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WO2024235225A1 - 取代嘧啶并环类抑制剂及其制备方法和应用 - Google Patents

取代嘧啶并环类抑制剂及其制备方法和应用 Download PDF

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Publication number
WO2024235225A1
WO2024235225A1 PCT/CN2024/093105 CN2024093105W WO2024235225A1 WO 2024235225 A1 WO2024235225 A1 WO 2024235225A1 CN 2024093105 W CN2024093105 W CN 2024093105W WO 2024235225 A1 WO2024235225 A1 WO 2024235225A1
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amino
alkyl
ethyl
methyl
membered
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French (fr)
Inventor
吕彬华
崔大为
刘连军
柴传柯
梁辉
庞旭东
廉昌明
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Application filed by Suzhou Zelgen Biopharmaceutical Co Ltd, Shanghai Zelgen Pharmatech Co Ltd filed Critical Suzhou Zelgen Biopharmaceutical Co Ltd
Publication of WO2024235225A1 publication Critical patent/WO2024235225A1/zh
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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
    • C07D471/04—Ortho-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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a substituted pyrimidocyclic inhibitor and a preparation method and application thereof.
  • KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mainly non-small cell lung cancer).
  • KRAS protein is a small GTPase encoded by the KRAS gene. It is an important regulatory protein for cell growth. Once KRAS is activated, it can activate multiple signaling pathways and promote cell proliferation.
  • the most common sites for gene mutations in KRAS protein are codons 12, 13, and 61, among which mutations in codon 12 are the most common.
  • the most important mutations in KRAS G12 mutations are G12A, G12C, G12D, G12V, G12S, etc., among which G12C, G12D, G12V, etc. mainly occur in NSCLC, CRC, and pancreatic cancer. So far, there are still no drugs approved for marketing that target multiple KRAS mutations at the same time.
  • KRAS mutant target proteins are pathologically associated with a variety of diseases, especially lung cancer, pancreatic cancer, colorectal cancer, etc.
  • new KRAS mutant inhibitors are currently needed for clinical treatment.
  • Highly active KRAS mutant inhibitors can more effectively treat diseases such as cancer caused by KRAS mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
  • the object of the present invention is to provide a novel class of compounds having an inhibitory effect on KRAS mutation and/or better pharmacodynamic properties and uses thereof.
  • a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug is provided:
  • ring B is selected from the following substituted or unsubstituted groups: C 6 -C 14 aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more R;
  • R 1a is independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 10 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered saturated or unsaturated heterocyclyl, C 3 -C 20 cycloalkyl C 1 -C 6 alkylene, 4-20 membered saturated or unsaturated heterocyclyl C 1 -C 6 alkylene; wherein the substitution refers to substitution by one or more R;
  • R 1b is independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 20 cycloalkyl, 4-20 membered saturated or unsaturated heterocyclyl, C 1 -C 10 alkoxy C 1 -C 6 alkylene, C 3 -C 20 cycloalkyl C 1 -C 6 alkylene, 4-20 membered saturated or unsaturated heterocyclyl C 1 -C 6 alkylene; wherein the substitution refers to substitution by one or more R;
  • R 1c is independently selected from the following substituted or unsubstituted groups: C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 20 cycloalkyl, 4-20 membered saturated or unsaturated heterocyclyl, C 1 -C 10 alkoxy C 1 -C 6 alkylene, C 3 -C 20 cycloalkyl C 1 -C 6 alkylene, 4-20 membered saturated or unsaturated heterocyclyl C 1 -C 6 alkylene; wherein the substitution refers to substitution by one or more R;
  • R 1a and R 1c are linked to form a 4-7 membered ring
  • R 2 is selected from the group consisting of substituted or unsubstituted C 6 -C 14 aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more R;
  • R 3 is independently selected from the following substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy , 4-6 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R;
  • n is an integer of 0, 1, 2, 3, 4, 5 or 6;
  • X is selected from: bond, O, NH, N(C 1 -C 3 alkyl), C ⁇ C;
  • Y is selected from: a bond, a substituted or unsubstituted C 1 -C 6 alkylene group; wherein the substitution refers to substitution by one or more R;
  • ring W 1 is selected from the following substituted or unsubstituted groups: C 3 -C 20 cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R;
  • R4 is selected from the group consisting of: H, deuterium, alkenyl, fluoroalkenyl, ethynyl, C1 - C6 alkyl, deuterated C1 - C6 alkyl, halogenated C1 - C6 alkyl, ( C3 - C6 cycloalkyl) C1 - C6 alkyl, (4-6 membered heterocyclyl)C1- C6 alkyl, ( C1 - C6 alkoxy) C1 - C6 alkyl, ( C3 - C6 cycloalkyloxy) C1 - C6 alkyl, (4-6 membered heterocyclyloxy) C1 - C6 alkyl, ( C1 - C6 alkyl)vinyl, deuterated (C1-C6 alkyl)vinyl, halogenated (C1-C6 alkyl ) vinyl , ( C1-C6 alkyl)ethynyl, deuter
  • n is an integer selected from: 0, 1, 2, 3, 4, 5 or 6;
  • Z is selected from: -L 4 -Q 2 or
  • ring W 2 is selected from the following substituted or unsubstituted groups: C 3 -C 6 cycloalkylene, 4-6 membered saturated or unsaturated heterocyclylene; wherein the substitution refers to substitution by one or more R;
  • Each L 4 is independently selected from the group consisting of a substituted or unsubstituted bond, a C 1 -C 6 alkylene group, and a deuterated C 1 -C 6 alkylene group; wherein the substitution refers to substitution by one or more R;
  • each Q 2 is independently selected from the group consisting of a substituted or unsubstituted C 1 -C 6 alkoxy group, a C 3 -C 10 cycloalkyloxy group, a 4-10 membered heterocyclyloxy group, a C 3 -C 10 cycloalkylC 1 -C 6 alkyleneoxy group, a 4-10 membered heterocyclylC 1 -C 6 alkyleneoxy group, a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclyl group, NHR 9 , NR 9 R 10 ;
  • R 9 and R 10 are each independently selected from the group consisting of a substituted or unsubstituted C 1 -C 6 alkyl group, a C 3 -C 10 cycloalkyl group, a 4-10 membered heterocyclyl group, a (C 3 -C 10 cycloalkyl)C 1 -C 6 alkylene group, a (4-10
  • Each R is the same or different and is independently selected from the group consisting of H, deuterium, alkenyl, fluoroalkenyl, ethynyl, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkylene, halogenated C 1 -C 6 alkylene, (C 3 -C 6 cycloalkyl)C 1 -C 6 alkyl, (4-6 membered heterocyclyl)C 1 -C 6 alkyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, (C 3 -C 6 cycloalkyloxy)C 1 -C 6 alkyl, (4-6 membered heterocyclyloxy)C 1 -C 6 alkyl, (C 1 -C 6 alkyl)vinyl, deuterated (C 1 -C 6 alkyl)vinyl, halogenated (
  • R 1a is independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 10 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered saturated or unsaturated heterocyclyl, C 3 -C 20 cycloalkyl C 1 -C 6 alkylene, 4-20 membered saturated or unsaturated heterocyclyl C 1 -C 6 alkylene; wherein the substitution refers to substitution by one or more R;
  • R 1b is independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 20 cycloalkyl, 4-20 membered saturated or unsaturated heterocyclyl, C 1 -C 10 alkoxy C 1 -C 6 alkylene, C 3 -C 20 cycloalkyl C 1 -C 6 alkylene, 4-20 membered saturated or unsaturated hetero
  • the compound has a structure shown by formula (II-A) or formula (II-B):
  • Ring B, R 1a , R 1b , R 1c , R 2 , R 3 , X, Y, Z and m are as defined above.
  • the compound has a structure shown by formula (III-A1), formula (III-A2) or formula (III-B1), formula (III-B2):
  • Ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , X, Y, W 1 , W 2 , L 4 , Q 2 , m and n have the same meanings as described above.
  • the compound has a structure represented by formula (III-A1) or formula (III-B1).
  • X is O.
  • the compound has a structure shown by formula (IV-A1), formula (IV-A2) or formula (IV-B1), formula (IV-B2):
  • Ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , Y, W 1 , W 2 , L 4 , Q 2 , m and n are as defined above.
  • the compound has a structure represented by formula (IV-A1) or formula (IV-B1).
  • R 1a is C 1 -C 10 alkyl; R 1b is hydrogen; and R 1c is C 1 -C 10 alkyl; preferably, R 1a is C 1 -C 4 alkyl; R 1b is hydrogen; and R 1c is C 1 -C 4 alkyl; more preferably, R 1a is methyl; R 1b is hydrogen; and R 1c is methyl.
  • the compound has a structure shown by formula (V-A1), formula (V-A2) or formula (V-B1), formula (V-B2):
  • the compound has a structure represented by formula (V-A1) or formula (V-B1).
  • the compound has a structure represented by formula (VI-A1) or formula (VI-B1):
  • Ring B, R 2 , R 3 , m and n are as defined in claim 1 , and each R 5 is the same or different and is independently selected from hydrogen or deuterium.
  • the compound has a structure shown in formula (VII-A1) or formula (VII-B1):
  • P 1 , P 2 , and P 3 are each independently selected from CH, CF, C—Cl, C—CN, C—CF 3 , or N;
  • Ring B, R 1a , R 1b , R 1c , R 3 , R 4 , X, Y, W 1 , W 2 , L 4 , Q 2 , m and n are as defined in claim 1;
  • the compound has a structure shown in formula (VII-B1).
  • Y is CH 2 or CD 2 .
  • R 3 are the same or different and are independently selected from the following group: H, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 alkoxy.
  • R 3 are the same or different and are independently selected from halogen.
  • W1 is selected from: substituted or unsubstituted 4-7 membered monocyclic heterocyclyl, substituted or unsubstituted C3 - C7 monocyclic cycloalkyl, substituted or unsubstituted 6-10 membered bicyclic heterocyclyl, substituted or unsubstituted C6-C10 bicyclic cycloalkyl, substituted or unsubstituted 7-12 membered tricyclic heterocyclyl, substituted or unsubstituted C7 - C12 tricyclic cycloalkyl, preferably, W1 is substituted or unsubstituted 8-12 membered N-containing heterocyclyl, wherein the substitution refers to substitution by one or more R, and R is defined as above;
  • n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R4, and n are as defined above, and R, R4 may be substituted on any one of the polycyclic rings (such as a bridged ring or a spiro ring);
  • n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, R4 and n are as defined above, and R may be substituted on any one of the polycyclic (eg, bridged or spiro) rings.
  • n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R, R4, and n are as defined above, and R, R4 may be substituted on any one of the polycyclic rings (such as a bridged ring or a spiro ring);
  • n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, R4 and n are as defined above, and R may be substituted on any one of the polycyclic (eg, bridged or spiro) rings.
  • each R is independently hydrogen or deuterium.
  • L 4 is selected from: a bond, CH 2 , CD 2 , and CH(CH 3 ).
  • Q 2 is selected from: NHCH 3 , N(CH 3 ) 2 ,
  • R 2 is selected from the following group which is substituted or unsubstituted: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyridyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, NH 2 , C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy , C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl (such as ethynyl or propynyl), ester, amine, amide, sulfone
  • R 2 is selected from the following substituted or unsubstituted groups: phenyl, 5-6 membered monocyclic heteroaryl (preferably the 5-6 membered monocyclic heteroaryl contains only 1, 2 or 3 nitrogen as heteroatoms, such as pyridyl), or naphthyl, wherein the substitution is as defined above.
  • the carbon to which R 2 is connected to other parts of the molecule is a chiral carbon
  • the chiral carbon is of R configuration or S configuration.
  • ring B is selected from the following substituted or unsubstituted groups: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following group: halogen, hydroxyl, cyano, NH2 , C1 - C6 alkyl, halogenated C1- C6 alkyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C6 cycloalkyl, 4-6 membered heterocyclyl, C2 - C6 alkenyl, C2 - C6 alkyny
  • ring B is selected from the following substituted groups: phenyl, 6-membered monocyclic heteroaryl (such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl); and the substitution refers to being substituted by one NH 2 (preferably, the NH 2 is substituted at the ortho position where the phenyl or monocyclic heteroaryl ring B is connected to the rest of the molecule) and optionally one or more substituents selected from the following group: halogen, hydroxyl, cyano, NH 2 , C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, ester, amine, amide,
  • ring B is selected from:
  • R 1a is selected from the group consisting of H, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, halogenated C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, C 1 -C 6 alkoxy C 1 -C 6 alkylene, halogenated C 1 -C 6 alkoxy C 1 -C 6 alkylene, C 3 -C 6 cycloalkyl C 1 -C 6 alkylene, 4-6 membered heterocyclyl C 1 -C 6 alkylene; preferably, R 1a is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CH 2 cyclopropyl, CH 2 CH 2 OCH 3 , CH(CH 3 )CH 2 OCH 3
  • R 1b is independently selected from the following group: H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, halogenated C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, C 1 -C 6 alkoxy C 1 -C 6 alkylene, halogenated C 1 -C 6 alkoxy C 1 -C 6 alkylene , C 3 -C 6 cycloalkyl C 1 -C 6 alkylene, 4-6 membered heterocyclyl C 1 -C 6 alkylene; preferably, R 1b is independently selected from the following group: H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl. More preferably, R 1b is independently
  • R 1c is independently selected from the following group: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, halogenated C 3 -C 6 cycloalkyl, halogenated 4-6 membered heterocyclyl, C 1 -C 6 alkoxy C 1 -C 6 alkylene, halogenated C 1 -C 6 alkoxy C 1 -C 6 alkylene, C 3 -C 6 cycloalkyl C 1 -C 6 alkylene, 4-6 membered heterocyclyl C 1 -C 6 alkylene; preferably, R 1c is independently selected from the following group: methyl, ethyl, isopropyl, cyclopropyl, oxetanyl. More preferably, R 1c is C 1
  • R 1a is selected from the group consisting of methyl and ethyl
  • R 1b is selected from H
  • R 1c is selected from methyl
  • the carbon atoms connected to R 1b and R 1c are of R configuration or S configuration.
  • ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , X, Y, W 1 , W 2 , L 4 , Q 2 , m and n have the groups corresponding to the specific compounds in the examples.
  • ring B, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , X, Y, W 1 , W 2 , L 4 , Q 2 , m and n have the groups corresponding to the following specific compounds.
  • the compound is selected from the following group:
  • the compound is preferably the compound prepared in the examples.
  • the present invention provides a method for preparing a compound of formula (I), a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, characterized in that it comprises the steps of:
  • LG 1 , LG 2 , LG 3 , LG 4 , and LG 5 are leaving groups, each independently selected from the group consisting of H, OH, halogen, OTf, OTs, OMs, -B(OH) 2 , -B(KBF 3 ), -Sn( n Bu) 3 , wait;
  • the Pd catalyst is selected from: Pd(OAc) 2 , Pd(dba) 2 , Pd 2 (dba) 3 , XPhos PdG2, RuPhos PdG2, XantPhos-Pd-G2, cataCXium A-Pd-G2, XPhos PdG3, RuPhos PdG3, XantPhos -Pd-G3, cataCXium A-Pd-G3, BrettPhos PdG3, SPhos PdG3, tBuXPhos-Pd-G3, XantPhos-Pd-G4, BrettPhos PG4, SPhos PdG4, cataCXium A-Pd-G4, Rockphos PdG4, etc.;
  • R 1a , R 1b , R 1c , R 2 , R 3 , Ring A, Ring B, X, Y, Z, and m are as defined above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds described in the first aspect, Stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and pharmaceutically acceptable carriers.
  • the pharmaceutical composition further comprises a drug selected from the group consisting of: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or the above drugs biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, o fatumumab, etc.
  • the present invention provides a use of the compound as described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described in the third aspect, for preparing a drug for preventing and/or treating a disease associated with the activity or expression of KRAS mutations, preferably, the disease is a tumor or a disorder.
  • the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the KRAS mutation is selected from the following group: G12D, G12V, G12R, G12S, G12A, G12C, or a combination thereof.
  • the KRAS mutation is selected from the following group: G12D, G12V, G12R, or a combination thereof. More preferably, the KRAS mutation is G12V.
  • the present invention provides a non-diagnostic, non-therapeutic method for inhibiting KRAS mutation, comprising the steps of: administering an effective amount of the compound as described in the first aspect, its stereoisomers, tautomers, Isomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition as described in the third aspect.
  • the subject is a mammal, preferably a human.
  • the present invention provides an in vitro method for inhibiting the activity of KRAS mutants, comprising the steps of contacting the compound as described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described in the third aspect with proteins or cells, thereby inhibiting the activity of KRAS mutants.
  • the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.
  • the cells are from rodents (such as mice and rats) or primates (such as humans).
  • the inventor unexpectedly prepared a new type of compound with inhibitory effect on KRAS mutation and/or better pharmacodynamic performance. On this basis, the inventor completed the present invention.
  • alkyl refers to a straight or branched alkane group or a cyclic hydrocarbon group (including hydrocarbon groups connected to other parts through carbon atoms on the ring or non-rings), preferably a straight or branched alkane group, containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms (C1-C10), more preferably 1-6 carbon atoms (C1-C6) or 1-3 carbon atoms (C1-C3).
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl,
  • alkyl refers to alkyl radicals such as pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc.
  • alkyl radicals also include substituted alkyl radicals.
  • Ring; R e can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring.
  • the above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring can be optionally substituted.
  • alkylene refers to a group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, such as methylene (eg or -CH 2 -), ethylene (such as ), propylene (such as ), isopropylidene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as ),
  • the term also includes a methylene group of an alkylene group (such as C1-C18 alkylene group) replaced by a cycloalkylene group (such as C3-C20 cycloalkylene group), for example, "C1-C18 alkylene group C3-C20 cycloalkylene group” or "C3-C20 cycloalkylene group C1-C18 alkylene group”.
  • alkylene group also includes substituted alkylene group, and the substituent group can be halogenated (such
  • C1-C18 alkylene C3-C20 cycloalkylene or "C3-C20 cycloalkylene C1-C18 alkylene” has the same meaning and refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, such as etc.
  • C1-C6 alkylene C3-C6 cycloalkylene Preferably C1-C6 alkylene C3-C6 cycloalkylene.
  • C1-C18 alkylene C3-C20 cycloalkylene or "C3-C20 cycloalkylene C1-C18 alkylene” also includes substituted “C1-C18 alkylene C3-C20 cycloalkylene” or "C3-C20 cycloalkylene C1-C18 alkylene", and the substituent may be halogen, hydroxyl, cyano, nitro, etc.
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more double bonds and generally having a length of 1 to 20 carbon atoms.
  • Alkenyl is preferably C1-C6 alkenyl, more preferably C1-C4 alkenyl or C2-C4 alkenyl.
  • Alkenyl can be a group that directly forms a double bond with a carbon atom on a cycloalkyl or heterocycloalkyl group, such as a methylene group (such as ).
  • Alkenyl includes, but is not limited to, for example, methenyl (e.g. ), vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc.
  • alkenyl includes substituted alkenyl.
  • alkenyl also includes substituted alkenyl, and the substituent may be halogenated (such as ), hydroxyl, cyano, nitro, etc.
  • alkynyl refers to a straight or branched hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms.
  • Alkynyl is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl.
  • Alkynyl includes, but is not limited to, ethynyl, propynyl or similar groups.
  • alkynyl also includes substituted alkynyl, and the substituent may be halo, hydroxyl, cyano, nitro, etc.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms.
  • C3 - C20 refers to a cycloalkyl containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • the cycloalkyl is preferably a C3 - C14 cycloalkyl, more preferably a C3 - C10 cycloalkyl, more preferably a C3 - C6 monocyclic cycloalkyl, a C7 - C10 bicyclic or tricyclic cycloalkyl.
  • Substituted cycloalkyl refers to a cycloalkyl in which one or more positions are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents can be optionally substituted.
  • Typical substitutions also include spirocyclic, pyrimidocyclic or fused ring substituents, especially spirocyclic alkyl, spirocyclic alkenyl, spirocyclic heterocyclic (excluding heteroaromatic rings), pyrimidocyclic alkyl, pyrimidocyclic alkenyl, pyrimidocyclic heterocyclic (excluding heteroaromatic rings), fused cycloalkyl, fused cycloalkenyl, fused heterocyclic or fused aromatic rings, and the above cycloalkyl, cycloalkenyl, heterocyclic and heteroaryl groups may be optionally substituted.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc.
  • C3-C20 cycloalkylene refers to a group formed by removing two hydrogen atoms from a cycloalkyl group.
  • the cycloalkylene group is preferably a C3 - C14 cycloalkylene group, more preferably a C3 - C10 cycloalkylene group, more preferably a C3 - C6 monocyclic cycloalkylene group, a C7 - C10 bicyclic or tricyclic cycloalkylene group.
  • the cycloalkylene group may be optionally further substituted.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including but not limited to a 3-7 membered monocyclic ring, a 4-7 membered monocyclic ring, a 6-11 membered bicyclic ring, or an 8-16 membered tricyclic or polycyclic ring system), wherein at least one heteroatom is present in a ring having at least one carbon atom.
  • the term “4-20 membered heterocyclyl” refers to a heterocyclyl containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms.
  • Heterocyclyl has the same meaning as "saturated or unsaturated heterocyclyl".
  • Heterocyclyl is preferably a 4-14 membered heterocyclyl (including but not limited to a 4-6 membered monocyclic ring, a 7-10 membered bicyclic ring, or an 8-14 membered tricyclic or polycyclic ring system), more preferably a 4-12 membered heterocyclyl, more preferably a 4-10 membered heterocyclyl.
  • Cyclic radical such as 4-6 yuan monocyclic heterocyclic radical, 7-11 yuan bicyclic or tricyclic heterocyclic radical, is more preferably 4-8 yuan heterocyclic radical, is more preferably 4-6 yuan heterocyclic radical.
  • Each heterocyclic radical contains heteroatomic heterocycle and can carry 1,2,3 or 4 heteroatoms, and these heteroatoms are independently selected from nitrogen atom, oxygen atom or sulphur atom, wherein nitrogen atom or sulphur atom can be oxidized, and nitrogen atom can also be quaternized.
  • Heterocyclic group can be connected to the residue of any heteroatom or carbon atom of ring or ring system molecule, preferably connected to N or C atom on ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl and tetrahydro-1,1-dioxythiophene, and the like.
  • the polycyclic heterocyclic group includes spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.
  • the term "4-20 membered heterocyclylene” refers to a group formed by removing two hydrogen atoms from a heterocyclyl group.
  • the "heterocyclylene” is preferably a 4-14 membered heterocyclylene (including but not limited to a 4-6 membered monocyclic, 7-10 membered bicyclic or 8-14 membered tricyclic or polycyclic system), more preferably a 4-12 membered heterocyclylene, more preferably a 4-10 membered heterocyclylene, such as a 4-6 membered monocyclic heterocyclylene, a 7-11 membered bicyclic or tricyclic heterocyclylene, more preferably a 4-8 membered heterocyclylene, more preferably a 4-6 membered heterocyclylene or a 4-5 membered heterocyclylene.
  • the heterocyclylene group may be optionally further substituted.
  • aryl refers to an aromatic cyclic hydrocarbon group having 1-5 rings, especially monocyclic and bicyclic groups.
  • C 6 -C 14 aryl refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms.
  • the aryl group is preferably a C 6 -C 10 aryl group.
  • the aryl group includes phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.).
  • Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic radical or fused ring aromatic ring radical, and the above cycloalkyl, cycloalkenyl, heterocyclic radical and heterocyclic aromatic radical may be optionally substituted.
  • heteroaryl refers to an aromatic cyclic hydrocarbon group containing 1 to 4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • heteroatoms are selected from oxygen, nitrogen and sulfur.
  • 5-14 membered heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms.
  • the heteroaryl is preferably 5 to 10 rings, more preferably 5 or 6, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl.
  • pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazoxinyl, triazolyl and tetrazolyl.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.
  • alkoxy refers to a straight chain or branched alkoxy group, including alkyl-O-, alkyl-O-alkyl, wherein "C 1 -C 18 alkoxy” refers to a straight chain or branched alkoxy group having 1 to 18 carbon atoms, including C 1 -C 18 alkyl-O-, -C 1 -C 6 alkyl-OC 1 -C 6 alkyl, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc.
  • it is C 1 -C 8 alkoxy, more preferably C1 -C 6 alkoxy.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein "C 3 -C 20 cycloalkyloxy” refers to C 3 -C 20 cycloalkyl-O-, wherein C 3 -C 20 cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein “4-20 membered heterocyclyloxy” refers to 4-20 membered heterocyclyl-O-, wherein the 4-20 membered heterocyclyl is as defined above.
  • C 1 -C 18 alkyleneoxy group refers to a group obtained by removing a hydrogen atom from a "C 1 -C 18 alkoxy group”.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • halogenated means substituted with halogen.
  • deuterated means substituted with deuterium.
  • hydroxyl refers to a group having the structure OH.
  • nitro refers to a group having the structure NO 2 .
  • cyano group refers to a group having the structure CN.
  • ester group refers to a group with the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • the ester group is preferably -COOC 1 -C 6 alkyl.
  • amine group refers to a group with the structure -NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment.
  • the amine group is preferably NH2 , NHC1 - C6 alkyl, N( C1 - C6 alkyl) 2 .
  • amide refers to a group having the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine fragment.
  • the amide is preferably It is CONH 2 , NHCO(C 1 -C 6 alkyl), NHCO(C 3 -C 6 cycloalkyl).
  • sulfone refers to a group with the structure -SO2R , wherein R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl , as defined above.
  • the sulfone group is preferably -SO2C1 - C6alkyl .
  • sulfonamido refers to a group with the structure -SO2NRR ', wherein R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, as defined above.
  • the sulfonamido is preferably -SO2NH2 , -SO2NH ( C1 - C6alkyl ), -SO2NH ( C3 - C6cycloalkyl ).
  • urea group refers to a group having the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, as defined above. R, R' and R" can be the same or different in the dialkylamine fragment.
  • the urea group is preferably -NHCONH2 , -NHCONH( C1 - C6 alkyl).
  • alkylaminoalkyl refers to a group with the structure -RNHR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, as defined above. R and R' can be the same or different.
  • Alkylaminoalkyl is preferably -C 1 -C 6 alkylene NHC 1 -C 6 alkyl.
  • dialkylaminoalkyl refers to a group with the structure -RNHR'R", wherein R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, as defined above. R, R' and R" can be the same or different in the dialkylamino fragment.
  • the dialkylaminoalkyl is preferably -C 1 -C 6 alkylene N(C 1 -C 6 alkyl) 2 .
  • heterocyclylalkyl refers to a group with the structure -RR', wherein R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.
  • substituted refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent.
  • the specific substituent is a substituent described above, or a substituent appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.
  • the substituents include, but are not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group (-NH2, -NH(C1-C6 alkyl) or -NH(C1-C6 alkyl)2), C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 urea group, etc.
  • any heteroatom with insufficient valence is assumed to have sufficient hydrogen atoms to complete its valence.
  • a substituent is a non-terminal substituent, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.
  • a plurality refers to 2, 3, 4, or 5.
  • compounds of the present invention refers to compounds represented by formula I0, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of formula I0.
  • salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts.
  • the term "salt” used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions (“inner salts”) that may be formed are included in the scope of the term "salt".
  • compositions of the present invention may form salts, for example, Compound I reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution.
  • the compounds of the present invention contain basic fragments, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide [0013]
  • the invention also includes but is not limited to the following: esters,
  • Some compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromides), etc.
  • alkyl halides such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl
  • dialkyl sulfates such as dimethyl sulfate, diethyl s
  • Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention.
  • the term "prodrug” herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All these tautomers are part of the present invention.
  • All stereoisomers of the compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer with a particular activity), or may be a mixture, such as a racemate, or with all other stereoisomers.
  • the chiral center of the present invention has two configurations, S or R, as defined by the International Union of Pure and Applied Chemistry (IUPAC) in 1974.
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization into diastereoisomers for separation and crystallization, or by chiral column chromatography.
  • Individual optical isomers can be obtained from the racemate by appropriate methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.
  • the compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.
  • All configurational isomers of the compounds of the present invention are within the scope of the invention, whether in mixture, pure or very pure form.
  • the definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures.
  • asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.
  • the ratio of isomers contained in the mixture of isomers can be various.
  • the mixture of only two isomers there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention.
  • Similar ratios that are easily understood by ordinary technicians in this profession, and ratios for more complex mixtures of isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number from the original atoms.
  • isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2H , 3H , 13C , 11C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F and 36Cl , respectively.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as radioactive isotopes of 3H and 14C , are also included, which are useful in tissue distribution experiments of drugs and substrates.
  • Tritium, i.e. 3H and carbon-14, i.e. 14C are relatively easy to prepare and detect. It is the first choice among isotopes.
  • heavier isotope substitutions such as deuterium, i.e.
  • the compounds can be prepared in the usual manner by substituting a readily available isotopically labeled reagent for a non-isotopic reagent using the disclosed exemplified schemes.
  • a synthesis of a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer.
  • a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.
  • the compounds of the present invention can be replaced with any number of substituents or functional groups to expand its scope.
  • substituted appears before or after the term “optional”, and the general formula including substituents in the formulation of the present invention refers to the use of a specified structural substituent to replace the hydrogen free radical.
  • substituents can be the same or different at each position.
  • substituted used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence.
  • the present invention is not intended to limit the allowed substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any restriction to the present invention.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by those skilled in the art to which the present invention belongs.
  • the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • the compounds of the present invention are prepared by the following method
  • LG 1 , LG 2 , LG 3, LG 4 , and LG 5 are leaving groups, each independently selected from the group consisting of: H, OH, halogen, OTf, OTs, OMs, -B(OH) 2 , -B(KBF 3 ), -Sn( n Bu) 3 , wait;
  • the Pd catalyst is selected from: Pd(OAc) 2 , Pd(dba) 2 , Pd 2 (dba) 3 , XPhos PdG2, RuPhos PdG2, XantPhos-Pd-G2, cataCXium A-Pd-G2, XPhos PdG3, RuPhos PdG3, XantPhos -Pd-G3, cataCXium A-Pd-G3, BrettPhos PdG3, SPhos PdG3, tBuXPhos-Pd-G3, XantPhos-Pd-G4, BrettPhos PG4, SPhos Pd G4, cataCXium A-Pd-G4, Rockphos PdG4, etc.;
  • R 1a , R 1b , R 1c , R 2 , R 3 , Ring A, Ring B, X, Y, Z, and m are as defined above.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.
  • the compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions.
  • the administration method and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used.
  • Drug combination also includes taking the compound of formula I and one or more other known drugs in overlapping time periods.
  • the dosage of the compound of formula I or the known drug may be lower than the dosage of them taken alone.
  • the drugs or active ingredients that can be used in combination with the compounds of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumuma
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • compositions of the present invention include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings. and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that may be used are polymeric substances and waxes. If necessary, the active compound may also be in microcapsule form with one or more of the above excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compounds of the general formula (I-A) and formula (I-B) of the present invention or their crystal forms, pharmaceutically acceptable salts, hydrates or solvates, thereby forming a pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the steps of administering the compound of general formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition described in the present invention to a subject in need of treatment, for inhibiting KRAS mutation.
  • the present invention has the following main advantages:
  • the compound has a good inhibitory effect on KRAS mutation
  • the compound has better pharmacodynamics, pharmacokinetic properties and lower toxic side effects.
  • the structure of the compound of the present invention is confirmed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • NMR was measured using a Bruker AVANCE-400 NMR spectrometer.
  • the measurement solvents included deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol (CD 3 OD).
  • Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).
  • LC-MS Liquid chromatography-mass spectrometry
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.
  • Step 1 Preparation of 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one
  • Step 2 Preparation of (R)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)vinyl)-2-methylpropane-2-sulfenamide
  • Step 3 Preparation of (R)-N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfenamide
  • Step 4 Preparation of 3-(1-aminoethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine hydrochloride
  • Step 1 Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2,7-dichloro-8-fluoropyridin[4,3-d]pyrimidin-4-amine
  • Step 2 Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine
  • Step 1 Preparation of methyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
  • pinacol borane (304g, 1.20mol, 1.50eq), KOAc (235g, 2.39mol, 3.00eq) and Pd(dppf)Cl 2 (40.8g, 55.8mmol, 0.07eq) were added to a solution of methyl 2-amino-4-bromo-3-fluorobenzoate (198g, 798mmol, 1.00eq) in dioxane (2000mL) at room temperature.
  • the mixture was reacted at 90°C for 16h under nitrogen protection, then cooled to room temperature and filtered.
  • the filter cake was washed with EtOAc (2L).
  • the filtrates were combined and diluted with H 2 O (2L) and extracted with EtOAc (2 x 1.5L).
  • Step 2 Preparation of methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3-fluorobenzoate
  • 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (47.3 g, 105 mmol, 1.00 eq)
  • Pd-118 (6.85 g, 10.5 mmol, 0.10 eq)
  • KF (18.3 g, 315 mmol, 3.00 eq)
  • methyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (31.0 g, 105 mmol, 1.00 eq) in dioxane (400 mL) and water (40 mL) at room temperature.
  • the mixture was reacted at 100°C for 1 h under nitrogen protection, then cooled to room temperature and filtered.
  • the filtrate was diluted with H 2 O (500 mL) and the mixture was purified by HPLC.
  • the mixture was extracted with EtOAc (3 x 500 mL).
  • the combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure and the residue was separated by silica gel column chromatography to obtain the target product (44.0 g, 75.4 mmol, 71.78% yield).
  • Step 3 Preparation of methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzoate
  • NCS (12.5 g, 94.2 mmol, 1.25 eq) was added to a solution of methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3-fluorobenzoate (44.0 g, 75.4 mmol, 1.00 eq) in NMP (500 mL).
  • NMP 500 mL
  • the mixture was reacted at 70°C for 3 h, then cooled to 0°C, diluted with H 2 O (500 mL), and extracted with EtOAc (3x200 mL).
  • the combined organic phase was washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate, and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (17.5 g, 28.3 mmol, 37.5% yield).
  • Step 4 Preparation of 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzoic acid
  • Step 5 Preparation of 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3-fluorobenzamide
  • Step 6 Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4(3H)-one
  • Intermediate 3-1 was subjected to SFC chiral separation (chiral column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 40%, isocratic elution mode) to obtain intermediate 3-1A and intermediate 3-1B.
  • SFC chiral separation chiral column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 40%, isocratic elution mode
  • Intermediate 3-4 was subjected to SFC chiral separation (chiral column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um ); mobile phase: [CO2-EtOH (0.1% NH3H2O )]; B%: 40%, isocratic elution mode) to obtain intermediate 3-4A and intermediate 3-4B.
  • N,N-bis(4-methoxybenzyl)-3-(1-(methylamino)ethyl)pyridin-2-amine (72.5 mg, 185 ⁇ mol, 1.00 eq)
  • DIEA (239 mg, 1.85 mmol, 322 ⁇ L, 10.0 eq)
  • Bop-Cl (188 mg, 741 ⁇ mol, 4.00 eq) were added to a solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-8-fluoroquinazolin-4(3H)-one (120 mg, 185 ⁇ mol, 1.00 eq) in DCM (3 mL).
  • Step 1 Preparation of methyl 4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-2-(2-cyanoacetyl)-3-fluorobenzoate
  • Step 2 Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2,4-dihydroquinoline-3-carbonitrile
  • Step 3 Preparation of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile
  • Step 1 Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine
  • N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-amine 630 mg, 958 ⁇ mol, 1.00 eq
  • 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropylsilane (589 mg, 1.15 mmol, 1.20 eq)
  • CataxciAm Pd G2 (64.1 mg, 95.9 ⁇ mol, 0.100 eq) in dioxane (10 mL) and H 2 O (2 mL) was reacted at 100
  • Step 2 Preparation of N-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridin[4,3-d]pyrimidin-4-amine
  • Step 3 Preparation of 4-(4-((1-(2-aminopyridin-3-yl)ethyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol
  • Step 4 Preparation of 4-(4-((1-(2-aminopyridin-3-yl)ethyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example A2 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine
  • Example A2-A 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-((R)-2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine
  • Example A2-B 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-((S)-2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine
  • Example A3 4-(4-((1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • Example A4 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylpyridin[4,3-d]pyrimidin-4-amine
  • Example A5 4-(4-((1-(2-2-aminopyridin-3-yl)ethyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
  • Example A6 4-(4-((1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example A10 Example A11 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-4-amine
  • Example A12 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-pyridin[4,3-d]pyrimidin-4-amine
  • Example A21 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-ethyl-8-fluoro-pyridin[4,3-d]pyrimidin-4-amine
  • Example A22 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl-N-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine
  • Example A22 was subjected to SFC chiral separation to obtain Examples A22-A and A22-B:
  • Example A23 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-(2-methoxyethyl)pyridin[4,3-d]pyrimidin-4-amine trifluoroacetate
  • Example A24 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)ethyl)-N-cyclopropyl-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-4-amine trifluoroacetate
  • Example A25 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(1-(2-aminopyridin-3-yl)propyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylpyridin[4,3-d]pyrimidin-4-amine trifluoroacetate
  • Example A26 4-(4-((1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example A31 4-(4-((1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate
  • Example A32 was chirally separated by SFC to give Examples A32-A and A32-B: N-((R)1-(2-aminopyridin-3-yl)ethyl)-N-ethyl-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-amine and N-((S)1-(2-aminopyridin-3-yl)ethyl)-N-ethyl-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)meth
  • Embodiment A32-A is a diagrammatic representation of Embodiment A32-A.
  • Embodiment A32-B is a diagrammatic representation of Embodiment A32-B.
  • Example A33 2-amino-4-(4-((1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-7-fluorophenylpropano[b]thiophene-3-carbonitrile trifluoroacetate
  • Example A33 was chirally separated by SFC to give Examples A33-A and A33-B: 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-7-fluorophenylpropyl[b]thiophene-3-carbonitrile and 2-amino-4-(4-(((S)-1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyr
  • Embodiment A33-A is a diagrammatic representation of Embodiment A33-A.
  • Embodiment A33-B is a diagrammatic representation of Embodiment A33-B.
  • Step 1 Preparation of (S)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine
  • Step 2 Preparation of (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine
  • the residue was alkalized with aqueous sodium bicarbonate solution and then The residue was extracted with ethyl acetate, and the combined organic phase was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation to obtain the target product (203 mg, yield: 51%).
  • Example B2 (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylquinazolin-4-amine
  • Example B3 (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine
  • Example B4 (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylquinazolin-4-amine
  • Example B5 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-N-ethyl-8-fluoroquinazolin-4-amine
  • Example B5 was separated by preparative liquid phase to obtain Examples B5-A and B5-B:
  • Embodiment B5-A is a diagrammatic representation of Embodiment B5-A.
  • Embodiment B5-B is a diagrammatic representation of Embodiment B5-B.
  • Example B6 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-(1-(2-aminopyridin-3-yl)ethyl)-6-chloro-N-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-amine
  • Example B6 was separated by preparative liquid phase to obtain Examples B6-A and B6-B:
  • Embodiment B6-B is a diagrammatic representation of Embodiment B6-B.
  • Example B7 (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methylquinazolin-4-amine
  • Example B8 (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylquinazolin-4-amine
  • Example B9 (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methylquinazolin-4-amine
  • Example B10 (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-N-methylquinazolin-4-amine
  • Example B11A (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((S)-1-(2-amino-5-fluoropyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine
  • Example B11B (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-amino-5-fluoropyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine
  • Example B12A (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(3-amino-pyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine
  • Example B12B (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((S)-1-(3-amino-pyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinazolin-4-amine
  • Example B13A and Example B13B (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (S)-2-amino -4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cycloprop
  • Example B14A and Example B14B (R)-7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl Quinazolin-4-amine and (S)-7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro
  • Example B15A and Example B15B (R)-7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl Quinazolin-4-amine and (S)-7-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3
  • Example B16A and Example B16B 7-((R)-3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl Quinazolin-4-amine and 7-((S)-3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3
  • Example B17A and Example B17B 7-((R)-3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methyl Quinazolin-4-amine and 7-((S)-3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro
  • Example B18A and Example B18B (S)-7-(6-amino-4-(prop-1-yn-1-yl)-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methyl Quinazolin-4-amine and (R)-7-(6-amino-4-(prop-1-yn-1-yl)-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-d
  • Example B19A and Example B19B (S)-7-(3-amino-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methyl Quinazolin-4-amine and (R)-7-(3-amino-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,
  • Example B20A and Example B20B (R)-7-(5-amino-4-fluoro-3-(prop-1-yn-1-yl)-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoro-N-methyl Quinazolin-4-amine and (S)-7-(5-amino-4-fluoro-3-(prop-1-yn-1-yl)-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((1S,7a'S)-2,
  • Example B21A and Example B21B (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl-N-((S)-1-(2-(methylamino)pyridin-3-yl) ethyl)quinazolin-4-amine and (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrol
  • Example B22 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazoline-6-carbonitrile
  • Examples B24A, B24B, B24C and B24D (R)-2-amino-4-(4-(((S)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl )-7-fluorobenzo[b]thiophene-3-carbonitrile, (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'
  • Examples B25A and B25B (R)-7-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methylquinol Quinazoline-4-amine and (S)-7-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3
  • Example B28 Preparation of (R)-2-amino-4-(4-(((R)-1-(2-2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B29 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-azetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B31 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-piperidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B32 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(4-(dimethylamino)-piperidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate
  • Example B33 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(6-methyl-1,6-diazaspiro[3.3]hept-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B34 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(1-methyl-1,6-diazaspiro[3.3]hept-6-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate
  • Example B35 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-methylazetidin-3-yl)oxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate
  • Example B36 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-methylazetidin-3-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate
  • Example B37 (R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoro-N-methylquinazolin-4-amine
  • Example B38 (4R)-4-(4-((1-(1H-pyrazol-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate
  • Example B39A and 39B (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-fluoro-8-(prop-1-yn-1-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiol phene-3-carbonitrile and (S)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro
  • Embodiment B39B is a diagrammatic representation of Embodiment B39B.
  • Examples B40A and B40B (S)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-7-fluorobenzo[b]thiol Thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1
  • Embodiment B40A is a diagrammatic representation of Embodiment B40A.
  • Embodiment B40B is a diagrammatic representation of Embodiment B40B.
  • Example B41 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate
  • Example B42 (R)-2-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Embodiment B43B is a diagrammatic representation of Embodiment B43B.
  • Example B46 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((trans)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B46 was chirally resolved to give the isomers
  • Example B46A and Example B46B (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4R)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thi
  • Example B47 was subjected to chiral separation to give the isomers
  • Example B48 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)oxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile trifluoroacetate
  • Example B50 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B51 (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B53 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((S)-1-((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)ethoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B54 (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B56 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((S)-4-(difluoromethylenyl)-1-methylpyrrolidin-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B58 (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((2S)-6,6-difluoro-3-methyl-3-azabicyclo[3.1.0]ethane-2-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Embodiments B63A, B63B, B63C and B63D are identical to Embodiments B63A, B63B, B63C and B63D:
  • Embodiments B64A, B64B, B64C and B64D are identical to Embodiments B64A, B64B, B64C and B64D:
  • Embodiments B65A, B65B, B65C and B65D are identical to Embodiments B65A, B65B, B65C and B65D:
  • Embodiments B66A, B66B, B66C and B66D are identical to Embodiments B66A, B66B, B66C and B66D:
  • Example B68 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B70 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(fluoromethylenyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B71 (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(fluoromethylenyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B72 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(difluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B73 (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8- Fluoro-2-((1-((4-(difluoromethylenyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B74 (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(difluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B75 (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((4-(difluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B76 (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-((1-((6-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B77 (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B78 (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((1,1-difluoro-5-azaspiro[2.4]heptane-5-yl)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B79 (4R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B80 (4R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B81 (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-((S)-2-(dimethylamino)propyl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B82 (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro -2-((S)-1-(dimethylamino-2-yl)propyl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B83 N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-N-methylquinazolin-4-amine
  • Example B84 N-((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-N-methylquinazolin-4-amine
  • Example B84 was subjected to chiral separation to give Examples B84A and B84B: N-((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-((S)-6-fluoro-5-methyl-1H-indazol-4-yl )-N-methylquinazolin-4-amine and N-((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused
  • Example B85 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile
  • Example B85 was subjected to chiral separation to give Examples B85A and B85B: (S)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,7-dihydro- Fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-diflu
  • Example B86 2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile
  • Example B86 was subjected to chiral separation to give Examples B86A and B86B: (S)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,7-dihydro- Fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-d
  • Example B87 2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile
  • Example B88 2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile
  • Embodiments B89A, B89B, B89C and B89D are identical to Embodiments B89A, B89B, B89C and B89D:
  • Example B90 (4R)-2-amino-4-(6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1-(imidazole[1,2-a]pyrazin-5-yl)ethyl)(methyl)amino)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B92 was subjected to chiral separation to give Examples B92A and B92B: (4R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (4R)-2-amino-4-(4-(((S)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (4R)-2-amino-4
  • Example B98A and Example B98B (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b] Thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((S)-1-(2-aminopyridin-3-yl)ethyl)(ethyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spir
  • Example B99A and Example B99B (R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b] Thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((S)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclo
  • Example B100A and Example B100B (R)-2-amino-4-(4-(((R)-1-(3-aminopyridazin-4-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b ]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((S)-1-(3-aminopyridazin-4-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-s
  • Example B101 (R)-2-amino-4-(4-((1-(5-amino-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B103 (4R)-4-(4-((1-(1H-indazol-7-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B104 (4R)-4-(4-((1-(1H-indazol-7-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B105 (4R)-4-(4-((1-(1H-pyrazol[3,4-c]pyridin-7-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B107 (4R)-4-(4-((1-(3H-imidazole [4,5-c] pyridin-4-yl) ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B109A and Example B109B (R)-2-amino-4-(6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(methyl((R)-1-(pyridazin-4-yl)ethyl)amino)quinazolin-7-yl)-7-fluorobenzo[ b]thiophene-3-carbonitrile and (R)-2-amino-4-(6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4
  • Example B110A and Example B110B (R)-2-amino-4-(6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro -1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(methyl((R)-1-(pyrazin-3-yl)ethyl)amino)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(
  • Example B111 (4R)-2-amino-4-(6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1-(5-methoxypyridin-3-yl)ethyl)(methyl)amino)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B112 (4R)-2-amino-4-(6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1-(2-methoxypyridin-3-yl)ethyl)(methyl)amino)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B113 2-(1-((7-((R)-2-amino-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)(methyl)amino)ethyl)-N,N-dimethylisonicotinamide
  • Example B115 was subjected to chiral separation to give Example B115A and Example B115B: (R)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl) Thiopheno[2,3-b]pyridine-3-carbonitrile and (S)-2-amino-4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'
  • Example B116 2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)thiophene[2,3-b]pyridine-3-carbonitrile
  • Example B117A and B117B (S)-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6 -fluoronaphthalen-2-ol and (R)-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-
  • Example B118 N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-7-(5,7-difluoro-1H-indol-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy-8-fluoro-N-methylquinazolin-4-amine
  • Example B120 4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example B124 2-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)ethyl)(methyl)amino)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-3-(trifluoromethyl)benzonitrile
  • Example B126 N-((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl-7-(4-methyl-1-(oxetane-3-yl)-1H-pyrazol-5-yl)quinazolin-4-amine
  • Example B127 N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl-7-(4-methyl-1-(oxetane-3-yl)-1H-pyrazol-3-yl)quinazolin-4-amine
  • Example B128 N-((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-N-methyl-7-(4-methyl-1-(oxetane-3-yl)-1H-pyrazol-3-yl)quinazolin-4-amine
  • Example B129 1-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro -1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)isoquinoline-8-carbonitrile
  • Example B130 1-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)isoquinoline-8-carbonitrile
  • Example B131 was subjected to chiral separation to give Example B131A and Example B131B: (R)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(5-fluoroquinoline- 8-yl)-N-methylquinazolin-4-amine and (S)-N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]
  • Example B132 N-((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(5-fluoroquinolin-8-yl)-N-methylquinazolin-4-amine
  • Example B133 N-((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(5-ethynylisoquinolin-4-yl)-8-fluoro-N-methylquinazolin-4-amine
  • Example B134 N-((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(5-ethynylisoquinolin-4-yl)-8-fluoro-N-methylquinazolin-4-amine
  • Example B135 4-(4-(((R)-1-(2-aminopyridin-3-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)isoquinoline-5-carbonitrile
  • Example B136 4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)-6-chloro-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)isoquinoline-5-carbonitrile
  • Example B137 was subjected to chiral separation to give Examples B137A and B137B: (S)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile and
  • Example B138 2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile
  • Example B138 was subjected to chiral separation to give Examples B138A and B138B: (S)-2-amino-4-(4-(((R)-1-(3- (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-7-yl)-5
  • Example B140 5-(1-((7-((R)-2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-4-yl)(methyl)amino)ethyl)-N,N,1-trimethyl-1H-pyrazole-3-carboxamide
  • Example B141 3-(1-((7-((R)-2-amino-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-6-chloro-2-(3-(dimethylamino)-3-methylazetidin-1-yl)-8-fluoroquinazolin-4-yl)(methyl)amino)ethyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide
  • Example B143 was chirally resolved to give the isomers
  • Example B143A and Example B143B (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4R)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b
  • Example B144 was chirally resolved to give isomers
  • Example B144A and Example B144B (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino -4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4R)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b
  • Example B145 was chirally resolved to give the isomers
  • Example B145A and Example B145B (R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4R)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b
  • Example B146 was chirally resolved to give the isomers
  • Example B146A and Example B146B (R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4S)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4R)-4-(dimethylamino)tetrahydrofuran-3-yl)oxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b
  • Example B149A and Example B149B (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1,2-dimethylpyrrolin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(3-aminopyrazin-2-yl)ethyl)(methyl)amino)-6-chloro-8-fluoro-2-(((2R,4R)-4-fluoro-1,2-dimethylpyrrolin-2-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Examples B156A and B156B (R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(((3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoroquinazolin-7-yl)-7- Fluorobenzo[b]thiophene-3-carbonitrile and (R)-2-amino-4-(4-(((R)-1-(4-aminopyrimidin-5-yl)ethyl)(methyl)amino)-6-chloro-2-(((3R,4R)-4-(difluoromethyl)-1,3-dimethylpiperidin-3-yl)methoxy)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-

