WO2021228248A1 - 氮杂稠环酰胺类化合物及其用途 - Google Patents

氮杂稠环酰胺类化合物及其用途 Download PDF

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WO2021228248A1
WO2021228248A1 PCT/CN2021/093930 CN2021093930W WO2021228248A1 WO 2021228248 A1 WO2021228248 A1 WO 2021228248A1 CN 2021093930 W CN2021093930 W CN 2021093930W WO 2021228248 A1 WO2021228248 A1 WO 2021228248A1
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compound
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substituted
alkyl
unsubstituted
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PCT/CN2021/093930
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French (fr)
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米国瑞
张颜
蒋春华
徐艳霞
范丽雪
张雪娇
秦亚楠
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石药集团中奇制药技术（石家庄）有限公司
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Priority to AU2021270672A priority Critical patent/AU2021270672B2/en
Priority to KR1020227043959A priority patent/KR20230012020A/ko
Priority to EP21803604.4A priority patent/EP4151635A4/en
Priority to US17/998,827 priority patent/US20230227460A1/en
Priority to CA3173804A priority patent/CA3173804A1/en
Priority to JP2022569535A priority patent/JP7495998B2/ja
Priority to CN202180033422.7A priority patent/CN115551859B/zh
Publication of WO2021228248A1 publication Critical patent/WO2021228248A1/zh

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    • A—HUMAN NECESSITIES
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    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
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    • 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 technical field of medicine, and specifically relates to a class of aza-fused cyclic amide compounds with kinase inhibitory activity or their tautomers, stereoisomers, optical isomers, solvates, isotopic derivatives, Nitrogen oxides, prodrugs, pharmaceutically acceptable salts, and pharmaceutical compositions containing them, and their use as drugs for preventing and/or treating TRK-mediated diseases.
  • Tropomyosin-related kinase or tropomyosin receptor kinase is a type of nerve growth factor receptor, its family consists of three highly homologous TRKA, TRKB and TRKC The subtypes are composed of neurotrophic receptor tyrosine kinase 1 (NTRK1), NTRK2 and NTRK3 genes.
  • NTRK1 neurotrophic receptor tyrosine kinase 1
  • TRK receptor protein When TRK receptor protein binds to the corresponding ligand, it can activate downstream signal pathways, such as RAS/MAPK pathway, PLC ⁇ pathway, and PI3K pathway to achieve different physiological functions.
  • TRK family proteins are normally expressed in nerve tissues, and are involved in the differentiation and survival of nerve cells, as well as the formation of axons and dendrites, and play an important role in embryonic development and the maintenance of normal nervous system functions.
  • TRK kinase is activated by a variety of mechanisms in malignant tumors, mainly due to structural rearrangement and changes in expression.
  • NTRK the gene encoding TRK kinase
  • rearranges with other genes to produce fusion oncogenes which leads to changes in the structure and expression of TRK kinase, and is no longer regulated and controlled by nerve growth factor ligands, and constitutive activation occurs, which promotes The occurrence and development of tumors.
  • TRK kinase is also closely related to the occurrence, metastasis and deterioration of a variety of tumors, and is expressed in a variety of tumors, such as non-small cell lung cancer, colorectal cancer, melanoma, gallbladder cancer, and thyroid. Cancer, malignant glioma, etc.
  • Larotrectinib Larotrectinib
  • RXDX-101 Entrectinib
  • FDA U.S. Food and Drug Administration
  • Larotrectinib is a potent, oral, and selective tropomyosin receptor kinase inhibitor. Its efficacy data was announced as early as the ASCO meeting in June 2017. It was recruited in Phase I and Phase II clinical trials. There were 55 subjects, 46 of which had an evaluable overall patient response rate (ORR) of 78%.
  • ORR overall patient response rate
  • Entrectinib is a potent inhibitor of TRK, ROS1 and ALK proteins, and can pass through the blood-brain barrier. In the phase I clinical trial, the ORR of 24 evaluable patients was 79%.
  • TRK inhibitors Similar to other targeted drugs, TRK inhibitors also face the problem of resistance. Mutations in the NTRK kinase region can cause changes in the conformation of the TRK family protein kinase domain or changes in its binding affinity to ATP, thereby affecting the binding of TRK inhibitors to the target.
  • the mutation types include G595R, G639R, G667C, and so on.
  • the second-generation TRK inhibitors such as LOXO-195 and TPX-005 have been studied.
  • the purpose of the present invention is to provide a class of aza-fused cyclic amide compounds with excellent TRK (wild-type and mutant) inhibitory activity and novel structures or their tautomers, stereoisomers, solvates, and isotope derivatives Compounds, nitrogen oxides, prodrugs, pharmaceutically acceptable salts.
  • Another object of the present invention is to provide a class of aza-fused cyclic amide compounds or their tautomers, stereoisomers, Solvates, isotopic derivatives, nitrogen oxides, prodrugs, pharmaceutically acceptable salts.
  • Another object of the present invention is to provide a novel structure of aza-fused cyclic amide compounds with better TRK (wild-type and mutant) inhibitory activity and TRK mutant tumor cell inhibitory activity compared with known compounds.
  • Another object of the present invention is to provide a class of aza-fused cyclic amide compounds or their tautomers and stereoisomers that have better TRK mutant tumor cell inhibitory activity and in vivo anti-tumor activity than known compounds Body, solvate, isotope derivative, nitrogen oxide, prodrug, pharmaceutically acceptable salt.
  • Another object of the present invention is to provide a class of aza-fused cyclic amide compounds or their interconversions that have better TRK mutant tumor cell inhibitory activity, in vivo anti-tumor activity, and better safety than known compounds Isomers, stereoisomers, solvates, isotopic derivatives, nitrogen oxides, prodrugs, pharmaceutically acceptable salts.
  • Another object of the present invention is to provide a class of compounds that have better TRK (wild-type and mutant) inhibitory activity, TRK mutant tumor cell inhibitory activity, anti-tumor activity in vivo, and better safety than known compounds.
  • the present invention provides a compound represented by formula (I) or its tautomers, stereoisomers, optical isomers, solvates, isotopic derivatives, nitrogen oxides, prodrugs, pharmaceuticals Acceptable salt,
  • X is selected from: bond, -O-, -S-, -NH- or -CH 2 -;
  • Y, Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from: -CH-, N or C;
  • X 2 is selected from: bond, -(CH 2 ) p -or -NH-, where p is 1, 2, 3 or 4;
  • R is selected from: C 5-12 aryl or heteroaryl, wherein each aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from R 1 ;
  • R 1 is independently selected from: hydrogen, halogen, -OH, amino, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , cyano, unsubstituted or R 1a is substituted with at least one of C 1 ⁇ 6 alkyl group, unsubstituted or substituted with at least one R 1a is C 1 ⁇ 6 alkoxy, unsubstituted or substituted with at least one of R 1a C 3 ⁇ 6 cycloalkyl Group, unsubstituted or substituted by at least one R 1a C 3-6 cycloalkoxy group or -SC 1-6 alkyl group;
  • R 1a is independently selected from: C 1-6 alkyl, C 1-6 alkoxy, nitro, halogen, -OH, amino, -NHC 1-6 alkyl, -N( C 1-6 alkyl) 2 or cyano;
  • R 2 is selected from: H, halogen, hydroxy, amino, or substituted or unsubstituted C 1-6 alkyl, and the substitution refers to substitution by 1, 2 or 3 substituents selected from halogen or hydroxy;
  • R 3 is selected from: H, halogen, -OH, amino, C 1-6 alkyl or C -6 alkoxy;
  • Ring A is selected from the group consisting of: cycloalkyl, heterocycloalkyl, bridged cyclic group, heterobridged cyclic group, cyclic group, heterocyclic group, spirocyclic group, heterospirocyclic group, wherein the heterocycloalkyl group, heterocyclic group
  • the heteroatoms in the bridged ring group, the heterocyclic group and the heterospiro ring group are independently selected from O, S or N, and the number of the heteroatoms is selected from 1, 2, 3 or 4;
  • R 4 is located at any substitutable position on ring A, which is independently selected from: -H, -OH, halogen, -CN, oxo, substituted or unsubstituted C 1-6 alkyl, -(CH 2 ) m -OH, -(CH 2 ) m -COOH, -(CH 2 ) m -CO-NH 2 , -CO-(CH 2 ) m -NH 2 , -CO-CR 4a R 4b -OH or -CO- R 4b ; wherein, the oxo group means that two H at the same substitution position are replaced by the same O to form a double bond; m is selected from 1, 2, 3 or 4; R 4a is selected from hydrogen, unsubstituted or substituted C 1-4 alkyl; R 4b is selected from H, unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted C 3-6 cycloalkyl, and the substitute
  • n is selected from 1, 2, 3, or 4.
  • a pharmaceutically acceptable salt wherein R is selected from: C 5-9 aryl or heteroaryl, wherein each aryl or heteroaryl is unsubstituted or substituted by at least one selected from R 1
  • R is selected from: C 5-6 aryl or heteroaryl, wherein each aryl or heteroaryl is unsubstituted or substituted by at least one substituent selected from R 1 .
  • the compound has a structure as shown in formula (I-1) or (I-2):
  • R 1 , R 2 , R 3 , R 4 , X, X 2 , Y, Y 1 , Y 2 , Y 3 , Y 4 , ring A and n are as described in the compound of formula (I) of the present invention, X 1 Selected from: -CH- or N.
  • the compound has a structure as shown in formula (I-A):
  • R 1 , R 2 , R 3 , R 4 , X, X 1 , X 2 , Y, Y 1 , Y 2 , Y 3 , Y 4 , ring A and n are the same as the formula (I-1) of the present invention or (I-2) As described in the compound.
  • the compound has a structure as shown in formula (I-A-1a), (I-A-1b) or (I-A-1c):
  • R 1 , R 2 , R 3 , R 4 , X, X 1 , X 2 , ring A and n are as described in the compound of formula (I-1) or (I-2) of the present invention.
  • the compound has a structure as shown in formula (I-B):
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , Y, Y 1 , Y 2 , Y 3 , Y 4 , ring A and n are the same as the formula (I-1) or (I -2) As described in the compound.
  • the compound has a structure as shown in formula (I-B-1a), (I-B-1b) or (I-B-1c):
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , ring A and n are the same as those described in the compound of formula (I-1) or (I-2) of the present invention.
  • the compound has a structure as shown in formula (I-C):
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , Y, Y 1 , Y 2 , Y 3 , Y 4 , ring A and n are the same as the formula (I-1) or (I -2) As described in the compound.
  • the compound has a structure as shown in formula (I-C-1a), (I-C-1b) or (I-C-1c):
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , ring A and n are as described in the compound of formula (I-1) or (I-2) of the present invention.
  • the compound provided by the present invention (the compound of formula (I), the compound of formula (I-1), the compound of formula (I-2), the compound of formula (IA), the compound of formula (IA-1a), the compound of formula ( IA-1b) compound, formula (IA-1c) compound, formula (IB) compound, formula (IB-1a) compound, formula (IB-1b) compound, formula (IB-1c) compound, formula (IC) compound, Compound of formula (IC-1a), compound of formula (IC-1b), compound of formula (IC-1c)) its tautomers, stereoisomers, optical isomers, solvates, isotopic derivatives, nitrogen oxides Compounds, prodrugs, pharmaceutically acceptable salts, wherein each occurrence of R 1 is independently selected from: hydrogen, halogen, -OH, amino, cyano, unsubstituted or substituted with at least one R 1a C 1-6 alkyl, unsubstituted or substituted by at least one R 1a C 1-6 al
  • each occurrence of R 1a is independently selected from: C 1-3 alkyl, C 1-3 alkoxy, nitro, halogen, -OH, amino, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2 or cyano; or, R 1a is selected from: halogen, -OH, amino, -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 or cyano; or, R 1a is selected from halogen, -OH, amino or cyano; or, R 1a is selected from: F, Cl or -OH.
  • the compound provided by the present invention (the compound of formula (I), the compound of formula (I-1), the compound of formula (I-2), the compound of formula (IA), the compound of formula (IA-1a), the compound of formula ( IA-1b) compound, formula (IA-1c) compound, formula (IB) compound, formula (IB-1a) compound, formula (IB-1b) compound, formula (IB-1c) compound, formula (IC) compound, Compound of formula (IC-1a), compound of formula (IC-1b), compound of formula (IC-1c)) its tautomers, stereoisomers, optical isomers, solvates, isotopic derivatives, nitrogen oxides Compounds, prodrugs, pharmaceutically acceptable salts, wherein R 2 is selected from: H, F, OH, or substituted or unsubstituted C 1-6 alkyl, and the substitution refers to being selected from 1, 2, or 3.
  • R 2 is selected from H, F, -OH or C 1-6 alkyl; or, R 2 is selected from H, F, -OH or C 1-3 alkyl; Alternatively, R 2 is selected from H or F.
  • the compound provided by the present invention (the compound of formula (I), the compound of formula (I-1), the compound of formula (I-2), the compound of formula (IA), the compound of formula (IA-1a), the compound of formula ( IA-1b) compound, formula (IA-1c) compound, formula (IB) compound, formula (IB-1a) compound, formula (IB-1b) compound, formula (IB-1c) compound, formula (IC) compound, Compound of formula (IC-1a), compound of formula (IC-1b), compound of formula (IC-1c)) its tautomers, stereoisomers, optical isomers, solvates, isotopic derivatives, nitrogen oxides Compounds, prodrugs, and pharmaceutically acceptable salts, wherein X 1 is selected from -CH- or N, and R 1 is selected from F or -OCH 3 .
  • X 1 is selected from -CH- and R 1 is selected from F; or, X 1 is selected from N, and R 1 is selected from -OCH 3 .
  • the compound has a structure as shown in formula (I-D):
  • R 3 , R 4 , X 2 , Y, Y 1 , Y 2 , Y 3 , Y 4 , ring A and n are the same as those described in the compound of formula (I) of the present invention.
  • the compound has a structure as shown in formula (I-D-a), formula (I-D-b) or formula (I-D-c):
  • R 3 , R 4 , X 2 , ring A and n are the same as those described in the compound of formula (I) of the present invention.
  • the compound provided by the present invention (the compound of formula (I), the compound of formula (I-1), the compound of formula (I-2), the compound of formula (IA), the compound of formula (IA-1a), the compound of formula ( IA-1b) compound, formula (IA-1c) compound, formula (IB) compound, formula (IB-1a) compound, formula (IB-1b) compound, formula (IB-1c) compound, formula (IC) compound, Compound of formula (IC-1a), compound of formula (IC-1b), compound of formula (IC-1c), compound of formula (ID), compound of formula (IDa), compound of formula (IDb), compound of formula (IDc)) their mutual Tautomers, stereoisomers, optical isomers, solvates, isotopic derivatives, nitrogen oxides, prodrugs, pharmaceutically acceptable salts, wherein R 3 is selected from: H, halogen, -OH, Amino, C 1-3 alkyl or C 1-3 alkoxy; or, R 3 is selected from: H, F,
  • the compound has a structure as shown in formula (I-D-1a), formula (I-D-1b) or formula (I-D-1c):
  • R 4 , X 2 , ring A and n are as described in the compound of formula (I) of the present invention.
  • the compound has a structure as shown in formula (I-C-1a-1):
  • R 4 , X 2 , ring A and n are the same as those described in the compound of formula (I) of the present invention.
  • the compound has a structure as shown in formula (I-C-1a-2):
  • R 4 , X 2 , ring A and n are the same as those described in the compound of formula (I) of the present invention.
  • the compound provided by the present invention (the compound of formula (I), the compound of formula (I-1), the compound of formula (I-2), the compound of formula (IA), the compound of formula (IA-1a), the compound of formula ( IA-1b) compound, formula (IA-1c) compound, formula (IB) compound, formula (IB-1a) compound, formula (IB-1b) compound, formula (IB-1c) compound, formula (IC) compound, Formula (IC-1a) compound, formula (IC-1b) compound, formula (IC-1c) compound, formula (ID) compound, formula (IDa) compound, formula (IDb) compound, formula (IDc) compound, formula (ID-1a) compound, formula (ID-1b) compound, formula (ID-1c) compound, formula (IC-1a-1) compound, and formula (IC-1a-2) compound, the same below) their interconversion Isomers, stereoisomers, optical isomers, solvates, isotopic derivatives, nitrogen oxides, prodrugs, pharmaceutically acceptable salts, where
  • ring A is selected from the following structures:
  • ring A is selected from the following structures:
  • ring A is selected from the following structures:
  • ring A is selected from the following structures:
  • the compound provided by the present invention (the compound of formula (I), the compound of formula (I-1), the compound of formula (I-2), the compound of formula (IA), the compound of formula (IA-1a), the compound of formula ( IA-1b) compound, formula (IA-1c) compound, formula (IB) compound, formula (IB-1a) compound, formula (IB-1b) compound, formula (IB-1c) compound, formula (IC) compound, Compound of formula (IC-1a), compound of formula (IC-1b), compound of formula (IC-1c), compound of formula (ID), compound of formula (IDa), compound of formula (IDb), compound of formula (IDc), (ID-1a) compound, formula (ID-1b) compound, formula (ID-1c) compound, formula (IC-1a-1) compound, and formula (IC-1a-2) compound) and its tautomers , Stereoisomers, optical isomers, solvates, isotopic derivatives, nitrogen oxides, prodrugs, pharmaceutically acceptable salts, wherein R 4 is
  • X is selected from: bond, -O-, -S-, -NH- or -CH 2 -;
  • X 1 is selected from: -CH- or N;
  • X 2 is selected from: bond, -(CH 2 ) p -or -NH-, where p is 1, 2, 3 or 4;
  • R 1 is selected from: H, halogen, -OH, amino, C 1-6 alkyl or C -6 alkoxy;
  • R 2 is selected from: H, F, OH, or substituted or unsubstituted C 1-6 alkyl, and the substitution refers to substitution by 1, 2 or 3 substituents selected from halogen or hydroxy;
  • R 3 is selected from: H, halogen, -OH, amino, C 1-6 alkyl or C -6 alkoxy;
  • Ring A is selected from the group consisting of: cycloalkyl, heterocycloalkyl, bridged cyclic group, heterobridged cyclic group, cyclic group, heterocyclic group, spirocyclic group, heterospirocyclic group, wherein the heterocycloalkyl group, heterocyclic group
  • the heteroatoms in the bridged ring group, the heterocyclic group and the heterospiro ring group are independently selected from O, S or N, and the number of the heteroatoms is selected from 1, 2, 3 or 4;
  • R 4 is located at any substitutable position on ring A, which is independently selected from: -H, -OH, halogen, -CN, oxo, substituted or unsubstituted C 1-6 alkyl, -(CH 2 ) m -OH, -(CH 2 ) m -COOH, -(CH 2 ) m -CO-NH 2 , -CO-(CH 2 ) m -NH 2 , -CO-CR 4a R 4b -OH or -CO- R 4b ; wherein, the oxo group means that two H at the same substitution position are replaced by the same O to form a double bond; m is selected from 1, 2, 3 or 4; R 4a is selected from hydrogen, unsubstituted or substituted C 1-4 alkyl; R 4b is selected from H, unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted C 3-6 cycloalkyl, and the substitute
  • n is selected from 1, 2, 3, or 4.
