WO2023198114A1 - Alk2 kinase inhibitor - Google Patents

Alk2 kinase inhibitor Download PDF

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Publication number
WO2023198114A1
WO2023198114A1 PCT/CN2023/087857 CN2023087857W WO2023198114A1 WO 2023198114 A1 WO2023198114 A1 WO 2023198114A1 CN 2023087857 W CN2023087857 W CN 2023087857W WO 2023198114 A1 WO2023198114 A1 WO 2023198114A1
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ring
alkyl
amino
halogen
membered
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PCT/CN2023/087857
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French (fr)
Chinese (zh)
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杨欣
崔荣
温俏冬
殷建明
郑鹛
吕裕斌
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杭州邦顺制药有限公司
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Publication of WO2023198114A1 publication Critical patent/WO2023198114A1/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
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
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    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry and relates to an ALK2 kinase inhibitor, its pharmaceutical composition, preparation method and its use in preparing, preventing and/or treating drugs for indications related to the ALK2 signaling pathway.
  • ALK2 (also known as ACVR1 protein) is an activin receptor-like kinase, bone morphogenetic protein (BMP) type I receptor, and a member of the transforming growth factor TGF- ⁇ family.
  • BMP bone morphogenetic protein
  • TGF- ⁇ family The binding of ligands to type II receptors induces the phosphorylation of type I receptors.
  • Type I receptors affect cell function by recruiting and phosphorylating downstream receptor-related Smads and further regulating the expression of related genes (PLoS One 2013 Apr 30;8(4):e62721).
  • ALK2 abnormal activation of ALK2 can lead to the occurrence and development of various diseases. For example, most patients with fibrodysplasia ossificans progressiva (FOP) are found to have ALK2 R206H mutations, which enhance downstream SMAD signaling and overactivate the BMP pathway. 20-32% of diffuse endophytic pontine gliomas (DIPG) have ACVR1 mutations. ALK2 has also been found to play a carcinogenic role in ovarian cancer, prostate cancer, and erythroleukemia (Cells 2019, 8, 1366).
  • FOP fibrodysplasia ossificans progressiva
  • DIPG diffuse endophytic pontine gliomas
  • ALK2 is a key receptor that regulates the iron-dependent upregulation of hepcidin expression, and high levels of hepcidin can lead to iron limitation erythropoiesis, manifested as iron-refractory iron deficiency anemia (IRIDA) and inflammatory anemia (AI).
  • IRIDA iron-refractory iron deficiency anemia
  • AI inflammatory anemia
  • Inflammatory anemia also known as anemia of chronic disease (ACD) is the second most common anemia disease in the world after iron deficiency anemia. It is common in patients with chronic diseases or hospitalization.
  • Inflammatory anemia refers to anemia caused by chronic infections (including tuberculosis, acquired immunodeficiency syndrome), autoimmune diseases (such as rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, etc.) and certain tumors (including those related to cytokines Anemia caused by long-term inflammation caused by increased related hematological tumors such as Hodgkin lymphoma, myelofibrosis, MDS, MM, etc., and common solid tumors such as ovarian cancer, lung cancer, etc.). This type of inflammatory anemia can seriously affect patients' quality of life, physiological functions, and reduce survival (N Engl J Med 2019;381:1148-57).
  • Patent WO2021102258 discloses the use of ALK2 inhibitors in combination with JAK2 inhibitors for the treatment of myeloproliferative neoplasms (MPN) and related anemia. This suggests the application potential of ALK2 inhibitors in this indication.
  • the object of the present invention is to provide an ALK2 kinase inhibitor, its pharmaceutical composition, preparation method and its use in the preparation, prevention and/or treatment of drugs for indications related to the ALK2 signaling pathway.
  • the present invention discloses a compound having the structure shown in general formula (I), its deuterated product, stereoisomer or pharmaceutically acceptable salt:
  • Ring A is a 5-10 membered heteroaryl group, optionally substituted by 1-3 R 3 ;
  • Ring B is a 6-15 membered ring group, and optionally 1-3 link carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
  • L 1 is selected from chemical bond, C 1-6 alkyl, imino, carbonyl, -CO-NH-, phenyl, 5-6 membered heteroaryl, -phenyl-CO-NH-;
  • L 2 is selected from chemical bond, -(CR a R b ) n -, imino group, ether bond, -C 1-6 alkyl-O-;
  • R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
  • R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
  • R 2 is selected from 4-10 membered heterocycloalkyl or cycloalkyl, and is optionally substituted by 1-3 R 6 ;
  • R 3 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl;
  • R 4 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl;
  • R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, -CO-NR c R d , C 1-6 alkyl, C 1-6 alkoxy, -(CR a R b ) n -OH;
  • R 6 is selected from halogen, hydroxyl, cyano, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, C 1-6 alkoxy, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
  • R a , R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl, or
  • R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group
  • R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
  • n is selected from an integer from 1 to 3.
  • Ring A is a 5-10 membered heteroaryl group, optionally substituted by 1-3 R 3 ;
  • Ring B is a 6-15 membered ring group, and optionally 1-3 link carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
  • L 1 is selected from chemical bond, C 1-6 alkyl, imino, carbonyl, -CO-NH-, phenyl, 5-6 membered heteroaryl, -phenyl-CO-NH-;
  • L 2 is selected from chemical bond, -(CR a R b ) n -, imino group, ether bond, -C 1-6 alkyl-O-;
  • R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
  • R 2 is selected from 4-10 membered heterocycloalkyl, and R 2 is optionally substituted by 1-3 R 6 ;
  • R 3 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl;
  • R 4 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl;
  • R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH;
  • R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
  • R a , R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl, or
  • R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group
  • R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
  • n is selected from an integer from 1 to 3.
  • Ring A is a 6-10 membered heteroaryl group, containing 1-3 heteroatoms selected from N, O, and S, optionally substituted by 1-3 R 3 ;
  • Ring B is selected from 6-9-membered carbocyclyl or 6-13-membered heterocyclyl, and optionally 1 link carbon atom is substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
  • L 1 is selected from imino, carbonyl, -CO-NH-, 5-6 membered heteroaryl, -phenyl-CO-NH-;
  • L 2 is selected from chemical bond, -(CR a R b ) n -, -C 1-3 alkyl-O-;
  • R 1 is selected from C 1-3 alkyl, 6-8 membered cycloalkyl, 6-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
  • R 2 is selected from 4-9 membered heterocycloalkyl, containing 1-2 heteroatoms selected from N, O, S, R 2 is optionally substituted by 1-3 R 6 ;
  • R 3 is selected from cyano, amino, C 1-3 alkyl
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 5 is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, -(CR a R b ) n -OH;
  • R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
  • R a , R b are independently selected from H or C 1-3 alkyl, or
  • R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group
  • R c and R d are independently selected from H or C 1-3 alkyl
  • R e is selected from halogen, cyano, C 1-3 alkoxy
  • n is selected from an integer from 1 to 3.
  • Ring A is selected from
  • L 1 is selected from imino, -CO-NH-, carbonyl, -phenyl-CO-NH-;
  • R 1 is selected from C 1-3 alkyl, the R 1 is optionally substituted by 1-3 R 5 ;
  • R 3 is selected from cyano, amino, C 1-3 alkyl
  • R 5 is selected from halogen, cyano, hydroxyl, C 1-6 alkyl, -(CR a R b ) n -OH;
  • R a and R b are independently selected from H or C 1-3 alkyl
  • n is selected from an integer from 1 to 3.
  • Ring B is selected from
  • Ring B is selected from
  • L 2 is selected from chemical bond, -(CR a R b ) n -, -C 1-3 alkyl-O-;
  • R 2 is selected from, H, halogen, hydroxyl, cyano, or
  • R 2 is selected from and optionally substituted by 1-3 R 6 ;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 6 is selected from halogen, hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, C 1-6 alkoxy, optionally substituted by 1-3 Re ;
  • R a , R b are independently selected from H or C 1-3 alkyl, or
  • R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group
  • R c and R d are independently selected from H or C 1-3 alkyl
  • R e is selected from halogen, hydroxyl, cyano, C 1-3 alkoxy;
  • n is selected from an integer from 1 to 3.
  • the compound provided by the present invention further has the structure shown in formula (II):
  • X 1 and X 2 are independently selected from CH or N;
  • R 1 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, optionally substituted by 1-3 R 5 ;
  • R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH;
  • Ring B is Y 1 , Y 2 , Y 3 are independently selected from CH or N.
  • Ring C is a parallel 5-6 membered ring group. Any one carbon atom in ring C is substituted by oxygen; ring B is optionally substituted by 1- 3 R 4 substitutions;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 2 is a 4-8 membered heterocycloalkyl group, containing 1-3 heteroatoms selected from N, O, S, and optionally substituted by 1-3 R 6 ;
  • R 6 is selected from -CO-R c , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
  • R a and R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
  • R c is independently selected from H, hydroxyl, amino or C 1-6 alkyl
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
  • n is selected from an integer from 1 to 3.
  • R 1 is selected from
  • R 5 is selected from hydroxyl, halogen, C 1-6 alkyl, -(CR a R b ) n -OH;
  • R a and R b are independently selected from H and C 1-3 alkyl
  • n is selected from an integer from 1 to 3.
  • R 1 is selected from
  • R 5 is selected from hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH.
  • the compound provided by the present invention further has the structure shown in formula (II-1):
  • Ring B is Y 1 , Y 2 , Y 3 are independently selected from CH or N.
  • Ring C is a parallel 5-6 membered ring group. Any one carbon atom in ring C is substituted by oxygen; ring B is optionally substituted by 1- 3 R 4 substitutions;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 2 is a 5-7 membered heterocycloalkyl group, containing 1-3 heteroatoms selected from N, O, S, and optionally substituted by 1-3 R 6 ;
  • R 6 is selected from -CO-R c , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
  • R c is independently selected from H, hydroxyl, amino or C 1-6 alkyl
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy.
  • Ring B is selected from
  • Ring B is Ring C is a parallel 5-membered carbocyclyl or heterocyclyl, and any one carbon atom in Ring C is substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • Ring B is selected from
  • Ring B is optionally substituted with 1-3 R 4 ;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • R 2 is selected from preferred and optionally substituted by 1 R 6 ;
  • R 6 is selected from -CO-R c , -SO 2 -R c , or
  • R 6 is selected from C 1-3 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
  • R c is independently selected from H or C 1-3 alkyl
  • R e is selected from halogen, cyano, C 1-3 alkoxy.
  • R 2 is selected from preferred and replaced by 1 R 6 ;
  • R 6 is a 4-6 membered heterocycloalkyl group, containing 1 O atom, preferably More preferred
  • the compound provided by the present invention further has the structure shown in formula (III):
  • Ring B is Ring C is a parallel 5-6 membered ring group, optionally containing 1-2 heteroatoms selected from N; Ring B is optionally substituted by 1-2 R 4 ;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 1 is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 2 heteroatoms selected from N, O, and S, preferably More preferred R 1 is optionally replaced by 1-3 R 5 ;
  • R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH, preferably hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH , -C(CH 3 ) 2 OH;
  • L 2 is selected from chemical bonds, -(CR a R b ) n -;
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, hydroxyl, amino, cyano, or
  • R 6 is selected from 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl containing 1-2 selected from N, O heteroatoms, C 1-3 alkyl, and is optionally replaced by 1-3 Re substitution ;
  • R a and R b are independently selected from H or C 1-3 alkyl, or R a , R b and the attached carbon atom form a 3-6 membered cycloalkyl group;
  • R e is halogen
  • n is an integer from 1 to 3.
  • Ring B is selected from
  • Ring B is selected from
  • L 2 is selected from chemical bond, C 1-3 alkylene
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, or
  • R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1-2 selected from N, O heteroatoms, C 1-3 alkyl, and is optionally replaced by 1-3 R e replaced.
  • Ring B is selected from
  • R 1 is selected from optionally substituted by 1 R 5 ;
  • R 5 is selected from hydroxyl, -CH 2 OH
  • L 2 is selected from chemical bonds
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1 R 6 ;
  • R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1 O, C 1-3 alkyl, and is optionally substituted by 1-3 R e ;
  • R e is halogen
  • R 2 is selected from preferred
  • R 6 is selected from Cyclohexyl, C 1-3 alkyl, preferably C 1-3 alkyl.
  • R 1 and R 5 form the following structure:
  • Ring B is selected from
  • R 1 is selected from optionally substituted by 1 R 5 ;
  • R 5 is selected from hydroxyl, -CH 2 OH
  • L 2 is selected from chemical bonds
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 N, substituted by 1 R 6 ;
  • R 6 is selected from 4-6 membered heterocycloalkyl groups containing 1-2 heteroatoms selected from N and O.
  • R 2 is selected from preferred
  • R 6 is selected from preferred
  • R 1 and R 5 form the following structure:
  • Ring B is selected from
  • R 1 is selected from optionally substituted by 1 R 5 ;
  • R 5 is selected from hydroxyl, -CH 2 OH
  • L 2 is selected from chemical bond, C 1-3 alkylene
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, or
  • R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1 O, and is optionally substituted by 1-3 R e ;
  • R e is halogen
  • R 2 is selected from preferred
  • R 6 is selected from halogen, or
  • R 6 is selected from Cyclohexyl, preferably and optionally substituted by 1-3 Re ;
  • R e is halogen
  • R 1 and R 5 form the following structure:
  • the compound provided by the present invention further has a structure represented by formula (IV):
  • X 1 and X 2 are independently selected from CH or N;
  • R 1 is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, preferably More preferred optionally substituted by 1-2 R5 ;
  • R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkyl-OH, halogen, OH, amino, amide group, and cyano group;
  • Ring B is r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH, Z 5 is CH or N; Z 6 is NH or O; any one carbon atom in ring B is replaced by oxygen; ring B is optionally replaced by 1-2 R 4 replace;
  • R 4 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, and hydroxyl;
  • L 2 is a chemical bond, -(CR a R b ) n -;
  • R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
  • R 2 is selected from 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, preferably 4-6 membered heterocycloalkyl or 4-6 membered containing 1-2 heteroatoms selected from N, O, S Cycloalkyl, more preferably Further preferred and optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, and cyano;
  • R a and R b are independently selected from H or C 1-3 alkyl, or R a , R b and the attached carbon atom form a 3-6 membered cycloalkyl group;
  • n is an integer from 1 to 3.
  • Ring B is selected from
  • Ring B is r or q is an integer from 1 to 3; Z 1 , Z 2 or Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O; when When it is a double bond, Z 4 is CH; Ring B is optionally replaced by 1-2 R 4 ;
  • R 4 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, and hydroxyl.
  • X 1 and X 2 are CH;
  • Ring B is r is an integer from 1 to 2, be a single bond or a double bond.
  • Ring B is preferred The * end is connected to pyridine, and the ** end is connected to L 2 Connection, r is an integer from 1 to 2, be a single bond or a double bond.
  • L 2 is a chemical bond or C 1-3 alkylene group
  • R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
  • R 2 is selected from 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, preferably 4-6 membered heterocycloalkyl or 4-6 membered containing 1-2 heteroatoms selected from N, O, S Cycloalkyl, more preferably Further preferred and optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, and cyano.
  • R 1 is selected from preferred optionally substituted by 1-2 R5 ;
  • R 5 is selected from halogen, OH, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkyl-OH, preferably F, Cl, -OH, methyl, -CH 2 -OH;
  • R 1 and R 5 form the following structure:
  • Ring B is selected from preferred Further preferred
  • the * end is connected to pyridine, and the ** end is connected to L 2 ;
  • L 2 is a chemical bond, C 1-3 alkylene group, preferably a chemical bond or isopropyl group;
  • R2 is H or Preferably H or
  • the compound provided by the present invention further has a structure represented by formula (V):
  • M is selected from CH or N;
  • R 6a is selected from C 1-3 alkoxy, preferably methoxy, ethoxy, propoxy;
  • R 6b is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, preferably methyl, ethyl, isopropyl, Isopropyl is more preferred.
  • Compounds represented by general formula (1) include the following specific compounds:
  • Another aspect of the present invention also provides a pharmaceutical composition, which contains the above-mentioned compound, its deuterated product, stereoisomer or pharmaceutically acceptable salt and its pharmaceutically acceptable carrier.
  • Another aspect of the present invention also provides the use of the above-mentioned compound, its deuterated product, stereoisomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in preparing a medicament for treating and/or preventing ALK2-related diseases.
  • the ALK2-related diseases include anemia, inflammation, tumors and some ALK2-related genetic diseases.
  • the ALK2-related diseases include fibrodysplasia ossificans progressiva, diffuse endogenous pontine glioma, iron-refractory iron deficiency anemia, inflammatory anemia, myelodysplastic syndrome, multiple Anemia associated with myeloma and myeloproliferative neoplasms.
  • the drug is used alone or in combination with other therapeutic agents.
  • the other therapeutic agent is a JAK2 inhibitor for the treatment of myeloproliferative neoplasm-related anemia.
  • the compound provided by the invention has strong medicinal efficacy, good pharmacokinetic properties and low toxic and side effects, and is an ideal ALK2 inhibitor.
  • the compound provided by the present invention has better ALK2 inhibitory activity, and its inhibitory activity on ALK2 is much greater than ALK5, and has better selectivity.
  • the compounds of the present invention are ideal highly active ALK2 inhibitors and can be used to treat and/or prevent diseases, including anemia, inflammation, tumors and some rare diseases, such as fibrodysplasia ossificans progressiva and diffuse endogenous pontine type.
  • Glioma iron-refractory iron deficiency anemia, inflammatory anemia, myelodysplastic syndrome, multiple myeloma, combined use of JAK2 inhibitors to treat anemia associated with myeloproliferative neoplasms.
  • group A is optionally substituted by 1 to 3 groups B
  • group A is unsubstituted by group B, group A being substituted by 1 group B, and group A being substituted by 2 groups B. Substitution, group A is replaced by three groups B. There are four cases.
  • Substituted or “substituted” as used herein means that any one or more hydrogen atoms on any atom in a certain group or fragment are replaced by substituents, which may include deuterium and hydrogen variants, as long as The valence state of a particular atom is normal and the substituted compound is stable.
  • substituents which may include deuterium and hydrogen variants, as long as The valence state of a particular atom is normal and the substituted compound is stable.
  • substituent oxygen
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically feasible.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • combinations of substituents and/or variants thereof may only be used if such combinations result in stable compounds. It is only allowed in the case of compounds.
  • a connecting group When the number of a connecting group is 0, such as -(CR a R b ) 0 -, it means that the connecting group is a single bond/chemical bond.
  • one of the variables is selected from chemical bond/single bond, it means that the two groups connected to it are directly connected.
  • L 1 in AL 1 -R 1 represents a single bond, it means that the structure is actually AR 1 .
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
  • the connection direction is arbitrary.
  • the linking group L 1 in ring AL 1 -R 1 is -MW-.
  • -MW- can be pressed from left to right.
  • the ring A and R 1 can be connected in the same direction in the right reading order to form the ring AMWR 1 , or the ring A and R 1 can be connected in the opposite direction to the reading order from left to right to form the ring AWMR 1 .
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned, and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced accordingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be in the form of a straight solid line bond. dashed key express.
  • the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in means that it is connected to other groups through both ends of the carbon atoms in the group;
  • the dotted lines in indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 4;
  • connection site of the group or fragment is located on the ring connected by the dotted line.
  • Any connection point on the nitrogen-containing spirocyclic ring of the group can be connected to other groups through a chemical bond, including at least These 3 connection methods;
  • Any connection point on the benzene ring of this group can be connected to other groups through a chemical bond, including at least These 4 connection methods.
  • connection site of the group or fragment can be any connection site.
  • Any connection point on the nitrogen-containing spirocyclic ring of the group can be connected to other groups through a chemical bond, including at least These two connection methods.
  • double bonds and single bonds have no limiting meaning.
  • Both refer to benzene ring or phenyl group, in which the double bond or Specifically refers to large ⁇ bonds delocalized on the plane of the benzene ring; , when ring C is limited to a 5-membered aryl or heteroaryl, ring B and ring C form a conjugated ring-aryl or ring-heteroaryl group, and non-limiting examples thereof include even though The left-center ring contains only two double bonds, but still includes For this group, the double bond at this time represents the large ⁇ bond delocalized on the aromatic ring.
  • numerical ranges include endpoint values and any number between the endpoint values.
  • “0-3” may include 0, 1, 2, or 3
  • “1-3” may include 1, 2, or 3.
  • C 1-n as used herein includes C 1-2 , C 1-3 ,...C 1-n .
  • a “C 1-6 " group means that there are 1 to 6 carbon atoms in the moiety, that is, the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl and tert-butyl. Numeric ranges, such as “1-6", in this document refer to each integer within the given range.
  • the link atoms refer to the non-hydrogen atoms used in the ring group to form the ring.
  • the link atoms in are 3 carbon atoms;
  • the middle link atoms are three carbon atoms and one oxygen atom;
  • the middle link atoms are 1 N atom and 5 carbon atoms;
  • the middle link atoms are 8 carbon atoms and 1 nitrogen atom.
  • n-m element refers to the number of link atoms in the ring group.
  • a "3-8 yuan” group means that the part has 3-8 link atoms, that is, the group contains 3 link atoms, 4 link atoms, 5 link atoms, 6 link atoms, 7 link atoms or 8 link atoms.
  • 3-8 membered cycloalkyl refers to a saturated cyclic hydrocarbon group containing 3-8 carbon atoms, that is, the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, Hexyl, cycloheptyl, cyclooctyl.
  • hydrocarbyl used herein alone or in combination refers to an atomic group consisting only of carbon and hydrogen, including saturated, unsaturated or aromatic hydrocarbon groups, such as alkyl, alkenyl, alkynyl, cyclic Alkyl, cycloalkenyl, cycloalkynyl, aryl. Unless otherwise specified, the “hydrocarbyl group” may be linear, branched or cyclic.
  • alkyl refers to an optionally substituted straight chain or optionally substituted branched chain saturated aliphatic hydrocarbon. This article The “alkyl group” may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms.
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl base, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-di Methyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl , isopentyl, neopentyl, tert-amyl, hexyl, etc.
  • alkyl when “alkyl” appears in a numerical range, for example, "C 1 - 6 alkyl” means that it can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, An alkyl group composed of 5 carbon atoms or 6 carbon atoms.
  • the alkyl group herein also includes cases where the numerical range is not specified.
  • Alkyl groups may be optionally substituted or unsubstituted.
  • Alkyl as used in combination herein refers to an alkyl group attached to another group, for example, an alkyl group in an alkoxy group, and is defined the same as when used alone.
  • alkylene refers to a saturated aliphatic divalent hydrocarbon radical obtained by removing two hydrogen atoms from a linear or branched saturated aliphatic hydrocarbon radical.
  • the "alkylene group” herein may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms.
  • Non-limiting examples of alkylene include -CH 2 - (i.e., methylene), -CH 2 -CH 2 - (i.e., ethylene), -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 -, -CH 2 -C(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -C(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -C(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, etc.
  • Alkylene groups may be optionally substituted or unsubstituted.
  • alkenyl refers to an optionally substituted straight chain or optionally substituted unsaturated aliphatic hydrocarbon having one or more carbon-carbon double bonds.
  • Alkenyl herein may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms.
  • Non-limiting examples of alkyl groups include vinyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3 -Pentadienyl, 1,4-pentadienyl and 1,4-hexadienyl groups/moieties. Unless otherwise stated, the term “alkenyl” does not include “cycloalkenyl”.
  • alkoxy or "-O-alkyl” as used herein, alone or in combination, means “alkyl-O-”.
  • alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • Alkoxy groups may be optionally substituted or unsubstituted.
  • cyclyl or "ring” as used herein alone or in combination refers to any organic compound having a cyclic structure, wherein the cyclic group may be saturated or unsaturated (including aryl) and may have at its carbon
  • the skeleton contains one or more heteroatoms such as N, O or S.
  • cyclic groups include carbocyclyl and heterocyclyl groups as discussed below, and may specifically be cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl.
  • any one of the rings is optionally selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl; when one or more of the rings is When it is an aryl group, the remaining ring may be an aryl group or a non-aromatic cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl group.
  • the number of rings in the ring group can be monocyclic, bicyclic or polycyclic.
  • bicyclic or polycyclic ring groups can be divided into spiro rings and bridged rings (including pendant rings or fused rings) according to different connection methods.
  • the ring group is a 3-15-membered ring group, which means that it contains 3 to 12 link atoms, preferably a 3-12-membered ring group, and more preferably a 3-10-membered ring group.
  • spiro ring refers to a cyclic group with two or more cyclic structures and the single rings share one atom (called a spiro atom) with each other.
  • the preferred value here is 7-15 yuan, and the more preferred value is 8-9 yuan.
  • spiro rings are divided into single spiro, double spiro or polyspiro ring groups.
  • single spiro and double spiro ring groups are preferred, and 4-membered/5-membered and 4-membered/6-membered are preferred.
  • 5-membered/5-membered or 5-membered/6-membered spirocyclic group include, but are not limited to, spiro[3.5]nonane, bicyclo[3.2.1]octane.
  • bridged ring refers to a polycyclic cyclic group containing two or more cyclic structures and sharing two or more atoms.
  • parallel ring or “fused ring” is a special bridged ring, which refers to a polycyclic ring group containing two or more cyclic structures and sharing a pair of atoms with each other.
  • the preferred value here is 7-15 yuan, and the more preferred value is 8-9 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups preferably bicyclic or tricyclic, here preferably bicyclic or tricyclic, more preferably 5-membered/5-membered, 5-membered/6-membered One-membered or 6-membered/6-membered bicyclic bridged ring base.
  • Non-limiting examples thereof include, but are not limited to, bicyclo[2.2.2]octane, spirocyclo[3.4]octane.
  • spiro rings and bridged rings can also be applied to cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl discussed below, including spirocycloalkyl, spirocycloalkenyl, and spiroheterocycles. Cycloalkyl, spiroheterocycloalkenyl, bridged cycloalkyl, bridged cycloalkenyl, bridged heterocycloalkyl, bridged heterocycloalkenyl.
  • Condensed rings include fused ring alkyl, fused ring alkenyl, fused heterocycloalkyl, fused heterocycloalkenyl, fused ring aryl, and fused ring heteroaryl.
  • the definitions of the above terms are similar to those of spiro ring, bridged ring, parallel ring or fused ring.
  • Carbocyclyl as used herein, alone or in combination, includes alicyclic and aryl groups, including monocyclic, fused, bridged and spirocyclic rings.
  • heterocyclyl groups include cycloalkyl, cycloalkenyl, and aryl groups as discussed below. Preferred here are 3-10 membered monocyclic, bicyclic or tricyclic carbocyclic groups.
  • cycloalkyl refers to a saturated monocyclic, bicyclic or polycyclic carbocyclic ring, which may be spiro or bridged.
  • a 3-12-membered cycloalkyl group is preferred, a 3-10-membered cycloalkyl group is more preferred, and a 3-8-membered cycloalkyl group is most preferred.
  • Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and other cycloalkyl groups, which may be optionally substituted or un replaced.
  • spiro ring refers to an all-carbon polycyclic group with two or more cyclic structures and each single ring shares one carbon atom (called a spiro atom).
  • a spiro atom it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan.
  • the spiro ring is divided into single spiro, double spiro or polyspiral cycloalkyl groups.
  • the preferred ones here are single spiro and double spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/ 6-membered, 5-membered/5-membered or 5-membered/6-membered spirocycloalkyl group.
  • fused ring refers to an all-carbon polycyclic group containing two or more cyclic structures and sharing a pair of carbon atoms with each other.
  • it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups.
  • bicyclic or tricyclic is preferred, and more preferably 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered.
  • bridged ring refers to a ring structure containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. all-carbon polycyclic groups. Here, it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic or tricyclic.
  • cycloalkenyl refers to a nonaromatic monocyclic, bicyclic or polycyclic carbocyclic ring having one or more carbon-carbon double bonds, which may be spirocyclic or bridged.
  • a 3-12-membered cyclic alkenyl group is preferred, a 3-10-membered cyclic alkenyl group is more preferred, and a 3-8-membered cyclic alkenyl group is most preferred.
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohex-1,3-dien-1-yl, which may are optionally substituted or unsubstituted.
  • aryl refers to an aromatic hydrocarbyl ring.
  • aryl includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons, in which all fused ring systems (excluding any ring systems that are part of or formed from optional substituents) ) is aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise stated, the term “aryl” does not include “heteroaryl”.
  • heterocyclyl as used herein, alone or in combination, includes alicyclic and heteroaryl groups in which one or more (such as one, two, three or four) link atoms are heteroatoms, such as oxygen, nitrogen , sulfur atoms, etc., including single ring, fused ring, bridged ring and spiro ring.
  • heterocyclyl groups include heterocycloalkyl, heterocycloalkenyl, and heteroaryl as discussed below.
  • Preferred here are 3-10 membered monocyclic, bicyclic or tricyclic heterocyclyl groups, which may contain 1, 2 or 3 ring atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include azetidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidine base, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolyl, oxothiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydrogen Pyranyl, thiyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl wait.
  • Heterocyclyl groups may be optionally substituted or unsubstituted.
  • spirocycle refers to a polycyclic ring group with two or more cyclic structures and the single rings share one atom with each other.
  • the ring contains several unsaturated bonds, but Aromatic systems in which none of the rings have fully conjugated ⁇ electrons, in which one or more link atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) n (where n is selected from 0, 1, or 2), and the remaining link atoms for carbon.
  • the preferred value here is 6-12 yuan, and the more preferred value is 8-9 yuan.
  • the spiro ring is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group, and 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 single spiroheterocyclic group.
  • Non-limiting examples thereof include, but are not limited to, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, and 2-azaspiro[3.4]octane.
  • bridged ring refers to a polycyclic ring group containing two or more cyclic structures and sharing two or more atoms with each other.
  • One or more rings may contain several An aromatic system with unsaturated bonds but none of the rings having fully conjugated ⁇ electrons, in which one or more link atoms are selected from nitrogen, oxygen, or S(O) n (where n is selected from 0, 1, or 2) Heteroatoms, the remaining link atoms are carbon.
  • the preferred value here is 6-12 yuan, and the more preferred value is 8-9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic or tricyclic.
  • fused ring refers to a polycyclic ring group containing two or more cyclic structures and sharing a pair of atoms with each other.
  • One or more rings may contain several unsaturated bonds.
  • the preferred value here is 6-12 yuan, and the more preferred value is 8-9 yuan.
  • 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.
  • heterocycloalkyl refers to a saturated monocyclic, bicyclic or polycyclic ring in which one or more (such as one, two, three or four) ring atoms are heteroatoms. Heterocyclyl, which can be a spiro ring or a bridged ring.
  • a 3-12-membered cycloalkyl group is preferred, a 3-10-membered cycloalkyl group is more preferred, and a 3-8-membered cycloalkyl group is most preferred.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, propylene oxide, thiirane, aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrofuran, Hydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.
  • heterocycloalkenyl refers to a nonaromatic monocyclic, bicyclic or polycyclic ring having one or more unsaturated double bonds, in which one or more (such as one, two (one, three or four) link atoms are heteroatoms in a saturated heterocyclyl group, which can be a spiro ring or a bridged ring.
  • it is preferably a 3-12-membered heterocyclic alkenyl group, more preferably a 3-10-membered heterocyclic alkenyl group, and most preferably a 3-8-membered heterocyclic alkenyl group.
  • Non-limiting examples of heterocycloalkenyl include, but are not limited to, aziridine, oxane, thiane, oxetene, pyran.
  • heteroaryl refers to a 5-12 membered (preferably 5-10 membered, more preferably 5-6 membered) monocyclic, bicyclic or tricyclic ring system in which at least one ring is aromatic, And at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and at the same time, the heteroaryl group also has one or more attachment points connected to the rest of the molecule.
  • heteroaryl group of the bicyclic or tricyclic system, if it contains a saturated or unsaturated heterocycloalkyl group or.
  • heteroaryl include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, Thiazolyl, etc.; also includes the following bicyclic rings, but is not limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolyl, imidazopyridine base, pyrazopyridinyl, pyrazopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazole, 1,8-naphthyridine, benzo[d]isoxazole, benzo[ d] Thiazole, pyrrole[3,2-b]pyridine, furan[
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy as used herein alone or in combination refers to -OH.
  • cyano as used herein alone or in combination refers to -CN.
  • methanesulfonyl as used herein alone or in combination refers to -S(O) 2 - CH3 .
  • substituted or “substituted by” means that one or more hydrogens on a particular atom are designated Groups (such as halogen, alkyl, etc.) are substituted. If the normal valency of the specified atom is not exceeded under the existing circumstances, then the result after substitution is a stable compound.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse effects biologically react or interact in an adverse manner with any component contained in the composition.
  • composition refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, a stabilizer, Diluents, dispersants, suspending agents, thickeners and/or excipients.
  • carrier refers to a relatively nontoxic chemical compound or agent that facilitates the introduction of a compound into cells or tissues.
  • stereoisomer as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.
  • enantiomers used herein refers to compounds with the same molecular formula that are enantiomers of each other due to the isomerism phenomenon caused by the different spatial arrangements of atoms or atomic groups (groups). Two compounds are mirror images of each other and cannot be superimposed.
  • cis-trans isomers used herein generally refers to the diastereomeric stereoisomerism phenomenon that occurs due to the different arrangement of each group in space due to the restriction of free rotation in the compound molecule.
  • Organic molecules containing such isomers, such as alkenes, azo compounds, alicyclic hydrocarbons, etc., are regarded as cis-trans isomers.
  • cis-trans isomerism is mainly reflected in the form of alicyclic hydrocarbons.
  • cis-trans isomerism occurs when cyclohexane is substituted by two substituents.
  • the two substituents are substituted on the same side of the ring, it is the "cis” isomer, and when the two substituents are substituted on the same side of the ring, it is the "trans” isomer.
  • Formula isomer.
  • 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, diastereoisomers, enantiomers, steric and geometric (conformational) isomers, and mixtures thereof , such as racemic mixtures, are within the scope of the present invention.
  • the structures described herein also include all isomers of this structure (e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformations) Isomeric forms), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, and steric isomers of biphenyl structures Structure (see Basic Organic Chemistry (Second Edition), Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193.
  • isomers of this structure e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformations) Isomeric forms
  • R and S configurations of each asymmetric center for example, R and S configurations of each asymmetric center, (Z) and (E) double bond
  • optional groups for each group may be:
  • Ring A is 5-10 membered heteroaryl.
  • the heteroaryl group can be in the form of a single ring or a branched ring.
  • Ring A is respectively connected to ring B through covalent bonds and connected to R 1 through L 1 , and is optionally substituted by 1 to 3 R 3s . If there is no special explanation, R 3 can be connected to ring A by replacing the H atom of any link atom of ring A, including C and N.
  • ring A is a monocyclic ring
  • a 6-membered heteroaryl group is more preferred
  • the number of heteroatoms is preferably 1-3
  • the heteroatoms are preferably N.
  • Non-limiting examples thereof include, but are not limited to, pyridine, pyrazine, pyrimidine, pyridazine, and triazine.
  • the connection sites of ring A, ring B and L 1 may be ortho, meta or para.
  • ring A When ring A is a cyclic ring, it is preferably a 5-6 cyclic ring or a 6-6 cyclic ring, and forms a conjugated bicyclic aryl group.
  • the number of heteroatoms is preferably 1-3, and the heteroatom is preferably N.
  • L 1 and ring B are respectively connected to different rings in the parallel ring A.
  • ring B When ring B is a heterocycloalkyl group, it preferably contains 1 heteroatom optionally selected from N, O, and S.
  • non-limiting examples of ring A include, but are not limited to, the following structures:
  • non-limiting examples of the group R3 substituted on ring A include, but are not limited to, halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, preferably cyano, amino, methyl .
  • L 1 is connected to R 1 through a covalent bond linking ring A, or L 1 itself is a chemical bond.
  • L include, but are not limited to, imino, carbonyl, -CO-NH-,
  • R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 , wherein Cycloalkyl or heterocycloalkyl includes but is not limited to monocyclic, paracyclic, spirocyclic and bridged ring forms, preferably 4-6 membered cycloalkyl or 4-6 membered containing 1-2 selected from N, O, S heteroatom heterocycloalkyl.
  • R 1 is a cycloalkyl or heterocycloalkyl group, it is preferably a 5-7 membered monocyclic ring, or a 7-9 membered bridged ring or spirocyclic ring.
  • the 7-9 membered spirocyclic form has a similar Structure, the dotted line represents the 4-6-membered cycloalkyl group (including the spiro atom) connected to the spiro atom. Any atom can be replaced with a heteroatom if it complies with the valency code of the compound.
  • R include, but are not limited to, cyclobutane, cyclopentyl, cyclohexyl, cycloheptyl, Methyl, ethyl, propyl, isopropyl.
  • R 1 is an asymmetric group, or the substitution site of R 5 is not on the symmetry axis or center of R 1 , different spatial isomers may appear, including enantiomers and cis-trans isomers. It should be noted that both enantiomers and cis-trans isomers have ALK2 inhibitory activity, but the inhibitory activities of different isomers may be different.
  • R 5 is OH, halogen, C 1-6 alkyl, -(CR a R b ) n -OH.
  • R a and R b are preferably H or C 1-3 alkyl, and n is preferably 1-3.
  • Non-limiting examples of R5 include, but are not limited to, hydroxyl, F, Cl, methyl, ethyl, propyl, isopropyl, -CH2OH , -C( CH3 ) 2OH .
  • Ring B is a 6-15 membered ring group, and optionally 1-3 ring carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R4 .
  • Ring B may be in the form of a single ring, a double ring, or a tricyclic ring. When Ring B is a double ring or a tricyclic ring, the connection form between the rings may be a parallel ring, a spiro ring, or a bridged ring. Unless otherwise specified, at least one ring in Ring B is an aromatic or heteroaromatic ring, the other rings are saturated or unsaturated cycloalkyl or heterocycloalkyl, or the other rings are parallel aromatic or heterocyclic rings. aromatic ring. If there is no special explanation, R 4 can be connected to ring B by replacing the H atom of any link atom of ring B, including C and N.
  • ring B is a monocyclic ring, it is more preferably a 6-membered aryl group or a heteroaryl group, and the number of heteroatoms is preferably 0-3, and the heteroatoms are preferably N.
  • Non-limiting examples thereof include, but are not limited to, benzene, pyridine, pyrazine, pyrimidine, pyridazine, and triazine.
  • the connection point between ring A and L2 on ring B can be ortho, meta or para.
  • Ring B When ring B is a parallel ring, it is form, which is preferably 5-6 cyclic ring or 6-6 cyclic ring, Y 1 , Y 2 , Y 3 are independently selected from CH or N.
  • Ring C is a 5-6 membered ring group, preferably a parallel cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group. Ring C optionally contains 1-3 N atoms, and the carbon atoms therein are optionally oxo-substituted to form a carbonyl group.
  • L 2 and ring A are respectively the same as those in parallel ring B. Different rings are connected.
  • Ring B can also be a tricyclic group, one of which is a benzene ring.
  • Ring B is r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH and Z 5 is CH or N; optionally one carbon atom in ring B is substituted by oxygen; ring B is optionally substituted by 1-2 R 4s .
  • Z 5 is defined as CH 2 or CH
  • Z 6 is defined as N and connected to L 2
  • p is 2.
  • ring B is r is an integer from 1 to 2, be a single bond or a double bond.
  • Non-limiting examples of Ring B include, but are not limited to, the following structures: Usually, the 6-membered aromatic ring or heteroaromatic ring is connected to (that is, the bond above ring B) is connected to ring A, and the other (i.e. the bond below ring B) is connected to L 2 .
  • non-limiting examples of the group R4 substituted on ring B include, but are not limited to, halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, preferably cyano, methyl, tri Fluoromethyl.
  • L 2 connects ring B and R 2 through a covalent bond, or L 2 itself is a chemical bond.
  • L 2 is defined as -(CR a R b ) n - , wherein Ra and R b are independently selected from H or C 1-3 alkyl, or Ra and R b are The attached carbon atoms form a 3-6 membered cycloalkyl group.
  • n can be an integer from 1 to 3.
  • L2 is -CR a R b -CR a 'R b '-.
  • R a , R b , R a ', and R b '- can be independent.
  • R a and R b , or R a ' and R b ' can form a 3-6 membered cycloalkyl group with the carbon atoms they are jointly connected to, such as
  • non-limiting examples of L include, but are not limited to, chemical bonds, methylene,
  • R 2 is optionally substituted by 1-2 R 6 , wherein heterocycloalkyl includes but is not limited to monocyclic, spirocyclic Formula, preferably a 4-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S. .
  • R 2 is a heterocycloalkyl group, it is preferably a 5-7-membered monocyclic ring, or a 7-9-membered bridged ring or spirocyclic ring.
  • the 7-9 membered spirocyclic form has a similar Structure, the dotted line represents the 4-6-membered cycloalkyl group (including the spiro atom) connected to the spiro atom. Any atom can be replaced with a heteroatom if it complies with the valency code of the compound.
  • 7-9 membered bridged ring form that is, two non-adjacent atoms on the ring base are connected by a covalent bond or one or more atoms.
  • R include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl,
  • R 2 is an asymmetric group, or the substitution site of R 6 is not on the symmetry axis of R 2 , different spatial isomers may appear, including enantiomers and cis-trans isomers. It should be noted that both enantiomers and cis-trans isomers have ALK2 inhibitory activity, but the inhibitory activities of different isomers may be different.
  • R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or R 6 is selected from C 1-6 alkyl, 4-8 1-membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 Re .
  • R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1- 6 alkoxy.
  • Non-limiting examples of R include - but are not limited to H, F, methyl, ethyl, isopropyl, hydroxyl,
  • Some of the compounds in this application can be divided into paracyclic compounds and tricyclic compounds according to different ring Bs. These compounds have better ALK2 inhibitory activity and cell activity, and have better selectivity than existing compounds.
  • ring B has the following structure: Among them, Y 1 , Y 2 and Y 3 are independently selected from CH or N, and ring C is a parallel 5-6 membered ring group.
  • ring C can be a 5- to 6-membered saturated or unsaturated cycloalkyl or heterocycloalkyl group, as well as an aryl or heteroaryl group.
  • the C atoms of ring C can be substituted by oxygen to form a carbonyl group.
  • Ring B has the following structure: Among them, Ring C can be further preferably a parallel 5-membered cycloalkyl group, nitrogen-containing heterocycloalkyl group, or nitrogen-containing heteroaryl group, for example
  • R 1 can be a 4-6 membered cycloalkyl group or a heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, etc., such as cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl , tetrahydrofuryl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl, hexahydropyridyl, morpholine; further, R 1 can be optionally substituted by 1-2 R 5 , and R 5 can be It is hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH.
  • connection sites of L 1 and R 5 on R 1 do not limit the connection sites of L 1 and R 5 on R 1 , so the two connection sites can be ortho, meta or para, preferably meta or para.
  • the substituent and the substitution site stereoisomerism may exist, including cis-trans isomerism and enantiomerism.
  • R 1 is R 5 is hydroxyl or unsubstituted.
  • L 2 is selected from a chemical bond or a simple ()alkylene group, connecting R 2 and Ring B.
  • R 2 is usually a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 , for example, R 2 can be L 2 is connected to any position of R 2 by replacing the hydrogen atom on R 2 .
  • R 6 can be something like halogen, hydroxyl, amino, cyanide
  • the simple substituent of the base can also be a 4-7-membered cycloalkyl group optionally substituted by R e , a 4-7-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, C 1 -3 alkyl.
  • connection sites of L 2 and R 6 on R 4 can be ortho, meta or para, preferably meta or para.
  • stereoisomerism may exist, including cis-trans isomerism and enantiomerism.
  • R e is usually halogen, and can also be other simple substituents similar to hydroxyl, amino or cyano. Also depending on its substitution position, it may form stereoisomerism with R 6 , including cis-trans isomerism and para-isomerism. Isomerism.
  • ring B has the following structure: r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH, Z 5 is CH or N; Z 6 is NH or O; any one carbon atom in ring B is replaced by oxygen.
  • the C atom of ring B can be replaced by oxygen to form a carbonyl group.
  • Ring B is r or q is an integer from 1 to 3; Z 1 , Z 2 or Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O; when When it is a double bond, Z 4 is CH; Ring B is optionally replaced by 1-2 R 4 ;
  • Ring B has the following structure: Among them, r takes 1 or 2, for example When ring B is further for When, the first end is usually connected to ring A, and the upper end is connected to L 2 .
  • R 1 can be a 4-6 membered cycloalkyl group or a heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, etc., such as cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl , tetrahydrofuryl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl, hexahydropyridyl, morpholine; further, R 1 can be optionally substituted by 1-2 R 5 , and R 5 can be It is hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH.
  • connection sites of L 1 and R 5 on R 1 can be ortho, meta or para, preferably para.
  • substituent and the substitution site stereoisomerism may exist, including cis-trans isomerism and enantiomerism.
  • R 1 is R 5 is hydroxyl or unsubstituted, and the substitution position is para-substitution.
  • L 2 is selected from a chemical bond or a simple ()alkylene group, connecting R 2 and Ring B.
  • R 2 is usually a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 , for example, R 2 can be R 6 is preferably a simple substituent of halogen, hydroxyl, amino, or cyano, and may not be substituted.
  • This scheme does not limit the connection sites of L 2 and R 6 on R 4 , so the two connection sites can be ortho, meta or para, preferably para.
  • substituents and substitution sites stereoisomerism may exist, including cis-trans isomerism and enantiomerism.
  • R2 is H or
  • Preparation Pre-HPLC conditions: Instrument: GILSON-GX281; Wavelength: 220nm&254nm; Column model: Waters X-bridge (30 ⁇ 100mm, 10 ⁇ m) or Luna C18 (30 ⁇ 75mm, 3 ⁇ m) or Luna C18 (30 ⁇ 75mm, 3 ⁇ m) ;Mobile phase: A: 10mM ammonium bicarbonate or H 2 O (0.1% formic acid) or H 2 O (0.1% trifluoroacetic acid), B: acetonitrile; running time: 15min; flow rate: 25mL/min.
  • Reverse column purification uses a C18 reverse silica gel column (Spherical C18, 40-60 ⁇ m, 40g-120g), with water/acetonitrile (95/5 ⁇ 30/70) as the mobile phase.
  • the synthesis of intermediate 1 refers to the synthesis steps of intermediate A3 in Example 34 of patent CN109641871B.
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (3 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piper Azine-1-carboxamide (40 mg, 0.11 mmol) and intermediate 3 (40 mg, 0.11 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (10 mL/2 mL), and PdCl 2 (dppf) was added (8mg, 0.01mmol) and potassium carbonate (30mg, 0.22mmol).
  • the reaction solution was heated to 100°C under nitrogen protection and stirred overnight.
  • the reaction solution was spun to dryness, dissolved in methanol, filtered, and concentrated under reduced pressure.
  • step (2) of Example 16 6-(4-(4-(dimethylcarbamoyl)piperazin-1-yl)phenyl)pyrazine-2-carboxylic acid (30 mg, 0.08 mmol ) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (11 mg, 0.08 mmol) were used as raw materials to obtain the title compound (13 mg, white solid), yield: 32.5%.
  • N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (45mg, 0.1mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (5mL/1mL), and 4 -(6-bromopyridin-3-yl)-N,N-dimethylpiperazine-1-carboxamide (41 mg, 0.13 mmol), potassium carbonate (45 mg, 0.33 mmol) and Pd(dppf)Cl 2 (50 mg ). The reaction solution was stirred under reflux overnight under nitrogen.
  • step (2) of Example 10 use 2-amino-5-bromo-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)nicotinamide (108 mg, 329umol, Example 32 step 1) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzyl)morpholine (100 mg, 329umol) was used as raw material to obtain the title compound (71.2 mg, white solid), yield: 50.62%.
  • step (2) in Example 10 use 3-amino-6-bromo-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (70 mg, 232.45umol) and 4 -(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (90mg, 296.83umol) as raw material, The title compound (34.6 mg, light yellow solid) was obtained, yield: 37.45%. MS (ESI): m/z 398.3[M+H] + .
  • step (2) of Example 10 use 2-amino-5-bromo-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3 -Nicotinamide (35.4 mg, 98.9umol, step 1 of Example 10) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle) Pentan-2-yl)benzyl)morpholine (30.0 mg, 98.9umol) was used as raw material to obtain the title compound (19.2 mg, yellow solid), yield: 42.69%. MS (ESI): m/z 455.2[M+H] + .
  • step (3) of Example 36 use 2-amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid (30 mg, 95.85umol, step 2 of Example 36) and piperidine- Using 4-alcohol (11 mg, 105.43umol) as raw material, the title compound (14.2 mg, yellow solid) was obtained, yield: 37.4%. MS (ESI): m/z 397.3[M+H] + .
  • step (3) of Example 36 use 2-amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid (30 mg, 95.85umol, step 2 of Example 36) and piperidine- 4-ylmethanol (12 mg, 105.43umol) was used as raw material to obtain the title compound (16.9 mg, yellow oil), yield: 43.0%.
  • intermediate 5 33.29 mg, 97.84umol
  • 1-(1-(oxetan-3-yl)piperidin-4-yl)-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 45 mg, 117.40umol
  • 1,4-dioxane 0.5 mL
  • sodium carbonate 31.11 mg, 293.51 umol
  • Pd(dppf)Cl 2 7.16 mg, 9.78 umol
  • reaction solution was heated to 100°C and stirred for 12 hours. After the reaction solution cooled to room temperature, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by Prep-TLC to obtain the title compound (90.0 mg, yellow oil), yield: 67.8%. MS(ESI):m/z 422.3[M+H] + .
  • reaction solution was replaced with nitrogen gas, then the temperature was raised to 110°C and stirred under nitrogen protection for 16 hours.
  • the reaction solution was cooled to room temperature, concentrated, diluted with methanol (2 mL), and filtered through a syringe filter.
  • step (2) of Example 50 4-(2-amino-5-bromopyridin-3-yl)benzoic acid methyl ester (500 mg, 1.63 mmol, step 1 of Example 50) and 4-(4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (592.31 mg, 1.95 mmol) was used as raw material to obtain the title Compound (600 mg, orange solid), yield: 91.4%. MS(ESI):m/z 404.3[M+H] + .
  • step (3) of Example 50 use 4-(2-amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)benzoate methyl ester (350 mg, 867.47umol) As raw material, the title compound (300 mg, orange solid) was obtained, and the crude product was used directly in the next step without purification. MS(ESI):m/z390.3[M+H] + .
  • step (4) of Example 50 use 4-(6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid (3 mg, 7.49umol) As raw material, the title compound (1 mg, yellow solid) was obtained, yield: 30.44%. MS (ESI): m/z 439.2[M+H] + .
  • step 1 4-bromo-3-fluorobenzaldehyde and (R)-2-methylpyrrolidine were used as raw materials, and the title compound (13.0 mg, white solid) was obtained through similar steps.
  • step 4 5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-aminonicotinic acid (35 mg, 0.11 mmol) and tetrahydro-2H-pyran-4-amine (34 mg, 0.34 mmol) were used as raw materials to obtain the title compound (15 mg, light yellow solid), yield: 34.6%.
  • the first step uses 4-bromo-3-fluorobenzaldehyde and (R)-2-methylpyrrolidine as raw materials
  • the third step uses (R)-2-amino-5-(2 -Fluoro-4-((2-methylpyrrolidin-1-yl)methyl)phenyl)nicotinic acid and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol Hydrochloride was used as raw material, and the title compound (10.0 mg, white solid) was obtained through similar steps.
  • reaction solution was heated to 80°C under nitrogen protection and stirred for 18 hours.
  • the crude product was further purified by Prep-HPLC to obtain the title compound (210 mg, light yellow oil), yield: 30 %.
  • 6-Bromo-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinoline 250 mg, 0.85 mmol
  • (6-amino-5-(methyl Oxycarbonyl)pyridin-3-yl)boronic acid (236mg, 0.85mmol)
  • PdCl 2 (dppf) 65mg, 0.08mmol
  • potassium carbonate 234mg, 1.7mmol

Abstract

An ALK2 kinase inhibitor as represented by general formula (I), a pharmaceutical composition thereof, a preparation method therefor, and use of the ALK2 kinase inhibitor in preparing a drug for the prevention and/or treatment of indications related to the ALK2 signaling pathway. A compound of the present invention is an ideal high-activity ALK2 kinase inhibitor, and can be used for treating and/or preventing diseases, including anemia, inflammation, tumors, and some rare diseases, such as fibrodysplasia ossificans progressiva, diffuse intrinsic pontine glioma, iron refractory iron deficiency anemia, inflammatory anemia, myelodysplastic syndrome, and multiple myeloma, and can also be combined with a JAK2 inhibitor to treat MPN-related anemia.

Description

ALK2激酶抑制剂ALK2 kinase inhibitor 技术领域Technical field
本发明属于药物化学领域，涉及一种ALK2激酶抑制剂，其药物组合物、制备方法及其在制备、预防和/或治疗与ALK2信号通路相关适应症的药物的用途。The invention belongs to the field of medicinal chemistry and relates to an ALK2 kinase inhibitor, its pharmaceutical composition, preparation method and its use in preparing, preventing and/or treating drugs for indications related to the ALK2 signaling pathway.
背景技术Background technique
ALK2(也称为ACVR1蛋白)，是一种激活素受体样激酶，即骨形态发生蛋白(BMP)Ⅰ型受体，是转化生长因子TGF-β家族的成员之一。配体与Ⅱ型受体的结合诱导Ⅰ型受体的磷酸化，Ⅰ型受体通过募集并磷酸化下游的受体相关Smad并进一步调控相关基因的表达来影响细胞的功能(PLoS One 2013 Apr 30；8(4):e62721)。ALK2 (also known as ACVR1 protein) is an activin receptor-like kinase, bone morphogenetic protein (BMP) type I receptor, and a member of the transforming growth factor TGF-β family. The binding of ligands to type II receptors induces the phosphorylation of type I receptors. Type I receptors affect cell function by recruiting and phosphorylating downstream receptor-related Smads and further regulating the expression of related genes (PLoS One 2013 Apr 30;8(4):e62721).
研究发现ALK2异常激活会导致多种疾病的发生发展。如进行性骨化性纤维发育不良(FOP)的绝大部分患者都发现有ALK2 R206H的突变，使下游SMAD信号增强，BMP通路被过度激活。弥漫内生型桥脑胶质瘤(DIPG)中的20-32％有ACVR1突变。而在卵巢癌、***癌以及红白血病中也发现ALK2可能起到致癌的作用(Cells 2019,8,1366)。Studies have found that abnormal activation of ALK2 can lead to the occurrence and development of various diseases. For example, most patients with fibrodysplasia ossificans progressiva (FOP) are found to have ALK2 R206H mutations, which enhance downstream SMAD signaling and overactivate the BMP pathway. 20-32% of diffuse endophytic pontine gliomas (DIPG) have ACVR1 mutations. ALK2 has also been found to play a carcinogenic role in ovarian cancer, prostate cancer, and erythroleukemia (Cells 2019, 8, 1366).
此外，在Laura Silvestri等人的研究中(Vitam Horm.2019；110:71-99)发现，ALK2是调节铁依赖铁调素表达上调的关键受体，而高水平的铁调素会导致铁限制性红细胞生成，表现为铁难治性缺铁性贫血(IRIDA)和炎症性贫血(AI)。炎症性贫血又称为慢性病贫血(ACD)，是全球仅次于缺铁性贫血的贫血疾病，常见于慢性病或住院患者。炎症性贫血是指由慢性感染(包括结核病、获得性免疫缺陷综合征)、自免性疾病(如类风湿性关节炎、红斑狼疮、炎症性肠病等)以及某些肿瘤(包括与细胞因子增加相关的血液瘤如霍奇金淋巴瘤、骨髓纤维化、MDS、MM等，常见实体瘤如卵巢癌、肺癌等)所引起的长期炎症导致的贫血。此类炎症性贫血会严重影响患者生活质量、生理功能并降低生存期(N Engl J Med 2019；381：1148-57)。在Maria Vittoria Verga Falzacappa等人的研究中(Blood 2007；109(1):353-358)则揭示IL-6是炎症性贫血相关的主要细胞因子，其通过JAK2-STAT3通路上调铁调素的表达。专利WO2021102258揭示了ALK2抑制剂与JAK2抑制剂联用用于治疗骨髓增生性肿瘤(MPN)及相关贫血的用法。提示ALK2抑制剂在此适应症的应用潜力。In addition, in the study of Laura Silvestri et al. (Vitam Horm. 2019; 110:71-99), it was found that ALK2 is a key receptor that regulates the iron-dependent upregulation of hepcidin expression, and high levels of hepcidin can lead to iron limitation erythropoiesis, manifested as iron-refractory iron deficiency anemia (IRIDA) and inflammatory anemia (AI). Inflammatory anemia, also known as anemia of chronic disease (ACD), is the second most common anemia disease in the world after iron deficiency anemia. It is common in patients with chronic diseases or hospitalization. Inflammatory anemia refers to anemia caused by chronic infections (including tuberculosis, acquired immunodeficiency syndrome), autoimmune diseases (such as rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, etc.) and certain tumors (including those related to cytokines Anemia caused by long-term inflammation caused by increased related hematological tumors such as Hodgkin lymphoma, myelofibrosis, MDS, MM, etc., and common solid tumors such as ovarian cancer, lung cancer, etc.). This type of inflammatory anemia can seriously affect patients' quality of life, physiological functions, and reduce survival (N Engl J Med 2019;381:1148-57). In the study of Maria Vittoria Verga Falzacappa et al. (Blood 2007;109(1):353-358), it was revealed that IL-6 is the main cytokine related to inflammatory anemia, which upregulates the expression of hepcidin through the JAK2-STAT3 pathway. . Patent WO2021102258 discloses the use of ALK2 inhibitors in combination with JAK2 inhibitors for the treatment of myeloproliferative neoplasms (MPN) and related anemia. This suggests the application potential of ALK2 inhibitors in this indication.
发明内容Contents of the invention
本发明的目的在于提供一种ALK2激酶抑制剂，其药物组合物、制备方法及其在制备、预防和/或治疗与ALK2信号通路相关适应症的药物的用途。The object of the present invention is to provide an ALK2 kinase inhibitor, its pharmaceutical composition, preparation method and its use in the preparation, prevention and/or treatment of drugs for indications related to the ALK2 signaling pathway.
为了解决现有技术的缺陷，本发明公开了一种具有通式(I)所示结构的化合物、其氘代物、立体异构体或药学上可接受的盐：
In order to solve the deficiencies of the prior art, the present invention discloses a compound having the structure shown in general formula (I), its deuterated product, stereoisomer or pharmaceutically acceptable salt:
其中，in,
环A为5-10元杂芳基，任选地被1-3个R3取代；Ring A is a 5-10 membered heteroaryl group, optionally substituted by 1-3 R 3 ;
环B为6-15元环基，且任选1-3个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is a 6-15 membered ring group, and optionally 1-3 link carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
L1选自化学键、C1-6烷基、亚氨基、羰基、-CO-NH-、苯基、5-6元杂芳基、-苯基-CO-NH-；L 1 is selected from chemical bond, C 1-6 alkyl, imino, carbonyl, -CO-NH-, phenyl, 5-6 membered heteroaryl, -phenyl-CO-NH-;
L2选自化学键、-(CRaRb)n-、亚氨基、醚键、-C1-6烷基-O-；L 2 is selected from chemical bond, -(CR a R b ) n -, imino group, ether bond, -C 1-6 alkyl-O-;
R1选自C1-6烷基、5-10元环烷基、5-10元杂环烷基，且任选地被1-3个R5取代；R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
R2选自H、卤素、羟基、氰基、氨基，或R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
R2选自4-10元杂环烷基或环烷基，且任选地被1-3个R6取代；R 2 is selected from 4-10 membered heterocycloalkyl or cycloalkyl, and is optionally substituted by 1-3 R 6 ;
R3选自卤素、羟基、硝基、氰基、氨基、C1-6烷基；R 3 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl;
R4选自卤素、羟基、硝基、氰基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基；R 4 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl;
R5选自卤素、羟基、硝基、氰基、氨基、-CO-NRcRd、C1-6烷基、C1-6烷氧基、-(CRaRb)n-OH；R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, -CO-NR c R d , C 1-6 alkyl, C 1-6 alkoxy, -(CR a R b ) n -OH;
R6选自卤素、羟基、氰基、-CO-Rc、-CO-NRcRd、-SO2-Rc，或R 6 is selected from halogen, hydroxyl, cyano, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
R6选自C1-6烷基、C1-6烷氧基、4-8元环烷基、4-8元杂环烷基，且任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, C 1-6 alkoxy, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
Ra、Rb独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基，或R a , R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl, or
Ra、Rb与所连的碳原子形成3-6元环烷基；R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group;
Rc、Rd独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基；R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
Re选自卤素、羟基、硝基、氰基、氨基、C1-6烷氧基； R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
n选自1-3的整数。n is selected from an integer from 1 to 3.
在一些优选的实施方式中：In some preferred embodiments:
环A为5-10元杂芳基，任选地被1-3个R3取代；Ring A is a 5-10 membered heteroaryl group, optionally substituted by 1-3 R 3 ;
环B为6-15元环基，且任选1-3个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is a 6-15 membered ring group, and optionally 1-3 link carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
L1选自化学键、C1-6烷基、亚氨基、羰基、-CO-NH-、苯基、5-6元杂芳基、-苯基-CO-NH-；L 1 is selected from chemical bond, C 1-6 alkyl, imino, carbonyl, -CO-NH-, phenyl, 5-6 membered heteroaryl, -phenyl-CO-NH-;
L2选自化学键、-(CRaRb)n-、亚氨基、醚键、-C1-6烷基-O-；L 2 is selected from chemical bond, -(CR a R b ) n -, imino group, ether bond, -C 1-6 alkyl-O-;
R1选自C1-6烷基、5-10元环烷基、5-10元杂环烷基，且任选地被1-3个R5取代；R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
R2选自4-10元杂环烷基，R2任选地被1-3个R6取代；R 2 is selected from 4-10 membered heterocycloalkyl, and R 2 is optionally substituted by 1-3 R 6 ;
R3选自卤素、羟基、硝基、氰基、氨基、C1-6烷基；R 3 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl;
R4选自卤素、羟基、硝基、氰基、氨基、C1-6烷基、卤代C1-6烷基；R 4 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl;
R5选自卤素、羟基、硝基、氰基、氨基、C1-6烷基、-(CRaRb)n-OH；R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH;
R6选自羟基、-CO-Rc、-CO-NRcRd、-SO2-Rc，或R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
R6选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，且任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
Ra、Rb独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基，或R a , R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl, or
Ra、Rb与所连的碳原子形成3-6元环烷基；R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group;
Rc、Rd独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基；R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
Re选自卤素、羟基、硝基、氰基、氨基、C1-6烷氧基；R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
n选自1-3的整数。n is selected from an integer from 1 to 3.