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Abstract

本发明涉及取代的胺基嘧啶并环类抑制剂及其制备方法和应用。具体地，本发明化合物具有式(I0)所示结构，本发明还公开了所述化合物的制备方法及其作为KRAS突变抑制剂的用途，对KRAS突变具有很好的抑制作用且具有更好的药效学、药代动力学性能和更低的毒副作用。

Description

取代嘧啶并环类抑制剂及其制备方法和应用 技术领域
本发明属于药物领域，具体涉及一种取代嘧啶并环类抑制剂及其制备方法和应用。
背景技术
在所有人类肿瘤中约四分之一是由RAS突变引起，每年有近一百万人因此而失去生命。在RAS家族中，KRAS突变占到了所有RAS突变的85％。在近90％的胰腺癌、30-40％的结肠癌中、以及15-20％的肺癌中(主要为非小细胞肺癌)中均发现KRAS突变。
KRAS蛋白是由KRAS基因编码的一种小GTP酶，是细胞生长的重要调节蛋白，一旦KRAS被激活后，可以激活多条信号通路，促进细胞的增殖。KRAS蛋白最常发生基因突变的位点是第12、13和61位密码子，其中以12位密码子的突变最为常见。在KRAS G12突变中最主要的突变是G12A、G12C、G12D、G12V、G12S等突变，其中G12C、G12D、G12V等突变主要发生在NSCLC、CRC和胰腺癌中。到目前为止，市场上仍然没有同时针对多种KRAS突变的药物被批准上市。
由于KRAS突变靶蛋白在病理学上与多种疾病相关，尤其肺癌、胰腺癌、结直肠癌等，因此目前需要新型的KRAS突变抑制剂用于临床治疗。高活性的KRAS突变抑制剂可以对KRAS突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。
发明内容
本发明的目的在于提供一类新型的对KRAS突变有抑制作用和/或更好药效学性能的化合物及其用途。
本发明的第一方面中，提供了一种式(I0)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药
式中，
选自下组：
在另一优选例中，提供了一种式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
其中，
选自下组：优选地,选自下组：
在另一优选例中，环B选自取代或未取代的下组基团：C6-C14芳基、5-14元环杂芳基；其中，所述取代是指被一个或多个R取代；
R1a独立地选自取代或未取代的下组基团：氢、氘、C1-C10烷基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
R1b独立地选自取代或未取代的下组基团：氢、氘、C1-C10烷基、C1-C10烷氧基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C1-C10烷氧基C1-C6亚烷基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
R1c独立地选自取代或未取代的下组基团：C1-C10烷基、C1-C10烷氧基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C1-C10烷氧基C1-C6亚烷基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
或者R1a和R1c连接起来形成4-7元环；
R2选自取代或未取代的下组基团：C6-C14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个R取代；
R3各自独立地选自取代或未取代的下组基团：H、氘、卤素、氰基、酯基、胺基、酰胺基、砜基、脲基、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C6环烷基、4-6元杂环基、C1-C6烷基氧基、C3-C6环烷基氧基、4-6元杂环基氧基；其中，所述取代是指被一个或多个R取代；
m为0、1、2、3、4、5或6的整数；
X选自：键、O、NH、N(C1-C3烷基)、C≡C；
Y选自：键、取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
1)Z选自：
其中，环W1选自取代或未取代的下组基团：C3-C20环烷基、4-20元饱和或不饱和的杂环基；其中，所述取代是指被一个或多个R取代；
R4选自：H、氘、烯基、氟代烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(＝O)、氰基、酯基、胺基、酰胺基、砜基或脲基；
n选自：0、1、2、3、4、5或6的整数；
或者
2)Z选自：-L4-Q2或者
其中，环W2选自取代或未取代的下组基团：C3-C6亚环烷基、4-6元饱和或不饱和的亚杂环基；其中，所述取代是指被一个或多个R取代；
各L4独立的选自取代或未取代的下组基团：键、C1-C6亚烷基、氘代C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
各Q2独立的选自取代或未取代的下组基团：C1-C6烷氧基、C3-C10环烷基氧基、4-10元杂环基氧基、C3-C10环烷基C1-C6亚烷基氧基、4-10元杂环基C1-C6亚烷基氧基、C3-C10环烷基、4-10元杂环基、NHR9、NR9R10；R9和R10各自独立地选自取代或未取代的下组基团：C1-C6烷基、C3-C10环烷基、4-10元杂环基、(C3-C10环烷基)C1-C6亚烷基、(4-10元杂环基)C1-C6亚烷基，或R9和R10与其连接的N原子共同形成取代或未取代的4-10元杂环基；其中，所述取代是指被一个或多个R取代；
各R相同或不同，各自独立地选自：H、氘、烯基、氟代烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、C1-C6亚烷基、卤代C1-C6亚烷基、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基(如-C≡C-CH3)、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(＝O)、氰基、酯基、胺基、酰胺基、砜 基或脲基。
在另一优选例中，R1a独立地选自取代或未取代的下组基团：氢、氘、C1-C10烷基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；R1b独立地选自取代或未取代的下组基团：氢、氘、C1-C10烷基、C1-C10烷氧基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C1-C10烷氧基C1-C6亚烷基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；R1c独立地选自取代或未取代的下组基团：C1-C10烷基、C1-C10烷氧基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C1-C10烷氧基C1-C6亚烷基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；其余变量如前定义。
在另一优选例中，所述化合物具有式(II-A)或式(II-B)所示的结构：
式中，
环B、R1a、R1b、R1c、R2、R3、X、Y、Z和m的定义如上所述。
在另一优选例中，所述化合物具有式(III-A1)、式(III-A2)或式(III-B1)、式(III-B2)所示的结构：
式中，环B、R1a、R1b、R1c、R2、R3、R4、X、Y、W1、W2、L4、Q2、m和n的定义如上所述。
在另一优选例中，所述化合物具有式(III-A1)或式(III-B1)所示的结构。
在另一优选例中，X为O。
在另一优选例中，所述化合物具有式(IV-A1)、式(IV-A2)或式(IV-B1)、式(IV-B2)所示的结构：

式中，
环B、R1a、R1b、R1c、R2、R3、R4、Y、W1、W2、L4、Q2、m和n的定义如上所述。
在另一优选例中，所述化合物具有式(IV-A1)或式(IV-B1)所示的结构。
在另一优选例中，R1a为C1-C10烷基；R1b为氢；和R1c为C1-C10烷基；较佳地，R1a为C1-C4烷基；R1b为氢；和R1c为C1-C4烷基；更佳地，R1a为甲基；R1b为氢；和R1c为甲基。
在另一优选例中，所述化合物具有式(V-A1)、式(V-A2)或式(V-B1)、式(V-B2)所示的结构：
式中，环B、R2、R3、R4、Y、W1、W2、L4、Q2、m和n的定义如权利要求1所述；
在另一优选例中，所述化合物具有式(V-A1)或式(V-B1)所示的结构。
在另一优选例中，所述化合物具有式(VI-A1)、或式(VI-B1)所示的结构：
式中，环B、R2、R3、m和n的定义如权利要求1所述，各R5相同或不同，各自独立地选自氢或氘。
在另一优选例中，所述化合物具有式(VII-A1)或式(VII-B1)所示的结构：
式中，
P1、P2、P3各自独立地选自C-H、C-F、C-Cl、C-CN、C-CF3、或N；
环B、R1a、R1b、R1c、R3、R4、X、Y、W1、W2、L4、Q2、m和n的定义如权利要求1所述；
在另一优选例中，所述化合物具有式(VII-B1)所示的结构。
在另一优选例中，Y为CH2、CD2。
在另一优选例中，为和/或为
在另一优选例中，R3相同或不同，各自独立的选自下组：H、氘、卤素、氰基、取代或非取代的C1-C6烷基、或取代或非取代的C1-C6烷氧基。
在另一优选例中，R3相同或不同，各自独立的选自卤素。
在另一优选例中，W1选自：取代或未取代的4-7元的单环杂环基、取代或未取代的C3-C7单环环烷基、取代或未取代的6-10元的双环杂环基、取代或未取代的C6-C10双环环烷基、取代或未取代的的7-12元的三环杂环基、取代或未取代的C7-C12三环环烷基，优选地，W1为取代或未取代的8-12元含N杂环基，其中，所述取代是指被一个或多个R取代，R的定义如上所述；
优选地，选自：

其中，n’为0、1、2、3、4、5、或6的整数；R、R4和n的定义如上所述，R、R4可以取代在多环(如桥环或螺环)的任意一个环上；
更优选地，选自：

其中，n’为0、1、2、3、4、5或6的整数；R、R4和n的定义如上所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
在另一优选例中，选自：
或者选自：

其中，n’为0、1、2、3、4、5、或6的整数；R、R4和n的定义如上所述，R、R4可以取代在多环(如桥环或螺环)的任意一个环上；
更优选地，选自：
其中，n’为0、1、2、3、4、5或6的整数；R、R4和n的定义如上所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
在另一优选例中，为较佳地，其中R各自独立地为氢或氘。
在另一优选例中，L4选自：键、CH2、CD2、CH(CH3)。
在另一优选例中，Q2选自：NHCH3、N(CH3)2、
在另一优选例中，选自：
在另一优选例中，为优选地，选自：
在另一优选例中，R2选自取代或未取代的下组基团：苯基、萘基、5-6元单环杂芳基(如吡啶基)、9-10元双环杂芳基(如吲唑基、苯并噻唑、苯并噻吩、苯并呋喃)，其中所述取代是被选自下组的一个或多个基团取代：卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基(如乙炔基或丙炔基)、酯基、胺基、酰胺基、砜基、脲基、磺酰胺基、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH(羟基取代的C3-C6环烷基)、4-6元杂环基OH(羟基取代的4-6元杂环基)；优选地，R2选自：
或者选自：
或者选自：

