WO2020064009A1 - 取代吡唑稠环类衍生物及其制备方法和应用 - Google Patents

取代吡唑稠环类衍生物及其制备方法和应用 Download PDF

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WO2020064009A1
WO2020064009A1 PCT/CN2019/109502 CN2019109502W WO2020064009A1 WO 2020064009 A1 WO2020064009 A1 WO 2020064009A1 CN 2019109502 W CN2019109502 W CN 2019109502W WO 2020064009 A1 WO2020064009 A1 WO 2020064009A1
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alkyl
membered
methyl
group
pyridin
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PCT/CN2019/109502
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English (en)
French (fr)
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王志健
钟俊
***
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北京志健金瑞生物医药科技有限公司
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Priority to US17/281,567 priority Critical patent/US20210379056A1/en
Priority to CN201980064157.1A priority patent/CN112771043B/zh
Priority to EP19865058.2A priority patent/EP3845531A4/en
Priority to KR1020217009429A priority patent/KR20210070286A/ko
Priority to JP2021542252A priority patent/JP7493251B2/ja
Publication of WO2020064009A1 publication Critical patent/WO2020064009A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 invention relates to the field of medicinal chemistry, in particular to substituted pyrazole fused ring derivatives, and a preparation method and application thereof.
  • the RET (Rearranged During Transfection) proto-oncogene was originally confirmed in 1985 by transfection of NIH3T3 (mouse embryo fibroblast cell) cells with human lymphoma DNA (Cell, 1985, 42 (2): 581-588 ).
  • the RET proto-oncogene is located on chromosome 10q11.2. Its full-length DNA is 60 kb, contains 21 exons, and encodes a RET protein consisting of 1,100 amino acids.
  • This RET protein is a tyrosine kinase receptor that contains An extracellular region composed of cysteine, a transmembrane region, and an intracellular region with catalytic tyrosine kinase action (Mol Cell Endocrinol, 2010, 322 (1-2): 2-7).
  • RET is involved in cell proliferation, nerve conduction, cell migration, and cell differentiation, and activates various downstream pathways such as RAS / RAF / MEK / ERK, PI3K / AKT, and STAT through signals from ligand / complex receptor / RET multiprotein complexes. Pathway to induce cell proliferation (J Clin Oncol, 2012, 30 (2): 200-202).
  • KIF5B-RET is the most common RET fusion gene in non-small cell lung cancer (Cancer, 2013,119 (8): 1486-1494).
  • KIF5B-RET is a fusion gene formed by the chromosome inversion (p11; q11) of the KIF5B (kinesin family member 5B) gene and the RET gene. It was first sequenced in non-smoker Korean adenocarcinomas by whole genome and transcriptome sequencing.
  • KIF5B-RET is very low in lung cancer, more common in non-smokers and patients with adenocarcinoma, and rejects other mutations such as EGFR, KRAS, BRAF, ErbB2, EML4-ALK (Genome Res, 2012 22 (3): 436-445).
  • the KIF5B-RET fusion protein contains a motor domain and a coiled-coil domain of KIF5B. Through the dimerization of the coiled-coil domain, the RET tyrosine kinase activity of the fusion protein can be abnormally activated, thereby promoting lung tumorigenesis (Cancer, 2011, 117 (12): 2709-2718). In the research by Qian et al.
  • KIF5B-RET fusion kinase has been shown to have significant oncogenic activity in vitro and in vivo, and the signal transduction pathway of STAT3 may be the main downstream mediator of tumorigenesis. .
  • KIF5B-RET regulates the sustained activation of STAT3.
  • KIF5B-RET fusion kinase can bind to STAT3 to directly phosphorylate and activate STAT3-Tyr705; it can also mediate activation of STAT3-Tyr705 through the JAK / STAT3 dependent pathway, and trigger the phosphorylation of Ser727 through the RAS / RAF / MEK / ERK1 pathway Into.
  • the present invention provides a compound represented by the following formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvents
  • Compound represented by the following formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvents
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 are the same or different and are independently selected from CR 1 , -CA or N, wherein each R 1 is the same or different and independently selected from each other H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R a : C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl , C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy , C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, NR 2 R 3 , -NHC (O) R 2 , -C (O) R 4 , -
  • B is selected from the group consisting of H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R c : C 1-40 alkyl, C 2-40 alkenyl, C 2- 40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 Alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, NR 2 R 3 , -C (O) R 4 , -NHC (O) R 4 , -OCR 5 , -S (O) 2 R 6 , OS (O) 2 R 7 ;
  • D is selected from C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 1-40 alkane, which are unsubstituted or optionally substituted with one, two or more Rd Alkoxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 6-20 aryl, 5-20 membered heteroaryl or 3-20 membered heterocyclic group;
  • E is selected from H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R e substituents of the following groups: C 1-40 alkyl, C 2-40 alkenyl, C 2- 40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 member heteroaryl, 3-20 member heterocyclic group , C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3 -40 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy or 3-20 membered heterocyclyloxy;
  • G is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R f : C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy Group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group or 3-20 membered heterocyclyloxy group;
  • K is selected from the group consisting of H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R g : C 1-40 alkyl, C 2-40 alkenyl, C 2- 40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 member heteroaryl, 3-20 member heterocyclic group , C 1-40 alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3 -40 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NR 2 R 3 , -C (O) R 4 , -OCR 5 , -S (O) 2 R 6 , OS (O
  • Each R 2 are the same or different, each independently selected from H, unsubstituted or optionally substituted by OH, NH 2 substituents of the following groups: C 1- 40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl , C 3-40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl,- C (O) R 4 , -S (O) 2 R 6 ;
  • Each R 3 is the same or different and is independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloolefin Group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5-20 member heteroaryl group, 3-20 member heterocyclic group, -C (O) R 4 , -S (O) 2 R 6 ;
  • R 2 and R 3 together with the attached N atom form a 5-20 membered heteroaryl group or a 3-20 membered heterocyclic group;
  • Each R 4 is the same or different and is independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloolefin , C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy , C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, C 6-20 aryloxy, 5 -20-membered heteroaryloxy, 3-20-membered heterocyclyloxy, NR 2 R 3 ;
  • Each R 5 is the same or different and is independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloolefin , C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 alkylcarbonyl, C 2-40 alkenylcarbonyl, C 2-40 alkynylcarbonyl, C 3-40 cycloalkylcarbonyl, C 3-40 cycloalkenylcarbonyl, C 3-40 cycloalkynylcarbonyl, C 6-20 arylcarbonyl, 5-20 membered heteroarylcarbonyl , 3-20 membered heterocyclic carbonyl group;
  • Each R 6 is the same or different and is independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloolefin , C 3-40 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 alkyloxy, C 2-40 alkenyloxy , C 2-40 alkynyloxy, C 3-40 cycloalkyloxy, C 3-40 cycloalkenyloxy, C 3-40 cycloalkynyloxy, C 6-20 aryloxy, 5 -20-membered heteroaryloxy, 3-20-membered heterocyclyloxy, NR 2 R 3 ;
  • Each R 7 is the same or different and is independently selected from H, C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 cycloolefin Group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5-20 member heteroaryl group, 3-20 member heterocyclic group;
  • two of the substituents may also form a bridge ring with the cyclic group, wherein the bridge atoms other than the bridgehead atom in the bridge ring may contain 1, 2 , 3, 4 or 5 divalent groups selected from CH 2 , O, NH;
  • the two substituent groups more atoms to which they may be attached together form a cyclic group (including but not limited to C 3- 40 cycloalkyl, C 3-40 cycloalkenyl, C 3-40 cycloalkynyl, 3-20 membered heterocyclyl, etc.).
  • the compound represented by the formula I is selected from the compounds represented by the following formula I ':
  • X 1 , X 2 , X 3 , X 4 , X 5 , A, B, D, E, G, K independently have the definitions described above.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 are the same or different and are independently selected from CR 1 , -CA or N, wherein each R 1 is the same or different and is independently selected from H, Halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R a : C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-8 cycloalkyloxy, C 3-8 cycloalkenyloxy, C 3-8 cycloalkynyloxy, NR 2 R 3 , -NHC (O) R 2 , -C (O) R 4 , -OCR 5 , -
  • B is selected from the group consisting of H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R c : C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 Alkynyloxy, C 3-8 cycloalkyloxy, C 3-8 cycloalkenyloxy, C 3-8 cycloalkynyloxy, NR 2 R 3 , -C (O) R 4 , -NHC (O) R 4 , -OCR 5 , -S (O) 2 R 6 , OS (O) 2 R 7 ;
  • D is selected from C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, C 6-10 aromatic which is unsubstituted or optionally substituted with one, two or more Rd Group, 5-10 membered heteroaryl or 3-10 membered heterocyclic group;
  • E is selected from H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R e substituents of the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl , C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-8 cycloalkyloxy, C 3-8 cycloalkenyloxy, C 3 -8 cycloalkynyloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy or 3-10 membered heterocyclyloxy;
  • G is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R f : C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 3-8 cycloalkyloxy, C 3-8 cycloalkenyloxy, C 3-8 cycloalkynyloxy C 6-10 aryloxy, 5-10 membered heteroaryloxy or 3-10 membered heterocyclyloxy;
  • K is selected from the group consisting of H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R g : C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl , C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-8 cycloalkyloxy, C 3-8 cycloalkenyloxy, C 3 -8 cycloalkynyloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy, 3-10 membered heterocyclyloxy, NR 2 R 3 , -C (O) R 4 , -OCR 5 , -S (O) 2 R 6
  • Each R 2 is the same or different, each independently selected from H, unsubstituted or optionally substituted by OH, NH 2 substituents of the following groups: C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl,- C (O) R 4 , -S (O) 2 R 6 ;
  • Each R 3 is the same or different and is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3- 8 cycloolefin , C 3-8 cycloalkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, -C (O) R 4 , -S (O) 2 R 6 ;
  • R 2 and R 3 together with the attached N atom form a 5-10 membered heteroaryl group or a 3-10 membered heterocyclic group;
  • Each R 4 is the same or different and is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3- 8 cycloolefin , C 3-8 cycloalkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 1-6 alkyloxy, C 2-6 alkenyloxy , C 2-6 alkynyloxy, C 3-8 cycloalkyloxy, C 3-8 cycloalkenyloxy, C 3-8 cycloalkynyloxy, C 6-10 aryloxy, 5 -10 membered heteroaryloxy, 3-10 membered heterocyclyloxy, NR 2 R 3 ;
  • Each R 5 is the same or different and is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3- 8 cycloolefin , C 3-8 cycloalkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 1-6 alkylcarbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl, C 3-8 cycloalkylcarbonyl, C 3-8 cycloalkenylcarbonyl, C 3-8 cycloalkynylcarbonyl, C 6-10 arylcarbonyl, 5-10 membered heteroarylcarbonyl , 3-10 membered heterocyclic carbonyl group;
  • Each R 6 is the same or different and is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3- 8 cycloolefin , C 3-8 cycloalkynyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C 1-6 alkyloxy, C 2-6 alkenyloxy , C 2-6 alkynyloxy, C 3-8 cycloalkyloxy, C 3-8 cycloalkenyloxy, C 3-8 cycloalkynyloxy, C 6-10 aryloxy, 5 -10 membered heteroaryloxy, 3-10 membered heterocyclyloxy, NR 2 R 3 ;
  • Each R 7 is the same or different and is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3- 8 cycloene Group, C 3-8 cycloalkynyl group, C 6-10 aryl group, 5-10 member heteroaryl group, 3-10 member heterocyclic group;
  • two of the substituents may also form a bridge ring with the cyclic group, wherein the bridge atoms other than the bridgehead atom in the bridge ring may contain 1, 2 , 3, 4 or 5 divalent groups selected from CH 2 , O, NH;
  • the two substituent groups more atoms to which they may be attached together form a cyclic group (including but not limited to C 3- 8 -cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, 3-10 membered heterocyclyl, etc.).
  • a cyclic group including but not limited to C 3- 8 -cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, 3-10 membered heterocyclyl, etc.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 are the same or different, and are independently selected from CR 1 , —CA or N, and R 1 is selected from NH 2 , CH 3 , N (CH 3 ) 2 , OH, H, NHC (O) CH 3 , NHCH 3 , F, OCH 3 , NHC 2 H 4 OH; for example, X 1 , X 2 , X 3 , X 4 and X 5 At least one of them is N, such as 1, 2, 3, 4 or 5 is N;
  • A may be selected from the group consisting of NH 2 , OH, H, halogen, cyano, unsubstituted or optionally substituted with one, two or more halogen, OH or NH 2 : C 1-6 alkyl,- NR 2 R 3 , -NH-C 1-6 alkyl-NR 2 R 3 , -NHCO-C 1-6 alkyl-NR 2 R 3 , -NH-C 1-6 alkyl-CO-NR 2 R 3 , -NHCO-C 1-6 alkyl-COO-C 1-6 alkyl, -NH-C 3-8 cycloalkyl-CO-NR 2 R 3 , -NH-C 2-8 alkenyl-CONR 2 R 3 , -NH-C 1-6 alkyl-CN, -NHCO-NH-R 2 , -CONR 2 R 3 or -CONH-C 1-6 alkyl-NR 2 R 3 , -NHCO-R 2 , -NH-C
  • each of R 2 and R 3 is the same or different and is independently selected from each other from H, OH, C 1-6 alkyl, 5-6 membered heterocyclyl, C 1-6 alkyl acyl Or C 1-6 alkylsulfonyl; or R 2 and R 3 together with the attached N atom form an unsubstituted or optionally oxo 5-6 membered heterocyclic group;
  • B may be selected from the group consisting of H, Cl, CN, Br, -COOH, unsubstituted or optionally substituted with one, two or more R c : -CH 3 ,- CH 2 CH 3 , -cyclopropyl, -COOCH 3 , -COOCH 2 CH 3 , -CONH 2 and -CONHCH 3 ;
  • D may be selected from the following groups which are unsubstituted or optionally substituted with one, two or more Rd : C1-6 alkyloxy-, 5-10 membered heteroaryl Or a 3-10 membered heterocyclic group;
  • E is selected from H, halogen, CN, unsubstituted or optionally substituted with one, two or more R e substituents of the following groups: C 1 ⁇ 6 alkyl, C 1-6 Alkoxy, C 1-6 cycloalkyl, 5- or 6-membered heteroaryl ring containing 1 to 3 ring heteroatoms of N, S and O, the 5- or 6-membered heteroaryl ring is optional Replaced by oxo;
  • G may be selected from the following groups which are unsubstituted or optionally substituted with one, two or more R f : 5-10 membered heteroaryl, 3-10 membered heterocyclyl, wherein
  • the heterocyclyl is selected from, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azetidinyl; or when different positions of the heterocyclyl are substituted with two or more substituents, Two of the substituents may also form a bridged ring with the heterocyclic group, wherein the bridged atom other than the bridgehead atom in the bridged ring may include 1, 2, 3, 4 or 5 selected from CH 2 , O, NH divalent groups;
  • K may be selected from H, OH, unsubstituted or optionally substituted with one or more substituents R g of the following groups: C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heteroaryl, C 1-6 alkyloxy, C 3-6 cycloalkyloxy, C 6-10 aryloxy, 5-10 membered heteroaryloxy, 3-10 membered heterocyclyloxy, N (C 1-6 alkyl) 2 , -C (O) R 4 , -OCR 5 , -S (O) 2 R 6 , -OS (O) 2 R 7 ;
  • K may be selected from the following groups which are unsubstituted or optionally substituted with one, two or more R g : C 1-6 alkyl, C 3-10 cycloalkyl,- C (O) R 4 , -OCR 5 , -S (O) 2 R 6 , -OS (O) 2 R 7 .
  • the R 4 , R 5 , R 6 , and R 7 are the same or different, and are independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkynyl, C 1-6 alkyloxy.
  • K may be selected from the following groups which are unsubstituted or optionally substituted with one, two or more Rh : C 6-10 aryl C 1-6 alkyl- or 3- 10-membered heterocyclyl C 1-6 alkyl-, such as phenyl C 1-6 alkyl- or pyridyl C 1-6 alkyl-;
  • two R g may also form a cyclic group with the atom to which it is commonly connected (including but not limited to C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, C 3-6 cycloalkynyl, 4-6 membered heterocyclyl, etc.);
  • X 6 is selected from -CA or N
  • A may be selected from H, unsubstituted or optionally substituted with one, two or more R b : NH 2 , C 1-6 alkyl, -NH (C 1-6 alkyl) 2 , OH, F, -NHC (O) C 1-6 alkyl, -NHC 1-6 alkyl, C 1-6 alkyl Oxygen, -NHC 1-6 alkyl-OH;
  • Each R b is the same or different, and is independently selected from C 1-6 alkyl and C 1-6 alkoxy;
  • B may be selected from H, CN, -CONH 2 , unsubstituted or C 1-6 alkyl optionally substituted by one, two or more R c ;
  • Each R c is the same or different and is independently selected from halogen, C 1-6 alkyl;
  • D may be selected from the following: unsubstituted or optionally substituted with one, two or more Rd : C1-6 alkyloxy or 5-14 membered heteroaryl, said Rd being selected from unsubstituted C 1-6 alkyl or 3-10 membered heterocyclyl substituted or optionally substituted by one or more of: oxo, halogen, OH, -N (C 1-6 alkyl) 2 or -S (O) 2 -C 1-6 alkyl;
  • E is selected from H, unsubstituted or optionally substituted by one, two or more of the following groups R e: C 1-6 alkyl, C 1-6 alkoxy;
  • Each R e is the same or different and is independently selected from OH, F, C 1-6 alkyl;
  • G is selected from unsubstituted or optionally oxo 3-10 membered heterocyclyl, such as unsubstituted or optionally oxo or C1-6 alkyl substituted piperazinyl, piperidinyl; or When the meta position of the heterocyclic group is substituted with two substituents, the substituent may form a bridge ring with the heterocyclic group, wherein the bridge atom other than the bridge head atom in the bridge ring may contain 1 , 2, 3, 4 or 5 divalent groups selected from CH 2 ;
  • K is selected from unsubstituted or optionally substituted by one, two or more R g of the following groups: C 1-6 alkyl, -C (O) R 4, said R g selected from oxo, OH , Unsubstituted or optionally substituted with one, two or more Rh , C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C6-14 aryl, 5 -14-membered heteroaryl, -SO 2 -C 6-14 aryl; each R 4 is the same or different, and is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 cycloalkynyl, C 6-14 aryl, 5-14 member heteroaryl, 3-10 member heterocyclic group , C 1-6 alkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy
  • X 6 is selected from -CA or N, and A may be selected from NH 2 , methyl, ethyl or propyl, -NH (CH 3 ) 2 , OH, F, -NH (O) CH 3 , -NHCH 3 , a Oxygen, -NHC 2 H 4 -OH;
  • B may be selected from H, CN, or - COCH 3;
  • D may be selected from the following groups: unsubstituted or optionally substituted with one, two or more Rd : pyrazolyl, methoxy or ethoxy, such as pyrazol-1-yl, pyrazole-3 -Yl, pyrazol-4-yl, pyrazol-5-yl;
  • Each R d is the same or different and is independently selected from OH, F, C 1-6 alkyl, hydroxy C 1-6 alkyl-, difluoro C 1-6 alkyl-, C 1-6 alkyl S (O) 2 -C 1-6 alkyl-, (C 1-6 alkyl) 2 NC (O) C 1-6 alkyl-, C 1-6 alkyloxy-, C 1-6 ring Alkyloxy, unsubstituted or 5-6 membered heterocyclic group optionally substituted with C 1-6 alkyl;
  • G is selected from unsubstituted or optionally oxo 5-6 membered heterocyclyl, such as unsubstituted or optionally substituted oxo or methyl substituted piperazinyl, piperidinyl; or, when said heterocyclyl When the meta position is substituted by two substituents, the substituent may form a bridge ring with the heterocyclic group, wherein the bridge atom other than the bridge head atom in the bridge ring may contain 1, 2 or 3 selected from A divalent group of CH 2 ;
  • K is selected from C 1-6 alkyl, -C (O) C 1-6 alkyl, unsubstituted or optionally substituted with one, two or more R g , said R g is selected from oxo, OH , Unsubstituted or optionally substituted with one, two or more Rh , C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C6-14 aryl, 5 -14-membered heteroaryl, -S (O) 2 -C 6-14 aryl; said Rh is selected from halogen, C 1-6 alkoxy, NH 2 , -N (C 1-6 alkyl) 2, -NHC 6-14 aryl, -NHC 1-6 alkyl; alternatively, when one atom (e.g., carbon atoms) K is substituted two or more R g, R g may be its two The co-attached atoms form a C 3-10 cycloalkyl.
  • R g
  • D may be selected from the following groups:
  • G may be selected from the following groups:
  • G is selected from
  • K is selected from the following groups:
  • K is selected from
  • the compound of formula I is selected from the following compounds:
  • the invention also provides a method for preparing a compound of formula I, comprising:
  • B, D, E, G, K, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 in formulae II and III have the definitions as described above;
  • B in formula III is a boron element;
  • Self-leaving groups such as halogen or OTf.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula I, a stereoisomer, a racemate, a tautomer, an isotope label, a nitrogen oxide, a pharmaceutically acceptable At least one of the accepted salts or solvates.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising associating a cell with an effective amount of a compound of formula I as defined herein, its stereoisomers, racemates, tautomers, isotopes A label, nitrogen oxide, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition thereof is contacted.
  • the present invention also provides a method for treating a RET kinase-mediated disease, which comprises administering to a patient a therapeutically effective amount of a compound represented by Formula I, a stereoisomer, a racemate, a tautomer, and an isotope label. At least one of nitrogen oxides, nitrogen oxides, pharmaceutically acceptable salts or solvates.
  • Also provided herein is a method of treating a RET-related disease or disorder in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a compound of formula I, a stereoisomer thereof, as defined herein , Racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions thereof.
  • IBS irritable bowel syndrome
  • a method of treating irritable bowel syndrome (IBS) and / or pain associated with IBS in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a formula as defined herein
  • gastrointestinal diseases e.g., diarrhea
  • chemotherapy including chemotherapy
  • IBS irritable bowel syndrome
  • the invention also provides a compound represented by Formula I as defined herein, its stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or solvates Or a pharmaceutical composition thereof for use in providing supportive care for cancer patients, including preventing or minimizing gastrointestinal conditions, such as diarrhea, associated with treatment, including chemotherapy.
  • the present invention also provides at least one of a compound represented by Formula I, a stereoisomer, a racemate, a tautomer, an isotope label, a nitrogen oxide, a pharmaceutically acceptable salt, or a solvate.
  • a compound represented by Formula I a stereoisomer, a racemate, a tautomer, an isotope label, a nitrogen oxide, a pharmaceutically acceptable salt, or a solvate.
  • IBS irritable bowel syndrome
  • Also provided herein is a method for treating cancer in a patient in need comprising (a) determining whether the cancer is associated with a disorder: the expression or activity of a RET gene, a RET kinase, or any one of them Or levels (e.g., RET-related cancers); (b) if the cancer is determined to be associated with a disorder: the expression or activity or level of the RET gene, RET kinase, or any of them (e.g., RET-related cancers) ), Administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof.
  • RET-related cancers such as RET-related cancers with one or more RET inhibitor resistance mutations
  • pharmaceutical combinations for treating cancer comprising (a) Formula I The compound shown, its stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or solvates, (b) other therapeutic agents, and (c ) Optionally at least one pharmaceutically acceptable carrier, wherein the compound of formula I, its stereoisomers, racemates, tautomers, isotopic labels, nitrogen oxides, pharmaceutically acceptable
  • the accepted salt or solvate and said other therapeutic agent are formulated into separate compositions or dosages for simultaneous, separate or sequential use in the treatment of cancer, wherein the compound of formula I, its stereoisomers, racemates Isomers, tautomers, isotope markers, nitrogen oxides, pharmaceutically acceptable salts or solvates, and the amount of the therapeutic agent together are effective to treat the cancer.
  • compositions comprising such a combination.
  • the use of such a combination in the manufacture of a medicament for treating cancer is also provided herein.
  • a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and relates to a method of treating cancer in a patient in need.
  • Also provided herein is a method for reversing or preventing acquired resistance to anticancer drugs, which method comprises treating a therapeutically effective amount of a compound of Formula I, its stereoisomers, racemates, tautomers
  • the conformers, isotope markers, nitrogen oxides, pharmaceutically acceptable salts or solvates are administered to patients at risk of developing anticancer drugs or having acquired resistance.
  • Also provided herein is a method of delaying and / or preventing the development of anticancer drug resistance in an individual, the method comprising administering an effective amount of a compound of formula I, a stereoisomer, a racemate, a tautomer, to the individual A conformer, an isotope label, a nitrogen oxide, a pharmaceutically acceptable salt, or a solvate, an effective amount of an anticancer drug is administered before, during, or after.
  • Also provided herein is a method of treating an individual with cancer and an increased likelihood of developing resistance to an anticancer drug, which comprises concomitantly administering to the individual (a) an effective amount of a compound of formula I, a stereoisomer thereof, Racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvates; and (b) an effective amount of an anticancer drug.
  • Methods of treating individuals with RET-associated cancers are also provided, the cancers having one or more RET inhibitor resistance mutations that increase the cancer against compounds other than those represented by Formula I Resistance to RET inhibitors, their stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvates (e.g., at amino acid position 804 (Such as V804M, V804L, or V804E), which includes administering a compound represented by Formula I, its stereoisomers, racemates, tautomers, before, during, or after administration of another other anticancer drug Conformers, isotopic labels, nitrogen oxides, pharmaceutically acceptable salts or solvates.
  • RET inhibitors their stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvates
  • isotopic labels e.g., at amino acid position 804 (Such as V804M, V804L, or V804E)
  • a compound represented by Formula I a stereoisomer thereof, racemate, before, during, or after administration of another other anticancer drug.
  • cancer eg, RET-related cancer
  • the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof Or a pharmaceutical composition thereof.
  • the cancer eg, RET-related cancer
  • the cancer is a hematological cancer.
  • the cancer eg, RET-related cancer
  • the cancer is a solid tumor.