在一些更优选的实施方式中：In some more preferred embodiments:
环A为6-10元杂芳基，含有1-3个选自N、O、S的杂原子，任选地被1-3个R3取代；Ring A is a 6-10 membered heteroaryl group, containing 1-3 heteroatoms selected from N, O, and S, optionally substituted by 1-3 R 3 ;
环B选自6-9元碳环基或6-13元杂环基，且任选1个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is selected from 6-9-membered carbocyclyl or 6-13-membered heterocyclyl, and optionally 1 link carbon atom is substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
L1选自亚氨基、羰基、-CO-NH-、5-6元杂芳基、-苯基-CO-NH-；L 1 is selected from imino, carbonyl, -CO-NH-, 5-6 membered heteroaryl, -phenyl-CO-NH-;
L2选自化学键、-(CRaRb)n-、-C1-3烷基-O-；L 2 is selected from chemical bond, -(CR a R b ) n -, -C 1-3 alkyl-O-;
R1选自C1-3烷基、6-8元环烷基、6-8元杂环烷基，且任选地被1-3个R5取代；R 1 is selected from C 1-3 alkyl, 6-8 membered cycloalkyl, 6-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
R2选自4-9元杂环烷基，含有1-2个选自N、O、S的杂原子，R2任选地被1-3个R6取代；R 2 is selected from 4-9 membered heterocycloalkyl, containing 1-2 heteroatoms selected from N, O, S, R 2 is optionally substituted by 1-3 R 6 ;
R3选自氰基、氨基、C1-3烷基；R 3 is selected from cyano, amino, C 1-3 alkyl;
R4选自卤素、C1-3烷基、卤代C1-3烷基；R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
R5选自卤素、羟基、氰基、C1-6烷基、-(CRaRb)n-OH；R 5 is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, -(CR a R b ) n -OH;
R6选自羟基、-CO-Rc、-CO-NRcRd、-SO2-Rc，或R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
R6选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，且任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
Ra、Rb独立地选自H或C1-3烷基，或R a , R b are independently selected from H or C 1-3 alkyl, or
Ra、Rb与所连的碳原子形成3-6元环烷基；R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group;
Rc、Rd独立地选自H或C1-3烷基；R c and R d are independently selected from H or C 1-3 alkyl;
Re选自卤素、氰基、C1-3烷氧基；R e is selected from halogen, cyano, C 1-3 alkoxy;
n选自1-3的整数。n is selected from an integer from 1 to 3.
在一些优选的实施方式中：In some preferred embodiments:
环A选自 Ring A is selected from
作为优选：As a preference:
L1选自亚氨基、-CO-NH-、羰基、-苯基-CO-NH-；L 1 is selected from imino, -CO-NH-, carbonyl, -phenyl-CO-NH-;
R1选自C1-3烷基，所述R1任选地被1-3个R5取代；R 1 is selected from C 1-3 alkyl, the R 1 is optionally substituted by 1-3 R 5 ;
R3选自氰基、氨基、C1-3烷基；R 3 is selected from cyano, amino, C 1-3 alkyl;
R5选自卤素、氰基、羟基、C1-6烷基、-(CRaRb)n-OH；R 5 is selected from halogen, cyano, hydroxyl, C 1-6 alkyl, -(CR a R b ) n -OH;
Ra、Rb独立地选自H或C1-3烷基；R a and R b are independently selected from H or C 1-3 alkyl;
n选自1-3的整数。 n is selected from an integer from 1 to 3.
在一些优选的实施方式中：In some preferred embodiments:
环B选自 Ring B is selected from
在一些更优选的实施方式中：In some more preferred embodiments:
环B选自 Ring B is selected from
在一些优选的实施方式中：In some preferred embodiments:
L2选自化学键、-(CRaRb)n-、-C1-3烷基-O-；L 2 is selected from chemical bond, -(CR a R b ) n -, -C 1-3 alkyl-O-;
R2选自、H、卤素、羟基、氰基，或R 2 is selected from, H, halogen, hydroxyl, cyano, or
R2选自 且任选地被1-3个R6取代；R 2 is selected from and optionally substituted by 1-3 R 6 ;
R4选自卤素、C1-3烷基、卤代C1-3烷基；R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
R6选自卤素、羟基、-CO-Rc、-CO-NRcRd、-SO2-Rc，或R 6 is selected from halogen, hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
R6选自C1-6烷基、C1-6烷氧基、任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, C 1-6 alkoxy, optionally substituted by 1-3 Re ;
Ra、Rb独立地选自H或C1-3烷基，或R a , R b are independently selected from H or C 1-3 alkyl, or
Ra、Rb与所连的碳原子形成3-6元环烷基；R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group;
Rc、Rd独立地选自H或C1-3烷基；R c and R d are independently selected from H or C 1-3 alkyl;
Re选自卤素、羟基、氰基、C1-3烷氧基；R e is selected from halogen, hydroxyl, cyano, C 1-3 alkoxy;
n选自1-3的整数。n is selected from an integer from 1 to 3.
在根据本发明的某些实施方式中，本发明提供的化合物进一步具有式(II)所示结构：
In certain embodiments according to the present invention, the compound provided by the present invention further has the structure shown in formula (II):
X1、X2独立地选自CH或N；X 1 and X 2 are independently selected from CH or N;
R1选自5-10元环烷基、5-10元杂环烷基，任选地被1-3个R5取代；R 1 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, optionally substituted by 1-3 R 5 ;
R5选自卤素、羟基、硝基、氰基、氨基、C1-6烷基、-(CRaRb)n-OH； R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH;
环B为Y1、Y2、Y3独立地选自CH或N，环C为并联的5-6元环基，环C中任选1个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is Y 1 , Y 2 , Y 3 are independently selected from CH or N. Ring C is a parallel 5-6 membered ring group. Any one carbon atom in ring C is substituted by oxygen; ring B is optionally substituted by 1- 3 R 4 substitutions;
R4选自卤素、C1-3烷基、卤代C1-3烷基；R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
R2为4-8元杂环烷基，含有1-3个选自N、O、S的杂原子，且任选地被1-3个R6取代；R 2 is a 4-8 membered heterocycloalkyl group, containing 1-3 heteroatoms selected from N, O, S, and optionally substituted by 1-3 R 6 ;
R6选自-CO-Rc、-SO2-Rc，或R 6 is selected from -CO-R c , -SO 2 -R c , or
R6选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
Ra、Rb独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基；R a and R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
Rc独立地选自H、羟基、氨基或C1-6烷基；R c is independently selected from H, hydroxyl, amino or C 1-6 alkyl;
Re选自卤素、羟基、硝基、氰基、氨基、C1-6烷氧基；R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
n选自1-3的整数。n is selected from an integer from 1 to 3.
在一些优选的实施方式中：In some preferred embodiments:
R1选自 R 1 is selected from
R5选自羟基、卤素、C1-6烷基、-(CRaRb)n-OH；R 5 is selected from hydroxyl, halogen, C 1-6 alkyl, -(CR a R b ) n -OH;
Ra、Rb独立地选自H、C1-3烷基；R a and R b are independently selected from H and C 1-3 alkyl;
n选自1-3的整数。n is selected from an integer from 1 to 3.
在一些更优选的实施方式中：In some more preferred embodiments:
R1选自 R 1 is selected from
R5选自羟基、卤素、C1-3烷基、-CH2OH、-C(CH3)2OH。R 5 is selected from hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH.
在根据本发明的某些实施方式中，本发明提供的化合物进一步具有式(II-1)所示结构：
In certain embodiments according to the present invention, the compound provided by the present invention further has the structure shown in formula (II-1):
环B为Y1、Y2、Y3独立地选自CH或N，环C为并联的5-6元环基，环C中任选1个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is Y 1 , Y 2 , Y 3 are independently selected from CH or N. Ring C is a parallel 5-6 membered ring group. Any one carbon atom in ring C is substituted by oxygen; ring B is optionally substituted by 1- 3 R 4 substitutions;
R4选自卤素、C1-3烷基、卤代C1-3烷基；R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
R2为5-7元杂环烷基，含有1-3个选自N、O、S的杂原子，且任选地被1-3个R6取代；R 2 is a 5-7 membered heterocycloalkyl group, containing 1-3 heteroatoms selected from N, O, S, and optionally substituted by 1-3 R 6 ;
R6选自-CO-Rc、-SO2-Rc，或R 6 is selected from -CO-R c , -SO 2 -R c , or
R6选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
Rc独立地选自H、羟基、氨基或C1-6烷基；R c is independently selected from H, hydroxyl, amino or C 1-6 alkyl;
Re选自卤素、羟基、硝基、氰基、氨基、C1-6烷氧基。R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy.
在一些优选的实施方式中： In some preferred embodiments:
环B选自 Ring B is selected from
在一些优选的实施方式中：In some preferred embodiments:
环B为环C为并联的5元碳环基或杂环基，环C中任选1个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is Ring C is a parallel 5-membered carbocyclyl or heterocyclyl, and any one carbon atom in Ring C is substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
R4选自卤素、C1-3烷基、卤代C1-3烷基。R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl.
在一些更优选的实施方式中：In some more preferred embodiments:
环B选自 Ring B is selected from
环B任选地被1-3个R4取代；Ring B is optionally substituted with 1-3 R 4 ;
R4选自卤素、C1-3烷基、卤代C1-3烷基。R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl.
在一些优选的实施方式中：In some preferred embodiments:
R2选自优选 且任选地被1个R6取代； R 2 is selected from preferred and optionally substituted by 1 R 6 ;
R6选自-CO-Rc、-SO2-Rc，或R 6 is selected from -CO-R c , -SO 2 -R c , or
R6选自C1-3烷基、4-6元环烷基、4-6元杂环烷基，任选被1-3个Re取代的；R 6 is selected from C 1-3 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
Rc独立地选自H或C1-3烷基；R c is independently selected from H or C 1-3 alkyl;
Re选自卤素、氰基、C1-3烷氧基。R e is selected from halogen, cyano, C 1-3 alkoxy.
在一些更优选的实施方式中：In some more preferred embodiments:
R2选自优选且被1个R6取代；R 2 is selected from preferred and replaced by 1 R 6 ;
R6为4-6元杂环烷基，含有1个O原子，优选更优选 R 6 is a 4-6 membered heterocycloalkyl group, containing 1 O atom, preferably More preferred
在根据本发明的某些实施方式中，本发明提供的化合物进一步具有式(III)所示结构：
In certain embodiments according to the present invention, the compound provided by the present invention further has the structure shown in formula (III):
环B为环C为并联的5-6元环基，任选地含有1-2个选自N的杂原子；环B任选地被1-2个R4取代；Ring B is Ring C is a parallel 5-6 membered ring group, optionally containing 1-2 heteroatoms selected from N; Ring B is optionally substituted by 1-2 R 4 ;
R4选自卤素、C1-3烷基、卤代C1-3烷基；R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
R1选自4-8元环烷基、4-8元含有2个选自N、O、S杂原子的杂环烷基，优选 更优选R1任选地被1-3个R5取代；R 1 is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 2 heteroatoms selected from N, O, and S, preferably More preferred R 1 is optionally replaced by 1-3 R 5 ;
R5选自卤素、羟基、硝基、氰基、氨基、C1-6烷基、-(CRaRb)n-OH，优选羟基、卤素、C1-3烷基、-CH2OH、-C(CH3)2OH；R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH, preferably hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH , -C(CH 3 ) 2 OH;
L2选自化学键、-(CRaRb)n-；L 2 is selected from chemical bonds, -(CR a R b ) n -;
R2为5-6元含有1-2个选自N、O杂原子的杂环烷基，任选地被1-2个R6取代；R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
R6选自卤素、羟基、氨基、氰基，或R 6 is selected from halogen, hydroxyl, amino, cyano, or
R6选自4-7元环烷基、4-7元含有1-2个选自N、O杂原子的杂环烷基、C1-3烷基，且任选地被1-3个Re取代； R 6 is selected from 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl containing 1-2 selected from N, O heteroatoms, C 1-3 alkyl, and is optionally replaced by 1-3 Re substitution ;
Ra、Rb独立地选自H或C1-3烷基，或Ra、Rb与所连的碳原子形成3-6元环烷基；R a and R b are independently selected from H or C 1-3 alkyl, or R a , R b and the attached carbon atom form a 3-6 membered cycloalkyl group;
Re为卤素；R e is halogen;
n为1-3的整数。n is an integer from 1 to 3.
在一些优选的实施方式中：In some preferred embodiments:
环B选自 Ring B is selected from
在一些更优选的实施方式中：In some more preferred embodiments:
环B选自 Ring B is selected from
L2选自化学键、C1-3亚烷基；L 2 is selected from chemical bond, C 1-3 alkylene;
R2为5-6元含有1-2个选自N、O杂原子的杂环烷基，任选地被1-2个R6取代；R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
R6选自卤素，或R 6 is selected from halogen, or
R6选自4-6元环烷基、4-6元含有1-2个选自N、O杂原子的杂环烷基、C1-3烷基，且任选地被1-3个Re取代。R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1-2 selected from N, O heteroatoms, C 1-3 alkyl, and is optionally replaced by 1-3 R e replaced.
在一些优选的实施方式中：In some preferred embodiments:
环B选自 Ring B is selected from
R1选自任选地被1个R5取代；R 1 is selected from optionally substituted by 1 R 5 ;
R5选自羟基、-CH2OH；R 5 is selected from hydroxyl, -CH 2 OH;
L2选自化学键；L 2 is selected from chemical bonds;
R2为5-6元含有1-2个选自N、O杂原子的杂环烷基，任选地被1个R6取代；R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1 R 6 ;
R6选自4-6元环烷基、4-6元含1个O的杂环烷基、C1-3烷基，且任选地被1-3个Re取代；R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1 O, C 1-3 alkyl, and is optionally substituted by 1-3 R e ;
Re为卤素。R e is halogen.
在一些优选的实施方式中：In some preferred embodiments:
R2选自优选 R 2 is selected from preferred
R6选自环己基、C1-3烷基，优选C1-3烷基。R 6 is selected from Cyclohexyl, C 1-3 alkyl, preferably C 1-3 alkyl.
在一些更优选的实施方式中：In some more preferred embodiments:
R1与R5形成如下结构： R 1 and R 5 form the following structure:
在一些优选的实施方式中：In some preferred embodiments:
环B选自 Ring B is selected from
R1选自任选地被1个R5取代；R 1 is selected from optionally substituted by 1 R 5 ;
R5选自羟基、-CH2OH；R 5 is selected from hydroxyl, -CH 2 OH;
L2选自化学键；L 2 is selected from chemical bonds;
R2为5-6元含有1-2个N的杂环烷基，被1个R6取代；R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 N, substituted by 1 R 6 ;
R6选自4-6元含1-2个选自N、O杂原子的杂环烷基。R 6 is selected from 4-6 membered heterocycloalkyl groups containing 1-2 heteroatoms selected from N and O.
在一些优选的实施方式中：In some preferred embodiments:
R2选自优选 R 2 is selected from preferred
R6选自优选 R 6 is selected from preferred
在一些更优选的实施方式中：In some more preferred embodiments:
R1与R5形成如下结构： R 1 and R 5 form the following structure:
在一些优选的实施方式中：In some preferred embodiments:
环B选自 Ring B is selected from
R1选自任选地被1个R5取代；R 1 is selected from optionally substituted by 1 R 5 ;
R5选自羟基、-CH2OH；R 5 is selected from hydroxyl, -CH 2 OH;
L2选自化学键、C1-3亚烷基；L 2 is selected from chemical bond, C 1-3 alkylene;
R2为5-6元含有1-2个选自N、O杂原子的杂环烷基，任选地被1-2个R6取代；R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
R6选自卤素，或R 6 is selected from halogen, or
R6选自4-6元环烷基、4-6元含1个O的杂环烷基，且任选地被1-3个Re取代；R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1 O, and is optionally substituted by 1-3 R e ;
Re为卤素。R e is halogen.
在一些优选的实施方式中：In some preferred embodiments:
R2选自优选 R 2 is selected from preferred
R6选自卤素，或R 6 is selected from halogen, or
R6选自环己基，优选且任选地被1-3个Re取代；R 6 is selected from Cyclohexyl, preferably and optionally substituted by 1-3 Re ;
Re为卤素。R e is halogen.
在一些更优选的实施方式中：In some more preferred embodiments:
R1与R5形成如下结构： R 1 and R 5 form the following structure:
在根据本发明的某些实施方式中，本发明提供的化合物进一步具有式(IV)所示结构：
In certain embodiments according to the present invention, the compound provided by the present invention further has a structure represented by formula (IV):
X1、X2独立地选自CH或N；X 1 and X 2 are independently selected from CH or N;
R1选自4-8元环烷基、4-8元含有1-2个选自N、O、S杂原子的杂环烷基，优选 更优选任选地被1-2个R5取代；R 1 is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, preferably More preferred optionally substituted by 1-2 R5 ;
R5选自C1-3烷基、C1-3烷氧基、-C1-3烷基-OH、卤素、OH、氨基、酰胺基、氰基；R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkyl-OH, halogen, OH, amino, amide group, and cyano group;
环B是r、p、q为1-3的整数；Z1、Z2、Z3独立地选自CH或N，且最多一个为N；为单键或双键；当为单键时，Z4为CH2或O，Z5为CH2或NH；当为双键时，Z4为CH，Z5为CH或N；Z6为NH或O；环B中任选1个环节碳原子被氧取代；环B任选地被1-2个R4取代；Ring B is r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH, Z 5 is CH or N; Z 6 is NH or O; any one carbon atom in ring B is replaced by oxygen; ring B is optionally replaced by 1-2 R 4 replace;
R4选自卤素、C1-3烷基、C1-3烷氧基、羟基；R 4 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, and hydroxyl;
L2为化学键、-(CRaRb)n-；L 2 is a chemical bond, -(CR a R b ) n -;
R2选自H、卤素、羟基、氰基、氨基，或R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
R2选自4-6元杂环烷基或4-6元环烷基，优选4-6元含有1-2个选自N、O、S杂原子的杂环烷基或4-6元环烷基，更优选进一步优选 且任选地被1-2个R6取代；R 2 is selected from 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, preferably 4-6 membered heterocycloalkyl or 4-6 membered containing 1-2 heteroatoms selected from N, O, S Cycloalkyl, more preferably Further preferred and optionally substituted by 1-2 R 6 ;
R6选自卤素、羟基、C1-3烷基、C1-3烷氧基、氰基；R 6 is selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, and cyano;
Ra、Rb独立地选自H或C1-3烷基，或Ra、Rb与所连的碳原子形成3-6元环烷基；R a and R b are independently selected from H or C 1-3 alkyl, or R a , R b and the attached carbon atom form a 3-6 membered cycloalkyl group;
n为1-3的整数。n is an integer from 1 to 3.
在一些优选的实施方式中：In some preferred embodiments:
环B选自 Ring B is selected from
在一些优选的实施方式中：In some preferred embodiments:
环B是r或q为1-3的整数；Z1、Z2或Z3独立地选自CH或N，且最多一个为N；为单键或双键；当为单键时Z4为CH2或O；当为双键时Z4为CH；环B任选地被1-2个R4取代；Ring B is r or q is an integer from 1 to 3; Z 1 , Z 2 or Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O; when When it is a double bond, Z 4 is CH; Ring B is optionally replaced by 1-2 R 4 ;
R4选自卤素、C1-3烷基、C1-3烷氧基、羟基。R 4 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, and hydroxyl.
在一些更优选的实施方式中：In some more preferred embodiments:
X1、X2为CH；X 1 and X 2 are CH;
环B是r为1-2的整数，为单键或双键。Ring B is r is an integer from 1 to 2, be a single bond or a double bond.
在一些更优选的实施方式中：In some more preferred embodiments:
环B是优选*端与吡啶连接，**端与L2 连接，r为1-2的整数，为单键或双键。Ring B is preferred The * end is connected to pyridine, and the ** end is connected to L 2 Connection, r is an integer from 1 to 2, be a single bond or a double bond.
L2为化学键或C1-3亚烷基；L 2 is a chemical bond or C 1-3 alkylene group;
R2选自H、卤素、羟基、氰基、氨基，或R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
R2选自4-6元杂环烷基或4-6元环烷基，优选4-6元含有1-2个选自N、O、S杂原子的杂环烷基或4-6元环烷基，更优选进一步优选 且任选地被1-2个R6取代；R 2 is selected from 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, preferably 4-6 membered heterocycloalkyl or 4-6 membered containing 1-2 heteroatoms selected from N, O, S Cycloalkyl, more preferably Further preferred and optionally substituted by 1-2 R 6 ;
R6选自卤素、羟基、C1-3烷基、C1-3烷氧基、氰基。R 6 is selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, and cyano.
在一些优选的实施方式中：In some preferred embodiments:
R1选自优选任选地被1-2个R5取代；R 1 is selected from preferred optionally substituted by 1-2 R5 ;
R5选自卤素、OH、C1-3烷基、C1-3烷氧基、-C1-3烷基-OH，优选F、Cl、-OH、甲基、-CH2-OH；R 5 is selected from halogen, OH, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkyl-OH, preferably F, Cl, -OH, methyl, -CH 2 -OH;
优选R1与R5形成如下结构： Preferably, R 1 and R 5 form the following structure:
在一些优选的实施方式中：In some preferred embodiments:
环B选自 优选 进一步优选*端与吡啶连接，**端与L2连接；Ring B is selected from preferred Further preferred The * end is connected to pyridine, and the ** end is connected to L 2 ;
L2为化学键、C1-3亚烷基，优选化学键或异丙基； L 2 is a chemical bond, C 1-3 alkylene group, preferably a chemical bond or isopropyl group;
R2为H或优选H或 R2 is H or Preferably H or
在根据本发明的某些实施方式中，本发明提供的化合物进一步具有式(V)所示结构：
In certain embodiments according to the present invention, the compound provided by the present invention further has a structure represented by formula (V):
M选自CH或N；M is selected from CH or N;
R6a选自C1-3烷氧基，优选甲氧基、乙氧基、丙氧基；R 6a is selected from C 1-3 alkoxy, preferably methoxy, ethoxy, propoxy;
R6b选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，优选甲基、乙基、异丙基、更优选异丙基。R 6b is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, preferably methyl, ethyl, isopropyl, Isopropyl is more preferred.
通式(1)所示化合物包括以下具体化合物：







Compounds represented by general formula (1) include the following specific compounds:







本发明另一方面还提供了一种药物组合物，所述药物组合物含有上述的化合物、其氘代物、立体异构体或药学上可接受的盐及其药物可接受的载体。Another aspect of the present invention also provides a pharmaceutical composition, which contains the above-mentioned compound, its deuterated product, stereoisomer or pharmaceutically acceptable salt and its pharmaceutically acceptable carrier.
本发明另一方面还提供了一种上述化合物、其氘代物、立体异构体或药学上可接受的盐或上述药物组合物制备治疗和/或预防ALK2相关的疾病的药物中的用途。Another aspect of the present invention also provides the use of the above-mentioned compound, its deuterated product, stereoisomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in preparing a medicament for treating and/or preventing ALK2-related diseases.
作为优选，所述ALK2相关的疾病包括贫血、炎症、肿瘤及部分ALK2相关的遗传病。Preferably, the ALK2-related diseases include anemia, inflammation, tumors and some ALK2-related genetic diseases.
作为优选，所述ALK2相关的疾病包括进行性骨化性纤维发育不良、弥漫内生型桥脑胶质瘤、铁难治性缺铁性贫血、炎症性贫血、骨髓增生异常综合征、多发性骨髓瘤、骨髓增生性肿瘤相关的贫血。Preferably, the ALK2-related diseases include fibrodysplasia ossificans progressiva, diffuse endogenous pontine glioma, iron-refractory iron deficiency anemia, inflammatory anemia, myelodysplastic syndrome, multiple Anemia associated with myeloma and myeloproliferative neoplasms.
作为优选，所述药物单独使用或与其他治疗剂联合使用。Preferably, the drug is used alone or in combination with other therapeutic agents.
作为优选，所述其他治疗剂为JAK2抑制剂，用于治疗骨髓增生性肿瘤相关的贫血。Preferably, the other therapeutic agent is a JAK2 inhibitor for the treatment of myeloproliferative neoplasm-related anemia.
本发明提供的化合物药效强、药代性质好、毒副作用低，是理想的ALK2抑制剂。本发明所提供的化合物具有更好的ALK2抑制活性，并且其对于ALK2的抑制活性远大于ALK5，具有较好的选择性。本发明的化合物是理想的高活性ALK2抑制剂，可用于治疗和/或预防的疾病，包括贫血、炎症、肿瘤以及部分罕见病，例如进行性骨化性纤维发育不良、弥漫内生型桥脑胶质瘤、铁难治性缺铁性贫血、炎症性贫血、骨髓增生异常综合征、多发性骨髓瘤、联用JAK2抑制剂治疗骨髓增生性肿瘤相关的贫血。The compound provided by the invention has strong medicinal efficacy, good pharmacokinetic properties and low toxic and side effects, and is an ideal ALK2 inhibitor. The compound provided by the present invention has better ALK2 inhibitory activity, and its inhibitory activity on ALK2 is much greater than ALK5, and has better selectivity. The compounds of the present invention are ideal highly active ALK2 inhibitors and can be used to treat and/or prevent diseases, including anemia, inflammation, tumors and some rare diseases, such as fibrodysplasia ossificans progressiva and diffuse endogenous pontine type. Glioma, iron-refractory iron deficiency anemia, inflammatory anemia, myelodysplastic syndrome, multiple myeloma, combined use of JAK2 inhibitors to treat anemia associated with myeloproliferative neoplasms.
定义definition
本文所使用的“任选”或“任选地”是指可以选择任意可选项或者不选。例如，“基团A任选地被1-3个基团B取代”包括基团A未被基团B取代，基团A被1个基团B取代，基团A被2个基团B取代，基团A被3个基团B取代这四种情况。As used herein, "optionally" or "optionally" means that any option may or may not be selected. For example, "group A is optionally substituted by 1 to 3 groups B" includes group A being unsubstituted by group B, group A being substituted by 1 group B, and group A being substituted by 2 groups B. Substitution, group A is replaced by three groups B. There are four cases.
本文所使用的“取代”或“被取代的”是指某一基团或片段中任一原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被氧取代，当氧取代的原子为碳原子时，即形成羰基(C＝O)。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，若无特殊说明，取代基的种类和数目在化学上可以实现的基础上可以是任意的。"Substituted" or "substituted" as used herein means that any one or more hydrogen atoms on any atom in a certain group or fragment are replaced by substituents, which may include deuterium and hydrogen variants, as long as The valence state of a particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced by oxygen. When the atom replaced by oxygen is a carbon atom, a carbonyl group (C=O) is formed. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically feasible.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化 合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof may only be used if such combinations result in stable compounds. It is only allowed in the case of compounds.
当一个连接基团的数量为0时，比如-(CRaRb)0-，表示该连接基团为单键/化学键。When the number of a connecting group is 0, such as -(CR a R b ) 0 -, it means that the connecting group is a single bond/chemical bond.
当其中一个变量选自化学键/单键时，表示其连接的两个基团直接相连，比如A-L1-R1中L1代表单键时表示该结构实际上是A-R1。When one of the variables is selected from chemical bond/single bond, it means that the two groups connected to it are directly connected. For example, when L 1 in AL 1 -R 1 represents a single bond, it means that the structure is actually AR 1 .
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，环A-L1-R1中连接基团L1为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和R1构成环A-M-W-R1，也可以按照与从左往右的读取顺序相反的方向连接环A和R1构成环A-W-M-R1。所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When the listed linking groups do not indicate their connection direction, the connection direction is arbitrary. For example, the linking group L 1 in ring AL 1 -R 1 is -MW-. In this case, -MW- can be pressed from left to right. The ring A and R 1 can be connected in the same direction in the right reading order to form the ring AMWR 1 , or the ring A and R 1 can be connected in the opposite direction to the reading order from left to right to form the ring AWMR 1 . Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
若无特殊说明，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而相应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的碳原子的两端与其他基团相连；中的虚线表示通过该苯基基团中的1和4位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。Unless otherwise specified, when a certain group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positioned, and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced accordingly with the number of connected chemical bonds and become the corresponding valence. group. The chemical bond connecting the site to other groups can be in the form of a straight solid line bond. dashed key express. For example, the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group; The straight dotted bond in means that it is connected to other groups through both ends of the carbon atoms in the group; The dotted lines in indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 4; Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if H atoms are drawn on -N-, still includes For groups with this type of connection, only when a chemical bond is connected, the H at that position will be reduced by one and become the corresponding monovalent piperidinyl group.
若无特殊说明，在螺环或并环基团中，基团或片段的连接位点位于处于虚线所连接的环上。例如，表示该基团的含氮螺环上的任意连接位点可以通过1个化学键与其他基团相连，至少包括这3种连接方式；表示该基团的苯环上的任意连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式。 Unless otherwise stated, in a spirocyclic or paracyclic group, the connection site of the group or fragment is located on the ring connected by the dotted line. For example, Any connection point on the nitrogen-containing spirocyclic ring of the group can be connected to other groups through a chemical bond, including at least These 3 connection methods; Any connection point on the benzene ring of this group can be connected to other groups through a chemical bond, including at least These 4 connection methods.
若无特殊说明，在桥环基团中，基团或片段的连接位点可以是任一连接位点。例如，表示该基团的含氮螺环上的任意连接位点可以通过1个化学键与其他基团相连，至少包括这2种连接方式。Unless otherwise specified, in the bridged ring group, the connection site of the group or fragment can be any connection site. For example, Any connection point on the nitrogen-containing spirocyclic ring of the group can be connected to other groups through a chemical bond, including at least These two connection methods.
一般情况下，在芳环或杂芳环中，双键及单键并无限定意义。例如，均指代苯环或苯基，其中双键或特指离域在苯环平面上的大π键；中，当环C限定为5元芳基或杂芳基时，环B与环C组成共轭的并环芳基或并环杂芳基，此时其非限定实施例包括 即使中左侧环中仅含有两个双键，但是仍包括这种基团，此时双键代表的是离域在该并环芳香环上的大π键。In general, in aromatic or heteroaromatic rings, double bonds and single bonds have no limiting meaning. For example, Both refer to benzene ring or phenyl group, in which the double bond or Specifically refers to large π bonds delocalized on the plane of the benzene ring; , when ring C is limited to a 5-membered aryl or heteroaryl, ring B and ring C form a conjugated ring-aryl or ring-heteroaryl group, and non-limiting examples thereof include even though The left-center ring contains only two double bonds, but still includes For this group, the double bond at this time represents the large π bond delocalized on the aromatic ring.
本文所使用的数值区间包括端点值以及端点值之间的任意数值。举例而言，“0-3”可包括0、1、2或3，“1-3”可包括1、2或3。As used herein, numerical ranges include endpoint values and any number between the endpoint values. For example, "0-3" may include 0, 1, 2, or 3, and "1-3" may include 1, 2, or 3.
本文所使用的“C1-n”包括C1-2、C1-3、……C1-n。举例而言，“C1-6”基团是指该部分中具有1-6个碳原子，即基团包含1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。因此，举例而言，“C1-4烷基”是指含有1-4个碳原子的烷基，即所述烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。本文中的数字范围，例如“1-6”是指给定范围中的各个整数。"C 1-n " as used herein includes C 1-2 , C 1-3 ,...C 1-n . For example, a "C 1-6 " group means that there are 1 to 6 carbon atoms in the moiety, that is, the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. Thus, for example, "C 1-4 alkyl" refers to an alkyl group containing 1 to 4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl and tert-butyl. Numeric ranges, such as "1-6", in this document refer to each integer within the given range.
环节原子是指环基中用于成环的非氢原子。例如中的环节原子为3个碳原子；中环节原子为三个碳原子和1个氧原子；中环节原子为1个N原子与5个碳原子；中环节原子为8个碳原子和1个氮原子。The link atoms refer to the non-hydrogen atoms used in the ring group to form the ring. For example The link atoms in are 3 carbon atoms; The middle link atoms are three carbon atoms and one oxygen atom; The middle link atoms are 1 N atom and 5 carbon atoms; The middle link atoms are 8 carbon atoms and 1 nitrogen atom.
本文所使用的“n-m元”是指环基中环节原子的个数。举例而言，“3-8元”基团是指该部分中具有3-8个环节原子，即基团包含3个环节原子、4个环节原子、5个环节原子、6个环节原子、7个环节原子或8个环节原子。因此，举例而言，“3-8元环烷基”是指含有3-8个碳原子的饱和环状烃基，即所述烷基选自环丙基、环丁基、环戊基、环己基、环庚基、环辛基。The "n-m element" used in this article refers to the number of link atoms in the ring group. For example, a "3-8 yuan" group means that the part has 3-8 link atoms, that is, the group contains 3 link atoms, 4 link atoms, 5 link atoms, 6 link atoms, 7 link atoms or 8 link atoms. Therefore, for example, "3-8 membered cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3-8 carbon atoms, that is, the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, Hexyl, cycloheptyl, cyclooctyl.
本文单独或组合使用的术语“烃基”是指仅由碳元素和氢元素构成的原子团，其包括饱和、不饱和或具有芳香性的碳氢基团，例如烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基。未具体说明的情况下，“烃基”可以是直链、支链或环状的。The term "hydrocarbyl" used herein alone or in combination refers to an atomic group consisting only of carbon and hydrogen, including saturated, unsaturated or aromatic hydrocarbon groups, such as alkyl, alkenyl, alkynyl, cyclic Alkyl, cycloalkenyl, cycloalkynyl, aryl. Unless otherwise specified, the "hydrocarbyl group" may be linear, branched or cyclic.
本文单独或组合使用的术语“烷基”是指任选取代的直链或任选取代的支链的饱和脂肪族烃类。本文 的“烷基”优选可具有1-6个碳原子，例如具有1-5个碳原子，或具有1-4个碳原子，或具有1-3个碳原子。烷基的非限定性示例包括甲基、乙基、正丙基、异丙基、2-甲基-l-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-l-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-l-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-l-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、己基等。本文定义的基团中，如“烷基”出现数字范围时，例如，“C1-6烷基”是指可由1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烷基，本文的烷基也包含未指定数字范围的情况。烷基可以是任选取代的或未取代的。The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain saturated aliphatic hydrocarbon. This article The "alkyl group" may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl base, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-di Methyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl , isopentyl, neopentyl, tert-amyl, hexyl, etc. In the groups defined herein, when "alkyl" appears in a numerical range, for example, "C 1 - 6 alkyl" means that it can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, An alkyl group composed of 5 carbon atoms or 6 carbon atoms. The alkyl group herein also includes cases where the numerical range is not specified. Alkyl groups may be optionally substituted or unsubstituted.
本文组合使用的“烷基”是指与其他基团连接的烷基，例如，烷氧基中的烷基，其定义与单独使用时相同。"Alkyl" as used in combination herein refers to an alkyl group attached to another group, for example, an alkyl group in an alkoxy group, and is defined the same as when used alone.
本文单独或组合使用的术语“亚烷基”是指从直链或支链的饱和脂肪族烃基中去掉两个氢原子所得到的饱和的脂肪族二价烃基基团。本文的“亚烷基”优选可具有1-6个碳原子，例如具有1-5个碳原子，或具有1-4个碳原子，或具有1-3个碳原子。亚烷基的非限定性示例包括-CH2-(即亚甲基)、-CH2-CH2-(即亚乙基)、-CH2-CH2-CH2-、-CH(CH3)CH2-、-C(CH3)2-、-CH2-C(CH3)-CH2-、-CH2-CH2-CH2-CH2-、-CH2-C(CH3)-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-等。亚烷基可以是任选取代的或未取代的。The term "alkylene" as used herein alone or in combination refers to a saturated aliphatic divalent hydrocarbon radical obtained by removing two hydrogen atoms from a linear or branched saturated aliphatic hydrocarbon radical. The "alkylene group" herein may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkylene include -CH 2 - (i.e., methylene), -CH 2 -CH 2 - (i.e., ethylene), -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 -, -CH 2 -C(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -C(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, etc. Alkylene groups may be optionally substituted or unsubstituted.
本文单独或组合使用的术语“烯基”是指任选取代的直链或任选取代的具有一个或多个碳-碳双键的不饱和脂肪族烃类。本文的“烯基”优选可具有1-6个碳原子，例如具有1-5个碳原子，或具有1-4个碳原子，或具有1-3个碳原子。烷基的非限定性示例包括乙烯基、丙烯基、1-丁烯基、2-丁烯基、1-戊烯基、1-己烯基、1,3-丁二烯基、1,3-戊二烯基、1,4-戊二烯基和1,4-己二烯基基团/部分。除非另外说明，否则术语“烯基”不包括“环烯基”。The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted unsaturated aliphatic hydrocarbon having one or more carbon-carbon double bonds. "Alkenyl" herein may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkyl groups include vinyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3 -Pentadienyl, 1,4-pentadienyl and 1,4-hexadienyl groups/moieties. Unless otherwise stated, the term "alkenyl" does not include "cycloalkenyl".
本文单独或组合使用的术语“烷氧基”或“-O-烷基”表示为“烷基-O-”。烷氧基的非限定性示例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。烷氧基可以是任选取代的或未取代的。The term "alkoxy" or "-O-alkyl" as used herein, alone or in combination, means "alkyl-O-". Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted.
本文单独或组合使用的术语“环基”或“环”是指是指任何具有环状结构的有机化合物，其中所述环基可为饱和或不饱和的(包括芳基)且可在其碳骨架中包括一个或多个杂原子例如N、O或S。环基的实例包括如下文所讨论的碳环基和杂环基，具体地可以是环烷基、环烯基、杂环烷基、杂环烯基、芳基和杂芳基。当环基为双环或多环时，其中任一环任选自环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基；当其中一个或多个环为芳基时，剩余的环可以是芳基，也可以是不具有芳香性的环烷基、杂环烷基、环烯基或杂环烯基。环基中环的个数可为单环、双环或多环。通常，双环或多环环基根据不同的连接方式可以分为螺环、桥环(包括并环或稠环)。若无特殊说明，环基为3-15元环基，意指其含有3至12个环节原子，优选为3-12元环基，更优选为3-10元环基。The term "cyclyl" or "ring" as used herein alone or in combination refers to any organic compound having a cyclic structure, wherein the cyclic group may be saturated or unsaturated (including aryl) and may have at its carbon The skeleton contains one or more heteroatoms such as N, O or S. Examples of cyclic groups include carbocyclyl and heterocyclyl groups as discussed below, and may specifically be cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. When the ring group is bicyclic or polycyclic, any one of the rings is optionally selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl; when one or more of the rings is When it is an aryl group, the remaining ring may be an aryl group or a non-aromatic cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl group. The number of rings in the ring group can be monocyclic, bicyclic or polycyclic. Generally, bicyclic or polycyclic ring groups can be divided into spiro rings and bridged rings (including pendant rings or fused rings) according to different connection methods. If there is no special explanation, the ring group is a 3-15-membered ring group, which means that it contains 3 to 12 link atoms, preferably a 3-12-membered ring group, and more preferably a 3-10-membered ring group.
“环基”的定义中，“螺环”是指两个或两个以上环状结构且单环之间彼此共用一个原子(称螺原子)的环基。本文优选为7-15元，更优选为8-9元。根据环与环之间共用螺原子的数目螺环分为单螺、双螺或多螺环基，本文优选为单螺和双螺环基，优选为4元/5元、4元/6元、5元/5元或5元/6元螺环基。其非限定性示例包括但不限于螺环[3.5]壬烷、双环[3.2.1]辛烷。In the definition of "cyclic group", "spiro ring" refers to a cyclic group with two or more cyclic structures and the single rings share one atom (called a spiro atom) with each other. The preferred value here is 7-15 yuan, and the more preferred value is 8-9 yuan. According to the number of shared spiro atoms between rings, spiro rings are divided into single spiro, double spiro or polyspiro ring groups. Herein, single spiro and double spiro ring groups are preferred, and 4-membered/5-membered and 4-membered/6-membered are preferred. , 5-membered/5-membered or 5-membered/6-membered spirocyclic group. Non-limiting examples thereof include, but are not limited to, spiro[3.5]nonane, bicyclo[3.2.1]octane.
“环基”的定义中，“桥环”是指含有两个或两个以上环状结构且共用两个以或两个以上上原子的多环环基。其中“并环”或“稠环”为特殊的桥环，指含有两个或两个以上环状结构且彼此共用一对原子的多环环基。本文优选为7-15元，更优选为8-9元。根据组成环的数目可以分为双环、三环、四环或多环桥环基，优选为双环或三环，本文优选为双环或三环，更优选为5元/5元、5元/6元或6元/6元双环桥环基。其非限定性示例包括但不限于双环[2.2.2]辛烷、螺环[3.4]辛烷。In the definition of "cyclic group", "bridged ring" refers to a polycyclic cyclic group containing two or more cyclic structures and sharing two or more atoms. Among them, "parallel ring" or "fused ring" is a special bridged ring, which refers to a polycyclic ring group containing two or more cyclic structures and sharing a pair of atoms with each other. The preferred value here is 7-15 yuan, and the more preferred value is 8-9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups, preferably bicyclic or tricyclic, here preferably bicyclic or tricyclic, more preferably 5-membered/5-membered, 5-membered/6-membered One-membered or 6-membered/6-membered bicyclic bridged ring base. Non-limiting examples thereof include, but are not limited to, bicyclo[2.2.2]octane, spirocyclo[3.4]octane.
若无特殊说明，螺环与桥环也可应用于下文所讨论的环烷基、环烯基、杂环烷基、杂环烯基中，包括螺环烷基、螺环烯基、螺杂环烷基、螺杂环烯基、桥环烷基、桥环烯基、桥杂环烷基、桥杂环烯基。稠环包括稠环烷基、稠环烯基、稠杂环烷基、稠杂环烯基、稠环芳基、稠环杂芳基。上述术语定义与螺环、桥环、并环或稠环类似。Unless otherwise specified, spiro rings and bridged rings can also be applied to cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl discussed below, including spirocycloalkyl, spirocycloalkenyl, and spiroheterocycles. Cycloalkyl, spiroheterocycloalkenyl, bridged cycloalkyl, bridged cycloalkenyl, bridged heterocycloalkyl, bridged heterocycloalkenyl. Condensed rings include fused ring alkyl, fused ring alkenyl, fused heterocycloalkyl, fused heterocycloalkenyl, fused ring aryl, and fused ring heteroaryl. The definitions of the above terms are similar to those of spiro ring, bridged ring, parallel ring or fused ring.
本文单独或组合使用的术语“碳环基”包括脂环基和芳基，包括单环、稠环、桥环和螺环。杂环基的实例包括如下所讨论的环烷基、环烯基和芳基。本文优选3-10元单环、双环或三环的碳环基。The term "carbocyclyl" as used herein, alone or in combination, includes alicyclic and aryl groups, including monocyclic, fused, bridged and spirocyclic rings. Examples of heterocyclyl groups include cycloalkyl, cycloalkenyl, and aryl groups as discussed below. Preferred here are 3-10 membered monocyclic, bicyclic or tricyclic carbocyclic groups.
本文单独或组合使用的术语“环烷基”是指饱和单环、双环或多环的碳环，其可以是螺环或桥环。本文优选为3-12元环烷基，更优选为3-10元环烷基，最优选为3-8元环烷基。单环环烷基的非限定性示例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等环烷基，其可以是任选取代的或未取代的。The term "cycloalkyl" as used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic carbocyclic ring, which may be spiro or bridged. Herein, a 3-12-membered cycloalkyl group is preferred, a 3-10-membered cycloalkyl group is more preferred, and a 3-8-membered cycloalkyl group is most preferred. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and other cycloalkyl groups, which may be optionally substituted or un replaced.
“环烷基”的定义中，“螺环”是指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)的全碳多环基团。本文优选为6至12元，更优选为8至9元。根据环与环之间共用螺原子的数目螺环分为单螺、双螺或多螺环烷基，本文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。In the definition of "cycloalkyl", "spiro ring" refers to an all-carbon polycyclic group with two or more cyclic structures and each single ring shares one carbon atom (called a spiro atom). Here, it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan. According to the number of shared spiro atoms between the rings, the spiro ring is divided into single spiro, double spiro or polyspiral cycloalkyl groups. The preferred ones here are single spiro and double spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/ 6-membered, 5-membered/5-membered or 5-membered/6-membered spirocycloalkyl group.
“环烷基”的定义中，“稠环”是指含有两个或两个以上环状结构且彼此公用一对碳原子的全碳多环基团。本文优选为6至12元，更优选为8至9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，本文优选为双环或三环，更优选为5元/5元、5元/6元或6元/6元双环烷基。In the definition of "cycloalkyl", "fused ring" refers to an all-carbon polycyclic group containing two or more cyclic structures and sharing a pair of carbon atoms with each other. Here, it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups. Herein, bicyclic or tricyclic is preferred, and more preferably 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered. One-membered bicycloalkyl.
“环烷基”的定义中，“桥环”是指含有两个或两个以上环状结构且彼此共用两个不直接相连接碳原子 的全碳多环基团。本文优选为6至12元，更优选为8至9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，优选为双环或三环。In the definition of "cycloalkyl", "bridged ring" refers to a ring structure containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. all-carbon polycyclic groups. Here, it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic or tricyclic.
本文单独或组合使用的术语“环烯基”是指具有1个或多个碳-碳双键的不具有芳香性的单环、双环或多环的碳环，其可以是螺环或桥环。本文优选为3-12元环烯基，更优选为3-10元环烯基，最优选为3-8元环烯基。环烯基的非限定性示例包括但不限于环戊-1-烯-1-基、环己-1-烯-1-基和环己-1,3-二烯-1-基，其可以是任选取代的或未取代的。The term "cycloalkenyl" as used herein alone or in combination refers to a nonaromatic monocyclic, bicyclic or polycyclic carbocyclic ring having one or more carbon-carbon double bonds, which may be spirocyclic or bridged. . Herein, a 3-12-membered cyclic alkenyl group is preferred, a 3-10-membered cyclic alkenyl group is more preferred, and a 3-8-membered cyclic alkenyl group is most preferred. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohex-1,3-dien-1-yl, which may are optionally substituted or unsubstituted.
本文单独或组合使用的术语“芳基”是指芳族烃基环。术语“芳基”包括单环状芳族烃和多环状稠环芳族烃，其中所有稠环***(不包括是任选的取代基的一部分或由任选的取代基形成的任何环***)为芳族的。芳基基团/部分的实例包括苯基、萘基、蒽基和菲基。除非另外说明，否则术语“芳基”不包括“杂芳基”。The term "aryl" as used herein alone or in combination refers to an aromatic hydrocarbyl ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons, in which all fused ring systems (excluding any ring systems that are part of or formed from optional substituents) ) is aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise stated, the term "aryl" does not include "heteroaryl".
本文单独或组合使用的术语“杂环基”包括脂杂环基和杂芳基，其中一个或多个(诸如一个、两个、三个或四个)环节原子是杂原子，如氧、氮、硫原子等，包括单环、稠环、桥环和螺环。杂环基的实例包括如下所讨论的杂环烷基、杂环烯基和杂芳基。本文优选3-10元单环、双环或三环的杂环基，其可以包含1、2或3个选自氮、氧和/或硫中的环节原子。“杂环基”的非限定性示例包括氮杂环丁烯基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、2-氧代-吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基、咪唑烷基、二氧杂环戊烷基、氧硫杂环戊烷基、哌啶基、2-氧代-哌啶基、四氢吡喃基、噻烷基、哌嗪基、哌嗪-2-酮、二氧杂环己烷基、吗啉基和硫代吗啉基、1,1-二氧代-硫代吗啉基等。杂环基可以是任选取代的或未取代的。The term "heterocyclyl" as used herein, alone or in combination, includes alicyclic and heteroaryl groups in which one or more (such as one, two, three or four) link atoms are heteroatoms, such as oxygen, nitrogen , sulfur atoms, etc., including single ring, fused ring, bridged ring and spiro ring. Examples of heterocyclyl groups include heterocycloalkyl, heterocycloalkenyl, and heteroaryl as discussed below. Preferred here are 3-10 membered monocyclic, bicyclic or tricyclic heterocyclyl groups, which may contain 1, 2 or 3 ring atoms selected from nitrogen, oxygen and/or sulfur. Non-limiting examples of "heterocyclyl" include azetidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidine base, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolyl, oxothiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydrogen Pyranyl, thiyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl wait. Heterocyclyl groups may be optionally substituted or unsubstituted.
“杂环基”的定义中，“螺环”是指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环基团，环内含有若干个不饱和键，但没有一个环具有完全共轭的π电子的芳香***，其中一个或多个环节原子选自氮、氧或S(O)n(其中n选自0、1或2)的杂原子，其余环节原子为碳。本文优选为6-12元，更优选为8-9元。根据环与环之间共用螺原子的数目将螺环分为单螺杂环基、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。其非限定性示例包括但不限于7-氮杂螺环[3.5]壬烷、2,7-二氮螺环[3.5]壬烷、2-氮杂螺环[3.4]辛烷。In the definition of "heterocyclyl", "spirocycle" refers to a polycyclic ring group with two or more cyclic structures and the single rings share one atom with each other. The ring contains several unsaturated bonds, but Aromatic systems in which none of the rings have fully conjugated π electrons, in which one or more link atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) n (where n is selected from 0, 1, or 2), and the remaining link atoms for carbon. The preferred value here is 6-12 yuan, and the more preferred value is 8-9 yuan. According to the number of shared spiro atoms between the rings, the spiro ring is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group, and 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 single spiroheterocyclic group. Non-limiting examples thereof include, but are not limited to, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, and 2-azaspiro[3.4]octane.
“杂环基”的定义中，“桥环”是指含有两个或两个以上环状结构且彼此共用两个或两个以上原子的多环环基团，一个或多个环可以含有若干个不饱和键，但没有一个环具有完全共轭的π电子的芳香***，其中一个或多个环节原子选自氮、氧或S(O)n(其中n选自0、1或2)的杂原子，其余环节原子为碳。本文优选为6-12元，更优选为8-9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，优选为双环或三环。In the definition of "heterocyclyl", "bridged ring" refers to a polycyclic ring group containing two or more cyclic structures and sharing two or more atoms with each other. One or more rings may contain several An aromatic system with unsaturated bonds but none of the rings having fully conjugated π electrons, in which one or more link atoms are selected from nitrogen, oxygen, or S(O) n (where n is selected from 0, 1, or 2) Heteroatoms, the remaining link atoms are carbon. The preferred value here is 6-12 yuan, and the more preferred value is 8-9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic or tricyclic.
“杂环基”的定义中，“稠环”是指含有两个或两个以上环状结构且彼此共用一对原子的多环环基团，一个或多个环可以含有若干个不饱和键，同时至少一个环具有完全共轭的π电子的芳香***，其中一个或多个环节原子选自氮、氧或S(O)n(其中n选自0、1或2)的杂原子，其余环节原子为碳。本文优选为6-12元，更优选为8-9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。In the definition of "heterocyclyl", "fused ring" refers to a polycyclic ring group containing two or more cyclic structures and sharing a pair of atoms with each other. One or more rings may contain several unsaturated bonds. , an aromatic system with at least one ring having fully conjugated π electrons, in which one or more link atoms are selected from nitrogen, oxygen or heteroatoms of S(O) n (where n is selected from 0, 1 or 2), and the rest The link atom is carbon. The preferred value here is 6-12 yuan, and the more preferred value is 8-9 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.
本文单独或组合使用的术语“杂环烷基”是指饱和单环、双环或多环的，其中一个或多个(诸如一个、两个、三个或四个)环节原子是杂原子的饱和杂环基，其可以是螺环或桥环。本文优选为3-12元环烷基，更优选为3-10元环烷基，最优选为3-8元环烷基。单环杂环烷基的非限定性示例包括但不限于环氧丙烷、硫杂环丙烷、氮杂环丙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、噁唑烷、噻唑烷、咪唑烷、四氢吡喃、哌啶、二氧六环、氮杂环庚烷。The term "heterocycloalkyl" as used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic ring in which one or more (such as one, two, three or four) ring atoms are heteroatoms. Heterocyclyl, which can be a spiro ring or a bridged ring. Herein, a 3-12-membered cycloalkyl group is preferred, a 3-10-membered cycloalkyl group is more preferred, and a 3-8-membered cycloalkyl group is most preferred. Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, propylene oxide, thiirane, aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrofuran, Hydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.
本文单独或组合使用的术语“杂环烯基”是指具有1个或多个不饱和双键的不具有芳香性的单环、双环或多环的，其中一个或多个(诸如一个、两个、三个或四个)环节原子是杂原子的饱和杂环基，其可以是螺环或桥环。本文优选为3-12元杂环烯基，更优选为3-10元杂环烯基，最优选为3-8元杂环烯基。杂环烯基的非限定性示例包括但不限于氮杂环丙烯、氧杂环丙烯、硫杂环丙烯、氧杂环丁烯、吡喃。The term "heterocycloalkenyl" as used herein, alone or in combination, refers to a nonaromatic monocyclic, bicyclic or polycyclic ring having one or more unsaturated double bonds, in which one or more (such as one, two (one, three or four) link atoms are heteroatoms in a saturated heterocyclyl group, which can be a spiro ring or a bridged ring. Here, it is preferably a 3-12-membered heterocyclic alkenyl group, more preferably a 3-10-membered heterocyclic alkenyl group, and most preferably a 3-8-membered heterocyclic alkenyl group. Non-limiting examples of heterocycloalkenyl include, but are not limited to, aziridine, oxane, thiane, oxetene, pyran.
本文单独或组合使用的术语“杂芳基”是指5-12元(优选5-10元、更优选5-6元)单环、双环或三环体系，其中至少一个环是芳香族的，且至少一个环包含一个或多个选自氮、氧、硫的杂原子，同时，所述杂芳基还有一个或多个附着点与分子其余部分相连。双环或三环体系的“杂芳基”中，若含有饱和或非饱和杂环烷基或。“杂芳基”的非限定性示例包括呋喃基、咪唑基、异噁唑基、噁唑基、吡咯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基等；也包括以下的双环，但不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、氧代吲哚基、二氢吲哚基、咪唑并吡啶基、吡唑并吡啶基、吡唑并嘧啶基、喹啉基、异喹啉基、喹唑啉基、吲唑、1,8-萘啶、苯并[d]异恶唑、苯并[d]噻唑、吡咯[3,2-b]吡啶、呋喃[3,2-b]吡啶、吡咯并[1,2-b]哒嗪、咪唑并[1,2-b]哒嗪、吡唑并[1,5-a]嘧啶、噻唑并[4,5-c]吡啶、噻吩并[3,2-b]吡啶、吡咯并[1,2-b]哒嗪、2,3-二氢苯并呋喃、苯并[c][1,2,5]恶二唑、1,3-二氢-2H-苯并[d]咪唑-2-酮、苯并[d]恶唑-2(3H)-酮等。杂芳基可以是任选取代的或未取代的。The term "heteroaryl" as used herein alone or in combination refers to a 5-12 membered (preferably 5-10 membered, more preferably 5-6 membered) monocyclic, bicyclic or tricyclic ring system in which at least one ring is aromatic, And at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and at the same time, the heteroaryl group also has one or more attachment points connected to the rest of the molecule. In the "heteroaryl group" of the bicyclic or tricyclic system, if it contains a saturated or unsaturated heterocycloalkyl group or. Non-limiting examples of "heteroaryl" include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, Thiazolyl, etc.; also includes the following bicyclic rings, but is not limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolyl, imidazopyridine base, pyrazopyridinyl, pyrazopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazole, 1,8-naphthyridine, benzo[d]isoxazole, benzo[ d] Thiazole, pyrrole[3,2-b]pyridine, furan[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-b]pyridazine, pyrazole And[1,5-a]pyrimidine, thiazolo[4,5-c]pyridine, thieno[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, 2,3-dihydro Benzofuran, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazole-2-one, benzo[d]oxazole-2( 3H)-ketone, etc. Heteroaryl groups may be optionally substituted or unsubstituted.
本文单独或组合使用的术语“卤素”是指氟、氯、溴或碘。The term "halogen" as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.
本文单独或组合使用的术语“羟基”是指-OH。The term "hydroxy" as used herein alone or in combination refers to -OH.
本文单独或组合使用的术语“氰基”是指-CN。The term "cyano" as used herein alone or in combination refers to -CN.
本文单独或组合使用的术语“甲磺酰基”是指-S(O)2-CH3。The term "methanesulfonyl" as used herein alone or in combination refers to -S(O) 2 - CH3 .
本文所使用的术语“(被)取代的”或“被……取代”是指在一个特定的原子上一个或更多的氢被指定的 基团(如卤素、烷基等)所替代，如果指定的原子的正常化合价在现有的情况下没有超出，那么取代后结果是一个稳定的化合物。As used herein, the term "substituted" or "substituted by" means that one or more hydrogens on a particular atom are designated Groups (such as halogen, alkyl, etc.) are substituted. If the normal valency of the specified atom is not exceeded under the existing circumstances, then the result after substitution is a stable compound.
本文所使用的术语“药学上可接受的盐”在所属领域是为本领域技术人员所熟知的。The term "pharmaceutically acceptable salt" as used herein is well known to those skilled in the art.
本文所使用的术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse effects biologically react or interact in an adverse manner with any component contained in the composition.
本文所使用的术语“药物组合物”是指任选地混合有至少一种药学上可接受的化学成分的生物活性化合物，所述药学上可接受的化学成分包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, a stabilizer, Diluents, dispersants, suspending agents, thickeners and/or excipients.
本文所使用的术语“载体”是指相对无毒的化学化合物或试剂，其有助于将化合物引入到细胞或组织中。The term "carrier" as used herein refers to a relatively nontoxic chemical compound or agent that facilitates the introduction of a compound into cells or tissues.
本文所使用的术语“立体异构体”包括但不限于对映异构体、顺反异构体等。The term "stereoisomer" as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.
本文所使用的术语“对映异构体”是指具有相同分子式的化合物中，由于原子或原子团(基团)在空间配制不同而引起的同分异构现象，互为对映异构体的两个化合物互为镜像且不能重合。本文所使用的术语“顺反异构体”通常是指化合物分子中由于具有自由旋转的限制因素，使各个基团在空间的排列方式不同而出现的非对映异构的立体异构现象。含有此类异构的有机分子如烯烃、偶氮化合物、脂环烃等被视作顺反异构。在本申请中，顺反异构主要以脂环烃形式体现。例如在环己烷中，环己烷被两个取代基取代时会出现顺反异构，两个取代基取代在环的同一侧时为“顺式”异构体，不同侧的为“反式”异构体。The term "enantiomers" used herein refers to compounds with the same molecular formula that are enantiomers of each other due to the isomerism phenomenon caused by the different spatial arrangements of atoms or atomic groups (groups). Two compounds are mirror images of each other and cannot be superimposed. The term "cis-trans isomers" used herein generally refers to the diastereomeric stereoisomerism phenomenon that occurs due to the different arrangement of each group in space due to the restriction of free rotation in the compound molecule. Organic molecules containing such isomers, such as alkenes, azo compounds, alicyclic hydrocarbons, etc., are regarded as cis-trans isomers. In this application, cis-trans isomerism is mainly reflected in the form of alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism occurs when cyclohexane is substituted by two substituents. When the two substituents are substituted on the same side of the ring, it is the "cis" isomer, and when the two substituents are substituted on the same side of the ring, it is the "trans" isomer. Formula" isomer.
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, diastereoisomers, enantiomers, steric 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、顺反异构体、位阻异构体、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、脂肪族环烃类顺反异构、联苯类结构的位阻异构体(参见《基础有机化学》(第二版)上册，邢其毅等，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, the structures described herein also include all isomers of this structure (e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformations) Isomeric forms), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, and steric isomers of biphenyl structures Structure (see Basic Organic Chemistry (Second Edition), Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z ) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric, diastereomeric, steric and geometric (conformational) isomer mixtures of the compounds of the invention are within the scope of the invention.
以下，将通过一些具体的实施方式进一步阐述本发明。例如：In the following, the present invention will be further explained through some specific embodiments. For example:
在通式I中，各基团的可选基团可以是：
In general formula I, optional groups for each group may be:
在一些具体的实施方式中，环A为5-10元杂芳基。其中，杂芳基可以是单环或并环形式。环A通过共价键分别与环B连接，并通过L1与R1相连，且任选地被1-3个R3取代。若无特殊说明，R3可通过取代环A任一环节原子的H原子与环A相连，环节原子包括C、N。In some specific embodiments, Ring A is 5-10 membered heteroaryl. Among them, the heteroaryl group can be in the form of a single ring or a branched ring. Ring A is respectively connected to ring B through covalent bonds and connected to R 1 through L 1 , and is optionally substituted by 1 to 3 R 3s . If there is no special explanation, R 3 can be connected to ring A by replacing the H atom of any link atom of ring A, including C and N.
当环A为单环时，更优选6元杂芳基，杂原子的个数优选1-3个，所述杂原子优选N。其非限定性示例包括但不限于吡啶、吡嗪、嘧啶、哒嗪、三嗪。若无特殊说明，环A上，环B及L1的连接位点可以是邻位、间位或者对位。When ring A is a monocyclic ring, a 6-membered heteroaryl group is more preferred, the number of heteroatoms is preferably 1-3, and the heteroatoms are preferably N. Non-limiting examples thereof include, but are not limited to, pyridine, pyrazine, pyrimidine, pyridazine, and triazine. Unless otherwise specified, the connection sites of ring A, ring B and L 1 may be ortho, meta or para.
当环A为并环时，其优选5-6并环或6-6并环，并形成共轭的双环芳基，杂原子的个数优选1-3个，所述杂原子优选N。若无特殊说明，L1与环B分别与并环环A中的不同环相连接。当环B为杂环烷基时，优选地含有1个任选自N、O、S的杂原子。此时，环A的非限定性示例包括但不限于以下结构： When ring A is a cyclic ring, it is preferably a 5-6 cyclic ring or a 6-6 cyclic ring, and forms a conjugated bicyclic aryl group. The number of heteroatoms is preferably 1-3, and the heteroatom is preferably N. Unless otherwise specified, L 1 and ring B are respectively connected to different rings in the parallel ring A. When ring B is a heterocycloalkyl group, it preferably contains 1 heteroatom optionally selected from N, O, and S. At this time, non-limiting examples of ring A include, but are not limited to, the following structures:
通常情况下，取代在环A上的基团R3的非限定性示例包括但不限于卤素、羟基、硝基、氰基、氨基、C1-6烷基，优选氰基、氨基、甲基。Typically, non-limiting examples of the group R3 substituted on ring A include, but are not limited to, halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, preferably cyano, amino, methyl .
在一些具体的实施方式中，L1通过共价键连接环A与R1相连，或L1本身为化学键。L1的非限定性示例包括但不限于亚氨基、羰基、-CO-NH-、 In some specific embodiments, L 1 is connected to R 1 through a covalent bond linking ring A, or L 1 itself is a chemical bond. Non-limiting examples of L include, but are not limited to, imino, carbonyl, -CO-NH-,
在一些具体的实施方式中，R1选自C1-6烷基、5-10元环烷基、5-10元杂环烷基，且任选地被1-3个R5取代，其中环烷基或杂环烷基包括但不限于单环、并环、螺环、桥环形式，优选4-6元环烷基或4-6元含有1-2个选自N、O、S杂原子的杂环烷基。当R1为环烷基或杂环烷基时，优选5-7元的单环形式，或7-9元的桥环或螺环形式。其中，7-9元螺环形式具有类似于结构，虚线表示与螺原子连接的4-6元环烷基(包括螺原子)，在符合化合物价电守则的情况下，任一原子可以更换为杂原子。7-9元的桥环形式，即在环基上两个不相邻的原子用1个共价键或1个或多个原子相连。R1的非限定性示例包括但不限于环丁烷、环戊基、环己基、环庚基、 甲基、乙基、丙基、异丙基。In some specific embodiments, R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 , wherein Cycloalkyl or heterocycloalkyl includes but is not limited to monocyclic, paracyclic, spirocyclic and bridged ring forms, preferably 4-6 membered cycloalkyl or 4-6 membered containing 1-2 selected from N, O, S heteroatom heterocycloalkyl. When R 1 is a cycloalkyl or heterocycloalkyl group, it is preferably a 5-7 membered monocyclic ring, or a 7-9 membered bridged ring or spirocyclic ring. Among them, the 7-9 membered spirocyclic form has a similar Structure, the dotted line represents the 4-6-membered cycloalkyl group (including the spiro atom) connected to the spiro atom. Any atom can be replaced with a heteroatom if it complies with the valency code of the compound. 7-9 membered bridged ring form, that is, two non-adjacent atoms on the ring base are connected by a covalent bond or one or more atoms. Non-limiting examples of R include, but are not limited to, cyclobutane, cyclopentyl, cyclohexyl, cycloheptyl, Methyl, ethyl, propyl, isopropyl.
