WO2022007869A1 - Pyridine or pyrimidine derivative and preparation method therefor and use thereof - Google Patents

Pyridine or pyrimidine derivative and preparation method therefor and use thereof Download PDF

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Publication number
WO2022007869A1
WO2022007869A1 PCT/CN2021/105100 CN2021105100W WO2022007869A1 WO 2022007869 A1 WO2022007869 A1 WO 2022007869A1 CN 2021105100 W CN2021105100 W CN 2021105100W WO 2022007869 A1 WO2022007869 A1 WO 2022007869A1
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Prior art keywords
amino
cyano
alkyl
group
dihydrospiro
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PCT/CN2021/105100
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French (fr)
Chinese (zh)
Inventor
黄贤贵
曹琪
别平彦
邢庆娜
王鑫
晏青燕
廖伟伟
郭阳辉
叶成
胡泰山
钱文建
陈磊
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浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Priority to CN202180044805.4A priority Critical patent/CN115916765A/en
Publication of WO2022007869A1 publication Critical patent/WO2022007869A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a novel pyridine or pyrimidine derivative, its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a SHP2 allosteric inhibitor.
  • Src homeodomain-2 phosphatase is one of the important members of the protein tyrosine phosphatase (PTP) family, encoded by the protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene, which catalyzes dephosphorylation of amino acids.
  • the N-terminus of SHP2 contains two SH2 domains, which control the subcellular localization and functional regulation of SHP2, and the C-terminus contains a catalytically active PTP domain and two tyrosine related to its activity. acid residue.
  • SHP2 is in a state of auto-inhibition. When stimulated by growth factors, cytokines or inflammatory factors, such as platelet-derived growth factors PDGF and FGF, the catalytic site is exposed, resulting in the activation of SHP2 enzymes. activation.
  • SHP2 is widely present in the human body and is involved in rat sarcoma (RAS)-extracellular signal-related kinase (ERK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B and NF-KB, activates fibroblast growth factor, epidermal growth factor Growth factors and insulin receptor downstream mitogen-activated protein kinase (MAPK/ERK) and other signaling pathways regulate cell proliferation, differentiation, migration and apoptosis.
  • RAS rat sarcoma
  • ERK extracellular signal-related kinase
  • PI3K phosphatidylinositol 3-kinase
  • NF-KB NF-KB
  • SHP2 Activating mutations in SHP2 have been found to be inextricably linked to the occurrence of Noonan syndrome, leopard spot syndrome, monocytic leukemia, melanoma, solid tumors, cardiovascular disease, immune disorders, fibrosis or visual disorders.
  • Overexpression of SHP2 increases the risk of chronic myeloid leukemia, mastocytosis, malignant glioma, lung cancer, breast cancer and other cancers, indicating that SHP2 has an important role in different types of cancer and different stages of cancer. Due to the multiple functions of SHP2 in tumors, the research on SHP2 target inhibitors also brings new hope and direction for tumor therapy.
  • SHP2 inhibitors can be divided into competitive inhibitors (including allosteric acid, phenylpyrazole hydrazine sulfonate and NSC-87877), non-competitive inhibitors (including indole salicylic acid) and furamoxinone) and irreversible inhibitors (including sodium stibogluconate and cryptotanshinone), which have been reported as irreversible inhibitors of SHP2 to inhibit the proliferation of rhabdomyosarcoma, melanoma, colon and breast cancer in vitro , and in vivo studies have shown that it can inhibit the proliferation of mouse prostate cancer, and whether it can further become a clinically effective drug still needs to be verified by many experiments.
  • competitive inhibitors including allosteric acid, phenylpyrazole hydrazine sulfonate and NSC-87877
  • non-competitive inhibitors including indole salicylic acid
  • furamoxinone furamoxinone
  • irreversible inhibitors including sodium sti
  • the compound RMC-4630 developed by REVOLUTION Medicines Inc has entered clinical phase II for the treatment of solid tumors, and there are also three clinical phase I compounds JAB-3068, JAB-3312 and TNO-155, which were respectively developed by Jacobio Pharmaceuticals Co Ltd and Novartis AG research and development.
  • REVOLUTION Medicines Inc and Novartis AG have published a series of SHP2 inhibitor patents, including WO-2019075265, WO-2018136265, WO-2018136264, WO-2017216706 and WO-2018013597, etc.
  • SHP2 inhibitors including WO-2019075265, WO-2018136265, WO-2018136264, WO-2017216706 and WO-2018013597, etc.
  • the present invention provides a new class of pyridine or pyrimidine compounds represented by the general formula (I) or their stereoisomers, tautomers or their pharmaceutically acceptable salts:
  • Ring A is selected from an aryl group, a heteroaryl group or a bicyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • X is selected from CR e or N;
  • R e is selected from hydrogen atom, alkyl, halogen or alkoxy, wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from hydroxyl, halogen or alkoxy;
  • R 1 is selected from alkyl, cycloalkyl, heterocyclyl, cyano, alkenyl, alkynyl, -OR 6 , -C(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein said alkyl, cycloalkyl, heterocyclyl, alkenyl or alkynyl is optionally further modified by one or more substituted by a substituent selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 ; preferably, R 1 is selected from methyl;
  • R 2 are the same or different, each independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, cyano, halogen, nitro, cycloalkyl, heterocyclyl, -OR 6 , -C(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl is further optionally substituted with one or more substituents selected from halo, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6, -C ( O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R
  • R 3 is selected from cyano, alkoxy, tetrazolyl, -C(O)R 6 , -C(O)OR 6 or -C(O)NR 7 R 8 ;
  • R 3 is selected from alkoxy, R 1 is not selected from -NR 7 R 8 ;
  • G and M are each independently selected from N or CR j ;
  • G and M are each independently selected from C;
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • E is selected from NR k , (CR p R q ) p , O or S;
  • F is selected from (CR p R q ) q ;
  • J is selected from CR p R q ;
  • K is selected from NR k , (CR p R q ) r , O or S;
  • r is 0 or 1;
  • R m , R n , R p and R q are the same or different, each independently selected from R A ;
  • R p and R q together with the attached carbon atoms form R B ;
  • R c and R d are the same or different and are each independently selected from a hydrogen atom, halogen, alkyl or -OR 6 , wherein said alkyl is optionally further substituted by hydroxy, halogen, alkoxy, cycloalkyl or -NR Substituents of 7 R 8 are substituted;
  • R c and R d together with the attached carbon atoms form R B ;
  • R j and R k are the same or different, each independently selected from a hydrogen atom or an alkyl group
  • R 6 , R 7 , and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, or a heterocyclyl group, wherein the alkyl group, cycloalkyl group, or heterocyclyl group is optionally further selected from one or more of Hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 9 , -C(O)OR 9 , Substituents of -OC(O)R 9 , -SO 2 R 9 , -NR 10 R 11 , -C(O)NR 10 R 11 , -SO 2 NR 10 R 11 or -NR 10 C(O)R 11 replaced;
  • R 7 and R 8 together with the N atom to which they are attached form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic ring contains one or more N, O, S atoms or SO 2 , and The 3-8 membered heterocycle is optionally further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;
  • R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group
  • the radical or heteroaryl is optionally further selected from one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxy substituted by the substituent of the ester group;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1, 2, 3 or 4;
  • p is selected from 1 or 2.
  • the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (II) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
  • ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
  • the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (III) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
  • ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
  • the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (IV) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
  • ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
  • the compound of general formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof wherein :
  • R 6 is as defined in general formula (I);
  • said spiro heterocyclyl is selected from:
  • R 6 is as defined in general formula (I); t is 1, 2 or 3.
  • the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (V) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
  • E is selected from NR k , (CR p R q ) p , O or S;
  • F is selected from (CR p R q ) q ;
  • R n is selected from hydrogen atom, methyl or -CH 2 OH
  • R p and R q are each independently selected from a hydrogen atom, halogen, amino, C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl or -OR 6 ;
  • Rings A, G, M, X, m, n, R 1 to R 3 , R 6 , R k and R g are defined as in the general formula (I).
  • the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (VI) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
  • J is selected from CR p R q ;
  • K is selected from NR k , (CR p R q ) r , O or S;
  • r is 0 or 1;
  • R n is selected from hydrogen atom, methyl or -CH 2 OH
  • R p and R q are each independently selected from a hydrogen atom, halogen, amino, C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl or -OR 6 ;
  • Rings A, G, M, X, m, n, R 1 to R 3 , R 6 , R k and R g are defined as in the general formula (I).
  • the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (VII) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
  • R c and R d together with the connected atoms form a 3- to 8-membered cycloalkyl
  • R n is selected from hydrogen atom, methyl or -CH 2 OH
  • Rings A, G, M, X, m, n, R 1 to R 3 and R g are defined as in the general formula (I).
  • the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (VIII) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • rings B, n, R 1 to R 2 and R g are as described in the general formula (I).
  • the compound of general formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer, interconversion or a pharmaceutically acceptable salt thereof wherein R 2 is selected from hydrogen, F, Cl, Br, amino, hydroxy, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl group, vinyl, -NHCH 3 or -N(CH 3 ) 2 .
  • Ring B is selected from:
  • the compound of general formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer, interconversion Isomers or pharmaceutically acceptable salts thereof wherein R g is the same or different, each independently selected from hydrogen atom, F, Cl, Br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH 3 or -N(CH 3 ) 2 ;
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention provides a pharmaceutical composition containing an effective dose of general formula (I), (II), (III), (IV), (V), (VI), (VII) ) or (VIII), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.
  • the present invention provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a compound thereof Use of a variant or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (ie, the pharmaceutical composition provided by the above technical solutions of the present invention) in the preparation of an SHP2 allosteric inhibitor.
  • the present invention also provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer thereof, Use of a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for treating a disease mediated by SHP2, wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, Cardiovascular disease, immune disorder, fibrosis or visual disorder; wherein said disease mediated by SHP2 is preferably selected from Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma , acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
  • the present invention further provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer thereof, Use of a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder.
  • the present invention provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a compound thereof Variants or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are used in the preparation and treatment of Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, Use in medicaments for breast cancer, esophagus cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma and glioblastoma.
  • the present invention also provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer thereof, Use of a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of a disease mediated by SHP2, wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, cardiovascular disease , immune disorder, fibrosis or visual disorder; wherein said disease mediated by SHP2 is preferably selected from Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
  • the disease mediated by SHP2 is preferably cancer
  • the present invention also provides a method of treatment of a disease mediated by SHP2, comprising the use of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) ) described compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered to subject; wherein said disease mediated by SHP2 is preferably cancer , cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder; wherein said disease mediated by SHP2 is preferably selected from Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma tumor, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma .
  • alkyl as a group or part of a group is meant to include C 1 -C 20 linear or branched aliphatic hydrocarbon group with a chain. Preferably it is a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
  • Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups can be optionally substituted or unsubstituted.
  • Alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preferred is C 2 -C 10 alkynyl group, more preferably C 2 -C 6 alkynyl group, most preferably C 2 -C 4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged and spirocyclic carbocyclic rings. Preferably it is C 3 -C 12 cycloalkyl, more preferably C 3 -C 8 cycloalkyl, most preferably C 3 -C 6 cycloalkyl.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons.
  • spiro atom carbon atom
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthryl.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-dicyclo[3.2.1]octyl Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl refers to a non-aromatic heterocyclyl in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, fused, bridged and spirocyclic. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, Heterocyclyl groups can be substituted or unsubstituted.
  • “Spiroheterocyclyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and single rings share one atom with each other, and the ring contains one or more double bonds, but no An aromatic system with fully conjugated pi electrons in one ring, wherein one or more ring atoms are selected from nitrogen, oxygen, or a heteroatom of S(O) n (wherein n is selected from 0, 1, or 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • Spirocycloalkyl groups are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl according to the number of spiro atoms shared between rings, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl Heterospiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, one or more rings may contain one or more double bonds, but no ring has complete Conjugated pi-electron aromatic systems in which one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon.
  • n is selected from 0, 1 or 2
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine and
  • “Bridged heterocyclyl” refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures that share two atoms that are not directly connected to each other, and one or more rings may be Aromatic systems containing one or more double bonds but none of the rings have fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo cyclo[3.3.2]decyl and
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups.
  • Aryl is preferably C 6 -C 10 aryl group, and more preferably aryl is phenyl and naphthyl, most preferably naphthyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include but are not limited to furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiazolyl oxadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl,
  • Heteroaryl groups can be substituted or unsubstituted.
  • “Fused ring” refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring is not completely conjugated A ⁇ -electron aromatic system, and at least one ring has a fully conjugated ⁇ -electron aromatic system, wherein the ring atoms are selected from 0, and one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (wherein n is selected from the heteroatoms of 0, 1 or 2) and the remaining ring atoms are carbon.
  • the condensed ring preferably includes a bicyclic or tricyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Preferred alkoxy is C 1 -C 6. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino means -NH 2.
  • Cyano refers to -CN.
  • Niro refers to -NO 2.
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxyl refers to -C(O)OH.
  • Carboxylate means -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
  • DMSO dimethyl sulfoxide
  • BOC refers to t-butoxycarbonyl
  • TFA trifluoroacetic acid
  • Ts refers to p-toluenesulfonyl.
  • Hydrochloroxy C 1 -C 4 alkyl refers to hydroxy substituted C 1 -C 4 alkyl.
  • amino C 1 -C 4 alkyl refers to an amino substituted with C 1 -C 4 alkyl.
  • leaving group is an atom or functional group that is removed from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions.
  • the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that is broken off with a pair of electrons from the substrate molecule is called the leaving group.
  • Groups that readily accept electrons and have a strong ability to withstand negative charges are good leaving groups. When the pKa of the conjugated acid of the leaving group is smaller, the easier it is for the leaving group to detach from other molecules.
  • Common leaving groups include, but are not limited to, halo, methanesulfonyl, -OTs, or -OH.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers, hindered isomers and geometric (conformational) isomers and mixtures thereof , such as racemic mixtures, are within the scope of the present invention.
  • structures depicted herein also include all isomeric (eg, diastereomeric, enantiomeric, hindered, and geometric (conformational) isomeric forms of such structures; for example , R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, sterically hindered isomers of biphenyl-like structures (see “Basic Organic Chemistry” (Second Edition) Volume 1, Criminal Qi Yi et al., p104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z) and (E) conformational isomers. Therefore, the compounds of the present invention have Individual stereoisomers as well as enantiomeric, diastereomeric, hindered and geometric (conformational) mixtures are within the scope of the present invention.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • R 6 , R 7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl optionally further selected from one or more groups selected from hydroxy, amino, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -SO 2 R 9 , -NR 10 R 11 , -C(O)NR 10 R 11 , -SO 2 NR 10 R 11 or -NR 10 C(O)R 11 is substituted with a substituent;
  • R 7 and R 8 together with the N atom to which they are attached form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic ring contains one or more N, O, S or SO 2 atoms, and 3-
  • the 8-membered heterocycle is further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;
  • R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group
  • the radical or heteroaryl is optionally further selected from one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxy Substituents of the ester group are substituted.
  • “Pharmaceutically acceptable salts” refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt formed with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the present invention provides a preparation method of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (Ia) is subjected to a nucleophilic substitution reaction with NHR 4 R 5 under basic conditions to obtain the compound of general formula (Ib); the compound of general formula (Ib) and the compound of general formula (Ic) are prepared in a palladium catalyst and basic Suzuki reaction is carried out under the conditions, and the obtained compound is optionally further deprotected to obtain the compound of general formula (I);
  • X 2 is selected from halogen
  • X 3 is selected from a leaving group, and the leaving group is selected from halogen or -SO 2 R t ;
  • R 3 is selected from alkoxy
  • R t is selected from alkyl
  • Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
  • the present invention provides a preparation method of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (Ia) and the compound of general formula (Ic) are subjected to Suzuki reaction under palladium catalyst and basic conditions to obtain the compound of general formula (Id); the compound of general formula (Id) and NHR 4 R 5 are carried out under basic conditions A nucleophilic substitution reaction is carried out, and the obtained compound is optionally further deprotected to obtain a compound of general formula (I);
  • X 2 is selected from halogen
  • X 3 is selected from a leaving group, and the leaving group is selected from halogen or -SO 2 R t ;
  • R 3 is selected from alkoxy
  • R t is selected from alkyl
  • Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
  • the present invention provides a preparation method of a compound of general formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIa) is subjected to a nucleophilic substitution reaction with NHR 4 R 5 under basic conditions to obtain the compound of general formula (IIb); the compound of general formula (IIb) and the compound of general formula (Ic) are prepared in the presence of a palladium catalyst and a basic Suzuki reaction is carried out under the conditions, and the obtained compound is optionally further deprotected to obtain the compound of general formula (IIc); the compound of general formula (IIc) is hydrolyzed under the condition of sodium hydroxide solution to obtain the compound of general formula (II);
  • X 2 is selected from halogen
  • X 3 is selected from a leaving group, and the leaving group is selected from halogen or -SO 2 R t ;
  • R t is selected from alkyl
  • Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (II).
  • the present invention provides a preparation method of a compound of general formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIa) and the compound of general formula (Ic) are subjected to Suzuki reaction under palladium catalyst and basic conditions to obtain the compound of general formula (IId); the compound of general formula (IId) and NHR 4 R 5 are carried out under basic conditions Carry out nucleophilic substitution reaction to obtain the compound of general formula (IIc); the compound of general formula (IIc) is hydrolyzed under the condition of sodium hydroxide solution to obtain the compound of general formula (II);
  • X 2 is selected from halogen
  • X 3 is selected from a leaving group, and the leaving group is selected from halogen or -SO 2 R t ;
  • R t is selected from alkyl
  • Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (II).
  • the present invention provides a preparation method of a compound of general formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (III).
  • the present invention provides a preparation method of a compound of general formula (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (IV).
  • Mass spectrum is obtained by LC/MS instrument, and the ionization mode can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • CD 3 OD deuterated methanol.
  • Argon atmosphere means that the reaction flask is connected to an argon balloon with a volume of about 1 L.
  • the compound is purified by silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane Methyl chloride and ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagents, such as acetic acid or triethylamine, can also be added for adjustment.
  • the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane Methyl chloride and ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagents, such as acetic acid or trieth
  • 5-Bromo-2,4-dichloro-6-methylpyrimidine 1a (480 mg, 2 mmol) was added to 5 mL of methanol, and 5 mL of methanol dissolved with sodium methoxide (102.6 mg, 1.9 mmol) was slowly added dropwise under ice bath. The solution was reacted at room temperature for 3 hours.
  • 5-Bromo-2,4-dichloropyrimidine-4-amine 2a (971.56 mg, 4 mmol) and sodium methoxide (216 mg, 4 mmol) were added to 10 mL of methanol, and 1 equivalent of sodium methoxide was added every 3 hours, The reaction was carried out at room temperature for 12 hours. After the reaction, concentrated under reduced pressure, added 20 mL of water, extracted with dichloromethane (10 mL ⁇ 2), combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-bromo-2 -Chloro-6-methoxypyrimidin-4-amine 2b (800 mg), the product was not purified and was directly used in the next step.
  • reaction solution was extracted with ethyl acetate (30 mL ⁇ 2), the combined organic phases were washed with saturated sodium chloride solution (30 mL ⁇ 2) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was passed through a silica gel column Further analysis and purification by chromatography (eluent: system A) gave (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl) tert-Butyl carbamate 3c (800 mg), 75.14% yield.
  • tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d (380 mg, 0.800 mmol) was added to 10 mL of concentrated hydrochloric acid, heated to 110° C., and reacted for 1.5 hours.
  • 6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 5e (30 mg, 0.08 mmol) was added to 0.5 mL of concentrated hydrochloric acid, heated to 110°C, and reacted for 4 hours.
  • 6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 5e (37.33 mg, 0.1 mmol) and 0.1 mL of 6M sodium hydroxide solution was added to 2 mL of ethanol, heated to 80°C, and reacted for 40 minutes.
  • tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d 50 mg, 0.105 mmol
  • zinc chloride 14.30 mg, 0.105 mmol
  • sodium azide 6.82 mg, 0.105 mmol
  • reaction solution was concentrated under reduced pressure, and 1M diluted hydrochloric acid was added to adjust the pH to 2-3, extracted with ethyl acetate (30 mL ⁇ 2), and the combined organic phases were washed with saturated sodium chloride solution (30 mL ⁇ 2) in turn. It was dried over sodium sulfate and concentrated under reduced pressure.
  • the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-((tert-butoxycarbonyl)amino)-4-methyl ylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 8a (40 mg), yield: 39.9%.
  • Trifluoroacetic acid (1 mL) was added to (S)-1-((((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine at room temperature ]-1'-carboxylate tert-butyl ester 20a (260 mg, 639.48 ⁇ mol) in dichloromethane (4 mL) solution, react at room temperature for 1 hour.
  • Trifluoroacetic acid (1 mL) was added to (S)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-1 at room temperature , 3-dihydrospiro[indene-2,4'-piperidin]-1-yl) tert-butyl carbamate 20 g (190 mg, 336.58 ⁇ mol) in dichloromethane (4 mL) solution, react at room temperature for 1 hour.
  • Trifluoroacetic acid (1 mL) was added to (S)-1-((((R)-tert-butylsulfinyl)amino)-6-methoxy-1,3-dihydrospiro[indene-2 at room temperature ,4'-piperidine]-1'-carboxylate tert-butyl ester 21a (200 mg, 455.97 ⁇ mol) in dichloromethane (5 mL) solution was reacted at room temperature for 1 hour.
  • Trifluoroacetic acid (1 mL) was added to (S)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5 at room temperature -Methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl) tert-butyl carbamate 21g (140mg, 235.48 ⁇ mol) in dichloromethane (4mL) solution, The reaction was carried out at room temperature for 40 minutes.
  • Trifluoroacetic acid (1.53 g, 13.42 mmol, 1 mL) and (R)-2-(((R)-tert-butylsulfinyl)amino)-2,3-dihydrospiro[indene-1,4' -Piperidine]-1'-carboxylate tert-butyl ester 23a (400 mg, 983.81 ⁇ mol) was added to 6 mL of dichloromethane and reacted at room temperature for 2 hours.
  • bromosuccinimide (109.52 mg, 615.31 ⁇ mol) was added to dissolve (R)-N-((S)-1'-(4-cyanopyrimidine-2-yl)-1 ,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 26b (210 mg, 512.76 ⁇ mol) in N,N-dimethylmethane amide (2 mL) solution at room temperature for 2 hours.
  • Trifluoroacetic acid (1.53 g, 13.42 mmol, 1 mL) was added to (S)-(1'-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl) at room temperature -1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 26f (150 mg, 272.49 ⁇ mol) in dichloromethane (4 mL), reaction 1 at room temperature Hour.
  • tert-butyl carbamate 27h (77 mg, 153.47 ⁇ mol) was dissolved in 2 mL of N,N-dimethylformamide, cooled to 0°C, and N-bromosuccinimide was added. Amine (30.05 mg, 168.81 ⁇ mol), warmed to room temperature and reacted overnight.
  • Example 28 (Comparative Example 4)
  • 6-amino-2-chloropyrimidine-4-carbonitrile 28a (100 mg, 647.01 ⁇ mol), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'- Piperidin]-1-yl)-2-methylpropane-2-sulfinamide 20b (218.11 mg, 711.71 ⁇ mol), N,N-dimethylacetamide (3 mL) and N,N-diisopropyl Ethylamine (418.10 mg, 3.24 mmol, 563.47 ⁇ L) was added to a 25 mL single-neck flask, and the temperature was raised to 90° C. to react for 3 hours.
  • Trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL) was added to ((1S)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidine- 2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 28e (150 mg, 265.26 ⁇ mol) in dichloromethane (4 mL), The reaction was carried out at room temperature for 1 hour.
  • reaction solution was lowered to room temperature to obtain (S)-2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1' -yl)-6-methylpyrimidine-4-carbonitrile 30c reaction solution, without treatment, directly added N,N-diisopropylethylamine (190.26mg, 1.47mmol) and di-tert-butyl dicarbonate to the reaction solution The ester (267.75 mg, 1.23 mmol) was reacted at room temperature for 4 hours. The reaction was complete as monitored by LC-MS.
  • the compound was purified by silica gel column chromatography (eluent: A system) to obtain ((5S)-1'-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidine) -2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)carbamate 30f (60 mg), yield: 88.31%.

Abstract

The present invention relates to a pyridine or pyrimidine derivative, a preparation method therefor, and a medical use thereof. Specifically, the present invention relates to a pyridine or pyrimidine derivative as shown in general formula (I), a preparation method therefor, and a pharmaceutical salt thereof, and use of same as a therapeutic agent, especially the use of an SHP2 allosteric inhibitor. The definition of each substituent group in general formula (I) is the same as the definition in the description.

Description

吡啶或嘧啶类衍生物及其制备方法和用途Pyridine or pyrimidine derivatives and preparation method and use thereof 技术领域technical field
本发明涉及一种新的吡啶或嘧啶类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为SHP2变构抑制剂的用途。The present invention relates to a novel pyridine or pyrimidine derivative, its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a SHP2 allosteric inhibitor.
背景技术Background technique
Src同源域-2磷酸酶(SHP2)是蛋白酪氨酸磷酸酶(PTP)家族的重要成员之一，由蛋白酪氨酸磷酸酶非受体型11(PTPN11)基因编码，催化蛋白质中酪氨酸的去磷酸化反应。SHP2的N端包含2个SH2结构域，这两个SH2结构域控制着SHP2的亚细胞定位和功能调节，C端包含1个具有催化活性的PTP结构域和2个与其活性相关的的酪氨酸残基。正常情况下，SHP2处于自抑制的状态，当受到生长因子、细胞因子或炎症因子等刺激时，如在血小板源性生长因子PDGF和FGF等刺激下，使得催化位点暴露，导致SHP2的酶的活化。Src homeodomain-2 phosphatase (SHP2) is one of the important members of the protein tyrosine phosphatase (PTP) family, encoded by the protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene, which catalyzes dephosphorylation of amino acids. The N-terminus of SHP2 contains two SH2 domains, which control the subcellular localization and functional regulation of SHP2, and the C-terminus contains a catalytically active PTP domain and two tyrosine related to its activity. acid residue. Under normal circumstances, SHP2 is in a state of auto-inhibition. When stimulated by growth factors, cytokines or inflammatory factors, such as platelet-derived growth factors PDGF and FGF, the catalytic site is exposed, resulting in the activation of SHP2 enzymes. activation.
SHP2在人体内广泛存在，参与大鼠肉瘤(RAS)-胞外信号相关激酶(ERK)，磷脂酰肌醇3激酶(PI3K)-蛋白激酶B和NF-KB，激活成纤维细胞生长因子、表皮生长因子及胰岛素受体下游丝裂原活化蛋白激酶(MAPK/ERK)等多条信号通路，进而调节细胞的增殖、分化、迁移和凋亡。目前已经发现SHP2的激活突变与努南综合征、豹斑综合征、单核细胞白血病、黑色素瘤、实体瘤、心血管疾病、免疫紊乱、纤维化或视觉紊乱的发生有着密不可分的联系，SHP2的过表达会增加慢性粒细胞白血病、肥大细胞增多症、恶性胶质瘤、肺癌、乳腺癌等癌症的风险，表明SHP2在不同类型的癌症及癌症的不同阶段有着重要的作用。由于SHP2在肿瘤中的多种功能，针对SHP2靶点抑制剂的研究也为肿瘤的治疗带来新的希望和方向。SHP2 is widely present in the human body and is involved in rat sarcoma (RAS)-extracellular signal-related kinase (ERK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B and NF-KB, activates fibroblast growth factor, epidermal growth factor Growth factors and insulin receptor downstream mitogen-activated protein kinase (MAPK/ERK) and other signaling pathways regulate cell proliferation, differentiation, migration and apoptosis. Activating mutations in SHP2 have been found to be inextricably linked to the occurrence of Noonan syndrome, leopard spot syndrome, monocytic leukemia, melanoma, solid tumors, cardiovascular disease, immune disorders, fibrosis or visual disorders. Overexpression of SHP2 increases the risk of chronic myeloid leukemia, mastocytosis, malignant glioma, lung cancer, breast cancer and other cancers, indicating that SHP2 has an important role in different types of cancer and different stages of cancer. Due to the multiple functions of SHP2 in tumors, the research on SHP2 target inhibitors also brings new hope and direction for tumor therapy.
SHP2抑制剂按照作用机制的不同，可以分为竞争性抑制剂(包括变构霉素、苯基吡唑肼基磺酸盐和NSC-87877)、非竞争性抑制剂(包括吲哚水杨酸和呋莫素酮)和不可逆性抑制剂(包括葡萄酸锑钠和隐丹参酮)，据报道隐丹参酮作为SHP2不可逆性抑制剂，在体外可抑制横纹肌肉瘤、黑色素瘤、结肠癌和乳腺癌的增殖，体内研究则表明其可抑制小鼠前列腺癌的增殖，其是否能够进一步成为临床有效的药物还需要诸多试验验证。According to different mechanisms of action, SHP2 inhibitors can be divided into competitive inhibitors (including allosteric acid, phenylpyrazole hydrazine sulfonate and NSC-87877), non-competitive inhibitors (including indole salicylic acid) and furamoxinone) and irreversible inhibitors (including sodium stibogluconate and cryptotanshinone), which have been reported as irreversible inhibitors of SHP2 to inhibit the proliferation of rhabdomyosarcoma, melanoma, colon and breast cancer in vitro , and in vivo studies have shown that it can inhibit the proliferation of mouse prostate cancer, and whether it can further become a clinically effective drug still needs to be verified by many experiments.
目前REVOLUTION Medicines Inc公司研发的化合物RMC-4630已经进入临床Ⅱ期，用于实体瘤的治疗，另外还有3个临床Ⅰ期的化合物JAB-3068、JAB-3312和TNO-155，分别由Jacobio Pharmaceuticals Co Ltd和Novartis AG研发。REVOLUTION Medicines Inc和Novartis AG已经公开了一系列的SHP2抑制剂专利，其中包括WO-2019075265、WO-2018136265、WO-2018136264、WO-2017216706和WO-2018013597等，虽然SHP2的研究已经取得一定的进展，但是目前仍未有行之有效的药物上市，所以仍有必要继续研究和开发新的SHP2抑制剂。At present, the compound RMC-4630 developed by REVOLUTION Medicines Inc has entered clinical phase II for the treatment of solid tumors, and there are also three clinical phase I compounds JAB-3068, JAB-3312 and TNO-155, which were respectively developed by Jacobio Pharmaceuticals Co Ltd and Novartis AG research and development. REVOLUTION Medicines Inc and Novartis AG have published a series of SHP2 inhibitor patents, including WO-2019075265, WO-2018136265, WO-2018136264, WO-2017216706 and WO-2018013597, etc. Although the research on SHP2 has made some progress, However, there is still no effective drug on the market, so it is still necessary to continue to research and develop new SHP2 inhibitors.
发明内容SUMMARY OF THE INVENTION
针对上述的技术问题，本发明提供一种通式(I)所示的一类新的吡啶或嘧啶类化合物或其立体异构体、互变异构体或其可药用的盐：In view of the above-mentioned technical problems, the present invention provides a new class of pyridine or pyrimidine compounds represented by the general formula (I) or their stereoisomers, tautomers or their pharmaceutically acceptable salts:
Figure PCTCN2021105100-appb-000001
Figure PCTCN2021105100-appb-000001
其中：in:
环A选自芳基、杂芳基或双环稠合环，其中所述的双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环；Ring A is selected from an aryl group, a heteroaryl group or a bicyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
X选自CR e或N； X is selected from CR e or N;
R e选自氢原子、烷基、卤素或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自羟基、卤素或烷氧基的取代基所取代； R e is selected from hydrogen atom, alkyl, halogen or alkoxy, wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from hydroxyl, halogen or alkoxy;
R 1选自烷基、环烷基、杂环基、氰基、烯基、炔基、-OR 6、-C(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHSO 2R 6或-C(O)NR 7R 8，其中所述的烷基、环烷基、杂环基、烯基或炔基任选进一步被一个或多个选自羟基、卤素、烷基、烷氧基、环烷基或-NR 7R 8的取代基所取代；优选地，R 1选自甲基； R 1 is selected from alkyl, cycloalkyl, heterocyclyl, cyano, alkenyl, alkynyl, -OR 6 , -C(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein said alkyl, cycloalkyl, heterocyclyl, alkenyl or alkynyl is optionally further modified by one or more substituted by a substituent selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 ; preferably, R 1 is selected from methyl;
R 2相同或不同，各自独立地选自氢原子、烷基、烯基、炔基、氰基、卤素、硝基、环烷基、杂环基、-OR 6、-C(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHSO 2R 6或-C(O)NR 7R 8，其中所述的烷基、烯基、炔基、环烷基或杂环基任选进一步被一个或多个选自卤素、硝基、氰基、烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHSO 2R 6或-C(O)NR 7R 8的取代基所取代； R 2 are the same or different, each independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, cyano, halogen, nitro, cycloalkyl, heterocyclyl, -OR 6 , -C(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl is further optionally substituted with one or more substituents selected from halo, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6, -C ( O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHSO 2 R 6 or -C( O) Substituents of NR 7 R 8 are substituted;
R 3选自氰基、烷氧基、四氮唑基、-C(O)R 6、-C(O)OR 6或-C(O)NR 7R 8； R 3 is selected from cyano, alkoxy, tetrazolyl, -C(O)R 6 , -C(O)OR 6 or -C(O)NR 7 R 8 ;
条件是，当R 3选自烷氧基时，R 1不选自-NR 7R 8； With the proviso that when R 3 is selected from alkoxy, R 1 is not selected from -NR 7 R 8 ;
R 4和R 5与其相连接的N原子一起形成4～11元杂环基，优选为5～11元杂环基，其中所述的杂环基内含有一个或多个N、O、S原子或SO 2，并且杂环基任选进一步被一个或多个选自卤素、硝基、氰基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8的取代基所取代，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被卤素、羟基、氨基或烷氧基的取代基所取代； R 4 and R 5 together with the N atom to which they are connected form a 4-11-membered heterocyclic group, preferably a 5-11-membered heterocyclic group, wherein the heterocyclic group contains one or more N, O, S atoms or SO 2 , and heterocyclyl is optionally further selected from one or more of halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH)NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 substituents, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle aryl, aryl or heteroaryl are optionally further substituted with halogen, hydroxy, amino or alkoxy substituents;
或者，R 4和R 5与其相连接的N原子一起形成基团： Huozhe, R 4 Yiqi and R 5 form a group with the N atom connected to:
Figure PCTCN2021105100-appb-000002
Figure PCTCN2021105100-appb-000002
Figure PCTCN2021105100-appb-000003
为单键或双键；
Figure PCTCN2021105100-appb-000003
is a single bond or a double bond;
当
Figure PCTCN2021105100-appb-000004
表示单键时，G和M各自独立地选自N或CR j； when
Figure PCTCN2021105100-appb-000004
When representing a single bond, G and M are each independently selected from N or CR j ;
当
Figure PCTCN2021105100-appb-000005
表示双键时，G和M各自独立地选自C； when
Figure PCTCN2021105100-appb-000005
When representing a double bond, G and M are each independently selected from C;
环B选自环烷基、杂环基、芳基或杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
E选自NR k、(CR pR q) p、O或S； E is selected from NR k , (CR p R q ) p , O or S;
F选自(CR pR q) q； F is selected from (CR p R q ) q ;
条件是，当E选自(CR pR q) p时，p为1，q为1；或者，p为2，q为0；当E选自NR k、O或S时，q为1； Provided that when E is selected from (CR p R q ) p , p is 1 and q is 1; alternatively, p is 2 and q is 0; when E is selected from NR k , O or S, q is 1;
J选自CR pR q； J is selected from CR p R q ;
K选自NR k、(CR pR q) r、O或S； K is selected from NR k , (CR p R q ) r , O or S;
r为0或1；r is 0 or 1;
R m、R n、R p和R q相同或不同，各自独立地选自R A； R m , R n , R p and R q are the same or different, each independently selected from R A ;
或者，R m和R n与相连接的同一个碳原子一起形成C＝O； Alternatively, R m and R n with the same carbon atom attached form C = O;
或者，R p和R q与相连接的碳原子一起形成R B； Alternatively, R p and R q together with the attached carbon atoms form R B ;
R c和R d相同或不同，各自独立地选自氢原子、卤素、烷基或-OR 6，其中所述的烷基任选进一步被羟基、卤素、烷氧基、环烷基或-NR 7R 8的取代基所取代； R c and R d are the same or different and are each independently selected from a hydrogen atom, halogen, alkyl or -OR 6 , wherein said alkyl is optionally further substituted by hydroxy, halogen, alkoxy, cycloalkyl or -NR Substituents of 7 R 8 are substituted;
或者，R c和R d与相连接的碳原子一起形成R B； Alternatively, R c and R d together with the attached carbon atoms form R B ;
R g相同或不同，各自独立地选自氢原子、卤素、硝基、烷基、烯基、炔基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被羟基、卤素、烷基、烷氧基、环烷基或-NR 7R 8的取代基所取代； R g is the same or different, each independently selected from hydrogen atom, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH) NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 substituent;
或者，两个R g与相连接的同一个碳原子一起形成C＝O； Alternatively, two R gs together form C=O with the same attached carbon atom;
R j和R k相同或不同，各自独立地选自氢原子或烷基； R j and R k are the same or different, each independently selected from a hydrogen atom or an alkyl group;
R A相同或不同，各自独立地选自氢原子、卤素、硝基、烷基、烯基、炔基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8，其中所述的烷基、烯基、炔基、 环烷基、杂环基、芳基或杂芳基任选进一步被羟基、卤素、烷基、烷氧基、环烷基或-NR 7R 8的取代基所取代； R A is the same or different, each independently selected from hydrogen atom, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH) NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 substituent;
R B相同或不同，各自独立地选自3～10元环烷基或3～10元杂环基，其中所述的环烷基或杂环基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8的取代基所取代； R and B are the same or different, and are independently selected from 3-10-membered cycloalkyl or 3-10-membered heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further selected from one or more groups selected from halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC( of O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH)NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 substituted by a substituent;
R 6、R 7和R 8各自独立地选自氢原子、烷基、环烷基或杂环基，其中所述烷基、环烷基或杂环基任选进一步被一个或多个选自羟基、氨基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R 9、-C(O)OR 9、-OC(O)R 9、-SO 2R 9、-NR 10R 11、-C(O)NR 10R 11、-SO 2NR 10R 11或-NR 10C(O)R 11的取代基所取代； R 6 , R 7 , and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, or a heterocyclyl group, wherein the alkyl group, cycloalkyl group, or heterocyclyl group is optionally further selected from one or more of Hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 9 , -C(O)OR 9 , Substituents of -OC(O)R 9 , -SO 2 R 9 , -NR 10 R 11 , -C(O)NR 10 R 11 , -SO 2 NR 10 R 11 or -NR 10 C(O)R 11 replaced;
或者，R 7和R 8与其相连接的N原子一起形成3～8元杂环基，其中所述的3～8元杂环内含有一个或多个N、O、S原子或SO 2，并且3～8元杂环上任选进一步被一个或多个选自羟基、卤素、氨基、烷基或烷氧基的取代基所取代； Alternatively, R 7 and R 8 together with the N atom to which they are attached form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic ring contains one or more N, O, S atoms or SO 2 , and The 3-8 membered heterocycle is optionally further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;
R 9、R 10和R 11各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代； R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group The radical or heteroaryl is optionally further selected from one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxy substituted by the substituent of the ester group;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
p选自1或2。p is selected from 1 or 2.
在本发明的优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐，In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (II) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
Figure PCTCN2021105100-appb-000006
Figure PCTCN2021105100-appb-000006
其中：环A、X、m、R 1、R 2、R 4和R 5的定义如通式(I)中所述。 wherein: ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
在本发明的优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐，In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (III) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
Figure PCTCN2021105100-appb-000007
Figure PCTCN2021105100-appb-000007
其中：环A、X、m、R 1、R 2、R 4和R 5的定义如通式(I)中所述。 wherein: ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
在本发明的优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(IV)所述的化合物或其立体异构体、互变异构体或其可药用的盐，In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (IV) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
Figure PCTCN2021105100-appb-000008
Figure PCTCN2021105100-appb-000008
其中：环A、X、m、R 1、R 2、R 4和R 5的定义如通式(I)中所述。 wherein: ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
在本发明的优选方案中，通式(I)、(II)、(III)或(IV)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：R 4和R 5与其相连接的N原子一起形成4～8元单环杂环基，优选为5～6元单环杂环基，更优选为哌啶基，其中所述的单环杂环基任选进一步被一个或多个选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2、＝O或-OR 6的取代基所取代；R 6的定义如通式(I)中所述。 In a preferred embodiment of the present invention, the compound of general formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein : R 4 and R 5 together with the N atom to which they are connected form a 4-8 membered monocyclic heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, more preferably a piperidinyl group, wherein the monocyclic heterocyclic group cycloalkyl group optionally further substituted with one or more substituents selected from methyl, amino, -CH 2 NH 2, -CH 2 OH, -NHC (= NH) NH 2, = O , or -OR 6 is substituted; R & lt 6 is defined as in the general formula (I).
在本发明的优选方案中，通式(I)、(II)、(III)或(IV)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：In a preferred embodiment of the present invention, the compound of general formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein :
R 4和R 5与其相连接的N原子一起形成7～11元螺杂环基，其中所述的螺杂环基任选进一步被一个或多个选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2、＝O或-OR 6的取代基所取代； R 4 and R 5 together with the N atom to which they are attached form a 7-11 membered spiro heterocyclic group, wherein said spiro heterocyclic group is optionally further selected from one or more groups selected from methyl, amino, -CH 2 NH 2 , -CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 substituent;
R 6的定义如通式(I)中所述； R 6 is as defined in general formula (I);
优选地，其中所述的螺杂环基选自：Preferably, wherein said spiro heterocyclyl is selected from:
Figure PCTCN2021105100-appb-000009
Figure PCTCN2021105100-appb-000009
R a相同或不同，各自独立地选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2或-OR 6；或者，两个R a与相连接的同一个碳原子一起形成C＝O；R 6的定义如通式(I)中所述；t为1、2或3。 R a are the same or different, are each independently selected from methyl, amino, -CH 2 NH 2, -CH 2 OH, -NHC (= NH) NH 2 , or -OR 6; or two R a and connected The same carbon atom together forms C=O; R 6 is as defined in general formula (I); t is 1, 2 or 3.
在本发明的优选方案中，通式(I)、(II)、(III)或(IV)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：R 4和R 5与其相连接的N原子一起形成7～11元桥杂环基，其中所述的桥杂环基任选进一步被一个或多个选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2、＝O或-OR 6的取代基所取代；R 6的定义如通式(I)中所述。 In a preferred embodiment of the present invention, the compound of general formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein : R 4 and R 5 together with the N atom to which they are attached form a 7-11-membered bridged heterocyclic group, wherein the bridged heterocyclic group is optionally further selected from one or more groups selected from methyl, amino, -CH 2 NH 2 , -CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 substituent; the definition of R 6 is as described in the general formula (I).
在本发明的优选方案中，通式(I)、(II)、(III)或(IV)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：R 4和R 5与其相连接的N原子一起形成7～11元稠杂环基，其中所述的稠杂环基任选进一步被一个或多个选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2、＝O或-OR 6的取代基所取代；R 6的定义如通式(I)中所述。 In a preferred embodiment of the present invention, the compound of general formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein : R 4 and R 5 together with the N atom to which they are attached form a 7-11 membered fused heterocyclic group, wherein the fused heterocyclic group is optionally further selected from one or more groups selected from methyl, amino, -CH 2 NH 2 , -CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 substituent; the definition of R 6 is as described in the general formula (I).
在本发明的优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(V)所述的化合物或其立体异构体、互变异构体或其可药用的盐：In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (V) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2021105100-appb-000010
Figure PCTCN2021105100-appb-000010
其中：in:
环B选自苯基、3～8元环烷基、4～8元杂环基或5～6元杂芳基；Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
E选自NR k、(CR pR q) p、O或S； E is selected from NR k , (CR p R q ) p , O or S;
F选自(CR pR q) q； F is selected from (CR p R q ) q ;
条件是，当E选自(CR pR q) p时，p为1，q为1；或者，p为2，q为0；当E选自NR k、O或S时，q为1； Provided that when E is selected from (CR p R q ) p , p is 1 and q is 1; alternatively, p is 2 and q is 0; when E is selected from NR k , O or S, q is 1;
R m选自氨基、-CH 2NH 2或-NHC(＝NH)NH 2； R m is selected from an amino group, -CH 2 NH 2 or -NHC (= NH) NH 2;
R n选自氢原子、甲基或-CH 2OH； R n is selected from hydrogen atom, methyl or -CH 2 OH;
或者，R m和R n与相连接的同一个碳原子一起形成C＝O； Alternatively, R m and R n with the same carbon atom attached form C = O;
R p和R q各自独立地选自氢原子、卤素、氨基、C 1-C 4烷基、羟基C 1-C 4烷基、氨基C 1-C 4烷基或-OR 6； R p and R q are each independently selected from a hydrogen atom, halogen, amino, C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl or -OR 6 ;
Figure PCTCN2021105100-appb-000011
环A、G、M、X、m、n、R 1～R 3、R 6、R k和R g的定义如通式(I)中所述。
Figure PCTCN2021105100-appb-000011
Rings A, G, M, X, m, n, R 1 to R 3 , R 6 , R k and R g are defined as in the general formula (I).
在本发明的优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VI)所述的化合物或其立体异构体、互变异构体或其可药用的盐：In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (VI) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2021105100-appb-000012
Figure PCTCN2021105100-appb-000012
其中：in:
环B选自苯基、3～8元环烷基、4～8元杂环基或5～6元杂芳基；Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
J选自CR pR q； J is selected from CR p R q ;
K选自NR k、(CR pR q) r、O或S； K is selected from NR k , (CR p R q ) r , O or S;
r为0或1；r is 0 or 1;
R m选自氨基、-CH 2NH 2或-NHC(＝NH)NH 2； R m is selected from an amino group, -CH 2 NH 2 or -NHC (= NH) NH 2;
R n选自氢原子、甲基或-CH 2OH； R n is selected from hydrogen atom, methyl or -CH 2 OH;
或者，R m和R n与相连接的同一个碳原子一起形成C＝O； Alternatively, R m and R n with the same carbon atom attached form C = O;
R p和R q各自独立地选自氢原子、卤素、氨基、C 1-C 4烷基、羟基C 1-C 4烷基、氨基C 1-C 4烷基或-OR 6； R p and R q are each independently selected from a hydrogen atom, halogen, amino, C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl or -OR 6 ;
Figure PCTCN2021105100-appb-000013
环A、G、M、X、m、n、R 1～R 3、R 6、R k和R g的定义如通式(I)中所述。
Figure PCTCN2021105100-appb-000013
Rings A, G, M, X, m, n, R 1 to R 3 , R 6 , R k and R g are defined as in the general formula (I).
在本发明的优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VII)所述的化合物或其立体异构体、互变异构体或其可药用的盐：In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (VII) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2021105100-appb-000014
Figure PCTCN2021105100-appb-000014
其中：in:
环B选自苯基、3～8元环烷基、4～8元杂环基或5～6元杂芳基；Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
R c和R d与相连接的原子一起形成3～8元环烷基； R c and R d together with the connected atoms form a 3- to 8-membered cycloalkyl;
R m选自氨基、-CH 2NH 2或-NHC(＝NH)NH 2； R m is selected from an amino group, -CH 2 NH 2 or -NHC (= NH) NH 2;
R n选自氢原子、甲基或-CH 2OH； R n is selected from hydrogen atom, methyl or -CH 2 OH;
或者，R m和R n与相连接的同一个碳原子一起形成C＝O； Alternatively, R m and R n with the same carbon atom attached form C = O;
Figure PCTCN2021105100-appb-000015
环A、G、M、X、m、n、R 1～R 3和R g的定义如通式(I)中所述。
Figure PCTCN2021105100-appb-000015
Rings A, G, M, X, m, n, R 1 to R 3 and R g are defined as in the general formula (I).
在本发明的优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐：In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound of general formula (VIII) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2021105100-appb-000016
Figure PCTCN2021105100-appb-000016
其中：in:
Figure PCTCN2021105100-appb-000017
环B、n、R 1～R 2和R g的定义如通式(I)中所述。
Figure PCTCN2021105100-appb-000017
The definitions of rings B, n, R 1 to R 2 and R g are as described in the general formula (I).
在本发明的优选方案中，通式(I)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 2选自氢原子、F、Cl、Br、氨基、羟基、氰基、硝基、甲氧基、乙氧基、甲基、乙基、乙炔基、乙烯基、-NHCH 3或-N(CH 3) 2。 In a preferred embodiment of the present invention, the compound of general formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer, interconversion or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, F, Cl, Br, amino, hydroxy, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl group, vinyl, -NHCH 3 or -N(CH 3 ) 2 .
在本发明的优选方案中，通式(V)、(VI)或(VII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 3选自-C(O)OH。 In a preferred embodiment of the present invention, the compound of general formula (V), (VI) or (VII) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from -C(O)OH.
在本发明的优选方案中，通式(I)、(III)、(IV)、(V)、(VI)或(VII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 6选自氢原子或烷基。 In a preferred embodiment of the present invention, the compound of general formula (I), (III), (IV), (V), (VI) or (VII) or its stereoisomer, tautomer or A pharmaceutically acceptable salt thereof, wherein R 6 is selected from a hydrogen atom or an alkyl group.
在本发明的优选方案中，通式(I)、(III)、(IV)、(V)、(VI)或(VII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中环A选自苯基。In a preferred embodiment of the present invention, the compound of general formula (I), (III), (IV), (V), (VI) or (VII) or its stereoisomer, tautomer or A pharmaceutically acceptable salt thereof, wherein Ring A is selected from phenyl.
