01 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.31 (d, J = 8.5 Hz, 1H), 6.31 (dd, J = 17.0, 10.3 Hz, 1H), 6.09 (dd, J = 17.0, 2.3 Hz, 1H), 5.65 (dd, J = 10.3 , 2.2Hz, 1H), 5.03 (s, 1H), 4.00 (s, 2H), 3.71 (m, 6H), 2.80 (s, 2H), 2.29 (s, 2H), 2.12 (s, 3H), 2.02 (m, 2H), 1.91 (s, 3H), 1.75 (bs, 2H), 1.19 (m, 4H).
实施例26：1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 26: 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(tetrahydro-2H-pyran -4-yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-ene-1- Synthesis of ketones
Figure PCTCN2020077192-appb-000075
Figure PCTCN2020077192-appb-000075
步骤一：在250mL三口瓶中加入四氢吡喃酮(5.0g,50mmol)，4-羟基哌啶(7.8g,77mmol) 和钛酸四异丙酯(30mL,101mmol)，于25℃下搅拌过夜。加入40mL甲醇，将反应液降温至0-5℃，分次加入硼氢化钠(3.8g,100mmol)，控制反应液温度＜15℃，然后0-5℃下搅拌2小时。加入50mL乙酸乙酯，然后滴加2N氢氧化钠水溶液30mL，搅拌10分钟后，用硅藻土过滤。分层，水层用20mL乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，减压浓缩除去溶剂，将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1→10：1，0.1％氨水溶液)纯化，得到1-羟基-4-(***啉-4-基)-环己烷(2.2g,11.8mmol)，收率为24％。ES-API:[M+H] +＝185.2。 Step 1: Add tetrahydropyrone (5.0g, 50mmol), 4-hydroxypiperidine (7.8g, 77mmol) and tetraisopropyl titanate (30mL, 101mmol) into a 250mL three-necked flask, and stir at 25℃ overnight. Add 40 mL of methanol, cool the reaction solution to 0-5°C, add sodium borohydride (3.8g, 100mmol) in portions, control the temperature of the reaction solution to be <15°C, and then stir at 0-5°C for 2 hours. 50 mL of ethyl acetate was added, and then 30 mL of 2N sodium hydroxide aqueous solution was added dropwise, and after stirring for 10 minutes, it was filtered with Celite. The layers were separated, the aqueous layer was extracted twice with 20 mL ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100:1→10: 1. Purification by 0.1% aqueous ammonia solution) to obtain 1-hydroxy-4-(morpholin-4-yl)-cyclohexane (2.2 g, 11.8 mmol) with a yield of 24%. ES-API: [M+H] + = 185.2.
步骤二：在100mL三口瓶中将2,4-二氯-7-溴-8-氟-6-氯喹唑啉(4.0g,12.12mmol)和2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(2.82g,12.48mmol)溶解于80mL二氧六环中，在15～25℃下滴加三乙胺(3.67g,36.36mmol)，滴毕，室温搅拌1小时，TLC监测反应完成。减压蒸馏除去溶剂，在所得油状物中加入80mL乙酸乙酯和80mL水，分层，有机层用1N盐水水溶液20mL洗涤一次，饱和碳酸氢钠溶液20mL洗涤一次，饱和食盐水20mL洗涤，用无水硫酸钠干燥，减压浓缩除去溶剂，加入25mL乙腈和20mL水，搅拌1小时，过滤，于50℃鼓风烘箱烘干燥3h，得到7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯5.3g,产率82％，粗品直接用于下一步反应。ES-API:[M+H] +＝519。 Step 2: Combine 2,4-dichloro-7-bromo-8-fluoro-6-chloroquinazoline (4.0g, 12.12mmol) and 2,7-diazaspiro[3.5]nonane in a 100mL three-neck flask Tert-Butyl-2-carboxylate (2.82g, 12.48mmol) was dissolved in 80mL of dioxane, and triethylamine (3.67g, 36.36mmol) was added dropwise at 15～25℃, after dropping, stirring at room temperature for 1 hour , TLC monitors the completion of the reaction. The solvent was distilled off under reduced pressure, and 80 mL of ethyl acetate and 80 mL of water were added to the resulting oily substance. The layers were separated. The organic layer was washed once with 20 mL of 1N brine solution, once with 20 mL of saturated sodium bicarbonate solution, and washed with 20 mL of saturated brine. Dry with sodium sulfate and concentrate under reduced pressure to remove the solvent, add 25 mL of acetonitrile and 20 mL of water, stir for 1 hour, filter, and dry in a forced air oven at 50°C for 3 hours to obtain 7-(7-bromo-2,6-dichloro-8 -Fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester is 5.3g, the yield is 82%, and the crude product is directly used in the next reaction. ES-API: [M+H] + =519.
步骤三：将7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.6g,3.07mmol)投入100mL三口瓶中，依次加入碳酸铯(3.0g,9.23mmol)和1-羟基-4-(***啉-4-基)-环己烷(1.26g,6.80mmol)，三乙烯二胺(52mg,0.46mmol)在60℃下搅拌反应过夜。冷却至室温后，在混合物中加入水50mL，用乙酸乙酯50mL萃取，有机相用30mL饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1→10：1)纯化，得到7-(7-溴-6-氯-8-氟-2-(((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(630mg,0.94mmol)，收率为31％。ES-API:[M+H] +＝668.2。 Step 3: Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Put the ester (1.6g, 3.07mmol) into a 100mL three-necked flask, add cesium carbonate (3.0g, 9.23mmol) and 1-hydroxy-4-(morpholin-4-yl)-cyclohexane (1.26g, 6.80mmol) in sequence ), triethylenediamine (52mg, 0.46mmol) was stirred overnight at 60°C. After cooling to room temperature, 50 mL of water was added to the mixture, extracted with 50 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100:1→10:1) to obtain 7-(7-bromo-6-chloro-8-fluoro-2-(((1-(tetrahydro -2H-pyran-4-yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (630mg, 0.94mmol), the yield was 31%. ES-API: [M+H] + =668.2.
步骤四：将7-(7-溴-6-氯-8-氟-2-(((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(620mg,0.93mmol)投入25mL微波管中，依次加入5-甲基-1H-吲唑-4-硼酸(295mg,1.67mmol)，三(二亚苄基丙酮)二钯(85mg,0.093mmo)，2-双环己基膦-2',6'-二甲氧基联苯(77mg,0.186mmol)，磷酸钾(394mg,1.86mmol)，二氧六环9mL和水2.0mL，用微波反应器于120℃下反应70分钟，冷却至室温后，在混合物中加入水30mL，用乙酸乙酯40mL萃取相。用20mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂。将残渣用硅胶柱色谱法(二氯甲烷：甲醇＝100：1－10：1)纯化，得到7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(610mg,0.85mmol)，收率为91％。ES-API:[M+H] +＝720.3。 Step 4: Add 7-(7-bromo-6-chloro-8-fluoro-2-(((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)quine (Azolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (620mg, 0.93mmol) was put into a 25mL microwave tube, and 5-methyl-1H- Indazole-4-boronic acid (295mg, 1.67mmol), tris(dibenzylideneacetone) dipalladium (85mg, 0.093mmo), 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (77mg , 0.186mmol), potassium phosphate (394mg, 1.86mmol), 9mL of dioxane and 2.0mL of water, reacted in a microwave reactor at 120°C for 70 minutes. After cooling to room temperature, add 30mL of water to the mixture and use acetic acid Ethyl 40mL extract phase. Wash the organic phase with 20mL saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent. The residue is subjected to silica gel column chromatography (dichloromethane: methanol = 100:1-10:1) Purified to obtain 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(tetrahydro-2H-pyran-4-yl )Piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (610mg, 0.85mmol), yield It is 91%. ES-API: [M+H] + =720.3.
步骤五：将7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(400mg,0.55mmol)溶解在6mL甲醇中，在0-5℃下滴加4.0mol/L盐酸二氧六环溶液6mL，接下来将混合物在室温下搅拌2 小时，LCMS监测原料反应完全。减压浓缩除去溶剂。将残渣直接用于下一步反应。ES-API:[M+H] +＝620.3。 Step 5: Add 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(tetrahydro-2H-pyran-4- (Yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.55mmol) was dissolved in In 6 mL of methanol, 6 mL of 4.0 mol/L hydrochloric acid dioxane solution was added dropwise at 0-5° C., and then the mixture was stirred at room temperature for 2 hours. LCMS monitored the complete reaction of the raw materials. The solvent was removed by concentration under reduced pressure. The residue was used directly in the next reaction. ES-API: [M+H] + = 620.3.
步骤六：在上述浓缩所得到的残渣中加入10mL四氢呋喃和1mL水，搅拌溶解，加入三乙胺(281mg,2.77mmol)调节pH至碱性(7.5-9.0)。在0-5℃下滴加丙烯酰氯(65mg,0.72mmol)，搅拌1小时，在混合物中加入水10mL和饱和碳酸氢钠溶液10mL，用二氯甲烷30mL萃取两次，合并有机相。用20mL饱和食盐水洗涤有机相，用无水硫酸钠干燥，减压浓缩除去溶剂，将残渣用制备液相法制备，得到1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(12mg,0.155mmol)，收率为27％。ES-API:[M+H] +＝674.3。 1H NMR(400MHz,DMSO-d 6)δ13.17(s,1H),7.90(d,J＝1.5Hz,1H),7.58(d,J＝8.9Hz,2H),7.38(d,J＝8.5Hz,1H),6.35(dd,J＝16.9,10.3Hz,1H),6.12(dd,J＝17.0,2.3Hz,1H),5.69(dd,J＝10.3,2.4Hz,1H),5.02(t,J＝4.2Hz,1H),4.04(s,2H),3.88(dd,J＝10.8,4.1Hz,2H),3.74(d,J＝7.1Hz,6H),3.33–3.20(m,2H),2.83(s,2H),2.32(d,J＝30.4Hz,3H),2.16(s,3H),2.03(s,2H),1.97–1.89(m,4H),1.68(d,J＝11.9Hz,4H),1.50–1.36(m,2H)。 Step 6: Add 10 mL of tetrahydrofuran and 1 mL of water to the residue obtained by the above concentration, stir to dissolve, and add triethylamine (281 mg, 2.77 mmol) to adjust the pH to alkaline (7.5-9.0). Add acryloyl chloride (65 mg, 0.72 mmol) dropwise at 0-5°C, stir for 1 hour, add 10 mL of water and 10 mL of saturated sodium bicarbonate solution to the mixture, extract twice with 30 mL of dichloromethane, and combine the organic phases. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was prepared by the preparative liquid method to obtain 1-(7-(6-chloro-8-fluoro-7-(5 -Methyl-1H-indazol-4-yl)-2-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)quinazolin-4-yl )-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (12mg, 0.155mmol), the yield was 27%. ES-API: [M+H] + =674.3. 1 H NMR (400MHz, DMSO-d 6 ) δ13.17 (s, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 8.5Hz, 1H), 6.35 (dd, J = 16.9, 10.3 Hz, 1H), 6.12 (dd, J = 17.0, 2.3 Hz, 1H), 5.69 (dd, J = 10.3, 2.4 Hz, 1H), 5.02 ( t,J=4.2Hz,1H),4.04(s,2H),3.88(dd,J=10.8,4.1Hz,2H), 3.74(d,J=7.1Hz,6H),3.33-3.20(m,2H ), 2.83 (s, 2H), 2.32 (d, J = 30.4 Hz, 3H), 2.16 (s, 3H), 2.03 (s, 2H), 1.97-1.89 (m, 4H), 1.68 (d, J = 11.9Hz, 4H), 1.50-1.36 (m, 2H).
步骤七：经过手性SFC拆分(柱型：OD-H 100mm*4.6mm*5um；流动相：EtOH(含1％甲醇的氨水)；流速1.8mL/min；时间6min；柱温41.5℃)得到Step 7: After chiral SFC resolution (column type: OD-H 100mm*4.6mm*5um; mobile phase: EtOH (ammonia water containing 1% methanol); flow rate 1.8mL/min; time 6min; column temperature 41.5℃) get
白色固体(R)-1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮Z26-1(28.1mg,峰2，保留时间3.47min)、ES-API:[M+H]+＝674.3。White solid (R)-1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(tetrahydro-2H- Pyran-4-yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-ene- 1-ketone Z26-1 (28.1 mg, peak 2, retention time 3.47 min), ES-API: [M+H]+=674.3.
白色固体(S)-1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(四氢-2H-吡喃-4-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮Z26-2(38.1mg,峰1，保留时间2.18min)。ES-API:[M+H]+＝674.3。White solid (S)-1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(tetrahydro-2H- Pyran-4-yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-ene- 1-ketone Z26-2 (38.1 mg, peak 1, retention time 2.18 min). ES-API: [M+H]+=674.3.
实施例28：1-(7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 28: 1-(7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(5-methyl-1H-indazole-4 -Yl)pyrido[2,3-d]pyrimidinepiperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000076
Figure PCTCN2020077192-appb-000076
步骤一：将6,7-二氯吡啶并[2,3-d]嘧啶-2,4-二醇(200mg,0.86mmoL)、(5-甲基-1H-吲唑-4-基)硼酸(225mg,1.29mmoL)、Pd(PPh 4) 3(99mg,0.086mmoL)和K 2CO 3(238mg,1.72mmoL)加入到20mL的微波反应器中，再加入1,4-二氧六环：H 2O(8mL:1mL)，氮气置换1分钟，微波加热到120℃，反应30分钟。反应结束后，加入15mL水，用乙酸乙酯萃取(20mL×3), 合并有机相，用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析(二氯甲烷/甲醇：10/1)纯化，得到6-氯-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-2,4-二醇(260mg,Y62％)。ES-API:[M+H] +＝328.1。 Step 1: Add 6,7-dichloropyrido[2,3-d]pyrimidine-2,4-diol (200mg, 0.86mmoL), (5-methyl-1H-indazol-4-yl)boronic acid (225mg, 1.29mmoL), Pd(PPh 4 ) 3 (99mg, 0.086mmoL) and K 2 CO 3 (238mg, 1.72mmoL) were added to a 20mL microwave reactor, and then 1,4-dioxane was added: H 2 O (8 mL: 1 mL), nitrogen replacement for 1 minute, microwave heating to 120° C., and reaction for 30 minutes. After the reaction, 15 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column (dichloromethane/methanol: 10 /1) Purification to obtain 6-chloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4-diol (260mg, Y62%) . ES-API: [M+H] + =328.1.
步骤二：将6-氯-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-2,4-二醇(100mg,0.306mmoL)、***(5mL)在95℃条件下搅拌一个小时，变为澄清溶液之后，缓慢滴加二异丙基乙胺(4mL)，继续保持95℃反应5小时。反应结束后，减压浓缩，加入15mL冰水，用乙酸乙酯萃取(20mL×3),合并有机相，用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析(石油醚/乙酸乙酯：1/2)纯化，得到2,4,6-三氯-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶(70mg,Y 60％)。ES-API:[M+H] +＝364.1。 Step 2: Combine 6-chloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4-diol (100mg, 0.306mmoL), oxygen Phosphorus chloride (5 mL) was stirred at 95°C for one hour. After it became a clear solution, diisopropylethylamine (4 mL) was slowly added dropwise, and the reaction was continued at 95°C for 5 hours. After the reaction is over, concentrate under reduced pressure, add 15mL ice water, extract with ethyl acetate (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography (petroleum ether /Ethyl acetate: 1/2) to obtain 2,4,6-trichloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine (70mg ,Y 60%). ES-API: [M+H] + = 364.1.
步骤三：将2,4,6-三氯-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶(100mg,0.274mmoL)、2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(62mg,0.274mmoL)溶解在二氯甲烷中，滴加三乙胺(28mg,0.274mmoL)在室温条件下搅拌30分钟。反应结束后，减压浓缩，加入15mL冰水，用乙酸乙酯萃取(20mL×3),合并有机相，用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析(石油醚/乙酸乙酯：3/1)纯化，得到7-(2,6-二氯-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(80mg,Y53％)。ES-API:[M+H] +＝554.2。 Step 3: Add 2,4,6-trichloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine (100mg, 0.274mmoL), 2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (62mg, 0.274mmoL) was dissolved in dichloromethane, triethylamine (28mg, 0.274mmoL) was added dropwise and stirred at room temperature for 30 minutes. After the reaction is over, concentrate under reduced pressure, add 15mL ice water, extract with ethyl acetate (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography (petroleum ether /Ethyl acetate: 3/1) to obtain 7-(2,6-dichloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine- 4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (80 mg, Y53%). ES-API: [M+H] + = 554.2.
步骤四：将7-(2,6-二氯-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(20mg,0.036mmoL)、3-(二甲氨基)氮杂环丁烷二盐酸盐(8mg,0.046mmoL)溶解在二氯甲烷中，滴加三乙胺(12mg,0.12mmoL)在室温条件下搅拌30分钟。反应结束后，减压浓缩，加入15mL冰水，用乙酸乙酯萃取,合并有机相，用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱层析(二氯甲烷/甲醇：10/1)纯化，得到7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-3-哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(20mg,Y90％)。ES-API:[M+H] +＝618.3。 Step 4: Add 7-(2,6-dichloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (20mg, 0.036mmoL), 3-(dimethylamino)azetidine dihydrochloride (8mg, 0.046mmoL) dissolved in two In methyl chloride, triethylamine (12mg, 0.12mmoL) was added dropwise and stirred at room temperature for 30 minutes. After the reaction, concentrate under reduced pressure, add 15 mL of ice water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph on silica gel column (dichloromethane/methanol: 10 /1) Purification to obtain 7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(5-methyl-1H-indazole-4- Yl)pyrido[2,3-d]pyrimidine-3-piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (20mg, Y90%) . ES-API: [M+H] + = 618.3.
步骤五：将7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-3-哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(20mg,0.032mmoL)溶解在2mL二氯甲烷中，滴加2mL三氟乙酸，在室温条件下搅拌2小时。反应结束后，减压浓缩，得到1-(6-氯-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶并[2,3-d]嘧啶吡啶-2-基)-N,N-二甲基氮杂环-3-胺(15mg,Y90％)。ES-API:[M+H] +＝518.3。 Step 5: Add 7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(5-methyl-1H-indazol-4-yl) Pyrido[2,3-d]pyrimidine-3-piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (20mg, 0.032mmoL) was dissolved in Add 2 mL of trifluoroacetic acid dropwise to 2 mL of dichloromethane, and stir at room temperature for 2 hours. After the reaction, it was concentrated under reduced pressure to obtain 1-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane) -7-yl)pyrido[2,3-d]pyrimidin-2-yl)-N,N-dimethylazacyclo-3-amine (15 mg, Y90%). ES-API: [M+H] + = 518.3.
步骤六：将1-(6-氯-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶并[2,3-d]嘧啶吡啶-2-基)-N,N-二甲基氮杂环-3-胺(15mg,0.029mmoL)溶解在2mL四氢呋喃和1mL水中，滴加丙烯酰氯，再滴加三乙胺5滴，再冰水浴条件下搅拌5分钟。反应结束后，减压浓缩，经HPLC制备纯化，得到1-(7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(1.73mg,Y16.6％)。Step 6: Add 1-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl) Pyrido[2,3-d]pyrimidin-2-yl)-N,N-dimethylazacyclo-3-amine (15mg, 0.029mmoL) was dissolved in 2mL tetrahydrofuran and 1mL water, and acryloyl chloride was added dropwise, Then add 5 drops of triethylamine, and stir for 5 minutes under ice-water bath. After the reaction, it was concentrated under reduced pressure and purified by HPLC to obtain 1-(7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(5 -Methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidinepiperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)propane -2-en-1-one (1.73 mg, Y 16.6%).
实施例29：1-(7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)吡啶并[2,3-d]嘧啶哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 29: 1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy) Synthesis of pyrido[2,3-d]pyrimidinepiperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000077
Figure PCTCN2020077192-appb-000077
步骤一：将7-(2,6-二氯-7-(5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(合成方法见Z28)(50mg,0.09mmoL)、1-甲基哌啶-4-醇(212mg,1.8mmoL)、Cs 2CO 3(60mg,0.18mmoL)和KF(52mg,0.9mmoL)加入到干燥的1-4-二氧六环/二甲亚砜(5mL/5mL)中，油浴60℃反应1个小时。冷却室温，反应液加入10mL水中，用乙酸乙酯萃取3次,合并有机相，减压浓缩,柱层析，得到7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)吡啶并[2,3-d]嘧啶-哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(30mg,Y55％)。ES-API:[M+H] +＝633.3。 Step 1: Add 7-(2,6-dichloro-7-(5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (see Z28 for synthesis method) (50mg, 0.09mmoL), 1-methylpiperidin-4-ol (212mg, 1.8mmoL), Cs 2 CO 3 (60mg, 0.18mmoL) and KF (52mg, 0.9mmoL) were added to dry 1-4-dioxane/dimethylsulfoxide (5mL/5mL), and reacted in an oil bath at 60°C for 1 hour. After cooling to room temperature, the reaction solution was added to 10 mL of water, extracted 3 times with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and column chromatography was used to obtain 7-(6-chloro-7-(5-methyl-1H-indazole- 4-yl)-2-((1-methylpiperidin-4-yl)oxy)pyrido[2,3-d]pyrimidine-piperidin-4-yl)-2,7-diazaspiro [3.5] Tert-butyl nonane-2-carboxylate (30 mg, Y55%). ES-API: [M+H] + = 633.3.