当R1为非对称基团，或R5的取代位点不在R1的对称轴或对称中心上时，可能会出现不同的空间异构体，包括对映异构和顺反异构。需要说明的是，无论是对映异构和顺反异构均具有ALK2抑制活性，但是不同的异构体抑制活性可能会有所区别。When R 1 is an asymmetric group, or the substitution site of R 5 is not on the symmetry axis or center of R 1 , different spatial isomers may appear, including enantiomers and cis-trans isomers. It should be noted that both enantiomers and cis-trans isomers have ALK2 inhibitory activity, but the inhibitory activities of different isomers may be different.
在一些具体的实施方式中，R5为OH、卤素、C1-6烷基、-(CRaRb)n-OH。其中Ra、Rb优选为H或C1-3烷基，n优选为1-3。R5的非限定性示例包括但不限于羟基、F、Cl、甲基、乙基、丙基、异丙基、-CH2OH、-C(CH3)2OH。In some specific embodiments, R 5 is OH, halogen, C 1-6 alkyl, -(CR a R b ) n -OH. Among them, R a and R b are preferably H or C 1-3 alkyl, and n is preferably 1-3. Non-limiting examples of R5 include, but are not limited to, hydroxyl, F, Cl, methyl, ethyl, propyl, isopropyl, -CH2OH , -C( CH3 ) 2OH .
在一些具体的实施方式中，环B为6-15元环基，且任选1-3个环节碳原子被氧取代；环B任选地被1-3个R4取代。环B可以是单环、双环或者三环形式，当环B为双环或三环时，其各环之间的连接形式可以是并环、螺环，或者桥环。若无特殊说明的情况下，环B中至少1个环为芳环或杂芳环，其他环为饱和或不饱和的环烷基或杂环烷基，或者其他环为并联的芳环或杂芳环。若无特殊说明，R4可通过取代环B任一环节原子的H原子与环B相连，环节原子包括C、N。In some specific embodiments, Ring B is a 6-15 membered ring group, and optionally 1-3 ring carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R4 . Ring B may be in the form of a single ring, a double ring, or a tricyclic ring. When Ring B is a double ring or a tricyclic ring, the connection form between the rings may be a parallel ring, a spiro ring, or a bridged ring. Unless otherwise specified, at least one ring in Ring B is an aromatic or heteroaromatic ring, the other rings are saturated or unsaturated cycloalkyl or heterocycloalkyl, or the other rings are parallel aromatic or heterocyclic rings. aromatic ring. If there is no special explanation, R 4 can be connected to ring B by replacing the H atom of any link atom of ring B, including C and N.
当环B为单环时，更优选6元芳基或者杂芳基，杂原子的个数优选0-3个，所述杂原子优选N。其非限定性示例包括但不限于苯、吡啶、吡嗪、嘧啶、哒嗪、三嗪。若无特殊说明，环B上，环A及L2的连接位点可以是邻位、间位或者对位。When ring B is a monocyclic ring, it is more preferably a 6-membered aryl group or a heteroaryl group, and the number of heteroatoms is preferably 0-3, and the heteroatoms are preferably N. Non-limiting examples thereof include, but are not limited to, benzene, pyridine, pyrazine, pyrimidine, pyridazine, and triazine. Unless otherwise specified, the connection point between ring A and L2 on ring B can be ortho, meta or para.
当环B为并环时，其为形式，其优选5-6并环或6-6并环，Y1、Y2、Y3独立地选自CH或N。其中环C为5-6元环基，优选为并联的环烷基、杂环烷基、芳基或者杂芳基。环C中任选地含有1-3个N原子，且其中的碳原子可选地被氧代，形成羰基。若无特殊说明，L2与环A分别与并环环B中的 不同环相连接。When ring B is a parallel ring, it is form, which is preferably 5-6 cyclic ring or 6-6 cyclic ring, Y 1 , Y 2 , Y 3 are independently selected from CH or N. Ring C is a 5-6 membered ring group, preferably a parallel cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group. Ring C optionally contains 1-3 N atoms, and the carbon atoms therein are optionally oxo-substituted to form a carbonyl group. Unless otherwise specified, L 2 and ring A are respectively the same as those in parallel ring B. Different rings are connected.
当环B为时，通常由*端连接环A，**端连接L2。When ring B is When, the first end is usually connected to ring A, and the upper end is connected to L 2 .
当环B也可以是三环基团，其中的一个环为苯环。在一些具体的实施方式中，环B是r、p、q为1-3的整数；Z1、Z2、Z3独立地选自CH或N，且最多一个为N；为单键或双键；当为单键时，Z4为CH2或O，Z5为CH2或NH；当为双键时，Z4为CH，Z5为CH或N；环B中任选1个环节碳原子被氧取代；环B任选地被1-2个R4取代。在进一步的优选方案中，Z5被限定为CH2或CH，Z6被限定为N且与L2相连，p取2。在一些更为具体的方案中，环B是r为1-2的整数，为单键或双键。Ring B can also be a tricyclic group, one of which is a benzene ring. In some specific embodiments, Ring B is r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH and Z 5 is CH or N; optionally one carbon atom in ring B is substituted by oxygen; ring B is optionally substituted by 1-2 R 4s . In a further preferred embodiment, Z 5 is defined as CH 2 or CH, Z 6 is defined as N and connected to L 2 , and p is 2. In some more specific schemes, ring B is r is an integer from 1 to 2, be a single bond or a double bond.
当环B为或进一步地为时，通常由*端连接环A，**端连接L2。When ring B is or further When, the first end is usually connected to ring A, and the upper end is connected to L 2 .
环B的非限定性示例包括但不限于以下结构： 通常情况下，6元芳环或杂芳环所连的(即环B上方的键)与环A相连，另一条(即环B下方的键)与L2相连。Non-limiting examples of Ring B include, but are not limited to, the following structures: Usually, the 6-membered aromatic ring or heteroaromatic ring is connected to (that is, the bond above ring B) is connected to ring A, and the other (i.e. the bond below ring B) is connected to L 2 .
通常情况下，取代在环B上的基团R4的非限定性示例包括但不限于卤素、羟基、硝基、氰基、氨基、C1-6烷基，优选氰基、甲基、三氟甲基。Typically, non-limiting examples of the group R4 substituted on ring B include, but are not limited to, halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, preferably cyano, methyl, tri Fluoromethyl.
在一些具体的实施方式中，L2通过共价键连接环B与R2，或L2本身为化学键。在一些具体的实施方式中，L2被定义为-(CRaRb)n-，其中Ra、Rb独立地选自H或C1-3烷基，或Ra、Rb与所连的碳原子形成3-6元环烷基。n可以取1-3的整数，当n为2时，L2即为-CRaRb-CRa’Rb’-，此时Ra、Rb、Ra’、Rb’-可以独立地选自H或C1-3烷基，同时Ra与Rb，或者Ra’与Rb’可以与其共同连接的碳原子形成3-6元的环烷基，例如在本申请中，L2的非限定性示例包括但不限于化学键、亚甲基、 In some specific embodiments, L 2 connects ring B and R 2 through a covalent bond, or L 2 itself is a chemical bond. In some specific embodiments, L 2 is defined as -(CR a R b ) n - , wherein Ra and R b are independently selected from H or C 1-3 alkyl, or Ra and R b are The attached carbon atoms form a 3-6 membered cycloalkyl group. n can be an integer from 1 to 3. When n is 2, L2 is -CR a R b -CR a 'R b '-. At this time, R a , R b , R a ', and R b '- can be independent. is selected from H or C 1-3 alkyl, while R a and R b , or R a ' and R b ' can form a 3-6 membered cycloalkyl group with the carbon atoms they are jointly connected to, such as In this application, non-limiting examples of L include, but are not limited to, chemical bonds, methylene,
在一些具体的实施方式中，R2任选地被1-2个R6取代，其中杂环烷基包括但不限于单环、螺环形 式，优选4-6元环烷基或4-6元含有1-2个选自N、O、S杂原子的杂环烷基。。当R2为杂环烷基时，优选5-7元的单环形式，或7-9元的桥环或螺环形式。其中，7-9元螺环形式具有类似于结构，虚线表示与螺原子连接的4-6元环烷基(包括螺原子)，在符合化合物价电守则的情况下，任一原子可以更换为杂原子。7-9元的桥环形式，即在环基上两个不相邻的原子用1个共价键或1个或多个原子相连。R2的非限定性示例包括但不限于环戊基、环己基、环庚基、 In some specific embodiments, R 2 is optionally substituted by 1-2 R 6 , wherein heterocycloalkyl includes but is not limited to monocyclic, spirocyclic Formula, preferably a 4-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S. . When R 2 is a heterocycloalkyl group, it is preferably a 5-7-membered monocyclic ring, or a 7-9-membered bridged ring or spirocyclic ring. Among them, the 7-9 membered spirocyclic form has a similar Structure, the dotted line represents the 4-6-membered cycloalkyl group (including the spiro atom) connected to the spiro atom. Any atom can be replaced with a heteroatom if it complies with the valency code of the compound. 7-9 membered bridged ring form, that is, two non-adjacent atoms on the ring base are connected by a covalent bond or one or more atoms. Non-limiting examples of R include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl,
当R2为非对称基团，或R6的取代位点不在R2的对称轴上时，可能会出现不同的空间异构体，包括对映异构和顺反异构。需要说明的是，无论是对映异构和顺反异构均具有ALK2抑制活性，但是不同的异构体抑制活性可能会有所区别。When R 2 is an asymmetric group, or the substitution site of R 6 is not on the symmetry axis of R 2 , different spatial isomers may appear, including enantiomers and cis-trans isomers. It should be noted that both enantiomers and cis-trans isomers have ALK2 inhibitory activity, but the inhibitory activities of different isomers may be different.
在一些具体的实施方式中，R6选自羟基、-CO-Rc、-CO-NRcRd、-SO2-Rc，或R6选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，任选地被1-3个Re取代。其中Rc、Rd独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基；Re选自卤素、羟基、硝基、氰基、氨基、C1-6烷氧基。R6的非限定性示例包括-但不限于H、F、甲基、乙基、异丙基、羟基、 In some specific embodiments, R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or R 6 is selected from C 1-6 alkyl, 4-8 1-membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 Re . Wherein R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl; R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1- 6 alkoxy. Non-limiting examples of R include - but are not limited to H, F, methyl, ethyl, isopropyl, hydroxyl,
本申请部分化合物根据环B不同，可以分为并环化合物及三环化合物。这些化合物具有较好的ALK2抑制活性以及细胞活性，且相较于现有化合物具有更好的选择性。Some of the compounds in this application can be divided into paracyclic compounds and tricyclic compounds according to different ring Bs. These compounds have better ALK2 inhibitory activity and cell activity, and have better selectivity than existing compounds.
方案一：并环化合物
Scheme 1: Paracyclic compounds
在该方案中，环B具有如下结构：其中Y1、Y2、Y3独立地选自CH或N，环C为并联的5-6元环基。在该方案中，环C可以是5-6元饱和或不饱和的环烷基或杂环烷基，以及芳基或杂芳基。且当环C为饱和或不饱和的环烷基、杂环烷基时，环C的环节C原子可以被氧取代，形成羰基。当环B为时，通常由*端连接环A，**端连接L2。In this scheme, ring B has the following structure: Among them, Y 1 , Y 2 and Y 3 are independently selected from CH or N, and ring C is a parallel 5-6 membered ring group. In this embodiment, ring C can be a 5- to 6-membered saturated or unsaturated cycloalkyl or heterocycloalkyl group, as well as an aryl or heteroaryl group. And when ring C is a saturated or unsaturated cycloalkyl or heterocycloalkyl group, the C atoms of ring C can be substituted by oxygen to form a carbonyl group. When ring B is When, the first end is usually connected to ring A, and the upper end is connected to L 2 .
在一些更优选的情况下，环B具有如下结构：其中，环C可以进一步优选为为并联的5元环烷基、含氮杂环烷基、含氮杂芳基，例如 In some more preferred cases, Ring B has the following structure: Among them, Ring C can be further preferably a parallel 5-membered cycloalkyl group, nitrogen-containing heterocycloalkyl group, or nitrogen-containing heteroaryl group, for example
此时，R1可取4-6元环烷基或含有1-2个选自N、O等杂原子的杂环烷基，例如环丁基、环戊基、环己基、氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、四氢吡咯基、六氢吡啶基、吗啉；进一步地，R1可任选地被1-2个R5取代，R5可以是羟基、卤素、C1-3烷基、-CH2OH、-C(CH3)2OH。本方案并未限定L1及R5在R1上的连接位点，因此这两个连接位点可以是邻位、间位或对位，优选间位或对位。更进一步地，根据R1的不同，取代基及取代位点的不同，可能存在立体异构，包括顺反异构及对映异构。通常情况下，R1为R5为羟基或不被取代。At this time, R 1 can be a 4-6 membered cycloalkyl group or a heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, etc., such as cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl , tetrahydrofuryl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl, hexahydropyridyl, morpholine; further, R 1 can be optionally substituted by 1-2 R 5 , and R 5 can be It is hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH. This scheme does not limit the connection sites of L 1 and R 5 on R 1 , so the two connection sites can be ortho, meta or para, preferably meta or para. Furthermore, depending on the difference in R 1 , the substituent and the substitution site, stereoisomerism may exist, including cis-trans isomerism and enantiomerism. Typically, R 1 is R 5 is hydroxyl or unsubstituted.
在本方案中，L2选自化学键或简单(亚)烷基，连接R2及环B。R2通常为5-6元含有1-2个选自N、O杂原子的杂环烷基，任选地被1-2个R6取代，例如R2可以是 L2通过取代R2上氢原子的方式连接于R2任一位点。R6可以是类似于卤素、羟基、氨基、氰 基的简单取代基，也可以是任选地被Re取代的自4-7元环烷基、4-7元含有1-2个选自N、O杂原子的杂环烷基、C1-3烷基。本方案并未限定L2及R6在R4上的连接位点，因此这两个连接位点可以是邻位、间位或对位，优选间位或对位。更进一步地，根据R2的不同，取代基及取代位点的不同，可能存在立体异构，包括顺反异构及对映异构。Re通常情况下为卤素，也可以是其他类似于羟基、氨基或氰基的简单取代基，同样根据其取代位点的不同其与R6可能形成立体异构，包括顺反异构及对映异构。In this scheme, L 2 is selected from a chemical bond or a simple ()alkylene group, connecting R 2 and Ring B. R 2 is usually a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 , for example, R 2 can be L 2 is connected to any position of R 2 by replacing the hydrogen atom on R 2 . R 6 can be something like halogen, hydroxyl, amino, cyanide The simple substituent of the base can also be a 4-7-membered cycloalkyl group optionally substituted by R e , a 4-7-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, C 1 -3 alkyl. This scheme does not limit the connection sites of L 2 and R 6 on R 4 , so the two connection sites can be ortho, meta or para, preferably meta or para. Furthermore, depending on the difference in R 2 , substituents and substitution sites, stereoisomerism may exist, including cis-trans isomerism and enantiomerism. R e is usually halogen, and can also be other simple substituents similar to hydroxyl, amino or cyano. Also depending on its substitution position, it may form stereoisomerism with R 6 , including cis-trans isomerism and para-isomerism. Isomerism.
方案二：三环化合物
Scheme 2: Tricyclic compounds
在该方案中，环B具有如下结构：r、p、q为1-3的整数；Z1、Z2、Z3独立地选自CH或N，且最多一个为N；为单键或双键；当为单键时，Z4为CH2或O，Z5为CH2或NH；当为双键时，Z4为CH，Z5为CH或N；Z6为NH或O；环B中任选1个环节碳原子被氧取代。环B的环节C原子可以被氧取代，形成羰基。In this scheme, ring B has the following structure: r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH, Z 5 is CH or N; Z 6 is NH or O; any one carbon atom in ring B is replaced by oxygen. The C atom of ring B can be replaced by oxygen to form a carbonyl group.
在一些优选的情况下，环B是r或q为1-3的整数；Z1、Z2或Z3独立地选自CH或N，且最多一个为N；为单键或双键；当为单键时Z4为CH2或O；当为双键时Z4为CH；环B任选地被1-2个R4取代；In some preferred cases, Ring B is r or q is an integer from 1 to 3; Z 1 , Z 2 or Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O; when When it is a double bond, Z 4 is CH; Ring B is optionally replaced by 1-2 R 4 ;
在一些更优选的情况下，环B具有如下结构：其中，r取1或2，例如 当环B为 进一步地为时，通常由*端连接环A，**端连接L2。In some more preferred cases, Ring B has the following structure: Among them, r takes 1 or 2, for example When ring B is further for When, the first end is usually connected to ring A, and the upper end is connected to L 2 .
此时，R1可取4-6元环烷基或含有1-2个选自N、O等杂原子的杂环烷基，例如环丁基、环戊基、环己基、氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、四氢吡咯基、六氢吡啶基、吗啉；进一步地，R1可任选地被1-2个R5取代，R5可以是羟基、卤素、C1-3烷基、-CH2OH、-C(CH3)2OH。本方案并未限定L1及R5在R1上的连接位点，因此这两个连接位点可以是邻位、间位或对位，优选对位。更进一步地，根据R1的不同，取代基及取代位点的不同，可能存在立体异构，包括顺反异构及对映异构。通常情况下，R1为R5为羟基或不被取代，取代位点为对位取代。At this time, R 1 can be a 4-6 membered cycloalkyl group or a heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, etc., such as cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl , tetrahydrofuryl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl, hexahydropyridyl, morpholine; further, R 1 can be optionally substituted by 1-2 R 5 , and R 5 can be It is hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH. This scheme does not limit the connection sites of L 1 and R 5 on R 1 , so the two connection sites can be ortho, meta or para, preferably para. Furthermore, depending on the difference in R 1 , the substituent and the substitution site, stereoisomerism may exist, including cis-trans isomerism and enantiomerism. Typically, R 1 is R 5 is hydroxyl or unsubstituted, and the substitution position is para-substitution.
在本方案中，L2选自化学键或简单(亚)烷基，连接R2及环B。R2通常为5-6元含有1-2个选自N、O杂原子的杂环烷基，任选地被1-2个R6取代，例如R2可以是 R6优选卤素、羟基、氨基、氰基的简单取代基，也可以不取代。本方案并未限定L2及R6在R4上的连接位点，因此这两个连接位点可以是邻位、间位或对位，优选对位。更进一步地，根据R2的不同，取代基及取代位点的不同，可能存在立体异构，包括顺反异构及对映异构。通常情况下，R2为H或 In this scheme, L 2 is selected from a chemical bond or a simple ()alkylene group, connecting R 2 and Ring B. R 2 is usually a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 , for example, R 2 can be R 6 is preferably a simple substituent of halogen, hydroxyl, amino, or cyano, and may not be substituted. This scheme does not limit the connection sites of L 2 and R 6 on R 4 , so the two connection sites can be ortho, meta or para, preferably para. Furthermore, depending on the difference in R 2 , substituents and substitution sites, stereoisomerism may exist, including cis-trans isomerism and enantiomerism. Typically, R2 is H or
具体实施方式Detailed ways
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。The present invention will be further described in detail below with reference to specific examples, but the present invention is not limited to the following examples.
实施例使用的部分制备条件如下：Some of the preparation conditions used in the examples are as follows:
制备Pre-HPLC条件：仪器：GILSON-GX281；波长：220nm&254nm；柱型号：Waters X-bridge(30×100mm,10μm)或Luna C18(30×75mm,3μm)或Luna C18(30×75mm,3μm)；流动相：A：10mM碳酸氢铵或H2O(0.1％甲酸)或H2O(0.1％三氟乙酸)，B：乙腈；运行时间：15min；流速：25mL/min。Preparation Pre-HPLC conditions: Instrument: GILSON-GX281; Wavelength: 220nm&254nm; Column model: Waters X-bridge (30×100mm, 10μm) or Luna C18 (30×75mm, 3μm) or Luna C18 (30×75mm, 3μm) ;Mobile phase: A: 10mM ammonium bicarbonate or H 2 O (0.1% formic acid) or H 2 O (0.1% trifluoroacetic acid), B: acetonitrile; running time: 15min; flow rate: 25mL/min.
反向柱纯化使用C18反向硅胶柱(Spherical C18,40-60μm,40g-120g)，以水/乙腈(95/5～30/70)为流动相。Reverse column purification uses a C18 reverse silica gel column (Spherical C18, 40-60μm, 40g-120g), with water/acetonitrile (95/5~30/70) as the mobile phase.
本发明中一些中间体的合成步骤如下：The synthesis steps of some intermediates in the present invention are as follows:
中间体1：(1R,5S)-1-(4-溴苯基)-3-(四氢-2H-吡喃-4-基)-3-氮杂双环[3.1.0]己烷
Intermediate 1: (1R,5S)-1-(4-bromophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane
中间体1的合成参考专利CN109641871B中实例34中间体A3的合成步骤。The synthesis of intermediate 1 refers to the synthesis steps of intermediate A3 in Example 34 of patent CN109641871B.
中间体2：(1S,5R)-1-(4-溴苯基)-3-(四氢-2H-吡喃-4-基)-3-氮杂双环[3.1.0]己烷
Intermediate 2: (1S,5R)-1-(4-bromophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane
参照中间体1的合成方法，第一步用(R)-2-(氯甲基)环氧乙烷替代(S)-2-(氯甲基)环氧乙烷为原料，经过类似的步骤得到中间体2。Referring to the synthesis method of intermediate 1, in the first step, (R)-2-(chloromethyl)oxirane is used as the raw material instead of (S)-2-(chloromethyl)oxirane, and similar steps are followed. Intermediate 2 was obtained.
中间体3：6-溴-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺
Intermediate 3: 6-bromo-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
(1)6-溴吡唑[1,5-a]嘧啶-3-羧酸(1)6-bromopyrazole[1,5-a]pyrimidine-3-carboxylic acid
将5-氨基-1H-吡唑-4-羧酸(5g,39mmol)，2-溴丙二醛(6g,39mmol)溶于乙醇和乙酸(10mL/30mL)的混合溶剂中。反应液在氮气保护下升温至90℃搅拌4小时。反应液降温，固体析出，过滤得到标题化合物(8.5g,黄色固体)，收率：89％。MS(ESI):m/z 241.9[M+H]+.Dissolve 5-amino-1H-pyrazole-4-carboxylic acid (5g, 39mmol) and 2-bromomalondialdehyde (6g, 39mmol) in a mixed solvent of ethanol and acetic acid (10mL/30mL). The reaction solution was heated to 90°C under nitrogen protection and stirred for 4 hours. The reaction solution was cooled down and a solid precipitated. The title compound (8.5 g, yellow solid) was obtained by filtration, yield: 89%. MS(ESI):m/z 241.9[M+H] + .
(5)6-溴-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(5)6-Bromo-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
将6-溴吡唑[1,5-a]嘧啶-3-羧酸(50mg,0.2mmol)溶于N,N-二甲基甲酰胺(1mL)中,加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(37mg,0.2mmol)，HATU(152mg,0.4mmol)和N,N-二异丙基乙胺(77mg,0.6mmol)，室温搅拌过夜。反应液经Prep-HPLC纯化得到标题化合物(60mg,白色固体)，收率：80％。MS(ESI):m/z 364.9[M+H]+.Dissolve 6-bromopyrazole[1,5-a]pyrimidine-3-carboxylic acid (50mg, 0.2mmol) in N,N-dimethylformamide (1mL), and add 4-aminobicyclo[2.2.2 ] Octan-1-ol hydrochloride (37 mg, 0.2 mmol), HATU (152 mg, 0.4 mmol) and N,N-diisopropylethylamine (77 mg, 0.6 mmol) were stirred at room temperature overnight. The reaction solution was purified by Prep-HPLC to obtain the title compound (60 mg, white solid), yield: 80%. MS(ESI):m/z 364.9[M+H] + .
中间体4：2-氨基-5-溴-N-(四氢-2H-吡喃-4-基)烟酰胺
Intermediate 4: 2-amino-5-bromo-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
在20℃下，向2-氨基-5-溴烟酸(1.00g,4.61mmol)的N,N-二甲基甲酰胺(10mL)溶液中依次加入HATU(1.93g,5.07mmol)和N,N-二异丙基乙胺(714mg,5.53mmol)。反应液在20℃下搅拌0.5小时，加入四氢-2H-吡喃-4-胺(699mg,6.91mmol)。反应液在20℃下搅拌12小时。反应液用水(40mL)稀释，用乙酸乙酯(40mL x 3)萃取。有机相用饱和食盐水(30mL)洗涤，减压浓缩得到标题化合物(1.00g,白色固体)。MS(ESI):m/z 300.0[M+H]+.At 20°C, HATU (1.93g, 5.07mmol) and N were added successively to a solution of 2-amino-5-bromonicotinic acid (1.00g, 4.61mmol) in N,N-dimethylformamide (10mL). N-diisopropylethylamine (714 mg, 5.53 mmol). The reaction solution was stirred at 20°C for 0.5 hours, and tetrahydro-2H-pyran-4-amine (699 mg, 6.91 mmol) was added. The reaction solution was stirred at 20°C for 12 hours. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic phase was washed with saturated brine (30 mL) and concentrated under reduced pressure to obtain the title compound (1.00 g, white solid). MS(ESI):m/z 300.0[M+H] + .
中间体5：2-氨基-5-溴-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺
Intermediate 5: 2-amino-5-bromo-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)nicotinamide
将2-氨基-5-溴烟酸(50mg,230.39umol)溶于N,N-二甲基甲酰胺(1.0mL)中，依次加入HATU(96mg,253.43umol)和N,N-二异丙基乙胺(89mg,691.18umol)。反应液在20℃下搅拌30分钟，加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(40mg,230.39umol)。最后将反应液在20℃下搅拌12小时。向反应液中加入食盐水(10mL)，用乙酸乙酯(10mL x 3)萃取。有机相用食盐水(10mL)洗涤，减压浓缩得到标题化合物(50mg,橙色固体)，粗品直接用于下一步。MS(ESI):m/z 340.1[M+H]+.Dissolve 2-amino-5-bromonicotinic acid (50 mg, 230.39umol) in N,N-dimethylformamide (1.0mL), then add HATU (96mg, 253.43umol) and N,N-diisopropyl Ethylamine (89mg, 691.18umol). The reaction solution was stirred at 20°C for 30 minutes, and 4-aminobicyclo[2.2.2]octane-1-ol hydrochloride (40 mg, 230.39umol) was added. Finally, the reaction solution was stirred at 20°C for 12 hours. Brine (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL) and concentrated under reduced pressure to obtain the title compound (50 mg, orange solid). The crude product was used directly in the next step. MS(ESI):m/z 340.1[M+H] + .
实施例1Example 1
化合物1：3-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-6-(4-((1R,5S)-3-(四氢-2H-吡喃-4-基)-3-氮杂双环[3.1.0]己烷-1-基)苯基)吡嗪-2-甲酰胺Compound 1: 3-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4) -yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)pyrazine-2-carboxamide
(1)3-氨基-6-溴-N-(4-羟基双环[2.2.2]辛-1-基)吡嗪-2-甲酰胺(1)3-Amino-6-bromo-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazine-2-carboxamide
将3-氨基-6-溴吡嗪-2-羧酸(50mg,229.35umol)溶于N,N-二甲基甲酰胺(1mL)中，依次加入N,N-二异丙基乙胺(88.92mg,688.05umol)和HATU(95.93mg,252.28umol)。反应液在20℃下搅拌30分钟后，向反应体系中加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(40.75mg,229.35umol)，反应液在20℃下搅拌16小时。将反应液缓慢倒入饱和氯化铵溶液(3mL)中，用乙酸乙酯(2mL x 3)萃取。合并有机相，用饱和食盐水(3mL x 2)洗涤，用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经Prep-TLC(石油醚/乙酸乙酯＝0/1)纯化得到标题化合物(30mg,白色固体)，收率：38.34％。MS(ESI):m/z 341.1[M+H]+.Dissolve 3-amino-6-bromopyrazine-2-carboxylic acid (50 mg, 229.35umol) in N,N-dimethylformamide (1mL), and add N,N-diisopropylethylamine ( 88.92mg, 688.05umol) and HATU (95.93mg, 252.28umol). After the reaction solution was stirred at 20°C for 30 minutes, 4-aminobicyclo[2.2.2]octane-1-ol hydrochloride (40.75mg, 229.35umol) was added to the reaction system, and the reaction solution was stirred at 20°C for 16 Hour. The reaction solution was slowly poured into saturated ammonium chloride solution (3 mL), and extracted with ethyl acetate (2 mL x 3). The organic phases were combined, washed with saturated brine (3mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product. The crude product was purified by Prep-TLC (petroleum ether/ethyl acetate = 0/1) to obtain the title compound (30 mg, white solid), yield: 38.34%. MS(ESI):m/z 341.1[M+H] + .
(2)(1R,5S)-3-(四氢-2H-吡喃-4-基)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-3-氮杂双环[3.1.0]己烷(2)(1R,5S)-3-(Tetrahydro-2H-pyran-4-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane
将中间体1(0.05g,155.16umol)溶于1,4-二氧六环(0.5mL)中，依次加入联硼酸频那醇酯(47.28mg,186.20umol)，醋酸钾(45.68mg,465.49umol)和Pd(dppf)Cl2(12.67mg,15.52umol)。体系用氮气置换3次，然后升温至80℃搅拌12小时。反应液冷却至室温，用乙酸乙酯(5mL)稀释，硅藻土过滤，滤饼用乙酸乙酯(3mL x 2)洗涤，滤液减压浓缩得到粗品。粗品经Prep-TLC(石油醚/乙酸乙酯＝0/1)纯化得到标题化合物(0.03g,淡黄色固体)，收率：52.35％。MS(ESI):m/z 370.3[M+H]+.Dissolve intermediate 1 (0.05g, 155.16umol) in 1,4-dioxane (0.5mL), add pinacol diborate (47.28mg, 186.20umol) and potassium acetate (45.68mg, 465.49) in sequence umol) and Pd(dppf)Cl 2 (12.67mg, 15.52umol). The system was replaced with nitrogen three times, then the temperature was raised to 80°C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (3 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-TLC (petroleum ether/ethyl acetate = 0/1) to obtain the title compound (0.03 g, light yellow solid), yield: 52.35%. MS(ESI):m/z 370.3[M+H] + .
(3)3-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-6-(4-((1R,5S)-3-(四氢-2H-吡喃-4-基)-3-氮杂双环[3.1.0]己烷-1-基)苯基)吡嗪-2-甲酰胺(3)3-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4) -yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)pyrazine-2-carboxamide
将(1R,5S)-3-(四氢-2H-吡喃-4-基)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-3-氮杂双环[3.1.0]己烷(0.03g,81.23umol)溶于1,4-二氧六环(3mL)和水(0.3mL)的混合溶液中，依次加入3-氨基-6-溴-N-(4-羟基双环[2.2.2]辛-1-基)吡嗪-2-甲酰胺(0.03g,87.92umol)，碳酸钾(33.68mg,243.70umol)和Pd(dppf)Cl2(5.94mg,8.12umol)。体系用氮气置换3次，然后升温至100℃搅拌12小时。反应液冷却至室温，用乙酸乙酯(5mL)稀释，硅藻土过滤，滤饼用乙酸乙酯(3mL x 2)洗涤，滤液减压浓缩得到粗品。粗品经Prep-HPLC纯化得到标题化合物(9.0mg,棕色固体)，收率：20.79％。MS(ESI):m/z 504.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.94-7.84(m,3H),7.64-7.53(m,2H),7.24(d,J＝7.7Hz,2H),4.36(s,1H),3.93-3.73(m,2H),3.44-3.36(m,1H),3.31-3.23(m,2H),3.09(d,J＝7.7Hz,1H),2.68-2.55(m,1H),2.46(d,J＝5.6Hz,1H),2.38-2.30(m,1H),2.10-2.03(m,6H),1.90-1.71(m,3H),1.69-1.62(m,6H),1.44-1.28(m,3H),0.88-0.65(m,1H).(1R,5S)-3-(Tetrahydro-2H-pyran-4-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa Borol-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane (0.03g, 81.23umol) was dissolved in 1,4-dioxane (3mL) and water (0.3 mL), add 3-amino-6-bromo-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazine-2-carboxamide (0.03g, 87.92umol) in sequence, Potassium carbonate (33.68mg, 243.70umol) and Pd(dppf)Cl 2 (5.94mg, 8.12umol). The system was replaced with nitrogen three times, then the temperature was raised to 100°C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (3 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the title compound (9.0 mg, brown solid), yield: 20.79%. MS(ESI):m/z 504.3[M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.79(s,1H),7.94-7.84(m,3H),7.64-7.53(m ,2H),7.24(d,J=7.7Hz,2H),4.36(s,1H),3.93-3.73(m,2H),3.44-3.36(m,1H),3.31-3.23(m,2H), 3.09(d,J＝7.7Hz,1H),2.68-2.55(m,1H),2.46(d,J＝5.6Hz,1H),2.38-2.30(m,1H),2.10-2.03(m,6H) ,1.90-1.71(m,3H),1.69-1.62(m,6H),1.44-1.28(m,3H),0.88-0.65(m,1H).
实施例2～实施例8Example 2 to Example 8
化合物2～化合物8的制备参照实施例1的方法，采用相应的原料和中间体经类似的步骤合成得到。

Compounds 2 to 8 were prepared by referring to the method of Example 1, and were synthesized through similar steps using corresponding raw materials and intermediates.

实施例9Example 9
化合物9：N-(4-羟基双环[2.2.2]辛-1-基)-6-(4-((1R,5S)-3-(四氢-2H-吡喃-4-基)-3-氮杂双环[3.1.0]己烷-1-基)苯基)吡唑并[1,5-a]嘧啶-3-甲酰胺Compound 9: N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)- 3-Azabicyclo[3.1.0]hexan-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
将(1R,5S)-3-(四氢-2H-吡喃-4-基)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-3-氮杂双环[3.1.0]己烷(0.03g,81.23umol,实施例1第2步)溶于1,4-二氧六环(3mL)和水(0.3mL)的混合溶液中，依次加入中间体3(0.035g,95.83umol)，碳酸钾(33.68mg,243.70umol)和Pd(dppf)Cl2(5.94mg,8.12umol)。体系用氮气置换3次，然后升温至100℃搅拌12小时。反应液冷却至室温，用乙酸乙酯(5mL)稀释，硅藻土过滤，滤饼用乙酸乙酯(3mL x 2)洗涤，滤液减压浓缩得到粗品。粗品经Prep-HPLC纯化得到标题化合物(7mg,淡黄色固体)，收率：16.10％。MS(ESI):m/z 528.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.62(d,J＝2.0Hz,1H),9.17(d,J＝2.0Hz,1H),8.52(s,1H),7.80(d,J＝8.2Hz,2H),7.59(s,1H),7.31(d,J＝8.2Hz,2H),4.36(s,1H),3.93-3.77(m,2H),3.41(d,J＝8.5Hz,1H),3.28(brs,2H),3.10(d,J＝8.6Hz,1H),2.59(d,J＝8.2Hz,1H),2.47-2.43(m,1H),2.36-2.30(m,1H),2.10-2.02(m,6H),1.90(td,J＝7.6,3.9,Hz,1H),1.85-1.73(m,2H),1.70-1.62(m,6H),1.39-1.34(m,3H),0.84-0.76(m,1H).(1R,5S)-3-(Tetrahydro-2H-pyran-4-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa Borol-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane (0.03g, 81.23umol, Example 1 step 2) was dissolved in 1,4-dioxane (3mL) and water (0.3mL), add intermediate 3 (0.035g, 95.83umol), potassium carbonate (33.68mg, 243.70umol) and Pd(dppf)Cl 2 (5.94mg, 8.12umol) in sequence. . The system was replaced with nitrogen three times, then the temperature was raised to 100°C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (3 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the title compound (7 mg, light yellow solid), yield: 16.10%. MS (ESI): m/z 528.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.62 (d, J = 2.0 Hz, 1H), 9.17 (d, J = 2.0 Hz, 1H),8.52(s,1H),7.80(d,J＝8.2Hz,2H),7.59(s,1H),7.31(d,J＝8.2Hz,2H),4.36(s,1H),3.93- 3.77(m,2H),3.41(d,J＝8.5Hz,1H),3.28(brs,2H),3.10(d,J＝8.6Hz,1H),2.59(d,J＝8.2Hz,1H), 2.47-2.43(m,1H),2.36-2.30(m,1H),2.10-2.02(m,6H),1.90(td,J＝7.6,3.9,Hz,1H),1.85-1.73(m,2H) ,1.70-1.62(m,6H),1.39-1.34(m,3H),0.84-0.76(m,1H).
实施例10Example 10
化合物10：2-氨基-N-((3R,6S)-6-(2-羟基丙-2-基)四氢-2H-吡喃-3-基)-5-(4-((1R,5S)-3-(四氢-2H-吡喃-4-基)-3-氮杂双环[3.1.0]己烷-1-基)苯基)烟酰胺Compound 10: 2-amino-N-((3R,6S)-6-(2-hydroxyprop-2-yl)tetrahydro-2H-pyran-3-yl)-5-(4-((1R, 5S)-3-(Tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide
(1)2-氨基-5-溴-N-((3R,6S)-6-(2-羟基丙-2-基)四氢-2H-吡喃-3-基)烟酰胺(1)2-Amino-5-bromo-N-((3R,6S)-6-(2-hydroxyprop-2-yl)tetrahydro-2H-pyran-3-yl)nicotinamide
将2-氨基-5-溴烟酸(143mg,659umol)，HATU(183mg,483umol)和N,N-二异丙基乙胺(198mg,1.54mmol)溶于N,N-二甲基甲酰胺(0.7mL)中。反应液在20℃下搅拌30分钟，加入2-((2S,5R)-5-氨基四氢-2H-吡喃-2-基)丙-2-醇(70.0mg,439umol)。反应液继续在20℃下搅拌12小时。反应液过滤，滤液经Prep-HPLC纯化得到标题化合物(60.0mg,白色固体)，收率：38.1％。MS(ESI):m/z 358.1[M+H]+.1H NMR(400MHz, DMSO-d6)δ8.25(d,J＝7.7Hz,1H),8.15(d,J＝2.4Hz,1H),8.09(d,J＝2.3Hz,1H),7.22(s,2H),4.24(s,1H),3.94-3.77(m,2H),3.10(t,J＝10.5Hz,1H),2.97(dd,J＝11.1,1.5Hz,1H),1.96(d,J＝11.7Hz,1H),1.80(d,J＝12.3Hz,1H),1.56-1.51(m,1H),1.43-1.30(m,1H),1.09(s,3H),1.04(s,3H).Dissolve 2-amino-5-bromonicotinic acid (143mg, 659umol), HATU (183mg, 483umol) and N,N-diisopropylethylamine (198mg, 1.54mmol) in N,N-dimethylformamide (0.7mL). The reaction solution was stirred at 20°C for 30 minutes, and 2-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)propan-2-ol (70.0 mg, 439umol) was added. The reaction solution was continued to stir at 20°C for 12 hours. The reaction solution was filtered, and the filtrate was purified by Prep-HPLC to obtain the title compound (60.0 mg, white solid), yield: 38.1%. MS(ESI):m/z 358.1[M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.25(d,J＝7.7Hz,1H),8.15(d,J＝2.4Hz,1H),8.09(d,J＝2.3Hz,1H),7.22(s,2H), 4.24(s,1H),3.94-3.77(m,2H),3.10(t,J＝10.5Hz,1H),2.97(dd,J＝11.1,1.5Hz,1H),1.96(d,J＝11.7Hz ,1H),1.80(d,J=12.3Hz,1H),1.56-1.51(m,1H),1.43-1.30(m,1H),1.09(s,3H),1.04(s,3H).
(2)2-氨基-N-((3R,6S)-6-(2-羟基丙-2-基)四氢-2H-吡喃-3-基)-5-(4-((1R,5S)-3-(四氢-2H-吡喃-4-基)-3-氮杂双环[3.1.0]己烷-1-基)苯基)烟酰胺(2)2-Amino-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-5-(4-((1R, 5S)-3-(Tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide
将2-氨基-5-溴-N-((3R,6S)-6-(2-羟基丙-2-基)四氢-2H-吡喃-3-基)烟酰胺(69.8mg,194umol)和(1R,5S)-3-(四氢-2H-吡喃-4-基)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-3-氮杂双环[3.1.0]己烷(60.0mg,162umol,实施例1第2步)溶于1,4-二氧六环(0.6mL)和水(0.12mL)的混合溶剂中，加入碳酸钾(44.9mg,324umol)。反应体系用氮气置换三次，并在氮气保护下向反应液中加入Pd(dppf)Cl2(11.8mg,16.2umol)。反应液升温到80℃搅拌12小时。反应液降至室温，过滤，滤液浓缩。粗品经Prep-HPLC纯化得到标题化合物(33.6mg,棕色固体)，收率：38.07％。MS(ESI):m/z 521.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.3Hz,1H),8.29(d,J＝7.8Hz,1H),8.13(d,J＝2.1Hz,1H),7.58(d,J＝8.3Hz,2H),7.23(d,J＝8.3Hz,2H),7.13(s,2H),4.26(s,1H),3.98-3.81(m,4H),3.39(d,J＝8.5Hz,1H),3.31-3.25(m,2H),3.18-3.06(m,2H),2.99(d,J＝10.1Hz,1H),2.56(d,J＝8.6Hz,2H),2.35-2.27(m,1H),2.04-1.97(m,1H),1.88-1.71(m,4H),1.59-1.57(m,1H),1.46-1.33(m,3H),1.31(t,J＝3.9Hz,1H),1.11(s,3H),1.05(s,3H),0.76(dd,J＝7.6,3.4Hz,1H).2-Amino-5-bromo-N-((3R,6S)-6-(2-hydroxyprop-2-yl)tetrahydro-2H-pyran-3-yl)nicotinamide (69.8 mg, 194umol) and (1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa Borol-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane (60.0 mg, 162umol, step 2 of Example 1) was dissolved in 1,4-dioxane ( To a mixed solvent of 0.6 mL) and water (0.12 mL), potassium carbonate (44.9 mg, 324 umol) was added. The reaction system was replaced with nitrogen three times, and Pd(dppf)Cl 2 (11.8 mg, 16.2umol) was added to the reaction solution under nitrogen protection. The reaction solution was heated to 80°C and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by Prep-HPLC to obtain the title compound (33.6 mg, brown solid), yield: 38.07%. MS (ESI): m/z 521.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.39 (d, J = 2.3Hz, 1H), 8.29 (d, J = 7.8Hz, 1H),8.13(d,J＝2.1Hz,1H),7.58(d,J＝8.3Hz,2H),7.23(d,J＝8.3Hz,2H),7.13(s,2H),4.26(s, 1H),3.98-3.81(m,4H),3.39(d,J＝8.5Hz,1H),3.31-3.25(m,2H),3.18-3.06(m,2H),2.99(d,J＝10.1Hz ,1H),2.56(d,J＝8.6Hz,2H),2.35-2.27(m,1H),2.04-1.97(m,1H),1.88-1.71(m,4H),1.59-1.57(m,1H) ),1.46-1.33(m,3H),1.31(t,J＝3.9Hz,1H),1.11(s,3H),1.05(s,3H),0.76(dd,J＝7.6,3.4Hz,1H) .
实施例11～实施例14Example 11 to Example 14
化合物11～化合物14的制备参照实施例10的方法，采用相应的原料和中间体经类似的步骤合成得到。
Compounds 11 to 14 were prepared by referring to the method of Example 10, and were synthesized through similar steps using corresponding raw materials and intermediates.
实施例15Example 15
化合物15：6-(4-(4-(二甲基氨基甲酰基)哌嗪-1-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺Compound 15: 6-(4-(4-(dimethylcarbamoyl)piperazin-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazole And[1,5-a]pyrimidine-3-carboxamide
(1)4-(4-溴苯基)-N,N-二甲基哌嗪-1-甲酰胺(1)4-(4-bromophenyl)-N,N-dimethylpiperazine-1-carboxamide
将1-(4-溴苯基)哌嗪(1g,4.1mmol)和三乙胺(828mg,8.2mmol)溶于二氯甲烷(5mL)中。在0℃下滴加二甲氨基甲酰氯(538mg,4.9mmol)，升温至室温搅拌反应过夜。向反应体系中加入水(20mL)，混合液使用乙酸乙酯(40mLx2)萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(100％乙酸乙酯)纯化得到标题化合物(1.2g,白色固体)，收率：92％。MS(ESI):m/z 311.9[M+H]+.1-(4-Bromophenyl)piperazine (1 g, 4.1 mmol) and triethylamine (828 mg, 8.2 mmol) were dissolved in dichloromethane (5 mL). Dimethylcarbamoyl chloride (538 mg, 4.9 mmol) was added dropwise at 0°C, and the temperature was raised to room temperature and the reaction was stirred overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (100% ethyl acetate) to obtain the title compound (1.2 g, white solid), yield: 92%. MS(ESI):m/z 311.9[M+H] + .
(2)N,N-二甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪-1-甲酰胺(2)N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )piperazine-1-carboxamide
将4-(4-溴苯基)-N,N-二甲基哌嗪-1-甲酰胺(100mg,0.32mmol)和联硼酸频那醇酯(90mg,0.35mmol)溶于1,4-二氧六环(5mL)中，加入PdCl2(dppf)(25mg,0.03mmol)和醋酸钾(63mg,0.64mmol)，反应体系在100℃氮气条件下搅拌反应过夜。反应液过滤，减压浓缩，残留物经反相柱纯化得到标题化合物(40mg, 黄色固体)，收率：35％。MS(ESI):m/z 360.2[M+H]+.Dissolve 4-(4-bromophenyl)-N,N-dimethylpiperazine-1-carboxamide (100 mg, 0.32 mmol) and pinacol diborate (90 mg, 0.35 mmol) in 1,4- To dioxane (5 mL), PdCl 2 (dppf) (25 mg, 0.03 mmol) and potassium acetate (63 mg, 0.64 mmol) were added, and the reaction system was stirred and reacted overnight at 100°C under nitrogen conditions. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by reverse-phase column to obtain the title compound (40 mg, yellow solid), yield: 35%. MS(ESI):m/z 360.2[M+H] + .
(3)6-(4-(4-(二甲基氨基甲酰基)哌嗪-1-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(3)6-(4-(4-(Dimethylcarbamoyl)piperazin-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazole And[1,5-a]pyrimidine-3-carboxamide
将N,N-二甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪-1-甲酰胺(40mg,0.11mmol)和中间体3(40mg,0.11mmol)溶于1,4-二氧六环和水(10mL/2mL)的混合溶剂中，加入PdCl2(dppf)(8mg,0.01mmol)和碳酸钾(30mg,0.22mmol)。反应液在氮气保护下加热至100℃搅拌过夜。反应液旋干，甲醇溶解，过滤，减压浓缩。残留物经Prep-HPLC纯化得到标题化合物(5.9mg,白色固体)，收率：10％。MS(ESI):m/z 518.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.53(d,J＝2.0Hz,1H),9.15(d,J＝2.0Hz,1H),8.48(s,1H),7.77(d,J＝8.8Hz,2H),7.58(s,1H),7.09(d,J＝9.2Hz,2H),4.34(s,1H),3.27-3.25(m,8H),2.79(s,6H),2.07-2.04(m,6H),1.67-1.63(m,6H).N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piper Azine-1-carboxamide (40 mg, 0.11 mmol) and intermediate 3 (40 mg, 0.11 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (10 mL/2 mL), and PdCl 2 (dppf) was added (8mg, 0.01mmol) and potassium carbonate (30mg, 0.22mmol). The reaction solution was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was spun to dryness, dissolved in methanol, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the title compound (5.9 mg, white solid), yield: 10%. MS (ESI): m/z 518.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.53 (d, J = 2.0 Hz, 1H), 9.15 (d, J = 2.0 Hz, 1H),8.48(s,1H),7.77(d,J＝8.8Hz,2H),7.58(s,1H),7.09(d,J＝9.2Hz,2H),4.34(s,1H),3.27- 3.25(m,8H),2.79(s,6H),2.07-2.04(m,6H),1.67-1.63(m,6H).
实施例16Example 16
化合物16：4-(4-(5-((4-羟基双环[2.2.2]辛-1-基)氨基甲酰基)吡啶-3-基)苯基)-N,N-二甲基哌嗪-1-羧酰胺Compound 16: 4-(4-(5-((4-hydroxybicyclo[2.2.2]oct-1-yl)carbamoyl)pyridin-3-yl)phenyl)-N,N-dimethylpiper Azine-1-carboxamide
(1)5-(4-(4-(二甲基氨基甲酰基)哌嗪-1-基)苯基)烟酸(1)5-(4-(4-(dimethylcarbamoyl)piperazin-1-yl)phenyl)nicotinic acid
将N,N-二甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪-1-甲酰胺(72mg,0.2mmol)溶于1,4-二氧六环(5mL)溶液中，加入Pd(dppf)Cl2(14.6mg,0.02mmol)，碳酸钾(82.8mg,0.6mmol)，5-溴烟酸(32.3mg,0.16mmol)和水(1mL)。混合物在100℃氮气保护下反应18小时。减压除去溶剂，粗品用甲醇溶解后过滤，滤液经反相柱纯化得到标题化合物(24mg,无色油状物)，收率：42％。MS(ESI):m/z 355.0[M+H]+.N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piper Azine-1-carboxamide (72mg, 0.2mmol) was dissolved in 1,4-dioxane (5mL) solution, and Pd(dppf)Cl 2 (14.6mg, 0.02mmol) and potassium carbonate (82.8mg, 0.6 were added mmol), 5-bromonicotinic acid (32.3 mg, 0.16 mmol) and water (1 mL). The mixture was reacted at 100°C under nitrogen protection for 18 hours. The solvent was removed under reduced pressure, and the crude product was dissolved in methanol and filtered. The filtrate was purified by reverse-phase column to obtain the title compound (24 mg, colorless oil), yield: 42%. MS(ESI):m/z 355.0[M+H] + .
(2)4-(4-(5-((4-羟基双环[2.2.2]辛-1-基)氨基甲酰基)吡啶-3-基)苯基)-N,N-二甲基哌嗪-1-羧酰胺(2)4-(4-(5-((4-hydroxybicyclo[2.2.2]oct-1-yl)carbamoyl)pyridin-3-yl)phenyl)-N,N-dimethylpiper Azine-1-carboxamide
将5-(4-(4-(二甲基氨基甲酰基)哌嗪-1-基)苯基)烟酸(24mg,0.068mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(12mg,0.068mmol)，HATU(51.7mg,0.136mmol)和N,N-二异丙基乙胺(43.9mg,0.34mmol)。反应液在室温下搅拌2小时。用滤膜过滤反应液，滤液经Prep-HPLC纯化得到标题化合物(13.8mg,白色固体)，收率：42％。MS(ESI):m/z 478.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.92(d,J＝2.0Hz,1H),8.78(d,J＝2.0Hz,1H),8.25(t,J＝2.2Hz,1H),7.91(s,1H),7.68(d,J＝8.8Hz,2H),7.08(d,J＝9.2Hz,2H),4.30(s,1H),3.27-3.24(m,8H),2.79(s,6H),2.07-2.03(m,6H),1.65-1.60(m,6H).Dissolve 5-(4-(4-(dimethylcarbamoyl)piperazin-1-yl)phenyl)nicotinic acid (24 mg, 0.068 mmol) in N,N-dimethylformamide (2 mL) , add 4-aminobicyclo[2.2.2]octane-1-ol hydrochloride (12mg, 0.068mmol), HATU (51.7mg, 0.136mmol) and N,N-diisopropylethylamine (43.9mg, 0.34mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered with a filter membrane, and the filtrate was purified by Prep-HPLC to obtain the title compound (13.8 mg, white solid), yield: 42%. MS (ESI): m/z 478.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.92 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H),8.25(t,J＝2.2Hz,1H),7.91(s,1H),7.68(d,J＝8.8Hz,2H),7.08(d,J＝9.2Hz,2H),4.30(s, 1H),3.27-3.24(m,8H),2.79(s,6H),2.07-2.03(m,6H),1.65-1.60(m,6H).
实施例17Example 17
化合物17：6-(4-(4-(二甲基氨基甲酰基)哌嗪-1-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)吡嗪-2-甲酰胺(1)6-(4-(4-(二甲基氨基甲酰基)哌嗪-1-基)苯基)吡嗪-2-羧酸Compound 17: 6-(4-(4-(dimethylcarbamoyl)piperazin-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazine -2-Carboxamide(1)6-(4-(4-(dimethylcarbamoyl)piperazin-1-yl)phenyl)pyrazine-2-carboxylic acid
参照实施例16步骤(1)的方法，以6-溴吡嗪-2-羧酸甲酯(110mg,0.5mmol)为原料，得到标题化合物(30mg,绿色固体)，收率：17.5％。MS(ESI):m/z 356.0[M+H]+.Referring to the method of step (1) in Example 16, using 6-bromopyrazine-2-carboxylic acid methyl ester (110 mg, 0.5 mmol) as raw material, the title compound (30 mg, green solid) was obtained, yield: 17.5%. MS(ESI):m/z 356.0[M+H] + .
(2)6-(4-(4-(二甲基氨基甲酰基)哌嗪-1-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)吡嗪-2-甲酰胺(2)6-(4-(4-(Dimethylcarbamoyl)piperazin-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazine -2-carboxamide
参照实施例16步骤(2)的方法，以6-(4-(4-(二甲基氨基甲酰基)哌嗪-1-基)苯基)吡嗪-2-羧酸(30mg,0.08mmol)和4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(11mg,0.08mmol)为原料，得到标题化合物(13mg,白色固体)，收率：32.5％。MS(ESI):m/z 479.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.92(s,1H),8.13(d,J＝8.8Hz,2H),7.89(s,1H),7.09(d,J＝8.8Hz,2H),4.35(s,1H),3.31-3.26(m,8H),2.79(s,6H),2.11-2.07(m,6H),1.67-1.63(m,6H).Referring to the method of step (2) of Example 16, 6-(4-(4-(dimethylcarbamoyl)piperazin-1-yl)phenyl)pyrazine-2-carboxylic acid (30 mg, 0.08 mmol ) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (11 mg, 0.08 mmol) were used as raw materials to obtain the title compound (13 mg, white solid), yield: 32.5%. MS (ESI): m/z 479.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.33 (s, 1H), 8.92 (s, 1H), 8.13 (d, J = 8.8 Hz,2H),7.89(s,1H),7.09(d,J＝8.8Hz,2H),4.35(s,1H),3.31-3.26(m,8H),2.79(s,6H),2.11-2.07 (m,6H),1.67-1.63(m,6H).
实施例18Example 18
化合物18：6-(4-(1-乙基哌啶-4-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺Compound 18: 6-(4-(1-ethylpiperidin-4-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
(1)4-(4-溴苯基)-1-乙基哌啶(1)4-(4-bromophenyl)-1-ethylpiperidine
向4-(4-溴苯基)哌啶(848mg,3.53mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入N,N-二异丙基乙胺(1.36g,10.6mmol)和碘乙烷(661mg,4.24mmol)，室温反应过夜。将反应液倒入水(100mL)中，用乙酸乙酯(2x 40mL)萃取，有机相合并后用饱和食盐水(2x 50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到标题化合物(540mg,淡黄色固体)，收率：57％。MS(ESI):m/z 267.9[M+H]+.To a solution of 4-(4-bromophenyl)piperidine (848 mg, 3.53 mmol) in N,N-dimethylformamide (15 mL) was added N,N-diisopropylethylamine (1.36 g, 10.6 mmol ) and ethyl iodide (661 mg, 4.24 mmol), react at room temperature overnight. The reaction solution was poured into water (100mL), extracted with ethyl acetate (2x 40mL), the organic phases were combined, washed with saturated brine (2x 50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound ( 540 mg, light yellow solid), yield: 57%. MS(ESI):m/z 267.9[M+H] + .
(2)1-乙基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌啶(2)1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine
向4-(4-溴苯基)-1-乙基哌啶(214mg,0.8mmol)的1,4-二氧六环(10mL)溶液中依次加入Pd(dppf)Cl2(58mg,0.08mmol)，醋酸钾(235mg,2.4mmol)和联硼酸频那醇酯(244mg,0.96mmol)，反应液在氮气保护下加热至100℃搅拌18小时。减压除去溶剂，粗品经柱层析(二氯甲烷/甲醇＝20/1)纯化得到标题化合物(200mg,棕色油状物)，收率：79％。MS(ESI):m/z 316.1[M+H]+.To a solution of 4-(4-bromophenyl)-1-ethylpiperidine (214 mg, 0.8 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl 2 (58 mg, 0.08 mmol). ), potassium acetate (235 mg, 2.4 mmol) and pinacol diborate (244 mg, 0.96 mmol), the reaction solution was heated to 100°C under nitrogen protection and stirred for 18 hours. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (200 mg, brown oil), yield: 79%. MS(ESI):m/z 316.1[M+H] + .
(3)6-(4-(1-乙基哌啶-4-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(3)6-(4-(1-ethylpiperidin-4-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
参照实施例15步骤(3)的方法，以1-乙基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌啶(41mg,0.13mmol)和中间体3(36.5mg,0.1mmol)为原料，得到标题化合物(16.1mg,白色固体)，收率：34％。MS(ESI):m/z 474.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.60(d,J＝2.4Hz,1H),9.15(d,J＝2.4Hz,1H),8.52(s,1H),7.81-7.79(m,2H),7.58(s,1H),7.42-7.40(m,2H),4.34(s,1H),3.01-3.98(m,2H),2.56-2.53(m,1H),2.36(q,J＝7.2Hz,2H),2.09-2.05(m,6H),2.01-1.95(m,2H),1.80-1.76(m,2H),1.74-1.70(m,1H),1.68-1.64(m,7H),1.03(t,J＝7.2Hz,3H).Referring to the method of step (3) of Example 15, 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl)piperidine (41 mg, 0.13 mmol) and intermediate 3 (36.5 mg, 0.1 mmol) were used as raw materials to obtain the title compound (16.1 mg, white solid), yield: 34%. MS (ESI): m/z 474.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.60 (d, J = 2.4Hz, 1H), 9.15 (d, J = 2.4Hz, 1H),8.52(s,1H),7.81-7.79(m,2H),7.58(s,1H),7.42-7.40(m,2H),4.34(s,1H),3.01-3.98(m,2H) ,2.56-2.53(m,1H),2.36(q,J＝7.2Hz,2H),2.09-2.05(m,6H),2.01-1.95(m,2H),1.80-1.76(m,2H),1.74 -1.70(m,1H),1.68-1.64(m,7H),1.03(t,J=7.2Hz,3H).
实施例19Example 19
化合物19：N-(4-羟基双环[2.2.2]辛-1-基)-6-(4-(1-(吡咯烷-1-基)乙基)苯基)吡唑并[1,5-a]嘧啶-3-甲酰 胺Compound 19: N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)pyrazolo[1, 5-a]pyrimidine-3-formyl amine
(1)6-(4-乙酰苯基)-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(1)6-(4-acetylphenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
将(4-乙酰苯基)硼酸(100mg,0.6mmol)和中间体3(220mg,0.6mmol)溶于1,4-二氧六环和水(10mL/2mL)的混合溶剂中，加入PdCl2(dppf)(43mg,0.06mmol)和碳酸钾(165mg,1.2mmol)，反应液在90℃氮气条件下搅拌过夜。反应液直接过滤旋干，残留物经反相柱纯化得到标题化合物(30mg,黄色固体)，收率：11.6％。MS(ESI):m/z 405.0[M+H]+.Dissolve (4-acetylphenyl)boronic acid (100 mg, 0.6 mmol) and intermediate 3 (220 mg, 0.6 mmol) in a mixed solvent of 1,4-dioxane and water (10 mL/2 mL), and add PdCl 2 (dppf) (43 mg, 0.06 mmol) and potassium carbonate (165 mg, 1.2 mmol), the reaction solution was stirred overnight at 90°C under nitrogen. The reaction solution was directly filtered and spun to dryness, and the residue was purified by reverse-phase column to obtain the title compound (30 mg, yellow solid), yield: 11.6%. MS(ESI):m/z 405.0[M+H] + .
(2)N-(4-羟基双环[2.2.2]辛-1-基)-6-(4-(1-(吡咯烷-1-基)乙基)苯基)吡唑并[1,5-a]嘧啶-3-甲酰胺(2)N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)pyrazolo[1, 5-a]pyrimidine-3-carboxamide
将6-(4-乙酰苯基)-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(30mg,0.07mmol)和吡咯烷(10mg,0.14mmol)溶于甲醇(3mL)中，反应液在50℃下搅拌0.5小时后加入氰基硼氢化钠(10mg,0.17mmol)，反应液继续在50℃下搅拌过夜。反应液经Prep-HPLC纯化得到标题化合物(5.4mg,白色固体)，收率：15.9％。MS(ESI):m/z 460.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.61(d,J＝2.4Hz,1H),9.17(d,J＝2.4Hz,1H),8.52(s,1H),7.82(d,J＝10.4Hz,2H),7.58(s,1H),7.47(d,J＝7.6Hz,2H),4.34(s,1H),2.33-2.32(m,3H),2.09-2.05(m,7H),1.68-1.64(m,11H),1.32(d,J＝6.4Hz,3H).6-(4-acetylphenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.07 mmol ) and pyrrolidine (10 mg, 0.14 mmol) were dissolved in methanol (3 mL). The reaction solution was stirred at 50°C for 0.5 hours, then sodium cyanoborohydride (10 mg, 0.17 mmol) was added, and the reaction solution was continued to stir at 50°C overnight. . The reaction solution was purified by Prep-HPLC to obtain the title compound (5.4 mg, white solid), yield: 15.9%. MS (ESI): m/z 460.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.61 (d, J = 2.4Hz, 1H), 9.17 (d, J = 2.4Hz, 1H),8.52(s,1H),7.82(d,J＝10.4Hz,2H),7.58(s,1H),7.47(d,J＝7.6Hz,2H),4.34(s,1H),2.33- 2.32(m,3H),2.09-2.05(m,7H),1.68-1.64(m,11H),1.32(d,J＝6.4Hz,3H).