或者选自：
在另一优选例中，R2选自取代或未取代的下组基团：苯基、5-6元单环杂芳基(较佳地所述5-6元单环杂芳基仅含1、2或3个氮作为杂原子，如吡啶基)、或萘基，其中所述取代如前定义。
在另一优选例中，当R2与分子其它部分连接的碳为手性碳，则该手性碳为R构型或S构型。
在另一优选例中，环B选自取代或未取代的下组基团：苯基、萘基、5-6元单环杂芳基(如吡唑基、噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基)、9-10元双环杂芳基(如吲唑基、苯并噻唑、苯并噻吩、苯并呋喃)，其中所述取代是被选自下组的一个或多个基团取代：卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基、酯基、胺基、酰胺基、砜基、脲基、磺酰胺基、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH(羟基取代的C3-C6环烷基)、4-6元杂环基OH(羟基取代的4-6元杂环基)；优选地，环B选自：

在另一优选例中，环B选自取代的下组基团：苯基、6元单环杂芳基(如吡啶基、嘧啶基、哒嗪基、吡嗪基)；并且所述取代是指被一个NH2(较佳地，该NH2取代于苯基或元单环杂芳基环B与分子其它部分连接的邻位)和任选地一个或多个选自下组取代基所取代的：卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基、酯基、胺基、酰胺基、砜基、脲基、磺酰胺基、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH、4-6元杂环基OH；较佳地，所述取代是指被一个NH2取代和0或一个或多个选自下组取代基取代的：卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基。
在另一优选例中，环B选自：
在另一优选例中，R1a选自下组：H、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、4-6元杂环基、卤代C3-C6环烷基、卤代4-6元杂环基、C1-C6烷氧基C1-C6亚烷基、卤代C1-C6烷氧基C1-C6亚烷基、C3-C6环烷基C1-C6亚烷基、4-6元杂环基C1-C6亚烷基；优选地，R1a选自下组：H、甲基、乙基、异丙基、环丙基、氧杂环丁基、CH2环丙基、CH2CH2OCH3、CH(CH3)CH2OCH3。更优选地，R1a选自下组：甲基、乙基。
在另一优选例中，R1b独立地选自下组：H、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、卤代C3-C6环烷基、卤代4-6元杂环基、C1-C6烷氧基C1-C6亚烷基、卤代C1-C6烷氧基C1-C6亚烷基、C3-C6环烷基C1-C6亚烷基、4-6元杂环基C1-C6亚烷基；优选地，R1b独立地选自下组：H、甲基、乙基、异丙基、环丙基、氧杂环丁基。更优选地，R1b为H。
在另一优选例中，R1c独立地选自下组：C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、卤代C3-C6环烷基、卤代4-6元杂环基、C1-C6烷氧基C1-C6亚烷基、卤代C1-C6烷氧基C1-C6亚烷基、C3-C6环烷基C1-C6亚烷基、4-6元杂环基C1-C6亚烷基；优选地，R1c独立地选自下组：甲基、乙基、异丙基、环丙基、氧杂环丁基。更优选地，R1c为C1-C6烷基(如甲基、乙基)。
在另一优选例中，R1a选自下组：甲基、乙基，R1b选自H，且R1c选自甲基。
在另一优选例中，当R1b和R1c不同时，则与R1b和R1c连接的碳为R构型或S构型的。
在另一优选例中，环B、R1a、R1b、R1c、R2、R3、R4、X、Y、W1、W2、L4、Q2、m和n具有实施例中各具体化合物所对应基团。
在另一优选例中，环B、R1a、R1b、R1c、R2、R3、R4、X、Y、W1、W2、L4、Q2、m和n具有如下各具体化合物所对应基团。
在另一优选例中，所述化合物选自下组：