步骤二：将7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)吡啶并[2,3-d]嘧啶-哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(30mg,0.047mmoL)溶解在2mL二氯甲烷中，滴加2mL三氟乙酸，在室温条件下搅拌2小时。反应结束后，减压浓缩，得到6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶并[2,3-d]嘧啶(22mg,Y90％)。ES-API:[M+H] +＝533.3。 Step 2: Add 7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)pyrido[ 2,3-d]pyrimidine-piperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (30mg, 0.047mmoL) dissolved in 2mL dichloromethane , 2mL trifluoroacetic acid was added dropwise, and stirred at room temperature for 2 hours. After the reaction, it was concentrated under reduced pressure to obtain 6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)- 4-(2,7-diazaspiro[3.5]nonane-7-yl)pyrido[2,3-d]pyrimidine (22 mg, Y90%). ES-API: [M+H] + =533.3.
步骤三：将6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶并[2,3-d]嘧啶(22mg,0.042mmoL)溶解在2mL四氢呋喃和1mL水中，滴加丙烯酰氯，再滴加三乙胺5滴，再冰水浴条件下搅拌5分钟。反应结束后，减压浓缩，经HPLC制备纯化，得到1-(7-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)吡啶并[2,3-d]嘧啶哌啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(1.50mg,Y:5％)。ES-API:[M+H] +＝587.3。 Step 3: Add 6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4-(2, 7-diazaspiro[3.5]nonane-7-yl)pyrido[2,3-d]pyrimidine (22mg, 0.042mmoL) was dissolved in 2mL tetrahydrofuran and 1mL water, acryloyl chloride was added dropwise, and then triethyl 5 drops of amine, then stir for 5 minutes under ice-water bath. After the reaction, it was concentrated under reduced pressure and purified by HPLC to obtain 1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methyl Piperidin-4-yl)oxy)pyrido[2,3-d]pyrimidinepiperidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)propan-2- En-1-one (1.50 mg, Y: 5%). ES-API: [M+H] + = 587.3.
实施例30：1-(2-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.4]辛烷-6-基)丙-2-烯-1-酮的合成Example 30: 1-(2-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl )Oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-6-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000078
Figure PCTCN2020077192-appb-000078
步骤一：7-溴-2,4,6-三氯-8-氟喹唑啉(500mg,1.5mmol)溶于二氯甲烷/乙腈(5mL/5mL)冷却至0℃。三乙胺(230mg,2.3mmol)及2,6-二氮杂螺[3.4]辛烷-6-羧酸叔丁酯(337mg,1.6mmol)加入其中，室温搅拌3小时。二氯甲烷(30mL x 2)萃取，有机相水洗，盐水洗涤， 无水硫酸钠干燥，旋蒸脱溶,得到2-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,6-二氮杂螺[3.4]辛烷-6-羧酸叔丁酯(黄色固体，545mg,Y：71％)。ES-API:[M+H] +＝505.0，507.0。 Step 1: 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (500mg, 1.5mmol) was dissolved in dichloromethane/acetonitrile (5mL/5mL) and cooled to 0°C. Triethylamine (230 mg, 2.3 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (337 mg, 1.6 mmol) were added thereto, and the mixture was stirred at room temperature for 3 hours. Extraction with dichloromethane (30mL x 2), wash the organic phase with water, brine, dry with anhydrous sodium sulfate, and spin off the solvent to obtain 2-(7-bromo-2,6-dichloro-8-fluoroquinazoline- 4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (yellow solid, 545 mg, Y: 71%). ES-API: [M+H] + =505.0, 507.0.
步骤二：2-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,6-二氮杂螺[3.4]辛烷-6-羧酸叔丁酯(227mg,0.45mmol)溶于N，N-二甲基甲酰胺/四氢呋喃(2mL/2mL)，向其中加入碳酸铯(437mg,1.3mmol)，三乙烯二胺(7.5mg,0.07mmol)及1-甲基哌啶-4-醇(155mg,1.3mmol)。反应液45℃反应16小时。乙酸乙酯(50mL x 2)萃取，有机相水洗，盐水洗，无水硫酸钠干燥，旋蒸过柱(二氯甲烷/甲醇＝20/1-10/1)得到2-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.4]辛烷-6的叔丁基-甲酸(黄色固体，156mg,Y：60％)。Step 2: 2-(7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (227mg, 0.45mmol) dissolved in N,N-dimethylformamide/tetrahydrofuran (2mL/2mL), to which was added cesium carbonate (437mg, 1.3mmol), triethylenediamine (7.5mg, 0.07mmol) and 1 -Methylpiperidin-4-ol (155 mg, 1.3 mmol). The reaction solution was reacted at 45°C for 16 hours. Extract with ethyl acetate (50mL x 2), wash the organic phase with water, wash with brine, dry with anhydrous sodium sulfate, and spin-evaporate through the column (dichloromethane/methanol=20/1-10/1) to obtain 2-(7-bromo- 6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-6 Tert-butyl-formic acid (yellow solid, 156 mg, Y: 60%).
ES-API:[M+H] +＝584.1，586.1。 ES-API: [M+H] + =584.1, 586.1.
步骤三：2-(7-溴-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.4]辛烷-6的叔丁基-甲酸(156mg,0.27mmol)溶于1,4-二氧六环/水(2mL/0.5mL)，加入(5-甲基-1H-吲唑-4-基)硼酸(94mg,0.53mmol)，三(二苄又丙酮)二钯(24mg,0.03mmol)，2-双环己基膦-2',6'-二甲氧基联苯(22mg,0.05mmol)，磷酸钾(113mg,0.53mmol)。反应液100℃氮气保护下搅拌16小时。乙酸乙酯(30mL x 3)萃取，合并有机相，无水硫酸镁干燥，旋干过柱(二氯甲烷/甲醇＝10/1-5/1)得到2-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)叔丁基)-2,6-二氮杂螺[3.4]辛烷-6-羧酸乙酯(黄色固体，65mg,Y:38％)。ES-API:[M+H] +＝580.2。 Step 3: 2-(7-Bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-di Azaspiro[3.4]octane-6 tert-butyl-formic acid (156mg, 0.27mmol) was dissolved in 1,4-dioxane/water (2mL/0.5mL), and (5-methyl-1H- Indazol-4-yl)boronic acid (94mg, 0.53mmol), tris(dibenzylacetone)dipalladium (24mg, 0.03mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl ( 22mg, 0.05mmol), potassium phosphate (113mg, 0.53mmol). The reaction solution was stirred at 100°C under nitrogen protection for 16 hours. Extract with ethyl acetate (30mL x 3), combine the organic phases, dry over anhydrous magnesium sulfate, spin-dry the column (dichloromethane/methanol=10/1-5/1) to obtain 2-(6-chloro-8-fluoro -7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)tert-butyl)- Ethyl 2,6-diazaspiro[3.4]octane-6-carboxylate (yellow solid, 65 mg, Y: 38%). ES-API: [M+H] + = 580.2.
步骤四：2-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)叔丁基)-2,6-二氮杂螺[3.4]辛烷-6-羧酸乙酯(65mg,0.1mmol)溶于二氯甲烷(0.5mL)，加入三氟醋酸(0.5mL)，反应液室温搅拌1小时，旋蒸脱溶得到6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,6-二氮杂螺[3.4]辛烷-2-基)喹唑啉(棕色固体，55mg)，无须纯化直接用于下步反应。ES-API:[M+H] +＝536.2。 Step 4: 2-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy) Quinazolin-4-yl)tert-butyl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid ethyl ester (65mg, 0.1mmol) was dissolved in dichloromethane (0.5mL) and added Trifluoroacetic acid (0.5 mL), the reaction solution was stirred at room temperature for 1 hour, and the solvent was evaporated to remove 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(( 1-Methylpiperidin-4-yl)oxy)-4-(2,6-diazaspiro[3.4]octane-2-yl)quinazoline (brown solid, 55mg), used directly without purification In the next step reaction. ES-API: [M+H] + =536.2.
步骤五：6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)-4-(2,6-二氮杂螺[3.4]辛烷-2-基)喹唑啉(55mg,0.1mmol)溶于二氯甲烷(1mL)，反应液降温至0℃，加入三乙胺(30mg,0.3mmol)及丙烯酸酐(9mg,0.07mmol)，反应液0℃反应1小时，脱溶，制备液相分离得到1-(2-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,6-二氮杂螺[3.4]辛烷-6-基)丙-2-烯-1-酮(白色固体，6.6mg,Y：11％)。ES-API:[M+H] +＝590.3。 1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),7.85(d,J＝1.5Hz,1H),7.56(d,J＝8.5Hz,1H),7.48(s,1H),7.36(d,J＝8.6Hz,1H),6.56(td,J＝17.5,10.3Hz,1H),6.14(dt,J＝16.8,2.7Hz,1H),5.67(dd,J＝10.3,2.4Hz,1H),5.05(s,1H),4.49(d,J＝92.1Hz,3H),3.86(s,1H),3.72–3.61(m,2H),3.47(t,J＝7.1Hz,1H),2.74(s,2H),2.36–2.21(m,6H),2.21–2.13(m,2H),2.12(s,3H),1.98(d,J＝5.7Hz,2H),1.74(s,2H). Step 5: 6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)-4- (2,6-diazaspiro[3.4]octane-2-yl)quinazoline (55mg, 0.1mmol) was dissolved in dichloromethane (1mL), the reaction solution was cooled to 0℃, and triethylamine (30mg , 0.3mmol) and acrylic anhydride (9mg, 0.07mmol), the reaction solution was reacted at 0°C for 1 hour, desolventized, and liquid phase separation was prepared to obtain 1-(2-(6-chloro-8-fluoro-7-(5-methyl) -1H-indazol-4-yl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2,6-diazaspiro[3.4] Octane-6-yl)prop-2-en-1-one (white solid, 6.6 mg, Y: 11%). ES-API: [M+H] + =590.3. 1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H), 7.85(d,J=1.5Hz,1H), 7.56(d,J=8.5Hz,1H), 7.48(s,1H), 7.36(d,J＝8.6Hz,1H), 6.56(td,J＝17.5,10.3Hz,1H), 6.14(dt,J＝16.8,2.7Hz,1H), 5.67(dd,J＝10.3,2.4Hz ,1H),5.05(s,1H),4.49(d,J=92.1Hz,3H),3.86(s,1H),3.72–3.61(m,2H),3.47(t,J=7.1Hz,1H) ,2.74(s,2H),2.36–2.21(m,6H),2.21–2.13(m,2H),2.12(s,3H),1.98(d,J=5.7Hz,2H),1.74(s,2H) ).
实施例31：1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(氧杂环丁-3-基)哌啶-4-基]氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 31: 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(oxetan-3- (Yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000079
Figure PCTCN2020077192-appb-000079
步骤一：7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(4.00g,7.69mmol)溶解在DMF(40ml)中，加入碳酸铯(6.25g,19.2mmol)、三乙烯二胺(155mg,1.38mmol)和1-(噁丁环烷-3-基)哌啶-4-醇(1.45g,9.28mmol)。氮气保护下，室温搅拌反应4小时。反应液用乙酸乙酯萃取，减压浓缩。粗品通过柱层析(石油醚/乙酸乙酯＝5/1-1/1)得到7-(7-溴-6-氯-8-氟-2-((1-(氧杂环丁-3-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(黄色固体，2.2g,Y：45％)。ES-API:[M+H] +＝640.2。 Step 1: 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (4.00g, 7.69mmol) was dissolved in DMF (40ml), cesium carbonate (6.25g, 19.2mmol), triethylenediamine (155mg, 1.38mmol) and 1-(oxbutacycloalkyl-3-yl) piper were added Pyridin-4-ol (1.45 g, 9.28 mmol). Under the protection of nitrogen, the reaction was stirred at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate and concentrated under reduced pressure. The crude product was passed through column chromatography (petroleum ether/ethyl acetate = 5/1-1/1) to obtain 7-(7-bromo-6-chloro-8-fluoro-2-((1-(oxetan-3 -Yl)piperidin-4-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (yellow solid, 2.2g, Y: 45%). ES-API: [M+H] + = 640.2.
步骤二：7-(7-溴-6-氯-8-氟-2-((1-(氧杂环丁-3-基)哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯溶解在二氧六环/水(15mL/4mL)中，加入磷酸钾(1.2g,5.63mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯(78mg,0.18mmol)和Pd 2(dba) 3(171mg,0.2mmol)。氮气保护下，100度反应5小时。反应液用乙酸乙酯萃取，减压浓缩，粗产品通过柱层析(二氯甲烷/甲醇＝100/0-20/1)纯化，得到7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(氧杂环丁-3-基)哌啶-4-基]氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(黄色固体，700mg,Y：54％)。ES-API:[(M-56)/2+H] +＝318.7。 Step 2: 7-(7-bromo-6-chloro-8-fluoro-2-((1-(oxetan-3-yl)piperidin-4-yl)oxy)quinazoline-4- Yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was dissolved in dioxane/water (15mL/4mL), potassium phosphate (1.2g, 5.63mmol) was added, 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (78 mg, 0.18 mmol) and Pd 2 (dba) 3 (171 mg, 0.2 mmol). Under nitrogen protection, react at 100°C for 5 hours. The reaction solution was extracted with ethyl acetate and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol=100/0-20/1) to obtain 7-(6-chloro-8-fluoro-7-( 5-methyl-1H-indazol-4-yl)-2-((1-(oxetan-3-yl)piperidin-4-yl)oxy)quinazolin-4-yl)- 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (yellow solid, 700mg, Y: 54%). ES-API: [(M-56)/2+H] + = 318.7.
步骤三：将7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(氧杂环丁-3-基)哌啶-4-基]氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(500mg,0.7mmol)溶解在二氯甲烷中(10mL)，加入三氟乙酸(2mL)。室温搅拌反应30分钟。反应液直接减压浓缩，得到粗品6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(((1-(氧杂环丁-3-基)哌啶-4-基)氧基]-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉(黄色液体，427mg)。ES-API:[M/2+H] +＝296.6。 Step 3: Add 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(oxetan-3-yl)piper (Pyridin-4-yl]oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (500mg, 0.7mmol) dissolved in dichloromethane (10mL), add trifluoroacetic acid (2mL). Stir the reaction at room temperature for 30 minutes. The reaction solution was directly concentrated under reduced pressure to obtain crude 6-chloro-8-fluoro-7-(5-methyl-1H-indazole-4 -Yl)-2-(((1-(oxetan-3-yl)piperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane-7 -Yl)quinazoline (yellow liquid, 427 mg). ES-API: [M/2+H] + =296.6.
步骤四：6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(((1-(氧杂环丁-3-基)哌啶-4-基)氧基]-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉(427mg,0.72mmol)溶解在二氯甲烷(10mL)中，冷却到0度，先后加入三乙胺(2mL)和丙烯酸酐(77mg,0.61mmol)。0度反应30分钟。反应液用二氯甲烷萃取，盐水洗涤，减压浓缩，得到1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-(氧杂环丁-3-基)哌啶-4-基]氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(白色固体，205mg,Y：44％)。ES-API:[M+H] +＝646.3。 1H NMR(400MHz,氯仿-d)δ10.21(s,1H),7.77(s,1H),7.59(s,1H),7.52(d,J＝8.4Hz,1H),7.39(d,J＝8.6Hz,1H),6.39(d,J＝16.8Hz,1H),6.29–6.17(m,1H),5.72(d,J＝10.3Hz,1H),5.22(s,1H),4.67(s,4H),4.03(s,2H),3.92(s,2H),3.75(d,J＝23.1Hz,4H),3.56(s,1H),2.72(s,2H),2.24(m,7H),2.06(m,6H). Step 4: 6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((1-(oxetan-3-yl)piperidine-4 -Yl)oxy]-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline (427mg, 0.72mmol) was dissolved in dichloromethane (10mL) and cooled to 0 Then add triethylamine (2mL) and acrylic anhydride (77mg, 0.61mmol) successively. Reaction at 0°C for 30 minutes. The reaction solution was extracted with dichloromethane, washed with brine, and concentrated under reduced pressure to obtain 1-(7-(6- Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-(oxetan-3-yl)piperidin-4-yl)oxy) Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (white solid, 205mg, Y: 44%). ES- API: [M+H] + ＝646.3. 1 H NMR (400MHz, chloroform-d) δ 10.21 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.52 (d, J = 8.4Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 6.39 (d, J = 16.8 Hz, 1H), 6.29-6.17 (m, 1H), 5.72 (d, J = 10.3 Hz, 1H) ,5.22(s,1H),4.67(s,4H),4.03(s,2H),3.92(s,2H),3.75(d,J=23.1Hz,4H),3.56(s,1H),2.72( s, 2H), 2.24 (m, 7H), 2.06 (m, 6H).
实施例32：3-((((4-(2-丙烯酰基-2,7-二氮杂螺[3.5]壬基-7-基]-6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-2-基)氧基)甲基)-1-甲基吡咯烷-2-酮的合成Example 32: 3-((((4-(2-acryloyl-2,7-diazaspiro[3.5]nonyl-7-yl]-6-chloro-8-fluoro-7-(5- Synthesis of (methyl-1H-indazol-4-yl)quinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one
Figure PCTCN2020077192-appb-000080
Figure PCTCN2020077192-appb-000080
步骤一：将7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(3g,5.77mmol)溶解在N,N-二异丙基乙胺(40mL)中，加入3-(羟甲基)-1-甲基吡咯烷酮-2-酮(893mg,6.92mmol)、碳酸铯(4.68g,14.4mmol)、1,4-二氮杂双环[2.2.2]辛烷(116mg,1.03mmol)，氮气保护下，室温搅拌反应3小时。反应液用乙酸乙酯萃取，减压浓缩，粗产品通过柱层析(二氯甲烷/甲醇＝40/1-20/1)纯化，得到7-(7-溴-6-氯-8-氟-2-((1-甲基-2-氧吡咯烷-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(棕色液体，3.24g,Y：92％)。ES-API:[M+H]+＝612.1。Step 1: Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (3g, 5.77mmol) was dissolved in N,N-diisopropylethylamine (40mL), and 3-(hydroxymethyl)-1-methylpyrrolidone-2-one (893mg, 6.92mmol), carbonic acid Cesium (4.68g, 14.4mmol), 1,4-diazabicyclo[2.2.2]octane (116mg, 1.03mmol), under nitrogen protection, the reaction was stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol=40/1-20/1) to obtain 7-(7-bromo-6-chloro-8-fluoro -2-((1-methyl-2-oxopyrrolidin-3-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxy Tert-butyl ester (brown liquid, 3.24 g, Y: 92%). ES-API: [M+H]+=612.1.
步骤二：7-(7-溴-6-氯-8-氟-2-((1-甲基-2-氧吡咯烷-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.20g,1.96mmol)溶解在二氧六环/水(15mL/4mL)中，加入(5-甲基-1H-吲唑-4-基)硼酸(517mg,2.94mmol)、磷酸钾(1.24g,5.88mmol)、三(二亚苄基丙酮)二钯(183mg,0.2mmol)和2-二环己基膦基-2′,6′-二甲氧基联苯(82mg,0.2mmol)。氮气保护下，100度反应5小时。反应液用乙酸乙酯萃取，减压浓缩。粗产物通过柱层析(二氯甲烷/甲醇＝40/1-20/1)纯化，得到7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基-2-氧吡咯烷-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(黄色固体，1.0g,Y：77％)。ES-API:[M+H] +＝664.2。 Step 2: 7-(7-bromo-6-chloro-8-fluoro-2-((1-methyl-2-oxopyrrolidin-3-yl)methoxy)quinazolin-4-yl)- 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.20g, 1.96mmol) was dissolved in dioxane/water (15mL/4mL), and (5-methyl- 1H-indazol-4-yl)boronic acid (517mg, 2.94mmol), potassium phosphate (1.24g, 5.88mmol), tris(dibenzylideneacetone)dipalladium (183mg, 0.2mmol) and 2-dicyclohexylphosphine Benzyl-2',6'-dimethoxybiphenyl (82mg, 0.2mmol). Under nitrogen protection, react at 100°C for 5 hours. The reaction solution was extracted with ethyl acetate and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol=40/1-20/1) to obtain 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazole-4- Yl)-2-((1-methyl-2-oxopyrrolidin-3-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2 -Tert-butyl carboxylate (yellow solid, 1.0 g, Y: 77%). ES-API: [M+H] + = 664.2.