实施例20Example 20
化合物20：6-(5-(4-(二甲基氨基甲酰基)哌嗪-1-基)吡啶-2-基)-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺Compound 20: 6-(5-(4-(dimethylcarbamoyl)piperazin-1-yl)pyridin-2-yl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl )Pyrazolo[1,5-a]pyrimidine-3-carboxamide
(1)4-(6-溴吡啶-3-基)哌嗪-1-羧酸叔丁酯(1) tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate
将2-溴-5-碘吡啶(1.8g,6.5mmol)，哌嗪-1-羧酸叔丁酯(1g,5.4mmol)，叔丁醇钠(1.5g,16mmol)，三(二亚苄基丙酮)二钯(100mg)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(100mg)溶于甲苯(20mL)中。反应液在氮气保护下升温至90℃搅拌过夜。向反应体系中加水(50mL)稀释，用乙酸乙酯(20mLx2)萃取，无水硫酸钠干燥，过滤，减压浓缩得到标题化合物(1.8g,粗品)，收率：100％。MS(ESI):m/z 341.9[M+H]+.Combine 2-bromo-5-iodopyridine (1.8g, 6.5mmol), piperazine-1-carboxylic acid tert-butyl ester (1g, 5.4mmol), sodium tert-butoxide (1.5g, 16mmol), tris(dibenzylidene) Acetone) dipalladium (100 mg) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (100 mg) were dissolved in toluene (20 mL). The reaction solution was heated to 90°C under nitrogen protection and stirred overnight. The reaction system was diluted with water (50 mL), extracted with ethyl acetate (20 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.8 g, crude product), yield: 100%. MS(ESI):m/z 341.9[M+H] + .
(2)1-(6-溴吡啶-3-基)哌嗪(2)1-(6-bromopyridin-3-yl)piperazine
将4-(6-溴吡啶-3-基)哌嗪-1-羧酸叔丁酯(1.8g,粗品)溶于二氯甲烷(5mL)中，加入三氟乙酸(5mL)，室温搅拌2小时。减压浓缩得到1-(6-溴吡啶-3-基)哌嗪(1.3g,粗品)，收率：100％。MS(ESI):m/z 241.9[M+H]+.Dissolve 4-(6-bromopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (1.8g, crude product) in dichloromethane (5mL), add trifluoroacetic acid (5mL), and stir at room temperature for 2 Hour. Concentrate under reduced pressure to obtain 1-(6-bromopyridin-3-yl)piperazine (1.3 g, crude product), yield: 100%. MS(ESI):m/z 241.9[M+H] + .
(3)4-(6-溴吡啶-3-基)-N,N-二甲基哌嗪-1-甲酰胺(3)4-(6-bromopyridin-3-yl)-N,N-dimethylpiperazine-1-carboxamide
将1-(6-溴吡啶-3-基)哌嗪(1.3g,5.4mmol)和三乙胺(5.4g,54mmol)溶于二氯甲烷(10mL)中，加入二甲氨基甲酰氯(870mg,8.1mmol)，反应液在室温条件下搅拌2小时。加水(50mL)稀释，用乙酸乙酯(20mLx2)萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物用柱层析(石油醚/乙酸乙酯＝1/1)纯化得到标题化合物(1.5g,黄色固体)。MS(ESI):m/z 312.9[M+H]+.Dissolve 1-(6-bromopyridin-3-yl)piperazine (1.3g, 5.4mmol) and triethylamine (5.4g, 54mmol) in dichloromethane (10mL), add dimethylcarbamoyl chloride (870mg , 8.1 mmol), the reaction solution was stirred at room temperature for 2 hours. Dilute with water (50 mL), extract with ethyl acetate (20 mLx2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the title compound (1.5 g, yellow solid). MS(ESI):m/z 312.9[M+H] + .
(4)N-(4-羟基双环[2.2.2]辛-1-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(4)N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
将中间体3(40mg,0.1mmol)溶于1,4-二氧六环(1mL)中,加入联硼酸频那醇酯(33mg,0.13mmol)，乙酸钾(43mg,0.44mmol)和Pd(dppf)Cl2(50mg)。反应液在氮气条件下回流搅拌过夜。反应液浓缩得到N-(4-羟基双环[2.2.2]辛-1-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(45mg,粗品)，收率：100％。Intermediate 3 (40 mg, 0.1 mmol) was dissolved in 1,4-dioxane (1 mL), and pinacol diborate (33 mg, 0.13 mmol), potassium acetate (43 mg, 0.44 mmol) and Pd ( dppf)Cl 2 (50 mg). The reaction solution was stirred under reflux overnight under nitrogen. The reaction solution was concentrated to obtain N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle) Pentan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (45 mg, crude product), yield: 100%.
(5)6-(5-(4-(二甲基氨基甲酰基)哌嗪-1-基)吡啶-2-基)-N-(4-羟基双环[2.2.2]辛-1-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(5)6-(5-(4-(Dimethylcarbamoyl)piperazin-1-yl)pyridin-2-yl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl )Pyrazolo[1,5-a]pyrimidine-3-carboxamide
将N-(4-羟基双环[2.2.2]辛-1-基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(45mg,0.1mmol)溶于1,4-二氧六环和水(5mL/1mL)的混合溶剂中，加入4-(6-溴吡啶-3-基)-N,N-二甲基哌嗪-1-甲酰胺(41mg,0.13mmol)，碳酸钾(45mg,0.33mmol)和Pd(dppf)Cl2(50mg)。反应液在氮气条件下回流搅拌过夜。向反应体系中加入水(10mL)，用乙酸乙酯(5mL x 2)萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经Prep-HPLC纯化得到标题化合物(1.4mg,黄色固体)，收率：2.5％。MS(ESI):m/z 519.2[M+H]+.1H NMR(400MHz,MeOD-d4)δ9.40(d,J＝2.0Hz,1H),9.25(d,J＝2.0Hz,1H),8.41(s,1H),8.40(d,J＝2.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),3.38-3.26(m,8H),2.81(s,6H),2.14-2.08(m,6H),1.74-1.70(m,6H).N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (45mg, 0.1mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (5mL/1mL), and 4 -(6-bromopyridin-3-yl)-N,N-dimethylpiperazine-1-carboxamide (41 mg, 0.13 mmol), potassium carbonate (45 mg, 0.33 mmol) and Pd(dppf)Cl 2 (50 mg ). The reaction solution was stirred under reflux overnight under nitrogen. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the title compound (1.4 mg, yellow solid), yield: 2.5%. MS (ESI): m/z 519.2[M+H] + . 1 H NMR (400MHz, MeOD-d 4 ) δ9.40 (d, J = 2.0 Hz, 1H), 9.25 (d, J = 2.0 Hz, 1H),8.41(s,1H),8.40(d,J＝2.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),3.38- 3.26(m,8H),2.81(s,6H),2.14-2.08(m,6H),1.74-1.70(m,6H).
实施例21Example 21
化合物21：N-(4-羟基双环[2.2.2]辛-1-基)-6-(4-(4-(甲基磺酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-甲酰胺Compound 21: N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide
(1)1-(4-溴苯基)-4-(甲磺酰基)哌嗪(1)1-(4-bromophenyl)-4-(methanesulfonyl)piperazine
将1-(4-溴苯基)哌嗪(1g,4.1mmol)，三乙胺(828mg,8.2mmol)溶于二氯甲烷(5mL)中，在0℃下滴加甲磺酰氯(563.5mg,4.9mmol)，反应液升至室温搅拌过夜。向反应体系中加入水(20mL)，用乙酸乙酯(40mL x 2)萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(100％乙酸乙酯)纯化得到1-(4-溴苯基)-4-(甲磺酰基)哌嗪(1.2g,白色固体)，收率：92％。MS(ESI):m/z 318.9[M+H]+.Dissolve 1-(4-bromophenyl)piperazine (1g, 4.1mmol) and triethylamine (828mg, 8.2mmol) in dichloromethane (5mL), and add methanesulfonyl chloride (563.5mg) dropwise at 0°C. ,4.9mmol), the reaction solution was raised to room temperature and stirred overnight. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (100% ethyl acetate) to obtain 1-(4-bromophenyl)-4-(methanesulfonyl)piperazine (1.2 g, white solid), yield: 92%. MS(ESI):m/z 318.9[M+H] + .
(2)1-(甲基磺酰基)-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪(2)1-(methylsulfonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene base)piperazine
将1-(4-溴苯基)-4-(甲磺酰基)哌嗪(120mg,0.38mmol)和联硼酸频那醇酯(115mg,0.45mmol)溶于1,4-二氧六环(5mL)中，加入PdCl2(dppf)(31mg,0.04mmol)和醋酸钾(75mg,0.76mmol)，反应液在100℃氮气条件下搅拌过夜。反应液过滤，减压浓缩，残留物经Pre-HPLC纯化得到标题化合物(15mg,白色固体)，收率：11％。MS(ESI):m/z 367.0[M+H]+. Dissolve 1-(4-bromophenyl)-4-(methanesulfonyl)piperazine (120 mg, 0.38 mmol) and pinacol diborate (115 mg, 0.45 mmol) in 1,4-dioxane ( 5 mL), add PdCl 2 (dppf) (31 mg, 0.04 mmol) and potassium acetate (75 mg, 0.76 mmol), and the reaction solution is stirred overnight at 100°C under nitrogen. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC to obtain the title compound (15 mg, white solid), yield: 11%. MS(ESI):m/z 367.0[M+H] + .
(3)N-(4-羟基双环[2.2.2]辛-1-基)-6-(4-(4-(甲基磺酰基)哌嗪-1-基)苯基)吡唑并[1,5-a]嘧啶-3-甲酰胺(3)N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide
将1-(甲基磺酰基)-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌嗪(15mg,0.04mmol)，中间体3(15mg,0.04mmol)，PdCl2(dppf)(4mg,0.004mmol)，碳酸钾(11mg,0.08mmol)溶于1,4-二氧六环和水(5mL/1mL)的混合溶剂中。反应液在氮气保护下升温至90℃搅拌过夜。反应液减压浓缩，残留物经Prep-HPLC纯化得到标题化合物(2.7mg,白色固体)，收率：13％。MS(ESI):m/z 525.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.54(d,J＝2.4Hz,1H),9.15(d,J＝2.4Hz,1H),8.49(s,1H),7.78(d,J＝8.8Hz,2H),7.58(s,1H),7.13(d,J＝9.2Hz,2H),4.35(s,1H),3.27-3.25(m,8H),2.93(s,3H),2.08-2.04(m,6H),1.68-1.64(m,6H).1-(methylsulfonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) Piperazine (15mg, 0.04mmol), intermediate 3 (15mg, 0.04mmol), PdCl 2 (dppf) (4mg, 0.004mmol), potassium carbonate (11mg, 0.08mmol) were dissolved in 1,4-dioxane and In a mixed solvent of water (5mL/1mL). The reaction solution was heated to 90°C under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound (2.7 mg, white solid), yield: 13%. MS (ESI): m/z 525.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.54 (d, J = 2.4Hz, 1H), 9.15 (d, J = 2.4Hz, 1H),8.49(s,1H),7.78(d,J＝8.8Hz,2H),7.58(s,1H),7.13(d,J＝9.2Hz,2H),4.35(s,1H),3.27- 3.25(m,8H),2.93(s,3H),2.08-2.04(m,6H),1.68-1.64(m,6H).
实施例22Example 22
化合物22：(R)-2-氨基-5-(4-((2-甲基吡咯烷-1-基)甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 22: (R)-2-amino-5-(4-((2-methylpyrrolidin-1-yl)methyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl )Nicotinamide
(1)(R)-1-(4-溴苄基)-2-甲基吡咯烷(1)(R)-1-(4-bromobenzyl)-2-methylpyrrolidine
将4-溴苯甲醛(500mg,2.7mmol)和(R)-2-甲基吡咯烷(230mg,2.7mmol)溶于二氯甲烷(10mL)中，室温搅拌半小时后加入氰基硼氢化钠(250mg,4mmol)，反应体系在室温条件下搅拌反应过夜。反应完全后减压浓缩，残留物经柱层析(乙酸乙酯/石油醚＝1/5)纯化得到标题化合物(120mg,黄色固体)，收率：17.5％。MS(ESI):m/z 254.0[M+H]+.Dissolve 4-bromobenzaldehyde (500mg, 2.7mmol) and (R)-2-methylpyrrolidine (230mg, 2.7mmol) in dichloromethane (10mL), stir at room temperature for half an hour and then add sodium cyanoborohydride. (250 mg, 4 mmol), the reaction system was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether = 1/5) to obtain the title compound (120 mg, yellow solid), yield: 17.5%. MS(ESI):m/z 254.0[M+H] + .
(2)(R)-2-氨基-5-(4-((2-甲基吡咯烷-1-基)甲基)苯基)烟酸(2)(R)-2-amino-5-(4-((2-methylpyrrolidin-1-yl)methyl)phenyl)nicotinic acid
将(R)-1-(4-溴苄基)-2-甲基吡咯烷(120mg,0.50mmol)溶于1,4-二氧六环(10mL)与水(2mL)的混合溶剂中，加入(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(98mg,0.50mmol)和碳酸钾(200mg,0.75mmol)，在氮气条件下加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(10mg,0.03mmol)，然后将该混合体系在氮气条件下加热至90℃搅拌12小时。向反应体系中加入水(20mL)，混合液使用乙酸乙酯(20mL x 2)萃取，有机相依次使用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残留物经反相柱纯化得到标题化合物(50mg,黄色固体)，收率：33％。MS(ESI):m/z 312.1[M+H]+.Dissolve (R)-1-(4-bromobenzyl)-2-methylpyrrolidine (120mg, 0.50mmol) in a mixed solvent of 1,4-dioxane (10mL) and water (2mL), Add (6-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (98mg, 0.50mmol) and potassium carbonate (200mg, 0.75mmol), and add [1,1'-bis( diphenylphosphine)ferrocene]palladium dichloride (10 mg, 0.03 mmol), and then the mixed system was heated to 90°C under nitrogen and stirred for 12 hours. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column to obtain the title compound (50 mg, yellow solid), yield: 33%. MS(ESI):m/z 312.1[M+H] + .
(3)(R)-2-氨基-5-(4-((2-甲基吡咯烷-1-基)甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺(3)(R)-2-Amino-5-(4-((2-methylpyrrolidin-1-yl)methyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl )Nicotinamide
将(R)-2-氨基-5-(4-((2-甲基吡咯烷-1-基)甲基)苯基)烟酸(50mg,0.16mmol)溶于二氯甲烷(5mL)中，依次加入四氢-2H-吡喃-4-胺(16mg,0.16mmol)，HATU(91mg,0.24mmol)，和N,N-二异丙基乙胺(41mg,0.32mmol)，反应体系在室温条件下搅拌3小时。浓缩反应液，残留物经Pre-HPLC纯化得到标题化合物(10mg,白色固体)，收率：15.8％。MS(ESI):m/z 395.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.42-8.39(m,2H),8.16(d,J＝4.0Hz,1H),7.60(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.12(s,2H),4.01-3.96(m,2H),3.91-3.87(m,2H),3.42-3.38(m,2H),3.17-3.13(m,1H),2.80-2.75(m,1H),2.41-2.36(m,1H),2.10-2.03(m,1H),1.92-1.88(m,1H),1.80-1.76(m,2H),1.62-1.53(m,4H),1.40-1.30(m,1H),1.12(d,J＝8.0Hz,3H).Dissolve (R)-2-amino-5-(4-((2-methylpyrrolidin-1-yl)methyl)phenyl)nicotinic acid (50 mg, 0.16 mmol) in dichloromethane (5 mL) , tetrahydro-2H-pyran-4-amine (16mg, 0.16mmol), HATU (91mg, 0.24mmol), and N,N-diisopropylethylamine (41mg, 0.32mmol) were added in sequence, and the reaction system was Stir at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified by Pre-HPLC to obtain the title compound (10 mg, white solid), yield: 15.8%. MS (ESI): m/z 395.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.42-8.39 (m, 2H), 8.16 (d, J = 4.0Hz, 1H), 7.60(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.12(s,2H),4.01-3.96(m,2H),3.91-3.87(m,2H),3.42 -3.38(m,2H),3.17-3.13(m,1H),2.80-2.75(m,1H),2.41-2.36(m,1H),2.10-2.03(m,1H),1.92-1.88(m, 1H),1.80-1.76(m,2H),1.62-1.53(m,4H),1.40-1.30(m,1H),1.12(d,J＝8.0Hz,3H).
实施例23Example 23
化合物23：2-氨基-5-(4-(吗啉甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 23: 2-amino-5-(4-(morpholinmethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
(1)2-氨基-5-(4-(吗啉甲基)苯基)烟酸甲酯(1) Methyl 2-amino-5-(4-(morpholinylmethyl)phenyl)nicotinate
将4-(4-溴苄基)吗啉(100mg,0.39mmol)，(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(76mg,0.39mmol)，Pd(dppf)Cl2(29mg,0.039mmol)和碳酸钾(108mg,0.78mmol)溶于1,4-二氧六环和水(10mL,v/v＝4/1)的混合溶剂中，置换氮气，反应体系在100℃条件下搅拌16小时。反应液直接拌样经柱层析(石油醚/乙酸乙酯＝1/1)纯化得到标题化合物(70mg,黄色固体)，收率：55.1％。MS(ESI):m/z 328.0[M+H]+.4-(4-bromobenzyl)morpholine (100mg, 0.39mmol), (6-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (76mg, 0.39mmol), Pd(dppf) Cl 2 (29 mg, 0.039 mmol) and potassium carbonate (108 mg, 0.78 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (10 mL, v/v=4/1), replacing nitrogen, and the reaction system Stir at 100°C for 16 hours. The reaction solution was directly stirred and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the title compound (70 mg, yellow solid), yield: 55.1%. MS(ESI):m/z 328.0[M+H] + .
(2)2-氨基-5-(4-(吗啉甲基)苯基)烟酸(2)2-Amino-5-(4-(morpholinylmethyl)phenyl)nicotinic acid
将2-氨基-5-(4-(吗啉甲基)苯基)烟酸甲酯(70mg,0.21mmol)和氢氧化锂(24mg,1.0mmol)溶于甲醇和水(5mL,v/v＝3/1)的混合溶剂中，反应体系在室温条件下搅拌3小时。反应液直接旋干得到标题化合物(50mg，白色固体)。收率：74.6％。Dissolve methyl 2-amino-5-(4-(morpholinmethyl)phenyl)nicotinate (70 mg, 0.21 mmol) and lithium hydroxide (24 mg, 1.0 mmol) in methanol and water (5 mL, v/v =3/1) in a mixed solvent, the reaction system was stirred at room temperature for 3 hours. The reaction solution was directly spun to dryness to obtain the title compound (50 mg, white solid). Yield: 74.6%.
(3)2-氨基-5-(4-(吗啉甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺(3)2-amino-5-(4-(morpholinmethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
将2-氨基-5-(4-(吗啉甲基)苯基)烟酸(50mg,0.16mmol)，四氢-2H-吡喃-4-胺(16mg,0.16mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入HATU(76mg,0.32mmol)和三乙胺(103mg,0.80mmol)。反应体系在25℃下搅拌16小时。反应液过滤，滤液浓缩后经Pre-HPLC纯化得到标题化合物(8.1mg,白色固体)，收率：12.7％。MS(ESI):m/z 397.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.40-8.39(m,2H),8.16(d,J＝2.4Hz,1H),7.61(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),7.13(s,2H),4.01-3.98(m,1H),3.91-3.87(m,2H),3.59-3.56(m,4H),3.48(s,2H),3.41-3.36(m,2H),2.37-2.33(m,4H),1.79-1.76(m,2H),1.61-1.55(m,2H).Dissolve 2-amino-5-(4-(morpholinylmethyl)phenyl)nicotinic acid (50mg, 0.16mmol) and tetrahydro-2H-pyran-4-amine (16mg, 0.16mmol) in N,N -To dimethylformamide (2 mL), add HATU (76 mg, 0.32 mmol) and triethylamine (103 mg, 0.80 mmol). The reaction system was stirred at 25°C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by Pre-HPLC to obtain the title compound (8.1 mg, white solid), yield: 12.7%. MS (ESI): m/z 397.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.40-8.39 (m, 2H), 8.16 (d, J = 2.4Hz, 1H), 7.61(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),7.13(s,2H),4.01-3.98(m,1H),3.91-3.87(m,2H),3.59 -3.56(m,4H),3.48(s,2H),3.41-3.36(m,2H),2.37-2.33(m,4H),1.79-1.76(m,2H),1.61-1.55(m,2H) .
实施例24Example 24
化合物24：5-(4-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)苯基)-2-氨基-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 24: 5-(4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)-2-amino-N-(tetrahydro-2H-pyra Phen-4-yl)nicotinamide
(1)(6-氨基-5-((四氢-2H-吡喃-4-基)氨基甲酰基)吡啶-3-基)硼酸(1) (6-amino-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-3-yl)boronic acid
将中间体4(100mg,0.33mmol)，联硼酸频那醇酯(83mg,0.33mmol)，Pd(dppf)Cl2(27mg,0.033mmol)和醋酸钾(65mg,0.66mmol)溶于1,4-二氧六环(10mL)中，置换氮气，反应体系在100℃条件下搅拌16小时。反应液直接用于下一步。Intermediate 4 (100mg, 0.33mmol), pinacol diborate (83mg, 0.33mmol), Pd(dppf)Cl 2 (27mg, 0.033mmol) and potassium acetate (65mg, 0.66mmol) were dissolved in 1,4 -Dioxane (10 mL) was replaced with nitrogen, and the reaction system was stirred at 100°C for 16 hours. The reaction solution was used directly in the next step.
(2)5-(4-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)苯基)-2-氨基-N-(四氢-2H-吡喃-4-基)烟酰胺(2)5-(4-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)phenyl)-2-amino-N-(tetrahydro-2H-pyra Phen-4-yl)nicotinamide
将上一步反应液冷却至室温，加入6-(4-溴苄基)-2-氧杂-6-氮杂螺[3.3]庚烷(88mg,0.33mmol)，Pd(dppf)Cl2(27mg,0.033mmol)，碳酸钾(91mg,0.66mmol)和水(3mL)，置换氮气，反应体系在100℃ 条件下搅拌16小时。反应液冷却至室温，过滤，滤液经Pre-HPLC纯化得到标题化合物(0.8mg,白色固体)，收率：0.5％。MS(ESI):m/z 409.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.48-8.42(m,2H),8.18(d,J＝2.0Hz,1H),7.83(d,J＝10.8Hz,2H),7.33(d,J＝11.2Hz,2H),7.18(s,2H),4.64(s,4H),4.06-3.91(m,4H),3.53-3.51(m,3H),3.31(s,4H),1.83-1.79(m,2H),1.65-1.58(m,2H).Cool the reaction solution in the previous step to room temperature, add 6-(4-bromobenzyl)-2-oxa-6-azaspiro[3.3]heptane (88mg, 0.33mmol), Pd(dppf)Cl 2 (27mg ,0.033mmol), potassium carbonate (91mg, 0.66mmol) and water (3mL), replacing nitrogen, the reaction system is at 100℃ Stir under these conditions for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was purified by Pre-HPLC to obtain the title compound (0.8 mg, white solid), yield: 0.5%. MS (ESI): m/z 409.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.48-8.42 (m, 2H), 8.18 (d, J = 2.0Hz, 1H), 7.83(d,J＝10.8Hz,2H),7.33(d,J＝11.2Hz,2H),7.18(s,2H),4.64(s,4H),4.06-3.91(m,4H),3.53-3.51 (m,3H),3.31(s,4H),1.83-1.79(m,2H),1.65-1.58(m,2H).
实施例25Example 25
化合物25：2-氨基-5-(4-(1-(吡咯烷-1-基)乙基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 25: 2-amino-5-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
(1)1-(1-(4-溴苯基)乙基)吡咯烷(1)1-(1-(4-bromophenyl)ethyl)pyrrolidine
在20℃下，向1-(4-溴苯基)乙酮(10.00g,50.24mmol)的甲醇(100mL)溶液中依次加入四氢吡咯(17.87g,251.20mmol)和氰基硼氢化钠(6.95g,110.53mmol)。反应液在20℃下搅拌12小时。反应液减压浓缩除去溶剂，加水(200mL)稀释，用乙酸乙酯(100mL x 2)萃取。合并有机相，用无水硫酸钠干燥后过滤，将滤液减压浓缩得到标题化合物(12.5g,无色油状物)。MS(ESI):m/z 254.1[M+H]+.At 20°C, to a solution of 1-(4-bromophenyl)ethanone (10.00g, 50.24mmol) in methanol (100mL) was added tetrahydropyrrole (17.87g, 251.20mmol) and sodium cyanoborohydride ( 6.95g, 110.53mmol). The reaction solution was stirred at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, diluted with water (200 mL), and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (12.5 g, colorless oil). MS(ESI):m/z 254.1[M+H] + .
(2)1-(1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)乙基)吡咯烷(2)1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)pyrrole alkyl
在20℃氮气保护下，将1-(1-(4-溴苯基)乙基)吡咯烷(12.50g,49.18mmol)溶于1,4-二氧六环(125mL)中，依次加入联硼酸频那醇酯(24.98g,98.36mmol)，乙酸钾(9.65g,98.36mmol)和Pd(dppf)Cl2(3.60g,4.92mmol)。反应体系置换氮气三次，随后在105℃下搅拌2小时。反应液冷却至室温后过滤，滤液减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝100/1～0/1)纯化得到标题化合物(3.00g,棕黑色固体)，收率：20.2％。MS(ESI):m/z 302.3[M+H]+.Under nitrogen protection at 20°C, dissolve 1-(1-(4-bromophenyl)ethyl)pyrrolidine (12.50g, 49.18mmol) in 1,4-dioxane (125mL), and add 1-(4-bromophenyl)ethyl)pyrrolidine (12.50g, 49.18mmol) in sequence. Pinacol borate (24.98g, 98.36mmol), potassium acetate (9.65g, 98.36mmol) and Pd(dppf) Cl2 (3.60g, 4.92mmol). The reaction system was replaced with nitrogen three times, and then stirred at 105°C for 2 hours. The reaction solution was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 100/1 to 0/1) to obtain the title compound (3.00 g, brown-black solid), yield: 20.2%. MS(ESI):m/z 302.3[M+H] + .
(3)2-氨基-5-(4-(1-(吡咯烷-1-基)乙基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺(3)2-Amino-5-(4-(1-(pyrrolidin-1-yl)ethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
在20℃氮气保护下，将1-(1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)乙基)吡咯烷(30mg,99.59umol)溶于1,4-二氧六环(0.15mL)和水(0.15mL)的混合溶剂中，加入中间体4(59mg,199.18umol)，碳酸钾(41mg,298.77umol)。在氮气保护下加入Pd(dppf)Cl2(14mg,19.92umol)。反应体系置换氮气三次，然后在80℃下搅拌12个小时。反应液冷却至室温，加水(5mL)稀释，用乙酸乙酯(5mL)萃取，有机相减压浓缩得到粗品。粗品经Prep-HPLC纯化得到标题化合物(5mg,白色固体)，收率：12.7％。MS(ESI):m/z 395.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.43-8.35(m,2H),8.16(d,J＝2.3Hz,1H),7.59(d,J＝8.1Hz,2H),7.39(d,J＝8.1Hz,2H),7.14(s,2H),4.07-3.96(m,1H),3.94-3.86(m,2H),3.43-3.36(m,2H),3.25(d,J＝6.1Hz,1H),2.50-2.45(m,2H),2.34(brs,2H),1.78(dd,J＝12.7,1.9Hz,2H),1.73-1.64(m,4H),1.63-1.52(m,2H),1.32(d,J＝6.5Hz,3H).Under nitrogen protection at 20°C, 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )Ethyl)pyrrolidine (30 mg, 99.59umol) was dissolved in a mixed solvent of 1,4-dioxane (0.15mL) and water (0.15mL), and intermediate 4 (59mg, 199.18umol) and potassium carbonate were added (41mg,298.77umol). Pd(dppf)Cl 2 (14 mg, 19.92umol) was added under nitrogen protection. The reaction system was replaced with nitrogen three times, and then stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (5 mL), and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the title compound (5 mg, white solid), yield: 12.7%. MS (ESI): m/z 395.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.43-8.35 (m, 2H), 8.16 (d, J = 2.3Hz, 1H), 7.59(d,J＝8.1Hz,2H),7.39(d,J＝8.1Hz,2H),7.14(s,2H),4.07-3.96(m,1H),3.94-3.86(m,2H),3.43 -3.36(m,2H),3.25(d,J＝6.1Hz,1H),2.50-2.45(m,2H),2.34(brs,2H),1.78(dd,J＝12.7,1.9Hz,2H), 1.73-1.64(m,4H),1.63-1.52(m,2H),1.32(d,J＝6.5Hz,3H).
实施例26Example 26
化合物26：2-氨基-5-(4-(2-吗啉代乙氧基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 26: 2-amino-5-(4-(2-morpholinoethoxy)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
将4-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基)乙基)吗啉(100mg,300umol)，中间体4(99.0mg,330umol)，碳酸钠(16.5mg,156umol)溶于1,4-二氧六环(1.0mL)和水(0.1mL)中。在氮气保护下，向反应液中加入Pd(dppf)Cl2(24.62mg,33.65umol)。反应混合物在90℃氮气保护下搅拌16小时。反应液冷却至室温，用甲醇(1mL)稀释并过滤，滤液经Prep-HPLC纯化得到标题化合物(75.6mg,淡黄色固体)，收率：59.07％。MS(ESI):m/z 427.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.41(d,J＝7.6Hz,1H),8.36(d,J＝2.4Hz,1H),8.12(d,J＝2.3Hz,1H),7.63-7.54(m,2H),7.07(s,2H),7.03(d,J＝8.7Hz,2H),4.12(t,J＝5.8Hz,2H),4.06-3.95(m,1H),3.90(dd,J＝11.7,2.3Hz,2H),3.62-3.56(m,4H),3.43-3.35(m,2H),2.71(t,J＝5.8Hz,2H),2.50-2.48(m,4H),1.78(dd,J＝12.5,2.2Hz,2H),1.60-1.52(m,2H).4-(2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (100mg, 300umol), intermediate 4 (99.0mg, 330umol), sodium carbonate (16.5mg, 156umol) were dissolved in 1,4-dioxane (1.0mL) and water (0.1mL). Under nitrogen protection, Pd(dppf)Cl 2 (24.62 mg, 33.65umol) was added to the reaction solution. The reaction mixture was stirred at 90°C under nitrogen protection for 16 hours. The reaction solution was cooled to room temperature, diluted with methanol (1 mL) and filtered. The filtrate was purified by Prep-HPLC to obtain the title compound (75.6 mg, light yellow solid), yield: 59.07%. MS (ESI): m/z 427.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.41 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H),8.12(d,J＝2.3Hz,1H),7.63-7.54(m,2H),7.07(s,2H),7.03(d,J＝8.7Hz,2H),4.12(t,J＝5.8 Hz,2H),4.06-3.95(m,1H),3.90(dd,J＝11.7,2.3Hz,2H),3.62-3.56(m,4H),3.43-3.35(m,2H),2.71(t, J＝5.8Hz,2H),2.50-2.48(m,4H),1.78(dd,J＝12.5,2.2Hz,2H),1.60-1.52(m,2H).
实施例27Example 27
化合物27：2-氨基-5-(4-(1-吗啉代环丙基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 27: 2-amino-5-(4-(1-morpholinocyclopropyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
参照实施例26的方法，以4-(1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)环丙基)吗啉(80.0mg,242umol)和中间体4(80.2mg,267.2umol)为原料，得到标题化合物(28.2mg,淡黄色固体)，收率：27.47％。MS(ESI):m/z 423.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.42-8.40(m,2H),8.17(d,J＝2.1Hz,1H),7.63(d,J＝8.1Hz,2H),7.33(d,J＝8.1Hz,2H),7.15(s,2H),4.08-3.95(m,1H),3.90(d,J＝9.4Hz,2H),3.50(t,J＝4.1Hz,4H),3.43-3.35(m,2H),2.45-2.43(m,4H),1.83-1.74(m,2H),1.64-1.51(m,2H),0.95-0.88(m,2H),0.80-0.73(m,2H).Referring to the method of Example 26, 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ) Cyclopropyl)morpholine (80.0 mg, 242umol) and intermediate 4 (80.2mg, 267.2umol) were used as raw materials to obtain the title compound (28.2mg, light yellow solid), yield: 27.47%. MS (ESI): m/z 423.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.42-8.40 (m, 2H), 8.17 (d, J = 2.1Hz, 1H), 7.63(d,J＝8.1Hz,2H),7.33(d,J＝8.1Hz,2H),7.15(s,2H),4.08-3.95(m,1H),3.90(d,J＝9.4Hz,2H ),3.50(t,J＝4.1Hz,4H),3.43-3.35(m,2H),2.45-2.43(m,4H),1.83-1.74(m,2H),1.64-1.51(m,2H), 0.95-0.88(m,2H),0.80-0.73(m,2H).
实施例28Example 28
化合物28：(R)-2-氨基-5-(4-((3-甲基吗啉代)甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 28: (R)-2-amino-5-(4-((3-methylmorpholino)methyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
(1)(R)-4-(4-溴苄基)-3-甲基吗啉(1)(R)-4-(4-bromobenzyl)-3-methylmorpholine
将(R)-3-甲基***啉(1.60g,15.82mmol)溶于乙腈(16mL)中，依次加入碘化钾(5.25g,31.64mmol)，碳酸钾(6.56g,47.46mmol)和对溴苄溴(4.35g,17.40mmol)。反应液升温至60℃并搅拌12小时。反应液降至室温后过滤，滤液减压浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝100/1～0/1)纯化得到标题化合物(3.50g,黄色油状物)，收率：81.9％。MS(ESI):m/z 270.2[M+H]+.Dissolve (R)-3-methylmorpholine (1.60g, 15.82mmol) in acetonitrile (16mL), add potassium iodide (5.25g, 31.64mmol), potassium carbonate (6.56g, 47.46mmol) and benzyl bromide in sequence. Bromine (4.35g, 17.40mmol). The reaction solution was heated to 60°C and stirred for 12 hours. The reaction solution was filtered after cooling to room temperature, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 100/1~0/1) to obtain the title compound (3.50 g, yellow oil), yield: 81.9%. MS(ESI):m/z 270.2[M+H] + .
(2)(R)-3-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吗啉(2)(R)-3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl base) morpholine
将(R)-4-(4-溴苄基)-3-甲基吗啉(800mg,2.96mmol)溶于N,N-二甲基甲酰胺(8mL)中，加入联硼酸频那醇酯(902mg,3.55mmol)，乙酸钾(435mg,4.44mmol)。然后在氮气保护下，加入Pd(dppf)Cl2(216mg,296.12umol)。反应液升温至80℃氮气保护下搅拌12小时。反应液冷却至室温后加入到水(20mL)中，用乙酸乙酯(10mL x 2)萃取。合并有机相，减压浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝100/1～10/1)纯化得到标题化合物(600mg,黄色油状物)，收率：63.8％。MS(ESI):m/z 318.3[M+H]+.Dissolve (R)-4-(4-bromobenzyl)-3-methylmorpholine (800mg, 2.96mmol) in N,N-dimethylformamide (8mL), and add pinacol diborate (902mg, 3.55mmol), potassium acetate (435mg, 4.44mmol). Then, under nitrogen protection, Pd(dppf)Cl 2 (216 mg, 296.12umol) was added. The reaction solution was heated to 80°C and stirred under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, added to water (20 mL), and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 100/1-10/1) to obtain the title compound (600 mg, yellow oil), yield: 63.8%. MS(ESI):m/z 318.3[M+H] + .
(3)(R)-2-氨基-5-(4-((3-甲基吗啉代)甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺 (3)(R)-2-Amino-5-(4-((3-methylmorpholino)methyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
将(R)-3-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吗啉(80mg,252.18umol)溶于1,4-二氧六环(4mL)和水(0.4mL)的混合溶剂中，加入碳酸钾(104mg,756.55umol)，中间体4(75mg,252.18umol)。然后在氮气保护下，向反应液中加入Pd(dppf)Cl2(18mg,25.22umol)。反应液在80℃氮气保护下搅拌12小时。反应液冷却后过滤。滤液经Pre-HPLC纯化得到标题化合物(36mg,白色固体)，收率：35.1％。MS(ESI):m/z 411.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.43-8.38(m,2H),8.17(d,J＝2.1Hz,1H),7.62(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.14(s,2H),4.02-3.97(m,2H),3.92-3.88(m,2H),3.66-3.61(m,2H),3.47-3.36(m,3H),3.21-3.13(m,2H),2.54-2.52(m,1H),2.45-2.36(m,1H),2.15-2.07(m,1H),1.79(dd,J＝12.9,1.9Hz,2H),1.62-1.56(m,2H),1.03(d,J＝6.3Hz,3H).(R)-3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) Morpholine (80 mg, 252.18umol) was dissolved in a mixed solvent of 1,4-dioxane (4mL) and water (0.4mL). Potassium carbonate (104mg, 756.55umol) was added. Intermediate 4 (75mg, 252.18umol) ). Then, under nitrogen protection, Pd(dppf)Cl 2 (18 mg, 25.22umol) was added to the reaction solution. The reaction solution was stirred at 80°C under nitrogen protection for 12 hours. The reaction solution was filtered after cooling. The filtrate was purified by Pre-HPLC to obtain the title compound (36 mg, white solid), yield: 35.1%. MS (ESI): m/z 411.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.43-8.38 (m, 2H), 8.17 (d, J = 2.1Hz, 1H), 7.62(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.14(s,2H),4.02-3.97(m,2H),3.92-3.88(m,2H),3.66 -3.61(m,2H),3.47-3.36(m,3H),3.21-3.13(m,2H),2.54-2.52(m,1H),2.45-2.36(m,1H),2.15-2.07(m, 1H), 1.79 (dd, J＝12.9, 1.9Hz, 2H), 1.62-1.56 (m, 2H), 1.03 (d, J＝6.3Hz, 3H).
实施例29Example 29
化合物29：2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)-5-(4-(2-吗啉代乙氧基)苯基)烟酰胺Compound 29: 2-amino-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5-(4-(2-morpholinoethoxy) )phenyl)nicotinamide
(1)4-(2-(4-溴苯氧基)乙基)吗啉(1)4-(2-(4-bromophenoxy)ethyl)morpholine
将4-(2-氯乙基)吗啉(870mg,5.8mmol)，4-溴苯酚(1.0g,5.8mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(1.6g,11.6mmol)，升温至70℃搅拌反应过夜。向反应体系中加入水(20mL)，混合液使用乙酸乙酯(40mLx2)萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(乙酸乙酯/石油醚＝1/3)纯化得到标题化合物(1.6g,无色油状物)，收率：96％。MS(ESI):m/z 285.9[M+H]+.Dissolve 4-(2-chloroethyl)morpholine (870mg, 5.8mmol) and 4-bromophenol (1.0g, 5.8mmol) in N,N-dimethylformamide (10mL), add potassium carbonate ( 1.6g, 11.6mmol), the temperature was raised to 70°C and the reaction was stirred overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/petroleum ether = 1/3) to obtain the title compound (1.6 g, colorless oil), yield: 96%. MS(ESI):m/z 285.9[M+H] + .
(2)2-氨基-5-(4-(2-吗啉乙氧基)苯基)烟酸甲酯(2) Methyl 2-amino-5-(4-(2-morpholineethoxy)phenyl)nicotinate
将4-(2-(4-溴苯氧基)乙基)吗啉(200mg,0.7mmol)，(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(137mg,0.7mmol)，PdCl2(dppf)(57mg,0.07mmol)，碳酸钾(193mg,1.4mmol)溶于1,4-二氧六环和水(5mL/1mL)的混合溶剂中。在氮气保护下升温至85℃搅拌反应过夜。反应液过滤，减压浓缩，残留物经反相柱纯化得到标题化合物(120mg,黄色油状物)，收率：48％。MS(ESI):m/z 358.0[M+H]+.4-(2-(4-Bromophenoxy)ethyl)morpholine (200mg, 0.7mmol), (6-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (137mg, 0.7 mmol), PdCl 2 (dppf) (57 mg, 0.07 mmol), and potassium carbonate (193 mg, 1.4 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (5 mL/1 mL). The temperature was raised to 85°C under nitrogen protection and the reaction was stirred overnight. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase column to obtain the title compound (120 mg, yellow oil), yield: 48%. MS(ESI):m/z 358.0[M+H] + .
(3)2-氨基-5-(4-(2-吗啉乙氧基)苯基)烟酸(3)2-Amino-5-(4-(2-morpholineethoxy)phenyl)nicotinic acid
将2-氨基-5-(4-(2-吗啉乙氧基)苯基)烟酸甲酯(120mg,0.34mmol)溶于四氢呋喃和水(5mL/1mL)的混合溶剂中，加入氢氧化锂(70mg,1.68mmol)，反应体系在40℃条件下搅拌反应过夜。反应液浓缩除去四氢呋喃，用稀盐酸调节pH值至3～4,减压浓缩。残留物经反相柱纯化得到标题化合物(60mg,白色固体)，收率：52％。MS(ESI):m/z 344.2[M+H]+.Dissolve 2-amino-5-(4-(2-morpholineethoxy)phenyl)nicotinic acid methyl ester (120mg, 0.34mmol) in a mixed solvent of tetrahydrofuran and water (5mL/1mL), add hydroxide Lithium (70 mg, 1.68 mmol), the reaction system was stirred at 40°C overnight. The reaction solution was concentrated to remove tetrahydrofuran, the pH value was adjusted to 3-4 with dilute hydrochloric acid, and concentrated under reduced pressure. The residue was purified by reverse-phase column to obtain the title compound (60 mg, white solid), yield: 52%. MS(ESI):m/z 344.2[M+H] + .
(4)2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)-5-(4-(2-吗啉代乙氧基)苯基)烟酰胺(4)2-Amino-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5-(4-(2-morpholinoethoxy) )phenyl)nicotinamide
将2-氨基-5-(4-(2-吗啉乙氧基)苯基)烟酸(60mg,0.17mmol)和((2S,5R)-5-氨基四氢-2H-吡喃-2-基)甲醇盐酸盐(28mg,0.17mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入HATU(129mg,0.34mmol)和N,N-二异丙基乙胺(66mg,0.5mmol)，室温搅拌过夜。反应液经Pre-HPLC纯化得到标题化合物(45mg,白色固体)，收率：56％。MS(ESI):m/z 457.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝2.0Hz,1H),8.27(d,J＝7.6Hz,1H),8.10(d,J＝2.0Hz,1H),7.58(d,J＝8.8Hz,2H),7.06-7.01(m,4H),4.63(t,J＝5.6Hz,1H),4.12(t,J＝5.6Hz,2H),3.91-3.89(m,2H),3.60-3.57(m,4H),3.40-3.35(m,1H),3.34-3.31(m,1H),3.13(t,J＝11.8Hz,1H),2.70(t,J＝6.0Hz,2H),2.47-2.45(m,4H),1.97(d,J＝12.4Hz,1H),1.73(d,J＝14.0Hz,1H),1.65-1.54(m,1H),1.36-1.26(m,1H).2-Amino-5-(4-(2-morpholinoethoxy)phenyl)nicotinic acid (60 mg, 0.17 mmol) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2 -Methanol hydrochloride (28mg, 0.17mmol) was dissolved in N,N-dimethylformamide (5mL), HATU (129mg, 0.34mmol) and N,N-diisopropylethylamine (66mg ,0.5mmol), stir at room temperature overnight. The reaction solution was purified by Pre-HPLC to obtain the title compound (45 mg, white solid), yield: 56%. MS (ESI): m/z 457.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.36 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H),8.10(d,J＝2.0Hz,1H),7.58(d,J＝8.8Hz,2H),7.06-7.01(m,4H),4.63(t,J＝5.6Hz,1H),4.12( t,J＝5.6Hz,2H),3.91-3.89(m,2H),3.60-3.57(m,4H),3.40-3.35(m,1H),3.34-3.31(m,1H),3.13(t, J＝11.8Hz,1H),2.70(t,J＝6.0Hz,2H),2.47-2.45(m,4H),1.97(d,J＝12.4Hz,1H),1.73(d,J＝14.0Hz, 1H),1.65-1.54(m,1H),1.36-1.26(m,1H).
实施例30Example 30
化合物30：5-(4-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)苯基)-2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)烟酰胺Compound 30: 5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-amino-N-((3R,6S)-6-(hydroxy Methyl)tetrahydro-2H-pyran-3-yl)nicotinamide
(1)6-(4-溴苯基)-2-氧杂-6-氮杂螺环[3.3]庚烷(1)6-(4-bromophenyl)-2-oxa-6-azaspiro[3.3]heptane
在25mL单口瓶中依次加入1,4-二溴苯(800mg,3.39mmol)，三(二亚苄基丙酮)二钯(30mg,0.033mmol)，1,1'-联萘-2,2'-双二苯膦(42mg,0.067mmol)，2-氧代-6-氮杂螺环[3.3]庚烷(224mg,2.26mmol)和碳酸铯(1.1g,3.37mmol)，加入甲苯(5mL)后在氮气保护下于100℃反应18小时。浓缩反应液，残留物经柱层析(石油醚/乙酸乙酯＝2/1)纯化得到标题化合物(190mg,白色固体)，收率：38％。MS(ESI):m/z253.9[M+H]+.In a 25mL single-neck bottle, add 1,4-dibromobenzene (800mg, 3.39mmol), tris(dibenzylideneacetone)dipalladium (30mg, 0.033mmol), and 1,1'-binaphthyl-2,2' in sequence. - Bisdiphenylphosphine (42 mg, 0.067 mmol), 2-oxo-6-azaspiro[3.3]heptane (224 mg, 2.26 mmol) and cesium carbonate (1.1 g, 3.37 mmol) were added to toluene (5 mL) Then react at 100°C for 18 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain the title compound (190 mg, white solid), yield: 38%. MS(ESI):m/z253.9[M+H] + .
(2)5-(4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)-2-氨基烟酸甲酯(2) Methyl 5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-aminonicotinate
在50mL单口瓶中依次加入6-(4-溴苯基)-2-氧杂-6-氮杂螺环[3.3]庚烷(158mg,0.62mmol)，(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(134mg,0.68mmol)，Pd(dppf)Cl2(45mg,0.062mmol)和碳酸钾(258mg,1.87mmol)，加入1,4-二氧六环(4mL)和水(2mL)后在氮气保护下于80℃反应16小时。减压除去溶剂，残留物经柱层析(二氯甲烷/甲醇＝20/1)纯化得到标题化合物(17mg,黄色固体)，收率：8.4％。MS(ESI):m/z326.0[M+H]+.Into a 50mL single-neck bottle, add 6-(4-bromophenyl)-2-oxa-6-azaspiro[3.3]heptane (158mg, 0.62mmol), (6-amino-5-(methoxy Carbonyl)pyridin-3-yl)boronic acid (134mg, 0.68mmol), Pd(dppf)Cl 2 (45mg, 0.062mmol) and potassium carbonate (258mg, 1.87mmol) were added to 1,4-dioxane (4mL ) and water (2 mL) and reacted at 80°C for 16 hours under nitrogen protection. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (17 mg, yellow solid), yield: 8.4%. MS(ESI):m/z326.0[M+H] + .
(3)5-(4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)-2-氨基烟酸(3)5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-aminonicotinic acid
将5-(4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)-2-氨基烟酸甲酯(17mg,0.052mmol)溶于甲醇(3mL)和水(1mL)，再加入氢氧化钠(6.24mg,0.156mmol)，反应液加热至50℃反应4小时。反应液旋干，残留物经反相柱纯化得到标题化合物(13mg,黄色固体)，收率：81％。MS(ESI):m/z 311.9[M+H]+.Dissolve 5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-aminonicotinic acid methyl ester (17 mg, 0.052 mmol) in methanol (3 mL ) and water (1 mL), then add sodium hydroxide (6.24 mg, 0.156 mmol), and heat the reaction solution to 50°C for 4 hours. The reaction solution was spun to dryness, and the residue was purified by reverse-phase column to obtain the title compound (13 mg, yellow solid), yield: 81%. MS(ESI):m/z 311.9[M+H] + .
(4)5-(4-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)苯基)-2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)烟酰胺(4)5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-amino-N-((3R,6S)-6-(hydroxy Methyl)tetrahydro-2H-pyran-3-yl)nicotinamide
将5-(4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)-2-氨基烟酸(13mg,0.042mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入((2S,5R)-5-氨基四氢-2H-吡喃-2-基)甲醇盐酸盐(8.4mg,0.05mmol)，HATU(32mg,0.084mmol)和N,N-二异丙基乙胺(27mg,0.21mmol)，反应液再室温搅拌3小时。反应液过滤，滤液经Pre-HPLC纯化得到标题化合物(13mg,淡黄色固体)，收率：48％。MS(ESI):m/z 425.1[M+H]+.1H NMR (400MHz,DMSO-d6)δ8.31(d,J＝2.4Hz,1H),8.25(d,J＝7.6Hz,1H),8.05(d,J＝2.0Hz,1H),7.47(d,J＝8.4Hz,2H),6.99(s,2H),6.51(d,J＝8.4Hz,2H),4.73(s,4H),4.64(t,J＝5.6Hz,1H),3.98(s,4H),3.92-3.85(m,2H),3.43-3.37(m,2H),3.28-3.22(m,1H),3.13(t,J＝11.6Hz,1H),1.98-1.95(m,1H),1.75-1.71(m,1H),1.64-1.55(m,1H),1.36-1.25(m,1H).Dissolve 5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-aminonicotinic acid (13 mg, 0.042 mmol) in N,N-di To methylformamide (2mL), add ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (8.4mg, 0.05mmol), HATU (32mg, 0.084mmol) ) and N,N-diisopropylethylamine (27 mg, 0.21 mmol), the reaction solution was stirred at room temperature for another 3 hours. The reaction solution was filtered, and the filtrate was purified by Pre-HPLC to obtain the title compound (13 mg, light yellow solid), yield: 48%. MS(ESI):m/z 425.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.31(d,J＝2.4Hz,1H),8.25(d,J＝7.6Hz,1H),8.05(d,J＝2.0Hz,1H),7.47(d, J＝8.4Hz,2H),6.99(s,2H),6.51(d,J＝8.4Hz,2H),4.73(s,4H),4.64(t,J＝5.6Hz,1H),3.98(s, 4H),3.92-3.85(m,2H),3.43-3.37(m,2H),3.28-3.22(m,1H),3.13(t,J＝11.6Hz,1H),1.98-1.95(m,1H) ,1.75-1.71(m,1H),1.64-1.55(m,1H),1.36-1.25(m,1H).
实施例31Example 31
化合物31：5-(4-(1-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙基)苯基)-2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)烟酰胺Compound 31: 5-(4-(1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((3R,6S )-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)nicotinamide
(1)6-(1-(4-溴苯基)乙基)-2-氧代-6-氮杂螺[3.3]庚烷(1)6-(1-(4-bromophenyl)ethyl)-2-oxo-6-azaspiro[3.3]heptane
将1-(4-溴苯基)乙酮(500mg,2.5mmol)溶于二氯甲烷(5mL)中，加入2-氧杂-6-氮杂螺[3.3]庚烷(273mg,2.72mmol)，反应液在室温下搅拌2小时，加入氰基硼氢化钠(473mg,7.5mmol)，室温下过夜。反应液经柱层析纯化得到标题化合物(200mg,黄色油状物)，收率：28％。MS(ESI):m/z 281.9[M+H]+.Dissolve 1-(4-bromophenyl)ethanone (500mg, 2.5mmol) in dichloromethane (5mL), and add 2-oxa-6-azaspiro[3.3]heptane (273mg, 2.72mmol) , the reaction solution was stirred at room temperature for 2 hours, sodium cyanoborohydride (473 mg, 7.5 mmol) was added, and the mixture was kept at room temperature overnight. The reaction solution was purified by column chromatography to obtain the title compound (200 mg, yellow oil), yield: 28%. MS(ESI):m/z 281.9[M+H] + .
(2)5-(4-(1-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙基)苯基)-2-氨基烟酸甲酯(2) Methyl 5-(4-(1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-aminonicotinate
将6-(1-(4-溴苯基)乙基)-2-氧代-6-氮杂螺[3.3]庚烷(200mg,0.71mmol)溶于1,4-二氧六环(2mL)和水(2mL)中，依次加入(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(138mg,0.71mmol)，碳酸钾(292mg,2.13mmol)和Pd(dppf)Cl2(50mg,0.071mmol)。反应液在70℃氮气保护下反应2.5小时。过滤，滤液浓缩，残留物经柱层析纯化得到标题化合物(60mg,黄色油状物)，收率：24％。MS(ESI):m/z 354.1[M+H]+.Dissolve 6-(1-(4-bromophenyl)ethyl)-2-oxo-6-azaspiro[3.3]heptane (200 mg, 0.71 mmol) in 1,4-dioxane (2 mL ) and water (2mL), add (6-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (138mg, 0.71mmol), potassium carbonate (292mg, 2.13mmol) and Pd (dppf) in sequence Cl 2 (50 mg, 0.071 mmol). The reaction solution was reacted at 70°C under nitrogen protection for 2.5 hours. Filtration, the filtrate was concentrated, and the residue was purified by column chromatography to obtain the title compound (60 mg, yellow oil), yield: 24%. MS(ESI):m/z 354.1[M+H] + .
(3)5-(4-(1-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙基)苯基)-2-氨基烟酸(3)5-(4-(1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-aminonicotinic acid
将5-(4-(1-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙基)苯基)-2-氨基烟酸甲酯(60mg,0.17mmol)溶于四氢呋喃(1mL)和水(1mL)的混合溶剂中，加入氢氧化钠(20mg,0.54mmol)。反应液在室温下搅拌4小时。反应液经反相柱纯化得到标题化合物(20mg,灰色固体)，收率：35％。MS(ESI):m/z 340.1[M+H]+.5-(4-(1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-aminonicotinic acid methyl ester (60 mg, 0.17 mmol) Dissolve in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), and add sodium hydroxide (20 mg, 0.54 mmol). The reaction solution was stirred at room temperature for 4 hours. The reaction solution was purified by reverse-phase column to obtain the title compound (20 mg, gray solid), yield: 35%. MS(ESI):m/z 340.1[M+H] + .
(4)5-(4-(1-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙基)苯基)-2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)烟酰胺(4)5-(4-(1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((3R,6S )-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)nicotinamide
将5-(4-(1-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)乙基)苯基)-2-氨基烟酸(10mg,0.03mmol)溶于N,N-二甲基甲酰胺(1mL)中，依次加入((2S,5R)-5-氨基四氢-2H-吡喃-2-基)甲醇盐酸盐(7.6mg,0.06mmol)，HATU(16mg,0.045mmol)和N,N-二异丙基乙胺(7.3mg,0.06mmol)。反应液在室温搅拌16小时。反应液经Pre-HPLC纯化得到标题化合物(2mg,白色固体)，收率：15％。MS(ESI):m/z 453.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.26(d,J＝7.6Hz,1H),8.14(s,1H),7.57(d,J＝8.0Hz,2H),7.33(d,J＝7.2Hz,2H),7.13(s,2H),4.64-4.59(m,5H),3.91-3.89(m,3H),3.16-3.09(m,5H),2.01-1.96(m,2H),1.77-1.54(m,3H),1.37-1.24(m,2H),1.10(d,J＝6.0Hz,3H).Dissolve 5-(4-(1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-aminonicotinic acid (10 mg, 0.03 mmol) in To N,N-dimethylformamide (1mL), ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (7.6mg, 0.06mmol) was added sequentially. HATU (16 mg, 0.045 mmol) and N,N-diisopropylethylamine (7.3 mg, 0.06 mmol). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was purified by Pre-HPLC to obtain the title compound (2 mg, white solid), yield: 15%. MS (ESI): m/z 453.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.36 (s, 1H), 8.26 (d, J = 7.6Hz, 1H), 8.14 ( s,1H),7.57(d,J＝8.0Hz,2H),7.33(d,J＝7.2Hz,2H),7.13(s,2H),4.64-4.59(m,5H),3.91-3.89(m ,3H),3.16-3.09(m,5H),2.01-1.96(m,2H),1.77-1.54(m,3H),1.37-1.24(m,2H),1.10(d,J＝6.0Hz,3H ).
实施例32Example 32
化合物32：2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)-5-(4-(1-(吡咯烷-1-基)乙基)苯基)烟酰胺(1)2-氨基-5-溴-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)烟酰胺Compound 32: 2-amino-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5-(4-(1-(pyrrolidine-1- ethyl)phenyl)nicotinamide (1)2-amino-5-bromo-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)nicotinamide Amide
参照实施例10步骤(1)的方法，以2-氨基-5-溴烟酸(1.61g,7.43mmol)和((2S,5R)-5-氨基四氢-2H-吡喃-2-基)甲醇(650mg,4.96mmol)为原料，得到标题化合物(300mg,白色固体)，收率：18.34％。MS(ESI):m/z 330.1[M+H]+.1H NMR(400MHz,CD3OD)δ8.11(d,J＝2.4Hz,1H),8.02(d,J＝2.4Hz,1H),4.09-3.98(m,2H),3.53(d,J＝5.2Hz,2H),3.44-3.38(m,1H),3.26-3.20(m,1H),2.12-2.08(m,1H),1.77(dd,J＝12.9,2.5Hz,1H),1.68-1.60(m,1H),1.53-1.41(m,1H).Referring to the method of step (1) in Example 10, 2-amino-5-bromonicotinic acid (1.61g, 7.43mmol) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl ) Methanol (650 mg, 4.96 mmol) was used as raw material to obtain the title compound (300 mg, white solid), yield: 18.34%. MS (ESI): m/z 330.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.11 (d, J = 2.4Hz, 1H), 8.02 (d, J = 2.4Hz, 1H ),4.09-3.98(m,2H),3.53(d,J＝5.2Hz,2H),3.44-3.38(m,1H),3.26-3.20(m,1H),2.12-2.08(m,1H), 1.77(dd,J＝12.9,2.5Hz,1H),1.68-1.60(m,1H),1.53-1.41(m,1H).
(2)2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)-5-(4-(1-(吡咯烷-1-基)乙基)苯基)烟酰胺(2)2-Amino-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5-(4-(1-(pyrrolidine-1- ethyl)phenyl)nicotinamide
将2-氨基-5-溴-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)烟酰胺(100mg,302.87umol)溶于1,4-二氧六环(0.5mL)和水(0.5mL)的混合溶剂中，依次加入1-(1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)乙基)吡咯烷(136mg,454.30umol,实施例25第2步)和碳酸钾(125mg,908.60umol)，在氮气保护下加入Pd(dppf)Cl2(44mg,60.57umol)。反应液在80℃搅拌12小时。反应液冷却至室温，加水稀释，用乙酸乙酯(5mL)萃取。有机相减压浓缩得到粗品。粗品经Prep-HPLC纯化得到标题化合物(4mg,灰色固体)，收率：3.2％。MS(ESI):m/z 425.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.1Hz,1H),8.28(d,J＝7.4Hz,1H),8.15(d,J＝2.3Hz,1H),7.58(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),7.14(s,2H),4.65(t,J＝5.8Hz,1H),3.95-3.83(m,2H),3.44-3.37(m,1H),3.36-3.33(m,1H),3.32-3.28(m,2H),3.27-3.19(m,2H),3.17-3.10(m,1H),2.33(m,2H),2.03-1.93(m,1H),1.77-1.56(m,6H),1.31(d,J＝6.6Hz,3H),1.30-1.24(m,1H).Dissolve 2-amino-5-bromo-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)nicotinamide (100mg, 302.87umol) in 1,4 -To a mixed solvent of dioxane (0.5mL) and water (0.5mL), add 1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)phenyl)ethyl)pyrrolidine (136mg, 454.30umol, step 2 of Example 25) and potassium carbonate (125mg, 908.60umol), add Pd ( dppf)Cl 2 (44mg, 60.57umol). The reaction solution was stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate (5 mL). The organic phase was concentrated under reduced pressure to obtain crude product. The crude product was purified by Prep-HPLC to obtain the title compound (4 mg, gray solid), yield: 3.2%. MS (ESI): m/z 425.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.39 (d, J = 2.1 Hz, 1H), 8.28 (d, J = 7.4 Hz, 1H),8.15(d,J＝2.3Hz,1H),7.58(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),7.14(s,2H),4.65(t, J＝5.8Hz,1H),3.95-3.83(m,2H),3.44-3.37(m,1H),3.36-3.33(m,1H),3.32-3.28(m,2H),3.27-3.19(m, 2H),3.17-3.10(m,1H),2.33(m,2H),2.03-1.93(m,1H),1.77-1.56(m,6H),1.31(d,J＝6.6Hz,3H),1.30 -1.24(m,1H).
实施例33Example 33
化合物33：2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)-5-(4-(吗啉代甲基)苯基)烟酰胺Compound 33: 2-amino-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5-(4-(morpholinomethyl)phenyl )Nicotinamide
参照实施例10步骤(2)的方法，以2-氨基-5-溴-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)烟酰胺(108mg,329umol,实施例32第1步)和4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吗啉(100mg,329umol)为原料，得到标题化合物(71.2mg,白色固体)，收率：50.62％。MS(ESI):m/z 427.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.41(d,J＝2.3Hz,1H),8.29(d,J＝7.5Hz,1H),8.16(d,J＝2.3Hz,1H),7.62(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),7.15(s,2H),4.65(t,J＝5.8Hz,1H),3.95-3.85(m,2H),3.58(t,J＝4.5Hz,4H),3.49(s,2H),3.44-3.37(m,1H),3.36-3.33(m,1H),3.30-3.22(m,1H),3.18-3.10(m,1H),2.40-2.32(m,4H),1.98(d,J＝12.2Hz,1H),1.74(d,J＝13.9Hz,1H),1.61-1.57(m,1H),1.37-1.23(m,1H).Referring to the method of step (2) of Example 10, use 2-amino-5-bromo-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)nicotinamide (108 mg, 329umol, Example 32 step 1) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzyl)morpholine (100 mg, 329umol) was used as raw material to obtain the title compound (71.2 mg, white solid), yield: 50.62%. MS (ESI): m/z 427.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.41 (d, J = 2.3Hz, 1H), 8.29 (d, J = 7.5Hz, 1H),8.16(d,J＝2.3Hz,1H),7.62(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),7.15(s,2H),4.65(t, J＝5.8Hz,1H),3.95-3.85(m,2H),3.58(t,J＝4.5Hz,4H),3.49(s,2H),3.44-3.37(m,1H),3.36-3.33(m ,1H),3.30-3.22(m,1H),3.18-3.10(m,1H),2.40-2.32(m,4H),1.98(d,J＝12.2Hz,1H),1.74(d,J＝13.9 Hz,1H),1.61-1.57(m,1H),1.37-1.23(m,1H).
实施例34Example 34
化合物34：3-氨基-6-(4-(吗啉代甲基)苯基)-N-(四氢-2H-吡喃-4-基)吡嗪-2-甲酰胺 Compound 34: 3-amino-6-(4-(morpholinomethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide
(1)3-氨基-6-溴-N-(四氢-2H-吡喃-4-基)吡嗪-2-甲酰胺(1) 3-Amino-6-bromo-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide
将四氢-2H-吡喃-4-胺(300mg,2.97mmol)和3-氨基-6-溴吡嗪-2-羧酸(500mg,2.29mmol)溶于二氯甲烷(5mL)中，加入三乙胺(465.28mg,4.60mmol)和三正丙基环磷酸酐(2.19g,3.44mmol,50％乙酸乙酯溶液)，反应液在15℃下搅拌16小时。反应液倒入水(10mL)中，水相用乙酸乙酯(5mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液浓缩。粗品经Prep-TLC(石油醚/乙酸乙酯＝1/1)纯化得到标题化合物(200mg,类白色固体)，收率：28.96％。MS(ESI):m/z 301.1[M+H]+.1H NMR(400MHz,CDCl3)δ8.15(s,1H),7.60-7.37(m,1H),4.10-3.89(m,3H),3.50-3.42(m,2H),1.93-1.85(m,2H),1.64-1.55(m,2H).Dissolve tetrahydro-2H-pyran-4-amine (300mg, 2.97mmol) and 3-amino-6-bromopyrazine-2-carboxylic acid (500mg, 2.29mmol) in dichloromethane (5mL), and add Triethylamine (465.28 mg, 4.60 mmol) and tri-n-propyl cyclic phosphoric anhydride (2.19 g, 3.44 mmol, 50% ethyl acetate solution) were stirred at 15°C for 16 hours. The reaction solution was poured into water (10 mL), and the aqueous phase was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by Prep-TLC (petroleum ether/ethyl acetate = 1/1) to obtain the title compound (200 mg, off-white solid), yield: 28.96%. MS(ESI):m/z 301.1[M+H] + . 1 H NMR(400MHz, CDCl 3 )δ8.15(s,1H),7.60-7.37(m,1H),4.10-3.89(m,3H) ),3.50-3.42(m,2H),1.93-1.85(m,2H),1.64-1.55(m,2H).