  • the cancer eg, RET-related cancer
  • lung cancer eg, small cell lung cancer or non-small cell lung cancer
  • papillary thyroid cancer medullary thyroid cancer
  • differentiated thyroid Cancer recurrent thyroid cancer
  • refractory differentiated thyroid cancer lung adenocarcinoma
  • bronchiolar lung cancer multiple endocrine tumors of type 2A or 2B (MEN2A or MEN2B, respectively)
  • pheochromocytoma parathyroid hyperplasia
  • breast Cancer colorectal cancer (eg, metastatic colorectal cancer)
  • papillary renal cell carcinoma gangliocytoma of the gastrointestinal mucosa
  • inflammatory myofibroblastoma or cervical cancer.
  • the cancer eg, RET-related cancer
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • ASML acute myeloid leukemia
  • ASML acute myeloid leukemia
  • ASML acute myeloid leukemia
  • Appendix cancer astrocytoma, atypical teratoma / striated tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkee Special lymphoma, carcinoid tumor, unknown primary cancer, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative tumor, colon cancer, Colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductal carcinoma in situ, embryonic tumors
  • ALL acute lymphocy
  • the hematological cancer is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma) And myeloma, for example, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloid Monocyte Leukemia (CMML), Chronic Neutrophil Leukemia (CNL), Acute Undifferentiated Leukemia (AUL), Anaplastic Large Cell Lymphoma (ALCL), Prolymphocytic Leukemia (PML), Juvenile Monocyte Leukemia (JMML), adult T cell ALL, triple AML (AML / TMDS), mixed line
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • hematological cancer eg, hematological cancer as a RET-related cancer
  • hematological cancer is AML or CMML.
  • the cancer is a solid tumor.
  • solid tumors include, for example, thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer), lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic duct Cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck tumors, neuroblastoma and melanoma. See, for example, Nature Reviews Cancer, 2014, 14, 173-186.
  • the cancer is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, 2A or 2B multiple endocrine tumors (respectively MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglion cell tumor, and cervical cancer.
  • lung cancer papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, 2A or 2B multiple endocrine tumors (respectively MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglion cell tumor, and cervical cancer.
  • the patient is a human.
  • a disorder such as the RET gene, RET kinase, or any one of them
  • B if it is determined that IBS is associated with a disorder: the RET gene, RET kinase, or the expression or activity or level of any of them, administer to the patient a therapeutically effective amount of a compound of formula I Or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • a pharmaceutical combination for treating irritable bowel syndrome (IBS) in a patient in need which comprises administering a compound of formula I, its stereoisomers, racemates, tautomers Conformers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvates, (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous use , Separately or sequentially for the treatment of IBS, wherein the compound of formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or solvates The amount of the substance and the amount of other therapeutic agents are collectively effective in treating IBS. Also provided herein are pharmaceutical compositions comprising such a combination.
  • a combination in the manufacture of a medicament for the treatment of IBS is also provided herein.
  • a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and relates to a method of treating IBS in a patient in need.
  • the compound of the present invention can be administered in the form of a pharmaceutical composition.
  • compositions can be prepared in a manner well known in the pharmaceutical arts and can be administered in a variety of ways, depending on whether local or systemic treatment is required and the area being treated.
  • Topical e.g., transdermal, skin, eye, and mucosal delivery including intranasal, vaginal, and rectal delivery
  • lungs e.g., by inhalation or insufflation of powder or aerosol, including via nebulizer; intratracheal, intranasal
  • parenterally e.g., transdermal, skin, eye, and mucosal delivery including intranasal, vaginal, and rectal delivery
  • lungs e.g., by inhalation or insufflation of powder or aerosol, including via nebulizer; intratracheal, intranasal
  • parenterally e.g., transdermal, skin, eye, and mucosal delivery including in
  • Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial such as intrathecal or intraventricular administration. It can be administered parenterally in a single large dose, or it can be administered, for example, by a continuous infusion pump.
  • Pharmaceutical compositions and preparations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, etc. may be necessary or required. Coated condoms, gloves, etc. may also be useful.
  • the active ingredient is usually mixed with excipients, diluted with the excipients or filled into such carriers in the form of capsules, sachets, paper or other containers.
  • excipients When an excipient is used as a diluent, it can be a solid, semi-solid or liquid substance, used as a vehicle, carrier or medium for the active ingredient.
  • the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble Liquid vehicle); ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing, for example, up to 10% by weight of active compound.
  • excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polysaccharide Vinyl pyrrolidone, cellulose, water, syrup and methyl cellulose.
  • the formulations may also contain: lubricants such as talc, magnesium stearate and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents.
  • the compositions of the invention may be formulated by using methods known in the art to provide the effect of an immediate, sustained or delayed release of the active ingredient upon administration to a patient.
  • composition can be formulated in unit dosage forms, each dosage containing from about 5 to 1000 mg, more usually about 100 to 500 mg of the active ingredient.
  • unit dosage form means a physically separated unit suitable for use as a single dosage unit for human patients and other mammals, each unit containing a predetermined amount of activity calculated in combination with a suitable pharmaceutical excipient to produce the desired therapeutic effect substance.
  • the effective dose of the active compound may vary widely, and is usually administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered is usually determined by the physician based on the circumstances, and includes the condition being treated, the route of administration chosen, the actual compound being administered; the age, weight and response of the individual patient; Severity, etc.
  • the main active ingredient is mixed with pharmaceutical excipients to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the invention.
  • a solid pre-formulation composition containing a homogeneous mixture of a compound of the invention.
  • the active ingredient is generally uniformly distributed throughout the composition, so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills, and capsules.
  • This solid pre-formulation is then divided into unit dosage forms of the above-mentioned type containing, for example, about 0.1 to 1000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or compounded to obtain a dosage form that provides the advantages of long-lasting effects.
  • a tablet or pill contains internal and external dose components, the latter being in the form of a coating of the former.
  • the two components can be separated by an enteric layer, which is used to prevent disintegration in the stomach, allowing the internal components to pass through the duodenum intact or to be delayed.
  • enteric layers or coatings such materials including a variety of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms for oral or injection administration include aqueous solutions, suitably flavored syrups, water or oil suspensions; and edible oils such as cottonseed oil, sesame oil, coconut Oil or peanut oil flavored emulsions; and tinctures and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions, powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof.
  • Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above.
  • the composition is administered by the oral or nasal respiratory route to achieve a local or systemic effect.
  • the composition can be atomized by using an inert gas.
  • the nebulizing solution can be inhaled directly from the nebulizing device, or the nebulizing device can be connected to a mask curtain or intermittent positive pressure ventilator.
  • the solution, suspension, or powder composition can be administered orally or by a device that delivers the formulation in an appropriate manner.
  • the amount of the compound or composition to be administered to a patient is not fixed, depending on the drug to be administered, the purpose of administration, such as prevention or treatment, the state of the patient, the manner of administration, and the like.
  • a composition can be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially inhibit the symptoms of the disease and its complications.
  • the effective dose will depend on the condition being treated and the judgment of the attending clinician, which will depend on factors such as the severity of the disease, the age, weight and general condition of the patient.
  • composition to be administered to a patient may be in the form of a pharmaceutical composition as described above. These compositions can be sterilized by conventional sterilization techniques or filter sterilizable.
  • the aqueous solution can be used as it is, or lyophilized. Before administration, the lyophilized preparation is mixed with a sterile aqueous carrier.
  • the pH of the compound preparation is usually 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of certain of the aforementioned excipients, carriers or stabilizers will lead to the formation of pharmaceutical salts.
  • the therapeutic dose of a compound of the present invention can be determined, for example, based on the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of a compound of the invention in a pharmaceutical composition may not be fixed, depending on a number of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.
  • the compound of the present invention can be provided by a physiological buffer solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical doses range from about 1 ⁇ g / kg to about 1 g / kg body weight / day.
  • the dosage ranges from about 0.01 mg / kg to about 100 mg / kg body weight / day.
  • the dosage is likely to depend on such variables as the type and degree of development of the disease or disorder, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipient and its route of administration. Effective doses can be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.
  • the numerical ranges described in this specification and the claims are equivalent to at least each specific integer value described therein.
  • the numerical range “1-40” corresponds to each integer value in the numerical range “1-10", which is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and the numerical range.
  • Each integer value in “11-40” is 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40.
  • "more” shall mean an integer ⁇ 3, such as 3, 4, 5, 6, 7, 8, 9, or 10 .
  • certain numerical ranges are defined as "numbers”, it should be understood that the two endpoints of the range, each integer in the range, and each decimal in the range are recorded.
  • a number from 0 to 10 should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also recording at least each of these integers separately And 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • halogen means fluorine, chlorine, bromine and iodine.
  • C 1-40 alkyl is understood to preferably mean a straight or branched chain saturated monovalent hydrocarbon group having 1 to 40 carbon atoms.
  • C 1-6 alkyl means straight and branched chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Methyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, and the like or their isomers.
  • C 2-40 alkenyl should be understood as preferably a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 40 carbon atoms, preferably “C 2-6 alkenyl” .
  • C 2-6 alkenyl is to be understood as preferably a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms (“C 2-3 alkenyl”), it should be understood that in the case where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z)- But-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -Pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-ene , Hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3- Alkenyl, (E) -hex-2-enyl, (Z) -hex-2
  • C 2 - 40 alkynyl group is understood to mean a straight or branched divalent hydrocarbon group, which contains one or more triple bonds and having 2 to 40 carbon atoms, preferably "C 2 -C 6 - alkynyl ".
  • C 2 -C 6 -alkynyl should be understood as preferably a straight or branched monovalent hydrocarbon group which contains one or more triple bonds and has 2, 3, 4, 5 or 6 carbon atoms, in particular Is 2 or 3 carbon atoms ("C 2 -C 3 -alkynyl").
  • the C 2 -C 6 -alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, Pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex 4-alkynyl, hex-5-alkynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methyl But-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl , 1-methylpent-4-ynyl, 2-methylp
  • C 3-40 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3 to 40 carbon atoms, preferably “C 3-10 cycloalkyl”.
  • C 3-10 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic A hydrocarbyl group such as a decalin ring.
  • 3-20 membered heterocyclyl means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which comprises a total number of ring atoms of 1-5 heteroatoms independently selected from N, O and S Non-aromatic cyclic groups of 3-20 (such as 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably “3-10 membered heterocyclic groups”.
  • 3-10 membered heterocyclyl means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane, which contains 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclyl can be attached to the rest of the molecule through any of the carbon atoms or nitrogen atoms, if present.
  • the heterocyclic group may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl, and a 5-membered ring such as tetrahydrofuranyl, dioxolyl, and pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or a 7-membered ring, such as diazacycloheptyl.
  • the heterocyclyl may be benzo-fused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -based ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrole And [1,2-a] pyrazine-2 (1H) -based ring.
  • the nitrogen atom-containing ring may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadi Azinyl, 4,5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • the carbon atom on the 3-20 membered heterocyclic group may be connected to other groups, or the 3-20 membered heterocyclic group may be connected.
  • Heterocyclic atoms on the ring are connected to other groups.
  • the nitrogen atom on the piperazinyl group may be connected to other groups.
  • the 3-20 membered heterocyclic group is selected from piperidinyl, it may be a nitrogen atom on the piperidinyl ring and a carbon atom in the para position thereof to be connected to other groups.
  • C 6-20 aryl is understood to mean preferably a monovalent, aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C 6-14 aryl” .
  • C 6-14 aryl should be understood to preferably represent a monovalent, partially aromatic, or monocyclic, bicyclic, or monocyclic aromatic moiety having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms.
  • Tricyclic hydrocarbon ring (“C 6-14 aryl”), especially a ring with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or 9 carbon atoms
  • a ring (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring with 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • the C 6-20 aryl group When the C 6-20 aryl group is substituted, it may be mono- or poly-substituted.
  • substitution site there is no limitation on the substitution site, and for example, it may be an ortho, para or meta substitution.
  • the term "5- to 20-membered heteroaryl” is understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system which has 5 to 20 ring atoms and contains 1-5 independently selected from N, O And S heteroatoms, such as "5- to 14-membered heteroaryl".
  • the term "5-14 membered heteroaryl” should be understood to include a monovalent monocyclic, bicyclic, or tricyclic aromatic ring system which has 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3, heteroatoms each independently selected from N, O and S and, in addition in each case The following may be benzo-fused.
  • the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazyl Diazolyl, thia-4H-pyrazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzene Benzotriazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinoline Group, quinazoline group, isoquinolinyl group, etc .; or acinoinyl group, indazinyl group, purinyl group, etc.
  • the 5-20 membered heteroaryl group When the 5-20 membered heteroaryl group is substituted, it may be mono- or poly-substituted. In addition, there is no restriction on the substitution site. For example, it may be that a hydrogen connected to a carbon atom on a heteroaryl ring is replaced, or a hydrogen connected to a hetero atom on a heteroaryl ring is replaced.
  • heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as its positional isomers. Therefore, for some illustrative non-limiting examples, it may include 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12 -Positions, etc.
  • thienyl or thienyl includes thien-2-yl, thienyl-2-yl, thien-3-yl, and thienyl-3 -Yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
  • C 1-6 alkyl also applies to C 1-6 alkyloxy, -N (C 1-6 alkyl ) 2 , -NHC 1-6 alkyl or -S (O) 2 -C 1-6 alkyl, and the like.
  • the compound represented by Formula I may exist in the form of various pharmaceutically acceptable salts. If these compounds have basic centers, they can form acid addition salts; if they have acidic centers, they can form base addition salts; if these compounds contain both acidic centers (such as carboxyl groups) and basic centers ( Such as amino), it can also form internal salts.
  • the number of salts formed by the compound in this application is determined by the basic center or the acidic center. For example, when a compound contains multiple salt-forming sites, the number of salt-forming sites is equal to the number of salt-forming sites.
  • Acid addition salts include, but are not limited to, hydrochloride, hydrofluoride, hydrobromide, hydroiodate, sulfate, pyrosulfate, phosphate, nitrate, mesylate, and ethanesulfonate , 2-hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetate, pyruvate, laurate, cinnamate, Benzoate, acetate, diglycolate, trifluoroacetate, trimethylacetate, propionate, butyrate, hexanoate, heptanoate, undecanoate, hard Fatty acid, ascorbate, camphorate, camphorsulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, salicylate, amber Acid
  • the compound of the present invention may exist in the form of a solvate such as a hydrate, wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol or ethanol.
  • the amount of polar solvents, especially water may be present in a stoichiometric or non-stoichiometric ratio.
  • the compounds of the invention may be chiral, and therefore various enantiomeric forms may exist. These compounds can therefore exist in racemic or optically active forms.
  • the compounds of the present invention or intermediates thereof can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in synthesis in this form. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution reagent.
  • suitable resolution reagents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N- Benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids.
  • optically active resolution reagents e.g. dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers
  • chromatographic enantiomeric resolution is performed.
  • a suitable eluent for this purpose is an aqueous or alcohol-containing solvent mixture, for example, hexane / isopropanol / acetonitrile.
  • tautomer refers to a functional group isomer produced by the rapid movement of an atom in two positions in a molecule.
  • the compounds of the invention may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Proton tautomers result from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium. When trying to separate a single tautomer, a mixture is usually produced, whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates; while in the phenol, the enol form predominates.
  • the invention encompasses all tautomeric forms of the compounds.
  • the corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is looking for in a tissue, system, animal, individual, or human to cause a biological or medical response.
  • the inventors have surprisingly found that the compounds prepared by the present invention have significant inhibitory activities against wild-type, mutant and fusion types of RET. And compared with the existing compounds, its activity is significantly improved. Compared with other RET inhibitors, the representative compounds of the present invention also have particularly excellent pharmacokinetic properties and can be administered to patients in smaller doses as an active ingredient, thereby reducing the cost of treatment for patients. In addition, the compound preparation method of the present application is simple and suitable for large-scale production.
  • the compound APS001 represented by the above formula can refer to the method disclosed in Example 342 of the patent document CN108349969A. After preparing the obtained APS001 trifluoroacetate, it is released under alkaline conditions (sodium bicarbonate) to obtain the target compound APS001.
  • Compound APS002 can be prepared by referring to the method disclosed in Patent Document CN108349969A Example 570 to obtain the target compound APS002.
  • Step A tert-butyl ((methanesulfonyl) oxy) carbamate
  • Step B 2-[(Aminooxy) sulfonyl] -1,3,5-trimethylbenzene
  • tert-butyl ((methanesulfonyl) oxy) carbamate (10.0g, 31.7mmol) was added to trifluoroacetic acid (80mL) in portions. After completion, the reaction system was stirred at zero degrees for 3 hours. Hours; TLC point plate confirms the completion of the reaction, pour the reaction system into a large amount of ice water, and stir for 15 minutes, a large amount of white solid precipitates, filter under reduced pressure, wash the filter cake with a large amount of water until the solid PH is neutral, and filter under reduced pressure. It is sufficient to reach a solid water content of about 20%, and it is directly used in the next step without further purification.
  • Step C 2,4,6-trimethylbenzenesulfonic acid 1-amino-3-bromo-5-methoxypyridine-1-ium
  • Step E 2-Amino-6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step F 2-amino-4-methoxy-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step G 2-amino-4-hydroxy-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step H 2-amino-3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridin-4-yltrifluoromethanesulfonate
  • Step J 2- (5-fluoropyridin-2-yl) ethyl acetate
  • Step K 2- (5-fluoropyridin-2-yl) acetic acid
  • aqueous phase was adjusted to pH with 1M hydrochloric acid to About 3, then extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product 2- (5-fluoropyridin-2-yl) acetic acid (2.04 g, 44% yield) .
  • Step L 1- (5-bromopyridine) -2-piperazine
  • Step M 1- (4- (5-Bromopyridin-2) piperazin-1-yl) -2- (5-fluoropyridin-2-yl) ethanone
  • Step N 2- (5-fluoropyridin-2-yl) -1- (4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxoboric acid-2-yl ) Pyridin-2-yl) piperazin-1-yl) ethanone
  • Step O 2-amino-4- (6- (4- (2- (5-fluoropyridin-2-yl) acetyl) piperazin-1-yl) pyridin-3-yl) -6- (1- Methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step N 2-amino-3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridin-4-yltri Flumesulfonate (26mg, 0.067mol), tetratriphenylphosphonium palladium (15mg, 0.013mol), potassium carbonate (36mg, 0.264mol), 1,4-dioxane (2mL), H 2 O ( 1 mL), replaced with nitrogen three times, and reacted at 90 ° C. for 2 hours.
  • LCMS confirmed that the reaction of the raw materials was completed and a product was formed. Water was added and extracted with ethyl acetate.
  • Step B 2- (piperidin-4-ylmethyl) pyridine hydrochloride
  • Step C 5-bromo-2- (4- (pyridin-2-ylmethyl) piperidin-1-yl) pyridine
  • Step D 2- (4- (pyridin-2-ylmethyl) piperidin-1-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxolane Borane-2-yl) pyridine
  • Step E 2-amino-6- (1-methyll-1hydro-pyrazol-4-yl) -4- (6- (4-pyridin-2-ylmethyl) piperidin-1-yl) Piperidin-3-yl) pyrazole [1,5-a] pyridine-3-carbonitrile
  • Step A 2-methyl-6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carboxylic acid ethyl ester
  • Step B 2-methyl-6-bromo-4-methoxypyrazolo [1,5-a] pyridine
  • Step C 2-methyl-6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carboxaldehyde
  • Step D (E) -2-methyl-6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carboxoxime
  • Step E 2-methyl-6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step F 2-methyl-4-methoxy-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step G 2-methyl-4-hydroxy-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step H 2-methyl-3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridin-4-yltrifluoromethanesulfonic acid ester
  • Step I 2- (5-fluoropyridin-2-yl) -1- (4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxoboric acid-2-yl ) Pyridin-2-yl) piperazin-1-yl) ethanone
  • Step J 2-methyl-4- (6- (4- (2- (5-fluoropyridin-2-yl) acetyl) piperazin-1-yl) pyridin-3-yl) -6- (1 -Methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step I To the reaction solution of Step I was added 2-methyl-3-cyano-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridin-4-yl Trifluoromethanesulfonate (50mg, 0.13mol), tetratriphenylphosphonium palladium (15mg, 0.01mol), potassium carbonate (36mg, 0.26mol), 1,4-dioxane (4mL), H 2 O (1 mL), replaced with nitrogen three times, and reacted at 90 ° C. for 2 hours.
  • LCMS confirmed that the reaction of the raw materials was completed and a product was formed. Water was added and extracted with ethyl acetate.
  • Step A 1- (5-bromopyridin-2-yl) -4-((5-fluoropyridin-3-yl) methyl) piperazine
  • Step B 1-((4-fluoropyridin-3-yl) methyl) -4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane 2-yl) pyridin-2-yl) piperazine
  • Step C 2-amino-4- (6- (4-((5-fluoropyridin-3-yl) methyl) piperazine-6- (1-methyl-1H-pyrazol-4-yl) pyridine Zolo [1,5-a] pyridine-3-carbonitrile
  • the preparation method is the same as that in Example 5, and 5-fluoronicotinaldehyde is replaced with 2-fluorobenzaldehyde to obtain 2-amino-4- (6- (4-((2-fluorobenzyl) piperazine-6- (1- Methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (12 mg, 31% yield).
  • the preparation method is the same as that in Example 1.
  • the 2- (5-fluoropyridin-2-yl) acetic acid is replaced with diethylcarbamoyl chloride to obtain 4- (5- (2-amino-3-cyano-6- (1- Methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridin-4-yl) pyridin-2-yl) -N, N-diethylpiperazine-1-carboxamide ( 5.1mg, yield 14%), 1 HNMR (400MHz, CDCl 3 ) ⁇ 8.79 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.74-7.83 (s, 2H), 7.70 (s, 1H), 7.52 (s, 1H), 6.83 (d, 1H), 4.00 (d, 3H), 3.70 (s, 4H), 3.39 (d, 4H), 3.24-3.30 (m, 4H), 1.16 (t, 6H
  • the preparation method is the same as that in Example 5, and 5-fluoronicotinaldehyde is replaced with 3-fluorobenzaldehyde to obtain 2-amino-4- (6- (4-((3-fluorobenzyl) piperazine-6- (1- Methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (26.9mg, yield 73%).
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced with 2,5-difluorobenzaldehyde to obtain 2-amino-4- (6- (4-((2,5-difluorobenzyl) piperazine).
  • 2-amino-4- (6- (4-((2,5-difluorobenzyl) piperazine).
  • -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (9.9 mg, yield 26%).
  • the preparation method is the same as that in Example 5, and 5-fluoronicotinaldehyde is replaced with 5-chloro-nicotinaldehyde to obtain 2-amino-4- (6- (4-((5-chloropyridin-3-yl) methyl) piperazine Azine-6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (21 mg, yield 55%).
  • the preparation method is the same as that in Example 5. Substituting 5-fluoronicotinaldehyde for 3-methyl-2-pyridinaldehyde to obtain 2-amino-6- (1-methyl-1H-pyrazol-4-yl) -4- (6-((3-methylpyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (5 mg, yield Rate 14%).
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced with 2,6-difluorobenzaldehyde to obtain 2-amino-4- (6- (4-((2,6-difluorobenzyl) piperazine).
  • 2-amino-4- (6- (4-((2,6-difluorobenzyl) piperazine).
  • -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (3.5 mg, yield 9%).
  • the preparation method is the same as in Example 5, and 5-fluoronicotinaldehyde is replaced with 4-methyl-2-pyridinaldehyde to obtain 2-amino-6- (1-methyl-1H-pyrazol-4-yl) -4- ( 6-((4-methylpyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (3.9 mg, yield Rate 11%).
  • the preparation method is the same as in Example 5.
  • 5-fluoronicotinaldehyde is replaced with 3-methoxybenzaldehyde to obtain 2-amino-4- (6- (4- (3-methoxybenzyl) piperazine-1- Yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (14.2 mg, yield 37%) .
  • the preparation method is the same as in Example 5, and 5-fluoronicotinaldehyde is replaced with 2-chlorobenzaldehyde to obtain 2-amino-4- (6- (4- (2-chlorobenzyl) piperazin-1-yl) pyridine- 3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (9.4 mg, yield 25%).
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced with 6-methoxy-2-pyridinecarboxaldehyde to obtain 2-amino-4- (6- (4-((6-methoxypyridine-2- Yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3- Nitrile (8.6 mg, yield 23%).
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced with 5-methoxynicotinaldehyde to obtain 2-amino-4- (6- (4-((5-methoxypyridin-2-yl) methyl) Yl) piperazin-1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (21.9 mg, yield 58%).
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced by 2-pyridinaldehyde to obtain 2-amino-6- (1-methyl-1H-pyrazol-4-yl) -4- (6- (4 -(4- (pyridin-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (12.7 mg, yield 35% ), 1 HNMR (400MHz, DMSO-d 6 ) ⁇ 8.79 (d, 1H), 8.52 (d, 1H), 8.33 (d, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.72 -8.80 (m, 2H), 7.48-7.51 (m, 2H), 7.24-7.31 (m, 1H), 6.91-6.96 (d, 1H), 6.29 (s, 2H), 3.86 (s, 3H), 3.59 -3.67 (m
  • Step A 3- (5-Bromopyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-tert-butyl carbonate
  • Step B 3- (5-Bromopyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane dihydrochloride
  • Step C 3- (5-bromopyridin-2-yl) -6- (pyridin-2-ylmethyl) -3,6-diazabicyclo [3.1.1] heptane
  • Step D 6- (pyridin-2-ylmethyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) Pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane
  • Step E At room temperature, add 6- (pyridin-2-ylmethyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane Alk-2-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane (34 mg, 0.087 mmol) and 2-amino-3-cyano-6- (1-methyl -1H-pyrazol-4-yl) pyrazole [1,5-a] pyridin-4-yl-trifluoromethanesulfonate (28 mg, 0.073 mmol) 1,4-dioxane (2.5 mL ) To the solution was added sodium carbonate (38 mg, 0.358 mmol, 2M) aqueous solution and nitrogen for 2 minutes, followed by tetratriphenylphosphine palladium (4 mg, 0.003 mmol), nitrogen for 2 minutes, and stirred at 90 ° C for 1 hour.