在本发明的优选方案中，通式(I)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中环B选自：In a preferred embodiment of the present invention, the compound of general formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer, interconversion Isomers or pharmaceutically acceptable salts thereof, wherein Ring B is selected from:
Figure PCTCN2021105100-appb-000018
Figure PCTCN2021105100-appb-000018
在本发明的优选方案中，通式(I)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R g相同或不同，各自独立地选自氢原子、F、Cl、Br、氨基、羟基、氰基、硝基、甲氧基、乙氧基、甲基、乙基、乙炔基、乙烯基、-NHCH 3或-N(CH 3) 2； In a preferred embodiment of the present invention, the compound of general formula (I), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer, interconversion Isomers or pharmaceutically acceptable salts thereof, wherein R g is the same or different, each independently selected from hydrogen atom, F, Cl, Br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH 3 or -N(CH 3 ) 2 ;
或者，两个R g与相连接的同一个碳原子可以一起形成C＝O。 Alternatively, two R g and the same carbon atom to which they are attached can be taken together to form C=O.
本发明的典型化合物包括，但不限于：Typical compounds of the present invention include, but are not limited to:
Figure PCTCN2021105100-appb-000019
Figure PCTCN2021105100-appb-000019
Figure PCTCN2021105100-appb-000020
Figure PCTCN2021105100-appb-000020
Figure PCTCN2021105100-appb-000021
Figure PCTCN2021105100-appb-000021
Figure PCTCN2021105100-appb-000022
Figure PCTCN2021105100-appb-000022
或其立体异构体、互变异构体或其可药用的盐。or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
更进一步，本发明提供一种药物组合物，所述的药物组合物含有有效剂量的通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。Further, the present invention provides a pharmaceutical composition containing an effective dose of general formula (I), (II), (III), (IV), (V), (VI), (VII) ) or (VIII), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.
本发明提供一种通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物(即本发明上述技术方案提供的药物组合物)在制备SHP2变构抑制剂中的用途。The present invention provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a compound thereof Use of a variant or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (ie, the pharmaceutical composition provided by the above technical solutions of the present invention) in the preparation of an SHP2 allosteric inhibitor.
本发明还提供一种通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备治疗由SHP2介导的疾病的药物中的用途，其中所述的由SHP2介导的疾病优选为癌症、癌转移、心血管疾病、免疫紊乱、纤维化或视觉紊乱；其中所述的由SHP2介导的疾病优选选自努南综合征、豹斑综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤。The present invention also provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer thereof, Use of a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for treating a disease mediated by SHP2, wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, Cardiovascular disease, immune disorder, fibrosis or visual disorder; wherein said disease mediated by SHP2 is preferably selected from Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma , acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
本发明进一步提供一种通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备治疗癌症、癌转移、心血管疾病、免疫紊乱、纤维化或视觉紊乱的药物中的用途。The present invention further provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer thereof, Use of a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder.
本发明提供一种通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其 立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备治疗努南综合征、豹斑综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤的药物中的用途。The present invention provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer, a compound thereof Variants or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are used in the preparation and treatment of Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, Use in medicaments for breast cancer, esophagus cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma and glioblastoma.
本发明还提供一种通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在治疗由SHP2介导的疾病中的用途，其中所述的由SHP2介导的疾病优选为癌症、癌转移、心血管疾病、免疫紊乱、纤维化或视觉紊乱；其中所述的由SHP2介导的疾病优选选自努南综合征、豹斑综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤。The present invention also provides a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a stereoisomer thereof, Use of a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of a disease mediated by SHP2, wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, cardiovascular disease , immune disorder, fibrosis or visual disorder; wherein said disease mediated by SHP2 is preferably selected from Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
本发明还提供一种由SHP2介导的疾病的治疗方法，包括使用通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物向受试者进行施用；其中所述的由SHP2介导的疾病优选为癌症、癌转移、心血管疾病、免疫紊乱、纤维化或视觉紊乱；其中所述的由SHP2介导的疾病优选选自努南综合征、豹斑综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤。The present invention also provides a method of treatment of a disease mediated by SHP2, comprising the use of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) ) described compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered to subject; wherein said disease mediated by SHP2 is preferably cancer , cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder; wherein said disease mediated by SHP2 is preferably selected from Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma tumor, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma .
发明的详细说明Detailed description of the invention
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：Unless stated to the contrary, some terms used in the specification and claims of the present invention are defined as follows:
“烷基”当作一基团或一基团的一部分时是指包括C 1-C 20直链或者带有支链的脂肪烃基团。优选为C 1-C 10烷基，更优选为C 1-C 6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。 When "alkyl" as a group or part of a group is meant to include C 1 -C 20 linear or branched aliphatic hydrocarbon group with a chain. Preferably it is a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。烯基可以是任选取代的或未取代的。"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups can be optionally substituted or unsubstituted.
“炔基”是指含有一个碳碳三键的脂肪烃基团，可为直链也可以带有支链。优先选择的是C 2-C 10的炔基，更优选C 2-C 6炔基，最优选C 2-C 4炔基。炔基基团的实施例包括，但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。 "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preferred is C 2 -C 10 alkynyl group, more preferably C 2 -C 6 alkynyl group, most preferably C 2 -C 4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C 3-C 12环烷 基，更优选为C 3-C 8环烷基，最优选为C 3-C 6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。环烷基可以是任选取代的或未取代的。 "Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged and spirocyclic carbocyclic rings. Preferably it is C 3 -C 12 cycloalkyl, more preferably C 3 -C 8 cycloalkyl, most preferably C 3 -C 6 cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
“螺环烷基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于：螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
“稠环烷基”指5至18元，含有两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。"Fused cycloalkyl" refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthryl.
“桥环烷基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环o[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。"Bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-dicyclo[3.2.1]octyl Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，都是指非芳香性杂环基，其中一个或多个成环的原子是杂原子，如氧、氮、硫原子等，包括单环、多环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双-或三环，其可以包含1，2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基、氧杂环丁烷基、硫代吗啉基、四氢吡喃基、1，1-二氧代-硫代吗啉基、哌啶基、2-氧代-哌啶基、吡咯烷基、2-氧代-吡咯烷基、哌嗪-2-酮、8-氧杂-3-氮杂-双环[3.2.1]辛基、哌嗪基、
Figure PCTCN2021105100-appb-000023
Figure PCTCN2021105100-appb-000024
杂环基可以是取代或未取代的。 "Heterocyclyl,""heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclyl in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, fused, bridged and spirocyclic. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl,
Figure PCTCN2021105100-appb-000023
Figure PCTCN2021105100-appb-000024
Heterocyclyl groups can be substituted or unsubstituted.
“螺杂环基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个原子的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧或S(O) n(其中n选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于：1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基、5-氧杂螺[2.4]庚基、
Figure PCTCN2021105100-appb-000025
"Spiroheterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and single rings share one atom with each other, and the ring contains one or more double bonds, but no An aromatic system with fully conjugated pi electrons in one ring, wherein one or more ring atoms are selected from nitrogen, oxygen, or a heteroatom of S(O) n (wherein n is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. Spirocycloalkyl groups are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl according to the number of spiro atoms shared between rings, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl Heterospiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,
Figure PCTCN2021105100-appb-000025
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧或S(O) n(其中n选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基、3-氮杂二环[3.1.0]己基、八氢苯并[b][1,4]二噁英(dioxine)和
Figure PCTCN2021105100-appb-000026
"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, one or more rings may contain one or more double bonds, but no ring has complete Conjugated pi-electron aromatic systems in which one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine and
Figure PCTCN2021105100-appb-000026
“桥杂环基”指5至14元，5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧或S(O) n(其中n选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于：2-氮杂二环[2.2.1]庚基、2-氮杂二环[2.2.2]辛基、2-氮杂二环[3.3.2]癸基和
Figure PCTCN2021105100-appb-000027
"Bridged heterocyclyl" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures that share two atoms that are not directly connected to each other, and one or more rings may be Aromatic systems containing one or more double bonds but none of the rings have fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo cyclo[3.3.2]decyl and
Figure PCTCN2021105100-appb-000027
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基，比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为萘基。芳基可以是取代或未取代的。 "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Aryl is preferably C 6 -C 10 aryl group, and more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups can be substituted or unsubstituted.
“杂芳基”是指芳香族5至6元单环或8至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。优选为双环杂芳基，“杂芳基”的实施例包括但不限于呋喃基、吡啶基、2-氧代-1，2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑 基、咪唑基、吡咯基、吡唑基、三唑基、四氮唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、苯并间二氧杂环戊烯基、苯并噻吩基、苯并咪唑基、吲哚基、异吲哚基、1,3-二氧代-异吲哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基、苯并异噁唑基、"Heteroaryl" refers to an aromatic 5 to 6 membered monocyclic or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Preferably bicyclic heteroaryl, examples of "heteroaryl" include but are not limited to furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiazolyl oxadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl , indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,
Figure PCTCN2021105100-appb-000028
Figure PCTCN2021105100-appb-000028
杂芳基可以是取代或未取代的。Heteroaryl groups can be substituted or unsubstituted.
“稠合环”是指两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但至少一个环不具有完全共轭的π电子的芳香系统，同时至少一个环具有完全共轭的π电子的芳香系统，其中环原子中选自0个、一个或多个环原子选自氮、氧或S(O) n(其中n选自0、1或2)的杂原子，其余环原子为碳。稠合环优选包括双环或三环的稠合环，其中双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环。优选为7至14元，更优选为8至10元。“稠合环”的实施例包括但不限于： "Fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring is not completely conjugated A π-electron aromatic system, and at least one ring has a fully conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, and one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (wherein n is selected from the heteroatoms of 0, 1 or 2) and the remaining ring atoms are carbon. The condensed ring preferably includes a bicyclic or tricyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
Figure PCTCN2021105100-appb-000029
Figure PCTCN2021105100-appb-000029
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C 1-C 6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。 "Alkoxy" refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Preferred alkoxy is C 1 -C 6. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
“羟基”指-OH基团。"Hydroxy" refers to the -OH group.
“卤素”是指氟、氯、溴和碘。"Halogen" refers to fluorine, chlorine, bromine and iodine.
“氨基”指-NH 2。 "Amino" means -NH 2.
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO 2。 "Nitro" refers to -NO 2.
“苄基”指-CH 2-苯基。 "Benzyl" refers to -CH 2 - phenyl.
“羧基”指-C(O)OH。"Carboxyl" refers to -C(O)OH.
“羧酸酯基”指-C(O)O-烷基或-C(O)O-环烷基，其中烷基、环烷基的定义如上所述。"Carboxylate" means -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
“DMSO”指二甲基亚砜。"DMSO" refers to dimethyl sulfoxide.
“BOC”指叔丁氧基羰基。"BOC" refers to t-butoxycarbonyl.
“TFA”指三氟醋酸。"TFA" refers to trifluoroacetic acid.
“Ts”指对甲苯磺酰基。"Ts" refers to p-toluenesulfonyl.
“羟基C 1-C 4烷基”指羟基取代的C 1-C 4烷基。 "Hydroxy C 1 -C 4 alkyl" refers to hydroxy substituted C 1 -C 4 alkyl.
“氨基C 1-C 4烷基”指氨基取代的C 1-C 4烷基。 "Amino C 1 -C 4 alkyl" refers to an amino substituted with C 1 -C 4 alkyl.
“离去基团(leaving group)”，或称离去基，在化学反应中从一较大分子中脱离的原子或官能基，是亲核取代反应与消除反应中应用的术语。在亲核取代反应中，被亲核试剂进攻的反应物称为底物(substrate)，而从底物分子中带着一对电子断裂出去的原子或原子团称为离去基团。易接受电子、承受负电荷能力强的基团是好的离去基团。当离去基团共轭酸的pKa越小，离去基团越容易从其他分子中脱离。原因是因为当其共轭酸的pKa越小，相应离去基团不需和其他原子结合，以阴离子(或电中性离去基团)的形式存在的趋势也就增强。常见的离去基团包括但不限于卤素、甲磺酰基、-OTs或-OH。"Leaving group", or leaving group, is an atom or functional group that is removed from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions. In the nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that is broken off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to withstand negative charges are good leaving groups. When the pKa of the conjugated acid of the leaving group is smaller, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugated acid is smaller, the corresponding leaving group does not need to be combined with other atoms, and the tendency to exist in the form of an anion (or a neutral leaving group) is also enhanced. Common leaving groups include, but are not limited to, halo, methanesulfonyl, -OTs, or -OH.
本发明化合物可以含有不对称中心或手性中心，因此以不同的立体异构体形式存在。所预期的是，本发明化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体、位阻异构体和几何(构象)异构体及它们的混合物，如外消旋体混合物，均在本发明的范围内。The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers, hindered isomers and geometric (conformational) isomers and mixtures thereof , such as racemic mixtures, are within the scope of the present invention.
除非另外指出，本发明描述的结构还包括此结构的所有异构体(如，非对映异构体、对映异构体、位阻异构体和几何(构象)异构体形式；例如，各不对称中心的R和S构型，(Z)和(E)双键异构体，联苯类结构的位阻异构体(参见《基础有机化学》(第二版)上册，刑其毅等，p104-105)；PAC,1996,68,2193.(Basic terminology of stereochemistry(IUPAC Recommendations 1996,on page 2201))，(Z)和(E)构象异构体。因此本发明化合物的单个立体异构体以及对映体混合物、非对映异构体混合物、位阻异构体和几何(构象)异构体混合物均在本发明范围内。Unless otherwise indicated, structures depicted herein also include all isomeric (eg, diastereomeric, enantiomeric, hindered, and geometric (conformational) isomeric forms of such structures; for example , R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, sterically hindered isomers of biphenyl-like structures (see "Basic Organic Chemistry" (Second Edition) Volume 1, Criminal Qi Yi et al., p104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z) and (E) conformational isomers. Therefore, the compounds of the present invention have Individual stereoisomers as well as enantiomeric, diastereomeric, hindered and geometric (conformational) mixtures are within the scope of the present invention.
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8的取代基所取代，其中所述的烷基或烷氧基任选进一步被卤素、羟基、氨基或烷氧基的取代基所取代； "Substituted" or "substituted" mentioned in this specification, unless otherwise specified, means that the group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC (O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH)NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 substituted by the substituent, wherein the alkyl or alkoxy is optionally further substituted by the substituent of halogen, hydroxyl, amino or alkoxy;
R 6、R 7和R 8各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、氨基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R 9、-C(O)OR 9、-OC(O)R 9、-SO 2R 9、-NR 10R 11、-C(O)NR 10R 11、-SO 2NR 10R 11或-NR 10C(O)R 11的取代基所取代； R 6 , R 7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl optionally further selected from one or more groups selected from hydroxy, amino, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -SO 2 R 9 , -NR 10 R 11 , -C(O)NR 10 R 11 , -SO 2 NR 10 R 11 or -NR 10 C(O)R 11 is substituted with a substituent;
R 7和R 8与其相连接的N原子一起形成3～8元杂环基，其中所述的3～8元杂环内含有一个或多个N、O、S或SO 2原子，并且3～8元杂环上进一步被一个或多个选自羟基、卤 素、氨基、烷基或烷氧基的取代基所取代； R 7 and R 8 together with the N atom to which they are attached form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic ring contains one or more N, O, S or SO 2 atoms, and 3- The 8-membered heterocycle is further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;
R 9、R 10和R 11各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代。 R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group The radical or heteroaryl is optionally further selected from one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxy Substituents of the ester group are substituted.
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。"Pharmaceutically acceptable salts" refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. The pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt formed with a suitable acid.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
本发明化合物的合成方法Synthetic method of the compound of the present invention
为了完成本发明的目的，本发明采用如下技术方案：In order to accomplish the purpose of the present invention, the present invention adopts following technical scheme:
本发明提供了一种通式(I)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，所述方法包括：The present invention provides a preparation method of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021105100-appb-000030
Figure PCTCN2021105100-appb-000030
通式(Ia)化合物与NHR 4R 5在碱性条件下进行亲核取代反应，得到通式(Ib)化合物；通式(Ib)化合物与通式(Ic)化合物，在钯催化剂和碱性条件下进行Suzuki反应，得到的化合物任选进一步脱去保护基，得到通式(I)化合物； The compound of general formula (Ia) is subjected to a nucleophilic substitution reaction with NHR 4 R 5 under basic conditions to obtain the compound of general formula (Ib); the compound of general formula (Ib) and the compound of general formula (Ic) are prepared in a palladium catalyst and basic Suzuki reaction is carried out under the conditions, and the obtained compound is optionally further deprotected to obtain the compound of general formula (I);
其中：in:
X 2选自卤素； X 2 is selected from halogen;
X 3选自离去基团，所述的离去基团选自卤素或-SO 2R t； X 3 is selected from a leaving group, and the leaving group is selected from halogen or -SO 2 R t ;
R 3选自烷氧基； R 3 is selected from alkoxy;
R t选自烷基； R t is selected from alkyl;
环A、X，m、R 1、R 2、R 4和R 5的定义如通式(I)中所述。 Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
本发明提供了一种通式(I)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，所述方法包括：The present invention provides a preparation method of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021105100-appb-000031
Figure PCTCN2021105100-appb-000031
通式(Ia)化合物与通式(Ic)化合物，在钯催化剂和碱性条件下进行Suzuki反应，得到通式(Id)化合物；通式(Id)化合物与NHR 4R 5在碱性条件下进行亲核取代反应，得到的化合物任选进一步脱去保护基，得到通式(I)化合物； The compound of general formula (Ia) and the compound of general formula (Ic) are subjected to Suzuki reaction under palladium catalyst and basic conditions to obtain the compound of general formula (Id); the compound of general formula (Id) and NHR 4 R 5 are carried out under basic conditions A nucleophilic substitution reaction is carried out, and the obtained compound is optionally further deprotected to obtain a compound of general formula (I);
其中：in:
X 2选自卤素； X 2 is selected from halogen;
X 3选自离去基团，所述的离去基团选自卤素或-SO 2R t； X 3 is selected from a leaving group, and the leaving group is selected from halogen or -SO 2 R t ;
R 3选自烷氧基； R 3 is selected from alkoxy;
R t选自烷基； R t is selected from alkyl;
环A，X，m、R 1、R 2、R 4和R 5的定义如通式(I)中所述。 Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (I).
本发明提供了一种通式(II)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，所述方法包括：The present invention provides a preparation method of a compound of general formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021105100-appb-000032
Figure PCTCN2021105100-appb-000032
通式(IIa)化合物与NHR 4R 5在碱性条件下进行亲核取代反应，得到通式(IIb)化合物；通式(IIb)化合物与通式(Ic)化合物，在钯催化剂和碱性条件下进行Suzuki反应，得到的化合物任选进一步脱去保护基，得到通式(IIc)化合物；通式(IIc)化合物在氢氧化钠溶液条件下水解，得到通式(II)化合物； The compound of general formula (IIa) is subjected to a nucleophilic substitution reaction with NHR 4 R 5 under basic conditions to obtain the compound of general formula (IIb); the compound of general formula (IIb) and the compound of general formula (Ic) are prepared in the presence of a palladium catalyst and a basic Suzuki reaction is carried out under the conditions, and the obtained compound is optionally further deprotected to obtain the compound of general formula (IIc); the compound of general formula (IIc) is hydrolyzed under the condition of sodium hydroxide solution to obtain the compound of general formula (II);
其中：in:
X 2选自卤素； X 2 is selected from halogen;
X 3选自离去基团，所述的离去基团选自卤素或-SO 2R t； X 3 is selected from a leaving group, and the leaving group is selected from halogen or -SO 2 R t ;
R t选自烷基； R t is selected from alkyl;
环A、X、m、R 1、R 2、R 4和R 5的定义如通式(II)中所述。 Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (II).
本发明提供了一种通式(II)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，所述方法包括：The present invention provides a preparation method of a compound of general formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021105100-appb-000033
Figure PCTCN2021105100-appb-000033
通式(IIa)化合物与通式(Ic)化合物，在钯催化剂和碱性条件下进行Suzuki反应，得到通式(IId)化合物；通式(IId)化合物与NHR 4R 5在碱性条件下进行亲核取代反应，得到通式(IIc)化合物；通式(IIc)化合物在氢氧化钠溶液条件下水解，得到通式(II)化合物； The compound of general formula (IIa) and the compound of general formula (Ic) are subjected to Suzuki reaction under palladium catalyst and basic conditions to obtain the compound of general formula (IId); the compound of general formula (IId) and NHR 4 R 5 are carried out under basic conditions Carry out nucleophilic substitution reaction to obtain the compound of general formula (IIc); the compound of general formula (IIc) is hydrolyzed under the condition of sodium hydroxide solution to obtain the compound of general formula (II);
其中：in:
X 2选自卤素； X 2 is selected from halogen;
X 3选自离去基团，所述的离去基团选自卤素或-SO 2R t； X 3 is selected from a leaving group, and the leaving group is selected from halogen or -SO 2 R t ;
R t选自烷基； R t is selected from alkyl;
环A、X、m、R 1、R 2、R 4和R 5的定义如通式(II)中所述。 Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (II).
本发明提供了一种通式(III)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，所述方法包括：The present invention provides a preparation method of a compound of general formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021105100-appb-000034
Figure PCTCN2021105100-appb-000034
通式(IIc)化合物在浓盐酸条件下，加热水解，得到通式(III)化合物；Under the condition of concentrated hydrochloric acid, the compound of general formula (IIc) is heated and hydrolyzed to obtain the compound of general formula (III);
其中：环A、X、m、R 1、R 2、R 4和R 5的定义如通式(III)中所述。 wherein: ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (III).
本发明提供了一种通式(IV)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，所述方法包括：The present invention provides a preparation method of a compound of general formula (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021105100-appb-000035
Figure PCTCN2021105100-appb-000035
通式(IIc)化合物在氯化锌和叠氮化钠存在下反应，得到的化合物任选进一步脱去保护基，得到通式(IV)化合物；The compound of general formula (IIc) is reacted in the presence of zinc chloride and sodium azide, and the obtained compound is optionally further deprotected to obtain the compound of general formula (IV);
其中：环A、X、m、R 1、R 2、R 4和R 5的定义如通式(IV)中所述。 wherein: ring A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in general formula (IV).
具体实施方式detailed description
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.
实施例Example
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。 1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。 The examples give the preparation and related structural identification data of the representative compounds represented by formula (I). It must be noted that the following examples are used to illustrate the present invention rather than limit it. The 1 H NMR spectrum was measured with a Bruker instrument (400 MHz), and the chemical shifts were expressed in ppm. A tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. When coupling constants are provided, they are in Hz.
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。Mass spectrum is obtained by LC/MS instrument, and the ionization mode can be ESI or APCI.
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
在下列实施例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于Aldrich Chemical Company，ABCR GmbH&Co.KG，Acros Organics，广赞化工科技有限公司和景颜化工科技有限公司等处购买。In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius, and unless otherwise indicated, various starting materials and reagents were obtained from commercially available or synthesized according to known methods without further Purified and used directly, unless otherwise specified, commercially available manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd. and other places to buy.
CD 3OD：氘代甲醇。 CD 3 OD: deuterated methanol.
CDCl 3：氘代氯仿。 CDCl 3 : deuterated chloroform.
DMSO-d 6：氘代二甲基亚砜。 DMSO-d 6 : deuterated dimethyl sulfoxide.
氩气氛是指反应瓶连接一个约1L容积的氩气气球。Argon atmosphere means that the reaction flask is connected to an argon balloon with a volume of about 1 L.
实施例中无特殊说明，反应中的溶液是指水溶液。There is no special description in the examples, and the solution in the reaction refers to an aqueous solution.
对化合物进行纯化，采用硅胶柱层析洗脱剂体系和薄层色谱法，其中洗脱剂体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：二氯甲烷和乙酸乙酯；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。The compound is purified by silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane Methyl chloride and ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagents, such as acetic acid or triethylamine, can also be added for adjustment.
实施例1Example 1
1-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-胺1-(5-(2,3-Dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-amine
Figure PCTCN2021105100-appb-000036
Figure PCTCN2021105100-appb-000036
Figure PCTCN2021105100-appb-000037
Figure PCTCN2021105100-appb-000037
第一步first step
5-溴-2-氯-4-甲氧基-6-甲基嘧啶5-Bromo-2-chloro-4-methoxy-6-methylpyrimidine
将5-溴-2,4-二氯-6-甲基嘧啶1a(480mg,2mmol)加到5mL的甲醇中，冰浴下缓慢滴加溶解有甲醇钠(102.6mg,1.9mmol)的5mL甲醇溶液，室温反应3小时。反应结束后，减压浓缩，加入10mL水，以二氯甲烷萃取(10mL×2)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到5-溴-2-氯-4-甲氧基-6-甲基嘧啶1b(448.4mg)，该产物未经纯化，直接进行下一步反应。5-Bromo-2,4-dichloro-6-methylpyrimidine 1a (480 mg, 2 mmol) was added to 5 mL of methanol, and 5 mL of methanol dissolved with sodium methoxide (102.6 mg, 1.9 mmol) was slowly added dropwise under ice bath. The solution was reacted at room temperature for 3 hours. After the reaction, concentrated under reduced pressure, added 10 mL of water, extracted with dichloromethane (10 mL×2), combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-bromo-2 -Chloro-4-methoxy-6-methylpyrimidine 1b (448.4 mg), the product was not purified and was directly used in the next step.
MS m/z(ESI):236.8[M+1]MS m/z(ESI): 236.8[M+1]
第二步second step
(1-(5-溴-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(5-Bromo-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
氩气保护下，将上述产物5-溴-2-氯-4-甲氧基-6-甲基嘧啶1b(448.4mg,1.9mmol)、(4-甲基哌啶-4-基)氨基甲酸叔丁酯1c(470mg,2.2mmol)和0.5mL的N,N-二异丙基乙胺加到5mL的二甲基亚砜，加热至130℃，反应1小时。反应结束后，冷却至室温，加入30mL水，以乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(5-溴-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯1d(210mg)，产率：26.7％。Under argon protection, the above product 5-bromo-2-chloro-4-methoxy-6-methylpyrimidine 1b (448.4 mg, 1.9 mmol), (4-methylpiperidin-4-yl)carbamic acid Tert-butyl ester 1c (470 mg, 2.2 mmol) and 0.5 mL of N,N-diisopropylethylamine were added to 5 mL of dimethyl sulfoxide, heated to 130° C., and reacted for 1 hour. After the reaction was completed, it was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was filtered through silica gel Further analytical purification by column chromatography (eluent: System A) gave (1-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidine-4- base) tert-butyl carbamate 1d (210 mg), yield: 26.7%.
MS m/z(ESI):415.0[M+1]MS m/z(ESI): 415.0[M+1]
第三步third step
(1-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(5-(2,3-Dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
氩气保护下，将(1-(5-溴-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯1d(140mg,0.338mmol)、(2,3-二氯苯基)硼酸1e(128mg,0.676mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(24mg,0.0338mmol)、四(三苯基膦)钯(39mg,0.0338mmol)、碳酸钠(143mg,1.35mmol)和0.5mL水加到3mL的N,N-二甲基甲酰胺中，加热至110℃，反应4小时。反应结束，冷却至室温，加入20mL水，以乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步 分析纯化(洗脱剂：A体系)，得到(1-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯1f(110mg)，产率：68.7％。Under argon, (1-(5-bromo-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 1d (140 mg , 0.338mmol), (2,3-dichlorophenyl)boronic acid 1e (128mg, 0.676mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (24mg, 0.0338 mmol), tetrakis(triphenylphosphine)palladium (39mg, 0.0338mmol), sodium carbonate (143mg, 1.35mmol) and 0.5mL of water were added to 3mL of N,N-dimethylformamide, heated to 110°C, The reaction was carried out for 4 hours. After the reaction was completed, cooled to room temperature, added 20 mL of water, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was passed through a silica gel column Further analysis and purification by chromatography (eluent: system A) gave (1-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4 -Methylpiperidin-4-yl)carbamate tert-butyl ester 1f (110 mg), yield: 68.7%.
MS m/z(ESI):480.9[M+1]MS m/z(ESI): 480.9[M+1]
第四步the fourth step
1-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-胺1-(5-(2,3-Dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-amine
将(1-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯1f(110mg,0.229mmol)和1mL的三氟乙酸加到4mL二氯甲烷中，室温反应2小时，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到1-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-胺1(60mg)，产率：69％。 (1-(5-(2,3-Dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl Ester 1f (110 mg, 0.229 mmol) and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane, reacted at room temperature for 2 hours, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID ; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 1-(5-(2,3-dichlorophenyl)-4-methoxyl -6-Methylpyrimidin-2-yl)-4-methylpiperidin-4-amine 1 (60 mg), yield: 69%.
MS m/z(ESI):380.9[M+1]MS m/z(ESI): 380.9[M+1]
1H NMR(400MHz,CD 3OD)δ7.61(d,J＝8.0Hz,1H),7.39(s,1H),7.21-7.27(m,1H),4.43(s,2H),3.95(s,3H),3.56-3.70(m,2H),2.17(s,3H),1.96(t,J＝5.8Hz,4H),1.54(s,3H). 1 H NMR (400MHz, CD 3 OD) δ 7.61(d, J=8.0Hz, 1H), 7.39(s, 1H), 7.21-7.27(m, 1H), 4.43(s, 2H), 3.95(s ,3H),3.56-3.70(m,2H),2.17(s,3H),1.96(t,J=5.8Hz,4H),1.54(s,3H).
实施例2Example 2
2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲氧嘧啶-4-胺2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-4-amine
Figure PCTCN2021105100-appb-000038
Figure PCTCN2021105100-appb-000038
第一步first step
5-溴-2-氯-6-甲氧基嘧啶-4-胺5-Bromo-2-chloro-6-methoxypyrimidin-4-amine
将5-溴-2,4-二氯嘧啶-4-胺2a(971.56mg,4mmol)和甲醇钠(216mg,4mmol)加到10mL的甲醇中，每隔3小时补加1当量的甲醇钠，室温反应12小时。反应结束后，减压浓缩，加入20mL水，以二氯甲烷萃取(10mL×2)，合并有机相，饱和氯化钠溶液洗涤，无水 硫酸钠干燥，减压浓缩，得到5-溴-2-氯-6-甲氧基嘧啶-4-胺2b(800mg)，该产物未经纯化，直接进行下一步反应。5-Bromo-2,4-dichloropyrimidine-4-amine 2a (971.56 mg, 4 mmol) and sodium methoxide (216 mg, 4 mmol) were added to 10 mL of methanol, and 1 equivalent of sodium methoxide was added every 3 hours, The reaction was carried out at room temperature for 12 hours. After the reaction, concentrated under reduced pressure, added 20 mL of water, extracted with dichloromethane (10 mL×2), combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-bromo-2 -Chloro-6-methoxypyrimidin-4-amine 2b (800 mg), the product was not purified and was directly used in the next step.
MS m/z(ESI):237.8[M+1]MS m/z(ESI): 237.8[M+1]
第二步second step
(1-(4-氨基-5-溴-6-甲氧基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(4-Amino-5-bromo-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
将5-溴-2-氯-6-甲氧基嘧啶-4-胺2b(473.86mg,2mmol)、(4-甲基哌啶-4-基)氨基甲酸叔丁酯1c(642mg,3mmol)和1mL的N,N-二异丙基乙胺加到5mL的N-甲基吡咯烷酮，加热至90℃，反应2小时。反应结束后，冷却至室温，加入20mL水，以乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(4-氨基-5-溴-6-甲氧基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯2c(360mg)，产率：43.4％。5-Bromo-2-chloro-6-methoxypyrimidin-4-amine 2b (473.86 mg, 2 mmol), tert-butyl (4-methylpiperidin-4-yl)carbamate 1c (642 mg, 3 mmol) And 1 mL of N,N-diisopropylethylamine was added to 5 mL of N-methylpyrrolidone, heated to 90°C, and reacted for 2 hours. After the reaction was completed, it was cooled to room temperature, 20 mL of water was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was filtered through silica gel Further analytical purification by column chromatography (eluent: system A) gave (1-(4-amino-5-bromo-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl ) tert-butyl carbamate 2c (360 mg), yield: 43.4%.
MS m/z(ESI):415.8[M+1]MS m/z(ESI): 415.8[M+1]
第三步third step
(1-(4-氨基-5-(2,3-二氯苯基)-6-甲氧基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(4-Amino-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
氩气保护下，将(1-(4-氨基-5-溴-6-甲氧基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯2c(100mg,0.24mmol)、(2,3-二氯苯基)硼酸1e(91.56mg,0.48mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(35mg,0.048mmol)、四(三苯基膦)钯(55mg,0.048mmol)、碳酸钠(102mg,0.96mmol)和0.5mL水加到3mL的N,N-二甲基甲酰胺中，加热至100℃，反应过夜。反应结束，冷却至室温，加入20mL水，以乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(4-氨基-5-(2,3-二氯苯基)-6-甲氧基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯2d(40mg)，产率：34.8％。Under argon, (1-(4-amino-5-bromo-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 2c (100 mg, 0.24 mmol), (2,3-dichlorophenyl)boronic acid 1e (91.56 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (35 mg, 0.048 mmol), tetrakis(triphenylphosphine)palladium (55mg, 0.048mmol), sodium carbonate (102mg, 0.96mmol) and 0.5mL of water were added to 3mL of N,N-dimethylformamide, heated to 100°C, React overnight. After the reaction was completed, cooled to room temperature, added 20 mL of water, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was passed through a silica gel column Further analysis and purification by chromatography (eluent: system A) gave (1-(4-amino-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-2-yl)-4- tert-Butyl methylpiperidin-4-yl)carbamate 2d (40 mg), yield: 34.8%.
MS m/z(ESI):481.9[M+1]MS m/z(ESI): 481.9[M+1]
第四步the fourth step
2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲氧嘧啶-4-胺2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-4-amine
将(1-(4-氨基-5-(2,3-二氯苯基)-6-甲氧基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯2d(40mg,0.083mmol)和0.5mL的三氟乙酸加到2mL二氯甲烷中，室温反应2小时，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲氧嘧啶-4-胺2(30mg)，产率：94％。 (1-(4-Amino-5-(2,3-dichlorophenyl)-6-methoxypyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 2d (40 mg, 0.083 mmol) and 0.5 mL of trifluoroacetic acid were added to 2 mL of dichloromethane, reacted at room temperature for 2 hours, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID ; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2-(4-amino-4-methylpiperidin-1-yl)-5- (2,3-Dichlorophenyl)-6-methoxypyrimidin-4-amine 2 (30 mg), yield: 94%.
MS m/z(ESI):381.9[M+1]MS m/z(ESI): 381.9[M+1]
1H NMR(400MHz,CDCl 3)δ7.43-7.48(m,1H),7.17-7.25(m,2H),4.35(s,2H),4.23(d,J＝14.0Hz,2H),3.80(s,3H),3.60(d,J＝11.2Hz,2H),1.73-1.94(m,4H),1.48(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ 7.43-7.48 (m, 1H), 7.17-7.25 (m, 2H), 4.35 (s, 2H), 4.23 (d, J=14.0Hz, 2H), 3.80 ( s, 3H), 3.60(d, J=11.2Hz, 2H), 1.73-1.94(m, 4H), 1.48(s, 3H).
实施例3Example 3
2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid
Figure PCTCN2021105100-appb-000039
Figure PCTCN2021105100-appb-000039
第一步first step
(1-(4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(4-Cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
将2-氯-6-甲基-嘧啶-4-腈3a(400mg,2.60mmol)、(4-甲基哌啶-4-基)氨基甲酸叔丁酯1c(558.20mg,2.60mmol)和N,N-二异丙基乙胺(336.63mg,2.60mmol)，依次加入到20mL的N,N-二甲基乙酰胺中，加热至90℃，反应3小时。反应结束后冷却至室温，反应液以乙酸乙酯(30mL×2)萃取，合并的有机相依次以饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3b(840mg)，产率97.31％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (400 mg, 2.60 mmol), tert-butyl (4-methylpiperidin-4-yl)carbamate 1c (558.20 mg, 2.60 mmol) and N , N-diisopropylethylamine (336.63 mg, 2.60 mmol) was sequentially added to 20 mL of N,N-dimethylacetamide, heated to 90° C., and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained The residue was further purified by silica gel column chromatography (eluent: system A) to give (1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl ) tert-butyl carbamate 3b (840 mg), 97.31% yield.
MS m/z(ESI):332.2[M+1]MS m/z(ESI): 332.2[M+1]
第二步second step
(1-(5-溴-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
将(1-(4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3b(840mg,2.53mmol)加入到10mL的N,N-二甲基甲酰胺中，0℃条件下加入溴代丁二酰亚胺(600.41mg,3.37mmol)，室温反应过夜。反应液以乙酸乙酯(30ml×2)萃取，合并的有机相依次以饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(5-溴-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3c(800mg)，产率75.14％。(1-(4-Cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 3b (840 mg, 2.53 mmol) was added to 10 mL of N, In N-dimethylformamide, bromosuccinimide (600.41 mg, 3.37 mmol) was added at 0°C, and the reaction was carried out at room temperature overnight. The reaction solution was extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was passed through a silica gel column Further analysis and purification by chromatography (eluent: system A) gave (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl) tert-Butyl carbamate 3c (800 mg), 75.14% yield.
MS m/z(ESI):355.9[M-56]MS m/z(ESI): 355.9[M-56]
第三步third step
(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
氩气保护下，将(1-(5-溴-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3c(800mg,1.95mmol)、(2,3-二氯苯基)硼酸1e(744.10mg,3.90mmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(163.25mg,0.195mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(181.97mg,0.390mmol)和磷酸钾(1.24g,5.85mmol)加到12mL的混合溶液中(1,4-二氧六环:水＝6:1)，加热至130℃，反应5小时。反应结束后冷却至室温，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3d(900mg)，产率：96.89％。Under argon, tert-butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3c (800 mg, 1.95mmol), (2,3-dichlorophenyl)boronic acid 1e (744.10mg, 3.90mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1, 1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (163.25mg, 0.195mmol), 2-dicyclohexylphosphorus-2',6'-diisopropoxy Base-1,1'-biphenyl (181.97mg, 0.390mmol) and potassium phosphate (1.24g, 5.85mmol) were added to 12mL of the mixed solution (1,4-dioxane:water=6:1), It was heated to 130°C and reacted for 5 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(5-(2,3-dichlorophenyl)- 4-Cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 3d (900 mg), yield: 96.89%.
MS m/z(ESI):476.1[M+1]MS m/z(ESI): 476.1[M+1]
第四步the fourth step
2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid
将(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3d(380mg,0.800mmol)加到10mL的浓盐酸中，加热至110℃，反应1.5小时。反应结束后冷却至室温，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸3(300mg)，产率：95.15％。 tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d (380 mg, 0.800 mmol) was added to 10 mL of concentrated hydrochloric acid, heated to 110° C., and reacted for 1.5 hours. After the reaction, it was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase A: 0.05% TFA+H 2 O, mobile phase phase B: CH 3 CN), to give 2- (4-amino-4-methyl-piperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methyl-pyrimidine-4-carboxylic acid 3 (300 mg), yield: 95.15%.
MS m/z(ESI):394.1[M+1]MS m/z(ESI): 394.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.62(dd,J＝8.1,1.4Hz,1H),7.39(t,J＝7.9Hz,1H),7.19(dd,J＝7.6,1.4Hz,1H),7.06(s,1H),4.10(dd,J＝13.6,3.7Hz,2H),3.25-3.37(m,2H),2.05(s,3H),1.74(d,J＝4.2Hz,4H),1.40(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.62 (dd, J=8.1, 1.4 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.19 (dd, J=7.6, 1.4 Hz, 1H), 7.06(s, 1H), 4.10(dd, J=13.6, 3.7Hz, 2H), 3.25-3.37(m, 2H), 2.05(s, 3H), 1.74(d, J=4.2Hz, 4H) ),1.40(s,3H).
实施例4Example 4
2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000040
Figure PCTCN2021105100-appb-000040
第一步first step
2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile
将(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3d(170mg,0.36mmol)和1.65mL的三氟乙酸加到6mL的二氯甲烷中，室温反应40分钟，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈4a(65.77mg)，产率：49％。 tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d (170 mg, 0.36 mmol) and 1.65 mL of trifluoroacetic acid were added to 6 mL of dichloromethane, reacted at room temperature for 40 minutes, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA + H 2 O, Mobile phase B: CH 3 CN), to give 2- (4-amino-4-methyl-piperidin-1-yl) -5 -(2,3-Dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 4a (65.77 mg), yield: 49%.
MS m/z(ESI):376.1[M+1]MS m/z(ESI): 376.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.07(s,2H),7.82(dd,J＝7.7,1.9Hz,1H),7.48-7.64(m,2H),4.27(s,2H),3.50(t,J＝9.4Hz,2H),2.09-2.24(m,3H),1.63-1.86(m,4H),1.40(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.07(s, 2H), 7.82(dd, J=7.7, 1.9Hz, 1H), 7.48-7.64(m, 2H), 4.27(s, 2H), 3.50(t, J＝9.4Hz, 2H), 2.09-2.24(m, 3H), 1.63-1.86(m, 4H), 1.40(s, 3H).
第二步second step
2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
将2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈4a(20mg,0.267mmol)和0.1mL的6M氢氧化钠溶液加到1.5mL的乙醇中，加热至80℃，反应40分钟。反应结束后冷却至室温，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺4(16.25mg)，产率：49％。 2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 4a (20 mg, 0.267 mmol) and 0.1 mL of 6M sodium hydroxide solution was added to 1.5 mL of ethanol, heated to 80°C, and reacted for 40 minutes. After the reaction, it was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase A: 0.05% TFA+H 2 O, mobile phase phase B: CH 3 CN), to give the product 2- (4-amino-4-methyl-piperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methyl-4 Formamide 4 (16.25 mg), yield: 49%.
MS m/z(ESI):394.1[M+1]MS m/z(ESI): 394.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.01(d,J＝9.7Hz,3H),7.61(dd,J＝8.1,1.3Hz,1H),7.45(s,1H),7.37(t,J＝7.9Hz,1H),7.16-7.24(m,1H),4.41(d,J＝13.3Hz,2H),3.46(dd,J＝14.0,5.8Hz,2H),2.04(s,3H),1.75(s,4H),1.41(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.01 (d, J=9.7 Hz, 3H), 7.61 (dd, J=8.1, 1.3 Hz, 1H), 7.45 (s, 1H), 7.37 (t, J=7.9Hz, 1H), 7.16-7.24(m, 1H), 4.41(d, J=13.3Hz, 2H), 3.46(dd, J=14.0, 5.8Hz, 2H), 2.04(s, 3H), 1.75(s, 4H), 1.41(s, 3H).
实施例5Example 5
6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟酸6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinic acid
Figure PCTCN2021105100-appb-000041
Figure PCTCN2021105100-appb-000041
Figure PCTCN2021105100-appb-000042
Figure PCTCN2021105100-appb-000042
第一步first step
(1-(4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯tert-Butyl (1-(4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate
将2-氯-6-甲基异烟碱腈5a(230mg,1.51mmol,根据专利WO 2009016498自制)、(4-甲基哌啶-4-基)氨基甲酸叔丁酯1c(389mg,1.82mmol)和N,N-二异丙基乙胺(391mg,3.03mmol)加到6mL的N-甲基吡咯烷酮中，加热至90℃，反应5小时，反应结束后，加入30mL水，以乙酸乙酯萃取(30mL×3)，合并有机相，以饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯5b(245mg)，产率：49％。2-Chloro-6-methylisonicotinonitrile 5a (230mg, 1.51mmol, self-made according to patent WO 2009016498), (4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 1c (389mg, 1.82mmol ) and N,N-diisopropylethylamine (391 mg, 3.03 mmol) were added to 6 mL of N-methylpyrrolidone, heated to 90°C, and reacted for 5 hours. After the reaction, 30 mL of water was added, and ethyl acetate was added. Extraction (30 mL×3), combined organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system), This gave (1-(4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 5b (245 mg), yield: 49%.
MS m/z(ESI):331.2[M+1]MS m/z(ESI): 331.2[M+1]
第二步second step
(1-(5-溴-4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(5-Bromo-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
将(1-(4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯5b(70mg,0.212mmol)和溴代丁二酰亚胺(42mg,0.233mmol)加到1.5mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束后，以乙酸乙酯(30ml×2)萃取，合并有机相，以饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(5-溴-4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯5c(64mg)，产率：73％。(1-(4-Cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 5b (70 mg, 0.212 mmol) and bromosuccinyl The imine (42 mg, 0.233 mmol) was added to 1.5 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction, extracted with ethyl acetate (30 mL×2), combined the organic phases, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was passed through a silica gel column layer Further analysis and purification (eluent: A system) gave (1-(5-bromo-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)amino tert-Butyl formate 5c (64 mg), yield: 73%.
MS m/z(ESI):409.1[M+1]MS m/z(ESI): 409.1[M+1]
第三步third step
(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
氩气保护下，将(1-(5-溴-4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯5c(150mg,0.368mmol)、(2,3-二氯苯基)硼酸1e(140mg,0.735mmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(31mg,0.039mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(34mg,0.074mmol)和磷酸钾(234mg,1.104mmol)加到3.5mL的混合溶液中(1,4-二氧六环:水＝6:1)，加热至130℃，反应5小时。反应结束后冷却至室温，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯5d(170mg)，产率：98％。Under argon, tert-butyl (1-(5-bromo-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate 5c (150 mg, 0.368 mmol), (2,3-dichlorophenyl)boronic acid 1e (140 mg, 0.735 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1 '-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (31 mg, 0.039 mmol), 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl (34mg, 0.074mmol) and potassium phosphate (234mg, 1.104mmol) were added to 3.5mL of the mixed solution (1,4-dioxane:water=6:1), heated to 130 ℃, the reaction was carried out for 5 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (1-(5-(2,3-dichlorophenyl)- 4-Cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester 5d (170 mg), yield: 98%.
MS m/z(ESI):475.0[M+1]MS m/z(ESI): 475.0[M+1]
第四步the fourth step
6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟碱腈6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile
将(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基吡啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯5d(170mg,0.359mmol)和1.5mL的三氟乙酸加到6mL的二氯甲烷中，室温反应40分钟，反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟碱腈5e(69.91mg)，产率：52％。 (1-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyridin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 5d (170 mg, 0.359 mmol) and 1.5 mL of trifluoroacetic acid were added to 6 mL of dichloromethane, and the reaction was carried out at room temperature for 40 minutes. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA + H 2 O, Mobile phase B: CH 3 CN), to give 6- (4-amino-4-methyl-piperidine-1 yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 5e (69.91 mg), yield: 52%.
MS m/z(ESI):375.0[M+1]MS m/z(ESI): 375.0[M+1]
第五步the fifth step
6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟酸6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinic acid
将6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟碱腈5e(30mg,0.08mmol)加到0.5mL的浓盐酸中，加热至110℃，反应4小时。反应结束后冷却至室温，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟酸5(12.08mg)，产率：39％。 6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 5e (30 mg, 0.08 mmol) was added to 0.5 mL of concentrated hydrochloric acid, heated to 110°C, and reacted for 4 hours. After the reaction, it was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase A: 0.05% TFA+H 2 O, mobile phase phase B: CH 3 CN), to give 6- (4-amino-4-methyl-piperidin-1-yl) -3- (2,3-dichlorophenyl) -2-methyl-isonicotinic acid 5 ( 12.08 mg), yield: 39%.
MS m/z(ESI):394.1[M+1]MS m/z(ESI): 394.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.01(s,3H),7.62(dd,J＝8.1,1.4Hz,1H),7.39(t,J＝7.9Hz,1H),7.19(dd,J＝7.6,1.4Hz,1H),7.06(s,1H),4.10(dd,J＝13.6,3.7Hz,2H),3.25-3.37(m,2H),2.05(s,3H),1.74(d,J＝4.2Hz,4H),1.40(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.01 (s, 3H), 7.62 (dd, J=8.1, 1.4 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.19 (dd, J=7.6, 1.4Hz, 1H), 7.06(s, 1H), 4.10(dd, J=13.6, 3.7Hz, 2H), 3.25-3.37(m, 2H), 2.05(s, 3H), 1.74(d , J=4.2Hz, 4H), 1.40(s, 3H).
实施例6Example 6
6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟酰胺6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinamide
Figure PCTCN2021105100-appb-000043
Figure PCTCN2021105100-appb-000043
第一步first step
6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟酰胺6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinamide
将6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟碱腈5e(37.33mg,0.1mmol)和0.1mL的6M氢氧化钠溶液加到2mL的乙醇中，加热至80℃，反应40分钟。反应结束后冷却至室温，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil； 250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-2-甲基异烟酰胺6(21.99mg)，产率：56％。 6-(4-Amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-2-methylisonicotinonitrile 5e (37.33 mg, 0.1 mmol) and 0.1 mL of 6M sodium hydroxide solution was added to 2 mL of ethanol, heated to 80°C, and reacted for 40 minutes. After the reaction, it was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase A: 0.05% TFA+H 2 O, mobile phase phase B: CH 3 CN), to give 6- (4-amino-4-methyl-piperidin-1-yl) -3- (2,3-dichlorophenyl) -2-methyl-isonicotinamide 6 ( 21.99 mg), yield: 56%.
MS m/z(ESI):393.1[M+1]MS m/z(ESI): 393.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.98(s,2H),7.70(s,1H),7.60(dd,J＝8.0,1.4Hz,1H),7.36(t,J＝7.9Hz,1H),7.30(s,1H),7.20(dd,J＝7.6,1.5Hz,1H),6.81(s,1H),4.11(d,J＝13.9Hz,2H),3.29(d,J＝5.1Hz,2H),2.03(s,3H),1.74(s,4H),1.40(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ7.98(s, 2H), 7.70(s, 1H), 7.60(dd, J=8.0, 1.4Hz, 1H), 7.36(t, J=7.9Hz, 1H), 7.30(s, 1H), 7.20(dd, J=7.6, 1.5Hz, 1H), 6.81(s, 1H), 4.11(d, J=13.9Hz, 2H), 3.29(d, J=5.1 Hz, 2H), 2.03(s, 3H), 1.74(s, 4H), 1.40(s, 3H).