(2)3-氨基-6-(4-(吗啉代甲基)苯基)-N-(四氢-2H-吡喃-4-基)吡嗪-2-甲酰胺(2)3-Amino-6-(4-(morpholinomethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide
参照实施例10步骤(2)的方法，以3-氨基-6-溴-N-(四氢-2H-吡喃-4-基)吡嗪-2-甲酰胺(70mg,232.45umol)和4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吗啉(90mg,296.83umol)为原料，得到标题化合物(34.6mg,淡黄色固体)，收率：37.45％。MS(ESI):m/z 398.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.52(d,J＝8.4Hz,1H),8.08(d,J＝8.0Hz,2H),7.62(brs,2H),7.41(d,J＝8.0Hz,2H),4.11-3.99(m,1H),3.96-3.87(m,2H),3.63-3.56(m,4H),3.52(s,2H),3.46-3.38(m,2H),2.39-2.37(m,4H),1.84-1.71(m,4H).Referring to the method of step (2) in Example 10, use 3-amino-6-bromo-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (70 mg, 232.45umol) and 4 -(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (90mg, 296.83umol) as raw material, The title compound (34.6 mg, light yellow solid) was obtained, yield: 37.45%. MS (ESI): m/z 398.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.82 (s, 1H), 8.52 (d, J = 8.4Hz, 1H), 8.08 ( d,J＝8.0Hz,2H),7.62(brs,2H),7.41(d,J＝8.0Hz,2H),4.11-3.99(m,1H),3.96-3.87(m,2H),3.63-3.56 (m,4H),3.52(s,2H),3.46-3.38(m,2H),2.39-2.37(m,4H),1.84-1.71(m,4H).
实施例35Example 35
化合物35：2-氨基-N-((3R,6S)-6-(2-羟基丙-2-基)四氢-2H-吡喃-3-基)-5-(4-(吗啉代甲基)苯基)烟酰胺Compound 35: 2-amino-N-((3R,6S)-6-(2-hydroxyprop-2-yl)tetrahydro-2H-pyran-3-yl)-5-(4-(morpholino) Methyl)phenyl)nicotinamide
参照实施例10步骤(2)的方法，以2-氨基-5-溴-N-((3R,6S)-6-(2-羟基丙-2-基)四氢-2H-吡喃-3-基)烟酰胺(35.4mg,98.9umol,实施例10第1步)和4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吗啉(30.0mg,98.9umol)为原料，得到标题化合物(19.2mg,黄色固体)，收率：42.69％。MS(ESI):m/z 455.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.41(d,J＝2.3Hz,1H),8.28(d,J＝7.6Hz,1H),8.16(d,J＝2.1Hz,1H),7.62(d,J＝8.1Hz,2H),7.38(d,J＝8.1Hz,2H),7.15(s,2H),4.25(s,1H),3.97-3.92(m,1H),3.91-3.84(m,1H),3.58(t,J＝4.4Hz,4H),3.49(s,2H),3.13(t,J＝10.3Hz,1H),2.98(d,J＝11.2Hz,1H),2.37-2.35(m,4H),2.00(d,J＝12.4Hz,1H),1.82(d,J＝13.0Hz,1H),1.60-1.55(m,1H),1.45-1.33(m,1H),1.10(s,3H),1.05(s,3H).Referring to the method of step (2) of Example 10, use 2-amino-5-bromo-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3 -Nicotinamide (35.4 mg, 98.9umol, step 1 of Example 10) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle) Pentan-2-yl)benzyl)morpholine (30.0 mg, 98.9umol) was used as raw material to obtain the title compound (19.2 mg, yellow solid), yield: 42.69%. MS (ESI): m/z 455.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.41 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 7.6 Hz, 1H),8.16(d,J＝2.1Hz,1H),7.62(d,J＝8.1Hz,2H),7.38(d,J＝8.1Hz,2H),7.15(s,2H),4.25(s, 1H),3.97-3.92(m,1H),3.91-3.84(m,1H),3.58(t,J＝4.4Hz,4H),3.49(s,2H),3.13(t,J＝10.3Hz,1H ),2.98(d,J＝11.2Hz,1H),2.37-2.35(m,4H),2.00(d,J＝12.4Hz,1H),1.82(d,J＝13.0Hz,1H),1.60-1.55 (m,1H),1.45-1.33(m,1H),1.10(s,3H),1.05(s,3H).
实施例36Example 36
化合物36：2-氨基-5-(4-(吗啉代甲基)苯基)-N-(2-氧杂螺[3.3]庚烷-6-基)烟酰胺Compound 36: 2-amino-5-(4-(morpholinomethyl)phenyl)-N-(2-oxaspiro[3.3]heptan-6-yl)nicotinamide
(1)2-氨基-5-(4-(吗啉代甲基)苯基)烟酸甲酯(1) Methyl 2-amino-5-(4-(morpholinomethyl)phenyl)nicotinate
将2-氨基-5-溴烟酸甲酯(175.85mg,761.10umol)和4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吗啉(300mg,989.44umol)溶于1,4-二氧六环(3mL)和水(0.6mL)中。向反应液中加入碳酸钠(242.01mg,2.28mmol)和Pd(dppf)Cl2(55.69mg,76.11umol)。反应液用氮气置换三次，升温至90℃搅拌16小时。反应液冷却至室温，过滤，滤液浓缩。粗品经Prep-TLC(乙酸乙酯/甲醇＝10/1)纯化得到标题化合物(180mg,黄色固体)，收率：72.24％。MS(ESI):m/z 328.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.42(d,J＝2.4Hz,1H),8.28(d,J＝2.4Hz,1H),7.40(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),6.38(brs,2H),3.85(s,3H),3.65(t,J＝4.4Hz,4H),3.46(s,2H),2.40(t,J＝4.4Hz,4H).Combine 2-amino-5-bromonicotinic acid methyl ester (175.85mg, 761.10umol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle) Pentan-2-yl)benzyl)morpholine (300 mg, 989.44umol) was dissolved in 1,4-dioxane (3 mL) and water (0.6 mL). Sodium carbonate (242.01 mg, 2.28 mmol) and Pd(dppf)Cl 2 (55.69 mg, 76.11 umol) were added to the reaction solution. The reaction solution was replaced with nitrogen three times, and the temperature was raised to 90°C and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by Prep-TLC (ethyl acetate/methanol=10/1) to obtain the title compound (180 mg, yellow solid), yield: 72.24%. MS (ESI): m/z 328.2[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.42 (d, J = 2.4Hz, 1H), 8.28 (d, J = 2.4Hz, 1H) ,7.40(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),6.38(brs,2H),3.85(s,3H),3.65(t,J＝4.4Hz,4H) ,3.46(s,2H),2.40(t,J＝4.4Hz,4H).
(2)2-氨基-5-(4-(吗啉代甲基)苯基)烟酸(2)2-Amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid
将2-氨基-5-(4-(吗啉代甲基)苯基)烟酸甲酯(100mg,305.46umol)溶于甲醇(1mL)和水(1mL)中，向反应液中加入氢氧化锂一水合物(30mg,714.91umol)。反应液在15℃下搅拌16小时。反应液浓缩除去甲醇，加入水(2mL)和乙酸乙酯(2mL)分液萃取。用1M稀盐酸调节水相pH值至2～3后直接冻干。粗品分散到甲醇(5mL)中搅拌2小时后过滤，滤液浓缩得到标题化合物(100mg,黄色固体)，粗品直接用于下一步。MS(ESI):m/z 314.2[M+H]+.Dissolve 2-amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid methyl ester (100mg, 305.46umol) in methanol (1mL) and water (1mL), add hydroxide to the reaction solution Lithium monohydrate (30mg, 714.91umol). The reaction solution was stirred at 15°C for 16 hours. The reaction solution was concentrated to remove methanol, and water (2 mL) and ethyl acetate (2 mL) were added for separation and extraction. Adjust the pH value of the aqueous phase to 2-3 with 1M dilute hydrochloric acid and freeze-dry directly. The crude product was dispersed in methanol (5 mL) and stirred for 2 hours, then filtered. The filtrate was concentrated to obtain the title compound (100 mg, yellow solid). The crude product was used directly in the next step. MS(ESI):m/z 314.2[M+H] + .
(3)2-氨基-5-(4-(吗啉代甲基)苯基)-N-(2-氧杂螺[3.3]庚烷-6-基)烟酰胺(3)2-Amino-5-(4-(morpholinomethyl)phenyl)-N-(2-oxaspiro[3.3]heptan-6-yl)nicotinamide
将2-氨基-5-(4-(吗啉代甲基)苯基)烟酸(30mg,95.74umol)和2-氧杂螺[3.3]庚-6-胺盐酸盐(15mg,100.26umol)，HATU(40.04mg,105.31umol)溶于N,N-二甲基甲酰胺(0.5mL)中，加入N,N-二异丙基乙胺(37.10mg,287.06umol)。反应液在15℃下搅拌3小时。反应液经Prep-HPLC纯化得到标题化合物(14.8mg,白色固体)，收率：37.84％。MS(ESI):m/z 409.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.64(d,J＝7.0Hz,1H),8.41(d,J＝2.1Hz,1H),8.16(d,J＝2.1Hz,1H),7.62(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.15(s,2H),4.64(s,2H),4.52(s,2H),4.30-4.17(m,1H),3.58(t,J＝4.5Hz,4H),3.49(s,2H),2.62-2.56(m,2H),2.37-2.35(m,4H),2.29-2.21(m,2H).2-Amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid (30mg, 95.74umol) and 2-oxaspiro[3.3]heptan-6-amine hydrochloride (15mg, 100.26umol) ), HATU (40.04 mg, 105.31umol) was dissolved in N,N-dimethylformamide (0.5mL), and N,N-diisopropylethylamine (37.10mg, 287.06umol) was added. The reaction solution was stirred at 15°C for 3 hours. The reaction solution was purified by Prep-HPLC to obtain the title compound (14.8 mg, white solid), yield: 37.84%. MS (ESI): m/z 409.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.64 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H),8.16(d,J＝2.1Hz,1H),7.62(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.15(s,2H),4.64(s, 2H),4.52(s,2H),4.30-4.17(m,1H),3.58(t,J＝4.5Hz,4H),3.49(s,2H),2.62-2.56(m,2H),2.37-2.35 (m,4H),2.29-2.21(m,2H).
实施例37Example 37
化合物37：2-氨基-5-(3-氟-4-(吗啉代甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 37: 2-amino-5-(3-fluoro-4-(morpholinomethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
参照实施例26的方法，以4-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吗啉(50mg,155.67umol)和中间体4(46mg,155.67umol)为原料，得到标题化合物(12mg,白色固体)，收率：18.9％。MS(ESI):m/z 415.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝2.3Hz,1H),8.40(d,J＝7.7Hz,1H),8.19(d,J＝2.3Hz,1H),7.55(d,J＝11.7Hz,1H),7.53-7.44(m,2H),7.24(s,2H),4.08-3.95(m,1H),3.93-3.87(m,2H),3.60-3.56(m,4H),3.55(s,2H),3.40(t,J＝11.0Hz,2H),2.41-2.39(m,4H),1.81-1.77(m,2H),1.64-1.53(m,2H).Referring to the method of Example 26, 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl base) morpholine (50 mg, 155.67umol) and intermediate 4 (46mg, 155.67umol) were used as raw materials to obtain the title compound (12mg, white solid), yield: 18.9%. MS (ESI): m/z 415.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.47 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 7.7 Hz, 1H),8.19(d,J＝2.3Hz,1H),7.55(d,J＝11.7Hz,1H),7.53-7.44(m,2H),7.24(s,2H),4.08-3.95(m,1H ),3.93-3.87(m,2H),3.60-3.56(m,4H),3.55(s,2H),3.40(t,J＝11.0Hz,2H),2.41-2.39(m,4H),1.81- 1.77(m,2H),1.64-1.53(m,2H).
实施例38Example 38
化合物38：2-氨基-5-(4-((4-羟基哌啶-1-基)甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 38: 2-amino-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
(1)1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌啶-4-醇 (1)1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-ol
将2-(4-(溴甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(200mg,673.41umol)溶于乙腈(2mL)中，加入三乙胺(136mg,1.35mmol)和哌啶-4-醇(136mg,1.35mmol)，反应液在20℃下搅拌3小时。反应液减压浓缩得到标题化合物(0.2g,棕色固体)，粗品不经纯化直接用于下一步。MS(ESI):m/z 318.3[M+H]+.Dissolve 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200mg, 673.41umol) in acetonitrile (2 mL), triethylamine (136 mg, 1.35 mmol) and piperidin-4-ol (136 mg, 1.35 mmol) were added, and the reaction solution was stirred at 20°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (0.2 g, brown solid). The crude product was used directly in the next step without purification. MS(ESI):m/z 318.3[M+H] + .
(2)2-氨基-5-(4-((4-羟基哌啶-1-基)甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺(2)2-Amino-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
参照实施例26的方法，以1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌啶-4-醇(50mg,157.61umol)和中间体4(47mg,157.61umol)为原料，得到标题化合物(12mg,白色固体)，收率：19.0％。MS(ESI):m/z 411.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.44-8.39(m,2H),8.17(d,J＝2.2Hz,1H),7.61(d,J＝8.1Hz,2H),7.35(d,J＝8.1Hz,2H),7.15(s,2H),4.55(d,J＝3.4Hz,1H),4.08-3.96(m,1H),3.90(dd,J＝11.2,2.2Hz,2H),3.46(s,2H),3.44-3.36(m,3H),2.72-2.62(m,2H),2.03(t,J＝9.8Hz,2H),1.79(dd,J＝12.5,2.1Hz,2H),1.74-1.67(m,2H),1.60-1.56(m,2H),1.44-1.33(m,2H).Referring to the method of Example 26, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine -4-Alcohol (50 mg, 157.61umol) and intermediate 4 (47mg, 157.61umol) were used as raw materials to obtain the title compound (12mg, white solid), yield: 19.0%. MS (ESI): m/z 411.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.44-8.39 (m, 2H), 8.17 (d, J = 2.2Hz, 1H), 7.61(d,J＝8.1Hz,2H),7.35(d,J＝8.1Hz,2H),7.15(s,2H),4.55(d,J＝3.4Hz,1H),4.08-3.96(m,1H ),3.90(dd,J＝11.2,2.2Hz,2H),3.46(s,2H),3.44-3.36(m,3H),2.72-2.62(m,2H),2.03(t,J＝9.8Hz, 2H),1.79(dd,J=12.5,2.1Hz,2H),1.74-1.67(m,2H),1.60-1.56(m,2H),1.44-1.33(m,2H).
实施例39Example 39
化合物39：(2-氨基-5-(4-(吗啉代甲基)苯基)吡啶-3-基)(4-羟基哌啶-1-基)甲酮Compound 39: (2-amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone
参照实施例36步骤(3)的方法，以2-氨基-5-(4-(吗啉代甲基)苯基)烟酸(30mg,95.85umol,实施例36第2步)和哌啶-4-醇(11mg,105.43umol)为原料，得到标题化合物(14.2mg,黄色固体)，收率：37.4％。MS(ESI):m/z 397.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝2.3Hz,1H),7.65(d,J＝2.1Hz,1H),7.56(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),6.05(s,2H),4.77(d,J＝3.3Hz,1H),4.01-3.62(m,3H),3.58(t,J＝4.3Hz,4H),3.47(s,2H),3.19(t,J＝9.4Hz,2H),2.37-2.35(m,4H),1.76-1.74(m,2H),1.41-1.39(m,2H).Referring to the method of step (3) of Example 36, use 2-amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid (30 mg, 95.85umol, step 2 of Example 36) and piperidine- Using 4-alcohol (11 mg, 105.43umol) as raw material, the title compound (14.2 mg, yellow solid) was obtained, yield: 37.4%. MS (ESI): m/z 397.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.35 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H),7.56(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),6.05(s,2H),4.77(d,J＝3.3Hz,1H),4.01-3.62( m,3H),3.58(t,J＝4.3Hz,4H),3.47(s,2H),3.19(t,J＝9.4Hz,2H),2.37-2.35(m,4H),1.76-1.74(m ,2H),1.41-1.39(m,2H).
实施例40Example 40
化合物40：(2-氨基-5-(4-(吗啉代甲基)苯基)吡啶-3-基)(4-(羟甲基)哌啶-1-基)甲酮Compound 40: (2-amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)(4-(hydroxymethyl)piperidin-1-yl)methanone
参照实施例36步骤(3)的方法，以2-氨基-5-(4-(吗啉代甲基)苯基)烟酸(30mg,95.85umol,实施例36第2步)和哌啶-4-基甲醇(12mg,105.43umol)为原料，得到标题化合物(16.9mg,黄色油状物)，收率：43.0％。MS(ESI):m/z 411.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝2.1Hz,1H),7.63(d,J＝2.1Hz,1H),7.56(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),6.04(s,2H),4.49(brs,1H),3.58(t,J＝4.4Hz,4H),3.47(s,2H),3.28-3.26(m,4H),2.92-2.89(m,2H),2.37-2.35(m,4H),1.76-1.57(m,3H),1.15-1.11(m,2H).Referring to the method of step (3) of Example 36, use 2-amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid (30 mg, 95.85umol, step 2 of Example 36) and piperidine- 4-ylmethanol (12 mg, 105.43umol) was used as raw material to obtain the title compound (16.9 mg, yellow oil), yield: 43.0%. MS (ESI): m/z 411.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.34 (d, J = 2.1 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H),7.56(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),6.04(s,2H),4.49(brs,1H),3.58(t,J＝4.4Hz, 4H),3.47(s,2H),3.28-3.26(m,4H),2.92-2.89(m,2H),2.37-2.35(m,4H),1.76-1.57(m,3H),1.15-1.11( m,2H).
实施例41Example 41
化合物41：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(氧杂环-3-基)哌啶-4-基)-1H-吲唑-5-基)烟酰胺Compound 41: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(oxaheterocyclyl-3-yl)piperidin-4-yl) -1H-indazol-5-yl)nicotinamide
(1)4-(5-溴-1H-吲唑-1-基)哌啶-1-羧酸叔丁酯(1) tert-butyl 4-(5-bromo-1H-indazol-1-yl)piperidine-1-carboxylate
在0℃下，将1-(叔丁氧羰基)-4-(甲磺酰氧基)哌啶(4.68g,16.75mmol)分批加入到5-溴吲唑(3g,15.23mmol)和氢化钠(670.06mg,16.75mmol,60％纯度)的N,N-二甲基甲酰胺(30mL)溶液中。反应液升温至100℃，在氮气保护下搅拌14小时。将反应液倒入饱和氯化铵(50mL)中淬灭，用乙酸乙酯(10mL x 3)萃取，有机相浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝3/1～1/1)纯化得到4-(5-溴-1H-吲唑-1-基)哌啶-1-羧酸叔丁酯(2.8g,白色固体)，收率：48.35％。1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.80(d,J＝1.5Hz,1H),7.37(dd,J＝8.9,1.6Hz,1H),7.26(d,J＝8.9Hz,1H),4.49-4.42(m,1H),4.25-4.22(m,2H),2.92-2.85(m,2H),2.20-2.07(m,2H),1.96-1.87(m,2H),1.42(s,9H).At 0°C, 1-(tert-butoxycarbonyl)-4-(methanesulfonyloxy)piperidine (4.68g, 16.75mmol) was added in portions to 5-bromoindazole (3g, 15.23mmol) and hydrogenated Sodium (670.06 mg, 16.75 mmol, 60% purity) in N,N-dimethylformamide (30 mL). The reaction solution was heated to 100°C and stirred for 14 hours under nitrogen protection. The reaction solution was poured into saturated ammonium chloride (50 mL) to quench, extracted with ethyl acetate (10 mL x 3), and the organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 3/1 ~ 1/1) to obtain 4-(5-bromo-1H-indazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester ( 2.8g, white solid), yield: 48.35%. 1 H NMR (400MHz, CDCl 3 ) δ7.86 (s, 1H), 7.80 (d, J = 1.5Hz, 1H), 7.37 (dd, J = 8.9, 1.6Hz, 1H), 7.26 (d, J = 8.9Hz,1H),4.49-4.42(m,1H),4.25-4.22(m,2H),2.92-2.85(m,2H),2.20-2.07(m,2H),1.96-1.87(m,2H) ,1.42(s,9H).
同时，该反应分离纯化得到另一个异构体4-(5-溴-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯(1.2g,白色固体)，收率：20.72％。1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.74(d,J＝1.3Hz,1H),7.52(d,J＝9.1Hz,1H),7.28(dd,J＝9.1,1.8Hz,1H),4.53-4.45(m,1H),4.31-4.19(m,2H),2.94-2.81(m,2H),2.17(dd,J＝12.1,1.8Hz,2H),2.09-1.95(m,2H),1.42(s,9H).At the same time, the reaction was separated and purified to obtain another isomer, 4-(5-bromo-2H-indazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (1.2g, white solid), yield: 20.72 %. 1 H NMR (400MHz, CDCl 3 ) δ7.83 (s, 1H), 7.74 (d, J = 1.3Hz, 1H), 7.52 (d, J = 9.1Hz, 1H), 7.28 (dd, J = 9.1, 1.8Hz,1H),4.53-4.45(m,1H),4.31-4.19(m,2H),2.94-2.81(m,2H),2.17(dd,J＝12.1,1.8Hz,2H),2.09-1.95 (m,2H),1.42(s,9H).
(2)5-溴-1-(哌啶-4-基)-1H-吲唑(2)5-Bromo-1-(piperidin-4-yl)-1H-indazole
将4-(5-溴-1H-吲唑-1-基)哌啶-1-羧酸叔丁酯(2g,5.26mmol)溶于二氯甲烷(8mL)中，加入盐酸/二氧六环(4M,25mL)溶液。反应液在15℃下搅拌12小时。反应液在45℃下浓缩，得到标题化合物(1.67g,盐酸盐,白色固体)，粗品直接用于下一步。MS(ESI):m/z 280.0[M+H]+.Dissolve 4-(5-bromo-1H-indazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (2g, 5.26mmol) in dichloromethane (8mL), add hydrochloric acid/dioxane (4M, 25mL) solution. The reaction solution was stirred at 15°C for 12 hours. The reaction solution was concentrated at 45°C to obtain the title compound (1.67 g, hydrochloride, white solid), and the crude product was used directly in the next step. MS(ESI):m/z 280.0[M+H] + .
(3)5-溴-1-(1-(氧杂环丁烷-3-基)哌啶-4-基)-1H-吲唑(3)5-Bromo-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indazole
在15℃下，将5-溴-1-(哌啶-4-基)-1H-吲唑(300mg,947.50umol,盐酸盐)溶于甲醇(3mL)中，加入三乙胺(95.88mg,947.50umol)和3-氧杂环丁酮(94.15mg,1.31mmol)。反应液在15℃下搅拌1小时后，向反应液中加入氰基硼氢化钠(120.0mg,1.91mmol)和醋酸(63.0mg,1.05mmol)。反应液在15℃下继续搅拌16小时。向反应液加入水(5mL)，用乙酸乙酯(5mL x 4)萃取，将有机相合并浓缩得到粗品。粗品经Prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到标题化合物(170mg,白色固体)，收率：53.36％。MS(ESI):m/z336.1[M+H]+.1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.80(s,1H),7.39-7.35(m,1H),7.31-7.27(m,1H),4.65-4.58(m,4H),4.41-4.30(m,1H),3.56-3.49(m,1H),2.88(d,J＝12.5Hz,2H),2.40-2.26(m,2H),2.10-1.94(m,4H).Dissolve 5-bromo-1-(piperidin-4-yl)-1H-indazole (300 mg, 947.50umol, hydrochloride) in methanol (3mL) at 15°C, and add triethylamine (95.88mg ,947.50umol) and 3-oxetanone (94.15mg, 1.31mmol). After the reaction liquid was stirred at 15° C. for 1 hour, sodium cyanoborohydride (120.0 mg, 1.91 mmol) and acetic acid (63.0 mg, 1.05 mmol) were added to the reaction liquid. The reaction solution was continued to stir at 15°C for 16 hours. Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL x 4), and the organic phases were combined and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (dichloromethane/methanol=10/1) to obtain the title compound (170 mg, white solid), yield: 53.36%. MS(ESI):m/z336.1[M+H] + . 1 H NMR(400MHz, CDCl 3 )δ7.86(s,1H),7.80(s,1H),7.39-7.35(m,1H) ,7.31-7.27(m,1H),4.65-4.58(m,4H),4.41-4.30(m,1H),3.56-3.49(m,1H),2.88(d,J＝12.5Hz,2H),2.40 -2.26(m,2H),2.10-1.94(m,4H).
(4)1-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑(4)1-(1-(oxetan-3-yl)piperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Heteraborol-2-yl)-1H-indazole
在15℃下，将联硼酸频那醇酯(79.30mg,312.29umol)和5-溴-1-(1-(氧杂环丁烷-3-基)哌啶-4-基)-1H-吲唑(70mg,208.19umol)溶于1,4-二氧六环(1mL)中，加入磷酸钾(132.58mg,624.58umol)和1,1-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(17.00mg,20.82umol)。反应液通入氮气鼓气置换，然后升温至 80℃搅拌16小时。反应液冷却至室温后，加入甲醇(5mL)进行稀释，过滤。滤液经Prep-TLC(乙酸乙酯/甲醇＝10/1)纯化得到标题化合物(45mg,白色固体)，收率：56.39％。MS(ESI):m/z 384.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.20(s,1H),7.93(s,1H),7.70(d,J＝8.2Hz,1H),7.38(d,J＝8.6Hz,1H),4.68-4.55(m,4H),4.39-4.34(m,1H),3.54-3.49(m,1H),2.91-2.81(m,2H),2.42-2.28(m,2H),2.07-1.94(m,4H),1.30(s,12H).At 15°C, combine pinacol diboronate (79.30 mg, 312.29umol) and 5-bromo-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H- Indazole (70mg, 208.19umol) was dissolved in 1,4-dioxane (1mL), potassium phosphate (132.58mg, 624.58umol) and 1,1-bis(diphenylphosphino)ferrocene dichloride were added Palladium (II) dichloromethane complex (17.00 mg, 20.82umol). The reaction solution was replaced by nitrogen gas and then heated to Stir at 80°C for 16 hours. After the reaction solution was cooled to room temperature, methanol (5 mL) was added for dilution and filtered. The filtrate was purified by Prep-TLC (ethyl acetate/methanol=10/1) to obtain the title compound (45 mg, white solid), yield: 56.39%. MS (ESI): m/z 384.3[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.20 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 8.2Hz, 1H),7.38(d,J＝8.6Hz,1H),4.68-4.55(m,4H),4.39-4.34(m,1H),3.54-3.49(m,1H),2.91-2.81(m,2H) ,2.42-2.28(m,2H),2.07-1.94(m,4H),1.30(s,12H).
(5)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(氧杂环-3-基)哌啶-4-基)-1H-吲唑-5-基)烟酰胺(5)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(oxaheterocyclyl-3-yl)piperidin-4-yl) -1H-indazol-5-yl)nicotinamide
在15℃下，将中间体5(33.29mg,97.84umol)和1-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑(45mg,117.40umol)溶于1,4-二氧六环(0.5mL)和水(0.1mL)的混合溶剂中，加入碳酸钠(31.11mg,293.51umol)和Pd(dppf)Cl2(7.16mg,9.78umol)。反应液用氮气鼓气，然后升温至80℃搅拌16小时。反应液冷却至室温后浓缩，粗品用甲醇(3mL)稀释后过滤，滤液经Prep-HPLC纯化得到标题化合物(5.5mg,白色固体)，收率：10.66％。MS(ESI):m/z 517.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.4Hz,1H),8.12(s,1H),8.04(d,J＝2.3Hz,1H),7.99(s,1H),7.81-7.78(m,2H),7.69(dd,J＝8.8,1.6Hz,1H),6.88(s,2H),4.72-4.63(m,1H),4.61-4.56(m,2H),4.48(t,J＝6.1Hz,2H),4.31(s,1H),3.54-3.44(m,1H),2.86(d,J＝10.9Hz,2H),2.22-2.11(m,2H),2.10-2.03(m,8H),1.95(d,J＝11.8Hz,2H),1.67-1.59(m,6H).At 15°C, intermediate 5 (33.29 mg, 97.84umol) and 1-(1-(oxetan-3-yl)piperidin-4-yl)-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (45 mg, 117.40umol) was dissolved in 1,4-dioxane (0.5 mL) To a mixed solvent of water (0.1 mL), sodium carbonate (31.11 mg, 293.51 umol) and Pd(dppf)Cl 2 (7.16 mg, 9.78 umol) were added. The reaction solution was sparged with nitrogen, then heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated. The crude product was diluted with methanol (3 mL) and filtered. The filtrate was purified by Prep-HPLC to obtain the title compound (5.5 mg, white solid), yield: 10.66%. MS (ESI): m/z 517.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.39 (d, J = 2.4Hz, 1H), 8.12 (s, 1H), 8.04 ( d,J＝2.3Hz,1H),7.99(s,1H),7.81-7.78(m,2H),7.69(dd,J＝8.8,1.6Hz,1H),6.88(s,2H),4.72-4.63 (m,1H),4.61-4.56(m,2H),4.48(t,J＝6.1Hz,2H),4.31(s,1H),3.54-3.44(m,1H),2.86(d,J＝10.9 Hz,2H),2.22-2.11(m,2H),2.10-2.03(m,8H),1.95(d,J＝11.8Hz,2H),1.67-1.59(m,6H).
实施例42Example 42
化合物42：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(4-(氧杂环-3-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)烟酰胺Compound 42: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(4-(oxaheterocyclyl-3-yl)piperazin-1-yl) -2,3-Dihydro-1H-inden-5-yl)nicotinamide
(1)1-(5-溴-2,3-二氢-1H-茚-1-基)-4-(氧杂环丁烷-3-基)哌嗪(1)1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-4-(oxetan-3-yl)piperazine
将5-溴-2,3-二氢-1H-茚-1-酮(3.00g,14.21mmol)溶于四氢呋喃(150mL)中，依次加入1-(氧杂环丁烷-3-基)哌嗪(4.04g,28.43mmol)，钛酸四异丙酯(12.12g,42.64mmol)，随后反应在70℃搅拌4小时。然后将反应降至20℃，向反应液中加入三乙酰氧基硼氢化钠(12.05g,56.86mmol)。反应液在20℃搅拌12小时。将反应液加入水(200mL)中，析出白色固体，过滤。滤液用乙酸乙酯(100mL x 2)萃取，合并有机相减压浓缩。残留物用柱层析(石油醚/乙酸乙酯＝100/1～0/1)纯化得到标题化合物(700mg,黑色油状物)，收率：14.6％。MS(ESI):m/z 337.1[M+H]+.Dissolve 5-bromo-2,3-dihydro-1H-inden-1-one (3.00g, 14.21mmol) in tetrahydrofuran (150mL), and add 1-(oxetan-3-yl)piper in sequence. (4.04g, 28.43mmol), tetraisopropyl titanate (12.12g, 42.64mmol), and the reaction was stirred at 70°C for 4 hours. Then the reaction was lowered to 20°C, and sodium triacetoxyborohydride (12.05g, 56.86mmol) was added to the reaction solution. The reaction solution was stirred at 20°C for 12 hours. The reaction solution was added to water (200 mL), and a white solid precipitated, which was filtered. The filtrate was extracted with ethyl acetate (100 mL x 2), and the combined organic phases were concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 100/1 to 0/1) to obtain the title compound (700 mg, black oil), yield: 14.6%. MS(ESI):m/z 337.1[M+H] + .
(2)1-(氧杂环丁烷-3-基)-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢-1H-茚-1-基)哌嗪(2)1-(oxetan-3-yl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-2,3-dihydro-1H-inden-1-yl)piperazine
将1-(5-溴-2,3-二氢-1H-茚-1-基)-4-(氧杂环丁烷-3-基)哌嗪(350mg,1.04mmol)溶于1,4-二氧六环(3.5mL)中，加入乙酸钾(305mg,3.11mmol)，联硼酸频那醇酯(316mg,1.25mmol)。在氮气保护下，加入Pd(dppf)Cl2(75mg,103.78umol)。反应液在80℃氮气保护下搅拌12小时。反应液冷却至室温，加入水(15mL)和乙酸乙酯(15mL)分液萃取，有机相减压浓缩得到粗品。粗品经Prep-TLC(乙酸乙酯/甲醇＝0/1)纯化得到标题化合物(200mg,黄色固体)，收率：50.1％。MS(ESI):m/z 385.3[M+H]+.Dissolve 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-4-(oxetan-3-yl)piperazine (350 mg, 1.04 mmol) in 1,4 -To dioxane (3.5 mL), add potassium acetate (305 mg, 3.11 mmol) and pinacol diborate (316 mg, 1.25 mmol). Under nitrogen protection, Pd(dppf)Cl 2 (75 mg, 103.78umol) was added. The reaction solution was stirred at 80°C under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, water (15 mL) and ethyl acetate (15 mL) were added for liquid separation extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-TLC (ethyl acetate/methanol=0/1) to obtain the title compound (200 mg, yellow solid), yield: 50.1%. MS(ESI):m/z 385.3[M+H] + .
(3)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(4-(氧杂环-3-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)烟酰胺(3) 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(4-(oxaheterocyclyl-3-yl)piperazin-1-yl) -2,3-Dihydro-1H-inden-5-yl)nicotinamide
将1-(氧杂环丁烷-3-基)-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢-1H-茚-1-基)哌嗪(50mg,130.10umol)溶于1,4-二氧六环(0.5mL)和水(0.5mL)的混合溶液中，加入中间体5(44mg,130.10umol)和碳酸钾(53mg,390.30umol)。在氮气保护下，向反应液中加入Pd(dppf)Cl2(9mg,13.01umol)。反应液在80℃氮气保护下搅拌12小时。反应液冷却至室温，加入水(5mL)和乙酸乙酯(5mL)分液萃取，有机相减压浓缩得到粗品。粗品经Prep-HPLC纯化得到(5mg,白色固体)，收率：7.4％。MS(ESI):m/z 518.4[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝2.3Hz,1H),8.00(d,J＝2.1Hz,1H),7.77(s,1H),7.49(s,1H),7.45(d,J＝7.7Hz,1H),7.31(d,J＝7.9Hz,1H),6.91(s,2H),4.55-4.49(m,2H),4.43-4.37(m,2H),4.31-4.29(m,2H),3.42-3.37(m,1H),2.99-2.88(m,1H),2.86-2.77(m,1H),2.55-2.52(m,2H),2.46-2.39(m,2H),2.35-2.14(m,4H),2.08-2.00(m,8H),1.65-1.59(m,6H).1-(oxetan-3-yl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- (2,3-dihydro-1H-inden-1-yl)piperazine (50 mg, 130.10umol) was dissolved in a mixed solution of 1,4-dioxane (0.5mL) and water (0.5mL) , add intermediate 5 (44mg, 130.10umol) and potassium carbonate (53mg, 390.30umol). Under nitrogen protection, Pd(dppf)Cl 2 (9 mg, 13.01umol) was added to the reaction solution. The reaction solution was stirred at 80°C under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, water (5 mL) and ethyl acetate (5 mL) were added for liquid separation extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC (5 mg, white solid), yield: 7.4%. MS (ESI): m/z 518.4[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.33 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H),7.77(s,1H),7.49(s,1H),7.45(d,J＝7.7Hz,1H),7.31(d,J＝7.9Hz,1H),6.91(s,2H),4.55- 4.49(m,2H),4.43-4.37(m,2H),4.31-4.29(m,2H),3.42-3.37(m,1H),2.99-2.88(m,1H),2.86-2.77(m,1H ),2.55-2.52(m,2H),2.46-2.39(m,2H),2.35-2.14(m,4H),2.08-2.00(m,8H),1.65-1.59(m,6H).
实施例43Example 43
化合物43：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酰胺Compound 43: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidine- 3-yl)-1H-indazol-5-yl)nicotinamide
(1)3-(5-溴-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁酯(1) tert-butyl 3-(5-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylate
将5-溴-1H-吲唑(3.00g,15.2mmol)溶于N,N-二甲基甲酰胺(30mL)中，降温至0℃，缓慢加入氢化钠(669mg,16.7mmol,60％纯度)，并在0℃搅拌30分钟。然后在0℃下将3-((甲基磺酰基)氧基)吡咯烷-1-羧酸叔丁酯(4.44g,16.7mmol)加到反应液中。反应液升温至100℃搅拌14小时。反应液降至室温，向反应液中加入水(100mL)，用二氯甲烷(50mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液浓缩。残留物用柱层析(石油醚/乙酸乙酯＝5/1～1/1)纯化得到3-(5-溴-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁酯(2.90g,白色固体)，收率：52.0％。MS(ESI):m/z 310.0[M+H-56]+.1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.81(s,1H),7.40(d,J＝8.7Hz,1H),7.25(d,J＝8.7Hz,1H),5.11-5.01(m,1H),3.92-3.46(m,4H),2.56-2.28(m,2H),1.40(s,9H).Dissolve 5-bromo-1H-indazole (3.00g, 15.2mmol) in N,N-dimethylformamide (30mL), cool to 0°C, and slowly add sodium hydride (669mg, 16.7mmol, 60% purity ) and stir at 0°C for 30 minutes. Then, 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (4.44g, 16.7mmol) was added to the reaction solution at 0°C. The reaction solution was heated to 100°C and stirred for 14 hours. The reaction solution was cooled to room temperature, water (100 mL) was added to the reaction solution, and extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain 3-(5-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. (2.90g, white solid), yield: 52.0%. MS (ESI): m/z 310.0[M+H-56] + . 1 H NMR (400MHz, CDCl 3 ) δ7.87 (s, 1H), 7.81 (s, 1H), 7.40 (d, J = 8.7 Hz,1H),7.25(d,J＝8.7Hz,1H),5.11-5.01(m,1H),3.92-3.46(m,4H),2.56-2.28(m,2H),1.40(s,9H) .
同时，该反应分离纯化得到另一个异构体3-(5-溴-2H-吲唑-2-基)吡咯烷-1-羧酸叔丁酯(2.0g,白色固体)，收率：35.86％。MS(ESI):m/z 310.0[M+H-56]+.1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.73(d,J＝1.1Hz,1H),7.51(d,J＝9.2Hz,1H),7.27(dd,J＝9.2,1.5Hz,1H),5.10-5.07(m,1H),3.96-3.72(m,2H),3.70-3.48(m,2H),2.48-2.40(m,2H),1.41(s,9H). At the same time, the reaction was separated and purified to obtain another isomer, 3-(5-bromo-2H-indazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.0g, white solid), yield: 35.86 %. MS (ESI): m/z 310.0[M+H-56] + . 1 H NMR (400MHz, CDCl 3 ) δ7.83 (s, 1H), 7.73 (d, J = 1.1Hz, 1H), 7.51 ( d,J＝9.2Hz,1H),7.27(dd,J＝9.2,1.5Hz,1H),5.10-5.07(m,1H),3.96-3.72(m,2H),3.70-3.48(m,2H) ,2.48-2.40(m,2H),1.41(s,9H).
(2)5-溴-1-(吡咯烷-3-基)-1H-吲唑(2)5-Bromo-1-(pyrrolidin-3-yl)-1H-indazole
将3-(5-溴-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁酯(500mg,1.37mmol)溶于二氯甲烷(5.0mL)中，缓慢滴加盐酸/二氧六环溶液(4.0M,1.02mL)。反应液在室温下搅拌12小时。反应液浓缩得到标题化合物(300mg,白色固体,盐酸盐)。MS(ESI):m/z 266.0[M+H]+.1H NMR(400MHz,CD3OD)δ8.10(s,1H),7.99(d,J＝1.2Hz,1H),7.66-7.63(m,1H),7.59-7.55(m,1H),5.71-5.63(m,1H),3.91-3.76(m,2H),3.73-3.55(m,2H),2.64-2.58(m,1H),2.41-2.31(m,1H).Dissolve 3-(5-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.37 mmol) in dichloromethane (5.0 mL), slowly add hydrochloric acid/dichloromethane dropwise Oxygen hexacyclic solution (4.0M, 1.02mL). The reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated to obtain the title compound (300 mg, white solid, hydrochloride). MS (ESI): m/z 266.0[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.10 (s, 1H), 7.99 (d, J = 1.2Hz, 1H), 7.66-7.63 (m,1H),7.59-7.55(m,1H),5.71-5.63(m,1H),3.91-3.76(m,2H),3.73-3.55(m,2H),2.64-2.58(m,1H) ,2.41-2.31(m,1H).
(3)5-溴-1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑(3)5-Bromo-1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazole
将5-溴-1-(吡咯烷-3-基)-1H-吲唑(300mg,991umol,盐酸盐)溶于甲醇(3.0mL)中，加入三乙胺(100mg,991umol)和四氢-4H-吡喃-4-酮(138mg,1.39mmol)，反应液在15℃下搅拌1小时。向反应液中加入氰基硼氢化钠(124mg,1.98mmol)和醋酸(65.4mg,1.09mmol)，继续搅拌12小时。向反应液中加入水(10mL)，用乙酸乙酯(5mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤。滤液浓缩得到标题化合物(110mg,黄色油状物)。MS(ESI):m/z 350.1[M+H]+.1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.80(s,1H),7.40(s,1H),7.19(s,1H),5.28-5.26(m,1H),3.98-3.94(m,2H),3.56-3.53(m,1H),3.37-3.31(m,2H),3.21-2.93(m,3H),2.72-2.44(m,2H),2.32-2.22(m,1H),1.87-1.66(m,4H).Dissolve 5-bromo-1-(pyrrolidin-3-yl)-1H-indazole (300 mg, 991umol, hydrochloride) in methanol (3.0mL), add triethylamine (100mg, 991umol) and tetrahydrogen -4H-pyran-4-one (138 mg, 1.39 mmol), the reaction solution was stirred at 15°C for 1 hour. Sodium cyanoborohydride (124 mg, 1.98 mmol) and acetic acid (65.4 mg, 1.09 mmol) were added to the reaction solution, and stirring was continued for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the title compound (110 mg, yellow oil). MS(ESI): m/z 350.1[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ7.87(s,1H),7.80(s,1H),7.40(s,1H),7.19( s,1H),5.28-5.26(m,1H),3.98-3.94(m,2H),3.56-3.53(m,1H),3.37-3.31(m,2H),3.21-2.93(m,3H), 2.72-2.44(m,2H),2.32-2.22(m,1H),1.87-1.66(m,4H).
(4)2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酸甲酯(4) Methyl 2-amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazol-5-yl)nicotinate
将5-溴-1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑(110mg,314umol)和2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(104mg,376umol)溶于1,4-二氧六环(1.1mL)和水(0.22mL)中，加入碳酸钾(86.8mg,628umol)。体系用氮气置换三次，并在氮气保护下加入Pd(dppf)Cl2(22.9mg,31.4umol)。反应液升温到100℃搅拌12小时。反应液降到室温后，向反应液中加入水(5mL)，用乙酸乙酯(3mL x 2)萃取。合并有机相，用无水硫酸钠干燥后过滤，滤液浓缩。粗品经Prep-TLC纯化得到标题化合物(90.0mg,黄色油状物)，收率：67.8％。MS(ESI):m/z 422.3[M+H]+.Combine 5-bromo-1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazole (110 mg, 314umol) and 2-amino-5-(4, Methyl 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (104mg, 376umol) was dissolved in 1,4-dioxane (1.1 mL) and water (0.22mL), add potassium carbonate (86.8mg, 628umol). The system was replaced with nitrogen three times, and Pd(dppf)Cl 2 (22.9 mg, 31.4umol) was added under nitrogen protection. The reaction solution was heated to 100°C and stirred for 12 hours. After the reaction solution cooled to room temperature, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by Prep-TLC to obtain the title compound (90.0 mg, yellow oil), yield: 67.8%. MS(ESI):m/z 422.3[M+H] + .
(5)2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酸(5)2-amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazol-5-yl)nicotinic acid
将2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酸甲酯(90.0mg,213umol)溶于甲醇(0.9mL)和水(0.9mL)中，加入氢氧化锂(10.2mg,427umol)。反应液在室温下搅拌12小时。浓缩反应液，粗品经Prep-HPLC纯化得到标题化合物(30.0mg,无色油状物)，收率：34.48％。MS(ESI):m/z 408.2[M+H]+.2-Amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazol-5-yl)nicotinic acid methyl ester (90.0 mg , 213umol) was dissolved in methanol (0.9mL) and water (0.9mL), and lithium hydroxide (10.2mg, 427umol) was added. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the crude product was purified by Prep-HPLC to obtain the title compound (30.0 mg, colorless oil), yield: 34.48%. MS(ESI):m/z 408.2[M+H] + .
(6)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酰胺(6)2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidine- 3-yl)-1H-indazol-5-yl)nicotinamide
将2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酸(30.0mg,73.6umol)，HATU(33.5mg,88.3umol)和N,N-二异丙基乙胺(28.5mg,220umol)溶于N,N-二甲基甲酰胺(0.3mL)中，反应液在室温下搅拌30分钟。向反应液中加入4-氨基双环[2.2.2]辛-1-醇盐酸盐(15.7mg,88.3umol)，继续在室温下搅拌12小时。过滤反应液，浓缩滤液得到粗品。粗品经Prep-HPLC纯化得到标题化合物(14.5mg,白色固体)，收率：37.11％。MS(ESI):m/z 531.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝2.4Hz,1H),8.10(s,1H),8.05(d,J＝2.3Hz,1H),7.99(s,1H),7.91(d,J＝8.9Hz,1H),7.80(s,1H),7.71(dd,J＝8.9,1.5Hz,1H),6.89(s,2H),5.44-5.34(m,1H),4.31(s,1H),3.91-3.82(m,2H),3.36-3.29(m,2H),3.16(t,J＝8.8Hz,1H),2.91-2.81(m,2H),2.79-2.77(m,1H),2.43-2.30(m,2H),2.28-2.16(m,1H),2.10-2.02(m,6H),1.81(d,J＝11.6Hz,2H),1.67-1.59(m,6H),1.49-1.36(m,2H).2-Amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazol-5-yl)nicotinic acid (30.0 mg, 73.6 umol), HATU (33.5mg, 88.3umol) and N,N-diisopropylethylamine (28.5mg, 220umol) were dissolved in N,N-dimethylformamide (0.3mL), and the reaction solution was at room temperature. Stir for 30 minutes. 4-Aminobicyclo[2.2.2]octan-1-ol hydrochloride (15.7 mg, 88.3 umol) was added to the reaction solution, and stirring was continued at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain crude product. The crude product was purified by Prep-HPLC to obtain the title compound (14.5 mg, white solid), yield: 37.11%. MS (ESI): m/z 531.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.40 (d, J = 2.4Hz, 1H), 8.10 (s, 1H), 8.05 ( d,J＝2.3Hz,1H),7.99(s,1H),7.91(d,J＝8.9Hz,1H),7.80(s,1H),7.71(dd,J＝8.9,1.5Hz,1H), 6.89(s,2H),5.44-5.34(m,1H),4.31(s,1H),3.91-3.82(m,2H),3.36-3.29(m,2H),3.16(t,J＝8.8Hz, 1H),2.91-2.81(m,2H),2.79-2.77(m,1H),2.43-2.30(m,2H),2.28-2.16(m,1H),2.10-2.02(m,6H),1.81( d,J＝11.6Hz,2H),1.67-1.59(m,6H),1.49-1.36(m,2H).
实施例44Example 44
化合物44：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酰胺Compound 44: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidine- 3-yl)-2H-indazol-5-yl)nicotinamide
(1)5-溴-2-(吡咯烷-3-基)-2H-吲唑(1)5-Bromo-2-(pyrrolidin-3-yl)-2H-indazole
将3-(5-溴-2H-吲唑-2-基)吡咯烷-1-羧酸叔丁酯(1.00g,2.73mmol,实施例43第1步异构体)溶于二氯甲烷(10mL)中，缓慢滴加盐酸/二氧六环溶液(4.0M,2.05mL)，在室温下反应12小时。反应液浓缩得到标题化合物(700mg,白色固体,盐酸盐)。MS(ESI):m/z 266.0[M+H]+.1H NMR(400MHz,CD3OD)δ8.00(s,1H),7.56(d,J＝1.6Hz,1H),7.23(d,J＝9.0Hz,1H),7.02(dd,J＝9.2,1.8Hz,1H),5.27-5.19(m,1H),3.50-3.45(m,2H),2.97-2.94(m,2H),2.40-2.07(m,2H).Dissolve 3-(5-bromo-2H-indazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.00g, 2.73mmol, the first isomer of Example 43) in dichloromethane ( 10 mL), slowly add hydrochloric acid/dioxane solution (4.0 M, 2.05 mL) dropwise, and react at room temperature for 12 hours. The reaction solution was concentrated to obtain the title compound (700 mg, white solid, hydrochloride). MS (ESI): m/z 266.0[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.00 (s, 1H), 7.56 (d, J = 1.6Hz, 1H), 7.23 (d ,J＝9.0Hz,1H),7.02(dd,J＝9.2,1.8Hz,1H),5.27-5.19(m,1H),3.50-3.45(m,2H),2.97-2.94(m,2H), 2.40-2.07(m,2H).
(2)5-溴-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑(2)5-Bromo-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazole
将5-溴-2-(吡咯烷-3-基)-2H-吲唑(700mg,2.63mmol,盐酸盐)溶于甲醇(7.0mL)中，加入三乙胺(266mg,2.63mmol)和四氢-4H-吡喃-4-酮(363mg,3.63mmol)。反应液在15℃下搅拌1小时，加入氰基硼氢化钠(333mg,5.31mmol)和醋酸(175mg,2.92mmol)。反应液在15℃下继续搅拌12小时。向反应液中加入水(20mL)，用乙酸乙酯(10mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物用柱层析(二氯甲烷/甲醇＝15/1～5/1)纯化得到标题化合物(330mg,无色油状物)，收率：35.82％。MS(ESI):m/z 350.1[M+H]+.1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.74(d,J＝1.2Hz,1H),7.50(d,J＝9.2Hz,1H),7.26(dd,J＝9.1,1.7Hz,1H),5.18-5.05(m,1H),3.97-3.90(m,2H),3.39-3.31(m,2H),3.16-3.03(m,3H),2.75-2.72(m,1H),2.59-2.37(m,2H),2.27-2.18(m,1H),1.80-1.76(m,2H),1.68-1.55(m,2H).Dissolve 5-bromo-2-(pyrrolidin-3-yl)-2H-indazole (700 mg, 2.63 mmol, hydrochloride) in methanol (7.0 mL), add triethylamine (266 mg, 2.63 mmol) and Tetrahydro-4H-pyran-4-one (363 mg, 3.63 mmol). The reaction solution was stirred at 15°C for 1 hour, and sodium cyanoborohydride (333 mg, 5.31 mmol) and acetic acid (175 mg, 2.92 mmol) were added. The reaction solution was continued to stir at 15°C for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane/methanol = 15/1 to 5/1) to obtain the title compound (330 mg, colorless oil), yield: 35.82%. MS (ESI): m/z 350.1[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.03 (s, 1H), 7.74 (d, J = 1.2Hz, 1H), 7.50 (d, J＝9.2Hz,1H),7.26(dd,J＝9.1,1.7Hz,1H),5.18-5.05(m,1H),3.97-3.90(m,2H),3.39-3.31(m,2H),3.16 -3.03(m,3H),2.75-2.72(m,1H),2.59-2.37(m,2H),2.27-2.18(m,1H),1.80-1.76(m,2H),1.68-1.55(m, 2H).
(3)2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸甲酯(3) Methyl 2-amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinate
将5-溴-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑(300mg,856umol)和2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(285mg,1.03mmol)溶于1,4-二氧六环(3.0mL)和水(0.6mL)中，加入碳酸钾(236mg,1.71mmol)。体系用氮气置换三次，并在氮气保护下加入Pd(dppf)Cl2(62.6mg, 85.6umol)。反应液升温到100℃搅拌12小时。反应液温度降到室温后，向反应液中加入水(5mL)，用乙酸乙酯(3mL x 2)萃取。合并有机相，用无水硫酸钠干燥后过滤，滤液浓缩得到粗品。粗品经Prep-TLC纯化得到标题化合物(200mg,黄色油状物)，收率：55.40％。MS(ESI):m/z 422.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.46(d,J＝2.4Hz,1H),8.32(d,J＝2.4Hz,1H),8.14(s,1H),7.72-7.68(m,2H),7.42-7.38(m,1H),6.34(brs,2H),5.17-5.08(m,1H),3.97-3.90(m,2H),3.86(s,3H),3.42-3.34(m,3H),3.12-3.03(m,2H),2.72-2.50(m,2H),2.42-2.20(m,2H),1.80-1.76(m,2H),1.65-1.53(m,2H).Combine 5-bromo-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazole (300 mg, 856umol) and 2-amino-5-(4, Methyl 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (285 mg, 1.03 mmol) was dissolved in 1,4-dioxane ( 3.0 mL) and water (0.6 mL), add potassium carbonate (236 mg, 1.71 mmol). The system was replaced with nitrogen three times, and Pd(dppf)Cl 2 (62.6 mg, 85.6umol). The reaction solution was heated to 100°C and stirred for 12 hours. After the temperature of the reaction solution dropped to room temperature, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain crude product. The crude product was purified by Prep-TLC to obtain the title compound (200 mg, yellow oil), yield: 55.40%. MS (ESI): m/z 422.3[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.46 (d, J = 2.4Hz, 1H), 8.32 (d, J = 2.4Hz, 1H) ,8.14(s,1H),7.72-7.68(m,2H),7.42-7.38(m,1H),6.34(brs,2H),5.17-5.08(m,1H),3.97-3.90(m,2H) ,3.86(s,3H),3.42-3.34(m,3H),3.12-3.03(m,2H),2.72-2.50(m,2H),2.42-2.20(m,2H),1.80-1.76(m, 2H),1.65-1.53(m,2H).
(4)2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸(4)2-Amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinic acid
将2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸甲酯(200mg,474umol)溶于甲醇(2.0mL)和水(2.0mL)中，加入氢氧化锂(22.7mg,949umol)。反应液在室温下搅拌12小时。浓缩反应液得到粗品，粗品经Prep-HPLC纯化得到标题化合物(100mg,黄色固体)，收率：51.72％。MS(ESI):m/z 408.2[M+H]+.2-Amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinic acid methyl ester (200 mg, 474umol) was dissolved in methanol (2.0mL) and water (2.0mL), and lithium hydroxide (22.7mg, 949umol) was added. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated to obtain a crude product, which was purified by Prep-HPLC to obtain the title compound (100 mg, yellow solid), yield: 51.72%. MS(ESI):m/z 408.2[M+H] + .
(5)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酰胺(5)2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidine- 3-yl)-2H-indazol-5-yl)nicotinamide
将2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸(50.0mg,122umol)，HATU(55.9mg,147umol)和N,N-二异丙基乙胺(47.5mg,368umol)溶于N,N-二甲基甲酰胺(0.5mL)中，反应液室温下搅拌30分钟。向反应液中加入4-氨基双环[2.2.2]辛-1-醇盐酸盐(26.1mg,147umol)，继续在室温下反应12小时。反应液过滤，浓缩滤液得到粗品。粗品经Prep-HPLC纯化得到标题化合物(27.7mg,淡黄色固体)，收率：42.54％。MS(ESI):m/z 531.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.38(d,J＝2.3Hz,1H),8.03(d,J＝2.3Hz,1H),7.91(s,1H),7.81(s,1H),7.71-7.65(m,1H),7.57(dd,J＝9.0,1.5Hz,1H),6.87(s,2H),5.23-5.20(m,1H),4.30(s,1H),3.90-3.82(m,2H),3.36-3.29(m,2H),3.15-3.04(m,1H),3.02-2.86(m,2H),2.74-2.63(m,1H),2.47-2.40(m,1H),2.38-2.17(m,2H),2.10-2.00(m,6H),1.81(d,J＝11.7Hz,2H),1.67-1.58(m,6H),1.49-1.36(m,2H).2-Amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinic acid (50.0 mg, 122umol ), HATU (55.9 mg, 147umol) and N,N-diisopropylethylamine (47.5mg, 368umol) were dissolved in N,N-dimethylformamide (0.5mL), and the reaction solution was stirred at room temperature for 30 minutes. . 4-Aminobicyclo[2.2.2]octan-1-ol hydrochloride (26.1 mg, 147umol) was added to the reaction solution, and the reaction was continued at room temperature for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain crude product. The crude product was purified by Prep-HPLC to obtain the title compound (27.7 mg, light yellow solid), yield: 42.54%. MS (ESI): m/z 531.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.47 (s, 1H), 8.38 (d, J = 2.3Hz, 1H), 8.03 ( d,J＝2.3Hz,1H),7.91(s,1H),7.81(s,1H),7.71-7.65(m,1H),7.57(dd,J＝9.0,1.5Hz,1H),6.87(s ,2H),5.23-5.20(m,1H),4.30(s,1H),3.90-3.82(m,2H),3.36-3.29(m,2H),3.15-3.04(m,1H),3.02-2.86 (m,2H),2.74-2.63(m,1H),2.47-2.40(m,1H),2.38-2.17(m,2H),2.10-2.00(m,6H),1.81(d,J＝11.7Hz ,2H),1.67-1.58(m,6H),1.49-1.36(m,2H).
实施例45Example 45
化合物45：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吲唑-5-基)烟酰胺Compound 45: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(tetrahydro-2H-pyran-4-yl)piperidine- 4-yl)-1H-indazol-5-yl)nicotinamide
(1)5-溴-1-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吲唑(1)5-Bromo-1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indazole
参照实施例41步骤(3)的方法，以5-溴-1-(哌啶-4-基)-1H-吲唑(400mg,1.26mmol,盐酸盐)和四氢-4H-吡喃-4-酮(174.40mg,1.74mmol)为原料，得到标题化合物(220mg,白色固体)，收率：47.8％。1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.80(d,J＝1.2Hz,1H),7.38-7.33(m,1H),7.31-7.27(m,1H),4.34-4.28(m,1H),3.98(dd,J＝11.1,4.0Hz,2H),3.37-3.30(m,2H),3.08-3.05(m,2H),2.53-2.50(m,1H),2.41-2.18(m,4H),1.97(d,J＝11.5Hz,2H),1.72(d,J＝11.9Hz,2H),1.60-1.56(m,2H).Referring to the method of step (3) of Example 41, use 5-bromo-1-(piperidin-4-yl)-1H-indazole (400 mg, 1.26 mmol, hydrochloride) and tetrahydro-4H-pyran- 4-one (174.40 mg, 1.74 mmol) was used as raw material to obtain the title compound (220 mg, white solid), yield: 47.8%. 1 H NMR (400MHz, CDCl 3 ) δ7.85 (s, 1H), 7.80 (d, J = 1.2Hz, 1H), 7.38-7.33 (m, 1H), 7.31-7.27 (m, 1H), 4.34- 4.28(m,1H),3.98(dd,J＝11.1,4.0Hz,2H),3.37-3.30(m,2H),3.08-3.05(m,2H),2.53-2.50(m,1H),2.41- 2.18(m,4H),1.97(d,J＝11.5Hz,2H),1.72(d,J＝11.9Hz,2H),1.60-1.56(m,2H).
(2)2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吲唑-5-基)烟酸甲酯(2) Methyl 2-amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indazol-5-yl)nicotinate
将2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(100mg,359.57umol)和5-溴-1-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吲唑(100mg,274.51umol)溶于1,4-二氧六环(2mL)和水(0.4mL)的混合溶剂中。在氮气保护下向反应体系中加入碳酸钾(75.88mg,549.03umol)和Pd(dppf)Cl2(20.09mg,27.45umol)。反应液用氮气鼓气置换，然后升温至110℃氮气保护下搅拌16小时。反应液冷却至室温，浓缩后加入甲醇(2mL)稀释，经注射器滤膜过滤。滤液经Prep-TLC(二氯甲烷/甲醇＝5/1)纯化得到标题化合物(80mg,黄色固体)，收率：66.91％。MS(ESI):m/z 436.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.45(d,J＝2.6Hz,1H),8.31(d,J＝2.4Hz,1H),7.96(s,1H),7.77(d,J＝1.2Hz,1H),7.50-7.43(m,2H),6.36(brs,2H),4.40-4.34(m,1H),3.99(dd,J＝11.0,3.8Hz,2H),3.86(s,3H),3.38-3.31(m,2H),3.09(d,J＝9.2Hz,2H),2.60-2.47(m,1H),2.44-2.23(m,4H),2.02(d,J＝11.9Hz,2H),1.74(d,J＝11.1Hz,2H),1.66-1.54(m,2H).2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinic acid methyl ester (100 mg, 359.57umol) and 5-Bromo-1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indazole (100 mg, 274.51umol) dissolved in 1,4-dioxane (2mL) and water (0.4mL) in a mixed solvent. Potassium carbonate (75.88mg, 549.03umol) and Pd(dppf)Cl 2 (20.09mg, 27.45umol) were added to the reaction system under nitrogen protection. The reaction solution was replaced with nitrogen gas, then the temperature was raised to 110°C and stirred under nitrogen protection for 16 hours. The reaction solution was cooled to room temperature, concentrated, diluted with methanol (2 mL), and filtered through a syringe filter. The filtrate was purified by Prep-TLC (dichloromethane/methanol=5/1) to obtain the title compound (80 mg, yellow solid), yield: 66.91%. MS (ESI): m/z 436.3[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.45 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H) ,7.96(s,1H),7.77(d,J＝1.2Hz,1H),7.50-7.43(m,2H),6.36(brs,2H),4.40-4.34(m,1H),3.99(dd,J ＝11.0,3.8Hz,2H),3.86(s,3H),3.38-3.31(m,2H),3.09(d,J＝9.2Hz,2H),2.60-2.47(m,1H),2.44-2.23( m,4H),2.02(d,J＝11.9Hz,2H),1.74(d,J＝11.1Hz,2H),1.66-1.54(m,2H).