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在另一优选例中，所述化合物优选为实施例中所制备的化合物。
本发明第二方面，提供一种制备式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，其特征在于，包括步骤：
(i)在惰性溶剂中，碱存在下，有或者没有Pd催化剂，有或者没有缩合剂存在下，式X-I化合物与式X-II化合物反应，得到式X-III化合物；
(ii)在惰性溶剂中，碱存在下，Pd或其他金属催化剂存在下，式X-III化合物与式X-IV化合物反应，得到式X-V化合物；
(iii)在惰性溶剂中，碱存在下，有或者没有Pd催化剂存在下，式X-V化合物与式X-VI化合物反应，得到式I化合物；
LG1、LG2、LG3、LG4、以及LG5为离去基团，各自独立地选自：H、OH、卤素、OTf、OTs、OMs、-B(OH)2、-B(KBF3)、-Sn(nBu)3、等；
Pd催化剂选自：Pd(OAc)2、Pd(dba)2、Pd2(dba)3、XPhos PdG2、RuPhos PdG2、XantPhos-Pd-G2、cataCXium A-Pd-G2、XPhos PdG3、RuPhos PdG3、XantPhos-Pd-G3、cataCXium A-Pd-G3、BrettPhos PdG3、SPhos PdG3、tBuXPhos-Pd-G3、XantPhos-Pd-G4、BrettPhos PG4、SPhos PdG4、cataCXium A-Pd-G4、Rockphos PdG4等；
R1a、R1b、R1c、R2、R3、环A、环B、X、Y、Z、和m的定义如上所述。
本发明第三方面，提供一种药物组合物，其包含一种或多种第一方面所述的化合物、 其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和药学上可接受的载体。
在另一优选例中，所述药物组合物还包含选自下组的药物：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、SOS1抑制剂(如BI 1701963)或其组合。
本发明第四方面，提供一种如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或如第三方面所述的药物组合物的用途，用于制备预防和/或治疗与KRAS突变的活性或表达量相关的疾病的药物，优选地，所述的疾病为肿瘤或失调性疾病。
在另一优选例中，所述疾病选自下组：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
在另一优选例中，所述KRAS突变选自下组：G12D、G12V、G12R、G12S、G12A、G12C、或其组合，优选地，所述KRAS突变选自下组：G12D、G12V、G12R、或其组合，更优选地，所述KRAS突变为G12V。
本发明第五方面，提供了一种非诊断性、非治疗性地抑制KRAS突变的方法，其包括步骤：向所需对象施用有效量的如第一方面所述的化合物、其立体异构体、互变 异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用如第三方面所述的药物组合物。
在另一优选例中，所述的对象为哺乳动物，较佳地为人。
本发明第六方面，提供一种体外抑制KRAS突变活性的方法，包括步骤：将如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或如第三方面所述的药物组合物与蛋白或者细胞接触，从而抑制KRAS突变体的活性。
在另一优选例中，所述的细胞选自下组：巨噬细胞、肠道细胞(包括肠干细胞、肠上皮细胞)、或其组合。
在另一优选例中，所述的细胞来自啮齿动物(如小鼠、大鼠)、或灵长动物(如人)。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一类新型的KRAS突变有抑制作用和/或更好药效学性能的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
术语“烷基”是指直链或支链烷烃基或环状烃基(包括通过环上碳或非环上与其它部分连接的烃基)，优选指直链或支链烷烃基，包含1-20个碳原子，如1-18个碳原子，尤其指1-18个碳原子，优选地包含1-10个碳原子(C1-C10)，更优选地包含1-6个碳原子(C1-C6)或包含1-3个碳原子(C1-C3)。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基，十二烷基等等。本发明中，烷基还包括取代烷基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)Ra、或NRbP(＝O)2Re，其中在此出现的Ra可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、5-14元杂环或C6-C14芳环，Rb、Rc和Rd可以独立表示氢、氘、C1-C6烷基、C3-C8环烷基、5-14元杂环或C6-C14芳环，或者说Rb和Rc与N原子一起可以形成杂 环；Re可以独立表示氢、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C6环烯基、C2-C6炔基、5-14元杂环或C6-C14芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“亚烷基”是指“烷基或取代的烷基”再脱掉一个氢原子所形成的基团，如亚甲基(如或-CH2-)、亚乙基(如)、亚丙基(如)、亚异丙基(如)、亚丁基(如)、亚戊基(如)、亚己基(如)、亚庚基(如)、等。此外，所述术语还包括亚烷基(如C1-C18亚烷基)的一个亚甲基被一个亚环烷基(如C3-C20亚环烷基)所替换，例如“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”。本发明中，亚烷基还包括取代亚烷基，取代基可以为卤代(如-CHF-或-CF2-)、羟基、氰基、硝基等。
术语“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”具有相同含义，是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，如 等。优选地C1-C6亚烷基C3-C6亚环烷基。本发明中，“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”还包括取代“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”，取代基可以为卤代、羟基、氰基、硝基等。
本发明中，术语“烯基”表示含一个或多个双键且通常长度为1至20个碳原子的直链或支链的烃基。烯基优选C1-C6烯基，更优选C1-C4烯基或C2-C4烯基。烯基可以为与环烷基或杂环烷基上的碳原子直接形成双键的基团，如甲烯基(如)。烯基包括但不限于例如甲烯基(如)、乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。本发明中，烯基包括取代的烯基。本发明中，烯基还包括取代烯基，取代基可以为卤代(如 )、羟基、氰基、硝基等。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子的直链或支链的烃基。炔基优选C2-C6炔基，更优选C2-C4炔基。炔基包括但不限于乙炔基、丙炔基或类似基团。本发明中，炔基还包括取代炔基，取代基可以为卤代、羟基、氰基、硝基等。
本发明中，术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。术语“C3-C20”是指包含3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子环烷基的。环烷基优选地为C3-C14环烷基，更优选地为C3-C10环烷基，更优选地为C3-C6单环环烷基、C7-C10双环或三环环烷基。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。本发明中，“环烷基”包含取代环烷基，典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe、P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe、NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)Ra、或NRbP(＝O)2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基。上述典型的取代基可以任选取代。典型的取代还包括螺环、嘧啶并环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、嘧啶并环烷基、嘧啶并环烯基、嘧啶并环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂芳基可以任选取代。环烷基的实例包括但不限于：环丙基、环丁基、环戊基、环己基、金刚烷基等。
术语“C3-C20亚环烷基”是指环烷基脱掉两个氢原子所形成的基团，亚环烷基优选地为C3-C14亚环烷基，更优选地为C3-C10亚环烷基，更优选地为C3-C6单环亚环烷基、C7-C10双环或三环亚环烷基。如：等。所述亚环烷基可任选进一步被取代。
本发明中，术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环、4-7元单环、6-11元双环或8-16元三环或多环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。术语“4-20元杂环基”是指包含4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个环原子的杂环基。“杂环基”与“饱和或不饱和的杂环基”具有相同含义。“杂环基”优选地为4-14元杂环基(包含但不限于如4-6元单环、7-10元双环或8-14元三环或多环系统)，更优选地为4-12元杂环基，更优选地为4-10元杂 环基，如4-6元单环杂环基、7-11元双环或三环杂环基，更优选地为4-8元杂环基，更优选地为4-6元杂环基。每个杂环基含有杂原子的杂环可以带有1、2、3或4个杂原子，这些杂原子各自独立地选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上，优选连接到环或环系分子上的N或C原子。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“4-20元亚杂环基”是指杂环基脱掉两个氢原子所形成的基团，亚杂环基”优选地为4-14元亚杂环基(包含但不限于如4-6元单环、7-10元双环或8-14元三环或多环系统)，更优选地为4-12元亚杂环基，更优选地为4-10元亚杂环基，如4-6元单环亚杂环基、7-11元双环或三环亚杂环基，更优选地为4-8元亚杂环基，更优选地为4-6元亚杂环基或4-5元亚杂环基。如：等。所述亚杂环基可任选地进一步被取代。
本发明中，术语“芳基”是指芳香环状烃基团，具有1-5个环，尤其指单环和双环基团。其中，“C6-C14芳基”是指包含6、7、8、9、10、11、12、13或14个环碳原子的芳香环状烃类化合物基团。芳基优选C6-C10芳基。芳基包括苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl3的烷基)、氰基、硝基、氧代基(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环基、芳基、杂芳基、ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe、P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe、NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)Ra、或NRbP(＝O)2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基或芳基，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立 表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环基或芳基。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指包含1-4个杂原子芳香环状烃基团，其中杂原子选自氧、氮和硫的。其中，“5-14元杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
本发明中，术语“烷氧基”是指具有直链或支链烷氧基，包含烷基-O-、烷基-O-烷基，其中，“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链烷氧基，包含C1-C18烷基-O-、-C1-C6烷基-O-C1-C6烷基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基，更优选C1-C6烷氧基。
本发明中，术语“环烷基氧基”是指环烷基-O-，其中，“C3-C20环烷基氧基”是指C3-C20环烷基-O-，其中，C3-C20环烷基的定义如上所述。
本发明中，术语“杂环基氧基”是指杂环基-O-，其中，“4-20元杂环基氧基”是指4-20元杂环基-O-，其中，4-20元杂环基的定义如上所述。
本发明中，术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团。
本发明中，术语“卤素”或“卤”是指氯、溴、氟、碘。
本发明中，术语“卤代”是指被卤素取代。
本发明中，术语“氘代”是指被氘取代。
本发明中，术语“羟基”是指带有结构OH的基团。
本发明中，术语“硝基”是指带有结构NO2的基团。
本发明中，术语“氰基”是指带有结构CN的基团。
本发明中，术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。酯基优选地为-COOC1-C6烷基。
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。胺基优选地为NH2、NHC1-C6烷基、N(C1-C6烷基)2。
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。酰胺基优选地 为CONH2、NHCO(C1-C6烷基)、NHCO(C3-C6环烷基)。
术语“砜基”是指带有结构-SO2R的基团，其中R可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基，如上文所定义。砜基优选-SO2C1-C6烷基。
术语“磺酰胺基”是指带有结构-SO2NRR'的基团，其中R可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基，如上文所定义。磺酰胺基优选地为-SO2NH2、-SO2NH(C1-C6烷基)、-SO2NH(C3-C6环烷基)。
术语“脲基”是指带有结构-NRCONR'R"的基团，其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。脲基优选-NHCONH2、-NHCONH(C1-C6烷基)。
术语"烷基胺基烷基"是指带有结构-RNHR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基，如上文所定义。R和R'可以相同或不同。烷基胺基烷基优选-C1-C6亚烷基NHC1-C6烷基。
术语"二烷基胺基烷基"是指带有结构-RNHR'R"的基团，其中R、R'和R"可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环基或取代的杂环基，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。二烷基胺基烷基优选-C1-C6亚烷基N(C1-C6烷基)2。
术语"杂环基烷基"是指带有结构-RR'的基团，其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环或取代的杂环。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基(-NH2、-NH(C1-C6烷基)或-NH(C1-C6烷基)2)、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
本发明中，多个是指2、3、4、5。
活性成分
如本文所用，“本发明化合物”指式I0所示的化合物，并且还包括及式I0化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体 异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的 化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
优选地，本发明化合物采用如下方法制备
(i)在惰性溶剂中，碱存在下，有或者没有Pd催化剂，有或者没有缩合剂存在下，式X-I化合物与式X-II化合物反应，得到式X-III化合物；
(ii)在惰性溶剂中，碱存在下，Pd或其他金属催化剂存在下，式X-III化合物与式X-IV化合物反应，得到式X-V化合物；
(iii)在惰性溶剂中，碱存在下，有或者没有Pd催化剂存在下，式X-V化合物与式X-VI化合物反应，得到式I化合物；
LG1、LG2、LG3、LG4、以及LG5为离去基团，各自独立地选自：H、OH、卤素、OTf、OTs、OMs、-B(OH)2、-B(KBF3)、-Sn(nBu)3、等；
Pd催化剂选自：Pd(OAc)2、Pd(dba)2、Pd2(dba)3、XPhos PdG2、RuPhos PdG2、XantPhos-Pd-G2、cataCXium A-Pd-G2、XPhos PdG3、RuPhos PdG3、XantPhos-Pd-G3、cataCXium A-Pd-G3、BrettPhos PdG3、SPhos PdG3、tBuXPhos-Pd-G3、XantPhos-Pd-G4、BrettPhos PG4、SPhos Pd G4、cataCXium A-Pd-G4、Rockphos PdG4等；
R1a、R1b、R1c、R2、R3、环A、环B、X、Y、Z、和m的定义如上所述。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、 Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣 和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I-A)和式(I-B)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于抑制KRAS突变。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物对KRAS突变具有很好的抑制作用；
(2)所述化合物具有更好的药效学、药代动力学性能和更低的毒副作用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而 不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d6)、氘代丙酮(CD3COCD3)、氘代氯仿(CDCl3)及氘代甲醇(CD3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent1100高压色谱仪(Microsorb 5micron C18 100 x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
实施例
中间体1-1 3-(1-胺基乙基)-N,N-双(4-甲氧基苄基)吡啶-2-胺盐酸盐的制备
第一步：1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙烷-1-酮的制备
1-(2-氯吡啶-3-基)乙烷-1-酮(28.4g,182mmol,1.00eq)的二氧六环(300mL)溶液中加入DIEA(117g,912mmol,159mL,5.00eq)和1-(4-甲氧基苯基)-N-[(4-甲氧基苯基)甲基]甲胺(70.5g,273mmol,1.50eq)。混合物在110℃反应16h，用冰水(100mL)稀释后再用EtOAC(250mL*2)萃取。合并的有机相用饱和食盐水(250mL*2)洗涤后再用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(24.3g,61.3mmol,33.6％产率)。
1H NMR(400MHz,DMSO-d6)δ8.27(dd,J＝4.69,1.81Hz,1H),7.84(dd,J＝7.57,1.81Hz,1H),7.04(d,J＝8.63Hz,4H),6.71-6.93(m,5H),4.42(s,4H),3.71(s,6H)2.42(s,3H)。
第二步：(R)-N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙烯基)-2-甲基丙烷-2-亚磺酰胺的制备
1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙烷-1-酮(24.3g,64.6mmol,1.00eq)的THF(300mL)溶液中加入Ti(OEt)4(58.9g,258mmol,53.5mL,4.00eq)和(R)-2-甲基丙烷-2-亚磺酰胺(11.7g,96.8mmol,1.50eq)。混合物在180℃反应16h，用冰水(100mL)稀释后再用EtOAC(250mL*2)萃取。合并的有机相用饱和食盐水(250mL*2)洗涤后再用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(11.0g,19.2mmol,30.8％产率)。
1H NMR(400MHz,DMSO-d6)δ8.24(dd,J＝4.58,1.53Hz,1H),7.63(dd,J＝7.40,1.53Hz,1H),7.04(br d,J＝8.44Hz,4H),6.94(dd,J＝7.40,4.83Hz,1H),6.84(d,J＝8.56Hz,4H),4.22-4.48(m,4H),3.71(s,6H),2.51(dt,J＝3.48,1.68Hz,3H),1.11-1.25(m,9H)。
第三步：(R)-N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备
氮气保护下，在0℃下，(R)-N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙烯基)-2-甲基丙烷-2-亚磺酰胺(11.0g,21.5mmol,1.00eq)的THF(100mL)和H2O(16mL)的混合溶液中加入NaBH4(670mg,17.7mmol,2.50eq)。混合物在25℃反应5h，然后0℃用饱和氯化铵水溶液(50mL)淬灭，再用EtOAc(100mL*2)萃取。合并的有机相用饱和食盐水(60mL*2)洗涤后，再用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(3.40g,7.06mmol,32.8％产率)。
1H NMR(400MHz,DMSO-d6)δ8.13-8.26(m,1H),7.75-7.96(m,1H),7.18(dd,J＝11.62,8.68Hz,4H),7.04-7.12(m,1H),6.83(d,J＝8.56Hz,4H),5.36-5.55(m,1H),4.90-5.14(m,1H),3.99-4.23(m,4H),3.70(s,6H),1.21-1.40(m,3H),0.99-1.13(m,9H)。
第四步：3-(1-胺基乙基)-N,N-双(4-甲氧基苄基)吡啶-2-胺盐酸盐的制备
(R)-N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-2-甲基丙烷-2-亚磺酰胺(3.40g,7.06mmol,1.00eq)的EtOAc(40mL)溶液中加入HCl/EtOAc(4M,5.29mL,3.00eq)。混合物在0℃反应5h，然后减压浓缩。残余物用硅胶柱层析分离得到目标产物(2.20g,5.83mmol,82.6％产率)。
LC-MS：m/z 378(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.80(br d,J＝2.32Hz,3H),8.20-8.44(m,2H),7.29(dd,J＝7.64,4.95Hz,1H),7.15(d,J＝8.68Hz,4H),6.86(d,J＝8.68Hz,4H),4.08-4.24(m,4H),3.72(s,6H),1.28-1.41(m,3H)。
按中间体1-1同样的合成方法以不同起始原料合成以下化合物：
中间体1-2 N,N-双(4-甲氧基苄基)-3-(1-(甲基胺基)乙基)吡啶-2-胺盐酸盐
LC-MS：m/z 392(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.17(dd,J＝4.62,1.98Hz,1H),7.78(dd,J＝7.59,1.87Hz,1H),7.17(d,J＝8.58Hz,4H),7.05(dd,J＝7.59,4.73Hz,1H),6.84(d,J＝8.58Hz,4H),4.13-4.21(m,1H),4.05-4.12(m,4H),3.70(s,6H),1.96(s,3H),1.14(d,J＝6.60Hz,3H)。
中间体1-2经SFC手性分离(手性柱:DAICEL CHIRALPAK IG(250mm*50mm,10um)；流动相:CO2-EtOH(0.1％NH3H2O)；B％:30％-100％,200min)得到异构体1-2A和1-2B。
中间体1-2A(S)-N,N-双(4-甲氧基苄基)-3-(1-(甲基胺基)乙基)吡啶-2-胺盐酸盐
RT：3.568min。LC-MS：m/z 392(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.17(dd,J＝4.63,1.88Hz,1H),7.79(dd,J＝7.63,1.75Hz,1H),7.17(d,J＝8.63Hz,4H),7.05(dd,J＝7.57,4.69Hz,1H),6.84(d,J＝8.50Hz,4H),4.12(m,5H),3.70(s,6H),1.97(s,3H),1.14(d,J＝6.38Hz,3H)。
中间体1-2B(R)-N,N-双(4-甲氧基苄基)-3-(1-(甲基胺基)乙基)吡啶-2-胺盐酸盐
RT：3.870min。LC-MS：m/z 392(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.21(dd,J＝4.63,1.88Hz,1H),7.83(dd,J＝7.63,1.75Hz,1H),7.16(d,J＝8.63Hz,4H),7.09(dd,J＝7.63,4.75Hz,1H),6.84(d,J＝8.63Hz,4H),4.25(q,J＝6.46Hz,1H),4.10(m,4H),3.70(s,6H),1.99(s,3H),1.17(d,J＝6.50Hz,3H)。
中间体1-3 N,N-双(4-甲氧基苄基)-5-(1-(甲基胺基)乙基)嘧啶-4-胺盐酸盐
LC-MS：m/z 393(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝6.11Hz,2H),7.14(d,J＝8.68Hz,4H),6.89(d,J＝8.68Hz,4H)4.41-4.63(m,4H),3.77(d,J＝6.48Hz,1H),3.73(s,6H),2.00(s,3H),1.28(d,J＝6.60Hz,3H)。
中间体1-4 3-(1-(乙基胺基)乙基)-N,N-双(4-甲氧基苄基)吡啶-2-胺盐酸盐
LC-MS：m/z 406(M+H)+。
中间体2-1 N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
第一步：N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-胺的制备
-40℃下，2,4,7-三氯-8-氟吡啶[4,3-d]嘧啶(400mg,1.58mmol,1.00eq)的DCM(10mL)溶液中加入3-(1-胺基乙基)-N,N-双(4-甲氧基苄基)吡啶-2-胺(668mg,1.62mmol,1.02eq,盐酸盐)和DIEA(614mg,4.75mmol,827μL,3.00eq)。混合物在25℃反应2h，然后加入H2O(50mL)淬灭后用EtOAc(100mL*2)萃取。合并的有机相用饱和食盐水(60mL*2)洗涤后再用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(0.750g,1.26mmol,79.7％产率)。
1H NMR(400MHz,DMSO-d6)δ9.61(br d,J＝6.97Hz,1H),9.34-9.47(m,1H),8.24(dd,J＝4.77,1.71Hz,1H),7.82(dd,J＝7.64,1.77Hz,1H),7.25(d,J＝8.68Hz,4H),7.08(dd,J＝7.58,4.77Hz,1H),6.80(d,J＝8.68Hz,4H),5.89(br t,J＝6.79Hz,1H),4.21-4.42(m,4H),3.60-3.78(m,6H),1.45(d,J＝6.85Hz,3H)。
第二步：N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-2,7-二氯-8-氟吡啶[4,3-d]嘧啶-4-胺(0.750g,1.26mmol,1.00eq)的CF3CH2OH(10mL)溶液中加入DIEA(489mg,3.79mmol,660μL,3.00eq)。反应液在70℃反应3h，然后减压浓缩，残余物加入H2O(30mL)再用EtOAc(25mL*2)萃取。合并的有机相用饱和食盐水(25mL*2)洗涤后再用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(0.770g,1.17mmol,92.7％产率)。
LC-MS：m/z 657(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.37-9.55(m,2H),8.24(dd,J＝4.71,1.77Hz,1H),7.86-7.97(m,1H),7.25(d,J＝8.56Hz,3H),7.08(dd,J＝7.58,4.77Hz,1H),6.69-6.86(m,4H),4.89-5.10(m,2H),4.15-4.45(m,3H),3.62-3.76(m,6H),1.47(br d,J＝6.72Hz,3H)。
按中间体2-1同样的合成方法以不同起始原料合成以下化合物：
中间体2-2 N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-8-氟-N-甲基-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
LC-MS：m/z 671(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.48–8.34(m,1H),8.00(d,J＝7.6Hz,1H),7.24(dd,J＝7.6,4.8Hz,1H),6.95(d,J＝8.3Hz,4H),6.60(t,J＝9.1Hz,4H),6.44(d,J＝6.9Hz,1H),5.26–4.98(m,2H),4.15–3.99(m,4H),3.66(s,6H),3.10(d,J＝10.0Hz,3H),1.51(d,J＝6.8Hz,3H).
中间体2-2A(S)-N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-8-氟-N-甲基-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
LC-MS：m/z 671(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.41(dd,J＝4.7,1.6Hz,1H),8.00(dd,J＝7.7,1.4Hz,1H),7.24(dd,J＝7.7,4.7Hz,1H),6.95(d,J＝8.4Hz,4H),6.58(d,J＝8.6Hz,4H),6.43(q,J＝6.7Hz,1H),5.24–5.01(m,2H),4.13–3.98(m,4H),3.66(s,6H),3.08(s,3H),1.51(d,J＝6.9Hz,3H).
中间体2-2B(R)-N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-8-氟-N-甲基-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
LC-MS：m/z 671(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.41(dd,J＝4.7,1.7Hz,1H),8.00(dd,J＝7.7,1.5Hz,1H),7.24(dd,J＝7.7,4.7Hz,1H),6.95(d,J＝8.5Hz,4H),6.58(d,J＝8.6Hz,4H),6.43(d,J＝6.9Hz,1H),5.26–4.95(m,2H),4.06(s,4H),3.66(s,6H),3.08(s,3H),1.51(d,J＝6.9Hz,3H).
中间体2-3 N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-N-乙基-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
LC-MS：m/z 685(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.38-8.48(m,1H),8.01-8.13(m,1H),7.25(dd,J＝7.63,4.75Hz,1H),6.75-6.93(m,4H),6.47-6.65(m,5H),4.94-5.25(m,2H),3.83-4.15(m,5H),3.66(s,7H),3.52-3.61(m,2H),1.40-1.58(m,3H),0.51(br t,J＝6.69Hz,3H)。
中间体2-4 N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)丙基)-7-氯-8-氟--N-甲基2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
LC-MS：m/z 685(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.72-8.91(m,1H),8.76(s,1H),8.43(dd,J＝4.51,1.43Hz,1H),7.91-8.04(m,1H),7.99(br d,J＝6.60Hz,1H),7.21-7.30(m,1H),7.17-7.35(m,1H),7.26(dd,J＝7.59,4.73Hz,1H),6.87-7.04(m,4H),6.49-6.65(m,4H),6.15-6.39(m,1H),5.06(br d,J＝3.52Hz,2H),4.02(q,J＝14.38Hz,4H),3.60-3.68(m,6H),3.03-3.19(m,3H),1.99(s,2H),1.81-1.83(m,1H),0.42-0.75(m,3H)。
中间体2-5 N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-N-环丙基-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
LC-MS：m/z 697(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.47-8.35(m,1H),8.10(br d,J＝7.5Hz,1H),7.31-7.18(m,1H),6.96(br d,J＝8.6Hz,4H),6.58(d,J＝8.6Hz,4H),6.28-6.12(m,1H),5.20-5.02(m,2H),4.17-3.97(m,4H),3.65(s,6H),2.69(br s,1H),1.61(br d,J＝7.3Hz,3H),1.27-1.16(m,1H),0.97-0.86(m,1H),0.78-0.68(m,1H),0.38-0.27(m,1H)。
中间体2-6 N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-N-(2-氟乙基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
LC-MS：m/z 703(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.93(s,1H)8.56(br dd,J＝4.69,1.69Hz,1H)7.82(br d,J＝6.25Hz,1H)7.22(dd,J＝7.75,4.75Hz,1H)6.67(m,8H)6.26(br d,J＝6.88Hz,1H)4.85(q,J＝8.42Hz,2H)4.25(m,1H)3.92(m,5H)3.78(m,6H)3.62(m,2H)1.51(br d,J＝7.00Hz,3H)。
中间体2-7 N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-N-(2-氟乙基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
LC-MS：m/z 715(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.7-8.8(m,1H),8.4-8.5(m,1H),7.71(dd,1H,J＝1.4,7.7Hz),7.08(dd,1H,J＝4.8,7.6Hz),6.7-6.8(m,4H),6.5-6.5(m,4H),6.3-6.4(m,1H),4.7-4.9(m,2H),4.03(d,2H,J＝13.3Hz),3.83(d,2H,J＝13.4Hz),3.6-3.7(m,6H),3.4-3.5(m,2H),3.0-3.1(m,3H),2.7-2.9(m,1H),2.3-2.4(m,1H),1.36(d,3H,J＝6.8Hz)。
中间体3-1 7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2,6-二氯-8-氟喹唑啉-4(3H)-酮的制备
第一步：2-胺基-3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酸甲酯的制备
氮气保护下，室温下2-胺基-4-溴-3-氟苯甲酸甲酯(198g,798mmol,1.00eq)的二氧六环(2000mL)溶液中加入频哪醇硼烷(304g,1.20mol,1.50eq)、KOAc(235g,2.39mol,3.00eq)和Pd(dppf)Cl2(40.8g,55.8mmol,0.07eq)。混合物在氮气保护下在90℃反应16h，然后冷却至室温后过滤。滤饼用EtOAc(2L)洗涤。滤液合并后加入H2O(2L)稀释后用EtOAc(2 x 1.5L)萃取。合并的有机相用饱和食盐水(2L)洗涤后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离后得到目标产物(250g,762mmol,95.5％产率)。
LC-MS：m/z 296(M+H)+。
第二步：2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-3-氟苯甲酸甲酯的制备
氮气保护下，室温下2-胺基-3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲酸甲酯(31.0g,105mmol,1.00eq)的二氧六环(400mL)和水(40mL)的混合溶液中加入6-氯-N,N-双(4-甲氧基苄基)-4-甲基-5-(三氟甲基)吡啶-2-胺(47.3g,105mmol,1.00eq)、Pd-118(6.85g,10.5mmol,0.10eq)和KF(18.3g,315mmol,3.00eq)。混合物在氮气保护下在100℃反应1h，然后冷却至室温后过滤。滤液加入H2O(500mL)稀释后 用EtOAc(3 x 500mL)萃取。合并的有机相用饱和食盐水(300mL)洗涤后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离后得到目标产物(44.0g,75.4mmol,71.78％产率)。
LC-MS：m/z 584(M+H)+。
第三步：2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-3-氟苯甲酸甲酯的制备
2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-3-氟苯甲酸甲酯(44.0g,75.4mmol,1.00eq)的NMP(500mL)溶液中加入NCS(12.5g,94.2mmol,1.25eq)。混合物在70℃反应3h，然后冷却至0℃后加入H2O(500mL)稀释后用EtOAc(3x200mL)萃取。合并的有机相用饱和食盐水(300mL)洗涤后经无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离后得到目标产物(17.5g,28.3mmol,37.5％产率)。
LC-MS：m/z 618(M+H)+。
第四步：2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-3-氟苯甲酸的制备
2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-3-氟苯甲酸甲酯(17.5g,28.3mmol,1.00eq)的MeOH(180mL)、THF(60mL)和H2O(60mL)的混合溶液中加入NaOH(16.9g,424mmol,15.0eq)。混合物在50℃反应3h，然后冷却室温后减压浓缩。残余物中加入H2O(300mL)稀释后用EtOAc(3x 200mL)萃取。合并的有机相用饱和食盐水(200mL)洗涤后经无水硫酸镁干燥后过滤。滤液减压浓缩，残余物无需纯化直接用于下一步反应(20.0g,粗产物)。
LC-MS：m/z 604(M+H)+。
第五步：2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-3-氟苯甲酰胺的制备
0℃下，2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-3-氟苯甲酸(9.00 14.9mmol,1.00eq)的DMF(80mL)溶液中加入NH4Cl(2.39g,44.7mmol,3.00eq)、DIEA(5.78g,44.7mmol,7.79mL,3.00eq)和HATU(11.3g,29.8mmol,2.00eq)。混合物在25℃反应2h，然后冷却室温后减压浓缩。0℃下，残余物中加入H2O(300mL)稀释后用EtOAc(3 x 200mL)萃取。合并的有机相用饱和食盐水(200mL)洗涤后经无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离后得到目标产物(9.00g,11.0mmol,74.1％产率)。
LC-MS：m/z 603(M+H)+。
第六步：7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2,6-二氯-8-氟喹唑啉-4(3H)-酮的制备
2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-3-氟苯甲酰胺(9.00g,14.9mmol,1.00eq)的dioxane(80mL)溶液中加入CSCl2(3.43g,29.8 mmol,2.29mL,2.00eq)。混合物在100℃反应1h，然后冷却室温后减压浓缩。残余物中加入H2O(300mL)稀释后用NaHCO3调节pH＝7。混合物用EtOAc(3x 200mL)萃取。合并的有机相用饱和食盐水(200mL)洗涤后经无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离后得到目标产物(4.60g,5.68mmol,38.0％产率)。
LC-MS：m/z 647(M+H)+。1H NMR(400MHz,DMSO-d6)δ13.34-13.92(m,1H),8.00(d,J＝0.98Hz,1H),7.16(d,J＝8.56Hz,4H),6.88(br d,J＝8.31Hz,4H),6.84(s,1H),4.54-4.82(m,4H),3.73(s,6H),2.40(br d,J＝1.10Hz,3H)。
中间体3-1经SFC手性分离(手性柱:DAICEL CHIRALPAK AD(250mm*50mm,10um)；流动相:[CO2-EtOH(0.1％NH3H2O)]；B％:40％％,isocratic elution mode)得到中间体3-1A和中间体3-1B。
中间体3-1A(S)-7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2,6-二氯-8-氟喹唑啉-4(3H)-酮
RT：0.891min。LC-MS：m/z 647(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.16(d,J＝8.56Hz,4H),6.88(br d,J＝8.31Hz,4H),6.84(s,1H),4.58-4.82(m,4H),3.73(s,6H),2.40(br d,J＝1.10Hz,3H)。
中间体3-1B(R)-7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2,6-二氯-8-氟喹唑啉-4(3H)-酮
RT：1.168min。LC-MS：m/z 647(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.16(d,J＝8.56Hz,4H),6.88(br d,J＝8.31Hz,4H),6.84(s,1H),4.58-4.82(m,4H),3.73(s,6H),2.40(br d,J＝1.10Hz,3H)。
按中间体3-1同样的合成方法以不同起始原料合成以下化合物：
中间体3-2 2,6-二氯-8-氟-7-(7-氟-8-((三异丙基硅基)乙炔基)萘-1-基)喹唑啉-4(3H)-酮
LC-MS：m/z 557(M+H)+。1H NMR(400MHz,DMSO-d6)δ14.08-13.58(m,1H),8.31-8.17(m,2H),7.94(s,1H),7.77-7.59(m,2H),7.51(br d,J＝7.0Hz,1H),0.98-0.82(m,18H),0.71-0.61(m,3H)。
中间体3-3(3-氰基-4-(2,6-二氯-8-氟-4-氧-3,4-二氢喹唑啉-7-基)-7-氟苯并[b]噻吩-2-基)甲酸叔丁酯
LC-MS：m/z 523(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.86(br s,1H),8.05(d,1H,J＝1.1Hz),7.4-7.5(m,2H),1.52(s,9H).
中间体3-4 7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2-氯-6,8-二氟喹唑啉-4(3H)-酮
LC-MS：m/z 631(M+H)+。
中间体3-4经SFC手性分离(手性柱:DAICEL CHIRALPAK AD(250mm*50mm,10um)；流动相:[CO2-EtOH(0.1％NH3H2O)]；B％:40％％,isocratic elution mode)得到中间体3-4A和中间体3-4B
中间体3-4A(R)-7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2-氯-6,8-二氟喹唑啉-4(3H)-酮
RT：1.507min。LC-MS：m/z 631(M+H)+。1H NMR(400MHz,CDCl3)δ10.88(br d,J＝11.00Hz,1H),7.81(dd,J＝8.03,1.43Hz,1H),7.14(d,J＝8.58Hz,4H),6.86(d,J＝8.58Hz,4H),6.42(s,1H),4.66(q,J＝16.07Hz,4H),3.81(s,6H),2.42(d,J＝1.76Hz,3H)。
中间体3-4B(S)-7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2-氯-6,8-二氟喹唑啉-4(3H)-酮
RT：1.784min。LC-MS：m/z 631(M+H)+。1H NMR(400MHz,CDCl3)δ10.22-10.79(m,1H)7.81(d,J＝7.92Hz,1H)7.14(d,J＝8.36Hz,4H)6.86(d,J＝8.36Hz,4H)6.42(s,1H)4.53-4.82(m,4H)3.81(s,6H)2.41(d,J＝1.54Hz,3H)。
中间体4-1 7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-(1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-2,6-二氯-8-氟-N-甲基喹唑啉-4-胺的制备
7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2,6-二氯-8-氟喹唑啉-4(3H)-酮(120mg,185μmol,1.00eq)的DCM(3mL)溶液中加入N,N-双(4-甲氧基苄基)-3-(1-(甲基氨基)乙基)吡啶-2-胺(72.5mg,185μmol,1.00eq)、DIEA(239mg,1.85mmol,322μL,10.0eq)和Bop-Cl(188mg,741μmol,4.00eq)。混合物在25℃反应16h，随后加入水(30mL)淬灭再用DCM(30mL*3)萃取。合并的有机相用饱和食盐水(100mL)洗涤，再经无水硫酸镁干燥后过滤。滤液减压浓缩，残余物经硅胶柱层析得到目标产物(105mg,47.0％产率)。
LC-MS：m/z 1020(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.29-8.39(m,1H)7.97-8.11(m,1H)7.84-7.95(m,1H)7.19(s,1H)7.13-7.18(m,4H)6.92(br s,4H)6.85-6.89(m,4H)6.60-6.67(m,4H)6.23-6.44(m,1H)4.52-4.86(m,4H)3.99-4.12(m,4H)3.71-3.73(m,6H)3.58-3.67(m,6H)3.10-3.19(m,3H)2.39(br s,3H)1.43-1.57(m,1H)1.43-1.56(m,3H)。
按中间体4-1同样的合成方法以不同起始原料合成以下化合物：
中间体4-2 7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-2,6-二氯-8-氟-N-甲基喹唑啉-4-胺
LC-MS：m/z 1020(M+H)+。
中间体4-2A(S)-7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-2,6-二氯-8-氟-N-甲基喹唑啉-4-胺
LC-MS：m/z 1020(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.36-8.34(m,1H),8.03(s,1H),7.92-7.90(m,1H),7.20-7.15(m,5H),7.00-6.98(m,4H),6.89-6.83(m,5H),6.64-6.62(m,4H),6.36-6.31(m,1H),4.81(s,2H),4.61(d,J＝16Hz,2H),4.10(s,4H),3.73(s,6H),3.61(s,6H),3.17(s,3H),2.40(s,3H),1.54(d,J＝8Hz,3H).
中间体4-2B(R)-7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-2,6-二氯-8-氟-N-甲基喹唑啉-4-胺
LC-MS：m/z 1020(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.36(dd,J＝4.7,1.8Hz,
1H),8.05(d,J＝1.6Hz,1H),7.94(dd,J＝7.7,1.8Hz,1H),7.21–7.12(m,5H),6.95(d,J＝8.2Hz,4H),6.89–6.81(m,5H),6.68–6.62(m,4H),6.42–6.34(m,1H),4.88–4.66(m,2H),4.63–4.50(m,2H),4.12–4.03(m,4H),3.71(s,6H),3.66(s,6H),3.12(s,3H),2.40(d,J＝2.0Hz,3H),1.47(d,J＝6.9Hz,3H).
中间体4-3 7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-(1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-2,6-二氯-N-乙基-8-氟喹唑啉-4-胺
LC-MS：m/z 1034(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.41(ddd,J＝9.74,4.68,1.65Hz,1H)8.00-8.08(m,1H)7.93(br s,1H)7.20-7.26(m,1H)7.13-7.19(m,4H)6.74-6.91(m,9H)6.58-6.67(m,4H)6.39-6.51(m,1H)4.45-4.92(m,4H)3.84-4.07(m,4H)3.77-3.84(m,1H)3.67-3.77(m,6H)3.65-3.67(m,2H)3.63(d,J＝15.19Hz,6H)2.41(br d,J＝2.20Hz,3H)1.44-1.56(m,3H)0.49-0.66(m,3H)
中间体4-4(4-(4-(((R)-1-(2-(bis(4-甲氧基苄基)氨基)吡啶-3-基)乙基)(甲基)氨基)-2,6-二氯-8-氟喹唑啉-7-基)-3-氰基-7-氟苯并[b]噻吩-2-基)甲酸叔丁酯
LC-MS：m/z 896(M+H)+。
中间体4-5(4-(4-(((R)-1-(2-(bis(4-甲氧基苄基)氨基)吡啶-3-基)乙基)(乙基)氨基)-2,6-二氯-8-氟喹唑啉-7-基)-3-氰基-7-氟苯并[b]噻吩-2-基)甲酸叔丁酯
LC-MS：m/z 910(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.89(br s,1H),8.4-8.5(m,1H),8.05(br d,1H,J＝6.9Hz),7.92(s,1H),7.4-7.5(m,2H),6.96(br d,4H,J＝8.4Hz),6.71(d,4H,J＝8.6Hz),6.5-6.6(m,1H),6.52(br d,1H,J＝6.6Hz),4.13(br d,2H,J＝13.5Hz),3.9-3.9(m,2H),3.7-3.7(m,6H),3.5-3.6(m,3H),1.36(s,9H),1.20(d,1H,J＝6.8Hz),1.2-1.2(m,3H),0.8-0.9(m,1H),0.8-0.9(m,3H)。
中间体4-6A(R)-7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-2-氯-6,8-二氟-N-甲基喹唑啉-4-胺
LC-MS：m/z 524(M+H)+。
中间体4-6B(S)-7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-2-氯-6,8-二氟-N-甲基喹唑啉-4-胺
LC-MS：m/z 524(M+H)+。
中间体5-1 7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2,4,6-三氯-8-氟喹啉-3-甲腈的制备
第一步：4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-2-(2-氰基乙酰基)-3-氟苯甲酸甲酯的制备
2-胺基-4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-3-氟苯甲酸甲酯(5.80g,9.38mmol,1.00eq)和2-氰基乙酸(1.60g,18.7mmol,2.00eq)的DCM(50mL)溶液中加入(3.60g,18.7mmol,2.00eq)。得到的混合物在25℃反应16h然后在0℃加入H2O(200mL)淬灭，再用DCM(100mL x 3)萃取。合并的有机相用饱和食盐水(300mL)洗涤后经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(3.77g,5.50mmol,58.6％产率)。
LC-MS：m/z 685(M+H)+。
第二步：7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氯-8-氟-2,4-二氢喹啉-3-甲腈的制备
4-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-2-(2-氰基乙酰 基)-3-氟苯甲酸甲酯(3.77g,5.50mmol,1.00eq)的MeOH(40mL)溶液中加入MeONa/MeOH(1.49g,8.25mmol,30％wt,1.50eq)。反应液在0℃反应1h，随后滴加入HCl水溶液(10％wt)调节pH至2～3。得到的混合物过滤，滤饼收集以后真空干燥得到目标产物(3.20g,4.90mmol,89.0％产率)。无需进一步纯化，直接用于下一步反应。
LC-MS：m/z 653(M+H)+。
第三步：7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2,4,6-三氯-8-氟喹啉-3-甲腈的制备
0℃下，7-(6-(双(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氯-8-氟-2,4-二氢喹啉-3-甲腈(2.00g,3.06mmol,1.00eq)和POCl3(1.41g,9.19mmol,856μL,3.00eq)的Tol.(20mL)混合物中加入DIEA(1.98g,15.3mmol,2.67mL,5.00eq)。得到的混合物在110℃反应16h然后减压浓缩。残余物倒入冰水中，然后用DCM(100mLx 3)萃取。合并的有机相用饱和食盐水(300mL)洗涤后经无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(0.52g,753μmol,24.6％产率)。
LC-MS：m/z 689(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.15(br d,J＝8.4Hz,4H),6.87(br d,J＝8.4Hz,4H),6.48(s,1H),4.81-4.68(m,2H),4.66-4.55(m,2H),3.82(s,6H),2.46(br s,3H).
实施例A1 4-(4-((1-(2-胺基吡啶-3-基)乙基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备
第一步：N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺的制备
氮气保护下，N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺(630mg,958μmol,1.00eq)、2-[2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)-1-萘]乙炔基-三异丙基硅烷(589mg,1.15mmol,1.20eq)、Cs2CO3(937mg,2.88mmol,3.00eq)和CataxciAm Pd G2(64.1mg,95.9μmol,0.100eq)的dioxane(10mL)和H2O(2mL)的混合物在100℃反应3h，然后 用水(30mL)稀释后再用EtOAc(25mL*2)萃取。合并的有机相用饱和食盐水(25mL*2)洗涤后再用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(0.66g,655μmol,68.3％产率)。
LC-MS：m/z 1007(M+H)+。1H NMR(400MHz,CDCl3)δ8.63-9.04(m,1H)8.29-8.56(m,1H)7.76-7.90(m,1H)7.64-7.73(m,1H)7.47-7.59(m,1H)7.29-7.41(m,3H)6.98-7.20(m,4H)6.84(d,J＝8.56Hz,1H)6.67(d,J＝8.68Hz,3H)5.89-6.07(m,1H)5.23-5.44(m,2H)4.26-4.49(m,4H)3.65-3.85(m,6H)1.41-1.56(m,3H)0.83-0.99(m,15H)0.71-0.82(m,5H)0.45-0.65(m,4H)。
第二步：N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)吡啶[4,3-d]嘧啶-4-胺的制备
((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇(30mg，0.149mmol)的甲苯(1mL)中加入钠氢(12mg,60％wt,0.297mmol)。混合物在室温搅拌2min，随后加入N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-胺(100mg，0.099mmol)。得到的混合物在110℃反应2h，然后用水稀释后再用EtOAc萃取。合并的有机相用饱和食盐水(25mL*2)洗涤后再用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(35mg,21.2％产率)。
LC-MS：m/z 1110(M+H)+。
第三步：4-(4-((1-(2-胺基吡啶-3-基)乙基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇的制备
将N-(1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)吡啶[4,3-d]嘧啶-4-胺(35mg，0.03mmol)的三氟乙酸(1mL)溶液在室温搅拌16h，然后减压浓缩(25mg粗产品)。无需进一步纯化，直接用于下一步反应。
LC-MS：m/z 826(M+H)+。
第四步：4-(4-((1-(2-胺基吡啶-3-基)乙基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的制备
上一步得到的4-(4-((1-(2-胺基吡啶-3-基)乙基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-醇(25mg)溶于DMF(1mL)中加入氟化铯(167mg，1.1mmol)。混合物在室温搅拌16h，然后用制备液相分离得到目标产物(3.2mg，两步16％产率)。
LC-MS：m/z 670(M+H)+。
按照实施例A1的方法以不同的起始原料合成了以下实施例：
实施例A2 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LC-MS：m/z 693(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),7.97(d,J＝3.7Hz,1H),7.64(d,J＝7.3Hz,1H),6.88(s,1H),6.66(dd,J＝7.3,5.0Hz,1H),6.46(s,1H),6.34(s,2H),6.16(s,1H),5.81(s,2H),4.23(t,J＝11.9Hz,2H),3.24(s,3H),3.14–3.06(m,1H),3.01(s,1H),2.72(d,J＝11.8Hz,1H),2.54(s,1H),2.06(dd,J＝20.5,16.4Hz,2H),1.90(d,J＝13.2Hz,1H),1.78(d,J＝18.4Hz,2H),1.67–1.53(m,5H),1.48(dd,J＝8.6,3.8Hz,1H)。
实施例A2经SFC手性分离(设备:SFC-150(Waters)；手性柱:OD 25*250mm,10um(Daicel)；柱温:35℃；流动相:CO2/MEOH[0.2％NH3(7M in MeOH)＝50/50)得到实施例A2-A和A2-B：
实施例A2-A：7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-((R)-2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
RT：1.782min。LCMS:m/z 693(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.99(d,J＝8Hz,1H),7.67(d,J＝8Hz,1H),6.90(s,1H),6.69-6.66(m,1H),6.47(s,1H),6.33(s,2H),6.20-6.15(m,1H),5.81(s,2H),4.31-4.20(m,2H),3.25(s,3H),3.14-3.10(m,1H),3.05-3.01(m,1H),2.76(d,J＝12Hz,1H),2.59-2.55(m,1H),2.12-2.07(m,1H),2.05-1.99(m,1H),1.94(d,J＝16Hz,1H),1.84-1.75(m,2H),1.67-1.54(m,5H),1.52-1.45(m,1H)。
实施例A2-B：7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-((S)-2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
RT：2.303min。LCMS:m/z 693(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.99(d,J＝8Hz,1H),7.67(d,J＝8Hz,1H),6.90(s,1H),6.69-6.66(m,1H),6.47(s,1H),6.33(s,2H),6.20-6.15(m,1H),5.81(s,2H),4.25(s,2H),3.25(s,3H),3.14-3.10(m,1H),3.05-3.01(m,1H),2.76(d,J＝12Hz,1H),2.59-2.55(m,1H),2.12-2.07(m,1H),2.05-1.99(m,1H),1.94(d,J＝16Hz,1H),1.84-1.75(m,2H),1.67-1.54(m,5H),1.52-1.45(m,1H)。
实施例A3 4-(4-((1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2--二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 688(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.28(d,J＝11.6Hz,1H),7.98(d,J＝4.9Hz,1H),7.77(dd,J＝9.1,6.0Hz,1H),7.66(d,J＝7.4Hz,1H),7.35(dd,J＝13.2,5.9Hz,2H),7.01(s,1H),6.19(s,1H),5.93(d,J＝13.2Hz,1H),5.78(d,J＝8.3Hz,1H),4.28(d,J＝11.6Hz,2H),3.28(d,J＝2.0Hz,3H),3.12(s,1H),3.03(s,1H),2.75(s,1H),2.36(d,J＝15.7Hz,1H),2.11(d,J＝12.9Hz,2H),2.02(s,1H),1.92(d,J＝13.0Hz,1H),1.79(d,J＝24.4Hz,2H),1.61(dd,J＝36.9,33.8Hz,6H),0.75(t,J＝6.8Hz,3H)。
实施例A4 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-2-胺基吡啶-3-基)乙基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 649(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.99(d,J＝8Hz,1H),7.66(d,J＝8Hz,1H),6.89(m,1H),6.69-6.66(m,1H),6.47(s,1H),6.32(m,2H),6.19-6.14(m,1H),5.80(s,2H),5.38-5.25(m,1H),4.22-4.10(m,2H),3.26(s,3H),3.14(m,2H),3.06(m,1H),2.87(m,1H),2.18-2.03(m,3H),1.89-1.81(m,3H),1.63(d,J＝8Hz,3H).
实施例A5 4-(4-((1-(2-2-胺基吡啶-3-基)乙基)(甲基)胺基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇
LCMS:m/z 644(M+H)+。
实施例A6 4-(4-((1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 640(M+H)+。
实施例A7 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-氨基吡啶-3-基)乙基)-2-((1-((二甲基胺基)甲基)环丙基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 619(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.98(d,J＝4Hz,1H),7.65(d,J＝8Hz,1H),6.88(s,1H),6.68-6.65(m,1H),6.46(s,1H),6.32(s,2H),6.18-6.13(m,1H),5.79(s,2H),4.39(s,1H),4.21(s,1H),3.52-3.41(m,1H),3.25(s,3H),3.16(s,1H),1.62(d,J＝8Hz,3H),1.24-1.17(m,6H),0.72-0.55(m,4H).
实施例A8 2-((1-(((1R,4R)-2-氧-5-氮杂双环[2.2.1]庚烷-5-基)甲基)环丙基)甲氧基)-7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 673(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),7.97(d,J＝8Hz,1H),7.64(d,J＝12Hz,1H),6.88(s,1H),6.67-6.64(m,1H),6.46(m,1H),6.31(s,2H),6.12(s,1H),5.77-5.75(m,2H),4.43-4.18(m,3H),3.79-3.77(m,1H),3.48-3.46(m,2H)，3.24(s,3H),2.86-2.84(m,1H),2.69-2.56(m,2H),2.41-2.38(m,1H),1.67-1.51(m,5H),0.588(s,2H),0.49-0.40(m,2H).
实施例A9 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基)-8-氟-N-甲基-2-((1-甲基哌啶-4-基)氧)吡啶[4,3-d]嘧啶-4-胺三氟乙酸盐
LCMS:m/z 605(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.83-9.73(m,1H),9.28(s,1H),8.05-7.97(m,2H),7.69-7.55(m,2H),6.90(s,2H),6.46-6.38(m,3H),6.04-6.01(m,1H),5.39(s,1H),5.20(s,1H)，3.38-3.18(m,4H),2.87-2.82(m,3H),2.34-2.03(m,4H),1.91-1.82(m,1H),1.68-1.66(m,3H).
实施例A10实施例A11 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2--二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 679(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.44(s,1H)，9.13(m,1H)，7.85(m,1H)，7.51(m,1H)，6.88(d,J＝2.20Hz,1H)，6.55(m,1H)，6.46(d,J＝2.24Hz,1H)，6.33(s,2H)，5.93(s,2H)，5.51(m,1H)，4.56(m,3H)，4.18(s,2H)，3.04(m,2H)，2.67(m,1H)，1.91(m,5H)，1.59(m,4H)。
实施例A11 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 635(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.43(s,1H)，9.19(d,J＝6.84Hz,1H)，7.85(d,d,J＝1.80Hz,J＝4.92Hz,1H)，7.52(m,1H)，6.56(d,d,J＝4.88Hz,J＝7.40Hz,1H)，6.45(s,1H)，6.33(s,1H)，5.97(s,2H)，5.47(m,1H)，5.40(br,0.5H)，5.27(br,0.5H)，4.20(m,3H)，3.48(m,1H)，3.42(m,1H)，2.94(m,1H)，2.03(m,1H)，1.56(d,J＝6.84Hz,3H)。
实施例A12 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2--二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 679(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.45(s,1H)，9.19(m,1H)，7.85(m,1H)，7.51(m,1H)，6.88(d,J＝2.20Hz,1H)，6.55(m,1H)，6.46(m,1H)，6.34(s,2H)，5.94(s,2H)，5.47(m,1H)，4.55(m,3H)，4.23(s,2H)，3.05(m,2H)，2.78(m,1H)，1.91(m,5H)，1.59(m,4H)。
实施例A13 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 635(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H)，9.12(d,J＝7.20Hz,1H)，7.85(m,1H)，7.50(m,1H)，6.88(m,1H)，6.45(m,1H)，6.32(s,1H)，5.93(s,2H)，5.46(m,1H)，5.29(br,0.5H)，5.16(br,0.5H)，4.56(m,2H)，4.07(s,2H)，3.06(m,2H)，2.80(m,1H)，1.95(m,2H)，1.77(m,3H)，1.56(d,J＝6.84Hz,3H)。
实施例A14 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-8-氟-N-甲基-2-((S)-1-甲基吡咯啶-2-基)甲氧基)吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 605(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),7.99(d,J＝4Hz,1H),7.67(d,J＝8Hz,1H),6.90(s,1H),6.70-6.67(m,1H),6.48(s,1H),6.33(s,2H),6.19-6.15(m,1H),5.76(d,J＝12Hz,2H),4.43(s,1H),4.28(s,1H),3.24(s,3H),2.99(s,1H),2.68(s,1H),2.40(s,3H),2.24(s,1H),2.01-1.96(m,1H),1.74-1.69(m,3H),1.63(d,J＝4Hz,3H).
实施例A15 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-8-氟-N-甲基-2-((S)-1-甲基吡咯啶-2-基)乙氧基)吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 619(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.20(d,J＝16Hz,1H),7.96(t,J＝4Hz 1H),7.62(t,J＝8Hz,1H),6.88(s,1H),6.68-6.63(m,1H),6.46(s,1H),6.31(s,2H),6.16-6.05(m,1H),5.72(d,J＝20Hz,2H),5.28(s,1H),3.25(d,J＝16Hz,3H),2.95(s,1H),2.63(s,1H),2.36(s,3H),2.17(s,1H),1.80-1.74(m,2H),1.67(m,2H),1.61(d,J＝4Hz,3H),1.29(d,J＝4Hz,2H),1.21(d,J＝4Hz,1H).
实施例A16 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((2S,4R)-4-氟-1-甲基吡咯啶-2-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 605(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.22(m,1H),7.99(d,J＝4Hz,1H),7.67(d,J＝8Hz,1H),6.90(s,1H),6.69-6.66(m,1H),6.48(s,1H),6.33(s,2H),6.18-6.15(m,1H),5.78(d,J＝8Hz,2H),5.28-5.14(m,1H),4.51-4.33(m,2H),3.52-3.41(m,2H),3.24(s,3H),2.99(s,1H),2.43(s,3H),2.22-2.10(m,1H),2.03-1.84(m,1H),1.63(d,J＝4Hz,3H).
实施例A17 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((3R,6S)-1,1-二氟-5-甲基-5-氮杂螺[2.4]庚烷-6-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 667(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.22(d,J＝4Hz,1H),7.99(d,J＝4Hz,1H),7.67(d,J＝8Hz,1H),6.90(s,1H),6.69-6.66(m,1H),6.47(s,1H),6.34(s,2H),6.18-6.14(m,1H),5.75(d,J＝8Hz,2H),4.51(s,1H),4.35(s,1H),3.24(s,3H),2.99(d,J＝12Hz,1H),2.92-2.90(m,1H),2.47-2.45(m,1H),2.39(s,3H),2.09-2.03(m,1H),1.96-1.89(m,1H),1.63(d,J＝4Hz,3H),1.53-1.42(m,2H).
实施例A18 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((3S,6S)-1,1-二氟-5-甲基-5-氮杂螺[2.4]庚烷-6-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 667(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.23(d,J＝4Hz,1H),7.99(d,J＝4Hz,1H),7.67(d,J＝8Hz,1H),6.90(s,1H),6.69-6.66(m,1H),6.47(s,1H),6.34(s,2H),6.18-6.14(m,1H),5.79(d,J＝16Hz,2H),4.50(s,1H),4.42(s,1H),3.25(s,3H),2.93(d,J＝8Hz,1H),2.84(m,1H),2.61-2.58(m,1H),2.39(s,3H),2.27-2.22(m,1H),1.84-1.76(m,1H),1.63(d,J＝4Hz,3H),1.58-1.55(m,1H),1.51-1.45(m,1H)。
实施例A19 2-((1-(((1S,4S)-2-氧-5-氮杂双环[2.2.1]庚烷-5-基)甲基)环丙基)甲氧基)-7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 605(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),7.97(d,J＝8Hz,1H),7.64(d,J＝12Hz,1H),6.88(s,1H),6.67-6.64(m,1H),6.46(m,1H),6.31(s,2H),6.12(s,1H),5.77-5.75(m,2H),4.43-4.18(m,3H),3.79-3.77(m,1H),3.48-3.46(m,2H)，3.24(s,3H),2.86-2.84(m,1H),2.69-2.55(m,2H),2.40-2.38(m,1H),1.67-1.51(m,5H),0.58(s,2H),0.49-0.40(m,2H).
实施例A20 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基)-8-氟-N-甲基-2-((四氢-2H-吡喃-4-基)氧)吡啶[4,3-d]嘧啶-4-胺三氟乙酸盐
LCMS:m/z 692(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.04-8.02(m,3H),6.95(t,J＝8Hz,1H),6.90(s,1H),6.46(s,1H),6.01-5.96(m,1H),5.20-5.15(m,1H),3.90-3.80(m,6H),3.54-3.42(m,5H),2.05-2.01(m,1H),1.80(s,1H),1.74-1.67(m,3H),1.63-1.54(m,1H).
实施例A21 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2--二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-乙基-8-氟-吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 707(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.01(d,J＝5.0Hz,1H),7.74(d,J＝7.5Hz,1H),6.91(d,J＝2.2Hz,1H),6.72(dd,J＝7.6,5.0Hz,1H),6.49(d,J＝2.4Hz,1H),6.39–6.23(m,2H),5.71(s,2H),4.65–4.42(m,2H),3.92–3.66(m,2H),3.07–2.85(m,2H),2.43–2.26(m,1H),2.25–2.11(m,2H),2.10–1.91(m,3H),1.89–1.70(m,3H),1.65(d,J＝6.8Hz,3H),1.31–1.18(m,3H),1.05–0.94(m,2H).
实施例A22 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基-N-乙基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 663(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.00(d,J＝4.8Hz,1H),7.71(d,J＝7.4Hz,1H),6.96–6.85(m,1H),6.70(m,1H),6.50(d,J＝9.7Hz,1H),6.31(m,3H),5.64(s,1H),5.30(m,1H),4.25–3.96(m,3H),3.71(m,2H),3.18 –2.95(m,3H),2.89–2.76(m,1H),2.10(m,3H),1.81(m,2H),1.63(d,J＝6.7Hz,3H),1.30(m,1H),1.02(m,3H).
实施例A22经SFC手性分离得到实施例A22-A和A22-B：
实施例A22-A
LCMS:m/z 663(M+H)+。
实施例A22-B
LCMS:m/z 663(M+H)+。
实施例A23 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2--二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-(2-甲氧基乙基)吡啶[4,3-d]嘧啶-4-胺三氟乙酸盐
LCMS:m/z 737(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),9.28(d,J＝8Hz,1H)，8.17(d,J＝8Hz,1H)，8.05(d,J＝8Hz,1H)，7.79(s,2H),6.97-6.91(m,2H),6.49-6.35(m,2H),6.06-6.05(m,1H),4.68-4.54(m,2H),4.13-4.01(m,3H),3.78-3.44(m,6H),3.18(s,1H),3.13(s,3H),2.34-2.17(m,3H),2.12-1.88(m,4H),1.71(d,J＝8Hz,3H)。
实施例A24 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)乙基)-N-环丙基-2-(((1S,7a'S)-2,2--二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-4-胺三氟乙酸盐
LCMS:m/z 719(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),9.63(s,1H),8.27(m,1H)，8.13-8.04(m,2H),,6.96-6.91(m,2H),6.52(m,1H),6.36(s,1H),5.74(s,1H),4.65-4.63(m,1H),4.54-4.48(m,1H),3.78-3.65(m,3H),3.47-3.43(m,3H),3.15-3.09(m,1H),2.46-2.41(m,1H),2.28-2.15(m,3H),2.10-1.94(m,2H),1.91-1.85(m,5H),0.94-0.93(m,2H),0.64(m,1H),0.26(m,1H)。
实施例A25 7-(5-胺基-3-氯-2-(三氟甲基)苯基)-N-(1-(2-胺基吡啶-3-基)丙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺三氟乙酸盐
LCMS:m/z 707(M+H)+。1H NMR(400MHz,DMSO-d6)δ0.96(s,1H),9.46(s,1H)，8.28-8.18(m,3H),8.10(d,J＝8Hz,1H),6.99(t,J＝8Hz,1H),6.92(m,1H),6.51-6.45(m,1H),5.99(s,1H),4.74-4.61(m,2H),3.83-3.66(m,5H),3.49-3.43(m,4H),3.18-3.11(m,1H),2.47-2.45(m,1H),2.34-2.17(m,4H),2.11-1.89(m,5H),0.98(s,3H)。
实施例A26 4-(4-((1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇
LCMS:m/z 684(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.60(s,1H),8.64(s,1H),8.29(s,1H),8.07–7.95(m,1H),7.65–7.35(m,3H),7.21(d,J＝3.3Hz,1H),4.56(m,3H),4.00(m,1H),2.22–1.74(m,8H),1.67(m,4H),1.25(s,3H).
实施例A27 2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基))-7-氟苯丙[b]噻吩-3-甲腈