实施例7Example 7
1-(5-(2,3-二氯苯基)-4-甲基-6-(2H-四唑-5-基)嘧啶-2-基)-4-甲基哌啶-4-胺1-(5-(2,3-Dichlorophenyl)-4-methyl-6-(2H-tetrazol-5-yl)pyrimidin-2-yl)-4-methylpiperidin-4-amine
Figure PCTCN2021105100-appb-000044
Figure PCTCN2021105100-appb-000044
第一步first step
(1-(5-(2,3-二氯苯基)-4-甲基-6-(2H-四唑-5-基)嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(5-(2,3-Dichlorophenyl)-4-methyl-6-(2H-tetrazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4- base) tert-butyl carbamate
将(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3d(50mg,0.105mmol)、氯化锌(14.30mg,0.105mmol)和叠氮化钠(6.82mg,0.105mmol)依次加到2mL甲醇中，室温反应2天。反应结束后，向反应液中缓慢滴加2mL的1M稀盐酸淬灭反应，反应液以乙酸乙酯(30mL×2)萃取，合并的有机相，以饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到(1-(5-(2,3-二氯苯基)-4-甲基-6-(2H-四唑-5-基)嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯7a(15mg)，产率：27.51％。 tert-butyl (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3d (50 mg, 0.105 mmol), zinc chloride (14.30 mg, 0.105 mmol) and sodium azide (6.82 mg, 0.105 mmol) were successively added to 2 mL of methanol and reacted at room temperature for 2 days. After the reaction, 2 mL of 1M dilute hydrochloric acid was slowly added dropwise to the reaction solution to quench the reaction, the reaction solution was extracted with ethyl acetate (30 mL×2), and the combined organic phases were washed with saturated sodium chloride solution (30 mL×2) , dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase A: 0.05% TFA+H 2 O, mobile phase phase B: CH 3 CN), to give (1- (5- (2,3-dichlorophenyl) -4-methyl -6- (2H- tetrazol-5-yl) pyrimidin-2-yl) - 4-Methylpiperidin-4-yl)carbamate tert-butyl ester 7a (15 mg), yield: 27.51%.
MS m/z(ESI):519.6[M+1]MS m/z(ESI): 519.6[M+1]
第二步second step
1-(5-(2,3-二氯苯基)-4-甲基-6-(2H-四唑-5-基)嘧啶-2-基)-4-甲基哌啶-4-胺1-(5-(2,3-Dichlorophenyl)-4-methyl-6-(2H-tetrazol-5-yl)pyrimidin-2-yl)-4-methylpiperidin-4-amine
将(1-(5-(2,3-二氯苯基)-4-甲基-6-(2H-四唑-5-基)嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯7a(15mg,0.029mmol)和0.5mL的三氟乙酸加到2mL的二氯甲烷中，室温反应1小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)， 得到1-(5-(2,3-二氯苯基)-4-甲基-6-(2H-四唑-5-基)嘧啶-2-基)-4-甲基哌啶-4-胺7(5mg)，产率：40.4％。 (1-(5-(2,3-Dichlorophenyl)-4-methyl-6-(2H-tetrazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4 -yl) tert-butyl carbamate 7a (15 mg, 0.029 mmol) and 0.5 mL of trifluoroacetic acid were added to 2 mL of dichloromethane, and reacted at room temperature for 1 hour. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 1- (5- (2,3-dichlorophenyl) -4-methyl -6- (2H- tetrazol-5-yl) pyrimidin-2-yl) -4-methyl Piperidin-4-amine 7 (5 mg), yield: 40.4%.
MS m/z(ESI):419.0[M+1]MS m/z(ESI): 419.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.03(s,3H),7.70-7.73(dd,J＝8.0,4.0Hz,1H),7.43(t,J＝8.0Hz,1H),7.28-7.31(dd,J＝8.0,4.0Hz,1H),4.50(s,2H),3.50-3.60(m,2H),2.13(s,3H),1.78(t,J＝4.0Hz,4H),1.43(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.03 (s, 3H), 7.70-7.73 (dd, J=8.0, 4.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.28- 7.31(dd, J＝8.0, 4.0Hz, 1H), 4.50(s, 2H), 3.50-3.60(m, 2H), 2.13(s, 3H), 1.78(t, J＝4.0Hz, 4H), 1.43 (s,3H).
实施例8Example 8
(2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羰基)甘氨酸(2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonyl)glycine
Figure PCTCN2021105100-appb-000045
Figure PCTCN2021105100-appb-000045
第一步first step
2-(4-((叔丁氧基羰基)氨基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid
将2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸3(80mg,0.202mmol)、二碳酸二叔丁酯(88.34mg,0.405mmol)和碳酸钠(85.8mg,0.809mmol)加到2mL混合溶液中(1,4-二氧六环:水＝5:1)，室温反应16小时。反应液减压浓缩，加入1M的稀盐酸调节pH至2-3，,以乙酸乙酯(30mL×2)萃取，合并的有机相，依次以饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：B体系)，得到2-(4-((叔丁氧基羰基)氨基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸8a(40mg)，产率：39.9％。2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 3 (80 mg, 0.202 mmol), Di-tert-butyl dicarbonate (88.34 mg, 0.405 mmol) and sodium carbonate (85.8 mg, 0.809 mmol) were added to 2 mL of the mixed solution (1,4-dioxane:water=5:1), and reacted at room temperature for 16 hours . The reaction solution was concentrated under reduced pressure, and 1M diluted hydrochloric acid was added to adjust the pH to 2-3, extracted with ethyl acetate (30 mL×2), and the combined organic phases were washed with saturated sodium chloride solution (30 mL×2) in turn. It was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-((tert-butoxycarbonyl)amino)-4-methyl ylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 8a (40 mg), yield: 39.9%.
MS m/z(ESI):495.1[M+1]MS m/z(ESI): 495.1[M+1]
第二步second step
(2-(4-((叔丁氧基羰基)氨基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羰基)甘氨酸 叔丁酯(2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- Carbonyl)glycine tert-butyl ester
将2-(4-((叔丁氧基羰基)氨基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸8a(50mg,0.128mmol)、2-氨基乙酸叔丁酯(33.52mg,0.256mmol)、N,N-二异丙基乙胺(16.52mg,0.128mmol)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(133.00mg,0.256mmol)加到2mL的N,N-二甲基甲酰胺中，室温反应2小时。反应结束，反应液以乙酸乙酯(30mL×2)萃取，合并的有机相，以饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(2-(4-((叔丁氧基羰基)氨基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羰基)甘氨酸叔丁酯8b(40mg)，产率：62％。2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- Formic acid 8a (50 mg, 0.128 mmol), tert-butyl 2-aminoacetate (33.52 mg, 0.256 mmol), N,N-diisopropylethylamine (16.52 mg, 0.128 mmol), benzotriazole hexafluorophosphate- 1-yl-oxytripyrrolidinophosphorus (133.00 mg, 0.256 mmol) was added to 2 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. The reaction was completed, the reaction solution was extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was filtered through silica gel Further analysis and purification by column chromatography (eluent: System A) gave (2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2, 3-Dichlorophenyl)-6-methylpyrimidine-4-carbonyl)glycine tert-butyl ester 8b (40 mg), yield: 62%.
MS m/z(ESI):608.3[M+1]MS m/z(ESI): 608.3[M+1]
第三步third step
(2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羰基)甘氨酸(2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonyl)glycine
将(2-(4-((叔丁氧基羰基)氨基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羰基)甘氨酸叔丁酯8b(40mg,0.079mmol)加入到2mL的6M稀盐酸中，加热至90℃，反应3小时。反应结束后，冷却至室温，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到(2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羰基)甘氨酸8(5mg)，产率：13.84％。 (2-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4 -Carbonyl)glycine tert-butyl ester 8b (40 mg, 0.079 mmol) was added to 2 mL of 6M dilute hydrochloric acid, heated to 90°C, and reacted for 3 hours. After the reaction, it was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, Mobile phase B: CH 3 CN), to give (2- (4-amino-4-methyl-piperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methyl-4 -carbonyl)glycine 8 (5 mg), yield: 13.84%.
MS m/z(ESI):452.1[M+1]MS m/z(ESI): 452.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.54(d,J＝8.0Hz,1H),7.32(t,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),4.36(s,2H),3.42(s,4H),2.00(s,3H),1.69-1.74(m,4H),1.37(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.54 (d, J=8.0 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 4.36 (s, 2H), 3.42(s, 4H), 2.00(s, 3H), 1.69-1.74(m, 4H), 1.37(s, 3H).
实施例9Example 9
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl) -6-Methylpyrimidine-4-carboxylic acid
Figure PCTCN2021105100-appb-000046
Figure PCTCN2021105100-appb-000046
Figure PCTCN2021105100-appb-000047
Figure PCTCN2021105100-appb-000047
第一步first step
(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)丙烷-2-亚磺酰胺(R)-2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfinamide
将(3S,4S)-4-(((R)-叔丁基亚磺酰基)氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯9a(670mg,1.79mmol)和1.5mL的三氟乙酸加到6mL的二氯甲烷中，室温反应1.5小时。反应结束后，减压浓缩，得到(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)丙烷-2-亚磺酰胺9b(490mg)，产物不经纯化，直接进行下一步反应。(3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert Butyl ester 9a (670 mg, 1.79 mmol) and 1.5 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 1.5 hours. After the reaction, concentrated under reduced pressure to obtain (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl ) propane-2-sulfinamide 9b (490 mg), the product was carried to the next step without purification.
MS m/z(ESI):275.1[M+1]MS m/z(ESI): 275.1[M+1]
第二步second step
(R)-N-((3S,4S)-8-(4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Dec-4-yl)-2-methylpropane-2-sulfenamide
将(R)-2-甲基-N-((3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)丙烷-2-亚磺酰胺9b(490mg,1.26mmol)、N,N-二异丙基乙胺(135.86mg,1.05mmol)和2-氯-6-甲基-嘧啶-4-腈3a(161.43mg,1.05mmol)加到5mL的N,N-二甲基乙酰胺中，加热至110℃，反应3小时。反应结束，加入30mL水，以乙酸乙酯(30mL×3)萃取，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-N-((3S,4S)-8-(4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)-2-甲基丙烷-2-亚磺酰胺9c(411mg)，产率：99.86％。(R)-2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfinamide 9b (490 mg, 1.26 mmol), N,N-diisopropylethylamine (135.86 mg, 1.05 mmol) and 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (161.43 mg, 1.05 mmol) were added 5 mL of N,N-dimethylacetamide, heated to 110° C., and reacted for 3 hours. After the reaction was completed, 30 mL of water was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was further analyzed by silica gel column chromatography Purification (eluent: system A) gave (R)-N-((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2- Oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfinamide 9c (411 mg), yield: 99.86%.
MS m/z(ESI):392.2[M+1]MS m/z(ESI): 392.2[M+1]
第三步third step
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile
将(R)-N-((3S,4S)-8-(4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)-2-甲基丙烷-2-亚磺酰胺9c(371mg,0.948mmol)和溴代丁二酰亚胺(185.51mg,1.04mmol)加到5mL的N,N-二甲基甲酰胺中，室温反应2小时。反应结束后，减压浓缩，得到产物2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈9d(272.29mg)，产率：100％，产物不经纯化，直接进行下一步反应。(R)-N-((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 ]dec-4-yl)-2-methylpropane-2-sulfinamide 9c (371 mg, 0.948 mmol) and bromosuccinimide (185.51 mg, 1.04 mmol) were added to 5 mL of N,N-di In methylformamide, the reaction was carried out at room temperature for 2 hours. After the reaction, concentrated under reduced pressure to obtain the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6- Methylpyrimidine-4-carbonitrile 9d (272.29 mg), yield: 100%, the product was directly used in the next step without purification.
MS m/z(ESI):288.1[M+1]MS m/z(ESI): 288.1[M+1]
第四步the fourth step
((3S,4S)-8-(4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl) tert-butyl carbamate
将2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈9d(272.29mg,0.948mmol)、二碳酸二叔丁酯(827.20mg,3.79mmol)和三乙胺(287.65mg,2.84mmol) 加到10mL的二氯甲烷中，室温反应3小时。反应结束后，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((3S,4S)-8-(4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9e(340mg)，产率：92.6％。2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 9d( 272.29 mg, 0.948 mmol), di-tert-butyl dicarbonate (827.20 mg, 3.79 mmol) and triethylamine (287.65 mg, 2.84 mmol) were added to 10 mL of dichloromethane and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain ((3S,4S)-8-(4-cyano-6-methylpyrimidine) -2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate tert-butyl ester 9e (340 mg), yield: 92.6%.
MS m/z(ESI):388.2[M+1]MS m/z(ESI): 388.2[M+1]
第五步the fifth step
((3S,4S)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯((3S,4S)-8-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane- 4-yl) tert-butyl carbamate
将((3S,4S)-8-(4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9e(340mg,0.877mmol)和溴代丁二酰亚胺(171.79mg,0.965mmol)加入5mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束后，加入30mL水，以乙酸乙酯(30mL×3)萃取，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((3S,4S)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9f(390mg)，产率：95.3％。((3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl ) tert-butyl carbamate 9e (340 mg, 0.877 mmol) and bromosuccinimide (171.79 mg, 0.965 mmol) were added to 5 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction, 30 mL of water was added, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further subjected to silica gel column chromatography. Analytical purification (eluent: system A) gave ((3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxo Hetero-8-azaspiro[4.5]dec-4-yl)carbamate tert-butyl ester 9f (390 mg), yield: 95.3%.
MS m/z(ESI):466.1[M+1]MS m/z(ESI): 466.1[M+1]
第六步Step 6
((3S,4S)-8-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯((3S,4S)-8-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8 - tert-butyl azaspiro[4.5]dec-4-yl)carbamate
氩气保护下，将((3S,4S)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9f(390mg,0.836mmol)、(2,3-二氯苯基)硼酸1e(319.14mg,1.67mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(70.03mg,0.084mmol)、四(三苯基膦)钯(78.05mg,0.167mmol)和磷酸钾(532.78mg,2.51mmol)加到8mL的混合溶液中(1,4-二氧六环:水＝7:1)，加热至135℃，反应3.5小时。反应结束后冷却，加入30mL水，以乙酸乙酯(30mL×3)萃取，饱和氯化钠溶液洗涤，合并有机相，以无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((3S,4S)-8-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9g(380mg)，产率：85.34％。Under argon, the ((3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-aza Spiro[4.5]dec-4-yl)carbamate tert-butyl ester 9f (390 mg, 0.836 mmol), (2,3-dichlorophenyl)boronic acid 1e (319.14 mg, 1.67 mmol), [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (70.03 mg, 0.084 mmol), tetrakis(triphenylphosphine)palladium (78.05 mg, 0.167 mmol) and potassium phosphate (532.78 mg, 2.51 mmol) were added to 8 mL of the mixed solution (1,4-dioxane:water=7:1), heated to 135°C, and reacted for 3.5 hours. After the reaction was completed, it was cooled, added with 30 mL of water, extracted with ethyl acetate (30 mL×3), washed with saturated sodium chloride solution, combined with the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was passed through a silica gel column layer. Further analysis and purification (eluent: A system) gave ((3S,4S)-8-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidine-2- yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate tert-butyl ester 9 g (380 mg), yield: 85.34%.
MS m/z(ESI):532.2[M+1]MS m/z(ESI): 532.2[M+1]
第七步Step 7
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl) -6-Methylpyrimidine-4-carboxylic acid
将((3S,4S)-8-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9g(29mg,0.055mmol)和0.5mL的浓盐酸加到压力管中，加热至110℃，反应1.5小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酸9(1.83mg)，产率：5.91％。 ((3S,4S)-8-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa- 9 g (29 mg, 0.055 mmol) of tert-butyl 8-azaspiro[4.5]dec-4-yl)carbamate and 0.5 mL of concentrated hydrochloric acid were added to a pressure tube, heated to 110° C., and reacted for 1.5 hours. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2, 3-Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 9 (1.83 mg), yield: 5.91%.
MS m/z(ESI):451.1[M+1]MS m/z(ESI): 451.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ13.30(s,1H),7.94(s,2H),7.68(d,J＝8.1Hz,1H),7.42(t,J＝7.8Hz,1H),7.26(d,J＝7.6Hz,1H),4.40-4.60(m,2H),4.14-4.31(m,1H),3.93(d,J＝9.2Hz,1H),3.73(d,J＝9.1Hz,1H),3.42(s,1H),3.07-3.24(m,2H),2.07(s,3H),1.73(s,3H),1.59(d,J＝13.7Hz,1H),1.23(d,J＝6.5Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 13.30 (s, 1H), 7.94 (s, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H) ,7.26(d,J＝7.6Hz,1H),4.40-4.60(m,2H),4.14-4.31(m,1H),3.93(d,J＝9.2Hz,1H),3.73(d,J＝9.1 Hz, 1H), 3.42(s, 1H), 3.07-3.24(m, 2H), 2.07(s, 3H), 1.73(s, 3H), 1.59(d, J＝13.7Hz, 1H), 1.23(d ,J=6.5Hz,3H).
实施例10Example 10
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl) -6-Methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000048
Figure PCTCN2021105100-appb-000048
第一步first step
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl) -6-Methylpyrimidine-4-carbonitrile
将((3S,4S)-8-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9g(180mg,0.338mmol)和1.5mL的三氟乙酸加到6mL的二氯甲烷中，室温反应1小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈10a(77.68mg)，产率：41.5％。 ((3S,4S)-8-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa- 9 g (180 mg, 0.338 mmol) of tert-butyl 8-azaspiro[4.5]dec-4-yl)carbamate and 1.5 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2, 3-Dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 10a (77.68 mg), yield: 41.5%.
MS m/z(ESI):432.1[M+1]MS m/z(ESI): 432.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.97(s,2H),7.83(dd,J＝7.7,1.9Hz,1H),7.45-7.62(m,2H),4.42(s,2H),4.16-4.29(m,1H),3.92(d,J＝9.1Hz,1H),3.73(d,J＝9.0Hz,1H),3.44(s,1H),3.13-3.29(m,2H),2.15(s,3H),1.72(d,J＝24.2Hz,3H),1.61(d,J＝13.6Hz,1H),1.23(d,J＝6.6Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.97(s, 2H), 7.83(dd, J=7.7, 1.9Hz, 1H), 7.45-7.62(m, 2H), 4.42(s, 2H), 4.16-4.29(m, 1H), 3.92(d, J=9.1Hz, 1H), 3.73(d, J=9.0Hz, 1H), 3.44(s, 1H), 3.13-3.29(m, 2H), 2.15 (s, 3H), 1.72 (d, J=24.2Hz, 3H), 1.61 (d, J=13.6Hz, 1H), 1.23 (d, J=6.6Hz, 3H).
第二步second step
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl) -6-Methylpyrimidine-4-carboxamide
将2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶 -4-腈10a(30mg,0.069mmol)和0.3mL的氢氧化钠加到1.2mL的乙醇中，加热至80℃，反应50分钟。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺10(5.13mg)，产率：16.2％。 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl )-6-methylpyrimidine-4-carbonitrile 10a (30 mg, 0.069 mmol) and 0.3 mL of sodium hydroxide were added to 1.2 mL of ethanol, heated to 80° C., and reacted for 50 minutes. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2, 3-Dichlorophenyl)-6-methylpyrimidine-4-carboxamide 10 (5.13 mg), yield: 16.2%.
MS m/z(ESI):450.1[M+1]MS m/z(ESI): 450.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.96(s,1H),7.56-7.62(m,1H),7.39(s,1H),7.36(t,J＝7.8Hz,1H),7.22(d,J＝6.2Hz,1H),4.16(s,2H),4.05-4.11(m,1H),3.71(d,J＝8.4Hz,1H),3.54(t,J＝12.9Hz,3H),2.93(d,J＝5.0Hz,1H),2.01(s,3H),1.74(s,1H),1.64(s,1H),1.53(d,J＝18.7Hz,2H),1.31(s,2H),1.10(d,J＝6.4Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.96(s, 1H), 7.56-7.62(m, 1H), 7.39(s, 1H), 7.36(t, J=7.8Hz, 1H), 7.22( d, J＝6.2Hz, 1H), 4.16(s, 2H), 4.05-4.11(m, 1H), 3.71(d, J＝8.4Hz, 1H), 3.54(t, J＝12.9Hz, 3H), 2.93(d, J＝5.0Hz, 1H), 2.01(s, 3H), 1.74(s, 1H), 1.64(s, 1H), 1.53(d, J＝18.7Hz, 2H), 1.31(s, 2H) ),1.10(d,J=6.4Hz,3H).
实施例11Example 11
2-(4-(氨基甲基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000049
Figure PCTCN2021105100-appb-000049
第一步first step
((1-(4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯tert-Butyl ((1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate
将2-氯-6-甲基-嘧啶-4-腈3a(100mg,0.651mmol)、((4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯11a(178.42mg,0.781mmol)和N,N-二异丙基乙胺(252.47mg,1.95mmol)加到1.2mL的N,N-二甲基乙酰胺中，加热至90℃，反应4小时。反应结束，加入20mL水，乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液洗涤，合并有机相，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((1-(4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯11b(223mg)，产率：99.1％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (100 mg, 0.651 mmol), tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate 11a (178.42 mg, 0.781 mmol) and N,N-diisopropylethylamine (252.47 mg, 1.95 mmol) were added to 1.2 mL of N,N-dimethylacetamide, heated to 90° C., and reacted for 4 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (Eluent: System A) to give tert-butyl ((1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 11b (223 mg), yield: 99.1%.
MS m/z(ESI):346.2[M+1]MS m/z(ESI): 346.2[M+1]
第二步second step
((1-(5-溴-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯((1-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester
将((1-(4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯11b(223mg,0.646mmol)和溴代丁二酰亚胺(120.64mg,0.678mmol)加到4mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束，加入20mL水，乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液洗涤，合并有机相，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((1-(5-溴-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯11c(260mg)，产率：94.91％。((1-(4-Cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate tert-butyl ester 11b (223 mg, 0.646 mmol) and bromine Succinimide (120.64 mg, 0.678 mmol) was added to 4 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: system A) to give ((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)amino tert-Butyl formate 11c (260 mg), yield: 94.91%.
MS m/z(ESI):424.1[M+1]MS m/z(ESI): 424.1[M+1]
第三步third step
((1-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯((1-(4-Cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester
氩气保护下，将((1-(5-溴-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯11c(260mg,0.613mmol)、(2,3-二氯苯基)硼酸1e(233.84mg,1.23mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(51.31mg,0.061mmol)、四(三苯基膦)钯(57.18mg,0.123mmol)和磷酸钾(390.37mg,1.84mmol)加到3.5mL的混合溶液中(1,4-二氧六环:水＝6:1)，加热至130℃，反应3.5小时。反应结束，加入30mL水，乙酸乙酯(30mL×3)萃取，饱和氯化钠溶液洗涤，合并有机相，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((1-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯11d(280mg)，产率：93.18％。Under argon, tert-butyl ((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate 11c (260mg, 0.613mmol), (2,3-dichlorophenyl)boronic acid 1e (233.84mg, 1.23mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (51.31 mg, 0.061 mmol), tetrakis(triphenylphosphine)palladium (57.18 mg, 0.123 mmol) and potassium phosphate (390.37 mg, 1.84 mmol) were added to 3.5 mL of the mixed solution (1,4-dioxane) :water=6:1), heated to 130°C, and reacted for 3.5 hours. After the reaction was completed, 30 mL of water was added, extracted with ethyl acetate (30 mL×3), washed with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to give ((1-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-4-methylpiperidine -4-yl)methyl)carbamate tert-butyl ester 11d (280 mg), yield: 93.18%.
MS m/z(ESI):490.1[M+1]MS m/z(ESI): 490.1[M+1]
第四步the fourth step
2-(4-(氨基甲基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile
将((1-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)甲基)氨基甲酸叔丁酯11d(80mg,0.163mmol)和1mL的三氟乙酸加到4mL的二氯甲烷中，室温反应50分钟。反应结束后，减压浓缩，得到产物2-(4-(氨基甲基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈11e(63mg)，产物不经纯化，直接进行下一步反应。((1-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)amino Tert-butyl formate 11d (80 mg, 0.163 mmol) and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane, and the reaction was carried out at room temperature for 50 minutes. After the reaction, concentrated under reduced pressure to obtain the product 2-(4-(aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methyl Pyrimidine-4-carbonitrile 11e (63 mg), the product was carried to the next step without purification.
MS m/z(ESI):390.1[M+1]MS m/z(ESI): 390.1[M+1]
第五步the fifth step
2-(4-(氨基甲基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
将2-(4-(氨基甲基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈11e(63mg,0.161mmol)和0.5mL的氢氧化钠加到2mL的乙醇中，加热至80℃，反应2小时。减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-(4-(氨基甲基)-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺11(11.03mg)，产率：16.4％。 2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 11e (63 mg, 0.161 mmol) and 0.5 mL of sodium hydroxide were added to 2 mL of ethanol, heated to 80°C, and reacted for 2 hours. Concentrated under reduced pressure, the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) , the product 2-(4-(aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 11 (11.03 mg), yield: 16.4%.
MS m/z(ESI):408.1[M+1]MS m/z(ESI): 408.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.93(s,1H),7.58(dd,J＝8.1,1.5Hz,1H),7.38(s,1H),7.34(dd,J＝9.6,6.1Hz,1H),7.20(dd,J＝7.6,1.5Hz,1H),4.16(d,J＝13.3Hz,2H),3.44-3.52(m,2H),2.42(s,2H),2.00(s,3H),1.44(t,J＝9.5Hz,2H),1.29(d,J＝13.9Hz,2H),0.95(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.93 (s, 1H), 7.58 (dd, J=8.1, 1.5Hz, 1H), 7.38 (s, 1H), 7.34 (dd, J=9.6, 6.1 Hz, 1H), 7.20(dd, J＝7.6, 1.5Hz, 1H), 4.16(d, J＝13.3Hz, 2H), 3.44-3.52(m, 2H), 2.42(s, 2H), 2.00(s ,3H),1.44(t,J＝9.5Hz,2H),1.29(d,J＝13.9Hz,2H),0.95(s,3H).
实施例12Example 12
2-(4-氨基-4-甲基哌啶-1-基)-5-(2-氯-3-甲基苯基)-6-甲基嘧啶-4-甲酰胺2-(4-Amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000050
Figure PCTCN2021105100-appb-000050
第一步first step
(1-(5-(2-氯-3-甲基苯基)-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(1-(5-(2-Chloro-3-methylphenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester
氩气保护下，将(1-(5-溴-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯3c(80mg,0.195mmol)、(2-氯-3-甲基苯基)硼酸12a(66.45mg,0.390mmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(16.33mg,0.0195mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(18.20mg,0.039mmol)和磷酸钾(124.22mg,0.585mmol)加到1.5mL的混合溶液中(1,4-二氧六环:水＝4:1)，加热至130℃，反应5小时。反应结束，加入20mL水，乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液洗涤，合并有机相，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(5-(2-氯-3-甲基苯基)-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯12b(86mg)，产率：96.7％。Under argon, tert-butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate 3c (80 mg, 0.195 mmol), (2-chloro-3-methylphenyl)boronic acid 12a (66.45 mg, 0.390 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (16.33 mg, 0.0195 mmol), 2-dicyclohexylphosphorus-2',6'-diiso Propoxy-1,1'-biphenyl (18.20 mg, 0.039 mmol) and potassium phosphate (124.22 mg, 0.585 mmol) were added to 1.5 mL of the mixed solution (1,4-dioxane:water=4: 1), heated to 130°C, and reacted for 5 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was further analyzed and purified by silica gel column chromatography (eluent: system A) to give (1-(5-(2-chloro-3-methylphenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidine tert-Butyl pyridin-4-yl)carbamate 12b (86 mg), yield: 96.7%.
MS m/z(ESI):456.2[M+1]MS m/z(ESI): 456.2[M+1]
第二步second step
2-(4-氨基-4-甲基哌啶-1-基)-5-(2-氯-3-甲基苯基)-6-甲基嘧啶-4-腈2-(4-Amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carbonitrile
将(1-(5-(2-氯-3-甲基苯基)-4-氰基-6-甲基嘧啶-2-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯12b(86mg,0.189mmol)和1.5mL的三氟乙酸加到6mL的二氯甲烷中，室温反应40分钟。反应结束后，减压浓缩，得到产物2-(4-氨基-4-甲基哌啶-1-基)-5-(2-氯-3-甲基苯基)-6-甲基嘧啶-4-腈12c(67.12mg)，产物不经纯化，直接进行下一步反应。(1-(5-(2-Chloro-3-methylphenyl)-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tertiary Butyl ester 12b (86 mg, 0.189 mmol) and 1.5 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 40 minutes. After the reaction, concentrated under reduced pressure to obtain the product 2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine- 4-Nitrile 12c (67.12 mg), the product was carried to the next step without purification.
MS m/z(ESI):356.1[M+1]MS m/z(ESI): 356.1[M+1]
第三步third step
2-(4-氨基-4-甲基哌啶-1-基)-5-(2-氯-3-甲基苯基)-6-甲基嘧啶-4-甲酰胺2-(4-Amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carboxamide
将2-(4-氨基-4-甲基哌啶-1-基)-5-(2-氯-3-甲基苯基)-6-甲基嘧啶-4-腈12c(67.12mg,0.189mmol)和0.5mL的氢氧化钠加到2mL的乙醇中，加热至80℃，反应40分钟。减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-(4-氨基-4-甲基哌啶-1-基)-5-(2-氯-3-甲基苯基)-6-甲基嘧啶-4-甲酰胺12(43.69mg)，产率：61.6％。 2-(4-Amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carbonitrile 12c (67.12 mg, 0.189 mmol) and 0.5 mL of sodium hydroxide were added to 2 mL of ethanol, heated to 80° C., and reacted for 40 minutes. Concentrated under reduced pressure, the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) , the product 2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-3-methylphenyl)-6-methylpyrimidine-4-carboxamide 12 (43.69 mg), yield: 61.6%.
MS m/z(ESI):374.1[M+1]MS m/z(ESI): 374.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.83(s,1H),7.30(d,J＝7.6Hz,2H),7.22(t,J＝7.5Hz,1H),7.06(d,J＝6.5Hz,1H),3.90-4.14(m,2H),3.60-3.76(m,2H),2.37(s,3H),1.99(s,3H),1.45(dd,J＝14.8,10.6Hz,6H),1.11(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.83 (s, 1H), 7.30 (d, J=7.6 Hz, 2H), 7.22 (t, J=7.5 Hz, 1H), 7.06 (d, J= 6.5Hz, 1H), 3.90-4.14(m, 2H), 3.60-3.76(m, 2H), 2.37(s, 3H), 1.99(s, 3H), 1.45(dd, J=14.8, 10.6Hz, 6H ),1.11(s,3H).
实施例13Example 13
2-((R)-1-氨基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((R)-1-Amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000051
Figure PCTCN2021105100-appb-000051
第一步first step
(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基)丙烷-2-亚磺酰胺(R)-2-Methyl-N-((R)-8-azaspiro[4.5]dec-1-yl)propane-2-sulfinamide
将(R)-1-(((R)-叔丁基亚磺酰基)氨基)叔丁基-8-氮杂螺[4.5]癸-8-甲酸叔丁酯13a(200mg,0.558mmol)和三氟乙酸(636.03mg,5.58mmol)加到2mL的二氯甲烷中，室温反应1.5小时。 反应结束后，减压浓缩，得到(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基)丙烷-2-亚磺酰胺13b(144.15mg)，产率：100.00％，产物未经纯化，直接进行下一步反应。(R)-1-(((R)-tert-butylsulfinyl)amino)tert-butyl-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester 13a (200 mg, 0.558 mmol) and Trifluoroacetic acid (636.03 mg, 5.58 mmol) was added to 2 mL of dichloromethane and reacted at room temperature for 1.5 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain (R)-2-methyl-N-((R)-8-azaspiro[4.5]dec-1-yl)propane-2-sulfinamide 13b (144.15 mg ), yield: 100.00%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):259.2[M+1]MS m/z(ESI): 259.2[M+1]
第二步second step
(R)-2-甲基-N-((R)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)-丙烷-2-亚磺酰胺(R)-2-Methyl-N-((R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)- Propane-2-sulfinamide
将(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基)丙烷-2-亚磺酰胺13b(373.55mg,1.04mmol)、2-氯-6-甲基-嘧啶-4-腈3a(80mg,0.521mmol)和N,N-二异丙基乙胺(67.33mg,0.521mmol)依次加到2mL的N,N-二甲基乙酰胺中，加热至90℃，反应3小时。反应结束后，冷却至室温，以乙酸乙酯(30ml×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-2-甲基-N-((R)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)-丙烷-2-亚磺酰胺13c(100mg)，产率：51.12％。(R)-2-methyl-N-((R)-8-azaspiro[4.5]dec-1-yl)propane-2-sulfinamide 13b (373.55 mg, 1.04 mmol), 2-chloro -6-Methyl-pyrimidine-4-carbonitrile 3a (80 mg, 0.521 mmol) and N,N-diisopropylethylamine (67.33 mg, 0.521 mmol) were added sequentially to 2 mL of N,N-dimethylacetamide , heated to 90°C, and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analysis and purification by silica gel column chromatography (eluent: A system) gave (R)-2-methyl-N-((R)-8-(4-cyano-6-methylpyrimidin-2-yl) )-8-Azaspiro[4.5]dec-1-yl)-propane-2-sulfinamide 13c (100 mg), yield: 51.12%.
MS m/z(ESI):376.1[M+1]MS m/z(ESI): 376.1[M+1]
第三步third step
(R)-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈(R)-2-(1-Amino-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile
将(R)-2-甲基-N-((R)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)-丙烷-2-亚磺酰胺13c(100mg,0.266mmol)和溴代丁二酰亚胺(52.13mg,0.293mmol)加到3mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束，减压浓缩，得到(R)-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈13d(72mg)，产率：99.64％，产物未经纯化，直接进行下一步反应。(R)-2-methyl-N-((R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl) -Propane-2-sulfinamide 13c (100 mg, 0.266 mmol) and bromosuccinimide (52.13 mg, 0.293 mmol) were added to 3 mL of N,N-dimethylformamide and reacted at room temperature overnight. The reaction was completed and concentrated under reduced pressure to obtain (R)-2-(1-amino-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 13d (72 mg) in yield : 99.64%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):272.2[M+1]MS m/z(ESI): 272.2[M+1]
第四步the fourth step
(R)-(8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯(R)-(8-(4-Cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester
将(R)-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈13d(72mg,0.265mmol)、二碳酸二叔丁酯(115.82mg,0.531mmol)和三乙胺(53.70mg,0.531mmol)加到2mL的二氯甲烷中，室温反应过夜。反应结束后，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-(8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯13e(80mg)，产率：81.17％。(R)-2-(1-Amino-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 13d (72 mg, 0.265 mmol), di-tert-butyl dicarbonate (115.82 mg, 0.531 mmol) and triethylamine (53.70 mg, 0.531 mmol) were added to 2 mL of dichloromethane and reacted at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: A system) to obtain (R)-(8-(4-cyano-6-methylpyrimidine-2). -yl)-8-azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester 13e (80 mg), yield: 81.17%.
MS m/z(ESI):372.2[M+1]MS m/z(ESI): 372.2[M+1]
第五步the fifth step
(R)-(8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯(R)-(8-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester
将(R)-(8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯13e(72mg,0.194mmol)和溴代丁二酰亚胺(37.95mg,0.213mmol)加到2mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束后，反应液以乙酸乙酯(30mL×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-(8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁 酯13f(80mg)。产率：91.65％。(R)-(8-(4-Cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester 13e (72 mg, 0.194 mmol ) and bromosuccinimide (37.95 mg, 0.213 mmol) were added to 2 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction, the reaction solution was extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and the obtained residue was further analyzed by silica gel column chromatography Purification (eluent: system A) gave (R)-(8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decane-1 -yl) tert-butyl carbamate 13f (80 mg). Yield: 91.65%.
MS m/z(ESI):395.9[M-56]MS m/z(ESI): 395.9[M-56]
第六步Step 6
((1R)-8-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯((1R)-8-(4-Cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl ) tert-butyl carbamate
氩气保护下，将(R)-(8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯13f(30mg,0.067mmol)、(2,3-二氯苯基)硼酸1e(25.42mg,0.133mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(11.15mg,0.013mmol)、四(三苯基膦)钯(12.43mg,0.027mmol)和磷酸钾(42.44mg,0.199mmol)加到2mL的混合溶液中(1,4-二氧六环:水＝5:1)，加热至130℃，反应4小时。反应结束后，冷却至室温，以乙酸乙酯(30mL×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((1R)-8-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯13g(30mg)，产率：87.20％。Under argon, (R)-(8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamic acid tert-Butyl ester 13f (30mg, 0.067mmol), (2,3-dichlorophenyl)boronic acid 1e (25.42mg, 0.133mmol), [1,1'-bis(diphenylphosphino)ferrocene]di Palladium chloride (11.15 mg, 0.013 mmol), tetrakis(triphenylphosphine) palladium (12.43 mg, 0.027 mmol) and potassium phosphate (42.44 mg, 0.199 mmol) were added to 2 mL of the mixed solution (1,4-dioxane) Hexacyclic:water=5:1), heated to 130°C, and reacted for 4 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analysis and purification by silica gel column chromatography (eluent: system A) gave ((1R)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidine-2 -yl)-8-azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester 13 g (30 mg), yield: 87.20%.
MS m/z(ESI):515.9[M+1]MS m/z(ESI): 515.9[M+1]
第七步Step 7
2-((R)-1-氨基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((R)-1-Amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile
将((1R)-8-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯13g(45mg,0.087mmol)和0.5mL的三氟乙酸加到2mL的二氯甲烷中，室温反应2小时。反应结束后，减压浓缩，得到2-((R)-1-氨基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈13h(36mg)，产率：99.24％，产物未经纯化，直接进行下一步反应。((1R)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decane-1- 13 g (45 mg, 0.087 mmol) of tert-butyl carbamate and 0.5 mL of trifluoroacetic acid were added to 2 mL of dichloromethane, and reacted at room temperature for 2 hours. After the reaction, concentrated under reduced pressure to obtain 2-((R)-1-amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6- Methylpyrimidine-4-carbonitrile 13h (36mg), yield: 99.24%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):416.1[M+1]MS m/z(ESI): 416.1[M+1]
第八步Step 8
2-((R)-1-氨基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((R)-1-Amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
将2-((R)-1-氨基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈13h(36mg,0.086mmol)和0.5mL的6M氢氧化钠加到2mL的乙醇中，加热至80℃，反应0.5小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-((R)-1-氨基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺13(6mg)，产率：15.70％。 2-((R)-1-Amino-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile for 13h (36 mg, 0.086 mmol) and 0.5 mL of 6M sodium hydroxide were added to 2 mL of ethanol, heated to 80°C, and reacted for 0.5 hours. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 2 - ((R) -1- amino-8-aza-spiro [4.5] dec-8-yl) -5- (2,3-dichlorophenyl) -6-methyl pyrimidine -4-Carboxamide 13 (6 mg), yield: 15.70%.
MS m/z(ESI):433.9[M+1]MS m/z(ESI): 433.9[M+1]
1H NMR(400MHz,CD3OD):δ7.52(d,J＝8.0Hz,1H),7.31(t,J＝8.0Hz,1H),7.15(d,J＝8.0Hz,1H),4.72(s,2H),3.21(d,J＝12.0Hz,2H),2.82(s,1H),2.09(s,3H),1.59-1.79(m,5H),1.32-1.48(m,5H). 1 H NMR (400MHz, CD3OD): δ7.52 (d, J=8.0Hz, 1H), 7.31 (t, J=8.0Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 4.72 (s ,2H),3.21(d,J＝12.0Hz,2H),2.82(s,1H),2.09(s,3H),1.59-1.79(m,5H),1.32-1.48(m,5H).
实施例14Example 14
2-(4-氨基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-(4-Aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000052
Figure PCTCN2021105100-appb-000052
第一步first step
(1-(4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯tert-Butyl (1-(4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate
将2-氯-6-甲基-嘧啶-4-腈3a(80mg,0.521mmol)、哌啶-4-氨基甲酸叔丁酯14a(125.20mg,0.625mmol)和N,N-二异丙基乙胺(201.98mg,1.56mmol)加到2mL的N,N-二甲基乙酰胺中，加热至90℃，反应3小时。反应结束后，加入20mL水，以乙酸乙酯(30mL×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯14b(160mg)，产率：96.77％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (80 mg, 0.521 mmol), tert-butyl piperidine-4-carbamate 14a (125.20 mg, 0.625 mmol) and N,N-diisopropyl Ethylamine (201.98 mg, 1.56 mmol) was added to 2 mL of N,N-dimethylacetamide, heated to 90° C., and reacted for 3 hours. After the reaction, 20 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analytical purification by silica gel column chromatography (eluent: system A) gave (1-(4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate tert-butyl ester 14b ( 160 mg), yield: 96.77%.
MS m/z(ESI):262.0[M+1-56]MS m/z(ESI): 262.0[M+1-56]
第二步second step
(1-(5-溴-4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(1-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester
将(1-(4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯14b(160mg,0.504mmol)和溴代丁二酰亚胺(107.67mg,0.605mmol)加到2mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束后，加入30mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(5-溴-4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯14c(180mg)，产率：90.1％。(1-(4-Cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate tert-butyl ester 14b (160 mg, 0.504 mmol) and bromosuccinimide (107.67 mg , 0.605 mmol) was added to 2 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction, 30 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analysis and purification by silica gel column chromatography (eluent: A system) gave (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamic acid tertiary Butyl ester 14c (180 mg), yield: 90.1%.
MS m/z(ESI):342.0[M+1-56]MS m/z(ESI): 342.0[M+1-56]
第三步third step
(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(1-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester
氩气保护下，将(1-(5-溴-4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯14c(100mg,0.252mmol)、(2,3-二氯苯基)硼酸1e(96.31mg,0.505mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(21.13mg,0.025mmol)、四(三苯基膦)钯(23.55mg,0.050mmol)和磷酸钾(160.69mg,0.757mmol)加到2.2mL的混合溶液中(1,4-二氧六环:水＝10:1)，加热至130℃，反应5小时。反应结束后，冷却至室温，加水20mL水,以乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯14d(100mg)，产率：85.71％。Under argon, tert-butyl (1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamate 14c (100 mg, 0.252 mmol), ( 2,3-Dichlorophenyl)boronic acid 1e (96.31 mg, 0.505 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (21.13 mg, 0.025 mmol), tetrakis (Triphenylphosphine)palladium (23.55 mg, 0.050 mmol) and potassium phosphate (160.69 mg, 0.757 mmol) were added to 2.2 mL of a mixed solution (1,4-dioxane:water=10:1), heated to 130°C and reacted for 5 hours. After the reaction, cooled to room temperature, added 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The residue was further purified by silica gel column chromatography (eluent: system A) to give (1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidine-2 -yl)piperidin-4-yl)carbamate tert-butyl ester 14d (100 mg), yield: 85.71%.
MS m/z(ESI):406.0[M+1-56]MS m/z(ESI): 406.0[M+1-56]
第四步the fourth step
2-(4-氨基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-(4-Aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile
将(1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯14d(100mg,0.216mmol)和三氟乙酸(24.66mg,0.216mmol)加到4mL的二氯甲烷中，室温反应1小时。反应结束后，减压浓缩，得到2-(4-氨基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈14e(100mg)，产率：97.08％，产物未经纯化，直接进行下一步反应。(1-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester 14d (100 mg, 0.216 mmol) and trifluoroacetic acid (24.66 mg, 0.216 mmol) were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 2-(4-aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 14e (100 mg), Yield: 97.08%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):361.9[M+1]MS m/z(ESI): 361.9[M+1]
第五步the fifth step
2-(4-氨基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-(4-Aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
将2-(4-氨基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈14e(100mg,0.210mmol)和0.3mL的6M氢氧化钠溶液加到2mL的乙醇中，加热至80℃，反应1小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-(4-氨基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺14(40mg)，产率：49.27％。 2-(4-Aminopiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 14e (100 mg, 0.210 mmol) and 0.3 mL of 6M hydrogen The sodium oxide solution was added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 2- (4-piperidin-1-yl) -5- (2,3-dichlorophenyl) -6-methyl-pyrimidine-4-carboxamide 14 (40mg), the yield of : 49.27%.
MS m/z(ESI):379.9[M+1]MS m/z(ESI): 379.9[M+1]
1H NMR(400MHz,CD3OD)δ7.50(dd,J＝8.0,1.6Hz,1H),7.29(t,J＝7.9Hz,1H),7.13(dd,J＝7.7,1.6Hz,1H),4.84(d,J＝3.4Hz,2H),3.02(ddd,J＝13.5,12.1,2.7Hz,2H),2.93(ddd,J＝10.8,6.7,4.1Hz,1H),2.08(s,3H),1.93(dd,J＝13.3,3.7Hz,2H),1.29-1.39(m,2H). 1 H NMR (400MHz, CD3OD) δ 7.50 (dd, J=8.0, 1.6Hz, 1H), 7.29 (t, J=7.9Hz, 1H), 7.13 (dd, J=7.7, 1.6Hz, 1H), 4.84(d,J＝3.4Hz,2H),3.02(ddd,J＝13.5,12.1,2.7Hz,2H),2.93(ddd,J＝10.8,6.7,4.1Hz,1H),2.08(s,3H) ,1.93(dd,J=13.3,3.7Hz,2H),1.29-1.39(m,2H).
实施例15Example 15
2-((R)-3-(氨基甲基)吡咯烷-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000053
Figure PCTCN2021105100-appb-000053
Figure PCTCN2021105100-appb-000054
Figure PCTCN2021105100-appb-000054
第一步first step
(R)-((1-(4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯(R)-((1-(4-Cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester
将2-氯-6-甲基-嘧啶-4-腈3a(50mg,0.326mmol)、(S)-(吡咯烷-3-基甲基)氨基甲酸叔丁酯15a(92.49mg,0.391mmol)和N,N-二异丙基乙胺(126.24mg,0.977mmol)加到2mL的N,N-二甲基乙酰胺中，加热至90℃，反应3小时。反应结束后，加入20mL水，以乙酸乙酯(30mL×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-((1-(4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯15b(80mg)，产率：77.42％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (50 mg, 0.326 mmol), (S)-(pyrrolidin-3-ylmethyl)carbamate tert-butyl ester 15a (92.49 mg, 0.391 mmol) and N,N-diisopropylethylamine (126.24 mg, 0.977 mmol) was added to 2 mL of N,N-dimethylacetamide, heated to 90°C, and reacted for 3 hours. After the reaction, 20 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analytical purification by silica gel column chromatography (eluent: System A) gave (R)-((1-(4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl ) tert-butyl carbamate 15b (80 mg), yield: 77.42%.
MS m/z(ESI):318.2[M+1]MS m/z(ESI): 318.2[M+1]
第二步second step
(R)-((1-(5-溴-4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯(R)-((1-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester
将(R)-((1-(4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯15b(80mg,0.252mmol)和溴代丁二酰亚胺(67.29mg,0.378mmol)加到2mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束后，加入30mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-((1-(5-溴-4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯15c(80mg)，产率：80.1％。(R)-((1-(4-Cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester 15b (80 mg, 0.252 mmol) and bromo Succinimide (67.29 mg, 0.378 mmol) was added to 2 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction, 30 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analytical purification by silica gel column chromatography (eluent: system A) gave (R)-((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)pyrrolidine-3- tert-butyl)methyl)carbamate 15c (80 mg), yield: 80.1%.
MS m/z(ESI):341.9[M+1-56]MS m/z(ESI): 341.9[M+1-56]
第三步third step
(((3R)-1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯(((3R)-1-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamic acid tert. Butyl ester
氩气保护下，将(R)-((1-(5-溴-4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯15c(80mg,0.202mmol)、(2,3-二氯苯基)硼酸1e(96.31mg,0.505mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(16.90mg,0.020mmol)、四(三苯基膦)钯(18.84mg,0.040mmol)和磷酸钾(128.55mg,0.606mmol)加到2.2mL的混合溶液中(1,4-二氧六环:水＝10:1)，加热至130℃，反应5小时。反应结束后，冷却至室温，加水20mL水，以乙酸乙酯(20mL×3)萃 取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(((3R)-1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯15d(70mg)，产率：74.99％。Under argon, (R)-((1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester 15c (80 mg, 0.202 mmol), (2,3-dichlorophenyl)boronic acid 1e (96.31 mg, 0.505 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 16.90mg, 0.020mmol), tetrakis(triphenylphosphine)palladium (18.84mg, 0.040mmol) and potassium phosphate (128.55mg, 0.606mmol) were added to 2.2mL of the mixed solution (1,4-dioxane: water=10:1), heated to 130°C, and reacted for 5 hours. After the reaction, cooled to room temperature, added 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The residue was further purified by silica gel column chromatography (eluent: system A) to give (((3R)-1-(5-(2,3-dichlorophenyl)-4-cyano-6- Methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester 15d (70 mg), yield: 74.99%.