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced with 6-dimethylaminonicotinaldehyde to obtain 2-amino-4- (6- (4-((6- (dimethylamino) pyridin-3-yl ) Methyl) piperazin-1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (22.2mg, yield 56%), 1 HNMR (400MHz, DMSO-d 6 ) ⁇ 8.79 (d, 1H), 8.28-8.33 (m, 2H), 8.02 (d, 2H), 7.74-7.77 (m , 1H), 7.55 (d, 1H), 7.46-7.49 (m, 1H), 6.94 (d, 1H), 6.64 (d, 1H), 6.28 (s, 2H), 3.86 (s, 3H), 3.57 (
  • the preparation method is the same as in Example 1.
  • 2- (5-fluoropyridin-2-yl) acetic acid was replaced with 2,6-difluorobenzoyl chloride to obtain 2-amino-4- (6- (4- (2,6 -Difluorobenzoyl) piperazin-1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine- 3-nitrile (28.7 mg, yield 73%).
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced with pyrazine-2-carbaldehyde to obtain 2-amino-6- (1-methyl-1H-pyrazol-4-yl) -4- (6- (4- (Pyrazin-2-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (9.5 mg, yield 26%) .
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced with 6-methoxy-3-pyridinecarboxaldehyde to obtain 2-amino-4- (6- (4-((6-methoxypyridine-3- Yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridin-3- Nitrile (20 mg, yield 53%).
  • the preparation method is the same as in Example 5, and 5-fluoronicotinaldehyde is replaced with benzaldehyde to obtain 2-amino-4- (6- (4-benzylpiperazin-1-yl) pyridin-3-yl) -6- ( 1-Methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (27 mg, yield 75%).
  • the preparation method is the same as that in Example 5, and 5-fluoronicotinaldehyde is replaced with nicotinaldehyde to obtain 2-amino-6- (1-methyl-1H-pyrazol-4-yl) -4- (6- (4- ( Pyridine-3-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (7 mg, 19%).
  • the preparation method is the same as in Example 5.
  • 5-fluoronicotinaldehyde is replaced with 4-fluorobenzaldehyde to obtain 2-amino-4- (6- (4- (4-fluorobenzyl) piperazin-1-yl) pyridine- 3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (10 mg, yield 27%).
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced by isonicotinaldehyde to obtain 2-amino-6- (1-methyl-1H-pyrazol-4-yl) -4- (6- (4- (Pyridin-4-ylmethyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (8.4 mg, yield 23%).
  • the preparation method is the same as in Example 5, and 5-fluoronicotinaldehyde is replaced with 3,4-difluorobenzaldehyde to obtain 2-amino-4- (6- (4- (3,4-difluorobenzyl) piperazine- 1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (12.7 mg, yield 33 %).
  • the preparation method is the same as that in Example 5.
  • the 5-fluoronicotinaldehyde is replaced with 2,6-difluorobenzaldehyde to obtain 2-amino-4- (6- (4- (2,6-difluorobenzyl) piperazine- 1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (27 mg, yield 70% ).
  • Step A 6-bromo-4-chloro- [1,2,3] triazol [1,5-a] pyridine-3-carbonitrile
  • Step B 4-Chloro-6- (1-methyl-1H-pyrazol-4-yl)-[1,2,3] triazol [1,5-a] pyridine-3-carbonitrile
  • the preparation method is the same as that in Step F of Example 1.
  • the 2-amino-6-bromo-4-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile is replaced with 6-bromo-4-chloro- [1. , 2,3] triazol [1,5-a] pyridine-3-carbonitrile to give 4-chloro-6- (1-methyl-1H-pyrazol-4-yl)-[1,2,3 ] Triazole [1,5-a] pyridine-3-carbonitrile (20 mg, yield 40%).
  • m / z 259 [M + 1] + .
  • Step C The preparation method is the same as that in Example 5, and 5-fluoronicotinaldehyde is replaced with 6-methoxynicotinaldehyde to obtain 4- (6- (4-((6-methoxypyridin-3-yl) methyl) ) Piperazin-1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,2,3] triazol [1,5- a] Pyridine-3-carbonitrile (10 mg, yield 27%).
  • the preparation method is the same as in Example 40, and 2-amino-4- (5- (6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] Heptane-3-yl) pyrazin-2-yl) -6-(((S) -morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridin-3-carbonitrile Fluoroacetate was replaced with 2-amino-4- (6- (4-((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile gives 7-fluoro-4- (6- (4-((6-methoxy Pyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (1
  • 2-amino-4- (6- (4-((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (1-methyl -1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (APS068) (20mg, 0.038mmol) was dissolved in acetic anhydride (2.0mL) and heated to 80 ° C for 4h. The reaction solution was added to water and extracted with ethyl acetate.
  • the preparation method is the same as in Example 34 to obtain 2-methylamino-4- (6- (4-((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (8 mg, yield 15%).
  • m / z 535 [M + 1] + .
  • Step A 3- (5-chloropyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane-6-tert-butyl carbonate
  • Step B 3- (5-chloropyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane dihydrochloride
  • Step C 3- (5-chloropyrazin-2-yl) -6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane alkyl
  • Step D 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane Borane-2-yl) pyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane
  • Step E 2-Amino-4-chloro-6-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step F 4-Chloro-2- (1,3-phthalimide-2-yl) -6-methoxypyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step G 4-Chloro-2- (1,3-phthalimide-2-yl) -6-hydroxypyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step H (S) -2-(((4-chloro-3-cyano-2- (1,3-phthalimide-2-yl) pyrazolo [1,5-a] Pyridine-6-yl) oxy) methyl) morpholine-4-tert-butyl carbonate
  • Step I At room temperature, add 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3, 2-dioxolane-2-yl) pyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane (37mg, 0.087mmol) and (S) -2- ( ((4-chloro-3-cyano-2- (1,3-phthalimide-2-yl) pyrazolo [1,5-a] pyridin-6-yl) oxy) form ) Morpholine-4-tert-butyl carbonate (39 mg, 0.073 mmol) in a solution of 1,4-dioxane (2.5 mL) was added with an aqueous solution of sodium carbonate (38 mg, 0.358 mmol, 2M), and then aerated with nitrogen for 2 minutes Then, tetratriphenylphosphine palla
  • Hydrogen chloride dioxane solution (0.5 mL, 4.0 M) was added to continue the reaction for 2 h. After reaching room temperature, 50% ammonia water was added and reacted at room temperature for 2h. After the TLC plate reaction was completed, water was added, and the mixture was extracted with ethyl acetate.
  • Step A 4-Chloro-2- (1,3--phthalimide-2-yl) -6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5 -a] pyridine-3-nitrile
  • Step B 2-Amino-4-chloro-6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile
  • Step C 3- (5-bromopyridin-2-yl) -6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane
  • Step D 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane Borane-2-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane
  • Step E At room temperature, add 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3, 2-dioxolane-2-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane (37mg, 0.087mmol) and 2-amino-4-chloro- A solution of 6- (2-hydroxy-2-methylpropoxy) pyrazolo [1,5-a] pyridine-3-carbonitrile (21 mg, 0.073 mmol) in 1,4-dioxane (2.5 mL) An aqueous solution of sodium carbonate (38mg, 0.358mmol, 2M) was added to the solution, and nitrogen was used for aeration for 2 minutes.
  • tetratriphenylphosphine palladium (4mg, 0.003mmol) was added to the solution for 2 minutes, and the mixture was stirred at 110 ° C for 4 hours. TLC After the spot reaction was completed, water was added, and the mixture was extracted with ethyl acetate.
  • the preparation method is the same as that in Example 44. 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2 -Dioxolane-2-yl) pyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane replaced with 6-((6-methoxypyridine-3- (Methyl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) pyridin-2-yl) -3, 6-Diazabicyclo [3.1.1] heptane to 2-amino-6-ethoxy-4- (6-((6-methoxypyridin-3-yl) methyl) -3,6- Diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbon
  • 6-ethoxy-2-fluoro-4- (6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3- Yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (APS096)
  • the preparation method is the same as in Example 40, and 2-amino-4- (5- (6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] Heptane-3-yl) pyrazin-2-yl) -6-(((S) -morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridin-3-carbonitrile Fluoroacetate (APS087) was replaced with 2-amino-6-ethoxy-4- (6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [ 3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (APS095) to give 6-ethoxy-2-fluoro-4- (6 -((6-methoxypyridin-3-yl) methyl) -3,6-
  • the preparation method is the same as in Example 47, and 2-iodoethane was replaced with 2-bromoethyl methyl ether to obtain 2-amino-6- (2-methoxyethoxy) -4- (6- (6-((6 -Methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] Pyridine-3-carbonitrile (20 mg, yield 52%).
  • the preparation method is the same as in Example 47, and 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2 -Dioxolane-2-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane replaced by 1-((6-methoxypyridin-3-yl ) Methyl) -4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) pyridin-2-yl) piperazine gives 2 -Amino-6-ethoxy-4- (6- (6-((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [ 1,5-a] pyridine-3-carbonitrile (8.9 mg, yield 25%).
  • the preparation method is the same as in Example 49, and 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2 -Dioxolane-2-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane replaced by 1-((6-methoxypyridin-3-yl ) Methyl) -4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) pyridin-2-yl) piperazine gives 2 -Amino-6- (2-methoxyethoxy) -4- (6- (4-((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridine-3 -Yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (5.1 mg, yield 13%).
  • 6-ethoxy-2-fluoro-4- (6- (4-((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (APS101)
  • the preparation method is the same as in Example 40, and 2-amino-4- (5- (6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] Heptane-3-yl) pyrazin-2-yl) -6-(((S) -morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridin-3-carbonitrile Fluoroacetate (APS087) was replaced with 2-amino-6-ethoxy-4- (6- (4-((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) Pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (APS099) gives 6-ethoxy-2-fluoro-4- (6- (4-((6-methoxy Pyridine-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazol
  • the preparation method is the same as in Example 40, and 2-amino-4- (5- (6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] Heptane-3-yl) pyrazin-2-yl) -6-(((S) -morpholin-2-yl) methoxy) pyrazolo [1,5-a] pyridin-3-carbonitrile Fluoroacetate (APS087) was replaced with 2-amino-6- (2-methoxyethoxy) -4- (6- (4-((6-methoxypyridin-3-yl) methyl) Piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridin-3-carbonitrile (APS100) to give 2-fluoro-6- (2-methoxyethoxy) -4 -(6- (4-((6-methoxypyridin-3-yl) methyl) piperazin
  • Step A 3- (5-bromopyridin-2-yl) -6-((5-chloro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1. 1] heptane
  • Step B 6-((5-chloro-6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2- Dioxolane-2-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane
  • Step C 4-Chloro-2- (1,3-phthalimide-2-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile
  • the preparation method is the same as step H in Example 39, and (2S) -2- (bromomethyl) -4-morpholinecarboxylic acid tert-butyl ester is replaced with iodoethane.
  • 4-chloro-2- (1,3-phthalimide-2-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3-carbonitrile 60 mg, yield 86%).
  • m / z 367 [M + 1] + .
  • Step D The preparation method is the same as that of Step 39 in Example 39, and 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl- 1,3,2-Dioxolane-2-yl) pyrazin-2-yl) -3,6-diazabicyclo [3.1.1] heptane was replaced with 6-((5-chloro- 6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) Pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane to give the product 2-amino-4- (6- (6-((5-chloro-6-methoxypyridine-3) -Yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) -6-ethoxypyrazolo
  • the preparation method is the same as in Example 52, and 6-((6-methoxypyridin-3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2 -Dioxolane-2-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane replaced by 6-((5-chloro-6-methoxypyridine -3-yl) methyl) -3- (5- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) pyridin-2-yl) -3,6-diazabicyclo [3.1.1] heptane to give 2-amino-4- (6- (6-((5-chloro-6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6- (2-methoxy
  • the preparation method is the same as that in Example 47, and the product 2-amino-6- (2-ethoxyethoxy) -4- (6- (6-(( 6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] Pyridine-3-carbonitrile (16.2 mg, yield 41%).
  • the preparation method is the same as that in Example 47, and the product iodoethane is replaced with 1-bromo-2-methoxy-2-methylpropane to obtain 2-amino-6- (2-methoxy-2-methylpropoxy ) -4- (6- (6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridine-3 -Yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (2.8 mg, yield 7%).
  • M / z 555 [M + 1] + .
  • the preparation method is the same as in Example 57.
  • 5-chloro-6-methoxynicotinaldehyde is replaced by 5-fluoronicotinaldehyde to obtain 2-amino-6-ethoxy-4- (6- (6-((5- Fluoropyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3 -Nitrile (3.6 mg, yield 10%).
  • the preparation method is the same as that in Example 57.
  • 5-chloro-6-methoxynicotinaldehyde is replaced with 5-chloronicotinaldehyde to obtain 2-amino-4- (6- (6-((5-chloropyridin-3-yl) ) Methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3 -Nitrile (13.6 mg, yield 37%).
  • the preparation method is the same as in Example 47, and the product iodoethane is replaced with 2-cyclopropoxyethyl p-toluenesulfonate to obtain 2-amino-6- (2-cyclopropoxyethoxy) -4- (6 -(6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile (31.5 mg, yield 78%).
  • the preparation method is the same as that in Example 47, and the product iodoethane was replaced with 1,1-difluoro-2-iodoethane to obtain 2-amino-6- (2,2-difluoroethoxy) -4- (6- (6-((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [ 1,5-a] pyridine-3-carbonitrile (3.8 mg, 9% yield).
  • the preparation method is the same as that in Example 47.
  • the product 2-amino-6- (difluoromethoxy) -4- (6- (6-((6-methoxypyridine- 3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] pyridine-3-carbonitrile ( 2.2mg, yield 5.8%).
  • m / z 519 [M + 1] + .
  • the preparation method is the same as in Example 57.
  • 5-chloro-6-methoxynicotinaldehyde is replaced with 5-chloropyridinaldehyde to obtain the product 2-amino-4- (6- (6-((5-chloropyridin-2-yl) ) Methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3 -Nitrile (7.0 mg, 19% yield).
  • the preparation method is the same as that in Example 57.
  • 5-chloro-6-methoxynicotinaldehyde is replaced with 5-fluoropyridinaldehyde to obtain 2-amino-4- (6- (6-((5-fluoropyridin-2-yl) ) Methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6-ethoxypyrazolo [1,5-a] pyridine-3 -Nitrile (10.8 mg, yield 30%).
  • the preparation method is the same as in Example 57.
  • 5-chloro-6-methoxynicotinaldehyde is replaced with 6-methoxypyridinaldehyde to obtain 2-amino-6-ethoxy-4- (6- (6-(( 6-methoxypyridin-2-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] Pyridine-3-carbonitrile (28 mg, 77% yield).
  • the preparation method is the same as in Example 47, and the product iodoethane was replaced with 1-fluoro-2-iodoethane to obtain 2-amino-6- (2-fluoroethoxy) -4- (6- (6-((6 -Methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a] Pyridine-3-carbonitrile (5.0 mg, yield 13%).
  • the preparation method is the same as in Example 47, and the product iodoethane was replaced with 2- (2-bromoethoxy) propane to obtain 2-amino-6- (2-isopropoxyethoxy) -4- (6- (6 -((6-methoxypyridin-3-yl) methyl) -3,6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1, 5-a] pyridine-3-carbonitrile (32.6 mg, yield 80%).
  • Transfection recombinant gene is a confirmed proto-oncogene. It encodes a single transmembrane receptor tyrosine kinase that is required for the development, maturation, and maintenance of many tissues and cell types. Under normal conditions, the binding of the neurotrophic factor (GDNF) family ligands derived from the glial cell line to RET on the cell surface results in the dimerization and autophosphorylation of tyrosine residues in the cell. This in turn leads to activation of downstream RAS-MAPK, PI3K-AKT and phospholipase C ⁇ (PLC ⁇ ) pathways, and increases cell survival and proliferation. Examples of activating RET mutations include C634W, M918T and gatekeeper mutations, V804L and V804M.
  • This test combines a peptide substrate and a single proprietary monoclonal antibody with HTRF technology, which is a highly sensitive and stable technology for detecting molecular interactions with proteins.
  • the enzyme phosphorylates the substrate, then the Eu-labeled antibody binds the phosphorylated substrate, and streptavidin-XL665 binds all the substrates.
  • the TR-FRET signal is generated by the HTRF principle. Once the inhibitor (test compound) is added, a weaker TR-FRET signal is obtained. From this, the suppression effect was evaluated.
  • CEP-32496 was diluted 3-fold from 10 mM and 1 mM in DMSO to 10 concentrations.
  • the inhibition rate% is calculated by:
  • Inhibition rate% [1- (test compound fluorescence signal value—positive control fluorescence signal value) / (negative control average ratio—positive control average ratio)] * 100%
  • the average ratio of positive controls is the average ratio of positive controls (200nM AT13148) in the sample plate;
  • the average ratio of negative controls is the average ratio of negative controls (0.1% DMSO) in the sample plate.