  • R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , ring A and n are the same as those described in the compound of formula (IA-1a) of the present invention.
  • R 1 , R 3 , R 4 , X 1 , X 2 , ring A and n are the same as those described in the compound of formula (IA-1a) of the present invention.
  • R 1 , R 3 , R 4 , X 1 , X 2 , ring A and n are the same as those described in the compound of formula (IA-1a) of the present invention.
  • R 4 , X 2 , ring A and n are the same as those described in the compound of formula (IA-1a) of the present invention.
  • R 4 , X 2 , ring A and n are the same as those described in the compound of formula (IA-1a) of the present invention.
  • the compound provided by the present invention or its tautomers, optical isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof wherein ring A is selected from: C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-8 bridged ring group, 6-8 membered hetero bridged ring group, C 8-10 ring group, 8-10 membered hetero ring group, C 7- 12 monospirocyclic group, 7-12 membered heteromonospirocyclic group, wherein the heteroatoms in the heterocycloalkyl group, heterobridged cyclic group, heterobocyclic group and heteromonospirocyclic group are independently selected from O, S Or N, the number of heteroatoms is selected from 1, 2 or 3.
  • ring A is selected from: C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-8 bridged ring group, 6-8 membered hetero bridged ring group, C 8-10 ring group, 8-10 member
  • ring A is selected from the following structures:
  • the compound provided by the present invention or its tautomers, optical isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof wherein R 4 is independently selected from: -H , -OH, halogen, -CN, oxo, substituted or unsubstituted C 1-6 alkyl, -COOH, -CONH 2 , -CO-CR 4a R 4b -OH or -CO-R 4b , wherein, The oxo group means that two H at the same substitution position are replaced by the same O to form a double bond; R 4a is selected from hydrogen, unsubstituted or substituted C 1-4 alkyl; R 4b is selected from unsubstituted or substituted C 1-6 alkyl or unsubstituted or substituted C 3-6 cycloalkyl, the substituted substituents are independently selected from -OH, -NH 2 , halogen, and the number of substituents is selected from 1, 2 or
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, Isotope derivatives or pharmaceutically acceptable salts thereof.
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, Isotope derivatives or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients.
  • Another aspect of the present invention also provides the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable compounds thereof.
  • the disease is selected from pain disease, cell proliferative disease, inflammatory disease, neurodegenerative disease or infectious disease.
  • the disease is mediated by one, two or three of TRKA, TRKB or TRKC.
  • the disease relates to NTRK gene, TRK protein, or their expression, activity or level imbalance; preferably, it relates to NTRK gene fusion, amplification, rearrangement, mutation or high expression; further preferably, it relates to NTRK Gene fusion or mutation.
  • Another aspect of the present invention also provides the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable compounds thereof.
  • the accepted salt or the pharmaceutical composition of the present invention is used to prevent and/or treat diseases mediated by TRK.
  • Another aspect of the present invention also provides a method for preventing and/or treating diseases mediated by TRK, which comprises: administering the compound of the present invention or its tautomers, stereoisomers, or optical isoforms to patients. Constructs, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention.
  • Another aspect of the present invention also provides the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable compounds thereof.
  • the medicament is used to treat diseases mediated by TRK, ALK, ROS1, or a combination thereof.
  • the drug is used to treat painful diseases, cell proliferative diseases, inflammatory diseases, neurodegenerative diseases or infectious diseases.
  • Another aspect of the present invention also provides the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable compounds thereof.
  • the inhibitor is used to treat diseases mediated by TRK, ALK, ROS1, or a combination thereof.
  • the inhibitor is used to treat painful diseases, cell proliferative diseases, inflammatory diseases, neurodegenerative diseases, or infectious diseases.
  • Another aspect of the present invention also provides the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable compounds thereof.
  • the accepted salt or the pharmaceutical composition of the present invention is used in the preparation of a medicament for the treatment of painful diseases, cell proliferative diseases, inflammatory diseases, neurodegenerative diseases or infectious diseases.
  • the pain disease, cell proliferative disease, inflammatory disease, neurodegenerative disease or infectious disease involves NTRK gene, TRK protein, or their expression, activity or level imbalance; preferably it involves NTRK gene fusion, expansion Increase, rearrangement, mutation or high expression; further preferably involving NTRK gene fusion or mutation.
  • the pain disease disease, cell proliferative disease, inflammatory disease, neurodegenerative disease or infectious disease involves ROS1 gene, ROS1 protein, or their expression, activity or level imbalance; preferably, it involves ROS1 gene fusion, Amplification, rearrangement, mutation or high expression; further preferably involving ROS1 gene fusion or mutation.
  • the pain disease, cell proliferative disease, inflammatory disease, neurodegenerative disease or infectious disease involves a gene, protein of TRK, ALK, ROS1 or a combination thereof, or their expression, activity or level disorder ; Preferably it relates to NTRK, ALK, ROS1 or their combination gene fusion, amplification, rearrangement, mutation or high expression; further preferably relates to NTRK, ALK, ROS1 or their combination gene fusion or mutation.
  • the cell proliferative disease is tumor or cancer.
  • the tumor or cancer is a solid tumor and hematological tumor, preferably a solid tumor.
  • the tumor or cancer is hematological malignancy, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma, colorectal cancer, melanoma, cancer of the head and neck, gallbladder Cancer, thyroid cancer, malignant glioma, gastric cancer, neurocytoma or salivary gland cancer; preferably, the lung cancer is non-small cell lung cancer.
  • Another aspect of the present invention also provides the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable compounds thereof.
  • the accepted salt or the pharmaceutical composition of the present invention is used for the treatment of pain, cell proliferative diseases, inflammation, neurodegenerative diseases or infectious diseases.
  • Another aspect of the present invention also provides a method for treating diseases, which comprises: administering the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides to a patient , A prodrug, an isotope derivative or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention, wherein the disease is pain, cell proliferative disease, inflammation, neurodegenerative disease or infectious disease.
  • the compound of the present invention or its tautomers, stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable is used in combination with another, two or more drugs for treating cell proliferative diseases.
  • Another aspect of the present invention also provides the compound of the present invention or its tautomers, optical isomers, stereoisomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable compounds thereof.
  • the disease is selected from pain disease, cell proliferative disease, inflammatory disease, neurodegenerative disease or infectious disease.
  • the disease involves a disorder of TRK, ALK, ROS1, or a combination of genes, proteins, or their expression, activity, or level.
  • the disease involves gene fusion, amplification, rearrangement, mutation or high expression of NTRK, ALK, ROS1, or a combination thereof; further preferably involves gene fusion or gene fusion of NTRK, ALK, ROS1, or a combination thereof mutation.
  • Another aspect of the present invention also provides a method for preventing and/or treating diseases mediated by TRK, ALK, ROS1 or a combination thereof, comprising: administering the compound of the present invention or its tautomer to a patient , Stereoisomers, optical isomers, solvates, nitrogen oxides, prodrugs, isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (ie C 1-10 alkyl), more preferably Contains 1-8 carbon atoms (C 1-8 alkyl), more preferably 1-6 carbon atoms (ie C 1-6 alkyl), for example, “C 1-6 alkyl” refers to this group It is an alkyl group, and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically, 1, 2, 3, 4, 5, or 6).
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl , N-octyl and so on.
  • carbobicyclic group or "carbocyclic ring” means a monovalent or multivalent saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms, wherein the monocyclic, bicyclic or tricyclic ring is not Contains aromatic rings.
  • the carbobicyclic group includes a bridged ring group, a spiro ring group, a bicyclic group, and the like. Bridged ring group means that any two rings share two directly connected or not directly connected atoms.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms, preferably containing 3-12 carbon atoms (ie C 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl), more preferably 3-6 carbon atoms (C 3-6 cycloalkyl), 4-6 carbon atoms (C 4-6 cycloalkyl), 5-6 carbon atoms (C 5-6 cycloalkyl).
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
  • alkoxy refers to -O-alkyl.
  • the alkyl group is as defined above, that is, contains 1-20 carbon atoms, preferably 1-10 carbon atoms, preferably 1-8 carbon atoms , More preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy Oxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-Dimethylpropoxy, 1-ethylpropoxy, etc.
  • halogen refers to F, Cl, Br, I.
  • haloalkyl means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above are replaced by halogen.
  • Representative examples of haloalkyl include CCl 3 , CF 3 , CHCl 2 , CH 2 Cl, CH 2 Br, CH 2 I, CH 2 CF 3 , CF 2 CF 3 and the like.
  • heterocyclic group refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure and contains 3-20 ring atoms, of which 1, 2, 3 or more One ring atom is selected from N, O or S, and the remaining ring atoms are C. It preferably contains 3 to 12 ring atoms (C 3-12 heterocyclic group), more preferably 3 to 10 ring atoms (C 3-10 heterocyclic group), or 3 to 8 ring atoms (C 3-8 heterocyclic group).
  • Cyclic group or 3-6 ring atoms (C 3-6 heterocyclic group), or 4-6 ring atoms (C 4-6 heterocyclic group), or 5-6 ring atoms (C 5-6 Heterocyclyl).
  • the heteroatoms are preferably 1 to 4, more preferably 1 to 3 (that is, 1, 2, or 3).
  • Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl and the like.
  • the polycyclic heterocyclic group includes heterocyclic groups such as a heterospirocyclic group, a heterocyclic group, a heterofused ring group, and a heterobridged ring group.
  • heterocycloalkyl refers to a saturated “heterocyclic group” as defined above, containing 3-20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S , The remaining ring atoms are C.
  • It preferably contains 3-12 ring atoms (C 3-12 heterocycloalkyl), more preferably 3-10 ring atoms (C 3-10 heterocycloalkyl), or 3-8 ring atoms (C 3- 8 heterocycloalkyl), or 3-7 ring atoms (C 3-7 heterocycloalkyl), or 3-6 ring atoms (C 3-6 heterocycloalkyl), or 4-6 ring atoms (C 4-6 heterocycloalkyl), or 5-6 ring atoms (C 5-6 heterocycloalkyl).
  • the heteroatoms are preferably 1 to 4, more preferably 1 to 3 (that is, 1, 2, or 3).
  • Examples include aziridinyl, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietidinyl, pyrrolidinyl, tetrahydrofuranyl, oxetane Cyclohexane, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithiocyclohexyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolinidine Wait.
  • aryl means a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms , Preferably 6-10 carbon atoms, the term “aryl” can be used interchangeably with the term “aromatic ring”.
  • aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, or pyrenyl, and the like.
  • heteroaryl means an aromatic monocyclic or polycyclic ring system containing 5-12 membered structure, or preferably 5-10 membered structure, 5-8 membered structure, more preferably 5-6 membered structure, of which one, Two, three or more ring atoms are heteroatoms and the remaining atoms are carbon.
  • the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2, or 3.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl , Tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridine, purinyl, indino Dole, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrole And [2,3-b]pyridyl, imidazo
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt” means that it is suitable for contact with mammals, especially human tissues within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reactions, etc., and with reasonable benefits. /Risk ratio commensurate with salt.
  • salt includes salts selected from inorganic acids, as well as salts prepared from organic acids. If the compound of the present invention is acidic, pharmaceutically acceptable non-toxic bases include inorganic bases and salts prepared with organic bases.
  • stereoisomers refers to the isomers produced by the different arrangements of atoms in the molecule in space, including configurational isomers and conformational isomers. Among them, configurational isomers also include geometric isomers. Isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers).
  • Geometric isomers may exist in this compound.
  • the compound of the present invention may contain a carbon-carbon double bond or a carbon-nitrogen double bond in the E or Z configuration, wherein the term “E” represents a higher order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, the term “Z” represents the higher order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond (determined by the Cahn-Ingold Prelog priority rule).
  • the compound of the present invention may also exist in the form of a mixture of "E” and "Z” isomers.
  • the substituents surrounding the cycloalkyl or heterocycloalkyl group are called the cis or trans configuration.
  • Optical isomers refer to substances with identical molecular structures, similar physical and chemical properties, but different optical rotations.
  • the compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, where the terms "R” and “S” are such as IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, As defined by 13-10.
  • R and S are such as IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, As defined by 13-10.
  • Compounds with asymmetrically substituted carbon atoms (having equal numbers of R and S configurations) are racemic at those carbon atoms.
  • the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.
  • nitrogen oxide means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides on nitrogen atoms of nitrogen-containing heterocycles.
  • solvate refers to an association formed by one or more solvent molecules with the compound of the present invention.
  • tautomers refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called proton transfer tautomers
  • Valence tautomers include interconversion through the recombination of some bond-forming electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • isotopic derivative means that the compound of the present invention can exist in isotopic traced or enriched form, containing one or more atoms, the atomic weight or mass number of these atoms is different from the atomic weight of the largest number of atoms found in nature Or mass number.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I.
  • Compounds containing other isotopes of these and/or other atoms are within the scope of the present invention.
  • the isotope-labeled compound contains deuterium ( 2 H), tritium ( 3 H), or 14 C isotopes.
  • the isotope-labeled compounds of the present invention can be prepared using general methods well known to those of ordinary skill in the art. In this regard, relevant documents include: Lizondo, J et al, Drugs Fut, 21(11), 1116 (1996); Brickner, SJ et al, J Med Chem, 39(3), 673 (1996); Mallesham, B et al, Org Lett, 5(7), 963 (2003).
  • drugs containing non-radioactive isotopes such as deuterated drugs called “heavy drugs”, can be used to treat related diseases and disorders.
  • the increase in the amount of isotopes present in the above compounds above their natural abundance is called enrichment.
  • Examples of the amount of enrichment include approximately 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%.
  • any possible position in the molecular structure can be replaced by an isotope to obtain an isotope derivative.
  • any possible position in the molecule can be substituted with deuterium ( 2 H) to obtain a deuterated form of the derivative.
  • Drugs traced with stable isotopes can change the physical and chemical properties of the drug, such as pKa and lipid solubility. If the isotope substitution affects the area involved in the ligand-receptor interaction, then these effects and changes can affect the pharmacodynamic response of the drug molecule. Although some of the physical properties of molecules traced by stable isotopes are different from those of unlabeled molecules, the chemical and biological properties are the same. An important difference is that due to the increase in the mass of heavy isotopes, heavy isotopes and Any bond of another atom is stronger than the same bond between a light isotope and that atom. Correspondingly, the binding of isotopes at sites of metabolism or enzymatic conversion can potentially slow the reaction, and can change the pharmacokinetic properties or effects relative to non-isotopic compounds.
  • prodrug or “prodrug” is a derivative of an active drug designed to improve certain undesirable physical or biological properties. Physical properties are usually related to solubility (too high or insufficient lipids or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which itself may be related to physicochemical properties.
  • Prodrugs are usually prepared as follows: a) esters, half esters, carbonates, nitrates, amides, hydroxamic acids, carbamates, imines, Mannich bases, phosphates, phosphates and Enamine, b) functionalize the drug with azo, glycoside, peptide and ether functional groups, c) use the aminal, hemi-aminal, polymer, salt, complex, phosphoramide, acetal, and semi-aminal of the drug Acetal and ketal forms. For example, see Andrejus Korolkovas’s, "Essentials of Medicinal Chemistry", John Wiley-Interscience Pulications, John Wiley and Sons, New York (1988), pp.
  • Esters can be prepared from substrates containing hydroxyl or carboxyl groups using general methods known to those skilled in the art. The typical reaction of these compounds is the substitution of a heteroatom with another atom.
  • Amides can be prepared in a similar manner from substrates containing amino or carboxyl groups. Esters can also react with amines or ammonia to form amides. Another way to prepare amides is to heat the carboxylic acid and amine together.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvant approved by the US Food and Drug Administration, the National Drug Administration, etc., which is acceptable for use in humans or domestic animals , Carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes, colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents , Solvent or emulsifier.
  • tumor includes benign tumors, malignant tumors and borderline tumors, among which malignant tumors are collectively referred to as cancer.
  • prevention refers to when used for a disease or condition (e.g., cancer), when compared with a subject who has not been administered a compound or drug (e.g., a combination product as claimed in this application), the compound or Drugs can reduce the frequency or delay the onset of medical symptoms in subjects.
  • a disease or condition e.g., cancer
  • a compound or drug e.g., a combination product as claimed in this application
  • treatment refers to alleviating, alleviating or ameliorating the symptoms of a disease or condition, ameliorating potential symptoms caused by metabolism, inhibiting the disease or symptom, such as preventing the development of the disease or condition, alleviating the disease or condition, or causing the disease Or the regression of the disease, the alleviation of the condition caused by the disease or the disease, or the prevention of the symptoms of the disease or the disease.
  • cell proliferative disease refers to a condition in which the growth rate of the cell population is lower than or higher than the expected rate under a given physiological state and condition.
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • DMF N,N-dimethylformamide
  • EA ethyl acetate
  • NBS N-bromosuccinimide
  • PE petroleum ether
  • DMSO dimethyl sulfoxide
  • TBTU O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid
  • BOP benzotriazol-1-yloxy three (Dimethylamino)phosphonium hexafluorophosphate
  • ATP 5'-adenosine triphosphate
  • DTT 1,4-dithiothreitol
  • MTT 3-(4,5-dimethyl-2-thiazole)- 2,5-Diphenyl tetrazolium thiazole blue bromide.
  • the nitrogen oxides, isotopic derivatives, stereoisomers, optical isomers, solvates, prodrugs, etc. of the compounds of the present invention can also produce similar effects as the compounds of the present invention in vivo and in vitro.
  • the present invention designs a class of compounds with novel structures.
  • In vitro kinase activity inhibition tests show that the compounds of the present invention have excellent effects on a variety of kinases (for example, TRK, ALK, ROS1) and their mutants, especially TRK and its mutant forms.
  • In vitro cell inhibitory activity test showed that the compound of the present invention has a strong inhibitory effect on a variety of TRK mutant cells, and the inhibitory activity on 6 types of cells has an IC 50 of less than 10 nM, preferably less than 5 nM, and more preferably 1nM or less; in vivo antitumor test results show that: compared with the control compound, the compound of the present invention has better antitumor effect in vivo, better tolerability, and higher possibility of drug preparation; in vivo mechanism of action research test shows: the compound of the present invention It can inhibit TRK in tumor tissues, thereby effectively inhibiting the phosphorylation of PLC ⁇ and AKT, and inhibiting tumor tissue growth.
  • Figure 1 Time-effect relationship of inhibitory effect of compound No. 4 of the present invention on phosphorylation of target proteins in tumor tissues of TRKA-G595R mutation-resistant tumor-bearing mice. Western blot.