MS m/z(ESI):461.9[M+1]MS m/z(ESI): 461.9[M+1]
第四步the fourth step
2-((R)-3-(氨基甲基)吡咯烷-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲腈2-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile
将(((3R)-1-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)吡咯烷-3-基)甲基)氨基甲酸叔丁酯15d(70mg,0.151mmol)和三氟乙酸(1.53g,13.42mmol)加到4mL的二氯甲烷中，室温反应1小时。反应结束后，减压浓缩，得到2-((R)-3-(氨基甲基)吡咯烷-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲腈15e(50mg)，产率：91.17％，产物未经纯化，直接进行下一步反应。(((3R)-1-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamic acid tert-Butyl ester 15d (70 mg, 0.151 mmol) and trifluoroacetic acid (1.53 g, 13.42 mmol) were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction, concentrated under reduced pressure to obtain 2-((R)-3-(aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carbonitrile 15e (50 mg), yield: 91.17%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):362.1[M+1]MS m/z(ESI): 362.1[M+1]
第五步the fifth step
2-((R)-3-(氨基甲基)吡咯烷-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
将2-((R)-3-(氨基甲基)吡咯烷-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲腈15e(50mg,0.138mmol)和0.3mL的6M氢氧化钠溶液加到2mL的乙醇中，加热至80℃，反应1小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-((R)-3-(氨基甲基)吡咯烷-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺15(20mg)，产率：36.85％。 2-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 15e (50 mg, 0.138 mmol) and 0.3 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 2 - ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5- (2,3-dichlorophenyl) -6-methyl-pyrimidine-4- Amide 15 (20 mg), yield: 36.85%.
MS m/z(ESI):380.0[M+1]MS m/z(ESI): 380.0[M+1]
1H NMR(400MHz,CD3OD)δ7.51(dd,J＝8.1,1.5Hz,1H),7.30(t,J＝7.9Hz,1H),7.15(dd,J＝7.7,1.4Hz,1H),3.90(dd,J＝11.4,7.3Hz,1H),3.81(ddd,J＝11.8,8.2,4.0Hz,1H),3.60(dt,J＝11.3,7.9Hz,1H),3.35(d,J＝7.7Hz,1H),2.76(d,J＝7.1Hz,2H),2.44(dt,J＝14.4,7.1Hz,1H),2.21(dt,J＝11.6,7.0Hz,1H),2.09(d,J＝3.8Hz,3H),1.72-1.85(m,1H). 1 H NMR (400MHz, CD3OD) δ 7.51 (dd, J=8.1, 1.5Hz, 1H), 7.30 (t, J=7.9Hz, 1H), 7.15 (dd, J=7.7, 1.4Hz, 1H), 3.90(dd,J＝11.4,7.3Hz,1H),3.81(ddd,J＝11.8,8.2,4.0Hz,1H),3.60(dt,J＝11.3,7.9Hz,1H),3.35(d,J＝ 7.7Hz, 1H), 2.76 (d, J=7.1Hz, 2H), 2.44 (dt, J=14.4, 7.1Hz, 1H), 2.21 (dt, J=11.6, 7.0Hz, 1H), 2.09 (d, J=3.8Hz, 3H), 1.72-1.85(m, 1H).
实施例16Example 16
2-((1R,5S)-3-氨基-8-氮杂双环[3.2.1]辛-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4 -Formamide
Figure PCTCN2021105100-appb-000055
Figure PCTCN2021105100-appb-000055
Figure PCTCN2021105100-appb-000056
Figure PCTCN2021105100-appb-000056
第一步first step
((1R,5S)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯tert-Butyl ((1R,5S)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate
将2-氯-6-甲基-嘧啶-4-腈3a(60mg,0.391mmol)、((1R,5S)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯16a(106.11mg,0.469mmol)、N,N-二异丙基乙胺(151.49mg,1.17mmol)加到2mL的N,N-二甲基乙酰胺中，加热至90℃，反应3小时。反应结束后，加入20mL水，以乙酸乙酯(30mL×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((1R,5S)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯16b(130mg)，产率：96.89％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (60 mg, 0.391 mmol), ((1R,5S)-8-azabicyclo[3.2.1]oct-3-yl)carbamic acid tert-butyl Ester 16a (106.11 mg, 0.469 mmol), N,N-diisopropylethylamine (151.49 mg, 1.17 mmol) were added to 2 mL of N,N-dimethylacetamide, heated to 90°C, and reacted for 3 hours . After the reaction, 20 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analysis and purification by silica gel column chromatography (eluent: A system) gave ((1R,5S)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2 .1] tert-Butyl oct-3-yl)carbamate 16b (130 mg), yield: 96.89%.
MS m/z(ESI):344.0[M+1]MS m/z(ESI): 344.0[M+1]
第二步second step
((1R,5S)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯((1R,5S)-8-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)carbamic acid tert-butyl ester
将((1R,5S)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯16b(130mg,0.379mmol)和溴代丁二酰亚胺(80.85mg,0.454mmol)加到2mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束后，加入30mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((1R,5S)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯16c(150mg)，产率：93.83％。((1R,5S)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester 16b ( 130 mg, 0.379 mmol) and bromosuccinimide (80.85 mg, 0.454 mmol) were added to 2 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction, 30 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analysis and purification by silica gel column chromatography (eluent: A system) gave ((1R,5S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-nitrogen Heterobicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester 16c (150 mg), yield: 93.83%.
MS m/z(ESI):365.9[M+1-56]MS m/z(ESI): 365.9[M+1-56]
第三步third step
((1R,5S)-8-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯((1R,5S)-8-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane -3-yl) tert-butyl carbamate
氩气保护下，将((1R,5S)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯16c(150mg,0.355mmol)、(2,3-二氯苯基)硼酸1e(169.44mg,0.888mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(29.74mg,0.036mmol)、四(三苯基膦)钯(33.15mg,0.071mmol)和磷酸钾(226.17mg,1.07mmol)加到2.2mL的混合溶液中(1,4-二氧六环:水＝10:1)，加热至130℃，反应5小时。反应结束后，冷却至室温，加水20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到((1R,5S)-8-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔 丁酯16d(150mg)，产率：86.48％。Under argon, the ((1R,5S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]octane-3- base) tert-butyl carbamate 16c (150mg, 0.355mmol), (2,3-dichlorophenyl)boronic acid 1e (169.44mg, 0.888mmol), [1,1'-bis(diphenylphosphino)di Ferrocene] palladium dichloride (29.74 mg, 0.036 mmol), tetrakis(triphenylphosphine) palladium (33.15 mg, 0.071 mmol) and potassium phosphate (226.17 mg, 1.07 mmol) were added to 2.2 mL of the mixed solution (1 , 4-dioxane:water=10:1), heated to 130°C, and reacted for 5 hours. After the reaction, cooled to room temperature, added 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The residue was further purified by silica gel column chromatography (eluent: System A) to give ((1R,5S)-8-(5-(2,3-dichlorophenyl)-4-cyano-6 -Methylpyrimidin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester 16d (150 mg), yield: 86.48%.
MS m/z(ESI):488.1[M+1]MS m/z(ESI): 488.1[M+1]
第四步the fourth step
2-((1R,5S)-3-氨基-8-氮杂双环[3.2.1]辛-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4 -Nitrile
将((1R,5S)-8-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-8-氮杂双环[3.2.1]辛-3-基)氨基甲酸叔丁酯16d(150mg,0.307mmol)和1mL的三氟乙酸加到4mL的二氯甲烷中，室温反应1小时。反应结束后，减压浓缩，得到2-((1R,5S)-3-氨基-8-氮杂双环[3.2.1]辛-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈16e(100mg)，产率：83.86％，产物未经纯化，直接进行下一步反应。((1R,5S)-8-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-8-azabicyclo[3.2.1] Oct-3-yl)carbamate tert-butyl ester 16d (150 mg, 0.307 mmol) and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction, concentrated under reduced pressure to obtain 2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl)-5-(2,3-dichlorophenyl )-6-methylpyrimidine-4-carbonitrile 16e (100 mg), yield: 83.86%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):387.9[M+1]MS m/z(ESI): 387.9[M+1]
第五步the fifth step
2-((1R,5S)-3-氨基-8-氮杂双环[3.2.1]辛-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4 -Formamide
将2-((1R,5S)-3-氨基-8-氮杂双环[3.2.1]辛-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈16e(100mg,0.258mmol)和0.3mL的6M氢氧化钠溶液加到2mL的乙醇中，加热至80℃，反应1小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-((1R,5S)-3-氨基-8-氮杂双环[3.2.1]辛-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺16(45mg)，产率：41.75％。 2-((1R,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-Nitrile 16e (100 mg, 0.258 mmol) and 0.3 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 2 - ((1R, 5S) -3- amino-8-azabicyclo [3.2.1] oct-8-yl) -5- (2,3-dichlorophenyl) -6 -Methylpyrimidine-4-carboxamide 16 (45 mg), yield: 41.75%.
MS m/z(ESI):405.9[M+1]MS m/z(ESI): 405.9[M+1]
1H NMR(400MHz,CD 3OD)δ7.51(dd,J＝8.1,1.5Hz,1H),7.30(t,J＝7.9Hz,1H),7.13(dd,J＝7.7,1.5Hz,1H),4.87(s,2H),3.33-3.38(m,1H),2.08(d,J＝6.4Hz,5H),1.83-1.96(m,4H),1.59(dd,J＝17.5,6.6Hz,2H). 1 H NMR (400 MHz, CD 3 OD) δ 7.51 (dd, J=8.1, 1.5 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.13 (dd, J=7.7, 1.5 Hz, 1H) ),4.87(s,2H),3.33-3.38(m,1H),2.08(d,J=6.4Hz,5H),1.83-1.96(m,4H),1.59(dd,J=17.5,6.6Hz, 2H).
实施例17Example 17
5-(2,3-二氯苯基)-2-(4-胍基-4-甲基-1-哌啶基)-6-甲基嘧啶-4-甲酰胺5-(2,3-Dichlorophenyl)-2-(4-guanidino-4-methyl-1-piperidinyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000057
Figure PCTCN2021105100-appb-000057
第一步first step
N-[(叔丁氧基羰基氨基)-[[1-[4-氨甲酰基-5-(2,3-二氯苯基)-6-甲基-嘧啶-2-基]-4-甲基-4-哌 啶基]氨基]亚甲基]氨基甲酸叔丁酯N-[(tert-butoxycarbonylamino)-[[1-[4-carbamoyl-5-(2,3-dichlorophenyl)-6-methyl-pyrimidin-2-yl]-4- tert-Butyl methyl-4-piperidinyl]amino]methylene]carbamate
将2-(4-氨基-4-甲基哌啶-1-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺4(14.0mg,35.51μmol)，1,3-二(叔丁氧羰基)-2-甲基异硫脲(11.34mg,39.06μmol)，碘化亚铜(13.52mg,71.01μmol)和碳酸钾(19.63mg,142.02μmol)，依次加入到1mL四氢呋喃中，氮气置换3次，外温加热至60℃持续搅拌24小时。反应液过滤，滤饼用乙酸乙酯(10mL)洗涤，合并滤液，减压浓缩干，得到粗品N-[(叔丁氧基羰基氨基)-[[1-[4-氨甲酰基-5-(2,3-二氯苯基)-6-甲基-嘧啶-2-基]-4-甲基-4-哌啶基]氨基]亚甲基]氨基甲酸叔丁酯17a(油状物)，产物不经纯化直接用于下一步反应。2-(4-Amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 4 (14.0 mg, 35.51 μmol ), 1,3-bis(tert-butoxycarbonyl)-2-methylisothiourea (11.34 mg, 39.06 μmol), cuprous iodide (13.52 mg, 71.01 μmol) and potassium carbonate (19.63 mg, 142.02 μmol) , were sequentially added to 1 mL of tetrahydrofuran, replaced with nitrogen three times, and heated to 60° C. for 24 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrates were combined and concentrated to dryness under reduced pressure to obtain crude N-[(tert-butoxycarbonylamino)-[[1-[4-carbamoyl-5- (2,3-Dichlorophenyl)-6-methyl-pyrimidin-2-yl]-4-methyl-4-piperidinyl]amino]methylene]carbamate tert-butyl ester 17a (oil) , the product was directly used in the next step without purification.
MS m/z(ESI):537.2[M-100]MS m/z(ESI): 537.2[M-100]
第二步second step
5-(2,3-二氯苯基)-2-(4-胍基-4-甲基-1-哌啶基)-6-甲基嘧啶-4-甲酰胺5-(2,3-Dichlorophenyl)-2-(4-guanidino-4-methyl-1-piperidinyl)-6-methylpyrimidine-4-carboxamide
将N-[(叔丁氧基羰基氨基)-[[1-[4-氨甲酰基-5-(2,3-二氯苯基)-6-甲基-嘧啶-2-基]-4-甲基-4-哌啶基]氨基]亚甲基]氨基甲酸叔丁酯17a(22mg,34.56μmol)，TFA(1.54g,13.51mmol,1mL)依次加入到3mL二氯甲烷中，室温条件下持续搅拌6小时。反应液减压浓缩，所得残余物加入乙酸乙酯(10ml)溶清，减压浓缩，得到的残留物用制备液相色谱纯化，冷冻干燥后得到5-(2,3-二氯苯基)-2-(4-胍基-4-甲基-1-哌啶基)-6-甲基嘧啶-4-甲酰胺17(7.5mg,两步反应总产率38.4％)。N-[(tert-butoxycarbonylamino)-[[1-[4-carbamoyl-5-(2,3-dichlorophenyl)-6-methyl-pyrimidin-2-yl]-4 -Methyl-4-piperidinyl]amino]methylene]carbamate tert-butyl ester 17a (22mg, 34.56μmol), TFA (1.54g, 13.51mmol, 1mL) were sequentially added to 3mL of dichloromethane, room temperature conditions Stirring was continued for 6 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate (10 ml), and concentrated under reduced pressure. The obtained residue was purified by preparative liquid chromatography, and lyophilized to obtain 5-(2,3-dichlorophenyl) -2-(4-guanidino-4-methyl-1-piperidinyl)-6-methylpyrimidine-4-carboxamide 17 (7.5 mg, 38.4% overall yield for two steps).
MS m/z(ESI):435.9[M+1]MS m/z(ESI): 435.9[M+1]
1H NMR(400MHz,CD 3OD)δ7.51(dd,J＝8.0,1.6Hz,1H),7.30(t,J＝7.8Hz,1H),7.13(dd,J＝7.6,1.6Hz,1H),4.38-4.33(m,2H),3.63-3.56(m,2H),2.09-2.02(m,5H),1.84-1.77(m,2H),1.51(s,3H). 1 H NMR (400 MHz, CD 3 OD) δ 7.51 (dd, J=8.0, 1.6 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.13 (dd, J=7.6, 1.6 Hz, 1H) ), 4.38-4.33(m, 2H), 3.63-3.56(m, 2H), 2.09-2.02(m, 5H), 1.84-1.77(m, 2H), 1.51(s, 3H).
实施例18Example 18
2-(6-氨基-3-氮杂双环[3.1.0]己-3-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000058
Figure PCTCN2021105100-appb-000058
Figure PCTCN2021105100-appb-000059
Figure PCTCN2021105100-appb-000059
第一步first step
(3-(4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯tert-Butyl (3-(4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6yl)carbamate
将2-氯-6-甲基-嘧啶-4-腈3a(70mg,0.355mmol)、(3-氮杂双环[3.1.0]己6-基)氨基甲酸叔丁酯17a(91.48mg,0.461mmol)N,N-二异丙基乙胺(137.62mg,1.06mmol)加到2mL的N,N-二甲基乙酰胺中，加热至90℃，反应3小时。反应结束后，加入20mL水，以乙酸乙酯(30mL×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(3-(4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯17b(110mg)，产率：98.27％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (70 mg, 0.355 mmol), tert-butyl (3-azabicyclo[3.1.0]hexyl 6-yl)carbamate 17a (91.48 mg, 0.461 mmol) N,N-diisopropylethylamine (137.62 mg, 1.06 mmol) was added to 2 mL of N,N-dimethylacetamide, heated to 90° C., and reacted for 3 hours. After the reaction, 20 mL of water was added, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analysis and purification by silica gel column chromatography (eluent: A system) gave (3-(4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6 base) tert-butyl carbamate 17b (110 mg), yield: 98.27%.
MS m/z(ESI):260.0[M+1-56]MS m/z(ESI): 260.0[M+1-56]
第二步second step
(3-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯tert-Butyl (3-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6yl)carbamate
将(3-(4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯17b(110mg,0.349mmol)和溴代丁二酰亚胺(93.12mg,0.523mmol)加到2mL的N,N-二甲基甲酰胺中，室温反应过夜。反应结束后，加入30mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(3-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯18c(110mg)，产率：79.99％。(3-(4-Cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6yl)carbamate tert-butyl ester 17b (110 mg, 0.349 mmol) and bromine Succinimide (93.12 mg, 0.523 mmol) was added to 2 mL of N,N-dimethylformamide and reacted at room temperature overnight. After the reaction, 30 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analysis and purification by silica gel column chromatography (eluent: A system) gave (3-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0 ] Hex-6yl)carbamate tert-butyl ester 18c (110 mg), yield: 79.99%.
MS m/z(ESI):340.0[M+1-56]MS m/z(ESI): 340.0[M+1-56]
第三步third step
(3-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯(3-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6yl)carbamic acid tert-butyl ester
氩气保护下，将(3-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯18c(110mg,0.279mmol)、(2,3-二氯苯基)硼酸1e(122.45mg,0.642mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(23.36mg,0.028mmol)、四(三苯基膦)钯(26.04mg,0.056mmol)和磷酸钾(177.67mg,0.837mmol)加到2.3mL的混合溶液中(1,4-二氧六环:水＝7:1)，加热至130℃，反应5小时。反应结束后，冷却至室温，加水20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(3-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯18d(100mg)，产率：77.86％。Under argon, tert-butyl (3-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6yl)carbamate 18c (110mg, 0.279mmol), (2,3-dichlorophenyl)boronic acid 1e (122.45mg, 0.642mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23.36 mg, 0.028 mmol), tetrakis(triphenylphosphine) palladium (26.04 mg, 0.056 mmol) and potassium phosphate (177.67 mg, 0.837 mmol) were added to 2.3 mL of the mixed solution (1,4-dioxane) :water=7:1), heated to 130°C, and reacted for 5 hours. After the reaction, cooled to room temperature, added 20 mL of water, extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The residue was further purified by silica gel column chromatography (eluent: system A) to give (3-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidine-2 -yl)-3-azabicyclo[3.1.0]hex-6yl)carbamate tert-butyl ester 18d (100 mg), yield: 77.86%.
MS m/z(ESI):403.8[M+1-56]MS m/z(ESI): 403.8[M+1-56]
第四步the fourth step
2-(6-氨基-3-氮杂双环[3.1.0]己-3-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile
将(3-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯18d(100mg,0.217mmol)和三氟乙酸(24.77mg,0.217mmol)加到4mL的二氯甲烷中，室温反应1小时。反应结束后，减压浓缩，得到2-(6-氨基-3-氮杂双环[3.1.0]己-3-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈18e(78mg)，产率：99.68％，产物未经纯化，直接进行下一步反应。(3-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6yl)amino Tert-butyl formate 18d (100 mg, 0.217 mmol) and trifluoroacetic acid (24.77 mg, 0.217 mmol) were added to 4 mL of dichloromethane and reacted at room temperature for 1 hour. After the reaction, concentrated under reduced pressure to obtain 2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methyl Pyrimidine-4-carbonitrile 18e (78 mg), yield: 99.68%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):359.7[M+1]MS m/z(ESI): 359.7[M+1]
第五步the fifth step
2-(6-氨基-3-氮杂双环[3.1.0]己-3-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide
将2-(6-氨基-3-氮杂双环[3.1.0]己-3-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈18e(78mg,0.217mmol)和0.3mL的6M氢氧化钠溶液加到2mL的乙醇中，加热至80℃，反应1小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-(6-氨基-3-氮杂双环[3.1.0]己-3-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺18(45mg)，产率：41.74％。 2-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 18e (78 mg , 0.217mmol) and 0.3mL of 6M sodium hydroxide solution were added to 2mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 2- (6-amino-3-azabicyclo [3.1.0] hex-3-yl) -5- (2,3-dichlorophenyl) -6-methyl-4 - Formamide 18 (45 mg), yield: 41.74%.
MS m/z(ESI):377.7[M+1]MS m/z(ESI): 377.7[M+1]
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝97.0Hz,3H),7.90(d,J＝10.2Hz,1H),7.60(t,J＝6.6Hz,1H),7.47(d,J＝21.5Hz,1H),7.36(dq,J＝8.2,5.0,4.3Hz,1H),7.23–7.08(m,1H),3.89(d,J＝32.7Hz,3H),3.60(d,J＝11.5Hz,2H),2.13–1.90(m,5H). 1 H NMR (400MHz, DMSO-d6)δ8.17(d,J=97.0Hz,3H),7.90(d,J=10.2Hz,1H),7.60(t,J=6.6Hz,1H),7.47( d, J=21.5Hz, 1H), 7.36 (dq, J=8.2, 5.0, 4.3Hz, 1H), 7.23–7.08 (m, 1H), 3.89 (d, J=32.7Hz, 3H), 3.60 (d , J=11.5Hz, 2H), 2.13–1.90 (m, 5H).
实施例19Example 19
2-((R)-6-氨基-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((R)-6-Amino-5,6-dihydrospiro[cyclopenta[b]pyridin-7,4'-piperidin]-1'-yl)-5-(2,3-dichloro Phenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000060
Figure PCTCN2021105100-appb-000060
Figure PCTCN2021105100-appb-000061
Figure PCTCN2021105100-appb-000061
第一步first step
(R)-N-((R)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((R)-5,6-Dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinyl Amide
将(R)-6-(((R)-叔丁基亚磺酰基)氨基)叔丁基-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-1'-甲酸叔丁酯19a(150mg,0.368mmol)和1mL的三氟乙酸加到6mL的二氯甲烷中，室温反应2小时。反应结束后，减压浓缩，得到(R)-N-((R)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺19b(113.15mg)，产率：100.00％，产物未经纯化，直接进行下一步反应。(R)-6-(((R)-tert-butylsulfinyl)amino)tert-butyl-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidine]- 1'-tert-butyl carboxylate 19a (150 mg, 0.368 mmol) and 1 mL of trifluoroacetic acid were added to 6 mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction, concentrated under reduced pressure to obtain (R)-N-((R)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidin]-6-yl)-2 -Methylpropane-2-sulfinamide 19b (113.15 mg), yield: 100.00%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):308.2[M+1]MS m/z(ESI): 308.2[M+1]
第二步second step
(R)-N-((R)-1'-(4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((R)-1'-(4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4' -Piperidin]-6-yl)-2-methylpropane-2-sulfinamide
将(R)-N-((R)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺19b(113.15mg,0.368mmol)、2-氯-6-甲基-嘧啶-4-腈3a(60mg,0.391mmol)和N,N-二异丙基乙胺(50.49mg,0.391mmol)依次加到3mL的N,N-二甲基乙酰胺中，加热至90℃，反应3小时。反应结束后，冷却至室温，以乙酸乙酯(30ml×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到(R)-N-((R)-1'-(4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺19c(130mg)，产率：78.37％，产物未经纯化，直接进行下一步反应。(R)-N-((R)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidin]-6-yl)-2-methylpropane-2-ylidene Sulfonamide 19b (113.15 mg, 0.368 mmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (60 mg, 0.391 mmol) and N,N-diisopropylethylamine (50.49 mg, 0.391 mmol) It was sequentially added to 3 mL of N,N-dimethylacetamide, heated to 90° C., and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)- N-((R)-1'-(4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidine] -6-yl)-2-methylpropane-2-sulfinamide 19c (130 mg), yield: 78.37%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):424.9[M+1]MS m/z(ESI): 424.9[M+1]
第三步third step
(R)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)氨基甲酸叔丁酯(R)-(1'-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidine pyridin]-6-yl)carbamate tert-butyl ester
将(R)-N-((R)-1'-(4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)-2-甲基丙烷-2-亚磺酰胺19c(130mg,0.306mmol)和碘代丁二酰亚胺(70.85mg,0.398mmol)加到2mL的N,N-二甲基甲酰胺中，室温反应2小时。反应结束后，加入碘代丁二酰亚胺(70.85mg,0.398mmol)，继续反应2小时，反应结束后，加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，饱和NaCl洗涤两次，无水硫酸钠干燥，减压浓缩。将得到的粗品、二碳酸二叔丁酯(200.48mg,0.919mmol)和N,N-二乙基乙胺(154.92mg,1.53mmol)加入5mL的二氯甲烷中，室温反应过夜。反应结束后，加入20mL水，以乙酸乙酯(20mL×3)萃取， 合并有机相，饱和NaCl洗涤两次，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)氨基甲酸叔丁酯19d(50mg)，产率：32.7％。(R)-N-((R)-1'-(4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4 '-piperidin]-6-yl)-2-methylpropane-2-sulfinamide 19c (130 mg, 0.306 mmol) and iodosuccinimide (70.85 mg, 0.398 mmol) were added to 2 mL of N, In N-dimethylformamide, the reaction was carried out at room temperature for 2 hours. After the reaction was completed, iodosuccinimide (70.85 mg, 0.398 mmol) was added, and the reaction was continued for 2 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, saturated NaCl Washed twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product, di-tert-butyl dicarbonate (200.48 mg, 0.919 mmol) and N,N-diethylethylamine (154.92 mg, 1.53 mmol) were added to 5 mL of dichloromethane and reacted at room temperature overnight. After the reaction, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed twice with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was further analyzed by silica gel column chromatography Purification (eluent: system A) gave (R)-(1'-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta] [b] Pyridin-7,4'-piperidin]-6-yl)carbamate tert-butyl ester 19d (50 mg), yield: 32.7%.
MS m/z(ESI):499.1[M+1]MS m/z(ESI): 499.1[M+1]
第四步the fourth step
(R)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)氨基甲酸叔丁酯(R)-(1'-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b ]pyridin-7,4'-piperidin]-6-yl)carbamic acid tert-butyl ester
氩气保护下，将(R)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)氨基甲酸叔丁酯19d(50mg,0.100mmol)、(2,3-二氯苯基)硼酸1e(47.76mg,0.250mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(8.38mg,0.010mmol)、四(三苯基膦)钯(9.34mg,0.020mmol)和磷酸钾(63.76mg,0.300mmol)加到2.3mL的混合溶液中(1,4-二氧六环:水＝7:1)，加热至130℃，反应4小时。反应结束后，冷却至室温，以乙酸乙酯(30mL×2)萃取，合并有机相，饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)氨基甲酸叔丁酯19e(45mg)，产率：79.48％。Under argon, (R)-(1'-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridine- 7,4'-Piperidin]-6-yl)carbamic acid tert-butyl ester 19d (50 mg, 0.100 mmol), (2,3-dichlorophenyl)boronic acid 1e (47.76 mg, 0.250 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride (8.38mg, 0.010mmol), tetrakis(triphenylphosphine)palladium (9.34mg, 0.020mmol) and potassium phosphate (63.76mg, 0.300mmol) ) was added to 2.3 mL of the mixed solution (1,4-dioxane:water=7:1), heated to 130°C, and reacted for 4 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Further analytical purification by silica gel column chromatography (eluent: A system) gave (R)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidine- 2-yl)-5,6-dihydrospiro[cyclopenta[b]pyridin-7,4'-piperidin]-6-yl)carbamate tert-butyl ester 19e (45 mg), yield: 79.48%.
MS m/z(ESI):564.5[M+1]MS m/z(ESI): 564.5[M+1]
第五步the fifth step
2-((R)-6-氨基-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((R)-6-Amino-5,6-dihydrospiro[cyclopenta[b]pyridin-7,4'-piperidin]-1'-yl)-5-(2,3-dichloro Phenyl)-6-methylpyrimidine-4-carbonitrile
将(R)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-6-基)氨基甲酸叔丁酯19e(45mg,0.080mmol)和1mL的三氟乙酸加到4mL的二氯甲烷中，室温反应1小时。反应结束后，减压浓缩，得到2-((R)-6-氨基-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈19f(37mg)，产率：100％，产物未经纯化，直接进行下一步反应。(R)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5,6-dihydrospiro[cyclopenta[ b]Pyridin-7,4'-piperidin]-6-yl)carbamate tert-butyl ester 19e (45 mg, 0.080 mmol) and 1 mL of trifluoroacetic acid were added to 4 mL of dichloromethane, and reacted at room temperature for 1 hour. After the reaction, concentrated under reduced pressure to obtain 2-((R)-6-amino-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidin]-1'-yl)- 5-(2,3-Dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 19f (37 mg), yield: 100%, the product was not purified, and the next reaction was carried out directly.
MS m/z(ESI):465.1[M+1]MS m/z(ESI): 465.1[M+1]
第六步Step 6
2-((R)-6-氨基-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((R)-6-Amino-5,6-dihydrospiro[cyclopenta[b]pyridin-7,4'-piperidin]-1'-yl)-5-(2,3-dichloro Phenyl)-6-methylpyrimidine-4-carboxamide
将2-((R)-6-氨基-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈19f(37mg,0.080mmol)和0.3mL的6M氢氧化钠加到2mL的乙醇中，加热至80℃，反应1小时。反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-((R)-6-氨基-5,6-二氢螺[环戊[b]吡啶-7,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺19(20mg)，产率：42.11％。 2-((R)-6-Amino-5,6-dihydrospiro[cyclopenta[b]pyridine-7,4'-piperidin]-1'-yl)-5-(2,3-dihydro Chlorophenyl)-6-methylpyrimidine-4-carbonitrile 19f (37 mg, 0.080 mmol) and 0.3 mL of 6M sodium hydroxide were added to 2 mL of ethanol, heated to 80°C, and reacted for 1 hour. After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 2 - ((R) -6- amino-5,6-dihydro-spiro [cyclopenta [b] pyridine-7,4'-piperidin] -1'-yl) -5- ( 2,3-Dichlorophenyl)-6-methylpyrimidine-4-carboxamide 19 (20 mg), yield: 42.11%.
MS m/z(ESI):482.7[M+1]MS m/z(ESI): 482.7[M+1]
1H NMR(400MHz,CD 3OD)δ8.50(m,1H),7.80(d,J＝7.6Hz,1H),7.52(dd,J＝8.1,1.5Hz,1H),7.36(m,2H),7.15(dt,J＝7.6,1.7Hz,1H),4.65–4.37(m,2H),4.18–3.90(m,3H),3.59(dd,J＝17.4,6.6Hz,1H),3.11–2.97(m,1H),2.25(t,J＝10.9Hz,1H),2.10(s,3H),1.94–1.67(m,3H). 1 H NMR (400MHz, CD 3 OD) δ 8.50 (m, 1H), 7.80 (d, J=7.6Hz, 1H), 7.52 (dd, J=8.1, 1.5Hz, 1H), 7.36 (m, 2H) ), 7.15 (dt, J=7.6, 1.7Hz, 1H), 4.65–4.37 (m, 2H), 4.18–3.90 (m, 3H), 3.59 (dd, J=17.4, 6.6Hz, 1H), 3.11– 2.97(m, 1H), 2.25(t, J=10.9Hz, 1H), 2.10(s, 3H), 1.94–1.67(m, 3H).
实施例20Example 20
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6 -Methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000062
Figure PCTCN2021105100-appb-000062
第一步first step
(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide
室温下，将三氟醋酸(1mL)加入(S)-1-(((R)-叔丁基亚磺酰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-甲酸叔丁酯20a(260mg,639.48μmol)的二氯甲烷(4mL)溶液中，室温反应1小时。将反应液减压浓缩，得到产物(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺20b(195.98mg)，产率：100.00％，产物不经分离纯化，直接用于下一步反应。Trifluoroacetic acid (1 mL) was added to (S)-1-((((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine at room temperature ]-1'-carboxylate tert-butyl ester 20a (260 mg, 639.48 μmol) in dichloromethane (4 mL) solution, react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the product (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane- 2-Sulfinamide 20b (195.98 mg), yield: 100.00%, the product was directly used in the next reaction without separation and purification.
MS m/z(ESI):307.2[M+1]MS m/z(ESI): 307.2[M+1]
第二步second step
(R)-N-((S)-1'-(4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰 胺(R)-N-((S)-1'-(4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]- 1-yl)-2-methylpropane-2-sulfinamide
室温下，将2-氯-6-甲基-嘧啶-4-腈3a(78.56mg,511.59μmol)、(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺20b(195.98mg,639.49μmol)、N,N-二甲基乙酰胺(2mL)、N,N-二异丙基乙胺(247.94mg,1.92mmol)依次加入15ml单口瓶中，升温至100℃反应4小时。反应液中加入20mL水，乙酸乙酯(20mL×3)萃取3次，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：洗脱剂A)纯化，得到(R)-N-((S)-1'-(4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺20c(265mg)，产率：97.83％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (78.56 mg, 511.59 μmol), (R)-N-((S)-1,3-dihydrospiro[indene-2, 4'-Piperidin]-1-yl)-2-methylpropane-2-sulfinamide 20b (195.98 mg, 639.49 μmol), N,N-dimethylacetamide (2 mL), N,N-di Isopropylethylamine (247.94 mg, 1.92 mmol) was successively added to a 15 ml single-neck flask, and the temperature was raised to 100° C. to react for 4 hours. 20 mL of water was added to the reaction solution, extracted three times with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was washed with silica gel Purification by column chromatography (eluent: eluent A) gave (R)-N-((S)-1'-(4-cyano-6-methylpyrimidin-2-yl)-1, 3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 20c (265 mg), yield: 97.83%.
MS m/z(ESI):424.2[M+1]MS m/z(ESI): 424.2[M+1]
第三步third step
(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-methylpyrimidine-4-carbonitrile
将溴代丁二酰亚胺(122.48mg,688.19μmol)和(R)-N-((S)-1'-(4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺20c(265mg,0.626mmol)加到3mL的N,N-二甲基甲酰胺中，室温反应2小时。减压浓缩，得到(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈20d(199.83mg)，产率：100％，产物不经分离纯化，直接用于下一步。Bromosuccinimide (122.48 mg, 688.19 μmol) and (R)-N-((S)-1'-(4-cyano-6-methylpyrimidin-2-yl)-1,3 - Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 20c (265 mg, 0.626 mmol) was added to 3 mL of N,N-dimethyl In formamide, the reaction was carried out at room temperature for 2 hours. Concentrate under reduced pressure to give (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-methylpyrimidine-4-carbonitrile 20d (199.83 mg), yield: 100%, the product was used directly in the next step without isolation and purification.
MS m/z(ESI):303.2[M-17+1]MS m/z(ESI): 303.2[M-17+1]
第四步the fourth step
(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(4-Cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamic acid tert-butyl ester
将(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈20d(199.83mg,625.64μmol)、二碳酸二叔丁酯(409.64mg,1.88mmol)、三乙胺(189.92mg,1.88mmol)、二氯甲烷(4mL)加入15ml单口瓶中，室温反应2小时。反应液中加入20mL水，乙酸乙酯(20mL×3)萃取3次，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A))纯化，得到(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯20e(180mg)，产率：68.58％。(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-methylpyrimidine-4-carbonitrile 20d (199.83 mg , 625.64 μmol), di-tert-butyl dicarbonate (409.64 mg, 1.88 mmol), triethylamine (189.92 mg, 1.88 mmol), and dichloromethane (4 mL) were added to a 15 ml single-necked flask and reacted at room temperature for 2 hours. 20 mL of water was added to the reaction solution, extracted three times with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was washed with silica gel Purification by column chromatography (eluent: system A)) gave (S)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene] -2,4'-Piperidin]-1-yl)carbamate tert-butyl ester 20e (180 mg), yield: 68.58%.
MS m/z(ESI):420.2[M+1]MS m/z(ESI): 420.2[M+1]
第五步the fifth step
(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1- base) tert-butyl carbamate
将溴代丁二酰亚胺(84.00mg,471.97μmol)和(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯20e(180mg,429.06μmol)加到2.5mL的N,N-二甲基甲酰胺中，逐渐升至室温反应过夜。反应液中加入20mL水，乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯20f(200mg)，产率：93.52％。Bromosuccinimide (84.00 mg, 471.97 μmol) and (S)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene] -2,4'-Piperidin]-1-yl)carbamate tert-butyl ester 20e (180 mg, 429.06 μmol) was added to 2.5 mL of N,N-dimethylformamide, and the reaction was gradually raised to room temperature overnight. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. was purified by analytical method (eluent: system A) to give (S)-(1'-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[ Indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 20f (200 mg), yield: 93.52%.
MS m/z(ESI):498.1[M+1]MS m/z(ESI): 498.1[M+1]
第六步Step 6
(S)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2, 4'-Piperidin]-1-yl)carbamate tert-butyl ester
氩气保护下，将(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯20f(200mg,401.27μmol)、(2,3-二氯苯基)硼酸1e(153.14mg,802.55μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(33.60mg,40.13μmol)、四(三苯基膦)钯(37.45mg,80.25μmol)和磷酸钾(255.65mg,1.20mmol)加到2.9mL的混合溶液中(1,4-二氧六环:水＝6:1)，升温至130℃反应4小时。反应液中加入20mL水，乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(S)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯20g(190mg)，产率：83.88％。Under argon, (S)-(1'-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'- Piperidin]-1-yl)carbamate tert-butyl ester 20f (200mg, 401.27μmol), (2,3-dichlorophenyl)boronic acid 1e (153.14mg, 802.55μmol), [1,1'-bis(di(di(dichlorophenyl)) Phenylphosphino)ferrocene]palladium dichloride (33.60 mg, 40.13 μmol), tetrakis(triphenylphosphine)palladium (37.45 mg, 80.25 μmol) and potassium phosphate (255.65 mg, 1.20 mmol) were added to 2.9 mL In the mixed solution of (1,4-dioxane:water=6:1), the temperature was raised to 130°C for 4 hours. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. analytical method (eluent: system A) to obtain (S)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl) -1,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl) tert-butyl carbamate 20 g (190 mg), yield: 83.88%.
MS m/z(ESI):507.7[M-56+1]MS m/z(ESI): 507.7[M-56+1]
第七步Step 7
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6 -methylpyrimidine-4-carbonitrile
室温下，将三氟醋酸(1mL)加入(S)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯20g(190mg,336.58μmol)的二氯甲烷(4mL)溶液中，室温反应1小时。反应液减压浓缩，得到的2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈20h(156.3mg)，产率：100％。Trifluoroacetic acid (1 mL) was added to (S)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-1 at room temperature , 3-dihydrospiro[indene-2,4'-piperidin]-1-yl) tert-butyl carbamate 20 g (190 mg, 336.58 μmol) in dichloromethane (4 mL) solution, react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3 -Dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 20h (156.3 mg), yield: 100%.
MS m/z(ESI):447.1[M-17+1]MS m/z(ESI): 447.1[M-17+1]
第八步Step 8
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6 -Methylpyrimidine-4-carboxamide
将2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈20h(156.3mg,336.57μmol)和0.5mL的6M氢氧化钠溶液加入到2mL乙醇中，升温至80℃反应40分钟。反应液减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺20(52.31mg)，产率：32.09％。 2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)- 6-Methylpyrimidine-4-carbonitrile 20h (156.3 mg, 336.57 μmol) and 0.5 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, and the temperature was raised to 80° C. to react for 40 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give the product 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichloro Phenyl)-6-methylpyrimidine-4-carboxamide 20 (52.31 mg), yield: 32.09%.
MS m/z(ESI):482.2[M+1]MS m/z(ESI): 482.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.94(s,1H),7.58(d,J＝8.0Hz,1H),7.26-7.43(m,3H),7.18(dt,J＝17.4,6.5Hz,4H),4.62(t,J＝16.8Hz,2H),3.84(s,1H),3.05-3.26(m,3H),2.64(d,J＝15.6Hz,1H),2.01(s,3H),1.69-1.94(m,3H),1.64(t,J＝12.6Hz,1H),1.52(d,J＝13.3Hz,1H),1.11(d,J＝13.2Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.94 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.26-7.43 (m, 3H), 7.18 (dt, J=17.4, 6.5 Hz, 4H), 4.62(t, J＝16.8Hz, 2H), 3.84(s, 1H), 3.05-3.26(m, 3H), 2.64(d, J＝15.6Hz, 1H), 2.01(s, 3H) ),1.69-1.94(m,3H),1.64(t,J＝12.6Hz,1H),1.52(d,J＝13.3Hz,1H),1.11(d,J＝13.2Hz,1H).
实施例21Example 21
2-((S)-1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-di Chlorophenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000063
Figure PCTCN2021105100-appb-000063
第一步first step
(R)-N-((S)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-5-Methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)-2-methylpropane-2-ylidene Sulfonamide
室温下，将三氟醋酸(1mL)加入(S)-1-(((R)-叔丁基亚磺酰基)氨基)-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-甲酸叔丁酯21a(200mg,455.97μmol)的二氯甲烷(5mL)溶液中，室温反应1小时。将反应液减压浓缩，得到产物(R)-N-((S)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺21b(154.35mg)，产率：100.00％，产物不经分离纯化，直接用于下一步反应。Trifluoroacetic acid (1 mL) was added to (S)-1-((((R)-tert-butylsulfinyl)amino)-6-methoxy-1,3-dihydrospiro[indene-2 at room temperature ,4'-piperidine]-1'-carboxylate tert-butyl ester 21a (200 mg, 455.97 μmol) in dichloromethane (5 mL) solution was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the product (R)-N-((S)-5-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)- 2-methylpropane-2-sulfinamide 21b (154.35 mg), yield: 100.00%, the product was directly used in the next reaction without separation and purification.
MS m/z(ESI):337.2[M+1]MS m/z(ESI): 337.2[M+1]
第二步second step
(R)-N-((S)-1'-(4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1'-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4 '-Piperidin]-3-yl)-2-methylpropane-2-sulfinamide
室温下，将2-氯-6-甲基-嘧啶-4-腈3a(63.66mg,414.52μmol)、(R)-N-((S)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺21b(154.35mg,455.97μmol)、N,N-二甲基乙酰胺(2.5mL)、N,N-二异丙基乙胺(267.86mg,2.07mmol)依次加入15ml单口瓶中，升温至100℃反应3.5小时。反应结束后，向反应液中加入20mL水，乙酸乙酯(20mL×3)萃 取3次，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：洗脱剂A)纯化，得到(R)-N-((S)-1'-(4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺21c(185mg)，产率：98.39％。At room temperature, 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (63.66 mg, 414.52 μmol), (R)-N-((S)-5-methoxy-1,3-dihydro Spiro[indene-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide 21b (154.35 mg, 455.97 μmol), N,N-dimethylacetamide (2.5 mL) ) and N,N-diisopropylethylamine (267.86 mg, 2.07 mmol) were successively added to a 15 ml single-necked flask, and the temperature was raised to 100° C. for reaction for 3.5 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted three times with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: eluent A) to give (R)-N-((S)-1'-(4-cyano-6-methylpyrimidine-2- yl)-5-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide 21c (185 mg), yielded Rate: 98.39%.
MS m/z(ESI):454.2[M+1]MS m/z(ESI): 454.2[M+1]
第三步third step
(S)-2-(1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈(S)-2-(1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-methylpyrimidine-4- Nitrile
将溴代丁二酰亚胺(72.27mg,406.04μmol)和(R)-N-((S)-1'-(4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺21c(184.18mg,406.04μmol)加到2mL的N,N-二甲基甲酰胺中，逐步升至室温反应2小时。反应结束后，减压浓缩，得到(S)-2-(1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈21d(141.88mg)，产率：100％，产物不经分离纯化，直接用于下一步。Bromosuccinimide (72.27 mg, 406.04 μmol) and (R)-N-((S)-1'-(4-cyano-6-methylpyrimidin-2-yl)-5-methyl Oxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide 21c (184.18 mg, 406.04 μmol) was added to 2 mL of In N,N-dimethylformamide, the reaction was gradually raised to room temperature for 2 hours. After the reaction, concentrated under reduced pressure to obtain (S)-2-(1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl) -6-Methylpyrimidine-4-carbonitrile 21d (141.88 mg), yield: 100%, the product was used directly in the next step without isolation and purification.
MS m/z(ESI):333.1[M-17+1]MS m/z(ESI): 333.1[M-17+1]
第四步the fourth step
(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(S)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]- 3-yl) tert-butyl carbamate
将(S)-2-(1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈21d(141.07mg,403.71μmol)、二碳酸二叔丁酯(264.33mg,1.21mmol)、三乙胺(204.25mg,2.02mmol)、二氯甲烷(4mL)加入15ml单口瓶中，室温反应3小时。反应结束后，向反应液中加入20mL水，二氯甲烷(20mL×3)萃取3次，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯21e(130mg)，产率：71.63％。(S)-2-(1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-methylpyrimidine-4 -Nitrile 21d (141.07mg, 403.71μmol), di-tert-butyl dicarbonate (264.33mg, 1.21mmol), triethylamine (204.25mg, 2.02mmol), and dichloromethane (4mL) were added to a 15ml single-neck flask, and the reaction was carried out at room temperature 3 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with dichloromethane (20 mL×3) for 3 times, washed with saturated sodium chloride solution (20 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: system A) to give (S)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy -1,3-Dihydrospiro[inden-2,4'-piperidin]-3-yl)carbamate tert-butyl ester 21e (130 mg), yield: 71.63%.
MS m/z(ESI):450.3[M+1]MS m/z(ESI): 450.3[M+1]
第五步the fifth step
(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(S)-(1'-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4'- tert-Butyl piperidin]-3-yl)carbamate
将溴代丁二酰亚胺(51.47mg,289.18μmol)和(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯21e(130mg,289.18μmol)加到2.5mL的N,N-二甲基甲酰胺中，逐渐升至室温反应5小时。反应结束后，向反应液中加入20mL水，乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯21f(150mg)，产率：98.16％。Bromosuccinimide (51.47 mg, 289.18 μmol) and (S)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3 - Dihydrospiro[indene-2,4'-piperidin]-3-yl)carbamate tert-butyl ester 21e (130 mg, 289.18 μmol) was added to 2.5 mL of N,N-dimethylformamide, gradually increased React to room temperature for 5 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain residual The compound was purified by silica gel column chromatography (eluent: system A) to give (S)-(1'-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5-methan Oxy-1,3-dihydrospiro[inden-2,4'-piperidin]-3-yl)carbamate tert-butyl ester 21f (150 mg), yield: 98.16%.
MS m/z(ESI):472.1[M-56+1]MS m/z(ESI): 472.1[M-56+1]
第六步Step 6
(S)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯(S)-(1'-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydro tert-Butyl spiro[indene-2,4'-piperidin]-3-yl)carbamate
氩气保护下，将(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯21f(150mg,283.85μmol)、(2,3-二氯苯基)硼酸1e(108.33mg,567.71μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(23.77mg,28.39μmol)、四(三苯基膦)钯(26.49mg,56.77μmol)和磷酸钾(180.85mg,851.56μmol)加到2.3mL的混合溶液中(1,4-二氧六环:水＝7:1)，升温至130℃反应4小时。反应结束后，向反应液中加入20mL水，乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(S)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯21g(140mg)，产率：82.96％。Under argon, (S)-(1'-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5-methoxy-1,3-dihydrospiro[indene -2,4'-Piperidin]-3-yl)carbamate tert-butyl ester 21f (150mg, 283.85μmol), (2,3-dichlorophenyl)boronic acid 1e (108.33mg, 567.71μmol), [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23.77mg, 28.39μmol), tetrakis(triphenylphosphine)palladium (26.49mg, 56.77μmol) and potassium phosphate (180.85mg, 851.56 μmol) was added to 2.3 mL of the mixed solution (1,4-dioxane:water=7:1), and the temperature was raised to 130° C. to react for 4 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain residual The compound was purified by silica gel column chromatography (eluent: system A) to give (S)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidine) -2-yl)-5-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester 21 g (140 mg), yield: 82.96% .
MS m/z(ESI):594.2[M+1]MS m/z(ESI): 594.2[M+1]
第七步Step 7
2-((S)-1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((S)-1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-di Chlorophenyl)-6-methylpyrimidine-4-carbonitrile
室温下，将三氟醋酸(1mL)加入(S)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-5-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-3-基)氨基甲酸叔丁酯21g(140mg,235.48μmol)的二氯甲烷(4mL)溶液中，室温反应40分钟。反应结束后，反应液减压浓缩，得到的2-((S)-1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈21h(116.42mg)，产率：100％，产物不经分离纯化，直接用于下一步。Trifluoroacetic acid (1 mL) was added to (S)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-5 at room temperature -Methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-3-yl) tert-butyl carbamate 21g (140mg, 235.48μmol) in dichloromethane (4mL) solution, The reaction was carried out at room temperature for 40 minutes. After the reaction, the reaction solution was concentrated under reduced pressure to obtain 2-((S)-1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1' -yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 21h (116.42 mg), yield: 100%, the product was used directly in the next step without separation and purification.
MS m/z(ESI):477.1[M-17+1]MS m/z(ESI): 477.1[M-17+1]
第八步Step 8
2-((S)-1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-di Chlorophenyl)-6-methylpyrimidine-4-carboxamide
将2-((S)-1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈21h(116.42mg,235.47μmol)和0.5mL的6M氢氧化钠溶液加入到2mL乙醇中，升温至80℃，反应40分钟。反应结束后，反应液减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((S)-1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺21(24.32mg)，产率：19.55％。 2-((S)-1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3- Dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 21h (116.42mg, 235.47μmol) and 0.5mL of 6M sodium hydroxide solution were added to 2mL of ethanol, the temperature was raised to 80°C, and the reaction was performed for 40 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give the product 2-((S)-1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl) -5-(2,3-Dichlorophenyl)-6-methylpyrimidine-4-carboxamide 21 (24.32 mg), yield: 19.55%.