步骤三：7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((1-甲基-2-氧吡咯烷-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(500mg,0.75mmol)溶解在二氯甲烷(10mL)中，加入三氟乙酸(2mL)。室温搅拌反应30分钟。反应液直接减压浓缩，得到3-(((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬-7-基)喹唑啉-2-基)氧基)甲基)-1-甲基吡咯烷-2-酮(黄色液体，424mg,Y：粗品)。ES-API:[M+H] +＝564.1。 Step 3: 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((1-methyl-2-oxopyrrolidin-3-yl) )Methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (500mg, 0.75mmol) dissolved in dichloromethane (10mL) , Add trifluoroacetic acid (2mL). The reaction was stirred at room temperature for 30 minutes. The reaction solution was directly concentrated under reduced pressure to obtain 3-(((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro [3.5] Non-7-yl)quinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one (yellow liquid, 424 mg, Y: crude product). ES-API: [M+H] + =564.1.
步骤四：3-(((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬-7-基)喹唑啉-2-基)氧基)甲基)-1-甲基吡咯烷-2-酮(424mg,0.75mmol)溶解在二氯甲烷(10mL)中，冷却到0度，先后加入三乙胺(2mL)和丙烯酸酐(81mg,0.64mmol)。0度搅拌反应30分钟。反应液用乙酸乙酯萃取，盐水洗涤，减压浓缩。粗产物通过制备液相色谱得到3-((((4-(2-丙烯酰基-2,7-二氮杂螺[3.5]壬基-7-基]-6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)喹唑啉-2-基)氧基)甲基)-1-甲基吡咯烷-2-酮(类白色固体，130mg,Y：23％)。ES-API:[M+H] +＝618.2。 1H NMR(400 MHz,氯仿-d)δ7.77(s,1H),7.59(s,1H),7.52(d,J＝8.1Hz,1H),7.38(d,J＝8.8Hz,1H),6.38(d,J＝17.2Hz,1H),6.30–6.17(m,1H),5.71(d,J＝10.2Hz,1H),4.75(s,1H),4.63(d,J＝9.2Hz,1H),3.97(d,J＝40.4Hz,4H),3.78(d,J＝31.4Hz,4H),3.38(d,J＝8.3Hz,2H),2.99(s,1H),2.87(s,3H),2.24(s,5H),2.05(s,4H). Step 4: 3-(((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]non- 7-yl)quinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one (424mg, 0.75mmol) was dissolved in dichloromethane (10mL) and cooled to 0°C, Triethylamine (2mL) and acrylic anhydride (81mg, 0.64mmol) were added sequentially. The reaction was stirred at 0°C for 30 minutes. The reaction solution was extracted with ethyl acetate, washed with brine, and concentrated under reduced pressure. The crude product was obtained by preparative liquid chromatography to obtain 3-((((4-(2-acryloyl-2,7-diazaspiro[3.5]nonyl-7-yl]-6-chloro-8-fluoro-7 -(5-Methyl-1H-indazol-4-yl)quinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one (off-white solid, 130mg, Y: 23%). ES-API: [M+H] + = 618.2. 1 H NMR (400 MHz, chloroform-d) δ 7.77 (s, 1H), 7.59 (s, 1H), 7.52 (d, J = 8.1Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 17.2 Hz, 1H), 6.30-6.17 (m, 1H), 5.71 (d, J = 10.2 Hz, 1H) ,4.75(s,1H), 4.63(d,J=9.2Hz,1H), 3.97(d,J=40.4Hz,4H), 3.78(d,J=31.4Hz,4H), 3.38(d,J= 8.3Hz, 2H), 2.99 (s, 1H), 2.87 (s, 3H), 2.24 (s, 5H), 2.05 (s, 4H)
实施例33：1-(7-(8-氟-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 33: 1-(7-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)-6-ethylene Synthesis of quinazolin-4-yl-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000081
Figure PCTCN2020077192-appb-000081
步骤一：7-(7-溴-6-碘-8-甲氧基-2-(((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(4.7g,6.69mmol)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼杂环戊烷(1.5g,10.04mmol)，碳酸钠(1.4g,13.38mmol)，1,1'-双(二苯基膦基)二茂铁]二氯化钯(400mg)，依次加入到二氧六环(50mL)水(5mL)的混合溶剂中，40度反应18小时。反应液冷却后倒入水(200mL)中，乙酸乙酯萃取(100mL x 3)，水洗盐水洗干燥旋干后柱层析(甲醇：二氯甲烷＝0～1:10)纯化得黄色油状物7-(7-溴8-甲氧基-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(3g,收率74％)。ES-API:[M-55] +＝534.2/536.2。 Step 1: 7-(7-bromo-6-iodo-8-methoxy-2-(((1-methylpiperidin-4-yl)oxy)quinazolin-4-yl)-2, 7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (4.7g, 6.69mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- Dioxaborolane (1.5g, 10.04mmol), sodium carbonate (1.4g, 13.38mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (400mg) , Added to the mixed solvent of dioxane (50mL) and water (5mL) in sequence, reacted at 40°C for 18 hours. After cooling, the reaction solution was poured into water (200mL), extracted with ethyl acetate (100mL x 3), washed with brine Wash, dry, spin dry, and purify by column chromatography (methanol: dichloromethane = 0～1:10) to obtain a yellow oily 7-(7-bromo8-methoxy-2-((1-methylpiperidine-4) -Yl)oxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (3g, yield 74%). ES-API: [M-55] + = 534.2/536.2.
步骤二：将7-(7-溴-8-氟-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(500mg,0.85mmol)溶解在二氧六环/水(5mL/1mL)中，加入(2-氟-6-羟基苯基)硼酸(264mg,1.69mmol)，磷酸钾(538mg,2.54mmol)，2-双环已基膦-2',6'-二异丙氧基联苯(78mg,0.17mmol)和三(二亚苄丙酮)二钯(77mg,0.09mmol)。氮气保护下，100度搅拌反应2小时。反应液用二氯甲烷萃取，减压浓缩，粗品通过柱层析(二氯甲烷/甲醇＝10/1)纯化，得到7-(8-氟-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(431mg,Y：78％，棕色固体)。ES-API:[M+1] +＝622.3 Step 2: Add 7-(7-bromo-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2,7 -Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (500mg, 0.85mmol) was dissolved in dioxane/water (5mL/1mL), and (2-fluoro-6-hydroxyphenyl ) Boric acid (264mg, 1.69mmol), potassium phosphate (538mg, 2.54mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (78mg, 0.17mmol) and tris(dibenzylidene) Acetone) Dipalladium (77 mg, 0.09 mmol). Under the protection of nitrogen, the reaction was stirred at 100°C for 2 hours. The reaction solution was extracted with dichloromethane, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol=10/1) to obtain 7-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl) )-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2- Tert-butyl carboxylate (431 mg, Y: 78%, brown solid). ES-API:[M+1] + ＝622.3
步骤三：将7-(8-氟-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(315mg,0.51mmol)溶解在二氯甲烷(3mL)中，加入三氟乙酸(3mL)。室温搅拌反应30分钟。反应液直接减压浓缩，得到3-氟-2-(8-氟-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)-6-乙烯基喹唑啉-7-基)苯酚(264mg,Y：100％)。直接用于下一步反应。ES-API:[M/2+1] +＝261.6。 Step 3: Add 7-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)oxy)-6-vinylquinazole (Alkolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (315mg, 0.51mmol) was dissolved in dichloromethane (3mL), and trifluoroacetic acid (3mL ). The reaction was stirred at room temperature for 30 minutes. The reaction solution was directly concentrated under reduced pressure to obtain 3-fluoro-2-(8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[ 3.5] Nonane-7-yl)-6-vinylquinazolin-7-yl)phenol (264 mg, Y: 100%). Used directly in the next reaction. ES-API: [M/2+1] + = 261.6.
步骤四：将3-氟-2-(8-氟-2-((1-甲基哌啶-4-基)氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)-6-乙烯基喹唑啉-7-基)苯酚(264mg,0.51mL)溶解在二氯甲烷(3mL)中，加入三乙胺(3mL)，冷却到0度，加入丙烯酸酐(54mg,0.43mmol)。室温搅拌反应30分钟。反应液用二氯甲烷萃取，减压浓缩，粗品通过制备高效液相色谱纯化得到1-(7-(8-氟-7-(2-氟-6-羟基苯基)-2-((1-甲基哌啶-4-基)氧基)-6-乙烯基喹唑啉-4-基-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(70.2mg,Y：23％，白色固体)。ES-API:[M+1] +＝576.2。 1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.25(d,J＝7.8Hz,1H),6.79–6.66(m,2H),6.57(dd,J＝17.4,10.9Hz,1H),6.36(d,J＝16.9Hz,1H),6.20(dd,J＝17.0,10.3Hz,1H),5.68(dd,J＝18.7,14.0Hz,2H),5.21(d,J＝10.6Hz,2H),3.99(s,2H),3.88(s,2H),3.79–3.56(m,4H),2.86–2.63(m,2H),2.31(s,5H),2.18–1.77(m,8H). Step 4: Add 3-fluoro-2-(8-fluoro-2-((1-methylpiperidin-4-yl)oxy)-4-(2,7-diazaspiro[3.5]nonane -7-yl)-6-vinylquinazolin-7-yl)phenol (264mg, 0.51mL) was dissolved in dichloromethane (3mL), triethylamine (3mL) was added, cooled to 0 degrees, acrylic acid was added Anhydride (54 mg, 0.43 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction solution was extracted with dichloromethane and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 1-(7-(8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1 -Methylpiperidin-4-yl)oxy)-6-vinylquinazolin-4-yl-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-ene- 1-ketone (70.2mg, Y: 23%, white solid). ES-API: [M+1] + = 576.2. 1 H NMR (400MHz, CDCl3) δ 7.83 (s, 1H), 7.25 (d, J = 7.8Hz, 1H), 6.79–6.66 (m, 2H), 6.57 (dd, J = 17.4, 10.9 Hz, 1H), 6.36 (d, J = 16.9 Hz, 1H), 6.20 (dd, J = 17.0 ,10.3Hz,1H),5.68(dd,J=18.7,14.0Hz,2H),5.21(d,J=10.6Hz,2H),3.99(s,2H),3.88(s,2H),3.79–3.56 (m,4H), 2.86-2.63(m,2H), 2.31(s,5H), 2.18-1.77(m,8H).
实施例34：1-(7-(6-氯-8-氟-2-((((2S，4S)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙烯-2-酮的合成Example 34: 1-(7-(6-chloro-8-fluoro-2-((((2S,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7 -(5-Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)propen-2-one
Figure PCTCN2020077192-appb-000082
Figure PCTCN2020077192-appb-000082
步骤一：将(2S，4S)-1-叔丁基-2-甲基-4-羟基吡咯烷-1,2-二甲酸酯(3.0g,12.2mmoL)溶解在60mL THF，冰浴冷却至0℃，缓慢分批加入LiAlH 4(3.8g,100mmol)，升至室温，搅拌过夜。反应完全后，依次加入3.8ml H 2O，3.8ml NaOH(15％)和11.4ml H 2O，搅拌至白色砂状固体析出，过滤，用DCM/i-PrOH(3/1)冲洗，收集母液，浓缩，反相柱纯化得到(3S,5S)-5-(羟甲基)-1-甲基吡咯烷-3-醇(1.2g,Y：75％)。ES-API:[M+H] +＝132.1。 Step 1: Dissolve (2S, 4S)-1-tert-butyl-2-methyl-4-hydroxypyrrolidine-1,2-dicarboxylate (3.0g, 12.2mmoL) in 60mL THF and cool in an ice bath To 0°C, slowly add LiAlH 4 (3.8 g, 100 mmol) in batches, warm to room temperature, and stir overnight. After the reaction is complete, add 3.8ml H 2 O, 3.8ml NaOH (15%) and 11.4ml H 2 O in sequence, stir until a white sandy solid precipitates, filter, rinse with DCM/i-PrOH (3/1), and collect The mother liquor was concentrated, and purified by reverse phase column to obtain (3S, 5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-ol (1.2 g, Y: 75%). ES-API: [M+H] + = 132.1.
步骤二：将7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(1.0g,1.92mmoL)和(3S,5S)-5-(羟甲基)-1-甲基吡咯烷-3-醇(630mg,4.81mmoL)溶解在5mL DMF和5mL THF混合液中，加入三乙烯二胺(96mg,0.86mmoL)和Cs 2CO 3(1.57g,4.81mmoL)，加热至50℃反应2小时后，冷却至室温，加入100ml乙酸乙酯，水洗(3x30ml)，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，经柱色谱纯化，得到7-(7-溴-6-氯-8-氟-2-((((2S，4S)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(510mg,43％)。ES-API:[M+H] +＝614.0。 Step 2: Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.0g,1.92mmoL) and (3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-ol (630mg, 4.81mmoL) dissolved in 5mL DMF and 5mL THF mixture, add Triethylenediamine (96mg, 0.86mmoL) and Cs 2 CO 3 (1.57g, 4.81mmoL), heated to 50℃ for 2 hours, cooled to room temperature, added 100ml ethyl acetate, washed with water (3x30ml), saturated brine Washed, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 7-(7-bromo-6-chloro-8-fluoro-2-((((2S,4S)-4-hydroxy- 1-Methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (510mg, 43%) .ES-API: [M+H] + = 614.0.
步骤三：将7-(7-溴-6-氯-8-氟-2-((((2S，4S)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(360mg,0.58mmoL)、(5-甲基-1H-吲唑-4-基)硼酸(204mg,1.16mmoL)、氯(2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯基)(2’-氨基-1,1’-联苯-2-基)钯(II)(42mg,0.058mmoL)、2-二环己基膦基-2′,6′-二甲氧基联苯(48mg,0.117mmoL) 和K 3PO 4(311mg,1.46mmoL)加入到1,4-二氧六环(2mL)和水(0.3mL)混合液中，氮气置换3次，微波加热到110℃，搅拌1h，反应完毕，冷却至室温，过滤，浓缩，加入100ml乙酸乙酯，依次用水(50ml)和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(甲醇/二氯甲烷：0～10％)得到7-(6-氯-8-氟-2-((((2S，4S)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(150mg,Y：38％)，ES-API:[M+H] +＝666.2。 Step 3: Add 7-(7-bromo-6-chloro-8-fluoro-2-((((2S, 4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)quine Oxazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (360mg, 0.58mmoL), (5-methyl-1H-indazol-4-yl) Boric acid (204mg, 1.16mmoL), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl) Phen-2-yl)palladium(II) (42mg, 0.058mmoL), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (48mg, 0.117mmoL) and K 3 PO 4 (311mg ,1.46mmoL) was added to the mixture of 1,4-dioxane (2mL) and water (0.3mL), replaced with nitrogen three times, heated to 110°C in microwave, stirred for 1h, after the reaction was completed, cooled to room temperature, filtered, Concentrate, add 100ml ethyl acetate, wash with water (50ml) and saturated brine successively, dry over anhydrous sodium sulfate, concentrate, and column chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(6-chloro- 8-Fluoro-2-((((2S,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(5-methyl-1H-indazole-4- Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, Y: 38%), ES-API: [M+H] + = 666.2.
步骤四：将7-(6-氯-8-氟-2-((((2S,4S)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(150mg,0.225mmoL)溶解在4ml二氯甲烷中，室温条件下，缓慢滴加2ml三氟乙酸，反应2小时后，加入10ml二氯甲烷，减压浓缩，得到(3S,5S)-5-((((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基-2-羟甲基)-1-甲基吡咯烷-4-醇(120mg,粗品)，直接用于下一步。ES-API:[M+H] +＝566.2。 Step 4: Add 7-(6-chloro-8-fluoro-2-((((2S,4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(5 -Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.225mmoL) dissolved in In 4ml of dichloromethane, slowly add 2ml of trifluoroacetic acid dropwise at room temperature. After reaction for 2 hours, add 10ml of dichloromethane and concentrate under reduced pressure to obtain (3S,5S)-5-((((6-chloro- 8-Fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl -2-hydroxymethyl)-1-methylpyrrolidin-4-ol (120 mg, crude product), used directly in the next step. ES-API: [M+H] + =566.2.
步骤五：将(3S,5S)-5-((((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基-2-羟甲基)-1-甲基吡咯烷-4-醇(120mg,0.212mmol)溶解在二氯甲烷中，冰水浴条件下，滴加三乙胺(64.2mg,0.636mmol)和丙烯酸酐(21mg,0.17mmol)，冰浴条件下搅拌10分钟。反应结束后，加入100ml DCM,依次用水(50ml)和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经过制备HPLC纯化，得到1-(7-(6-氯-8-氟-2-((((2S，4S)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙烯-2-酮(44mg,Y：34％)，ES-API:[M+H] +＝620.2。 Step 5: Add (3S,5S)-5-((((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-two Azaspiro[3.5]nonane-7-yl)quinazolin-2-yl-2-hydroxymethyl)-1-methylpyrrolidin-4-ol (120mg, 0.212mmol) dissolved in dichloromethane Under ice-water bath conditions, add triethylamine (64.2mg, 0.636mmol) and acrylic anhydride (21mg, 0.17mmol) dropwise, and stir under ice-bath conditions for 10 minutes. After the reaction is over, add 100ml DCM, followed by water (50ml) and Washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to obtain 1-(7-(6-chloro-8-fluoro-2-((((2S, 4S)-4-hydroxy-1- Methylpyrrolidin-2-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro(3.5 ]Nonane-2-yl)propene-2-one (44 mg, Y: 34%), ES-API: [M+H] + =620.2.
步骤六：将1-(7-(6-氯-8-氟-2-((((2S，4S)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙烯-2-酮(30mg)经手性柱拆分得到化合物Z34-1(6.2mg)和化合物Z34-2(10mg)。拆分条件：柱型：Chiralpak IB250mm*4.6mm 5um；流动相：Hex:EtOH:氨甲醇＝70:30:0.2，流速：1ml/min；T＝30min。Step 6: Add 1-(7-(6-chloro-8-fluoro-2-((((2S, 4S)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7 -(5-Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)propen-2-one (30mg ) After chiral column resolution, compound Z34-1 (6.2mg) and compound Z34-2 (10mg) were obtained. Resolution conditions: column type: Chiralpak IB250mm*4.6mm 5um; mobile phase: Hex: EtOH: ammonia methanol = 70: 30:0.2, flow rate: 1ml/min; T=30min.
实施例35：1-(7-(6-氯-8-氟-2-((((3S，5S)-5-(羟甲基)-1-甲基吡咯烷-3-基)氧基])-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 35: 1-(7-(6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy ])-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)propan-2 -En-1-one synthesis
Figure PCTCN2020077192-appb-000083
Figure PCTCN2020077192-appb-000083
步骤一：将7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(1.0g,1.92mmoL)和(3S,5S)-5-(羟甲基)-1-甲基吡咯烷-3-醇(630mg,4.81mmoL)溶解在5mL DMF和5mL THF混合液中，加入三乙烯二胺(96mg,0.86mmoL)和Cs 2CO 3(1.57g,4.81mmoL)， 加热至50℃反应2小时后，冷却至室温，加入100ml乙酸乙酯，水洗(3x30ml)，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，经柱色谱纯化，得到7-溴-6-氯-8-氟-2-((((3S，5S)-5-(羟甲基)-1-甲基吡咯烷基-3-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(295mg,25％)。ES-API:[M+H] +＝614.0。 Step 1: Add 7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.0g ,1.92mmoL) and (3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-ol (630mg, 4.81mmoL) dissolved in 5mL DMF and 5mL THF mixture, add triethylene Amine (96mg, 0.86mmoL) and Cs 2 CO 3 (1.57g, 4.81mmoL), heated to 50°C for 2 hours, cooled to room temperature, added 100ml ethyl acetate, washed with water (3x30ml), saturated brine, no Dried with sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 7-bromo-6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1- Methylpyrrolidin-3-yl)oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (295 mg, 25%). ES-API: [M+H] + = 614.0.
步骤二：将7-溴-6-氯-8-氟-2-((((3S，5S)-5-(羟甲基)-1-甲基吡咯烷基-3-基)氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(295mg,0.48mmoL)、氯(2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯基)(2’-氨基-1,1’-联苯-2-基)钯(II)(35mg,0.048mmoL)、2-二环己基膦基-2′,6′-二甲氧基联苯(20mg,0.048mmoL)和K 3PO 4(254mg,1.2mmoL)加入到1,4-二氧六环(2mL)和水(0.3mL)混合液中，氮气置换3次，微波加热到110℃，搅拌1h，反应完毕，冷却至室温，过滤，浓缩，加入100ml乙酸乙酯，依次用水(50ml)和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(甲醇/二氯甲烷：0～10％)得到6-氯-8-氟-2-((((3S，5S)-5-(羟甲基)-1-甲基吡咯烷-3-基)氧基]-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(127mg,Y40％)，ES-API:[M+H] +＝666.2。 Step 2: Add 7-bromo-6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy) Quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (295mg, 0.48mmoL), chloro(2-dicyclohexylphosphino-2',6 '-Dimethoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (35mg, 0.048mmoL), 2-dicyclohexyl Phosphine-2′,6′-dimethoxybiphenyl (20mg, 0.048mmoL) and K 3 PO 4 (254mg, 1.2mmoL) were added to 1,4-dioxane (2mL) and water (0.3mL ) In the mixed solution, replace with nitrogen 3 times, heat to 110°C in microwave, stir for 1h, after the reaction is complete, cool to room temperature, filter, concentrate, add 100ml ethyl acetate, wash with water (50ml) and saturated brine in turn, anhydrous sulfuric acid The sodium was dried, concentrated, and column chromatography (methanol/dichloromethane: 0-10%) to obtain 6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1- Methylpyrrolidin-3-yl)oxy]-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5] Tert-butyl nonane-2-carboxylate (127 mg, Y40%), ES-API: [M+H] + =666.2.