  • the raw materials, reaction reagents, catalysts or solvents involved in the following specific embodiments can all be purchased through commercial channels or prepared by conventional methods in the prior art.
  • Step a Add (R)-2-(2,5-difluorophenyl)pyrrolidine (5.0g, 27.292mmol), 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl
  • a mixed solution of ester (6.14g, 27.292mmol), n-butanol (70mL) and diisopropylamine (6.9g, 68.230mmol) was refluxed and stirred at 100°C for 4h, concentrated under reduced pressure to obtain an orange viscous solid, and anhydrous was added Ethyl ether, a large amount of solid precipitated out after stirring, and filtered with suction to obtain (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3 -Crude ethyl carboxylate (6.224g). Without purification, it was directly used in the next reaction, (ES,
  • Step b (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester ( 6.224g, 16.714mmol) was dissolved in absolute ethanol (40mL), stirred at 75°C until the mixed solution was clear and transparent, and then LiOH (2.805g, 66.856mmol) aqueous solution (40mL) was added and stirred at 75°C for 3h. After cooling to room temperature, it was concentrated under reduced pressure to remove absolute ethanol.
  • Step a Add (2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine (5.826g, 28.958mmol), 5-chloropyrazolo[1,5-a]pyrimidine
  • a mixed solution of ethyl-3-carboxylate (6.534g, 28.958mmol), n-butanol (50mL) and diisopropylamine (8.790g, 86.874mmol) was reacted at 100°C for 4h, and concentrated under reduced pressure to obtain 5-(( 2R,4S)-2-(2,5-Difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester crude product. Without purification, it was directly used in the next reaction, (ES, m/z): 391.05[M+H] + .
  • Step b Add 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-
  • the crude ethyl carboxylate was dissolved in absolute ethanol (50mL), stirred at 75°C until the system was clear and transparent, and then LiOH (4.86g, 115.832mmol) aqueous solution (50mL) was added, and the reaction was stirred at 75°C for 5h. After cooling to room temperature, it was concentrated under reduced pressure to remove absolute ethanol.
  • Step b Add 2-amino-2-(2,5-difluorophenyl)acetonitrile (21.92g, 130mmol) to 2mol/L NaOH aqueous solution (130mL), react for 6h under reflux conditions; cool to 0°C, Adjust the pH to 3 with concentrated hydrochloric acid, and concentrate to dryness under reduced pressure; add tetrahydrofuran (200 mL) to the residue, stir for 30 min, filter, and dry the filtrate with anhydrous sodium sulfate overnight, filter, and concentrate under reduced pressure to obtain 2-amino-2 -(2,5-Difluorophenyl)acetic acid crude product (20.78g), used in the next reaction without purification, (ES, m/z): 186.02[MH] - .
  • Step c Under the protection of nitrogen, add 2-amino-2-(2,5-difluorophenyl)acetic acid (20.78g, 111mmol) in tetrahydrofuran (600mL) solution, cool to -10 ⁇ -5°C, add tetrahydrofuran (600mL) in batches.
  • Step d Under the protection of nitrogen, at 0°C, add 2-amino-2-(2,5-difluorophenyl)ethanol (7.177g, 41.447mmol) and triethylamine (8.388g, 82.894mmol) in tetrahydrofuran
  • chloroacetyl chloride (5.62g, 49.736mmol) to the solution (200ml), keep stirring and react for 30min; add 60% NaH (4.974g, 124.341mmol) to the reaction system in batches, and react at room temperature for 2h after the addition is complete;
  • Step e Under the protection of nitrogen, to a solution of 5-(2,5-difluorophenyl)morpholin-3-one (4.532g, 21.271mmol) in tetrahydrofuran (100mL) at 0°C, add tetrahydrofuran (100mL) in batches.
  • Step g To 5-(3-(2,5-difluorophenyl)morpholinyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (6.066g, 15.623mmol) ethanol ( To the 60 mL) solution, LiOH (2.622 g, 62.492 mmol) aqueous solution (60 mL) was added, and the temperature was raised to 75° C. to react overnight. After cooling to room temperature, it was concentrated under reduced pressure.
  • Step a Add 1-Boc-4-(4-aminophenyl)piperazine (850mg, 3.067mmol) to (R)-5-(2-(2,5-difluorophenyl)pyrrolidine-1 -Yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (880mg, 2.556mmol) and TBTU (985mg, 3.067mmol) in anhydrous DMF (10mL) solution, then added dropwise at 0°C DIPEA (991 mg, 7.668 mmol), react at room temperature overnight. The reaction solution was added with water (50mL) and mixed and stirred. A solid precipitated out.
  • the filter cake was obtained by vacuum filtration and dried in a vacuum drying oven to obtain (R)-tert-butyl 4-(4-(5-(2-(2, 5-Difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)piperazine-1-carboxylate (1.450g, 94%) , (ES, m/z): 604.52[M+H] + .
  • Step a Add 1-Boc-4-(4-aminophenyl)piperazine (918mg, 3.312mmol) containing 5-((2R,4S)-2-(2,5-difluorophenyl)-4 -Fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate A2, 1000mg, 2.76mmol) and TBTU (1063mg, 3.312mmol) in anhydrous DMF (10mL) In the solution, DIPEA (1284 mg, 9.936 mmol) was added dropwise at 0°C, and the reaction was carried out at room temperature overnight.
  • DIPEA (1284 mg, 9.936 mmol
  • Filter cake was obtained by suction filtration under reduced pressure. The filter cake was rinsed with a small amount of water, dried and weighed to obtain 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-( 4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (907mg, 82%), (ES, m/z): 522.09[M+H] + .
  • Step a Add 1-Boc-4-(4-aminophenyl)piperidine (458mg, 1.656mmol) to 5-((2R,4S)-2-(2,5-difluorophenyl)-4 -Fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate A2, 500mg, 1.380mmol) and TBTU (532mg, 1.656mmol) in anhydrous DMF (5mL) In the solution, DIPEA (535mg, 4.140mmol) was added dropwise at 0°C, and reacted overnight at room temperature for 18h.
  • DIPEA 535mg, 4.140mmol
  • Step a Under nitrogen protection, add 1-Boc-4-(4-aminophenyl)piperazine (3.812g, 13.756mmol) containing 5-(3-(2,5-difluorophenyl)morpholino ) Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4.127g, 11.46mmol) and TBTU (4.417g, 13.756mmol) in anhydrous DMF (20mL) solution, then added dropwise at 0°C DIPEA (4.441g, 34.362mmol), react at room temperature overnight.
  • 1-Boc-4-(4-aminophenyl)piperazine (3.812g, 13.756mmol) containing 5-(3-(2,5-difluorophenyl)morpholino ) Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4.127g, 11.46mmol) and TBTU (4.417g, 13.756mmol) in anhydr
  • Step b To 4-(4-(5-(3-(2,5-difluorophenyl)morpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl tert To a solution of tert-butyl butylpiperazine-1-carboxylate (3.924 g, 6.332 mmol) in DCM (30 ml), CF 3 COOH (10 ml) was added, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure.
  • Step a Under nitrogen protection, add 1-Boc-4-(4-aminophenyl)piperazine (3.813g, 13.747mmol) containing 5-(3-(5-fluoro-2-methoxypyridine-3) -Yl)morpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4.277g, 11.46mmol) and TBTU (4.414g, 13.747mmol) in anhydrous DMF (20mL) solution, then DIPEA (4.441g, 34.368mmol) was added dropwise at 0°C and reacted overnight at room temperature.
  • 1-Boc-4-(4-aminophenyl)piperazine (3.813g, 13.747mmol) containing 5-(3-(5-fluoro-2-methoxypyridine-3) -Yl)morpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4.277g, 11.46mmol) and TBTU
  • Step a Add 3-oxetanamine (124mg, 1.701mmol) to a DMSO (3mL) solution containing p-fluoronitrobenzene (200mg, 1.417mmol), and then add DIPEA (366mg, 2.834mmol) at 120 The reaction was stirred at °C for 5h, water (20mL) was added to the reaction solution, a large amount of solid precipitated out after stirring, and vacuum filtration was carried out to obtain filter cake N-(4-nitrophenyl)oxetan-3-amine (268mg, 97%), (ES, m/z): 195.01 [M+H] + .
  • Step b Add the filter cake N-(4-nitrophenyl)oxa-3-amine (268mg, 1.380mmol) and methanol (15mL) obtained in the previous step into the reaction flask, add 10% Pd/C, Stir for 4h after H 2 replacement. Pd/C was filtered off with suction, and the filtrate was spin-dried to obtain N-1-(oxetan-3-yl)benzene-1,4-diamine solid product (110mg), (ES, m/z): 164.92[M +H] + .
  • Steps a to c refer to the first to third step method in Example 1 of patent CN108794484B to prepare (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-[1,2 ,4] Triazolo[4,3-a]pyrazine-3-carboxylic acid, (ES, m/z): 346.02 [M+H] + .
  • Steps a to c refer to the process steps of Intermediate Preparation Example 25 to prepare 6-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)- [1,2,4]Triazolo[4,3-a]pyrazine-3-carboxylic acid, (ES, m/z): 364.03[M+H] + .
  • reaction solution was mixed with water (20 mL), the mixture was extracted with EA (15 mL ⁇ 2), and the combined organic phase was washed with H 2 O (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure
  • the residue was eluted with a column chromatography silica gel column, first with 1% (v/v) MeOH-DCM, and then with 2% (v/v) MeOH-DCM.
  • Example 18 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-(4-(4-(2-(2 -Hydroxyacetyl)piperazin-1-yl)methyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (compound 18)
  • Step a Add 3-(4-aminophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (442mg, 1.528mmol) (Intermediate B5) 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (middle Body A2, 460mg, 1.270mmol) and TBTU (491mg, 1.528mmol) in anhydrous DMF (5mL) solution, then DIPEA (494mg, 3.819mmol) was added dropwise at 0°C, and the reaction was stirred overnight at room temperature for 14h.
  • DIPEA 494mg, 3.819mmol
  • Step b The tert-butyl 3-(4-(5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo [1,5-a]pyrimidine-3-carboxamido)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate solid crude was dissolved in DCM (25mL), added CF 3 COOH (5 mL) was stirred at room temperature for 3 h. Rotate the reaction solution to dryness, add water to dilute and adjust the alkalinity with ammonia water. A solid precipitates out.
  • Step c Add glycolic acid (35mg, 0.450mmol) to N-(4-(3,6-diazabicyclo[3.1.1]heptyl-3-yl)phenyl)-5-((2R, 4S)-2-(2,5-Difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (200mg, 0.375mmol) and TBTU (145mg, 0.450mmol) in anhydrous DMF (5mL) solution, then DIPEA (146mg, 1.125mmol) was added dropwise at 0°C, and the reaction was stirred at room temperature for 4h.
  • DIPEA 146mg, 1.125mmol
  • the reaction solution was mixed with water (30 mL), the mixture was extracted with EA (20 mL ⁇ 2), and the combined organic phase was washed with H 2 O (30 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure The residue was obtained and eluted with a column chromatography silica gel column, first with 1% MeOH-DCM, and then with 2% MeOH-DCM.
  • Step a Add 6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (178mg, 0.607mmol) (Intermediate B8) to the compound containing 5- ((2R,4S)-2-(2,5-Difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate A2 , 200mg, 0.552mmol) and TBTU (217mg, 0.607mmol) in anhydrous DMF (5mL) solution, then DIPEA (217mg, 1.656mmol) was added dropwise at 0°C, and the reaction was stirred overnight at room temperature for 14h.
  • DIPEA 217mg, 1.656mmol
  • Step b The tert-butyl 6-(4-(5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo [1,5-a]pyrimidine-3-carboxamido)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate solid crude was dissolved in DCM (6mL), and CF 3 was added COOH (2mL) was stirred at room temperature for 3h. Rotate the reaction solution to dryness, add water to dilute and adjust the alkalinity with ammonia water. A solid precipitates out.
  • Step c Add glycolic acid (37mg, 0.490mmol) to N-(4-(2,6-diazaspiro[3.3]heptyl-2-yl)phenyl)-5-((2R,4S )-2-(2,5-Difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (218mg, 0.409mmol) and TBTU( 157 mg, 0.490 mmol) in anhydrous DMF (10 mL) solution, then DIPEA (158 mg, 1.226 mmol) was added dropwise at 0° C., and the reaction was stirred at room temperature for 4 h.
  • DIPEA 158 mg, 1.226 mmol
  • reaction solution was mixed with water (100 mL), extracted with EA (80 mL ⁇ 2), and the organic phases were combined; the organic phase was washed with H 2 O (100 mL), brine (110 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure
  • reaction solution was mixed with water (100 mL), extracted with EA (80 mL ⁇ 2), and the organic phases were combined; the organic phase was washed with H 2 O (100 mL), brine (110 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure
  • kinase buffer (1X kinase buffer (Cisbio, Cat#62EZBFDD), pH 7.5; 5mM MgCl 2 , 1mM DTT) to the negative control well
  • centrifuge at 1000 rpm 30 seconds Seal the plate and incubate the plate in a constant temperature incubator at 25°C for 30 minutes.
  • TK-Sub-biotin (Cisbio, Cat#61TKOBL) and ATP (Sigma, Cat#R0441) substrate solutions and add the substrate mixed solution to a 384-well plate, and centrifuge at 1000 rpm for 30 seconds. Seal the plate and incubate the plate in a constant temperature incubator at 25°C for 60 minutes.
  • TK antibody and XL665 were diluted, mixed and added to the assay plate, and centrifuged at 1000 rpm for 30 seconds. Seal the plate and incubate the plate in a constant temperature incubator at 25°C for 60 minutes. Place the assay plate on the Envision machine for reading. (HTRF 665/615 ratio: 665nm signal value/615nm signal value)
  • Inhibition rate (Ratio negative control well -Ratio compound well ) / (Ratio negative control well -Ratio no enzyme control well ) ⁇ 100%
  • the data was fitted in XLFit excel plug-in version 5.4.0.8 to obtain IC 50 values.
  • Reference compound are included in each plate, and an IC 50 less than 3 times each time.
  • RXDX-101, LOXO-195, and LOXO-101 are all disclosed compounds, and are commercially available products (pharmaceuticals or chemical grade products).
  • the compound of the present invention exhibits high kinase inhibitory activity in a variety of kinases, and the activity in TRKA, TRKB, TRKC and TRKC-G696A is better than or equivalent to RXDX-101, LOXO-195 and LOXO-101, while The inhibitory activity of multiple mutant resistant kinases (G595R, G667C, G623R) is significantly better than RXDX-101, LOXO-195 and LOXO-101.
  • the compound was diluted with DMSO to a certain concentration, and was diluted in a 4-fold gradient. Add a certain concentration of compound, enzyme solution and DMSO to a 384-well plate, and incubate at room temperature for 10 minutes; add fluorescein-labeled peptide, ATP (sigma, Cat. No.: A7699-1G, Lot No.: 987-65-5) 28 Incubate for a certain time at °C; add stop solution. reading.
  • OD optical density
  • Inhibition ratio (control wells OD- test hole OD) / (control wells OD- blank wells OD) * 100%, according to the inhibition rate at each concentration, using SPSS software to calculate the median inhibitory concentration 50 value IC.
  • Test Example 4 Study on the mechanism of the compound in vivo
  • the administration volume is 10ml/kg.
  • Compound No. 4 uses "3%DMSO+96%HP- ⁇ -CD(0.5g/mL)+1%HCL" to configure to the required dosage. Drug concentration.
  • the other groups were given 100 mg/kg of compound No. 4 of the present invention, and tumor tissues were taken and frozen at 0.25h, 1h, 4h, 8h, 12h and 24h, respectively.
  • Test Example 5 In vivo pharmacodynamic experiment of the compound on NTRK mutation drug-resistant tumor model
  • Animal body weight Weigh the animal every morning before administration. A weight loss greater than 20% is defined as a toxic reaction to the drug (observed until the day after the last administration);
  • T/C(%) TRTV/CRTV ⁇ 100% (TRTV: RTV in the administration group, CRTV: RTV in the control group);
  • Tumor growth inhibition rate [1-(Ti-T0)/(Vi-V0)] ⁇ 100%.
  • Ti represents the average tumor volume of a certain drug group on a certain day
  • T0 is the average tumor volume of the drug group at the beginning of the drug
  • Vi is the average tumor volume of the vehicle control group on a certain day (the same day as Ti)
  • V0 is The average tumor volume of the vehicle control group at the start of administration
  • Tumor inhibition rate (average tumor weight of the control group-average tumor weight of the administration group)/average tumor of the control group Weight ⁇ 100%.
  • the body weight of each compound and each dose group has a rising trend, and the rising trend is more obvious than that of the control group.
  • the body weight of each compound in each dose group increased significantly, which may be related to the compound, or may be due to the inhibition of tumor growth, which made the mice better and the weight gain was obvious. The results are shown in Table 5.
  • the body weight of each compound and each dose group has a rising trend, and the rising trend is more obvious than that of the control group.
  • the body weight of each compound in each dose group increased significantly, which may be related to the compound, or may be due to the inhibition of tumor growth, which made the mice better and the weight gain was obvious. The results are shown in Table 6.