MS m/z(ESI):512.2[M+1]MS m/z(ESI): 512.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.94(s,1H),7.58(d,J＝8.0Hz,1H),7.36(dd,J＝15.1,6.9Hz,2H),7.21(d,J＝7.8Hz,1H),7.09(d,J＝8.1Hz,1H),6.89(s,1H),6.71(d,J＝8.4Hz,1H),4.63(t,J＝16.3Hz,2H),3.80(s,1H),3.73(s,3H),3.18(dd,J＝24.7,12.4Hz,2H),3.02(d,J＝15.2Hz,1H),2.55(d,J＝15.0Hz,1H),2.00(s,3H),1.71-1.91(m,2H),1.35-1.71(m,3H),1.10(d,J＝13.6Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.94 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.36 (dd, J=15.1, 6.9 Hz, 2H), 7.21 (d, J=7.8Hz, 1H), 7.09(d, J=8.1Hz, 1H), 6.89(s, 1H), 6.71(d, J=8.4Hz, 1H), 4.63(t, J=16.3Hz, 2H) ,3.80(s,1H),3.73(s,3H),3.18(dd,J＝24.7,12.4Hz,2H),3.02(d,J＝15.2Hz,1H),2.55(d,J＝15.0Hz, 1H), 2.00(s, 3H), 1.71-1.91(m, 2H), 1.35-1.71(m, 3H), 1.10(d, J=13.6Hz, 1H).
实施例22Example 22
(1S)-1'-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺(1S)-1'-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2, 4'-Piperidin]-1-amine
Figure PCTCN2021105100-appb-000064
Figure PCTCN2021105100-appb-000064
第一步first step
(R)-N-((1S)-1'-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((1S)-1'-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-1,3-di Hydrospiro[indene-2,4'-piperidin]-1'-yl)-2-methylpropane-2-sulfinamide
室温下，将5-(2,3-二氯苯基)-4-甲氧基-6-甲基-2-(甲磺酰基)嘧啶22a(75mg,216μmol)、(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺20b(79mg,260μmol)、N-甲基吡咯烷酮(1mL)、N,N-二异丙基乙胺(28mg,216μmol)依次加入15mL单口瓶中，加热至100℃，反应18小时。反应结束后，向反应液中加入5mL水，乙酸乙酯(20mL×3)萃取，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：洗脱剂A)纯化，得到(R)-N-((1S)-1'-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-2-甲基丙烷-2-亚磺酰胺22b(70mg)，产率：56.5％。5-(2,3-Dichlorophenyl)-4-methoxy-6-methyl-2-(methylsulfonyl)pyrimidine 22a (75 mg, 216 μmol), (R)-N-( (S)-1,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 20b (79 mg, 260 μmol), N-methyl Pyrrolidone (1 mL) and N,N-diisopropylethylamine (28 mg, 216 μmol) were sequentially added to a 15 mL single-neck flask, heated to 100° C., and reacted for 18 hours. After the reaction, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was used Purification by silica gel column chromatography (eluent: eluent A) to give (R)-N-((1S)-1'-(5-(2,3-dichlorophenyl)-4-methoxy (yl)-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2-methylpropane-2-sulfinamide 22b (70 mg), yield: 56.5%.
MS m/z(ESI):573.2[M+1]MS m/z(ESI): 573.2[M+1]
第二步second step
(1S)-1'-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺(1S)-1'-(5-(2,3-dichlorophenyl)-4-methoxy-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2, 4'-Piperidin]-1-amine
将溴代丁二酰亚胺(20mg,115μmol)和(R)-N-((1S)-1'-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-2-甲基丙烷-2-亚磺酰胺22b(60mg,104μmol)加到1mL的N,N-二甲基甲酰胺中，室温反应2小时。反应结束后，反应液减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物(1S)-1'-(5-(2,3-二氯苯基)-4-甲氧基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺22(5.0mg)，产率：10％。 Bromosuccinimide (20 mg, 115 μmol) and (R)-N-((1S)-1'-(5-(2,3-dichlorophenyl)-4-methoxy-6- Methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-2-methylpropane-2-sulfinamide 22b (60 mg, 104 μmol ) was added to 1 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to afford the product (1S) -1 '- (5- (2,3- dichlorophenyl) -4-methoxy-6-methyl-2-yl) -1,3 - Dihydrospiro[indene-2,4'-piperidin]-1-amine 22 (5.0 mg), yield: 10%.
MS m/z(ESI):468.5[M+1]MS m/z(ESI): 468.5[M+1]
1H NMR(400MHz,Methanol-d 4)δ7.50(dd,J＝8.1,1.6Hz,1H),7.33-7.40(m,1H),7.29(t,J＝7.8Hz,1H),7.10-7.24(m,4H),4.63(dt,J＝13.5,4.1Hz,2H),3.94(s,1H),3.80(s,3H), 3.20-3.29(m,2H),3.16(d,J＝15.7Hz,1H),2.80(d,J＝15.7Hz,1H),1.99(s,3H),1.65-1.88(m,2H),1.50-1.62(m,1H),1.35-1.42(m,1H). 1 H NMR(400MHz,Methanol-d 4 )δ7.50(dd,J=8.1,1.6Hz,1H),7.33-7.40(m,1H),7.29(t,J=7.8Hz,1H),7.10- 7.24(m, 4H), 4.63(dt, J=13.5, 4.1Hz, 2H), 3.94(s, 1H), 3.80(s, 3H), 3.20-3.29(m, 2H), 3.16(d, J= 15.7Hz, 1H), 2.80(d, J=15.7Hz, 1H), 1.99(s, 3H), 1.65-1.88(m, 2H), 1.50-1.62(m, 1H), 1.35-1.42(m, 1H) ).
实施例23Example 23
2-((R)-2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((R)-2-Amino-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6 -Methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000065
Figure PCTCN2021105100-appb-000065
第一步first step
(R)-N-((R)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((R)-2,3-Dihydrospiro[indene-1,4'-piperidin]-2-yl)-2-methylpropane-2-sulfinamide
将三氟乙酸(1.53g,13.42mmol,1mL)和(R)-2-(((R)-叔丁基亚磺酰基)氨基)-2,3-二氢螺[茚-1,4'-哌啶]-1'-甲酸叔丁酯23a(400mg,983.81μmol)加到6mL的二氯甲烷中，室温反应2小时。反应结束后，减压浓缩，得到产物(R)-N-((R)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)-2-甲基丙烷-2-亚磺酰胺23b(287mg)，产率：95.19％，未经纯化，直接用于下一步。Trifluoroacetic acid (1.53 g, 13.42 mmol, 1 mL) and (R)-2-(((R)-tert-butylsulfinyl)amino)-2,3-dihydrospiro[indene-1,4' -Piperidine]-1'-carboxylate tert-butyl ester 23a (400 mg, 983.81 μmol) was added to 6 mL of dichloromethane and reacted at room temperature for 2 hours. After the reaction, concentrated under reduced pressure to obtain the product (R)-N-((R)-2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl)-2-methylpropane -2-Sulfinamide 23b (287 mg), yield: 95.19%, used directly in the next step without purification.
MS m/z(ESI):307.3[M+1]MS m/z(ESI): 307.3[M+1]
第二步second step
(R)-N-((R)-1'-(4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((R)-1'-(4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]- 2-yl)-2-methylpropane-2-sulfinamide
将2-氯-6-甲基-嘧啶-4-腈3a(120mg,781.41μmol)、(R)-N-((R)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)-2-甲基丙烷-2-亚磺酰胺23b(287.37mg,937.69μmol)和N,N-二异丙基乙胺(302.97mg,2.34mmol)依次加到2mL的N,N-二甲基乙酰胺中，升温至90℃，反应2小时。反应结束 后，向反应液中加入20mL水，以乙酸乙酯(30mL×2)萃取，分去水层，合并的有机相依次以饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-N-((R)-1'-(4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)-2-甲基丙烷-2-亚磺酰胺23c(170mg)，产率：51.36％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (120 mg, 781.41 μmol), (R)-N-((R)-2,3-dihydrospiro[indene-1,4'-piperidine Perid]-2-yl)-2-methylpropane-2-sulfinamide 23b (287.37 mg, 937.69 μmol) and N,N-diisopropylethylamine (302.97 mg, 2.34 mmol) were sequentially added to 2 mL of In N,N-dimethylacetamide, the temperature was raised to 90°C, and the reaction was carried out for 2 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×2), the aqueous layer was separated, the combined organic phases were washed with saturated sodium chloride solution (30 mL×2) in turn, and anhydrous sodium sulfate Drying, filtration, and concentration under reduced pressure, the obtained residue was further analyzed and purified by silica gel column chromatography (eluent: System A) to give (R)-N-((R)-1'-(4-cyano- 6-Methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl)-2-methylpropane-2-sulfinamide 23c (170 mg) , Yield: 51.36%.
MS m/z(ESI):424.0[M+1]MS m/z(ESI): 424.0[M+1]
第三步third step
(R)-2-(2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈(R)-2-(2-Amino-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-6-methylpyrimidine-4-carbonitrile
将(R)-N-((R)-1'-(4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)-2-甲基丙烷-2-亚磺酰胺23c(170mg,401.35μmol)和溴代丁二酰亚胺(85.72mg,481.62μmol)加到2mL的N,N-二甲基甲酰胺中，室温反应2小时。反应结束后，减压浓缩，得到产物(R)-2-(2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈23d(128mg)，产率：99.85％，未经纯化，直接用于下一步。(R)-N-((R)-1'-(4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidine] -2-yl)-2-methylpropane-2-sulfinamide 23c (170 mg, 401.35 μmol) and bromosuccinimide (85.72 mg, 481.62 μmol) were added to 2 mL of N,N-dimethyl In formamide, the reaction was carried out at room temperature for 2 hours. After the reaction was completed, concentrated under reduced pressure to obtain the product (R)-2-(2-amino-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-6-methyl Pyrimidine-4-carbonitrile 23d (128 mg), yield: 99.85%, used directly in the next step without purification.
MS m/z(ESI):320.1[M+H]MS m/z(ESI): 320.1[M+H]
第四步the fourth step
(R)-(1'-(4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯(R)-(1'-(4-Cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl)carbamic acid tert-butyl ester
将(R)-2-(2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈23d(128mg,400.75μmol)、二碳酸二叔丁酯(262.39mg,1.20mmol,276.20μL)和三乙胺(202.76mg,2.00mmol,278.51μL)依次加入4mL二氯甲烷中，室温反应3小时。反应结束后，加入20mL水，以二氯甲烷(20mL×3)萃取，饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-(1'-(4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯23e(60mg)，产率：35.69％。(R)-2-(2-Amino-2,3-dihydrospiro[inden-1,4'-piperidin]-1'-yl)-6-methylpyrimidine-4-carbonitrile 23d (128 mg, 400.75 μmol), di-tert-butyl dicarbonate (262.39 mg, 1.20 mmol, 276.20 μL) and triethylamine (202.76 mg, 2.00 mmol, 278.51 μL) were sequentially added to 4 mL of dichloromethane and reacted at room temperature for 3 hours. After the reaction, 20 mL of water was added, extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was filtered through silica gel Further analytical purification by column chromatography (eluent: System A) gave (R)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene] -1,4'-Piperidin]-2-yl)carbamate tert-butyl ester 23e (60 mg), yield: 35.69%.
MS m/z(ESI):420.1[M+1]MS m/z(ESI): 420.1[M+1]
第五步the fifth step
(R)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯(R)-(1'-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-2- base) tert-butyl carbamate
将(R)-(1'-(4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯23e(60mg,143.02μmol)和溴代丁二酰亚胺(33.09mg,185.93μmol)加到2mL的N,N-二甲基甲酰胺中，室温反应2小时。反应结束后，向反应液中加入30mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到(R)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯23f(70mg)，产率：98.20％，未经纯化，直接用于下一步。(R)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl)amino Tert-butyl formate 23e (60 mg, 143.02 μmol) and bromosuccinimide (33.09 mg, 185.93 μmol) were added to 2 mL of N,N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction, 30 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)- (1'-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl)carbamic acid tert-Butyl ester 23f (70 mg), yield: 98.20%, used directly in the next step without purification.
MS m/z(ESI):498.1[M+1]MS m/z(ESI): 498.1[M+1]
第六步Step 6
(R)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯(R)-(1'-(5-(2,3-Dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1, 4'-Piperidin]-2-yl)carbamic acid tert-butyl ester
氩气保护下，将(R)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯23f(70mg,140.45μmol)、(2,3-二氯苯基)硼酸1e(67.00mg,351.11μmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(13.11mg,28.09μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(11.76mg,14.04μmol)和磷酸钾(89.44mg,421.34μmol)加到2.3mL的混合溶液中(1,4-二氧六环:水＝7:1)，升温至130℃，反应4小时。反应结束后，向反应液中加入20mL水，以乙酸乙酯(30mL×3)萃取，合并有机相，饱和氯化钠洗涤两次，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂：A体系)，得到(R)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯23g(70mg)，产率：88.29％。Under argon, (R)-(1'-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1,4'- Piperidin]-2-yl)carbamate tert-butyl ester 23f (70mg, 140.45μmol), (2,3-dichlorophenyl)boronic acid 1e (67.00mg, 351.11μmol), 2-dicyclohexylphosphorus-2' ,6'-diisopropoxy-1,1'-biphenyl (13.11mg, 28.09μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1 ,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (11.76mg, 14.04μmol) and potassium phosphate (89.44mg, 421.34μmol) were added to 2.3mL of mixed solution (1,4-dioxane:water=7:1), heat up to 130 degreeC, and react for 4 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound was further analyzed and purified by silica gel column chromatography (eluent: system A) to give (R)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methyl) Pyrimidine-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-2-yl)carbamate tert-butyl ester 23 g (70 mg), yield: 88.29%.
MS m/z(ESI):565.2[M+1]MS m/z(ESI): 565.2[M+1]
第七步Step 7
2-((R)-2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((R)-2-Amino-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6 -methylpyrimidine-4-carbonitrile
将(R)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-2,3-二氢螺[茚-1,4'-哌啶]-2-基)氨基甲酸叔丁酯23g(80mg,141.72μmol)和三氟乙酸(1.53g,13.42mmol,1mL)加到4mL二氯甲烷中，室温反应1小时。反应结束后，减压浓缩，得到2-((R)-2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈23h(65.8mg)，产率：99.98％，未经纯化，直接用于下一步。(R)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-2,3-dihydrospiro[indene-1 ,4'-piperidin]-2-yl) tert-butyl carbamate 23g (80mg, 141.72μmol) and trifluoroacetic acid (1.53g, 13.42mmol, 1mL) were added to 4mL of dichloromethane, and reacted at room temperature for 1 hour. After the reaction, concentrated under reduced pressure to obtain 2-((R)-2-amino-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 23h (65.8 mg), yield: 99.98%, used directly in the next step without purification.
MS m/z(ESI):463.9[M+1]MS m/z(ESI): 463.9[M+1]
第八步Step 8
2-((R)-2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((R)-2-Amino-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6 -Methylpyrimidine-4-carboxamide
将2-((R)-2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈23h(65.8mg,141.69μmol)和6M的氢氧化钠溶液0.3mL加到2mL的乙醇中，加热至80℃，反应40分钟。反应结束后，反应液减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((R)-2-氨基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺23(23mg)，产率：33.31％。 2-((R)-2-amino-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)- 6-Methylpyrimidine-4-carbonitrile 23h (65.8 mg, 141.69 μmol) and 0.3 mL of 6M sodium hydroxide solution were added to 2 mL of ethanol, heated to 80° C., and reacted for 40 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give the product 2-((R)-2-amino-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)-6-methylpyrimidine-4-carboxamide 23 (23 mg), yield: 33.31%.
MS m/z(ESI):482.1[M+1]MS m/z(ESI): 482.1[M+1]
1H NMR(400MHz,Methanol-d 4)δ7.51(dd,J＝8.0,1.5Hz,1H),7.33-7.37(m,1H),7.30(t,J＝7.8Hz,1H),7.23-7.28(m,1H),7.13-7.22(m,3H),4.46(td,J＝12.7,12.2,6.3Hz,2H),3.66-3.87(m,3H),3.34(d,J＝6.2Hz,1H),3.29(s,1H),2.68-2.77(m,1H),2.10(s,3H),1.88-1.98(m,1H),1.80(dt,J＝13.6,4.7Hz,1H),1.64(ddd,J＝13.7,9.4,4.3Hz,1H). 1 H NMR(400MHz,Methanol-d 4 )δ7.51(dd,J=8.0,1.5Hz,1H),7.33-7.37(m,1H),7.30(t,J=7.8Hz,1H),7.23- 7.28(m,1H),7.13-7.22(m,3H),4.46(td,J=12.7,12.2,6.3Hz,2H),3.66-3.87(m,3H),3.34(d,J=6.2Hz, 1H), 3.29(s, 1H), 2.68-2.77(m, 1H), 2.10(s, 3H), 1.88-1.98(m, 1H), 1.80(dt, J=13.6, 4.7Hz, 1H), 1.64 (ddd,J=13.7,9.4,4.3Hz,1H).
实施例26Example 26
(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)pyrimidine- 4-Carboxamide
Figure PCTCN2021105100-appb-000066
Figure PCTCN2021105100-appb-000066
第一步first step
(R)-N-((S)-1'-(4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1'-(4-Cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin-1-yl)- 2-Methylpropane-2-sulfinamide
室温下，将2-氯嘧啶-4-腈26a(80mg,573.30μmol)、(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺20b(226mg,737.44μmol)、N,N-二甲基乙酰胺(3mL)和N,N-二异丙基乙胺(370.48mg,2.87mmol,499.29μL)依次加入25mL单口瓶中，升温至90℃,反应3小时。反应结束后，向反应液中加入20mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(R)-N-((S)-1'-(4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺26b(210mg)，产率：89.44％。At room temperature, 2-chloropyrimidine-4-carbonitrile 26a (80 mg, 573.30 μmol), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidine]- 1-yl)-2-methylpropane-2-sulfinamide 20b (226 mg, 737.44 μmol), N,N-dimethylacetamide (3 mL) and N,N-diisopropylethylamine (370.48 mg , 2.87mmol, 499.29μL) were successively added to the 25mL single-neck flask, heated to 90° C., and reacted for 3 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and then reduced was concentrated under pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give (R)-N-((S)-1'-(4-cyanopyrimidine-2-yl)- 1,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 26b (210 mg), yield: 89.44%.
MS m/z(ESI):410.2[M+1]MS m/z(ESI): 410.2[M+1]
第二步second step
(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile
冰浴下，将溴代丁二酰亚胺(109.52mg,615.31μmol)加至溶有(R)-N-((S)-1'-(4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺26b(210mg,512.76μmol)的N,N-二甲基甲酰胺(2mL)溶液中，室温反应2小时。反应结束后，减压浓缩，得到(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈26c(156mg)，产率：99.63％，产物不经分离纯化，直接用于下一步。Under ice bath, bromosuccinimide (109.52 mg, 615.31 μmol) was added to dissolve (R)-N-((S)-1'-(4-cyanopyrimidine-2-yl)-1 ,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 26b (210 mg, 512.76 μmol) in N,N-dimethylmethane amide (2 mL) solution at room temperature for 2 hours. After the reaction, concentrated under reduced pressure to obtain (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile 26c (156 mg), yield: 99.63%, the product was used directly in the next step without isolation and purification.
MS m/z(ESI):289.1[M-17+1]MS m/z(ESI): 289.1[M-17+1]
第三步third step
(S)-(1'-(4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(4-Cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester
将(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈26c(156mg,510.85μmol)、二碳酸二叔丁酯(334.47mg,1.53mmol)、二氯甲烷(5mL)和三乙胺(258.46mg,2.55mmol)依次加入15mL单口瓶中，室温反应3小时。反应结束后，反应液中加入20mL水，以二氯甲烷(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-(1'-(4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯26d(120mg)，产率：57.93％。(S)-2-(1-Amino-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile 26c (156 mg, 510.85 μmol), bis Di-tert-butyl carbonate (334.47 mg, 1.53 mmol), dichloromethane (5 mL) and triethylamine (258.46 mg, 2.55 mmol) were successively added to a 15 mL one-neck flask, and reacted at room temperature for 3 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and reduced in pressure. Concentration, the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (S)-(1'-(4-cyanopyrimidine-2-yl)-1,3-dihydrospiro [Indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 26d (120 mg), yield: 57.93%.
MS m/z(ESI):406.0[M+1]MS m/z(ESI): 406.0[M+1]
第四步the fourth step
(S)-(1'-(5-溴-4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(5-Bromo-4-cyanopyrimidine-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamic acid tert. Butyl ester
0℃下，向(S)-(1'-(4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯26d(120mg,295.94μmol)的二氯甲烷(2mL)溶液中慢慢加入溴代丁二酰亚胺(63.21mg,355.12μmol)，加毕，反应液升至室温，室温下反应2小时。反应结束后，向反应液中加入水(30mL)，用二氯甲烷(20mL×3)萃取，合并有机相，有机相以饱和氯化钠溶液(50mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-(1'-(5-溴-4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯26e(140mg)，产率：7.66％。To (S)-(1'-(4-cyanopyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamic acid at 0°C To a solution of tert-butyl ester 26d (120mg, 295.94μmol) in dichloromethane (2mL) was slowly added bromosuccinimide (63.21mg, 355.12μmol), after the addition, the reaction solution was warmed to room temperature, and the reaction was carried out at room temperature for 2 Hour. After the reaction, water (30 mL) was added to the reaction solution, extracted with dichloromethane (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. , concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give (S)-(1'-(5-bromo-4-cyanopyrimidine-2-yl)- 1,3-Dihydrospiro[inden-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 26e (140 mg), yield: 7.66%.
MS m/z(ESI):428.1[M+1-56]MS m/z(ESI): 428.1[M+1-56]
第五步the fifth step
(S)-(1'-(4-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine ]-1-yl) tert-butyl carbamate
氩气保护下，向微波管中依次加入(S)-(1'-(5-溴-4-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯26e(140mg,289.02μmol)、(2,3-二氯苯基)硼酸1e(137.88mg,722.56μmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(26.97mg,57.80μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(24.20mg,28.90μmol)、磷酸钾(184.05mg,867.07μmol)和2.3mL的混合溶液(1,4-二氧六环：水＝7:1)，升温至130℃，反应4小时。反应结束后，冷却至室温。向反应液中加入水(20mL)，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(30mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-(1'-(4-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯26f(150mg)，产率：94.28％。Under the protection of argon, add (S)-(1'-(5-bromo-4-cyanopyrimidine-2-yl)-1,3-dihydrospiro[indene-2,4'- Piperidin]-1-yl)carbamate tert-butyl ester 26e (140mg, 289.02μmol), (2,3-dichlorophenyl)boronic acid 1e (137.88mg, 722.56μmol), 2-dicyclohexylphosphorus-2' ,6'-diisopropoxy-1,1'-biphenyl (26.97mg, 57.80μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1 ,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (24.20 mg, 28.90 μmol), potassium phosphate (184.05 mg, 867.07 μmol) and 2.3 mL of The mixed solution (1,4-dioxane:water=7:1) was heated to 130°C and reacted for 4 hours. After the reaction was completed, it was cooled to room temperature. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure , the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain (S)-(1'-(4-cyano-5-(2,3-dichlorophenyl)pyrimidine- 2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 26f (150 mg), yield: 94.28%.
MS m/z(ESI):493.9[M+1-56]MS m/z(ESI): 493.9[M+1-56]
第六步Step 6
(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)pyrimidine- 4-Nitrile
室温下，将三氟乙酸(1.53g,13.42mmol,1mL)加至(S)-(1'-(4-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯26f(150mg,272.49μmol)的二氯甲烷(4mL)溶液中，室温下反应1小时。反应结束后，减压浓缩，得到(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈26g(122mg)，产率：99.41％。Trifluoroacetic acid (1.53 g, 13.42 mmol, 1 mL) was added to (S)-(1'-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl) at room temperature -1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 26f (150 mg, 272.49 μmol) in dichloromethane (4 mL), reaction 1 at room temperature Hour. After the reaction, concentrated under reduced pressure to obtain (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)pyrimidine-4-carbonitrile 26 g (122 mg), yield: 99.41%.
MS m/z(ESI):433.1[M-17+1]MS m/z(ESI): 433.1[M-17+1]
第七步Step 7
(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)pyrimidine- 4-Carboxamide
向(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈26g(122mg)的乙醇(2mL)溶液中加入氢氧化钠溶液(6M,0.3mL)，80℃下反应40分钟。LC-MS检测反应不完全，补加氢氧化钠溶液(6M,0.3mL)和乙醇(2mL)，80℃下继续反应40分钟。反应结束后，减压浓缩，得到的残留物用制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺26(15mg)，产率：95.41％。 To (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)pyrimidine Sodium hydroxide solution (6M, 0.3 mL) was added to a solution of 26 g (122 mg) of -4-carbonitrile in ethanol (2 mL), and the reaction was carried out at 80° C. for 40 minutes. LC-MS detected that the reaction was incomplete, sodium hydroxide solution (6M, 0.3 mL) and ethanol (2 mL) were added, and the reaction was continued at 80° C. for 40 minutes. After the reaction, it was concentrated under reduced pressure, and the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B : CH 3 CN) to give (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3- Dichlorophenyl)pyrimidine-4-carboxamide 26 (15 mg), yield: 95.41%.
MS m/z(ESI):468.2[M+1]MS m/z(ESI): 468.2[M+1]
1H NMR(400MHz,Methanol-d 4)δ8.30(d,J＝1.0Hz,1H),7.54-7.47(m,2H),7.43-7.40(m,2H),7.37-7.29(m,2H),7.22(dd,J＝7.6,1.6Hz,1H),4.82(d,J＝14.0Hz,1H),4.73(d,J＝14.2Hz,1H),4.41(s,1H),3.48-3.35(m,3H),3.23(s,2H),1.89-1.72(m,3H),1.65(d,J＝13.8Hz,1H). 1 H NMR(400MHz,Methanol-d 4 )δ8.30(d,J=1.0Hz,1H),7.54-7.47(m,2H),7.43-7.40(m,2H),7.37-7.29(m,2H) ),7.22(dd,J=7.6,1.6Hz,1H),4.82(d,J=14.0Hz,1H),4.73(d,J=14.2Hz,1H),4.41(s,1H),3.48-3.35 (m,3H),3.23(s,2H),1.89-1.72(m,3H),1.65(d,J=13.8Hz,1H).
实施例27Example 27
2-((1R,3R)-1-氨基-3-羟基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine -4-Carboxamide
Figure PCTCN2021105100-appb-000067
Figure PCTCN2021105100-appb-000067
Figure PCTCN2021105100-appb-000068
Figure PCTCN2021105100-appb-000068
第一步first step
8-氮杂螺[4.5]癸-2-烯-1-酮8-Azaspiro[4.5]dec-2-en-1-one
将1-氧代-8-氮杂螺[4.5]癸-2-烯-8-羧酸叔丁酯27a(1.1g,4.38mmol)和三氟乙酸(499.05mg,4.38mmol)溶于2mL二氯甲烷中，室温下反应1小时。反应结束后，减压浓缩，得到8-氮杂螺[4.5]癸-2-烯-1-酮27b(661mg)，产率：99.88％。1-Oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylate tert-butyl ester 27a (1.1 g, 4.38 mmol) and trifluoroacetic acid (499.05 mg, 4.38 mmol) were dissolved in 2 mL of dilute In methyl chloride, the reaction was carried out at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain 8-azaspiro[4.5]dec-2-en-1-one 27b (661 mg), yield: 99.88%.
MS m/z(ESI):152.1[M+1]MS m/z(ESI): 152.1[M+1]
第二步second step
6-甲基-2-(1-氧代-8-氮杂螺[4.5]癸-2-烯-8-基)嘧啶-4-腈6-Methyl-2-(1-oxo-8-azaspiro[4.5]dec-2-en-8-yl)pyrimidine-4-carbonitrile
将2-氯-6-甲基-嘧啶-4-腈3a(479.52mg,3.12mmol)、8-氮杂螺[4.5]癸-2-烯-1-酮27b(661mg,4.37mmol)和N,N-二异丙基乙胺(403.56mg,3.12mmol)依次溶于5mL的N,N-二甲基乙酰胺中，55℃下反应3小时。反应结束后，以乙酸乙酯(30mL)萃取，分去水层，有机相以饱和氯化钠溶液(30mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到6-甲基-2-(1-氧代-8-氮杂螺[4.5]癸-2-烯-8-基)嘧啶-4-腈27c(550mg)，产率：65.65％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (479.52 mg, 3.12 mmol), 8-azaspiro[4.5]dec-2-en-1-one 27b (661 mg, 4.37 mmol) and N , N-diisopropylethylamine (403.56 mg, 3.12 mmol) was successively dissolved in 5 mL of N,N-dimethylacetamide, and reacted at 55° C. for 3 hours. After the reaction, extracted with ethyl acetate (30 mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-methylmethane. yl-2-(1-oxo-8-azaspiro[4.5]dec-2-en-8-yl)pyrimidine-4-carbonitrile 27c (550 mg), yield: 65.65%.
MS m/z(ESI):269.1[M+1]MS m/z(ESI): 269.1[M+1]
第三步third step
(R)-2-(3-羟基-1-氧代-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈(R)-2-(3-Hydroxy-1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile
氩气保护下，将氯化亚铜(6.09mg,61.50μmol)、[1-[2-(双-对甲苯基膦酰基)-1-萘基]-2-萘基]-双(对甲苯基)膦(41.74mg,61.50umol)和叔丁醇钠(5.91mg,61.50μmol)依次溶于10mL四氢呋喃中，置换氩气，室温下搅拌30分钟后，加入联硼酸频那醇酯(572.59mg,2.25mmol)(溶于2mL四氢呋喃中)，继续搅拌10分钟后，加入6-甲基-2-(1-氧代-8-氮杂螺[4.5]癸-2-烯-8-基)嘧啶-4-腈27c(550mg,2.05mmol)(溶于2mL四氢呋喃中)，随后加入甲醇(131.35mg,4.10mmol)，置换氩气，室温下反应过夜。反应结束后，加入7mL水，随后加入过硼酸钠(1.58g,10.25mmol)，室温下剧烈搅拌1小时。过滤除去固体杂质，滤液倾入5mL碳酸氢钠和亚硫酸钠的混合溶液(V:V＝1:1)中，以乙酸乙酯(20mL×2)萃取，合并有机相， 以饱和氯化钠溶液(30mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到(R)-2-(3-羟基-1-氧代-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈27d(320mg)，产率：54.54％。Under argon, cuprous chloride (6.09 mg, 61.50 μmol), [1-[2-(bis-p-tolylphosphono)-1-naphthyl]-2-naphthyl]-bis(p-toluene base) phosphine (41.74mg, 61.50umol) and sodium tert-butoxide (5.91mg, 61.50umol) were dissolved in 10mL of tetrahydrofuran in turn, replaced with argon, stirred at room temperature for 30 minutes, added pinacol biborate (572.59mg , 2.25 mmol) (dissolved in 2 mL of tetrahydrofuran), continued stirring for 10 minutes, then added 6-methyl-2-(1-oxo-8-azaspiro[4.5]dec-2-en-8-yl) Pyrimidine-4-carbonitrile 27c (550 mg, 2.05 mmol) (dissolved in 2 mL of tetrahydrofuran), followed by methanol (131.35 mg, 4.10 mmol), replaced argon, and reacted at room temperature overnight. After the reaction, 7 mL of water was added, followed by sodium perborate (1.58 g, 10.25 mmol), and vigorously stirred at room temperature for 1 hour. The solid impurities were removed by filtration, the filtrate was poured into 5 mL of a mixed solution of sodium bicarbonate and sodium sulfite (V:V=1:1), extracted with ethyl acetate (20 mL×2), the organic phases were combined, and saturated sodium chloride solution ( 30mL×2) washed, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-2-(3-hydroxy-1-oxo-8-azaspiro[4.5]dec-8-yl) -6-Methylpyrimidine-4-carbonitrile 27d (320 mg), yield: 54.54%.
MS m/z(ESI):287.2[M+1]MS m/z(ESI): 287.2[M+1]
第四步the fourth step
(R)-2-(3-((叔丁基二甲基甲硅烷基)氧基)-1-氧代-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈(R)-2-(3-((tert-butyldimethylsilyl)oxy)-1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine -4-Nitrile
将(R)-2-(3-羟基-1-氧代-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈27d(210mg,733.42μmol)溶于3mL二氯甲烷中，冷却至-78℃，加入2,6-二甲基吡啶(157.17mg,1.47mmol)，随后滴加入叔丁基二甲硅基三氟甲磺酸酯(213.26mg,806.77μmol)(溶于3mL二氯甲烷中)，-78℃继续反应1小时。反应结束后，滴加饱和氯化铵溶液(10mL)淬灭反应，以乙酸乙酯(30mL)萃取，有机相以饱和氯化钠溶液(30mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(R)-2-(3-((叔丁基二甲基甲硅烷基)氧基)-1-氧代-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈27e(228mg)，产率：77.60％。(R)-2-(3-Hydroxy-1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 27d (210 mg, 733.42 μmol) was dissolved in In 3 mL of dichloromethane, cooled to -78°C, 2,6-lutidine (157.17 mg, 1.47 mmol) was added, followed by dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (213.26 mg, 806.77 μmol) (dissolved in 3 mL of dichloromethane), and the reaction was continued for 1 hour at -78°C. After the reaction, saturated ammonium chloride solution (10 mL) was added dropwise to quench the reaction, extracted with ethyl acetate (30 mL), the organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered , concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain (R)-2-(3-((tert-butyldimethylsilyl)oxy) -1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methylpyrimidine-4-carbonitrile 27e (228 mg), yield: 77.60%.
MS m/z(ESI):401.2[M+1]MS m/z(ESI): 401.2[M+1]
第五步the fifth step
(R)-N-((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-6-methylpyrimidin-2-yl)- 8-Azaspiro[4.5]dec-1-yl)-2-methylpropane-2-sulfinamide
将(R)-2-(3-((叔丁基二甲基甲硅烷基)氧基)-1-氧代-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈27e(236.27mg,589.81μmol)、(R)-2-甲基丙烷-2-亚磺酰胺(142.97mg,1.18mmol)和钛酸乙酯(269.13mg,1.18mmol)依次溶于3mL四氢呋喃中，65℃条件下反应16小时。随后加入0.5mL甲醇，再加入硼氢化锂(16.70mg,766.76μmol)，反应1小时。加入饱和氯化铵溶液(6mL)淬灭反应，反应液以乙酸乙酯(30mL)萃取，分去水层，有机相以饱和氯化钠溶液(30mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(R)-N-((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺27f(100mg)，产率：33.52％。(R)-2-(3-((tert-butyldimethylsilyl)oxy)-1-oxo-8-azaspiro[4.5]dec-8-yl)-6-methyl Pyrimidine-4-carbonitrile 27e (236.27mg, 589.81μmol), (R)-2-methylpropane-2-sulfinamide (142.97mg, 1.18mmol) and ethyl titanate (269.13mg, 1.18mmol) were dissolved in this order In 3 mL of tetrahydrofuran, the reaction was carried out at 65°C for 16 hours. Then, 0.5 mL of methanol was added, and then lithium borohydride (16.70 mg, 766.76 μmol) was added, and the reaction was carried out for 1 hour. Saturated ammonium chloride solution (6 mL) was added to quench the reaction, the reaction solution was extracted with ethyl acetate (30 mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (30 mL×2), and dried over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain (R)-N-((1R,3R)-3-((tert-butyldimethylformaldehyde) (ylsilyl)oxy)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)-2-methylpropane-2 - Sulfinamide 27f (100 mg), yield: 33.52%.
MS m/z(ESI):506.3[M+1]MS m/z(ESI): 506.3[M+1]
第六步Step 6
2-((1R,3R)-1-氨基-3-((叔丁基二甲基甲硅烷基)氧基)-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈2-((1R,3R)-1-amino-3-((tert-butyldimethylsilyl)oxy)-8-azaspiro[4.5]dec-8-yl)-6-methyl Pyrimidine-4-carbonitrile
将(R)-N-((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺27f(100mg,197.71μmol)溶于3mL N,N-二甲基甲酰胺中，冷却至0℃，加入N-溴代丁二酰亚胺(38.71mg,217.48μmol)，升至室温，反应过夜。反应结束后，减压浓缩，得到粗品2-((1R,3R)-1-氨基-3-((叔丁基二甲基甲硅烷基)氧基)-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈27g(79mg)，产率：99.49％。(R)-N-((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-6-methylpyrimidin-2-yl) -8-Azaspiro[4.5]dec-1-yl)-2-methylpropane-2-sulfinamide 27f (100 mg, 197.71 μmol) was dissolved in 3 mL of N,N-dimethylformamide and cooled to At 0° C., N-bromosuccinimide (38.71 mg, 217.48 μmol) was added, the temperature was raised to room temperature, and the reaction was performed overnight. After the reaction, concentrated under reduced pressure to obtain crude 2-((1R,3R)-1-amino-3-((tert-butyldimethylsilyl)oxy)-8-azaspiro[4.5]decane -8-yl)-6-methylpyrimidine-4-carbonitrile 27 g (79 mg), yield: 99.49%.
MS m/z(ESI):402.1[M+1]MS m/z(ESI): 402.1[M+1]
第七步Step 7
((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1- 基)氨基甲酸叔丁酯((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[ 4.5] Dec-1-yl) tert-butyl carbamate
将2-((1R,3R)-1-氨基-3-((叔丁基二甲基甲硅烷基)氧基)-8-氮杂螺[4.5]癸-8-基)-6-甲基嘧啶-4-腈27g(79mg,196.70μmol)、二碳酸二叔丁酯(85.86mg,393.41μmol)和N,N-二乙基乙胺(39.81mg,393.41μmol)溶于3mL二氯甲烷中，室温下反应过夜。反应结束后，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯27h(77mg)，产率：78.02％。2-((1R,3R)-1-amino-3-((tert-butyldimethylsilyl)oxy)-8-azaspiro[4.5]dec-8-yl)-6-methyl pyrimidine-4-carbonitrile 27 g (79 mg, 196.70 μmol), di-tert-butyl dicarbonate (85.86 mg, 393.41 μmol) and N,N-diethylethylamine (39.81 mg, 393.41 μmol) were dissolved in 3 mL of dichloromethane , reacted overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain ((1R,3R)-3-((tert-butyldimethylsilyl) oxy)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester 27h (77 mg), yield: 78.02%.
MS m/z(ESI):502.3[M+1]MS m/z(ESI): 502.3[M+1]
第八步Step 8
((1R,3R)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-((叔丁基二甲基甲硅烷基)氧基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯((1R,3R)-8-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-8- tert-Butyl azaspiro[4.5]dec-1-yl)carbamate
将((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯27h(77mg,153.47μmol)溶于2mL的N,N-二甲基甲酰胺中，冷却至0℃，加入N-溴代丁二酰亚胺(30.05mg,168.81μmol)，升至室温，反应过夜。反应结束后，加入20mL水，以乙酸乙酯(30mL)萃取，分去水层，有机相以饱和氯化钠溶液(30mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到((1R,3R)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-((叔丁基二甲基甲硅烷基)氧基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯27i(87mg)，产率：97.63％。((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro [4.5] tert-butyl carbamate 27h (77 mg, 153.47 μmol) was dissolved in 2 mL of N,N-dimethylformamide, cooled to 0°C, and N-bromosuccinimide was added. Amine (30.05 mg, 168.81 μmol), warmed to room temperature and reacted overnight. After the reaction, 20 mL of water was added, extracted with ethyl acetate (30 mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: system A) to give ((1R,3R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl) - tert-butyl 3-((tert-butyldimethylsilyl)oxy)-8-azaspiro[4.5]dec-1-yl)carbamate 27i (87 mg), yield: 97.63%.
MS m/z(ESI):524.2[M-56+1]MS m/z(ESI): 524.2[M-56+1]
第九步Step 9
((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methyl pyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester
将((1R,3R)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-((叔丁基二甲基甲硅烷基)氧基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯27i(87mg,149.84μmol)、(2,3-二氯苯基)硼酸1e(57.18mg,299.67μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(12.55mg,14.98μmol，RuPhos-Pd-G3)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(13.98mg,29.97μmol，RuPhos)和磷酸钾(95.46mg,449.51μmol)依次溶于2.5mL混合溶剂(1,4-二氧六环:水＝4：1)中，130℃下反应4小时。反应结束后，冷却至室温，以乙酸乙酯(30mL)萃取，分去水层，有机相以饱和氯化钠溶液(30mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯27j(70mg)，产率：72.24％。((1R,3R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-8 -Azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester 27i (87mg, 149.84μmol), (2,3-dichlorophenyl)boronic acid 1e (57.18mg, 299.67μmol), methanesulfonic acid ( 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (12.55mg, 14.98μmol, RuPhos-Pd-G3), 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (13.98mg, 29.97μmol, RuPhos) and Potassium phosphate (95.46 mg, 449.51 μmol) was sequentially dissolved in 2.5 mL of mixed solvent (1,4-dioxane:water=4:1), and reacted at 130° C. for 4 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (30 mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: system A) to give ((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4 -Cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamic acid tert-butyl ester 27j (70 mg ), yield: 72.24%.
MS m/z(ESI):646.3[M+1]MS m/z(ESI): 646.3[M+1]
第十步Step 10
2-((1R,3R)-1-氨基-3-羟基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine -4-Nitrile
将((1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-8-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯27j(70mg,108.24μmol)溶于2mL甲醇中，冷却至0℃，加入盐酸甲醇溶液(1.86mL,2M/MeOH)，室温下反应1小时后，减压浓缩，加入2mL三氟乙酸和0.5mL二氯甲烷，室温下继续反应1小时。反应结束后，减压浓缩，得到2-((1R,3R)-1-氨基-3-羟基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈27k(40mg)，产率：85.48％。((1R,3R)-3-((tert-butyldimethylsilyl)oxy)-8-(4-cyano-5-(2,3-dichlorophenyl)-6-methyl pyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate tert-butyl ester 27j (70 mg, 108.24 μmol) was dissolved in 2 mL of methanol, cooled to 0 °C, and a methanolic hydrochloric acid solution ( 1.86 mL, 2M/MeOH), reacted at room temperature for 1 hour, concentrated under reduced pressure, added 2 mL of trifluoroacetic acid and 0.5 mL of dichloromethane, and continued to react at room temperature for 1 hour. After the reaction was completed, concentrated under reduced pressure to obtain 2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichloro Phenyl)-6-methylpyrimidine-4-carbonitrile 27k (40 mg), yield: 85.48%.
MS m/z(ESI):432.1[M+1]MS m/z(ESI): 432.1[M+1]
第十一步Step 11
2-((1R,3R)-1-氨基-3-羟基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine -4-Carboxamide
将2-((1R,3R)-1-氨基-3-羟基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈27k(40mg,92.52μmol)和6M氢氧化钠水溶液(0.3mL)依次溶于2mL乙醇中，升至80℃，反应0.5小时。反应结束后，减压浓缩，得到的残留物用制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-((1R,3R)-1-氨基-3-羟基-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺27(7mg)，产率：16.80％。 2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl)-6-methyl Pyrimidine-4-carbonitrile 27k (40 mg, 92.52 μmol) and 6M aqueous sodium hydroxide solution (0.3 mL) were dissolved in 2 mL of ethanol successively, and the temperature was raised to 80° C. and reacted for 0.5 hour. After the reaction, concentrated under reduced pressure, and the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B : CH 3 CN) to give 2-((1R,3R)-1-amino-3-hydroxy-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichlorophenyl) )-6-methylpyrimidine-4-carboxamide 27 (7 mg), yield: 16.80%.
MS m/z(ESI):449.9[M+1]MS m/z(ESI): 449.9[M+1]
1H NMR(400MHz,CD 3OD)δ7.50-7.48(m,1H),7.28(t,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),4.79-4.68(m,2H),4.32(s,1H),3.19-3.13(m,2H),2.87(s,1H),2.36-2.33(m,2H),2.06(s,3H),1.66(s,4H),1.32-1.29(d,J＝12.0Hz,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.50-7.48 (m, 1H), 7.28 (t, J=8.0Hz, 1H), 7.12 (d, J=8.0Hz, 1H), 4.79-4.68 (m ,2H),4.32(s,1H),3.19-3.13(m,2H),2.87(s,1H),2.36-2.33(m,2H),2.06(s,3H),1.66(s,4H), 1.32-1.29(d, J=12.0Hz, 4H).
实施例28(对比例4)Example 28 (Comparative Example 4)
6-氨基-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺6-Amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorobenzene yl)pyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000069
Figure PCTCN2021105100-appb-000069
第一步first step
(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1'-(4-Amino-6-cyanopyrimidine-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1 -yl)-2-methylpropane-2-sulfinamide
室温下，将6-氨基-2-氯嘧啶-4-腈28a(100mg,647.01μmol)、(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺20b(218.11mg,711.71μmol)、N,N-二甲基乙酰胺(3mL)和N,N-二异丙基乙胺(418.10mg,3.24mmol,563.47μL)加入25mL单口瓶中，升温至90℃反应3小时，LC-MS监测反应不完全，90℃下继续反应过夜。反应结束后，加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺28b(274mg)，产率：99.75％。At room temperature, 6-amino-2-chloropyrimidine-4-carbonitrile 28a (100 mg, 647.01 μmol), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'- Piperidin]-1-yl)-2-methylpropane-2-sulfinamide 20b (218.11 mg, 711.71 μmol), N,N-dimethylacetamide (3 mL) and N,N-diisopropyl Ethylamine (418.10 mg, 3.24 mmol, 563.47 μL) was added to a 25 mL single-neck flask, and the temperature was raised to 90° C. to react for 3 hours. LC-MS monitored the reaction to be incomplete, and the reaction was continued at 90° C. overnight. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain residual The compound was purified by silica gel column chromatography (eluent: A system) to obtain (R)-N-((S)-1'-(4-amino-6-cyanopyrimidine-2-yl)-1, 3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 28b (274 mg), yield: 99.75%.
MS m/z(ESI):425.0[M+1]MS m/z(ESI): 425.0[M+1]
第二步second step
(S)-6-氨基-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-溴嘧啶-4-腈(S)-6-Amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-bromopyrimidine-4-carbonitrile
冰浴下，将N-溴代丁二酰亚胺(149.32mg,838.98μmol)加至(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺28b(274mg,645.37μmol)的二氯甲烷(6mL)溶液中，升至室温，反应3小时。反应结束后，减压浓缩，得到(S)-6-氨基-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-溴嘧啶-4-腈28c(257mg)，产率：99.73％，直接用于下一步。Under ice bath, N-bromosuccinimide (149.32 mg, 838.98 μmol) was added to (R)-N-((S)-1'-(4-amino-6-cyanopyrimidine-2- ( 6mL) solution, warmed to room temperature, and reacted for 3 hours. After the reaction, concentrated under reduced pressure to obtain (S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5 -Bromopyrimidine-4-carbonitrile 28c (257 mg), yield: 99.73%, used directly in the next step.
MS m/z(ESI):381.9[M+H-17]MS m/z(ESI): 381.9[M+H-17]
第三步third step
(S)-(1'-(4-氨基-5-溴-6-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(4-Amino-5-bromo-6-cyanopyrimidine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidin]-1-yl ) tert-butyl carbamate
将(S)-6-氨基-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-溴嘧啶-4-腈28c(257mg,643.65μmol)、二碳酸二叔丁酯(421.43mg,1.93mmol,443.61μL)、二氯甲烷(10mL)和三乙胺(325.65mg,3.22mmol,446.10μL)依次加入25mL单口瓶中，室温下反应2小时。反应结束后，反应液中加入20mL水，以二氯甲烷(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-(1'-(4-氨基-5-溴-6-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯28d(150mg)，产率：46.67％。.(S)-6-Amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-bromopyrimidine-4-carbonitrile 28c (257mg, 643.65μmol), di-tert-butyl dicarbonate (421.43mg, 1.93mmol, 443.61μL), dichloromethane (10mL) and triethylamine (325.65mg, 3.22mmol, 446.10μL) were sequentially added to a 25mL single-neck bottle , at room temperature for 2 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain (S)-(1'-(4-amino-5-bromo-6-cyanopyrimidine-2-yl)-1 ,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 28d (150 mg), yield: 46.67%. .
MS m/z(ESI):499.2[M+1]MS m/z(ESI): 499.2[M+1]
第四步the fourth step
((1S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯((1S)-1'-(4-Amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4 '-Piperidin]-1-yl)carbamate tert-butyl ester
氩气保护下，向微波管中依次加入(S)-(1'-(4-氨基-5-溴-6-氰基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯28d(150mg,300.36μmol)、(2,3-二氯苯基)硼酸1e(143.29 mg,750.90μmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(28.03mg,60.07μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.15mg,30.04μmol)、磷酸钾(191.27mg,901.08μmol)、1,4-二氧六环(2mL)和水(0.3mL)，氩气吹1分钟后，密封，升温至130℃，反应4小时。反应结束后，向反应液中加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(50mL×2)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到((1S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯28e(150mg)，产率：88.6％。Under the protection of argon, (S)-(1'-(4-amino-5-bromo-6-cyanopyrimidine-2-yl)-1,3-dihydrospiro[indene-2] was added to the microwave tube successively. ,4'-Piperidin-1-yl)carbamate tert-butyl ester 28d (150mg, 300.36μmol), (2,3-dichlorophenyl)boronic acid 1e (143.29 mg, 750.90μmol), 2-dicyclohexyl Phosphorus-2',6'-diisopropoxy-1,1'-biphenyl (28.03mg, 60.07μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropyl) Oxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.15 mg, 30.04 μmol), potassium phosphate (191.27 mg, 901.08 μmol) , 1,4-dioxane (2 mL) and water (0.3 mL), and after blowing with argon for 1 minute, sealed, heated to 130° C., and reacted for 4 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered , concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain ((1S)-1'-(4-amino-6-cyano-5-(2,3) -Dichlorophenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 28e (150 mg), yield: 88.6 %.