  • the compounds of the embodiments of the present invention have improved wild-type, mutant and / or fusion-type inhibitory activity of RET, especially such as APS014, APS015, APS019, APS020, APS022, APS024, APS025, APS026, APS027, APS035 , APS038, APS068, APS069, APS070, APS087, APS089, APS092, APS095, APS097, APS099, APS100, APS104, APS105, APS107, APS108, APS109, APS111, APS113, APS114, APS119, APS120 and other compounds have achieved excellent activity.

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Abstract

涉及药物化学领域，主要涉及式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、或其药学上可接受的盐及其制备方法和在制备用于治疗RET激酶介导的疾病的药物中的用途。

Description

取代吡唑稠环类衍生物及其制备方法和应用
本申请要求享有2018年9月30日向中国国家知识产权局提交的申请号为201811162497.1、发明名称为“取代吡唑稠环类衍生物及其制备方法和应用”的在先专利申请的优先权权益。该在先专利申请的全文以引用的方式结合至本文中。
技术领域
本发明涉及药物化学领域，具体涉及取代吡唑稠环类衍生物及其制备方法和应用。
背景技术
RET(Rearranged During Transfection)原癌基因最初是在1985年，通过NIH3T3(小鼠胚胎成纤维细胞系)细胞与人类淋巴瘤DNA的转染被证实(Cell,1985,42(2):581-588)。RET原癌基因定位于染色体10q11.2，其DNA全长为60kb，含有外显子21个，编码由1100个氨基酸组成的RET蛋白：这种RET蛋白是一种酪氨酸激酶受体，含有一个由半胱氨酸组成的细胞外区、一个跨膜区和一个具有催化酪氨酸激酶作用的细胞内区(Mol Cell Endocrinol,2010,322(1-2):2-7)。RET参与细胞增殖、神经传导、细胞迁移和细胞分化，通过配体/复合受体/RET多蛋白复合物的信号，激活各种下游途径，如RAS/RAF/MEK/ERK，PI3K/AKT和STAT通路，诱导细胞增生(J Clin Oncol,2012,30(2):200-202)。
随着研究的逐步进展，现已发现多种疾病的发生与RET基因突变有密切联系，包括甲状腺***状癌(papillary thyroid carcinoma，PTC)(Cell,1990,60(4):557-563)、甲状腺髓样癌(medullary thyroid carcinoma，MTC)(hyroid,2009,19(6):565-612)、多发性内分泌腺瘤病2型(multiple endocrineneoplasia typeⅡ,MEN2)(Endocr Rev,2006,27(5):535-560)、先天性巨结肠(Proc Natl Acad Sci USA,2000,97(1):268-273)、肺腺癌(Nat Med,2012,18(3):375-377)等。目前只有KIF5B-RET、CCDC6-RET、TRIM33-RET、NCOA4-RET这四种RET融合基因在非小细胞肺癌中被报道，而KIF5B-RET是非小细胞肺癌中最常见的RET融合基因(Cancer,2013,119(8):1486-1494)。KIF5B-RET是KIF5B(kinesin family member 5B)基因和RET基因的染色体倒置(p11；q11)形成的一种融合基因，通过全基因组和转录组测序，第一次在非吸烟韩国人的腺癌中被证实；KIF5B-RET在肺癌中的比例很低，在非吸烟者和腺癌患者中更常见，并与其它突变，如EGFR、KRAS、BRAF、ErbB2、EML4-ALK相排斥(Genome Res,2012,22(3):436-445)。KIF5B-RET融合蛋白包含马达结构域和KIF5B的卷曲螺旋结构域，通过卷曲螺旋结构域的二聚化作用，该融合蛋白的RET酪氨酸激酶活性可异常活化，从而促进肺肿瘤发生(Cancer,2011,117(12):2709-2718)。在Qian等的研究中(Mol Cancer,2014,13:176)，KIF5B-RET融合激酶被证实在体外和体内都具有显着的致癌活性，STAT3的信号转导途径可能是肿瘤发生的主要下游介质。有证据显示KIF5B-RET可调节STAT3的持续活化。KIF5B-RET融合激酶可以结合STAT3，直接磷酸化和激活STAT3-Tyr705；它也可以通过JAK/STAT3依赖性途径，介导激活STAT3-Tyr705，并通过RAS/RAF/MEK/ERK1途径触发Ser727的磷酸化。
证明RET融合物在一些癌症中是驱动者，这件事促进了已具有RET抑制活性的多激酶抑制剂(multi-kinase inhibitor)的应用，用于治疗c负载RET融合物蛋白质的肿瘤病人。目前尚未有批准药剂可以用来针对性地靶向这一致癌基因，目前RET特异性癌症的治疗方式仅限于多激酶抑制剂和化疗，但这些非特异性治疗临床表现ORR(客观缓释率)不好并且有很大的脱靶毒性。再 者，癌症治疗的最大挑战之一是肿瘤细胞对于治疗一定阶段后出现耐药，一旦耐药，病人的治疗方式通常极为有限，且大多数例子中，癌症一直进展、不受抑制。为了能在这方面获得突破，需要一些化合物可以选择性专门靶向致癌RET融合和基因突变。
发明内容
为改善上述问题，本发明提供一种如下式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物：
Figure PCTCN2019109502-appb-000001
其中，X 1、X 2、X 3、X 4、X 5、X 6相同或不同，彼此独立地选自CR 1、-C-A或N，其中每一个R 1相同或不同，彼此独立地选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R a取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-NHC(O)R 2、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；A选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R b取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、-OS(O) 2R 7、-NHC(O)R 2；
B选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R c取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-C(O)R 4、-NHC(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
D选自无取代或任选被一个、两个或更多个R d取代的C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 6-20芳基、5-20元杂芳基或3-20元杂环基；
E选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R e取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基或3-20元杂环基氧基；
G选自无取代或任选被一个、两个或更多个R f取代的下列基团：C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基或3-20元杂环基氧基；
K选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R g取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
每一个R 2相同或不同，彼此独立地选自H、无取代或任选被OH、NH 2取代的如下基团：C 1- 40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳 基、3-20元杂环基、-C(O)R 4、-S(O) 2R 6；
每一个R 3相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R 4、-S(O) 2R 6；
或者，R 2和R 3与所连的N原子一起形成5-20元杂芳基或3-20元杂环基；
每一个R 4相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3；
每一个R 5相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基羰基、C 2-40烯基羰基、C 2-40炔基羰基、C 3-40环烷基羰基、C 3-40环烯基羰基、C 3-40环炔基羰基、C 6-20芳基羰基、5-20元杂芳基羰基、3-20元杂环基羰基；
每一个R 6相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3；
每一个R 7相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基；
每一个R a、R b、R c、R d、R e、R f、R g相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2，无取代或任选被一个、两个或更多个R h取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
每一个R h相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2，无取代或任选被一个、两个或更多个R j取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；或者，当环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时，所述取代基中的两个也可以与所述环状基团形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团；
每一个R j相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2、无取代或任选被一个、两个或更多个R h取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
或者，当环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时，所述取代基中的两个也可以与所述环状基团形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团；
或者，当一个原子(如碳原子)被两个或更多个取代基取代时，所述取代基中的两个也可以与其共同连接的原子形成环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20 元杂环基等)。
根据本发明的实施方案，式I所示的化合物选自下列式I’所示的化合物：
Figure PCTCN2019109502-appb-000002
其中，X 1、X 2、X 3、X 4、X 5、A、B、D、E、G、K独立地具有上文所述的定义。
根据本发明的实施方案，其中：
X 1、X 2、X 3、X 4、X 5、X 6相同或不同，彼此独立地选自CR 1、-C-A或N，其中每一个R 1相同或不同，彼此独立地选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R a取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、NR 2R 3、-NHC(O)R 2、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；A选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R b取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
B选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R c取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、NR 2R 3、-C(O)R 4、-NHC(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
D选自无取代或任选被一个、两个或更多个R d取代的C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基或3-10元杂环基；
E选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R e取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、C 6-10芳基氧基、5-10元杂芳基氧基或3-10元杂环基氧基；
G选自无取代或任选被一个、两个或更多个R f取代的下列基团：C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、C 6-10芳基氧基、5-10元杂芳基氧基或3-10元杂环基氧基；
K选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R g取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、C 6-10芳基氧基、5-10元杂芳基氧基、3-10元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
每一个R 2相同或不同，彼此独立地选自H、无取代或任选被OH、NH 2取代的如下基团：C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、-C(O)R 4、-S(O) 2R 6；
每一个R 3相同或不同，彼此独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3- 8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、-C(O)R 4、-S(O) 2R 6；
或者，R 2和R 3与所连的N原子一起形成5-10元杂芳基或3-10元杂环基；
每一个R 4相同或不同，彼此独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3- 8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、C 6-10芳基氧基、5-10元杂芳基氧基、3-10元杂环基氧基、NR 2R 3；
每一个R 5相同或不同，彼此独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3- 8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1-6烷基羰基、C 2-6烯基羰基、C 2-6炔基羰基、C 3-8环烷基羰基、C 3-8环烯基羰基、C 3-8环炔基羰基、C 6-10芳基羰基、5-10元杂芳基羰基、3-10元杂环基羰基；
每一个R 6相同或不同，彼此独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3- 8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、C 6-10芳基氧基、5-10元杂芳基氧基、3-10元杂环基氧基、NR 2R 3；
每一个R 7相同或不同，彼此独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3- 8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基；
每一个R a、R b、R c、R d、R e、R f、R g相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2，无取代或任选被一个、两个或更多个R h取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1- 6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、C 6-10芳基氧基、5-10元杂芳基氧基、3-10元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、-OS(O) 2R 7；
每一个R h相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2，无取代或任选被一个、两个或更多个R j取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3- 8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、C 6-10芳基氧基、5-10元杂芳基氧基、3-10元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；或者，当环状基团(包括但不限于C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、3-10元杂环基等)的不同位置被两个或更多个取代基取代时，所述取代基中的两个也可以与所述环状基团形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团；
每一个R j相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2、无取代或任选被一个、两个或更多个R h取代的下列基团：C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-8环烷基氧基、C 3-8环烯基氧基、C 3-8环炔基氧基、C 6-20芳基氧基、5-10元杂芳基氧基、3-10元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
或者，当环状基团(包括但不限于C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、3-10元杂环基等)的不同位置被两个或更多个取代基取代时，所述取代基中的两个也可以与所述环状基团形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团；
或者，当一个原子(如碳原子)被两个或更多个取代基取代时，所述取代基中的两个也可以与其共同连接的原子形成环状基团(包括但不限于C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、3-10元杂环基等)。
根据本发明的实施方案，其中X 1、X 2、X 3、X 4、X 5、X 6相同或不同，彼此独立地选自CR 1、-C-A或N，R 1选自NH 2、CH 3、N(CH 3) 2、OH、H、NHC(O)CH 3、NHCH 3、F、OCH 3、NHC 2H 4OH；例如，X 1，X 2，X 3，X 4和X 5中的至少一个为N，如1、2、3、4或5个为N；
A可以选自NH 2、OH、H、卤素、氰基，无取代或任选被一个、两个或更多个卤素、OH或NH 2取代的下列基团：C 1-6烷基、-NR 2R 3、-NH-C 1-6烷基-NR 2R 3、-NHCO-C 1-6烷基-NR 2R 3、-NH-C 1-6烷基-CO-NR 2R 3、-NHCO-C 1-6烷基-COO-C 1-6烷基、-NH-C 3-8环烷基-CO-NR 2R 3、-NH-C 2-8烯基-CONR 2R 3、-NH-C 1-6烷基-CN、-NHCO-NH-R 2、-CONR 2R 3或-CONH-C 1-6烷基-NR 2R 3、-NHCO-R 2、-NH-C 1-6烷基、C 1-6烷基氧基、-NH-C 1-6烷基-OH；
根据本发明的实施方案，其中每一个R 2和R 3相同或不同，彼此独立地选自H、OH、C 1-6烷基、5-6元杂环基、C 1-6烷基酰基或C 1-6烷基磺酰基；或者R 2和R 3与所连N原子一起形成无取代或任选被氧代的5-6元杂环基；
根据本发明的实施方案，其中B可以选自H、Cl、CN、Br、-COOH，无取代或任选被一个、两个或更多个R c取代的下列基团：-CH 3，-CH 2CH 3，-环丙基，-COOCH 3，-COOCH 2CH 3，-CONH 2和-CONHCH 3；
根据本发明的实施方案，其中D可以选自无取代或任选被一个、两个或更多个R d取代的如下基团：C 1-6烷基氧基-、5-10元杂芳基或3-10元杂环基；
根据本发明的实施方案，每一个R c、R d相同或不同，彼此独立地选自OH、卤素、C 1-6烷基-、C 1-6烷基氧基-、C 1-6环烷基氧基、羟基C 1-6烷基-、单氟代C 1-6烷基-、二氟代C 1-6烷基-、三氟代C 1-6烷基-、氰基C 1-6烷基-、(C 1-6烷氧基)C 1-6烷基-、(C 1-6烷氧基)CH 2C(＝O)-、(C 1-6烷氧基)C(＝O)C 1-6烷基-、C 3-8环烷基-、(R 2R 3N)C 1-6烷基-、(R 2R 3N)C(＝O)C 1-6烷基-、C 1-6烷基S(O) 2-C 1- 6烷基-、C 1-6烷基氧基苄基，无取代或任选被下列基团取代的3-10元杂环基：卤素、C 1～6烷基、氟代C 1～6烷基、二氟代C 1-6烷基、三氟代C 1-6烷基、(C 1-6烷氧基)C 1～6烷基、(C 1-6烷基) 2NCH 2C(O)-、(C 1-6烷氧基)C(O)-或(C 1～6烷氧基)CH 2C(O)-、(C 1-6烷基) 2NC 1-6烷基-、(C 1-6烷基) 2NC(＝O)C 1-6烷基-；
根据本发明的实施方案，其中E选自H、卤素、CN、无取代或任选被一个、两个或更多个R e取代的下列基团：C 1～6烷基、C 1-6烷氧基，C 1～6环烷基，含N、S和O的1～3个环杂原子的5元或六元杂芳基环，所述5元或6元杂芳基环任选被氧代取代；
根据本发明的实施方案，其中G可以选自无取代或任选被一个、两个或多个R f取代的下列基团：5-10元杂芳基，3-10元杂环基，其中所述杂环基选自例如吡咯烷基、哌啶基、哌嗪基、吗啉基或吖丁啶基；或者，当所述杂环基的不同位置被两个或更多个取代基取代时，所述取代基中的两个也可以与所述杂环基形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团；
根据本发明的实施方案，其中R f可以选自卤素、CN、OH、SH、氧代(＝O)、NO 2、无取代或任选被一个、两个或更多个R h取代的下列基团：C 1-6烷基、C 3-8环烷基。
根据本发明的实施方案，其中K可以选自H、OH，无取代或任选被一个或多个R g取代的下列基团：C 1-6烷基、C 3-8环烷基、C 6-10芳基、5-10元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 3-6环烷基氧基、C 6-10芳基氧基、5-10元杂芳基氧基、3-10元杂环基氧基、N(C 1-6烷基) 2、-C(O)R 4、-OCR 5、-S(O) 2R 6、-OS(O) 2R 7；
根据本发明的实施方案，其中K可以选自无取代或任选被一个、两个或更多个R g取代的下列基团：C 1-6烷基、C 3-10环烷基、-C(O)R 4、-OCR 5、-S(O) 2R 6、-OS(O) 2R 7。
根据本发明的实施方案，所述R 4、R 5、R 6、R 7相同或不同，彼此独立地选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烯基、C 3-8环炔基、C 1-6烷基氧基。
根据本发明的实施方案，其中K可以选自无取代或任选被一个、两个或更多个R h取代的下列基团：C 6-10芳基C 1-6烷基-或3-10元杂环基C 1-6烷基-，例如苯基C 1-6烷基-或吡啶基C 1-6烷基-；
根据本发明的实施方案，其中R g可以选自卤素、CN、OH、SH、氧代(＝O)、NO 2，无取代或任选被一个、两个或更多个R h取代的下列基团：C 1-6烷基、C 3-10环烷基、C 6-10芳基、5-10元杂 芳基、3-10元杂环基；
或者，当K中的一个原子(如碳原子)被两个或更多个R g取代时，两个R g也可以与其共同连接的原子形成环状基团(包括但不限于C 3-6环烷基、C 3-6环烯基、C 3-6环炔基、4-6元杂环基等)；
根据本发明示例性的实施方案，例如：X 6选自-C-A或N，A可以选自H，无取代或任选被一个、两个或更多个R b取代的下列基团：NH 2、C 1-6烷基、-NH(C 1-6烷基) 2、OH、F、-NHC(O)C 1-6烷基、-NHC 1-6烷基、C 1-6烷基氧基、-NHC 1-6烷基-OH；
每一个R b相同或不同，彼此独立地选自C 1-6烷基、C 1-6烷氧基；
B可以选自H、CN、-CONH 2，无取代或任选被一个、两个或更多个R c取代的C 1-6烷基；
每一个R c相同或不同，彼此独立地选自卤素、C 1-6烷基；
D可以选自无取代或任选被一个、两个或更多个R d取代的如下基团：C 1-6烷基氧基或5-14元杂芳基，所述R d选自无取代或任选被一个或多个如下基团取代的C 1-6烷基或3-10元杂环基：氧代、卤素、OH、-N(C 1-6烷基) 2或-S(O) 2-C 1-6烷基；
E选自H，无取代或任选被一个、两个或更多个R e取代的下列基团：C 1-6烷基、C 1-6烷氧基；
每一个R e相同或不同，彼此独立地选自OH、F、C 1-6烷基；
G选自无取代或任选被氧代的3-10元杂环基，例如无取代或任选被氧代或被C 1-6烷基取代的哌嗪基、哌啶基；或者，所述当所述杂环基的间位被两个取代基取代时，所述取代基可以与所述杂环基形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2的二价基团；
K选自无取代或任选被一个、两个或更多个R g取代的下列基团：C 1-6烷基、-C(O)R 4，所述R g选自氧代、OH、无取代或任选被一个、两个或更多个R h取代的C 1-6烷基、C 1-6烷氧基，C 3-10环烷基、C 6-14芳基、5-14元杂芳基、-SO 2-C 6-14芳基；每一个R 4相同或不同，彼此独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烯基、C 3-10环炔基、C 6-14芳基、5-14元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-10环烷基氧基、C 3-10环烯基氧基、C 3-10环炔基氧基、C 6-14芳基氧基、5-14元杂芳基氧基、3-10元杂环基氧基、-N(C 1-6烷基) 2；所述R h选自卤素、C 1-6烷氧基、NH 2、-N(C 1-6烷基) 2、-NHC 6-14芳基、-NHC 1-6烷基；或者，当K中的一个原子(如碳原子)被两个或更多个R g取代时，两个R g也可以与其共同连接的原子形成环状基团(包括但不限于C 3-10环烷基、C 3-10环烯基、C 3-10环炔基、3-10元杂环基等)；
根据本发明示例性的实施方案，例如：
X 6选自-C-A或N，A可以选自NH 2、甲基、乙基或丙基、-NH(CH 3) 2、OH、F、-NH(O)CH 3、-NHCH 3、甲氧基、-NHC 2H 4-OH；
B可以选自H、CN或 -COCH 3；
D可以选自无取代或任选被一个、两个或更多个R d取代的如下基团：吡唑基、甲氧基或乙氧基，例如吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基；
每一个R d相同或不同，彼此独立地选自OH、F、C 1-6烷基、羟基C 1-6烷基-、二氟代C 1-6烷基-、C 1-6烷基S(O) 2-C 1-6烷基-、(C 1-6烷基) 2N-C(O)C 1-6烷基-，C 1-6烷基氧基-、C 1-6环烷基氧基、无取代或任选被C 1～6烷基取代的5-6元杂环基；
G选自无取代或任选被氧代的5-6元杂环基，例如无取代或任选被氧代或甲基取代的哌嗪基、哌啶基；或者，当所述杂环基的间位被两个取代基取代时，所述取代基可以与所述杂环基形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2或3个选自CH 2的二价基团；
K选自无取代或任选被一个、两个或更多个R g取代的C 1-6烷基、-C(O)C 1-6烷基，所述R g选自氧代、OH、无取代或任选被一个、两个或更多个R h取代的C 1-6烷基、C 1-6烷氧基，C 3-10环烷 基、C 6-14芳基、5-14元杂芳基、-S(O) 2-C 6-14芳基；所述R h选自卤素、C 1-6烷氧基、NH 2、-N(C 1-6烷基) 2、-NHC 6-14芳基、-NHC 1-6烷基；或者，当K中的一个原子(如碳原子)被两个或更多个R g取代时，两个R g也可以与其共同连接的原子形成C 3-10环烷基。
作为实例，D可以选自如下基团：
Figure PCTCN2019109502-appb-000003
其中
Figure PCTCN2019109502-appb-000004
处表示连接位点；
作为实例，G可以选自如下基团：
Figure PCTCN2019109502-appb-000005
其中
Figure PCTCN2019109502-appb-000006
处表示连接位点；
优选地，G选自
Figure PCTCN2019109502-appb-000007
根据本发明的实施方案，K选自如下基团：
Figure PCTCN2019109502-appb-000008
，其中
Figure PCTCN2019109502-appb-000009
处表示连接位点；
优选地，K选自
Figure PCTCN2019109502-appb-000010
作为实例，所述式I化合物选自如下化合物：
Figure PCTCN2019109502-appb-000011
Figure PCTCN2019109502-appb-000012
Figure PCTCN2019109502-appb-000013
Figure PCTCN2019109502-appb-000014
Figure PCTCN2019109502-appb-000015
Figure PCTCN2019109502-appb-000016
Figure PCTCN2019109502-appb-000017
Figure PCTCN2019109502-appb-000018
Figure PCTCN2019109502-appb-000019
Figure PCTCN2019109502-appb-000020
Figure PCTCN2019109502-appb-000021
Figure PCTCN2019109502-appb-000022
Figure PCTCN2019109502-appb-000023
本发明还提供式I化合物的制备方法，包括：
Figure PCTCN2019109502-appb-000024
化合物II与化合物III发生铃木反应得到式I化合物；
其中，式II和III中B、D、E、G、K、X 1、X 2、X 3、X 4、X 5、X 6具有如上所述定义；式III中B为硼元素；L选自离去基团如卤素或者OTf。
本领域技术人员应当理解，除非如式III定义中的专门定义，或者根据有机化学反应常识能够确定为硼元素的情况外，其他通式化合物中的B应理解为说明书对于取代基的定义符号。
本发明还提供一种药物组合物，其包含治疗有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物中的至少一种。
根据本发明，所述药物组合物还包括一种或多种药学上可接受的载体或赋形剂。
根据本发明，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。
本文还提供体外或体内抑制细胞增殖的方法，所述方法包括使细胞与有效量的本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物或其药物组合物接触。
本发明还提供一种治疗RET激酶介导的疾病的方法，包括给予患者治疗有效量的如式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物中的至少一种。
本文还提供了在有治疗需要的患者中治疗RET相关疾病或病症的方法，所述方法包括向所述患者施用治疗有效量的如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物或其药物组合物。
本文还提供了在有治疗需要的患者中治疗癌症和/或抑制与特定癌症相关的转移的方法，所述方法包括向所述患者施用治疗有效量的如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物或其药物组合物。
本文还提供了在有治疗需要的患者中治疗肠易激综合征(IBS)和/或与IBS相关的疼痛的方法，所述方法包括向所述患者施用治疗有效量的如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物或其药物组合物。
本文还提供了为癌症患者提供支持护理的方法，包括预防或最小化与治疗(包括化疗治疗)相关的胃肠疾病(例如腹泻)，所述方法包括给予患者治疗有效量的如本文所限定的化合物或其药物组合物。
本文还提供了用于治疗的如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物，或其药物组合物。
本文还提供用于治疗癌症和/或抑制与特定癌症相关的转移的如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物或其药物组合物。
本文还提供用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物或其药物组合物。
本发明还提供了如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物或其药物组合物，其用于为癌症患者提供支持性护理，包括预防或最小化与治疗(包括化疗治疗)相关的胃肠病症，例如腹泻。
本文还提供了用于抑制RET激酶活性的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物。
本文还提供用于治疗RET相关疾病或病症的如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物或其药物组合物。
本发明还提供式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物中的至少一种在制备用于治疗RET激酶介导的疾病的药物中的用途。
本文还提供如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物在制备用于治疗癌症和/或抑制与特定癌症相关的转移的药物中的用途。
本文还提供如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物在制备用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的药物中的用途。
本文还提供了如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物在制备用于向癌症患者提供支持护理的药物中的用途，所述支持护理包括预防或最小化与治疗(包括化疗治疗)相关的胃肠病症，例如腹泻。
本文还提供了如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物在制备用于抑制RET激酶活性的药物中的用途。
本文还提供了如本文所限定的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物在制备用于治疗RET相关疾病或病症的药物中的用途。
本文还提供用于在有需要的患者中治疗癌症的方法，所述方法包括(a)确定所述癌症是否与下述的失调有关：RET基因、RET激酶、或其中任何一者的表达或活性或水平(例如，RET相关的癌症)；(b)如果确定所述癌症与下述的失调有关：RET基因、RET激酶、或其中任何一者的表达或活性或水平(例如，RET相关的癌症)，向患者施用治疗有效量的通式I化合物或其药学上可接受的盐或溶剂合物，或其药物组合物。
本文还提供了用于在有需要的患者中治疗癌症(例如，RET相关癌症，如具有一种或多种RET抑制剂抗性突变的RET相关癌症)的药物组合，其包含(a)式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物，(b)其他治疗剂，和(c)任选的至少一种药学上可接受的运载体，其中式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物和所述其他治疗剂被配制成单独的组合物或剂量用于同时、分开或顺序用于治疗癌症，其中式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物和所述治疗剂的量一起有效治疗所述癌症。本文还提供了包含这种组合的药物组合物。本文还提供了这种组合在制备用于治疗癌症的药物中的用途。本文还提供了商业包装或产品，其包含这种组合作为用于同时、单独或顺序使用的组合制剂；并涉及一种治疗有需要的患者的癌症的方法。
本文还提供了用于逆转或预防对抗癌药物的获得性抗性的方法，所述方法包括将治疗有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物给予处于对抗癌药物发展或具有获得性抗性的风险的患者。
本文还提供延迟和/或预防个体中抗癌药抗药性发展的方法，所述方法包括在个体中施用有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物，在此之前、期间或之后施用有效量的抗癌药物。
本文还提供了治疗患有癌症且对抗癌药物发展抗性的可能性增加的个体的方法，其包括对个体伴随施用(a)有效量的式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物；和(b)有效量的抗癌药物。
还提供了治疗患有RET相关癌症的个体的方法，所述癌症具有一种或多种RET抑制剂抗性 突变，所述RET抑制剂抗性突变增加所述癌症对不是式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物的RET抑制剂的抗性(例如，在氨基酸位置804处的取代，例如V804M、V804L或V804E)，其包括在给予另一种其他的抗癌药物之前、期间或之后，给予式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物。
还提供了治疗患有RET相关癌症的个体的方法，所述方法包括在给予另一种其他的抗癌药物之前、期间或之后，给予式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物。
本文提供了在有需要的患者中治疗癌症(例如RET相关癌症)的方法，所述方法包括向所述患者施用治疗有效量的通式I的化合物或其药学上可接受的盐或溶剂合物或其药物组合物。
在本文所述的任何方法或用途的一些实施方案中，癌症(例如RET相关癌症)是血液学癌症。在本文所述的任何方法或用途的一些实施方案中，癌症(例如RET相关癌症)是实体瘤。在本文所述的任何方法或用途的一些实施方案中，癌症(例如RET相关癌症)是肺癌(例如，小细胞肺癌或非小细胞肺癌)，***状甲状腺癌，甲状腺髓样癌，分化型甲状腺癌，复发性甲状腺癌，难治性分化型甲状腺癌，肺腺癌，细支气管肺癌，2A或2B型多发性内分泌肿瘤(分别为MEN2A或MEN2B)，嗜铬细胞瘤，甲状旁腺增生，乳腺癌，结直肠癌(例如转移性结肠直肠癌)，***状肾细胞癌，胃肠粘膜的神经节细胞瘤病，炎性肌纤维母细胞瘤或***。在本文所述的任何方法或用途的一些实施方案中，癌症(例如RET相关癌症)选自：急性淋巴细胞白血病(ALL)，急性髓性白血病(AML)，青少年癌症，肾上腺皮质癌，***癌、阑尾癌，星形细胞瘤，非典型性畸胎瘤/横纹肌样瘤，基底细胞癌，胆管癌，膀胱癌，骨癌，脑干胶质瘤，脑肿瘤，乳腺癌，支气管肿瘤，伯基特淋巴瘤，类癌瘤，未知原发癌，心脏肿瘤，***，儿童癌症，脊索瘤，慢性淋巴细胞白血病(CLL)，慢性骨髓性白血病(CML)，慢性骨髓增殖性肿瘤，结肠癌，结肠直肠癌，颅咽管瘤，皮肤T细胞淋巴瘤，胆管癌，原位导管癌，胚胎性肿瘤，子宫内膜癌，室管膜瘤，食道癌，成感觉神经细胞瘤，尤因肉瘤，颅外生殖细胞肿瘤，性腺外生殖细胞瘤，肝外胆管癌，眼癌，输卵管癌，骨纤维组织细胞瘤，胆囊癌，胃癌，胃肠类癌瘤，胃肠道间质瘤(GIST)，生殖细胞瘤，妊娠滋养细胞疾病，神经胶质瘤，多毛细胞瘤，多毛细胞白血病，头颈癌，心脏癌，肝细胞癌，组织细胞增多症，霍奇金淋巴瘤，下咽癌，眼内黑色素瘤，胰岛细胞瘤，胰腺神经内分泌瘤，卡波西肉瘤，肾癌，朗格汉斯细胞组织细胞增多症，喉癌，白血病，唇和口腔癌，肝癌，肺癌，淋巴瘤，巨球蛋白血症，骨恶性纤维组织细胞瘤，骨癌，黑色素瘤，梅克尔细胞癌，间皮瘤，转移性鳞状颈癌，中线状癌，口癌，多发性内分泌瘤综合征，多发性骨髓瘤，真菌病蕈样肉芽肿，骨髓增生异常综合征，骨髓增生异常/骨髓增殖性肿瘤，髓性白血病，骨髓性白血病，多发性骨髓瘤，骨髓增殖性肿瘤，鼻腔和鼻窦癌，鼻咽癌，成神经细胞瘤，非霍奇金淋巴瘤，非小细胞肺癌，口部癌，口腔癌，唇癌，口咽癌，骨肉瘤，卵巢癌，胰腺癌，***状瘤病，副神经节瘤，鼻旁窦和鼻腔癌，甲状旁腺癌，***癌，咽癌，嗜铬细胞瘤，垂体癌，浆细胞瘤，胸膜肺胚细胞瘤，妊娠和乳腺癌，原发性中枢神经***淋巴瘤，原发腹膜癌，***癌，直肠癌，肾细胞癌，视网膜母细胞瘤，横纹肌肉瘤，唾液腺癌，肉瘤，塞扎里综合征，皮肤癌，小细胞肺癌，小肠癌，软组织肉瘤，鳞状细胞癌，鳞状颈癌，胃癌，T细胞淋巴瘤，睾丸癌，咽喉癌，胸腺瘤和胸腺癌，甲状腺癌症，肾盂和输尿管的移行细胞癌，未知原发癌，尿道癌，子宫癌，子宫肉瘤，***癌，外阴癌和威尔姆氏瘤。