LCMS:m/z 690(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.09(s,2H),7.98(d,J＝8Hz 1H),7.66(d,J＝8Hz 1H),7.40-7.37(m,1H),7.15(t,J＝8Hz 1H),6.68-6.65(m,1H),6.19-6.14(m,1H),5.81(s,2H),4.31-4.20(m,2H),3.24(s,3H),3.14-3.04(m,2H),2.75-2.68(m,1H),2.58-2.55(m,1H),2.13-2.00(m,2H),1.93-1.90(m,1H),1.81-1.76(m,1H),1.65-1.55(m,6H),1.51-1.45(m,1H).
实施例A28 2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-7-氟苯丙[b]噻吩-3-甲腈
LCMS:m/z 605(M+H)+。
实施例A29 N-((R)-1-(2-胺基吡啶-3-基)乙基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 624(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.36(d,J＝7.2Hz,1H),8.43(d,J＝4.7Hz,1H),8.31–8.17(m,2H),7.96(m,1H),7.74–7.58(m,3H),7.37(m,1H),5.24(d,J＝54.1Hz,1H),4.08(m,3H),3.89–3.80(m,1H),3.05(m,2H),2.98(m,1H),2.86–2.75(m,1H),2.21(d,J＝11.9Hz,3H),2.02(m,3H),1.85–1.63(m,3H),1.33(dd,J＝15.6,6.6Hz,3H).
实施例A30 N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-N-甲基吡啶[4,3-d]嘧啶-4-胺
LCMS:m/z 668(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.35(d,J＝6.8Hz,1H),8.47–8.36(m,1H),8.23(m,2H),7.99–7.90(m,1H),7.77–7.57(m,3H),7.35(m,1H),4.16(m,3H),3.82(m,1H),3.09–2.91(m,2H),2.68(d,J＝11.5Hz,1H),2.19(d,J＝10.7Hz,3H),2.04–1.88(m,2H),1.87–1.63(m,3H),1.49(m,m 3H),1.31(m,3H).
实施例A31 4-(4-((1-(2-胺基吡啶-3-基)乙基)(乙基)胺基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇三氟乙酸盐
LCMS:m/z 654(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.83(s,1H),10.27(s,1H),9.61(d,J＝8Hz,1H),9.12-8.93(m,2H),8.65(m,1H),8.28(m,1H),8.04-8.01(m,1H),7.68(s,1H),7.51(t,J＝8Hz,1H),7.44(m,1H),7.26-7.13(m,1H),5.58-5.45(m,1H),4.64-4.48(m,4H),4.00-3.84(m,5H),3.28(s,2H),2.90(s,1H),2.75-2.68(m,1H),2.43(m,1H),2.26-2.13(m,4H),1.96(s,1H),1.69-1.60(m,3H),1.25-1.15(m,4H)。
实施例A32 N-(1-(2-胺基吡啶-3-基)乙基)-N-乙基-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-胺三氟 乙酸盐
LCMS:m/z 638(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.83(s,1H),9.63(d,J＝12Hz,1H)，9.09(s,1H),8.94(m,1H),8.65(m,1H),8.30-8.24(m,3H),7.74(t,J＝4Hz,1H),7.69-7.63(m,3H),5.58-5.45(m,1H),4.54-4.48(m,4H),4.09-4.02(m,2H),3.27(s,2H),2.88(s,1H),2.43(m,1H),2.28-2.15(m,4H),1.97(s,1H),1.69-1.60(m,3H),1.25-1.15(m,4H)。
实施例A32经SFC手性分离得到实施例A32-A和A32-B：N-((R)1-(2-胺基吡啶-3-基)乙基)-N-乙基-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-胺和N-((S)1-(2-胺基吡啶-3-基)乙基)-N-乙基-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-胺
实施例A32-A：
LCMS:m/z 638(M+H)+。
实施例A32-B：
LCMS:m/z 638(M+H)+。
实施例A33 2-胺基-4-(4-((1-(2-氨基吡啶-3-基)乙基)(乙基)胺基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-7-氟苯丙[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 660(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),9.27(s,1H)，8.10-8.15(m,3H),7.42-7.39(m,1H),7.20-7.11(m,1H),6.94-6.91(m,1H),6.24-6.19(m,1H),5.66-5.53(m,1H),4.67-4.50(m,2H),4.05-3.99(m,1H),3.92-3.73(m,6H),3.35-3.29(m,2H),2.36-2.33(m,1H),2.19-1.88(m,4H),1.69-1.61(m,3H),1.13-1.08(m,3H)。
实施例A33经SFC手性分离得到实施例A33-A和A33-B：2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(乙基)胺基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-7-氟苯丙[b]噻吩-3-甲腈和2-胺基-4-(4-(((S)-1-(2-氨基吡啶-3-基)乙基)(乙基)胺基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲 氧基)吡啶[4,3-d]嘧啶-7-基)-7-氟苯丙[b]噻吩-3-甲腈
实施例A33-A：
LCMS:m/z 660(M+H)+。
实施例A33-B：
LCMS:m/z 660(M+H)+。
实施例B1(S)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺的制备
第一步：(S)-7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺的制备
((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇的四氢呋喃溶液(5mL)中加入叔丁醇钠(198mg,2.06mmol)。混合物在室温反应10分钟，随后加入(S)-7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-2,6-二氯-8-氟-N-甲基喹唑啉-4-胺(700mg,0.68mmol)。得到的混合物在室温反应5小时，随后加入水淬灭，再用乙酸乙酯萃取。合并的有机相减压浓缩，残余物用硅胶柱层析分离得到目标产物(650mg,产率：80％)。
LCMS:m/z 1187(M+H)+。
第二步：(S)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺的制备
(S)-7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-(双(4-甲氧基苄基)氨基)吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺(650mg,0.55mmol)的三氟乙酸(5mL)在55℃反应7小时，然后减压浓缩。残余物用碳酸氢钠水溶液碱化后再 用乙酸乙酯萃取。合并的有机相减压浓缩，残余物用制备液相分离得到目标产物(203mg,产率：51％)。
LCMS:m/z 707(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.96-7.94(m,1H),7.63(d,J＝8Hz,1H),6.85(s,2H),6.66-6.63(m,1H),6.48(s,1H),6.01-5.98(m,3H),4.24-4.12(m,2H),3.18(s,3H),3.12-3.07(m,1H),3.04-2.99(m,1H),2.73-2.67(m,1H),2.56-2.54(m,1H),2.37(s,3H),2.10-1.97(m,2H),1.92-1.88(m,1H),1.83-1.73(m,2H),1.65-1.53(m,5H),1.50-1.44(m,1H)。
按照实施例B1的方法以不同的起始原料合成了以下实施例：
实施例B2：(S)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-N-甲基喹唑啉-4-胺
LCMS:m/z 663(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.96-7.95(m,1H),7.63-7.61(s,1H),6.84(s,2H),6.66-6.63(m,1H),6.49(s,1H),6.07-5.97(m,3H),5.36-5.22(m,1H),4.08(s,2H),3.18(s,3H),3.15-3.11(m,2H),3.04(s,1H),2.85(s,1H),2.37(m,3H),2.20-2.14(m,1H),2.07-2.03(m,2H),1.87-1.80(m,3H),1.61-1.59(m,3H).
实施例B3：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 707(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.01(d,J＝1.5Hz,1H),7.97(dd,J＝4.9,1.7Hz,1H),7.63(dd,J＝7.6,1.7Hz,1H),6.87(s,2H),6.66(dd,J＝7.5,4.9Hz,1H),6.50(s,1H),6.03–5.95(m,1H),5.80(s,2H),4.19(q,J＝10.5Hz,2H),3.15(s,3H),3.13–3.07(m,1H),3.06–2.99(m,1H),2.76–2.70(m,1H),2.38(d,J＝2.2Hz,3H),2.13–2.06(m,1H),2.05–1.97(m,1H),1.95–1.88(m,1H),1.86–1.71(m,2H),1.68–1.44(m,6H).
实施例B4：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-N-甲基喹唑啉-4-胺
LCMS:m/z 663(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.00(d,J＝1.6Hz,1H),7.96(dd,J＝4.9,1.7Hz,1H),7.62(dd,J＝7.7,1.8Hz,1H),6.85(s,2H),6.65(dd,J＝7.5,4.9Hz,1H),6.49(s,1H),6.02–5.93(m,1H),5.77(s,2H),5.36–5.22(m,1H),4.19–3.97(m,2H),3.19–3.01(m,7H),2.90–2.79(m,1H),2.37(d,J＝2.2Hz,3H),2.23–1.97(m,3H),1.91–1.75(m,3H),1.61(d,J＝6.7Hz,3H).
实施例B5：7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-(1-(2-氨基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-乙基-8-氟喹唑啉-4-胺
LCMS:m/z 721(M+H)+。
实施例B5经制备液相拆分得到实施例B5-A和B5-B：
实施例B5-A：
LCMS:m/z 721(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.16–10.68(m,1H),8.19(d,J＝7.4Hz,1H),8.13–7.96(m,3H),7.03–6.79(m,3H),6.56–6.52(m,1H),6.00–5.89(m,1H),4.68–4.61(m,2H),4.56–4.48(m,2H),3.89–3.84(m,2H),3.82–3.74(m,1H),3.71–3.63(m,1H),3.48–3.40(m,1H),3.18–3.07(m,1H),2.47–1.87(m,13H),1.70–1.64(m,3H),1.09(t,J＝6.9Hz,3H).
实施例B5-B：
LCMS:m/z 721(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.16–10.79(m,1H),8.21–8.03(m,4H),7.03–6.80(m,3H),6.52(s,1H),5.99–5.91(m,1H),4.67–4.53(m,3H),4.03–3.95(m,1H),3.81–3.65(m,3H),3.49–3.43(m,1H),3.18–3.09(m,1H),2.49–1.87(m,12H),1.67(d,J＝6.8Hz,3H),1.17–1.05(m,3H).
实施例B6：7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-(1-(2-胺基吡啶-3-基)乙基)-6-氯-N-乙基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)喹唑啉-4-胺
LCMS:m/z 677(M+H)+。
实施例B6经制备液相拆分得到实施例B6-A和B6-B：
实施例B6-A：
LCMS:m/z 677(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.16–10.72(m,2H),8.68–8.55(m,1H),8.21–8.15(m,1H),8.13–7.97(m,3H),7.02–6.77(m,3H),6.56–6.49(m,1H),5.98–5.87(m,1H),5.69–5.51(m,1H),4.64–4.37(m,3H),3.92–3.82(m,3H),2.44–2.00(m,11H),1.66(d,J＝6.7Hz,3H),1.12–1.04(m,3H).
实施例B6-B：
LCMS:m/z 677(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.13(m,1H),8.07–7.82(m,3H),7.02–6.78(m,3H),6.53–6.49(m,1H),5.99–5.87(m,1H),5.93–5.54(m,1H),4.67–4.37(m,3H),3.97–3.78(m,4H),2.40–2.05(m,12H),1.66(d,J＝6.7Hz,3H),1.12–1.03(m,3H).
实施例B7：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺
LCMS:m/z 691(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.95(dd,J＝4.9,1.7Hz,1H),7.81(dd,J＝11.1,1.7Hz,1H),7.63(dd,J＝7.5,1.8Hz,1H),6.87(s,2H),6.65(dd,J＝7.5,4.9Hz,1H),6.51(s,1H),6.06–5.95(m,1H),5.79(s,2H),4.27–4.10(m,2H),3.18–3.02(m,5H),2.73(d,J＝11.9Hz,1H),2.60–2.52(m,1H),2.37(d,J＝2.3Hz,3H),2.13–2.05(m,1H),2.04–1.97(m,1H),1.94–1.87(m,1H),1.85–1.72(m,2H),1.62–1.45(m,5H).
实施例B8：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6,8-二氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-N-甲基喹唑啉-4-胺
LCMS:m/z 647(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.97(dd,J＝4.9,1.7Hz,1H),7.83(dd,J＝11.2Hz,1.7Hz,1H),7.64(dd,J＝7.5Hz,1.7Hz,1H),6.89(s,2H),6.67(dd,J＝7.5,4.9Hz,1H),6.52(s,1H),6.05–5.97(m,1H),5.79(s,2H),5.38(s,0.5H),5.25(s,0.5H),4.21–4.02(m,2H),3.22–3.02(m,6H),2.93–2.82(m,1H),2.38 (d,J＝2.2Hz,3H),2.25–2.01(m,3H),1.93–1.75(m,3H),1.62(d,J＝6.8Hz,3H).
实施例B9：(S)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺
LCMS:m/z 691(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.95(dd,J＝4.9,1.7Hz,1H),7.82(dd,J＝11.1,1.7Hz,1H),7.63(dd,J＝7.5,1.8Hz,1H),6.87(s,2H),6.65(dd,J＝7.5,4.9Hz,1H),6.50(s,1H),6.06–5.93(m,3H),4.28–4.08(m,2H),3.21–3.06(m,5H),2.74(d,J＝11.9Hz,1H),2.60–2.52(m,1H),2.37(d,J＝2.2Hz,3H),2.13–1.97(m,2H),1.95–1.88(m,1H),1.85–1.74(m,2H),1.63–1.46(m,6H).
实施例B10：(S)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6,8-二氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-N-甲基喹唑啉-4-胺
LCMS:m/z 647(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.97(dd,J＝5.0,1.7Hz,1H),7.83(dd,J＝11.2Hz,1.7Hz,1H),7.64(dd,J＝7.6,1.7Hz,1H),6.89(s,2H),6.66(dd,J＝7.5,4.9Hz,1H),6.52(s,1H),6.07–5.93(m,3H),5.38(s,0.5H),5.25(s,0.5H),4.10(s,2H),3.22–3.02(m,6H),2.93–2.82(m,1H),2.38(d,J＝2.4Hz,3H),2.25–2.01(m,3H),1.95–1.77(m,3H),1.61(d,J＝6.7Hz,3H).
实施例B11A：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((S)-1-(2-胺基-5-氟吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 725(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.95–7.94(d,J＝2.8Hz,1H),7.61–7.58(dd,J＝9.7,2.9Hz,1H),6.87(s,2H),6.50(s,1H),6.02–5.84(m,3H),4.28–4.07(m,2H),3.23(s,3H),3.18–3.00(m,2H),2.81–2.67(m,1H),2.38(d,J＝2.2Hz,3H),2.13–1.73(m,5H),1.71–1.46(m,6H).
实施例B11B：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基-5-氟吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 725(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.02(d,J＝1.5Hz,1H),7.95–7.94(d,J＝2.8Hz,1H),7.63–7.60(dd,J＝9.5,2.9Hz,1H),6.88(s,2H),6.50(s,1H),5.98–5.88(m,1H),5.75(s,2H),4.30–4.08(m,2H),3.25–2.92(m,5H),2.83–2.68(m,1H),2.38(d,J＝2.2Hz,3H),2.15–1.72(m,5H),1.70–1.44(m,6H).
实施例B12A：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(3-胺基-吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 708(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.10–8.04(m,1H),7.95(d,J＝2.7Hz,1H),7.79(d,J＝2.5Hz,1H),6.88(s,2H),6.50(s,1H),6.46(s,2H),6.07–5.99(m,1H),4.27–4.06(m,2H),3.35(s,3H),3.19–2.99(m,2H),2.83–2.67(m,1H),2.62–2.53(m,1H),2.38(d,J＝2.3Hz,3H),2.13–1.72(m,5H),1.68–1.46(m,6H).
实施例B12B：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((S)-1-(3-胺基-吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 708(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.95(d,J＝2.7Hz,1H),7.79(d,J＝2.7Hz,1H),6.89(s,2H),6.61(s,2H),6.50(s,1H),6.05–5.97(m,1H),4.39–4.05(m,2H),3.41(s,3H),3.26–3.02(m,2H),2.89–2.71(m,1H),2.69–2.55(m,1H),2.38(d,J＝2.2Hz,3H),2.19–1.74(m,5H),1.70–1.45(m,6H).
实施例B13A和实施例B13B：(R)-2-氨基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(S)-2-氨基 -4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B13A
LCMS:m/z 723(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.11(s,2H),8.03(s,1H),7.97-7.95(m,1H),7.64-7.61(m,1H),7.24-7.21(m,1H),7.17-7.12(m,1H),6.67-6.64(m,1H),6.01-5.96(m,1H),5.83(s,2H),4.25-4.14(m,2H),3.17(s,3H),3.12-3.08(m,1H),3.04-2.99(m,1H),2.74-2.66(m,1H),2.56-2.52(m,1H),2.11-2.06(m,1H),.03-1.98(m,1H),1.92-1.88(m,1H),1.83-1.72(m,2H),1.64(d,J＝8Hz,3H),1.60-1.54(m,2H),1.50-1.43(m,1H).
实施例B13B
LCMS:m/z 723(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.10(s,3H),7.97-7.95(m,1H),7.65-7.63(m,1H),7.25-7.22(m,1H),7.17-7.13(m,1H),6.67-6.64(m,1H),6.11-6.06(m,1H),5.93(s,2H),4.24-4.14(m,2H),3.17(s,3H),3.13-3.09(m,1H),3.03-3.01(m,1H),2.74-2.67(m,1H),2.56-2.52(m,1H),2.12-2.07(m,1H),2.04-1.98(m,1H),1.92-1.89(m,1H),1.83-1.72(m,2H),1.66-1.54(m,5H),1.49-1.43(m,1H).
实施例B14A和实施例B14B：(R)-7-(5-氨基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺和(S)-7-(5-氨基-3-氯-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
实施例B14A
LCMS:m/z 726(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.97(d,J＝4Hz,1H),7.64(d,J＝8Hz,1H),6.90(s,1H),6.68-6.65(m,1H),6.36-6.33(m,3H),6.04-5.99(m,1H),5.85(s,2H),4.24-4.15(m,2H),3.17(s,3H),3.14-3.08(m,1H),3.06-3.00(m,1H),2.75-2.68(m,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.04-1.98(m,1H),1.93-1.89(m,1H),1.84-1.72(m,2H),1.66-1.44(m,6H).
实施例B14B
LCMS:m/z 726(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.97(d, J＝4Hz,1H),7.64(d,J＝8Hz,1H),6.90(s,1H),6.68-6.65(m,1H),6.36-6.33(m,3H),6.05-6.00(m,1H),5.92(s,2H),4.25-4.13(m,2H),3.19(s,3H),3.13-3.08(m,1H),3.05-3.00(m,1H),2.74-2.68(m,1H),2.57-2.55(m,1H),2.10-2.06(m,1H),2.04-1.98(m,1H),1.93-1.89(m,1H),1.85-1.72(m,2H),1.66-1.45(m,6H).
实施例B15A和实施例B15B：(R)-7-(3-氨基-2-氟-5-甲基-6-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺和(S)-7-(3-氨基-2-氟-5-甲基-6-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
实施例B15A
LCMS:m/z 724(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.97(d,J＝4Hz,1H),7.64(d,J＝8Hz,1H),6.86-6.83(m,1H),6.68-6.65(m,1H),6.07-6.02(m,3H),5.89(s,2H),4.25-4.15(m,2H),3.19(s,3H),3.14-3.09(m,1H),3.06-3.00(m,1H),2.75-2.68(m,1H),2.57-2.55(m,1H),2.37-2.34(m,3H),2.11-2.06(m,1H),2.04-1.98(m,1H),1.93-1.89(m,1H),1.85-1.73(m,2H),1.66-1.54(m,5H),1.51-1.45(m,1H).
实施例B15B
LCMS:m/z 724(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.98(d,J＝4Hz,1H),7.65(d,J＝8Hz,1H),6.86-6.84(m,1H),6.68-6.65(m,1H),6.05-6.00(m,3H),5.86(s,2H),4.27-4.16(m,2H),3.20(s,3H),3.14-3.04(m,2H),2.77-2.69(m,1H),2.59-2.56(m,1H),2.37-2.33(m,3H),2.12-2.00(m,2H),1.94-1.90(m,1H),1.83-1.74(m,2H),1.67-1.55(m,5H),1.52-1.46(m,1H).
实施例B16A和实施例B16B：7-((R)-3-氨基-8-乙炔基-7-氟萘-1-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺和7-((S)-3-氨基-8-乙炔基-7-氟萘-1-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
实施例B16A
LCMS:m/z 718(M+H)+。
实施例B16B
LCMS:m/z 718(M+H)+。
实施例B17A和实施例B17B：7-((R)-3-氨基-8-乙炔基-7-氟萘-1-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺和7-((S)-3-氨基-8-乙炔基-7-氟萘-1-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺
实施例B17A
LCMS:m/z 702(M+H)+。
实施例B17B
LCMS:m/z 702(M+H)+。
实施例B18A和实施例B18B：(S)-7-(6-氨基-4-(丙-1-炔-1-基)-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺和(R)-7-(6-氨基-4-(丙-1-炔-1-基)-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺
实施例B18A
LCMS:m/z 731(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.97(d,J＝8Hz,1H),7.64(d,J＝8Hz,1H),7.07(s,2H),6.67-6.65(m,2H),6.00-5.96(m,1H),5.80(s,2H),4.23-4.16(m,2H),3.15(s,3H),3.10(m,1H),3.03(m,1H),2.74-2.68(m,1H),2.57-2.55(m,1H),2.12(s,3H),2.10-2.07(m,1H),2.04-1.98(m,1H),1.93-1.89(m,1H),1.84-1.70(m,2H)1.63-1.54(m,5H),1.51-1.45(m,1H).
实施例B18B
LCMS:m/z 731(M+H)+。1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.97(d,J＝8Hz,1H),7.64(d,J＝8Hz,1H),7.07(s,2H),6.67-6.64(m,2H),6.02-5.97(m,3H),4.27-4.14(m,2H),3.19(s,3H),3.12-3.02(m,1H), 2.78-2.68(m,1H),2.59-2.55(m,1H),2.12(s,3H),2.10-2.07(m,1H),2.05-1.99(m,1H),1.94-1.91(m,1H),1.87-1.75(m,2H),1.68-1.46(m,7H).
实施例B19A和实施例B19B：(S)-7-(3-氨基-2-氟-5-(丙-1-炔-1-基)-6-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺和(R)-7-(3-氨基-2-氟-5-(丙-1-炔-1-基)-6-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺
实施例B19A
LCMS:m/z 748(M+H)+。
实施例B19B
LCMS:m/z 748(M+H)+。
实施例B20A和实施例B20B：(R)-7-(5-氨基-4-氟-3-(丙-1-炔-1-基)-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺和(S)-7-(5-氨基-4-氟-3-(丙-1-炔-1-基)-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟-N-甲基喹唑啉-4-胺
实施例B20A
LCMS:m/z 748(M+H)+。
实施例B20B
LCMS:m/z 748(M+H)+。
实施例B21A和实施例B21B：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基-N-((S)-1-(2-(甲基氨基)吡啶-3-基)乙基)喹唑啉-4-胺和(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基-N-((R)-1-(2-(甲基氨基)吡啶-3-基)乙基)喹唑 啉-4-胺
实施例B21A
LCMS:m/z 721(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝4Hz,1H),8.02(s,1H),7.61(d,J＝8Hz,1H),6.85(s,2H),6.67-6.64(m,1H),6.62-6.59(m,1H),6.49(s,1H),6.00-5.95(m,1H),4.25-4.23(m,1H),4.13-4.11(m,1H),3.19(s,3H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.83(d,J＝4Hz,3H),2.74-2.67(m,1H),2.57-2.55(m,1H),2.37-2.33(m,3H),2.11-1.99(m,2H),1.92-1.88(m,1H),1.83-1.71(m,2H),1.65-1.44(m,6H).
实施例B21B
LCMS:m/z 721(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝4Hz,1H),8.01(s,1H),7.63(d,J＝8Hz,1H),6.99-6.96(m,1H),6.85(s,2H),6.62-6.59(m,1H),6.49(s,1H),5.96-5.91(m,1H),4.25-4.14(m,2H),3.22(s,3H),3.14-3.03(m,2H),2.85(d,J＝4Hz,3H),2.75-2.67(m,1H),2.58-2.54(m,1H),2.37-2.33(m,3H),2.14-2.10(m,1H),2.04-1.99(m,1H),1.94-1.91(m,1H),1.83-1.76(m,2H),1.61-1.47(m,6H).
实施例B22 7-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)氨基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-6-甲腈
LCMS:m/z 698(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.53–8.46(m,1H),8.00–7.93(m,1H),7.67–7.60(m,1H),6.94(s,2H),6.69–6.62(m,1H),6.53(s,1H),6.13–5.99(m,1H),5.89(s,1H),5.75(s,1H),4.29–4.09(m,2H),3.25–3.16(m,3H),3.13–2.96(m,2H),2.77–2.69(m,1H),2.54(dd,J＝8.9,6.2Hz,1H),2.39(q,J＝2.1Hz,3H),2.11–1.94(m,2H),1.92–1.70(m,3H),1.66–1.42(m,6H).
实施例B23A和B23B：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-三甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-三甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B23A
LCMS:m/z 634(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.11(s,2H),7.95(d,J＝4.5Hz,2H),7.60(d,J＝7.3Hz,1H),7.21(dd,J＝8.3,5.4Hz,1H),7.14(t,J＝8.9Hz,1H),6.64(dd,J＝7.3,5.0Hz,1H),6.04(m,3H),3.94(m,2H),3.79(m,2H),3.11(s,3H),2.21(s,6H),1.60(d,J＝6.7Hz,3H),1.32(s,3H).
实施例B23B
LCMS:m/z 634(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.11(s,2H),7.94(dd,J＝4.8,1.4Hz,1H),7.89(s,1H),7.59(d,J＝7.3Hz,1H),7.26–7.06(m,2H),6.64(dd,J＝7.4,5.0Hz,1H),5.96(d,J＝10.3Hz,3H),3.92(m,2H),3.76(m,2H),3.12(s,3H),2.17(s,6H),1.61(d,J＝6.8Hz,3H),1.38–1.26(m,3H).
实施例B24A、B24B、B24C和B24D：(R)-2-氨基-4-(4-(((S)-1-(3-氨基吡嗪-2-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、(R)-2-氨基-4-(4-(((R)-1-(3-氨基吡嗪-2-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、(S)-2-氨基-4-(4-(((S)-1-(3-氨基吡嗪-2-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、和(S)-2-氨基-4-(4-(((R)-1-(3-氨基吡嗪-2-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B24A
LCMS:m/z 724(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.08(s,1H),7.94(d,J＝4Hz,1H),7.77(d,J＝4Hz,1H),7.24-7.21(m,1H),7.17-7.13(m,1H),6.49(s,2H),6.02-5.97(m,1H),4.17-4.08(m,2H),3.40(s,3H),3.13-3.00(m,2H),2.73-2.68(m,1H),2.58-2.55(m,1H),2.09-2.04(m,1H),1.99-1.95(m,1H),1.91-1.87(m,1H),1.81-1.72(m,2H),1.65-1.42(m,6H).
实施例B24B
LCMS:m/z 724(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),8.12(s,2H),7.93(d,J＝4Hz,1H),7.77(d,J＝4Hz,1H),7.27-7.23(m,1H),7.18-7.13(m,1H),6.57(s,2H), 6.05-6.00(m,1H),4.18-4.06(m,2H),3.40(s,3H),3.06-3.03(m,2H),2.73-2.67(m,1H),2.58-2.53(m,1H),2.08-1.95(m,2H),1.90-1.75(m,3H),1.65-1.45(m,6H).
实施例B24C
LCMS:m/z 724(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.08(s,1H),7.94(d,J＝4Hz,1H),7.78(d,J＝4Hz,1H),7.24-7.21(m,1H),7.17-7.13(m,1H),6.51(s,2H),6.04-5.99(m,1H),4.21-4.05(m,2H),3.39(s,3H),3.11-3.00(m,2H),2.73-2.67(m,1H),2.57-2.54(m,1H),2.08-1.95(m,2H),1.89-1.86(m,1H),1.80-1.74(m,2H),1.65-1.42(m,6H).
实施例B24D
LCMS:m/z 724(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),8.12(s,2H),7.93(d,J＝4Hz,1H),7.77(d,J＝4Hz,1H),7.27-7.23(m,1H),7.18-7.13(m,1H),6.53(s,2H),6.04-5.99(m,1H),4.16-4.06(m,2H),3.41(s,3H),3.12-3.00(m,2H),2.73-2.67(m,1H),2.56-2.53(m,1H),2.07-1.72(m,5H),1.65-1.44(m,6H).
实施例B25A和B25B：(R)-7-(5-胺基-4-氟-3-甲基-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺和(S)-7-(5-胺基-4-氟-3-甲基-2-(三氟甲基)苯基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
实施例B25A
LCMS:m/z 724(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.98-7.97(m,1H),7.65(d,J＝8Hz,1H),6.69-6.66(m,1H),6.44(d,J＝8Hz,1H),6.10(s,2H),6.05-6.00(m,1H),5.88(s,2H),4.26-4.16(m,2H),3.18(s,3H),3.16-3.04(m,2H),2.76-2.70(m,1H),2.59-2.57(m,1H),2.36(s,3H),2.12-1.99(m,2H),1.94(d,J＝12Hz,1H),1.85-1.75(m,2H),1.64-1.62(m,3H),1.59-1.48(m,3H).
实施例B25B
LCMS:m/z 724(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.96(d,J＝4Hz,1H),7.63(d,J＝8Hz,1H),6.66-6.63(m,1H),6.41(d,J＝8Hz,1H),6.08(s,2H),6.03-5.98(m,1H),5.93(s,2H),4.23-4.12(m,2H),3.18(s,3H),3.12-3.00(m,2H),2.74-2.67(m,1H),2.56-2.54(m,1H),2.33(s,3H),2.10-1.97(m,2H),1.92(d,J＝12Hz,1H),1.81-1.71(m,2H),1.65-1.45(m,6H).
实施例B26：(R)-2-胺基-4-(4-(((R)-1-(2-2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(4-甲基哌嗪-1-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈的制备
LCMS:m/z 620(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.22–7.86(m,7H),7.17(m,2H),7.01–6.87(m,1H),5.91–5.79(m,1H),4.75(m,2H),3.48(m,2H),3.31(m,5H),3.04(m,2H),2.82(s,3H),1.66(d,J＝6.7Hz,3H).
实施例B27：(R)-2-胺基-4-(4-(((R)-1-(2-2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈的制备
LCMS:m/z 635(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.10(m,7H),7.25–7.16(m,1H),7.00–6.94(m,1H),5.89(m,1H),4.75(m,1H),4.48(m,1H),3.83(m,1H),3.62(m,1H),3.38(s,3H),3.15(m,1H),2.97(s,3H),2.80(m,1H),2.27(m,1H),2.07(d,J＝13.8Hz,1H),1.93(m,2H),1.70(d,J＝6.8Hz,3H),1.51(d,J＝6.6Hz,1H).
实施例B28：(R)-2-胺基-4-(4-(((R)-1-(2-2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-((1-((二甲基胺基)甲基)环丙基)甲氧基)-8-氟喹唑啉-7-基)-氟苯并[b]噻吩-3-甲腈的制备
LCMS:m/z 649(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.15(s,2H),8.04(s,1H),7.96(d,J＝4.1Hz,1H),7.62(d,J＝7.0Hz,1H),7.27–7.09(m,2H),6.66(dd,J＝7.3,4.9Hz,1H),5.98(d,J＝6.5Hz,1H),5.84(s,2H),4.33(d,J＝11.4Hz,1H),4.21(d,J＝11.4Hz,1H),3.18(s,3H),1.63(d,J＝6.6Hz,3H),1.40–1.05(m,5H),0.80(m,4H).
实施例B29：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 620(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.14(s,2H),7.95(dd,J＝4.9,1.4Hz,1H),7.91(d,J＝1.1Hz,1H),7.61(d,J＝6.6Hz,1H),7.24–7.06(m,2H), 6.65(dd,J＝7.4,5.0Hz,1H),6.11–5.90(m,3H),4.23–4.10(m,2H),4.07–3.89(m,2H),3.12(s,3H),2.30(s,6H),1.61(d,J＝6.8Hz,3H).
实施例B30：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-吡咯啉-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 634(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.02(m,7H),7.37(s,1H),7.23–7.11(m,1H),6.94(m,1H),5.88–5.75(m,1H),3.95(m,2H),3.77–3.63(m,2H),3.34(s,3H),2.84(s,6H),2.38(s,1H),2.25–2.08(m,1H),1.67(d,J＝6.7Hz,3H),1.52(t,J＝8.7Hz,1H).
实施例B31：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-哌啶-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 620(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.00–7.94(m,1H),7.87–7.83(m,1H),7.60(dd,J＝12.6,7.4Hz,1H),7.26–7.11(m,2H),6.73–6.64(m,1H),5.98–5.88(m,1H),5.69(s,2H),4.89–4.71(m,1H),4.57–4.40(m,1H),3.11(d,J＝12.2Hz,3H),2.70–2.55(m,2H),2.08–1.96(m,2H),1.88–1.74(m,1H),1.63(d,J＝6.7Hz,3H),1.55–1.38(m,2H),1.25(s,6H),0.87(t,J＝6.6Hz,1H).
实施例B32：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(4-(二甲基胺基)-哌啶-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 620(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.39–7.89(m,6H),7.29–7.08(m,2H),6.95(t,J＝6.8Hz,1H),5.78(q,J＝6.7Hz,1H),4.85(d,J＝12.5Hz,2H),3.48(m,1H),3.34(s,3H),2.88(m,2H),2.81–2.60(m,6H),2.09–1.91(m,2H),1.67(d,J＝6.8Hz,3H),1.52(m,1H),1.43–1.23(m,1H).
实施例B33：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(6-甲基-1,6-二氮杂螺[3.3]庚-1-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 632(M+H)+。
实施例B34：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(1-甲基-1,6-二氮杂螺[3.3]庚-6-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 632(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.32–7.94(m,7H),7.24–7.10(m,2H),7.05–6.94(m,1H),5.80(d,J＝6.6Hz,1H),4.53(m,4H),4.29(m,2H),3.28(s,3H),2.92(s,3H),2.75(t,J＝8.3Hz,2H),1.69(d,J＝6.7Hz,3H).
实施例B35：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-甲基氮杂环丁烷-3-基)氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 607(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.26–8.05(m,5H),7.81(s,2H),7.20(m,2H),7.05–6.94(m,1H),5.85(s,1H),5.43(m,1H),4.68(s,1H),4.41(s,2H),4.20(s,1H),3.26(s,3H),2.94(s,3H),1.69(d,J＝6.6Hz,3H).
实施例B36：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-甲基氮杂环丁烷-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 621(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.39–7.91(m,7H),7.29–7.09(m,2H),6.97(t,J＝6.7Hz,1H),5.91(d,J＝6.6Hz,1H),4.52(m,2H),4.31(m,1H),4.18(m,1H),4.05(m,1H),3.92(m,1H),3.26(m,4H),2.86(d,J＝9.3Hz,3H),1.69(d,J＝6.6Hz,3H).
实施例B37：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 618(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.94(dd,J＝4.8,1.4Hz,1H),7.86(s,1H),7.58(d,J＝7.2Hz,1H),6.84(s,2H),6.63(dd,J＝7.4,4.9Hz,1H),6.47(s,1H),6.01–5.83(m,3H),3.97–3.78(m,2H),3.72(m,2H),3.09(s,3H),2.36(s,3H),2.12(s,6H),1.58(d,J＝6.8Hz,3H),1.25(s,3H).
实施例B38：(4R)-4-(4-((1-(1H-吡唑-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 697(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.33–8.10(m,3H),7.76–7.70(m,1H),7.32(s,1H),7.30–7.23(m,1H),7.22–7.14(m,2H),7.06(s,1H),6.42–6.34(m,1H),6.11–5.99(m,1H),4.67–4.64(m,1H),3.81–3.75(m,1H),3.71–3.64(m,1H),3.48–3.43(m,1H),3.21–3.07(m,4H),2.31–2.12(m,3H),2.09–2.02(m,1H),1.99–1.93(m,1H),1.91–1.82(m,2H),1.69–1.60(m,3H).
实施例B39A和39B：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6-氟-8-(丙-1-炔-1-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6-氟-8-(丙-1-炔-1-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B39A
LCMS:m/z 728(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.06(s,2H),7.94(d,J＝4Hz,1H),7.90(d,J＝12Hz,1H),7.79(d,J＝4Hz,1H),7.25-7.22(m,1H),7.14(t,J＝8Hz,1H),6.50(s,2H),6.03-5.99(m,1H),4.29-4.14(m,2H),3.11-3.04(m,3H),2.74-2.68(m,1H),2.57-2.55(m,1H),2.12-2.07(m,1H),2.04-1.98(m,1H),1.91-1.75(m,7H),1.65-1.45(m,7H).
实施例B39B：
LCMS:m/z 728(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.06(s,2H),7.97(d,J＝8Hz,1H),7.93(d,J＝4Hz,1H),7.78(d,J＝4Hz,1H),7.29-7.25(m,1H),7.14(t,J＝8Hz,1H),6.60(s,2H),6.05-5.99(m,1H),4.24-4.14(m,2H),3.12-3.02(m,3H),2.74-2.68(m,1H),2.57-2.55(m,1H),2.09-2.04(m,1H),2.00-1.96(m,1H),1.90-1.73(m,7H),1.65-1.45(m,7H).
实施例B40A和B40B：(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-6,8-二氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B40A：
LCMS:m/z 708(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.17(s,2H),7.95(d,J＝4Hz,1H),7.90(d,J＝12Hz,1H),7.79(d,J＝4Hz,1H),7.35-7.31(m,1H),7.17(t,J＝8Hz,1H),6.53(s,2H),6.08-6.03(m,1H),4.21-4.06(m,2H),3.38(s,3H),3.12-3.02(m,2H),2.73-2.70(m,1H),2.57-2.55(m,1H),2.09-2.04(m,1H),2.02-1.96(m,1H),1.91(d,J＝12Hz,1H),1.83-1.71(m,2H),1.66(d,J＝8Hz,3H),1.60-1.45(m,3H).
实施例B40B：
LCMS:m/z 708(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.17(s,2H),7.95-7.92(m,2H),7.79(d,J＝4Hz,1H)7.36-7.33(m,1H),7.17(t,J＝8Hz,1H),6.59(s,2H),6.09-6.04(m,1H),4.19-4.04(m,2H),3.39(s,3H),3.12-3.02(m,2H),2.72-2.69(m,1H),2.57-2.55(m,1H),2.08-2.03(m,1H),2.00-1.94(m,1H),1.89(d,J＝12Hz,1H),1.83-1.71(m,2H),1.65(d,J＝8Hz,3H),1.60-1.45(m,3H).
实施例B41：2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 689(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.12-8.09(m,3H),7.95-7.93(m,1H),7.79(t,J＝4Hz,1H),7.27-7.23(m,2H),7.17-7.12(m,1H),6.66(s,1H),6.55(s,1H),6.13-6.06(m,1H),4.37(s,3H),3.45(d,J＝20Hz,4H),2.22-1.89(m,6H),1.67-1.65(m,5H).
实施例B42：(R)-2-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 632(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.10(s,2H),7.93(dd,J＝23.4,8.5Hz,2H),7.73(d,J＝1.9Hz,1H),7.20(dd,J＝8.4,5.4Hz,1H),7.13(t,J＝8.9Hz,1H),6.54(d,J＝20.0Hz,2H),5.89(s,1H),3.99–3.56(m,4H),2.11(s,6H),1.61(d,J＝6.8Hz,3H),1.33–1.18(m,6H).
实施例B43A和B43B：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-6-氟-8-(丙-1-炔-1-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((S)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-6-氟-8-(丙-1-炔-1-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B43A
LCMS:m/z 639(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.02(s,2H),7.90(d,J＝4Hz,1H),7.75-7.73(m,2H),7.22-7.19(m,1H),7.12(t,J＝12Hz,1H),6.55(s,2H),5.93-5.87(m,1H),3.86(s,1H),3.71-3.62(m,3H),3.31(s,3H),2.11(s,6H),1.82(s,3H),1.62(d,J＝8Hz,3H),1.25(s,3H).
实施例B43B：
LCMS:m/z 639(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.02(s,2H),7.89(d,J＝4Hz,1H),7.73-7.72(m,1H),7.26-7.23(m,1H),7.13(t,J＝12Hz,2H),6.64(s,2H),5.87(s,1H),3.85-3.80(m,1H),3.68-3.56(m,3H),3.38(s,3H),2.10(s,6H),1.83(s,3H),1.61(d,J＝8Hz,3H),1.23(s,3H).
实施例B44：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-3-基)氧)喹唑啉-7-yl)-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 621(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.11(m, 5H),7.78(m,1H),7.31–7.08(m,2H),7.01–6.92(m,1H),5.87(d,J＝6.6Hz,1H),5.65(m,1H),3.25(m,4H),3.20–3.10(m,2H),2.89(s,3H),2.68(m,1H),2.28(m,2H),1.70(d,J＝6.6Hz,3H),1.47(m,1H).
实施例B45：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R)-1-甲基吡咯啶-3-基)氧)喹唑啉-7-yl)-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 621(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.12(m,7H),7.29–7.12(m,3H),6.98(t,J＝6.7Hz,1H),5.89(s,1H),5.64(s,1H),3.30(m,5H),3.17(m,1H),2.90(m,4H),2.25(m,2H),1.70(d,J＝6.6Hz,3H).
实施例B46：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((反式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 651(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.15(s,2H),8.02(s,1H),7.98(d,J＝4.9Hz,1H),7.62(d,J＝7.7Hz,1H),7.24(dd,J＝8.5,5.2Hz,1H),7.16(t,J＝8.9Hz,1H),6.68(dd,J＝7.6,4.8Hz,1H),5.96–5.89(m,1H),5.72(s,2H),5.45–5.39(m,1H),4.11(dd,J＝10.5,5.4Hz,1H),4.02(dd,J＝9.4,6.7Hz,1H),3.85(dd,J＝10.6,2.5Hz,1H),3.62(dd,J＝9.4,6.2Hz,1H),3.19(s,3H),3.12–3.04(m,1H),2.25(s,6H),1.64(d,J＝5.9Hz,3H).
实施例B46经手性拆分得到异构体实施例B46A和实施例B46B:(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B46A
LCMS:m/z 651(M+H)+。
实施例B46B
LCMS:m/z 651(M+H)+。
实施例B47：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((顺式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 651(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.15(s,2H),8.02(s,1H),7.98(dd,J＝4.9,1.8Hz,1H),7.61(dd,J＝7.7,1.7Hz,1H),7.24(dd,J＝8.4,5.3Hz,1H),7.16(t,J＝8.9Hz,1H),6.67(dd,J＝7.5,4.8Hz,1H),5.96–5.89(m,1H),5.72(s,2H),5.40(dd,J＝5.4,2.7Hz,1H),4.10(dd,J＝10.7,5.5Hz,1H),4.01(dd,J＝9.2,6.6Hz,1H),3.85(dd,J＝10.4,2.5Hz,1H),3.61(dd,J＝9.2,6.2Hz,1H),3.19(s,3H),3.07–3.01(m,1H),2.23(s,6H),1.63(d,J＝6.5Hz,3H).
实施例B47经手性拆分得到异构体实施例B47A和实施例B47B:(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B47A
LCMS:m/z 651(M+H)+。
实施例B47B
LCMS:m/z 651(M+H)+。
实施例B48：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-甲基哌啶-4-基)氧)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 635(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.14(m,3H),8.05(m,3H),7.30(m,1H),7.26–7.11(m,3H),7.05(m,1H),6.92(m,1H),5.89(m,1H),5.34(m,1H),3.33(m,3H),3.19(m,4H),2.84(m,3H),2.34～2.20(m,4H),1.88(m,1H),1.69(s,3H).
实施例B49：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-(甲氧基乙基)哌啶-4-基)氧)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 679(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.24–7.85(m,6H),7.19(m,2H),6.92(m,1H),5.88(m,1H),5.23(m,1H),3.68(m,3H),3.33(m,7H),3.15(m,3H),2.39–1.83(m,6H),1.68(s,3H).
实施例B50：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((2S,4R)-4-氟-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 653(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.11(s,2H),7.96(d,J＝4.0Hz,1H),7.89(s,1H),7.61(d,J＝7.1Hz,1H),7.26–7.03(m,2H),6.65(dd,J＝7.4,5.0Hz,1H),5.96(s,3H),4.16–3.90(m,4H),3.71(s,1H),3.11(s,3H),2.78(s,2H),2.56(m,2H),2.31(s,3H),2.11(t,J＝6.9Hz,2H),1.61(d,J＝6.8Hz,3H).
实施例B51：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((2S,4R)-4-氟-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 654(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝7.4Hz,2H),8.28(s,1H),8.15(s,2H),7.27(dd,J＝8.3,5.3Hz,1H),7.17(t,J＝8.9Hz,1H),5.14(d,J＝57.1Hz,1H),4.34(dd,J＝11.1,4.3Hz,1H),4.26(dd,J＝11.0,5.5Hz,1H),4.17(s,1H),3.51–3.42(m,2H),2.86(m,1H),2.45(m,1H),2.43–2.23(m,7H),2.17–1.97(m,1H),1.95–1.75(m,1H),1.41(t,J＝7.9Hz,3H).
实施例B52：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((S)-1-((S)-1-甲基吡咯啶-2-基)乙氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 649(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.14(s,2H),7.98(d,J＝6.0Hz,2H),7.63(d,J＝6.5Hz,1H),7.24(dd,J＝8.4,5.3Hz,1H),7.15(t,J＝8.9Hz,1H),6.68(dd,J＝7.4,4.9Hz,1H),5.91(q,J＝6.5Hz,1H),5.71(s,2H),5.25(dd,J＝12.1,6.1Hz,1H),3.15(s,3H),2.98(s,1H),2.68(s,1H),2.40(s,3H),2.23(s,1H),1.87–1.57(m,7H),1.29(d,J＝6.3Hz,3H).
实施例B53：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((S)-1-((2S,4R)-4-氟-1-甲基吡咯啶-2-基)乙氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 667(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.00–7.94(m,2H),7.61(dd,J＝7.5,1.8Hz,1H),7.23(dd,J＝8.4,5.3Hz,1H),7.15(t,J＝8.9Hz,1H),6.66(dd,J＝7.5,4.9Hz,1H),5.93–5.84(m,1H),5.70(s,2H),5.30–5.04(m,2H),3.46–3.36(m,1H),3.15(s,3H),3.00–2.91(m,1H),2.48–2.35(m,4H),2.08–1.83(m,2H),1.63(d,J＝6.7Hz,3H),1.26(d,J＝6.3Hz,3H).
实施例B54：(4R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((S)-1,2-二甲基吡咯啶-2-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 649(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.02(d,J＝1.6Hz,1H),7.96(dd,J＝4.9,1.7Hz,1H),7.61(dd,J＝7.5,1.8Hz,1H),7.22(dd,J＝8.4,5.3Hz,1H),7.15(t,J＝8.9Hz,1H),6.65(dd,J＝7.5,4.9Hz,1H),6.00–5.91(m,1H),5.83(s,2H),4.19(d,J＝11.0Hz,2H),3.19(s,3H),2.92–2.80(m,1H),2.65–2.55(m,1H),2.30(s,3H),1.98–1.87(m,1H),1.74–1.56(m,6H),1.05(s,3H).
实施例B55：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((S)-4,4-二氟-1-甲基吡咯啶-2-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 671(M+H)+。
实施例B56：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((S)-4-(二氟甲烯基)-1-甲基吡咯啶-2-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 683(M+H)+。
实施例B57：(4R)-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((S)-4-(二氟甲基)-1-甲基吡咯啶-2-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 685(M+H)+。
实施例B58：(4R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((2S)-6,6-二氟-3-甲基-3-氮杂双环[3.1.0]乙烷-2-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 683(M+H)+。
实施例B59：(4R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((6S)-1,1-二氟-5-甲基-5-氮杂螺[2.4]庚烷-6-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 697(M+H)+。
实施例B60A和B60B：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二氟甲基)-1-甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈及(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二氟甲基)-1-甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B60A
LCMS:m/z 699(M+H)+。
实施例B60B
LCMS:m/z 699(M+H)+。
实施例B61A和B61B：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺 基)-6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈及(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B61A
LCMS:m/z 713(M+H)+。
实施例B61B
LCMS:m/z 713(M+H)+。
实施例B62A和B62B：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈及(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B62A
LCMS:m/z 714(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.13(s,2H),8.09–8.06(m,1H),7.95(d,J＝2.6Hz,1H),7.80(d,J＝2.7Hz,1H),7.25–7.19(m,1H),7.18–7.11(m,1H),6.51(s,2H),6.04–5.90(m,1H),4.50–4.37(m,1H),4.36–4.25(m,1H),3.40(s,3H),2.92–2.70(m,2H),2.11(s,3H),1.95–1.39(m,9H),1.11(s,3H).
实施例B62B
LCMS:m/z 714(M+H)+。
实施例B63A、B63B、B63C和B63D：
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4R)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4S)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3- 甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B63A
LCMS:m/z 711(M+H)+。
实施例B63B
LCMS:m/z 711(M+H)+。
实施例B63C
LCMS:m/z 711(M+H)+。
实施例B63D
LCMS:m/z 711(M+H)+。
实施例B64A、B64B、B64C和B64D：
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4R)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4S)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B64A
LCMS:m/z 712(M+H)+。
实施例B64B
LCMS:m/z 712(M+H)+。
实施例B64C
LCMS:m/z 712(M+H)+。
实施例B64D
LCMS:m/z 712(M+H)+。
实施例B65A、B65B、B65C和B65D：
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6S,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6S,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6R,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6R,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B65A
LCMS:m/z 691(M+H)+。
实施例B65B
LCMS:m/z 691(M+H)+。
实施例B65C
LCMS:m/z 691(M+H)+。
实施例B65D
LCMS:m/z 691(M+H)+。
实施例B66A、B66B、B66C和B66D：
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6S,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6S,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟 -2-(((3R,6R,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6R,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B66A
LCMS:m/z 691(M+H)+。
实施例B66B
LCMS:m/z 691(M+H)+。
实施例B66C
LCMS:m/z 691(M+H)+。
实施例B66D
LCMS:m/z 691(M+H)+。
实施例B67：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 632(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.28–7.85(m,7H),7.23–7.10(m,2H),7.03–6.93(m,1H),5.81(d,J＝6.8Hz,1H),4.42(m,2H),4.27(m,4H),4.15(m,2H),3.26(s,3H),2.83(d,J＝2.9Hz,3H),1.68(d,J＝6.8Hz,3H).
实施例B68：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(6-甲基-2,6-二氮杂螺[3.4]辛烷-2-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 646(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.11(s,2H),7.96(d,J＝4.0Hz,1H),7.89(s,1H),7.61(d,J＝7.1Hz,1H),7.26–7.03(m,2H),6.65(dd,J＝7.4,5.0Hz,1H),5.96(s,3H),4.16–3.90(m,4H),3.71(s,1H),3.11(s,3H),2.78(s,2H),2.56(m,2H),2.31(s,3H),2.11(t,J＝6.9Hz,2H),1.61(d,J＝6.8Hz,3H).
实施例B69：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(2-甲基-2,6-二氮杂螺[3.4]辛烷-6-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈三氟乙酸盐
LCMS:m/z 646(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.03(m,7H),7.24–7.09(m,2H),6.97(s,1H),5.85(s,1H),4.34–3.92(m,6H),3.47–3.35(m,2H),3.27(s,3H),2.88(d,J＝4.4Hz,3H),2.25(s,2H),1.68(d,J＝5.9Hz,3H).
实施例B70：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 719(M+H)+。
实施例B71：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 720(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.14(s,2H),8.08(s,1H),7.94(d,J＝2.8Hz,1H),7.77(d,J＝2.7Hz,1H),7.25–7.21(m,1H),7.16(t,J＝8.9Hz,1H),6.49(s,2H),6.01–5.94(m,1H),4.29–4.24(m,1H),4.12–4.05(m,1H),3.41(s,3H),2.49–2.30(m,5H),2.31–2.16(m,3H),2.08–1.94(m,2H),1.64(d,J＝6.8Hz,3H),0.69–0.54(m,2H),0.45–0.29(m,2H).
实施例B72：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(二氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 737(M+H)+。
实施例B73：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8- 氟-2-((1-((4-(二氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 738(M+H)+。
实施例B74：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(二氟甲基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 739(M+H)+。
实施例B75：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(二氟甲基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 740(M+H)+。
实施例B76：(4R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((6-氟-3-氮杂双环[3.1.0]己烷-3-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 705(M+H)+。
实施例B77：(4R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-((1-((6,6-二氟-3-氮杂双环[3.1.0]己烷-3-基)甲基)环丙基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 723(M+H)+。
实施例B78：(4R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-((1-((1,1-二氟-5-氮杂螺[2.4]庚烷-5-基)甲基)环丙基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 737(M+H)+。
实施例B79：(4R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-((1-((二甲基胺基)甲基)-2,2-二氟环丙基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 685(M+H)+。
实施例B80：(4R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-((1-((二甲基胺基)甲基)-2,2-二氟环丙基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 686(M+H)+。
实施例B81：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-((S)-2-(二甲基胺基)丙基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 623(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.49–7.94(m,7H),7.35–7.10(m,2H),6.96(t,J＝6.8Hz,1H),5.90(d,J＝6.7Hz,1H),4.64(m,1H),4.52(m,1H),3.85(m,1H),3.36(s,3H),2.82(s,6H),1.70(d,J＝6.6Hz,3H),1.35(d,J＝6.8Hz,3H).
实施例B82：(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯 -2-((S)-1-(二甲基胺基-2-基)丙基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 623(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.13(s,2H),8.00(d,J＝1.6Hz,1H),7.96(dd,J＝4.9,1.7Hz,1H),7.61(dd,J＝7.6,1.8Hz,1H),7.22(dd,J＝8.4,5.3Hz,1H),7.15(t,J＝8.9Hz,1H),6.66(dd,J＝7.5,4.8Hz,1H),5.98–5.88(m,1H),5.73(s,2H),5.44–5.33(m,1H),3.78–3.63(m,2H),3.17(s,3H),2.39–2.25(m,5H),1.62(d,J＝6.8Hz,3H),1.51–1.42(m,1H),1.33(d,J＝6.2Hz,3H).
实施例B83：N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-(6-氟-5-甲基-1H-吲唑-4-基)-N-甲基喹唑啉-4-胺
LCMS:m/z 681(M+H)+。
实施例B84：N-((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-(6-氟-5-甲基-1H-吲唑-4-基)-N-甲基喹唑啉-4-胺
LCMS:m/z 682(M+H)+。
实施例B84经手性拆分得到实施例B84A和B84B：N-((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-((S)-6-氟-5-甲基-1H-吲唑-4-基)-N-甲基喹唑啉-4-胺和N-((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-((R)-6-氟-5-甲基-1H-吲唑-4-基)-N-甲基喹唑啉-4-胺
实施例B84A
LCMS:m/z 682(M+H)+。1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),8.22(s,1H),7.95(d,J＝2.8Hz,1H),7.79(d,J＝2.7Hz,1H),7.48(d,J＝9.8Hz,1H),7.20(s,1H), 6.66(s,1H),6.53(s,2H),6.09(d,J＝6.7Hz,1H),4.25–4.04(m,2H),3.05–2.98(m,2H),2.09–1.99(m,6H),1.64(d,J＝6.7Hz,3H),1.51–1.39(m,7H),0.90–0.81(m,2H).
实施例B84B