步骤三：将6-氯-8-氟-2-((((3S，5S)-5-(羟甲基)-1-甲基吡咯烷-3-基)氧基]-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(127mg,0.19mmoL)溶解在4ml二氯甲烷中，室温条件下，缓慢滴加2ml三氟乙酸，反应2小时后，加入10ml二氯甲烷，减压浓缩，得到(2S，4S)-4-((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基)氧基)-1-甲基吡咯烷-2-基)甲醇(107mg,粗品)，直接用于下一步。ES-API:[M+H] +＝566.2。 Step 3: Add 6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy]-7-(5 -Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (127mg, 0.19mmoL) dissolved In 4ml of dichloromethane, at room temperature, slowly add 2ml of trifluoroacetic acid dropwise, after reaction for 2 hours, add 10ml of dichloromethane, and concentrate under reduced pressure to obtain (2S, 4S)-4-((6-chloro-8 -Fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl) (Oxy)-1-methylpyrrolidin-2-yl)methanol (107 mg, crude product), used directly in the next step. ES-API: [M+H] + =566.2.
步骤四：将(2S，4S)-4-((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基)氧基)-1-甲基吡咯烷-2-基)甲醇(107mg,0.19mmol)溶解在二氯甲烷中，冰水浴条件下，滴加三乙胺(57mg,0.57mmol)和丙烯酸酐(19mg,0.15mmol)，冰浴条件下搅拌10分钟。反应结束后，加入30ml DCM,依次用水(20ml)和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经过制备HPLC纯化，得到1-(7-(6-氯-8-氟-2-((((3S，5S)-5-(羟甲基)-1-甲基吡咯烷-3-基)氧基])-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(22mg,Y20％)，ES-API:[M+H] +＝620.2。 Step 4: Add (2S, 4S)-4-((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diaza Spiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)-1-methylpyrrolidin-2-yl)methanol (107mg, 0.19mmol) dissolved in dichloromethane, ice-water bath Under conditions, triethylamine (57mg, 0.57mmol) and acrylic anhydride (19mg, 0.15mmol) were added dropwise, and stirred for 10 minutes under ice bath conditions. After the reaction, 30ml DCM was added, washed with water (20ml) and saturated brine successively, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to obtain 1-(7-(6-chloro-8-fluoro-2-( (((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy))-7-(5-methyl-1H-indazol-4-yl)quine Azolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (22mg, Y20%), ES-API: [M+H ] + = 620.2.
步骤五：将1-(7-(6-氯-8-氟-2-((((3S，5S)-5-(羟甲基)-1-甲基吡咯烷-3-基)氧基])-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(17mg)经手性柱拆分得到化合物Z35-1(3.8mg)和化合物Z35-2(8.9mg)。拆分条件：柱型：Chiralpak IB250mm*4.6mm 5um；流动相：Hex:EtOH:氨甲醇＝70:30:0.2，流速：1ml/min；T＝30min。Step 5: Add 1-(7-(6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy ])-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)propan-2 -En-1-one (17mg) was resolved by chiral column to obtain compound Z35-1 (3.8mg) and compound Z35-2 (8.9mg). Resolution conditions: column type: Chiralpak IB250mm*4.6mm 5um; mobile phase: Hex: EtOH: ammonia methanol=70:30:0.2, flow rate: 1ml/min; T=30min.
实施例36：1-(7-(6-氯-8-氟-2-((((3S，5S)-5-(羟甲基)-1-甲基吡咯烷-3-基)氧基])-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 36: 1-(7-(6-chloro-8-fluoro-2-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl)oxy ])-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)propan-2 -En-1-one synthesis
Figure PCTCN2020077192-appb-000084
Figure PCTCN2020077192-appb-000084
步骤一：将(2S，4R)-1-叔丁基-2-甲基-4-羟基吡咯烷-1,2-二甲酸酯(5.0g,20.4mmoL)溶解在60mL THF，冰浴冷却至0℃，缓慢分批加入LiAlH 4(5.03g,132mmol)，升至室温，搅拌过夜。反应完全后，依次加入6ml H 2O、6ml NaOH(15％)和18ml H 2O，搅拌至白色砂状固体析出，过滤，用DCM/i-PrOH(3/1)冲洗，收集母液，浓缩，反相柱纯化得到(3R,5S)-5-(羟甲基)-1-甲基吡咯烷-3-醇(2.5g,Y93％)。ES-API:[M+H] +＝132.1。 Step 1: Dissolve (2S, 4R)-1-tert-butyl-2-methyl-4-hydroxypyrrolidine-1,2-dicarboxylate (5.0g, 20.4mmoL) in 60mL THF and cool in an ice bath To 0°C, slowly add LiAlH 4 (5.03 g, 132 mmol) in batches, warm to room temperature, and stir overnight. After the reaction is complete, add 6ml H 2 O, 6ml NaOH (15%) and 18ml H 2 O successively, stir until a white sandy solid precipitates, filter, rinse with DCM/i-PrOH (3/1), collect the mother liquor, and concentrate , Reversed-phase column purification to obtain (3R,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-ol (2.5g, Y93%). ES-API: [M+H] + = 132.1.
步骤二：将7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.58g,12.01mmoL)和(3R,5S)-5-(羟甲基)-1-甲基吡咯烷-3-醇(2.5g,4.81mmoL)溶解在20mL DMF和20mL THF混合液中，加入三乙烯二胺(270mg,2.4mmoL)和Cs 2CO 3(3.9g,12.01mmoL)，加热至50℃反应26小时后，冷却至室温，加入100ml乙酸乙酯，水洗(3x30ml)，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，经柱色谱纯化，得到7-(7-溴-6-氯-8-氟-2-((((2S，4R)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(800mg,27％)。ES-API:[M+H] +＝614.0。 Step 2: Add 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (1.58g, 12.01mmoL) and (3R,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-ol (2.5g, 4.81mmoL) were dissolved in a mixture of 20mL DMF and 20mL THF , Add triethylenediamine (270mg, 2.4mmoL) and Cs 2 CO 3 (3.9g, 12.01mmoL), heat to 50℃ for 26 hours, cool to room temperature, add 100ml ethyl acetate, wash with water (3x30ml), saturated Washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 7-(7-bromo-6-chloro-8-fluoro-2-((((2S, 4R)-4- Hydroxy-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (800mg, 27%).ES-API: [M+H] + =614.0.
步骤三：将7-(7-溴-6-氯-8-氟-2-((((2S，4R)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(700mg,1.14mmoL)、(5-甲基-1H-吲唑-4-基)硼酸(300mg,1.71mmoL)、氯(2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯基)(2’-氨基-1,1’-联苯-2-基)钯(II)(82mg,0.11mmoL)、2-二环己基膦基-2′,6′-二甲氧基联苯(93mg,0.22mmoL)和K 3PO 4(604mg,2.85mmoL)加入到1,4-二氧六环(8mL)和水(1mL)混合液中，氮气置换3次，微波加热到120℃，搅拌0.5h，反应完毕，冷却至室温，过滤，浓缩，加入100ml乙酸乙酯，依次用水(50ml)和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析(甲醇/二氯甲烷：0～10％)得到7-(6-氯-8-氟-2-((((2S，4R)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(110mg,Y：30％)，ES-API:[M+H] +＝666.2。 Step 3: Add 7-(7-bromo-6-chloro-8-fluoro-2-((((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)quine Oxazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (700mg, 1.14mmoL), (5-methyl-1H-indazol-4-yl) ) Boric acid (300mg, 1.71mmoL), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2'-amino-1,1'- Biphenyl-2-yl)palladium(II) (82mg, 0.11mmoL), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (93mg, 0.22mmoL) and K 3 PO 4 ( 604mg, 2.85mmoL) was added to the mixture of 1,4-dioxane (8mL) and water (1mL), replaced with nitrogen three times, heated to 120℃ in microwave, stirred for 0.5h, after the reaction was completed, cooled to room temperature, filtered Concentrate, add 100ml ethyl acetate, wash with water (50ml) and saturated brine successively, dry with anhydrous sodium sulfate, concentrate, column chromatography (methanol/dichloromethane: 0-10%) to obtain 7-(6-chloro -8-Fluoro-2-((((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(5-methyl-1H-indazole-4 -Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (110mg, Y: 30%), ES-API: [M+H ] + =666.2.
步骤四：将7-(6-氯-8-氟-2-((((2S,4R)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(110mg,0.165mmoL)溶解在4ml二氯甲烷中，室温条件下，缓慢滴加2ml三氟乙酸，反应2小时后，加入10ml二氯甲烷，减压浓缩，得到(3R,5S)-5-((((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基-2-羟甲基)-1-甲基吡咯烷-4-醇(93mg,粗品)，直接用于下一步。 ES-API:[M+H] +＝566.2。 Step 4: Add 7-(6-chloro-8-fluoro-2-((((2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl)methoxy)-7-(5 -Methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (110mg, 0.165mmoL) dissolved In 4ml of dichloromethane, 2ml of trifluoroacetic acid was slowly added dropwise at room temperature. After reaction for 2 hours, 10ml of dichloromethane was added and concentrated under reduced pressure to obtain (3R,5S)-5-((((6-chloro -8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazoline-2- 2-hydroxymethyl)-1-methylpyrrolidin-4-ol (93 mg, crude product), used directly in the next step. ES-API: [M+H] + =566.2.
步骤五：将(3R,5S)-5-((((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基-2-羟甲基)-1-甲基吡咯烷-4-醇(120mg,0.212mmol)溶解在二氯甲烷中，冰水浴条件下，滴加三乙胺(64.2mg,0.636mmol)和丙烯酸酐(21mg,0.17mmol)，冰浴条件下搅拌10分钟。反应结束后，加入100ml DCM,依次用水(50ml)和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经过制备HPLC纯化，得到1-(7-(6-氯-8-氟-2-((((2S，4R)-4-羟基-1-甲基吡咯烷-2-基)甲氧基)-7-(5-甲基-1H-吲唑-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙烯-2-酮(30mg,Y：30％)，ES-API:[M+H] +＝620.2。 Step 5: Add (3R,5S)-5-((((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-4-(2,7-two Azaspiro[3.5]nonane-7-yl)quinazolin-2-yl-2-hydroxymethyl)-1-methylpyrrolidin-4-ol (120mg, 0.212mmol) dissolved in dichloromethane Under ice-water bath conditions, add triethylamine (64.2mg, 0.636mmol) and acrylic anhydride (21mg, 0.17mmol) dropwise, and stir under ice-bath conditions for 10 minutes. After the reaction is over, add 100ml DCM, followed by water (50ml) and Washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to obtain 1-(7-(6-chloro-8-fluoro-2-((((2S, 4R)-4-hydroxy-1- Methylpyrrolidin-2-yl)methoxy)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,7-diazaspiro(3.5 ]Nonane-2-yl)propene-2-one (30 mg, Y: 30%), ES-API: [M+H] + = 620.2.
实施例37：1-(7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 37: 1-(7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)pyridine Synthesis of and [2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000085
Figure PCTCN2020077192-appb-000085
步骤一：向25mL微波反应管加入6,7-二氯吡啶并[2,3-d]嘧啶-2,4-二醇(1g,4.31mmol)、(2-氟-6-甲氧基苯基)硼酸(1.1g,6.46mmol)、Pd(dppf)Cl 2(457mg,0.56mmol)、K 2CO 3(1.189g,8.62mmol)、14mL 1,4-二氧六环，2.5mL水，氮气置换保护，100℃反应1小时。冷却至室温，加入30mL乙酸乙酯和30mL水，萃取，有机层浓缩后过柱纯化得到6-氯-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶-2,4-二醇(750mg,Y:54％)。ES-API:[M+H] +＝322.0。 Step 1: Add 6,7-dichloropyrido[2,3-d]pyrimidine-2,4-diol (1g, 4.31mmol), (2-fluoro-6-methoxybenzene) to a 25mL microwave reaction tube Base) Boric acid (1.1g, 6.46mmol), Pd(dppf)Cl 2 (457mg, 0.56mmol), K 2 CO 3 (1.189g, 8.62mmol), 14mL 1,4-dioxane, 2.5mL water, Under nitrogen replacement protection, react at 100°C for 1 hour. Cool to room temperature, add 30mL ethyl acetate and 30mL water, extract, concentrate the organic layer and purify by column to obtain 6-chloro-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d ] Pyrimidine-2,4-diol (750 mg, Y: 54%). ES-API: [M+H] + = 322.0.
步骤二：向100mL圆底烧瓶中加入6-氯-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶-2,4-二醇(400mg,1.24mmol)、10mL POCl 3，80℃搅拌0.5小时。加入15mL甲苯，逐滴加入10mL DIPEA，80～90℃搅拌2小时。浓缩除去溶剂，加入30mL乙酸乙酯和30mL冰水，萃取，有机层干燥后浓缩，过柱纯化得到2,4,6-三氯-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶(50mg,Y:11.2％)。ES-API:[M+H] +＝360.0。 Step 2: Add 6-chloro-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d]pyrimidine-2,4-diol (400mg, 1.24) to a 100mL round bottom flask mmol), 10 mL POCl 3 , and stirring at 80°C for 0.5 hour. Add 15 mL of toluene, add 10 mL of DIPEA dropwise, and stir at 80-90°C for 2 hours. Concentrate to remove the solvent, add 30mL ethyl acetate and 30mL ice water, extract, dry the organic layer, concentrate, and purify by column to obtain 2,4,6-trichloro-7-(2-fluoro-6-methoxyphenyl) Pyrido[2,3-d]pyrimidine (50 mg, Y: 11.2%). ES-API: [M+H] + = 360.0.
步骤三：向50mL圆底烧瓶中加入2,4,6-三氯-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶(50mg,0.139mmol)、2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(31mg,0.139mmol)、5mL 1,4-二氧六环、TEA(42mg,0.417mmol)，室温反应1小时。加入20mL乙酸乙酯和20mL水，萃取，有机层干燥后浓缩得到7-(2,6-二氯-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(76mg)粗品，直接用于下一步反应。ES-API:[M+H] +＝548.2。 Step 3: Add 2,4,6-trichloro-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d]pyrimidine (50mg, 0.139mmol) into a 50mL round bottom flask , 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (31mg, 0.139mmol), 5mL 1,4-dioxane, TEA (42mg, 0.417mmol), reaction at room temperature 1 hour. Add 20mL ethyl acetate and 20mL water, extract, dry the organic layer and concentrate to obtain 7-(2,6-dichloro-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d ]Pyrimidine-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (76mg) crude product, directly used in the next reaction. ES-API: [M+H] + = 548.2.
步骤四：向50mL圆底烧瓶中加入7-(2,6-二氯-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(76mg,0.139mmol)、N,N-二甲基氮杂环丁烷 -3-胺二盐酸盐(31mg,0.18mmol)，5mL 1,4-二氧六环、DIPEA(89mg,0.695mmol)，60℃反应2小时。加入20mL乙酸乙酯和20mL水，萃取，有机层干燥后浓缩得7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶-4-基-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(70mg)粗品，直接用于下一步反应。ES-API:[M+H] +＝612.3。 Step 4: Add 7-(2,6-dichloro-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d]pyrimidin-4-yl) into a 50mL round bottom flask -2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (76mg, 0.139mmol), N,N-dimethylazetidine-3-amine dihydrochloride ( 31 mg, 0.18 mmol), 5 mL of 1,4-dioxane, DIPEA (89 mg, 0.695 mmol), and react at 60°C for 2 hours. Add 20mL ethyl acetate and 20mL water, extract, dry the organic layer and concentrate to obtain 7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(2 -Fluoro-6-methoxyphenyl)pyrido[2,3-d]pyrimidin-4-yl-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (70mg) The crude product was directly used in the next reaction. ES-API: [M+H] + = 612.3.
步骤五：向50mL圆底烧瓶中加入7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶-4-基-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(30mg,0.048mmol)、3mL甲醇、4M HCl/二氧六环(3mL,12mmol)，室温反应1.5小时。浓缩除去溶剂得到1-(6-氯-7-(2-氟-6-甲氧基苯基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶基[2,3-d]嘧啶-2-基–N,N-二甲基氮杂环丁烷-3-胺粗品，直接用于下一步反应。ES-API:[M+H] +＝512.2 Step 5: Add 7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(2-fluoro-6-methoxy) into a 50mL round bottom flask Phenyl)pyrido[2,3-d]pyrimidin-4-yl-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (30mg, 0.048mmol), 3mL methanol, 4M HCl/dioxane (3mL, 12mmol), react at room temperature for 1.5 hours. Concentrate to remove the solvent to obtain 1-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-(2, 7-diazaspiro[3.5]nonane-7-yl)pyridyl[2,3-d]pyrimidin-2-yl–N,N-dimethylazetidine-3-amine crude, direct Used in the next reaction. ES-API: [M+H] + = 512.2
步骤六：向上述1-(6-氯-7-(2-氟-6-甲氧基苯基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶基[2,3-d]嘧啶-2-基–N,N-二甲基氮杂环丁烷-3-胺粗品中加入3mL DCM、TEA(15mg,0.15mmol)，置于冰水浴下冷却，加入丙烯酸酐(6mg,0.048mmol)，反应1小时。加入5mL DCM、5mL水、2mL饱和碳酸氢钠，萃取，有机层干燥后浓缩得到1-(7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮粗品，直接用于下一步反应。ES-API:[M+H] +＝566.2 Step 6: To the above 1-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)pyridine Add 3mL DCM, TEA (15mg, 0.15mmol) to the crude product of [2,3-d]pyrimidin-2-yl-N,N-dimethylazetidine-3-amine, and cool in an ice-water bath Acrylic anhydride (6mg, 0.048mmol) was added and reacted for 1 hour. 5mL DCM, 5mL water, 2mL saturated sodium bicarbonate were added, extracted, the organic layer was dried and concentrated to obtain 1-(7-(6-chloro-2-(3 -(Dimethylamino)azetidin-1-yl)-7-(2-fluoro-6-methoxyphenyl)pyrido[2,3-d]pyrimidin-4-yl)-2 ,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one crude product, directly used in the next reaction. ES-API: [M+H] + =566.2
步骤七：向上述-(7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(2-氟-6-甲氧基苯基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮粗品中加入5mL DCM，置于冰盐浴下，加入1M BBr 3/DCM(0.5mL,0.5mmol)，-10℃～20℃反应2小时。加入20mL乙酸乙酯、10ml水、5mL饱和碳酸氢钠，萃取，有机层干燥后浓缩，制备HPLC，得到1-(7-(6-氯-2-(3-(二甲基氨基)氮杂环丁烷-1-基)-7-(2-氟-6-羟基苯基)吡啶并[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(1.81mg)。ES-API:[M+H] +＝552.2。 Step 7: To the above-(7-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-7-(2-fluoro-6-methoxyphenyl )Pyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one crude product was added with 5mL DCM, Place in an ice-salt bath, add 1M BBr 3 / DCM (0.5 mL, 0.5 mmol), and react at -10°C to 20°C for 2 hours. Add 20mL ethyl acetate, 10mL water, 5mL saturated sodium bicarbonate, extract, dry the organic layer and concentrate, prepare HPLC, obtain 1-(7-(6-chloro-2-(3-(dimethylamino)azide Cyclobutan-1-yl)-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]non Alk-2-yl)prop-2-en-1-one (1.81 mg). ES-API: [M+H] + = 552.2.
实施例39：7-(4-(2-丙烯酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)异吲哚啉-1-酮的合成Example 39: 7-(4-(2-acryloyl-2,7-diazaspiro[3.5]nonane-7-yl)-6-chloro-8-fluoro-2-(((S)- Synthesis of 1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)isoindolin-1-one
Figure PCTCN2020077192-appb-000086
Figure PCTCN2020077192-appb-000086
步骤一：2-溴-6-甲基苯甲酸甲酯(7g,31mmol)，NBS(5.75g,32.5mmol)和偶氮二异丁腈(262mg,1.6mmol)一锅加到四氯化碳溶液(100mL)中密封回流(85度)过夜后，冷却，过 滤，石油醚洗涤滤出固体。滤液浓缩，加THF(80mL)，氨水(20mL)，室温搅拌过夜后加乙酸乙酯(300mL)，水洗(50mL x 2)。乙酸乙酯相用无水硫酸钠干燥，过滤浓缩过硅胶柱(PE/EA＝1/1～1/2)得7-溴异吲哚啉-1-酮(白色固体，4.1g,Y:63％)。ES-API:[M+H] +＝212.0/214.0。 Step 1: Methyl 2-bromo-6-methylbenzoate (7g, 31mmol), NBS (5.75g, 32.5mmol) and azobisisobutyronitrile (262mg, 1.6mmol) are added to carbon tetrachloride in one pot The solution (100 mL) was sealed and refluxed (85 degrees) overnight, cooled, filtered, and washed with petroleum ether to filter out the solid. The filtrate was concentrated, THF (80 mL), ammonia water (20 mL) were added, stirred at room temperature overnight, ethyl acetate (300 mL) was added, and washed with water (50 mL x 2). The ethyl acetate phase was dried with anhydrous sodium sulfate, filtered and concentrated through a silica gel column (PE/EA=1/1～1/2) to obtain 7-bromoisoindolin-1-one (white solid, 4.1g, Y: 63%). ES-API: [M+H] + = 212.0/214.0.