在一些实施方案中，血液学癌症(例如，与RET相关的癌症的血液学癌症)选自白血病，淋巴瘤(非霍奇金淋巴瘤)，霍奇金病(也称霍奇金淋巴瘤)和骨髓瘤，例如，急性淋巴细胞白血病(ALL)，急性骨髓性白血病(AML)，急性早幼粒细胞白血病(APL)，慢性淋巴细胞白血病(CLL)，慢性粒细胞白血病(CML)，慢性髓单核细胞白血病(CMML)，慢性嗜中性白血病(CNL)，急性未分化型白血 病(AUL)，间变性大细胞淋巴瘤(ALCL)，幼淋巴细胞白血病(PML)，幼年型单核细胞白血病(JMML)，成人T细胞ALL，三联型骨髓发育不良的AML(AML/TMDS)，混合谱系白血病(MLL)，骨髓增生异常综合征(MDS)，骨髓增殖性疾病(MPD)和多发性骨髓瘤(MM)。血液癌症的其它示例包括骨髓增`殖性疾病(MPD)，如真性红细胞增多症(PV)，原发性血小板减少症(ET)和特发性原发性骨髓纤维化(IMF/IPF/PMF)。在一个实施方案中，血液学癌症(例如，作为与RET相关癌症的血液学癌症)是AML或CMML。
在一些实施方案中，癌症(例如RET相关癌症)是实体瘤。实体瘤(例如，作为与RET相关癌症的实体瘤)的示例包括例如甲状腺癌(例如***状甲状腺癌，甲状腺髓样癌)，肺癌(例如肺腺癌，小细胞肺癌)，胰腺癌，胰腺导管癌，乳腺癌，结肠癌，结直肠癌，***癌，肾细胞癌，头颈肿瘤，神经母细胞瘤和黑素瘤。参见，例如，NatureReviewsCancer,2014,14,173-186。
在一些实施方案中，癌症选自肺癌，***状甲状腺癌，甲状腺髓样癌，分化的甲状腺癌，复发性甲状腺癌，难治性分化型甲状腺癌，2A或2B型多发性内分泌瘤(分别为MEN2A或MEN2B)，嗜铬细胞瘤，甲状旁腺增生，乳腺癌，结直肠癌，***状肾细胞癌，胃肠粘膜神经节细胞瘤和***。
在一些实施方案中，所述患者是人。
式I化合物及其药学上可接受的盐和溶剂合物也可用于治疗RET相关的癌症。
本文还提供用于在有需要的患者中治疗肠易激综合征(IBS)的方法，所述方法包括(a)确定IBS是否与下述的失调有关：RET基因、RET激酶、或其中任何一者的表达或活性或水平；(b)如果确定IBS与下述的失调有关：RET基因、RET激酶、或其中任何一者的表达或活性或水平，向患者施用治疗有效量的通式I化合物或其药学上可接受的盐或溶剂合物，或其药物组合物。
本文还提供了用于治疗有需要的患者的肠易激综合征(IBS)的药物组合，其包括施用(a)式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物，(b)其他治疗剂，和(c)任选的至少一种药学上可接受的运载体，用于同时、分开或依次用于治疗IBS，其中式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物的量和其他治疗剂的量在治疗IBS方面共同有效。本文还提供了包含这种组合的药物组合物。本文还提供了这种组合在制备用于治疗IBS的药物中的用途。本文还提供了商业包装或产品，其包含这种组合作为用于同时、单独或顺序使用的组合制剂；并涉及一种治疗有需要的患者的IBS的方法。
作为药物时，可按药物组合物的形式给予本发明化合物。可按药剂领域中熟知的方式制备这些组合物，可通过多种途径给予它们，这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如，透皮、皮肤、眼和粘膜包括鼻内、***和直肠递药)、肺(例如，通过吸入或吹入粉末或气雾剂，包括通过喷雾器；气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药，或可通过例如连续灌注泵给药。局部给予的药用组合物和制剂可包括透皮贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂和散剂。常规药物载体、水、粉末或油性基质、增稠剂等可能是必须的或需要的。包衣避孕套(Coated condoms)、手套等也可以是有用的。
在制备本发明的组合物时，通常将活性成分与赋形剂混合，通过赋形剂稀释或装入例如胶囊、小药囊、纸或其它容器形式的这种载体内。当赋形剂用作稀释剂时，它可以是固体、半固体或液体物质，用作溶媒、载体或活性成分的介质。因此，组合物可以是以下形式：片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒)；含例如高达10％重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
适宜的赋形剂的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、***胶、磷 酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。制剂还可含有：润滑剂例如滑石粉、硬脂酸镁和矿物油；湿润剂；乳化剂和悬浮剂；防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯；甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物，以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。
可按单位剂型配制组合物，每一剂量含约5～1000mg，更通常约100～500mg活性成分。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的单一剂量单位，各单位含有与适宜的药物赋形剂混合的经计算可产生所需疗效的预定量的活性物质。
活性化合物的有效剂量的范围可很大，通常按药用有效量给药。但是，可以理解实际给予的化合物的量通常由医师根据相关情况决定，它们包括所治疗的病症、所选择的给药途径、所给予的实际化合物；患者个体的年龄、重量和反应；患者症状的严重程度等。
对于制备固体组合物例如片剂，将主要的活性成分与药物赋形剂混合，形成含本发明化合物的均匀混合物的固体预制剂组合物。当称这些预制剂组合物为均匀时，是指活性成分通常均匀地分布在整个组合物中，致使该组合物可容易地划分为同等有效的单位剂型例如片剂、丸剂和胶囊剂。然后将该固体预制剂划分为上述类型的含例如约0.1～1000mg本发明活性成分的单位剂型。
可将本发明片剂或丸剂包衣或复合，得到提供长效作用优点的剂型。例如，片剂或丸剂含内剂量和外剂量组分，后者是前者的被膜形式。可通过肠溶层将两种组分隔离，肠溶层用于在胃中阻止崩解，以使内组分完整通过十二指肠或延迟释放。多种物质可用于此类肠溶层或包衣剂，此类物质包括多种高分子酸和高分子酸与此类物质如虫胶、鲸蜡醇和醋酸纤维素的混合物。
其中可掺入本发明化合物和组合物，用于口服或注射给药的液体形式包括水溶液、适当矫味的糖浆剂、水或油混悬液；和用食用油例如棉子油、芝麻油、椰子油或花生油矫味的乳剂；以及酏剂和类似的药用溶媒。
用于吸入或吹入的组合物包括溶于药学上可接受的水或有机溶剂或其混合物的溶液剂和混悬液、散剂。液体或固体组合物可含有如上所述适宜的药学上可接受的赋形剂。在某些实施方案中，通过口服或鼻呼吸途径给予组合物，实现局部或全身作用。可通过使用惰性气体，使组合物成雾化。可直接由雾化装置吸入雾化溶液，或雾化装置可与面罩帷或间歇正压呼吸机连接。可通过口服或由按适当方式递送制剂的装置通过鼻给予溶液、混悬液或粉末组合物。
给予患者的化合物或组合物的量不固定，取决于给予的药物、给药的目的例如预防或治疗；患者的状态、给药的方式等。在治疗应用时，可给予已患疾病的患者足够治愈或至少部分抑制疾病及其并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断，该判断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的组合物可以是上述药用组合物形式。可通过常规灭菌技术或可过滤灭菌，将这些组合物灭菌。可将水溶液包装原样使用，或冻干，给药前，将冻干制剂与无菌水性载体混合。化合物制剂的pH通常为3～11，更优选5～9，最优选7～8。可以理解，使用某些前述赋形剂、载体或稳定剂会导致形成药物盐。
本发明化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本发明化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本发明化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验***导出的剂量-反应曲线外推，得到有效剂量。
术语与定义
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-40”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10，以及数值范围“11-40”中的每一个整数数值即11、12、13、14、15、......、35、36、37、38、39、40。应当理解，本文在描述取代基时使用的一个、两个或更多个中，“更多个”应当是指≥3的整数，例如3、4、5、6、7、8、9或10。此外，当某些数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“卤素”表示氟、氯、溴和碘。
术语“C 1-40烷基”应理解为优选表示具有1～40个碳原子的直链或支链饱和一价烃基。例如，“C 1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“C 2-40烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2～40个碳原子，优选“C 2-6烯基”。“C 2-6烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子，特别是2或3个碳原子(“C 2-3烯基”)，应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C 2- 40炔基”应理解为表示直连或支链的一价烃基，其包含一个或多个三键并且具有2～40个碳原子，优选“C 2-C 6-炔基”。术语“C 2-C 6-炔基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5或6个碳原子，特别是2或3个碳原子(“C 2-C 3-炔基”)。所述C 2-C 6-炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁 -3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C 3-40环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃，其具有3～40个碳原子，优选“C 3-10环烷基”。术语“C 3-10环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃，其具有3、4、5、6、7、8、9或10个碳原子。所述C 3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃，其包含1-5个独立选自N、O和S的杂原子的总成环原子数为3-20(如原子数为3、4、5、6、7、8、9、10等)的非芳族环状基团，优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢恶唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。所述3-20元杂环基与其它基团相连构成本发明的化合物时，可以为3-20元杂环基上的碳原子与其它基团相连，也可以为3-20元杂环基环上杂环原子与其它基团相连。例如当3-20元杂环基选自哌嗪基时，可以为哌嗪基上的氮原子与其它基团相连。或当3-20元杂环基选自哌啶基时，可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。
术语“C 6-20芳基”应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C 6-14芳基”。术语“C 6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C 6-14芳基”)，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C 13芳基”)，例如芴基，或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。当所述C 6-20芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5～20个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、恶唑基、噻唑基、咪唑基、吡唑基、异恶唑基、异噻唑基、恶二唑基、***基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并恶唑基、苯并异恶唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基等。当所述5-20元杂芳基与其它基团相连构成本发明的化合物时，可以为5-20元杂芳基环上的碳原子与其它基团相连，也可以为5-20元杂芳基环上的杂原子与其它基团相连。当所述5-20元杂芳基被取代时，其可以为单取代或 者多取代。并且，对其取代位点没有限制，例如可以为杂芳基环上与碳原子相连的氢被取代，或者杂芳基环上与杂原子相连的氢被取代。
除非另有说明，杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式，包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基；吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
术语“氧代”是指取代基中的碳原子、氮原子或硫原子被氧化后形成的氧基取代(＝O)。
除非另有说明，本文中术语的定义同样适用于包含该术语的基团，例如C 1-6烷基的定义也适用于C 1-6烷基氧基、-N(C 1-6烷基) 2、-NHC 1-6烷基或-S(O) 2-C 1-6烷基等。
本领域技术人员可以理解，式I所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。本申请中化合物成盐的个数由碱性中心或酸性中心决定。例如当化合物中含有多个成盐位点时，则成盐个数等于成盐位点数。酸加成盐包括但不限于：盐酸盐、氢氟酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、焦硫酸盐、磷酸盐、硝酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、氨基磺酸盐、2-萘磺酸盐、甲酸盐、乙酰乙酸、丙酮酸、月硅酸酯、肉桂酸酯、苯甲酸盐、醋酸盐、二羟乙酸盐、三氟乙酸盐、三甲基乙酸盐、丙酸盐、丁酸盐、己酸盐、庚酸盐、十一酸盐、硬脂酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、富马酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、草酸盐、水杨酸盐、琥珀酸盐、葡萄糖酸盐、奎尼酸盐、双羟萘酸盐、甘醇酸盐、酒石酸盐、乳酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、环戊烷丙酸盐、二葡糖酸盐、3-羟基-2-萘甲酸盐、烟酸盐、扑酸盐、果胶酯酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、衣康酸盐、三氟甲磺酸盐、十二烷基硫酸盐、对甲苯磺酸盐、萘二磺酸盐、丙二酸盐、己二酸盐、藻酸盐、扁桃酸盐、葡庚酸盐、甘油磷酸盐、磺基水杨酸盐、半硫酸或硫氰酸盐、天冬氨酸盐等；碱加成盐例如碱金属盐、碱土金属盐和铵盐等，具体包括但不限于：钠盐、锂盐、钾盐、铵盐、铝盐、镁盐、钙盐、钡盐、铁盐、亚铁盐、锰盐、亚锰盐、锌盐、铵盐(包括与NH 3和有机胺形成的盐(NH 4盐)、甲铵盐、三甲铵盐、二乙铵盐、三乙铵盐、丙铵盐、三丙铵盐、异丙铵盐、叔丁铵盐、N,N'-二苄基乙二铵盐、二环己铵盐、1,6-己二铵盐、苄铵盐、乙醇铵盐、N,N-二甲基乙醇铵盐、N,N-二乙基乙醇铵盐、三乙醇铵盐、氨丁三醇盐、赖氨酸盐、精氨酸盐、组氨酸盐、葡糖铵盐、N-甲基葡糖铵盐、二甲基葡糖铵盐、乙基葡糖铵盐、葡甲铵盐、甜菜碱盐、咖啡因盐、氯普鲁卡因盐、普鲁卡因盐、利多卡因盐、吡啶盐、甲基吡啶盐、哌啶盐、吗啉盐、哌嗪盐、嘌呤盐、可可碱盐、胆碱盐)等。
本发明的化合物可以溶剂合物(如水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
根据其分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙 酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
可以根据已知的方法，例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
本文中使用的短语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、***、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
有益效果
发明人惊讶地发现，本发明制备的化合物具有显著的抑制RET野生型、突变型和融合型抑制活性。并且相对于现有化合物其活性有明显改善。与其他RET抑制剂相比，本发明的代表性实施例化合物还具有特别优异的药代动力学性质，作为活性成分时可以较小的剂量给患者施用，从而降低患者的治疗成本。并且，本申请的化合物制备方法简单，适于规模化生产。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
对比例1
Figure PCTCN2019109502-appb-000025
上式所示化合物APS001可参考专利文献CN108349969A的实施例342公开的方法，在制备得到 的APS001三氟乙酸盐后，在碱性条件下(碳酸氢钠)游离，得到目标化合物APS001。
化合物APS002可参考专利文献CN108349969A实施例570公开的方法进行制备，得到目标化合物APS002。
实施例1
2-氨基-4-(6-(4-(2-(5-氟吡啶-2-基)乙酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS069)
Figure PCTCN2019109502-appb-000026
步骤A：叔丁基((甲磺酰基)氧基)氨基甲酸酯
Figure PCTCN2019109502-appb-000027
冰浴搅拌下，向盛有2,4,6-三甲基苯磺酰氯(20.0g,91.5mmol)和N-羟基氨基甲酸叔丁酯(12.2g,91.5mmol)的甲基叔丁基醚(500mL)溶液中，恒压滴液漏斗缓慢滴加三乙胺(13.0mL,93.3mmol)，滴加过程中保持反应体系温度小于5℃。在冰浴下，反应体系搅拌4.0小时，减压过滤移去三乙胺盐酸盐，并用甲基叔丁基醚冲洗三次，所有滤液在小于15℃水浴温度下减压浓缩除去大部分甲基叔丁基醚；在冰浴下，向浓缩的残留物中加入正己烷，强烈搅拌10分钟，析出大量白色固体，减压过滤，滤饼用正己烷冲洗两次，真空干燥得到叔丁基((甲磺酰基)氧基)氨基甲酸酯(26.1g,90％收率)。m/z＝316[M+1] +。
步骤B：2-[(氨基氧基)磺酰]-1,3,5-三甲基苯
Figure PCTCN2019109502-appb-000028
零度下，向三氟乙酸(80mL)中分批次加入叔丁基((甲磺酰基)氧基)氨基甲酸酯(10.0g,31.7mmol)，完毕后，反应体系在零度下继续搅拌3小时；TLC点板确认反应完毕，将反应体系倒入大量的冰水中，并搅拌15分钟，析出大量白色固体，减压过滤，大量水洗涤滤饼直到固体PH值为中性，减压抽滤至固体含水量20％左右即可，无须再次纯化，直接用于下一步反应。
步骤C：2,4,6-三甲基苯磺酸1-氨基-3-溴-5-甲氧基吡啶-1-鎓
Figure PCTCN2019109502-appb-000029
零度下，向2-[(氨基氧基)磺酰]-1,3,5-三甲基苯(6.8g,31.7mmol)的二氯甲烷(50mL)溶液中加入3-溴-5-甲氧基吡啶(6.0g,32.0mmol)，并在零度下继续搅拌3小时，析出大量白色固体；反应完毕后，零度下向反应体系中加入***(50mL)并搅拌10分钟，减压过滤，***冲洗，真空干燥得到2,4,6-三甲基苯磺酸1-氨基-3-溴-5-甲氧基吡啶-1-鎓(12.8g,100％收率)，无须再次纯化，直接用于下一步反应。
m/z＝204[M+1] +。
步骤D：乙基2-氰基亚氨代乙酸酯盐酸盐
Figure PCTCN2019109502-appb-000030
向封管中加入丙二腈(4.9g,74.2mmol)、无水乙醇(3.4g,74.2mmol)和乙酸乙酯(6mL)，反应体系冷却至0℃，向反应体系中滴加2M HCl***溶液(41mL,82mmol)，加料完毕后升温至室温，析出大量白色固体，室温下反应过夜，TLC点板监测反应完毕，减压过滤，***洗涤，真空干燥得到乙基2-氰基亚氨代乙酸酯盐酸盐(9.0g,82％收率)，无须再次纯化，直接用于下一步反应。
步骤E：2-氨基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000031
室温下，向装有2,4,6-三甲基苯磺酸1-氨基-3-溴-5-甲氧基吡啶-1-鎓(4.0g,10.0mmol)的DMF(30mL)溶液中加入碳酸钾(4.2g,30.0mmol)；反应体系冷却至0℃，分批次加入乙基2-氰基亚氨代乙酸酯盐酸盐(3.0g,20.0mmol)，升至室温下搅拌1小时，再90℃下搅拌1小时；反应完毕并冷却至室温，加水淬灭，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品2-氨基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈(420mg,16％收率)。
1HNMR(400MHz,DMSO-d6)δ8.48(d,J＝0.8Hz,1H),7.08(s,1H),6.34(brs,2H),3.95(s,3H)。m/z＝267[M+1] +。
步骤F：2-氨基-4-甲氧基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000032
室温下，向装有2-氨基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈(220mg,0.824mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(206mg,0.989mmol)的1,4-二氧六环(10mL)溶液中加入碳酸钠(262mg,2.472mmol,2M)水溶液，氮气换气2分钟，随后加入四三苯基膦钯(190mg,0.165mmol)，氮气换气2分钟，在80℃下搅拌3小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品2-氨基-4-甲氧基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(220mg,100％收率)。 1HNMR(400MHz,DMSO-d6)δ8.42(s,1H),8.27(s,1H),8.00(s,1H),7.12(s,1H),6.22(s,2H),4.05(s,3H),3.89(d,3H).m/z＝269[M+1] +。
步骤G：2-氨基-4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000033
室温下，向装有2-氨基-4-甲氧基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(220mg,0.824mmol)的1,2-二氯乙烷(15mL)的混悬液中加入无水三氯化铝(550mg,4.12mmol)，移至80℃下搅拌3小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品2-氨基-4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(70mg,33％收率)。m/z＝255[M+1] +。
步骤H：2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯
Figure PCTCN2019109502-appb-000034
室温下，向装有2-氨基-4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(70mg,0.275mmol)的DMA(5mL)溶液中加入DIEA(71mg,0.55mmol)和N-苯基双(三氟甲烷)磺酰亚胺(148mg,0.413mmol)，搅拌反应3小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(26mg,25％收率)。m/z＝387[M+1] +。
步骤I：2-(5-氟吡啶-2-基)丙二酸二乙酯
Figure PCTCN2019109502-appb-000035
向1000mL单口瓶中加入2-溴-5-氟吡啶(20g,0.114mol)，二吡啶甲酸(11.22g,0.091mol)，丙二酸二乙酯(73g,0.457mol)，碘化亚铜(8.66g,0.046mol)，碳酸铯(111.49g,0.342mol)，1,4-二氧六环(400mL)，100℃反应24小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品2-(5-氟吡啶-2-基)丙二酸二乙酯(16.6g,57％收率)。m/z＝256[M+1] +。
步骤J：2-(5-氟吡啶-2-基)乙酸乙酯
Figure PCTCN2019109502-appb-000036
向250mL单口瓶中加入2-(5-氟吡啶-2-基)丙二酸二乙酯(16.6g,0.065mol),氯化钠(15.1g,0.26mol)，水(4.68g,0.26mol)，DMSO(50mL)，150℃下反应48小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品2-(5-氟吡啶-2-基)乙酸乙酯(9.1g,76％收率)。m/z＝184[M+1] +。
步骤K：2-(5-氟吡啶-2-基)乙酸
Figure PCTCN2019109502-appb-000037
室温下，向250mL单口瓶中加入2-(5-氟吡啶-2-基)乙酸乙酯(5.5g,0.03mol)，四氢呋喃(50mL)，水(10mL)，氢氧化锂(1.44g,0.06mol)，60℃反应24小时，TLC检测原料反应完，将反应液浓缩至原反应液的三分之一体积，加乙酸乙酯萃取，分层得水相，水相用1M盐酸调节pH至3左右，再用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得到产品2-(5-氟吡啶-2-基)乙酸(2.04g,44％收率)。
步骤L：1-(5-溴吡啶)-2-哌嗪
Figure PCTCN2019109502-appb-000038
室温下，向250mL单口瓶中加入2,5-二溴吡啶(12.2g,0.052mol)，哌嗪(5.0g,0.058mol)，加入DMSO(20mL)中，120℃下反应过夜。经LCMS确认反应完全，减压除去DMSO，加入甲醇使其溶解，冰水浴下慢慢加入饱和氢氧化钠溶液，调节pH至13左右，再搅拌2小时。减压浓缩出甲醇，二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，柱层析分离得到产品(4.6g,37％收率)。 m/z＝242[M+1] +。
步骤M：1-(4-(5-溴吡啶-2)哌嗪-1-基)-2-(5-氟吡啶-2-基)乙酮
Figure PCTCN2019109502-appb-000039
向100mL单口瓶中，加入2-(5-氟吡啶-2-基)乙酸(500mg,3.22mmol)，HATU(1.34g,3.54mmol)，DIEA(830mg,6.44mmol)，DMF(20mL)，室温搅拌15分钟，加入1-(5-溴吡啶)-2-哌嗪(780mg,3.22mmol)，搅拌2小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品1-(4-(5-溴吡啶-2)哌嗪-1-基)-2-(5-氟吡啶-2-基)乙酮(350mg,29％收率)。m/z＝379[M+1] +。
步骤N：2-(5-氟吡啶-2-基)-1-(4-(5-(4,4,5,5-四甲基-1,3,2-二恶硼酸-2-基)吡啶-2-基)哌嗪-1-基)乙酮
Figure PCTCN2019109502-appb-000040
向10mL封管中，加入1-(4-(5-溴吡啶-2)哌嗪-1-基)-2-(5-氟吡啶-2-基)ethan-1-酮(50mg,0.132mmol)，双联频哪醇硼酸酯(50mg,0.198mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol)，醋酸钾(39mg,0.396mmol)，1,4-二氧六环(20mL)，氮气置换三次，100℃反应3小时，LCMS确认原料反应完，有产品生成，无须后处理，直接进行下一步反应。m/z＝427[M+1] +。
步骤O：2-氨基-4-(6-(4-(2-(5-氟吡啶-2-基)乙酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000041
向步骤N的反应液中加入2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(26mg,0.067mol)，四三苯基磷钯(15mg,0.013mol)，碳酸钾(36mg,0.264mol)，1,4-二氧六环(2mL)，H 2O(1mL)，氮气置换三次，90℃反应2小时，LCMS确认原料反应完，有产品生成。加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品2-氨基-4-(6-(4-(2-(5-氟吡啶-2-基)乙酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(5mg,13％收率)。
1HNMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.49(d,J＝3.0Hz,1H),8.35(d,J＝2.5Hz,1H),8.28(s,1H),8.02(s,1H),7.80-7.78(m,1H),7.71-7.66(m,1H),7.57-7.54(m,1H),7.42-7.38(m,1H),6.98(d,J＝8.8Hz,1H),6.29(s,2H),3.98(s,2H),3.86(s,3H),3.70–3.69(d,J＝4.4Hz,2H),3.613-3.604(d,J＝3.6Hz,6H)。m/z＝537[M+1] +。
实施例2
2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(吡啶-2-基甲基)哌啶-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS070)
Figure PCTCN2019109502-appb-000042
步骤A：1-叔丁氧羰基-4-(吡啶-2-基甲基)哌啶
Figure PCTCN2019109502-appb-000043
将1-叔丁氧羰基-4-亚甲基哌啶(6.0g,30.4mmol)和9-硼杂双环[3,3,2]壬烷(60.8mL,30.4mmol,形成的THF溶液浓度为2M)的混合物在氮气保护下加热回流3小时，冷却至室温，向反应混合物中加入2-溴吡啶(5.28g,33.44mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(666mg,0.91mmol)，碳酸钾(5.04g,36.48mmol)，DMF(80mL)，H 2O(12mL)；反应混合物在60℃下搅拌过夜，TLC点板反应完毕，加入水，用10％氢氧化钠水溶液调节反应混合物pH值至11，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品1-叔丁氧羰基-4-(吡啶-2-基甲基)哌啶(5.8g,69％收率)。m/z＝277[M+1] +。
步骤B：2-(哌啶-4-基甲基)吡啶盐酸盐
Figure PCTCN2019109502-appb-000044
室温下，向装有1-叔丁基氧羰基-4-(吡啶2-基甲基)哌啶(5.66g,20.507mmol)的1,4-二氧六环(21mL)溶液中滴加氯化氢的1,4-二氧六环溶液(21mL,84.000mmol,4M)，在室温下搅拌1小时，TLC点板反应完毕，减压浓缩，乙酸乙酯(100mL)打浆得到产品2-(哌啶-4-基甲基)吡啶盐酸盐(6.10g,140％收率)，直接用于下一步反应。m/z＝177[M+1] +。
步骤C：5-溴-2-(4-(吡啶-2-基甲基)哌啶-1-基)吡啶
Figure PCTCN2019109502-appb-000045
室温下，向装有2-(哌啶-4-基甲基)吡啶盐酸盐(7.60g,35.681mmol)的二甲基亚砜(80mL)溶液中加入2,5-二溴吡啶(10.00g,42.195mmol)，无水磷酸钾(38.00g,179.245mmol)，在120℃下搅拌12小时，TLC点板反应完毕，降至室温，过滤出多余的磷酸钾固体，用乙酸乙酯洗滤饼，滤液加入水洗涤，收集有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得到产品5-溴-2-(4-(吡啶-2-基甲基)哌啶-1-基)吡啶(7.00g,59％收率)。m/z＝332[M+1] +。
步骤D：2-(4-(吡啶-2-基甲基)哌啶-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶
Figure PCTCN2019109502-appb-000046
室温下，向装有5-溴-2-(4-(吡啶-2-基甲基)哌啶-1-基)吡啶(500mg,1.505mmol)和联硼酸频那醇酯(421mg,1.656mmol)的1,4-二氧六环(4.5mL)溶液中加入乙酸钾(443mg,4.515mmol)，氮气换气2分钟，随后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(110mg,0.151mmol)，氮气换气2分钟，在100℃下搅拌1小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，打浆得到产品2-(4-(吡啶-2-基甲基)哌啶-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶(480mg,84％收率)。m/z＝380[M+1] +。
步骤E：2-氨基-6-(1-甲基l-1氢-吡唑-4-基)-4-(6-(4-吡啶-2-基甲基)哌啶-1-基)哌啶-3-基)吡唑[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000047
室温下，向装有2-(4-(吡啶-2-基甲基)哌啶-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶(33mg,0.087mmol)和2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基-三氟甲磺酸盐(28mg,0.073mmol)的1,4-二氧六环(2.5mL)溶液中加入碳酸钠(38mg,0.358mmol,2M)水溶液，氮气换气2分钟，随后加入四三苯基膦钯(4mg,0.003mmol)，氮气换气2分钟，在90℃下搅拌1小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，2-氨基-6-(1-甲基-1氢-吡唑-4-基)-4-(6-(4-吡啶-2-基甲基)哌啶-1-基)哌啶-3-基)吡唑[1,5-a]吡啶-3-腈(10mg,28％收率)。
1HNMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.50(s,1H),8.30-8.27(t,J＝2.4Hz,2H),8.01(s,1H),7.77-7.68(m,2H),7.53(s,1H),7.30-7.19(m,2H),6.96-6.89(m,1H),6.26(brs,2H),4.42-4.31(m,2H),3.86(s,3H),2.90-2.80(m,2H),2.70-2.68(m,2H),2.12-1.99(m,1H),1.70-1.61(m,2H),1.31-1.18(m,2H)。m/z＝490[M+1] +。
实施例3
2-甲基-4-(6-(4-(2-(5-氟吡啶-2-基)乙酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS071)
Figure PCTCN2019109502-appb-000048
步骤A：2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲酸乙酯
Figure PCTCN2019109502-appb-000049
室温下，向装有2,4,6-三甲基苯磺酸1-氨基-3-溴-5-甲氧基吡啶-1-鎓(2.79g,6.91mmol)的DMF(25mL)溶液中加入三乙胺(1.93mL,13.82mmol)；反应体系冷却至0℃，分批次加入丁炔酸乙酯(1.62mL,13.82mmol)，升至室温下搅拌过夜；反应完毕，加水淬灭，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲酸乙酯(510mg,24％收率)。
1HNMR(400MHz,CDCl 3)δ8.13(d,J＝1.2Hz,1H),6.58(d,J＝13.2Hz,1H),4.31-4.17(m,2H),3.85(t,J＝20.8Hz,3H),2.51(s,3H),1.39-1.31(m,3H)。m/z＝313[M+1] +。
步骤B：2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶
Figure PCTCN2019109502-appb-000050
室温下，向装有2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲酸乙酯(510mg,1.63mmol)的封管中加入48％氢溴酸(10mL)，密封好，加热至80℃，并在80℃下搅拌2.0小时，冷却至室温，真空除去溶剂，干法柱层析得到产品2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶(392mg,100％收率)，直接投入下一步反应。m/z＝241[M+1] +。
步骤C：2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲醛
Figure PCTCN2019109502-appb-000051
在0℃下，向2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶(392mg,1.63mmol)的DMF(10mL)溶液中加入三氯氧磷(0.45mL,4.89mmol)，升至室温下搅拌4.0小时，TLC点板反应完毕，加入水稀释，混合物用氢氧化钠水溶液(1M)调节PH值为10左右并搅拌1.0小时，真空过滤，滤饼用水洗，甲基叔丁基醚洗，真空干燥得到产品2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲醛(414mg,100％收率)，直接投入下一步反应。m/z＝269[M+1] +。
步骤D：(E)-2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲醛肟