LCMS:m/z 682(M+H)+。1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.21(s,1H),7.95(d,J＝2.6Hz,1H),7.79(d,J＝2.6Hz,1H),7.59(s,1H),7.49(d,J＝10.2Hz,1H),6.66(s,1H),6.53(s,2H),6.11–6.03(m,1H),4.21–4.05(m,2H),3.04–2.96(m,2H),2.10–2.02(m,6H),1.65(d,J＝6.8Hz,3H),1.51–1.41(m,7H),0.88–0.82(m,2H).
实施例B85：2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 741(M+H)+。
实施例B85经手性拆分得到实施例B85A和B85B：(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B85A
LCMS:m/z 741(M+H)+。
实施例B85B
LCMS:m/z 741(M+H)+。
实施例B86：2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 742(M+H)+。
实施例B86经手性拆分得到实施例B86A和B86B：(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B86A
LCMS:m/z 742(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.30(s,2H),8.11(s,1H),7.95(d,J＝4Hz,1H),7.79(d,J＝4Hz,1H),7.32(t,J＝8Hz,1H),6.48(s,2H),6.03-5.98(m,1H),4.21-4.05(m,2H),3.38(s,3H),3.10-2.99(m,2H),2.71-2.68(m,1H),2.55-2.53(m,1H),2.07-2.03(m,1H),2.00-1.94(m,1H),1.89-1.70(m,3H),1.65-1.43(m,6H).
实施例B86B
LCMS:m/z 742(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.30(s,2H),8.20(s,1H),7.93(d,J＝4Hz,1H),7.77(d,J＝4Hz,1H),7.32(t,J＝8Hz,1H),6.56(s,2H),6.06-6.01(m,1H),4.18-4.02(m,2H),3.41(s,3H),3.10-2.99(m,2H),2.70-2.67(m,1H),2.55-2.53(m,1H),2.06-2.01(m,1H),1.98-1.92(m,1H),1.87-1.84(m,1H),1.81-1.69(m,2H),1.65-1.43(m,6H).
实施例B87：2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 652(M+H)+。
实施例B88：2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 653(M+H)+。
实施例B89A、B89B、B89C和B89D：
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((S)-1-((2S,4R)-4-氟-1,2-二甲基吡咯啶-2-基)乙氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩 -3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((S)-1-((2R,4R)-4-氟-1,2-二甲基吡咯啶-2-基)乙氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((R)-1-((2S,4R)-4-氟-1,2-二甲基吡咯啶-2-基)乙氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((R)-1-((2R,4R)-4-氟-1,2-二甲基吡咯啶-2-基)乙氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B89A
LCMS:m/z 681(M+H)+。
实施例B89B
LCMS:m/z 681(M+H)+。
实施例B89C
LCMS:m/z 681(M+H)+。
实施例B89D
LCMS:m/z 681(M+H)+。
实施例B90(4R)-2-胺基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((1-(咪唑[1,2-a]吡嗪-5-基)乙基)(甲基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 748(M+H)+。
实施例B91(4R)-2-胺基-4-(6-氯-2-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-8-氟-4-((1-(咪唑[1,2-a]吡嗪-5-基)乙基)(甲基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 659(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.10(s,3H),7.88(d,J＝1.1Hz,1H),7.85(s,1H),7.81(s,1H),7.23(dd,J＝8.3,5.3Hz,1H),7.14(t,J＝8.9Hz,1H),6.29–6.16(m,1H),3.77(d,J＝8.4Hz,1H),3.47–3.38(m,3H),3.23(s, 3H),2.06(s,6H),1.85(d,J＝6.9Hz,3H),1.20(s,3H).
实施例B92(4R)-2-胺基-4-(4-((1-(4-胺基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 635(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.09(s,2H),7.93(d,J＝1.6Hz,1H),7.89(d,J＝2.7Hz,1H),7.73(d,J＝2.7Hz,1H),7.20(dd,J＝8.4,5.3Hz,1H),7.13(t,J＝8.9Hz,1H),6.52(s,2H),5.97–5.79(m,1H),3.93–3.76(m,1H),3.68(d,J＝8.3Hz,1H),3.64–3.57(m,1H),3.36(s,3H),2.08(s,6H),1.61(d,J＝6.8Hz,3H),1.22(s,3H).
实施例B92经手性拆分得到实施例B92A和B92B：(4R)-2-胺基-4-(4-(((R)-1-(4-胺基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(4R)-2-胺基-4-(4-(((S)-1-(4-胺基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B92A
LCMS:m/z 635(M+H)+。
实施例B92B
LCMS:m/z 635(M+H)+。
实施例B93(4R)-2-胺基-4-(4-((1-(5-胺基-1-甲基-1H-吡唑-4-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 637(M+H)+。
实施例B94(4R)-2-胺基-4-(4-((1-(3-胺基-1-甲基-1H-吡唑-4-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-7-氟苯并[b] 噻吩-3-甲腈
LCMS:m/z 637(M+H)+。
实施例B95(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)氧)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 675(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.13(s,2H),8.02(d,1H),7.97(m,1H),7.60(m,1H),7.23(m,1H),7.16(t,1H),6.67(m,1H),5.94(d,1H),5.71(s,2H),5.20(t,1H),3.17(s,3H),2.44–2.21(m,6H),2.18(s,3H),1.86(d,2H),1.63(d,3H),1.59(t,4H).
实施例B96(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(3-甲氧基-3-甲基氮杂环丁烷-1-基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 621(M+H)+。
实施例B97(R)-4-(2-([1,3'-双氮杂环丁烷]-1'-基)-4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 632(M+H)+。
实施例B98A和实施例B98B(R)-2-氨基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(乙基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-氨基-4-(4-(((S)-1-(2-氨基吡啶-3-基)乙基)(乙基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B98A
LCMS:m/z 737(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.00–7.85(m,2H),7.69(d,J＝7.3Hz,1H),7.25(dd,J＝8.4,5.3Hz,1H),7.22–7.12(m,1H),6.68(dd,J＝7.3,5.0Hz,1H),6.03(d,J＝6.4Hz,1H),5.57(s,2H),4.22(d,J＝18.4Hz,2H),3.65(d,J＝6.9Hz,3H),3.11(m,2H),2.74(m,1H),2.09(m,1H),2.01(m,1H),1.90(m,1H),1.78(d,J＝22.8Hz,4H),1.62(t,J＝15.0Hz,5H),1.47(m,1H),1.00(t,J＝6.8Hz,3H).
实施例B98B
LCMS:m/z 737(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.02(s,1H),7.96(d,J＝3.8Hz,1H),7.69(d,J＝7.1Hz,1H),7.25(m,,1H),7.15(t,J＝8.9Hz,1H),6.67(m,1H),6.18(d,J＝6.7Hz,1H),5.80(s,2H),4.19(s,2H),3.87–3.71(m,3H),3.06(d,J＝31.6Hz,2H),2.77–2.65(m,1H),2.11(m,12H),2.02(m,1H),1.92(m,1H),1.78(m,2H),1.61(m,5H),1.47(m,1H),0.91(t,J＝6.8Hz,3H).
实施例B99A和实施例B99B(R)-2-氨基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-氨基-4-(4-(((S)-1-(4-氨基嘧啶-5-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B99A
LCMS:m/z 724(M+H)+。
实施例B99B
LCMS:m/z 724(M+H)+。
实施例B100A和实施例B100B(R)-2-氨基-4-(4-(((R)-1-(3-氨基哒嗪-4-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-氨基-4-(4-(((S)-1-(3-氨基哒嗪-4-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B100A
LCMS:m/z 724(M+H)+。
实施例B100B
LCMS:m/z 724(M+H)+。
实施例B101(R)-2-氨基-4-(4-((1-(5-氨基-1-甲基-1H-吡唑-4-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 726(M+H)+。
实施例B102(R)-2-氨基-4-(4-((1-(3-氨基-1-甲基-1H-吡唑-4-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 726(M+H)+。
实施例B103(4R)-4-(4-((1-(1H-吲唑-7-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 747(M+H)+。
实施例B104(4R)-4-(4-((1-(1H-吲唑-7-基)乙基)(甲基)氨基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 658(M+H)+。
实施例B105(4R)-4-(4-((1-(1H-吡唑[3,4-c]吡啶-7-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 748(M+H)+。
实施例B106(4R)-4-(4-((1-(1H-吡唑[3,4-c]吡啶-7-基)乙基)(甲基)氨基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 659(M+H)+。
实施例B107(4R)-4-(4-((1-(3H-咪唑[4,5-c]吡啶-4-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 748(M+H)+。
实施例B108(4R)-4-(4-((1-(3H-咪唑[4,5-c]吡啶-4-基)乙基)(甲基)氨基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 659(M+H)+。
实施例B109A和实施例B109B：(R)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(甲基((R)-1-(哒嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(甲基((S)-1-(哒嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B109A
LCMS:m/z 709(M+H)+。
实施例B109B
LCMS:m/z 709(M+H)+。
实施例B110A和实施例B110B(R)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢 -1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(甲基((R)-1-(吡嗪-3-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(甲基((S)-1-(吡嗪-3-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 709(M+H)+。
实施例B111(4R)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((1-(5-甲氧基吡啶-3-基)乙基)(甲基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 738(M+H)+。1H NMR(600MHz,DMSO-d6)δ11.05(s,1H),8.31(s,2H),8.14(d,2H),7.49(d,1H),7.34–7.04(m,2H),6.11(d,1H),4.64–4.55(m,2H),3.87(d,3H),3.76(s,1H),3.70–3.60(m,1H),3.44(m,1H),3.28(d,3H),3.13(m,1H),2.43(s,2H),2.31–2.09(m,3H),2.09–1.90(m,2H),1.89–1.64(m,4H).
实施例B112(4R)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-((1-(2-甲氧基吡啶-3-基)乙基)(甲基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 738(M+H)+。1H NMR(600MHz,DMSO-d6)δ10.94(s,1H),8.14(m,3H),8.00(d,1H),7.85(t,1H),7.27(m,1H),7.17(m,1H),7.07(m,1H),5.91(m,1H),4.67–4.54(m,2H),3.78(d,1H),3.64(d,3H),3.44(d,1H),3.23–2.93(m,4H),2.47–2.34(m,1H),2.19(m,3H),2.08–1.91(m,2H),1.85(m,2H),1.75(m,,3H).
实施例B1132-(1-((7-((R)-2-胺基-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-4-基)(甲基)胺基)乙基)-N,N-二甲基异烟酰胺
LCMS:m/z 779(M+H)+。
实施例B1142-(1-((7-((R)-2-胺基-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-2-(3-(二甲 基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-4-基)(甲基)胺基)乙基)-N,N-二甲基异烟酰胺
LCMS:m/z 690(M+H)+。
实施例B115 2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)噻吩[2,3-b]吡啶-3-甲腈
LCMS:m/z 706(M+H)+。
实施例B115经手性拆分得到实施例B115A和实施例B115B：(R)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)噻吩[2,3-b]吡啶-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)噻吩[2,3-b]吡啶-3-甲腈
实施例B115A
LCMS:m/z 706(M+H)+。1H NMR(600MHz,DMSO-d6)δ8.34(d,J＝4Hz,1H),8.24(s,2H),8.07(s,1H),7.97-7.95(m,1H),7.64(d,J＝8Hz,1H),7.26(d,J＝4Hz,1H),6.68-6.64(m,1H),6.02-5.97(m,1H),5.85(s,2H),4.26-4.16(m,2H),3.19(s,3H),3.11-3.01(m,2H),2.75-2.67(m,1H),2.56-2.55(m,1H),2.12-2.07(m,1H),2.03-1.98(m,1H),1.93-1.89(m,1H),1.81-1.75(m,2H),1.64-1.55(m,5H),1.51-1.48(m,1H).
实施例B115B
LCMS:m/z 706(M+H)+。1H NMR(600MHz,DMSO-d6)δ8.34(d,J＝4Hz,1H),8.24(s,2H),8.13(s,1H),7.97-7.95(m,1H),7.65(d,J＝8Hz,1H),7.27(d,J＝4Hz,1H),6.68-6.65(m,1H),6.10-6.05(m,1H),5.91(s,2H),4.24-4.14(m,2H),3.17(s,3H),3.13-3.08(m,1H),3.04-2.99(m,1H),2.73-2.67(m,1H),2.56-2.55(m,1H),2.11-2.06(m,1H),2.03-1.98(m,1H),1.92-1.89(m,1H),1.83-1.71(m,2H),1.63-1.53(m,5H),1.50-1.44(m,1H).
实施例B116 2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)噻吩[2,3-b]吡啶-3-甲腈
LCMS:m/z 707(M+H)+。
实施例B117A和B117B(S)-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇和(R)-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇
实施例B117A
LCMS:m/z 718(M+H)+。
实施例B117B
LCMS:m/z 718(M+H)+。
实施例B118 N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-7-(5,7-二氟-1H-吲哚-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 684(M+H)+。1H NMR(600MHz,DMSO-d6)δ12.32(s,1H),8.09(s,1H),7.97(d,J＝8Hz,1H),7.81(s,1H),7.64(d,J＝8Hz,1H),7.11-7.05(m,1H),6.92(t,J＝12Hz,1H),6.68-6.65(m,1H),6.04-5.99(m,1H),5.90(s,2H),4.25-4.15(m,2H),3.19(s,3H),3.13-3.08(m,1H),2.73-2.67(m,1H),2.56-2.55(m,1H),2.10-2.06(m,1H),2.03-1.97(m,1H),1.92-1.88(m,1H),1.84-1.71(m,2H),1.65-1.53(m,5H),1.50-1.44(m,1H).
实施例B119 N-((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-7-(5,7-二氟-1H-吲哚-3-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 685(M+H)+。
实施例B120 4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 708(M+H)+。
实施例B121 N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-7-(8-氯-7-氟萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 711(M+H)+。1H NMR(600MHz,DMSO-d6)δ8.43(d,J＝12.6Hz,2H),8.33–8.17(m,3H),8.02(s,1H),7.75(dd,J＝13.7,8.1Hz,3H),7.66–7.56(m,1H),7.41(m,1H),4.19–4.09(m,2H),3.92(m,1H),3.00(d,J＝25.6Hz,2H),2.70(m,1H),2.26(m,J＝30.9Hz,4H),2.03–1.60(m,8H),1.60–0.97(m,3H).
实施例B122 N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-7-(2,3-二氯苯基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 677(M+H)+。
实施例B123 2-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-3-(三氟甲基)苯腈
LCMS:m/z 702(M+H)+。
实施例B124 2-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-3-(三氟甲基)苯腈
LCMS:m/z 703(M+H)+。
实施例B125 N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基-7-(4-甲基-1-(氧杂环丁烷-3-基)-1H-吡唑-5-基)喹唑啉-4-胺
LCMS:m/z 669(M+H)+。
实施例B126 N-((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基-7-(4-甲基-1-(氧杂环丁烷-3-基)-1H-吡唑-5-基)喹唑啉-4-胺
LCMS:m/z 670(M+H)+。
实施例B127 N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基-7-(4-甲基-1-(氧杂环丁烷-3-基)-1H-吡唑-3-基)喹唑啉-4-胺
LCMS:m/z 669(M+H)+。
实施例B128 N-((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基-7-(4-甲基-1-(氧杂环丁烷-3-基)-1H-吡唑-3-基)喹唑啉-4-胺
LCMS:m/z 670(M+H)+。
实施例B129 1-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢 -1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)异喹啉-8-甲腈
LCMS:m/z 685(M+H)+。
实施例B130 1-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)异喹啉-8-甲腈
LCMS:m/z 686(M+H)+。
实施例B131 N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-(5-氟喹啉-8-基)-N-甲基喹唑啉-4-胺
LCMS:m/z 678(M+H)+。
实施例B131经手性拆分得到实施例B131A和实施例B131B：(R)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-(5-氟喹啉-8-基)-N-甲基喹唑啉-4-胺和(S)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-(5-氟喹啉-8-基)-N-甲基喹唑啉-4-胺
实施例B131A
LCMS:m/z 678(M+H)+。1H NMR(600MHz,DMSO-d6)δ8.92(d,J＝8Hz,1H),8.62(d,J＝12Hz,1H),8.10(s,1H),7.97(d,J＝4Hz,1H),7.84-7.80(m,1H),7.73-7.69(m,1H),7.66-7.62(m,2H),6.68-6.65(m,1H),6.07-6.02(m,1H),5.92(s,2H),4.24-4.14(m,2H),3.21(s,3H),3.11-3.07(m,1H),3.03-2.98(m,1H),2.72-2.67(m,1H),2.55-2.53(m,1H),2.10-2.05(m,1H),2.03-1.97(m,1H),1.91-1.88(d,J＝12Hz,1H),1.83-1.70(m,2H),1.65-1.52(m,5H),1.49-1.43(m,1H).
实施例B131B
LCMS:m/z 678(M+H)+。1H NMR(600MHz,DMSO-d6)δ8.93(d,J＝8Hz,1H),8.62(d,J＝8Hz,1H),8.08(s,1H),7.97(d,J＝4Hz,1H),7.84-7.80(m,1H),7.73-7.69(m,1H),7.66-7.62(m,2H),6.68-6.65(m,1H),6.04-5.99(m,1H),5.87(s,2H),4.24-4.14(m,2H),3.21(s,3H),3.12-3.07(m,1H),3.03-2.98(m,1H),2.73-2.67(m,1H),2.56-2.53(m,1H),2.10-2.06(m,1H),2.03-1.97(m,1H),1.91-1.88(d,J＝12Hz,1H),1.84-1.71(m,2H),1.64-1.52(m,5H),1.49-1.43(m,1H).
实施例B132 N-((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-7-(5-氟喹啉-8-基)-N-甲基喹唑啉-4-胺
LCMS:m/z 679(M+H)+。
实施例B133 N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(5-乙炔异喹啉-4-基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 684(M+H)+。
实施例B134 N-((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-7-(5-乙炔异喹啉-4-基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 685(M+H)+。
实施例B135 4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)异喹啉-5-甲腈
LCMS:m/z 685(M+H)+。
实施例B136 4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)异喹啉-5-甲腈
LCMS:m/z 686(M+H)+。
实施例B137 2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 653(M+H)+。
实施例B137经手性拆分得到实施例B137A和B137B：(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B137A
LCMS:m/z 653(M+H)+。
实施例B137B
LCMS:m/z 653(M+H)+。
实施例B138 2-胺基-4-(4-(((R)-1-(3-氨基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 653(M+H)+。
实施例B138经手性拆分得到实施例B138A和B138B：(S)-2-胺基-4-(4-(((R)-1-(3- 氨基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(3-氨基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B138A
LCMS:m/z 653(M+H)+。
实施例B138B
LCMS:m/z 653(M+H)+。
实施例B139 2-(1-((7-((R)-2-胺基-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-4-基)(甲基)胺基)乙基)-N,N-二甲基异烟酰胺
LCMS:m/z 690(M+H)+。
实施例B140 5-(1-((7-((R)-2-胺基-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-4-基)(甲基)胺基)乙基)-N,N,1-三甲基-1H-吡唑-3-甲酰胺
LCMS:m/z 693(M+H)+。
实施例B141 3-(1-((7-((R)-2-胺基-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹唑啉-4-基)(甲基)胺基)乙基)-N,N,1-三甲基-1H-吡唑-5-甲酰胺
LCMS:m/z 693(M+H)+。
实施例B142(S)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3)环丁基氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 635(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.15(s,2H),8.04(d,1H),7.98(m,1H),7.62(m,1H),7.24(m,1H),7.16(t,1H),6.68(m,1H),5.97(d,1H),5.71(s,2H),4.96(t,1H),3.17(d,3H),2.81–2.60(m,2H),2.44–2.22(s,6H),2.11(s,2H),1.63(d,3H).
实施例B143(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((反式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 652(M+H)+。
实施例B143经手性拆分得到异构体实施例B143A和实施例B143B:(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B143A
LCMS:m/z 652(M+H)+。
实施例B143B
LCMS:m/z 652(M+H)+。
实施例B144(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((顺式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 652(M+H)+。
实施例B144经手性拆分得到异构体实施例B144A和实施例B144B:(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基 -4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B144A
LCMS:m/z 652(M+H)+。
实施例B144B
LCMS:m/z 652(M+H)+。
实施例B145(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((反式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 652(M+H)+。
实施例B145经手性拆分得到异构体实施例B145A和实施例B145B:(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B145A
LCMS:m/z 652(M+H)+。
实施例B145B
LCMS:m/z 652(M+H)+。
实施例B146(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((顺式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 652(M+H)+。
实施例B146经手性拆分得到异构体实施例B146A和实施例B146B:(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B146A
LCMS:m/z 652(M+H)+。
实施例B146B
LCMS:m/z 652(M+H)+。
实施例B147(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((反式)-4-甲氧基-1-甲基吡咯啉-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 652(M+H)+。
实施例B148(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((顺式)-4-甲氧基-1-甲基吡咯啉-3-基)氧)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 652(M+H)+。
实施例B149A和实施例B149B:(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((2S,4R)-4-氟-1,2-二甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((2R,4R)-4-氟-1,2-二甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B149A
LCMS:m/z 667(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.13(t,J＝22.4Hz,3H),7.93(d,J＝2.3Hz,1H),7.79(t,J＝11.3Hz,1H),7.23(dd,J＝8.3,5.3Hz,1H),7.15(t,J＝8.9Hz,1H),6.51(d,J＝23.3Hz,2H),6.05–5.96(m,1H),5.16(m,1H),4.23(m,1H),4.17–4.05(m,1H),3.41(s,3H),3.01(m,m1H),2.91–2.77(m,1H),2.26(d,J＝6.7Hz,3H),2.20–1.94(m,2H),1.65(d,J＝6.7Hz,4H),0.99(d,J＝12.0Hz,3H).
实施例B149A
LCMS:m/z 667(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝13.0Hz,3H),7.94(d,J＝2.6Hz,1H),7.75(d,J＝2.6Hz,1H),7.24(dd,J＝8.4,5.3Hz,1H),7.16(t,J＝8.9Hz,1H),6.54(s,2H),5.96(q,J＝6.8Hz,1H),5.20(d,J＝56.0Hz,1H),4.26(m,1H),4.01(m,1H),3.47(s,3H),3.19(m,1H),2.87(m,1H),2.31(m,4H),1.82(m,1H),1.65(d,J＝6.8Hz,3H),1.14(s,3H).
实施例B150(4R)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-((4,4-二氟-1,2-二甲基吡咯啉-2-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 685(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.09(dd,J＝29.2,8.9Hz,3H),7.98–7.91(m,1H),7.78(m,1H),7.24(dd,J＝8.4,5.3Hz,1H),7.16(t,J＝8.9Hz,1H),6.49(m,2H),6.01–5.93(m,1H),4.32(m,1H),4.12(m,1H),3.45(s,,3H),3.31–3.22(m,1H),3.04(m,1H),2.41(m,1H),2.29(t,J＝24.7Hz,3H),2.15(m,,1H),1.66(d,J＝6.7Hz,3H),1.11(d,J＝8.4Hz,3H).
实施例B151A和B151B(R)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 665(M+H)+。
实施例B152A和B152B(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 666(M+H)+。
实施例B153A和B153B(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 666(M+H)+。
实施例B154(4R)-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((S)-4-(二氟甲基)-1-甲基吡咯啶-2-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 686(M+H)+。
实施例B155(4R)-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((S)-4-(二氟甲基)-1-甲基吡咯啶-2-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 686(M+H)+。
实施例B156A和B156B：(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-7- 氟苯并[b]噻吩-3-甲腈及(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B156A
LCMS:m/z 714(M+H)+。
实施例B156B
LCMS:m/z 714(M+H)+。
实施例B157A和B157B：(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈及(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B157A
LCMS:m/z 732(M+H)+。
实施例B157B
LCMS:m/z 732(M+H)+。
实施例B158A和B158B：(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈及(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B158A
LCMS:m/z 732(M+H)+。
实施例B158B
LCMS:m/z 732(M+H)+。
实施例B159A、159B、159C、和B159D：
(R)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
和(R)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B159A
LCMS:m/z 693(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.02(s,1H),7.97(d,J＝4Hz,1H),7.65(d,J＝8Hz,1H),7.24-7.20(m,1H),7.14(t,J＝8Hz,1H),6.85(s,0.5H),6.68-6.64(m,1.5H),5.98-5.91(m,3H),4.53(d,J＝12Hz,1H),4.35(d,J＝12Hz,1H),3.20(s,3H),2.69-2.66(m,2H),2.51(s,1H),2.23-2.20(m,1H),2.15(s,3H),1.93-1.83(m,2H),1.65(d,J＝8Hz,3H),1.11(s,3H).
实施例B159B
LCMS:m/z 693(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.12(s,2H),8.00(s,1H),7.97(d,J＝8Hz,1H),7.65(d,J＝8Hz,1H),7.24-7.20(m,1H),7.15(t,J＝8Hz,1H),6.73(s,0.5H),6.68-6.65(m,1H),6.51(s,0.5H),5.97-5.92(m,1H),5.82(s,2H),4.65(d,J＝12Hz,1H),4.34(d,J＝12Hz,1H),3.17(s,3H),2.51(s,1H),2.21-2.15(m,4H),2.10-1.98(m,4H),1.64(d,J＝8Hz,3H),1.32(d,J＝4Hz,3H).
实施例B159C
LCMS:m/z 693(M+H)+。
实施例B159D
LCMS:m/z 693(M+H)+。
实施例B160A、160B、160C、和B160D：
(S)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈、
(S)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈、
(S)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
和(S)-2-胺基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B160A
LCMS:m/z711(M+H)+。
实施例B160B
LCMS:m/z711(M+H)+。
实施例B160C
LCMS:m/z711(M+H)+。
实施例B160D
LCMS:m/z711(M+H)+。
实施例B161A、161B、161C、和B161D：
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
和(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B161A
LCMS:m/z 694(M+H)+。
实施例B161B
LCMS:m/z 694(M+H)+。
实施例B161C
LCMS:m/z 694(M+H)+。
实施例B161D
LCMS:m/z 694(M+H)+。
实施例B162A、162B、162C、和B162D：
(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈、
(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈、
(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
和(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B162A
LCMS:m/z712(M+H)+。
实施例B162B
LCMS:m/z712(M+H)+。
实施例B162C
LCMS:m/z712(M+H)+。
实施例B162D
LCMS:m/z712(M+H)+。
实施例B163A、163B、163C、和B163D：
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
和(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B163A
LCMS:m/z 694(M+H)+。
实施例B163B
LCMS:m/z 694(M+H)+。
实施例B163C
LCMS:m/z 694(M+H)+。
实施例B163D
LCMS:m/z 694(M+H)+。
实施例B164A、164B、164C、和B164D：
(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈、
(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((S,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈、
(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
和(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((R,Z)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B164A
LCMS:m/z712(M+H)+。
实施例B164B
LCMS:m/z712(M+H)+。
实施例B164C
LCMS:m/z712(M+H)+。
实施例B164D
LCMS:m/z712(M+H)+。
实施例B165A、B165B、B165C和B165D：
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4R)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4S)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-1,1-二氟-6-甲基-6-氮杂螺[2.5]辛烷-4-基))甲氧基)-8-氟喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B165A
LCMS:m/z 712(M+H)+。
实施例B165B
LCMS:m/z 712(M+H)+。
实施例B165C
LCMS:m/z 712(M+H)+。
实施例B165D
LCMS:m/z 712(M+H)+
实施例B166A、B166B、B166C和B166D：
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6S,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟 -2-(((3S,6S,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6R,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6R,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B166A
LCMS:m/z 692(M+H)+
实施例B166B
LCMS:m/z 692(M+H)+
实施例B166C
LCMS:m/z 692(M+H)+
实施例B166D
LCMS:m/z 692(M+H)+
实施例B167A、B167B、B167C和B167D：
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6S,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6S,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6R,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6R,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B167A
LCMS:m/z 692(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝19.3Hz,3H),7.94(d,J＝2.6Hz,1H),7.77(d,J＝2.6Hz,1H),7.24(dd,J＝8.4,5.3Hz,1H),7.20–7.09(m,1H),6.43(s,2H),5.99(q,J＝6.7Hz,1H),4.33(m,1H),4.24(m,1H),3.90(m,1H),3.61(m,1H),3.43(d,J＝13.9Hz,4H),2.91(d,J＝10.9Hz,1H),2.62(s,1H),2.34(m,1H),2.16(s,1H),1.93–1.76(m,1H),1.65(d,J＝6.8Hz,4H),1.56(m,1H),1.29(m,1H),1.17(d,J＝6.6Hz,3H).
实施例B167B
LCMS:m/z 692(M+H)+.
实施例B167C
LCMS:m/z 692(M+H)+.
实施例B167D
LCMS:m/z 692(M+H)+.
实施例B168A、B168B、B168C和B168D：
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6S,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6S,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6R,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3S,6R,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B168A
LCMS:m/z 692(M+H)+.
实施例B168B
LCMS:m/z 692(M+H)+.
实施例B168C
LCMS:m/z 692(M+H)+.
实施例B168D
LCMS:m/z 692(M+H)+.
实施例B169A、B169B、B169C和B169D：
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6S,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6S,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6R,8aS)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈、
及(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-(((3R,6R,8aR)-3-甲基六氢-1H-吡咯[2,1-c][1,4]恶嗪-6-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B169A
LCMS:m/z 692(M+H)+.
实施例B169B
LCMS:m/z 692(M+H)+.
实施例B169C
LCMS:m/z 692(M+H)+.
实施例B169D
LCMS:m/z 692(M+H)+.
实施例B170(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 737(M+H)+。
实施例B171(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 738(M+H)+。
实施例B172(R)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 720(M+H)+。
实施例B173(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-8-氟-2-((1-((4-(氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 738(M+H)+。
实施例B174 1-(4-(((R)-1-(2-2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-8-乙基-7-氟异喹啉-3(2H)-酮
LCMS:m/z 722(M+H)+。
实施例B175 1-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-8-乙基-7-氟异喹啉-3(2H)-酮
LCMS:m/z 723(M+H)+。
实施例B176 1-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-8-乙基-7-氟异喹啉-3(2H)-酮
LCMS:m/z 723(M+H)+。
实施例B177 1-(4-(((R)-1-(2-2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-8-乙炔基-7-氟异喹啉-3(2H)-酮
LCMS:m/z 718(M+H)+。
实施例B178 1-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-8-乙炔基-7-氟异喹啉-3(2H)-酮
LCMS:m/z 719(M+H)+。
实施例B179 1-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-8-乙炔基-7-氟异喹啉-3(2H)-酮
LCMS:m/z 719(M+H)+。
实施例B180A和B180B(S)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(甲基((R)-1-(哒嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(甲基((S)-1-(哒嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B180A
LCMS:m/z 727(M+H)+。
实施例B180B
LCMS:m/z 727(M+H)+。
实施例B181A和实施例181B(S)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(甲基((R)-1-(吡嗪-3-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-氨基-4-(6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-4-(甲基((S)-1-(吡嗪-3-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B181A
LCMS:m/z 727(M+H)+。
实施例B181B
LCMS:m/z 727(M+H)+。
实施例B182：(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((反式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 669(M+H)+。
实施例B182经手性拆分得到异构体实施例B182A和实施例B182B:(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B182A
LCMS:m/z 669(M+H)+。
实施例B182B
LCMS:m/z 669(M+H)+。
实施例B183：(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((顺式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 651(M+H)+。
实施例B183经手性拆分得到异构体实施例B183A和实施例B183B:(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B183A
LCMS:m/z 669(M+H)+。
实施例B183B
LCMS:m/z 669(M+H)+。
实施例B184(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((反式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 670(M+H)+。
实施例B184经手性拆分得到异构体实施例B184A和实施例B184B:(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B184A
LCMS:m/z 670(M+H)+。
实施例B184B
LCMS:m/z 670(M+H)+。
实施例B185(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((顺式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 670(M+H)+。
实施例B185经手性拆分得到异构体实施例B185A和实施例B185B:(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B185A
LCMS:m/z 670(M+H)+。
实施例B185B
LCMS:m/z 670(M+H)+。
实施例B186(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((反式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 670(M+H)+。
实施例B186经手性拆分得到异构体实施例B186A和实施例B186B:(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B186A
LCMS:m/z 670(M+H)+。
实施例B186B
LCMS:m/z 670(M+H)+。
实施例B187(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((顺式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 670(M+H)+。
实施例B187经手性拆分得到异构体实施例B187A和实施例B187B:(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)胺基)-6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B187A
LCMS:m/z 670(M+H)+。
实施例B187B
LCMS:m/z 670(M+H)+。
实施例B188(R)-2-胺基-4-(6-氯-2-(((反式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 637(M+H)+。
实施例B188经手性拆分得到异构体实施例B188A和实施例B188B:(R)-2-胺基-4-(6-氯-2-(((3S,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(6-氯-2-(((3R,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B188A
LCMS:m/z 637(M+H)+。
实施例B188B
LCMS:m/z 637(M+H)+。
实施例B189(R)-2-胺基-4-(6-氯-2-(((顺式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 637(M+H)+。
实施例B189经手性拆分得到异构体实施例B189A和实施例B189B:(R)-2-胺基-4-(6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈和(R)-2-胺基-4-(6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
实施例B189A
LCMS:m/z 637(M+H)+。
实施例B189B
LCMS:m/z 637(M+H)+。
实施例B190(S)-2-胺基-4-(6-氯-2-(((反式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟 -4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 655(M+H)+。
实施例B190经手性拆分得到异构体实施例B190A和实施例B190B:(S)-2-胺基-4-(6-氯-2-(((3S,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(6-氯-2-(((3R,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B190A
LCMS:m/z 655(M+H)+。
实施例B190B
LCMS:m/z 655(M+H)+。
实施例B191(S)-2-胺基-4-(6-氯-2-(((顺式)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 655(M+H)+。
实施例B191经手性拆分得到异构体实施例B191A和实施例B191B:(S)-2-胺基-4-(6-氯-2-(((3S,4S)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈和(S)-2-胺基-4-(6-氯-2-(((3R,4R)-4-(二甲基胺基)四氢呋喃-3-基)氧)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
实施例B191A
LCMS:m/z 655(M+H)+。
实施例B191B
LCMS:m/z 655(M+H)+。
实施例B192(R)-2-胺基-4-(6-氯-2-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 620(M+H)+。
实施例B193(S)-2-胺基-4-(6-氯-2-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 620(M+H)+。
实施例B194：(R)-2-胺基-4-(6-氯-8-氟-2-(((2S,4R)-4-4-氟-1-甲基吡咯啶-2-基)甲氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 639(M+H)+。
实施例B195：(S)-2-胺基-4-(6-氯-8-氟-2-(((2S,4R)-4-4-氟-1-甲基吡咯啶-2-基)甲氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 657(M+H)+。
实施例B196：(R)-2-胺基-4-(6-氯-8-氟-2-((S)-1-((2S,4R)-4-氟-1-甲基吡咯啶-2-基)乙氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 653(M+H)+。
实施例B197：(S)-2-胺基-4-(6-氯-8-氟-2-((S)-1-((2S,4R)-4-氟-1-甲基吡咯啶-2-基)乙氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 671(M+H)+。
实施例B198：(R)-2-胺基-4-(6-氯-2-(((S)-1,2-二甲基吡咯啶-2-基)甲氧基)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 635(M+H)+。
实施例B199：(S)-2-胺基-4-(6-氯-2-(((S)-1,2-二甲基吡咯啶-2-基)甲氧基)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 635(M+H)+。
实施例B200：(R)-2-胺基-4-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 699(M+H)+。
实施例B201：(S)-2-胺基-4-(6-氯-2-(((3S,4S)-4-(二氟甲基)-1,3-二甲基哌啶-3-基)甲氧基)-8-氟-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 717(M+H)+。
实施例B202：(R)-2-胺基-4-(6-氯-8-氟-2-(((S,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲 腈
LCMS:m/z 679(M+H)+。
实施例B203：(S)-2-胺基-4-(6-氯-8-氟-2-(((S,E)-4-(氟甲烯基)-1,3-二甲基哌啶-3-基)甲氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 698(M+H)+。
实施例B204：(R)-2-胺基-4-(6-氯-8-氟-2-((1-((4-(氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 705(M+H)+。
实施例B205：(S)-2-胺基-4-(6-氯-8-氟-2-((1-((4-(氟甲烯基)哌啶-1-基)甲基)环丙基)甲氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 705(M+H)+。
实施例B206：(R)-2-氨基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)氨基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 679(M+H)+。
实施例B207：(S)-2-氨基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)氨基)-6-氯-8- 氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 697(M+H)+。
实施例B208：(R)-2-氨基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)氨基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 680(M+H)+。
实施例B209：(S)-2-氨基-4-(4-(((R)-1-(3-胺基吡嗪-2-基)乙基)(甲基)氨基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 698(M+H)+。
实施例B210：(R)-2-氨基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)氨基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 680(M+H)+。
实施例B211：(S)-2-氨基-4-(4-(((R)-1-(4-氨基嘧啶-5-基)乙基)(甲基)氨基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 698(M+H)+。
实施例B212：(R)-2-胺基-4-(6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶 -7a(5H)-基)甲氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-7-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 665(M+H)+。
实施例B213：(R)-2-胺基-4-(6-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-双稠吡咯啶-7a(5H)-基)甲氧基)-4-(甲基((R)-1-(吡嗪-4-基)乙基)胺基)喹唑啉-7-基)-5,7-二氟苯并[b]噻吩-3-甲腈
LCMS:m/z 683(M+H)+。
实施例B214：2-氨基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-氟苯并[b]噻吩-3-甲腈
LCMS:m/z 723(M+H)+。
实施例B214经手性拆分得到实施例B214A和实施例B214B：(R)-2-氨基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-氟苯并[b]噻吩-3-甲腈和(S)-2-氨基-4-(4-(((R)-1-(2-氨基吡啶-3-基)乙基)(甲基)氨基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-氟苯并[b]噻吩-3-甲腈
实施例B214A
LCMS:m/z 723(M+H)+。
实施例B214B
LCMS:m/z 723(M+H)+。
实施例BD1：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶 -3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基-5',5'-d2)甲氧基-d2)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 711(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.97(d,J＝3.7Hz,1H),7.64(d,J＝7.2Hz,1H),6.86(s,2H),6.67(dd,J＝7.4,4.9Hz,1H),6.50(s,1H),6.00(m,1H),5.81(s,2H),3.16(s,3H),3.09(m,2H),2.38(s,3H),1.96(m,5H),1.63(m,6H).
实施例BD2：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-(甲基-d3)喹唑啉-4-胺
LCMS:m/z 710(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.95(dd,J＝4.8,1.7Hz,1H),7.62(dd,J＝7.5,1.7Hz,1H),6.82(s,2H),6.65(dd,J＝7.5,4.9Hz,1H),6.49(s,1H),6.04–5.89(m,3H),4.26(s,2H),3.05–3.13(m,2H),2.85(m,1H),2.63(m,1H),2.37(d,J＝2.2Hz,3H),2.18–2.13(m,1H),2.08–1.92(m,3H),1.70–1.53(m,6H).
实施例BD3：(7R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-(1-(2-胺基吡啶-3-基)乙基-1,2,2,2-d4)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
LCMS:m/z 711(M+H)+。
实施例BD3经手性拆分得到异构体实施例BD3A和实施例BD3B：(7R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((R)-1-(2-胺基吡啶-3-基)乙基-1,2,2,2-d4)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺和(7R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-N-((S)-1-(2-胺基吡啶-3-基)乙基-1,2,2,2-d4)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟-N-甲基喹唑啉-4-胺
实施例BD3A
LCMS:m/z 711(M+H)+。
实施例BD3B
LCMS:m/z 711(M+H)+。
实施例C1：N-((R)-1-(2-氨基吡啶-3-基)乙基)-7-(8-氯萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-甲基-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺三氟乙酸盐
第一步：7-(8-氯萘-1-基)-2-(甲硫基)-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-基三氟甲磺酸酯的制备
将7-(8-氯萘-1-基)-2-(甲硫基)-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-醇(200mg，0.56mmol)和DIPEA(145mg，1.12mmol)溶于二氯甲烷(5mL)中，冰水浴下滴加三氟甲磺酸酐(285mg，1.01mmol)。反应液保持冰水浴搅拌1h，随后加入二氯甲烷稀释，再用水和饱和氯化钠溶液洗后用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用柱层析分离得到目标产物(150mg)。
第二步：N-((R)-1-(2-(bis(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-(8-氯萘-1-基)-N-甲基-2-(甲硫基)-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺的制备
氩气保护下，将7-(8-氯萘-1-基)-2-(甲硫基)-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-基三氟甲磺酸酯(150mg，0.31mmol)和(R)-N,N-双(4-甲氧基苄基)-3-(1-(甲氨基)乙基)吡啶-2-胺(242mg，0.62mmol)溶于DMSO(2mL)中，加入DIPEA(120mg，0.93mmol)。反应液在80℃搅拌1h后加入乙酸乙酯稀释，再用水和饱和氯化钠溶液洗后用无水硫酸 钠干燥后过滤。滤液减压浓缩，残余物用柱层析分离得到目标产物(106mg)
第三步：N-((R)-1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-(8-氯萘-1-基)-N-甲基-2-(甲基亚砜基)-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺的制备
0℃下，将N-((R)-1-(2-(bis(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-(8-氯萘-1-基)-N-甲基-2-(甲硫基)-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺(106mg，0.15)溶于乙酸乙酯(2mL)中，随后滴加间氯过氧苯甲酸(63mg，0.36)的乙酸乙酯溶液(2mL)。反应液在0℃搅拌10min，随后用饱和低亚硫酸钠溶液(30mL)淬灭，再加入水(30mL)稀释，然后用乙酸乙酯萃取(30mLx3)。合并的有机相用饱和氯化钠溶液(30mL)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用柱层析分离得到目标产物(95mg)。
第四步：N-((R)-1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-(8-氯萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-甲基-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺的制备
将((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇(79mg，0.39mmol)溶于四氢呋喃(1mL)中，加入叔丁醇钠(79mg，0.39mmol)。混合物搅拌1min后，加入N-((R)-1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-(8-氯萘-1-基)-N-甲基-2-(甲基亚砜基)-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺(95mg，0.13mmol)的四氢呋喃(1mL)溶液。加完后反应液室温搅拌搅拌1h后加入水淬灭，再用乙酸乙酯萃取(30mLx 3)。合并的有机相用饱和氯化钠溶液(30mL)洗涤后用无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用柱层析分离得到目标产物(60mg)。
第五步：N-((R)-1-(2-氨基吡啶-3-基)乙基)-7-(8-氯萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-甲基-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺三氟乙酸盐的制备
将N-((R)-1-(2-(双(4-甲氧基苄基)胺基)吡啶-3-基)乙基)-7-(8-氯萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-甲基-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺(60mg，0.07mmol)溶于三氟乙酸(2mL)中。得到的混合物在60℃搅拌2h，然后减压浓缩，残余物用制备液相分离得到目标产物(10mg)。
LCMS:m/z 647(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.69–8.40(m,1H),8.12–7.77(m,6H),7.76–7.69(m,1H),7.69–7.60(m,1H),7.56–7.47(m,1H),6.99–6.90(m,1H),6.35–6.26(m,1H),5.78–5.65(m,1H),5.28–4.99(m,2H),4.52–4.27(m,2H),3.76–3.60(m,2H),3.48–3.28(m,2H),3.17–3.05(m,1H),2.99(s,1.5H),2.89(s,1.5H),2.81–2.66(m,1H),2.46–2.29(m,1H),2.26–1.82(m,7H),1.58(t,J＝6.6Hz,3H).
按照实施例C1同样方法以不同起始原料合成以下化合物。
实施例C2：7-(3-氨基-8-乙炔基-7-氟萘-1-基)-N-((R)-1-(2-氨基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧 基)-N-甲基-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺
LCMS:m/z 670(M+H)+。
实施例C3：7-(3-氨基-2-氟-5-(丙-1-炔-1-基)-6-(三氟甲基)苯基)-N-((R)-1-(2-氨基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-甲基-7,8-二氢-5H-吡喃[4,3-d]嘧啶-4-胺
LCMS:m/z 702(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.95–7.88(m,1H),7.59–7.44(m,1H),7.17(s,2H),6.88(d,J＝8.4Hz,1H),6.67–6.55(m,1H),6.21 -6.05(m,2H),5.77–5.54(m,1H),5.38–5.29(m,1H),5.04–4.94(m,1H),4.94–4.70(m,2H),4.12–3.95(m,2H),3.12–2.97(m,3H),2.81–2.74(m,2H),2.71–2.61(m,3H),2.06–2.00(m,4H),1.88–1.83(m,1H),1.80–1.69(m,2H),1.56–1.44(m,7H).
实施例D1：N-((R)-1-(2-氨基吡啶-3-基)乙基)-7-(8-氯-7-氟萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-甲基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-胺
LCMS:m/z 664(M+H)+。
实施例D2：7-(3-氨基-8-乙炔-7-氟萘-1-基)-N-((R)-1-(2-氨基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-N-甲基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-胺
LCMS:m/z 669(M+H)+。
实施例D3：7-(3-氨基-2-氟-5-(丙-1-yn炔1-基)-6-(三氟甲基)苯基)-N-((R)-1-(2-氨基吡啶-3-基)乙基)-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯 啶]-7a'(5'H)-基)甲氧基)-N-甲基-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-胺
LCMS:m/z 701(M+H)+。
实施例F1：7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹啉-3-甲腈
第一步：7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-(双(-4-甲氧基苄)氨基)吡啶-3-基)乙基)(甲基)氨基)-2,6-二氯-8-氟喹啉-3-甲腈三氟乙酸盐的制备
将7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2,4,6-三氯-8-氟喹啉-3-甲腈(250mg,0.36mmol)溶于N,N-二甲基乙酰胺(3mL)，加入N,N-二异丙基乙胺(140mg,1.09mmol)和(R)-N,N-双(4-甲氧基苄基)-3-(1-(甲氨基)乙基)吡啶-2-胺(156mg,0.40mmol)。得到的混合物在100℃反应2小时随后冷却至室温，然后直接用中压过柱机制备得到目标产物(0.25g,产率:60％)。
LCMS:m/z 1044(M+H)+。
第二步：7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-(双(4-甲氧基苯基)氨基)吡啶-3-基)乙基)(甲基)氨基)-6-氯-2-(((1S，7a’S)-2,2-二氟二氢-1'H，3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹啉 -3-甲腈的制备
((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺环[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲醇(46mg,0.23mmol)溶于四氢呋喃(2mL)中，随后加入叔丁醇钠(33mg,0.34mmol)。得到的混合物反应10分钟，随后加入7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-(双(-4-甲氧基苄)氨基)吡啶-3-基)乙基)(甲基)氨基)-2,6-二氯-8-氟喹啉-3-甲腈三氟乙酸盐(130mg,0.11mmol)。得到的混合物在室温反应1小时，然后加入水，再用乙酸乙酯萃取。合并的有机相经无水硫酸钠干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到标产物(90mg,产率:67％)。
LCMS:m/z 1212(M+H)+。
第三步：7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹啉-3-甲腈的制备
7-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-(双(4-甲氧基苯基)氨基)吡啶-3-基)乙基)(甲基)氨基)-6-氯-2-(((1S，7a’S)-2,2-二氟二氢-1'H，3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹啉-3-甲腈(90mg,0.074mmol)的三氟乙酸(3mL)溶液在50℃反应2小时，然后减压浓缩。残余物用制备液相分离得到目标产物(11mg,产率:20％)。
LCMS:m/z 731(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.27(s,1H),7.85(s,1H),7.22(d,J＝8Hz,2H),6.86(d,J＝8Hz,2H),6.58(s,1H),4.42-4.30(m,2H),4.23(s,2H),3.71(s,3H),3.36-3.35(m,3H),3.18-3.06(m,2H),2.70(s,1H),2.36(s,3H),2.10-2.01(m,2H),1.91-1.81(m,3H),1.64-1.43(m,4H).
实施例F1经手性分离得到异构体实施例F1A和实施例F1B：(R)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹啉-3-甲腈和(S)-7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1,2'-双稠吡咯啶]-7a'(5'H)-基)甲氧基)-8-氟喹啉-3-甲腈
实施例F1A
LCMS:m/z 731(M+H)+。
实施例F1B
LCMS:m/z 731(M+H)+。
按照实施例F1同样方法以不同起始原料合成以下化合物：
实施例F2：7-(6--胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹啉-3-甲腈
LCMS:m/z 642(M+H)+。
实施例F2经手性分离得到异构体实施例F2A和实施例F2B：(R)-7-(6--胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹啉-3-甲腈和(S)-7-(6--胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-(((R)-1-(2-胺基吡啶-3-基)乙基)(甲基)胺基)-6-氯-2-(3-(二甲基胺基)-3-甲基氮杂环丁烷-1-基)-8-氟喹啉-3-甲腈
实施例F2A
LCMS:m/z 642(M+H)+。
实施例F2B
LCMS:m/z 642(M+H)+。
实施例药物组合物
口服片剂：
实施例A2或A3加入辅料填充剂微晶纤维素(101)和一水乳糖、内加崩解剂交联羧甲纤维素钠、粘合剂羟丙甲纤维素(E15)、外加崩解剂交联羧甲纤维素钠、润滑剂硬脂酸镁制备成10mg口服片剂。
注射剂：
实施例A2或A3加入磺丁基倍他环糊精钠、氯化钠、注射用水等制备成注射制剂。
生物学测试例
生物学测试评价
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围。
1.细胞增殖检测
阳性参照：MRTX1133
实验步骤
利用纳升移液系统将稀释好的待测化合物加入384孔细胞培养板中，设置复孔。阳性对照组加入等体积的培养基；阴性对照组加入等体积的DMSO，1000rpm室温离心1min。
将细胞接种到a)384培养板中，阴性对照组加入等量等体积细胞，阳性对照组仅加入等体积的培养基。1000rpm室温离心1min，最终化合物的DMSO终浓度为0.5％，放置于37℃，5％CO2恒温培养箱孵育7天。
加入20μL/孔的3D至b)384孔细胞培养板中，避光320rpm震荡20min，避光室温孵育2hrs。
用Envision多功能酶标仪读取发光值。
3.数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括最小抑制率，最大抑制率及IC50。
结果表明，本发明实施例化合物对于KRAS突变显示出了很好的抑制活性。
表1化合物抗细胞增殖活性