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Abstract

本发明提供一种如式(I)所示的化合物或其互变异构体、立体异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，对多种激酶(例如，TRK、ALK、ROS1)及其突变体，特别是对TRK及其突变形式显现了优良的激酶抑制活性，体外细胞抑制活性试验及体内抗肿瘤模型试验显示，这些化合物对多种含有TRK突变的细胞及肿瘤具有较强的抑制作用，且安全性良好，作为药物具有较好的临床价值。

Description

氮杂稠环酰胺类化合物及其用途
相关申请的引用
本发明要求2020年5月15日在中国提交的、名称为“吡唑并嘧啶酰胺化合物及其用途”、申请号为202010411386.0的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。
技术领域
本发明属于医药技术领域，具体而言涉及一类具有激酶抑制活性的氮杂稠环酰胺类化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，及含有其的药物组合物及作为预防和/或治疗TRK介导的疾病的药物的用途。
背景技术
原肌球蛋白相关激酶或原肌球蛋白受体激酶(Tropomyosin-related kinase或Tropomyosin receptor kinase，TRK)是一类神经生长因子受体，其家族由高度同源性的TRKA、TRKB和TRKC三个亚型组成，分别由神经营养性受体酪氨酸激酶1(NTRK1)、NTRK2和NTRK3基因编码。当TRK受体蛋白与相应配体结合，可通过激活下游信号途径，例如RAS/MAPK通路、PLCγ通路和PI3K通路，实现不同生理功能。TRK家族蛋白正常情况下主要表达于神经组织，参与神经细胞的分化和存活，以及轴突和树突的形成，在胚胎发育和神经系统正常功能的维持中起着重要的作用。
TRK激酶在恶性肿瘤中通过多种机制激活，主要是结构重排和表达的改变。例如，TRK激酶的编码基因NTRK与其它的基因重排产生融合癌基因，导致TRK激酶在结构上和表达上发生改变，不再受到神经生长因子配体的调节和控制，发生组成型激活，促进肿瘤发生发展。此外，基因测序结果也表明，TRK激酶与多种肿瘤的发生、转移和恶化也有密切的关系，并在多种肿瘤中表达，如非小细胞肺癌、结直肠癌、黑色素瘤、胆囊癌、甲状腺癌、恶性胶质瘤等。
目前，第一代TRK抑制剂Larotrectinib(LOXO-101)和Entrectinib(RXDX-101)分别于2018年和2019年获美国食品及药物管理局(FDA)批准上市。Larotrectinib是一种强效、口服、选择性原肌球蛋白受体激酶抑制剂，其疗效数据早在2017年6月的ASCO会议就已公布，在I期和II期临床试验中，共招募了55例受试者，其中46例可评估的患者整 体反应率(ORR)达78％。Entrectinib是TRK、ROS1和ALK蛋白强效抑制剂，且可以通过血脑屏障，在I期临床试验中，24个可评估患者的ORR为79％。
与其它靶向药物类似，TRK抑制剂也面临着耐药问题。NTRK激酶区突变会引起TRK家族蛋白激酶域构象改变或与ATP结合亲和力改变，从而影响TRK抑制剂与靶标结合，突变类型有G595R、G639R、G667C等。为解决第一代TRK抑制剂的耐药问题，第二代TRK抑制剂如LOXO-195、TPX-005等已在研究中。
Figure PCTCN2021093930-appb-000001
发明内容
本发明的目的在于，提供一类具有优良TRK(野生型和突变型)抑制活性、结构新颖的氮杂稠环酰胺类化合物或其互变异构体、立体异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐。
本发明的另一个目的在于，提供一类相比已知化合物具有更好的TRK突变肿瘤细胞抑制活性、结构新颖的氮杂稠环酰胺类化合物或其互变异构体、立体异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐。
本发明的另一个目的在于，提供一类相比已知化合物具有更好的TRK(野生型和突变型)抑制活性及TRK突变肿瘤细胞抑制活性、结构新颖的氮杂稠环酰胺类化合物或其互变异构体、立体异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐。
本发明的另一个目的在于，提供一类相比已知化合物具有更好的TRK突变肿瘤细胞抑制活性及体内抗肿瘤活性的氮杂稠环酰胺类化合物或其互变异构体、立体异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐。
本发明的另一个目的在于，提供一类相比已知化合物具有更好的TRK突变肿瘤细胞抑 制活性及体内抗肿瘤活性、及更好的安全性的氮杂稠环酰胺类化合物或其互变异构体、立体异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐。
本发明的另一个目的在于，提供一类相比已知化合物具有更好的TRK(野生型和突变型)抑制活性、TRK突变肿瘤细胞抑制活性及体内抗肿瘤活性、及更好的安全性的氮杂稠环酰胺类化合物或其互变异构体、立体异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐。
具体来说，本发明提供一种式(I)所示的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，
Figure PCTCN2021093930-appb-000002
其中，X选自：键、-O-、-S-、-NH-或-CH 2-；
Y，Y 1，Y 2，Y 3，Y 4各自独立的选自：-CH-、N或C；
X 2选自：键、-(CH 2) p-或-NH-，其中，p为1、2、3或4；
Figure PCTCN2021093930-appb-000003
表示：键存在或不存在；
R选自：C 5～12的芳基或杂芳基，其中每个芳基或杂芳基是未被取代的或被至少一个选自R 1的取代基取代；
R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、-NHC 1～6烷基、-N(C 1～6烷基) 2、氰基、未被取代或被至少一个R 1a取代的C 1～6烷基、未被取代或被至少一个R 1a取代的C 1～6烷氧基、未被取代或被至少一个R 1a取代的C 3～6环烷基、未被取代或被至少一个R 1a取代的C 3～6环烷氧基或-SC 1～6烷基；
R 1a在每次出现时，各自独立地选自：C 1-6烷基、C 1-6烷氧基、硝基、卤素、-OH、氨基、-NHC 1～6烷基、-N(C 1～6烷基) 2或氰基；
R 2选自：H、卤素、羟基、氨基、或取代或未取代的C 1～6烷基，所述取代是指被1、2或3个选自卤素或羟基的取代基所取代；
R 3选自：H、卤素、-OH、氨基、C 1～6烷基或C 1～6烷氧基；
环A选自：环烷基、杂环烷基、桥环基、杂桥环基、并环基、杂并环基、螺环基、杂螺环基，其中所述杂环烷基、杂桥环基、杂并环基和杂螺环基中的杂原子独立地选自O、S或N，所述杂原子数选自1、2、3或4个；
R 4位于环A上的任意可取代位置，其独立的选自：-H、-OH、卤素、-CN、氧代基、取代或未取代的C 1～6烷基、-(CH 2) m-OH、-(CH 2) m-COOH、-(CH 2) m-CO-NH 2、-CO-(CH 2) m-NH 2、-CO-CR 4aR 4b-OH或-CO-R 4b；其中，所述氧代基是指相同取代位的两个H被同一个O替代形成双键；m选自1、2、3或4；R 4a选自氢、未取代或取代的C 1～4烷基；R 4b选自H、未取代或取代的C 1～6烷基或未取代或取代的C 3～6环烷基，所述取代的取代基独立地选自-OH、-NH 2、卤素，取代基个数选自1、2或3；
n选自1、2、3或4。
在一个实施方案中，本发明所提供的式(I)所示的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，其中，R选自：C 5～9的芳基或杂芳基，其中每个芳基或杂芳基是未被取代的或被至少一个选自R 1的取代基取代；或者，R选自：C 5～6的芳基或杂芳基，其中每个芳基或杂芳基是未被取代的或被至少一个选自R 1的取代基取代。
在一个实施方案中，所述化合物具有如式(I-1)或(I-2)所示的结构：
Figure PCTCN2021093930-appb-000004
其中，R 1，R 2，R 3，R 4，X，X 2，Y，Y 1，Y 2，Y 3，Y 4，环A和n同本发明式(I)化合物所述，X 1选自：-CH-或N。
在一个实施方案中，所述化合物具有如式(I-A)所示的结构：
Figure PCTCN2021093930-appb-000005
其中，R 1，R 2，R 3，R 4，X，X 1，X 2，Y，Y 1，Y 2，Y 3，Y 4，环A和n同本发明式(I-1)或(I-2)化合物所述。
在一个实施方案中，所述化合物具有如式(I-A-1a)、(I-A-1b)或(I-A-1c)所示的结构：
Figure PCTCN2021093930-appb-000006
其中，R 1，R 2，R 3，R 4，X，X 1，X 2，环A和n同本发明式(I-1)或(I-2)化合物所述。
在一个实施方案中，所述化合物具有如式(I-B)所示的结构：
Figure PCTCN2021093930-appb-000007
其中，R 1，R 2，R 3，R 4，X 1，X 2，Y，Y 1，Y 2，Y 3，Y 4，环A和n同本发明式(I-1)或(I-2)化合物所述。
在一个实施方案中，所述化合物具有如式(I-B-1a)、(I-B-1b)或(I-B-1c)所示的结构：
Figure PCTCN2021093930-appb-000008
Figure PCTCN2021093930-appb-000009
其中，R 1，R 2，R 3，R 4，X 1，X 2，环A和n同本发明式(I-1)或(I-2)化合物所述。
在一个实施方案中，所述化合物具有如式(I-C)所示的结构：
Figure PCTCN2021093930-appb-000010
其中，R 1，R 2，R 3，R 4，X 1，X 2，Y，Y 1，Y 2，Y 3，Y 4，环A和n同本发明式(I-1)或(I-2)化合物所述。
在一个实施方案中，所述化合物具有如式(I-C-1a)、(I-C-1b)或(I-C-1c)所示的结构：
Figure PCTCN2021093930-appb-000011
其中，R 1，R 2，R 3，R 4，X 1，X 2，环A和n同本发明式(I-1)或(I-2)化合物所述。
在一个实施方案中，本发明提供的化合物(式(I)化合物、式(I-1)化合物、式(I-2)化合物、式(I-A)化合物、式(I-A-1a)化合物、式(I-A-1b)化合物、式(I-A-1c)化合物、式(I-B)化合物、式(I-B-1a)化合物、式(I-B-1b)化合物、式(I-B-1c)化合物、式(I-C)化合物、式(I-C-1a)化合物、式(I-C-1b)化合物、式(I-C-1c)化合物)其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，其中，R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、氰基、未被取代或被至少一个R 1a取代的C 1～6烷基、未被取代或被至少一个R 1a 取代的C 1～6烷氧基、未被取代或被至少一个R 1a取代的C 3～6环烷基或未被取代或被至少一个R 1a取代的C 3～6环烷氧基；或者，R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、氰基、未被取代或被至少一个R 1a取代的C 1～6烷基或未被取代或被至少一个R 1a取代的C 1～6烷氧基；或者，R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、C 1～6烷基或C 1～6烷氧基；或者，R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、C 1～3烷基或C 1～3烷氧基；或者，R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、甲基、乙基、甲氧基或乙氧基；或者，R 1在每次出现时，各自独立地选自：氢、F、Cl、-OH、甲基或甲氧基；或者，R 1在每次出现时，各自独立地选自：F、-OH、甲基或甲氧基。
在一个实施方案中，R 1a在每次出现时，各自独立地选自：C 1-3烷基、C 1-3烷氧基、硝基、卤素、-OH、氨基、-NHC 1～6烷基、-N(C 1～6烷基) 2或氰基；或者，R 1a选自：卤素、-OH、氨基、-NHC 1～3烷基、-N(C 1～3烷基) 2或氰基；或者，R 1a选自：卤素、-OH、氨基或氰基；或者，R 1a选自：F、Cl或-OH。
在一个实施方案中，本发明提供的化合物(式(I)化合物、式(I-1)化合物、式(I-2)化合物、式(I-A)化合物、式(I-A-1a)化合物、式(I-A-1b)化合物、式(I-A-1c)化合物、式(I-B)化合物、式(I-B-1a)化合物、式(I-B-1b)化合物、式(I-B-1c)化合物、式(I-C)化合物、式(I-C-1a)化合物、式(I-C-1b)化合物、式(I-C-1c)化合物)其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，其中，R 2选自：H、F、OH或取代或未取代的C 1～6烷基，所述取代是指被1、2或3个选自卤素或羟基的取代基所取代；或者，R 2选自H、F、-OH或C 1～6烷基；或者，R 2选自H、F、-OH或C 1～3烷基；或者，R 2选自H或F。
在一个实施方案中，本发明提供的化合物(式(I)化合物、式(I-1)化合物、式(I-2)化合物、式(I-A)化合物、式(I-A-1a)化合物、式(I-A-1b)化合物、式(I-A-1c)化合物、式(I-B)化合物、式(I-B-1a)化合物、式(I-B-1b)化合物、式(I-B-1c)化合物、式(I-C)化合物、式(I-C-1a)化合物、式(I-C-1b)化合物、式(I-C-1c)化合物)其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，其中，X 1选自-CH-或N，R 1选自F或-OCH 3。
在一个实施方案中，X 1选自-CH-，R 1选自F；或者，X 1选自N，R 1选自-OCH 3。
在一个实施方案中，所述化合物具有如式(I-D)所示的结构：
Figure PCTCN2021093930-appb-000012
其中，R 3，R 4，X 2，Y，Y 1，Y 2，Y 3，Y 4，环A和n同本发明式(I)化合物所述。
在一个实施方案中，所述化合物具有如式(I-D-a)、式(I-D-b)或式(I-D-c)所示的结构：
Figure PCTCN2021093930-appb-000013
其中，R 3，R 4，X 2，环A和n同本发明式(I)化合物所述。
在一个实施方案中，本发明提供的化合物(式(I)化合物、式(I-1)化合物、式(I-2)化合物、式(I-A)化合物、式(I-A-1a)化合物、式(I-A-1b)化合物、式(I-A-1c)化合物、式(I-B)化合物、式(I-B-1a)化合物、式(I-B-1b)化合物、式(I-B-1c)化合物、式(I-C)化合物、式(I-C-1a)化合物、式(I-C-1b)化合物、式(I-C-1c)化合物、式(I-D)化合物、式(I-D-a)化合物、式(I-D-b)化合物、式(I-D-c)化合物)其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，其中，R 3选自：H、卤素、-OH、氨基、C 1～3烷基或C 1～3烷氧基；或者，R 3选自：H、F、Cl、-OH、甲基或甲氧基；或者，R 3选自：H或F。
在一个实施方案中，所述化合物具有如式(I-D-1a)、式(I-D-1b)或式(I-D-1c)所示的结构：
Figure PCTCN2021093930-appb-000014
其中，R 4，X 2，环A和n同本发明式(I)化合物所述。
在一个实施方案中，所述化合物具有如式(I-C-1a-1)所示的结构：
Figure PCTCN2021093930-appb-000015
其中，R 4，X 2、环A和n同本发明式(I)化合物所述。
在一个实施方案中，所述化合物具有如式(I-C-1a-2)所示的结构：
Figure PCTCN2021093930-appb-000016
其中，R 4，X 2、环A和n同本发明式(I)化合物所述。
在一个实施方案中，本发明提供的化合物(式(I)化合物、式(I-1)化合物、式(I-2)化合物、式(I-A)化合物、式(I-A-1a)化合物、式(I-A-1b)化合物、式(I-A-1c)化合物、式(I-B)化合物、式(I-B-1a)化合物、式(I-B-1b)化合物、式(I-B-1c)化合物、式(I-C)化合物、式(I-C-1a)化合物、式(I-C-1b)化合物、式(I-C-1c)化合物、式(I-D)化合物、、式(I-D-a)化合物、式(I-D-b)化合物、式(I-D-c)化合物、式(I-D-1a)化合物、式(I-D-1b)化合物、式(I-D-1c)化合物、式(I-C-1a-1)化合物、和式(I-C-1a-2)化合物，下同)其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，其中，环A选自：C 3-6环烷基、4-6元杂环烷基、C 6-8桥环基、6-8元杂桥环基、C 8-10并环基、8-10元杂并环基、C 7-12单螺环基、7-12元杂单螺环 基；或者，环A选自：4-6元杂环烷基、6-8元杂桥环基、8-10元杂并环基、7-12元杂单螺环基；其中所述杂环烷基、杂桥环基、杂并环基和杂单螺环基中的杂原子独立地选自O、S或N，所述杂原子个数选自1、2、3或4个；或者，环A选自如下结构：
Figure PCTCN2021093930-appb-000017
或者，环A选自如下结构：
Figure PCTCN2021093930-appb-000018
或者，环A选自如下结构：
Figure PCTCN2021093930-appb-000019
或者，环A选自如下结构：
Figure PCTCN2021093930-appb-000020
或者，环A选自如下结构：
Figure PCTCN2021093930-appb-000021
在一个实施方案中，本发明提供的化合物(式(I)化合物、式(I-1)化合物、式(I-2)化合物、式(I-A)化合物、式(I-A-1a)化合物、式(I-A-1b)化合物、式(I-A-1c)化合物、式(I-B)化合物、式(I-B-1a)化合物、式(I-B-1b)化合物、式(I-B-1c)化合物、式(I-C)化合物、式(I-C-1a)化合物、式(I-C-1b)化合物、式(I-C-1c)化合物、式(I-D) 化合物、、式(I-D-a)化合物、式(I-D-b)化合物、式(I-D-c)化合物、式(I-D-1a)化合物、式(I-D-1b)化合物、式(I-D-1c)化合物、式(I-C-1a-1)化合物、和式(I-C-1a-2)化合物)其互变异构体、立体异构体、光学异构体、溶剂化物、同位素衍生物、氮氧化物、前药、药学上可接受的盐，其中，R 4独立的选自：-H、-OH、卤素、-CN、氧代基、取代或未取代的C 1～6烷基、-COOH、-CONH 2、-CO-CR 4aR 4b-OH或-CO-R 4b；或者，R 4独立的选自：-H、-OH、卤素、-CN、氧代基、取代或未取代的C 1～6烷基、-CO-CR 4aR 4b-OH或-CO-R 4b；或者，R 4独立的选自：-H、-OH、卤素、取代或未取代的C 1～6烷基、-CO-CR 4aR 4b-OH或-CO-R 4b；或者，R 4独立的选自：-H、-OH、卤素、取代或未取代的C 1～3烷基、-CO-CR 4aR 4b-OH或-CO-R 4b；或者，R 4独立的选自：-H、-OH、取代或未取代的C 1～3烷基、-CO-CR 4aR 4b-OH或-CO-R 4b；或者，R 4独立的选自：-CO-CR 4aR 4b-OH或-CO-R 4b；其中，所述氧代基是指相同取代位的两个H被同一个O替代形成双键；R 4a选自氢、未取代或取代的C 1～4烷基；R 4b选自未取代或取代的C 1～6烷基或未取代或取代的C 3～6环烷基，所述取代的取代基独立地选自-OH、-NH 2、或卤素，取代基个数选自1、2或3；或者，所述取代的取代基独立地选自-OH或F，取代基个数选自1、2或3。
在一个实施方案中，本发明提供的化合物或(及)其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-A-1a)所示的结构：
Figure PCTCN2021093930-appb-000022
其中，X选自：键、-O-、-S-、-NH-或-CH 2-；
X 1选自：-CH-或N；
X 2选自：键、-(CH 2) p-或-NH-，其中，p为1、2、3或4；
R 1选自：H、卤素、-OH、氨基、C 1～6烷基或C 1～6烷氧基；
R 2选自：H、F、OH或取代或未取代的C 1～6烷基，所述取代是指被1、2或3个选自卤素或羟基的取代基所取代；
R 3选自：H、卤素、-OH、氨基、C 1～6烷基或C 1～6烷氧基；
环A选自：环烷基、杂环烷基、桥环基、杂桥环基、并环基、杂并环基、螺环基、杂螺环基，其中所述杂环烷基、杂桥环基、杂并环基和杂螺环基中的杂原子独立地选自O、S或N，所述杂原子数选自1、2、3或4个；
R 4位于环A上的任意可取代位置，其独立的选自：-H、-OH、卤素、-CN、氧代基、取代或未取代的C 1～6烷基、-(CH 2) m-OH、-(CH 2) m-COOH、-(CH 2) m-CO-NH 2、-CO-(CH 2) m-NH 2、-CO-CR 4aR 4b-OH或-CO-R 4b；其中，所述氧代基是指相同取代位的两个H被同一个O替代形成双键；m选自1、2、3或4；R 4a选自氢、未取代或取代的C 1～4烷基；R 4b选自H、未取代或取代的C 1～6烷基或未取代或取代的C 3～6环烷基，所述取代的取代基独立地选自-OH、-NH 2、卤素，取代基个数选自1、2或3；
n选自1、2、3或4。
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-B-1a)所示的结构：
Figure PCTCN2021093930-appb-000023
其中，R 1，R 2，R 3，R 4，X 1，X 2、环A和n同本发明式(I-A-1a)化合物所述。
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-D-1a)所示的结构：
Figure PCTCN2021093930-appb-000024
其中，R 1，R 3，R 4，X 1，X 2、环A和n同本发明式(I-A-1a)化合物所述。
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-C-1a)所示的结构：
Figure PCTCN2021093930-appb-000025
其中，R 1，R 3，R 4，X 1，X 2、环A和n同本发明式(I-A-1a)化合物所述。