(3)2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吲唑-5-基)烟酸(3)2-Amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indazol-5-yl)nicotinic acid
将2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吲唑-5-基)烟酸甲酯(80mg,183.69umol)溶于甲醇(2.4mL)和水(2.4mL)中，加入氢氧化锂一水合物(16.00mg,381.28umol)，反应液在20℃下搅拌16小时。反应液浓缩，加入乙酸乙酯(3mL)和水(5mL)萃取，分出水相，用1M稀盐酸调节水相pH至3～4，有胶状固体析出，过滤。滤饼干燥得到标题化合物(50mg,类白色固体)，收率：64.58％。MS(ESI):m/z422.2[M+H]+.2-Amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indazol-5-yl)nicotinic acid methyl ester (80 mg, 183.69umol) was dissolved in methanol (2.4mL) and water (2.4mL), lithium hydroxide monohydrate (16.00mg, 381.28umol) was added, and the reaction solution was stirred at 20°C for 16 hours. The reaction solution was concentrated, and ethyl acetate (3 mL) and water (5 mL) were added for extraction. The aqueous phase was separated, and the pH of the aqueous phase was adjusted to 3-4 with 1M dilute hydrochloric acid. A colloidal solid precipitated and was filtered. The filter cake was dried to obtain the title compound (50 mg, off-white solid), yield: 64.58%. MS(ESI):m/z422.2[M+H] + .
(4)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吲唑-5-基)烟酰胺(4)2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(tetrahydro-2H-pyran-4-yl)piperidine- 4-yl)-1H-indazol-5-yl)nicotinamide
将2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吲唑-5-基)烟酸(30mg,71.18umol)和4-氨基二环[2.2.2]辛-1-醇盐酸盐(15mg,84.43umol)溶于N,N-二甲基甲酰胺(0.5mL)中，加入HATU(32.48mg,85.41umol)和N,N-二异丙基乙胺(29.68mg,229.64umol)。反应液在15℃下搅拌2小时。反应液经Prep-HPLC纯化得到标题化合物(21.6mg,白色固体)，收率：55.06％。MS(ESI):m/z 545.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.3Hz,1H),8.10(s,1H),8.04(d,J＝2.4Hz,1H),7.98(d,J＝0.8Hz,1H),7.83-7.76(m,2H),7.69(dd,J＝8.8,1.7Hz,1H),6.88(s,2H),4.67-4.56(m,1H),4.30(s,1H),3.92(dd,J＝10.4,3.3Hz,2H),3.31-3.27(m,2H),3.04(d,J＝11.4Hz,2H),2.57-2.56(m,1H),2.44-2.37(m,2H),2.17-2.01(m,8H),1.94(d,J＝10.0Hz,2H),1.72(d,J＝13.6Hz,2H),1.66-1.59(m,6H),1.51-1.48(m,2H).2-Amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indazol-5-yl)nicotinic acid (30 mg, 71.18umol ) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (15 mg, 84.43umol) were dissolved in N,N-dimethylformamide (0.5mL), and HATU (32.48mg, 85.41 umol) and N,N-diisopropylethylamine (29.68mg, 229.64umol). The reaction solution was stirred at 15°C for 2 hours. The reaction solution was purified by Prep-HPLC to obtain the title compound (21.6 mg, white solid), yield: 55.06%. MS (ESI): m/z 545.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.39 (d, J = 2.3Hz, 1H), 8.10 (s, 1H), 8.04 ( d,J＝2.4Hz,1H),7.98(d,J＝0.8Hz,1H),7.83-7.76(m,2H),7.69(dd,J＝8.8,1.7Hz,1H),6.88(s,2H ),4.67-4.56(m,1H),4.30(s,1H),3.92(dd,J＝10.4,3.3Hz,2H),3.31-3.27(m,2H),3.04(d,J＝11.4Hz, 2H),2.57-2.56(m,1H),2.44-2.37(m,2H),2.17-2.01(m,8H),1.94(d,J＝10.0Hz,2H),1.72(d,J＝13.6Hz ,2H),1.66-1.59(m,6H),1.51-1.48(m,2H).
实施例46 Example 46
化合物46：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-(氧杂环-3-基)哌啶-4-基)-2H-吲唑-5-基)烟酰胺Compound 46: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-(oxaheterocyclyl-3-yl)piperidin-4-yl) -2H-indazol-5-yl)nicotinamide
(1)5-溴-2-(哌啶-4-基)-2H-吲唑(1)5-Bromo-2-(piperidin-4-yl)-2H-indazole
将4-(5-溴-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯(1.2g,3.16mmol,实施例41第1步异构体)溶于二氯甲烷(5mL)中，加入盐酸/二氧六环(4M,24.00mL)溶液。反应液在15℃下搅拌16小时。反应液直接在45℃下浓缩得到标题化合物(1g,白色固体,盐酸盐)，所得粗品直接用于下一步。MS(ESI):m/z 280.1[M+H]+.Dissolve 4-(5-bromo-2H-indazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (1.2g, 3.16mmol, the first isomer of Example 41) in dichloromethane ( 5 mL), add hydrochloric acid/dioxane (4M, 24.00 mL) solution. The reaction solution was stirred at 15°C for 16 hours. The reaction solution was directly concentrated at 45°C to obtain the title compound (1g, white solid, hydrochloride), and the crude product was directly used in the next step. MS(ESI):m/z 280.1[M+H] + .
(2)5-溴-2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑(2)5-Bromo-2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazole
将3-氧杂环丁酮(150.21mg,2.09mmol)溶于甲醇(5mL)中，加入三乙胺(159.80mg,1.58mmol)和5-溴-2-(哌啶-4-基)-2H-吲唑(500.00mg,1.58mmol,盐酸盐)，反应液在25℃下搅拌1小时。再加入氰基硼氢化钠(199.99mg,3.18mmol)和醋酸(105.00mg,1.75mmol)，反应液在25℃继续搅拌15小时。向反应液中加入水(5mL)，用乙酸乙酯(5mL x 4)萃取，合并有机相，浓缩。粗品经Prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到标题化合物(150mg,白色固体)，收率：28.24％。MS(ESI):m/z 336.1[M+H]+.1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.75(s,1H),7.51(d,J＝9.1Hz,1H),7.26(d,J＝9.1Hz,1H),4.66-4.55(m,4H),4.44-4.33(m,1H),3.53-3.46(m,1H),2.86(d,J＝11.3Hz,2H),2.27-2.09(m,4H),2.06-1.96(m,2H).Dissolve 3-oxetanone (150.21mg, 2.09mmol) in methanol (5mL), add triethylamine (159.80mg, 1.58mmol) and 5-bromo-2-(piperidin-4-yl)- 2H-indazole (500.00 mg, 1.58 mmol, hydrochloride), the reaction solution was stirred at 25°C for 1 hour. Sodium cyanoborohydride (199.99 mg, 3.18 mmol) and acetic acid (105.00 mg, 1.75 mmol) were then added, and the reaction solution was continued to stir at 25°C for 15 hours. Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL x 4), the organic phases were combined and concentrated. The crude product was purified by Prep-TLC (dichloromethane/methanol=10/1) to obtain the title compound (150 mg, white solid), yield: 28.24%. MS (ESI): m/z 336.1[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ7.85 (s, 1H), 7.75 (s, 1H), 7.51 (d, J = 9.1Hz, 1H),7.26(d,J＝9.1Hz,1H),4.66-4.55(m,4H),4.44-4.33(m,1H),3.53-3.46(m,1H),2.86(d,J＝11.3Hz ,2H),2.27-2.09(m,4H),2.06-1.96(m,2H).
(3)2-氨基-5-(2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑-5-基)烟酸甲酯(3) Methyl 2-amino-5-(2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazol-5-yl)nicotinate
将5-溴-2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑(100mg,297.42umol)和2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(110mg,395.53umol)溶于1,4-二氧六环(2mL)和水(0.4mL)的混合溶剂中，加入碳酸钾(82.21mg,594.84umol)和Pd(dppf)Cl2(21.76mg,29.74umol)。向反应液中鼓入氮气，升温至110℃搅拌16小时。反应液冷却至室温后过滤，滤液浓缩得到粗品。粗品经Prep-TLC(石油醚/甲醇＝10/1)纯化得到标题化合物(60mg,黄色固体)，收率：49.51％。MS(ESI):m/z 408.2[M+H]+.Combine 5-bromo-2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazole (100 mg, 297.42umol) and 2-amino-5-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinic acid methyl ester (110mg, 395.53umol) was dissolved in 1,4-dioxane (2mL ) and water (0.4mL), add potassium carbonate (82.21mg, 594.84umol) and Pd(dppf)Cl 2 (21.76mg, 29.74umol). Nitrogen gas was bubbled into the reaction solution, and the temperature was raised to 110°C and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated to obtain crude product. The crude product was purified by Prep-TLC (petroleum ether/methanol=10/1) to obtain the title compound (60 mg, yellow solid), yield: 49.51%. MS(ESI):m/z 408.2[M+H] + .
(4)2-氨基-5-(2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑-5-基)烟酸(4)2-Amino-5-(2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazol-5-yl)nicotinic acid
将2-氨基-5-(2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑-5-基)烟酸甲酯(60mg,147.25umol)溶于甲醇(1mL)和水(1mL)中，加入氢氧化锂一水合物(12.36mg,294.50umol)。反应液在20℃下搅拌16小时。反应液浓缩，然后加入水(3mL)和乙酸乙酯(1mL)进行萃取，水相用1M稀盐酸调节pH至3～4。所得溶液冻干得到黄色固体。固体分散到甲醇(5mL)中搅拌2小时，然后过滤。滤液浓缩得到标题化合物(30mg,黄色固体)，所得粗品直接用于下一步。MS(ESI):m/z 394.2[M+H]+.2-Amino-5-(2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazol-5-yl)nicotinic acid methyl ester (60 mg, 147.25umol ) was dissolved in methanol (1mL) and water (1mL), and lithium hydroxide monohydrate (12.36mg, 294.50umol) was added. The reaction solution was stirred at 20°C for 16 hours. The reaction solution was concentrated, and then water (3 mL) and ethyl acetate (1 mL) were added for extraction. The pH of the aqueous phase was adjusted to 3-4 with 1M dilute hydrochloric acid. The resulting solution was lyophilized to give a yellow solid. The solid was dispersed into methanol (5 mL) and stirred for 2 hours, then filtered. The filtrate was concentrated to obtain the title compound (30 mg, yellow solid), and the crude product was used directly in the next step. MS(ESI):m/z 394.2[M+H] + .
(5)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-(氧杂环-3-基)哌啶-4-基)-2H-吲唑-5-基)烟酰胺(5)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-(oxaheterocyclyl-3-yl)piperidin-4-yl) -2H-indazol-5-yl)nicotinamide
将2-氨基-5-(2-(1-(氧杂环丁烷-3-基)哌啶-4-基)-2H-吲唑-5-基)烟酸(30mg,76.25umol)，4-氨基二环[2.2.2]辛-1-醇盐酸盐(15mg,84.43umol)和HATU(35mg,92.05umol)溶于N,N-二甲基甲酰胺(1mL)中，加入N,N-二异丙基乙胺(29.68mg,229.64umol)。反应液在15℃下搅拌16小时。向反应液中加甲醇(0.5mL)稀释，溶液经Prep-HPLC纯化得到标题化合物(3.7mg,棕色固体)，收率：9.39％。MS(ESI):m/z 517.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.38(d,J＝1.5Hz,1H),8.03(s,1H),7.90(s,1H),7.82(s,1H),7.71-7.66(m,1H),7.57(d,J＝8.8Hz,1H),6.87(s,2H),4.61-4.55(m,2H),4.54-4.52(m,1H),4.50-4.43(m,2H),4.30(s,1H),3.51-3.44(m,1H),2.86(d,J＝10.4Hz,2H),2.20-2.10(m,4H),2.09-2.00(m,8H),1.66-1.59(m,6H).2-Amino-5-(2-(1-(oxetan-3-yl)piperidin-4-yl)-2H-indazol-5-yl)nicotinic acid (30 mg, 76.25umol), 4-Aminobicyclo[2.2.2]octan-1-ol hydrochloride (15 mg, 84.43umol) and HATU (35mg, 92.05umol) were dissolved in N,N-dimethylformamide (1mL), and N , N-diisopropylethylamine (29.68mg, 229.64umol). The reaction solution was stirred at 15°C for 16 hours. Methanol (0.5 mL) was added to the reaction solution to dilute, and the solution was purified by Prep-HPLC to obtain the title compound (3.7 mg, brown solid), yield: 9.39%. MS (ESI): m/z 517.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.46 (s, 1H), 8.38 (d, J = 1.5Hz, 1H), 8.03 ( s,1H),7.90(s,1H),7.82(s,1H),7.71-7.66(m,1H),7.57(d,J＝8.8Hz,1H),6.87(s,2H),4.61-4.55 (m,2H),4.54-4.52(m,1H),4.50-4.43(m,2H),4.30(s,1H),3.51-3.44(m,1H),2.86(d,J＝10.4Hz,2H ),2.20-2.10(m,4H),2.09-2.00(m,8H),1.66-1.59(m,6H).
实施例47Example 47
化合物47：2-氨基-5-(1-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 47: 2-amino-5-(1-(4-(oxetan-3-yl)piperazin-1-yl)-2,3-dihydro-1H-inden-5-yl)- N-(tetrahydro-2H-pyran-4-yl)nicotinamide
将1-(氧杂环丁烷-3-基)-4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢-1H-茚-1-基)哌嗪(80mg,208.16umol,实施例42第2步)溶于1,4-二氧六环(0.8mL)和水(0.16mL)的混合溶剂中，加入中间体4(62.48mg,208.16umol)和碳酸钾(86.31mg,624.48umol)。在氮气保护下向反应液中加入Pd(dppf)Cl2(15.23mg,20.82umol)。反应液加热至80℃氮气保护下搅拌12小时。反应液冷却至室温，加入水(5mL)和乙酸乙酯(5mL)分液萃取，有机相减压浓缩得到粗品。粗品经Prep-HPLC纯化得到标题化合物(12mg,白色固体)，收率：12.07％。MS(ESI):m/z 478.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.42-8.38(m,2H),8.16(d,J＝2.3Hz,1H),7.52(s,1H),7.47(d,J＝7.5Hz,1H),7.32(d,J＝7.7Hz,1H),7.13(s,2H),4.54-4.49(m,2H),4.43-4.37(m,2H),4.34-4.28(m,1H),4.06-3.96(m,1H),3.93-3.86(m,2H),3.43-3.36(m,4H),2.97-2.90(m,1H),2.87-2.81(m,1H),2.46-2.36(m,4H),2.30-2.23(m,3H),2.10-2.02(m,2H),1.82-1.75(m,2H),1.64-1.54(m,2H).1-(oxetan-3-yl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- (80mg, 208.16umol, step 2 of Example 42)-2,3-dihydro-1H-inden-1-yl)piperazine (80mg, 208.16umol, step 2 of Example 42) was dissolved in 1,4-dioxane (0.8mL) and water ( To the mixed solvent (0.16 mL), intermediate 4 (62.48 mg, 208.16 umol) and potassium carbonate (86.31 mg, 624.48 umol) were added. Pd(dppf)Cl 2 (15.23 mg, 20.82umol) was added to the reaction solution under nitrogen protection. The reaction solution was heated to 80°C and stirred under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, water (5 mL) and ethyl acetate (5 mL) were added for liquid separation extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the title compound (12 mg, white solid), yield: 12.07%. MS (ESI): m/z 478.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.42-8.38 (m, 2H), 8.16 (d, J = 2.3Hz, 1H), 7.52(s,1H),7.47(d,J＝7.5Hz,1H),7.32(d,J＝7.7Hz,1H),7.13(s,2H),4.54-4.49(m,2H),4.43-4.37 (m,2H),4.34-4.28(m,1H),4.06-3.96(m,1H),3.93-3.86(m,2H),3.43-3.36(m,4H),2.97-2.90(m,1H) ,2.87-2.81(m,1H),2.46-2.36(m,4H),2.30-2.23(m,3H),2.10-2.02(m,2H),1.82-1.75(m,2H),1.64-1.54( m,2H).
实施例48Example 48
化合物48：(R)-5-(4-((2-甲基吡咯烷-1-基)甲基)苯基)-N-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺Compound 48: (R)-5-(4-((2-methylpyrrolidin-1-yl)methyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)-1H- Pyrazolo[3,4-b]pyridin-3-amine
(1)(R)-1-(4-溴苄基)-2-甲基吡咯烷(1)(R)-1-(4-bromobenzyl)-2-methylpyrrolidine
参照实施例28步骤(1)的方法，以1-溴-4-(溴甲基)苯(2.94g,11.74mmol)和(R)-2-甲基吡咯烷(1g,11.74mmol)为原料，得到标题化合物(1.0g,淡黄色固体)，收率：33.5％。MS(ESI):m/z 254.0[M+H]+.Refer to the method of step (1) in Example 28, using 1-bromo-4-(bromomethyl)benzene (2.94g, 11.74mmol) and (R)-2-methylpyrrolidine (1g, 11.74mmol) as raw materials , the title compound (1.0g, light yellow solid) was obtained, yield: 33.5%. MS(ESI):m/z 254.0[M+H] + .
(2)(R)-2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吡咯烷(2)(R)-2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl pyrrolidine
参照实施例28步骤(2)的方法，以(R)-1-(4-溴苄基)-2-甲基吡咯烷(1.00g,3.93mmol)为原料，得到标题化合物(600mg,棕色固体)，收率：53.6％。MS(ESI):m/z 302.2[M+H]+.Referring to the method of step (2) in Example 28, using (R)-1-(4-bromobenzyl)-2-methylpyrrolidine (1.00g, 3.93mmol) as raw material, the title compound (600mg, brown solid ), yield: 53.6%. MS(ESI):m/z 302.2[M+H] + .
(3)5-溴-N-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺(3)5-Bromo-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine
将原料3-氨基-5-溴-1H-吡唑并[3,4-b]吡啶(2.00g,9.39mmol)溶于冰醋酸(20.0mL)中，在50℃下， 向反应液中加入四氢-4H-吡喃-4-酮(1.88g,18.7mmol)，搅拌30分钟。再向反应液中分批加入氰基硼氢化钠(1.18g,18.7mmol)，反应混合物继续搅拌2小时。反应液冷却至室温，减压浓缩，用5％氢氧化钠水溶液(20mL)溶解残渣，用二氯甲烷(20mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，浓缩得到标题化合物(1.0g,棕色固体)，收率：35.85％。MS(ESI):m/z 297.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.43-8.40(m,2H),6.21(d,J＝7.0Hz,1H),3.93-3.87(m,2H),3.74-3.66(m,1H),3.46-3.39(m,2H),2.01(d,J＝11.7Hz,2H),1.52-1.44(m,2H).The raw material 3-amino-5-bromo-1H-pyrazolo[3,4-b]pyridine (2.00g, 9.39mmol) was dissolved in glacial acetic acid (20.0mL) at 50°C. Tetrahydro-4H-pyran-4-one (1.88g, 18.7mmol) was added to the reaction liquid, and stirred for 30 minutes. Sodium cyanoborohydride (1.18g, 18.7mmol) was added to the reaction solution in batches, and the reaction mixture was continued to stir for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in 5% sodium hydroxide aqueous solution (20 mL), and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (1.0 g, brown solid), yield: 35.85%. MS(ESI):m/z 297.1[M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ12.23(s,1H),8.43-8.40(m,2H),6.21(d,J ＝7.0Hz,1H),3.93-3.87(m,2H),3.74-3.66(m,1H),3.46-3.39(m,2H),2.01(d,J＝11.7Hz,2H),1.52-1.44( m,2H).
(4)(R)-5-(4-((2-甲基吡咯烷-1-基)甲基)苯基)-N-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺(4)(R)-5-(4-((2-methylpyrrolidin-1-yl)methyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)-1H- Pyrazolo[3,4-b]pyridin-3-amine
将5-溴-N-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺(100mg,336umol)，(R)-2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吡咯烷(101mg,336umol)和碳酸钠(16.5mg,156umol)溶于1,4-二氧六环(1.0mL)和水(0.1mL)的混合溶剂中。在氮气保护下，向反应体系中加入Pd(dppf)Cl2(21.96mg,30.01umol)，反应液在90℃氮气保护下搅拌16小时。反应液冷却至室温，用甲醇(1.0mL)稀释并过滤，滤液经Prep-HPLC纯化得到标题化合物(10.6mg,黄色固体)，收率：8.05％。MS(ESI):m/z 392.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.68(d,J＝2.1Hz,1H),8.47(d,J＝2.0Hz,1H),7.63(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,2H),6.21(d,J＝7.0Hz,1H),4.01(d,J＝13.1Hz,1H),3.95-3.87(m,2H),3.81-3.69(m,1H),3.50-3.38(m,2H),3.17(d,J＝13.1Hz,1H),2.87-2.76(m,1H),2.42-2.40(m,1H),2.15-2.01(m,3H),1.99-1.86(m,1H),1.70-1.57(m,2H),1.56-1.44(m,2H),1.43-1.29(m,1H),1.13(d,J＝6.0Hz,3H).5-Bromo-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (100 mg, 336umol), (R)-2- Methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine (101 mg, 336umol) and sodium carbonate (16.5 mg, 156umol) were dissolved in a mixed solvent of 1,4-dioxane (1.0 mL) and water (0.1 mL). Under nitrogen protection, Pd(dppf)Cl 2 (21.96 mg, 30.01umol) was added to the reaction system, and the reaction solution was stirred at 90°C under nitrogen protection for 16 hours. The reaction solution was cooled to room temperature, diluted with methanol (1.0 mL) and filtered. The filtrate was purified by Prep-HPLC to obtain the title compound (10.6 mg, yellow solid), yield: 8.05%. MS (ESI): m/z 392.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.04 (s, 1H), 8.68 (d, J = 2.1Hz, 1H), 8.47 ( d,J＝2.0Hz,1H),7.63(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,2H),6.21(d,J＝7.0Hz,1H),4.01(d, J＝13.1Hz,1H),3.95-3.87(m,2H),3.81-3.69(m,1H),3.50-3.38(m,2H),3.17(d,J＝13.1Hz,1H),2.87-2.76 (m,1H),2.42-2.40(m,1H),2.15-2.01(m,3H),1.99-1.86(m,1H),1.70-1.57(m,2H),1.56-1.44(m,2H) ,1.43-1.29(m,1H),1.13(d,J=6.0Hz,3H).
实施例49Example 49
化合物49：(R)-5-(4-((2-甲基吡咯烷-1-基)甲基)苯基)-3-(1-(四氢-2H-吡喃-4-基)-1H-1,2,3-***-4-基)吡啶-2-胺Compound 49: (R)-5-(4-((2-methylpyrrolidin-1-yl)methyl)phenyl)-3-(1-(tetrahydro-2H-pyran-4-yl) -1H-1,2,3-triazol-4-yl)pyridin-2-amine
(1)4-叠氮基四氢-2H-吡喃(1)4-azidotetrahydro-2H-pyran
将4-碘四氢-2H-吡喃(1.00g,3.93mmol)，叠氮钠(430mg,3.93mmol)溶于N,N-二甲基甲酰胺(10.0mL)中，加入N,N-二异丙基乙胺(609.54mg,4.72mmol)。反应混合物加热至80℃搅拌2小时。反应液冷却至室温，用饱和碳酸氢钠水溶液调节反应液pH至大于9，用乙酸乙酯(10mL x 3)进行萃取。合并有机相，用无水硫酸钠干燥，过滤，浓缩得到标题化合物(600mg,黄色固体)，粗品直接用于下一步。Dissolve 4-iodotetrahydro-2H-pyran (1.00g, 3.93mmol) and sodium azide (430mg, 3.93mmol) in N,N-dimethylformamide (10.0mL), add N,N- Diisopropylethylamine (609.54 mg, 4.72 mmol). The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature, and the pH of the reaction solution was adjusted to greater than 9 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (10mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (600 mg, yellow solid). The crude product was used directly in the next step.
(2)5-溴-3-(1-(四氢-2H-吡喃-4-基)-1H-1,2,3-***-4-基)吡啶-2-胺(2)5-Bromo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine
将5-溴-3-乙炔基吡啶-2-胺(100mg,507umol)和4-叠氮基四氢-2H-吡喃(129mg,1.02mmol)溶于叔丁醇(0.5mL)和水(1.0mL)中，加入碘化亚铜(9.67mg,50.75umol)。反应混合物加热至80℃搅拌16小时。反应液冷却至室温，向反应体系中加水(10mL)淬灭反应，用乙酸乙酯(10mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，浓缩得到标题化合物(120mg,黄色固体)，收率：72.9％。MS(ESI):m/z 324.1[M+H]+.Dissolve 5-bromo-3-ethynylpyridin-2-amine (100mg, 507umol) and 4-azidotetrahydro-2H-pyran (129mg, 1.02mmol) in tert-butanol (0.5mL) and water ( 1.0 mL), add copper iodide (9.67 mg, 50.75umol). The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, water (10 mL) was added to the reaction system to quench the reaction, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (120 mg, yellow solid), yield: 72.9%. MS(ESI):m/z 324.1[M+H] + .
(3)(R)-5-(4-((2-甲基吡咯烷-1-基)甲基)苯基)-3-(1-(四氢-2H-吡喃-4-基)-1H-1,2,3-***-4-基)吡啶-2-胺(3)(R)-5-(4-((2-methylpyrrolidin-1-yl)methyl)phenyl)-3-(1-(tetrahydro-2H-pyran-4-yl) -1H-1,2,3-triazol-4-yl)pyridin-2-amine
将5-溴-3-(1-(四氢-2H-吡喃-4-基)-1H-1,2,3-***-4-基)吡啶-2-胺(30.0mg,92.5umol)，(R)-2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吡咯烷(55.7mg,185umol,实施例48第2步)和碳酸铯(90.4mg,277umol)溶于1,4-二氧六环(1.0mL)和水(0.05mL)中。在氮气保护下，向反应液中加入Pd(dppf)Cl2(6.77mg,9.25umol)。反应混合物加热至100℃搅拌16小时。反应液冷却至室温，用甲醇(1.0mL)稀释并过滤，滤液经Prep-HPLC纯化得到标题化合物(8.70mg,黄色固体)，收率：22.46％。MS(ESI):m/z 419.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.32(d,J＝2.4Hz,1H),8.21(d,J＝2.4Hz,1H),7.62(d,J＝8.2Hz,2H),7.36(d,J＝8.1Hz,2H),7.07(s,2H),5.00-4.73(m,1H),4.07-3.95(m,3H),3.56(dt,J＝11.7,2.0Hz,2H),3.16(d,J＝13.1Hz,1H),2.84-2.75(m,1H),2.41-2.39(m,1H),2.20-2.13(m,2H),2.11-2.02(m,3H),1.97-1.85(m,1H),1.66-1.54(m,2H),1.42-1.30(m,1H),1.12(d,J＝6.0Hz,3H).5-Bromo-3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)pyridin-2-amine (30.0 mg, 92.5umol ), (R)-2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl ) Pyrrolidine (55.7 mg, 185umol, step 2 of Example 48) and cesium carbonate (90.4mg, 277umol) were dissolved in 1,4-dioxane (1.0mL) and water (0.05mL). Under nitrogen protection, Pd(dppf)Cl 2 (6.77 mg, 9.25umol) was added to the reaction solution. The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with methanol (1.0 mL) and filtered. The filtrate was purified by Prep-HPLC to obtain the title compound (8.70 mg, yellow solid), yield: 22.46%. MS (ESI): m/z 419.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.00 (s, 1H), 8.32 (d, J = 2.4Hz, 1H), 8.21 ( d,J＝2.4Hz,1H),7.62(d,J＝8.2Hz,2H),7.36(d,J＝8.1Hz,2H),7.07(s,2H),5.00-4.73(m,1H), 4.07-3.95(m,3H),3.56(dt,J＝11.7,2.0Hz,2H),3.16(d,J＝13.1Hz,1H),2.84-2.75(m,1H),2.41-2.39(m, 1H),2.20-2.13(m,2H),2.11-2.02(m,3H),1.97-1.85(m,1H),1.66-1.54(m,2H),1.42-1.30(m,1H),1.12( d,J＝6.0Hz,3H).
实施例50Example 50
化合物50：4-(2-氨基-5-(4-吗啉代苯基)吡啶-3-基)-N-(氰基甲基)苯甲酰胺Compound 50: 4-(2-amino-5-(4-morpholinophenyl)pyridin-3-yl)-N-(cyanomethyl)benzamide
(1)4-(2-氨基-5-溴吡啶-3-基)苯甲酸甲酯(1) Methyl 4-(2-amino-5-bromopyridin-3-yl)benzoate
将5-溴-3-碘吡啶-2-胺(500mg,1.67mmol)溶于甲苯(10mL)，乙醇(5mL)和水(2.5mL)的混合溶剂中，依次加入4-甲氧羰基苯硼酸(340mg,1.89mmol)和碳酸钠(637mg,6.02mmol)。在氮气保护下，向反应液中加入Pd(PPh3)4(96mg,83.64umol)。反应液在135℃微波条件下反应0.5小时。反应液冷却至室温，加入水(15mL)和乙酸乙酯(5mL)分液萃取，浓缩有机相得到标题化合物(550mg,黄色固体)，粗品不经纯化直接用于下一步。MS(ESI):m/z 307.1[M+H]+.Dissolve 5-bromo-3-iodopyridin-2-amine (500 mg, 1.67 mmol) in a mixed solvent of toluene (10 mL), ethanol (5 mL) and water (2.5 mL), and add 4-methoxycarbonylphenylboronic acid in sequence (340mg, 1.89mmol) and sodium carbonate (637mg, 6.02mmol). Under nitrogen protection, Pd(PPh 3 ) 4 (96 mg, 83.64umol) was added to the reaction solution. The reaction solution was reacted under microwave conditions at 135°C for 0.5 hours. The reaction solution was cooled to room temperature, water (15 mL) and ethyl acetate (5 mL) were added for liquid separation extraction, and the organic phase was concentrated to obtain the title compound (550 mg, yellow solid). The crude product was used directly in the next step without purification. MS(ESI):m/z 307.1[M+H] + .
(2)4-(2-氨基-5-(4-吗啉代苯基)吡啶-3-基)苯甲酸甲酯(2) Methyl 4-(2-amino-5-(4-morpholinophenyl)pyridin-3-yl)benzoate
将4-(2-氨基-5-溴吡啶-3-基)苯甲酸甲酯(500mg,1.63mmol)溶于乙二醇二甲醚(5mL)和水(1mL)的混合溶剂中，加入(4-吗啉代苯基)硼酸(404mg,1.95mmol)和碳酸钠(517mg,4.88mmol)。在氮气保护下，向反应液中加入Pd(PPh3)4(188mg,162.79umol)。反应液加热至80℃氮气保护下搅拌3小时。反应液冷却至室温，加入水(20mL)和乙酸乙酯(20mL)分液萃取，浓缩有机相得到标题化合物(0.6g,黄色固体)，粗品不经纯化直接用于下一步。MS(ESI):m/z 390.3[M+H]+.Dissolve 4-(2-amino-5-bromopyridin-3-yl)benzoic acid methyl ester (500 mg, 1.63 mmol) in a mixed solvent of ethylene glycol dimethyl ether (5 mL) and water (1 mL), and add ( 4-morpholinophenyl)boronic acid (404 mg, 1.95 mmol) and sodium carbonate (517 mg, 4.88 mmol). Under nitrogen protection, Pd(PPh 3 ) 4 (188 mg, 162.79umol) was added to the reaction solution. The reaction solution was heated to 80°C and stirred under nitrogen protection for 3 hours. The reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added for liquid separation extraction, and the organic phase was concentrated to obtain the title compound (0.6 g, yellow solid). The crude product was used directly in the next step without purification. MS(ESI):m/z 390.3[M+H] + .
(3)4-(2-氨基-5-(4-吗啉代苯基)吡啶-3-基)苯甲酸(3)4-(2-amino-5-(4-morpholinophenyl)pyridin-3-yl)benzoic acid
将4-(2-氨基-5-(4-吗啉代苯基)吡啶-3-基)苯甲酸甲酯(0.3g,770.32umol)溶于甲醇(6mL)和水(3mL)的混合溶剂中，加入氢氧化钠(61.62mg,1.54mmol)，反应液在20℃下搅拌12小时。反应液减压浓缩，向反应液中加入水(10mL)和乙酸乙酯(10mL)萃取，弃除有机相。水相用2M盐酸水溶液调节pH至2 左右，水相浓缩得到黄色固体。固体分散在甲醇(10mL)中搅拌2小时后过滤，滤液浓缩得到标题化合物(150mg,黄色固体)，粗品不经纯化直接用于下一步。MS(ESI):m/z 376.3[M+H]+.Dissolve methyl 4-(2-amino-5-(4-morpholinophenyl)pyridin-3-yl)benzoate (0.3g, 770.32umol) in a mixed solvent of methanol (6mL) and water (3mL) , sodium hydroxide (61.62 mg, 1.54 mmol) was added, and the reaction solution was stirred at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution for extraction, and the organic phase was discarded. The aqueous phase was adjusted to pH 2 with 2M hydrochloric acid aqueous solution. The aqueous phase was concentrated to obtain a yellow solid. The solid was dispersed in methanol (10 mL) and stirred for 2 hours, then filtered. The filtrate was concentrated to obtain the title compound (150 mg, yellow solid). The crude product was used directly in the next step without purification. MS(ESI):m/z 376.3[M+H] + .
(4)4-(2-氨基-5-(4-吗啉代苯基)吡啶-3-基)-N-(氰基甲基)苯甲酰胺(4)4-(2-amino-5-(4-morpholinophenyl)pyridin-3-yl)-N-(cyanomethyl)benzamide
将4-(2-氨基-5-(4-吗啉代苯基)吡啶-3-基)苯甲酸(100mg,266.37umol)溶于N,N-二甲基甲酰胺(1mL)中，依次加入HATU(111mg,293.01umol)和N,N-二异丙基乙胺(172mg,1.33mmol)。反应液在20℃下搅拌30分钟，加入2-氨基乙腈盐酸盐(36mg,399.55umol)，继续搅拌3小时。反应液过滤，滤液经Pre-HPLC纯化得到标题化合物(3mg,白色固体)，收率：3.0％。MS(ESI):m/z 414.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.31-9.23(m,1H),8.27(d,J＝2.3Hz,1H),7.98(d,J＝8.2Hz,2H),7.68(d,J＝8.2Hz,2H),7.60(d,J＝2.3Hz,1H),7.53(d,J＝8.7Hz,2H),7.00(d,J＝8.7Hz,2H),5.74(s,2H),4.35(d,J＝5.4Hz,2H),3.78-3.73(m,4H),3.16-3.11(m,4H).Dissolve 4-(2-amino-5-(4-morpholinophenyl)pyridin-3-yl)benzoic acid (100mg, 266.37umol) in N,N-dimethylformamide (1mL), followed by HATU (111 mg, 293.01umol) and N,N-diisopropylethylamine (172mg, 1.33mmol) were added. The reaction solution was stirred at 20°C for 30 minutes, 2-aminoacetonitrile hydrochloride (36 mg, 399.55umol) was added, and stirring was continued for 3 hours. The reaction solution was filtered, and the filtrate was purified by Pre-HPLC to obtain the title compound (3 mg, white solid), yield: 3.0%. MS (ESI): m/z 414.0[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.31-9.23 (m, 1H), 8.27 (d, J = 2.3Hz, 1H), 7.98(d,J＝8.2Hz,2H),7.68(d,J＝8.2Hz,2H),7.60(d,J＝2.3Hz,1H),7.53(d,J＝8.7Hz,2H),7.00( d,J＝8.7Hz,2H),5.74(s,2H),4.35(d,J＝5.4Hz,2H),3.78-3.73(m,4H),3.16-3.11(m,4H).
实施例51Example 51
化合物51：4-(2-氨基-5-(4-(吗啉代甲基)苯基)吡啶-3-基)-N-(氰基甲基)苯甲酰胺Compound 51: 4-(2-amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)-N-(cyanomethyl)benzamide
(1)4-(2-氨基-5-(4-(吗啉代甲基)苯基)吡啶-3-基)苯甲酸甲酯(1) Methyl 4-(2-amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)benzoate
参照实施例50步骤(2)的方法，以4-(2-氨基-5-溴吡啶-3-基)苯甲酸甲酯(500mg,1.63mmol,实施例50第1步)和4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)吗啉(592.31mg,1.95mmol)为原料，得到标题化合物(600mg,橙色固体)，收率：91.4％。MS(ESI):m/z 404.3[M+H]+.Referring to the method of step (2) of Example 50, 4-(2-amino-5-bromopyridin-3-yl)benzoic acid methyl ester (500 mg, 1.63 mmol, step 1 of Example 50) and 4-(4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (592.31 mg, 1.95 mmol) was used as raw material to obtain the title Compound (600 mg, orange solid), yield: 91.4%. MS(ESI):m/z 404.3[M+H] + .
(2)4-(2-氨基-5-(4-(吗啉代甲基)苯基)吡啶-3-基)苯甲酸(2)4-(2-Amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)benzoic acid
参照实施例50步骤(3)的方法，以4-(2-氨基-5-(4-(吗啉代甲基)苯基)吡啶-3-基)苯甲酸甲酯(350mg,867.47umol)为原料，得到标题化合物(300mg,橙色固体)，粗品不经纯化直接用于下一步。MS(ESI):m/z390.3[M+H]+.Referring to the method of step (3) of Example 50, use 4-(2-amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)benzoate methyl ester (350 mg, 867.47umol) As raw material, the title compound (300 mg, orange solid) was obtained, and the crude product was used directly in the next step without purification. MS(ESI):m/z390.3[M+H] + .
(3)4-(2-氨基-5-(4-(吗啉代甲基)苯基)吡啶-3-基)-N-(氰基甲基)苯甲酰胺(3)4-(2-Amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)-N-(cyanomethyl)benzamide
参照实施例50步骤(4)的方法，以4-(2-氨基-5-(4-(吗啉代甲基)苯基)吡啶-3-基)苯甲酸(150mg,385.16umol)为原料，得到标题化合物(5mg,白色固体)，收率：3.4％。MS(ESI):m/z 428.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.27(t,J＝5.4Hz,1H),8.33(d,J＝2.4Hz,1H),7.99(d,J＝8.3Hz,2H),7.68(d,J＝8.3Hz,2H),7.66(d,J＝2.3Hz,1H),7.61(d,J＝8.2Hz,2H),7.35(d,J＝8.1Hz,2H),5.86(s,2H),4.35(d,J＝5.4Hz,2H),3.58(t,J＝4.4Hz,4H),3.48(s,2H),2.38-2.36(m,4H).Refer to the method of step (4) of Example 50, using 4-(2-amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)benzoic acid (150 mg, 385.16umol) as raw material , the title compound (5 mg, white solid) was obtained, yield: 3.4%. MS (ESI): m/z 428.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.27 (t, J = 5.4Hz, 1H), 8.33 (d, J = 2.4Hz, 1H),7.99(d,J＝8.3Hz,2H),7.68(d,J＝8.3Hz,2H),7.66(d,J＝2.3Hz,1H),7.61(d,J＝8.2Hz,2H) ,7.35(d,J＝8.1Hz,2H),5.86(s,2H),4.35(d,J＝5.4Hz,2H),3.58(t,J＝4.4Hz,4H),3.48(s,2H) ,2.38-2.36(m,4H).
实施例52Example 52
化合物52：N-(氰基甲基)-4-(6-(4-吗啉代苯基)吡唑并[1,5-a]嘧啶-3-基)苯甲酰胺Compound 52: N-(cyanomethyl)-4-(6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide
(1)4-(6-溴吡唑并[1,5-a]嘧啶-3-基)苯甲酸甲酯(1) Methyl 4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)benzoate
参照实施例50步骤(1)的方法，以6-溴-3-碘吡唑并[1,5-a]嘧啶(300mg,926.17umol)和4-甲氧羰基苯硼酸(188.35mg,1.05mmol)为原料，得到标题化合物(100mg,黄色固体)，收率：32.51％。MS(ESI):m/z332.0[M+H]+.1H NMR(400MHz,CDCl3)δ8.79(d,J＝2.2Hz,1H),8.52(d,J＝2.2Hz,1H),8.40(s,1H),8.05(s,4H),3.87(s,3H).Referring to the method of step (1) of Example 50, use 6-bromo-3-iodopyrazolo[1,5-a]pyrimidine (300 mg, 926.17umol) and 4-methoxycarbonylphenylboronic acid (188.35mg, 1.05mmol). ) was used as raw material to obtain the title compound (100 mg, yellow solid), yield: 32.51%. MS (ESI): m/z332.0[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.79 (d, J = 2.2 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H ),8.40(s,1H),8.05(s,4H),3.87(s,3H).
(2)4-(6-(4-吗啉代苯基)吡唑并[1,5-a]嘧啶-3-基)苯甲酸(2)4-(6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid
将4-(6-溴吡唑并[1,5-a]嘧啶-3-基)苯甲酸甲酯(50mg,150.53umol)和(4-吗啉代苯基)硼酸(40.00mg,193.21umol)溶于1,4-二氧六环(1mL)和水(0.5mL)的混合溶剂中，加入碳酸铯(147.14mg,451.60umol)和Pd(dppf)Cl2(11.01mg,15.05umol)。反应液用氮气置换三次，然后升温至110℃搅拌16小时。反应液冷却至室温后浓缩。粗品用甲醇(5mL)分散后过滤，滤饼用二甲基亚砜(5mL)溶解后经Prep-HPLC纯化得到标题化合物(3mg,黄色固体)，收率：4.98％。MS(ESI):m/z 401.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.80(brs,1H),9.46(d,J＝2.0Hz,1H),9.10(d,J＝2.0Hz,1H),8.88(s,1H),8.33(d,J＝8.3Hz,2H),8.02(d,J＝8.3Hz,2H),7.78(d,J＝8.7Hz,2H),7.11(d,J＝8.7Hz,2H),3.81-3.74(m,4H),3.23-3.19(m,4H).4-(6-Bromopyrazolo[1,5-a]pyrimidin-3-yl)benzoate methyl ester (50mg, 150.53umol) and (4-morpholinophenyl)boronic acid (40.00mg, 193.21umol) ) was dissolved in a mixed solvent of 1,4-dioxane (1mL) and water (0.5mL), and cesium carbonate (147.14mg, 451.60umol) and Pd(dppf)Cl 2 (11.01mg, 15.05umol) were added. The reaction solution was replaced with nitrogen three times, then the temperature was raised to 110°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated. The crude product was dispersed in methanol (5 mL) and filtered. The filter cake was dissolved in dimethyl sulfoxide (5 mL) and purified by Prep-HPLC to obtain the title compound (3 mg, yellow solid). Yield: 4.98%. MS (ESI): m/z 401.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.80 (brs, 1H), 9.46 (d, J = 2.0Hz, 1H), 9.10 ( d,J＝2.0Hz,1H),8.88(s,1H),8.33(d,J＝8.3Hz,2H),8.02(d,J＝8.3Hz,2H),7.78(d,J＝8.7Hz, 2H),7.11(d,J＝8.7Hz,2H),3.81-3.74(m,4H),3.23-3.19(m,4H).
(3)N-(氰基甲基)-4-(6-(4-吗啉代苯基)吡唑并[1,5-a]嘧啶-3-基)苯甲酰胺(3)N-(cyanomethyl)-4-(6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide
参照实施例50步骤(4)的方法，以4-(6-(4-吗啉代苯基)吡唑并[1,5-a]嘧啶-3-基)苯甲酸(3mg,7.49umol)为原料，得到标题化合物(1mg,黄色固体)，收率：30.44％。MS(ESI):m/z 439.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.46(d,J＝2.4Hz,1H),9.20(brs,1H),9.11(d,J＝2.3Hz,1H),8.88(s,1H),8.33(d,J＝8.6Hz,2H),7.97(d,J＝8.6Hz,2H),7.78(d,J＝8.8Hz,2H),7.11(d,J＝8.8Hz,2H),4.34(d,J＝4.8Hz,2H),3.81-3.75(m,4H),3.23-3.20(m,4H).Referring to the method of step (4) of Example 50, use 4-(6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid (3 mg, 7.49umol) As raw material, the title compound (1 mg, yellow solid) was obtained, yield: 30.44%. MS (ESI): m/z 439.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.46 (d, J = 2.4Hz, 1H), 9.20 (brs, 1H), 9.11 ( d,J＝2.3Hz,1H),8.88(s,1H),8.33(d,J＝8.6Hz,2H),7.97(d,J＝8.6Hz,2H),7.78(d,J＝8.8Hz, 2H),7.11(d,J＝8.8Hz,2H),4.34(d,J＝4.8Hz,2H),3.81-3.75(m,4H),3.23-3.20(m,4H).
实施例53Example 53
化合物53：(R)-2-氨基-5-(2-氟-4-(2-甲基吡咯烷-1-基)甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 53: (R)-2-amino-5-(2-fluoro-4-(2-methylpyrrolidin-1-yl)methyl)phenyl)-N-(tetrahydro-2H-pyran- 4-yl)nicotinamide
参照实施例22的方法，第1步以4-溴-3-氟苯甲醛和(R)-2-甲基吡咯烷为原料，经类似的步骤得到标题化合物(13.0mg,白色固体)。MS(ESI):m/z 413.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝7.6Hz,1H),8.26(d,J＝2.0Hz,1H),8.07(d,J＝2.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.23-7.19(m,4H),4.02-3.94(m,2H),3.87(dd,J＝12.0,2.4Hz,2H),3.41-3.35(m,2H),3.20(d,J＝13.6Hz,1H),2.83-2.78(m,1H),2.45-2.93(m,1H),2.09(q,J＝8.8Hz,1H),1.94-1.88(m,1H),1.78-1.74(m,2H),1.67-1.50(m,4H),1.40-1.31(m,1H),1.10(d,J＝6.0Hz,3H).Referring to the method of Example 22, in step 1, 4-bromo-3-fluorobenzaldehyde and (R)-2-methylpyrrolidine were used as raw materials, and the title compound (13.0 mg, white solid) was obtained through similar steps. MS (ESI): m/z 413.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.35 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H),8.07(d,J＝2.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.23-7.19(m,4H),4.02-3.94(m,2H),3.87(dd,J ＝12.0,2.4Hz,2H),3.41-3.35(m,2H),3.20(d,J＝13.6Hz,1H),2.83-2.78(m,1H),2.45-2.93(m,1H),2.09( q,J＝8.8Hz,1H),1.94-1.88(m,1H),1.78-1.74(m,2H),1.67-1.50(m,4H),1.40-1.31(m,1H),1.10(d, J＝6.0Hz,3H).
实施例54Example 54
化合物54：5-(4-(2-氧-6-氮杂螺环[3.3]庚烷-6-基)苯基)-2-氨基-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 54: 5-(4-(2-oxo-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-amino-N-(tetrahydro-2H-pyran-4- nicotinamide
参照实施例30的方法，第4步以5-(4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)-2-氨基烟酸(35mg, 0.11mmol)和四氢-2H-吡喃-4-胺(34mg,0.34mmol)为原料，得到标题化合物(15mg,淡黄色固体)，收率：34.6％。MS(ESI):m/z 395.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝8.0Hz,1H),8.30(d,J＝2.0Hz,1H),8.06(d,J＝2.4Hz,1H),7.48(d,J＝8.8Hz,2H),6.99(s,2H),7.51(d,J＝8.4Hz,2H),4.73(s,4H),4.02-3.96(m,5H),3.91-3.87(m,2H),3.41-3.35(m,2H),1.79-1.75(m,2H),1.62-1.52(m,2H).Referring to the method of Example 30, in step 4, 5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-aminonicotinic acid (35 mg, 0.11 mmol) and tetrahydro-2H-pyran-4-amine (34 mg, 0.34 mmol) were used as raw materials to obtain the title compound (15 mg, light yellow solid), yield: 34.6%. MS (ESI): m/z 395.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.38 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H),8.06(d,J＝2.4Hz,1H),7.48(d,J＝8.8Hz,2H),6.99(s,2H),7.51(d,J＝8.4Hz,2H),4.73(s, 4H),4.02-3.96(m,5H),3.91-3.87(m,2H),3.41-3.35(m,2H),1.79-1.75(m,2H),1.62-1.52(m,2H).
实施例55Example 55
化合物58：(R)-2-氨基-5-(2-氟-4-(2-甲基吡咯烷-1-基)甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 58: (R)-2-amino-5-(2-fluoro-4-(2-methylpyrrolidin-1-yl)methyl)phenyl)-N-(tetrahydro-2H-pyran- 4-yl)nicotinamide
参照实施例22的方法，第1步以4-溴-3-氟苯甲醛和(R)-2-甲基吡咯烷为原料，第3步以(R)-2-氨基-5-(2-氟-4-((2-甲基吡咯烷-1-基)甲基)苯基)烟酸和((2S,5R)-5-氨基四氢-2H-吡喃-2-基)甲醇盐酸盐为原料，经类似的步骤得到标题化合物(10.0mg,白色固体)。MS(ESI):m/z 443.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.27-8.21(m,2H),8.06(d,J＝1.2Hz,1H),7.49(t,J＝8.0Hz,1H),7.23-7.18(m,4H),4.62(t,J＝6.0Hz,1H),3.98(d,J＝13.6Hz,1H),3.89-3.86(m,2H),3.40-3.36(m,1H),3.24-3.08(m,4H),2.82-2.78(m,1H),2.43-2.38(m,1H),2.08(q,J＝8.8Hz,1H),1.97-1.90(m,2H),1.74-1.54(m,4H),1.38-1.29(m,2H),1.10(d,J＝5.6Hz,3H).Referring to the method of Example 22, the first step uses 4-bromo-3-fluorobenzaldehyde and (R)-2-methylpyrrolidine as raw materials, and the third step uses (R)-2-amino-5-(2 -Fluoro-4-((2-methylpyrrolidin-1-yl)methyl)phenyl)nicotinic acid and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol Hydrochloride was used as raw material, and the title compound (10.0 mg, white solid) was obtained through similar steps. MS (ESI): m/z 443.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.27-8.21 (m, 2H), 8.06 (d, J = 1.2Hz, 1H), 7.49(t,J＝8.0Hz,1H),7.23-7.18(m,4H),4.62(t,J＝6.0Hz,1H),3.98(d,J＝13.6Hz,1H),3.89-3.86(m ,2H),3.40-3.36(m,1H),3.24-3.08(m,4H),2.82-2.78(m,1H),2.43-2.38(m,1H),2.08(q,J＝8.8Hz,1H ),1.97-1.90(m,2H),1.74-1.54(m,4H),1.38-1.29(m,2H),1.10(d,J=5.6Hz,3H).
实施例56Example 56
化合物88：2-氨基-5-(2-(1-(4,4-二氟环己基)吡咯烷-3-基)-2H-吲唑-5-基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺Compound 88: 2-amino-5-(2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-2H-indazol-5-yl)-N-(4-hydroxybicyclo [2.2.2]oct-1-yl)nicotinamide
(1)3-(5-溴-2H-吲唑-2-基)吡咯烷-1-羧酸叔丁酯(1) tert-butyl 3-(5-bromo-2H-indazol-2-yl)pyrrolidine-1-carboxylate
将5-溴-1H-吲唑(3.20g,16.3mmol)，3-((甲基磺酰基)氧基)吡咯烷-1-羧酸叔丁酯(5.19g,19.6mmol)，碳酸钾(4.50g,32.6mmol)溶于N,N-二甲基甲酰胺(30mL)中。反应液升温至100℃搅拌过夜。向反应体系中加入水(50mL)，混合液用乙酸乙酯(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，粗产物用柱层析(石油醚/乙酸乙酯＝10/1)纯化得到3-(5-溴-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁酯(1.2g,黄色固体,收率:20.1％)和3-(5-溴-2H-吲唑-2-基)吡咯烷-1-羧酸叔丁酯(1.0g,黄色固体,收率:16.8％)。MS(ESI):m/z 310.0[M+H-56]+.5-Bromo-1H-indazole (3.20g, 16.3mmol), 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (5.19g, 19.6mmol), potassium carbonate ( 4.50 g, 32.6 mmol) was dissolved in N,N-dimethylformamide (30 mL). The reaction solution was heated to 100°C and stirred overnight. Water (50mL) was added to the reaction system, the mixture was extracted with ethyl acetate (20mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (petroleum ether/ethyl acetate =10/1) purified to obtain 3-(5-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2g, yellow solid, yield: 20.1%) and 3-( 5-Bromo-2H-indazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.0g, yellow solid, yield: 16.8%). MS(ESI):m/z 310.0[M+H-56] + .
(2)5-溴-2-(吡咯烷-3-基)-2H-吲唑盐酸盐(2)5-Bromo-2-(pyrrolidin-3-yl)-2H-indazole hydrochloride
将3-(5-溴-2H-吲唑-2-基)吡咯烷-1-羧酸叔丁酯(600mg,1.64mmol)溶于二氯甲烷(5mL)中，加入4N盐酸二氧六环溶液(4mL)，继续搅拌3小时，有大量固体析出。反应液旋干，得到标题化合物(436mg,白色固体)。MS(ESI):m/z 266.0[M+H]+.Dissolve 3-(5-bromo-2H-indazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 1.64 mmol) in dichloromethane (5 mL), and add 4N dioxane hydrochloride solution (4 mL) and continued stirring for 3 hours, a large amount of solid precipitated. The reaction liquid was spun to dryness to obtain the title compound (436 mg, white solid). MS(ESI):m/z 266.0[M+H] + .
(3)5-溴-2-(1-(4,4-二氟环己基)吡咯烷-3-基)-2H-吲唑(3)5-Bromo-2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-2H-indazole
将5-溴-2-(吡咯烷-3-基)-2H-吲唑盐酸盐(436mg,1.6mmol)溶于二氯甲烷(10mL)中，加入4,4-二氟环己酮(322mg,2.4mmol)和2滴乙酸，搅拌反应20分钟。加入氰基硼氢化钠(202mg,3.2mmol)，继续搅拌过夜。向反应体系中加入水(20mL)，混合液用二氯甲烷(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，残留物用柱层析(二氯甲烷/甲醇＝30/1)纯化得到标题化合物(321mg,黄色油状物)，收率：51％。MS(ESI):m/z 384.0[M+H]+.Dissolve 5-bromo-2-(pyrrolidin-3-yl)-2H-indazole hydrochloride (436 mg, 1.6 mmol) in dichloromethane (10 mL), and add 4,4-difluorocyclohexanone ( 322mg, 2.4mmol) and 2 drops of acetic acid, stir and react for 20 minutes. Sodium cyanoborohydride (202 mg, 3.2 mmol) was added and stirring was continued overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (dichloromethane/methanol = 30/1) was purified to obtain the title compound (321 mg, yellow oil), yield: 51%. MS(ESI):m/z 384.0[M+H] + .
(4)2-氨基-5-(2-(1-(4,4-二氟环己基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸甲酯(4)2-Amino-5-(2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinic acid methyl ester
将5-溴-2-(1-(4,4-二氟环己基)吡咯烷-3-基)-2H-吲唑(250mg,0.6mmol)溶于1,4-二氧六环(3mL)与水(0.3mL)中，加入(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(158mg,0.8mmol)，碳酸钾(221mg,1.6mmol)和Pd(dppf)Cl2(44mg,0.06mmol)。混合物在氮气氛围下回流搅拌反应过夜。向反应体系中加入水(20mL)，混合液用乙酸乙酯(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，粗产物用柱层析(二氯甲烷/甲醇＝40/1)纯化得到标题化合物(200mg,黄色油状物)，收率：67％。MS(ESI):m/z 456.2[M+H]+.Dissolve 5-bromo-2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-2H-indazole (250 mg, 0.6 mmol) in 1,4-dioxane (3 mL ) and water (0.3mL), add (6-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (158mg, 0.8mmol), potassium carbonate (221mg, 1.6mmol) and Pd (dppf) Cl 2 (44 mg, 0.06 mmol). The mixture was stirred under reflux overnight under nitrogen atmosphere. Water (20 mL) was added to the reaction system, the mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (dichloromethane/methanol = 40/1) was purified to obtain the title compound (200 mg, yellow oil), yield: 67%. MS(ESI):m/z 456.2[M+H] + .
(5)2-氨基-5-(2-(1-(4,4-二氟环己基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸(5)2-Amino-5-(2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinic acid
将2-氨基-5-(2-(1-(4,4-二氟环己基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸甲酯(200mg,0.44mmol)溶于甲醇(2mL)和水(2mL)的混合溶剂中，加入氢氧化钠(53mg,1.32mmol)。反应液加热至50℃反应3小时。减压浓缩，加水，水相用1N盐酸调节pH值为2，冻干得到标题化合物(194mg,灰色固体)。MS(ESI):m/z440.2[M-H]-.2-Amino-5-(2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinic acid methyl ester (200 mg, 0.44 mmol) Dissolve in a mixed solvent of methanol (2 mL) and water (2 mL), and add sodium hydroxide (53 mg, 1.32 mmol). The reaction solution was heated to 50°C for 3 hours. Concentrate under reduced pressure, add water, adjust the pH value of the aqueous phase to 2 with 1N hydrochloric acid, and freeze-dry to obtain the title compound (194 mg, gray solid). MS(ESI):m/z440.2[MH] - .
(6)2-氨基-5-(2-(1-(4,4-二氟环己基)吡咯烷-3-基)-2H-吲唑-5-基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺(6)2-Amino-5-(2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-2H-indazol-5-yl)-N-(4-hydroxybicyclo [2.2.2]oct-1-yl)nicotinamide
将2-氨基-5-(2-(1-(4,4-二氟环己基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸(50mg,0.11mmol)溶于N,N-二甲基甲酰胺(3mL)中，加入HATU(84mg,0.22mmol)，N,N-二异丙基乙胺(43mg,0.33mmol)和4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(22mg,0.12mmol)。混合物在室温条件下搅拌过夜。反应液经Prep-HPLC纯化得到标题化合物(0.8mg,白色固体)，收率：1.2％。MS(ESI):m/z 565.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.38(d,J＝2.0Hz,1H),8.03(d,J＝2.4Hz,1H),7.91(s,1H),7.81(s,1H),7.67(d,J＝9.2Hz,1H),7.57(d,J＝8.8Hz,1H),6.86(s,2H),5.25-5.20(m,1H),4.30(s,1H),3.12-3.08(m,1H),3.02-2.96(m,2H),2.74-2.66(m,1H),2.35-2.33(m,1H),2.27-2.21(m,1H),2.08-2.00(m,9H),1.85-1.82(m,4H),1.65-1.61(m,8H).Dissolve 2-amino-5-(2-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinic acid (50 mg, 0.11 mmol) in To N,N-dimethylformamide (3mL), add HATU (84mg, 0.22mmol), N,N-diisopropylethylamine (43mg, 0.33mmol) and 4-aminobicyclo[2.2.2]octane Alkan-1-ol hydrochloride (22 mg, 0.12 mmol). The mixture was stirred at room temperature overnight. The reaction solution was purified by Prep-HPLC to obtain the title compound (0.8 mg, white solid), yield: 1.2%. MS (ESI): m/z 565.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.45 (s, 1H), 8.38 (d, J = 2.0Hz, 1H), 8.03 ( d,J＝2.4Hz,1H),7.91(s,1H),7.81(s,1H),7.67(d,J＝9.2Hz,1H),7.57(d,J＝8.8Hz,1H),6.86( s,2H),5.25-5.20(m,1H),4.30(s,1H),3.12-3.08(m,1H),3.02-2.96(m,2H),2.74-2.66(m,1H),2.35- 2.33(m,1H),2.27-2.21(m,1H),2.08-2.00(m,9H),1.85-1.82(m,4H),1.65-1.61(m,8H).
实施例57Example 57
化合物115：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺Compound 115: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3- Dihydrospiro[indene-1,3'-pyrrolidine]-5-yl)nicotinamide
参照实施例67第8步的方法，以2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酸和4-氨基双环[2.2.2]辛烷-1-醇盐酸盐为原料，得到标题化合物(4.7mg,白色固体)。MS(ESI):m/z517.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝2.4Hz,1H),7.97(d,J＝2.4Hz,1H),7.76(s, 1H),7.45-7.43(m,2H),7.33(d,J＝8.4Hz,1H),6.89(s,2H),4.32(s,1H),3.88-3.84(m,2H),3.33-3.30(m,2H),2.89(t,J＝7.2Hz,2H),2.78(t,J＝6.8Hz,2H),2.73-2.60(m,2H),2.34-2.24(m,1H),2.17-2.10(m,1H),2.09-2.01(m,7H),1.97-1.92(m,2H),1.80-1.77(m,2H),1.65-1.61(m,6H),1.47-1.39(m,2H).Referring to the method in step 8 of Example 67, use 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'- Pyrrolidin]-5-yl)nicotinic acid and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride were used as raw materials to obtain the title compound (4.7 mg, white solid). MS (ESI): m/z517.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.32 (d, J = 2.4Hz, 1H), 7.97 (d, J = 2.4Hz ,1H),7.76(s, 1H),7.45-7.43(m,2H),7.33(d,J＝8.4Hz,1H),6.89(s,2H),4.32(s,1H),3.88-3.84(m,2H),3.33-3.30 (m,2H),2.89(t,J＝7.2Hz,2H),2.78(t,J＝6.8Hz,2H),2.73-2.60(m,2H),2.34-2.24(m,1H),2.17- 2.10(m,1H),2.09-2.01(m,7H),1.97-1.92(m,2H),1.80-1.77(m,2H),1.65-1.61(m,6H),1.47-1.39(m,2H ).
实施例58Example 58
化合物124：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(4-吗啉代哌啶-1-基)-2,3-二氢-1H-茚-5-基)烟酰胺Compound 124: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(4-morpholinopiperidin-1-yl)-2,3-di Hydro-1H-inden-5-yl)nicotinamide
(1)4-(1-(5-溴-2,3-二氢-1H-茚-1-基)哌啶-4-基)吗啉(1)4-(1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidin-4-yl)morpholine
将4-(哌啶-4-基)吗啉(408mg,2.4mmol)，5-溴-2,3-二氢-1H-茚-1-酮(500mg,2.4mmol)溶于四氢呋喃(10mL)中，加入钛酸四乙酯(602mg,2.6mmol)。混合物在60℃下搅拌1小时，再加入氰基硼氢化钠(302mg,4.8mmol)和乙醇(10mL)，继续在室温下搅拌过夜。向反应体系中加入水(20mL)，混合液用乙酸乙酯(40mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(二氯甲烷/甲醇＝20/1)纯化得到标题化合物(170mg,黄色油状物)，收率：20％。MS(ESI):m/z 365.0[M+H]+.Dissolve 4-(piperidin-4-yl)morpholine (408mg, 2.4mmol) and 5-bromo-2,3-dihydro-1H-inden-1-one (500mg, 2.4mmol) in tetrahydrofuran (10mL) , add tetraethyl titanate (602 mg, 2.6 mmol). The mixture was stirred at 60°C for 1 hour, then sodium cyanoborohydride (302 mg, 4.8 mmol) and ethanol (10 mL) were added, and stirring was continued at room temperature overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (170 mg, yellow oil), yield: 20%. MS(ESI):m/z 365.0[M+H] + .