药代动力学测试评价
雄性ICR小鼠，体重18-25g左右，禁食过夜后，口服给予100mg/kg本发明化合物或对照化合物的溶液[10％DMSO/60％聚乙二醇400/30％水溶液为载体]。分别在给予本发明化合物后0.25，0.5，1.0，2.0，4.0，6.0，8.0，10.0和24h采血，用LC/MS/MS测定血浆中本发明化合物或对照化合物的浓度。
表2血浆中的主要药代动力学参数
由检测结果看出，本发明化合物具有良好的口服药代动力学特性。
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，口服给予100mg/kg本发明化合物或对照化合物的溶液[10％DMSO/60％聚乙二醇400/30％水溶液为载体]。分别在给予本发明化合物后0.25，0.5，1.0，2.0，4.0，6.0，8.0，10.0和24h采血，用LC/MS/MS测定血浆中本发明化合物或对照化合物的浓度。
表3血浆中的主要药代动力学参数

表4血浆中的主要药代动力学参数
由检测结果看出，本发明化合物具有良好的口服药代动力学特性。
抗肿瘤活性药效学测试评价(NCI-H727 CDX肿瘤模型)
将100uL含5x106NCI-H727肿瘤细胞悬液皮下接种到裸鼠右后侧腹部。每天监测小鼠健康状况，当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW2，其中L、W分别代表肿瘤长、宽。肿瘤长至～200mm3，对小鼠进行随机分组。小鼠每天灌胃给予相应剂量化合物，同时对其一般状态进行监测。肿瘤每周测量3次，体重每周测量两次。
由检测结果看出，本发明化合物具有良好的抗肿瘤效果。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 式(I0)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
    式中，
    选自下组：
    其中，
    选自下组：
    环B选自取代或未取代的下组基团：C6-C14芳基、5-14元环杂芳基；其中，所述取代是指被一个或多个R取代；
    R1a独立地选自取代或未取代的下组基团：氢、氘、C1-C10烷基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    R1b独立地选自取代或未取代的下组基团：氢、氘、C1-C10烷基、C1-C10烷氧基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C1-C10烷氧基C1-C6亚烷基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    R1c独立地选自取代或未取代的下组基团：C1-C10烷基、C1-C10烷氧基、C3-C20环烷基、4-20元饱和或不饱和的杂环基、C1-C10烷氧基C1-C6亚烷基、C3-C20环烷基C1-C6亚烷基、4-20元饱和或不饱和的杂环基C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    或者R1a和R1c连接起来形成4-7元环；
    R2选自取代或未取代的下组基团：C6-C14芳基、5-14元杂芳基；其中，所述取代是指被一个或多个R取代；
    R3各自独立地选自取代或未取代的下组基团：H、氘、卤素、氰基、酯基、胺基、酰胺基、砜基、脲基、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C3-C6环烷基、4-6元杂环基、C1-C6烷基氧基、C3-C6环烷基氧基、4-6元杂环基氧基；其中，所述取代是指被一个 或多个R取代；
    m为0、1、2、3、4、5或6的整数；
    X选自：键、O、NH、N(C1-C3烷基)、C≡C；
    Y选自：键、取代或未取代的C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    1)Z选自：
    其中，环W1选自取代或未取代的下组基团：C3-C20环烷基、4-20元饱和或不饱和的杂环基；其中，所述取代是指被一个或多个R取代；
    R4选自：H、氘、烯基、氟代烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(＝O)、氰基、酯基、胺基、酰胺基、砜基或脲基；
    n选自：0、1、2、3、4、5或6的整数；
    或者
    2)Z选自：-L4-Q2或者
    其中，环W2选自取代或未取代的下组基团：C3-C6亚环烷基、4-6元饱和或不饱和的亚杂环基；其中，所述取代是指被一个或多个R取代；
    各L4独立的选自取代或未取代的下组基团：键、C1-C6亚烷基、氘代C1-C6亚烷基；其中，所述取代是指被一个或多个R取代；
    各Q2独立的选自取代或未取代的下组基团：C1-C6烷氧基、C3-C10环烷基氧基、4-10元杂环基氧基、C3-C10环烷基C1-C6亚烷基氧基、4-10元杂环基C1-C6亚烷基氧基、C3-C10环烷基、4-10元杂环基、NHR9、NR9R10；R9和R10各自独立地选自取代或未取代的下组基团：C1-C6烷基、C3-C10环烷基、4-10元杂环基、(C3-C10环烷基)C1-C6亚烷基、(4-10元杂环基)C1-C6亚烷基，或R9和R10与其连接的N原子共同形成取代或未取代的4-10元杂环基；其中，所述取代是指被一个或多个R取代；
    各R相同或不同，各自独立地选自：H、氘、烯基、氟代烯基、乙炔基、C1-C6烷基、氘代C1-C6烷基、卤代C1-C6烷基、C1-C6亚烷基、卤代C1-C6亚烷基、(C3-C6环烷基)C1-C6烷基、(4-6元杂环基)C1-C6烷基、(C1-C6烷氧基)C1-C6烷基、(C3-C6环烷基氧基)C1-C6烷基、(4-6元杂环基氧基)C1-C6烷基、(C1-C6烷基)乙烯基、氘代(C1-C6烷基)乙烯基、卤代(C1-C6烷基)乙烯基、(C1-C6烷基)乙炔基、氘代(C1-C6烷基)乙炔基、卤代(C1-C6烷基)乙炔基、(C3-C6环烷基)乙炔基、(4-6元杂环基)乙炔基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、 C3-C6环烷基氧基、4-6元杂环基氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、5-10元杂芳基、卤素、硝基、羟基、氧代基(＝O)、氰基、酯基、胺基、酰胺基、砜基或脲基。
  2. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(I)所示的结构：
    式中，
    B、R1a、R1b、R1c、R2、R3、X、Y、Z和m的定义如权利要求1所述。
  3. 如权利要求2所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(II-A)或式(II-B)所示的结构：
    式中，
    环B、R1a、R1b、R1c、R2、R3、X、Y、Z和m的定义如权利要求1所述。
  4. 如权利要求1-3中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(III-A1)、式(III-A2)或式(III-B1)、式(III-B2)所示的结构：
    式中，环B、R1a、R1b、R1c、R2、R3、R4、X、Y、W1、W2、L4、Q2、m和n的定义如权利要求1所述；
    优选地，具有式(III-A1)或式(III-B1)所示的结构。
  5. 如权利要求1-4中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(IV-A1)、式(IV-A2)或式(IV-B1)、式(IV-B2)所示的结构：
    式中，
    环B、R1a、R1b、R1c、R2、R3、R4、Y、W1、W2、L4、Q2、m和n的定义如权利要求1所述。
  6. 如权利要求1-5中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(V-A1)、式(V-A2)或式(V-B1)、式(V-B2)所示的结构：
    式中，环B、R2、R3、R4、Y、W1、W2、L4、Q2、m和n的定义如权利要求1所述。
  7. 如权利要求1-6中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VI-A1)、或式(VI-B1)所示的结构：
    式中，环B、R2、R3、m和n的定义如权利要求1所述；各R5相同或不同，各自独立地选在氢或氘。
  8. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VII-A1)或式(VII-B1)所示的结构：
    式中，
    P1、P2、P3各自独立地选自C-H、C-F、C-Cl、C-CN、C-CF3、或N；
    环B、R1a、R1b、R1c、R3、R4、X、Y、W1、W2、L4、Q2、m和n的定义如权利要求1所述。
  9. 如权利要求1-8中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，W1选自：取代或未取代的4-7元的单环杂环基、取代或未取代的C3-C7单环环烷基、取代或未取代的6-10元的双环杂环基、取代或未取代的C6-C10双环环烷基、取代或未取代的的7-12元的三环杂环基、取代或未取代的C7-C12三环环烷基，优选地，W1为取代或未取代的8-12元含N杂环基，其中，所述取代是指被一个或多个R取代，R的定义如权利要求1所述；
    优选地，选自：