MS m/z(ESI):564.8[M+1]MS m/z(ESI): 564.8[M+1]
第五步the fifth step
6-氨基-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈6-Amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorobenzene base)pyrimidine-4-carbonitrile
室温下，将三氟乙酸(1.54g,13.51mmol,1mL)加至((1S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯28e(150mg,265.26μmol)的二氯甲烷(4mL)溶液中，室温下反应1小时。反应结束后，减压浓缩，得到6-氨基-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈28f(123mg)，产率：99.64％。Trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL) was added to ((1S)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidine- 2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 28e (150 mg, 265.26 μmol) in dichloromethane (4 mL), The reaction was carried out at room temperature for 1 hour. After the reaction, concentrated under reduced pressure to obtain 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5 -(2,3-Dichlorophenyl)pyrimidine-4-carbonitrile 28f (123 mg), yield: 99.64%.
MS m/z(ESI):464.9[M+1]MS m/z(ESI): 464.9[M+1]
第六步Step 6
6-氨基-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺6-Amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorobenzene yl)pyrimidine-4-carboxamide
向6-氨基-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈28f(123mg,265.08μmol)的乙醇(2mL)溶液中加入6M的氢氧化钠溶液(0.3mL)，80℃下反应40分钟。LC-MS检测反应不完全，补加氢氧化钠溶液(6M,0.3mL)和乙醇(2mL)，80℃下继续反应40分钟。反应结束后，减压浓缩，得到的残留物用制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到6-氨基-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺28(85mg)，产率：66.4％。 To 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichloro To a solution of phenyl)pyrimidine-4-carbonitrile 28f (123 mg, 265.08 μmol) in ethanol (2 mL) was added 6 M sodium hydroxide solution (0.3 mL), and the reaction was carried out at 80° C. for 40 minutes. LC-MS detected that the reaction was incomplete, sodium hydroxide solution (6M, 0.3 mL) and ethanol (2 mL) were added, and the reaction was continued at 80° C. for 40 minutes. After the reaction, it was concentrated under reduced pressure, and the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B : CH 3 CN) to give 6-amino-2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-( 2,3-Dichlorophenyl)pyrimidine-4-carboxamide 28 (85 mg), yield: 66.4%.
MS m/z(ESI):482.9[M+1]MS m/z(ESI): 482.9[M+1]
1H NMR(400MHz,Methanol-d 4)δ7.56(d,J＝8.1Hz,1H),7.50(d,J＝7.5Hz,1H),7.41(d,J＝6.1Hz,2H),7.34(dd,J＝10.0,6.0Hz,2H),7.21(d,J＝7.6Hz,1H),4.67(d,J＝13.9Hz,1H),4.55(d,J＝14.2Hz,1H),4.41(s,1H),3.44-3.32(m,2H),3.20(s,2H),1.91-1.68(m,3H),1.61(d,J＝13.5Hz,1H). 1 H NMR(400MHz,Methanol-d 4 )δ7.56(d,J=8.1Hz,1H),7.50(d,J=7.5Hz,1H),7.41(d,J=6.1Hz,2H),7.34 (dd,J＝10.0,6.0Hz,2H),7.21(d,J＝7.6Hz,1H),4.67(d,J＝13.9Hz,1H),4.55(d,J＝14.2Hz,1H),4.41 (s,1H),3.44-3.32(m,2H),3.20(s,2H),1.91-1.68(m,3H),1.61(d,J=13.5Hz,1H).
实施例29Example 29
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6 -Methylpyrimidine-4-carboxylic acid
Figure PCTCN2021105100-appb-000070
Figure PCTCN2021105100-appb-000070
将(S)-(1'-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯20g(1.1g,1.95mmol)和浓盐酸(6mL)加入25mL单口瓶中，升至110℃回流反应1.5小时，减压浓缩，得到的残留物用制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸29(370mg),产率：34.44％。 (S)-(1'-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2 , 4'-piperidin]-1-yl) tert-butyl carbamate 20g (1.1g, 1.95mmol) and concentrated hydrochloric acid (6mL) were added in a 25mL single-neck flask, rose to 110 ° C for reflux reaction for 1.5 hours, concentrated under reduced pressure, The resulting residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2 -((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6- Methylpyrimidine-4-carboxylic acid 29 (370 mg), yield: 34.44%.
MS m/z(ESI):483.1[M+1]MS m/z(ESI): 483.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ13.37(s,1H),8.27(s,2H),7.67(dd,J＝8.1,1.5Hz,1H),7.52(d,J＝7.3Hz,1H),7.47-7.29(m,4H),7.25(d,J＝7.6Hz,1H),4.60(dd,J＝26.0,13.5Hz,2H),4.41(d,J＝5.2Hz,1H),3.30-3.21(m,2H),3.18(s,1H),3.05(d,J＝16.2Hz,1H),2.07(s,3H),1.72(q,J＝12.4Hz,2H),1.54(d,J＝11.1Hz,2H). 1H NMR (400MHz, DMSO-d 6 ) δ 13.37(s, 1H), 8.27(s, 2H), 7.67(dd, J=8.1, 1.5Hz, 1H), 7.52(d, J=7.3Hz, 1H) ),7.47-7.29(m,4H),7.25(d,J＝7.6Hz,1H),4.60(dd,J＝26.0,13.5Hz,2H),4.41(d,J＝5.2Hz,1H),3.30 -3.21(m, 2H), 3.18(s, 1H), 3.05(d, J=16.2Hz, 1H), 2.07(s, 3H), 1.72(q, J=12.4Hz, 2H), 1.54(d, J=11.1Hz, 2H).
实施例30Example 30
2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((S)-5-Amino-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-1'-yl)-5-(2,3-dichloro Phenyl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000071
Figure PCTCN2021105100-appb-000071
Figure PCTCN2021105100-appb-000072
Figure PCTCN2021105100-appb-000072
第一步first step
(R)-N-((S)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-5,7-Dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinyl Amide
将(S)-5-(((R)-叔丁基亚磺酰基)氨基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-羧酸叔丁酯30a(200mg,490.71μmol)溶于4mL二氯甲烷中，加入三氟乙酸(1mL)，室温反应40分钟。LC-MS检测反应完全。减压浓缩，得到(R)-N-((S)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺30b(150.87mg)，直接用于下一步。(S)-5-(((R)-tert-butylsulfinyl)amino)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'- The tert-butyl carboxylate 30a (200 mg, 490.71 μmol) was dissolved in 4 mL of dichloromethane, trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 40 minutes. The reaction was complete as detected by LC-MS. Concentrate under reduced pressure to give (R)-N-((S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane -2-Sulfinamide 30b (150.87 mg), used directly in the next step.
MS m/z(ESI):308.2[M+1]MS m/z(ESI): 308.2[M+1]
第二步和第三步Second and third steps
(S)-2-(5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈30c(S)-2-(5-Amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-6-methylpyrimidine-4-carbonitrile 30c
(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯30d(S)-(1'-(4-Cyano-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5 - base) tert-butyl carbamate 30d
将(R)-N-((S)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺30b(150.87mg,490.71μmol)、2-氯-6-甲基-嘧啶-4-腈3a(75.36mg,490.71μmol)、N,N-二甲基乙酰胺(4mL)和N,N-二异丙基乙胺(317.10mg,2.45mmol)依次加入15mL单口瓶中，升至90℃反应6小时。反应结束后，将反应液降至室温，得到含有(S)-2-(5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-6-甲基嘧啶-4-腈30c的反应液，不处理，直接向反应液中加入N,N-二异丙基乙胺(190.26mg,1.47mmol)和二碳酸二叔丁酯(267.75mg,1.23mmol)，室温下反应4小时。LC-MS监测反应完全。向反应液中加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的 残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯30d(80mg)，产率：38.77％。(R)-N-((S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-ylidene Sulfonamide 30b (150.87 mg, 490.71 μmol), 2-chloro-6-methyl-pyrimidine-4-carbonitrile 3a (75.36 mg, 490.71 μmol), N,N-dimethylacetamide (4 mL) and N,N - Diisopropylethylamine (317.10 mg, 2.45 mmol) was successively added to a 15 mL single-neck flask, and the temperature was raised to 90° C. to react for 6 hours. After the reaction, the reaction solution was lowered to room temperature to obtain (S)-2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1' -yl)-6-methylpyrimidine-4-carbonitrile 30c reaction solution, without treatment, directly added N,N-diisopropylethylamine (190.26mg, 1.47mmol) and di-tert-butyl dicarbonate to the reaction solution The ester (267.75 mg, 1.23 mmol) was reacted at room temperature for 4 hours. The reaction was complete as monitored by LC-MS. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The compound was purified by silica gel column chromatography (eluent: A system) to obtain (S)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-5,7-dihydrospiro [Cyclopenta[b]pyridin-6,4'-piperidin]-5-yl)carbamate tert-butyl ester 30d (80 mg), yield: 38.77%.
MS m/z(ESI):421.2[M+1]MS m/z(ESI): 421.2[M+1]
第四步the fourth step
(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯(S)-(1'-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine tert-butyl pyridin]-5-yl)carbamate
将(S)-(1'-(4-氰基-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯30d(80mg,190.25μmol)溶于4mL二氯甲烷中，加入N-溴代丁二酰亚胺(37.25mg,209.27μmol)，反应过夜。LC-MS显示反应完。减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯30e(60mg)，产率：63.15％。(S)-(1'-(4-cyano-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]- 5-yl) tert-butyl carbamate 30d (80 mg, 190.25 μmol) was dissolved in 4 mL of dichloromethane, N-bromosuccinimide (37.25 mg, 209.27 μmol) was added, and the reaction was carried out overnight. LC-MS showed the reaction was complete. Concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (S)-(1'-(5-bromo-4-cyano-6-methylpyrimidine-2) -yl)-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-5-yl)carbamate tert-butyl ester 30e (60 mg), yield: 63.15%.
MS m/z(ESI):499.1[M+1]MS m/z(ESI): 499.1[M+1]
第五步the fifth step
((5S)-1'-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯((5S)-1'-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b ]pyridin-6,4'-piperidin]-5-yl)carbamic acid tert-butyl ester
室温下，将(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯30e(60mg,120.14μmol)、(2,3-二氯苯基)硼酸1e(68.78mg,360.43μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(10.06mg,12.01μmol,RuPhos-Pd-G3)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(11.21mg,24.03μmol,RuPhos)、磷酸钾(76.54mg,360.43μmol)、2mL 1,4-二氧六环和0.3mL水加入10mL微波管中，置换氩气3次，密封，升温至140℃反应4小时。LC-MS监测反应完全。向反应液中加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到((5S)-1'-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯30f(60mg)，产率：88.31％。At room temperature, (S)-(1'-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6, 4'-Piperidin]-5-yl)carbamate tert-butyl ester 30e (60mg, 120.14μmol), (2,3-dichlorophenyl)boronic acid 1e (68.78mg, 360.43μmol), methanesulfonic acid (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (10.06 mg, 12.01μmol, RuPhos-Pd-G3), 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (11.21mg, 24.03μmol, RuPhos), potassium phosphate (76.54 mg, 360.43 μmol), 2 mL of 1,4-dioxane and 0.3 mL of water were added to a 10 mL microwave tube, argon was replaced for 3 times, sealed, and the temperature was raised to 140° C. to react for 4 hours. The reaction was complete as monitored by LC-MS. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The compound was purified by silica gel column chromatography (eluent: A system) to obtain ((5S)-1'-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidine) -2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)carbamate 30f (60 mg), yield: 88.31%.
MS m/z(ESI):565.2[M+1]MS m/z(ESI): 565.2[M+1]
第六步Step 6
2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈2-((S)-5-Amino-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-1'-yl)-5-(2,3-dichloro Phenyl)-6-methylpyrimidine-4-carbonitrile
室温下，将((5S)-1'-(4-氰基-5-(2,3-二氯苯基)-6-甲基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)氨基甲酸叔丁酯30f(60mg,106.10μmol)溶于4mL二氯甲烷中，加入1mL三氟乙酸，室温反应40分钟。LC-MS监测反应完全。减压浓缩，得到2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈30g(49.38mg)，直接用于下一步。At room temperature, ((5S)-1'-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-5,7-dihydrospiro[ Cyclopenta[b]pyridin-6,4'-piperidin]-5-yl)carbamate tert-butyl ester 30f (60 mg, 106.10 μmol) was dissolved in 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 40 minutes . The reaction was complete as monitored by LC-MS. Concentrate under reduced pressure to give 2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2 , 3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile 30 g (49.38 mg) was used directly in the next step.
MS m/z(ESI):465.1[M+1]MS m/z(ESI): 465.1[M+1]
第七步Step 7
2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺2-((S)-5-Amino-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-1'-yl)-5-(2,3-dichloro Phenyl)-6-methylpyrimidine-4-carboxamide
将2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-腈30g(49.38mg,106.11μmol)、甲醇(1.5mL)、饱和氢氧化钠溶液(1mL)和双氧水(0.5mL)依次加入15mL单口瓶中，室温搅拌40分钟。LC-MS监测反应完全。减压浓缩，得到的残留物用制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-甲酰胺30(4.16mg)，产率：7.67％。 2-((S)-5-Amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2,3-dihydro Chlorophenyl)-6-methylpyrimidine-4-carbonitrile 30g (49.38mg, 106.11μmol), methanol (1.5mL), saturated sodium hydroxide solution (1mL) and hydrogen peroxide (0.5mL) were sequentially added to a 15mL single-neck flask, Stir at room temperature for 40 minutes. The reaction was complete as monitored by LC-MS. Concentrated under reduced pressure, the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN ) to give 2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2,3 -Dichlorophenyl)-6-methylpyrimidine-4-carboxamide 30 (4.16 mg), yield: 7.67%.
MS m/z(ESI):483.1[M+1]MS m/z(ESI): 483.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.62-8.51(m,1H),8.37(s,2H),8.00(s,1H),7.92(d,J＝7.7Hz,1H),7.60(dd,J＝8.1,1.5Hz,1H),7.43(s,1H),7.40-7.30(m,2H),7.20(d,J＝7.5Hz,1H),4.75(d,J＝12.4Hz,1H),4.67(s,1H),4.48(s,1H),3.25(q,J＝15.3,12.3Hz,3H),3.14(d,J＝16.8Hz,1H),2.03(s,3H),1.74(s,2H),1.56(t,J＝15.1Hz,2H). 1H NMR (400MHz, DMSO-d 6 ) δ 8.62-8.51(m, 1H), 8.37(s, 2H), 8.00(s, 1H), 7.92(d, J=7.7Hz, 1H), 7.60(dd , J＝8.1, 1.5Hz, 1H), 7.43(s, 1H), 7.40-7.30(m, 2H), 7.20(d, J＝7.5Hz, 1H), 4.75(d, J＝12.4Hz, 1H) ,4.67(s,1H),4.48(s,1H),3.25(q,J=15.3,12.3Hz,3H),3.14(d,J=16.8Hz,1H),2.03(s,3H),1.74( s,2H),1.56(t,J＝15.1Hz,2H).
实施例31Example 31
6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)pyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000073
Figure PCTCN2021105100-appb-000073
Figure PCTCN2021105100-appb-000074
Figure PCTCN2021105100-appb-000074
第一步first step
(R)-N-((S)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinyl Amide
室温下，将(S)-5-(((R)-叔丁基亚磺酰基)氨基)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-羧酸叔丁酯31a(300mg,736.07μmol)溶于4mL二氯甲烷中，加入三氟乙酸(1mL)。室温反应1小时。LC-MS监测反应完全。减压浓缩，得到(R)-N-((S)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺31b(226mg)，产率：99.86％，粗品直接用于下一步反应。At room temperature, (S)-5-(((R)-tert-butylsulfinyl)amino)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine]- 1'-Carboxylic acid tert-butyl ester 31a (300 mg, 736.07 μmol) was dissolved in 4 mL of dichloromethane and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction was complete as monitored by LC-MS. Concentrate under reduced pressure to give (R)-N-((S)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane -2-Sulfinamide 31b (226 mg), yield: 99.86%, the crude product was directly used in the next reaction.
MS m/z(ESI):308.1[M+1]MS m/z(ESI): 308.1[M+1]
第二步second step
(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1'-(4-Amino-6-cyanopyrimidine-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'- piperidin]-5-yl)-2-methylpropane-2-sulfinamide
向单口瓶中加入(R)-N-((S)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺31b(150mg,487.88μmol)、1,2-二氯乙烷(5mL)和N,N-二异丙基乙胺(150.52mg,1.16mmol)，搅拌1分钟后，加入6-氨基-2-氯嘧啶-4-腈28a(60mg,388.21μmol)，升温至66℃反应3小时。LC-MS检测反应完全。将反应液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺31c(130mg)，产率：78.69％。Add (R)-N-((S)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane to the one-necked flask -2-Sulfinamide 31b (150 mg, 487.88 μmol), 1,2-dichloroethane (5 mL) and N,N-diisopropylethylamine (150.52 mg, 1.16 mmol), after stirring for 1 min, added 6-Amino-2-chloropyrimidine-4-carbonitrile 28a (60 mg, 388.21 μmol) was heated to 66° C. and reacted for 3 hours. The reaction was complete as detected by LC-MS. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain (R)-N-((S)-1'-(4-amino-6-cyano) ( 130 mg), yield: 78.69%.
MS m/z(ESI):426.0[M+1]MS m/z(ESI): 426.0[M+1]
第三步third step
6-氨基-5-溴-2-(5-氧代-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈6-Amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile
将(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺31c(130mg,305.49μmol)溶于2mL二氯甲烷中，冰浴下加入N-溴代丁二酰亚胺(70.68mg,397.13μmol)，升至室温反应3小时。LC-MS监测反应完全，减压浓缩，得到6-氨基-5-溴-2-(5-氧代-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈31d(110mg)，产率：90.19％，直接用于下一步。(R)-N-((S)-1'-(4-amino-6-cyanopyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4' -Piperidin]-5-yl)-2-methylpropane-2-sulfinamide 31c (130 mg, 305.49 μmol) was dissolved in 2 mL of dichloromethane, and N-bromosuccinimide ( 70.68 mg, 397.13 μmol), warmed to room temperature and reacted for 3 hours. LC-MS monitored the completion of the reaction, and concentrated under reduced pressure to obtain 6-amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine) ]-1'-yl)pyrimidine-4-carbonitrile 31d (110 mg), yield: 90.19%, used directly in the next step.
MS m/z(ESI):399.0[M+H]MS m/z(ESI): 399.0[M+H]
第四步the fourth step
6-氨基-5-(2,3-二氯苯基)-2-(5-氧代-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈6-Amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine]-1 '-yl)pyrimidine-4-carbonitrile
向微波管中依次加入6-氨基-5-溴-2-(5-氧代-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈31d(110mg,275.52μmol)、(2,3-二氯苯基)硼酸1e(131.44mg,688.80μmol)、2-二环 己基磷-2',6'-二异丙氧基-1,1'-联苯(25.71mg,55.10μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(23.07mg,27.55μmol)、磷酸钾(175.45mg,826.56μmol)、1,4-二氧六环(2mL)和水(0.3mL)，置换氩气3次后封管，升温至130℃，反应4小时。LC-MS监测反应完全。向反应夜中加入水(10mL)，以乙酸乙酯(10mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到6-氨基-5-(2,3-二氯苯基)-2-(5-氧代-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈31e(100mg)，产率：78.00％。6-Amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridin-6,4'-piperidin]-1'-yl was sequentially added to the microwave tube ) pyrimidine-4-carbonitrile 31d (110mg, 275.52μmol), (2,3-dichlorophenyl)boronic acid 1e (131.44mg, 688.80μmol), 2-dicyclohexylphosphorus-2',6'-diisopropyl Oxy-1,1'-biphenyl (25.71 mg, 55.10 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl ) (2-amino-1,1'-biphenyl-2-yl)palladium(II) (23.07 mg, 27.55 μmol), potassium phosphate (175.45 mg, 826.56 μmol), 1,4-dioxane (2 mL) ) and water (0.3 mL), replace the argon gas for 3 times, seal the tube, raise the temperature to 130° C., and react for 4 hours. The reaction was complete as monitored by LC-MS. Water (10 mL) was added to the reaction night, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 6-amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7- Dihydrospiro[cyclopenta[c]pyridin-6,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile 31e (100 mg), yield: 78.00%.
MS m/z(ESI):465.0[M+1]MS m/z(ESI): 465.0[M+1]
第五步the fifth step
(R)-N-((Z)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)螺[环戊[c]吡啶-6,4'-哌啶]-5(7H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((Z)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)spiro[cyclopenta[c]pyridine -6,4'-Piperidine]-5(7H)-Alkylene)-2-methylpropane-2-sulfinamide
将6-氨基-5-(2,3-二氯苯基)-2-(5-氧代-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈31e(160mg,343.84μmol)、(R)-2-甲基丙烷-2-亚磺酰胺(104.18mg,859.60μmol)和钛酸四乙酯(2mL)依次溶于1mL四氢呋喃中，90℃下反应3小时。反应结束后，向反应液中加入水(10mL)，以乙酸乙酯(20mL)萃取，分去水层，有机相以饱和氯化钠溶液(20mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到(R)-N-((Z)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)螺[环戊[c]吡啶-6,4'-哌啶]-5(7H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺31f(195mg)，产率：99.75％。6-amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidine]- 1'-yl)pyrimidine-4-carbonitrile 31e (160 mg, 343.84 μmol), (R)-2-methylpropane-2-sulfinamide (104.18 mg, 859.60 μmol) and tetraethyl titanate (2 mL) in turn It was dissolved in 1 mL of tetrahydrofuran and reacted at 90°C for 3 hours. After the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (20 mL×2), and dried over anhydrous sodium sulfate, Filtration and concentration under reduced pressure gave (R)-N-((Z)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)spiro [Cyclopenta[c]pyridine-6,4'-piperidine]-5(7H)-alkylene)-2-methylpropane-2-sulfinamide 31f (195 mg), yield: 99.75%.
第六步Step 6
(R)-N-((5S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((5S)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro [Cyclopenta[c]pyridin-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide
将(R)-N-((Z)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)螺[环戊[c]吡啶-6,4'-哌啶]-5(7H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺31f(195mg,343.00μmol)溶于8mL四氢呋喃中，室温下加入9-硼双环[3.3.1]壬烷(1.37mL,0.5M in THF)，室温下反应2小时。LC-MS监测反应完全。向反应液中加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-N-((5S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺31g(90mg)，产率：45.99％。(R)-N-((Z)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)spiro[cyclopenta[c] Pyridine-6,4'-piperidine]-5(7H)-alkylene)-2-methylpropane-2-sulfinamide 31f (195 mg, 343.00 μmol) was dissolved in 8 mL of tetrahydrofuran, and 9- Borabicyclo[3.3.1]nonane (1.37 mL, 0.5 M in THF), react at room temperature for 2 hours. The reaction was complete as monitored by LC-MS. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The compound was purified by silica gel column chromatography (eluent: B system) to obtain (R)-N-((5S)-1'-(4-amino-6-cyano-5-(2,3-di Chlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinyl Amide 31 g (90 mg), yield: 45.99%.
MS m/z(ESI):570.2[M+1]MS m/z(ESI): 570.2[M+1]
第七步Step 7
6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)pyrimidine-4-carbonitrile
室温下，将(R)-N-((5S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺31g(90.16mg,158.02μmol)溶于的4mL二氯甲烷中，加入盐酸甲醇溶液(2mL,4M)，室温反应2小时。LC-MS检测反应完全。减压浓缩，得到6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧 啶-4-腈31h(70mg)，直接用于下一步反应。At room temperature, (R)-N-((5S)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7 - Dihydrospiro[cyclopenta[c]pyridin-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide 31 g (90.16 mg, 158.02 μmol) dissolved in 4 mL of In methyl chloride, methanol solution of hydrochloric acid (2 mL, 4M) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was complete as detected by LC-MS. Concentration under reduced pressure gave 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridin-6,4'-piperidin]-1'-yl)- 5-(2,3-Dichlorophenyl)pyrimidine-4-carbonitrile 31h (70 mg) was used directly in the next reaction.
MS m/z(ESI):466.1[M+1]MS m/z(ESI): 466.1[M+1]
第八步Step 8
6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)pyrimidine-4-carboxamide
将6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈31h(70mg,150.42μmol)溶于2mL乙醇中，加入氢氧化钠溶液(0.3mL,6M)，80℃下反应40分钟。LC-MS检测反应完全。减压浓缩，得到的残留物通过制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[c]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺31(25mg)，产率：27.77％。 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-1'-yl)-5-(2 ,3-Dichlorophenyl)pyrimidine-4-carbonitrile 31h (70mg, 150.42μmol) was dissolved in 2mL of ethanol, sodium hydroxide solution (0.3mL, 6M) was added, and the reaction was carried out at 80°C for 40 minutes. The reaction was complete as detected by LC-MS. Concentrated under reduced pressure, the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN ) to give 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4'-piperidin]-1'-yl)-5- (2,3-Dichlorophenyl)pyrimidine-4-carboxamide 31 (25 mg), yield: 27.77%.
MS m/z(ESI):484.1[M+1]MS m/z(ESI): 484.1[M+1]
1H NMR(400MHz,Methanol-d 4)δ8.81-8.69(m,2H),7.88(d,J＝5.5Hz,1H),7.56(dd,J＝8.1,1.5Hz,1H),7.34(t,J＝7.9Hz,1H),7.21(dd,J＝7.7,1.5Hz,1H),4.73(d,J＝6.7Hz,3H),3.49(d,J＝16.8Hz,1H),3.35(d,J＝2.6Hz,2H),3.27(d,J＝9.6Hz,1H),1.96(t,J＝11.0Hz,1H),1.78(dt,J＝19.7,8.4Hz,2H),1.61(d,J＝13.4Hz,1H). 1H NMR(400MHz,Methanol-d 4 )δ8.81-8.69(m,2H),7.88(d,J=5.5Hz,1H),7.56(dd,J=8.1,1.5Hz,1H),7.34(t , J＝7.9Hz, 1H), 7.21(dd, J＝7.7, 1.5Hz, 1H), 4.73(d, J＝6.7Hz, 3H), 3.49(d, J＝16.8Hz, 1H), 3.35(d , J=2.6Hz, 2H), 3.27(d, J=9.6Hz, 1H), 1.96(t, J=11.0Hz, 1H), 1.78(dt, J=19.7, 8.4Hz, 2H), 1.61(d ,J=13.4Hz,1H).
实施例32Example 32
6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)pyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000075
Figure PCTCN2021105100-appb-000075
Figure PCTCN2021105100-appb-000076
Figure PCTCN2021105100-appb-000076
第一步first step
(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1'-(4-amino-6-cyanopyrimidine-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'- piperidin]-5-yl)-2-methylpropane-2-sulfinamide
向单口瓶中加入(R)-N-((S)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺30b(226mg,735.07μmol)、1,2-二氯乙烷(5mL)和N,N-二异丙基乙胺(250.86mg,1.94mmol)，搅拌1分钟后，加入6-氨基-2-氯嘧啶-4-腈28a(100mg,647.01μmol)，升温至66℃反应3小时。LC-MS检测反应完全。将反应液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺32a(275mg)，产率：99.88％。Add (R)-N-((S)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane to the single-necked flask -2-Sulfinamide 30b (226 mg, 735.07 μmol), 1,2-dichloroethane (5 mL) and N,N-diisopropylethylamine (250.86 mg, 1.94 mmol), after stirring for 1 minute, added 6-Amino-2-chloropyrimidine-4-carbonitrile 28a (100 mg, 647.01 μmol) was heated to 66° C. and reacted for 3 hours. The reaction was complete as detected by LC-MS. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain (R)-N-((S)-1'-(4-amino-6-cyano) ( 275 mg), yield: 99.88%.
MS m/z(ESI):425.9[M+1]MS m/z(ESI): 425.9[M+1]
第二步second step
6-氨基-5-溴-2-(5-氧代-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈6-Amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile
将(R)-N-((S)-1'-(4-氨基-6-氰基嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺32a(275mg,646.22μmol)溶于5mL二氯甲烷中，冰浴下加入N-溴代丁二酰亚胺(172.53mg,969.34μmol)，升至室温反应2小时。LC-MS监测反应完全，向反应液中加入水(10mL)，以二氯甲烷萃取(10mL×2)，合并有机相，以饱和氯化钠溶液(10mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到6-氨基-5-溴-2-(5-氧代-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈32b(258mg)，产率：99.74％。(R)-N-((S)-1'-(4-amino-6-cyanopyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4' -Piperidin]-5-yl)-2-methylpropane-2-sulfinamide 32a (275 mg, 646.22 μmol) was dissolved in 5 mL of dichloromethane, and N-bromosuccinimide ( 172.53 mg, 969.34 μmol), warmed to room temperature and reacted for 2 hours. LC-MS monitored the completion of the reaction, water (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), and dried over anhydrous sodium sulfate, Filtration and concentration under reduced pressure gave 6-amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'- yl)pyrimidine-4-carbonitrile 32b (258 mg), yield: 99.74%.
MS m/z(ESI):399.1[M+H]MS m/z(ESI): 399.1[M+H]
第三步third step
6-氨基-5-(2,3-二氯苯基)-2-(5-氧代-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈6-Amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1 '-yl)pyrimidine-4-carbonitrile
向微波管中依次加入6-氨基-5-溴-2-(5-氧代-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈32b(250mg,626.18μmol)、(2,3-二氯苯基)硼酸1e(298.72mg,1.57mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(58.44mg,125.24μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(52.43mg,62.62μmol)、磷酸钾(398.75mg,1.88mmol)、1,4-二氧六环(2mL)和水(0.3mL)，置换氩气3次后封管，升温至130℃，反应4小时。LC-MS监测反应完全。向反应夜中加入水(10mL)，以乙酸乙酯(10mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得 到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到6-氨基-5-(2,3-二氯苯基)-2-(5-氧代-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈32c(120mg)，产率：41.18％。Add 6-amino-5-bromo-2-(5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-1'-yl in turn to the microwave tube ) pyrimidine-4-carbonitrile 32b (250mg, 626.18μmol), (2,3-dichlorophenyl)boronic acid 1e (298.72mg, 1.57mmol), 2-dicyclohexylphosphorus-2',6'-diisopropyl Oxy-1,1'-biphenyl (58.44mg, 125.24μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) ) (2-amino-1,1'-biphenyl-2-yl)palladium(II) (52.43 mg, 62.62 μmol), potassium phosphate (398.75 mg, 1.88 mmol), 1,4-dioxane (2 mL) ) and water (0.3 mL), replace the argon gas for 3 times, seal the tube, raise the temperature to 130° C., and react for 4 hours. The reaction was complete as monitored by LC-MS. Water (10 mL) was added to the reaction night, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 6-amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7- Dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile 32c (120 mg), yield: 41.18%.
MS m/z(ESI):465.2[M+1]MS m/z(ESI): 465.2[M+1]
第四步the fourth step
(R)-N-((Z)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)螺[环戊[b]吡啶-6,4'-哌啶]-5(7H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((Z)-1'-(4-Amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)spiro[cyclopenta[b]pyridine -6,4'-Piperidine]-5(7H)-Alkylene)-2-methylpropane-2-sulfinamide
将6-氨基-5-(2,3-二氯苯基)-2-(5-氧代-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)嘧啶-4-腈32c(120mg,257.88μmol)、(R)-2-甲基丙烷-2-亚磺酰胺(78.14mg,644.70μmol)和钛酸四乙酯(2mL)依次溶于1mL四氢呋喃中，90℃下反应3小时。反应结束后，向反应液中加入水(10mL)，以乙酸乙酯(20mL)萃取，分去水层，有机相依次以饱和氯化钠溶液(20mL×2)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到(R)-N-((Z)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)螺[环戊[b]吡啶-6,4'-哌啶]-5(7H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺32d(146mg)，产率：99.58％。6-amino-5-(2,3-dichlorophenyl)-2-(5-oxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]- 1'-yl)pyrimidine-4-carbonitrile 32c (120 mg, 257.88 μmol), (R)-2-methylpropane-2-sulfinamide (78.14 mg, 644.70 μmol) and tetraethyl titanate (2 mL) in turn It was dissolved in 1 mL of tetrahydrofuran and reacted at 90°C for 3 hours. After the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL), the aqueous layer was separated, the organic phase was washed with saturated sodium chloride solution (20 mL×2) in turn, and dried over anhydrous sodium sulfate. , filtered and concentrated under reduced pressure to give (R)-N-((Z)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl) Spiro[cyclopenta[b]pyridine-6,4'-piperidine]-5(7H)-alkylene)-2-methylpropane-2-sulfinamide 32d (146 mg), yield: 99.58%.
MS m/z(ESI):568.2[M+1]MS m/z(ESI): 568.2[M+1]
第五步the fifth step
(R)-N-((5S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((5S)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro [Cyclopenta[b]pyridin-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinamide
室温下，将(R)-N-((Z)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)螺[环戊[b]吡啶-6,4'-哌啶]-5(7H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺32d(146mg,256.81μmol)溶于4mL四氢呋喃中，加入9-硼双环[3.3.1]壬烷(0.5M in THF,1.03mL)，室温下反应2小时，LC-MS监测反应完全。向反应液中加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)纯化，得到(R)-N-((5S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺32e(100mg)，产率：68.25％。(R)-N-((Z)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)spiro[cyclopenta] [b]Pyridine-6,4'-piperidine]-5(7H)-alkylene)-2-methylpropane-2-sulfinamide 32d (146 mg, 256.81 μmol) was dissolved in 4 mL of tetrahydrofuran, and 9 -borabicyclo[3.3.1]nonane (0.5M in THF, 1.03mL), react at room temperature for 2 hours, and the reaction is complete by LC-MS monitoring. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The compound was purified by silica gel column chromatography (eluent: B system) to obtain (R)-N-((5S)-1'-(4-amino-6-cyano-5-(2,3-di Chlorophenyl)pyrimidin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfinyl Amide 32e (100 mg), yield: 68.25%.
MS m/z(ESI):570.2[M+1]MS m/z(ESI): 570.2[M+1]
第六步Step 6
6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)pyrimidine-4-carbonitrile
室温下，将(R)-N-((5S)-1'-(4-氨基-6-氰基-5-(2,3-二氯苯基)嘧啶-2-基)-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺32e(100mg,175.27μmol)溶于的4mL二氯甲烷中，加入盐酸甲醇溶液(2mL，4M)，室温反应2小时。LC-MS检测显示反应完全。减压浓缩，得到6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈32f(81mg)，直接用于下一步反应。At room temperature, (R)-N-((5S)-1'-(4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-5,7 - Dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfenamide 32e (100 mg, 175.27 μmol) in 4 mL of dichloro In methane, methanol solution of hydrochloric acid (2 mL, 4M) was added, and the reaction was carried out at room temperature for 2 hours. LC-MS showed the reaction was complete. Concentration under reduced pressure gave 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridin-6,4'-piperidin]-1'-yl)- 5-(2,3-Dichlorophenyl)pyrimidine-4-carbonitrile 32f (81 mg) was used directly in the next reaction.
MS m/z(ESI):466.1[M+1]MS m/z(ESI): 466.1[M+1]
第七步Step 7
6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)pyrimidine-4-carboxamide
将6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-腈32f(49mg,105.07μmol)溶于3mL乙醇中，加入氢氧化钠溶液(0.3mL,6M)，80℃下反应40分钟。LC-MS检测显示反应完全。减压浓缩，得到的残留物通过制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺32(20mg)，产率：39.30％。 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2 ,3-dichlorophenyl)pyrimidine-4-carbonitrile 32f (49 mg, 105.07 μmol) was dissolved in 3 mL of ethanol, sodium hydroxide solution (0.3 mL, 6 M) was added, and the reaction was carried out at 80° C. for 40 minutes. LC-MS showed the reaction was complete. Concentrated under reduced pressure, the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN ) to give 6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5- (2,3-Dichlorophenyl)pyrimidine-4-carboxamide 32 (20 mg), yield: 39.30%.
MS m/z(ESI):483.9[M+1]MS m/z(ESI): 483.9[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.31(d,J＝5.0Hz,1H),7.74(s,1H),7.65(d,J＝7.5Hz,1H),7.51(dd,J＝8.1,1.5Hz,1H),7.29(t,J＝7.8Hz,1H),7.23-7.08(m,3H),6.12(s,2H),4.56(t,J＝13.3Hz,2H),3.88(s,1H),3.10(dd,J＝15.2,4.8Hz,3H),2.74(d,J＝16.3Hz,1H),1.80-1.70(m,2H),1.63(dd,J＝13.3,9.6Hz,1H),1.49(d,J＝13.4Hz,2H),1.06(dd,J＝15.6,9.8Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.31 (d, J=5.0 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.51 (dd, J= 8.1,1.5Hz,1H),7.29(t,J＝7.8Hz,1H),7.23-7.08(m,3H),6.12(s,2H),4.56(t,J＝13.3Hz,2H),3.88( s,1H),3.10(dd,J＝15.2,4.8Hz,3H),2.74(d,J＝16.3Hz,1H),1.80-1.70(m,2H),1.63(dd,J＝13.3,9.6Hz ,1H),1.49(d,J＝13.4Hz,2H),1.06(dd,J＝15.6,9.8Hz,1H).
实施例35Example 35
6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟酸6-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichlorophenyl)-2 - Methylisonicotinic acid
Figure PCTCN2021105100-appb-000077
Figure PCTCN2021105100-appb-000077
第一步first step
(R)-N-((S)-1'-(4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1'-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]- 1-yl)-2-methylpropane-2-sulfinamide
将(R)-N-((S)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺20b(309mg,1.01mmol)、2-氯-6-甲基异烟碱腈5a(153.84mg,1.01mmol)、碳酸钾(696.72mg,5.04mmol)和 N-甲基吡咯烷酮(8mL)加入25mL微波管中，密封，升至130℃，反应5小时。反应结束后，向反应液中加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(R)-N-((S)-1'-(4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺35a(160mg)，产率：37.55％。(R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 20b (309 mg , 1.01mmol), 2-chloro-6-methylisonicotinonitrile 5a (153.84mg, 1.01mmol), potassium carbonate (696.72mg, 5.04mmol) and N-methylpyrrolidone (8mL) were added to a 25mL microwave tube, Sealed, warmed to 130°C, and reacted for 5 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure , the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain (R)-N-((S)-1'-(4-cyano-6-methylpyridine-2- yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 35a (160 mg), yield: 37.55%.
MS m/z(ESI):423.2[M+1]MS m/z(ESI): 423.2[M+1]
第二步second step
(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基异烟腈(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-methylisonicotinonitrile
将(R)-N-((S)-1'-(4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺35a(160mg,378.62μmol)溶于3mL甲醇中，加入浓盐酸(0.5mL)，室温下反应过夜。反应结束后，减压浓缩，得到(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基异烟腈35b(120.56mg)，直接用于下一步。(R)-N-((S)-1'-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine] -1-yl)-2-methylpropane-2-sulfinamide 35a (160 mg, 378.62 μmol) was dissolved in 3 mL of methanol, concentrated hydrochloric acid (0.5 mL) was added, and the reaction was carried out at room temperature overnight. After the reaction, concentrated under reduced pressure to obtain (S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-methyliso Nicotinonitrile 35b (120.56 mg) was used directly in the next step.
MS m/z(ESI):319.2[M+1]MS m/z(ESI): 319.2[M+1]
第三步third step
(S)-(1'-(4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(4-Cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamic acid tert-butyl ester
将(S)-2-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-甲基异烟腈35b(120.56mg,378.63μmol)、二氯甲烷(5mL)、三乙胺(191.49mg,1.89mmol)和二碳酸二叔丁酯(247.91mg,1.14mmol)依次加入15mL单口瓶中，室温下反应4小时。LC-MS监测反应完全。向反应液中加入20mL水，以二氯甲烷(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-(1'-(4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯35c(100mg)，产率：63.10％。(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-methylisonicotinonitrile 35b (120.56 mg, 378.63 μmol), dichloromethane (5 mL), triethylamine (191.49 mg, 1.89 mmol) and di-tert-butyl dicarbonate (247.91 mg, 1.14 mmol) were successively added to a 15 mL single-neck flask, and reacted at room temperature for 4 hours. The reaction was complete as monitored by LC-MS. 20 mL of water was added to the reaction solution, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: A system) to give (S)-(1'-(4-cyano-6-methylpyridin-2-yl)-1,3-di Hydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 35c (100 mg), yield: 63.10%.
MS m/z(ESI):419.2[M+1]MS m/z(ESI): 419.2[M+1]
第四步the fourth step
(S)-(1'-(5-溴-4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯(S)-(1'-(5-Bromo-4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1- base) tert-butyl carbamate
将(S)-(1'-(4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯35c(100mg,238.93μmol)溶于二氯甲烷(5mL)中，加入N-溴代丁二酰亚胺(42.53mg,238.93μmol)，室温下反应过夜。LC-MS监测反应完全。向反应液中加入20mL水，以二氯甲烷(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(S)-(1'-(5-溴-4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯35d(115mg)，产率：96.76％。(S)-(1'-(4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)amino Tert-butyl formate 35c (100 mg, 238.93 μmol) was dissolved in dichloromethane (5 mL), N-bromosuccinimide (42.53 mg, 238.93 μmol) was added, and the reaction was carried out at room temperature overnight. The reaction was complete as monitored by LC-MS. 20 mL of water was added to the reaction solution, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: A system) to give (S)-(1'-(5-bromo-4-cyano-6-methylpyridin-2-yl)-1 ,3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 35d (115 mg), yield: 96.76%.
MS m/z(ESI):497.1[M+1]MS m/z(ESI): 497.1[M+1]
第五步the fifth step
((1S)-1'-(4-氰基-5-(2,3-二氯苯基)-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸 叔丁酯((1S)-1'-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2, 4'-Piperidin]-1-yl)carbamate tert-butyl ester
将(S)-(1'-(5-溴-4-氰基-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯35d(115mg,231.19μmol)、(2,3-二氯苯基)硼酸1e(88.23mg,462.38μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(19.36mg,23.12μmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(21.58mg,46.24μmol)、磷酸钾(147.29mg,693.57μmol)、1,4-二氧六环(2.5mL)和水(0.3mL)加入10mL微波管中，氩气吹1分钟，密封，升至130℃，反应3小时。反应结束后，向反应液中加入20mL水，以乙酸乙酯(20mL×3)萃取，合并有机相，以饱和氯化钠溶液(20mL)洗涤，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到((1S)-1'-(4-氰基-5-(2,3-二氯苯基)-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯35e(130mg)，产率：99.79％。(S)-(1'-(5-Bromo-4-cyano-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1 -yl) tert-butyl carbamate 35d (115mg, 231.19μmol), (2,3-dichlorophenyl)boronic acid 1e (88.23mg, 462.38μmol), methanesulfonic acid (2-dicyclohexylphosphino-2' ,6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (19.36 mg, 23.12 μmol), 2- Dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (21.58mg, 46.24μmol), potassium phosphate (147.29mg, 693.57μmol), 1,4-dioxane (2.5 mL) and water (0.3 mL) were added to a 10 mL microwave tube, blown with argon for 1 minute, sealed, heated to 130° C., and reacted for 3 hours. After the reaction, 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and then reduced was concentrated under pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain ((1S)-1'-(4-cyano-5-(2,3-dichlorophenyl)) -6-Methylpyridin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 35e (130 mg), yield: 99.79% .
MS m/z(ESI):563.2[M+1]MS m/z(ESI): 563.2[M+1]
第六步Step 6
6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟酸6-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichlorophenyl)-2 - Methylisonicotinic acid
将((1S)-1'-(4-氰基-5-(2,3-二氯苯基)-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯35e(60mg,106.47μmol)和浓盐酸(1.5mL)加入10mL微波管中，升至130℃反应3小时。减压浓缩，得到的残留物通过制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟酸35(10.55mg)，产率：18％。 ((1S)-1'-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2 ,4'-piperidin]-1-yl)carbamate tert-butyl ester 35e (60 mg, 106.47 μmol) and concentrated hydrochloric acid (1.5 mL) were added to a 10 mL microwave tube, and the reaction was heated to 130° C. for 3 hours. Concentrated under reduced pressure, the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN ) to give 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichlorophenyl )-2-methylisonicotinic acid 35 (10.55 mg), yield: 18%.
MS m/z(ESI):482.1[M+1]MS m/z(ESI): 482.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ13.04(s,1H),8.25(s,2H),7.62(dd,J＝8.1,1.4Hz,1H),7.52(d,J＝7.3Hz,1H),7.46-7.27(m,4H),7.23-7.15(m,1H),7.05(s,1H),4.37(dd,J＝16.4,9.7Hz,2H),4.24(d,J＝13.5Hz,1H),3.23-3.10(m,3H),3.05(d,J＝16.2Hz,1H),2.04(s,3H),1.74(t,J＝12.6Hz,2H),1.53(dd,J＝23.5,13.1Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 8.25 (s, 2H), 7.62 (dd, J=8.1, 1.4 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.46-7.27(m, 4H), 7.23-7.15(m, 1H), 7.05(s, 1H), 4.37(dd, J=16.4, 9.7Hz, 2H), 4.24(d, J=13.5Hz ,1H),3.23-3.10(m,3H),3.05(d,J=16.2Hz,1H),2.04(s,3H),1.74(t,J=12.6Hz,2H),1.53(dd,J= 23.5, 13.1Hz, 2H).
实施例36Example 36
6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟酰胺6-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichlorophenyl)-2 - Methylisonicotinamide
Figure PCTCN2021105100-appb-000078
Figure PCTCN2021105100-appb-000078
Figure PCTCN2021105100-appb-000079
Figure PCTCN2021105100-appb-000079
第一步first step
6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟腈6-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichlorophenyl)-2 - Methylisonicotinonitrile
将((1S)-1'-(4-氰基-5-(2,3-二氯苯基)-6-甲基吡啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯35e(33mg,58.56μmol)溶于二氯甲烷(2mL)中，加入三乙胺(0.5mL)，室温下反应40分钟。减压浓缩，得到6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟腈36a(27.14mg)，直接用于下一步。((1S)-1'-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyridin-2-yl)-1,3-dihydrospiro[indene-2 ,4'-piperidin]-1-yl)carbamate tert-butyl ester 35e (33 mg, 58.56 μmol) was dissolved in dichloromethane (2 mL), triethylamine (0.5 mL) was added, and the reaction was carried out at room temperature for 40 minutes. Concentration under reduced pressure gave 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichloro Phenyl)-2-methylisonicotinonitrile 36a (27.14 mg) was used directly in the next step.
MS m/z(ESI):463.1[M+1]MS m/z(ESI): 463.1[M+1]
第二步second step
6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟酰胺6-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichlorophenyl)-2 - Methylisonicotinamide
室温下，将6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟腈36a(27.14mg,58.57μmol)、甲醇(1.5mL)、饱和氢氧化钠溶液(1mL)和双氧水(0.5mL)依次加入15mL单口瓶中，室温下反应2小时。LC-MS显示反应完全。减压浓缩，得到的残留物通过制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到6-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-3-(2,3-二氯苯基)-2-甲基异烟酰胺36(11.02mg)，产率：31.28％。 At room temperature, 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichlorobenzene base)-2-methylisonicotinonitrile 36a (27.14mg, 58.57μmol), methanol (1.5mL), saturated sodium hydroxide solution (1mL) and hydrogen peroxide (0.5mL) were sequentially added to a 15mL single-neck flask, and the reaction was carried out at room temperature for 2 Hour. LC-MS showed the reaction was complete. Concentrated under reduced pressure, the obtained residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN ) to give 6-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-3-(2,3-dichlorophenyl )-2-methylisonicotinamide 36 (11.02 mg), yield: 31.28%.
MS m/z(ESI):481.1[M+1]MS m/z(ESI): 481.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.24(s,2H),7.67(s,1H),7.59(d,J＝8.1Hz,1H),7.52(d,J＝7.4Hz,1H),7.45-7.31(m,4H),7.28(s,1H),7.20(d,J＝7.5Hz,1H),6.79(s,1H),4.48-4.30(m,2H),4.29-4.17(m,1H),3.16(q,J＝14.9,13.2Hz,3H),3.04(d,J＝16.3Hz,1H),2.03(s,3H),1.79-1.68(m,2H),1.54(dd,J＝28.7,13.3Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.24(s, 2H), 7.67(s, 1H), 7.59(d, J=8.1Hz, 1H), 7.52(d, J=7.4Hz, 1H) ,7.45-7.31(m,4H),7.28(s,1H),7.20(d,J=7.5Hz,1H),6.79(s,1H),4.48-4.30(m,2H),4.29-4.17(m ,1H),3.16(q,J＝14.9,13.2Hz,3H),3.04(d,J＝16.3Hz,1H),2.03(s,3H),1.79-1.68(m,2H),1.54(dd, J=28.7, 13.3Hz, 2H).
实施例37和38Examples 37 and 38
(S)-6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺37(S)-6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5 -(2,3-Dichlorophenyl)pyrimidine-4-carboxamide 37
(R)-6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺38(R)-6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5 -(2,3-Dichlorophenyl)pyrimidine-4-carboxamide 38
Figure PCTCN2021105100-appb-000080
Figure PCTCN2021105100-appb-000080
6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺32(960mg，1.99mmol)通过SFC手性拆分(柱型号：ChiralPak IC,250×30mm I.D.,10μm；流动相：A for CO 2and B for Ethanol(0.1％NH 3H 2O)；柱压：100bar；流速：80mL/min；检测波长：220nm；柱温：38℃)，纯化后，得到(S)-6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺37(保留时间(T R)：4.037min；360mg)和(R)-6-氨基-2-((S)-5-氨基-5,7-二氢螺[环戊[b]吡啶-6,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)嘧啶-4-甲酰胺38(保留时间(T R)：6.957min；564mg)。 6-Amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)pyrimidine-4-carboxamide 32 (960 mg, 1.99 mmol) was chiral resolved by SFC (column type: ChiralPak IC, 250×30 mm ID, 10 μm; mobile phase: A for CO 2 and B for Ethanol (0.1% NH 3 H 2 O); column pressure: 100 bar; flow rate: 80 mL/min; detection wavelength: 220 nm; column temperature: 38° C.), after purification, (S)-6-amino-2-(( S)-5-Amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)pyrimidine -4-Carboxamide 37 (retention time ( TR ): 4.037 min; 360 mg) and (R)-6-amino-2-((S)-5-amino-5,7-dihydrospiro[cyclopenta[ b] Pyridin-6,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide 38 (retention time ( TR ): 6.957 min; 564 mg ).