Figure PCTCN2019109502-appb-000052
将2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲醛(414mg,1.63mmol)、盐酸羟胺(170mg,2.45mmol)、水(6mL)和乙醇(3mL)的混合物在50℃下搅拌4.0小时，TLC点板反应完毕，反应体系冷却至室温，减压除去乙醇，饱和碳酸氢钠水溶液中和反应体系，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品(E)-2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲醛肟(463mg,100％收率)，直接投入下一步反应。m/z＝284[M+1] +。
步骤E：2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000053
将2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈(463mg,1.63mmol)的乙酸酐(10mL)混合物加热到120℃并搅拌过夜，TLC点板反应完毕，反应体系冷却至室温，减压除去乙酸酐，加水稀释，饱和碳酸氢钠水溶液中和反应体系，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈(300mg,69％收率)。m/z＝266[M+1] +。
步骤F：2-甲基-4-甲氧基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000054
将2-甲基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈(300mg,1.13mmol)，1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(282mg,1.35mmol)，四三苯基膦钯(26mg,0.02mmol)，碳酸钾(467mg,3.39mmol)，1,4-二氧六环(5mL)和H 2O(1mL)放于20mL封管中，氮气置换三次，80℃反应3小时,TLC检测反应完，浓缩反应液，乙酸乙酯稀释，水洗，有机相用无水硫酸钠干燥， 减压浓缩，柱层析分离得到产品2-氨基-4-甲氧基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(300mg,99％收率)。m/z＝268[M+1] +。
步骤G：2-甲基-4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000055
将2-氨基-4-甲氧基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(300mg,1.12mmol)，DCE(20mL)，氯化铝(446mg,3.36mmol)放于100mL单口瓶中，氮气保护，80℃加热搅拌，颜色逐渐变深棕色，反应3小时,TLC检测反应完，加水搅拌淬灭，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，柱层析分离得到产品2-甲基-4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(150mg,53％收率)。m/z＝254[M+1] +。
步骤H：2-甲基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯
Figure PCTCN2019109502-appb-000056
将2-甲基-4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(150mg,0.59mmol)，DMF(15mL)，DIEA(152mg,1.17mmol)，N-苯基双(三氟甲烷)磺酰亚胺(317mg,0.89mmol)放于100mL单口瓶中，室温搅拌2小时，TLC检测反应完，加水稀释，乙酸乙酯萃取，合并有机层，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，减压浓缩，柱层析分离得到2-甲基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(180mg,79％收率)。m/z＝386[M+1] +。
步骤I：2-(5-氟吡啶-2-基)-1-(4-(5-(4,4,5,5-四甲基-1,3,2-二恶硼酸-2-基)吡啶-2-基)哌嗪-1-基)乙酮
Figure PCTCN2019109502-appb-000057
向10mL封管中，加入1-(4-(5-溴吡啶-2)哌嗪-1-基)-2-(5-氟吡啶-2-基)ethan-1-酮(50mg,0.132mmol)，双联频哪醇硼酸酯(50mg,0.198mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol)，醋酸钾(39mg,0.396mmol)，1,4-二氧六环(20mL)，氮气置换三次，100℃反应3小时，LCMS确认原料反应完，有产品生成，无须后处理，直接进行下一步反应。m/z＝427[M+1] +。
步骤J：2-甲基-4-(6-(4-(2-(5-氟吡啶-2-基)乙酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000058
向步骤I的反应液中加入2-甲基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(50mg,0.13mol)，四三苯基磷钯(15mg,0.01mol)，碳酸钾(36mg,0.26mol)，1,4-二氧六环(4mL)，H 2O(1mL)，氮气置换三次，90℃反应2小时，LCMS确认原料反应完，有产品生成。加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层 析分离得到产品2-甲基-4-(6-(4-(2-(5-氟吡啶-2-基)乙酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(14mg,20％收率)。
1HNMR(400MHz,DMSO-d 6)δ9.12(s,1H),8.49(d,J＝1.2Hz,1H),8.39-8.36(m,2H),8.09(s,1H),7.84(brs,1H),7.81-7.65(m,2H),7.48-7.36(m,1H),7.01(d,J＝9.2Hz,1H),3.98(s,3H),3.88(s,3H),3.80-3.56(m,8H),3.89(t,J＝2.8Hz,2H)。m/z＝536[M+1] +。
实施例4
2-甲基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(吡啶-2-基甲基)哌啶-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS072)
Figure PCTCN2019109502-appb-000059
室温下，向装有-(4-(吡啶-2-基甲基)哌啶-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶(45mg,0.12mmol)和2-甲基-3-氰基-6-(1-甲基-1氢-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲磺酸盐(38mg,0.10mmol)的1,4-二氧六环(3mL)溶液中加入碳酸钠(53mg,0.50mmol,2M)水溶液，氮气换气2分钟，随后加入四三苯基膦钯(12mg,0.01mmol)，氮气换气2分钟，在80℃下搅拌3小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得到产品2-甲基-6-(1-甲基l-1氢-吡唑-4-基)-4-(6-(4-吡啶-2-基甲基)哌啶-1-基)哌啶-3-基)吡唑[1,5-a]吡啶-3-腈(12mg,25％收率)。
1HNMR(400MHz,DMSO-d 6)δ9.1(s,1H),8.55-8.50(m,1H),8.36-8.34(m,2H),8.09(s,1H),7.79-7.76(m,1H),7.73-7.68(m,2H),7.26-7.19(m,2H),6.95-6.93(d,J＝9.2Hz,1H),4.40-4.37(d,J＝12.8Hz,2H),3.93(s,3H),2.92-2.79(m,2H),2.75-2.66(m,3H),2.33(s,2H),2.07(brs,1H),1.67-1.64(d,J＝12.8Hz,2H),1.29-1.19(m,2H)。m/z＝489[M+1] +。
实施例5
2-氨基-4-(6-(4-((5-氟吡啶-3-基)甲基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS014)
步骤A：1-(5-溴吡啶-2-基)-4-((5-氟吡啶-3-基)甲基)哌嗪
Figure PCTCN2019109502-appb-000060
向100mL单口瓶中，加入5-氟烟醛(2.4g,19.2mmol)，1-(5-溴吡啶)-2-哌嗪(4.6g,19.2mmol)，醋酸硼氢化钠(12.2g,57.6mmol)，二氯甲烷200mL，室温搅拌12小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品1-(5-溴吡啶-2-基)-4-((5-氟吡啶-3-基)甲基)哌嗪(1.7g，收率25％)。m/z＝352[M+1] +。
步骤B：1-((4-氟吡啶-3-基)甲基)-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)哌嗪
Figure PCTCN2019109502-appb-000061
向10mL封管中，加入1-(5-溴吡啶-2-基)-4-((5-氟吡啶-3-基)甲基)哌嗪(47mg,0.132mmol)，双联频哪醇硼酸酯(50mg,0.198mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol)，醋酸钾(39mg,0.396mmol)，1,4-二氧六环(20mL)，氮气置换三次，100℃反应3小时，LCMS确认原料反应完，有产品生成，无需后处理，直接进行下一步反应。m/z＝399[M+1] +。
步骤C：2-氨基-4-(6-(4-((5-氟吡啶-3-基)甲基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000062
室温下，向装有1-((4-氟吡啶-3-基)甲基)-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)哌嗪(35mg,0.087mmol)和2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基-三氟甲磺酸盐(28mg,0.073mmol)的1,4-二氧六环(2.5mL)溶液中加入碳酸钠(38mg,0.358mmol,2M)水溶液，氮气换气2分钟，随后加入四三苯基膦钯(4mg,0.003mmol)，氮气换气2分钟，在90℃下搅拌1小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，2-氨基-4-(6-(4-((5-氟吡啶-3-基)甲基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(17mg,46％收率)。
1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.51(d,1H),8.50(d,1H),8.33(d,1H),8.28(s,1H),8.02(s,1H),7.75-7.78(m,1H),7.72(d,1H),7.55(d,1H),6.95(d,1H),6.29(s,2H),4.08-4.12(m,1H),3.86(s,3H),3.59-3.64(m,6H),3.17(d,2H),2.50(s,3H).m/z＝509[M+1] +。
实施例6
2-氨基-4-(6-(4-((2-氟苄基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS015)
Figure PCTCN2019109502-appb-000063
制备方法同实施例5，将5-氟烟醛替换为2-氟苯甲醛，得2-氨基-4-(6-(4-((2-氟苄基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(12mg,31％收率)。 1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.33(d,1H),8.28(s,1H),8.02(s,1H),7.75(d,1H),7.55(s,1H),7.42-7.48(m,1H),7.35(s,1H),7.20-7.21(m,2H),6.94(d,1H),6.29(s,2H),3.86(s,3H),3.61(d,6H),3.49(s,1H),1.24(s,3H).m/z＝508[M+1] +。
实施例7
4-(5-(2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-N,N-二乙基哌嗪-1-甲酰胺(APS016)
Figure PCTCN2019109502-appb-000064
制备方法同实施例1，将2-(5-氟吡啶-2-基)乙酸替换为二乙氨基甲酰氯，得4-(5-(2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-N,N-二乙基哌嗪-1-甲酰胺(5.1mg,收率14％)， 1HNMR(400MHz,CDCl 3)δ8.79(s,1H),8.39(s,1H),8.30(s,1H),7.74-7.83(s,2H),7.70(s,1H),7.52(s,1H),6.83(d,1H),4.00(d,3H),3.70(s,4H),3.39(d,4H),3.24-3.30(m,4H),1.16(t,6H).m/z＝489[M+1] +。
实施例8
2-氨基-4-(6-(4-((3-氟苄基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS019)
Figure PCTCN2019109502-appb-000065
制备方法同实施例5，将5-氟烟醛替换为3-氟苯甲醛，得2-氨基-4-(6-(4-((3-氟苄基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(26.9mg,收率73％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.78(d,1H),8.32(s,1H),8.02(s,1H),7.75(d,2H),7.55(d,1H),7.37-7.42(m,1H),7.17-7.21(m,2H),7.08-7.13(m,1H),6.92-6.95(d,1H),6.29(s,2H),4.08-4.12(m,1H),3.86(s,3H),3.57-3.61(m,6H),3.18(d,2H).m/z＝508[M+1] +。
实施例9
2-氨基-4-(6-(4-((2,5-二氟苄基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS020)
Figure PCTCN2019109502-appb-000066
制备方法同实施例5，将5-氟烟醛替换为2,5-二氟苯甲醛，得2-氨基-4-(6-(4-((2,5-二氟苄基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(9.9mg,收率26％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.33(d,1H),8.28(s,1H),8.02(s,1H),7.75-7.78(dd,1H),7.55(d,1H),6.95-7.33(m,3H),6.92(d,1H),6.28(s,2H),3.86(s,3H),3.60(s,6H).m/z＝526[M+1] +。
实施例10
2-氨基-4-(6-(4-((5-氯吡啶-3-基)甲基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS021)
Figure PCTCN2019109502-appb-000067
制备方法同实施例5，将5-氟烟醛替换为5-氯-烟醛，得2-氨基-4-(6-(4-((5-氯吡啶-3-基)甲基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(21mg,收率55％)。 1HNMR(400MHz,CDCl 3)δ8.39-8.44(m,2H),8.25-8.29(m,2H),7.65-7.71(m,2H),7.54-7.59(m,1H),7.19-7.21(m,4H),6.63-6.71(m,1H),4.45(s,1H),3.90(s,2H),3.53-3.72(d,7H),2.54(s,4H),m/z＝525[M+1] +。
实施例11
2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-((3-甲基吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS022)
Figure PCTCN2019109502-appb-000068
制备方法同实施例5，将5-氟烟醛替换为3-甲基-2-吡啶甲醛，得2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-((3-甲基吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(5mg,收率14％)。 1HNMR(400MHz,DMSO-d 6)δ8.8.79(s,1H),8.28-8.78(m,3H),8.02(s,1H),7.74-7.77(m,1H),7.54-7.60(m,2H),7.21-7.24(m,1H),6.93(d,1H),6.28(d,2H),4.08-4.11(m,1H),3.86(s,3H),3.65(s,2H), 3.58(s,4H),3.3(s,1H),3.17(d,2H),2.43(s,3H).m/z＝505[M+1] +。
实施例12
2-氨基-4-(6-(4-((2,6-二氟苄基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS024)
Figure PCTCN2019109502-appb-000069
制备方法同实施例5，将5-氟烟醛替换为2,6-二氟苯甲醛，得2-氨基-4-(6-(4-((2,6-二氟苄基)哌嗪-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(3.5mg,收率9％)。 1HNMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.31(d,2H),8.27-8.31(m,2H),8.01(s,1H),7.73(d,1H),7.54(s,1H),7.42-7.48(m,1H),7.13(t,2H),6.28(s,2H),3.86(s,3H),3.56-3.65(s,7H),3.27(s,1H).m/z＝526[M+1] +。
实施例13
2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-((4-甲基吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS025)
Figure PCTCN2019109502-appb-000070
制备方法同实施例5，将5-氟烟醛替换为4-甲基-2-吡啶甲醛得2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-((4-甲基吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(3.9mg,收率11％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.29-8.33(m,3H),8.02(s,1H),8.75(d,1H),7.55(d,1H),7.33(s,1H),7.23(d,1H),6.95(d,2H),6.30(s,2H),3.86(s,3H),3.62(d,6H),3.32(s,2H)2.55(s,4H),2.34(s,3H).1.23(s,1H).m/z＝505[M+1] +。
实施例14
2-氨基-4-(6-(4-(3-甲氧基苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS026)
Figure PCTCN2019109502-appb-000071
制备方法同实施例5，将5-氟烟醛替换为3-甲氧基苯甲醛，得2-氨基-4-(6-(4-(3-甲氧基苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(14.2mg,收率37％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.51(d,1H),8.45(s,1H),8.33(d,1H),8.28(s,1H),8.02(s,1H),7.75-7.78(d,1H),7.72(d,1H),7.55(d,1H),6.95(d,1H),6.29(s,2H),4.11(t,1H),3.86(s,3H),3.59-3.64(m,6H),3.17(d,2H),2.53(s,3H).m/z＝520[M+1] +。
实施例15
2-氨基-4-(6-(4-(2-氯苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS027)
Figure PCTCN2019109502-appb-000072
制备方法同实施例5，将5-氟烟醛替换为2-氯苯甲醛，得2-氨基-4-(6-(4-(2-氯苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(9.4mg,收率25％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.80(d,1H),8.28(s,1H),8.02(s,1H),7.78(d,1H),7.56-7.58(m,3H),7.45-7.47(m,2m/z＝524[M+1] +。
实施例16
2-氨基-4-(6-(4-((6-甲氧基吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS030)
Figure PCTCN2019109502-appb-000073
制备方法同实施例5，将5-氟烟醛替换为6-甲氧基-2-吡啶甲醛，得2-氨基-4-(6-(4-((6-甲氧基吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(8.6mg,收率23％)。 1HNMR(400MHz,CDCl 3)δ8.27(d,2H),7.65-7.68(m,2H),7.45-7.54(m,2H),7.21(s,1H),7.01(s,1H),6.71(d,1H),6.59(d,1H),4.45(s,2H),3.86-3.90(d,6H),3.66(s,6H),2.69(brs,4H),1.54(brs,4H),m/z＝521[M+1] +。
实施例17
2-氨基-4-(6-(4-((5-甲氧基吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS033)
Figure PCTCN2019109502-appb-000074
制备方法同实施例5，将5-氟烟醛替换为5-甲氧基烟醛，得2-氨基-4-(6-(4-((5-甲氧基吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(21.9mg,收率58％). 1HNMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.32(d,1H),8.27(d,1H),8.22(d,1H),8.01(s,1H),7.77(dd,1H),7.54(s,1H),7.37-7.43(m,2H),6.94(d,1H),6.26(s,2H),4.08(s,1H),3.83-3.86(m,6H),3.60(s,6H),3.28(s,2H),3.18(d,2H).m/z＝521[M+1] +。
实施例18
2-氨基-4-(6-(4-(4-(二甲氨基)苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS034)
Figure PCTCN2019109502-appb-000075
制备方法同实施例5，将5-氟烟醛替换为4-二甲氨基苯甲醛，得2-氨基-4-(6-(4-(4-(二甲氨基)苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(7.0mg,收率18％)， 1HNMR(400MHz,DMSO-d 6)δ8.78(d,1H),8.28-8.32(m,2H),8.02(s,1H),7.74-7.76(d,1H),7.54(d,1H),7.15(d,2H),6.93(d,1H),6.71(d,1H),6.28(s,2H),4.08-4.11(m,1H),3.86(s,3H),3.56(s,4H),3.41(s,2H),3.17(s,2H),2.88(s,6H),2.44-2.50(m,4H).m/z＝533[M+1] +。
实施例19
2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(4-(吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS035)
Figure PCTCN2019109502-appb-000076
制备方法同实施例5，将5-氟烟醛替换为2-吡啶甲醛，得2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(4-(吡啶-2-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(12.7mg,收率35％), 1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.52(d,1H),8.33(d,1H),8.28(s,1H),8.02(s,1H),7.72-8.80(m,2H),7.48-7.51(m,2H),7.24-7.31(m,1H),6.91-6.96(d,1H),6.29(s,2H),3.86(s,3H),3.59-3.67(m,8H),2.56(s,2H).m/z＝491[M+1] +。
实施例20
2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS038)
Figure PCTCN2019109502-appb-000077
步骤A：3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯
Figure PCTCN2019109502-appb-000078
室温下，向250mL单口瓶中加入2,5-二溴吡啶(12.2g,0.052mol)，3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯(11.5g,0.058mol)，加入DMSO(20mL)中，120℃下反应过夜。经LCMS确认反应完全，减压除去DMSO，加入甲醇使其溶解，冰水浴下慢慢加入饱和氢氧化钠溶液，调节pH至13左右，再搅拌2小时。减压浓缩出甲醇，二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，柱层析分离得到产品(5.2g,28％收率)。m/z＝355[M+1] +。
步骤B：3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐
Figure PCTCN2019109502-appb-000079
向100mL单口瓶中，加入3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯(5.0g,14mmol)，氯化氢二氧六环溶液(15mL)，室温搅拌2h，直接浓缩后用于下步反应。m/z＝255[M+1] +。
步骤C：3-(5-溴吡啶-2-基)-6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019109502-appb-000080
向100mL单口瓶中，加入2-吡啶甲醛(0.21g,1.9mmol)，3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐(0.6g,1.9mmol)，醋酸硼氢化钠(1.2g,5.8mmol)， 二氯甲烷20mL，室温搅拌12小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品3-(5-溴吡啶-2-基)-6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷(0.6g，收率85％)。m/z＝346[M+1] +。
步骤D：6-(吡啶-2-基甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019109502-appb-000081
向10mL封管中，加入3-(5-溴吡啶-2-基)-6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷(46mg,0.132mmol)，双联频哪醇硼酸酯(50mg,0.198mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol)，醋酸钾(39mg,0.396mmol)，1,4-二氧六环(20mL)，氮气置换三次，100℃反应3小时，LCMS确认原料反应完，有产品生成，无须后处理，直接进行下一步反应。
步骤E：室温下，向装有6-(吡啶-2-基甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷(34mg,0.087mmol)和2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基-三氟甲磺酸盐(28mg,0.073mmol)的1,4-二氧六环(2.5mL)溶液中加入碳酸钠(38mg,0.358mmol,2M)水溶液，氮气换气2分钟，随后加入四三苯基膦钯(4mg,0.003mmol)，氮气换气2分钟，在90℃下搅拌1小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(10mg,28％收率)。
1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.46(d,1H),8.39(d,1H),8.29(s,1H),8.03(s,1H),7.76-7.83(m,2H),7.57(d,1H),7.49(d,1H),6.79(d,1H),6.29(s,2H),3.86(s,2H),3.73(d,2H),3.57(s,2H),3.52-3.55(m,2H),3.31(s,1H),1.98-2.00(m,1H),1.74(brs,1H).m/z＝503[M+1] +。
实施例21
2-氨基-4-(6-(4-((6-(二甲氨基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS041)
Figure PCTCN2019109502-appb-000082
制备方法同实施例5，将5-氟烟醛替换为6-二甲氨基烟醛，得2-氨基-4-(6-(4-((6-(二甲氨基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(22.2mg,收率56％), 1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.28-8.33(m,2H),8.02(d,2H),7.74-7.77(m,1H),7.55(d,1H),7.46-7.49(m,1H),6.94(d,1H),6.64(d,1H),6.28(s,2H),3.86(s,3H),3.57(s,4H),3.40(s,2H),3.30(s,1H),3.02(s,6H),2.50(s,4H).m/z＝534[M+1] +。
实施例22
2-氨基-4-(6-(4-(2,6-二氟苯甲酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS062)
Figure PCTCN2019109502-appb-000083
制备方法同实施例1，将2-(5-氟吡啶-2-基)乙酸替换为2,6-二氟苯甲酰氯，得2-氨基-4-(6-(4-(2,6-二氟苯甲酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(28.7mg,收率73％)。 1HNMR(400MHz,DMSO-d 6)δ9.25(d,1H),8.66(s,1H),8.40-8.43(m,2H),8.13(s,1H),7.90(d,1H),7.80(d,1H),7.5-7.63(m,1H),7.25-7.29(m,2H),7.04(d,1H),4.08-4.12(m,1H),3.89(s,3H),3.82-3.85(m,2H),3.72-3.75(d,2H),3.61-3.63(m,2H),3.42(d,2H),3.18(d,3H).m/z＝539[M+1] +。
实施例23
2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(吡嗪-2-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS064)
Figure PCTCN2019109502-appb-000084
制备方法同实施例5，将5-氟烟醛替换为吡嗪-2-甲醛，得2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(吡嗪-2-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(9.5mg,收率26％)。 1HNMR(400MHz,CDCl 3)δ8.82(s,1H),8.60(s,1H),8.56(s,1H),8.34-8.37(m,2H),7.75-7.78(m,2H),7.63(s,1H),7.30(s,1H),6.81(d,1H),4.54(s,2H),3.99(s,3H),3.78-3.88(brs,5H),2.76(brs,3H).m/z＝492[M+1] +。
实施例24
2-氨基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS068)
Figure PCTCN2019109502-appb-000085
制备方法同实施例5，将5-氟烟醛替换为6-甲氧基-3-吡啶甲醛，得2-氨基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(20mg,收率53％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.34(d,2H),8.20(d,2H),7.68-7.77(m,2H),7.55(s,1H),6.81-6.94(dd,2H),6.29(s,2H),3.86(d,6H),3.49-3.58(d,6H).m/z＝521[M+1] +。
实施例25
(R)-2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(3-甲基-4-(吡啶-2-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS073)
Figure PCTCN2019109502-appb-000086
制备方法同实施例20，将3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯替换为(R)-4-N-叔丁氧羰基-2-甲基哌嗪，得(R)-2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(3-甲基-4-(吡啶-2-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(23mg，收率62％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.52(d,1H),8.32(d,1H),8.28(s,1H),8.02(s,1H),7.74-7.81(m,2H),7.50-7.55(m,2H),7.26-7.29(m,1m/z＝505[M+1] +。
实施例26
2-氨基-4-(6-(4-苄基哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS074)
Figure PCTCN2019109502-appb-000087
制备方法同实施例5，将5-氟烟醛替换为苯甲醛，得2-氨基-4-(6-(4-苄基哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(27mg，收率75％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.33(d,1H),8.28(s,1H),8.02(s,1H),7.75-7.77(m,1H),7.55(d,1H),7.37(d,4H),7.29(s,1H),6.95(d,1H),6.28(s,2H).3.86(s,3H),3.55-3.59(m,7H),1.24(s,3H).m/z＝490[M+1] +。
实施例27
2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(吡啶-3-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS075)
Figure PCTCN2019109502-appb-000088
制备方法同实施例5，将5-氟烟醛替换为烟醛，得2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(吡啶-3-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(7mg,19％)。 1HNMR(400MHz,CDCl 3)δ8.62(d,2H),8.36(dd,2H),7.74-7.77(m,2H),7.63(s,1H),7.36(s,1H),7.28(s,1H),6.81(d,1H),4.53(s,2H),3.99(s,3H),3.65(s,6H),2.70(s,4H)。m/z＝491[M+1] +。
实施例28
(R)-2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(2-甲基-4-(吡啶-2-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS076)
Figure PCTCN2019109502-appb-000089
制备方法同实施例20，将3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯替换为(R)-4-N-叔丁氧羰基-3-甲基哌嗪制备得到(R)-2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(2-甲基-4-(吡啶-2-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(12mg,33％)。 1HNMR(400MHz,DMSO-d 6)δ8.94(s,1H),8.78(s,1H),8.52(d,2H),8.05(s,1H),7.74-7.84(m,2H),7.56 9d,2H),7.31(t,1H),6.89(d,1H),6.27(s,1H),3.70(s,3H),3.62-3.86(m,1H),3.30(s,5H),3.12(t,1H),2.95(d,1H),2.74(d,1H),1.23(t,3H).m/z＝505[M+1] +。
实施例29
2-氨基-4-(6-(4-(4-氟苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS077)
Figure PCTCN2019109502-appb-000090