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、 同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-C-1a-1)所示的结构：
Figure PCTCN2021093930-appb-000026
其中，R 4，X 2、环A和n同本发明式(I-A-1a)化合物所述。
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如式(I-C-1a-2)所示的结构：
Figure PCTCN2021093930-appb-000027
其中，R 4，X 2、环A和n同本发明式(I-A-1a)化合物所述。
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，环A选自：C 3-6环烷基、4-6元杂环烷基、C 6-8桥环基、6-8元杂桥环基、C 8-10并环基、8-10元杂并环基、C 7-12单螺环基、7-12元杂单螺环基，其中所述杂环烷基、杂桥环基、杂并环基和杂单螺环基中的杂原子独立地选自O、S或N，所述杂原子个数选自1、2或3个。
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，环A选自如下结构：
Figure PCTCN2021093930-appb-000028
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，R 4独立的选自：-H、-OH、卤素、-CN、氧代基、取代或未取代的C 1～6烷基、-COOH、-CONH 2、-CO-CR 4aR 4b-OH或-CO-R 4b，其中，所述氧代基是指相同取代位的两个H被同一个O替代形成双键；R 4a选自氢、未取代或取代的 C 1～4烷基；R 4b选自未取代或取代的C 1～6烷基或未取代或取代的C 3～6环烷基，所述取代的取代基独立地选自-OH、-NH 2、卤素，取代基个数选自1、2或3。
在一个实施方案中，本发明提供的化合物或其互变异构体、光学异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其中，所述化合物具有如下结构：
Figure PCTCN2021093930-appb-000029
Figure PCTCN2021093930-appb-000030
Figure PCTCN2021093930-appb-000031
Figure PCTCN2021093930-appb-000032
Figure PCTCN2021093930-appb-000033
Figure PCTCN2021093930-appb-000034
本发明另一方面还提供了一种药物组合物，其包含本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐。
本发明另一方面还提供了一种药物组合物，其包含本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐及药学上可接受的辅料。
本发明另一方面还提供了本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物在制备用于预防和/或治疗通过TRK介导的疾病的药物中的用途。
在一个实施方案中，所述疾病选自疼痛疾病、细胞增殖性疾病、炎症疾病、神经退行性疾病或感染疾病。
在一个实施方案中，所述疾病通过TRKA、TRKB或TRKC中的一个、两个或三个介导。
在一个实施方案中，所属疾病涉及NTRK基因、TRK蛋白、或它们的表达、活性或水平失调；优选地，涉及NTRK基因融合、扩增、重排、突变或高表达；进一步优选地，涉及NTRK基因融合或突变。
本发明另一方面还提供了本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物，用于预防和/或治疗通过TRK介导的疾病。
本发明另一方面还提供了一种预防和/或治疗通过TRK介导的疾病的方法，包括：向患者施用本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物。
本发明另一方面还提供了本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物作为药物的用途。
在一个实施方案中，所述药物用于治疗TRK、ALK、ROS1或它们的组合介导的疾病。
在一个实施方案中，所属药物用于治疗疼痛疾病、细胞增殖性疾病、炎症疾病、神经退行性疾病或感染疾病。
本发明另一方面还提供了本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物在制备TRK激酶抑制剂、ALK激酶抑制剂、或ROS1激酶抑制剂中的用途。
在一个实施方案中，所述抑制剂用于治疗TRK、ALK、ROS1或其组合介导的疾病。
在一个实施方案中，所属抑制剂用于治疗疼痛疾病、细胞增殖性疾病、炎症疾病、神经退行性疾病或感染疾病。
本发明另一方面还提供了本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物在制备用于治疗疼痛疾病、细胞增殖性疾病、炎症疾病、神经退行性疾病或感染疾病的药物的用途。
在一个实施方案中，所述疼痛疾病、细胞增殖性疾病、炎症疾病、神经退行性疾病或感染疾病涉及NTRK基因、TRK蛋白、或它们的表达、活性或水平失调；优选涉及NTRK基因融合、扩增、重排、突变或高表达；进一步优选涉及NTRK基因融合或突变。
在一个实施方案中，所述疼痛疾病疾病、细胞增殖性疾病、炎症疾病、神经退行性疾病或感染疾病涉及ROS1基因、ROS1蛋白、或它们的表达、活性或水平失调；优选涉及ROS1基因融合、扩增、重排、突变或高表达；进一步优选涉及ROS1基因融合或突变。
在一个实施方案中，所述疼痛疾病、细胞增殖性疾病、炎症疾病、神经退行性疾病或感染疾病涉及TRK、ALK、ROS1或它们的组合的基因、蛋白、或它们的表达、活性或水平失调；优选涉及NTRK、ALK、ROS1或它们的组合基因融合、扩增、重排、突变或高表达；进一步优选涉及NTRK、ALK、ROS1或它们的组合基因融合或突变。
在一个实施方案中，所述细胞增殖性疾病为肿瘤或癌症。
在一个实施方案中，所述肿瘤或癌症为实体瘤和血液肿瘤，优选为实体瘤。
在一个实施方案中，所述肿瘤或癌症是恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、胰腺癌、脑胶质瘤、结肠直肠癌、黑色素瘤、头和颈部的癌症、胆囊癌、甲状腺癌、恶性胶质瘤、胃癌、神经细胞瘤或唾液腺癌；优选地，所述肺癌为非小细胞肺癌。
本发明另一方面还提供了本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物，用于治疗疼痛、细胞增殖性疾病、炎症、神经退行性疾病或感染疾病。
本发明另一方面还提供了一种治疗疾病的方法，包括：向患者施用本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物，其中，所述疾病为疼痛、细胞增殖性疾病、炎症、神经退行性疾病或感染疾病。
在一个实施方案中，本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物与另一种、两种或多种具有治疗细胞增殖性疾病的药物组合使用。
本发明另一方面还提供了本发明所述的化合物或其互变异构体、光学异构体、立体异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物在制备用于预防和/或治疗TRK、ALK、ROS1或它们的组合介导的疾病的药物的用途。
在一个实施方案中，所述疾病选自疼痛疾病、细胞增殖性疾病、炎症疾病、神经退行性疾病或感染疾病。
在一个实施方案中，所述疾病涉及TRK、ALK、ROS1或它们的组合的基因、蛋白、或它们的表达、活性或水平失调。
在一个实施方案中，所述疾病涉及NTRK、ALK、ROS1或它们的组合的基因融合、扩增、重排、突变或高表达；进一步优选涉及NTRK、ALK、ROS1或它们的组合的基因融合或突变。
本发明另一方面还提供了一种预防和/或治疗通过TRK、ALK、ROS1或它们的组合介导的疾病的方法，包括：向患者施用本发明所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或本发明药物组合物。
定义
除另有规定外，本发明所指的以下术语具有下述定义。
术语“烷基”指一价饱和脂肪族烃基团，包含1-20个碳原子的直链或支链基团，优选包含1-10个碳原子(即C 1-10烷基)，进一步优选包含1-8个碳原子(C 1-8烷基)，更优选包含1-6个碳原子(即C 1-6烷基)，例如“C 1-6烷基”指的是该基团为烷基，且碳链上的碳原子数量在1-6之间(具体地为1个、2个、3个、4个、5个或6个)。实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、新戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、正庚基、正辛基等。
术语“碳环基”或“碳环”表示含有3-12个碳原子的，单价或多价的饱和或部分不饱和单环、双环或者三环体系，其中单环、双环或三环中不包含芳香环。碳双环基包括桥环基、螺环基、并环基等。桥环基是指任意两个环公用两个直接相连或不直接相连的原子。
术语“环烷基”指的是具有特定碳原子数的单环饱和脂烃基，优选地包含3-12个碳原子(即C 3-12环烷基)，更优选包含3-10个碳原子(C 3-10环烷基)，进一步优选3-6个碳原子(C 3-6环烷基)、4-6个碳原子(C 4-6环烷基)、5-6个碳原子(C 5-6环烷基)。实例包括但不限于环丙基、环丁基、环戊基、环己基、甲基环丙基、2-乙基-环戊基、二甲基环丁基等。
术语“烷氧基”指-O-烷基，所述烷基的定义同上，即包含1-20个碳原子，优选地，包含1-10个碳原子，较佳地1-8个碳原子，更佳地1～6个碳原子(具体地为1个、2个、3个、4个、5个或6个)。代表的例子包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、1-甲基丙氧基、2-甲基丙氧基、叔丁氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基、1,1-二甲基丙氧基、1,2-二甲基丙氧基、2,2-二甲基丙氧基、1-乙基丙氧基等。
术语“卤素”或“卤代”是指F、Cl、Br、I。术语“卤代烷基”是指如上所定义的烷基中一个、两个或多个氢原子或全部氢原子被卤素取代。卤代烷基的代表性例子包括CCl 3、CF 3、CHCl 2、CH 2Cl、CH 2Br、CH 2I、CH 2CF 3、CF 2CF 3等。
术语“杂环基”指饱和或部分不饱和单环、双环或多环环状烃取代基，为非芳香结构，包含3-20个环原子，其中1个、2个、3个或更多个环原子选自N、O或S，其余环原子为C。优选包含3～12个环原子(C 3-12杂环基)，进一步优选包含3-10个环原子(C 3-10杂环基)，或3～8个环原子(C 3-8杂环基)，或3～6个环原子(C 3-6杂环基)，或4～6个环原子(C 4-6 杂环基)，或5～6个环原子(C 5-6杂环基)。杂原子优选1-4个，更优选1～3个(即1个、2个或3个)。单环杂环基的实例包括吡咯烷基、咪唑烷基、四氢呋喃基、二氢吡咯基、哌啶基、哌嗪基、吡喃基等。多环杂环基包括杂螺环基、杂并环基、杂稠环基和杂桥环基等的杂环基。
术语“杂环烷基”是指饱和的如上定义的“杂环基”，包含3-20个环原子，其中1个、2个、3个或更多个环原子选自N、O或S，其余环原子为C。优选包含3-12个环原子(C 3-12杂环烷基)，进一步优选包含3-10个环原子(C 3-10杂环烷基)，或3-8个环原子(C 3-8杂环烷基)，或3-7个环原子(C 3-7杂环烷基)，或3-6个环原子(C 3-6杂环烷基)，或4-6个环原子(C 4-6杂环烷基)，或5-6个环原子(C 5-6杂环烷基)。杂原子优选1-4个，更优选1～3个(即1个、2个或3个)。实例包括氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、四氢呋喃基、氧杂环己烷、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二噁烷基、二硫杂环己基、噁唑烷基、噻唑烷基、吡唑烷基、咪唑啉啶等。
术语“芳基”表示含有6-16个碳原子，或6-14个碳原子，或6-12个碳原子，或6-10个碳原子的单环、双环和三环的芳香碳环体系，优选6-10个碳原子，术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括但不限于苯基、萘基、蒽基、菲基或芘基等。
术语“杂芳基”表示含有5-12元结构，或优选5-10元结构，5-8元结构，更优选5-6元结构的芳香单环或者多环环状系统，其中1个、2个、3个或更多个环原子为杂原子且其余原子为碳，杂原子独立地选自O、N或S，杂原子数量优选为1个、2个或3个。杂芳基的实例包括但不限于呋喃基、噻吩基、噁唑基、噻唑基、异噁唑基、噁二唑基、噻二唑基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、硫代二唑基、三嗪基、酞嗪基、喹啉基、异喹啉基、喋啶基、嘌呤基、吲哚基、异吲哚基、吲唑基、苯并呋喃基、苯并噻吩基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、苯并咪唑基、苯并酞嗪基、吡咯并[2,3-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基等。
术语“药学上可接受的盐”或“可药用盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐。
术语“盐”包含选自无机酸制备的盐，也包括选自有机酸制备的盐。如果本发明的化合物为酸性的，则药学上可接受的无毒碱包括无机碱及有机碱制备的盐。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括构型异构体和构象异构体，其中，构型异构体又包括几何异构体(或顺反异构体)和光学异 构体(包含对映异构体和非对映异构体)。
几何异构体可以存在于本化合物中。本发明的化合物可以含有E或Z构型的碳-碳双键或碳-氮双键，其中术语“E”代表碳-碳或碳-氮双键的对侧的更高顺序取代基，术语“Z”代表碳-碳或碳-氮双键的同侧上的更高顺序取代基(利用Cahn-Ingold Prelog优先规则确定)。本发明的化合物还可以以“E”和“Z”异构体的混合物形态存在。将环烷基或杂环烷基周围的取代基称为顺式或反式构型。
光学异构体指的是分子结构完全相同，物理化学性质相近，但旋光性不同的物质。本发明的化合物在R或S构型中可以含有不对称取代的碳原子，其中术语“R”和“S”如IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem.(1976)45,13-10所定义。具有不对称取代的碳原子的化合物(具有相等数量的R和S构型)在那些碳原子处是外消旋的。具有过量的一种构型(相对于另一个)的原子使该构型存在更高数量，优选过量大约85％-90％，更优选过量大约95％-99％，更加优选过量大于大约99％。相应地，本发明包括外消旋混合物、相对和绝对光学异构体和相对与绝对光学异构体的混合物。
术语“氮氧化物”是指当化合物含有几个胺官能团时，可将1个或大于1个氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子上的N-氧化物。
术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。
术语“互变异构体”是指具有不同能量的可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(也称为质子转移互变异构体)包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组来进行的互相转化。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
术语“同位素衍生物”是指本发明的化合物可以以同位素示踪的或富集形式存在，含有一个或多个原子，这些原子的原子量或质量数不同于自然界中发现的最大量的原子的原子量或质量数。同位素可以是放射性或非放射性的同位素。原子例如氢、碳、磷、硫、氟、氯和碘的同位素包括但不局限于： 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl和 125I。含有这些和/或其它原子的其它同位素的化合物在本发明范围之内。
在另一个实施方案中，同位素标记的化合物含有氘( 2H)、氚( 3H)或 14C同位素。本发明的同位素标记的化合物可以利用本领域普通技术人员熟知的一般方法来制备。在这方面，相关的文献包括：Lizondo,J et al,Drugs Fut,21(11),1116(1996)；Brickner,S J et al,J Med Chem,39(3),673(1996)；Mallesham,B et al,Org Lett,5(7),963(2003)。
含有同位素的化合物已经用于药物研究，通过评价非同位素示踪的母体化合物的作用机 理和代谢途径，研究化合物的体内代谢结果(Blake et al,J.Pharm.Sci.64,3,367-391(1975))。在安全、有效的治疗药物设计方面，这种代谢研究是重要的，这是因为给予患者的体内活性化合物或因为母体化合物产生的代谢物被证明是毒性的或致癌的(Kushner et al,Can.J.Physiol.Pharmacol.,77,79-88(1999)；Foster et al,Advances in Drug Research Vol.14,pp.2-36,Academic press,London,1985；Kato et al,J.Labelled Comp.Radiopharmaceut.,36(10):927-932(1995))。
另外，含有非放射性活性同位素的药物，例如称为“重药物”的氘代药物，可以用于治疗相关的疾病和病症。存在于上面化合物中的同位素的量提高到其天然丰度以上被称作富集。富集的量的例子包括大约0.5，1，2，3，4，5，6，7，8，9，10，12，16，21，25，29，33，37，42，46，50，54，58，63，67，71，75，79，84，88，92，96至大约100mol％。
分子结构中任意可能的位点均可被同位素取代，得到同位素衍生物。例如，在分子中任意可能的位点可被氘( 2H)取代，得到氘代形式的衍生物。
用稳定同位素示踪的药物，可以改变药物的理化性质，例如pKa和脂质溶解度。如果同位素取代影响参与配体-受体相互作用的区域，那么这些效果和改变可以影响药物分子的药效响应。尽管稳定同位素示踪的分子的一些物理性能不同于未示踪的分子的物理性能，但化学和生物学特性是相同的，一种重要的不同是：由于重同位素的质量增加，涉及重同位素和另一个原子的任何键比轻同位素和该原子之间的相同的键更强。相应地，在代谢或酶催转化的位点结合同位素可以使所述反应潜在地减缓，相对于非同位素化合物，可以改变药物动力学特性或效果。
术语“前药”或“前体药物”是设计的活性药物的衍生物，其可以改善一些确定的、不合需要的物理或生物学性质。物理性能通常是相关的溶解度(过高或不足的脂质或水溶性)或稳定性，而有问题的生物学特性包括代谢太快或生物利用率差，这本身可能与物理化学性质相关。
前体药物通常如下制备：a)形成活性药物的酯、半酯、碳酸脂、硝酸酯、酰胺、异羟肟酸、氨基甲酸酯、亚胺、曼尼希碱、磷酸盐、磷酸酯和烯胺，b)用偶氮、糖苷、肽和醚官能团使药物功能化，c)使用药物的缩醛胺、半缩醛胺、聚合物、盐、复合物、磷酰胺、乙缩醛、半缩醛和缩酮形式。例如，参见Andrejus Korolkovas’s,“Essentials of Medicinal Chemistry”,John Wiley-Interscience Pulications,John Wiley and Sons,New York(1988),pp.97-118，本文结合其所有内容作为参考。酯可以利用本领域技术人员已知的一般方法，由含有羟基或羧基的底物来制备。这些化合物的典型反应是用另一个原子替代一个杂原子的取代。酰胺可以用类似的方式、由含有氨基或羧基的底物来制备。酯还可以与胺或氨反应，形成酰胺。制备酰胺的另一种方式是将羧酸和胺一起加热。
术语“药学上可接受的辅料”或“药学上可接受的载体”包含但不限于由美国食品与药物管理局、国家药品监督管理局等批准可接受用于人类或家养动物的任一佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料、着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“肿瘤”包含良性肿瘤、恶性肿瘤和交界性肿瘤，其中恶性肿瘤又统称为癌症。
在本文使用的术语“预防”是指当用于疾病或病症(例如癌症)时，与未施用化合物或药物(例如，本申请要求保护的组合产品)的受试者相比，所述化合物或药物能降低受试者体内的医学病症症状的频率或推迟其发病。
在本文中使用的术语“治疗”是指减轻、缓解或改善疾病或病症的症状，改善潜在的代谢引起的症状，抑制疾病或症状，例如阻止疾病或病症的发展、缓解疾病或病症、引起疾病或病症的消退、缓解疾病或病症引起的病况、或阻止疾病或病症的症状。
在本文中使用的术语“细胞增殖性疾病”是指其中的细胞群生长速率低于或高于给定生理状态和条件下的预期速率的病症。
在本发明中，使用的术语如下所述：
DCM：二氯甲烷；DIPEA：二异丙基乙胺；DMF：N,N-二甲基甲酰胺；EA：乙酸乙酯；NBS：N-溴代丁二酰亚胺；PE：石油醚；DMSO：二甲基亚砜；TBTU：O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸；BOP：苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐；ATP：5'-三磷酸腺苷；DTT：1,4-二硫苏糖醇；MTT：3-(4,5-二甲基-2-噻唑)-2,5-二苯基溴化四氮唑噻唑蓝。
基于药物化学知识，本发明化合物的氮氧化物、同位素衍生物、立体异构体、光学异构体、溶剂合物、前药等在体内外也能产生与本发明化合物类似的效果。
本发明的有益效果为：
本发明设计了一类结构新颖的化合物，体外激酶活性抑制试验显示：本发明化合物对多种激酶(例如，TRK、ALK、ROS1)及其突变体，特别是对TRK及其突变形式显现了优良的抑制活性；体外细胞抑制活性试验显示：本发明化合物对多种TRK突变的细胞具有较强的抑制作用，对6种细胞的抑制活性具有IC 50在10nM以下，优选在5nM以下，进一步优选在1nM以下；体内抑瘤试验结果显示：与对照化合物相比，本发明化合物具有更好的体内抗肿瘤效果，耐受性更好，成药可能性较高；体内作用机制研究试验显示：本发明化合物能够抑制肿瘤组织中的TRK，进而有效抑制PLCγ及AKT的磷酸化，抑制肿瘤组织生长。
附图说明
附图1本发明4号化合物对TRKA-G595R突变耐药荷瘤小鼠瘤组织内下游靶蛋白磷酸化的抑制作用时效关系western blot图。
具体实施方式