(2)2-氨基-5-(1-(4-吗啉代哌啶-1-基)-2,3-二氢-1H-茚-5-基)烟酸甲酯(2) Methyl 2-amino-5-(1-(4-morpholinopiperidin-1-yl)-2,3-dihydro-1H-inden-5-yl)nicotinate
将4-(1-(5-溴-2,3-二氢-1H-茚-1-基)哌啶-4-基)吗啉(100mg,0.3mmol)，(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(83mg,0.3mmol)，PdCl2(dppf)(24mg,0.03mmol)，碳酸钾(83mg,0.6mmol)溶于1,4-二氧六环/水(5mL/1mL)的混合溶剂中。混合物在氮气保护下升温至100℃搅拌过夜。反应液减压浓缩，残留物经柱层析(100％乙酸乙酯)纯化得到标题化合物(60mg,无色油状物)，收率：50％。MS(ESI):m/z 437.2[M+H]+.4-(1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperidin-4-yl)morpholine (100 mg, 0.3 mmol), (6-amino-5-( Methoxycarbonyl)pyridin-3-yl)boronic acid (83mg, 0.3mmol), PdCl 2 (dppf) (24mg, 0.03mmol), potassium carbonate (83mg, 0.6mmol) dissolved in 1,4-dioxane/ In a mixed solvent of water (5mL/1mL). The mixture was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (100% ethyl acetate) to obtain the title compound (60 mg, colorless oil), yield: 50%. MS(ESI):m/z 437.2[M+H] + .
(3)2-氨基-5-(1-(4-吗啉代哌啶-1-基)-2,3-二氢-1H-茚-5-基)烟酸(3)2-amino-5-(1-(4-morpholinopiperidin-1-yl)-2,3-dihydro-1H-inden-5-yl)nicotinic acid
将2-氨基-5-(1-(4-吗啉代哌啶-1-基)-2,3-二氢-1H-茚-5-基)烟酸甲酯(60mg,0.1mmol)溶于甲醇/水(5mL/5mL)的混合溶剂中，加入氢氧化钠(12mg,0.3mmol)，反应液在50℃条件下搅拌过夜。反应液旋干甲醇，用稀盐酸调节pH值为3-4，减压浓缩，残留物经反相柱纯化得到标题化合物(40mg,无色油状物)，收率：69％。MS(ESI):m/z 423.2[M+H]+.Dissolve 2-amino-5-(1-(4-morpholinopiperidin-1-yl)-2,3-dihydro-1H-inden-5-yl)nicotinic acid methyl ester (60 mg, 0.1 mmol) To the mixed solvent of methanol/water (5mL/5mL), sodium hydroxide (12mg, 0.3mmol) was added, and the reaction solution was stirred at 50°C overnight. The reaction solution was evaporated from methanol, adjusted to pH 3-4 with dilute hydrochloric acid, and concentrated under reduced pressure. The residue was purified by a reversed-phase column to obtain the title compound (40 mg, colorless oil), yield: 69%. MS(ESI):m/z 423.2[M+H] + .
(4)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(4-吗啉代哌啶-1-基)-2,3-二氢-1H-茚-5-基)烟酰胺(4)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(4-morpholinopiperidin-1-yl)-2,3-di Hydro-1H-inden-5-yl)nicotinamide
将2-氨基-5-(1-(4-吗啉代哌啶-1-基)-2,3-二氢-1H-茚-5-基)烟酸(40mg,0.09mmol)，4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(17mg,0.09mmol)溶于N,N-二甲基甲酰胺(5mL)中，反应液中加入HATU(51mg,0.14mmol)和N,N-二异丙基乙胺(23mg,0.18mmol)，室温搅拌过夜。反应液直接经Pre-HPLC纯化得到标题化合物(10mg,白色固体)，收率:19％。MS(ESI):m/z 546.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),7.76(s,1H),7.47-7.43(m,2H),7.30(d,J＝8.0Hz,1H),6.90(s,2H),4.32-4.28(m,2H),3.56-3.54(m,4H),2.95-2.78(m,3H),2.45-2.44(m,4H),2.27-2.22(m,1H),2.12-2.02(m,9H),1.79-1.69(m,2H),1.64-1.60(m,6H),1.47-1.24(m,4H).2-Amino-5-(1-(4-morpholinopiperidin-1-yl)-2,3-dihydro-1H-inden-5-yl)nicotinic acid (40 mg, 0.09 mmol), 4- Aminobicyclo[2.2.2]octane-1-ol hydrochloride (17mg, 0.09mmol) was dissolved in N,N-dimethylformamide (5mL), and HATU (51mg, 0.14mmol) and HATU were added to the reaction solution. N,N-diisopropylethylamine (23 mg, 0.18 mmol), stirred at room temperature overnight. The reaction solution was directly purified by Pre-HPLC to obtain the title compound (10 mg, white solid), yield: 19%. MS (ESI): m/z 546.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.33 (d, J = 2.4Hz, 1H), 7.99 (d, J = 2.4Hz, 1H),7.76(s,1H),7.47-7.43(m,2H),7.30(d,J＝8.0Hz,1H),6.90(s,2H),4.32-4.28(m,2H),3.56-3.54 (m,4H),2.95-2.78(m,3H),2.45-2.44(m,4H),2.27-2.22(m,1H),2.12-2.02(m,9H),1.79-1.69(m,2H) ,1.64-1.60(m,6H),1.47-1.24(m,4H).
实施例59Example 59
化合物125：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)烟酰胺Compound 125: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(4-(tetrahydro-2H-pyran-4-yl)piperazine- 1-yl)-2,3-dihydro-1H-inden-5-yl)nicotinamide
(1)4-(5-溴-2,3-二氢-1H-茚-1-基)哌嗪-1-羧酸叔丁酯(1) tert-butyl 4-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate
将5-溴-2,3-二氢-1H-茚-1-酮(3.00g,14.36mmol)和哌嗪-1-羧酸叔丁酯(2.94g,15.79mmol)溶于四氢呋喃(30mL)中，加入钛酸四乙酯(3.6g,15.79mmol)。反应液升温至60℃搅拌2小时，冷却至室温，加入乙醇(75mL)和氰基硼氢化钠(1.81g,28.72mmol)，氮气保护条件下继续在室温反应过夜。加水(50mL)淬灭反应液，用硅藻土过滤，滤液减压浓缩，乙酸乙酯(50mL x 3)萃取，无水硫酸钠干燥，浓缩。残留物经柱层析(二氯甲烷/甲醇＝100/1)纯化得到标题化合物(970mg,棕色油状物)，收率：17.8％。MS(ESI):m/z 381.1[M+H]+.Dissolve 5-bromo-2,3-dihydro-1H-inden-1-one (3.00g, 14.36mmol) and piperazine-1-carboxylic acid tert-butyl ester (2.94g, 15.79mmol) in tetrahydrofuran (30mL) , add tetraethyl titanate (3.6g, 15.79mmol). The reaction solution was heated to 60°C and stirred for 2 hours, cooled to room temperature, ethanol (75 mL) and sodium cyanoborohydride (1.81 g, 28.72 mmol) were added, and the reaction was continued at room temperature overnight under nitrogen protection. Add water (50 mL) to quench the reaction solution, filter through diatomaceous earth, concentrate the filtrate under reduced pressure, extract with ethyl acetate (50 mL x 3), dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane/methanol=100/1) to obtain the title compound (970 mg, brown oil), yield: 17.8%. MS(ESI):m/z 381.1[M+H] + .
(2)1-(5-溴-2,3-二氢-1H-茚-1-基)哌嗪(2)1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazine
将4-(5-溴-2,3-二氢-1H-茚-1-基)哌嗪-1-羧酸叔丁酯(970mg,2.56mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(3mL)，室温反应2小时。反应液用饱和碳酸氢钠溶液调至中性，用二氯甲烷(15mL x 3)萃取，无水硫酸钠干燥，浓缩得到标题化合物(700mg,棕色油状物)，直接用于下一步。MS(ESI):m/z 281.1[M+H]+.Dissolve 4-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylic acid tert-butyl ester (970 mg, 2.56 mmol) in dichloromethane (10 mL), and add Trifluoroacetic acid (3 mL), react at room temperature for 2 hours. The reaction solution was adjusted to neutrality with saturated sodium bicarbonate solution, extracted with dichloromethane (15 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (700 mg, brown oil), which was used directly in the next step. MS(ESI):m/z 281.1[M+H] + .
(3)1-(5-溴-2,3-二氢-1H-茚-1-基)-4-(四氢-2H-吡喃-4-基)哌嗪(3)1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-4-(tetrahydro-2H-pyran-4-yl)piperazine
将1-(5-溴-2,3-二氢-1H-茚-1-基)哌嗪(500mg,1.79mmol)和四氢-4H-吡喃-4-酮(200mg,1.97mmol)溶于四氢呋喃(20mL)中，加入钛酸四乙酯(450mg,1.97mmol)。反应液升温至60℃搅拌2小时，冷却至室温，加入乙醇(30mL)和氰基硼氢化钠(226mg,3.58mmol)，氮气保护条件下继续在室温反应过夜。加水(20mL)淬灭反应液，用硅藻土过滤，滤液减压浓缩，乙酸乙酯(20mL x 3)萃取，无水硫酸钠干燥，浓缩。残留物经柱层析(二氯甲烷/甲醇＝10/1)纯化得到标题化合物(90mg,白色固体)，收率:11.8％。MS(ESI):m/z 365.1[M+H]+.Dissolve 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)piperazine (500mg, 1.79mmol) and tetrahydro-4H-pyran-4-one (200mg, 1.97mmol) To tetrahydrofuran (20 mL), tetraethyl titanate (450 mg, 1.97 mmol) was added. The reaction solution was heated to 60°C and stirred for 2 hours, cooled to room temperature, ethanol (30 mL) and sodium cyanoborohydride (226 mg, 3.58 mmol) were added, and the reaction was continued at room temperature overnight under nitrogen protection. Add water (20 mL) to quench the reaction solution, filter through diatomaceous earth, concentrate the filtrate under reduced pressure, extract with ethyl acetate (20 mL x 3), dry over anhydrous sodium sulfate, and concentrate. The residue was purified by column chromatography (dichloromethane/methanol=10/1) to obtain the title compound (90 mg, white solid), yield: 11.8%. MS(ESI):m/z 365.1[M+H] + .
(4)2-氨基-5-(1-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)烟酸甲酯(4)2-Amino-5-(1-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-2,3-dihydro-1H-indene-5-yl ) methyl nicotinate
将1-(5-溴-2,3-二氢-1H-茚-1-基)-4-(四氢-2H-吡喃-4-基)哌嗪(90mg,0.25mmol)和2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(83.4mg,0.30mmol)溶于1,4-二氧六环/水(2mL/0.5mL)的混合溶剂中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(22mg,0.03mmol)和碳酸钾(103.5mg,0.75mmol)。反应液用氮气置换，加热至80℃搅拌16小时。浓缩反应液，残留物经柱层析(二氯甲烷/甲醇＝100/1～10/1)纯化得到标题化合物(70mg,橙色油状物)，收率：64.2％。MS(ESI):m/z 437.2[M+H]+. 1-(5-Bromo-2,3-dihydro-1H-inden-1-yl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (90 mg, 0.25 mmol) and 2- Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinic acid methyl ester (83.4 mg, 0.30 mmol) was dissolved in 1 , to a mixed solvent of 4-dioxane/water (2mL/0.5mL), add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22mg, 0.03mmol) and carbonic acid Potassium (103.5mg, 0.75mmol). The reaction liquid was replaced with nitrogen, heated to 80°C, and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol=100/1~10/1) to obtain the title compound (70 mg, orange oil), yield: 64.2%. MS(ESI):m/z 437.2[M+H] + .
(5)2-氨基-5-(1-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)烟酸(5)2-Amino-5-(1-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-2,3-dihydro-1H-indene-5-yl )niacin
将2-氨基-5-(1-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)烟酸甲酯(70mg,0.16mmol)溶于甲醇/水(2mL/2mL)的混合溶液中，加入氢氧化钠(20mg,0.48mmol),反应液加热至50℃搅拌2小时。减压浓缩除去甲醇，用2N盐酸溶液调节pH至中性，再经反相柱纯化得到标题化合物(30mg,白色固体)，收率：44.4％。MS(ESI):m/z 423.2[M+H]+.2-Amino-5-(1-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-2,3-dihydro-1H-inden-5-yl) smoke Methyl acid ester (70 mg, 0.16 mmol) was dissolved in a mixed solution of methanol/water (2 mL/2 mL), sodium hydroxide (20 mg, 0.48 mmol) was added, and the reaction solution was heated to 50°C and stirred for 2 hours. Concentrate under reduced pressure to remove methanol, adjust the pH to neutral with 2N hydrochloric acid solution, and then purify through reversed-phase column to obtain the title compound (30 mg, white solid), yield: 44.4%. MS(ESI):m/z 423.2[M+H] + .
(6)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)烟酰胺(6)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(4-(tetrahydro-2H-pyran-4-yl)piperazine- 1-yl)-2,3-dihydro-1H-inden-5-yl)nicotinamide
将2-氨基-5-(1-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-2,3-二氢-1H-茚-5-基)烟酸(30mg,0.07mmol)溶于N,N-二甲基甲酰胺(1mL)中，加入HATU(53.2mg,0.14mmol)和N,N-二异丙基乙胺(27.3mg,0.21mmol)，然后加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(13.84mg,0.08mmol)，反应液在室温条件下搅拌3小时。反应液经Pre-HPLC纯化得到标题化合物(10.9mg,白色固体)，收率：28.6％。MS(ESI):m/z 546.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),7.76(s,1H),7.48(s,1H),7.44(d,J＝8.0Hz,1H),7.30(d,J＝7.6Hz,1H),6.90(s,2H),4.31(s,1H),4.26(t,J＝7.2Hz,1H),3.86(d,J＝8.8Hz,2H),3.25(t,J＝11.6Hz,2H),2.96-2.88(m,1H),2.84-2.77(m,1H),2.48-2.29(m,7H),2.06-2.00(m,8H),1.69-1.60(m,8H),1.40-1.24(m,4H).2-Amino-5-(1-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-2,3-dihydro-1H-inden-5-yl) smoke Acid (30mg, 0.07mmol) was dissolved in N,N-dimethylformamide (1mL), HATU (53.2mg, 0.14mmol) and N,N-diisopropylethylamine (27.3mg, 0.21mmol) were added , then added 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (13.84 mg, 0.08 mmol), and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was purified by Pre-HPLC to obtain the title compound (10.9 mg, white solid), yield: 28.6%. MS (ESI): m/z 546.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.33 (d, J = 2.4Hz, 1H), 7.99 (d, J = 2.4Hz, 1H),7.76(s,1H),7.48(s,1H),7.44(d,J＝8.0Hz,1H),7.30(d,J＝7.6Hz,1H),6.90(s,2H),4.31( s,1H),4.26(t,J＝7.2Hz,1H),3.86(d,J＝8.8Hz,2H),3.25(t,J＝11.6Hz,2H),2.96-2.88(m,1H), 2.84-2.77(m,1H),2.48-2.29(m,7H),2.06-2.00(m,8H),1.69-1.60(m,8H),1.40-1.24(m,4H).
实施例60Example 60
化合物126：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-基)烟酰胺Compound 126: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazole- 5-yl)nicotinamide
(1)5-溴-1-(四氢-2H-吡喃-4-基)-1H-吲唑(1)5-Bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole
将5-溴-1H-吲唑(1.5g,7.6mmol)，四氢-2H-吡喃-4-基甲磺酸酯(2.0g,11.4mmol)，碳酸铯(4.96g,15.2mmol)溶于N,N-二甲基甲酰胺(20mL)中。升温至100℃搅拌反应过夜。向反应体系中加入水(50mL)，混合液使用乙酸乙酯(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，粗产物用柱层析(石油醚/乙酸乙酯＝10/1)纯化得到5-溴-1-(四氢-2H-吡喃-4-基)-1H-吲唑(1.6g,黄色固体,收率:49％)和5-溴-2-(四氢-2H-吡喃-4-基)-2H-吲唑(1.2g,黄色固体,收率:38％)。MS(ESI):m/z 281.0[M+H]+.Dissolve 5-bromo-1H-indazole (1.5g, 7.6mmol), tetrahydro-2H-pyran-4-ylmethanesulfonate (2.0g, 11.4mmol), and cesium carbonate (4.96g, 15.2mmol) in N,N-dimethylformamide (20 mL). The temperature was raised to 100°C and the reaction was stirred overnight. Water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL =10/1) purified to obtain 5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (1.6g, yellow solid, yield: 49%) and 5-bromo-2 -(Tetrahydro-2H-pyran-4-yl)-2H-indazole (1.2g, yellow solid, yield: 38%). MS(ESI):m/z 281.0[M+H] + .
(2)1-(四氢-2H-吡喃-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑(2)1-(Tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -base)-1H-indazole
将5-溴-1-(四氢-2H-吡喃-4-基)-1H-吲唑(100mg,0.357mmol)溶于1,4-二氧六环(2mL)中，加入联硼酸频哪醇酯(136mg,0.54mmol)，乙酸钾(88mg,1.07mmol)和Pd(dppf)Cl2(30mg,0.041mmol)。混合物在氮气氛围下回流搅拌反应过夜。向反应体系中加入水(50mL)，混合液使用乙酸乙酯(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，粗产物用柱层析(石油醚/乙酸乙酯＝10/1)纯化得到标题化合物(30mg)，收率：25.6％。MS(ESI):m/z 329.2[M+H]+.Dissolve 5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (100mg, 0.357mmol) in 1,4-dioxane (2mL), add diboronic acid which alcohol ester (136 mg, 0.54 mmol), potassium acetate (88 mg, 1.07 mmol) and Pd(dppf)Cl 2 (30 mg, 0.041 mmol). The mixture was stirred under reflux overnight under nitrogen atmosphere. Water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL =10/1) to obtain the title compound (30 mg), yield: 25.6%. MS(ESI):m/z 329.2[M+H] + .
(3)2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-基)烟酸甲酯(3) Methyl 2-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)nicotinate
将1-(四氢-2H-吡喃-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑(118mg,0.357mmol)溶于1,4-二氧六环(2mL)和水(0.2mL)的混合溶剂中，加入2-氨基-5-溴烟酸甲酯(99mg,0.429mmol)，碳酸钾(148mg，1.07mmol)和Pd(dppf)Cl2(30mg,0.041mmol)。混合物在氮气氛围下回流搅拌反应过夜。向反应体系中加入水(50mL)，混合液使用乙酸乙酯(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，粗产物用柱层析(二氯甲烷/甲醇＝30/1)纯化得到标题化合物(100mg)，收率：79％。MS(ESI):m/z 353.2[M+H]+.1-(Tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-indazole (118mg, 0.357mmol) was dissolved in a mixed solvent of 1,4-dioxane (2mL) and water (0.2mL), and 2-amino-5-bromonicotinic acid methyl ester (99mg ,0.429mmol), potassium carbonate (148mg, 1.07mmol) and Pd(dppf)Cl 2 (30mg, 0.041mmol). The mixture was stirred under reflux overnight under nitrogen atmosphere. Water (50mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (dichloromethane/methanol= 30/1) was purified to obtain the title compound (100 mg), yield: 79%. MS(ESI):m/z 353.2[M+H] + .
(4)2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-基)烟酸(4)2-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)nicotinic acid
将2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-基)烟酸甲酯(100mg,0.283mmol)，氢氧化钠(35mg,0.85mmol)溶于甲醇/水(1.5mL/0.5mL)混合溶剂中，反应液升温至50℃搅拌2小时。向反应体系中加入水(2mL)，浓缩。水相用2N盐酸水溶液调节pH值为2，固体析出。固体经过滤，干燥，得到标题化合物(38mg,黄色固体)，收率：40％。MS(ESI):m/z 339.1[M+H]+.2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)nicotinic acid methyl ester (100 mg, 0.283 mmol), sodium hydroxide (35 mg, 0.85mmol) was dissolved in methanol/water (1.5mL/0.5mL) mixed solvent, and the reaction solution was heated to 50°C and stirred for 2 hours. Water (2 mL) was added to the reaction system and concentrated. Use 2N hydrochloric acid aqueous solution to adjust the pH value of the aqueous phase to 2, and the solid will precipitate. The solid was filtered and dried to obtain the title compound (38 mg, yellow solid), yield: 40%. MS(ESI):m/z 339.1[M+H] + .
(5)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-基)烟酰胺(5)2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazole- 5-yl)nicotinamide
将2-氨基-5-(1-(四氢-2H-吡喃-4-基)-1H-吲唑-5-基)烟酸(30mg,0.09mmol)和4-氨基双环[2.2.2]辛-1-醇盐酸盐(19mg,0.11mmol)溶于N,N-二甲基甲酰胺(2mL)中,加入HATU(68mg,0.18mmol)和N,N-二异丙基乙胺(35mg,0.27mmol)。混合物在室温下搅拌反应过夜。向反应体系中加入水(5mL)，混合液用乙酸乙酯(5mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经Prep-HPLC纯化得到标题化合物(16mg,白色固体)，收率：39％。MS(ESI):m/z 462.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.39(d,J＝2.4Hz,1H),8.12(s,1H),8.03(d,J＝2.4Hz,1H),7.99(s,1H),7.83-7.80(m,2H),7.70(dd,J＝8.8,1.6Hz,1H),6.88(s,2H),4.93-4.90(m,1H),4.31(s,1H),4.02(dd,J＝10.8,3.6Hz,2H),3.58(dd,J＝11.6,10.4Hz,2H),2.18-1.98(m,8H),1.94-1.84(m,2H),1.71-1.56(m,6H).2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)nicotinic acid (30 mg, 0.09 mmol) and 4-aminobicyclo [2.2.2 ] Octan-1-ol hydrochloride (19 mg, 0.11 mmol) was dissolved in N, N-dimethylformamide (2 mL), and HATU (68 mg, 0.18 mmol) and N, N-diisopropylethylamine were added (35mg,0.27mmol). The mixture was stirred at room temperature overnight. Water (5 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the title compound (16 mg, white solid), yield: 39%. MS (ESI): m/z 462.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.39 (d, J = 2.4Hz, 1H), 8.12 (s, 1H), 8.03 ( d,J＝2.4Hz,1H),7.99(s,1H),7.83-7.80(m,2H),7.70(dd,J＝8.8,1.6Hz,1H),6.88(s,2H),4.93-4.90 (m,1H),4.31(s,1H),4.02(dd,J＝10.8,3.6Hz,2H),3.58(dd,J＝11.6,10.4Hz,2H),2.18-1.98(m,8H), 1.94-1.84(m,2H),1.71-1.56(m,6H).
实施例61Example 61
化合物127：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(四氢-2H-吡喃-4-基)-2H-吲唑-5-基)烟酰胺Compound 127: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(tetrahydro-2H-pyran-4-yl)-2H-indazole- 5-yl)nicotinamide
(1)2-氨基-5-(2-(四氢-2H-吡喃-4-基)-2H-吲唑-5-基)烟酸甲酯(1) Methyl 2-amino-5-(2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl)nicotinate
将5-溴-2-(四氢-2H-吡喃-4-基)-2H-吲唑(250mg,0.89mmol,实施例60第1步)溶于1,4-二氧六环(3mL)和水(0.3mL)的混合溶剂中，加入(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(210mg,1.07mmol)，碳酸钾(307mg,2.23mmol)和Pd(dppf)Cl2(66mg,0.09mmol)。混合物在氮气氛围下回流搅拌反应过夜。向反应体系中加入水(20mL)，混合液使用乙酸乙酯(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，粗产物用柱层析(二氯甲烷/甲醇＝30/1)纯化得到标题化合物(232mg,黄色固体)，收率：74％。MS(ESI):m/z 353.1[M+H]+. Dissolve 5-bromo-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole (250 mg, 0.89 mmol, step 1 of Example 60) in 1,4-dioxane (3 mL ) and water (0.3 mL), add (6-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid (210 mg, 1.07 mmol), potassium carbonate (307 mg, 2.23 mmol) and Pd (dppf)Cl 2 (66 mg, 0.09 mmol). The mixture was stirred under reflux overnight under nitrogen atmosphere. Water (20mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (dichloromethane/methanol= 30/1) was purified to obtain the title compound (232 mg, yellow solid), yield: 74%. MS(ESI):m/z 353.1[M+H] + .
(2)2-氨基-5-(2-(四氢-2H-吡喃-4-基)-2H-吲唑-5-基)烟酸(2)2-Amino-5-(2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl)nicotinic acid
将2-氨基-5-(2-(四氢-2H-吡喃-4-基)-2H-吲唑-5-基)烟酸甲酯(230mg,0.65mmol)，氢氧化钠(78mg,1.95mmol)溶于甲醇/水(6mL/2mL)混合溶剂中。反应液升温至50℃搅拌2小时。向反应体系中加入水(5mL)，浓缩。水相用2N盐酸水溶液调节pH值为2，固体析出。固体过滤，干燥，得到标题化合物(194mg,黄色固体)，收率：80％。MS(ESI):m/z 339.1[M+H]+.2-Amino-5-(2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl)nicotinic acid methyl ester (230 mg, 0.65 mmol), sodium hydroxide (78 mg, 1.95mmol) was dissolved in methanol/water (6mL/2mL) mixed solvent. The reaction solution was heated to 50°C and stirred for 2 hours. Water (5 mL) was added to the reaction system and concentrated. Use 2N hydrochloric acid aqueous solution to adjust the pH value of the aqueous phase to 2, and the solid will precipitate. The solid was filtered and dried to obtain the title compound (194 mg, yellow solid), yield: 80%. MS(ESI):m/z 339.1[M+H] + .
(3)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(四氢-2H-吡喃-4-基)-2H-吲唑-5-基)烟酰胺(3)2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(tetrahydro-2H-pyran-4-yl)-2H-indazole- 5-yl)nicotinamide
将2-氨基-5-(2-(四氢-2H-吡喃-4-基)-2H-吲唑-5-基)烟酸(40mg,0.12mmol)和4-氨基双环[2.2.2]辛-1-醇盐酸盐(25mg,0.14mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入HATU(91mg,0.24mmol)和N,N-二异丙基乙胺(46mg,0.36mmol)。混合物在室温下搅拌反应过夜。向反应体系中加入水(5mL)，混合液用乙酸乙酯(5mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经Prep-HPLC纯化得到标题化合物(10mg,白色固体)，收率：18.5％。MS(ESI):m/z 462.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.38(d,J＝2.4Hz,1H),8.02(d,J＝2.4Hz,1H),7.91(s,1H),7.82(s,1H),7.68(d,J＝8.8Hz,1H),7.58(dd,J＝8.8,1.6Hz,1H),6.87(s,2H),4.79-4.73(m,1H),4.30(s,1H),4.04-4.01(m,2H),3.57-3.50(m,2H),2.18-2.03(m,10H),1.64-1.60(m,6H).2-Amino-5-(2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl)nicotinic acid (40 mg, 0.12 mmol) and 4-aminobicyclo [2.2.2 ] Octan-1-ol hydrochloride (25 mg, 0.14 mmol) was dissolved in N, N-dimethylformamide (2 mL), and HATU (91 mg, 0.24 mmol) and N, N-diisopropylethylamine were added (46mg,0.36mmol). The mixture was stirred at room temperature overnight. Water (5 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain the title compound (10 mg, white solid), yield: 18.5%. MS (ESI): m/z 462.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.46 (s, 1H), 8.38 (d, J = 2.4Hz, 1H), 8.02 ( d,J＝2.4Hz,1H),7.91(s,1H),7.82(s,1H),7.68(d,J＝8.8Hz,1H),7.58(dd,J＝8.8,1.6Hz,1H), 6.87(s,2H),4.79-4.73(m,1H),4.30(s,1H),4.04-4.01(m,2H),3.57-3.50(m,2H),2.18-2.03(m,10H), 1.64-1.60(m,6H).
实施例62Example 62
化合物128：2-氨基-5-(1-(1-(4,4-二氟环己基)吡咯烷-3-基)-1H-吲唑-5-基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺Compound 128: 2-amino-5-(1-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-indazol-5-yl)-N-(4-hydroxybicyclo [2.2.2]oct-1-yl)nicotinamide
参照实施例56的方法，以3-(5-溴-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁酯(80.0mg,242umol,实施例56第1步)为原料，经类似的步骤得到标题化合物(3.0mg,白色固体)。MS(ESI):m/z 565.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝2.4Hz,1H),8.09(s,1H),8.03(d,J＝2.0Hz,1H),7.97(s,1H),7.88(d,J＝8.8Hz,1H),7.79(s,1H),7.68(d,J＝8.8Hz,1H),6.87(s,2H),5.40-5.32(m,1H),4.30(s,1H),3.17-3.09(m,2H),2.96-2.73(m,4H),2.37-2.22(m,5H),2.09-2.00(m,6H),1.91-1.77(m,4H),1.69-1.56(m,6H).Referring to the method of Example 56, using 3-(5-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (80.0 mg, 242umol, step 1 of Example 56) as raw material, A similar procedure gave the title compound (3.0 mg, white solid). MS (ESI): m/z 565.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.38 (d, J = 2.4Hz, 1H), 8.09 (s, 1H), 8.03 ( d,J＝2.0Hz,1H),7.97(s,1H),7.88(d,J＝8.8Hz,1H),7.79(s,1H),7.68(d,J＝8.8Hz,1H),6.87( s,2H),5.40-5.32(m,1H),4.30(s,1H),3.17-3.09(m,2H),2.96-2.73(m,4H),2.37-2.22(m,5H),2.09- 2.00(m,6H),1.91-1.77(m,4H),1.69-1.56(m,6H).
实施例63Example 63
化合物129：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(2-吗啉代乙基)-2H-吲唑-5-基)烟酰胺Compound 129: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(2-morpholinoethyl)-2H-indazol-5-yl) Nicotinamide
(1)4-(2-(5-溴-2H-吲唑-2-基)乙基)吗啉(1)4-(2-(5-bromo-2H-indazol-2-yl)ethyl)morpholine
将5-溴-2-硝基苯甲醛(230.0mg,1.0mmol)和N-(2-氨基乙基)吗啉(143.0mg,1.1mmol)溶于异丙醇(3mL)中，反应液在80℃下搅拌4小时。冷却至室温，再加入三丁基膦(0.74mL)，并继续在80℃下搅拌12小时。向反应液中加入水(40mL)，用乙酸乙酯(30mL x 3)萃取，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，减压浓缩得到粗品。粗品经柱层析(二氯甲烷/甲醇＝100/1～50/1)纯化得到标题化合物(309.0mg,黄色油状物)，收率：>99％。MS(ESI):m/z 310.1[M+H]+.Dissolve 5-bromo-2-nitrobenzaldehyde (230.0 mg, 1.0 mmol) and N-(2-aminoethyl)morpholine (143.0 mg, 1.1 mmol) in isopropanol (3 mL), and the reaction solution is Stir at 80°C for 4 hours. Cool to room temperature, add tributylphosphine (0.74 mL), and continue stirring at 80°C for 12 hours. Water (40 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL x 3), washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane/methanol=100/1~50/1) to obtain the title compound (309.0 mg, yellow oil), yield: >99%. MS(ESI):m/z 310.1[M+H] + .
(2)2-氨基-5-(2-(2-吗啉代乙基)-2H-吲唑-5-基)烟酸甲酯(2)2-Amino-5-(2-(2-morpholinoethyl)-2H-indazol-5-yl)nicotinic acid methyl ester
将4-(2-(5-溴-2H-吲唑-2-基)乙基)吗啉(500.0mg,1.6mmol)溶于1,4-二氧六环和水(24mL/6mL)的混合溶剂中，加入2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(445.0mg,1.6mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(117mg,0.16mmol)和碳酸钾(662.0mg,4.8mmol)。反应液在氮气氛围下加热至80℃搅拌过夜。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝40/1)纯化得到标题化合物(314.0mg,黄色油状物)，收率：62％。MS(ESI):m/z 382.1[M+H]+.Dissolve 4-(2-(5-bromo-2H-indazol-2-yl)ethyl)morpholine (500.0 mg, 1.6 mmol) in 1,4-dioxane and water (24 mL/6 mL) To the mixed solvent, add methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (445.0 mg ,1.6mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (117mg, 0.16mmol) and potassium carbonate (662.0mg, 4.8mmol). The reaction solution was heated to 80°C under nitrogen atmosphere and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=40/1) to obtain the title compound (314.0 mg, yellow oil), yield: 62%. MS(ESI):m/z 382.1[M+H] + .
(3)2-氨基-5-(2-(2-吗啉代乙基)-2H-吲唑-5-基)烟酸(3)2-Amino-5-(2-(2-morpholinoethyl)-2H-indazol-5-yl)nicotinic acid
将2-氨基-5-(2-(2-吗啉代乙基)-2H-吲唑-5-基)烟酸甲酯(314.0mg,0.82mmol)溶于甲醇和水(7mL/3mL)混合溶剂中，加入氢氧化钠(98.0mg,2.46mmol)，混合物加热至50℃搅拌过夜。反应液减压浓缩，残留物经反相柱纯化得到标题化合物(110mg,黄色固体)，收率：37％。MS(ESI):m/z 368.1[M+H]+.Dissolve 2-amino-5-(2-(2-morpholinoethyl)-2H-indazol-5-yl)nicotinic acid methyl ester (314.0mg, 0.82mmol) in methanol and water (7mL/3mL) To the mixed solvent, sodium hydroxide (98.0 mg, 2.46 mmol) was added, and the mixture was heated to 50°C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase column to obtain the title compound (110 mg, yellow solid), yield: 37%. MS(ESI):m/z 368.1[M+H] + .
(4)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(2-吗啉代乙基)-2H-吲唑-5-基)烟酰胺(4)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(2-morpholinoethyl)-2H-indazol-5-yl) Nicotinamide
将2-氨基-5-(2-(2-吗啉代乙基)-2H-吲唑-5-基)烟酸(110mg,0.3mmol)溶于N,N-二甲基甲酰胺(10mL)中，依次加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(53.0mg,0.3mmol)，HATU(228.0mg,0.6mmol)和N,N-二异丙基乙胺(155.0mg,1.2mmol)，反应液在室温下搅拌3小时。向反应液中加入水(40mL)，用乙酸乙酯(30mL x 3)萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥。残留物经Prep-HPLC纯化得到标题化合物(40.2mg,白色固体)，收率：27％。MS(ESI):m/z 491.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.38(d,J＝2.4Hz,1H),8.03(d,J＝2.0Hz,1H),7.91(s,1H),7.80(s,1H),7.66(d,J＝9.2Hz,1H),7.56(dd,J＝8.8,1.6Hz,1H),6.87(s,2H),4.55(t,J＝6.4Hz,2H),4.30(s,1H),3.53(t,J＝4.8Hz,4H),2.86(t,J＝6.4Hz,2H),2.44-2.42(m,4H),2.07-2.03(m,6H),1.64-1.60(m,6H).Dissolve 2-amino-5-(2-(2-morpholinoethyl)-2H-indazol-5-yl)nicotinic acid (110 mg, 0.3 mmol) in N,N-dimethylformamide (10 mL ), add 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (53.0mg, 0.3mmol), HATU (228.0mg, 0.6mmol) and N,N-diisopropylethylamine in sequence (155.0 mg, 1.2 mmol), the reaction solution was stirred at room temperature for 3 hours. Water (40 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL x 3), washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The residue was purified by Prep-HPLC to obtain the title compound (40.2 mg, white solid), yield: 27%. MS (ESI): m/z 491.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.42 (s, 1H), 8.38 (d, J = 2.4Hz, 1H), 8.03 ( d,J＝2.0Hz,1H),7.91(s,1H),7.80(s,1H),7.66(d,J＝9.2Hz,1H),7.56(dd,J＝8.8,1.6Hz,1H), 6.87(s,2H),4.55(t,J＝6.4Hz,2H),4.30(s,1H),3.53(t,J＝4.8Hz,4H),2.86(t,J＝6.4Hz,2H), 2.44-2.42(m,4H),2.07-2.03(m,6H),1.64-1.60(m,6H).
实施例64Example 64
化合物130：2-氨基-5-(1-(1-(4,4-二氟环己基)哌啶-4-基)-1H-吲唑-5-基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺Compound 130: 2-amino-5-(1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-indazol-5-yl)-N-(4-hydroxybicyclo [2.2.2]oct-1-yl)nicotinamide
(1)4-(5-溴-1H-吲唑-1-基)哌啶-1-羧酸叔丁酯(1) tert-butyl 4-(5-bromo-1H-indazol-1-yl)piperidine-1-carboxylate
将5-溴-1H-吲唑(1.00g,5.0mmol)溶于N,N-二甲基甲酰胺(10mL)中，依次加入碳酸钾(1.42g,10.0mmol)，4-((甲基磺酰基)氧基)哌啶-1-羧酸叔丁酯(1.70g,6.0mmol)，混合物在100℃条件下反应12小时。反应液中加水(100mL)，用乙酸乙酯(40mL x 3)萃取，饱和碳酸氢钠溶液洗涤3次，无水硫酸钠干燥，减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝15/1)纯化得到标题化合物(900mg,白色固体)，收率：47％。MS(ESI):m/z 324.0[M+H-56]+.1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.87(s,1H),7.44(dd,J＝9.2,1.6Hz,1H)7.33(d,J＝9.2Hz,1H),4.55-4.49(m,1H),4.31-4.27(m,2H),2.98-2.92(m,2H),2.26-2.15(m, 2H),2.01-1.98(m,2H),1.49(s,9H).Dissolve 5-bromo-1H-indazole (1.00g, 5.0mmol) in N,N-dimethylformamide (10mL), add potassium carbonate (1.42g, 10.0mmol), 4-((methyl Sulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (1.70g, 6.0mmol), the mixture was reacted at 100°C for 12 hours. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (40 mL x 3), washed three times with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 15/1) to obtain the title compound (900 mg, white solid), yield: 47%. MS (ESI): m/z 324.0[M+H-56] + . 1 H NMR (400MHz, CDCl 3 ) δ7.93 (s, 1H), 7.87 (s, 1H), 7.44 (dd, J = 9.2 ,1.6Hz,1H)7.33(d,J＝9.2Hz,1H),4.55-4.49(m,1H),4.31-4.27(m,2H),2.98-2.92(m,2H),2.26-2.15(m , 2H),2.01-1.98(m,2H),1.49(s,9H).
(2)5-溴-1-(哌啶-4-基)-1H-吲唑盐酸盐(2)5-Bromo-1-(piperidin-4-yl)-1H-indazole hydrochloride
将4-(5-溴-1H-吲唑-1-基)哌啶-1-羧酸叔丁酯(900.0mg,2.37mmol)加入到4M盐酸二氧六环溶液(9mL)中，在室温条件下搅拌2小时。将反应液减压浓缩，直接用于下一步。MS(ESI):m/z 280.0[M+H]+.4-(5-Bromo-1H-indazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (900.0 mg, 2.37 mmol) was added to 4M dioxane hydrochloride solution (9 mL) at room temperature. Stir under these conditions for 2 hours. The reaction solution was concentrated under reduced pressure and used directly in the next step. MS(ESI):m/z 280.0[M+H] + .
(3)5-溴-1-(1-(4,4-二氟环己基)哌啶-4-基)-1H-吲唑(3)5-Bromo-1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-indazole
将5-溴-1-(哌啶-4-基)-1H-吲唑盐酸盐(300.0mg,1.07mmol)溶于甲醇(3mL)中，依次加入醋酸(400uL)，4,4-二氟环己酮(158.0mg,1.07mmol)，混合物在50℃下搅拌两小时。然后加入氰基硼氢化钠(135.0mg,2.14mmol)，继续反应3小时。向反应体系中加入水(20mL)，混合液用二氯甲烷(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，残留物经柱层析(100％乙酸乙酯)纯化得到标题化合物(60mg,无色油状物)，收率：14％。MS(ESI):m/z 398.0[M+H]+.Dissolve 5-bromo-1-(piperidin-4-yl)-1H-indazole hydrochloride (300.0mg, 1.07mmol) in methanol (3mL), add acetic acid (400uL), 4,4-di Fluorocyclohexanone (158.0 mg, 1.07 mmol), the mixture was stirred at 50°C for two hours. Then sodium cyanoborohydride (135.0 mg, 2.14 mmol) was added, and the reaction was continued for 3 hours. Water (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (100% ethyl acetate). Purification gave the title compound (60 mg, colorless oil), yield: 14%. MS(ESI):m/z 398.0[M+H] + .
(4)1-(1-(4,4-二氟环己基)哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑(4)1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Borol-2-yl)-1H-indazole
将5-溴-1-(1-(4,4-二氟环己基)哌啶-4-基)-1H-吲唑(60mg,0.15mmol)溶于1,4-二氧六环(1mL)中，依次加入联硼酸频哪醇酯(42mg,0.16mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(11mg,0.015mmol)和醋酸钾(29mg,0.30mmol)。反应液在氮气保护下加热至70℃搅拌18小时。反应液减压浓缩，残留物经柱层析(100％乙酸乙酯)纯化得到标题化合物(30mg,棕色油状物)，收率：55％。MS(ESI):m/z 446.2[M+H]+.Dissolve 5-bromo-1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-indazole (60 mg, 0.15 mmol) in 1,4-dioxane (1 mL ), add pinacol diborate (42mg, 0.16mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (11mg, 0.015mmol) and potassium acetate (29mg ,0.30mmol). The reaction solution was heated to 70°C under nitrogen protection and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (100% ethyl acetate) to obtain the title compound (30 mg, brown oil), yield: 55%. MS(ESI):m/z 446.2[M+H] + .
(5)2-氨基-5-(1-(1-(4,4-二氟环己基)哌啶-4-基)-1H-吲唑-5-基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺(5)2-Amino-5-(1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-indazol-5-yl)-N-(4-hydroxybicyclo [2.2.2]oct-1-yl)nicotinamide
将1-(1-(4,4-二氟环己基)哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑(30.0mg,0.067mmol)溶于1,4-二氧六环/水(4mL/1mL)的混合溶剂中，依次加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(5mg,0.0067mmol)，碳酸钾(27mg,0.20mmol)和中间体5(22mg,0.0067mmol)。反应液在氮气保护下加热至70℃搅拌5小时。反应液用硅藻土过滤，滤液用乙酸乙酯(10mL x 3)萃取，饱和食盐水洗涤3次，无水硫酸钠干燥，减压浓缩。残留物经Pre-HPLC纯化得到标题化合物(1mg,白色固体)。MS(ESI):m/z 579.2[M+H]+.1-(1-(4,4-Difluorocyclohexyl)piperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxabora Cyclopentan-2-yl)-1H-indazole (30.0mg, 0.067mmol) was dissolved in a mixed solvent of 1,4-dioxane/water (4mL/1mL), and [1,1'- Bis(diphenylphosphine)ferrocene]palladium dichloride (5 mg, 0.0067 mmol), potassium carbonate (27 mg, 0.20 mmol) and intermediate 5 (22 mg, 0.0067 mmol). The reaction solution was heated to 70°C under nitrogen protection and stirred for 5 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (10 mL x 3), washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Pre-HPLC to obtain the title compound (1 mg, white solid). MS(ESI):m/z 579.2[M+H] + .
实施例65Example 65
化合物131：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-异丙基哌啶-4-基)-1H-吲唑-5-基)烟酰胺Compound 131: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-indazole- 5-yl)nicotinamide
(1)5-溴-1-(哌啶-4-基)-1H-吲唑(1)5-Bromo-1-(piperidin-4-yl)-1H-indazole
将4-(5-溴-1H-吲唑-1-基)哌啶-1-羧酸叔丁酯(300mg,0.79mmol,实施例64第1步)溶于二氯甲烷(5mL)中，加入三氟乙酸(5mL)，室温搅拌反应过夜。反应液直接减压浓缩，得到标题化合物(220mg,无色油状物)。MS(ESI):m/z 282.0[M+H]+.Dissolve 4-(5-bromo-1H-indazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.79 mmol, step 1 of Example 64) in dichloromethane (5 mL), Trifluoroacetic acid (5 mL) was added, and the reaction was stirred at room temperature overnight. The reaction solution was directly concentrated under reduced pressure to obtain the title compound (220 mg, colorless oil). MS(ESI):m/z 282.0[M+H] + .
(2)5-溴-1-(1-异丙基哌啶-4-基)-1H-吲唑(2)5-Bromo-1-(1-isopropylpiperidin-4-yl)-1H-indazole
将5-溴-1-(哌啶-4-基)-1H-吲唑(220mg,0.80mmol)，2-溴丙烷(97mg,0.80mmol)溶于乙腈(10mL)中，加入碳酸钾(220mg,1.60mmol)，混合物加热至80℃搅拌过夜。向反应体系中加入水(20mL)，用乙酸乙酯(40mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(二氯甲烷/甲醇＝30/1)纯化得到标题化合物(120mg,黄色油状物)，收率：47％。MS(ESI):m/z 322.0[M+H]+.Dissolve 5-bromo-1-(piperidin-4-yl)-1H-indazole (220mg, 0.80mmol) and 2-bromopropane (97mg, 0.80mmol) in acetonitrile (10mL), add potassium carbonate (220mg ,1.60mmol), the mixture was heated to 80°C and stirred overnight. Add water (20 mL) to the reaction system, conduct liquid separation extraction with ethyl acetate (40 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=30/1) to obtain the title compound (120 mg, yellow oil), yield: 47%. MS(ESI):m/z 322.0[M+H] + .
(3)2-氨基-5-(1-(1-异丙基哌啶-4-基)-1H-吲唑-5-基)烟酸甲酯(3) Methyl 2-amino-5-(1-(1-isopropylpiperidin-4-yl)-1H-indazol-5-yl)nicotinate
将5-溴-1-(1-异丙基哌啶-4-基)-1H-吲唑(120mg,0.37mmol)，2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(104mg,0.37mmol)，PdCl2(dppf)(33mg,0.04mmol)和碳酸钾(102mg,0.74mmol)溶于1,4-二氧六环/水(10mL/2mL)的混合溶剂中。混合物在氮气保护下升温至100℃搅拌过夜。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝30/1)纯化得到标题化合物(70mg,黄色油状物)，收率：48％。MS(ESI):m/z 394.1[M+H]+.5-Bromo-1-(1-isopropylpiperidin-4-yl)-1H-indazole (120 mg, 0.37 mmol), 2-amino-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)nicotinic acid methyl ester (104mg, 0.37mmol), PdCl 2 (dppf) (33mg, 0.04mmol) and potassium carbonate (102mg, 0.74mmol) ) was dissolved in a mixed solvent of 1,4-dioxane/water (10mL/2mL). The mixture was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=30/1) to obtain the title compound (70 mg, yellow oil), yield: 48%. MS(ESI):m/z 394.1[M+H] + .
(4)2-氨基-5-(1-(1-异丙基哌啶-4-基)-1H-吲唑-5-基)烟酸(4)2-Amino-5-(1-(1-isopropylpiperidin-4-yl)-1H-indazol-5-yl)nicotinic acid
将2-氨基-5-(1-(1-异丙基哌啶-4-基)-1H-吲唑-5-基)烟酸甲酯(70mg,0.18mmol)溶于甲醇/水(1mL/1mL)的混合溶剂中，加入氢氧化钠(22mg,0.55mmol)。反应体系在50℃条件下搅拌2小时。反应液用1N盐酸调节pH值为4，减压浓缩。残留物经反相柱纯化得到标题化合物(50mg,淡黄色固体)，收率：75％。MS(ESI):m/z 380.1[M+H]+.Dissolve 2-amino-5-(1-(1-isopropylpiperidin-4-yl)-1H-indazol-5-yl)nicotinic acid methyl ester (70 mg, 0.18 mmol) in methanol/water (1 mL /1mL), add sodium hydroxide (22 mg, 0.55 mmol). The reaction system was stirred at 50°C for 2 hours. The reaction solution was adjusted to pH 4 with 1N hydrochloric acid and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain the title compound (50 mg, light yellow solid), yield: 75%. MS(ESI):m/z 380.1[M+H] + .
(5)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-异丙基哌啶-4-基)-1H-吲唑-5-基)烟酰胺(5)2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-indazole- 5-yl)nicotinamide
将2-氨基-5-(1-(1-异丙基哌啶-4-基)-1H-吲唑-5-基)烟酸(50mg,0.14mmol)，4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(29mg,0.16mmol)溶于N,N-二甲基甲酰胺(1mL)中，加入HATU(107mg,0.28mmol)和N,N-二异丙基乙基胺(55mg,0.42mmol)，混合物在室温下搅拌过夜。反应液直接经Pre-HPLC纯化得到标题化合物(2.2mg,白色固体)，收率：3.1％。MS(ESI):m/z 503.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝2.0Hz,1H),8.11(s,1H),8.05(d,J＝2.0Hz,1H),7.99(s,1H),7.82-7.78(m,2H),7.71-7.69(m,1H),6.89(s,2H),4.64-4.57(m,1H),4.31(s,1H),2.94(d,J＝11.6Hz,2H),2.82-2.79(m,1H),2.43-2.37(m,2H),2.12-2.03(m,8H),1.96-1.92(m,2H),1.66-1.62(m,6H),1.29(d,J＝6.8Hz,6H).2-Amino-5-(1-(1-isopropylpiperidin-4-yl)-1H-indazol-5-yl)nicotinic acid (50 mg, 0.14 mmol), 4-aminobicyclo [2.2.2 ] Octan-1-ol hydrochloride (29 mg, 0.16 mmol) was dissolved in N, N-dimethylformamide (1 mL), and HATU (107 mg, 0.28 mmol) and N, N-diisopropylethyl ethyl were added. amine (55 mg, 0.42 mmol) and the mixture was stirred at room temperature overnight. The reaction solution was directly purified by Pre-HPLC to obtain the title compound (2.2 mg, white solid), yield: 3.1%. MS (ESI): m/z 503.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.40 (d, J = 2.0Hz, 1H), 8.11 (s, 1H), 8.05 ( d,J＝2.0Hz,1H),7.99(s,1H),7.82-7.78(m,2H),7.71-7.69(m,1H),6.89(s,2H),4.64-4.57(m,1H) ,4.31(s,1H),2.94(d,J＝11.6Hz,2H),2.82-2.79(m,1H),2.43-2.37(m,2H),2.12-2.03(m,8H),1.96-1.92 (m,2H),1.66-1.62(m,6H),1.29(d,J＝6.8Hz,6H).
实施例66Example 66
化合物132：2-氨基-5-(2-(2-(4,4-二氟哌啶-1-基)乙基)-2H-吲唑-5-基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺Compound 132: 2-amino-5-(2-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2H-indazol-5-yl)-N-(4-hydroxybicyclo [2.2.2]oct-1-yl)nicotinamide
(1)2-(5-溴-2H-吲唑-2-基)乙-1-醇(1)2-(5-bromo-2H-indazol-2-yl)ethan-1-ol
冰浴条件下向5-溴-1H-吲唑(4g,20mmol)的N,N-二甲基甲酰胺(100mL)溶液中加入氢化钠(960mg,24mmol,60％纯度)。混合物升至室温搅拌1小时后加入1,3-二氧戊环-2-酮(7.16g,80mmol)，再升温至80℃搅拌3小时。将反应液倒入水(500mL)中，用乙酸乙酯(2x 200mL)萃取，有机相合并后用饱和食 盐水(2x 200mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝1/1)纯化得到标题化合物(1.2g,白色固体)，收率：25％。MS(ESI):m/z 241.0[M+H]+.To a solution of 5-bromo-1H-indazole (4 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (960 mg, 24 mmol, 60% purity) under ice bath conditions. The mixture was heated to room temperature and stirred for 1 hour, then 1,3-dioxolane-2-one (7.16g, 80mmol) was added, and then the temperature was raised to 80°C and stirred for 3 hours. Pour the reaction solution into water (500mL), extract with ethyl acetate (2x 200mL), combine the organic phases and wash with saturated food. Wash with brine (2x 200mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain the title compound (1.2 g, white solid), yield: 25%. MS(ESI):m/z 241.0[M+H] + .
(2)2-(5-溴-2H-吲唑-2-基)甲磺酸乙酯(2) Ethyl 2-(5-bromo-2H-indazol-2-yl)methanesulfonate
将2-(5-溴-2H-吲唑-2-基)乙-1-醇(964mg,4mmol)溶于无水二氯甲烷(20mL)中，加入三乙胺(1.21g,13mmol)。混合物降温至0℃后滴加甲磺酰氯(687mg,6mmol)，升至室温搅拌1小时。将反应液倒入水(50mL)中，水相用二氯甲烷(20mL)萃取，有机相合并后用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到标题化合物(1.27g,无色油状物)，收率：98％。MS(ESI):m/z 319.0[M+H]+.2-(5-Bromo-2H-indazol-2-yl)ethan-1-ol (964 mg, 4 mmol) was dissolved in anhydrous dichloromethane (20 mL), and triethylamine (1.21 g, 13 mmol) was added. After the mixture was cooled to 0°C, methanesulfonyl chloride (687 mg, 6 mmol) was added dropwise, and the mixture was raised to room temperature and stirred for 1 hour. The reaction solution was poured into water (50 mL), the aqueous phase was extracted with dichloromethane (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound ( 1.27g, colorless oil), yield: 98%. MS(ESI):m/z 319.0[M+H] + .
(3)5-溴-2-(2-(4,4-二氟哌啶-1-基)乙基)-2H-吲唑(3)5-Bromo-2-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2H-indazole
将2-(5-溴-2H-吲唑-2-基)甲磺酸乙酯(1.26g,3.95mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入4,4-二氟哌啶盐酸盐(934mg,5.9mmol)和三乙胺(2g,19.7mmol)。反应液在氮气保护下加热至80℃搅拌18小时。将反应液倒入水(150mL)中，用乙酸乙酯(2x 75mL)萃取，有机相合并后用饱和食盐水(2x 100mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝10/1)纯化得到标题化合物(260mg,橘黄色固体)，收率：19.2％。MS(ESI):m/z 344.0[M+H]+.Dissolve ethyl 2-(5-bromo-2H-indazol-2-yl)methanesulfonate (1.26g, 3.95mmol) in N,N-dimethylformamide (20mL), and add 4,4- Difluoroperidine hydrochloride (934 mg, 5.9 mmol) and triethylamine (2 g, 19.7 mmol). The reaction solution was heated to 80°C under nitrogen protection and stirred for 18 hours. The reaction solution was poured into water (150 mL), extracted with ethyl acetate (2x 75mL), the organic phases were combined, washed with saturated brine (2x 100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the title compound (260 mg, orange solid), yield: 19.2%. MS(ESI):m/z 344.0[M+H] + .
(4)2-氨基-5-(2-(2-(4,4-二氟哌啶-1-基)乙基)-2H-吲唑-5-基)烟酸甲酯(4) Methyl 2-amino-5-(2-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2H-indazol-5-yl)nicotinate
将5-溴-2-(2-(4,4-二氟哌啶-1-基)乙基)-2H-吲唑(103mg,0.3mmol)溶于1,4-二氧六环(5mL)中，加入2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(100mg,0.36mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(22mg,0.03mmol)，碳酸钾(124mg,0.9mmol)和水(1mL)，混合物在氮气保护下于80℃搅拌18小时。减压浓缩反应液，残留物经柱层析(二氯甲烷/甲醇＝40/1)纯化得到标题化合物(80mg,淡黄色油状物)，收率：64％。MS(ESI):m/z 416.1[M+H]+.Dissolve 5-bromo-2-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2H-indazole (103 mg, 0.3 mmol) in 1,4-dioxane (5 mL ), add methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (100 mg, 0.36 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22mg, 0.03mmol), potassium carbonate (124mg, 0.9mmol) and water (1mL), the mixture was under nitrogen protection Stir at 80°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=40/1) to obtain the title compound (80 mg, light yellow oil), yield: 64%. MS(ESI):m/z 416.1[M+H] + .
(5)2-氨基-5-(2-(2-(4,4-二氟哌啶-1-基)乙基)-2H-吲唑-5-基)烟酸(5)2-Amino-5-(2-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2H-indazol-5-yl)nicotinic acid
将2-氨基-5-(2-(2-(4,4-二氟哌啶-1-基)乙基)-2H-吲唑-5-基)烟酸甲酯(80mg,0.19mmol)溶于甲醇(10mL)中，加入一水合氢氧化锂(23mg,0.57mmol)和水(5mL)，室温反应18小时。减压浓缩反应液，残留物经反相柱纯化得到标题化合物(40mg,白色固体)，收率：52％。MS(ESI):m/z 402.1[M+H]+.2-Amino-5-(2-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2H-indazol-5-yl)nicotinic acid methyl ester (80 mg, 0.19 mmol) Dissolve in methanol (10 mL), add lithium hydroxide monohydrate (23 mg, 0.57 mmol) and water (5 mL), and react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase column to obtain the title compound (40 mg, white solid), yield: 52%. MS(ESI):m/z 402.1[M+H] + .
(6)2-氨基-5-(2-(2-(4,4-二氟哌啶-1-基)乙基)-2H-吲唑-5-基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺(6)2-Amino-5-(2-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2H-indazol-5-yl)-N-(4-hydroxybicyclo [2.2.2]oct-1-yl)nicotinamide
将2-氨基-5-(2-(2-(4,4-二氟哌啶-1-基)乙基)-2H-吲唑-5-基)烟酸(40mg,0.1mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入HATU(76mg,0.2mmol)和N,N-二异丙基乙胺(65mg,0.5mmol)。混合物在室温下搅拌10分钟，加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(21mg,0.12mmol)，继续在室温下搅拌3小时。反应液过滤后经Prep-HPLC纯化得到标题化合物(23.4mg,白色固体)，收率：44.6％。MS(ESI):m/z 525.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.39(d,J＝2.0Hz,1H),8.04(d,J＝2.4Hz,1H),7.92(s,1H),7.81(s,1H),7.67(d,J＝9.2Hz,1H),7.56(dd,J＝8.8,1.2Hz,1H),6.87(s,2H),4.55(t,J＝6.4Hz,2H),4.32(s,1H),2.95(t,J＝6.4Hz,2H),2.58(t,J＝5.2Hz,4H),2.08-2.04(m,6H),1.96-1.86(m,4H),1.65-1.61(m,6H).2-Amino-5-(2-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2H-indazol-5-yl)nicotinic acid (40 mg, 0.1 mmol) was dissolved in To N,N-dimethylformamide (2 mL), HATU (76 mg, 0.2 mmol) and N,N-diisopropylethylamine (65 mg, 0.5 mmol) were added. The mixture was stirred at room temperature for 10 minutes, 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (21 mg, 0.12 mmol) was added, and stirring was continued at room temperature for 3 hours. The reaction solution was filtered and purified by Prep-HPLC to obtain the title compound (23.4 mg, white solid), yield: 44.6%. MS (ESI): m/z 525.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.42 (s, 1H), 8.39 (d, J = 2.0Hz, 1H), 8.04 ( d,J＝2.4Hz,1H),7.92(s,1H),7.81(s,1H),7.67(d,J＝9.2Hz,1H),7.56(dd,J＝8.8,1.2Hz,1H), 6.87(s,2H),4.55(t,J＝6.4Hz,2H),4.32(s,1H),2.95(t,J＝6.4Hz,2H),2.58(t,J＝5.2Hz,4H), 2.08-2.04(m,6H),1.96-1.86(m,4H),1.65-1.61(m,6H).
实施例67Example 67
化合物133：2-氨基-N-(四氢-2H-吡喃-4-基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺Compound 133: 2-amino-N-(tetrahydro-2H-pyran-4-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro [Inden-1,3'-pyrrolidin]-5-yl)nicotinamide
(1)2-(5-溴-2,3-二氢-1H-茚-1-亚基)乙酸甲酯(1) Methyl 2-(5-bromo-2,3-dihydro-1H-indene-1-ylidene)acetate
向2-(二甲氧基膦酰基)乙酸甲酯(9.46g,52mmol)的N,N-二甲基甲酰胺(80mL)溶液中加入叔丁醇钾(5.82g,52mmol)，室温搅拌2小时后分批加入5-溴-2,3-二氢-1H-茚-1-酮(8.44g,40mmol)，氮气保护下于室温反应18小时。将反应液倒入水(500mL)中，用乙酸乙酯(2x150mL)萃取，有机相合并后用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物经柱层析(石油醚/乙酸乙酯＝30/1)纯化得到标题化合物(4.38g,黄色油状物)，收率：41％。MS(ESI):m/z 267.0[M+H]+.To a solution of methyl 2-(dimethoxyphosphono)acetate (9.46g, 52mmol) in N,N-dimethylformamide (80mL) was added potassium tert-butoxide (5.82g, 52mmol), and stirred at room temperature for 2 Hours later, 5-bromo-2,3-dihydro-1H-inden-1-one (8.44g, 40mmol) was added in batches, and the reaction was carried out at room temperature for 18 hours under nitrogen protection. Pour the reaction solution into water (500 mL), extract with ethyl acetate (2x150 mL), combine the organic phases, wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter and concentrate. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 30/1) to obtain the title compound (4.38 g, yellow oil), yield: 41%. MS(ESI):m/z 267.0[M+H] + .
(2)2-(5-溴-1-(硝基甲基)-2,3-二氢-1H-茚-1-基)乙酸甲酯(2) Methyl 2-(5-bromo-1-(nitromethyl)-2,3-dihydro-1H-inden-1-yl)acetate
向2-(5-溴-2,3-二氢-1H-茚-1-亚基)乙酸甲酯(4.38g,16.4mmol)的二甲基亚砜(40mL)溶液中加入碳酸铯(4.27g,13.1mmol)，滴加硝基甲烷(3g,49.2mmol)，反应液在氮气保护下加热至70℃搅拌18小时。将反应液倒入水(300mL)中，用乙酸乙酯(2x100mL)萃取，有机相合并后用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物经柱层析(石油醚/乙酸乙酯＝40/1)纯化得到标题化合物(1.86g,棕色油状物)，收率：32％。To a solution of methyl 2-(5-bromo-2,3-dihydro-1H-inden-1-ylidene)acetate (4.38g, 16.4mmol) in dimethyl sulfoxide (40mL) was added cesium carbonate (4.27 g, 13.1 mmol), nitromethane (3 g, 49.2 mmol) was added dropwise, and the reaction solution was heated to 70°C under nitrogen protection and stirred for 18 hours. Pour the reaction solution into water (300 mL), extract with ethyl acetate (2x100 mL), combine the organic phases, wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter and concentrate. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 40/1) to obtain the title compound (1.86 g, brown oil), yield: 32%.
(3)5-溴-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮(3)5-Bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-5'-one
向2-(5-溴-1-(硝基甲基)-2,3-二氢-1H-茚-1-基)乙酸甲酯(1.86g,5.2mmol)的甲醇(30mL)溶液中加入水(10mL)，氯化铵(835mg,15.6mmol)和还原铁粉(870mg,15.6mmol)。反应液在氮气保护下于80℃搅拌18小时。反应液用硅藻土过滤，甲醇(20mL)洗涤滤饼，滤液减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝1/2)纯化得到标题化合物(1.4g,白色固体)，收率:78％。MS(ESI):m/z 266.0[M+H]+.To a solution of methyl 2-(5-bromo-1-(nitromethyl)-2,3-dihydro-1H-inden-1-yl)acetate (1.86 g, 5.2 mmol) in methanol (30 mL) was added Water (10 mL), ammonium chloride (835 mg, 15.6 mmol) and reduced iron powder (870 mg, 15.6 mmol). The reaction solution was stirred at 80°C for 18 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/2) to obtain the title compound (1.4 g, white solid), yield: 78%. MS(ESI):m/z 266.0[M+H] + .