37 MS m/z(ESI):483.9[M+1]37 MS m/z(ESI): 483.9[M+1]
1H NMR(400MHz,CD 3OD)δ8.34(d,J＝5.2Hz,1H),7.83(d,J＝7.6Hz,1H),7.49(dd,J＝8.1,1.5Hz,1H),7.35–7.23(m,2H),7.14(dd,J＝7.6,1.5Hz,1H),4.67(d,J＝14.3Hz,3H),4.02(s,1H),3.28–3.17(m,3H),2.92(d,J＝16.5Hz,1H),1.82(dtd,J＝31.3,12.6,4.4Hz,2H),1.64–1.51(m,1H),1.42–1.33(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.34 (d, J=5.2Hz, 1H), 7.83 (d, J=7.6Hz, 1H), 7.49 (dd, J=8.1, 1.5Hz, 1H), 7.35–7.23 (m, 2H), 7.14 (dd, J=7.6, 1.5Hz, 1H), 4.67 (d, J=14.3Hz, 3H), 4.02 (s, 1H), 3.28–3.17 (m, 3H) ,2.92(d,J＝16.5Hz,1H),1.82(dtd,J＝31.3,12.6,4.4Hz,2H),1.64–1.51(m,1H),1.42–1.33(m,1H).
38 MS m/z(ESI):483.9[M+1]38 MS m/z(ESI): 483.9[M+1]
1H NMR(400MHz,CD 3OD)δ8.55(d,J＝5.0Hz,1H),8.00(d,J＝7.7Hz,1H),7.50(dd,J＝8.1,1.4Hz,1H),7.44–7.26(m,2H),7.15(dd,J＝7.6,1.5Hz,1H),4.73(ddt,J＝37.2,14.3,4.2Hz,2H),4.52(s,1H),3.36–3.31(m,1H),3.26(ddd,J＝13.7,9.7,7.3Hz,3H),1.83(dtd,J＝26.0,12.4,4.4Hz,2H),1.75–1.67(m,1H),1.66–1.56(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.55 (d, J=5.0Hz, 1H), 8.00 (d, J=7.7Hz, 1H), 7.50 (dd, J=8.1, 1.4Hz, 1H), 7.44–7.26 (m, 2H), 7.15 (dd, J=7.6, 1.5Hz, 1H), 4.73 (ddt, J=37.2, 14.3, 4.2Hz, 2H), 4.52 (s, 1H), 3.36–3.31 ( m, 1H), 3.26 (ddd, J=13.7, 9.7, 7.3Hz, 3H), 1.83 (dtd, J=26.0, 12.4, 4.4Hz, 2H), 1.75–1.67 (m, 1H), 1.66–1.56 ( m,1H).
实施例39和40Examples 39 and 40
(R)-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39(R)-2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorobenzene base)-6-methylpyrimidine-4-carboxylic acid 39
(S)-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸 40(S)-2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorobenzene base)-6-methylpyrimidine-4-carboxylic acid 40
Figure PCTCN2021105100-appb-000081
Figure PCTCN2021105100-appb-000081
第一步first step
2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid
将2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸29(350mg,724.05μmol)溶于10mL二氯甲烷中，依次加入三乙胺(366.34mg,3.62mmol)和二碳酸二叔丁酯(474.08mg,2.17mmol)，室温搅拌反应3小时。反应结束后，减压浓缩，得到2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39a(422.49mg)。2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)- 6-Methylpyrimidine-4-carboxylic acid 29 (350 mg, 724.05 μmol) was dissolved in 10 mL of dichloromethane, followed by addition of triethylamine (366.34 mg, 3.62 mmol) and di-tert-butyl dicarbonate (474.08 mg, 2.17 mmol) ), and the reaction was stirred at room temperature for 3 hours. After the reaction, concentrated under reduced pressure to obtain 2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1' -yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39a (422.49 mg).
MS m/z(ESI):583.2[M+1]MS m/z(ESI): 583.2[M+1]
第二步second step
(R)-2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39b(R)-2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5 -(2,3-Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39b
(S)-2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39c(S)-2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5 -(2,3-Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39c
2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39a(422.49mg,724.06μmol)经SFC手性拆分(柱型号：ChiralPak IC,250×30mm I.D.,10μm；流动相：A for CO 2and B for Methanol(0.1％NH 3H 2O)；比例：B 40％；柱压：100bar；流速：60mL/min；检测波长：220nm；柱温：38℃)纯化后，得到(R)-2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39b(保留时间(T R)：1.578min；147mg)和(S)-2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39c(保留时间(T R)：2.389min；107mg)。 2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2, 3-Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39a (422.49 mg, 724.06 μmol) was chiral resolved by SFC (column type: ChiralPak IC, 250×30 mm ID, 10 μm; mobile phase: A for CO 2 and B for Methanol (0.1% NH 3 H 2 O); ratio: B 40%; column pressure: 100 bar; flow rate: 60 mL/min; detection wavelength: 220 nm; column temperature: 38 °C) After purification, ( R)-2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5- (2,3-Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39b (retention time ( TR ): 1.578 min; 147 mg) and (S)-2-((S)-1-( (tert-Butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6- Methylpyrimidine-4-carboxylic acid 39c (retention time ( TR ): 2.389 min; 107 mg).
39b MS m/z(ESI):583.2[M+1]39b MS m/z(ESI): 583.2[M+1]
39c MS m/z(ESI):583.2[M+1]39c MS m/z(ESI): 583.2[M+1]
第三步third step
(R)-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39(R)-2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorobenzene base)-6-methylpyrimidine-4-carboxylic acid 39
将(R)-2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39b(140mg,239.93μmol)溶于5mL二氧六环中，加入4M的氯化氢的1,4-二氧六环溶液(43.74mg,1.20mmol)，室温下搅拌反应过夜。反应结束后，减压浓缩，将所得固体溶于正己烷中，打浆后浓缩干，得到(R)-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39(105mg)，产率：84.18％。(R)-2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)- 5-(2,3-Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39b (140 mg, 239.93 μmol) was dissolved in 5 mL of dioxane, and 4M of hydrogen chloride in 1,4-dioxane was added The hexacyclic solution (43.74 mg, 1.20 mmol) was stirred at room temperature overnight. After the reaction, concentrated under reduced pressure, the obtained solid was dissolved in n-hexane, beaten and concentrated to dryness to obtain (R)-2-((S)-1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39 (105 mg), yield: 84.18%.
MS m/z(ESI):483.1[M+1]MS m/z(ESI): 483.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.75-8.36(m,3H),7.67(d,J＝8.0Hz,1H),7.62(d,J＝7.4Hz,1H),7.46-7.29(m,4H),7.26(d,J＝7.4Hz,1H),4.60(dd,J＝29.3,13.4Hz,2H),4.37(d,J＝5.4Hz,1H),3.31-3.15(m,3H),3.07-3.03(m,1H),2.07(s,3H),1.87-1.66(m,2H),1.55(t,J＝15.2Hz,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.75-8.36(m,3H),7.67(d,J=8.0Hz,1H),7.62(d,J=7.4Hz,1H),7.46-7.29( m, 4H), 7.26 (d, J=7.4Hz, 1H), 4.60 (dd, J=29.3, 13.4Hz, 2H), 4.37 (d, J=5.4Hz, 1H), 3.31-3.15 (m, 3H) ), 3.07-3.03(m, 1H), 2.07(s, 3H), 1.87-1.66(m, 2H), 1.55(t, J=15.2Hz, 2H).
第四步the fourth step
(S)-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸40(S)-2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichlorobenzene base)-6-methylpyrimidine-4-carboxylic acid 40
将(S)-2-((S)-1-((叔丁氧基羰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸39c(105mg,179.95μmol)溶于5mL二氧六环中，加入4M的氯化氢的1,4-二氧六环溶液(32.80mg,899.74μmol)，室温下搅拌反应过夜。反应结束后，减压浓缩，将所得固体溶于正己烷中，打浆后浓缩干，得到(S)-2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯苯基)-6-甲基嘧啶-4-羧酸40(68mg)，产率：72.69％。(S)-2-((S)-1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)- 5-(2,3-Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 39c (105mg, 179.95μmol) was dissolved in 5mL dioxane, and 4M hydrogen chloride in 1,4-dioxane was added Hexacyclic solution (32.80 mg, 899.74 μmol) was stirred at room temperature overnight. After the reaction, concentrated under reduced pressure, the obtained solid was dissolved in n-hexane, beaten and concentrated to dryness to obtain (S)-2-((S)-1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidin]-1'-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 40 (68 mg), yield: 72.69%.
MS m/z(ESI):483.1[M+1]MS m/z(ESI): 483.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.52(s,3H),7.67(dd,J＝8.1,1.5Hz,1H),7.61(d,J＝7.4Hz,1H),7.42(t,J＝7.9Hz,1H),7.36(d,J＝6.0Hz,2H),7.30-7.20(m,2H),4.61(dd,J＝28.3,13.5 Hz,2H),4.37(d,J＝5.4Hz,1H),3.22(d,J＝15.6Hz,3H),3.03(d,J＝16.2Hz,1H),2.07(s,3H),1.75(dd,J＝12.3,4.1Hz,2H),1.55(t,J＝14.7Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (s, 3H), 7.67 (dd, J=8.1, 1.5 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.42 (t, J＝7.9Hz, 1H), 7.36(d, J＝6.0Hz, 2H), 7.30-7.20(m, 2H), 4.61(dd, J＝28.3, 13.5 Hz, 2H), 4.37(d, J＝5.4 Hz, 1H), 3.22(d, J＝15.6Hz, 3H), 3.03(d, J＝16.2Hz, 1H), 2.07(s, 3H), 1.75(dd, J＝12.3, 4.1Hz, 2H), 1.55(t,J=14.7Hz,2H).
实施例41Example 41
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(3-氯-2-氟吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(3-chloro-2-fluoropyridine-4- yl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000082
Figure PCTCN2021105100-appb-000082
第一步first step
((S)-1'-(5-(3-氯-2-氟吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯((S)-1'-(5-(3-Chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[ tert-butyl indene-2,4'-piperidin]-1-yl)carbamate
将(S)-(1'-(5-溴-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯20f(300mg,601.91μmol)、(3-氯-2-氟吡啶-4-基)硼酸41a(158.32mg,902.86μmol)、甲烷磺酸(2-二环己基膦-2',6'-二甲氧基联苯)(2'-甲胺基-1,1'-联苯-2-基)钯(102.37mg,120.38μmol)和磷酸钾(510.42mg,2.41mmol)依次加入到3.6mL的混合溶液中(1,4-二氧六环:水＝5:1)，氩气置换三次，用冷凝管回流，100℃下持续搅拌1小时，冷到室温，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到((S)-1'-(5-(3-氯-2-氟吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯41b(140mg)，产率：42.36％。(S)-(1'-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1 -yl) tert-butyl carbamate 20f (300mg, 601.91μmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid 41a (158.32mg, 902.86μmol), methanesulfonic acid (2-dicyclohexylphosphine) -2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium (102.37mg, 120.38μmol) and potassium phosphate (510.42mg, 2.41 mmol) was successively added to 3.6 mL of mixed solution (1,4-dioxane: water=5:1), replaced with argon three times, refluxed with a condenser, continued stirring at 100 ° C for 1 hour, cooled to room temperature, Concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: system A) to give ((S)-1'-(5-(3-chloro-2-fluoropyridin-4-yl)) -4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 41b (140 mg), Yield: 42.36%.
MS m/z(ESI):549.2[M+1]MS m/z(ESI): 549.2[M+1]
第二步second step
((S)-1'-(5-(3-氯-2-氟吡啶-4-基)-4-氨基甲酰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯((S)-1'-(5-(3-Chloro-2-fluoropyridin-4-yl)-4-carbamoyl-6-methylpyrimidin-2-yl)-1,3-dihydrospiro [Indene-2,4'-piperidin]-1-yl)carbamic acid tert-butyl ester
将碳酸钾(7.54mg,54.64μmol)和((S)-1'-(5-(3-氯-2-氟吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯41b(15mg,27.32μmol)加到1mL的二甲基亚砜中，冰浴下，将0.25mL的30％的双氧水慢慢滴加到反应液中，在冰浴下搅拌30分钟，反应结束后，向反应液中加入水(20mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，减压浓缩，得到((S)-1'-(5-(3-氯-2-氟吡啶-4-基)-4-氨基甲酰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯41c(15mg)，产率：96.82％，未经纯化，直接进行下一步反应。Potassium carbonate (7.54 mg, 54.64 μmol) and ((S)-1'-(5-(3-chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidine-2- yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 41b (15 mg, 27.32 μmol) was added to 1 mL of dimethyl sulfoxide, ice Under the bath, 0.25 mL of 30% hydrogen peroxide was slowly added dropwise to the reaction solution, and stirred under an ice bath for 30 minutes. After the reaction was completed, water (20 mL) was added to the reaction solution, and ethyl acetate (10 mL×3 ) extraction, the organic phases were combined and concentrated under reduced pressure to give ((S)-1'-(5-(3-chloro-2-fluoropyridin-4-yl)-4-carbamoyl-6-methylpyrimidine- 2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 41c (15 mg), yield: 96.82%, proceeded directly without purification next reaction.
MS m/z(ESI):567.2[M+1]MS m/z(ESI): 567.2[M+1]
第三步third step
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(3-氯-2-氟吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(3-chloro-2-fluoropyridine-4- yl)-6-methylpyrimidine-4-carboxamide
将((S)-1'-(5-(3-氯-2-氟吡啶-4-基)-4-氨基甲酰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯41c(15mg,26.45μmol)和0.5mL的三氟乙酸加到2mL的二氯甲烷中，室温搅拌2小时，反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(3-氯-2-氟吡啶-4-基)-6-甲基嘧啶-4-甲酰胺41(5mg)，产率：31.88％。 ((S)-1'-(5-(3-Chloro-2-fluoropyridin-4-yl)-4-carbamoyl-6-methylpyrimidin-2-yl)-1,3-dihydro Spiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 41c (15mg, 26.45μmol) and 0.5mL of trifluoroacetic acid were added to 2mL of dichloromethane, stirred at room temperature for 2 hours, After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give the product 2 - ((S) -1- amino-1,3-dihydro-spiro [indene-2,4'-piperidin] -1'-yl) -5- (3-chloro - 2-Fluoropyridin-4-yl)-6-methylpyrimidine-4-carboxamide 41 (5 mg), yield: 31.88%.
MS m/z(ESI):467.2[M+1]MS m/z(ESI): 467.2[M+1]
实施例42Example 42
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(3-氯-2-氨基吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(3-chloro-2-aminopyridine-4- yl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000083
Figure PCTCN2021105100-appb-000083
第一步first step
((S)-1'-(5-(3-氯-2-氨基吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯((S)-1'-(5-(3-Chloro-2-aminopyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[ tert-butyl indene-2,4'-piperidin]-1-yl)carbamate
将((S)-1'-(5-(3-氯-2-氟吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯41b(80mg,145.71μmol)和8mL的28％的一水合氨加到3mL的二甲基亚砜中，密封，加热到115℃，反应4.5小时，冷却至室温，减压浓缩，用稀盐酸调pH＝7-8，再用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到((S)-1'-(5-(3-氯-2-氨基吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯42a(10mg)，产率：12.17％。((S)-1'-(5-(3-Chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro [Indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 41b (80 mg, 145.71 μmol) and 8 mL of 28% ammonia monohydrate were added to 3 mL of dimethyl sulfoxide, sealed, Heated to 115°C, reacted for 4.5 hours, cooled to room temperature, concentrated under reduced pressure, adjusted pH=7-8 with dilute hydrochloric acid, extracted with ethyl acetate (10 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, reduced was concentrated under pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give ((S)-1'-(5-(3-chloro-2-aminopyridin-4-yl)- 4-Cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamic acid tert-butyl ester 42a (10 mg), yielded Rate: 12.17%.
MS m/z(ESI):546.3[M+1]MS m/z(ESI): 546.3[M+1]
第二步second step
((S)-1'-(5-(3-氯-2-氨基吡啶-4-基)-4-氨基甲酰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯((S)-1'-(5-(3-Chloro-2-aminopyridin-4-yl)-4-carbamoyl-6-methylpyrimidin-2-yl)-1,3-dihydrospiro [Indene-2,4'-piperidin]-1-yl)carbamic acid tert-butyl ester
将((S)-1'-(5-(3-氯-2-氨基吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯42a(12mg,26.73μmol)和0.5mL的6N的氢氧化钠溶液加到2mL的乙醇中，加热到80℃，反应1小时，反应结束后，直接减压浓缩，得到((S)-1'-(5-(3-氯-2-氨基吡啶-4-基)-4-氨基甲酰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯42b(10mg)，产率：66.33％，未经纯化，直接进行下一步反应。((S)-1'-(5-(3-Chloro-2-aminopyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-1,3-dihydrospiro [Indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 42a (12 mg, 26.73 μmol) and 0.5 mL of 6N sodium hydroxide solution were added to 2 mL of ethanol, heated to 80 °C, The reaction was carried out for 1 hour. After the reaction was completed, it was directly concentrated under reduced pressure to obtain ((S)-1'-(5-(3-chloro-2-aminopyridin-4-yl)-4-carbamoyl-6-methyl) Pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 42b (10 mg), yield: 66.33%, without purification, Proceed directly to the next reaction.
MS m/z(ESI):564.2[M+1]MS m/z(ESI): 564.2[M+1]
第三步third step
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(3-氯-2-氨基吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(3-chloro-2-aminopyridine-4- yl)-6-methylpyrimidine-4-carboxamide
将((S)-1'-(5-(3-氯-2-氨基吡啶-4-基)-4-氨基甲酰基-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)氨基甲酸叔丁酯42b(10mg,17.73μmol)和0.6mL的三氟乙酸加到2mL的二氯甲烷中，室温搅拌1小时，反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(3-氯-2-氨基吡啶-4-基)-6-甲基嘧啶-4-甲酰胺42(3mg)，产率：34.65％。 ((S)-1'-(5-(3-Chloro-2-aminopyridin-4-yl)-4-carbamoyl-6-methylpyrimidin-2-yl)-1,3-dihydro Spiro[indene-2,4'-piperidin]-1-yl)carbamate tert-butyl ester 42b (10 mg, 17.73 μmol) and 0.6 mL of trifluoroacetic acid were added to 2 mL of dichloromethane, stirred at room temperature for 1 hour, After the reaction, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give the product 2 - ((S) -1- amino-1,3-dihydro-spiro [indene-2,4'-piperidin] -1'-yl) -5- (3-chloro - 2-Aminopyridin-4-yl)-6-methylpyrimidine-4-carboxamide 42 (3 mg), yield: 34.65%.
MS m/z(ESI):464.1[M+1]MS m/z(ESI): 464.1[M+1]
实施例43Example 43
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichloropyridin-4-yl )-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000084
Figure PCTCN2021105100-appb-000084
第一步first step
5-(3-氯-2-甲氧基吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈5-(3-Chloro-2-methoxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine] ]-1'-yl)pyrimidine-4-carbonitrile
将5-溴-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈43a(200mg,503.44μmol)、(3-氯-2-甲氧基吡啶-4-基)硼酸43b(141.51mg,755.16μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(42.16mg,50.34μmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(46.92mg,100.69μmol)和磷酸钾(320.19mg,1.51mmol)依次加入到1.2mL的混合溶液中(1,4-二氧六环:水＝5:1)，氩气置换三次，115℃反应3小时，冷到室温，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到5-(3-氯-2-甲氧基吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈43c(190mg)，产率：82％。5-Bromo-6-methyl-2-(1-oxo-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile 43a ( 200mg, 503.44μmol), (3-chloro-2-methoxypyridin-4-yl)boronic acid 43b (141.51mg, 755.16μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (42.16mg, 50.34μmol), 2-dicyclohexylphosphorus-2' ,6'-diisopropoxy-1,1'-biphenyl (46.92mg, 100.69μmol) and potassium phosphate (320.19mg, 1.51mmol) were added to 1.2mL of mixed solution (1,4-dioxo Hexacyclic:water=5:1), replaced by argon three times, reacted at 115°C for 3 hours, cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-(3-Chloro-2-methoxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine] ]-1'-yl)pyrimidine-4-carbonitrile 43c (190 mg), yield: 82%.
MS m/z(ESI):460.2[M+1]MS m/z(ESI): 460.2[M+1]
第二步second step
5-(3-氯-2-羟基吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈5-(3-Chloro-2-hydroxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]- 1'-yl)pyrimidine-4-carbonitrile
将5-(3-氯-2-甲氧基吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈43c(200mg,434.85μmol)和3mL的4M的盐酸二氧六环溶液加到1mL的二氯甲烷中，密封加热到100℃，反应2小时，反应结束后，加入少许氨甲醇溶液中和，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到5-(3-氯-2-羟基吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈43d(140mg)，产率：72.20％。5-(3-Chloro-2-methoxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine] pyridine]-1'-yl)pyrimidine-4-carbonitrile 43c (200mg, 434.85μmol) and 3mL of 4M hydrochloric acid in dioxane were added to 1mL of dichloromethane, sealed and heated to 100°C, reacted for 2 hours, After the reaction, a little ammonia methanol solution was added to neutralize and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-(3-chloro-2-hydroxypyridine-4). -yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[inden-2,4'-piperidin]-1'-yl)pyrimidine-4-carbonitrile 43d (140 mg ), yield: 72.20%.
MS m/z(ESI):446.1[M+1]MS m/z(ESI): 446.1[M+1]
第三步third step
5-(2,3-二氯吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈5-(2,3-Dichloropyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1 '-yl)pyrimidine-4-carbonitrile
将5-(3-氯-2-羟基吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈43d(140mg,313.97μmol)加入到3mL的三氯氧磷中，加热到90℃，反应3小时，冷到室温，倒入冰水中，搅拌0.5小时，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和碳酸氢钠溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到5-(2,3-二氯吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈43e(90mg)，产率：61.73％。5-(3-Chloro-2-hydroxypyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine] -1'-yl)pyrimidine-4-carbonitrile 43d (140 mg, 313.97 μmol) was added to 3 mL of phosphorus oxychloride, heated to 90 °C, reacted for 3 hours, cooled to room temperature, poured into ice water, stirred for 0.5 hour, Extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with saturated sodium bicarbonate solution, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent). : System A) purification to give 5-(2,3-dichloropyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4] '-Piperidin]-1'-yl)pyrimidine-4-carbonitrile 43e (90 mg), yield: 61.73%.
MS m/z(ESI):464.0[M+1]MS m/z(ESI): 464.0[M+1]
第四步the fourth step
(R)-N-((Z)-1'-(4-氰基-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-2-基)螺[茚-2,4'-哌啶]-1(3H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((Z)-1'-(4-cyano-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidin-2-yl)spiro[indene- 2,4'-Piperidine]-1(3H)-Alkylene)-2-methylpropane-2-sulfinamide
将5-(2,3-二氯吡啶-4-基)-6-甲基-2-(1-氧代-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)嘧啶-4-腈43e(90mg,193.82μmol)和(R)-2-甲基丙烷-2-亚磺酰胺(70.47mg,581.46μmol)加入到1mL的钛酸四乙酯，加热100℃，反应5小时。冷至室温后加入10mL水和10mL乙酸乙酯， 过滤除去不溶固体，滤液分离出有机相，干燥过滤，减压浓缩，薄层色谱制备，得到(R)-N-((Z)-1'-(4-氰基-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-2-基)螺[茚-2,4'-哌啶]-1(3H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺43f(20mg)，产率：18.18％。5-(2,3-Dichloropyridin-4-yl)-6-methyl-2-(1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]- 1'-yl)pyrimidine-4-carbonitrile 43e (90 mg, 193.82 μmol) and (R)-2-methylpropane-2-sulfinamide (70.47 mg, 581.46 μmol) were added to 1 mL of tetraethyl titanate, Heated at 100°C and reacted for 5 hours. After cooling to room temperature, 10 mL of water and 10 mL of ethyl acetate were added, the insoluble solids were removed by filtration, the organic phase was separated from the filtrate, dried and filtered, concentrated under reduced pressure, and prepared by thin layer chromatography to obtain (R)-N-((Z)-1' -(4-cyano-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidin-2-yl)spiro[indene-2,4'-piperidine]-1(3H) -Alkylene)-2-methylpropane-2-sulfinamide 43f (20 mg), yield: 18.18%.
MS m/z(ESI):567.2[M+1]MS m/z(ESI): 567.2[M+1]
第五步the fifth step
(R)-N-((S)-1'-(4-氰基-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1'-(4-cyano-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidin-2-yl)-1,3 -Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide
将(R)-N-((Z)-1'-(4-氰基-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-2-基)螺[茚-2,4'-哌啶]-1(3H)-亚烷基)-2-甲基丙烷-2-亚磺酰胺43f(100mg,176.20μmol)加到2mL四氢呋喃中，冰浴下加入9-硼双环(3,3,1)-壬烷(0.5M,704.81μL)，再升到室温反应2小时。加入饱和氯化铵溶液淬灭，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，得到(R)-N-((S)-1'-(4-氰基-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺43g(80mg)，产率：79.72％，未经纯化，直接进行下一步反应。(R)-N-((Z)-1'-(4-cyano-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidin-2-yl)spiro[indene -2,4'-Piperidine]-1(3H)-alkylene)-2-methylpropane-2-sulfinamide 43f (100 mg, 176.20 μmol) was added to 2 mL of tetrahydrofuran, and 9- borabicyclo(3,3,1)-nonane (0.5M, 704.81 μL), and then warmed to room temperature to react for 2 hours. Saturated ammonium chloride solution was added to quench, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)-N-((S)-1'-( 4-cyano-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine] -1-yl)-2-methylpropane-2-sulfinamide 43 g (80 mg), yield: 79.72%, without purification, the next reaction was carried out directly.
MS m/z(ESI):568.8[M+1]MS m/z(ESI): 568.8[M+1]
第六步Step 6
2-((S)-1-(((R)-叔丁基亚磺酰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)- 5-(2,3-Dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide
将(R)-N-((S)-1'-(4-氰基-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-2-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-基)-2-甲基丙烷-2-亚磺酰胺43g(80mg,140.46μmol)和0.5mL的6N的氢氧化钠溶液加到2mL的乙醇中，加热到80℃，反应0.5小时，反应结束后，用1N的稀盐酸调pH值＝7-8，减压浓缩，水相用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，得到2-((S)-1-(((R)-叔丁基亚磺酰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺43h(50mg)，产率：60.58％，未经纯化，直接进行下一步反应。(R)-N-((S)-1'-(4-cyano-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidin-2-yl)-1, 3-Dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide 43 g (80 mg, 140.46 μmol) and 0.5 mL of 6N sodium hydroxide solution It was added to 2 mL of ethanol, heated to 80°C, and reacted for 0.5 hours. After the reaction, the pH value was adjusted to 7-8 with 1N dilute hydrochloric acid, concentrated under reduced pressure, and the aqueous phase was extracted with ethyl acetate (10 mL×3), The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene- 2,4'-Piperidin-1'-yl)-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide 43h (50 mg), yield: 60.58 %, without purification, proceed directly to the next reaction.
MS m/z(ESI):586.8[M+1]MS m/z(ESI): 586.8[M+1]
第七步Step 7
2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((S)-1-Amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-5-(2,3-dichloropyridin-4-yl )-6-methylpyrimidine-4-carboxamide
将2-((S)-1-(((R)-叔丁基亚磺酰基)氨基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺43h(50mg,85.10μmol)加在4mL的二氯甲烷中，室温下加入0.4mL的4M的盐酸二氧六环溶液，搅拌0.5小时，反应结束后，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺43(11mg)，产率：24.52％。 2-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl) -5-(2,3-Dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide 43h (50 mg, 85.10 μmol) was added to 4 mL of dichloromethane, and 0.4 mL of 4M was added at room temperature The solution of hydrochloric acid in dioxane was stirred for 0.5 hours. After the reaction was completed, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give the product 2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1 '-yl)-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide 43 (11 mg), yield: 24.52%.
MS m/z(ESI):482.9[M+1]MS m/z(ESI): 482.9[M+1]
1H NMR(400MHz,Methanol-d 4)δ8.28(d,J＝4.9Hz,1H),7.47(d,J＝7.3Hz,1H),7.33(dd,J＝19.9,4.4Hz,3H),7.23(dd,J＝4.9,1.9Hz,1H),4.68-4.85(m,3H),3.38(d,J＝8.6Hz,2H),3.13(s,1H),2.10(s,3H),1.79(tt,J＝11.8,6.4Hz,2H),1.64(t,J＝12.8Hz,3H). 1 H NMR(400MHz,Methanol-d 4 )δ8.28(d,J=4.9Hz,1H),7.47(d,J=7.3Hz,1H),7.33(dd,J=19.9,4.4Hz,3H) ,7.23(dd,J＝4.9,1.9Hz,1H),4.68-4.85(m,3H),3.38(d,J＝8.6Hz,2H),3.13(s,1H),2.10(s,3H), 1.79(tt,J＝11.8,6.4Hz,2H),1.64(t,J＝12.8Hz,3H).
实施例44Example 44
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichloropyridine-4 -yl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000085
Figure PCTCN2021105100-appb-000085
第一步first step
((3S,4S)-8-(5-(3-氯-2-羟基吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯((3S,4S)-8-(5-(3-Chloro-2-hydroxypyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2- tert-Butyl oxa-8-azaspiro[4.5]dec-4-yl)carbamate
将((3S,4S)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9f(90mg,192.98μmol)、(3-氯-2-氟吡啶-4-基)硼酸41a(135.36mg,771.92μmol)、甲烷磺酸(2-二环己基膦-2',6'-二甲氧基联苯)(2'-甲胺基-1,1'-联苯-2-基)钯(32.82mg,38.60μmol)和磷酸钾(163.65mg,771.92μmol)依次加入到2.2mL的混合溶液中(1,4-二氧六环:水＝10:1)，氩气置换三次，用冷凝管回流，100℃下持续搅拌1.5小时，冷到室温，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到((3S,4S)-8-(5-(3-氯-2-羟基吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯44a(30mg)，产率：30.19％。((3S,4S)-8-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane -4-yl) tert-butyl carbamate 9f (90 mg, 192.98 μmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid 41a (135.36 mg, 771.92 μmol), methanesulfonic acid (2-bicyclic Hexylphosphine-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium (32.82mg, 38.60μmol) and potassium phosphate (163.65mg , 771.92 μmol) was added to 2.2 mL of mixed solution (1,4-dioxane: water = 10:1) in turn, replaced with argon three times, refluxed with a condenser, continued stirring at 100 ° C for 1.5 hours, cooled to At room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain ((3S,4S)-8-(5-(3-chloro-2-hydroxypyridine-4). -yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamic acid tert-butyl ester 44a (30 mg), yield: 30.19%.
MS m/z(ESI):459.0[M+1-56]MS m/z(ESI): 459.0[M+1-56]
第二步second step
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-腈2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichloropyridine-4 -yl)-6-methylpyrimidine-4-carbonitrile
将((3S,4S)-8-(5-(3-氯-2-羟基吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯44a(30mg,58.25μmol)和0.05mL的N,N-二异丙基乙胺加到1mL的三氯氧磷中，加热至100℃，搅拌8小时。反应结束后，冷到室温，将反应液倒入碎冰中，搅拌0.5小时，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和碳酸氢钠洗，无水硫酸钠干燥，过滤，减压浓缩，得到2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺 [4.5]癸-8-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-腈44b(20mg)，产率：79.23％，未经纯化，直接进行下一步反应。((3S,4S)-8-(5-(3-Chloro-2-hydroxypyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2 -oxa-8-azaspiro[4.5]dec-4-yl)carbamate tert-butyl ester 44a (30 mg, 58.25 μmol) and 0.05 mL of N,N-diisopropylethylamine were added to 1 mL of trichloromethane In phosphorus oxon, it was heated to 100°C and stirred for 8 hours. After the reaction, cooled to room temperature, poured the reaction solution into crushed ice, stirred for 0.5 hours, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed the organic phases with saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. , filtered, and concentrated under reduced pressure to give 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2 ,3-Dichloropyridin-4-yl)-6-methylpyrimidine-4-carbonitrile 44b (20 mg), yield: 79.23%, without purification, the next reaction was carried out directly.
MS m/z(ESI):433.1[M+1]MS m/z(ESI): 433.1[M+1]
第三步third step
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichloropyridine-4 -yl)-6-methylpyrimidine-4-carboxamide
将2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-腈44b(20mg,46.15μmol)和0.5mL的5M的氢氧化钠溶液加到0.5mL的甲醇中，低温条件下再加入0.25mL的30％的双氧水，冰浴下搅拌1小时。反应结束后，加入少量的三氟乙酸调节PH值到7-8，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2,3-二氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺44(11mg)，产率：33.72％。 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2,3-dichloropyridine- 4-yl)-6-methylpyrimidine-4-carbonitrile 44b (20 mg, 46.15 μmol) and 0.5 mL of 5M sodium hydroxide solution were added to 0.5 mL of methanol, and then 0.25 mL of 30% NaOH was added at low temperature. Hydrogen peroxide was stirred under ice bath for 1 hour. After the reaction, a small amount of trifluoroacetic acid was added to adjust the pH to 7-8, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), the product 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[ 4.5] Dec-8-yl)-5-(2,3-dichloropyridin-4-yl)-6-methylpyrimidine-4-carboxamide 44 (11 mg), yield: 33.72%.
MS m/z(ESI):450.9[M+1]MS m/z(ESI): 450.9[M+1]
实施例45Example 45
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2-溴-3-氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2-bromo-3-chloropyridine- 4-yl)-6-methylpyrimidine-4-carboxamide
Figure PCTCN2021105100-appb-000086
Figure PCTCN2021105100-appb-000086
第一步first step
((3S,4S)-8-(5-(3-氯-2-氟吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯((3S,4S)-8-(5-(3-Chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2- tert-Butyl oxa-8-azaspiro[4.5]dec-4-yl)carbamate
将((3S,4S)-8-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯9f(120mg,257.31μmol)、(3-氯-2-氟吡啶-4-基)硼酸41a(112.80mg,643.26μmol)、甲烷磺酸(2-二环己基膦-2',6'-二甲氧基联苯)(2'-甲胺基-1,1'-联苯-2-基)钯(43.76mg,51.46μmol)和磷酸钾(272.74mg,1.29mmol)依次加入到4.4mL的混合溶液中(1,4-二氧六环:水 ＝10:1)，氩气置换三次，用冷凝管回流，100℃下持续搅拌1小时，冷到室温，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到((3S,4S)-8-(5-(3-氯-2-氟吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯45a(75mg)，产率：56.38％。((3S,4S)-8-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane -4-yl) tert-butyl carbamate 9f (120 mg, 257.31 μmol), (3-chloro-2-fluoropyridin-4-yl)boronic acid 41a (112.80 mg, 643.26 μmol), methanesulfonic acid (2-bicyclo Hexylphosphine-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium (43.76mg, 51.46μmol) and potassium phosphate (272.74mg , 1.29 mmol) was added to 4.4 mL of mixed solution (1,4-dioxane: water=10:1) in turn, replaced with argon three times, refluxed with a condenser tube, continued stirring at 100 ° C for 1 hour, cooled to At room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain ((3S,4S)-8-(5-(3-chloro-2-fluoropyridine-4). -yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamic acid tert-butyl ester 45a (75 mg), yield: 56.38%.
MS m/z(ESI):517.3[M+1]MS m/z(ESI): 517.3[M+1]
第二步second step
2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2-溴-3-氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺2-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2-bromo-3-chloropyridine- 4-yl)-6-methylpyrimidine-4-carboxamide
将((3S,4S)-8-(5-(3-氯-2-氟吡啶-4-基)-4-氰基-6-甲基嘧啶-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-4-基)氨基甲酸叔丁酯45a(70mg,135.40μmol)加到1mL的48％氢溴酸的醋酸溶液中，密封加热到90℃，反应1小时，反应结束后，冷到室温，减压浓缩，加入饱和碳酸氢钠中和，用二氯甲烷(10mL×3)萃取，合并有机相，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸-8-基)-5-(2-溴-3-氯吡啶-4-基)-6-甲基嘧啶-4-甲酰胺45(12mg)，产率：10.90％。 ((3S,4S)-8-(5-(3-Chloro-2-fluoropyridin-4-yl)-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2 -oxa-8-azaspiro[4.5]dec-4-yl)carbamate tert-butyl ester 45a (70mg, 135.40μmol) was added to 1mL of 48% hydrobromic acid in acetic acid solution, sealed and heated to 90°C, The reaction was performed for 1 hour. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, neutralized by adding saturated sodium bicarbonate, extracted with dichloromethane (10 mL×3), combined with the organic phases, concentrated under reduced pressure, and the obtained residue was prepared as a liquid phase Separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) gave the product 2-((3S,4S) -4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-(2-bromo-3-chloropyridin-4-yl)-6-methyl pyrimidine-4-carboxamide 45 (12 mg), yield: 10.90%.
MS m/z(ESI):495.0[M+1]MS m/z(ESI): 495.0[M+1]
实施例46Example 46
2-((S)-3'-氨基-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-基)-5-(2,3-(二氯苯基)-6-甲基嘧啶-4-甲酸2-((S)-3'-Amino-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidin]-1"-yl)-5-(2, 3-(Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid
Figure PCTCN2021105100-appb-000087
Figure PCTCN2021105100-appb-000087
Figure PCTCN2021105100-appb-000088
Figure PCTCN2021105100-appb-000088
第一步first step
1-亚甲基-1,3-二氢螺[茚-2,4'-哌啶]-1'-甲酸叔丁酯1-Methylene-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester
将1-氧代-1,3-二氢螺[茚-2,4'-哌啶]-1'-甲酸叔丁酯46a(4g,13.27mmol)和甲基三苯基溴化磷(11.85g,33.18mmol)加到150mL的四氢呋喃中，温度控制在0℃，加入叔丁醇钾(4.46g,39.82mmol)，再升到30℃，搅拌4小时，反应结束后，减压浓缩，加入1N的稀盐酸调pH为8，用乙酸乙酯(20mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到1-亚甲基-1,3-二氢螺[茚-2,4'-哌啶]-1'-甲酸叔丁酯46b(3.8g)，产率：95.63％。1-Oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester 46a (4 g, 13.27 mmol) and methyltriphenylphosphonium bromide (11.85 g, 33.18 mmol) was added to 150 mL of tetrahydrofuran, the temperature was controlled at 0 ° C, potassium tert-butoxide (4.46 g, 39.82 mmol) was added, then raised to 30 ° C, stirred for 4 hours, after the reaction was completed, concentrated under reduced pressure, added The pH was adjusted to 8 with 1N dilute hydrochloric acid, extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent). : System A) purification to give 1-methylene-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester 46b (3.8 g), yield: 95.63% .
第二步second step
3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]3'H-Dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]
将二乙基锌溶液(2.31g,18.70mmol)和二氯甲烷(150mL)的混合物冷却到0℃，然后将三氟乙酸(2.13g,18.70mmol,1.39mL)溶于20mL二氯甲烷中，并加到反应中，15分钟后，再将二碘甲烷(4.99g,18.70mmol,1.50mL)加入，加完再在0℃搅拌15分钟，将1-亚甲基-1,3-二氢螺[茚-2,4'-哌啶]-1'-甲酸叔丁酯46b(1.4g,4.68mmol)溶在二氯甲烷(5mL)，保持在0℃加入上述混合物中，加完升到室温搅拌过夜，反应结束后，加入饱和氯化铵溶液淬灭，并用二氯甲烷(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得到3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]46c(550mg)，产率：55.14％，未经纯化，直接进行下一步反应。A mixture of diethylzinc solution (2.31 g, 18.70 mmol) and dichloromethane (150 mL) was cooled to 0°C, then trifluoroacetic acid (2.13 g, 18.70 mmol, 1.39 mL) was dissolved in 20 mL of dichloromethane, and added to the reaction. After 15 minutes, diiodomethane (4.99 g, 18.70 mmol, 1.50 mL) was added, and after the addition was completed, it was stirred at 0 °C for 15 minutes, and the 1-methylene-1,3-dihydrogen Spiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl ester 46b (1.4 g, 4.68 mmol) was dissolved in dichloromethane (5 mL), kept at 0 °C, and added to the above mixture, and after the addition was increased to It was stirred at room temperature overnight, after the reaction was completed, saturated ammonium chloride solution was added to quench, and extracted with dichloromethane (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3'H-dichloromethane. Spiro[cyclopropane-1,1'-indene-2',4"-piperidine]46c (550 mg), yield: 55.14%, without purification, the next reaction was carried out directly.
MS m/z(ESI):214.0[M+1]MS m/z(ESI): 214.0[M+1]
第三步third step
3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯3'H-Dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]-1"-carboxylic acid tert-butyl ester
将3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]46c(1.8g,8.44mmol)、二碳酸二叔丁酯(3.68g,16.88mmol)、4-二甲氨基吡啶(51.54mg,421.91μmol)和三乙胺(2.56g,25.31mmol,3.55mL)加到20mL的二氯甲烷中，室温搅拌4小时，反应结束后，加入20mL水，分离有机相， 无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯46d(1.5g)，产率：45.37％。3'H-Dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]46c (1.8 g, 8.44 mmol), di-tert-butyl dicarbonate (3.68 g, 16.88 mmol), 4-Dimethylaminopyridine (51.54 mg, 421.91 μmol) and triethylamine (2.56 g, 25.31 mmol, 3.55 mL) were added to 20 mL of dichloromethane, and stirred at room temperature for 4 hours. After the reaction was completed, 20 mL of water was added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 3'H-dispiro[cyclopropane-1,1' -Indene-2',4"-piperidine]-1"-carboxylate tert-butyl ester 46d (1.5 g), yield: 45.37%.
MS m/z(ESI):258.0[M+1-56]MS m/z(ESI): 258.0[M+1-56]
1H NMR(400MHz,Chloroform-d)δ7.15-7.23(m,1H),7.12(ddd,J＝6.5,4.4,1.4Hz,2H),6.69(dd,J＝6.4,2.0Hz,1H),4.11(s,2H),2.86(s,2H),1.46(s,9H),1.39(dd,J＝14.2,3.1Hz,2H),1.23-1.34(m,2H),1.18(td,J＝13.2,4.9Hz,2H),0.87(t,J＝3.3Hz,2H),0.74(q,J＝4.6Hz,2H). 1 H NMR (400MHz, Chloroform-d) δ 7.15-7.23 (m, 1H), 7.12 (ddd, J=6.5, 4.4, 1.4Hz, 2H), 6.69 (dd, J=6.4, 2.0Hz, 1H) ,4.11(s,2H),2.86(s,2H),1.46(s,9H),1.39(dd,J=14.2,3.1Hz,2H),1.23-1.34(m,2H),1.18(td,J =13.2,4.9Hz,2H),0.87(t,J=3.3Hz,2H),0.74(q,J=4.6Hz,2H).
第四步the fourth step
3'-氧代-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯3'-Oxo-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]-1"-carboxylic acid tert-butyl ester
将3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯46d(1.5g,4.79mmol)、1.5M的硫酸镁溶液(5mL)和高锰酸钾(3.02g,19.14mmol)加到20mL的丙酮中，加热到40℃，反应8小时。反应结束后，硅藻土过滤，滤液除去丙酮，用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到3'-氧代-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯46e(600mg)，产率：38.29％。3'H-Dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]-1"-carboxylate tert-butyl ester 46d (1.5 g, 4.79 mmol), 1.5 M solution of magnesium sulfate (5 mL) and potassium permanganate (3.02 g, 19.14 mmol) were added to 20 mL of acetone, heated to 40° C., and reacted for 8 hours. After the reaction, the filtrate was filtered with celite, acetone was removed from the filtrate, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. (Eluent: System A) Purification to give 3'-oxo-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]-1"-carboxylic acid tert-butyl Ester 46e (600 mg), yield: 38.29%.
MS m/z(ESI):272.0[M+1-56]MS m/z(ESI): 272.0[M+1-56]
第五步the fifth step
(R,Z)-3'-((叔丁基亚磺酰基)亚氨基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯(R,Z)-3'-((tert-butylsulfinyl)imino)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]-1 ”-tert-Butyl formate
将(R)-2-甲基丙烷-2-亚磺酰胺(370.17mg,3.05mmol)、3'-氧代-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯46e(400mg,1.22mmol)加到2mL钛酸四乙酯和0.5mL四氢呋喃中，加热到100℃，搅拌18小时，反应结束后，冷到室温，加入10mL甲基叔丁基醚，用冰水浴冷却，加入10mL冰水，搅拌15分钟，过滤，滤液有机相分离，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(R,Z)-3'-((叔丁基亚磺酰基)亚氨基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯46f(290mg)，产率：55.13％。(R)-2-methylpropane-2-sulfinamide (370.17 mg, 3.05 mmol), 3'-oxo-3'H-dispiro[cyclopropane-1,1'-indene-2', 4"-piperidine]-1"-carboxylate tert-butyl ester 46e (400 mg, 1.22 mmol) was added to 2 mL of tetraethyl titanate and 0.5 mL of tetrahydrofuran, heated to 100 ° C, stirred for 18 hours, after the reaction was completed, cooled to At room temperature, add 10 mL of methyl tert-butyl ether, cool with an ice-water bath, add 10 mL of ice-water, stir for 15 minutes, filter, separate the organic phase of the filtrate, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purification by column chromatography (eluent: system A) gave (R,Z)-3'-((tert-butylsulfinyl)imino)-3'H-dispiro[cyclopropane-1,1 '-Indene-2',4"-piperidine]-1"-carboxylate tert-butyl ester 46f (290 mg), yield: 55.13%.
MS m/z(ESI):331.0[M+1-100]MS m/z(ESI): 331.0[M+1-100]
第六步Step 6
(S)-3'-(((R)-叔丁基亚磺酰基)氨基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯(S)-3'-(((R)-tert-butylsulfinyl)amino)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]- 1"-tert-butyl formate
将(R,Z)-3'-((叔丁基亚磺酰基)亚氨基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯46f(290mg,673.48μmol)加到3mL的四氢呋喃中，用冰水浴冷却，加入9-硼双环(3,3,1)-壬烷(0.5M,2.69mL)，升到室温搅拌2小时，加入饱和氯化铵溶液淬灭，有机相分离，无水硫酸钠干燥，过滤，减压浓缩，得到(S)-3'-(((R)-叔丁基亚磺酰基)氨基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯46g(180mg)，产率：61.78％，未经纯化，直接进行下一步反应。(R,Z)-3'-((tert-butylsulfinyl)imino)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]- 1"-tert-butyl formate 46f (290 mg, 673.48 μmol) was added to 3 mL of tetrahydrofuran, cooled with an ice-water bath, 9-borabicyclo(3,3,1)-nonane (0.5 M, 2.69 mL) was added, liter The mixture was stirred at room temperature for 2 hours, quenched by adding saturated ammonium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-3'-((((R)-tert-butylsulfinic acid) Acyl)amino)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]-1"-carboxylic acid tert-butyl ester 46g (180mg), yield: 61.78%, Without purification, the next reaction was carried out directly.
MS m/z(ESI):433.0[M+1]MS m/z(ESI): 433.0[M+1]
第七步Step 7
(R)-N-((S)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-3'H-Dispiro[cyclopropane-1,1'-indene-2',4"-piperidin]-3'-yl)-2-methylpropane- 2-Sulfenamide
将(S)-3'-(((R)-叔丁基亚磺酰基)氨基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-甲酸叔丁酯46g(180mg,416.07μmol)和1mL的三氟乙酸加到4mL的二氯甲烷中，室温搅拌1小时，反应结束后，减压浓缩，得到(R)-N-((S)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)-2-甲基丙烷-2-亚磺酰胺46h(138mg)，产率：99.75％，未经纯化，直接进行下一步反应。(S)-3'-(((R)-tert-butylsulfinyl)amino)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine] -1"-tert-butyl formate 46g (180mg, 416.07μmol) and 1mL of trifluoroacetic acid were added to 4mL of dichloromethane, stirred at room temperature for 1 hour, after the reaction was completed, concentrated under reduced pressure to obtain (R)-N- ((S)-3'H-Dispiro[cyclopropane-1,1'-indene-2',4"-piperidin]-3'-yl)-2-methylpropane-2-sulfinamide 46h (138 mg), yield: 99.75%, without purification, proceed directly to the next reaction.
MS m/z(ESI):333.2[M+1]MS m/z(ESI): 333.2[M+1]
第八步Step 8
(R)-N-((S)-1”-(4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)-2-甲基丙烷-2-亚磺酰胺(R)-N-((S)-1"-(4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1,1'-indene-2' ,4"-Piperidin]-3'-yl)-2-methylpropane-2-sulfinamide
将2-氯-6-甲基-嘧啶-4-腈3a(63.74mg,415.03μmol)、(R)-N-((S)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)-2-甲基丙烷-2-亚磺酰胺46h(138mg,415.03μmol)和N,N-二异丙基乙胺(160.92mg,1.25mmol)加到3mL的N,N-二甲基甲酰胺中，然后加热到90℃，反应1.5小时，反应结束后，冷到室温，倒入10mL的水中，乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(R)-N-((S)-1”-(4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)-2-甲基丙烷-2-亚磺酰胺46i(160mg)，产率：85.74％。2-Chloro-6-methyl-pyrimidine-4-carbonitrile 3a (63.74 mg, 415.03 μmol), (R)-N-((S)-3'H-dispiro[cyclopropane-1,1'- Indene-2',4"-piperidin]-3'-yl)-2-methylpropane-2-sulfinamide 46h (138 mg, 415.03 μmol) and N,N-diisopropylethylamine (160.92 mg , 1.25mmol) was added to 3mL of N,N-dimethylformamide, then heated to 90°C, and reacted for 1.5 hours. After the reaction was completed, cooled to room temperature, poured into 10mL of water, ethyl acetate (10mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (R)-N-((S) -1"-(4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]-3' -yl)-2-methylpropane-2-sulfinamide 46i (160 mg), yield: 85.74%.