以下具体实施方式中涉及的原料、反应试剂、催化剂或溶剂，均可通过商业途径购买得到或现有技术常规方法制备得到。
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，通常按照常规条件或者按照制造厂商所建议的条件。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专业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之中。文中所示的较佳实施方法与材料仅做示范之用。
制备例A：6-氯咪唑并[1,2-b]哒嗪-3-羧酸乙酯的制备
Figure PCTCN2021093930-appb-000035
将(E)-3-乙氧基丙烯酸乙酯(5.00g,34.7mmol,1eq)的1,4-二氧六环(50mL)和水(50mL)溶液降温至-10℃，分批加入NBS(6.80g,38.15mmol,1.1eq)，自然升至室温反应2h；加入6-氯-3-氨基哒嗪(4.5g,34.7mmol，1eq)，升温至80℃反应1.5h，降温至室温；减压浓缩，残留物加水(100mL)和EA(100mL)，搅拌，分液，水相用EA(20mL×2)萃取，合并有机相；有机相用H 2O(50mL)、饱和食盐水(50mL)洗涤，减压浓缩除去有机溶剂，残留物用硅胶柱层析进行分离(洗脱剂：正己烷:EA＝5:1～1:1，v/v)，得6-氯咪唑并[1,2-b]哒嗪-3-羧酸乙酯(5.2g,收率59.75％)，(ES,m/z):225.91[M+H] +。
中间体制备例1：(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(中间体A1)
Figure PCTCN2021093930-appb-000036
步骤a：将(R)-2-(2,5-二氟苯基)吡咯烷(5.0g，27.292mmol)，5-氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯(6.14g，27.292mmol)，正丁醇(70mL)和二异丙胺(6.9g，68.230mmol)的混 合溶液在100℃下回流搅拌4h，减压浓缩得到橙色粘稠状固体，加入无水乙醚，搅拌有大量固体析出，抽滤得到(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯粗品(6.224g)。未进行纯化，直接用于下步反应，(ES,m/z):373.02[M+H] +。
步骤b：将(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯粗品(6.224g，16.714mmol)溶于无水乙醇(40mL)，75℃搅拌直至混合溶液澄清透明，再加入LiOH(2.805g，66.856mmol)水溶液(40mL)，75℃搅拌3h。冷却至室温后，减压浓缩，除去无水乙醇。缓慢滴加1N HCl水溶液调节pH 3～4，有大量白色固体析出，室温搅拌30min后抽滤，滤饼再用少量纯化水洗涤。收集滤饼，晾干后称重，得到(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(5.64g，98％)，(ES,m/z):345.02[M+H] +。
中间体制备例2：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(中间体A2)
Figure PCTCN2021093930-appb-000037
步骤a：将(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷(5.826g，28.958mmol)，5-氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯(6.534g，28.958mmol)，正丁醇(50mL)和二异丙胺(8.790g，86.874mmol)的混合溶液在100℃下反应4h，减压浓缩得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯粗品。未进行纯化，直接用于下步反应，(ES,m/z):391.05[M+H] +。
步骤b：将5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯粗品溶于无水乙醇(50mL)，75℃下搅拌直至体系澄清透明，再加入LiOH(4.86g，115.832mmol)水溶液(50mL)，75℃搅拌反应5h。冷却至室温后，减压浓缩，除去无水乙醇。缓慢滴加1N HCl水溶液调节pH 3～4，有大量白色固体析出，室温搅拌30min后抽滤，滤饼再用少量纯化水洗涤。收集滤饼，晾干后称重，得到白色粉末状固体5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(9.9g)。滤液用EA(2×50mL)萃取，合并有机相，用水(2×50mL)及饱和NaCl水溶液(50mL)洗涤，用无水Na 2SO 4干燥，过滤并减压浓缩。柱层析纯化(PE：EA＝4:1～2:1，v/v)，收集产物点，减压浓缩，得到白色粉末状固体5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(386mg)。共得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸纯品(10.286g，98％)，(ES,m/z):363.04[M+H] +。
中间体制备例1a～2a：
参照中间体制备例1和2的工艺步骤，采用以下相应的起始原料及制备方法制备中间体A1a～A2a：
Figure PCTCN2021093930-appb-000038
中间体制备例3：5-(3-(2,5-二氟苯基)吗啉基)吡唑并[1,5-a]嘧啶-3-羧酸(中间体A3)
Figure PCTCN2021093930-appb-000039
步骤a：氮气保护下，0℃条件下，向2,5-二氟苯甲醛(28.4g，0.2mol)的7mol/L NH 3/CH 3OH液(30mL)中，滴加三甲基氰硅烷(39.66g，0.4mol)，滴毕后室温过夜搅拌反应；反应液减压浓缩，残留物柱层析纯化(CH 2Cl 2:CH 3OH＝50:1，V/V)，得到2-氨基-2-(2,5-二氟苯基)乙腈(21.92g，65.2％)，(ES,m/z):169[M+H] +。
步骤b：将2-氨基-2-(2,5-二氟苯基)乙腈(21.92g，130mmol)加入到2mol/L NaOH水 溶液(130mL)中，回流条件下反应6h；降温至0℃，用浓盐酸调节pH至3，减压浓缩至干；残留物中加入四氢呋喃(200mL)，搅拌30min，过滤，滤液用无水硫酸钠过夜干燥，过滤，减压浓缩干，得到2-氨基-2-(2,5-二氟苯基)乙酸粗品(20.78g)，未纯化直接用于下步反应，(ES,m/z):186.02[M-H] -。
步骤c：氮气保护下，将2-氨基-2-(2,5-二氟苯基)乙酸(20.78g，111mmol)四氢呋喃(600mL)溶液，降温至-10～-5℃，分批加入四氢铝锂(10.53g，278mmol)，加完后室温过夜反应；向反应液中加入饱和氯化铵液(500mL)淬灭反应，过硅藻土过滤，滤液分层，水相用EA(2×100mL)萃取，合并有机相；有机相无水硫酸钠干燥，过滤，滤液减压浓缩；残留物经柱层析纯化(CH 2Cl 2:CH 3OH＝10:1，V/V)，得到2-氨基-2-(2,5-二氟苯基)乙醇(7.177g，两步总收率32％)，(ES,m/z):174.02[M+H] +。
步骤d：氮气保护下，0℃条件下，向2-氨基-2-(2,5-二氟苯基)乙醇(7.177g，41.447mmol)、三乙胺(8.388g，82.894mmol)的四氢呋喃(200ml)溶液中，加入氯乙酰氯(5.62g，49.736mmol)，保温搅拌反应30min；向反应体系中分批加入60％NaH(4.974g，124.341mmol)，加完后室温反应2h；用饱和氯化铵(100ml)淬灭反应，分液，水相用EA(2×50ml)萃取，合并有机相；有机相用无水硫酸钠干燥，过滤，减压浓缩；残留物经柱层析纯化(CH 2Cl 2:CH 3OH＝80:1～20:1，V/V)，得到5-(2,5-二氟苯基)吗啉-3-酮(4.532g，51.3％)，(ES,m/z):214.01[M+H] +。
步骤e：氮气保护下，0℃条件下，向5-(2,5-二氟苯基)吗啉-3-酮(4.532g，21.271mmol)的四氢呋喃(100mL)溶液中，分批加入四氢铝锂(3.229g，85.849mmol)，加完后50℃反应2h；降温至0℃，用饱和氯化铵(90mL)淬灭反应，减压浓缩，水相用EA(3×50mL)萃取，合并有机相；有机相用水(50mL)，盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩；残留物经柱层析纯化(CH 2Cl 2:CH 3OH＝50:1～25:1，V/V)，得到3-(2,5-二氟苯基)吗啉(3.40g，80.3％)，(ES,m/z):200.03[M+H] +。
步骤f：将3-(2,5-二氟苯基)吗啉(3.40g，17.068mmol)，5-氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯(3.851g，17.068mmol)，正丁醇(50mL)和二异丙胺(5.181g，51.204mmol)的混合溶液在100℃下过夜反应；减压浓缩，向残留物中加入EA(100mL)和水(100mL)，搅拌，分液，水相用EA(2×50mL)萃取，合并有机相；有机相用水(100mL)，盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩；残留物经柱层析纯化(正己烷：乙酸乙酯＝50:1～10:1，V/V)，得到5-(3-(2,5-二氟苯基)吗啉基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯(6.066g，91.5％)，(ES,m/z):389.05[M+H] +。
步骤g：向5-(3-(2,5-二氟苯基)吗啉基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯(6.066g，15.623mmol)乙醇(60mL)溶液中，加入LiOH(2.622g，62.492mmol)水溶液(60mL)， 升温至75℃过夜反应。冷却至室温后，减压浓缩，水相用1N盐酸水溶液调节pH至2～3，用EA(3×60mL)萃取，合并有机相；有机相用水(100mL)及盐水(50mL)洗涤，无水Na 2SO 4干燥，过滤并减压浓缩，柱层析纯化(PE：EA＝4:1～1:1，v/v)，得到5-(3-(2,5-二氟苯基)吗啉基)吡唑并[1,5-a]嘧啶-3-羧酸(5.324g，94.6％)，(ES,m/z):361.09[M+H] +。
中间体制备例4：5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉代)吡唑并[1,5-a]嘧啶-3-羧酸(中间体A4)
Figure PCTCN2021093930-appb-000040
参照中间体制备例3步骤a-f方法，以5-氟-2-甲氧基-3-吡啶甲醛为原料，制备得到5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯。
向5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯(5.00g，12.46mmol)无水乙醇(50mL)溶液中，加入LiOH(2.091g，49.827mmol)水溶液(50mL)，75℃过夜反应。冷却至室温后，减压浓缩，水相用1N盐酸水溶液调节pH至2～3，用EA(3×50ml)萃取，合并有机相；有机相用水(50ml)及盐水(50ml)洗涤，无水Na 2SO 4干燥，过滤并减压浓缩，柱层析纯化(PE：EA＝4:1～1:1，v/v)，得到5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉代)吡唑并[1,5-a]嘧啶-3-羧酸(4.277g，92％)，(ES,m/z):374.02[M+H] +。
中间体制备例5：(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A5)
Figure PCTCN2021093930-appb-000041
步骤a：将1-Boc-4-(4-氨基苯基)哌嗪(850mg，3.067mmol)加入含(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(880mg，2.556mmol)与TBTU(985mg，3.067mmol)的无水DMF(10mL)溶液中，然后0℃条件下滴加DIPEA(991mg，7.668mmol)，室温过夜反应。反应液加入水(50mL)混合搅拌，有固体析出，通过减压抽滤得到滤饼，真空干燥箱干燥，得到(R)-叔丁基4-(4-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基)哌嗪-1-羧酸酯(1.450g，94％)，(ES,m/z):604.52[M+H] +。
步骤b：向(R)-叔丁基4-(4-(5-(2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基)哌嗪-1-羧酸酯(1.45g，2.402mmol)中加入DCM和CF 3COOH(12mL，3/1，v/v)，室温搅拌2.5h，将反应液减压浓缩，向残留物中加入水(12mL)和EA(6mL)，用氨水调碱(pH＝9)，搅拌有固体析出，通过减压抽滤得到滤饼，用少量水淋洗滤饼，晾干后称重，得到(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(999mg)，(ES,m/z):504.13[M+H] +。
中间体制备例5a和6～9：
参照中间体制备例5的工艺步骤，采用以下相应的起始原料及制备方法制备中间体A5a及A6～A9：
Figure PCTCN2021093930-appb-000042
Figure PCTCN2021093930-appb-000043
中间体制备例10：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A10)
Figure PCTCN2021093930-appb-000044
步骤a：将1-Boc-4-(4-氨基苯基)哌嗪(918mg，3.312mmol)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(中间体A2，1000mg，2.76mmol)与TBTU(1063mg，3.312mmol)的无水DMF(10mL)溶液中，然后0℃条件下滴加DIPEA(1284mg，9.936mmol)，室温过夜反应。反应液加入水(50mL)混合搅拌，有固体析出，通过减压抽滤得到滤饼，真空干燥箱干燥，得到叔丁基4-(4-(5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基哌嗪-1-羧酸酯(1320mg，77％)。(ES,m/z):622.09[M+H] +。
步骤b：向叔丁基4-(4-(5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基哌嗪-1-羧酸酯(1.320g，2.125mmol)中加入DCM和CF 3COOH(12mL，3/1，v/v)，室温搅拌4h，将反应液减压浓缩，向残留物中加入水(80mL)和EA(10mL)，用氨水调碱(pH＝9)，搅拌有固体析出，通过减压抽滤得到滤饼，用少量水淋洗滤饼，晾干后称重，得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(907mg，82％)，(ES,m/z):522.09[M+H] +。
中间体制备例10a：
参照中间体制备例10的工艺步骤，采用以下相应的起始原料及制备方法制备中间体 A10a：
Figure PCTCN2021093930-appb-000045
中间体制备例11：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(哌啶-4-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A11)
Figure PCTCN2021093930-appb-000046
步骤a：将1-Boc-4-(4-氨基苯基)哌啶(458mg，1.656mmol)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(中间体A2，500mg，1.380mmol)与TBTU(532mg，1.656mmol)的无水DMF(5mL)溶液中，然后0℃条件下滴加DIPEA(535mg，4.140mmol)，室温过夜反应18h。反应液加入水(50mL)混合搅拌，有固体析出，通过减压抽滤得到滤饼，真空干燥箱干燥，得到叔丁基4-(4-(5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基哌啶-1-羧酸酯(627mg，73％)。(ES,m/z):621.15[M+H] +。
步骤b：向叔丁基4-(4-(5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基哌啶-1-羧酸酯(627mg，1.101mmol)中加入DCM和CF 3COOH(8mL，3/1，v/v)，室温搅拌4h，将反应液减压浓缩，向残留物中加入水(80mL)和EA(50mL)，用氨水调碱(pH＝9)，用EA(55mL×2)萃取该水相，并用H 2O(20mL)、盐水(20mL)洗涤合并的萃取相，无水硫酸钠干燥，过滤，滤液减压浓缩残留物，残留物用柱层析硅胶柱进行洗脱，先用3％(v/v)MeOH-DCM洗掉极性偏小后的杂质后，换用10％(v/v)MeOH-DCM 洗脱，收集产物点并浓缩，得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(哌啶-4-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(437mg，76％)，(ES,m/z):521.14[M+H] +。
中间体制备例11a和12：
参照中间体制备例11的工艺步骤，采用以下相应的起始原料及制备方法制备中间体A11a和A12：
Figure PCTCN2021093930-appb-000047
中间体制备例13：5-(3-(2,5-二氟苯基)吗啉基)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A13)
Figure PCTCN2021093930-appb-000048
步骤a：氮气保护下，将1-Boc-4-(4-氨基苯基)哌嗪(3.812g，13.756mmol)加入含5-(3-(2,5-二氟苯基)吗啉代)吡唑并[1,5-a]嘧啶-3-羧酸(4.127g，11.46mmol)与TBTU(4.417g，13.756mmol)的无水DMF(20mL)溶液中，然后0℃条件下滴加DIPEA(4.441g，34.362mmol)，室温过夜反应。反应液加入EA(100ml)和水(100mL)混合搅拌，分液；水相用EA(2×50ml)萃取，合并有机相；有机相用水(2×50mL)及盐水(50mL)洗涤，无水Na 2SO 4干燥，过滤并减压浓缩，柱层析纯化(PE：EA＝80:1～60:1，v/v)，得到4-(4-(5-(3-(2,5-二氟苯基)吗啉代)吡唑并[1,5-a]嘧啶-3-羧酰胺基)苯基叔丁基哌嗪-1-羧酸叔丁酯(3.924g，55.3％)，(ES,m/z):620.49[M+H] +。
步骤b：向4-(4-(5-(3-(2,5-二氟苯基)吗啉代)吡唑并[1,5-a]嘧啶-3-羧酰胺基)苯基叔丁基哌嗪-1-羧酸叔丁酯(3.924g，6.332mmol)的DCM(30ml)溶液中，加入CF 3COOH(10ml)，室温搅拌4h，将反应液减压浓缩，向残留物中加入水(100mL)和EA(100ml)，用氨水调节pH至9，分液，水相用EA(2×50ml)萃取，合并有机相；有机相用水(100mL)、盐水(50mL)洗涤；无水硫酸钠干燥，过滤，减压浓缩，残留物用柱层析纯化(CH 2Cl 2:CH 3OH＝50:1～10:1,v/v)，得到5-(3-(2,5-二氟苯基)吗啉基)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(2.978g，90.5％)，(ES,m/z):520.11[M+H] +。
中间体制备例14：
参照中间体制备例13的工艺步骤，采用以下相应的起始原料及制备方法制备中间体A14：
Figure PCTCN2021093930-appb-000049
中间体制备例15：5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉基)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A15)
Figure PCTCN2021093930-appb-000050
步骤a：氮气保护下，将1-Boc-4-(4-氨基苯基)哌嗪(3.813g，13.747mmol)加入含5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉代)吡唑并[1,5-a]嘧啶-3-羧酸(4.277g，11.46mmol)与TBTU(4.414g，13.747mmol)的无水DMF(20mL)溶液中，然后0℃条件下滴加DIPEA(4.441g，34.368mmol)，室温过夜反应。反应液加入EA(100ml)和水(100mL)混合搅拌，分液；水相用EA(2×50ml)萃取，合并有机相；有机相用水(2×50mL)及盐水(50mL)洗涤，无水Na 2SO 4干燥，过滤并减压浓缩，柱层析纯化(PE：EA＝100:1～50:1，v/v)，得到4-(4-(5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉代)吡唑并[1,5-a]嘧啶-3-羧酰胺基)苯基)哌嗪-1-甲酸叔丁酯(4.736g，65.3％)，(ES,m/z):633.09[M+H] +。
步骤b：向4-(4-(5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉代)吡唑并[1,5-a]嘧啶-3-羧酰胺基)苯基)哌嗪-1-甲酸叔丁酯(4.736g，7.485mmol)的DCM(30ml)溶液中，加入CF 3COOH(10ml)，室温搅拌4h，将反应液减压浓缩，向残留物中加入水(100mL)和EA(100ml)，用氨水调节pH至9，分液，水相用EA(2×50ml)萃取，合并有机相；有机相用水(100mL)、盐水(50mL)洗涤；无水硫酸钠干燥，过滤，减压浓缩，残留物用柱层析纯化(CH 2Cl 2:CH 3OH＝50:1～10:1,v/v)，得到5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉代)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(3.685g，92.5％)，(ES,m/z):533.10[M+H] +。