步骤二：7-溴异吲哚啉-1-酮(500mg,2.4mmol),双联频哪醇硼酸酯(663mg,2.61mmol)，Pd(dppf)Cl 2(88mg,0.12mmol)和乙酸钾(480mg,4.8mmol)加到二氧六环(10mL)中，氩气保护下90度搅拌3小时，待冷却过滤。滤液浓缩得7-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)异吲哚啉-1-酮(黑色固体，700mg,Y:9％)。ES-API:[M+H] +＝260.1。 Step 2: 7-Bromoisoindolin-1-one (500mg, 2.4mmol), double pinacol borate (663mg, 2.61mmol), Pd(dppf)Cl 2 (88mg, 0.12mmol) and acetic acid Potassium (480mg, 4.8mmol) was added to dioxane (10mL), stirred at 90° under argon protection for 3 hours, and filtered after cooling. The filtrate was concentrated to obtain 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (black solid, 700mg, Y: 9%). ES-API: [M+H] + = 260.1.
步骤三：7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.04g,2mmol)，(S)-(1-甲基吡咯烷-2-基)甲醇(460mg,4mmol)，三乙烯二胺(45mg,0.4mmol)和碳酸铯(2g,6mmol)加到DMF(12mL)中，氩气保护下50度搅拌过夜。冷却后加EA(50mL)稀释溶解，水洗(20mLx3)，无水硫酸钠干燥，过滤浓缩，过硅胶柱(DCM/MeOH＝1/0～50/1)得到(S)-7-(7-溴-6-氯-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(黄色固体，560mg,Y:48％)。ES-API:[M+H] +＝598.1。 Step 3: 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.04g, 2mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (460mg, 4mmol), triethylenediamine (45mg, 0.4mmol) and cesium carbonate (2g, 6mmol) were added to In DMF (12mL), stir overnight at 50°C under argon protection. After cooling, add EA (50mL) to dilute and dissolve, wash with water (20mLx3), dry with anhydrous sodium sulfate, filter and concentrate, and pass through silica gel column (DCM/MeOH=1/0～50/1) to obtain (S)-7-(7- Bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non Tert-Butyl alkane-2-carboxylate (yellow solid, 560 mg, Y: 48%). ES-API: [M+H] + =598.1.
步骤四：(S)-7-(7-溴-6-氯-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(300mg,0.5mmol)，7-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)异吲哚啉-1-酮(194mg,0.75mmol)，Pd 2(dba) 3(46mg,0.05mmol),2-二环己基膦基-2′,6′-二甲氧基联苯(41mg,0.1mmol),Na 2CO 3(190mg,1.8mmol)加到装有二氧六环/水(4/1,5mL)的微波管(20mL)中，微波90度反应150分钟，冷却后加EA(30mL)，水洗(10mL x 1)。EA相用无水硫酸钠干燥，过滤浓缩，过硅胶柱纯化(DCM/MeOH＝100/1～30/1)得到白色固体(120mg,纯度93％)。再由pre-HPLC纯化得到7-(6-氯-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(3-氧代-2,3-二氢-1H-茚-叔丁基)哌啶-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(100mg,Y:30％)。ES-API:[M+H] +＝650.3。 Step 4: (S)-7-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)- 2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (300mg, 0.5mmol), 7-(4,4,5,5-tetramethyl-1,3,2-bis Oxyborolan-2-yl) isoindolin-1-one (194mg, 0.75mmol), Pd 2 (dba) 3 (46mg, 0.05mmol), 2-Dicyclohexylphosphino-2′,6′ -Dimethoxybiphenyl (41mg, 0.1mmol), Na 2 CO 3 (190mg, 1.8mmol) was added to a microwave tube (20mL) containing dioxane/water (4/1,5mL), microwave React at 90 degrees for 150 minutes, add EA (30 mL) after cooling, and wash with water (10 mL x 1). The EA phase was dried with anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column (DCM/MeOH=100/1-30/1) to obtain a white solid (120 mg, purity 93%). Then purified by pre-HPLC to obtain 7-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-oxo- 2,3-Dihydro-1H-indene-tert-butyl)piperidin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert Butyl ester (100mg, Y: 30%). ES-API: [M+H] + = 650.3.
步骤五：7-(6-氯-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-7-(3-氧代-2,3-二氢-1H-茚-叔丁基)哌啶-4-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(100mg,0.15mmol)溶于盐酸二氧六环(4M)和甲醇的混合液(2/2mL)中，室温搅拌1小时后旋干得到7-(6-氯-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-7-基)-2,3-二氢-1H-茚-1-酮(盐酸盐白色固体，35mg,Y:100％)。ES-API:[M+H] +＝550.2。 Step 5: 7-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(3-oxo-2,3- Dihydro-1H-indene-tert-butyl)piperidin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (100mg ,0.15mmol) was dissolved in a mixture of dioxane hydrochloride (4M) and methanol (2/2mL), stirred at room temperature for 1 hour and then spin-dried to obtain 7-(6-chloro-8-fluoro-2-((( S)-1-Methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-7-yl)-2 ,3-Dihydro-1H-inden-1-one (hydrochloride white solid, 35mg, Y: 100%). ES-API: [M+H] + =550.2.
步骤六：7-(6-氯-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-7-基)-2,3-二氢-1H-茚-1-酮盐酸盐(100mg,0.15mmol)溶于TEA(150mg)的DCM(5mL)溶液中，室温搅拌30分钟后降温到-70度滴加丙烯酰氯(30mg,0.30mmol)，继续搅拌30分钟后加甲醇(2mL)淬灭，回到室温旋干，加EA(20mL)溶解，水洗(5mL x 2)。EA相浓缩，由pre-HPLC(0.1％HCl)纯化后冻干得到7-(4-(2-丙烯酰基-2,7-二氮杂螺[3.5]壬烷-7-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)喹唑啉-7-基)异吲哚啉-1-酮(白色固体盐酸盐，35mg,Y:40％)。ES-API:[M+H] +＝605.2。 1H NMR(400MHz,DMSO-d 6)δ10.49(br,1H),8.63(s,1H),7.86(s,1H),7.76-7.71(m,2H),7.38(d,J＝6.0,1H),6.38-6.31(m,1H),m 6.12(d,J＝16.8,1H),5.69(d,J＝10.8,1H),4.70-4.69(m,2H),4.45(s,2H),4.04(s,2 H),3.72-3.69(m,3H),3.60-3.57(m,2H),3.39(s,2H),3.13-3.09(m,1H),2.93(d,J＝4.4,3H),2.27-2.25(m,1H),1.95-1.84(m,8H). Step 6: 7-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[ 3.5] Nonane-7-yl)quinazolin-7-yl)-2,3-dihydro-1H-inden-1-one hydrochloride (100mg, 0.15mmol) dissolved in TEA (150mg) in DCM ( 5mL) in the solution, stirred at room temperature for 30 minutes and then cooled to -70 degrees acryloyl chloride (30mg, 0.30mmol) dropwise add acryloyl chloride (30mg, 0.30mmol), continue to stir for 30 minutes, add methanol (2mL) to quench, return to room temperature and spin dry, add EA (20mL) Dissolve and wash with water (5mL x 2). The EA phase was concentrated, purified by pre-HPLC (0.1% HCl) and lyophilized to obtain 7-(4-(2-acryloyl-2,7-diazaspiro[3.5]nonane-7-yl)-6- Chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)isoindolin-1-one (white solid hydrochloric acid Salt, 35mg, Y: 40%). ES-API: [M+H] + = 605.2. 1 H NMR(400MHz,DMSO-d 6 )δ10.49(br,1H),8.63(s,1H),7.86(s,1H),7.76-7.71(m,2H),7.38(d,J=6.0 ,1H),6.38-6.31(m,1H),m 6.12(d,J=16.8,1H), 5.69(d,J=10.8,1H), 4.70-4.69(m,2H), 4.45(s,2H ),4.04(s,2 H),3.72-3.69(m,3H), 3.60-3.57(m,2H), 3.39(s,2H),3.13-3.09(m,1H), 2.93(d,J= 4.4, 3H), 2.27-2.25 (m, 1H), 1.95-1.84 (m, 8H).
实施例40：1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(喹脲-3-氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 40: 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(quinurea-3-oxy)quinazoline -4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000087
Figure PCTCN2020077192-appb-000087
步骤一：7-(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(300mg,0.576mmol)，奎宁基-3-醇(225mg,1.73mmol)，碳酸铯(570mg,1.73mmol)和1,4-二氮杂二环[2.2.2]辛烷(15mg,0.116mmol)加入无水干燥的四氢呋喃(5.0mL)和N,N-二甲基甲酰胺(5.0mL)中。反应液60度下搅拌16小时。然后降至室温并且倒入冰水中，用乙酸乙酯萃取三次(10.0mLx3)，合并有机相。有机相依次用水，饱和食盐水洗涤，然后用无水硫酸钠干燥。然后在真空下浓缩得到黄色固体粗产品7-(7-溴-6-氯-8-氟-2-(喹脲-3-氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬烷-2-羧酸叔丁酯(352mg,Y:100％)。ES-API:[M+H] +＝610.2，612.2。 Step 1: 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (300mg, 0.576mmol), quininyl-3-ol (225mg, 1.73mmol), cesium carbonate (570mg, 1.73mmol) and 1,4-diazabicyclo[2.2.2]octane (15mg, 0.116 mmol) was added to dry tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL). The reaction solution was stirred at 60 degrees for 16 hours. Then it was cooled to room temperature and poured into ice water, extracted three times with ethyl acetate (10.0 mL×3), and the organic phases were combined. The organic phase was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. Then concentrated under vacuum to obtain the crude product 7-(7-bromo-6-chloro-8-fluoro-2-(quinurea-3-oxy)quinazolin-4-yl)-2,7-two as a yellow solid Azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (352mg, Y: 100%). ES-API: [M+H] + = 610.2, 612.2.
步骤二：7-(7-溴-6-氯-8-氟-2-(喹脲-3-氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬烷-2-羧酸叔丁酯(352mg,0.576mmol，粗品)，(5-甲基-1H-吲唑-4-基)硼酸(160mg,0.864mmol)，碳酸钠(130mg,1.16mmol)，三(二亚苄基丙酮)二钯(30mg,0.029mmol)和2-双环己基膦-2',6'-二甲氧基联苯(29mg,0.058mmol)加入二氧六环(2.0mL)和水(2.0mL)中，氩气置换三到五次。然后反应液在微波中加热100度，搅拌90分钟。反应降至室温，过滤，滤液用乙酸乙酯萃取三次(10.0mLx3)，合并有机相。有机相依次用水，饱和食盐水洗涤，然后用无水硫酸钠干燥。所得粗品纯化得到白色固体7-(6-氯-8-氟-7-(4-甲基-1H-吲唑-3-基)-2-(喹脲-3-氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬烷-2-羧酸叔丁酯(150mg,Y:40％)。ES-API:[M+H] +＝662.3。 Step 2: 7-(7-bromo-6-chloro-8-fluoro-2-(quinurea-3-oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non Tert-butyl alkane-2-carboxylate (352mg, 0.576mmol, crude product), (5-methyl-1H-indazol-4-yl)boronic acid (160mg, 0.864mmol), sodium carbonate (130mg, 1.16mmol), Tris(dibenzylideneacetone)dipalladium (30mg, 0.029mmol) and 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl (29mg, 0.058mmol) add dioxane (2.0mL) In water (2.0 mL), replace with argon three to five times. Then the reaction solution was heated at 100 degrees in the microwave and stirred for 90 minutes. The reaction was cooled to room temperature, filtered, and the filtrate was extracted three times with ethyl acetate (10.0 mL×3), and the organic phases were combined. The organic phase was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The resulting crude product was purified to obtain a white solid 7-(6-chloro-8-fluoro-7-(4-methyl-1H-indazol-3-yl)-2-(quinurea-3-oxy)quinazoline- 4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150 mg, Y: 40%). ES-API: [M+H] + = 662.3.
步骤三:7-(6-氯-8-氟-7-(4-甲基-1H-吲唑-3-基)-2-(喹脲-3-氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬烷-2-羧酸叔丁酯(150mg,0.23mmol)和盐酸二氧六环(10.0mL)加入到甲醇(10mL)中，反应液25度反应2小时；反应液浓缩得到黄色固体为3-((6-氯-8-氟-7-(5-甲基-1H-吲哚唑-4-基)-4-(2,7-二氮螺环[3.5]壬烷-7-基)喹唑啉-2-基)氧基)喹唑啶(127mg,Y:90％)。ES-API:[M+H] +＝562.2。 Step 3: 7-(6-chloro-8-fluoro-7-(4-methyl-1H-indazol-3-yl)-2-(quinurea-3-oxy)quinazolin-4-yl )-2,7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (150mg, 0.23mmol) and dioxane hydrochloride (10.0mL) were added to methanol (10mL), reaction solution 25 The reaction time was 2 hours; the reaction solution was concentrated to obtain a yellow solid as 3-((6-chloro-8-fluoro-7-(5-methyl-1H-indolazol-4-yl)-4-(2,7- Diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)quinazolidine (127 mg, Y: 90%). ES-API: [M+H] + =562.2.
步骤四:3-((6-氯-8-氟-7-(5-甲基-1H-吲哚唑-4-基)-4-(2,7-二氮螺环[3.5]壬烷-7-基)喹唑 啉-2-基)氧基)喹唑啶(127mg,0.21mmol)加入二氯甲烷(5.0mL)中，然后加N,N-二异丙基乙胺直至反应液呈现弱碱性(pH＝6～7)。然后在零下70度缓慢加入丙烯酰氯(19mg,0.21mmol)的二氯甲烷溶液。反应液在零下70度下搅拌30分钟后，加入甲醇淬灭反应。反应液升到25度，浓缩。所得物用反相制备得到白色固体为1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(喹脲-3-氧基)喹唑啉-4-基)-2,7-二氮螺环[3.5]壬烷-2-基)丙-2-烯-1-酮(2.5mg,Y:2％)。ES-API:[M+H] +＝616.3。 1H NMR(400MHz,DMSO-d 6)δ13.1(br,1H),δ7.90(s,1H),δ7.56,(m,2H),δ7.39(d,J＝8.0Hz,1H),δ6.38(m,1H),δ6.14(m,1H),δ5.70(m,1H),δ5.00(m,1H),δ4.00(m,4H),δ3.93(m,3H),δ3.75(m,4H),δ2.67(m,3H),δ2.15(m,3H),δ1.95(m,4H),δ1.66(s,1H),δ1.57(m,1H),δ1.40(s,2H),δ1.53(m,1H). Step 4: 3-((6-chloro-8-fluoro-7-(5-methyl-1H-indolazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane -7-yl)quinazolin-2-yl)oxy)quinazolidine (127mg, 0.21mmol) was added to dichloromethane (5.0mL), and then N,N-diisopropylethylamine was added until the reaction solution It is slightly alkaline (pH=6～7). Then slowly add acryloyl chloride (19mg, 0.21mmol) in dichloromethane at minus 70 degrees. After the reaction solution was stirred at minus 70 degrees for 30 minutes, methanol was added to quench the reaction. The reaction solution was raised to 25 degrees and concentrated. The resultant was prepared by reverse phase to obtain a white solid as 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(quinurea-3- (Oxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (2.5 mg, Y: 2%). ES-API: [M+H] + = 616.3. 1 H NMR(400MHz,DMSO-d 6 )δ13.1(br,1H),δ7.90(s,1H),δ7.56,(m,2H),δ7.39(d,J=8.0Hz, 1H), δ6.38(m,1H), δ6.14(m,1H), δ5.70(m,1H), δ5.00(m,1H), δ4.00(m,4H), δ3. 93(m,3H),δ3.75(m,4H),δ2.67(m,3H),δ2.15(m,3H),δ1.95(m,4H),δ1.66(s,1H ), δ1.57(m,1H), δ1.40(s,2H), δ1.53(m,1H).
实施例41:1-(7-(6-氯-7-(3,5-二甲基-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶基[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 41: 1-(7-(6-Chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-2-(3-(dimethylamino)azetidin Alk-1-yl)pyridyl(2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one synthesis
Figure PCTCN2020077192-appb-000088
Figure PCTCN2020077192-appb-000088
步骤一:将6,7-二氯吡啶并[2,3-d]嘧啶-2,4-二醇(0.3g,1.29mmoL)、(3,5-二甲基-1-甲苯基-1H-吲唑-4-基)硼酸(0.53g,1.55mmoL)、氯(2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯基)(2’-氨基-1,1’-联苯-2-基)钯(II)(93mg,0.129mmoL)、2-二环己基膦基-2′,6′-二甲氧基联苯(53mg,0.129mmoL)和K 3PO 4(820mg,3.87mmoL)加入到1,4-二氧六环(10mL)和水(1mL)混合液中，氮气置换3次，加热到110℃，搅拌1.5小时，反应完毕，冷却至室温，过滤，浓缩，加入100ml乙酸乙酯，依次用水(3x50ml)和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析得到6-氯-7-(3,5-二甲基-1-甲苯基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-2,4-二醇(70mg,Y11％)。ES-API:[M+H] +＝496.1。 Step 1: Add 6,7-dichloropyrido[2,3-d]pyrimidine-2,4-diol (0.3g, 1.29mmoL), (3,5-dimethyl-1-tolyl-1H -Indazol-4-yl)boronic acid (0.53g, 1.55mmoL), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (93mg, 0.129mmoL), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (53mg, 0.129 mmoL) and K 3 PO 4 (820mg, 3.87mmoL) were added to the mixture of 1,4-dioxane (10mL) and water (1mL), replaced with nitrogen three times, heated to 110℃, stirred for 1.5 hours, and reacted When finished, cool to room temperature, filter, concentrate, add 100ml ethyl acetate, wash with water (3x50ml) and saturated brine successively, dry with anhydrous sodium sulfate, concentrate, column chromatography to obtain 6-chloro-7-(3,5- Dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4-diol (70mg, Y11%). ES-API: [M+H] + =496.1.
步骤二:将6-氯-7-(3,5-二甲基-1-甲苯基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-2,4-二醇(70mg,0.141mmoL)溶解在3ml甲苯中，室温条件下，缓慢滴加3ml三氯氧磷和3ml二异丙基乙胺，加热到110℃反应2小时后，减压浓缩，柱层析得到2,4,6-三氯-7-(3,5-二甲基-1-甲苯基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶(45mg,Y:60％)。ES-API:[M+H] +＝532.0。 Step 2: Add 6-chloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4-diol (70mg, 0.141mmoL) dissolved in 3ml of toluene, slowly dripped 3ml of phosphorus oxychloride and 3ml of diisopropylethylamine at room temperature, heated to 110℃ for 2 hours, concentrated under reduced pressure, and obtained by column chromatography 2,4,6-Trichloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine (45mg, Y: 60 %). ES-API: [M+H] + =532.0.
步骤三:将2,4,6-三氯-7-(3,5-二甲基-1-甲苯基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶(45mg,0.084mmol)溶解在3ml二氯甲烷中，冰水浴条件下，滴加三乙胺(26mg,0.254mmol)。加入2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(57mg,0.254mmol)，冰浴条件下搅拌10分钟。随后加入N,N-二甲基氮杂环丁烷-3-胺(25.4mg,0.254mmol)，40℃反应30分钟。加入10ml DCM,浓缩，经过纯化，得到7-(6-氯-7-(3,5-二甲基-1-甲苯基-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮 杂环丁烷-1-基)吡啶[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(7mg,Y:10％)，ES-API:[M+H] +＝786.3。 Step 3: Add 2,4,6-trichloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine (45mg , 0.084mmol) was dissolved in 3ml of dichloromethane, and triethylamine (26mg, 0.254mmol) was added dropwise under ice-water bath conditions. Add 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (57mg, 0.254mmol), and stir under ice bath for 10 minutes. Subsequently, N,N-dimethylazetidine-3-amine (25.4 mg, 0.254 mmol) was added and reacted at 40° C. for 30 minutes. Add 10ml DCM, concentrate and purify to obtain 7-(6-chloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)-2-(3-(two Methylamino)azetidin-1-yl)pyridine[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (7mg, Y: 10%), ES-API: [M+H] + =786.3.