MS m/z(ESI):450.1[M+1]MS m/z(ESI): 450.1[M+1]
第九步Step 9
(S)-2-(3'-氨基-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-基)-6-甲基嘧啶-4-腈(S)-2-(3'-Amino-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidin]-1"-yl)-6-methylpyrimidine -4-Nitrile
将(R)-N-((S)-1”-(4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)-2-甲基丙烷-2-亚磺酰胺46i(160mg,355.86μmol)和溴代丁二酰亚胺(69.67mg,391.45μmol)加到2mL的N,N-二甲基乙酰胺中，低温反应1.5小时，反应结束后，将反应液倒入10mL水，乙酸乙酯(10mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得到(S)-2-(3'-氨基-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-基)-6-甲基嘧啶-4-腈46j(123mg)，产率：100％，未经纯化，直接进行下一步反应。(R)-N-((S)-1"-(4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1,1'-indene-2 ',4"-piperidin]-3'-yl)-2-methylpropane-2-sulfinamide 46i (160 mg, 355.86 μmol) and bromosuccinimide (69.67 mg, 391.45 μmol) were added to In 2 mL of N,N-dimethylacetamide, react at low temperature for 1.5 hours. After the reaction, pour the reaction solution into 10 mL of water, extract with ethyl acetate (10 mL×2), combine the organic phases, and dry over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave (S)-2-(3'-amino-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidin]-1"-yl )-6-methylpyrimidine-4-carbonitrile 46j (123 mg), yield: 100%, without purification, proceed directly to the next reaction.
MS m/z(ESI):329.0[M+1-17]MS m/z(ESI): 329.0[M+1-17]
第十步Step 10
(S)-(1”-(4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯(S)-(1"-(4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine ]-3'-yl) tert-butyl carbamate
将(S)-2-(3'-氨基-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-基)-6-甲基嘧啶-4-腈46j(123mg,356.07μmol)、三乙胺(107.89mg,1.07mmol)和二碳酸二叔丁酯(116.43mg,534.10μmol)加到3mL的二氯甲烷中，室温反应4小时，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(S)-(1”-(4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯46k(110mg)，产率：69.34％。(S)-2-(3'-Amino-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidin]-1"-yl)-6-methyl Pyrimidine-4-carbonitrile 46j (123 mg, 356.07 μmol), triethylamine (107.89 mg, 1.07 mmol) and di-tert-butyl dicarbonate (116.43 mg, 534.10 μmol) were added to 3 mL of dichloromethane and reacted at room temperature for 4 hours , concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give (S)-(1"-(4-cyano-6-methylpyrimidin-2-yl) -3'H-Dispiro[cyclopropan-1,1'-indene-2',4"-piperidin]-3'-yl)carbamate tert-butyl ester 46k (110 mg), yield: 69.34%.
MS m/z(ESI):446.2[M+1]MS m/z(ESI): 446.2[M+1]
第十一步Step 11
(S)-(1”-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯(S)-(1"-(5-Bromo-4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1,1'-indene-2',4 "-Piperidin]-3'-yl) tert-butyl carbamate
将(S)-(1”-(4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯46k(110mg,246.88μmol)加到3mL的二氯甲烷中，用冰水浴冷却，加入溴代丁二酰亚胺(48.33mg,271.57μmol)，升到室温反应2小时，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(S)-(1”-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯46l(110mg)，产率：84.96％。(S)-(1"-(4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine pyridin]-3'-yl)carbamate tert-butyl ester 46k (110 mg, 246.88 μmol) was added to 3 mL of dichloromethane, cooled with an ice-water bath, and bromosuccinimide (48.33 mg, 271.57 μmol) was added, Raised to room temperature to react for 2 hours, concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (S)-(1"-(5-bromo-4-cyano- 6-Methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidin]-3'-yl)carbamate 46l( 110 mg), yield: 84.96%.
MS m/z(ESI):524.0[M+1]MS m/z(ESI): 524.0[M+1]
第十二步Step 12
(S)-(1”-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯(S)-(1"-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1, 1'-Indene-2',4"-piperidin]-3'-yl) tert-butyl carbamate
将(S)-(1”-(5-溴-4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯46l(89.31mg,170.29μmol)、2,3-二氯苯硼酸(48.74mg,255.44μmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(28.52mg,34.06μmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(31.74mg,68.12μmol)和磷酸钾(108.31mg,510.87μmol)依次加入到3.4mL的混合溶液中(1,4-二氧六环:水＝7.5:1)，氩气置换三次，加热到105℃，反应2小时，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：体系A)纯化，得到(S)-(1”-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯46m(95mg)，产率：94.47％。(S)-(1"-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1,1'-indene-2', 4"-piperidin]-3'-yl) tert-butyl carbamate 46l (89.31 mg, 170.29 μmol), 2,3-dichlorophenylboronic acid (48.74 mg, 255.44 μmol), methanesulfonic acid (2-bicyclo Hexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (28.52mg, 34.06μmol) , 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (31.74mg, 68.12μmol) and potassium phosphate (108.31mg, 510.87μmol) were added to 3.4mL of In the mixed solution (1,4-dioxane:water=7.5:1), argon was replaced three times, heated to 105°C, reacted for 2 hours, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (washed). Removal: System A) Purification to give (S)-(1"-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3'H - Dispiro[cyclopropan-1,1'-indene-2',4"-piperidin]-3'-yl)carbamate tert-butyl ester 46m (95 mg), yield: 94.47%.
MS m/z(ESI):[M+1]589.9MS m/z(ESI): [M+1]589.9
第十三步step thirteen
2-((S)-3'-氨基-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-基)-5-(2,3-(二氯苯基)-6-甲基嘧啶-4-甲酸2-((S)-3'-Amino-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidin]-1"-yl)-5-(2, 3-(Dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid
将(S)-(1”-(5-(2,3-二氯苯基)-4-氰基-6-甲基嘧啶-2-基)-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-3'-基)氨基甲酸叔丁酯46m(95mg,160.87μmol)加到3mL的浓盐酸中，加热至90℃，搅拌9小时，反应结束后，冷却至室温，减压浓缩，得到的残留物制备液相分离(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到产物2-((S)-3'-氨基-3'H-二螺[环丙烷-1,1'-茚-2',4”-哌啶]-1”-基)-5-(2,3-(二氯苯基)-6-甲基嘧啶-4-甲酸46(2mg)，产率：1.4％。 (S)-(1"-(5-(2,3-dichlorophenyl)-4-cyano-6-methylpyrimidin-2-yl)-3'H-dispiro[cyclopropane-1 ,1'-Indene-2',4"-piperidin]-3'-yl)carbamic acid tert-butyl ester 46m (95mg, 160.87μmol) was added to 3mL of concentrated hydrochloric acid, heated to 90 ℃, stirred for 9 hours, After the reaction, it was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was prepared for liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, Mobile phase B: CH 3 CN) to give the product 2-((S)-3'-amino-3'H-dispiro[cyclopropane-1,1'-indene-2',4"-piperidine]- 1"-yl)-5-(2,3-(dichlorophenyl)-6-methylpyrimidine-4-carboxylic acid 46 (2 mg), yield: 1.4%.
MS m/z(ESI):508.9[M+1]MS m/z(ESI): 508.9[M+1]
对比例1Comparative Example 1
对比例1为WO 2020063760的化合物4，根据WO 2020063760公开的实施例4制备而得，具体结构如下：Comparative example 1 is compound 4 of WO 2020063760, prepared according to Example 4 disclosed in WO 2020063760, and the specific structure is as follows:
Figure PCTCN2021105100-appb-000089
Figure PCTCN2021105100-appb-000089
对比例2Comparative Example 2
对比例2为WO 2020181283的实施例119化合物，根据WO 2020181283的实施例119制备而得，具体结构如下：Comparative example 2 is the compound of Example 119 of WO 2020181283, prepared according to Example 119 of WO 2020181283, and the specific structure is as follows:
Figure PCTCN2021105100-appb-000090
Figure PCTCN2021105100-appb-000090
对比例3Comparative Example 3
对比例3为WO 2020181283的实施例117化合物，根据WO 2020181283的实施例117制备而得，具体结构如下：Comparative Example 3 is the compound of Example 117 of WO 2020181283, prepared according to Example 117 of WO 2020181283, and the specific structure is as follows:
Figure PCTCN2021105100-appb-000091
Figure PCTCN2021105100-appb-000091
对比例4Comparative Example 4
对比例4为WO 2020181283的实施例117化合物的消旋体化合物，操作步骤见本发明实施例28，具体结构如下：Comparative Example 4 is the racemic compound of the compound of Example 117 of WO 2020181283. The operation steps are shown in Example 28 of the present invention, and the specific structure is as follows:
Figure PCTCN2021105100-appb-000092
Figure PCTCN2021105100-appb-000092
生物学评价Biological evaluation
测试例1本发明化合物对SHP2变构抑制活性的测定Test Example 1 Determination of the allosteric inhibitory activity of the compounds of the present invention on SHP2
以下方法用于测定本发明化合物在体外条件下对重组人源全长SHP2活性的抑制程度。 SHP2通过二-酪氨酰-磷酸化肽与其Src同源2(SH2)结构域的结合而变构激活。后者的激活步骤导致SHP2的自抑制界面释放，随后使得SHP2蛋白酪氨酸磷酸酶(PTP)活化，可用于底物识别和反应催化。The following method was used to determine the degree of inhibition of recombinant human full-length SHP2 activity by the compounds of the present invention under in vitro conditions. SHP2 is allosterically activated by the binding of a di-tyrosyl-phosphorylated peptide to its Src homology 2 (SH2) domain. The latter activation step leads to the release of SHP2 from the self-inhibitory interface, which subsequently activates SHP2 protein tyrosine phosphatase (PTP), which is available for substrate recognition and reaction catalysis.
将实验流程简述如下：受试化合物首先溶解于DMSO中制备为贮存液。反应在384孔Small VolumeTM HiBase微孔板(Greiner，784075)中进行，首先向孔中加入SHP2(signalchem，P38-20G-10μg)和SHP-2 Activating Peptide(IRS1_pY1172(dPEG8)pY1222)(BPS，79319-1)，终浓度分别为0.5nM和0.5μM，继而加入待测化合物，浓度范围为0.00004-10μM，于25℃孵育60分钟。随后向反应中加入DiFMUP(Thermo，D6567)，于25℃孵育30分钟。孵育结束后，使用微量板读数仪(BMG)读数，激发和发射波长分别为340nm和450nm。通过与对照组(0.1％DMSO)的荧光强度比值进行比较，计算化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以化合物浓度对数值-抑制率进行非线性回归分析，获得化合物的IC 50值，见表1。 The experimental procedure is briefly described as follows: The test compounds were first dissolved in DMSO to prepare a stock solution. Reactions were carried out in 384-well Small VolumeTM HiBase microplates (Greiner, 784075) by first adding SHP2 (signalchem, P38-20G-10 μg) and SHP-2 Activating Peptide (IRS1_pY1172(dPEG8)pY1222) (BPS, 79319) to the wells -1), the final concentrations were 0.5 nM and 0.5 μM, respectively, and then the compounds to be tested were added at a concentration range of 0.00004-10 μM, and incubated at 25° C. for 60 minutes. DiFMUP (Thermo, D6567) was then added to the reaction and incubated at 25°C for 30 minutes. After the incubation, read using a microplate reader (BMG) with excitation and emission wavelengths of 340 nm and 450 nm, respectively. By comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), the percentage inhibition rate of the compound at each concentration was calculated, and the compound concentration logarithm-inhibition rate was subjected to nonlinear regression analysis by GraphPad Prism 5 software to obtain the compound concentration. IC 50 values shown in Table 1.
表1本发明化合物对全长SHP2酶活性抑制的IC 50数据 Table 1 IC 50 data of the compounds of the present invention for inhibition of full-length SHP2 enzymatic activity
化合物编号Compound number SHP2/IC 50(nM) SHP2 / IC 50 (nM)
2626 4.514.51
2929 0.980.98
3030 11.3711.37
3131 5.605.60
3232 3.583.58
3636 4.694.69
3737 1.551.55
3939 0.740.74
4040 19.419.4
结论：从表1可以看出，本发明的化合物对SHP2酶均具有较好的变构抑制作用。Conclusion: It can be seen from Table 1 that the compounds of the present invention all have a good allosteric inhibitory effect on SHP2 enzyme.
测试例2药代动力学测试Test Example 2 Pharmacokinetic test
1、实验目的1. The purpose of the experiment
以ICR小鼠为受试动物，灌胃给予对比例1、化合物29和化合物37，采用LC/MS/MS法测定不同时刻血浆中的药物浓度，研究本发明化合物和对比例化合物在小鼠体内的药代动力学特征。ICR mice were used as test animals, and Comparative Example 1, Compound 29 and Compound 37 were administered by gavage, and the drug concentrations in the plasma at different times were measured by LC/MS/MS method to study the compounds of the present invention and Comparative Examples in mice. pharmacokinetic characteristics.
2、实验方案2. Experimental scheme
2.1实验药品与动物2.1 Experimental drugs and animals
实验药品：对比例1、化合物29和化合物37；Experimental drugs: Comparative Example 1, Compound 29 and Compound 37;
动物：ICR小鼠，雄性，29.0～33.8g，购买于北京维通利华实验动物技术有限公司。Animals: ICR mice, male, 29.0-33.8 g, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
2.2药物配制2.2 Drug preparation
称取适量药物，加入适量羧甲基纤维素钠(CMC-Na，含0.5％Tween 80)中，涡旋振荡、超声制备0.5mg/mL悬浮液。Weigh an appropriate amount of the drug, add an appropriate amount of sodium carboxymethyl cellulose (CMC-Na, containing 0.5% Tween 80), vortex and sonicate to prepare a 0.5 mg/mL suspension.
2.3给药2.3 Administration
每个待测化合物灌胃组(每组9只)的ICR小鼠禁食过夜后灌胃给药(PO，给药剂量5mg/kg，给药体积10mL/kg)，给药4小时后进食。ICR mice in each test compound gavage group (nine mice in each group) were fasted overnight and then administered intragastric administration (PO, administration dose 5 mg/kg, administration volume 10 mL/kg), and ate after administration for 4 hours .
3、操作3. Operation
于给药前和给药后0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时、12小时和24小时经颈静脉采约0.2mL血液，肝素钠抗凝。血液样本采集后置于冰上，离心分离血浆(离心条件：1500g，10分钟)。收集的血浆分析前存放于–40～–20℃。About 0.2 mL of blood was collected from the jugular vein before administration and 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, and heparin sodium was used for anticoagulation. The blood samples were placed on ice after collection, and the plasma was separated by centrifugation (centrifugation conditions: 1500 g, 10 minutes). The collected plasma was stored at –40 to –20°C until analysis.
用LC-MS/MS测定灌胃给药后小鼠血浆中待测化合物含量。LC-MS/MS was used to determine the content of the test compound in the plasma of mice after intragastric administration.
4、药代动力学参数结果4. Pharmacokinetic parameter results
本发明的化合物与对比例1的药代动力学参数如表2所示。The pharmacokinetic parameters of the compounds of the present invention and Comparative Example 1 are shown in Table 2.
表2药代动力学结果Table 2 Pharmacokinetic results
Figure PCTCN2021105100-appb-000093
Figure PCTCN2021105100-appb-000093
结论：化合物29、化合物37和对比例1相比，血药浓度和曲线下面积均有明显改善。Conclusion: Compared with compound 29, compound 37 and comparative example 1, the plasma concentration and the area under the curve were significantly improved.
测试例3化合物的hERG钾离子通道抑制活性测试Test example 3 compound hERG potassium channel inhibitory activity test
1、细胞培养1. Cell culture
1.1本试验所用的细胞为转染有hERG cDNA与稳定表达hERG通道的CHO细胞系(由丹麦Sophion Bioscience公司提供)，细胞代数为P17。细胞培养在含有下列成分的培养基中(皆来源于Invitrogen)：Ham’s F12培养基，10％(v/v)灭活的胎牛血清，100μg/mL潮霉素B，100μg/mL Geneticin。1.1 The cells used in this experiment were CHO cell lines transfected with hERG cDNA and stably expressing hERG channel (provided by Sophion Bioscience, Denmark), and the cell passage was P17. Cells were grown in medium (all from Invitrogen) containing the following components: Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 μg/mL hygromycin B, 100 μg/mL Geneticin.
1.2 CHO hERG细胞生长于含上述培养液的培养皿中，并在37℃、含5％CO 2的培养箱中进行培养。电生理实验之前24到48小时，CHO hERG细胞被转移到放置于培养皿中的圆形玻璃片上，并在以上相同的培养液及培养条件下生长。每个圆形玻片上CHO hERG细胞的 密度需要达到绝大多数细胞是独立、单个的要求。 1.2 CHO hERG cells were grown in petri dishes containing the above medium and cultured at 37°C in an incubator containing 5% CO 2 . Twenty-four to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to circular glass slides placed in petri dishes and grown in the same medium and culture conditions as above. The density of CHO hERG cells on each circular slide needs to be such that the vast majority of cells are independent and single.
2、实验溶液2. Experimental solution
表3的溶液(由Sophion推荐)用于电生理记录。The solutions of Table 3 (recommended by Sophion) were used for electrophysiological recordings.
表3细胞内液和外液的组成成分Table 3 Composition of intracellular fluid and extracellular fluid
Figure PCTCN2021105100-appb-000094
Figure PCTCN2021105100-appb-000094
3、电生理记录过程3. Electrophysiological recording process
3.1电生理记录系统3.1 Electrophysiological recording system
全自动QPatch系统(Sophion，丹麦)用于作全细胞电流的记录。细胞钳制在-80mV的电压下。细胞钳制电压去极化到+20mV以激活hERG钾通道，2.5秒后再钳制到-50mV以消除失活并产生外向尾电流。尾电流峰值用作hERG电流大小的数值。A fully automated QPatch system (Sophion, Denmark) was used for whole-cell current recordings. Cells were clamped at -80mV. The cell-clamp voltage was depolarized to +20 mV to activate the hERG potassium channel, and re-clamped to -50 mV for 2.5 s to abolish inactivation and generate an outward tail current. The peak tail current was used as a numerical value for the magnitude of hERG current.
3.2 QPatch实验步骤3.2 QPatch experimental steps
在初始阶段达成破膜的全细胞配置状态后，细胞记录至少120秒，以达到稳定。然后在整个过程中，上述的电压模式每15秒被应用到细胞。以上参数阈值记录中只有稳定细胞被允许进入药物处置的过程。含0.1％二甲基亚砜(溶剂)的外液应用到细胞，建立基线，再允许电流稳定3分钟。化合物溶液加入后细胞保持在测试环境中，直至该化合物的效果达到了稳定状态或以4分钟为限。在化合物不同浓度梯度的测试实验中，化合物由低到高浓度加至所钳制的细胞上。完成化合物测试后用外液清洗细胞直到电流恢复到稳定的状态。Cells were recorded for at least 120 s after reaching a permeabilized whole-cell configuration state in the initial phase to reach stabilization. The voltage pattern described above was then applied to the cells every 15 seconds throughout the process. Only stable cells were allowed to enter the process of drug treatment in the above parameter threshold records. External solution containing 0.1% dimethyl sulfoxide (solvent) was applied to the cells to establish a baseline and the current was allowed to stabilize for an additional 3 minutes. The cells were maintained in the test environment after the compound solution was added until the effect of the compound reached a steady state or up to 4 minutes. In testing experiments with different concentration gradients of compounds, compounds were added to the clamped cells from low to high concentrations. Cells were washed with exosome after compound testing until the current returned to a steady state.
4、化合物准备4. Compound preparation
4.1将10mM的化合物贮备液以梯度稀释的方式用细胞外液稀释成最终的μM浓度。4.1 Dilute the 10 mM compound stock solution with the extracellular fluid in a serial dilution to the final μM concentration.
4.2最高测试浓度为30μM，依次为30、10、3、1、0.3和0.1μM共6个浓度。4.2 The highest test concentration is 30 μM, followed by 6 concentrations of 30, 10, 3, 1, 0.3 and 0.1 μM.
4.3除了30μM的化合物DMSO的最终浓度为0.3％外，其它浓度化合物溶液中DMSO 的最终浓度都为0.1％。所有的化合物溶液都经过常规的5到10分钟超声和振荡以保证化合物完全溶解。4.3 The final concentration of DMSO in compound solutions of other concentrations is 0.1%, except that the final concentration of 30 μM compound DMSO is 0.3%. All compound solutions were routinely sonicated and shaken for 5 to 10 minutes to ensure complete compound dissolution.
5、数据分析5. Data analysis
试验数据由Sophion提供的Qpatch分析软件、Excel以及Graphpad Prism等进行分析。The experimental data were analyzed by Qpatch analysis software, Excel and Graphpad Prism provided by Sophion.
6、质量控制6. Quality control
试剂：所用实验试剂购买于Sigma公司。Reagents: The experimental reagents used were purchased from Sigma Company.
报告中的试验数据需要满足以下标准：The test data in the report needs to meet the following criteria:
膜电阻Rm>100MΩ；Membrane resistance Rm>100MΩ;
接入电阻(Ra)<15MΩ；Access resistance (Ra)<15MΩ;
尾电流幅度>200pA；Tail current amplitude>200pA;
细胞hERG电流自发性减低(rundown)每分钟<2％；Spontaneous rundown of cellular hERG currents <2% per minute;
漏电流小于200pA或者小于hERG电流峰值的10％(在90％的记录时间内)；The leakage current is less than 200pA or less than 10% of the peak hERG current (in 90% of the recording time);
多浓度Cisapride对hERG通道的抑制效应为阳性对照。The inhibitory effect of multiple concentrations of Cisapride on hERG channel was a positive control.
7、实验结果7. Experimental results
本发明化合物和对比例化合物对hERG电流的抑制结果如表4所示。Table 4 shows the inhibition results of the compounds of the present invention and the compounds of the comparative example on hERG current.
表4化合物对hERG电流的抑制结果Table 4 Inhibitory results of compounds on hERG current
化合物编号Compound number hERG IC 50(μM) hERG IC 50 (μM) 1μM抑制率(％)1μM inhibition rate (%) 10μM抑制率(％)10μM inhibition rate (%)
对比例2Comparative Example 2 2.032.03 28.128.1 91.991.9
对比例3Comparative Example 3 ---- 8.18.1 69.969.9
化合物29Compound 29 ---- 0.770.77 21.9821.98
化合物39Compound 39 >30>30 ---- ----
结论：药物对于心脏hERG钾离子通道的抑制是药物导致QT延长综合症的主要原因。从实验结果可以看出来，本发明的实施例化合物29和39与对比例2和3相比，对心脏hERG钾离子通道没有明显抑制作用，可以避免高剂量时的心脏毒副作用。Conclusion: The inhibition of cardiac hERG potassium ion channel by drugs is the main reason for the drug-induced QT prolongation syndrome. It can be seen from the experimental results that, compared with Comparative Examples 2 and 3, Example Compounds 29 and 39 of the present invention have no obvious inhibitory effect on the cardiac hERG potassium ion channel, and can avoid cardiotoxic side effects at high doses.
测试例4化合物对L-02肝细胞和HK-2肾细胞的毒性测定Test Example 4 Toxicity Determination of Compounds on L-02 Hepatocytes and HK-2 Renal Cells
以下方法用于测定本发明化合物和对比例化合物对体外肝肾细胞的毒性。L-02和HK-2购于中国科学院上海生命科学研究院细胞资源中心。使用上述两株细胞系进行化合物肝肾细胞毒性测定，L-02肝细胞培养于含10％胎牛血清的DMEM培养基中，HK-2肾细胞培养于含10％胎牛血清的MEM培养基中。细胞活力通过Cell Counting Kit-8试剂盒(DOJINDO，货号CK04)进行测定。The following methods were used to determine the toxicity of the compounds of the present invention and the compounds of the comparative examples to liver and kidney cells in vitro. L-02 and HK-2 were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. The above two cell lines were used for compound liver and kidney cytotoxicity assay. L-02 hepatocytes were cultured in DMEM medium containing 10% fetal bovine serum, and HK-2 kidney cells were cultured in MEM medium containing 10% fetal bovine serum. middle. Cell viability was determined by Cell Counting Kit-8 kit (DOJINDO, Cat. No. CK04).
实验方法按照试剂盒说明书的步骤操作，简述如下：受试化合物首先溶解于DMSO中制备为贮存液，随后以对应细胞的培养基进行梯度稀释，配制成测试样品，化合物的终浓 度范围在50μM-7.5nM。将处于对数生长期的细胞以适宜的密度接种至96孔细胞培养板中，在37℃，5％CO 2培养箱内过夜后，加入测试化合物样品后继续培养细胞72小时。培养结束后，向每孔加入100μL Cell Counting Kit-8显色液(10％)，震荡后于37℃、5％CO 2培养箱中孵育1-3h，随后在酶标仪上使用Absorbance模式450nm波长下读取样品各孔光吸收值。通过与对照组(0.5％DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率，之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析，得到化合物细胞毒性的IC 50值，见表5。 The experimental method was operated in accordance with the steps in the kit instructions, which are briefly described as follows: the test compounds were first dissolved in DMSO to prepare a stock solution, and then serially diluted with the culture medium of the corresponding cells to prepare the test samples. The final concentration of the compounds was in the range of 50 μM. -7.5nM. The cells in logarithmic growth phase were seeded at a density appropriate to the cell culture in 96 well plates, after overnight in 37 ℃, 5% CO 2 incubator, after addition of the test compound sample cells cultured for 72 hours. After incubation, add 100 μL of Cell Counting Kit-8 chromogenic solution (10%) to each well , incubate for 1-3 h in a 37°C, 5% CO 2 incubator after shaking, and then use Absorbance mode on a microplate reader at 450 nm Read the light absorption value of each well of the sample at the wavelength. The percentage inhibition rate of the compound at each concentration point was calculated by comparing with the value of the control group (0.5% DMSO), and then a nonlinear regression analysis was performed in the GraphPad Prism 5 software with the compound concentration logarithm-inhibition rate to obtain the compound cytotoxicity. IC 50 values, are shown in Table 5.
表5化合物对L-02和HK-2细胞毒性的IC 50数据 Table 5 IC 50 data of compound cytotoxicity to L-02 and HK-2
化合物编号Compound number IC 50(μM)/L-02 IC 50 (μM) / L- 02 IC 50(μM)/HK-2 IC 50 (μM) / HK- 2
对比例2Comparative Example 2 3.523.52 ----
对比例4Comparative Example 4 29.1229.12 3.873.87
化合物29Compound 29 >50>50 23.3723.37
结论：本发明的实施例化合物29与对比例2和4相比，肝肾毒性较低，具有较好的安全性。Conclusion: Compared with Comparative Examples 2 and 4, the Example Compound 29 of the present invention has lower liver and kidney toxicity and better safety.
除非特别限定，本发明所用术语均为本领域技术人员通常理解的含义。Unless otherwise defined, the terms used in the present invention are the meanings commonly understood by those skilled in the art.
本发明所描述的实施方式仅出于示例性目的，并非用以限制本发明的保护范围，本领域技术人员可在本发明的范围内作出各种其他替换、改变和改进，因而，本发明不限于上述实施方式，而仅由权利要求限定。The embodiments described in the present invention are only for exemplary purposes and are not intended to limit the protection scope of the present invention. Those skilled in the art can make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention does not It is limited to the above-described embodiments, but only by the claims.

Claims (23)

  1. 一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐：A compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021105100-appb-100001
    Figure PCTCN2021105100-appb-100001
    其中：in:
    环A选自芳基、杂芳基或双环稠合环，其中所述的双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环；Ring A is selected from an aryl group, a heteroaryl group or a bicyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
    X选自CR e或N； X is selected from CR e or N;
    R e选自氢原子、烷基、卤素或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自羟基、卤素或烷氧基的取代基所取代； R e is selected from hydrogen atom, alkyl, halogen or alkoxy, wherein said alkyl or alkoxy is optionally further substituted by one or more substituents selected from hydroxyl, halogen or alkoxy;
    R 1选自烷基、环烷基、杂环基、氰基、烯基、炔基、-OR 6、-C(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHSO 2R 6或-C(O)NR 7R 8，其中所述的烷基、环烷基、杂环基、烯基或炔基任选进一步被一个或多个选自羟基、卤素、烷基、烷氧基、环烷基或-NR 7R 8的取代基所取代；优选地，R 1选自甲基； R 1 is selected from alkyl, cycloalkyl, heterocyclyl, cyano, alkenyl, alkynyl, -OR 6 , -C(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein said alkyl, cycloalkyl, heterocyclyl, alkenyl or alkynyl is optionally further modified by one or more substituted by a substituent selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 ; preferably, R 1 is selected from methyl;
    R 2相同或不同，各自独立地选自氢原子、烷基、烯基、炔基、氰基、卤素、硝基、环烷基、杂环基、-OR 6、-C(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHSO 2R 6或-C(O)NR 7R 8，其中所述的烷基、烯基、炔基、环烷基或杂环基任选进一步被一个或多个选自卤素、硝基、氰基、烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHSO 2R 6或-C(O)NR 7R 8的取代基所取代； R 2 are the same or different, each independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, cyano, halogen, nitro, cycloalkyl, heterocyclyl, -OR 6 , -C(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl is further optionally substituted with one or more substituents selected from halo, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6, -C ( O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHSO 2 R 6 or -C( O) Substituents of NR 7 R 8 are substituted;
    R 3选自氰基、烷氧基、四氮唑基、-C(O)R 6或-C(O)OR 6； R 3 is selected from cyano, alkoxy, tetrazolyl, -C(O)R 6 or -C(O)OR 6 ;
    条件是，当R 3选自烷氧基时，R 1不选自-NR 7R 8； With the proviso that when R 3 is selected from alkoxy, R 1 is not selected from -NR 7 R 8 ;
    R 4和R 5与其相连接的N原子一起形成4～11元杂环基，优选为5～11元杂环基，其中所述的杂环基内含有一个或多个N、O、S原子或SO 2，并且杂环基任选进一步被一个或多个选自卤素、硝基、氰基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8的取代基所取代，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被卤素、羟基、氨基或烷氧基的取代基所取代； R 4 and R 5 together with the N atom to which they are connected form a 4-11-membered heterocyclic group, preferably a 5-11-membered heterocyclic group, wherein the heterocyclic group contains one or more N, O, S atoms or SO 2 , and heterocyclyl is optionally further selected from one or more of halogen, nitro, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH)NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 substituents, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle aryl, aryl or heteroaryl are optionally further substituted with halogen, hydroxy, amino or alkoxy substituents;
    或者，R 4和R 5与其相连接的N原子一起形成基团： Alternatively, R 4 together form a group and R 5 with the N atom connected to:
    Figure PCTCN2021105100-appb-100002
    Figure PCTCN2021105100-appb-100002
    Figure PCTCN2021105100-appb-100003
    为单键或双键；
    Figure PCTCN2021105100-appb-100003
    is a single bond or a double bond;
    当
    Figure PCTCN2021105100-appb-100004
    表示单键时，G和M各自独立地选自N或CR j；     when
    Figure PCTCN2021105100-appb-100004
    When representing a single bond, G and M are each independently selected from N or CR j ;
    当
    Figure PCTCN2021105100-appb-100005
    表示双键时，G和M各自独立地选自C；     when
    Figure PCTCN2021105100-appb-100005
    When representing a double bond, G and M are each independently selected from C;
    环B选自环烷基、杂环基、芳基或杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
    E选自NR k、(CR pR q) p、O或S； E is selected from NR k , (CR p R q ) p , O or S;
    F选自(CR pR q) q； F is selected from (CR p R q ) q ;
    条件是，当E选自(CR pR q) p时，p为1，q为1；或者，p为2，q为0；当E选自NR k、O或S时，q为1； Provided that when E is selected from (CR p R q ) p , p is 1 and q is 1; alternatively, p is 2 and q is 0; when E is selected from NR k , O or S, q is 1;
    J选自CR pR q； J is selected from CR p R q ;
    K选自NR k、(CR pR q) r、O或S； K is selected from NR k , (CR p R q ) r , O or S;
    r为0或1；r is 0 or 1;
    R m、R n、R p和R q相同或不同，各自独立地选自R A； R m , R n , R p and R q are the same or different, each independently selected from R A ;
    或者，R m和R n与相连接的同一个碳原子一起形成C＝O； Alternatively, R m and R n with the same carbon atom attached form C = O;
    或者，R p和R q与相连接的碳原子一起形成R B； Alternatively, R p and R q together with the attached carbon atoms form R B ;
    R c和R d相同或不同，各自独立地选自氢原子、卤素、烷基或-OR 6，其中所述的烷基任选进一步被羟基、卤素、烷氧基、环烷基或-NR 7R 8的取代基所取代； R c and R d are the same or different and are each independently selected from a hydrogen atom, halogen, alkyl or -OR 6 , wherein said alkyl is optionally further substituted by hydroxy, halogen, alkoxy, cycloalkyl or -NR Substituents of 7 R 8 are substituted;
    或者，R c和R d与相连接的碳原子一起形成R B； Alternatively, R c and R d together with the attached carbon atoms form R B ;
    R g相同或不同，各自独立地选自氢原子、卤素、硝基、烷基、烯基、炔基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被羟基、卤素、烷基、烷氧基、环烷基或-NR 7R 8的取代基所取代； R g is the same or different, each independently selected from hydrogen atom, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH) NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 substituent;
    或者，两个R g与相连接的同一个碳原子一起形成C＝O； Alternatively, two R gs together form C=O with the same attached carbon atom;
    R j和R k相同或不同，各自独立地选自氢原子或烷基； R j and R k are the same or different, each independently selected from a hydrogen atom or an alkyl group;
    R A相同或不同，各自独立地选自氢原子、卤素、硝基、烷基、烯基、炔基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8，其中所述的烷基、烯基、炔基、 环烷基、杂环基、芳基或杂芳基任选进一步被羟基、卤素、烷基、烷氧基、环烷基或-NR 7R 8的取代基所取代； R A is the same or different, each independently selected from hydrogen atom, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH) NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by hydroxyl, halogen, alkyl, alkoxy, cycloalkyl or -NR 7 R 8 substituent;
    R B相同或不同，各自独立地选自3～10元环烷基或3～10元杂环基，其中所述的环烷基或杂环基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 6、-C(O)R 6、-C(O)OR 6、-OC(O)R 6、-SO 2R 6、-NR 7R 8、-SO 2NR 7R 8、-NHC(＝NH)NH 2、-NHSO 2R 6或-C(O)NR 7R 8的取代基所取代； R and B are the same or different, and are independently selected from 3-10-membered cycloalkyl or 3-10-membered heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further selected from one or more groups selected from halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 6 , -C(O)R 6 , -C(O)OR 6 , -OC( of O)R 6 , -SO 2 R 6 , -NR 7 R 8 , -SO 2 NR 7 R 8 , -NHC(=NH)NH 2 , -NHSO 2 R 6 or -C(O)NR 7 R 8 substituted by a substituent;
    R 6、R 7和R 8各自独立地选自氢原子、烷基、环烷基或杂环基，其中所述烷基、环烷基或杂环基任选进一步被一个或多个选自羟基、氨基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R 9、-C(O)OR 9、-OC(O)R 9、-SO 2R 9、-NR 10R 11、-C(O)NR 10R 11、-SO 2NR 10R 11或-NR 10C(O)R 11的取代基所取代； R 6 , R 7 , and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, or a heterocyclyl group, wherein the alkyl group, cycloalkyl group, or heterocyclyl group is optionally further selected from one or more of Hydroxy, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 9 , -C(O)OR 9 , Substituents of -OC(O)R 9 , -SO 2 R 9 , -NR 10 R 11 , -C(O)NR 10 R 11 , -SO 2 NR 10 R 11 or -NR 10 C(O)R 11 replaced;
    或者，R 7和R 8与其相连接的N原子一起形成3～8元杂环基，其中所述的3～8元杂环内含有一个或多个N、O、S原子或SO 2，并且3～8元杂环上任选进一步被一个或多个选自羟基、卤素、氨基、烷基或烷氧基的取代基所取代； Alternatively, R 7 and R 8 together with the N atom to which they are attached form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic ring contains one or more N, O, S atoms or SO 2 , and The 3-8 membered heterocycle is optionally further substituted by one or more substituents selected from hydroxyl, halogen, amino, alkyl or alkoxy;
    R 9、R 10和R 11各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代； R 9 , R 10 and R 11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group The radical or heteroaryl is optionally further selected from one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxy substituted by the substituent of the ester group;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
    p选自1或2。p is selected from 1 or 2.
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐，The compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutically acceptable salt, which is the compound of general formula (III) or its stereoisomer, tautomer body or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021105100-appb-100006
    Figure PCTCN2021105100-appb-100006
    其中：环A、X、m、R 1、R 2、R 4和R 5的定义如权利要求1中所述。 wherein: Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in claim 1 .
  3. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(IV)所述的化合物或其立体异构体、互变异构体或其可药用的盐，The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is the compound of general formula (IV) or its stereoisomer, tautomer body or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021105100-appb-100007
    Figure PCTCN2021105100-appb-100007
    其中：环A、X、m、R 1、R 2、R 4和R 5的定义如权利要求1中所述。 wherein: Rings A, X, m, R 1 , R 2 , R 4 and R 5 are as defined in claim 1 .
  4. 根据权利要求1～3中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：The compound according to any one of claims 1 to 3 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
    R 4和R 5与其相连接的N原子一起形成4～8元单环杂环基，优选为5～6元单环杂环基，更优选为哌啶基，其中所述的单环杂环基任选进一步被一个或多个选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2、＝O或-OR 6的取代基所取代； R 4 and R 5 together with the N atom to which they are attached form a 4-8 membered monocyclic heterocyclic group, preferably a 5-6 membered monocyclic heterocyclic group, more preferably a piperidinyl group, wherein the monocyclic heterocyclic group group optionally further substituted with one or more substituents selected from methyl, amino, -CH 2 NH 2, -CH 2 OH, -NHC (= NH) NH 2, = O, or -OR 6 is substituted with a substituent;
    R 6的定义如权利要求1中所述。 R 6 as defined in claim 1.
  5. 根据权利要求1～3中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：The compound according to any one of claims 1 to 3 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
    R 4和R 5与其相连接的N原子一起形成7～11元螺杂环基，其中所述的螺杂环基任选进一步被一个或多个选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2、＝O或-OR 6的取代基所取代； R 4 and R 5 together with the N atom to which they are attached form a 7-11 membered spiro heterocyclic group, wherein said spiro heterocyclic group is optionally further selected from one or more groups selected from methyl, amino, -CH 2 NH 2 , -CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 substituent;
    R 6的定义如权利要求1中所述。 R 6 as defined in claim 1.
  6. 根据权利要求5所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中所述的螺杂环基选自：The compound according to claim 5 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said spiroheterocyclyl is selected from:
    Figure PCTCN2021105100-appb-100008
    Figure PCTCN2021105100-appb-100008
    R a相同或不同，各自独立地选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2或-OR 6； R a are the same or different, each independently selected from methyl, amino, -CH 2 NH 2 , -CH 2 OH, -NHC(=NH)NH 2 or -OR 6 ;
    或者，两个R a与相连接的同一个碳原子一起形成C＝O； Alternatively, two R a together with the same carbon atom to which they are attached form C=O;
    R 6的定义如权利要求1中所述； R 6 as defined in claim 1;
    t为1、2或3。t is 1, 2 or 3.
  7. 根据权利要求1～3中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：The compound according to any one of claims 1 to 3 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
    R 4和R 5与其相连接的N原子一起形成7～11元桥杂环基，其中所述的桥杂环基任选进一步被一个或多个选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2、＝O或-OR 6的取代基所取代； R 4 and R 5 together with the N atom to which they are attached form a 7-11 membered bridged heterocyclic group, wherein the bridged heterocyclic group is optionally further selected from one or more groups selected from methyl, amino, -CH 2 NH 2 , -CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 substituent;
    R 6的定义如权利要求1中所述。 R 6 as defined in claim 1.
  8. 根据权利要求1～3中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：The compound according to any one of claims 1 to 3 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
    R 4和R 5与其相连接的N原子一起形成7～11元稠杂环基，其中所述的稠杂环基任选进一步被一个或多个选自甲基、氨基、-CH 2NH 2、-CH 2OH、-NHC(＝NH)NH 2、＝O或-OR 6的取代基所取代； R 4 and R 5 together with the N atom to which they are attached form a 7-11 membered fused heterocyclic group, wherein the fused heterocyclic group is optionally further selected from one or more groups selected from methyl, amino, -CH 2 NH 2 , -CH 2 OH, -NHC(=NH)NH 2 , =O or -OR 6 substituent;
    R 6的定义如权利要求1中所述。 R 6 as defined in claim 1.
  9. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(V)所述的化合物或其立体异构体、互变异构体或其可药用的盐：The compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutically acceptable salt, which is the compound of general formula (V) or its stereoisomer, tautomer body or its pharmaceutically acceptable salt:
    Figure PCTCN2021105100-appb-100009
    Figure PCTCN2021105100-appb-100009
    其中：in:
    环B选自苯基、3～8元环烷基、4～8元杂环基或5～6元杂芳基；Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
    E选自NR k、(CR pR q) p、O或S； E is selected from NR k , (CR p R q ) p , O or S;
    F选自(CR pR q) q； F is selected from (CR p R q ) q ;
    条件是，当E选自(CR pR q) p时，p为1，q为1；或者，p为2，q为0；当E选自NR k、O或S时，q为1； Provided that when E is selected from (CR p R q ) p , p is 1 and q is 1; alternatively, p is 2 and q is 0; when E is selected from NR k , O or S, q is 1;
    R m选自氨基、-CH 2NH 2或-NHC(＝NH)NH 2； R m is selected from an amino group, -CH 2 NH 2 or -NHC (= NH) NH 2;
    R n选自氢原子、甲基或-CH 2OH； R n is selected from hydrogen atom, methyl or -CH 2 OH;
    或者，R m和R n与相连接的同一个碳原子一起形成C＝O； Alternatively, R m and R n with the same carbon atom attached form C = O;
    R p和R q各自独立地选自氢原子、卤素、氨基、C 1-C 4烷基、羟基C 1-C 4烷基、氨基C 1-C 4烷基或-OR 6； R p and R q are each independently selected from a hydrogen atom, halogen, amino, C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl or -OR 6 ;
    Figure PCTCN2021105100-appb-100010
    环A、G、M、X、m、n、R 1～R 3、R 6、R k和R g的定义如权利要求1中所述。
    Figure PCTCN2021105100-appb-100010
    Rings A, G, M, X, m, n, R 1 to R 3 , R 6 , R k and R g are as defined in claim 1 .
  10. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VI)所述的化合物或其立体异构体、互变异构体或其可药用的盐：The compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutically acceptable salt, which is the compound of general formula (VI) or its stereoisomer, tautomer body or its pharmaceutically acceptable salt:
    Figure PCTCN2021105100-appb-100011
    Figure PCTCN2021105100-appb-100011
    其中：in:
    环B选自苯基、3～8元环烷基、4～8元杂环基或5～6元杂芳基；Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
    J选自CR pR q； J is selected from CR p R q ;
    K选自NR k、(CR pR q) r、O或S； K is selected from NR k , (CR p R q ) r , O or S;
    r为0或1；r is 0 or 1;
    R m选自氨基、-CH 2NH 2或-NHC(＝NH)NH 2； R m is selected from an amino group, -CH 2 NH 2 or -NHC (= NH) NH 2;
    R n选自氢原子、甲基或-CH 2OH； R n is selected from hydrogen atom, methyl or -CH 2 OH;
    或者，R m和R n与相连接的同一个碳原子一起形成C＝O； Alternatively, R m and R n with the same carbon atom attached form C = O;
    R p和R q各自独立地选自氢原子、卤素、氨基、C 1-C 4烷基、羟基C 1-C 4烷基、氨基C 1-C 4烷基或-OR 6； R p and R q are each independently selected from a hydrogen atom, halogen, amino, C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, amino C 1 -C 4 alkyl or -OR 6 ;
    Figure PCTCN2021105100-appb-100012
    环A、G、M、X、m、n、R 1～R 3、R 6、R k和R g的定义如权利要求1中所述。
    Figure PCTCN2021105100-appb-100012
    Rings A, G, M, X, m, n, R 1 to R 3 , R 6 , R k and R g are as defined in claim 1 .
  11. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VII)所述的化合物或其立体异构体、互变异构体或其可药用的盐：The compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutically acceptable salt, which is the compound of general formula (VII) or its stereoisomer, tautomer body or its pharmaceutically acceptable salt:
    Figure PCTCN2021105100-appb-100013
    Figure PCTCN2021105100-appb-100013
    其中：in:
    环B选自苯基、3～8元环烷基、4～8元杂环基或5～6元杂芳基；Ring B is selected from phenyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl or 5-6 membered heteroaryl;
    R c和R d与相连接的原子一起形成3～8元环烷基； R c and R d together with the connected atoms form a 3- to 8-membered cycloalkyl;
    R m选自氨基、-CH 2NH 2或-NHC(＝NH)NH 2； R m is selected from an amino group, -CH 2 NH 2 or -NHC (= NH) NH 2;
    R n选自氢原子、甲基或-CH 2OH； R n is selected from hydrogen atom, methyl or -CH 2 OH;
    或者，R m和R n与相连接的同一个碳原子一起形成C＝O； Alternatively, R m and R n with the same carbon atom attached form C = O;
    Figure PCTCN2021105100-appb-100014
    环A、G、M、X、m、n、R 1～R 3和R g的定义如权利要求1中所述。
    Figure PCTCN2021105100-appb-100014
    Rings A, G, M, X, m, n, R 1 to R 3 and R g are as defined in claim 1 .
  12. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐：The compound according to claim 1 or its stereoisomer, tautomer or its pharmaceutically acceptable salt, which is the compound of general formula (VIII) or its stereoisomer, tautomer body or its pharmaceutically acceptable salt:
    Figure PCTCN2021105100-appb-100015
    Figure PCTCN2021105100-appb-100015
    其中：in:
    Figure PCTCN2021105100-appb-100016
    环B、n、R 1～R 2和R g的定义如权利要求1中所述。
    Figure PCTCN2021105100-appb-100016
    Rings B, n, R 1 to R 2 and R g are as defined in claim 1 .
  13. 根据权利要求1～3、9～12中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 2选自氢原子、F、Cl、Br、氨基、羟基、氰基、硝基、甲氧基、乙氧基、甲基、乙基、乙炔基、乙烯基、-NHCH 3或-N(CH 3) 2。 The compound according to any one of claims 1 to 3 and 9 to 12 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen atom, F, Cl, br, amino, hydroxy, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH 3 or -N (CH 3) 2.
  14. 根据权利要求9～11中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 3选自-C(O)OH。 The compound according to any one of claims 9 to 11 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 3 is selected from -C(O)OH.
  15. 根据权利要求1～10中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 6选自氢原子或烷基。 The compound according to any one of claims 1 to 10, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 6 is selected from a hydrogen atom or an alkyl group.
  16. 根据权利要求1～4、9～11中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中环A选自苯基。The compound according to any one of claims 1 to 4, 9 to 11, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from phenyl.
  17. 根据权利要求9～12中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中环B选自：The compound according to any one of claims 9 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Ring B is selected from:
    Figure PCTCN2021105100-appb-100017
    Figure PCTCN2021105100-appb-100017
  18. 根据权利要求9～12中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R g相同或不同，各自独立地选自氢原子、F、Cl、Br、氨基、羟基、氰基、硝基、甲氧基、乙氧基、甲基、乙基、乙炔基、乙烯基、-NHCH 3或-N(CH 3) 2； The compound according to any one of claims 9 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R g is the same or different, and each is independently selected from a hydrogen atom, F , Cl, Br, amino, hydroxyl, cyano, nitro, methoxy, ethoxy, methyl, ethyl, ethynyl, vinyl, -NHCH 3 or -N(CH 3 ) 2 ;
    或者，两个R g与相连接的同一个碳原子可以一起形成C＝O。 Alternatively, two R g and the same carbon atom to which they are attached can be taken together to form C=O.
  19. 根据权利要求1～18中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中所述的化合物选自：The compound according to any one of claims 1 to 18 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
    Figure PCTCN2021105100-appb-100018
    Figure PCTCN2021105100-appb-100018
    Figure PCTCN2021105100-appb-100019
    Figure PCTCN2021105100-appb-100019
  20. 一种药物组合物，所述的药物组合物含有有效剂量的权利要求1～19中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。A pharmaceutical composition containing an effective dose of the compound according to any one of claims 1 to 19 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and Pharmaceutically acceptable carriers, excipients or combinations thereof.
  21. 根据权利要求1～19中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求20所述的药物组合物在制备SHP2变构抑制剂中的用途。The compound according to any one of claims 1 to 19 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 is in the preparation of SHP2 allosteric Use in inhibitors.
  22. 根据权利要求1～19中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求20所述的药物组合物在制备治疗由SHP2介导的疾病的药物中的用途，其中所述的由SHP2介导的疾病优选为癌症、癌转移、心血管疾病、免疫紊乱、纤维化或视觉紊乱。The compound according to any one of claims 1 to 19 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 is prepared for the treatment of SHP2 Use in medicine for a disease mediated by SHP2, wherein the disease mediated by SHP2 is preferably cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder.
  23. 根据权利要求22所述的用途，其中所述的由SHP2介导的疾病选自努南综合征、豹斑综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤。The use according to claim 22, wherein the disease mediated by SHP2 is selected from the group consisting of Noonan syndrome, Leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
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