中间体制备例16：
参照中间体制备例15的工艺步骤，采用以下相应的起始原料及制备方法制备中间体A16：
Figure PCTCN2021093930-appb-000051
中间体制备例17：N1-(氧杂环丁-3-基)苯-1,4-二胺(中间体B1)
Figure PCTCN2021093930-appb-000052
步骤a：将3-氧杂环丁胺(124mg，1.701mmol)加入含有对氟硝基苯(200mg，1.417mmol)的DMSO(3mL)溶液中，然后添加DIPEA(366mg，2.834mmol)，在120℃条件下搅拌反应5h，向反应液中加入水(20mL)，搅拌有大量固体析出，减压抽滤，得到滤饼N-(4-硝基苯基)氧杂-3-胺(268mg，97％)，(ES,m/z):195.01[M+H] +。
步骤b：将上一步中得到的滤饼N-(4-硝基苯基)氧杂-3-胺(268mg，1.380mmol)和甲醇(15mL)加入反应瓶中，加入10％Pd/C，H 2置换后搅拌4h。抽滤出Pd/C，旋干滤液得到N-1-(氧杂环丁-3-基)苯-1,4-二胺固体产品(110mg)，(ES,m/z):164.92[M+H] +。
中间体制备例18～24：
参照中间体制备例17的工艺步骤，采用以下相应的起始原料、对氟硝基苯及制备方法制备中间体B2～B8：
Figure PCTCN2021093930-appb-000053
中间体制备例25：(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-3-羧酸(中间体C1)
Figure PCTCN2021093930-appb-000054
步骤a～c:参照专利CN108794484B实施例1第一至三步骤方法，制备(R)-6-(2-(2,5-二氟苯基)吡咯烷-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-3-羧酸，(ES,m/z):346.02[M+H] +。
中间体制备例26：6-((2R，4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-3-羧酸(中间体C2)
Figure PCTCN2021093930-appb-000055
步骤a～c：参照中间体制备例25的工艺步骤方法，制备6-((2R，4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-[1,2,4]三唑并[4,3-a]吡嗪-3-羧酸，(ES,m/z):364.03[M+H] +。
中间体制备例27～30：
参照中间体制备例5的工艺步骤，采用以下相应的起始原料及制备方法制备中间体C3～C6：
Figure PCTCN2021093930-appb-000056
Figure PCTCN2021093930-appb-000057
以下为本发明化合物的实施例。
实施例1：(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-(4-(2-羟基乙酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(化合物1)
Figure PCTCN2021093930-appb-000058
将羟基乙酸(32mg，0.417mmol)加入含(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A5，70mg，0.139mmol)与BOP(74mg，0.167mmol)的无水DMF(3mL)溶液中，然后0℃条件下滴加DIPEA(54mg，0.417mmol)，室温搅拌反应4h。反应液加入水(20mL)混合，用EA(15mL×2)萃取该混合物，并用H 2O(20mL)、盐水(20mL)洗涤合并的有机相，无水硫酸钠干燥，过滤，滤液减压浓缩残留物，用柱层析硅胶柱进行洗脱，先用1％(v/v)MeOH-DCM，后用2％(v/v)MeOH-DCM洗脱，收集产物点并浓缩，得到(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-(4-(2-羟基乙酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(44mg，56％)，(ES,m/z):562.13[M+H] +。
实施例1a、1b和2～3：
参照实施例1的制备工艺路线及操作，采用以下物料和中间体A5、A5a或C3作为起始原料，制备化合物1a、1b和2～3。
Figure PCTCN2021093930-appb-000059
Figure PCTCN2021093930-appb-000060
实施例4：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(4-(2-羟基乙酰基)哌嗪-1-基)苯基)吡唑[1,5-a]嘧啶-3-羧酰胺(化合物4)
Figure PCTCN2021093930-appb-000061
将羟基乙酸(306mg，4.026mmol)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(哌嗪-4-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A10，700mg，1.342mmol)与BOP(712mg，1.610mmol)的无水DMF(10mL)溶液中，然后0℃条件下滴加DIPEA(520mg，4.026mmol)，室温搅拌反应4h。反应液加入水(80mL)混合，用EA(55mL×2) 萃取该混合物，并用H 2O(80mL)、盐水(80mL)洗涤合并的有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用柱层析硅胶柱进行洗脱，先用1％(v/v)MeOH-DCM，后用2％(v/v)MeOH-DCM洗脱，收集产物点并浓缩，得到(R)-5-(2-(2,5-二氟苯基)吡咯烷-1-基)-N-(4-(4-(2-羟基乙酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(666mg，86％)，(ES,m/z):580.14[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ9.810(s,1H),8.906-8.723(m,1H),8.283-8.229(m,1H),7.623(s,1H),7.343(s,1H),7.210(s,2H),7.061-6.842(m,4H),5.711-5.495(m,2H),4.631(t,J＝5.4Hz,1H),4.556-4.548(m,1H),4.318-4.225(m,1H),4.150(d,J＝5.4Hz，2H)，3.637(s,2H),3.513(s,2H),3.124-3.106(m,4H),2.957-2.912(m,1H)。
实施例4a～4b、5a、7a～7b和5～9：
按照实施例4的制备工艺路线及操作，采用中间体A10、A10a或C4和以下物料作为起始原料，制备化合物4a～4b、5a、7a～7b和5～9。
Figure PCTCN2021093930-appb-000062
Figure PCTCN2021093930-appb-000063
Figure PCTCN2021093930-appb-000064
实施例10：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(1-(2-羟基乙酰基)哌啶-4-基)苯基)吡唑[1,5-a]嘧啶-3-羧酰胺(化合物10)
Figure PCTCN2021093930-appb-000065
将羟基乙酸(438mg，5.763mmol)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(哌啶-4-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A11，1000mg，1.921mmol)与BOP(1274mg，2.882mmol)的无水DMF(10mL)溶液中，然后0℃条件下滴加DIPEA(745mg，5.763mmol)，室温过夜搅拌反应。反应液加入水(100mL)混合，用EA(80mL×2)萃取该混合物，并用H 2O(100mL)、盐水(110mL)洗涤合并的有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到残留物，用柱层析硅胶柱进行洗脱，先用1％(v/v)MeOH-DCM，5后用2％(v/v)MeOH-DCM洗脱，收集产物点并浓缩，得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(1-(2-羟基乙酰基)哌啶-4-基)苯基)吡唑[1,5-a]嘧啶-3-羧酰胺(820mg，74％)，(ES,m/z)：579.14[M+H] +。 1H NMR(600MHz,DMSO-d 6)δ9.952(s,1H),9.022-8.753(m,1H),8.355-8.152(m,2H),7.663(s,1H),7.343-7.042(m,6H),5.773-5.552(m,2H),4.529-4.481(m,2H),4.358-4.115(m,3H),3.803-3.779(m,1H),3.640-3.603(m,1H),3.090-3.049(m,1H),2.968-2.957(m,1H),2.792-2.752(m,1H),2.722-2.682(m,1H),2.241-2.212(m,1H),1.808(s,2H),1.608-1.589(m,1H),1.492-1.476(m,1H)。
实施例10a～10b，11a～11b和11～17：
按照实施例10的制备工艺路线及操作，采用中间体A11、A11a或C6和以下物料作为起始原料，制备化合物10a～10b，11a～11b和11～17。
Figure PCTCN2021093930-appb-000066
Figure PCTCN2021093930-appb-000067
实施例18：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(4-(2-(2-羟基乙酰基)哌嗪-1-基)甲基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(化合物18)
Figure PCTCN2021093930-appb-000068
将羟基乙酸(51mg，0.672mmol)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(哌嗪-1-基甲基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A12，120mg，0.224mmol)与BOP试剂(149mg，0.336mmol)的无水DMF(12mL)溶液中，然后0℃条件下滴加DIPEA(87mg，0.672mmol)，室温搅拌反应4h。反应液加入水(20mL)混合，用EA(10mL×2)萃取该混合物，并用H 2O(10mL)、盐水(10mL)洗涤合并的有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到残留物，用柱层析硅胶柱进行洗脱，先用1％(v/v)MeOH-DCM，后增加至2％(v/v)MeOH-DCM，得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(4-(2-(2-羟基乙酰基)哌嗪-1-基)甲基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(30mg，22％)，(ES,m/z)：594.12[M+H] +。
实施例19：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(氧杂环丁-3-基氨基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(化合物19)
Figure PCTCN2021093930-appb-000069
将N1-(氧杂环丁-3-基)苯-1,4-二胺(105mg，0.640mmol)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(1,2,3,4-四氢异喹啉-7-基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A2，193mg，0.534mmol)与TBTU(205mg，0.640mmol)的无水DMF(5mL)溶液中，然后0℃条件下滴加DIPEA(205mg，1.602mmol)，室温过夜搅拌反应14h。反应液加入水(25mL)混合，用EA(15mL×2)萃取该混合物，并用H 2O(20mL)、盐水(20mL)洗涤合并的有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到残留物，制备液相色谱柱分离(X-Bridge C18 19*150mm 5um，洗脱体系：5-25％的乙腈水溶液梯度洗脱，0.05％NH 4HCO 3改性)，得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(氧杂环丁-3-基氨基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(60mg，22.1％)，(ES,m/z):509.12[M+H] +。
实施例19a～19b和20～24：
按照实施例19的制备工艺路线及操作，采用以下中间体作为起始原料，制备化合物19a～19b和20～24：
Figure PCTCN2021093930-appb-000070
Figure PCTCN2021093930-appb-000071
实施例25：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(6-(2-羟基乙酰基)-3,6-二氮杂双环[3.1.1]庚-3-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(化合物25)
Figure PCTCN2021093930-appb-000072
步骤a：将3-(4-氨基苯基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(442mg，1.528mmol)(中间体B5)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(中间体A2，460mg，1.270mmol)与TBTU(491mg，1.528mmol)的无水DMF(5mL)溶液中，然后0℃条件下滴加DIPEA(494mg，3.819mmol)，室温过夜搅拌反应14h。反应液加入水(100mL)混合搅拌，有大量固体析出，减压抽滤后干燥，得到叔丁基3-(4-(5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸酯固体粗品。
步骤b：将上述所得叔丁基3-(4-(5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸酯固体粗品溶于DCM(25mL)，加入CF 3COOH(5mL)室温搅拌3h。旋干反应液，加入水稀释后氨水调碱，有固体析出，抽滤后晾干，得到N-(4-(3,6-二氮杂双环[3.1.1]庚基-3-基)苯 基)-5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酰胺固体产品(450mg)。
步骤c：将羟基乙酸(35mg，0.450mmol)加入含N-(4-(3,6-二氮杂双环[3.1.1]庚基-3-基)苯基)-5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酰胺(200mg，0.375mmol)与TBTU(145mg，0.450mmol)的无水DMF(5mL)溶液中，然后0℃条件下滴加DIPEA(146mg，1.125mmol)，室温搅拌反应4h。反应液加入水(30mL)混合，用EA(20mL×2)萃取该混合物，并用H 2O(30mL)、盐水(40mL)洗涤合并的有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到残留物，用柱层析硅胶柱进行洗脱，先用1％MeOH-DCM，后用2％MeOH-DCM洗脱，收集产物点并浓缩，得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(6-(2-羟基乙酰基)-3,6-二氮杂双环[3.1.1]庚-3-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(180mg，81％)，(ES,m/z):592.02[M+H] +。
实施例26：5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(6-(2-羟基乙酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(化合物26)
Figure PCTCN2021093930-appb-000073
步骤a：将6-(4-氨基苯基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(178mg，0.607mmol)(中间体B8)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(中间体A2，200mg，0.552mmol)与TBTU(217mg，0.607mmol)的无水DMF(5mL)溶液中，然后0℃条件下滴加DIPEA(217mg，1.656mmol)，室温过夜搅拌反应14h。反应液加入水(30mL)混合搅拌，有大量固体析出，减压抽滤后干燥，得到叔丁基6-(4-(5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸酯固体粗品，(ES,m/z):534.12[M+H] +。
步骤b：将上述所得叔丁基6-(4-(5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺基)苯基)-2,6-二氮杂螺[3.3]庚烷-2-羧酸酯固体粗品溶于DCM(6mL)， 加入CF 3COOH(2mL)室温搅拌3h。旋干反应液，加入水稀释后氨水调碱，有固体析出，抽滤后晾干，得到N-(4-(2,6-二氮杂螺并[3.3]庚基-2-基)苯基)-5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酰胺固体产品(218mg)。
步骤c：将羟基乙酸(37mg，0.490mmol)加入含N-(4-(2,6-二氮杂螺并[3.3]庚基-2-基)苯基)-5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酰胺(218mg，0.409mmol)与TBTU(157mg，0.490mmol)的无水DMF(10mL)溶液中，然后0℃条件下滴加DIPEA(158mg，1.226mmol)，室温搅拌反应4h。反应液加入水(30mL)混合，用EA(20mL×2)萃取该混合物，并用H 2O(30mL)、盐水(40mL)洗涤合并的有机相，无水硫酸钠干燥，过滤，滤液减压浓缩残留物，制备板分离纯化(展开剂极性为DCM:MeOH＝15:1)得到5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(6-(2-羟基乙酰基)-2,6-二氮杂螺[3.3]庚烷-2-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(51mg，94％),(ES,m/z):592.12[M+H] +。
实施例27：5-(3-(2,5-二氟苯基)吗啉基)-N-(4-(4-(2-羟基乙酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(化合物27)
Figure PCTCN2021093930-appb-000074
将羟基乙酸(584mg，7.676mmol)加入含5-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-N-(4-(哌啶-4-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A13，997mg，1.919mmol)与BOP(1274mg，2.878mmol)的无水DMF(10mL)溶液中，然后0℃条件下滴加DIPEA(744mg，5.756mmol)，室温过夜搅拌反应。反应液加入水(100mL)混合，用EA(80mL×2)萃取，合并有机相；有机相用H 2O(100mL)、盐水(110mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩残留物，用柱层析硅胶柱进行洗脱，洗脱剂(DCM:CH 3OH＝100:1～50:1，v/v)，收集产物点并浓缩，得到5-(3-(2,5-二氟苯基)吗啉基)-N-(4-(4-(2-羟基乙酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(609.8mg，55％)，(ES,m/z)：578.12[M+H] +。
实施例28：
按照实施例27的制备工艺路线及操作，采用A14和羟基乙酸作为起始原料，制备化合物28。
Figure PCTCN2021093930-appb-000075
实施例29：5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉基)-N-(4-(4-(2-羟基乙酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(化合物29)
Figure PCTCN2021093930-appb-000076
将羟基乙酸(511mg，6.723mmol)加入含5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉代)-N-(4-(哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(中间体A15，1.022g，1.92mmol)与BOP(1274mg，2.878mmol)的无水DMF(10mL)溶液中，然后0℃条件下滴加DIPEA(744mg，5.763mmol)，室温过夜搅拌反应。反应液加入水(100mL)混合，用EA(80mL×2)萃取，合并有机相；有机相用H 2O(100mL)、盐水(110mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩残留物，用柱层析硅胶柱进行洗脱，洗脱剂(DCM:CH 3OH＝100:1～50:1)，收集产物点并浓缩，得到5-(3-(5-氟-2-甲氧基吡啶-3-基)吗啉基)-N-(4-(4-(2-羟基乙酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-羧酰胺(737mg，65.02％)，(ES,m/z)：591.20[M+H] +。