步骤四:将7-(6-氯-7-(3,5-二甲基-1-甲苯基-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(7mg,0.009mmol)溶解在3ml甲醇中，加入2M氢氧化钠水溶液3ml，加热80℃反应2h，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到7-(6-氯-7-(3,5-二甲基-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(5mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝632.3。 Step 4: Add 7-(6-chloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)-2-(3-(dimethylamino)aza Cyclobutan-1-yl)pyridine[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (7mg, 0.009mmol) Dissolve in 3ml methanol, add 3ml 2M sodium hydroxide aqueous solution, heat at 80℃ to react for 2h, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain 7-(6-chloro-7-(3,5-dimethyl Yl-1H-indazol-4-yl)-2-(3-(dimethylamino)azetidin-1-yl)pyridine[2,3-d]pyrimidin-4-yl)-2, 7-Diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (5mg, crude product) was directly used in the next reaction. ES-API: [M+H] + = 632.3.
步骤五:将7-(6-氯-7-(3,5-二甲基-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(5mg,粗品)溶解在2ml二氯甲烷中，加入1ml三氟乙酸，室温反应1h，反应结束后，浓缩，得到1-(6-氯-7-(3,5-二甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶基[2,3-d]嘧啶-2-基)-N,N-二甲基氮杂环丁烷-3-胺(6mg,粗品)。ES-API:[M+H] +＝532.2。 Step 5: Add 7-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-2-(3-(dimethylamino)azetidine-1 -Yl)pyridine[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (5mg, crude product) dissolved in 2ml dichloromethane Add 1ml of trifluoroacetic acid and react at room temperature for 1h. After the reaction is over, concentrate to obtain 1-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-4-( 2,7-diazaspiro[3.5]nonane-7-yl)pyridyl[2,3-d]pyrimidin-2-yl)-N,N-dimethylazetidine-3-amine (6mg, crude product). ES-API: [M+H] + =532.2.
步骤六:将1-(6-氯-7-(3,5-二甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶基[2,3-d]嘧啶-2-基)-N，N-二甲基氮杂环丁烷-3-胺(6mg,粗品)溶解在2ml二氯甲烷中，滴加三乙胺(20mg)和丙烯酰氯(2mg)，冰浴条件下搅拌10分钟。饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经过制备HPLC纯化，得到1-(7-(6-氯-7-(3,5-二甲基-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶基[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(1.5mg,Y22％)，ES-API:[M+H] +＝586.3。 Step 6: Add 1-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7 -Yl)pyridyl[2,3-d]pyrimidin-2-yl)-N,N-dimethylazetidine-3-amine (6mg, crude product) was dissolved in 2ml of dichloromethane and added dropwise Triethylamine (20mg) and acryloyl chloride (2mg) were stirred under ice bath for 10 minutes. Wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify by preparative HPLC to obtain 1-(7-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)- 2-(3-(Dimethylamino)azetidin-1-yl)pyridyl[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane -2-yl)prop-2-en-1-one (1.5 mg, Y22%), ES-API: [M+H] + =586.3.
实施例42:1-(7-(6-氯-7-(3-氯-5-甲基-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶基[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 42: 1-(7-(6-Chloro-7-(3-chloro-5-methyl-1H-indazol-4-yl)-2-(3-(dimethylamino)azacyclo Butane-1-yl)pyridinyl[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one Synthesis
Figure PCTCN2020077192-appb-000089
Figure PCTCN2020077192-appb-000089
步骤一:将6,7-二氯吡啶并[2,3-d]嘧啶-2,4-二醇(0.3g,1.29mmoL)、(3-氯-5-甲基-1H-吲唑-4-基)硼酸(325mg,1.55mmoL)、Pd(PPh 3) 4(149mg,0.129mmoL)和K 2CO 3(820mg,3.87mmoL)加入到1,4-二氧六环(10mL)和水(1mL)混合液中，氮气置换3次，加热到110℃，搅拌1.5小时，反应完毕，冷却至室温，过滤，浓缩，加入100ml乙酸乙酯，依次用水(3x50ml)和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析得到6-氯-7-(3-氯-5-甲基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-2,4-二醇(60mg,Y13％)。ES-API:[M+H] +＝362.1。 Step 1: Add 6,7-dichloropyrido[2,3-d]pyrimidine-2,4-diol (0.3g, 1.29mmoL), (3-chloro-5-methyl-1H-indazole- 4-yl)boronic acid (325mg, 1.55mmoL), Pd(PPh 3 ) 4 (149mg, 0.129mmoL) and K 2 CO 3 (820mg, 3.87mmoL) were added to 1,4-dioxane (10mL) and water (1mL) in the mixed solution, replace with nitrogen for 3 times, heat to 110°C, stir for 1.5 hours, after the reaction is complete, cool to room temperature, filter, concentrate, add 100ml ethyl acetate, wash with water (3x50ml) and saturated brine in turn. Drying with sodium sulfate, concentration, column chromatography to obtain 6-chloro-7-(3-chloro-5-methyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4 -Diol (60mg, Y13%). ES-API: [M+H] + = 362.1.
步骤二:将6-氯-7-(3,5-二甲基-1-甲苯基-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-2,4-二醇(70mg,0.165mmoL)溶解在5ml二氯甲烷中，室温条件下，缓慢滴加对甲苯磺酸(2.8mg, 0.0165)和THP(139mg,1.65mmol)，室温反应16小时后，减压浓缩，柱层析得到6-氯-7-(3-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-2,4-二醇(44mg,Y60％)。ES-API:[M+H] +＝446.1。 Step 2: Add 6-chloro-7-(3,5-dimethyl-1-tolyl-1H-indazol-4-yl)pyrido[2,3-d]pyrimidine-2,4-diol (70mg, 0.165mmoL) was dissolved in 5ml of dichloromethane, p-toluenesulfonic acid (2.8mg, 0.0165) and THP (139mg, 1.65mmol) were slowly added dropwise at room temperature. After 16 hours of reaction at room temperature, it was concentrated under reduced pressure. Column chromatography to obtain 6-chloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrido[2, 3-d] Pyrimidine-2,4-diol (44 mg, Y60%). ES-API: [M+H] + = 446.1.
步骤三:将6-氯-7-(3-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-2,4-二醇(44mg,0.099mmol)溶解在3ml甲苯中，室温条件下，缓慢滴加3ml三氯氧磷和3ml二异丙基乙胺，加热到110℃反应2小时后，减压浓缩，柱层析得到2,4,6-三氯-7-(3-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶[2,3-d]嘧啶(28mg,Y60％)。ES-API:[M+H] +＝482.0。 Step 3: Add 6-chloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrido(2, 3-d]Pyrimidine-2,4-diol (44mg, 0.099mmol) was dissolved in 3ml of toluene. At room temperature, slowly add 3ml of phosphorus oxychloride and 3ml of diisopropylethylamine, and heat to 110℃ to react. After 2 hours, concentrate under reduced pressure and column chromatography to obtain 2,4,6-trichloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H -Indazol-4-yl)pyridine[2,3-d]pyrimidine (28mg, Y60%). ES-API: [M+H] + =482.0.
步骤四:将2,4,6-三氯-7-(3-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶[2,3-d]嘧啶(28mg,0.058mmol)溶解在3ml二氯甲烷中，冰水浴条件下，滴加三乙胺(26mg,0.254mmol)。加入2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(57mg,0.254mmol)，冰浴条件下搅拌10分钟。随后加入N，N-二甲基氮杂环丁烷-3-胺(25.4mg,0.254mmol)，40℃反应30分钟。加入10ml DCM,浓缩，经过纯化，得到7-(6-氯-7-(3-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(15mg,Y:25％)，ES-API:[M+H] +＝735.3。 Step 4: Add 2,4,6-trichloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) Pyridine[2,3-d]pyrimidine (28mg, 0.058mmol) was dissolved in 3ml of dichloromethane, and triethylamine (26mg, 0.254mmol) was added dropwise under ice-water bath conditions. Add 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (57mg, 0.254mmol), and stir under ice bath for 10 minutes. Subsequently, N,N-dimethylazetidine-3-amine (25.4 mg, 0.254 mmol) was added and reacted at 40° C. for 30 minutes. Add 10ml DCM, concentrate and purify to obtain 7-(6-chloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-yl)-2-(3-(dimethylamino)azetidin-1-yl)pyridine[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[ 3.5] Tert-butyl nonane-2-carboxylate (15 mg, Y: 25%), ES-API: [M+H] + =735.3.
步骤五:将7-(6-氯-7-(3-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(15mg,粗品)溶解在2ml二氯甲烷中，加入2ml三氟乙酸，室温反应2h，反应结束后，浓缩，得到1-(6-氯-7-(3-氯-5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶基[2,3-d]嘧啶-2-基)-N，N-二甲基氮杂环丁烷-3-胺(8mg,粗品)。ES-API:[M+H] +＝552.2。 Step 5: Add 7-(6-chloro-7-(3-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2 -(3-(Dimethylamino)azetidin-1-yl)pyridine[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2 -Tert-butyl carboxylate (15mg, crude product) was dissolved in 2ml of dichloromethane, 2ml of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2h. After the reaction, it was concentrated to obtain 1-(6-chloro-7-(3-chloro- 5-Methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)pyridyl[2,3-d]pyrimidin-2-yl ) -N,N-Dimethylazetidine-3-amine (8mg, crude). ES-API: [M+H] + = 552.2.
步骤六:将1-(6-氯-7-(3-氯-5-甲基-1H-吲唑-4-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)吡啶基[2,3-d]嘧啶-2-基)-N，N-二甲基氮杂环丁烷-3-胺(8mg,粗品)溶解在2ml二氯甲烷中，滴加三乙胺(10mg)和丙烯酰氯(2mg)，冰浴条件下搅拌10分钟。饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经过制备HPLC纯化，得到1-(7-(6-氯-7-(3-氯-5-甲基-1H-吲唑-4-基)-2-(3-(二甲基氨基)氮杂环丁烷-1-基)吡啶基[2,3-d]嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(1.3mg,Y:18％)，ES-API:[M+H] +＝606.2。 Step 6: Add 1-(6-chloro-7-(3-chloro-5-methyl-1H-indazol-4-yl)-4-(2,7-diazaspiro[3.5]nonane- 7-yl)pyridyl[2,3-d]pyrimidin-2-yl)-N,N-dimethylazetidine-3-amine (8mg, crude product) was dissolved in 2ml of dichloromethane and dropped Add triethylamine (10mg) and acryloyl chloride (2mg), and stir for 10 minutes under ice bath conditions. Wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify by preparative HPLC to obtain 1-(7-(6-chloro-7-(3-chloro-5-methyl-1H-indazol-4-yl) -2-(3-(Dimethylamino)azetidin-1-yl)pyridinyl[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]non Alk-2-yl)prop-2-en-1-one (1.3 mg, Y: 18%), ES-API: [M+H] + =606.2.
实施例43:1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(((R)-4-甲基吗啉-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 43: 1-(7-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((R)-4-methylmorpholine -3-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000090
Figure PCTCN2020077192-appb-000090
步骤一:7-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(2g,3.8mmol)，(R)-(4-甲基吗啉-3-基)甲醇(1g,7.7mmol)，1,4-二氮杂二环[2.2.2]辛烷(86mg,0.77mmol)，碳酸铯(2.5g,7.7mmol)的N,N-二甲基甲酰胺(1.5mL)和四氢呋喃(1.5mL)的混合液置于微波管中，120℃微波反应1小时。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，快速硅胶柱(甲醇/二氯甲烷，0-5％)纯化得到(R)-7-(7-溴-6-氯-8-氟-2-((4-甲基吗啉-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.25g)。ES-API:[M+H] +＝614.0。 Step 1: 7-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2g, 3.8mmol), (R)-(4-methylmorpholin-3-yl)methanol (1g, 7.7mmol), 1,4-diazabicyclo[2.2.2]octane (86mg, A mixture of 0.77 mmol), cesium carbonate (2.5 g, 7.7 mmol) in N,N-dimethylformamide (1.5 mL) and tetrahydrofuran (1.5 mL) was placed in a microwave tube and reacted in a microwave at 120°C for 1 hour. 30mL of water was added to the reaction solution, extracted 3 times with 30mL of ethyl acetate, the organic phase was dried and concentrated, and purified by rapid silica gel column (methanol/dichloromethane, 0-5%) to obtain (R)-7-(7-bromo -6-Chloro-8-fluoro-2-((4-methylmorpholin-3-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane Tert-Butyl-2-carboxylate (1.25 g). ES-API: [M+H] + = 614.0.
步骤二:向10mL微波反应管中加入(R)-7-(7-溴-6-氯-8-氟-2-((4-甲基吗啉-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1g,1.63mmol)，(5-甲基-1H-吲唑-4-基)硼酸(430mg,2.45mmol)，2-二环己基膦基-2′,6′-二甲氧基联苯(70mg,0.17mmol)，氯(2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯基)(2’-氨基-1,1’-联苯-2-基)钯(II)(120mg,0.17mmol)，磷酸钾(400mg,1.89mmol)，10mL二氧六环和2mL水。氮气保护下，120℃微波反应1小时。向反应液中加入10mL水，用10mL乙酸乙酯萃取3次，有机相干燥后浓缩，快速硅胶柱(甲醇/二氯甲烷:0～10％)纯化，得到7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((((R)-4-甲基吗啉-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(750mg)。ES-API:[M+H] +＝666.2。 Step 2: Add (R)-7-(7-bromo-6-chloro-8-fluoro-2-((4-methylmorpholin-3-yl)methoxy)quinazole to the 10mL microwave reaction tube Lin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1g, 1.63mmol), (5-methyl-1H-indazol-4-yl) Boric acid (430mg, 2.45mmol), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (70mg, 0.17mmol), Chlorine (2-Dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (120mg, 0.17mmol), potassium phosphate (400mg, 1.89 mmol), 10 mL dioxane and 2 mL water. Under nitrogen protection, microwave reaction at 120°C for 1 hour. 10mL of water was added to the reaction solution, extracted 3 times with 10mL of ethyl acetate, the organic phase was dried and concentrated, and purified by a flash silica gel column (methanol/dichloromethane: 0-10%) to obtain 7-(6-chloro-8- Fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((((R)-4-methylmorpholin-3-yl)methoxy)quinazoline-4- Yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (750 mg). ES-API: [M+H] + =666.2.
步骤三:往7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-((((R)-4-甲基吗啉-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(400mg,0.60mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸(2.5mL)。室温搅拌1小时。反应液直接旋干，得到粗品(3R)-3-((((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基))-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基)氧基)甲基)-4-甲基吗啉(350mg)。ES-API:[M+H] +＝566.2。 Step 3: To 7-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-((((R)-4-methylmorpholine-3 -Yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.60mmol) in dichloromethane (5mL) Trifluoroacetic acid (2.5 mL) was added to the solution. Stirred at room temperature for 1 hour. The reaction solution was directly spin-dried to obtain the crude product (3R)-3-((((6-chloro-8-fluoro-7-(5-methyl- 1H-indazol-4-yl))-4-(2,7-diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)methyl)-4-methyl Glymorpholine (350 mg). ES-API: [M+H] + =566.2.
步骤四:往上步得到的粗品(3R)-3-((((6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基))-4-(2,7-二氮杂螺[3.5]壬烷-7-基)喹唑啉-2-基)氧基)甲基)-4-甲基吗啉(350mg)中加入二氯甲烷(10mL)，三乙胺(300mg,2.97mmol)。溶液澄清后，冰水浴中，缓慢滴加丙烯酸酐(62mg,0.49mmol)，搅拌30分钟。向反应液中加入30mL水，用30mL乙酸乙酯萃取3次，有机相干燥后浓缩，制备HPLC纯化得到1-(7-(6-氯-8-氟-7-(5-甲基-1H-吲唑-4-基)-2-(((R)-4-甲基吗啉-3-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(180mg)。ES-API:[M+H] +＝620.2。 Step 4: The crude product (3R)-3-((((6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl))-4-(2 , 7-diazaspiro[3.5]nonane-7-yl)quinazolin-2-yl)oxy)methyl)-4-methylmorpholine (350mg) was added dichloromethane (10mL), Triethylamine (300mg, 2.97mmol). After the solution is clear, slowly add acrylic anhydride (62 mg, 0.49 mmol) dropwise in an ice-water bath, and stir for 30 minutes. 30mL of water was added to the reaction solution, extracted 3 times with 30mL of ethyl acetate, the organic phase was dried and concentrated, and purified by preparative HPLC to obtain 1-(7-(6-chloro-8-fluoro-7-(5-methyl-1H) -Indazol-4-yl)-2-(((R)-4-methylmorpholin-3-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[ 3.5] Nonan-2-yl)prop-2-en-1-one (180 mg). ES-API: [M+H] + = 620.2.
实施例44:1-(7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-((((S)-1-甲基吡咯烷-2-基)甲氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 44: 1-(7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((((S)-1-methylpyrrolidin-2-yl) (Methoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000091
Figure PCTCN2020077192-appb-000091
步骤一：向圆底烧瓶中加入7-溴-2,4-二氯-8-氟-6-碘喹唑啉(1g，2.37mmol)，2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.54g，2.37mmol)，三乙胺(0.48g，4.74mmol)和20mL二氧六环。反应在50℃下搅拌30分钟。反应结束后，减压浓缩，加入15mL冰水，用乙酸乙酯萃取(20mL×3),合并有机相，用无水硫酸钠干燥,过滤,滤液减压浓缩得到7-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.4g，收率96％)。ES-API:[M+H] +＝610.1。 Step 1: Add 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (1g, 2.37mmol), 2,7-diazaspiro[3.5]nonane to the round bottom flask Tert-Butyl-2-carboxylate (0.54 g, 2.37 mmol), triethylamine (0.48 g, 4.74 mmol) and 20 mL of dioxane. The reaction was stirred at 50°C for 30 minutes. After the reaction, concentrate under reduced pressure, add 15 mL ice water, extract with ethyl acetate (20 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 7-(7-bromo-2 -Chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.4g, yield 96%). ES-API: [M+H] + = 610.1.
步骤二：向圆底烧瓶中加入7-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.4g,2.29mmol)，(S)-(1-甲基吡咯烷-2-基)甲醇(0.79g,6.87mmol)，三乙烯二胺(0.025g,0.23mmol)，碳酸铯(2.2g,6.87mmol)，5mL干燥N，N-二甲基甲酰胺和10mL干燥四氢呋喃。反应在25℃下搅拌16小时。LCMS监测反应完毕，将反应液倾倒入约50mL冰水中，用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤。滤液浓缩。粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-4％)得到(S)-7-(7-溴-8-氟-6-碘-2-((1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.8g,收率50％)。ES-API:[M+H] +＝690.2。 Step 2: Add 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane- to the round bottom flask Tert-Butyl 2-carboxylate (1.4g, 2.29mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (0.79g, 6.87mmol), triethylenediamine (0.025g, 0.23mmol) ), cesium carbonate (2.2 g, 6.87 mmol), 5 mL dry N,N-dimethylformamide and 10 mL dry tetrahydrofuran. The reaction was stirred at 25°C for 16 hours. LCMS monitored the completion of the reaction, the reaction solution was poured into about 50 mL of ice water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-4%) to obtain (S)-7-(7-bromo-8-fluoro-6-iodo-2-((1-methylpyrrolidine-2) -Yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.8g, yield 50%). ES-API: [M+H] + =690.2.
步骤三：向圆底烧瓶中加入(S)-7-(7-溴-8-氟-6-碘-2-((1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.8g,1.16mmol)，1M的乙醇钠的乙醇溶液(1.8mL)和四氢呋喃(25mL)。反应在60℃下搅拌30分钟。LC-MS检测反应完成。反应液用1M盐酸淬灭。用乙酸乙酯萃取3次。有机相干燥后浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到(S)-7-(7-溴-8-乙氧基-6-碘-2-((1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(300mg，收率36％)。ES-API:[M+H] +＝715.2。 Step 3: Add (S)-7-(7-bromo-8-fluoro-6-iodo-2-((1-methylpyrrolidin-2-yl)methoxy)quinazoline to the round bottom flask -4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.8g, 1.16mmol), 1M sodium ethoxide in ethanol (1.8mL) and tetrahydrofuran (25mL ). The reaction was stirred at 60°C for 30 minutes. LC-MS detects that the reaction is complete. The reaction solution was quenched with 1M hydrochloric acid. Extract 3 times with ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-8%) to obtain (S)-7-(7-bromo-8-ethoxy-6-iodo-2-(( 1-Methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (300mg, yield 36%). ES-API: [M+H] + = 715.2.