制备方法同实施例5，将5-氟烟醛替换为4-氟苯甲醛，得2-氨基-4-(6-(4-(4-氟苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(10mg,收率27％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.33(d,1H),8.28(s,1H),8.02(s,1H),7.75(d,1H),7.55(d,1H),7.38-7.40(m,1H),7.17-7.20(m,2H),6.95(d,1H),6.28(s,2H),3.86(s,3H),3.53-3.59(m,6H).m/z＝508[M+1] +。
实施例30
2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(吡啶-4-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS078)
Figure PCTCN2019109502-appb-000091
制备方法同实施例5，将5-氟烟醛替换为异烟醛，得2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(4-(吡啶-4-基甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(8.4mg,收率23％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.53(d,2H),8.29-8.32(m,2H),8.02(s,1H),7.78(d,1H),7.52(s,1H),7.40(d,2H),6.98(d,1H),6.29(s,2H),3.86(s,3H),3.62)d,7H).m/z＝491[M+1] +。
实施例31
2-氨基-4-(6-(4-(3,4-二氟苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS079)
Figure PCTCN2019109502-appb-000092
制备方法同实施例5，将5-氟烟醛替换为3,4-二氟苯甲醛，得2-氨基-4-(6-(4-(3,4-二氟苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(12.7mg,收率33％)。 1HNMR(400MHz,CDCl 3)δ8.27(d,1H),7.65(s,1H),7.41(s,1H),7.20(s,4H),7.02-7.08(m,2H),6.70(d,1H),4.45(s,1H),4.07(s,2H),3.59(s,3H),3.45(s,1H),2.50(s,2H),2.01(s,1H)。m/z＝526[M+1] +。
实施例32
2-氨基-4-(6-(4-(2,6-二氟苄基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS024)
Figure PCTCN2019109502-appb-000093
制备方法同实施例5，将5-氟烟醛替换为2,6-二氟苯甲醛，得2-氨基-4-(6-(4-(2,6-二氟苄基)哌 嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(27mg,收率70％)。 1HNMR(400MHz,DMSO-d 6)δ10.9(brs,1H),9.27(d,1H),8.67(s,1H),8.46(d,1H),8.40(s,1H),8.13(s,1H),7.94-7.97(m,1H),7.80(d,1H),7.75-7.68(m,1H),7.28-7.32(m,2H),7.14(d,1H),7.48-7.56(m,4H),3.89(s,4H),3.25-3.45(m,5H).m/z＝526[M+1] +。
实施例33
4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,2,3]三氮唑[1,5-a]吡啶-3-腈(APS081)
Figure PCTCN2019109502-appb-000094
步骤A：6-溴-4-氯-[1,2,3]三氮唑[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000095
将2-(5-溴-3-氯吡啶-2-基)乙腈(1.2g,5mmol)，对甲苯磺酰叠氮(1.2g,6mmol)，碳酸铯(3.3g,10mmol)分别加入到DMF(50mL)中，加热100℃反应12h。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品6-溴-4-氯-[1,2,3]三氮唑[1,5-a]吡啶-3-腈(450mg，收率35％)。m/z＝258[M+1] +。
步骤B：4-氯-6-(1-甲基-1H-吡唑-4-基)-[1,2,3]三氮唑[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000096
制备方法同实施例1步骤F，将2-氨基-6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈替换为6-溴-4-氯-[1,2,3]三氮唑[1,5-a]吡啶-3-腈，得4-氯-6-(1-甲基-1H-吡唑-4-基)-[1,2,3]三氮唑[1,5-a]吡啶-3-腈(20mg,收率40％)。m/z＝259[M+1] +。
步骤C：制备方法同实施例5，将5-氟烟醛替换为6-甲氧基烟醛，得4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,2,3]三氮唑[1,5-a]吡啶-3-腈(10mg,收率27％)。 1HNMR(400MHz,DMSO-d 6)δ9.64(d,1H),8.46-8.51(m,2H),8.23(s,1H),8.01(d,1H),7.91(d,1H),7.69(d,2H),7.02(d,1H),6.83(d,1H),3.91(s,3H),3.85(s,3H),3.62(s,4H),3.49(s,2H),3.32(s,1H),2.50(s,3H)。m/z＝507[M+1] +。
实施例34
2-(二甲氨基)-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS082)
Figure PCTCN2019109502-appb-000097
将2-氨基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡 唑并[1,5-a]吡啶-3-腈(APS068)(50mg,0.1mmol)溶于DMF(5.0mL)中，冰水冷却至0度，加入60％矿物油NaH(8mg,0.2mmol)搅拌30分钟后，加入碘甲烷(28mg,0.2mmol)，自然升至室温反应12h。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品2-(二甲氨基)-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(9.1mg,收率16％)。 1HNMR(400MHz,CDCl 3)δ8.31-8.37(m,2H),8.09(s,1H),7.68-7.72(m,2H),7.61-7.63(m,2H),7.22(s,1H),6.76(d,2H),3.97(d,6H),3.64(s,3H),3.49(s,2H),3.19(s,6H),2.56(s,3H).m/z＝549[M+1] +。
实施例35
2-氟-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS084)
Figure PCTCN2019109502-appb-000098
制备方法同实施例40，将2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐替换为2-氨基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈得7-氟-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(20mg,收率47％)。 1HNMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.37(s,2H),8.10(d,2H),7.94(d,1H),7.70(d,1H),7.55(d,1H),6.98(d,1H),6.81(d,1H),3.93(s,3H),3.85(s,3H),3.60(s,4H),3.49(s,2H),2.51(s,4H).m/z＝524[M+1] +。
实施例36
2-羟基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS083)
Figure PCTCN2019109502-appb-000099
将2-氟-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS084)(50mg，0.1mmol)和碳酸钾(41mg,0.3mmol)加入DMSO(2.0mL)中，再加入水(0.5mL)加热至100℃反应6h。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品2-羟基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(7.3mg,收率14％)。m/z＝522[M+1] +。
实施例37
N-(3-氰基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-2-基)乙酰胺(APS085)
Figure PCTCN2019109502-appb-000100
将2-氨基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS068)(20mg,0.038mmol)溶于醋酸酐(2.0mL)加热至80℃反应4h。将反应液加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品N-(3-氰基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-2-基)乙酰胺(14mg,收率65％)。m/z＝563[M+1] +。
实施例38
2-甲氨基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(APS086)
Figure PCTCN2019109502-appb-000101
制备方法同实施例34，得2-甲氨基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-腈(8mg,收率15％)。m/z＝535[M+1] +。
实施例39
2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS087)
Figure PCTCN2019109502-appb-000102
步骤A：3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯
Figure PCTCN2019109502-appb-000103
室温下，向250mL单口瓶中加入2-氯-5-氟吡嗪(6.9g,0.052mol)，3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯(11.5g,0.058mol)，加入DMSO(20mL)中，120℃下反应过夜。经LCMS确认反应完全，减压除去DMSO，加入甲醇使其溶解，冰水浴下慢慢加入饱和氢氧化钠溶液，调节pH至13左右，再搅拌2小时。减压浓缩出甲醇，二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，柱层析分离得到产品(12g,74％收率)。m/z＝311[M+1] +。
步骤B：3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐
Figure PCTCN2019109502-appb-000104
向100mL单口瓶中，加入3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-碳酸叔丁酯(5.0g, 14mmol)，氯化氢二氧六环溶液(15mL)，室温搅拌2h，直接浓缩后用于下步反应。m/z＝211[M+1] +。
步骤C：3-(5-氯吡嗪-2-基)-6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019109502-appb-000105
向100mL单口瓶中，加入6-甲氧基烟醛(0.21g,1.9mmol)，3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐(0.4g,1.9mmol)，醋酸硼氢化钠(1.2g,5.8mmol)，二氯甲烷20mL，室温搅拌12小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品3-(5-氯吡嗪-2-基)-6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷(0.5g，收率80％)。m/z＝332[M+1] +。
步骤D：6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019109502-appb-000106
向10mL封管中，加入3-(5-氯吡嗪-2-基)-6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷(44mg,0.132mmol)，双联频哪醇硼酸酯(50mg,0.198mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol)，醋酸钾(39mg,0.396mmol)，1,4-二氧六环(20mL)，氮气置换三次，100℃反应3小时，LCMS确认原料反应完，有产品生成，无须后处理，直接进行下一步反应。
步骤E：2-氨基-4-氯-6-甲氧基吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000107
室温下，向装有2,4,6-三甲基苯磺酸1-氨基-3-氯-5-甲氧基吡啶-1-鎓(4.0g,10.0mmol)的DMF(30mL)溶液中加入碳酸钾(4.2g,30.0mmol)；反应体系冷却至0℃，分批次加入乙基2-氰基亚氨代乙酸酯盐酸盐(3.0g,20.0mmol)，升至室温下搅拌1小时，再90℃下搅拌1小时；反应完毕并冷却至室温，加水淬灭，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品2-氨基-4-氯-6-甲氧基吡唑并[1,5-a]吡啶-3-腈(89mg,4％收率)。m/z＝223[M+1] +。
步骤F：4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-甲氧基吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000108
将2-氨基-4-氯-6-甲氧基吡唑并[1,5-a]吡啶-3-腈(80mg,0.35mmol)和邻苯二甲酸酐(78mg,0.53mmol)加入到冰醋酸(5.0mL)，加热至100℃反应5h，减压浓缩，柱层析分离得到产品4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-甲氧基吡唑并[1,5-a]吡啶-3-腈(80mg,收率65％)。m/z＝353[M+1] +。
步骤G：4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-羟基吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000109
将4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-甲氧基吡唑并[1,5-a]吡啶-3-腈(80mg,0.22mmol)和无水三氯化铝(146mg,1.1mmol)加入到乙腈(5.0mL)中，加热至80℃反应2h。反应完毕并冷却至室温，加水淬灭，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-羟基吡唑并[1,5-a]吡啶-3-腈(62mg,收率84％)。m/z＝339[M+1] +。
步骤H：(S)-2-(((4-氯-3-氰基-2-(1,3-邻苯二甲酰亚胺-2-基)吡唑并[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-碳酸叔丁酯
Figure PCTCN2019109502-appb-000110
将4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-羟基吡唑并[1,5-a]吡啶-3-腈(60mg,0.17mmol)，(2S)-2-(溴甲基)-4-吗啉羧酸叔丁酯(52mg,0.19mmol),碳酸铯(166mg,0.51mmol)加入到DMF(10mL)中，加热60℃反应12h。反应完毕并冷却至室温，加水淬灭，用乙酸乙酯萃取，合并有机相，并用水洗涤，减压浓缩，柱层析分离得到产品(S)-2-(((4-氯-3-氰基-2-(1,3-邻苯二甲酰亚胺-2-基)吡唑并[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-碳酸叔丁酯(77mg,收率85％).m/z＝538[M+1] +。
步骤I：室温下，向装有6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷(37mg,0.087mmol)和(S)-2-(((4-氯-3-氰基-2-(1,3-邻苯二甲酰亚胺-2-基)吡唑并[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-碳酸叔丁酯(39mg,0.073mmol)的1,4-二氧六环(2.5mL)溶液中加入碳酸钠(38mg,0.358mmol,2M)水溶液，氮气换气2分钟，随后加入四三苯基膦钯(4mg,0.003mmol)，氮气换气2分钟，在90℃下搅拌1小时，TLC点板反应完毕。加入氯化氢二氧六环溶液(0.5mL,4.0M)继续反应2h。将至室温，再加入50％氨水室温反应2h。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，反相柱层析分离得到产品2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)哌嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(12mg,25％收率)。 1HNMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.99(s,2H),8.55-8.65(m,1H),8.25-8.38(m,3H),7.83-7.90(m,1H),7.38-7.44(m,1H),6.91-6.95(m,1H),6.18(s,1H),4.65(d,2H),4.49(d,1H),4.26(s,1H),4.11-4.20(m,5H),4.00-4.11(m,3H),3.93-4.00(m,1H),3.89(s,3H),3.67-3.74(m,1H),3.5-3.26(m,1H),2.97-3.04(m,1H).m/z＝569[M+1] +。
实施例40
2-氟-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS088)
Figure PCTCN2019109502-appb-000111
将2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS087)(50mg,0.08mmol)溶于四 氟硼酸(5.0mL)中，冰水浴冷却至0℃，将亚硝酸钠(71mg,1.0mmol)加入，自然升至室温反应12h，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得到产品2-氟-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈(3.4mg,收率7.4％)。m/z＝572[M+1] +。
实施例41
2-氨基-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS089)
Figure PCTCN2019109502-appb-000112
步骤A：4-氯-2-(1,3--邻苯二甲酰亚胺-2-基)-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000113
将4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-羟基吡唑并[1,5-a]吡啶-3-腈(250mg,0.71mmol)，氧化异丁烯(500mg,7.1mmol)，碳酸钾(300mg,2.13mmol)加入DMF(5.0mL)中，加入60℃反应16h。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得到产品4-氯-2-(1,3--邻苯二甲酰亚胺-2-基)-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-腈(30mg,收率10％).m/z＝411[M+1] +。
步骤B：2-氨基-4-氯-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000114
将4-氯-2-(1,3--邻苯二甲酰亚胺-2-基)-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-腈(30mg,0.073mmol)溶于THF(4.0mL)中，加入0.5mL 50％氨水，室温搅拌1h。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得到产品2-氨基-4-氯-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-腈(18mg,收率87％)。m/z＝281[M+1] +。
步骤C：3-(5-溴吡啶-2-基)-6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019109502-appb-000115
向100mL单口瓶中，加入6-甲氧基烟醛(0.26g,1.9mmol)，3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐(0.6g,1.9mmol)，醋酸硼氢化钠(1.2g,5.8mmol)，二氯甲烷20mL，室温搅拌12小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品3-(5-溴吡啶-2-基)-6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷(356mg，收率50％)。m/z＝375[M+1] +。
步骤D：6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019109502-appb-000116
向10mL封管中，加入3-(5-溴吡啶-2-基)-6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷(49mg,0.132mmol)，双联频哪醇硼酸酯(50mg,0.198mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol)，醋酸钾(39mg,0.396mmol)，1,4-二氧六环(20mL)，氮气置换三次，100℃反应3小时，LCMS确认原料反应完，有产品生成，无须后处理，直接进行下一步反应。
步骤E：室温下，向装有6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷(37mg,0.087mmol)和2-氨基-4-氯-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-腈(21mg,0.073mmol)的1,4-二氧六环(2.5mL)溶液中加入碳酸钠(38mg,0.358mmol,2M)水溶液，氮气换气2分钟，随后加入四三苯基膦钯(4mg,0.003mmol)，氮气换气2分钟，在110℃下搅拌4小时，TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得2-氨基-6-(1-甲基-1H-吡唑-4-基)-4-(6-(6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(11.3mg,28％收率)。 1HNMR(400MHz,DMSO-d 6)δ8.35(d,1H),8.27(d,1H),8.07(s,1H),7.81(d,1H),7.67(d,1H),7.10(d,1H),6.78(d,2H),6.15(s,2H),4.67(s,1H),3.82(d,5H),3.62-3.68(m,4H),3.48-3.55(m,4H),1.58(s,1H),1.21(s,6H)。m/z＝541[M+1] +。
实施例42
2-氟-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS090)
Figure PCTCN2019109502-appb-000117
制备方法同实施例40，将2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS087)替换为2-氨基-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS089)得产品(2.8mg,收率6.8％) 1HNMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.42(s,1H),8.07(s,1H),7.87(s,1H),7.69(s,1H),7.44(s,1H),6.79(s,2H),4.74(s,1H),3.82-3.88(m,5H),3.68-3.72(m 4H),3.51(brs,5H),1.59(s,1H),1.23(s,6H).m/z＝544[M+1] +。
实施例43
6-(2-羟基-2-2甲基丙氧基)-2-甲氧基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS091)
Figure PCTCN2019109502-appb-000118
将2-氟-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3- 基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS090)(15mg,0.028mmol)，碳酸钾(11mg,0.08mmol)加入甲醇(2.0mL)中，60℃封管反应12h。加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得6-(2-羟基-2-2甲基丙氧基)-2-甲氧基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(14mg,收率89％)。 1HNMR(400MHz,DMSO-d 6)δ8.55(d,1H),8.39(d,1H),8.07(d,1H),7.83(dd,1H),7.69(dd,1H),7.29(d,1H),6.79(dd,2H),4.70(s,1H),4.05(s,3H),3.85(s,2H),3.82(s,3H),3.62-3.78(m,4H),3.50-3.55(m,4H),1.59(d,1H),1.22(s,6H).m/z＝556[M+1] +。
实施例44
2-氨基-6-乙氧基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑并[1,5-a]吡啶-3-腈(APS092)
Figure PCTCN2019109502-appb-000119
制备方法同实施例39，将(2S)-2-(溴甲基)-4-吗啉羧酸叔丁酯替换为碘乙烷得2-氨基-6-乙氧基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑并[1,5-a]吡啶-3-腈(2.9mg,收率8％)。 1HNMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.30(d,2H),8.10(s,1H),7.83-8.04(m,1H),7.71(d,1H),7.35(s,1H),6.78(d,1H),6.11(s,2H),4.12(d,2H),3.55-3.82(m,12H),1.63(s,1H),1.36(brs,3H).m/z＝498[M+1] +。
实施例45
N-(3-氰基-6-(2-羟基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS093)
Figure PCTCN2019109502-appb-000120
将2-氨基-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS089)(50mg,0.093mmol)，溶于DCM(2.0mL)，加入三乙胺(28mg,0.3mmol)，冰水浴冷却至0℃，加入乙酰氯(8mg,0.1mmol)自然升至室温反应12h。加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得N-(3-氰基-6-(2-羟基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(2.7mg,收率5％)。 1HNMR(400MHz,DMSO-d 6)δ10.67(s,1H),8.55(d,1H),8.38(d,1H),8.07(s,1H),7.82(dd,1H),7.69(dd,1H),7.27(d,1H),6.80(t,2H),4.72(s,1H),3.87(s,2H),3.82(s,3H),3.67-3.75(m,4H),3.50-3.59(m,5H),2.10(s,3H),1.60(d,1H),1.23(s,6H).m/z＝583[M+1] +。
实施例46
6-(2-羟基-2-甲基丙氧基)-2-((2-2-羟基乙基)氨基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS094)
Figure PCTCN2019109502-appb-000121
2-氨基-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS089)(100mg,0.17mmol)和2-溴乙醇(21mg,0.17mmol)加入到DMF(2.0mL)中，加热120℃反应12h。加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得6-(2-羟基-2-甲基丙氧基)-2-((2-2-羟基乙基)氨基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(5.0mg,收率5％)。 1HNMR(400MHz,DMSO-d 6)δ8.38(dd,2H),8.07(s,1H),7.79(dd,1H),7.69(dd,1H),7.12(d,1H),6.78(d,2H),6.36(t,1H),4.66-4.72(m,2H),3.82(d,5H),3.62-3.78(m,4H),3.45-3.61(m,6H),1.60(d,1H),1.21(s,6H).m/z＝585[M+1] +。
实施例47
2-氨基-6-乙氧基-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS095)
Figure PCTCN2019109502-appb-000122
制备方法同实施例44，将6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷替换为6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷得2-氨基-6-乙氧基-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(9.2mg,收率25％)。 1HNMR(400MHz,DMSO-d 6)δ8.35(d,1H),8.26(d,1H),8.08(d,1H),7.79(dd,1H),7.70(dd,1H),7.08(d,1H),6.75-6.78(m,2H),6.15(s,2H),4.06-4.12(m,2H),3.82(s,3H),3.67-3.74(m,4H),3.51-3.55(m,4H),2.08(s,1H),1.59(d,1H),1.35(t,3H).m/z＝497[M+1] +。
实施例48
6-乙氧基-2-氟-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS096)
Figure PCTCN2019109502-appb-000123
制备方法同实施例40，将2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS087)替换为2-氨基-6-乙氧基-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS095)得6-乙氧基-2-氟-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(7.1mg,收率19％)。m/z＝500[M+1] +。
实施例49
2-氨基-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS097)
Figure PCTCN2019109502-appb-000124
制备方法同实施例47，将碘乙烷替换为2-溴乙基甲基醚得2-氨基-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(20mg,收率52％)。 1HNMR(400MHz,DMSO-d 6)δ8.35(d,1H),8.30(d,1H),8.08(d,1H),7.79(dd,1H),7.70(dd,1H),7.10(d,1H),6.77(t,2H),6.16(s,2H),4.19(dd,2H),3.82(s,3H),3.66-3.74(m,6H),3.50(s,4H),1.60(d,1H).m/z＝527[M+1] +。
实施例50
2-氟-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS098)
Figure PCTCN2019109502-appb-000125
制备方法同实施例40，将2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS087)替换为2-氨基-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS097)得2-氟-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(5.2mg,收率14％) 1HNMR(400MHz,DMSO-d 6)δ8.65(d,1H),8.42(d,1H),8.07(d,2H),7.82(dd,1H),7.70(dd,1H),7.45(d,1H),6.81(t,2H),4.25(t,2H),3.82(s,3H),3.68-3.82(m,6H),3.44-3.58(m,5H),1.23(d,1H),1.21(s,1H).m/z＝530[M+1] +。
实施例51
2-氨基-6-乙氧基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS099)
Figure PCTCN2019109502-appb-000126
制备方法同实施例47，将6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷替换为1-((6-甲氧基吡啶-3-基)甲基)-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)哌嗪得2-氨基-6-乙氧基-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(8.9mg,收率25％)。 1HNMR(400MHz,DMSO-d 6)δ8.27(dd,2H),8.09(d,1H),7.66-7.72(m,2H),7.06(d,1H),6.91(d,1H),6.82(d,1H),6.14(s,2H),4.05-4.10(m,2H),3.84(s,3H),3.55(brs,4H),3.48(s,2H),2.49(s,4H),1.34(t,3H).m/z＝485[M+1] +。
实施例52
2-氨基-6-(2-甲氧基乙氧基)-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS100)
Figure PCTCN2019109502-appb-000127
制备方法同实施例49，将6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷替换为1-((6-甲氧基吡啶-3-基)甲基)-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)哌嗪得2-氨基-6-(2-甲氧基乙氧基)-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(5.1mg,收率13％)。 1HNMR(400MHz,DMSO-d 6)δ8.29(dd,2H),8.09(d,1H),7.62-7.71(m,2H),7.90(d,1H),6.89(d,1H),6.82(d,1H),6.16(s,2H),4.16(d,2H),3.84(s,3H),3.66-3.67(m,2H),3.55-3.57(s,4H),3.48(s,2H),3.31(s,3H),2.46(s,3H).m/z＝515[M+1] +。
实施例53
6-乙氧基-2-氟-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS101)
Figure PCTCN2019109502-appb-000128
制备方法同实施例40，将2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS087)替换为2-氨基-6-乙氧基-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS099)得6-乙氧基-2-氟-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(3.4mg,收率9％)。 1HNMR(400MHz,DMSO-d 6)δ8.61(d,1H),8.33(d,1H),8.09(d,1H),7.78(dd,1H),7.68(dd,1H),7.41(d,1H),6.91(d,1H),6.82(d,1H),4.15(d,2H),3.84(s,3H),3.57-3.59(m,4H),3.48(s,2H),1.39(t,3H).m/z＝488[M+1] +。
实施例54
2-氟-6-(2-甲氧基乙氧基)-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS102)
Figure PCTCN2019109502-appb-000129
制备方法同实施例40，将2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS087)替换为2-氨基-6-(2-甲氧基乙氧基)-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS100)得2-氟-6-(2-甲氧基乙氧基)-4-(6-(4-((6-甲氧基吡啶-3-基)甲基)哌嗪-1-基)吡啶- 3-基)吡唑并[1,5-a]吡啶-3-腈(5.3mg,14％)。 1HNMR(400MHz,DMSO-d 6)δ8.64(d,1H),8.33(d,1H),8.09(d,1H),7.80(dd,1H),7.69(dd,1H),7.44(d,1H),6.95(d,1H),6.82(d,1H),4.24(t,2H),3.84(s,3H),3.68-3.70(m,2H),3.57-3.60(m,4H),3.48(s,4H),2.45(t,3H).m/z＝518[M+1] +。
实施例55
N-(3-氰基-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS103)
Figure PCTCN2019109502-appb-000130