    其中，n’为0、1、2、3、4、5、或6的整数；R、R4和n的定义如权利要求1所述，R、R4可以取代在多环(如桥环或螺环)的任意一个环上；
    更优选地，选自：

    其中，n’为0、1、2、3、4、5或6的整数；R、R4和n的定义如权利要求1所述，R可以取代在多环(如桥环或螺环)的任意一个环上。
  10. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，为优选地，选自：
    或者选自：
  11. 如权利要求1-10中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R2选自取代或未取代的下组基团：苯基、萘基、5-6元单环杂芳基(如吡啶基)、9-10元双环杂芳基(如吲唑基、苯并噻唑、苯并噻吩、苯并呋喃)，其中所述取代是被选自下组的一个或多个基团取代：卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基、酯基、胺基、酰胺基、砜基、脲基、磺酰胺基、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH、4-6元杂环基OH；优选地，R2选自：
    或者选自：
    或者选自：

    或者选自：
  12. 如权利要求1-11中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，环B选自取代或未取代的下组基团：苯基、萘基、5-6元单环杂芳基(如吡唑基、噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基)、9-10元双环杂芳基(如吲唑基、苯并噻唑、苯并噻吩、苯并呋喃)，其中所述取代是被选自下组的一个或多个基团取代：卤素、羟基、氰基、NH2、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基、酯基、胺基、酰胺基、砜基、脲基、磺酰胺基、C3-C6环烷基O-、4-6元杂环基O-、C3-C6环烷基OH、4-6元杂环基OH；优选地，环B选自：

    或者选自：
    更优选地，环B选自：
    或者选自：
  13. 如权利要求1-12中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，所述化合物选自下组：






    或者选自：







    或者选自：
    或者选自：
    或者选自：

    或者选自：


    或者选自：



    或者选自：




    或者选自：

    或者选自：
    或者选自：

    或者选自：
    或者选自：

    或者选自：

    或者选自：



  14. 一种药物组合物，其特征在于，包含一种或多种如权利要求1-13中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和药学上可接受的载体。
  15. 一种如权利要求1-13中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或如权利要求14所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与KRAS突变的活性或表达量相关的疾病的药物，优选地，所述的疾病为肿瘤或失调性疾病。
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