实施例30：
按照实施例29的制备工艺路线及操作，采用A16和羟基乙酸作为起始原料，制备化合物30。
Figure PCTCN2021093930-appb-000077
实施例31-47：
参照中间体制备例1～30及实施例1～30的制备工艺路线、操作，参考CN111936500A中公开的方法，以(2R)-2-(2,5-二氟苯基)-3-氮杂双环[3.1.0]己烷和各中间体为原料，制备化合物31～47。
Figure PCTCN2021093930-appb-000078
Figure PCTCN2021093930-appb-000079
Figure PCTCN2021093930-appb-000080
对照品制备例1-5：
另：参照WO2019029629A1和WO2012034095A1专利文件中制备工艺路线、操作制备化合物D1～D5。
Figure PCTCN2021093930-appb-000081
Figure PCTCN2021093930-appb-000082
试验例1、化合物对TRK的激酶抑制试验
1.操作步骤：
1.1激酶反应：
在化合物板中依次加入一定浓度梯度的待测化合物、酶溶液(阴性对照孔加入激酶缓冲液(1X kinase buffer(Cisbio,Cat#62EZBFDD)，pH 7.5；5mM MgCl 2，1mM DTT))，1000rpm离心30秒。封板，并将板子放在25℃的恒温培养箱中孵育30分钟。制备TK-Sub-biotin(Cisbio，Cat#61TKOBL)以及ATP(Sigma，Cat#R0441)的底物溶液，并将底物混合溶液加入到384孔板中，1000rpm离心30秒。封板，并将板子放在25℃的恒温培养箱中孵育60分钟。
Figure PCTCN2021093930-appb-000083
1.2激酶检测：
将TK抗体和XL665稀释、混合并加入assay板中，1000rpm离心30秒。封板，并将板子放在25℃的恒温培养箱中孵育60分钟。将assay板放置在Envision机器上读数。 (HTRF 665/615比值：665nm信号值/615nm信号值)
抑制率＝(比值 阴性对照孔-比值 化合物孔)/(比值 阴性对照孔-比值 无酶对照孔)×100％
1.3数据分析和曲线拟合
在XLFit excel插件版本5.4.0.8中拟合数据以获得IC 50值。
1.4 QC参数
参考化合物被包含在每块板中，且其IC 50每次都在3倍以内。
2.试验结果：如表1所示
表1本发明化合物对NTRK的激酶抑制活性
Figure PCTCN2021093930-appb-000084
备注：以上RXDX-101、LOXO-195、LOXO-101均为已公开的化合物，并可市售获得上市产品(药品或化工级产品)。
结果表明：本发明化合物在多种激酶中展现了较高的激酶抑制活性，在TRKA、TRKB、TRKC和TRKC-G696A中活性优于RXDX-101、LOXO-195和LOXO-101或相当，而在多种突变耐药型激酶中(G595R、G667C、G623R)抑制活性显著优于RXDX-101、LOXO-195和LOXO-101。
试验例2、化合物对ALK和ROS1的激酶抑制试验
1.操作步骤：
1.1激酶反应：
化合物用DMSO稀释成一定浓度，并4倍梯度稀释。在384孔板中分别加入一定浓度化合物，酶溶液和DMSO，室温孵育10min；加入荧光素标记肽，ATP(sigma,Cat.No.:A7699-1G,Lot No.:987-65-5)28℃孵育一定时间；加入终止液。读数。
单个浓度对应的抑制率公式：抑制率＝(OD 阴性对照孔-OD 化合物孔)/(OD 阴性对照孔-OD 无酶对照孔)×100％
Figure PCTCN2021093930-appb-000085
1.2数据分析和曲线拟合
在XLFit excel插件版本4.3.1中拟合数据以获得IC 50值，结果如表2。
表2本发明化合物对ALK和ROS1激酶抑制活性
Figure PCTCN2021093930-appb-000086
结果表明：本发明多个化合物在ROS1激酶中表现出较强的抑制活性，显著优于RXDX-101和LOXO-101，优于LOXO-195；对ALK激酶也具有良好的抑制活性，显著优于LOXO-101和LOXO-195。
试验例3、化合物对细胞的体外抑制试验
1、细胞系
6种试验用细胞系来源：康源博创生物技术(北京)有限公司
细胞类型：鼠源B细胞
培养基：RPMI-1640+10％FBS
2、试验方法
收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。将一定密度的细胞悬液吹打均匀接种于96孔板，每孔100μL，震荡，使其均匀分散至孔内；每孔加入100μl一定浓度梯度的药物溶液，每个药物浓度设置三个复孔；37℃CO 2培养箱培养72小时；加入MTT工作液(5mg/ml)，每孔20μl；37℃作用4小时；平板离心机1000rpm/min离心5min，吸弃培养基180μl后加入150μl DMSO，微孔振荡器震荡混匀，将板底擦拭干净，酶标仪550nm处检测光密度值(OD)。
3、数据分析
抑制率＝(对照孔OD-受试孔OD)/(对照孔OD-空白孔OD)*100％，根据各浓度抑制率， 采用SPSS软件计算半数抑制浓度IC 50值。
4、试验结果：结果如表3所示：
表3本发明化合物对TRK突变细胞株的抑制活性
Figure PCTCN2021093930-appb-000087
注：——为未检测。
表4对照化合物对TRK突变细胞株的抑制活性
Figure PCTCN2021093930-appb-000088
结果表明：本发明多个化合物在多种野生型及突变耐药型细胞株中表现出较好的体外细胞活性，显著优于RXDX-101、LOXO-195、LOXO-101及现有技术化合物D1-D5。
试验例4：化合物在体内机制的研究
1.试验方法
1.1模型制备：
取对数生长期的突变耐药细胞Ba/F3LMNA-NTRK1-G595R，收集、重悬至无血清培养基中，使细胞浓度为6×10 7-10×10 7个/mL，并向细胞悬液中加入等体积的Matrigel，使细胞 的终浓度为3×10 7-5×10 7个/mL。于NuNu鼠(北京维通利华，4-6周，雌性)前肢腋下皮下接种0.1mL肿瘤细胞悬液，接种量为3×10 6-5×10 6个/只，制备动物模型。
1.2试验分组：
用游标卡尺测量裸鼠移植瘤的最大瘤径和最小瘤径，计算肿瘤体积：肿瘤体积(Tumor volume，TV)的计算公式为：V＝1/2×a×b 2，其中a和b分别表示瘤块的最大直径和最小直径。选择肿瘤体积合适的裸鼠，采用随机数字法按肿瘤体积将动物均衡分成7组(200-300mm 3)，每组3只。
1.3给药
根据动物体重进行灌胃给药，给药体积为10ml/kg，4号化合物使用“3％DMSO+96％HP-β-CD(0.5g/mL)+1％HCL”配置成所需要的给药浓度。
对照组共三只，给予溶媒后4h取肿瘤组织冻存。其他组均给予本发明4号化合物100mg/kg，分别在0.25h、1h、4h、8h、12h和24h取肿瘤组织冻存。
1.4蛋白提取及定量
取一定质量的肿瘤组织加入相应体积的蛋白裂解液(RIPA裂解液(Thermo Fisher，货号89900)：蛋白酶抑制剂(cOmplete,Mini,EDTA-free,EASYpack；Roche，货号04693159001)：磷酸酶抑制剂(PhosStop,EASY pack；Roche，货号04906837001)＝8:1:1)，匀浆，冰浴裂解30min。低温高速离心，取上清液进行BCA蛋白定量(依据BCA蛋白定量试剂盒(天根，货号：#PA115-01)操作)。最后将蛋白浓度用裂解液调成统一浓度后，加入loading buffer，100℃煮沸10min。
1.5 Western-blot
采用4-20％的10孔预制胶；上样量100ug；140V电泳1-1.5h；300mA湿转1.5h-2h；5％BSA封闭2-3h；一抗4℃孵育过夜(Trk 1:5000，p-Trk、PLCγ1、p-PLCγ1、AKT、p-AKT、actin 1:1000)；4×5min 0.1％TBST洗涤；二抗室温孵育2h(1:5000)，ECL发光，曝光。
Figure PCTCN2021093930-appb-000089
Figure PCTCN2021093930-appb-000090
2.试验结果：如附图1所示。
由试验结果可知：随着时间延长，图1中TRK，p-TRK，p-PLCγ1和p-AKT均明显降低，证明本发明4号化合物可明显降低TRK，p-TRK的蛋白水平，进而有效抑制p-PLCγ1/PLCγ1及p-AKT/AKT的磷酸化，以调控细胞生长与增殖。
试验例5：化合物对NTRK突变耐药肿瘤模型的体内药效实验
试验方法
1.1模型制备
取对数生长期的细胞，收集、重悬至无血清培养基中，使细胞浓度为6×10 7-10×10 7个/mL，并向细胞悬液中加入等体积的Matrigel，使细胞的终浓度为3×10 7-5×10 7个/mL。于NuNu鼠(北京维通利华，4-6周，雌性)前肢腋下皮下接种0.1mL肿瘤细胞悬液，接种量为3×10 6-5×10 6个/只，制备动物模型。
1.2试验分组
用游标卡尺测量裸鼠移植瘤的最大瘤径和最小瘤径，计算肿瘤体积：肿瘤体积(Tumor volume，TV)的计算公式为：V＝1/2×a×b 2，其中a和b分别表示瘤块的最大直径和最小直径。选择肿瘤体积合适的裸鼠，采用随机数字法按肿瘤体积将动物均衡分成7组(100-200mm 3)，每组6只。
1.3观察指标
分组当天开始根据动物体重进行灌胃给药，给药体积为10ml/kg，LOXO-195使用0.5％CMC-Na配置成所需要的给药溶液，4号和10号化合物使用“3％DMSO+96％HP-β-CD(0.5g/mL)+1％HCL”配置成所需要的给药溶液。每周两次测量瘤径，计算肿瘤体积。具体指标如下：
动物体重：每天上午给药前对动物进行称重，体重降低大于20％定义为药物有毒性反应(观察至末次给药次日)；
肿瘤体积(Tumor volume，TV)＝V＝1/2×a×b 2，其中a和b分别表示瘤块的最大直径和最小直径(观察至末次给药次日)；
相对肿瘤增殖率T/C(％)：T/C(％)＝TRTV/CRTV×100％(TRTV：给药组RTV，CRTV:对照组RTV)；
肿瘤生长抑制率(TGI)＝[1-(Ti-T0)/(Vi-V0)]×100％。(其中Ti表示某一天某给药组的 平均肿瘤体积；T0为此给药组在开始给药时平均肿瘤体积；Vi为某一天(与Ti同一天)溶媒对照组的平均肿瘤体积；V0为溶媒对照组在开始给药时的平均肿瘤体积)；
肿瘤抑制率：实验结束时，脱颈处死动物，剥离瘤块并称重，拍照，计算抑瘤率，肿瘤抑制率＝(对照组平均瘤重-给药组平均瘤重)/对照组平均瘤重×100％。
试验结果
2.1 Ba/F3LMNA-NTRK1-G667C模型
2.1.1药物对荷瘤小鼠体重的影响
各化合物各剂量组体重具有上升趋势，且上升趋势比对照组明显。各化合物各剂量组体重上升明显，可能与化合物有关，也可能由于抑制肿瘤生长，使小鼠状态较好，体重增长明显。结果见表5。
2.1.2药物对荷瘤小鼠瘤重及抑瘤率的影响
数据结果表明：同等给药剂量(100mg/kg)下，与LOXO-195相比，本发明4号化合物和10号化合物对肿瘤生长的抑制更显著；进一步地，与更高给药剂量的LOXO-195组(200mg/kg)相比，本发明4号化合物和10号化合物(100mg/kg)亦表现出更好的抑瘤效果。结果见表5。
表5 Ba/F3LMNA-NTRK1-G667C模型体内结果
Figure PCTCN2021093930-appb-000091
2.2 Ba/F3LMNA-NTRK1-G595R模型
2.2.1药物对荷瘤小鼠体重的影响
各化合物各剂量组体重具有上升趋势，且上升趋势比对照组明显。各化合物各剂量组体重上升明显，可能与化合物有关，也可能由于抑制肿瘤生长，使小鼠状态较好，体重增长明显。结果见表6。
2.2.2药物对荷瘤小鼠瘤重及抑瘤率的影响
数据结果表明：与LOXO-195(100mg/kg)相比，在更低的给药剂量(50mg/kg)下，本发明4号化合物和本发明10号化合物即可实现对肿瘤组织重量的显著抑制，瘤重抑制率 ＞90％。结果见表6。
表6 Ba/F3LMNA-NTRK1-G595R模型体内结果
Figure PCTCN2021093930-appb-000092

Claims (20)

  1. 一种式(I)所示的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，
    Figure PCTCN2021093930-appb-100001
    其中，X选自：键、-O-、-S-、-NH-或-CH 2-；
    Y，Y 1，Y 2，Y 3，Y 4独立的选自：-CH-、N或C；
    X 2选自：键、-(CH 2) p-或-NH-，其中，p为1、2、3或4；
    Figure PCTCN2021093930-appb-100002
    表示：键存在或不存在；
    R选自：C 5～12的芳基或杂芳基，其中每个芳基或杂芳基是未被取代的或被至少一个选自R 1的取代基取代；
    R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、-NHC 1～6烷基、-N(C 1～6烷基) 2、氰基、未被取代或被至少一个R 1a取代的C 1～6烷基、未被取代或被至少一个R 1a取代的C 1～6烷氧基、未被取代或被至少一个R 1a取代的C 3～6环烷基、未被取代或被至少一个R 1a取代的C 3～6环烷氧基、或-SC 1～6烷基；
    R 1a在每次出现时，各自独立地选自：C 1-6烷基、C 1-6烷氧基、硝基、卤素、-OH、氨基、-NHC 1～6烷基、-N(C 1～6烷基) 2、或氰基；
    R 2选自：H、卤素、羟基、氨基、或取代或未取代的C 1～6烷基，所述取代是指被1、2或3个选自卤素或羟基的取代基所取代；
    R 3选自：H、卤素、-OH、氨基、C 1～6烷基或C 1～6烷氧基；
    环A选自：环烷基、杂环烷基、桥环基、杂桥环基、并环基、杂并环基、螺环基、杂螺环基，其中所述杂环烷基、杂桥环基、杂并环基和杂螺环基中的杂原子独立地选自O、S或N，所述杂原子数选自1、2、3或4个；
    R 4位于环A上的任意可取代位置，其独立的选自：-H、-OH、卤素、-CN、氧代基、取代或未取代的C 1～6烷基、-(CH 2) m-OH、-(CH 2) m-COOH、-(CH 2) m-CO-NH 2、-CO-(CH 2) m-NH 2、-CO-CR 4aR 4b-OH或-CO-R 4b；其中，所述氧代基是指相同取代位的两个H被同一个O替代形成双键；m选自1、2、3或4；R 4a选自氢、未取代或取代的C 1～4 烷基；R 4b选自H、未取代或取代的C 1～6烷基或未取代或取代的C 3～6环烷基，所述取代的取代基独立地选自-OH、-NH 2、卤素，取代基个数选自1、2或3；
    n选自1、2、3或4。
  2. 根据权利要求1所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述R选自：C 5～9的芳基或杂芳基，其中每个芳基或杂芳基是未被取代的或被至少一个选自R 1的取代基取代；或者，所述R选自：C 5～6的芳基或杂芳基，其中每个芳基或杂芳基是未被取代的或被至少一个选自R 1的取代基取代。
  3. 根据权利要求2所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述化合物具有如式(I-1)或(I-2)所示的结构：
    Figure PCTCN2021093930-appb-100003
    其中，X 1选自：-CH-或N。
  4. 根据权利要求3所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述化合物具有如式(I-A)所示的结构：
    Figure PCTCN2021093930-appb-100004
  5. 根据权利要求4所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述化合物具有如式(I-A-1a)、(I-A-1b)或(I-A-1c)所示的结构：
    Figure PCTCN2021093930-appb-100005
  6. 根据权利要求3所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述化合物具有如式(I-B)所示的结构：
    Figure PCTCN2021093930-appb-100006
  7. 根据权利要求6所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述化合物具有如式(I-B-1a)、(I-B-1b)或(I-B-1c)所示的结构：
    Figure PCTCN2021093930-appb-100007
    Figure PCTCN2021093930-appb-100008
  8. 根据权利要求1-7任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、氰基、未被取代或被至少一个R 1a取代的C 1～6烷基、未被取代或被至少一个R 1a取代的C 1～6烷氧基、未被取代或被至少一个R 1a取代的C 3～6环烷基、或未被取代或被至少一个R 1a取代的C 3～6环烷氧基；或者，R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、氰基、未被取代或被至少一个R 1a取代的C 1～6烷基或未被取代或被至少一个R 1a取代的C 1～6烷氧基；或者，R 1在每次出现时，各自独立地选自：氢、卤素、-OH、氨基、C 1～6烷基或C 1～6烷氧基。
  9. 根据权利要求1-8任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述R 1a在每次出现时，各自独立地选自：C 1-3烷基、C 1-3烷氧基、硝基、卤素、-OH、氨基、-NHC 1～6烷基、-N(C 1～6烷基) 2或氰基；或者，R 1a在每次出现时，各自独立地选自：卤素、-OH、氨基、-NHC 1～3烷基、-N(C 1～3烷基) 2或氰基。
  10. 根据权利要求1-9任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述R 2选自：H、F、OH或取代或未取代的C 1～6烷基，所述取代是指被1、2或3个选自卤素或羟基的取代基所取代；或者，R 2选自H、F、-OH或C 1～6烷基。
  11. 根据权利要求4所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述化合物具有如式(I-D)所示的结构：
    Figure PCTCN2021093930-appb-100009
  12. 根据权利要求11所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂 化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述化合物具有如式(I-D-a)、(I-D-b)或(I-D-c)所示的结构：
    Figure PCTCN2021093930-appb-100010
  13. 根据权利要求1-12任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述R 3选自：H、卤素、-OH、氨基、C 1～3烷基或C 1～3烷氧基；或者，R 3选自：H、F、Cl、-OH、甲基或甲氧基。
  14. 根据权利要求1-13任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述环A选自：C 3-6环烷基、4-6元杂环烷基、C 6-8桥环基、6-8元杂桥环基、C 8-10并环基、8-10元杂并环基、C 7-12单螺环基、7-12元杂单螺环基；或者，环A选自：4-6元杂环烷基、6-8元杂桥环基、8-10元杂并环基、7-12元杂单螺环基；其中所述杂环烷基、杂桥环基、杂并环基和杂单螺环基中的杂原子独立地选自O、S或N，所述杂原子个数选自1、2、3或4个；或者，环A选自如下结构：
    Figure PCTCN2021093930-appb-100011
  15. 根据权利要求1-14任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述R 4独立的选自：-H、-OH、卤素、-CN、氧代基、取代或未取代的C 1～6烷基、-COOH、 -CONH 2、-CO-CR 4aR 4b-OH或-CO-R 4b；或者，R 4独立的选自：-H、-OH、卤素、-CN、氧代基、取代或未取代的C 1～6烷基、-CO-CR 4aR 4b-OH或-CO-R 4b；其中，所述氧代基是指相同取代位的两个H被同一个O替代形成双键；R 4a选自氢、未取代或取代的C 1～4烷基；R 4b选自未取代或取代的C 1～6烷基或未取代或取代的C 3～6环烷基，所述取代的取代基独立地选自-OH、-NH 2、卤素，取代基个数选自1、2或3。
  16. 根据权利要求1-15任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐，其特征在于，所述化合物具有如下结构：
    Figure PCTCN2021093930-appb-100012
    Figure PCTCN2021093930-appb-100013
    Figure PCTCN2021093930-appb-100014
    Figure PCTCN2021093930-appb-100015
    Figure PCTCN2021093930-appb-100016
    Figure PCTCN2021093930-appb-100017
  17. 一种药物组合物，其包含权利要求1～16中任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐。
  18. 权利要求1～16中任一项所述的化合物或其互变异构体、立体异构体、光学异构体、溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或根据权利要求17所述的药物组合物在制备用于预防和/或治疗通过TRK、ALK、ROS1或它们的组合介导的疾病的药物中的用途。
  19. 权利要求1～16中任一项所述的化合物或其互变异构体、立体异构体、光学异构体、 溶剂化物、氮氧化物、前药、同位素衍生物或其药学上可接受的盐或根据权利要求17所述的药物组合物在制备用于治疗疼痛疾病、过度增殖性疾病、炎症疾病、神经退行性疾病或感染疾病的药物的用途。
  20. 权利要求18或19所述的用途，所述疾病涉及NTRK、ALK、ROS1或它们的组合基因融合、扩增、重排、突变或高表达。
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