将2-氨基-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS097)(50mg,0.09mmol)加入到醋酸酐中(2.0mL)，加热至80℃反应4h。加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得N-(3-氰基-6-(2-甲氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(30mg,收率58％)。 1HNMR(400MHz,DMSO-d 6)δ10.65(s,1H),8.57(d,1H),8.37(d,1H),8.07(d,1H),7.79(d,1H),7.67(d,1H),7.28(d,1H),6.76-6.79(m,2H),4.23-4.25(m,2H),3.82(s,3H),3.66-3.71(m,6H),3.50-3.59(m,4H),2.10(s,3H),1.60(d,1H).m/z＝569[M+1] +。
实施例56
2-氟-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-4-甲基吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈(APS104)
Figure PCTCN2019109502-appb-000131
将2-氟-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS088)(120mg,0.21mmol)，37％甲醛水溶液(120mg,1.48mmol)，醋酸硼氢化钠(133mg,0.63mmol)，二氯甲烷(10mL)室温搅拌12小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品2-氟-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-4-甲基吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈(8.2mg，收率6％)。m/z＝586[M+1] +。
实施例57
2-氨基-4-(6-(6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈(APS105)
Figure PCTCN2019109502-appb-000132
步骤A：3-(5-溴吡啶-2-基)-6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019109502-appb-000133
向100mL单口瓶中，加入5-氯-6-甲氧基烟醛(0.32g,1.9mmol)，3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷二盐酸盐(0.6g,1.9mmol)，醋酸硼氢化钠(1.2g,5.8mmol)，二氯甲烷20mL，室温搅拌12小时。TLC点板反应完毕，加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离得到产品3-(5-溴吡啶-2-基)-6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷(0.4g，收率51％)。m/z＝409[M+1] +。
步骤B：6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019109502-appb-000134
向10mL封管中，加入3-(5-溴吡啶-2-基)-6-(吡啶-2-基甲基)-3,6-二氮杂双环[3.1.1]庚烷(53mg,0.132mmol)，双联频哪醇硼酸酯(50mg,0.198mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.013mmol)，醋酸钾(39mg,0.396mmol)，1,4-二氧六环(20mL)，氮气置换三次，100℃反应3小时，LCMS确认原料反应完，有产品生成，无须后处理，直接进行下一步反应。
步骤C：4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈
Figure PCTCN2019109502-appb-000135
制备方法同实施例39步骤H，将(2S)-2-(溴甲基)-4-吗啉羧酸叔丁酯替换为碘乙烷。得4-氯-2-(1,3-邻苯二甲酰亚胺-2-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈(60mg,收率86％)。m/z＝367[M+1] +。
步骤D：制备方法同实施例39步骤I，将6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷替换为6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷得产品2-氨基-4-(6-(6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈(14mg,收率36％)。 1HNMR(400MHz,CDCl 3)δ8.38(d,1H),8.01(d,1H),7.86(d,1H),7.80(dd,2H),7.02(d,1H),6.69(d,1H),4.45(d,2H),4.01-4.42(m,5H),3.82(brs,4H),3.60(brs,4H),2.75(s,1H),1.63-1.67(m,1H),1.47(t,3H).m/z＝531[M+1] +。
实施例58
2-氨基-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲酰胺(APS106)
Figure PCTCN2019109502-appb-000136
将2-氨基-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS089)(40mg,0.074mol)溶于DMSO(2.0mL)，加入双氧水(0.2mL)，加热65℃反应6h。加入水，用乙酸乙酯萃取，合并有机相，并用饱和食盐水洗涤，减压浓缩，柱层析分离得2-氨基-6-(2-羟基-2-甲基丙氧基)-4-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲酰胺(3.5mg,收率8％)。 1HNMR(400MHz,DMSO-d 6)δ8.27(d,1H),8.17(d,1H),8.08(d,1H),7.63-7.69(m,2H),6.96(d,1H),6.78(d,1H),6.72(d,1H),5.76(s,2H),4.66(s,1H),3.79-3.82(m,5H),3.61-3.68(m,4H),3.48(brs,4H),1.55(d,1H),1.21(s,6H).m/z＝559[M+1] +。
实施例59
2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-4-甲基吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈(APS107)
Figure PCTCN2019109502-appb-000137
制备方法同实施例56，将2-氟-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS088)替换为2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈三氟乙酸盐(APS087)得产品2-氨基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((S)-4-甲基吗啉-2-基)甲氧基)吡唑并[1,5-a]吡啶-3-腈(30mg,收率24％)。 1HNMR(400MHz,CDCl 3)δ8.48(d,1H),8.25(d,1H),8.11(d,1H),7.94(d,1H),7.64(dd,1H),7.33(d,1H),6.73(d,1H),4.53(s,2H),3.93-4.18(m,4H),3.90-3.92(m,3H),3.81-3.90(m,2H),3.71-3.80(m,3H),3.67-3.75(m,2H),3.59-3.62(m,2H),2.86(d,1H),2.68-2.75(m,2H),2.34(s,3H),2.20(t,1H),2.08(t,1H),1.65(d,1H).m/z＝583[M+1] +。
实施例60
2-氨基-4-(6-(6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(2-甲氧基乙氧基)吡唑并[1,5-a]吡啶-3-腈(APS108)
Figure PCTCN2019109502-appb-000138
制备方法同实施例52，将6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷替换为6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷得产品2-氨基-4-(6-(6-((5-氯-6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(2-甲氧基乙氧基) 吡唑并[1,5-a]吡啶-3-腈(10.6mg,收率26％)。 1HNMR(400MHz,CDCl 3)δ8.38(d,1H),8.02(s,1H),7.92(d,1H),7.79(dd,2H),7.08(d,1H),6.69(d,1H),4.45(d,2H),4.13-4.15(m,2H),4.03(d,3H),3.78-3.84(m,6H),3.61(brs,4H),3.41(s,3H),2.76(s,1H),1.70(d,1H).m/z＝561[M+1] +。
实施例61
2-氨基-6-(2-乙氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS109)
Figure PCTCN2019109502-appb-000139
制备方法同实施例47，将碘乙烷替换为2-溴乙基乙基醚得产品2-氨基-6-(2-乙氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(16.2mg,收率41％)。 1HNMR(400MHz,DMSO-d 6)δ8.30-8.36(m,2H),8.08(s,1H),7.77-7.80(m,1H),7.70(d,1H),7.11(d,1H),6.75-6.77(m,2H),6.17(s,2H),4.16-4.18(m,2H),3.82(s,3H),3.70-3.74(m,6H),3.48-3.53(m,6H),1.60(d,1H),1.15(t,3H).m/z＝541[M+1] +。
实施例62
2-氨基-6-(2-甲氧基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS110)
Figure PCTCN2019109502-appb-000140
制备方法同实施例47，将碘乙烷替换为1-溴-2-甲氧基-2-甲基丙烷得产品2-氨基-6-(2-甲氧基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(2.8mg,收率7％).m/z＝555[M+1] +。
实施例63
2-氨基-6-乙氧基-4-(6-(6-((5-氟吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS111)
Figure PCTCN2019109502-appb-000141
制备方法同实施例57，将5-氯-6-甲氧基烟醛替换为5-氟烟醛得产品2-氨基-6-乙氧基-4-(6-(6-((5-氟吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(3.6mg,收率10％)。 1HNMR(400MHz,DMSO-d 6)δ8.44(d,2H),8.35(d,1H),8.26(d,1H),7.79(dd,1H),7.71(d,1H),7.07(d,1H),6.77(d,1H),6.16(s,1H),4.10(d,2H),3.72-3.74(m,5H),3.65(s,2H),2.51(brs,1H),2.01(d,1H),1.62(d,1H),1.23(s,3H)。m/z＝485[M+1] +。
实施例64
2-氨基-4-(6-(6-((5-氯吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-乙氧基吡唑 并[1,5-a]吡啶-3-腈(APS112)
Figure PCTCN2019109502-appb-000142
制备方法同实施例57，将5-氯-6-甲氧基烟醛替换为5-氯烟醛得产品2-氨基-4-(6-(6-((5-氯吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈(13.6mg,收率37％)。 1HNMR(400MHz,DMSO-d 6)δ8.40-8.51(m,2H),8.35(d,1H),8.26(d,1H),7.90(s,1H),7.79(dd,1H),7.07(d,1H),6.77(d,1H),6.16(s,2H),4.90(q,2H),3.72-3.74(d,4H),3.63(s,2H),3.52(brs,2H),2.00(s,1H),1.61(d,1H),1.37(t,3H).m/z＝501[M+1] +。
实施例65
2-氨基-6-(2-环丙氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS113)
Figure PCTCN2019109502-appb-000143
制备方法同实施例47，将碘乙烷替换为对甲苯磺酸2-环丙氧基乙基酯得产品2-氨基-6-(2-环丙氧基乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(31.5mg,收率78％)。 1HNMR(400MHz,DMSO-d 6)δ8.36(d,1H),8.30(d,1H),8.08(d,1H),7.80(dd,1H),7.70(dd,1H),7.10(d,1H),6.78(dd,2H),6.18(s,2H),4.18(t,2H),3.82(s,3H),3.64-3.78(m,6H),3.50-3.55(m,4H),3.35-3.40(m,1H),1.60(d,1H),0.43-0.52(m,4H).m/z＝553[M+1] +。
实施例66
2-氨基-6-(2,2-二氟乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS114)
Figure PCTCN2019109502-appb-000144
制备方法同实施例47，将碘乙烷替换为1,1-二氟-2-碘乙烷得产品2-氨基-6-(2,2-二氟乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(3.8mg,收率9％)。 1HNMR(400MHz,DMSO-d 6)δ8.43(d,1H),8.37(d,1H),8.08(s,1H),7.81(dd,1H),7.70(dd,1H),7.18(d,1H),6.78(d,2H),6.23(s,2H),4.39-4.47(m,2H),3.82(s,3H),3.67-3.74(m,4H),3.50-3.55(m,4H),1.60(d,1H).m/z＝533[M+1] +。
实施例67
2-氨基-6-(二氟甲氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS115)
Figure PCTCN2019109502-appb-000145
制备方法同实施例47，将碘乙烷替换为二氟碘甲烷得产品2-氨基-6-(二氟甲氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(2.2mg,收率5.8％)。m/z＝519[M+1] +。
实施例68
2-氨基-4-(6-(6-((5-氯吡啶-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈(APS116)
Figure PCTCN2019109502-appb-000146
制备方法同实施例57，将5-氯-6-甲氧基烟醛替换为5-氯吡啶甲醛得产品2-氨基-4-(6-(6-((5-氯吡啶-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈(7.0mg,收率19％)。 1HNMR(400MHz,DMSO-d 6)δ8.51(d,1H),8.34(d,1H),8.26(d,1H),7.88(dd,1H),7.78(dd,1H),7.53(d,1H),7.08(d,1H),6.75(d,1H),6.17(s,2H),4.10(d,2H),3.72-3.74(m,4H),3.65(s,2H),3.55(brs,2H),2.52(s,1H),2.08(s,3H),2.60(d,1H).m/z＝501[M+1] +。
实施例69
2-氨基-4-(6-(6-((5-氟吡啶-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈(APS117)
Figure PCTCN2019109502-appb-000147
制备方法同实施例57，将5-氯-6-甲氧基烟醛替换为5-氟吡啶甲醛得产品2-氨基-4-(6-(6-((5-氟吡啶-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-乙氧基吡唑并[1,5-a]吡啶-3-腈(10.8mg,收率30％)。 1HNMR(400MHz,DMSO-d 6)δ8.46(d,1H),8.34(d,1H),8.26(d,1H),7.78(t,1H),7.67-7.72(m,1H),7.53-7.56(m,1H),7.08(d,1H),6.76(d,1H),6.17(s,2H),4.06-4.11(t,2H),3.71-3.79(m,4H),3.64(s,2H),3.55(d,2H),2.08(s,1H),1.62(d,1H),1.37(t,3H).m/z＝485[M+1] +。
实施例70
2-氨基-6-乙氧基-4-(6-(6-((6-甲氧基吡啶-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS118)
Figure PCTCN2019109502-appb-000148
制备方法同实施例57，将5-氯-6-甲氧基烟醛替换为6-甲氧基吡啶甲醛得产品2-氨基-6-乙氧基-4-(6-(6-((6-甲氧基吡啶-2-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(28mg,收率77％)。 1HNMR(400MHz,DMSO-d 6)δ8.34(d,1H),8.26(d,1H),7.78(dd,1H),7.65(t,1H),7.02-7.08(m,2H),6.77(d,1H),6.66(d,1H),6.17(s,2H),4.06-4.11(t,2H),3.77-3.83(m,7H),3.60(brs,4H),2.54-2.57(m,1H),1.63(d,1H),1.35(t,3H).m/z＝497[M+1] +。
实施例71
2-氨基-6-(2-氟乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS119)
Figure PCTCN2019109502-appb-000149
制备方法同实施例47，将碘乙烷替换为1-氟-2-碘乙烷得产品2-氨基-6-(2-氟乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(5.0mg,收率13％)。 1HNMR(400MHz,DMSO-d 6)8.36(dd,2H),8.08(d,1H),7.80(dd,1H),7.68(dd,1H),7.14(d,1H),6.78(d,2H),6.20(s,2H),4.84(t,1H),4.72(t,1H),4.38(t,1H),4.31(t,1H),3.82(s,3H),3.64-3.74(m,4H),3.50-3.55(m,4H),1.60(d,1H).m/z＝515[M+1] +。
实施例72
2-氨基-6-(2-异丙氧乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(APS120)
Figure PCTCN2019109502-appb-000150
制备方法同实施例47，将碘乙烷替换为2-(2-溴乙氧基)丙烷得产品2-氨基-6-(2-异丙氧乙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-腈(32.6mg,收率80％)。 1HNMR(400MHz,CDCl 3)δ8.39(s,1H),8.13(s,1H),7.93(s,1H),7.80(d,1H),7.08(d,1H),6.68-6.76(m,2H),4.44(d,1H),4.14(d,2H),3.86(s,4H),3.80-3.82(m,3H),3.64-3.76(m,3H),1.23-1.25(m,10H)。m/z＝555[M+1] +。
参考上述实施例的方法，还制备得到了其他化合物。将这些化合物与上述化合物的表征数据汇总于如下表1中：
表1
化合物编号 MS[M+1] + 化合物编号 MS[M+1] +
APS007 532 APS038 503
APS008 548 APS039 535
APS009 544 APS040 568
APS010 548 APS041 534
APS011 534 APS042 555
APS012 545 APS043 535
APS013 486 APS044 539
APS014 509 APS045 590
APS015 508 APS046 533
APS016 489 APS047 557
APS017 533 APS048 507
APS018 534 APS049 591
APS019 508 APS050 606
APS020 526 APS051 579
APS021 525 APS052 547
APS022 505 APS053 547
APS023 494 APS054 564
APS024 526 APS055 565
APS025 505 APS056 579
APS026 520 APS057 641
APS027 524 APS058 604
APS028 516 APS059 572
APS029 527 APS060 520
APS030 521 APS061 519
APS031 504 APS062 540
APS032 521 APS063 520
APS033 521 APS064 492
APS034 533 APS065 543
APS035 491 APS066 534
APS036 476 APS067 548
APS037 518 APS068 521
激酶活性测试
转染重组基因(RET)是一个已经确认的原癌基因。它编码的单次跨膜受体酪氨酸激酶，是许多组织和细胞类型的发育，成熟和维持所必需的。在正常条件下，神经胶质细胞系衍生的神经营养因子(GDNF)家族配体与细胞表面上的RET的结合导致细胞内酪氨酸残基的二聚化和自磷酸化。这反过来导致下游RAS-MAPK，PI3K-AKT和磷脂酶Cγ(PLCγ)通路的激活，并增加细胞存活和增殖。激活RET突变的实例包括C634W，M918T和关守突变，V804L和V804M。
该试验将肽底物和单一专有单克隆抗体与HTRF技术相结合，HTRF技术是一种高灵敏度和稳定的技术，用于检测蛋白质的分子相互作用。酶将底物磷酸化，然后Eu标记的抗体结合磷酸化底物，链霉抗生物素蛋白-XL665结合所有底物。TR-FRET信号由HTRF原理产生。一旦添加抑制剂(受试化合物)，就获得较弱的TR-FRET信号。据此，评估抑制效果。
5.1.试剂和耗材
Figure PCTCN2019109502-appb-000151
Figure PCTCN2019109502-appb-000152
星形孢菌素
Figure PCTCN2019109502-appb-000153
5.2配制溶液
用DMSO将CEP-32496从10mM和1mM分别梯度稀释3倍，共10个浓度。
其他化合物从10mM的原液用DMSO梯度稀释3倍，共10个浓度。
制备1000×阳性对照(1mM CEP-32496和0.2mMStaurosporine)和1000×阴性对照(100％DMSO)。
在平板振荡器上振荡5分钟。
5.3制备1x激酶缓冲液
将4体积蒸馏水加入1体积酶缓冲液5X；5mM MgCl 2；1mM DTT。
5.4筛选方法
a)将10nl化合物稀释液(5.2中制备)转移到测试板(784075，Greiner)的每个孔中；
b)在1000g下将化合物板离心1分钟。
c)密封测试板。
d)制备1x激酶缓冲液中的5X Ret wt(0.2ng/μl)和5X Ret V804L(0.5ng/μl)/5X Ret V804M(0.5ng/μl)。
e)加入2μl的5X Ret wt或2μl的Ret V804L/RET V804M至384孔测试板(784075，Greiner)。
f)将4μl的1x激酶缓冲液加入测试板的每个孔中，在1000g下离心样品板30秒，在室温放置10分钟。
g)制备激酶缓冲液中的5x TK-底物-生物素(5μM)和激酶缓冲液中的5x ATP(50μM)的溶液。
h)通过加入2μl STK-底物-生物素和2μlATP(步骤g中制备的)开始反应。
i)在1000g下离心样品板30秒。密封测试板，室温放置30分钟。
j)制备在HTRF检测缓冲液中的4X Sa-XL 665(250nM)。
k)将5μl的Sa-XL 665和5μl的TK-antibody-Cryptate(在步骤i中制备的)加入到测试板的每个孔中。
l)在1000g下离心30秒，室温放置1小时。
m)在Envision 2104读板仪上读取615nm(Cryptate)和665nm(XL665)的荧光信号值。
5.5数据分析
计算每个孔的比率(665nm/615nm)。
抑制率％通过如下方式计算：
抑制率％＝[1-(受试化合物荧光信号值—阳性对照荧光信号值)/(阴性对照平均比率—阳性对照平均比率)]*100％
比率：由测得的荧光信号值产生
阳性对照平均比率为样品板中阳性对照(200nM AT13148)的平均比率；
阴性对照平均比率为样品板中阴性对照(0.1％DMSO)的平均比率。
利用GraphPad 6.0将抑制率％与化合物浓度的对数拟合为非线性回归(剂量响应-可变斜率)计算IC 50值。
表2
Figure PCTCN2019109502-appb-000154
细胞抑制活性测试
1、在96孔板中配置90μl的细胞悬液，4000细胞/孔。将培养板在培养箱预培养24小时(37℃，5％CO 2)。
2、向每孔细胞中加入10μl不同浓度的待测化合物，每个化合物均有复孔。
3、将培养板在培养箱孵育72小时。
4、向每孔加入10μl CCK8溶液(注意不要在孔中生成气泡，它们会影响OD值的读数)。
5、将培养板在培养箱内孵育1-2小时。
6、用酶标仪测定在450nm处的吸光度。
7、根据化合物浓度及吸光度值，利用GraphpadPrism软件计算每个化合物的IC 50。
计算结果如下表所示：
表3
Figure PCTCN2019109502-appb-000155
Figure PCTCN2019109502-appb-000156
Figure PCTCN2019109502-appb-000157
上表中“N/A”表示未测试活性。
如上表所示，本发明实施例化合物具有改善的抑制RET野生型、突变型和/或融合型抑制活性，特别是诸如APS014、APS015、APS019、APS020、APS022、APS024、APS025、APS026、APS027、APS035、APS038、APS068、APS069、APS070、APS087、APS089、APS092、APS095、APS097、APS099、APS100、APS104、APS105、APS107、APS108、APS109、APS111、APS113、APS114、APS119、APS120等化合物取得了优异的活性。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内

Claims (10)

  1. 式I所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物：
    Figure PCTCN2019109502-appb-100001
    其中，X 1、X 2、X 3、X 4、X 5、X 6相同或不同，彼此独立地选自CR 1、-C-A或N，其中每一个R 1相同或不同，彼此独立地选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R a取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-NHC(O)R 2、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；A选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R b取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、-OS(O) 2R 7、-NHC(O)R 2；
    B选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R c取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、NR 2R 3、-C(O)R 4、-NHC(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
    D选自无取代或任选被一个、两个或更多个R d取代的C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 6-20芳基、5-20元杂芳基或3-20元杂环基；
    E选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R e取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基或3-20元杂环基氧基；
    G选自无取代或任选被一个、两个或更多个R f取代的下列基团：C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基或3-20元杂环基氧基；
    K选自H、卤素、CN、OH，无取代或任选被一个、两个或更多个R g取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
    每一个R 2相同或不同，彼此独立地选自H、无取代或任选被OH、NH 2取代的如下基团：C 1- 40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R 4、-S(O) 2R 6；
    每一个R 3相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、 C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、-C(O)R 4、-S(O) 2R 6；
    或者，R 2和R 3与所连的N原子一起形成5-20元杂芳基或3-20元杂环基；
    每一个R 4相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3；
    每一个R 5相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基羰基、C 2-40烯基羰基、C 2-40炔基羰基、C 3-40环烷基羰基、C 3-40环烯基羰基、C 3-40环炔基羰基、C 6-20芳基羰基、5-20元杂芳基羰基、3-20元杂环基羰基；
    每一个R 6相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3；
    每一个R 7相同或不同，彼此独立地选自H、C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基；
    每一个R a、R b、R c、R d、R e、R f、R g相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2，无取代或任选被一个、两个或更多个R h取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
    每一个R h相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2，无取代或任选被一个、两个或更多个R j取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；或者，当环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时，所述取代基中的两个也可以与所述环状基团形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团；
    每一个R j相同或不同，彼此独立地选自卤素、CN、OH、SH、氧代(＝O)、NO 2、无取代或任选被一个、两个或更多个R h取代的下列基团：C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、C 6-20芳基、5-20元杂芳基、3-20元杂环基、C 1-40烷基氧基、C 2-40烯基氧基、C 2-40炔基氧基、C 3-40环烷基氧基、C 3-40环烯基氧基、C 3-40环炔基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、NR 2R 3、-C(O)R 4、-OCR 5、-S(O) 2R 6、OS(O) 2R 7；
    或者，当环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)的不同位置被两个或更多个取代基取代时，所述取代基中的两个也可以与所述环状基团形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2、O、NH的二价基团；
    或者，当一个原子(如碳原子)被两个或更多个取代基取代时，所述取代基中的两个也可以与其共同连接的原子形成环状基团(包括但不限于C 3-40环烷基、C 3-40环烯基、C 3-40环炔基、3-20元杂环基等)。
  2. 根据权利要求1所述的化合物，其中：
    式I所示的化合物选自下列式I’所示的化合物，
    Figure PCTCN2019109502-appb-100002
    其中，X 1、X 2、X 3、X 4、X 5、A、B、D、E、G、K独立地具有权利要求1所述的定义。
  3. 根据权利要求1或2所述的化合物，其中：
    X 6选自-C-A或N，A可以选自H，无取代或任选被一个、两个或更多个R b取代的下列基团：NH 2、C 1-6烷基、-NH(C 1-6烷基) 2、OH、F、-NHC(O)C 1-6烷基、-NHC 1-6烷基、C 1-6烷基氧基、-NHC 1-6烷基-OH；
    每一个R b相同或不同，彼此独立地选自C 1-6烷基、C 1-6烷氧基；
    B可以选自H、CN、-CONH 2，无取代或任选被一个、两个或更多个R c取代的C 1-6烷基；
    每一个R c相同或不同，彼此独立地选自卤素、C 1-6烷基；
    D可以选自无取代或任选被一个、两个或更多个R d取代的如下基团：C 1-6烷基氧基或5-14元杂芳基，所述R d选自无取代或任选被一个或多个如下基团取代的C 1-6烷基或3-10元杂环基：氧代、卤素、OH、-N(C 1-6烷基) 2或-S(O) 2-C 1-6烷基；
    E选自H，无取代或任选被一个、两个或更多个R e取代的下列基团：C 1-6烷基、C 1-6烷氧基；
    每一个R e相同或不同，彼此独立地选自OH、F、C 1-6烷基；
    G选自无取代或任选被氧代的3-10元杂环基，例如无取代或任选被氧代或被C 1-6烷基取代的哌嗪基、哌啶基；或者，所述当所述杂环基的间位被两个取代基取代时，所述取代基可以与所述杂环基形成桥环，其中所述桥环中除桥头原子之外的桥原子可以包含1、2、3、4或5个选自CH 2的二价基团；
    K选自无取代或任选被一个、两个或更多个R g取代的下列基团：C 1-6烷基、-C(O)R 4，所述R g选自氧代、OH、无取代或任选被一个、两个或更多个R h取代的C 1-6烷基、C 1-6烷氧基，C 3-10环烷基、C 6-14芳基、5-14元杂芳基、-SO 2-C 6-14芳基；每一个R 4相同或不同，彼此独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10环烯基、C 3-10环炔基、C 6-14芳基、5-14元杂芳基、3-10元杂环基、C 1-6烷基氧基、C 2-6烯基氧基、C 2-6炔基氧基、C 3-10环烷基氧基、C 3-10环烯基氧基、C 3-10环炔基氧基、C 6-14芳基氧基、5-14元杂芳基氧基、3-10元杂环基氧基、-N(C 1-6烷基) 2；所述R h选自卤素、C 1-6烷氧基、NH 2、-N(C 1-6烷基) 2、-NHC 6-14芳基、-NHC 1-6烷基；或者，当K中的一个原子(如碳原子)被两个或更多个R g取代时，两个R g也可以与其共同连接的原子形成环状基团(包括但不限于C 3-10环烷基、C 3-10环烯基、C 3-10环炔基、3-10元杂环基等)。
  4. 根据权利要求1-3任一项所述的化合物，其中：
    所述式I化合物选自如下化合物：
    Figure PCTCN2019109502-appb-100003
    Figure PCTCN2019109502-appb-100004
    Figure PCTCN2019109502-appb-100005
    Figure PCTCN2019109502-appb-100006
    Figure PCTCN2019109502-appb-100007
    Figure PCTCN2019109502-appb-100008
    Figure PCTCN2019109502-appb-100009
    Figure PCTCN2019109502-appb-100010
    Figure PCTCN2019109502-appb-100011
    Figure PCTCN2019109502-appb-100012
    Figure PCTCN2019109502-appb-100013
    Figure PCTCN2019109502-appb-100014
    Figure PCTCN2019109502-appb-100015
  5. 权利要求1-4任一项所述化合物的制备方法，其特征在于，包括：
    Figure PCTCN2019109502-appb-100016
    化合物II与化合物III发生铃木反应得到化合物I；
    其中，B、D、E、G、K、X 1、X 2、X 3、X 4、X 5、X 6具有权利要求1-4任一项所述的定义，
    条件是式III中的B代表硼；L选自离去基团如卤素或者OTf。
  6. 一种药物组合物，其特征在于，包含治疗有效量的权利要求1-4任一项所述的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物中的至少一种。
  7. 根据权利要求8所述的药物组合物，其特征在于，所述药物组合物还包括一种或多种药学上可接受的载体或赋形剂。
  8. 根据权利要求6或7所述的药物组合物，其特征在于，所述药物组合物进一步含有一种或多种额外的治疗剂。
  9. 权利要求1-4任一项所述的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、药学上可接受的盐或溶剂合物中的至少一种在制备用于治疗RET激酶介导的疾病的药物中的用途；或者，
    用于抑制RET激酶活性的用途；或者
    用于治疗RET相关疾病或病症的用途；或者
    制备用于治疗癌症和/或抑制与特定癌症相关的转移的药物中的用途；或者
    在制备用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的药物中的用途；或者
    制备用于向癌症患者提供支持护理的药物中的用途；或者
    在制备用于抑制RET激酶活性的药物中的用途；或者
    在制备用于治疗RET相关疾病或病症的药物中的用途。
  10. 根据权利要求9所述的用途，其特征在于，所述RET激酶介导的疾病包括癌症、肠易激综合征或与他们相关的疼痛。
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