步骤四：向反应瓶中加入(S)-7-(7-溴-8-乙氧基-6-碘-2-((1-甲基吡咯烷-2-基)甲氧基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(250mg，0.35mmol)、乙烯基氟硼酸钾(75mg，0.56mmol)、Pd(dppf)Cl 2-DCM(28mg，0.035mmol)、磷酸钾(223mg，1.05mmol)，8mL二氧六环和2mL水。反应在氮气保护，80℃条件下搅拌2小时，停止反应。向反应液中加入20mL水，用20mL乙酸乙酯萃取3次，有机相干燥后浓缩。粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-10％)得到(S)-7-(7-溴-8-乙氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(120mg，56％)，黄色固体。ES-API:[M+H] +＝616.2。 Step 4: Add (S)-7-(7-bromo-8-ethoxy-6-iodo-2-((1-methylpyrrolidin-2-yl)methoxy)quinazole to the reaction flask Lin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (250mg, 0.35mmol), potassium vinyl fluoroborate (75mg, 0.56mmol), Pd(dppf ) Cl 2 -DCM (28 mg, 0.035 mmol), potassium phosphate (223 mg, 1.05 mmol), 8 mL dioxane and 2 mL water. The reaction was protected by nitrogen and stirred at 80°C for 2 hours to stop the reaction. 20 mL of water was added to the reaction solution, extracted with 20 mL of ethyl acetate three times, and the organic phase was dried and concentrated. The crude product was purified by a flash silica gel column (methanol/dichloromethane: 0-10%) to obtain (S)-7-(7-bromo-8-ethoxy-2-((1-methylpyrrolidin-2-yl) )Methoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (120 mg, 56%), yellow solid. ES-API: [M+H] + = 616.2.
步骤五：向反应瓶中加入(S)-7-(7-溴-8-乙氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-6-乙烯 基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(90mg，0.15mmol)、(2-氟-6-羟基苯基)硼酸(68mg，0.44mmol)、氯(2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯基)(2’-氨基-1,1’-联苯-2-基)钯(II)(11mg，0.015mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯(6mg，0.015mmol)、磷酸钾(93mg，0.44mmol)，5mL二氧六环和1mL水。反应在氮气保护，90℃条件下搅拌1小时，停止反应。向反应液中加入20mL水，用20mL乙酸乙酯萃取3次，有机相干燥后浓缩。粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-8％)得到7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-((((S)-1-甲基吡咯烷-2-基)甲氧基)-6-乙烯基喹唑啉-4-基]-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(80mg，82％)，黄色固体。ES-API:[M+H] +＝648.3。 Step 5: Add (S)-7-(7-bromo-8-ethoxy-2-((1-methylpyrrolidin-2-yl)methoxy)-6-vinylquine to the reaction flask (Azolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (90mg, 0.15mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (68mg , 0.44mmol), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2 -Base) palladium(II) (11mg, 0.015mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (6mg, 0.015mmol), potassium phosphate (93mg, 0.44mmol), 5mL dioxane and 1mL water. The reaction was protected by nitrogen and stirred at 90°C for 1 hour to stop the reaction. 20 mL of water was added to the reaction solution, extracted with 20 mL of ethyl acetate three times, and the organic phase was dried and concentrated. The crude product was purified with a flash silica gel column (methanol/dichloromethane: 0-8%) to obtain 7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-(((((S)) -1-Methylpyrrolidin-2-yl)methoxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (80 mg, 82%), yellow solid. ES-API: [M+H] + =648.3.
步骤六：向圆底烧瓶中加入7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-((((S)-1-甲基吡咯烷-2-基)甲氧基)-6-乙烯基喹唑啉-4-基]-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(80mg，0.12mmol)、1mL甲醇和4M氯化氢/二氧六环溶液(1mL)。室温搅拌1小时，LC-MS检测反应完毕。反应液浓缩，得到粗产品2-(8-乙氧基-2-((((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)-6-乙烯基喹唑啉-7-基)-3-氟苯酚(67mg,收率100％)，黄色固体。ES-API:[M+H] +＝548.3。 Step 6: Add 7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-((((S)-1-methylpyrrolidine-2- Yl)methoxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (80mg, 0.12mmol), 1mL methanol And 4M hydrogen chloride/dioxane solution (1mL). Stir at room temperature for 1 hour, LC-MS detected the completion of the reaction. The reaction solution was concentrated to obtain the crude product 2-(8-ethoxy-2-(((((S)- 1-Methylpyrrolidin-2-yl)methoxy)-4-(2,7-diazaspiro[3.5]nonane-7-yl)-6-vinylquinazolin-7-yl) -3-fluorophenol (67mg, yield 100%), yellow solid. ES-API: [M+H] + =548.3.
步骤七：向圆底烧瓶中加入2-(8-乙氧基-2-((((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)-6-乙烯基喹唑啉-7-基)-3-氟苯酚(67mg，0.12mmol)，5mL二氯甲烷和三乙胺(71mg，0.7mmol)。将反应冷至0℃，向反应液中滴加丙烯酸酐的二氯甲烷溶液(12mg，0.1mmol,0.5mL)。反应在0℃搅拌10分钟。向反应液中加入40mL饱和碳酸氢钠水溶液，用20mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用制备HPLC纯化得到1-(7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-((((S)-1-甲基吡咯烷-2-基)甲氧基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(25.98mg，收率36％)，白色固体。ES-API:[M+H] +＝602.2。 1HNMR(400MHz,CDCl 3)7.84(s,1H),7.31-7.26(m,1H),6.91-6.80(m,1H),6.77-6.75(m,1H),6.50-6.20(m,3H),5.72-5.58(m,2H),5.21-5.18(m,1H),4.59-4.40(m,3H),4.10-4.09(m,1H),4.02(s,2H),3.91(s,2H),3.80-3.62(m,4H),3.15-3.14(m,1H),2.81-2.78(m,1H),2.54(s,3H),2.34-2.30(m,1H),2.05-1.79(m,8H),1.10(t,J＝6.8Hz,3H). Step 7: Add 2-(8-ethoxy-2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(2,7- Diazaspiro[3.5]nonane-7-yl)-6-vinylquinazolin-7-yl)-3-fluorophenol (67mg, 0.12mmol), 5mL dichloromethane and triethylamine (71mg, 0.7mmol). The reaction was cooled to 0°C, and a dichloromethane solution of acrylic anhydride (12mg, 0.1mmol, 0.5mL) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 10 minutes. 40mL saturated carbonic acid was added to the reaction solution The aqueous sodium hydrogen solution was extracted 3 times with 20 mL of dichloromethane. The organic phase was dried and concentrated, and the crude product was purified by preparative HPLC to obtain 1-(7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)) -2-((((S)-1-Methylpyrrolidin-2-yl)methoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5] Nonane-2-yl)prop-2-en-1-one (25.98mg, yield 36%), white solid. ES-API: [M+H] + = 602.2. 1 HNMR (400MHz, CDCl 3 ) 7.84(s,1H),7.31-7.26(m,1H),6.91-6.80(m,1H),6.77-6.75(m,1H),6.50-6.20(m,3H),5.72-5.58(m,2H) ),5.21-5.18(m,1H),4.59-4.40(m,3H),4.10-4.09(m,1H),4.02(s,2H),3.91(s,2H),3.80-3.62(m,4H) ),3.15-3.14(m,1H),2.81-2.78(m,1H),2.54(s,3H),2.34-2.30(m,1H),2.05-1.79(m,8H),1.10(t,J =6.8Hz,3H).
实施例45:1-(7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-(4-甲基哌嗪-1-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮的合成Example 45: 1-(7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-(4-methylpiperazin-1-yl)-6-vinylquine Synthesis of oxazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one
Figure PCTCN2020077192-appb-000092
Figure PCTCN2020077192-appb-000092
步骤一：7-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(2g,3.27mmol),1-甲基哌嗪(654mg,6.54mmol)，碳酸铯(3.18mg,9.81mmol)加入到DMF(20mL)中，然后加入三乙烯二胺(73mg,0.65mmol),室温反应16小时，反应液倒入水中淬灭，乙酸乙酯萃取，粗品柱层析分离得到黄色固体7-(7-溴-8-氟-6-碘-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.4g,收率63.6％)。ES-API:[M+1] -＝675。 Step 1: 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl Ester (2g, 3.27mmol), 1-methylpiperazine (654mg, 6.54mmol), cesium carbonate (3.18mg, 9.81mmol) was added to DMF (20mL), then triethylenediamine (73mg, 0.65mmol) , React at room temperature for 16 hours, pour the reaction solution into water for quenching, extract with ethyl acetate, and separate the crude product by column chromatography to obtain a yellow solid 7-(7-bromo-8-fluoro-6-iodo-2-(4-methylpiperidine) (Azin-1-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.4g, yield 63.6%). ES-API: [M+1] - =675.
步骤二：7-(7-溴-8-氟-6-碘-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.3g,1.92mmol)，溶于乙腈(10mL)中,加入乙醇钠(130mg,1.92mmol)，加完升温80度反应2小时，反应液降至室温倒入水(20mL)中，乙酸乙酯萃取(50mL x 2)，粗品7-(7-溴-8-乙氧基-6-碘-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯直接用于下一步。(1.4g,收率100％)。ES-API:[M-55] +＝646.1。 Step 2: 7-(7-bromo-8-fluoro-6-iodo-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,7-diazaspiro[ 3.5] Nonane-2-carboxylic acid tert-butyl ester (1.3g, 1.92mmol), dissolved in acetonitrile (10mL), add sodium ethoxide (130mg, 1.92mmol), after the addition, increase the temperature to 80 degrees and react for 2 hours, the reaction liquid drops Pour into water (20mL) at room temperature, extract with ethyl acetate (50mL x 2), the crude product 7-(7-bromo-8-ethoxy-6-iodo-2-(4-methylpiperazine-1- (Yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was used directly in the next step. (1.4g, yield 100%). ES-API: [M-55] + = 646.1.
步骤三：7-(7-溴-8-乙氧基-6-碘-2-(4-甲基哌嗪-1-基)喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(1.4g,1.5mmol)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼杂环戊烷(296mg,1.92mmol)，碳酸钠(407mg,3.0mmol)，1,1'-双(二苯基膦基)二茂铁]二氯化钯(140mg)，依次加入到二氧六环(10mL)水(2mL)的混合溶剂中，氮气置换三次，35度反应1小时。反应液冷却后倒入水(100mL)中，乙酸乙酯萃取(50mL x 3)，盐水洗干燥旋干后柱层析(甲醇：二氯甲烷＝0～5％)纯化得黄色固体7-(7-溴-8-乙氧基-2-(4-甲基哌嗪-1-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(600mg,收率52％):[M+1] +＝601.1。 Step 3: 7-(7-bromo-8-ethoxy-6-iodo-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-2,7-diazepine Spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.4g, 1.5mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborole Cyclopentane (296mg, 1.92mmol), sodium carbonate (407mg, 3.0mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (140mg), were added to dioxane in sequence In the mixed solvent of ring (10 mL) and water (2 mL), replace with nitrogen three times and react at 35 degrees for 1 hour. The reaction solution was cooled and poured into water (100mL), extracted with ethyl acetate (50mL x 3), washed with brine, dried and then purified by column chromatography (methanol: dichloromethane=0~5%) to obtain a yellow solid 7-( 7-bromo-8-ethoxy-2-(4-methylpiperazin-1-yl)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non Tert-butyl alkane-2-carboxylate (600 mg, yield 52%): [M+1] + =601.1.
步骤四：7-(7-溴-8-乙氧基-2-(4-甲基哌嗪-1-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(600mg,1.0mmol)，(2-氟-6-羟基苯基)硼酸(312mg,2.0mmol)，磷酸三钾(636mg,3.0mmol)，氯(2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯基)(2’-氨基-1,1’-联苯-2-基)钯(II)(72mg)，2-二环己基膦基-2′,6′-二甲氧基联苯(82mg),依次加入到二氧六环(8mL)水(2mL)中，氮气置换三次后120度微波反应0.5小时。冷却至室温后倒入水中，乙酸乙酯萃取(50mL x 3)，盐水洗一次后伴硅胶过柱纯化(甲醇：二氯甲烷＝0～1:10)得棕色固体7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-(4-甲基哌嗪-1-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(400mg，收率63.3％)。ES-API:[M+1] +＝633.4。 Step 4: 7-(7-bromo-8-ethoxy-2-(4-methylpiperazin-1-yl)-6-vinylquinazolin-4-yl)-2,7-diazepine Heterosspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (600mg, 1.0mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (312mg, 2.0mmol), tripotassium phosphate (636mg, 3.0mmol) , Chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (72mg), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (82mg), added to dioxane (8mL) water (2mL) successively, and replaced with nitrogen three times After microwave reaction at 120 degrees for 0.5 hours. After cooling to room temperature, it was poured into water, extracted with ethyl acetate (50mL x 3), washed with brine and purified by silica gel column (methanol: dichloromethane=0～1:10) to obtain brown solid 7-(8-ethoxy) Base-7-(2-fluoro-6-hydroxyphenyl)-2-(4-methylpiperazin-1-yl)-6-vinylquinazolin-4-yl)-2,7-diazide Heterosspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400 mg, yield 63.3%). ES-API: [M+1] + = 633.4.
步骤五：7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-(4-甲基哌嗪-1-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(400mg,0.2mmol)，溶于二氯甲烷(3mL)中，加入三氟乙酸(1mL)室温下反应1小时，浓缩干得2-(8-乙氧基-2-(4-甲基哌嗪-1-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)-6-乙烯基喹唑啉-7-基)-3-氟苯酚粗品(400mg,收率100％)，直接用于下一步。Step 5: 7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-(4-methylpiperazin-1-yl)-6-vinylquinazoline-4 -Yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400mg, 0.2mmol), dissolved in dichloromethane (3mL), add trifluoroacetic acid (1mL) at room temperature React for 1 hour and concentrate to dry to obtain 2-(8-ethoxy-2-(4-methylpiperazin-1-yl)-4-(2,7-diazaspiro[3.5]nonane-7 -Yl)-6-vinylquinazolin-7-yl)-3-fluorophenol crude product (400mg, yield 100%), used directly in the next step.
步骤六：2-(8-乙氧基-2-(4-甲基哌嗪-1-基)-4-(2,7-二氮杂螺[3.5]壬烷-7-基)-6-乙烯基喹唑啉-7-基)-3-氟苯酚粗品(400mg,0.63mmol)和三乙胺(128mg,1.28mmol)，溶于二氯甲烷(3mL)中，降温0度后加入丙烯酸酐(71mg,0.57mmol)，保温0度反应1小时。反应液浓缩，制备板纯化得1-(7-(8-乙氧基-7-(2-氟-6-羟基苯基)-2-(4-甲基哌嗪-1-基)-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)丙-2-烯-1-酮(15mg,收率8％)。ES-API:[M+1] +＝587.1。 1HNMR(400MHz,氯仿-d)δ7.76(s,1H),6.88(d,J＝8.2Hz,1H),6.75(t,J＝8.6Hz,1H),6.42(dd,J＝35.6,15.0Hz,2H),6.23(dd,J＝17.2,10.0Hz,1H),5.70(d,J＝10.4Hz,1H), 5.58(d,J＝17.3Hz,1H),5.12(d,J＝11.0Hz,1H),4.05–3.83(m,9H),3.67(s,4H),2.69(s,4H),2.48(s,3H),2.01(s,4H),1.25(s,2H),1.09(t,J＝7.2Hz,3H)。 Step 6: 2-(8-Ethoxy-2-(4-methylpiperazin-1-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)-6 -Vinylquinazolin-7-yl)-3-fluorophenol crude product (400mg, 0.63mmol) and triethylamine (128mg, 1.28mmol), dissolved in dichloromethane (3mL), add acrylic acid after cooling to 0 degrees Anhydride (71mg, 0.57mmol), incubate at 0 degrees and react for 1 hour. The reaction solution was concentrated, and the preparation plate was purified to obtain 1-(7-(8-ethoxy-7-(2-fluoro-6-hydroxyphenyl)-2-(4-methylpiperazin-1-yl)-6 -Vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one (15mg, yield 8%). ES-API: [M+1] + = 587.1. 1 HNMR(400MHz, chloroform-d)δ7.76(s,1H), 6.88(d,J=8.2Hz,1H), 6.75(t,J=8.6Hz,1H), 6.42(dd,J=35.6, 15.0Hz, 2H), 6.23 (dd, J = 17.2, 10.0 Hz, 1H), 5.70 (d, J = 10.4 Hz, 1H), 5.58 (d, J = 17.3 Hz, 1H), 5.12 (d, J = 11.0Hz, 1H), 4.05-3.83 (m, 9H), 3.67 (s, 4H), 2.69 (s, 4H), 2.48 (s, 3H), 2.01 (s, 4H), 1.25 (s, 2H), 1.09 (t, J=7.2 Hz, 3H).
实施例46-58参照实施例19或45的合成方法或上述其他实施例类似的方法制备得到：Examples 46-58 are prepared by referring to the synthesis method of Example 19 or 45 or the similar method of other examples above:
Figure PCTCN2020077192-appb-000093
Figure PCTCN2020077192-appb-000093
Figure PCTCN2020077192-appb-000094
Figure PCTCN2020077192-appb-000094
Figure PCTCN2020077192-appb-000095
Figure PCTCN2020077192-appb-000095
测试例1细胞增殖抑制实验Test Example 1 Cell Proliferation Inhibition Experiment
NCI-H358为Kras G12C突变的人非小细胞肺癌细胞株，培养于10％FBS RPMI-1640培养基中；A549为Kras G12S突变的人肺腺癌细胞株，培养于10％FBS F-12K培养基中。取对数生长期的细胞，胰酶EDTA消化细胞收集计数并使用2％FBS RPMI-1640培养基将H358调整至1.8E4细胞/ml，用2％FBS F-12K培养基将A549调整至8.9E3细胞/ml；分别接种800个(45μl)H358或400个(45μl)A549细胞于384孔球体板中，培养过夜建立3D细胞模型。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用2％FBS培养基稀释100倍至10X化合物储液，于细胞接种后的第二天，每个细胞培养孔加入5μl 10X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照(control)，2％FBS培养基作为空白对照(blank)。加入化合物细胞培养5天后，每孔加入25μl CellTiter-Glo工作液，400rpm混匀孵育30分钟,室温静止30分钟后转移40μl混液到白色底透384孔板中，读取luminescence化学发光值，计算细胞增殖抑制率IR(％)＝(RLU对照–RLU化合物)/(RLU对照–RLU空白)×100％，使用Prism 6四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值，结果如下表1所示。 NCI-H358 is a human non-small cell lung cancer cell line with Kras G12C mutation, cultured in 10% FBS RPMI-1640 medium; A549 is a human lung adenocarcinoma cell line with Kras G12S mutation, cultured in 10% FBS F-12K基中. Take the cells in the logarithmic growth phase, digest the cells with trypsin EDTA, collect and count them, adjust H358 to 1.8E4 cells/ml with 2% FBS RPMI-1640 medium, and adjust A549 to 8.9E3 with 2% FBS F-12K medium Cells/ml; respectively inoculate 800 (45μl) H358 or 400 (45μl) A549 cells in a 384-well sphere plate, culture overnight to establish a 3D cell model. Use DMSO to prepare 1000X compound 3.16-fold gradient concentration stock solution, and use 2% FBS medium to dilute 100-fold to 10X compound stock solution. On the second day after cell seeding, add 5μl of 10X compound stock solution to each cell culture well. The concentration is 1X, and the DMSO content is 0.1%. DMSO was used as an experimental control (control), and 2% FBS medium was used as a blank control (blank). After adding the compound and culturing the cells for 5 days, add 25μl of CellTiter-Glo working solution to each well, mix at 400rpm and incubate for 30 minutes. After 30 minutes at room temperature, transfer 40μl of the mixture to a white bottom permeable 384-well plate, read the luminescence chemiluminescence value, and calculate the cells Proliferation inhibition rate IR (%) = (RLU control-RLU compound) / (RLU control-RLU blank) × 100%, use Prism 6 four-parameter method to fit the compound's gradient dilution concentration and the corresponding cell proliferation inhibition rate, and calculate the IC The value of 50 is shown in Table 1 below.
表1化合物对H358和A549细胞的抑制活性Table 1 Inhibitory activity of compounds on H358 and A549 cells
化合物编号Compound number H358IC 50(μM) H358IC 50 (μM) A549IC 50(μM) A549IC 50 (μM)
Z1Z1 ＜0.5＜0.5 ＞10＞10
Z2Z2 0.0160.016 3.2663.266
Z2-2Z2-2 0.0230.023 2.1652.165
Z6Z6 0.0610.061 5.4305.430
Z17Z17 ＜0.5＜0.5 ＞10＞10
Z19Z19 0.0730.073 4.9754.975
Z24Z24 0.0930.093 16.96416.964
Z24-2Z24-2 0.0060.006 3.2623.262
Z25Z25 0.0790.079 2.7712.771
Z25-2Z25-2 0.0440.044 3.4243.424
Z26Z26 0.0520.052 3.7673.767
Z30Z30 ＜0.5＜0.5 ＞10＞10
Z31Z31 0.0650.065 9.2969.296
Z33Z33 0.0610.061 3.0833.083
Z49Z49 0.0310.031 >10>10
Z50-2Z50-2 0.0110.011 >10>10
Z53Z53 0.0920.092 >10>10
Z57Z57 0.0280.028 >10>10
从表1可以看出，本发明的示例化合物对Kras G12C突变的NCI-H358细胞具有较高的抑制活性，而对A549细胞的抑制活性较低，具有明显的选择抑制活性。It can be seen from Table 1 that the exemplary compounds of the present invention have high inhibitory activity against Kras G12C mutant NCI-H358 cells, but have low inhibitory activity against A549 cells and have obvious selective inhibitory activity.
尽管本发明的具体实施方式已经得到详细的描述，根据已经公开的所有教导，本领域技术人员可以对本发明技术方案的细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。Although the specific embodiments of the present invention have been described in detail, according to all the teachings that have been disclosed, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present invention, and these changes are all within the protection scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (24)

  1. 一种螺环取代的嘧啶并环类化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或其前药，所述化合物的结构如式(I)所示：A spirocyclic substituted pyrimidocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, the structure of the compound is as shown in formula (I):
    Figure PCTCN2020077192-appb-100001
    Figure PCTCN2020077192-appb-100001
    式中，Where
    m为1或2；n为1；m is 1 or 2; n is 1;
    B为取代或未取代的C 6-14芳基、或取代或未取代的C 5-14杂芳基； B is a substituted or unsubstituted C 6-14 aryl group, or a substituted or unsubstituted C 5-14 heteroaryl group;
    Z为N或CR 3； Z is N or CR 3 ;
    R 1、R 3各自独立地为氢、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、或取代或未取代的C 3-20环烷基； R 1 and R 3 are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, substituted or unsubstituted C 2-8 alkenyl, A substituted or unsubstituted C 2-8 alkynyl group, or a substituted or unsubstituted C 3-20 cycloalkyl group;
    L为一个键、CR 11R 12、O-(CR 11R 12) t1或NH-(CR 13R 14) t2； L is a bond, CR 11 R 12 , O-(CR 11 R 12 ) t1 or NH-(CR 13 R 14 ) t2 ;
    R 2为卤素、羟基、-SO 2C 1-6烷基、取代或未取代的C 3-20杂环基、取代或未取代的C 3-20环烷基、取代或未取代的5或6元单杂芳基、或NR 21R 22； R 2 is halogen, hydroxyl, -SO 2 C 1-6 alkyl, substituted or unsubstituted C 3-20 heterocyclyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl group, or NR 21 R 22 ;
    R 11、R 12、R 13、R 14相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、C 1-3烷基或氧代基； R 11 , R 12 , R 13 , and R 14 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or oxo;
    R 21、R 22各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基、-C(O)卤代C 1-6烷基；或者R 21和R 22与相连的氮原子共同形成取代或未取代的C 3-20杂环基； R 21 and R 22 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)halo C 1-6 alkyl; or R 21 and R 22 and the connected nitrogen atom together form a substituted or unsubstituted C 3-20 heterocyclic group;
    t1、t2各自独立地为0、1、2、3或4；t1 and t2 are each independently 0, 1, 2, 3 or 4;
    上述基团中，所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自下述S组取代基所取代：羟基、卤素、硝基、氧代基、C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-C 3-6单环杂环基、-(CH 2) u-5或6元单杂芳基、-(CH 2) u-C 3-8单环环烷基、-(CH 2) u-O-(CH 2) v-C 3-8单环环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中所述C 3-6单环杂环基、5或6元单杂芳基任选地被1、2或3个选自卤素、氰基、C 1-3烷基、C 1-3烷氧基和C 3-6单环环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基。 In the above group, the "substituted" means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the following S group: hydroxyl, halogen, nitro, oxygen Substitute, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl, -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -( CH 2 ) u -halo C 1-6 alkoxy, -(CH 2 ) u -halo C 1-6 alkyl, -(CH 2 ) u -C 3-6 monocyclic heterocyclic group, -( CH 2 ) u -5 or 6-membered monoheteroaryl, -(CH 2 ) u -C 3-8 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 Monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 1-6 alkoxy, -(CH 2 ) u -O-(CH 2 ) v OH, -(CH 2 ) u -SO 2 C 1-6 alkyl, -(CH 2 ) u -NR a0 R b0 , -(CH 2 ) u -C(O)NR a0 R b0 , -(CH 2 ) u -C(O) C 1-6 alkyl, -C(O)OC 1-6 alkyl, NR a0 C(O)-(CH 2 ) u -NR a0 R b0 , NR a0 C(O)-(CH 2 ) u OH , NR a0 C(O)-halo C 1-6 alkyl; wherein the C 3-6 monocyclic heterocyclic group, 5 or 6-membered monoheteroaryl group is optionally selected from 1, 2 or 3 Substituent substitution of halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 monocyclic cycloalkyl; u and v are each independently 0, 1, 2, 3 or 4 ; R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，R 1为氢、卤素、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基、取代或未取代的C 2-4烯基、取代或未取代的C 2-4炔基、或取代或未取代的C 3-6环烷基。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein R 1 is hydrogen, halogen, substituted or unsubstituted C 1-3 alkyl, Substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 alkynyl, or substituted or unsubstituted C 3-6 cycloalkyl .
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，Z为N。The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof, wherein Z is N.
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，Z为CR 3。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof, wherein Z is CR 3 .
  5. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，R 3为氢或卤素。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein R 3 is hydrogen or halogen.
  6. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，L为一个键；R 2为NR 21R 22；其中R 21和R 22与相连的氮原子共同形成取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein L is a bond; R 2 is NR 21 R 22 ; wherein R 21 and R 22 Together with the connected nitrogen atom to form a substituted or unsubstituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, a substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted Substituted 7 to 11 membered spiro heterocyclic group; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from the S group.
  7. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，L为CR 11R 12、O-(CR 11R 12) t1或NH-(CR 13R 14) t2；R 2为卤素、羟基、-SO 2C 1-6烷基、取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基、取代或未取代的C 3-8环烷基、取代或未取代的5或6元单杂芳基、或NR 21R 22；其中R 11、R 12、R 13、R 14相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、C 1-3烷基或氧代基；R 21、R 22各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基、-C(O)卤代C 1-6烷基；或者R 21和R 22与相连的氮原子共同形成取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基；t1、t2各自独立地为0、1、2、3或4；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein L is CR 11 R 12 , O-(CR 11 R 12 ) t1 or NH- (CR 13 R 14 ) t2 ; R 2 is halogen, hydroxyl, -SO 2 C 1-6 alkyl, substituted or unsubstituted 3 to 6-membered saturated or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11 membered spiro heterocyclic group, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5 or 6 One-membered mono-heteroaryl group, or NR 21 R 22 ; wherein R 11 , R 12 , R 13 , and R 14 are the same or different, each independently being hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, C 1-3 Alkyl or oxo group; R 21 and R 22 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl , -C(O)C 1-6 alkyl, -C(O) halo C 1-6 alkyl; or R 21 and R 22 together with the connected nitrogen atom form a substituted or unsubstituted 3 to 6-membered saturated Or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11 membered spiro heterocyclic group; t1 and t2 are each independently Is 0, 1, 2, 3, or 4; the “substituted” means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the S group.
  8. 一种螺环取代的嘧啶并环类化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或其前药，所述化合物的结构如式(II)所示：A spirocyclic substituted pyrimidocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, the structure of the compound is as shown in formula (II):
    Figure PCTCN2020077192-appb-100002
    Figure PCTCN2020077192-appb-100002
    式中，Where
    A为取代或未取代的C 6-14芳基、或取代或未取代的C 5-14杂芳基； A is a substituted or unsubstituted C 6-14 aryl group, or a substituted or unsubstituted C 5-14 heteroaryl group;
    W、R a为选自下组的组合： W, R a is selected from the group consisting of a combination of:
    (i)W为N；R a为氢、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、或取代或未取代的C 3-20环烷基； (i) W is N; R a is hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, substituted or unsubstituted C 2-8 alkenyl group , Substituted or unsubstituted C 2-8 alkynyl, or substituted or unsubstituted C 3-20 cycloalkyl;
    (ii)W为CR c；R a、R c各自独立地为氢、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、或取代或未取代的C 3-20环烷基； (ii) W is CR c ; R a and R c are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, or substituted or unsubstituted C 3-20 cycloalkyl;
    Q为一个键、CR a1R b1、O-(CR a1R b1) q1或NH-(CR c1R d1) q2； Q is a bond, CR a1 R b1 , O-(CR a1 R b1 ) q1 or NH-(CR c1 R d1 ) q2 ;
    R b为卤素、羟基、-SO 2C 1-6烷基、取代或未取代的C 3-20杂环基、取代或未取代的C 3-20环烷基、取代或未取代的5或6元单杂芳基、或NR a2R b2； R b is halogen, hydroxy, -SO 2 C 1-6 alkyl, substituted or unsubstituted C 3-20 heterocyclyl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted 5 or 6-membered monoheteroaryl group, or NR a2 R b2 ;
    R a1、R b1、R c1、R d1相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、C 1-3烷基或氧代基； R a1 , R b1 , R c1 , and R d1 are the same or different, and are each independently hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, C 1-3 alkyl or oxo;
    R a2、R b2各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基、-C(O)卤代C 1-6烷基；或者R a2和R b2与相连的氮原子共同形成取代或未取代的C 3-20杂环基； R a2 and R b2 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)halo C 1-6 alkyl; or Ra2 and R b2 together with the connected nitrogen atom to form a substituted or unsubstituted C 3-20 heterocyclic group;
    q1、q2各自独立地为0、1、2、3或4；q1 and q2 are each independently 0, 1, 2, 3 or 4;
    上述基团中，所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自下述S组取代基所取代：羟基、卤素、硝基、氧代基、C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-C 3-6单环杂环基、-(CH 2) u-5或6元单杂芳基、-(CH 2) u-C 3-8单环环烷基、-(CH 2) u-O-(CH 2) v-C 3-8单环环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中所述C 3-6单环杂环基、5或6元单杂芳基任选地被1、2或3个选自卤素、氰基、C 1-3烷基、C 1-3烷氧基和C 3-6单环环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基。 In the above group, the "substituted" means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the following S group: hydroxyl, halogen, nitro, oxygen Substitute, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl, -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -( CH 2 ) u -halo C 1-6 alkoxy, -(CH 2 ) u -halo C 1-6 alkyl, -(CH 2 ) u -C 3-6 monocyclic heterocyclic group, -( CH 2 ) u -5 or 6-membered monoheteroaryl, -(CH 2 ) u -C 3-8 monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 Monocyclic cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 1-6 alkoxy, -(CH 2 ) u -O-(CH 2 ) v OH, -(CH 2 ) u -SO 2 C 1-6 alkyl, -(CH 2 ) u -NR a0 R b0 , -(CH 2 ) u -C(O)NR a0 R b0 , -(CH 2 ) u -C(O) C 1-6 alkyl, -C(O)OC 1-6 alkyl, NR a0 C(O)-(CH 2 ) u -NR a0 R b0 , NR a0 C(O)-(CH 2 ) u OH , NR a0 C(O)-halo C 1-6 alkyl; wherein the C 3-6 monocyclic heterocyclic group, 5 or 6-membered monoheteroaryl group is optionally selected from 1, 2 or 3 Substituent substitution of halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 monocyclic cycloalkyl; u and v are each independently 0, 1, 2, 3 or 4 ; R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
  9. 如权利要求8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，R a为氢或卤素。 The compound according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein Ra is hydrogen or halogen.
  10. 如权利要求8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，W为N。The compound of claim 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof, wherein W is N.
  11. 如权利要求8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，W为CR c。 The compound according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein W is CR c .
  12. 如权利要求8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，R c为氢或卤素。 The compound of claim 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein R c is hydrogen or halogen.
  13. 如权利要求8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，Q为一个键；R b为NR a2R b2；其中R a2和R b2与相连的氮原子共同形成取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。 The compound of claim 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein Q is a bond; R b is NR a2 R b2 ; wherein R a2 and R b2 Together with the connected nitrogen atom to form a substituted or unsubstituted 3 to 6 membered saturated or partially unsaturated monocyclic heterocyclic group, a substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted Substituted 7 to 11 membered spiro heterocyclic group; the "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are replaced by substituents independently selected from the S group.
  14. 如权利要求8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物 或前药，其中，Q为CR a1R b1、O-(CR a1R b1) q1或NH-(CR c1R d1) q2；R b为卤素、羟基、-SO 2C 1-6烷基、取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基、取代或未取代的C 3-8环烷基、取代或未取代的5或6元单杂芳基、或NR a2R b2；其中R a1、R b1、R c1、R d1相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、C 1-3烷基或氧代基；R a2、R b2各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基、-C(O)卤代C 1-6烷基；或者R a2和R b2与相连的氮原子共同形成取代或未取代的3至6元饱和或部分不饱和单环杂环基、取代或未取代的6至10元饱和或部分不饱和稠杂环基、或取代或未取代的7至11元螺杂环基；q1、q2各自独立地为0、1、2、3或4；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。 The compound according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein Q is CR a1 R b1 , O-(CR a1 R b1 ) q1 or NH- (CR c1 R d1 ) q2 ; R b is halogen, hydroxyl, -SO 2 C 1-6 alkyl, substituted or unsubstituted 3 to 6-membered saturated or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11 membered spiro heterocyclic group, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5 or 6 A membered monoheteroaryl group, or NR a2 R b2 ; wherein R a1 , R b1 , R c1 , R d1 are the same or different, and each independently is hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, C 1-3 Alkyl or oxo group; R a2 and R b2 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 3-6 cycloalkyl , -C(O)C 1-6 alkyl, -C(O) halo C 1-6 alkyl; or R a2 and R b2 together with the connected nitrogen atom form a substituted or unsubstituted 3 to 6-membered saturated Or partially unsaturated monocyclic heterocyclic group, substituted or unsubstituted 6 to 10 membered saturated or partially unsaturated fused heterocyclic group, or substituted or unsubstituted 7 to 11 membered spiro heterocyclic group; q1 and q2 are each independently Is 0, 1, 2, 3, or 4; the “substituted” means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the S group.
  15. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，B或A中所述的C 6-14芳基为苯基、萘基、或为苯基与一个非芳香环稠合形成的9或10元芳香稠合双环，所述的非芳香环为3至6元饱和或部分不饱和单环杂环基、或3至6元饱和或部分不饱和单环环烷基，其中所述的3至6元饱和或部分不饱和单环杂环基选自：氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、恶唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、恶唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-恶嗪烷、六氢嘧啶、1,4-二恶烷、四氢嘧啶-2(1H)-酮、1,4-二恶烷-2-酮、5,6-二氢-2H-吡喃-2-酮；所述的3至6元饱和或部分不饱和单环环烷基选自：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环丁酮、环丁烷-1,2-二酮、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮；所述9或10元芳香稠合双环为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 The compound according to claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein the C 6-14 aryl group in B or A is phenyl, Naphthyl, or a 9- or 10-membered aromatic fused bicyclic ring formed by the fusion of a phenyl and a non-aromatic ring, the non-aromatic ring is a 3 to 6-membered saturated or partially unsaturated monocyclic heterocyclic group, or a 3- to 6-membered saturated or partially unsaturated monocyclic cycloalkyl, wherein the 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group is selected from the group consisting of aziridine, ethylene oxide, azetidine, nitrogen Etan-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3- Dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyridine An-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidine-2-one, piperidine, Piperazine, piperazine-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thio Morpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H -Pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4- Tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydro Pyrimidine-2(1H)-one, 1,4-dioxan-2-one, 5,6-dihydro-2H-pyran-2-one; said 3 to 6-membered saturated or partially unsaturated mono Cyclocycloalkyl is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2- Diketone, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione; the 9- or 10-membered aromatic fused bicyclic ring is unsubstituted or substituted by 1 , 2, 3, or 4 substituents each independently selected from the S group.
  16. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，B或A中所述的C 5-14杂芳基为5或6元单杂芳基，其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述5或6元单杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 The compound according to claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein the C 5-14 heteroaryl group in B or A is 5 or 6-membered monoheteroaryl group, wherein the 5- or 6-membered monoheteroaryl group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3- Triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole , 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine; the 5 or 6 The membered monoheteroaryl group is unsubstituted or substituted with 1, 2, 3, or 4 substituents each independently selected from the S group.
  17. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，B或A中所述的C 5-14杂芳基为苯基与5或6元单杂芳基稠合形成的9或10元双杂芳基，其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、 异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述9或10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 The compound according to claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein the C 5-14 heteroaryl group in B or A is phenyl A 9- or 10-membered diheteroaryl group formed by condensing with a 5- or 6-membered monoheteroaryl group, wherein the 5- or 6-membered monoheteroaryl group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole , Pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxa Azole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, Pyridine, pyridazine, pyrimidine or pyrazine; the 9- or 10-membered biheteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from the S group.
  18. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，B或A中所述的C 5-14杂芳基为5或6元单杂芳基与5或6元单杂芳基稠合形成的8至10元双杂芳基，其中所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述8至10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 The compound according to claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein the C 5-14 heteroaryl group in B or A is 5 or An 8- to 10-membered diheteroaryl group formed by condensing a 6-membered monoheteroaryl group with a 5- or 6-membered monoheteroaryl group, wherein the 5- or 6-membered monoheteroaryl group is selected from: thiophene, furan, thiazole, iso Thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole , Tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole Azole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine; the 8- to 10-membered bis-heteroaryl group is unsubstituted or is substituted by 1, 2, 3, or 4 substituents each independently selected from the S group Replaced.
  19. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，B和A中所述的C 5-14杂芳基为5或6元单杂芳基与一个非芳香环稠合形成的8至10元双杂芳基，所述的非芳香环为3至6元饱和或部分不饱和单环杂环基、或3至6元饱和或部分不饱和单环环烷基，其中，所述的5或6元单杂芳基选自：噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、***、1,2,3-***、1,2,4-***、1,2,5-***、1,3,4-***、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪；所述的3至6元饱和或部分不饱和单环杂环基选自：氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、恶唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、恶唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-恶嗪烷、六氢嘧啶、1,4-二恶烷、四氢嘧啶-2(1H)-酮、1,4-二恶烷-2-酮、5,6-二氢-2H-吡喃-2-酮；所述的3至6元饱和或部分不饱和单环环烷基选自：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环丁酮、环丁烷-1,2-二酮、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮；所述8至10元双杂芳基为未取代的或被1、2、3或4个各自独立地选自S组的取代基所取代。 The compound according to claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein the C 5-14 heteroaryl group in B and A is 5 or An 8- to 10-membered bi-heteroaryl group formed by the fusion of a 6-membered monoheteroaryl group with a non-aromatic ring, the non-aromatic ring being a 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group, or a 3- to 6-membered A saturated or partially unsaturated monocyclic cycloalkyl group, wherein the 5- or 6-membered monoheteroaryl group is selected from: thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2 ,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine ; The 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group is selected from: aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetan Alkane, oxetane-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H) -Ketone, dihydrofuran-2,5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydro Thiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, Morpholine-3-one, morpholin-2-one, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydro Pyran, 1,2-dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2, 3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H- Pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2(1H)-one, 1,4- Dioxan-2-one, 5,6-dihydro-2H-pyran-2-one; the 3- to 6-membered saturated or partially unsaturated monocyclic cycloalkyl group is selected from: cyclopropyl, cyclobutyl Cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1, 3-diketone, cyclohexanone, cyclohexane-1,3-diketone; the 8- to 10-membered bisheteroaryl group is unsubstituted or 1, 2, 3, or 4 are each independently selected from S Group of substituents.
  20. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，式(I)中的-L-R 2和式(II)中的-Q-R b独立选自： The compound according to claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, wherein -LR 2 in formula (I) and-in formula (II) QR b is independently selected from:
    Figure PCTCN2020077192-appb-100003
    Figure PCTCN2020077192-appb-100003
    Figure PCTCN2020077192-appb-100004
    Figure PCTCN2020077192-appb-100004
    Figure PCTCN2020077192-appb-100005
    Figure PCTCN2020077192-appb-100005
    Figure PCTCN2020077192-appb-100006
    Figure PCTCN2020077192-appb-100006
    Figure PCTCN2020077192-appb-100007
    Figure PCTCN2020077192-appb-100007
    Figure PCTCN2020077192-appb-100008
    Figure PCTCN2020077192-appb-100008
  21. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化合物或前药，其中，B和A独立选自：The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof, wherein B and A are independently selected from:
    Figure PCTCN2020077192-appb-100009
    Figure PCTCN2020077192-appb-100009
    Figure PCTCN2020077192-appb-100010
    Figure PCTCN2020077192-appb-100010
  22. 一种药物组合物，所述药物组合物包括权利要求1至21中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。A pharmaceutical composition comprising the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable Carrier.
  23. 如权利要求1至21中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备预防和/或治疗癌症的药物中的用途。Use of the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof in the preparation of a medicine for preventing and/or treating cancer.
  24. 如权利要求1至21中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备KRAS突变抑制剂中的用途。Use of the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof in the preparation of a KRAS mutation inhibitor.
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