(4)5-溴-2,3-二氢螺[茚-1,3'-吡咯烷](4)5-Bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidine]
向5-溴-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮(800mg,3.0mmol)的无水四氢呋喃(20mL)溶液中加入硼烷四氢呋喃溶液(15mL,1M)。反应液加热至80℃搅拌16小时，降至室温后，加入盐酸(20mL,2M)，再加热至100℃搅拌6小时。向反应液中缓慢加入碳酸氢钠调节pH值大于10，加水(100mL)稀释后用二氯甲烷(2x 75mL)萃取，有机相合并后用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到标题化合物(756mg,白色油状物)。MS(ESI):m/z 252.0[M+H]+.To a solution of 5-bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one (800 mg, 3.0 mmol) in anhydrous tetrahydrofuran (20 mL) was added a borane tetrahydrofuran solution (15 mL ,1M). The reaction solution was heated to 80°C and stirred for 16 hours. After cooling to room temperature, hydrochloric acid (20 mL, 2M) was added, and then heated to 100°C and stirred for 6 hours. Slowly add sodium bicarbonate to the reaction solution to adjust the pH to greater than 10. Add water (100 mL) to dilute and extract with dichloromethane (2x 75 mL). The organic phases are combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filtration and concentration gave the title compound (756 mg, white oil). MS(ESI):m/z 252.0[M+H] + .
(5)5-溴-1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷] (5)5-Bromo-1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]
向5-溴-2,3-二氢螺[茚-1,3'-吡咯烷](756mg,3mmol)的甲醇(15mL)溶液中加入四氢-4H-吡喃-4-酮(600mg,6mmol)和乙酸(1.5mL)。混合物加热至50℃搅拌3小时后降至室温，分批加入氰基硼氢化钠(540mg,9mmol)，室温反应2小时。To a solution of 5-bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidine] (756 mg, 3 mmol) in methanol (15 mL) was added tetrahydro-4H-pyran-4-one (600 mg, 6mmol) and acetic acid (1.5mL). The mixture was heated to 50°C and stirred for 3 hours and then cooled to room temperature. Sodium cyanoborohydride (540 mg, 9 mmol) was added in portions and the mixture was reacted at room temperature for 2 hours.
反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝30/1)纯化得到标题化合物(580mg,黄色油状物)，收率：57.5％。MS(ESI):m/z 336.1[M+H]+.The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=30/1) to obtain the title compound (580 mg, yellow oil), yield: 57.5%. MS(ESI):m/z 336.1[M+H] + .
(6)2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酸甲酯(6) 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5-yl) Methyl nicotinate
向5-溴-1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷](570mg,1.7mmol)的1,4-二氧六环(20mL)溶液中加入2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(473mg,1.7mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(124mg,0.17mmol)，碳酸钾(704mg,5.1mmol)和水(2mL)。反应液在氮气保护下加热至80℃搅拌18小时。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝30/1)纯化得到粗品，粗品再经Prep-HPLC纯化得到标题化合物(210mg,淡黄色油状物)，收率：30％。MS(ESI):m/z 408.2[M+H]+.To 1,4 of 5-bromo-1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine] (570 mg, 1.7 mmol) -Add 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) fumes to the dioxane (20 mL) solution Methyl acid ester (473 mg, 1.7 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (124 mg, 0.17 mmol), potassium carbonate (704 mg, 5.1 mmol) and water (2 mL ). The reaction solution was heated to 80°C under nitrogen protection and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=30/1) to obtain a crude product. The crude product was further purified by Prep-HPLC to obtain the title compound (210 mg, light yellow oil), yield: 30 %. MS(ESI):m/z 408.2[M+H] + .
(7)2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酸(7) 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5-yl) niacin
向2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酸甲酯(210mg,0.52mmol)的甲醇(5mL)溶液中加入氢氧化钠(62mg,1.54mmol)和水(5mL)，室温反应18小时。反应液减压浓缩，残留物经反相柱纯化得到标题化合物(117mg,白色固体)，收率：57.6％。MS(ESI):m/z 394.1[M+H]+.To 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5-yl)nicotinic acid Sodium hydroxide (62 mg, 1.54 mmol) and water (5 mL) were added to a solution of methyl ester (210 mg, 0.52 mmol) in methanol (5 mL), and the reaction was carried out at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase column to obtain the title compound (117 mg, white solid), yield: 57.6%. MS(ESI):m/z 394.1[M+H] + .
(8)2-氨基-N-(四氢-2H-吡喃-4-基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺(8)2-amino-N-(tetrahydro-2H-pyran-4-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro [Inden-1,3'-pyrrolidin]-5-yl)nicotinamide
向2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酸(19.6mg,0.05mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入HATU(38mg,0.1mmol)和N,N-二异丙基乙胺(38.7mg,0.3mmol)，室温搅拌10分钟后加入四氢-2H-吡喃-4-胺(10mg,0.1mmol)，室温反应3小时。反应液过滤，再经Prep-HPLC纯化得到标题化合物(13.2mg,白色固体)，收率：54％。MS(ESI):m/z 477.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝7.6Hz,1H),8.36(d,J＝2.0Hz,1H),8.13(d,J＝2.4Hz,1H),7.47-7.45(m,2H),7.34(d,J＝8.0Hz,1H),7.10(s,2H),4.05-3.97(m,1H),3.91-3.84(m,4H),3.42-3.36(m,3H),3.29-3.27(m,1H),2.90(t,J＝7.2Hz,2H),2.80-2.71(m,3H),2.63-2.61(m,1H),2.33-2.29(m,1H),2.17-1.91(m,4H),1.80-1.76(m,4H),1.63-1.53(m,2H),1.43-1.37(m,2H).To 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5-yl)nicotinic acid To a solution of N,N-dimethylformamide (2mL) (19.6mg, 0.05mmol), HATU (38mg, 0.1mmol) and N,N-diisopropylethylamine (38.7mg, 0.3mmol) were added, at room temperature. After stirring for 10 minutes, tetrahydro-2H-pyran-4-amine (10 mg, 0.1 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction solution was filtered and purified by Prep-HPLC to obtain the title compound (13.2 mg, white solid), yield: 54%. MS (ESI): m/z 477.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.38 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H),8.13(d,J＝2.4Hz,1H),7.47-7.45(m,2H),7.34(d,J＝8.0Hz,1H),7.10(s,2H),4.05-3.97(m,1H ),3.91-3.84(m,4H),3.42-3.36(m,3H),3.29-3.27(m,1H),2.90(t,J＝7.2Hz,2H),2.80-2.71(m,3H), 2.63-2.61(m,1H),2.33-2.29(m,1H),2.17-1.91(m,4H),1.80-1.76(m,4H),1.63-1.53(m,2H),1.43-1.37(m ,2H).
实施例68Example 68
化合物134：2-氨基-N-(反式-4-羟基环己基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺Compound 134: 2-amino-N-(trans-4-hydroxycyclohexyl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene- 1,3'-pyrrolidin]-5-yl)nicotinamide
参照实施例67第8步的方法，以2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酸(19.6mg,0.05mmol)和反式-4-氨基环己烷-1-醇(8.6mg,0.075mmol)为原料得到标题化合物(12.3mg,白色固体)，收率：49％。MS(ESI):m/z 491.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝2.0Hz,1H),8.26(d,J＝7.6Hz,1H),8.09(d,J＝2.0Hz,1H),7.46-7.44(m,2H),7.33(d,J＝8.0Hz,1H),7.08(s,2H),4.57(d,J＝4.4Hz,1H),3.87-3.83(m,2H),3.75-3.71(m,1H),3.43-3.29(m,2H),2.89(t,J＝7.2Hz,2H),2.77(t,J＝7.2Hz,2H),2.72-2.59(m,2H),2.29-2.27(m,1H),2.17-1.76(m,10H),1.48-1.20(m,7H).Referring to the method in step 8 of Example 67, use 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'- Pyrrolidin]-5-yl)nicotinic acid (19.6 mg, 0.05 mmol) and trans-4-aminocyclohexan-1-ol (8.6 mg, 0.075 mmol) were used as raw materials to obtain the title compound (12.3 mg, white solid) , Yield: 49%. MS (ESI): m/z 491.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.35 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H),8.09(d,J＝2.0Hz,1H),7.46-7.44(m,2H),7.33(d,J＝8.0Hz,1H),7.08(s,2H),4.57(d,J＝4.4 Hz,1H),3.87-3.83(m,2H),3.75-3.71(m,1H),3.43-3.29(m,2H),2.89(t,J＝7.2Hz,2H),2.77(t,J＝ 7.2Hz,2H),2.72-2.59(m,2H),2.29-2.27(m,1H),2.17-1.76(m,10H),1.48-1.20(m,7H).
实施例69Example 69
化合物135：2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺Compound 135: 2-amino-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5-(1'-(tetrahydro-2H-pyran) -4-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-5-yl)nicotinamide
参照实施例67第8步的方法，以2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酸(19.6mg,0.05mmol)和((2S,5R)-5-氨基四氢-2H-吡喃-2-基)甲醇盐酸盐(12.5mg,0.075mmol)为原料得到标题化合物(12.8mg,白色固体)，收率：50％。MS(ESI):m/z 507.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝2.4Hz,1H),8.26(d,J＝7.6Hz,1H),8.11(d,J＝2.4Hz,1H),7.46-7.43(m,2H),7.34(d,J＝8.0Hz,1H),7.10(s,2H),4.64(t,J＝5.6Hz,1H),3.92-3.83(m,4H),3.43-3.38(m,2H),3.30-3.11(m,4H),2.89(t,J＝6.8Hz,2H),2.77(t,J＝6.8Hz,2H),2.72-2.60(m,2H),2.33-2.27(m,1H),2.17-1.90(m,5H),1.79-1.72(m,3H),1.67-1.55(m,1H),1.48-1.24(m,3H).Referring to the method in step 8 of Example 67, use 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'- Pyrrolidin]-5-yl)nicotinic acid (19.6mg, 0.05mmol) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (12.5mg, 0.075mmol) ) was used as raw material to obtain the title compound (12.8 mg, white solid), yield: 50%. MS (ESI): m/z 507.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.37 (d, J = 2.4Hz, 1H), 8.26 (d, J = 7.6Hz, 1H),8.11(d,J＝2.4Hz,1H),7.46-7.43(m,2H),7.34(d,J＝8.0Hz,1H),7.10(s,2H),4.64(t,J＝5.6 Hz,1H),3.92-3.83(m,4H),3.43-3.38(m,2H),3.30-3.11(m,4H),2.89(t,J＝6.8Hz,2H),2.77(t,J＝ 6.8Hz,2H),2.72-2.60(m,2H),2.33-2.27(m,1H),2.17-1.90(m,5H),1.79-1.72(m,3H),1.67-1.55(m,1H) ,1.48-1.24(m,3H).
实施例70Example 70
化合物136：2-氨基-N-((1r,4r)-4-羟基-4-甲基环己基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺Compound 136: 2-amino-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-2, 3-Dihydrospiro[indene-1,3'-pyrrolidine]-5-yl)nicotinamide
参照实施例67第8步的方法，以2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酸和(1r,4r)-4-氨基-1-甲基环己-1-醇为原料得到标题化合物(16.9mg,白色固体)。MS(ESI):m/z 505.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝2.4Hz,1H),8.24(d,J＝7.6Hz,1H),8.08(d,J＝2.4Hz,1H),7.46-7.44(m,2H),7.34(d,J＝8.4Hz,1H),7.06(s,2H),4.33(s,1H),3.87-3.80(m,3H),3.32-3.29(m,2H),2.89(t,J＝7.2Hz,2H),2.78(t,J＝6.4Hz,2H),2.74-2.61(m,2H),2.35-2.25(m,1H),2.17-1.98(m,2H),1.96-1.90(m,2H),1.79-1.73(m,4H),1.61-1.59(m,2H),1.51-1.38(m,6H),1.16(s,3H).Referring to the method in step 8 of Example 67, use 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrospiro[indene-1,3'- Pyrrolidin]-5-yl)nicotinic acid and (1r,4r)-4-amino-1-methylcyclohexan-1-ol were used as raw materials to obtain the title compound (16.9 mg, white solid). MS (ESI): m/z 505.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.34 (d, J = 2.4Hz, 1H), 8.24 (d, J = 7.6Hz, 1H),8.08(d,J＝2.4Hz,1H),7.46-7.44(m,2H),7.34(d,J＝8.4Hz,1H),7.06(s,2H),4.33(s,1H), 3.87-3.80(m,3H),3.32-3.29(m,2H),2.89(t,J＝7.2Hz,2H),2.78(t,J＝6.4Hz,2H),2.74-2.61(m,2H) ,2.35-2.25(m,1H),2.17-1.98(m,2H),1.96-1.90(m,2H),1.79-1.73(m,4H),1.61-1.59(m,2H),1.51-1.38( m,6H),1.16(s,3H).
实施例71Example 71
化合物137：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-5-基)烟酰胺Compound 137: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1] ,4'-piperidin]-5-yl)nicotinamide
(1)5-溴螺[茚-1,4'-哌啶]-1'-羧酸叔丁酯(1) 5-bromospiro[indene-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester
将5-溴-1H-茚(2.0g,10.2mmol)溶于四氢呋喃(20mL)中，在0℃下滴加双三甲基硅基胺基锂(20.4mL,20.4mmol)的1M四氢呋喃溶液，在0℃下搅拌1小时.再向反应液中滴加双(2-氯乙基)氨基甲酸叔丁 酯(2.5g,10.2mmol)的四氢呋喃(20mL)溶液，室温搅拌过夜。向反应体系中加入水(20mL)，混合液用乙酸乙酯(40mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝20/1)纯化得到标题化合物和其异构体6-溴螺[茚-1,4'-哌啶]-1'-羧酸叔丁酯的混合物(2.4g,黄色油状物)，收率：65％。MS(ESI):m/z 308.0[M+H-56]+.Dissolve 5-bromo-1H-indene (2.0g, 10.2mmol) in tetrahydrofuran (20mL), and add dropwise a 1M tetrahydrofuran solution of lithium bistrimethylsilylamide (20.4mL, 20.4mmol) at 0°C. Stir at 0°C for 1 hour. Then add tert-butyl bis(2-chloroethyl)carbamic acid dropwise to the reaction solution. A solution of the ester (2.5 g, 10.2 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 20/1) to obtain the title compound and its isomer 6-bromospiro[indene-1,4'-piperidine]-1'-carboxylic acid tert-butyl Mixture of esters (2.4g, yellow oil), yield: 65%. MS(ESI):m/z 308.0[M+H-56] + .
(2)5-溴螺[茚-1,4'-哌啶](2)5-bromospiro[indene-1,4'-piperidine]
将5-溴螺[茚-1,4'-哌啶]-1'-羧酸叔丁酯和其异构体6-溴螺[茚-1,4'-哌啶]-1'-羧酸叔丁酯的混合物(500mg,1.4mmol)溶于二氯甲烷(5mL)中，滴加三氟乙酸(5mL)，室温搅拌1小时。反应液旋干，加入饱和碳酸氢钠水溶液(10mL)，混合液用二氯甲烷(10mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩得到标题化合物和其异构体6-溴螺[茚-1,4'-哌啶]的混合物(362mg,黄色油状物)，收率:97.9％。MS(ESI):m/z 264.0[M+H]+.5-bromospiro[indene-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester and its isomer 6-bromospiro[indene-1,4'-piperidine]-1'-carboxylic acid The mixture of acid tert-butyl ester (500 mg, 1.4 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was spun to dryness, and saturated aqueous sodium bicarbonate solution (10 mL) was added. The mixture was extracted with dichloromethane (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound and its isomer 6. -A mixture of bromospiro[indene-1,4'-piperidine] (362 mg, yellow oil), yield: 97.9%. MS(ESI):m/z 264.0[M+H] + .
(3)5-溴-1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶](3)5-Bromo-1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidine]
将5-溴螺[茚-1,4'-哌啶]和其异构体6-溴螺[茚-1,4'-哌啶]的混合物(362mg,1.4mmol)，四氢-4H-吡喃-4-酮(165mg,1.7mmol)溶于甲醇(5mL)中，室温搅拌半小时，加入氰基硼氢化钠(170mg,2.7mmol)，室温搅拌反应过夜。向反应液中加入水(20mL)，混合液用乙酸乙酯(40mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(100％乙酸乙酯)纯化得到标题化合物和其异构体6-溴-1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]的混合物(290mg,黄色油状物)，收率：60％。MS(ESI):m/z 348.1[M+H]+.A mixture of 5-bromospiro[indene-1,4'-piperidine] and its isomer 6-bromospiro[indene-1,4'-piperidine] (362 mg, 1.4 mmol), tetrahydro-4H- Dissolve pyran-4-one (165 mg, 1.7 mmol) in methanol (5 mL), stir at room temperature for half an hour, add sodium cyanoborohydride (170 mg, 2.7 mmol), and stir at room temperature for overnight reaction. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (100% ethyl acetate) to obtain the title compound and its isomer 6-bromo-1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4' -piperidine] mixture (290 mg, yellow oil), yield: 60%. MS(ESI):m/z 348.1[M+H] + .
(4)2-氨基-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-5-基)烟酸甲酯(4) Methyl 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidin]-5-yl)nicotinate
将5-溴-1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]和其异构体6-溴-1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]的混合物(640mg,1.8mmol)，2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(513mg,1.8mmol)，PdCl2(dppf)(147mg,0.2mmol)和碳酸钾(497mg,3.6mmol)溶于1,4-二氧六环/水(10mL/2mL)的混合溶剂中。在氮气保护下升温至100℃搅拌过夜。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝30/1)纯化得到标题化合物和其异构体2-氨基-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-6-基)烟酸甲酯的混合物(400mg,黄色固体)，收率：52％。MS(ESI):m/z 420.1[M+H]+.5-bromo-1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidine] and its isomer 6-bromo-1'-(tetrahydro-2H -pyran-4-yl)spiro[indene-1,4'-piperidine] mixture (640 mg, 1.8 mmol), 2-amino-5-(4,4,5,5-tetramethyl-1, Methyl 3,2-dioxaborolan-2-yl)nicotinate (513 mg, 1.8 mmol), PdCl 2 (dppf) (147 mg, 0.2 mmol) and potassium carbonate (497 mg, 3.6 mmol) were dissolved in In a mixed solvent of 1,4-dioxane/water (10mL/2mL). The temperature was raised to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=30/1) to obtain the title compound and its isomer 2-amino-5-(1'-(tetrahydro-2H-pyran) A mixture of -4-yl)spiro[indene-1,4'-piperidin]-6-yl)nicotinic acid methyl ester (400 mg, yellow solid), yield: 52%. MS(ESI):m/z 420.1[M+H] + .
(5)2-氨基-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-5-基)烟酸(5)2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidin]-5-yl)nicotinic acid
将2-氨基-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-5-基)烟酸甲酯和其异构体2-氨基-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-6-基)烟酸甲酯的混合物(200mg,0.5mmol)溶于甲醇/水(5mL/5mL)的混合溶剂中，加入氢氧化钠(57mg,1.4mmol)，反应液在50℃下搅拌2小时。反应液旋干除去甲醇，用稀盐酸调节pH值为3-4,减压浓缩。残留物经反相柱纯化得到标题化合物和其异构体2-氨基-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-6-基)烟酸的混合物(170mg,黄色固体)，收率：88％。MS(ESI):m/z 406.1[M+H]+.2-Amino-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidin]-5-yl)nicotinic acid methyl ester and its isomers Mixture of methyl 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidin]-6-yl)nicotinate (200 mg, 0.5 mmol) was dissolved in a mixed solvent of methanol/water (5mL/5mL), sodium hydroxide (57mg, 1.4mmol) was added, and the reaction solution was stirred at 50°C for 2 hours. The reaction solution was spun dry to remove methanol, the pH value was adjusted to 3-4 with dilute hydrochloric acid, and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain the title compound and its isomer 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidine] -6-yl) mixture of nicotinic acid (170 mg, yellow solid), yield: 88%. MS(ESI):m/z 406.1[M+H] + .
(6)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-5-基)烟酰胺(6) 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1] ,4'-piperidin]-5-yl)nicotinamide
将2-氨基-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-5-基)烟酸和其异构体2-氨基-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-6-基)烟酸的混合物(170mg,0.42mmol)，4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(75mg,0.42mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入HATU(319mg,0.84mmol)和N,N-二异丙基乙胺(155mg,1.20mmol)，室温搅拌过夜。向反应液中加入水(20mL)，用二氯甲烷(20mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经反相柱纯化得到140mg混合物粗品。取40mg混合物粗品经Pre-HPLC纯化得到标题化合物(8.2mg,白色固体)和另一个异构体。MS(ESI):m/z 529.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝2.4Hz,1H),8.00(d,J＝2.4Hz,1H),7.74(s,1H),7.56(d,J＝1.2Hz,1H),7.50-7.41(m,2H),6.99(d,J＝6.0Hz,1H),6.90(s,2H),6.83(d,J＝5.6Hz,1H),4.29(s,1H),3.94-3.90(m,2H),3.31-3.29(m,2H),2.99-2.96(m,2H),2.56-2.54(m,3H),2.11-2.02(m,8H),1.79-1.76(m,2H),1.63-1.59(m,6H),1.55-1.45(m,2H),1.26-1.23(m,2H).2-Amino-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidin]-5-yl)nicotinic acid and its isomer 2- Mixture of amino-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1,4'-piperidin]-6-yl)nicotinic acid (170 mg, 0.42 mmol), 4 -Aminobicyclo[2.2.2]octane-1-ol hydrochloride (75mg, 0.42mmol) was dissolved in N,N-dimethylformamide (5mL), HATU (319mg, 0.84mmol) and N were added, N-diisopropylethylamine (155 mg, 1.20 mmol), stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain 140 mg of crude mixture. 40 mg of the crude mixture was purified by Pre-HPLC to obtain the title compound (8.2 mg, white solid) and another isomer. MS (ESI): m/z 529.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.33 (d, J = 2.4Hz, 1H), 8.00 (d, J = 2.4Hz, 1H),7.74(s,1H),7.56(d,J＝1.2Hz,1H),7.50-7.41(m,2H),6.99(d,J＝6.0Hz,1H),6.90(s,2H), 6.83(d,J＝5.6Hz,1H),4.29(s,1H),3.94-3.90(m,2H),3.31-3.29(m,2H),2.99-2.96(m,2H),2.56-2.54( m,3H),2.11-2.02(m,8H),1.79-1.76(m,2H),1.63-1.59(m,6H),1.55-1.45(m,2H),1.26-1.23(m,2H).
实施例72Example 72
化合物138：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)螺[茚-1,4'-哌啶]-6-基)烟酰胺Compound 138: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)spiro[indene-1] ,4'-piperidin]-6-yl)nicotinamide
参照实施例71第6步，该40mg混合物粗品经Pre-HPLC纯化得到另一个异构体，即标题化合物(16mg,白色固体)。MS(ESI):m/z 529.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝2.4Hz,1H),7.98(d,J＝2.4Hz,1H),7.79(s,1H),7.69(s,1H),7.50-7.47(m,2H),6.96(d,J＝5.6Hz,1H),6.87(s,2H),6.80(d,J＝5.6Hz,1H),4.30(s,1H),3.94-3.90(m,2H),3.31-3.28(m,2H),3.01-2.98(m,2H),2.53-2.48(m,3H),2.21-2.15(m,2H),2.07-2.03(m,6H),1.79-1.77(m,2H),1.64-1.60(m,6H),1.55-1.46(m,2H),1.26-1.23(m,2H).Referring to step 6 of Example 71, 40 mg of the crude mixture was purified by Pre-HPLC to obtain another isomer, the title compound (16 mg, white solid). MS (ESI): m/z 529.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.38 (d, J = 2.4Hz, 1H), 7.98 (d, J = 2.4Hz, 1H),7.79(s,1H),7.69(s,1H),7.50-7.47(m,2H),6.96(d,J＝5.6Hz,1H),6.87(s,2H),6.80(d,J =5.6Hz,1H),4.30(s,1H),3.94-3.90(m,2H),3.31-3.28(m,2H),3.01-2.98(m,2H),2.53-2.48(m,3H), 2.21-2.15(m,2H),2.07-2.03(m,6H),1.79-1.77(m,2H),1.64-1.60(m,6H),1.55-1.46(m,2H),1.26-1.23(m ,2H).
实施例73Example 73
化合物139：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,4'-哌啶]-5-基)烟酰胺Compound 139: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3- Dihydrospiro[indene-1,4'-piperidin]-5-yl)nicotinamide
将实施例71第6步得到的混合物粗品(100mg,0.19mmol)溶于甲醇(5mL)中，加入钯碳(10mg)，反应液在氢气条件下室温搅拌过夜。用硅藻土过滤，减压浓缩，残留物经Pre-HPLC纯化得到标题化合物标题化合物(21.5mg,白色固体)和另一个异构体。MS(ESI):m/z 531.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.30(d,J＝2.4Hz,1H),7.96(d,J＝2.8Hz,1H),7.74(s,1H),7.43-7.40(m,2H),7.25(d,J＝8.0Hz,1H),6.88(s,2H),4.31(s,1H),3.91-3.88(m,2H),3.31-3.26(m,2H),2.90-2.84(m,4H),2.47-2.41(m,1H),2.29(t,J＝11.2Hz,2H),2.05-2.01(m,6H),1.97(t,J＝7.6Hz,2H),1.83-1.70(m,4H),1.63-1.59(m,6H), 1.50-1.41(m,4H).The crude mixture obtained in step 6 of Example 71 (100 mg, 0.19 mmol) was dissolved in methanol (5 mL), palladium on carbon (10 mg) was added, and the reaction solution was stirred at room temperature overnight under hydrogen. It was filtered through celite, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain the title compound (21.5 mg, white solid) and another isomer. MS (ESI): m/z 531.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.30 (d, J = 2.4Hz, 1H), 7.96 (d, J = 2.8Hz, 1H),7.74(s,1H),7.43-7.40(m,2H),7.25(d,J＝8.0Hz,1H),6.88(s,2H),4.31(s,1H),3.91-3.88(m ,2H),3.31-3.26(m,2H),2.90-2.84(m,4H),2.47-2.41(m,1H),2.29(t,J＝11.2Hz,2H),2.05-2.01(m,6H ),1.97(t,J＝7.6Hz,2H),1.83-1.70(m,4H),1.63-1.59(m,6H), 1.50-1.41(m,4H).
实施例74Example 74
化合物140：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,4'-哌啶]-6-基)烟酰胺Compound 140: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-2,3- Dihydrospiro[indene-1,4'-piperidin]-6-yl)nicotinamide
参照实施例73，该步骤经Pre-HPLC纯化得到另一个异构体，即标题化合物(12.5mg,白色固体)。MS(ESI):m/z 531.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝2.4Hz,1H),7.92(d,J＝2.4Hz,1H),7.78(s,1H),7.44(s,1H),7.40-7.38(m,1H),7.24(d,J＝7.6Hz,1H),6.85(s,2H),4.29(s,1H),3.92-3.88(m,2H),3.29-3.26(m,2H),2.89-2.83(m,4H),2.47-2.46(m,1H),2.30(t,J＝12.0Hz,2H),2.06-2.02(m,6H),1.97(t,J＝7.6Hz,2H),1.93-1.86(m,2H),1.74-1.71(m,2H),1.64-1.60(m,6H),1.49-1.43(m,4H).Referring to Example 73, this step was purified by Pre-HPLC to obtain another isomer, the title compound (12.5 mg, white solid). MS (ESI): m/z 531.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.33 (d, J = 2.4Hz, 1H), 7.92 (d, J = 2.4Hz, 1H),7.78(s,1H),7.44(s,1H),7.40-7.38(m,1H),7.24(d,J＝7.6Hz,1H),6.85(s,2H),4.29(s,1H ),3.92-3.88(m,2H),3.29-3.26(m,2H),2.89-2.83(m,4H),2.47-2.46(m,1H),2.30(t,J＝12.0Hz,2H), 2.06-2.02(m,6H),1.97(t,J＝7.6Hz,2H),1.93-1.86(m,2H),1.74-1.71(m,2H),1.64-1.60(m,6H),1.49- 1.43(m,4H).
实施例75Example 75
化合物141：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酰胺Compound 141: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-3H-spiro[ Isobenzofuran-1,4'-piperidin]-5-yl)nicotinamide
(1)5-溴-3-氧代-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-羧酸叔丁酯(1) 5-Bromo-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester
将5-溴-2-碘苯甲酸甲酯(5.0g,14.70mmol)和4-氧代哌啶-1-羧酸叔丁酯(3.2g,16.20mmol)溶于四氢呋喃(50mL)中。冷却至-78℃，向反应液中滴加异丙基氯化镁氯化锂络合物(1.3M,12.5mL,16.20mmol)的四氢呋喃溶液。反应液在氮气保护下室温搅拌过夜。向反应液中加入水(20mL)，硅藻土过滤，滤液用乙酸乙酯(20mL x 2)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物经柱层析(石油醚/乙酸乙酯＝10/1)纯化得到标题化合物(3.9g,白色固体)，收率：70％。MS(ESI):m/z 326.0[M+H-56]+.5-Bromo-2-iodobenzoic acid methyl ester (5.0 g, 14.70 mmol) and 4-oxopiperidine-1-carboxylic acid tert-butyl ester (3.2 g, 16.20 mmol) were dissolved in tetrahydrofuran (50 mL). Cool to -78°C, and a tetrahydrofuran solution of isopropylmagnesium chloride lithium chloride complex (1.3M, 12.5mL, 16.20mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature overnight under nitrogen protection. Water (20 mL) was added to the reaction solution, filtered through diatomaceous earth, the filtrate was extracted with ethyl acetate (20 mL x 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain the title compound (3.9 g, white solid), yield: 70%. MS(ESI):m/z 326.0[M+H-56] + .
(2)4-(4-溴-2-(羟甲基)苯基)-4-羟基哌啶-1-羧酸叔丁酯(2) tert-butyl 4-(4-bromo-2-(hydroxymethyl)phenyl)-4-hydroxypiperidine-1-carboxylate
将5-溴-3-氧代-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-羧酸叔丁酯(3.8g,9.97mmol)溶于四氢呋喃(40mL)中，0℃的条件下滴加硼氢化锂(2M,10mL,19.94mmol)的四氢呋喃溶液。反应液在氮气保护下室温搅拌过夜。向反应体系中加入水(20mL)，用乙酸乙酯(20mL x 2)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝3/1)纯化得到标题化合物(3.8g,无色油状物)，收率：99％。MS(ESI):m/z 312.0[M+H-56-H2O]+.Dissolve 5-bromo-3-oxo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (3.8g, 9.97mmol) in tetrahydrofuran (40mL) , add dropwise a solution of lithium borohydride (2M, 10mL, 19.94mmol) in tetrahydrofuran at 0°C. The reaction solution was stirred at room temperature overnight under nitrogen protection. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL x 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain the title compound (3.8 g, colorless oil), yield: 99%. MS(ESI):m/z 312.0[M+H-56-H 2 O] + .
(3)5-溴-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-羧酸叔丁酯(3)5-Bromo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester
将4-(4-溴-2-(羟甲基)苯基)-4-羟基哌啶-1-羧酸叔丁酯(2.0g,5.2mmol)溶于四氢呋喃(20mL)中，在0℃条件下加入三乙胺(2.6g,26.0mmol)和对甲苯磺酸酐(2.2g,6.8mmol)。反应液在氮气保护下室温搅拌反应过夜。向反应体系中加入水(20mL)，用乙酸乙酯(20mL x 2)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝15/1)纯化得到标题化合物(1.2g,无色油状物)，收率：63％。MS(ESI):m/z 268.0[M+H-100]+.Dissolve 4-(4-bromo-2-(hydroxymethyl)phenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.0g, 5.2mmol) in tetrahydrofuran (20mL) at 0°C. Add triethylamine (2.6g, 26.0mmol) and p-toluenesulfonic anhydride (2.2g, 6.8mmol) under the same conditions. The reaction solution was stirred at room temperature under nitrogen protection overnight. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL x 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 15/1) to obtain the title compound (1.2 g, colorless oil), yield: 63%. MS(ESI):m/z 268.0[M+H-100] + .
(4)5-溴-3H-螺[异苯并呋喃-1,4'-哌啶](4)5-bromo-3H-spiro[isobenzofuran-1,4'-piperidine]
将5-溴-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-羧酸叔丁酯(300mg,0.82mmol)溶于二氯甲烷(5mL)中，滴加三氟乙酸(5mL)，室温搅拌反应1小时。反应液旋干，向反应体系中加入饱和碳酸氢钠水溶液(10mL)，用二氯甲烷(10mL x 2)分液萃取，无水硫酸钠干燥，过滤，浓缩得到标题化合物(210mg,白色固体)，收率：96％。MS(ESI):m/z 268.0[M+H]+.Dissolve 5-bromo-3H-spiro[isobenzofuran-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (300 mg, 0.82 mmol) in dichloromethane (5 mL), add three drops of Fluoroacetic acid (5 mL), stirred at room temperature for 1 hour. Spin the reaction solution to dryness, add saturated aqueous sodium bicarbonate solution (10 mL) to the reaction system, conduct liquid separation extraction with dichloromethane (10 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (210 mg, white solid) , Yield: 96%. MS(ESI):m/z 268.0[M+H] + .
(5)5-溴-1'-(四氢-2H-吡喃-4-基)-3H-螺[异苯并呋喃-1,4'-哌啶](5)5-Bromo-1'-(tetrahydro-2H-pyran-4-yl)-3H-spiro[isobenzofuran-1,4'-piperidine]
将5-溴-3H-螺[异苯并呋喃-1,4'-哌啶](210mg,0.79mmol)，四氢-4H-吡喃-4-酮(157mg,1.57mmol)溶于甲醇(5mL)中，室温搅拌半小时，加入氰基硼氢化钠(151mg,2.37mmol)，继续在室温下搅拌过夜。旋干甲醇，向反应体系中加入水(20mL)，用乙酸乙酯(40mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩，经柱层析(100％乙酸乙酯)纯化得到标题化合物(120mg,白色固体)，收率：43％。MS(ESI):m/z352.1[M+H]+.Dissolve 5-bromo-3H-spiro[isobenzofuran-1,4'-piperidine] (210mg, 0.79mmol) and tetrahydro-4H-pyran-4-one (157mg, 1.57mmol) in methanol ( 5 mL), stir at room temperature for half an hour, add sodium cyanoborohydride (151 mg, 2.37 mmol), and continue stirring at room temperature overnight. Spin the methanol to dryness, add water (20 mL) to the reaction system, perform liquid extraction with ethyl acetate (40 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and perform column chromatography (100% ethyl acetate). Purification gave the title compound (120 mg, white solid), yield: 43%. MS(ESI):m/z352.1[M+H] + .
(6)2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酸甲酯(6) 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-3H-spiro[isobenzofuran-1,4'-piperidine]-5-yl) smoke acid methyl ester
将5-溴-1'-(四氢-2H-吡喃-4-基)-3H-螺[异苯并呋喃-1,4'-哌啶](120mg,0.34mmol)，2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(95mg,0.34mmol)，PdCl2(dppf)(25mg,0.03mmol)和碳酸钾(94mg,0.68mmol)溶于1,4-二氧六环/水(10mL/2mL)的混合溶剂中。反应液在氮气保护下升温至100℃搅拌过夜。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝20/1)纯化得到标题化合物(100mg,黄色固体)，收率：69％。MS(ESI):m/z 424.2[M+H]+.5-Bromo-1'-(tetrahydro-2H-pyran-4-yl)-3H-spiro[isobenzofuran-1,4'-piperidine] (120 mg, 0.34 mmol), 2-amino- Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (95 mg, 0.34 mmol), PdCl 2 (dppf) (25 mg, 0.03 mmol) and potassium carbonate (94 mg, 0.68 mmol) were dissolved in a mixed solvent of 1,4-dioxane/water (10 mL/2 mL). The reaction solution was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (100 mg, yellow solid), yield: 69%. MS(ESI):m/z 424.2[M+H] + .
(7)2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酸(7) 2-amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-3H-spiro[isobenzofuran-1,4'-piperidine]-5-yl) smoke acid
将2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酸甲酯(100mg,0.24mmol)溶于甲醇/水(5mL/5mL)的混合溶剂中，加入氢氧化钠(29mg,0.72mmol)，反应体系在50℃条件下搅拌2小时。反应液旋干甲醇，用稀盐酸调节pH值为3-4,减压浓缩。残留物经反相柱纯化得到标题化合物(50mg,白色固体)，收率：52％。MS(ESI):m/z 410.1[M+H]+.2-Amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-3H-spiro[isobenzofuran-1,4'-piperidin]-5-yl)nicotinic acid methyl The ester (100 mg, 0.24 mmol) was dissolved in a mixed solvent of methanol/water (5 mL/5 mL), sodium hydroxide (29 mg, 0.72 mmol) was added, and the reaction system was stirred at 50°C for 2 hours. The reaction solution was spun off the methanol, adjusted to pH 3-4 with dilute hydrochloric acid, and concentrated under reduced pressure. The residue was purified by reverse-phase column to obtain the title compound (50 mg, white solid), yield: 52%. MS(ESI):m/z 410.1[M+H] + .
(8)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酰胺(8) 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)-3H-spiro[ Isobenzofuran-1,4'-piperidin]-5-yl)nicotinamide
将2-氨基-5-(1'-(四氢-2H-吡喃-4-基)-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酸(30mg,0.07mmol)，4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(13mg,0.07mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入HATU(42mg,0.11mmol)和N,N-二异丙基乙胺(18mg,0.14mmol)，反应液在室温下搅拌过夜。反应液直接经Pre-HPLC纯化得到标题化合物(14mg,白色固体)，收率：36％。MS(ESI):m/z 533.2[M+H]+.1H NMR(400MHz, DMSO-d6)δ8.34(d,J＝2.0Hz,1H),7.99(d,J＝2.0Hz,1H),7.74(s,1H),7.54-7.52(m,2H),7.33(d,J＝7.6Hz,1H),6.92(s,2H),5.01(s,2H),4.29(s,1H),3.93-3.89(m,2H),3.30-3.27(m,2H),2.82-2.80(m,2H),2.51-2.50(m,3H),2.06-2.02(m,6H),1.93-1.86(m,2H),1.74-1.60(m,10H),1.53-1.44(m,2H).2-Amino-5-(1'-(tetrahydro-2H-pyran-4-yl)-3H-spiro[isobenzofuran-1,4'-piperidin]-5-yl)nicotinic acid ( 30 mg, 0.07 mmol), 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (13 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (5 mL), and HATU (42 mg ,0.11mmol) and N,N-diisopropylethylamine (18mg, 0.14mmol), the reaction solution was stirred at room temperature overnight. The reaction solution was directly purified by Pre-HPLC to obtain the title compound (14 mg, white solid), yield: 36%. MS(ESI):m/z 533.2[M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.34(d,J＝2.0Hz,1H),7.99(d,J＝2.0Hz,1H),7.74(s,1H),7.54-7.52(m,2H),7.33(d ,J＝7.6Hz,1H),6.92(s,2H),5.01(s,2H),4.29(s,1H),3.93-3.89(m,2H),3.30-3.27(m,2H),2.82- 2.80(m,2H),2.51-2.50(m,3H),2.06-2.02(m,6H),1.93-1.86(m,2H),1.74-1.60(m,10H),1.53-1.44(m,2H ).
实施例76Example 76
化合物142：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-异丙基-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酰胺Compound 142: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-isopropyl-3H-spiro[isobenzofuran-1,4'- Piperidin]-5-yl)nicotinamide
(1)5-溴-1'-异丙基-3H-螺[异苯并呋喃-1,4'-哌啶](1)5-Bromo-1'-isopropyl-3H-spiro[isobenzofuran-1,4'-piperidine]
将5-溴-3H-螺[异苯并呋喃-1,4'-哌啶](218mg,0.80mmol,实施例75第4步)，2-溴丙烷(200mg,1.60mmol)溶于乙腈(10mL)中，加入碳酸钾(331mg,2.40mmol)，混合物加热至80℃搅拌过夜。向反应体系中加入水(20mL)，用乙酸乙酯(40mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(100％乙酸乙酯)纯化得到标题化合物(150mg,无色油状物)，收率：60％。MS(ESI):m/z 310.1[M+H]+.Dissolve 5-bromo-3H-spiro[isobenzofuran-1,4'-piperidine] (218 mg, 0.80 mmol, step 4 of Example 75) and 2-bromopropane (200 mg, 1.60 mmol) in acetonitrile ( 10 mL), add potassium carbonate (331 mg, 2.40 mmol), heat the mixture to 80°C and stir overnight. Add water (20 mL) to the reaction system, conduct liquid separation extraction with ethyl acetate (40 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (100% ethyl acetate) to obtain the title compound (150 mg, colorless oil), yield: 60%. MS(ESI):m/z 310.1[M+H] + .
(2)2-氨基-5-(1'-异丙基-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酸甲酯(2) Methyl 2-amino-5-(1'-isopropyl-3H-spiro[isobenzofuran-1,4'-piperidin]-5-yl)nicotinate
将5-溴-1'-异丙基-3H-螺[异苯并呋喃-1,4'-哌啶](150mg,0.49mmol)，2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(135mg,0.49mmol)，PdCl2(dppf)(41mg,0.05mmol)，碳酸钾(138mg,1.00mmol)溶于1,4-二氧六环/水(10mL/2mL)的混合溶剂中。混合物在氮气保护下升温至100℃搅拌过夜。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝20/1)纯化得到标题化合物(160mg,白色固体)，收率：86％。MS(ESI):m/z 382.2[M+H]+.5-Bromo-1'-isopropyl-3H-spiro[isobenzofuran-1,4'-piperidine] (150 mg, 0.49 mmol), 2-amino-5-(4,4,5,5 -Methyl tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (135 mg, 0.49 mmol), PdCl 2 (dppf) (41 mg, 0.05 mmol), potassium carbonate ( 138 mg, 1.00 mmol) was dissolved in a mixed solvent of 1,4-dioxane/water (10 mL/2 mL). The mixture was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (160 mg, white solid), yield: 86%. MS(ESI):m/z 382.2[M+H] + .
(3)2-氨基-5-(1'-异丙基-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酸(3)2-Amino-5-(1'-isopropyl-3H-spiro[isobenzofuran-1,4'-piperidin]-5-yl)nicotinic acid
将2-氨基-5-(1'-异丙基-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酸甲酯(160mg,0.42mmol)溶于甲醇/水(5mL/5mL)的混合溶剂中，加入氢氧化钠(50mg,1.26mmol)。混合物在50℃条件下搅拌2小时。反应液旋干甲醇，用稀盐酸调节pH值为3-4，减压浓缩，残留物经反相柱纯化得到标题化合物(78mg,白色固体)，收率：50％。MS(ESI):m/z 368.2[M+H]+.Dissolve 2-amino-5-(1'-isopropyl-3H-spiro[isobenzofuran-1,4'-piperidin]-5-yl)nicotinic acid methyl ester (160 mg, 0.42 mmol) in methanol /water (5mL/5mL), add sodium hydroxide (50mg, 1.26mmol). The mixture was stirred at 50°C for 2 hours. The reaction solution was evaporated from methanol, adjusted to pH 3-4 with dilute hydrochloric acid, and concentrated under reduced pressure. The residue was purified by a reversed-phase column to obtain the title compound (78 mg, white solid), yield: 50%. MS(ESI):m/z 368.2[M+H] + .
(4)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-异丙基-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酰胺(4)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-isopropyl-3H-spiro[isobenzofuran-1,4'- Piperidin]-5-yl)nicotinamide
将2-氨基-5-(1'-异丙基-3H-螺[异苯并呋喃-1,4'-哌啶]-5-基)烟酸(40mg,0.11mmol)，4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(19mg,0.11mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入HATU(63mg,0.17mmol)和N,N-二异丙基乙胺(28mg,0.22mmol)，室温搅拌过夜。反应液经Pre-HPLC纯化得到标题化合物(27mg,白色固体)，收率：51％。MS(ESI):m/z 491.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),7.74(s,1H),7.54-7.52(m,2H),7.32(d,J＝7.6Hz,1H),6.92(s,2H),5.01(s,2H),4.29(s,1H),2.77-2.69(m,3H),2.53-2.48(m,2H),2.06-2.02(m,6H),1.92-1.85(m,2H),1.66-1.60(m,8H),1.02(d,J＝6.8Hz,6H).2-Amino-5-(1'-isopropyl-3H-spiro[isobenzofuran-1,4'-piperidin]-5-yl)nicotinic acid (40 mg, 0.11 mmol), 4-aminobicyclo [2.2.2] Octan-1-ol hydrochloride (19 mg, 0.11 mmol) was dissolved in N, N-dimethylformamide (5 mL), and HATU (63 mg, 0.17 mmol) and N, N-dimethylformamide were added. Isopropylethylamine (28 mg, 0.22 mmol), stirred at room temperature overnight. The reaction solution was purified by Pre-HPLC to obtain the title compound (27 mg, white solid), yield: 51%. MS (ESI): m/z 491.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.34 (d, J = 2.4Hz, 1H), 7.99 (d, J = 2.4Hz, 1H),7.74(s,1H),7.54-7.52(m,2H),7.32(d,J＝7.6Hz,1H),6.92(s,2H),5.01(s,2H),4.29(s,1H ),2.77-2.69(m,3H),2.53-2.48(m,2H),2.06-2.02(m,6H),1.92-1.85(m,2H),1.66-1.60(m,8H),1.02(d ,J＝6.8Hz,6H).
实施例77Example 77
化合物143：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉-6-基)烟酰胺Compound 143: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(tetrahydro-2H-pyran-4-yl)-1,2,3 ,4-tetrahydroisoquinolin-6-yl)nicotinamide
(1)6-溴-2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉(1)6-Bromo-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinoline
将6-溴-1,2,3,4-四氢异喹啉(500mg,2.4mmol)，四氢-4H-吡喃-4-酮(237mg,2.4mmol)溶于甲醇(10mL)中，室温搅拌半小时，加入氰基硼氢化钠(296.1mg,4.7mmol)，室温搅拌反应过夜。向反应体系中加入水(20mL)，混合液用乙酸乙酯(40mL x 2)分液萃取，无水硫酸钠干燥，过滤，减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝2/1)纯化得到标题化合物(550mg,黄色固体)，收率：79％。MS(ESI):m/z 296.0[M+H]+.Dissolve 6-bromo-1,2,3,4-tetrahydroisoquinoline (500mg, 2.4mmol) and tetrahydro-4H-pyran-4-one (237mg, 2.4mmol) in methanol (10mL). Stir at room temperature for half an hour, add sodium cyanoborohydride (296.1 mg, 4.7 mmol), and stir at room temperature overnight. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain the title compound (550 mg, yellow solid), yield: 79%. MS(ESI):m/z 296.0[M+H] + .
(2)2-氨基-5-(2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉-6-基)烟酸甲酯(2) Methyl 2-amino-5-(2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)nicotinate
将6-溴-2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉(250mg,0.85mmol)，(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸(236mg,0.85mmol)，PdCl2(dppf)(65mg,0.08mmol)和碳酸钾(234mg,1.7mmol)溶于二氧六环/水(5mL/1mL)的混合溶剂中。在氮气保护下升温至100℃搅拌反应过夜。反应液浓缩，残留物经柱层析(100％乙酸乙酯)纯化得到标题化合物(110mg,黄色固体)，收率：35％。MS(ESI):m/z 368.1[M+H]+.6-Bromo-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinoline (250 mg, 0.85 mmol), (6-amino-5-(methyl Oxycarbonyl)pyridin-3-yl)boronic acid (236mg, 0.85mmol), PdCl 2 (dppf) (65mg, 0.08mmol) and potassium carbonate (234mg, 1.7mmol) were dissolved in dioxane/water (5mL/1mL ) in a mixed solvent. The temperature was raised to 100°C under nitrogen protection and the reaction was stirred overnight. The reaction solution was concentrated, and the residue was purified by column chromatography (100% ethyl acetate) to obtain the title compound (110 mg, yellow solid), yield: 35%. MS(ESI):m/z 368.1[M+H] + .
(3)2-氨基-5-(2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉-6-基)烟酸(3)2-Amino-5-(2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)nicotinic acid
将2-氨基-5-(2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉-6-基)烟酸甲酯(110mg,0.3mmol)溶于甲醇/水(5mL/5mL)的混合溶剂中，加入氢氧化钠(36mg,0.9mmol)，反应液在室温下搅拌过夜。反应液旋干除去甲醇，用稀盐酸调节pH值为3-4，减压浓缩，残留物经反相柱纯化得到标题化合物(100mg,黄色固体)，收率：94％。MS(ESI):m/z 354.1[M+H]+.2-Amino-5-(2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)nicotinic acid methyl ester (110 mg, 0.3 mmol) was dissolved in a mixed solvent of methanol/water (5 mL/5 mL), sodium hydroxide (36 mg, 0.9 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was spun to dryness to remove methanol, and the pH value was adjusted to 3-4 with dilute hydrochloric acid. The mixture was concentrated under reduced pressure. The residue was purified by a reverse-phase column to obtain the title compound (100 mg, yellow solid). Yield: 94%. MS(ESI):m/z 354.1[M+H] + .
(4)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉-6-基)烟酰胺(4)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(tetrahydro-2H-pyran-4-yl)-1,2,3 ,4-tetrahydroisoquinolin-6-yl)nicotinamide
将2-氨基-5-(2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉-6-基)烟酸(80mg,0.23mmol)，4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(40mg,0.23mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入HATU(175mg,0.46mmol)和N,N-二异丙基乙胺(89mg,0.69mmol)，室温搅拌过夜。反应液直接经Pre-HPLC纯化得到标题化合物(16mg,白色固体)，收率：15％。MS(ESI):m/z 477.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝2.4Hz,1H),7.96(d,J＝2.0Hz,1H),7.77(s,1H),7.39(d,J＝8.0Hz,1H),7.36(s,1H),7.11(d,J＝8.0Hz,1H),6.87(s,2H),4.29(s,1H),3.92(dd,J＝11.6,2.8Hz,2H),3.71(s,2H),3.34-3.29(m,2H),2.83-2.77(m,4H),2.60-2.58(m,1H),2.06-2.02(m,6H),1.80-1.77(m,2H),1.63-1.59(m,6H),1.57-1.47(m,2H).2-Amino-5-(2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)nicotinic acid (80 mg, 0.23 mmol) , 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (40 mg, 0.23 mmol) was dissolved in N, N-dimethylformamide (5 mL), HATU (175 mg, 0.46 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol), stirred at room temperature overnight. The reaction solution was directly purified by Pre-HPLC to obtain the title compound (16 mg, white solid), yield: 15%. MS (ESI): m/z 477.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.32 (d, J = 2.4Hz, 1H), 7.96 (d, J = 2.0Hz, 1H),7.77(s,1H),7.39(d,J＝8.0Hz,1H),7.36(s,1H),7.11(d,J＝8.0Hz,1H),6.87(s,2H),4.29( s,1H),3.92(dd,J＝11.6,2.8Hz,2H),3.71(s,2H),3.34-3.29(m,2H),2.83-2.77(m,4H),2.60-2.58(m, 1H),2.06-2.02(m,6H),1.80-1.77(m,2H),1.63-1.59(m,6H),1.57-1.47(m,2H).
实施例78Example 78
化合物144：2-氨基-5-(4-(4-乙氧基-1-异丙基哌啶-4-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺 Compound 144: 2-amino-5-(4-(4-ethoxy-1-isopropylpiperidin-4-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octane-1 -Nicotinamide
(1)4-(4-溴苯基)-4-乙氧基哌啶-1-羧酸叔丁酯(1) tert-butyl 4-(4-bromophenyl)-4-ethoxypiperidine-1-carboxylate
将4-(4-溴苯基)-4-羟基哌啶-1-羧酸叔丁酯(900.0mg,2.5mmol)溶于N,N-二甲基甲酰胺(15mL)中，在0℃条件下加入氢化钠(91.0mg,3.8mmol)，搅拌2小时。然后加入碘乙烷(593.0mg,3.8mmol)的N,N-二甲基甲酰胺(3mL)溶液，反应液在室温条件下搅拌过夜。向反应液加入水(80mL)，用乙酸乙酯(40mL x 3)萃取，饱和氯化钠溶液洗涤3次，无水硫酸钠干燥，减压浓缩。残留物经柱层析(二氯甲烷/甲醇＝15/1)纯化得到标题化合物(320.0mg,白色固体)，收率：33％。MS(ESI):m/z 284.0[M+H-100]+.Dissolve 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (900.0 mg, 2.5 mmol) in N,N-dimethylformamide (15 mL) at 0°C. Sodium hydride (91.0 mg, 3.8 mmol) was added under the conditions and stirred for 2 hours. Then a solution of ethyl iodide (593.0 mg, 3.8 mmol) in N,N-dimethylformamide (3 mL) was added, and the reaction solution was stirred at room temperature overnight. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (40 mL x 3), washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=15/1) to obtain the title compound (320.0 mg, white solid), yield: 33%. MS(ESI):m/z 284.0[M+H-100] + .
(2)4-(4-溴苯基)-4-乙氧基哌啶盐酸盐(2)4-(4-Bromophenyl)-4-ethoxypiperidine hydrochloride
将4-(4-溴苯基)-4-乙氧基哌啶-1-羧酸叔丁酯(320.0mg,0.83mmol)溶于二氯甲烷(5mL)中，加入4M盐酸二氧六环溶液(2mL,8mmol)，在室温条件下搅拌2小时。反应液浓缩得到标题化合物，直接用于下一步反应。MS(ESI):m/z 284.0[M+H]+.Dissolve 4-(4-bromophenyl)-4-ethoxypiperidine-1-carboxylic acid tert-butyl ester (320.0 mg, 0.83 mmol) in dichloromethane (5 mL), and add 4M dioxane hydrochloride The solution (2 mL, 8 mmol) was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound, which was directly used in the next reaction. MS(ESI):m/z 284.0[M+H] + .
(3)4-(4-溴苯基)-4-乙氧基-1-异丙基哌啶(3)4-(4-bromophenyl)-4-ethoxy-1-isopropylpiperidine
将上一步得到的粗品溶于乙腈(10mL)中，依次加入2-溴丙烷(510.0mg,4.15mmol)，碳酸钾(344.0mg,2.49mmol)，混合物在氮气保护下加热至80℃搅拌过夜。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝40/1～20/1)纯化得到标题化合物(202mg,白色固体)，收率：75％。MS(ESI):m/z 326.1[M+H]+.Dissolve the crude product obtained in the previous step in acetonitrile (10 mL), add 2-bromopropane (510.0 mg, 4.15 mmol) and potassium carbonate (344.0 mg, 2.49 mmol) in sequence, and heat the mixture to 80°C under nitrogen protection and stir overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=40/1-20/1) to obtain the title compound (202 mg, white solid), yield: 75%. MS(ESI):m/z 326.1[M+H] + .
(4)2-氨基-5-(4-(4-乙氧基-1-异丙基哌啶-4-基)苯基)烟酸甲酯(4) Methyl 2-amino-5-(4-(4-ethoxy-1-isopropylpiperidin-4-yl)phenyl)nicotinate
将4-(4-溴苯基)-4-乙氧基-1-异丙基哌啶(202mg,0.62mmol)溶于1,4-二氧六环/水(7mL/1.5mL)的混合溶剂中，依次加入2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(207mg,0.74mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(45mg,0.06mmol)和碳酸钾(257mg,1.86mmol)。反应液在氮气保护下加热至80℃搅拌18小时。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝50/1～25/1)纯化得到标题化合物(140mg,棕色油状物)，收率：57％。MS(ESI):m/z 398.2[M+H]+.Dissolve 4-(4-bromophenyl)-4-ethoxy-1-isopropylpiperidine (202 mg, 0.62 mmol) in a mixture of 1,4-dioxane/water (7 mL/1.5 mL) To the solvent, methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (207 mg, 0.74mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (45mg, 0.06mmol) and potassium carbonate (257mg, 1.86mmol). The reaction solution was heated to 80°C under nitrogen protection and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=50/1~25/1) to obtain the title compound (140 mg, brown oil), yield: 57%. MS(ESI):m/z 398.2[M+H] + .
(5)2-氨基-5-(4-(4-乙氧基-1-异丙基哌啶-4-基)苯基)烟酸(5)2-Amino-5-(4-(4-ethoxy-1-isopropylpiperidin-4-yl)phenyl)nicotinic acid
将2-氨基-5-(4-(4-乙氧基-1-异丙基哌啶-4-基)苯基)烟酸甲酯(100.0mg,0.25mmol)溶于甲醇/水(4mL/1mL)的混合溶剂中，加入氢氧化钠(30.0mg,0.75mmol)。反应液在50℃条件下搅拌2小时。反应液减压浓缩，残留物经反相柱纯化得到标题化合物(66mg,黄色固体)，收率：69％。MS(ESI):m/z 384.1[M+H]+.Dissolve methyl 2-amino-5-(4-(4-ethoxy-1-isopropylpiperidin-4-yl)phenyl)nicotinate (100.0 mg, 0.25 mmol) in methanol/water (4 mL /1mL), add sodium hydroxide (30.0 mg, 0.75 mmol). The reaction solution was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase column to obtain the title compound (66 mg, yellow solid), yield: 69%. MS(ESI):m/z 384.1[M+H] + .
(6)2-氨基-5-(4-(4-乙氧基-1-异丙基哌啶-4-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)烟酰胺(6) 2-Amino-5-(4-(4-ethoxy-1-isopropylpiperidin-4-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octane-1 -Nicotinamide
将2-氨基-5-(4-(4-乙氧基-1-异丙基哌啶-4-基)苯基)烟酸(66.0mg,0.17mmol)溶于N,N-二甲基甲酰胺(3mL)中，依次加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(30.0mg,0.17mmol)，HATU(129.0mg,0.34mmol)和N,N-二异丙基乙胺(132.0mg,1.02mmol)。反应液在室温条件下搅拌2小时。反应液减压浓缩，残留物经Prep-HPLC纯化得到标题化合物(17.6mg,白色固体)，收率：20％。MS(ESI):m/z 507.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.36(d,J＝2.0Hz,1H),8.02(d,J＝2.4Hz,1H),7.77(s,1H),7.62-7.60(m,2H),7.46-7.44(m,2H),6.94(s,2H),4.30(s,1H),3.04(q,J＝7.2Hz,2H),2.71-2.54(m,5H),2.06-1.94(m,8H),1.87-1.80(m,2H),1.63-1.60(m,6H),1.06(t,J＝7.2Hz,3H),0.99(d,J＝6.8Hz,6H).Dissolve 2-amino-5-(4-(4-ethoxy-1-isopropylpiperidin-4-yl)phenyl)nicotinic acid (66.0 mg, 0.17mmol) in N,N-dimethyl To formamide (3 mL), add 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (30.0 mg, 0.17 mmol), HATU (129.0 mg, 0.34 mmol) and N, N-diiso Propylethylamine (132.0 mg, 1.02 mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound (17.6 mg, white solid), yield: 20%. MS (ESI): m/z 507.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.36 (d, J = 2.0Hz, 1H), 8.02 (d, J = 2.4Hz, 1H),7.77(s,1H),7.62-7.60(m,2H),7.46-7.44(m,2H),6.94(s,2H),4.30(s,1H),3.04(q,J＝7.2Hz ,2H),2.71-2.54(m,5H),2.06-1.94(m,8H),1.87-1.80(m,2H),1.63-1.60(m,6H),1.06(t,J＝7.2Hz,3H ),0.99(d,J＝6.8Hz,6H).
实施例79Example 79
化合物145：6'-氨基-5-(4-乙氧基-1-异丙基哌啶-4-基)-N-(4-羟基双环[2.2.2]辛-1-基)-[2,3'-联吡啶]-5'-羧酰胺Compound 145: 6'-amino-5-(4-ethoxy-1-isopropylpiperidin-4-yl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-[ 2,3'-bipyridyl]-5'-carboxamide
(1)4-(6-溴吡啶-3-基)-4-羟基哌啶-1-羧酸叔丁酯(1) tert-butyl 4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate
将2-溴-5-碘吡啶(4g,14mmol)溶于四氢呋喃(50mL)中，在-78℃条件下逐滴加入正丁基锂/正己烷溶液(2.5M,6.4mL,16mmol)，在-78℃条件下搅拌2小时。然后加入4-氧代哌啶-1-羧酸叔丁酯(2.8g,14mmol)的四氢呋喃(10mL)溶液，继续在-78℃条件下搅拌1小时。向反应液中慢慢加水(80mL)淬灭反应，用乙酸乙酯(30mL x 3)萃取，有机相用饱和氯化钠溶液洗涤(100mL x 2)，无水硫酸钠干燥，减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝5/1)纯化得到标题化合物(2.3g,浅黄色油状物)，收率：46％。MS(ESI):m/z 357.1[M+H]+.Dissolve 2-bromo-5-iodopyridine (4g, 14mmol) in tetrahydrofuran (50mL), add n-butyllithium/n-hexane solution (2.5M, 6.4mL, 16mmol) dropwise at -78°C, and add Stir for 2 hours at -78°C. Then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.8g, 14mmol) in tetrahydrofuran (10mL) was added, and stirring was continued at -78°C for 1 hour. Slowly add water (80 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (30 mL x 3), wash the organic phase with saturated sodium chloride solution (100 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the title compound (2.3 g, light yellow oil), yield: 46%. MS(ESI):m/z 357.1[M+H] + .
(2)4-(6-溴吡啶-3-基)-4-乙氧基哌啶-1-羧酸叔丁酯(2) tert-butyl 4-(6-bromopyridin-3-yl)-4-ethoxypiperidine-1-carboxylate
将4-(6-溴吡啶-3-基)-4-羟基哌啶-1-羧酸叔丁酯(1g,2.8mmol)溶于N,N-二甲基甲酰胺(20mL)中，在0℃条件下加入氢化钠(336mg,8.4mmol)，搅拌2小时。然后加入碘乙烷(655mg,4.2mmol)的N,N-二甲基甲酰胺(3mL)溶液，混合物升至室温搅拌过夜。向反应液中加入水(200mL)，用乙酸乙酯(100mL x 3)萃取，饱和氯化钠溶液洗涤2次，无水硫酸钠干燥，减压浓缩。残留物经柱层析(石油醚/乙酸乙酯＝5/1)纯化得到标题化合物(500.0mg,浅黄色油状物)，收率：20％。MS(ESI):m/z 385.0[M+H]+.Dissolve 4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1g, 2.8mmol) in N,N-dimethylformamide (20mL). Add sodium hydride (336 mg, 8.4 mmol) at 0°C and stir for 2 hours. Then a solution of ethyl iodide (655 mg, 4.2 mmol) in N,N-dimethylformamide (3 mL) was added, and the mixture was warmed to room temperature and stirred overnight. Water (200 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL x 3), washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the title compound (500.0 mg, light yellow oil), yield: 20%. MS(ESI):m/z 385.0[M+H] + .
(3)2-溴-5-(4-乙氧基哌啶-4-基)吡啶盐酸盐(3)2-Bromo-5-(4-ethoxypiperidin-4-yl)pyridine hydrochloride
将4-(6-溴吡啶-3-基)-4-乙氧基哌啶-1-羧酸叔丁酯(500mg,1.3mmol)溶于二氯甲烷(7mL)中，加入4M盐酸二氧六环溶液(3mL,12mmol)，在室温条件下搅拌2小时。反应液减压浓缩得到标题化合物，直接用于下一步反应。MS(ESI):m/z 285.0[M+H]+.Dissolve 4-(6-bromopyridin-3-yl)-4-ethoxypiperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.3 mmol) in dichloromethane (7 mL), add 4M dioxychloride Six-ring solution (3 mL, 12 mmol), stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound, which was directly used in the next reaction. MS(ESI):m/z 285.0[M+H] + .
(4)2-氯-5-(4-乙氧基-1-异丙基哌啶-4-基)吡啶(4)2-Chloro-5-(4-ethoxy-1-isopropylpiperidin-4-yl)pyridine
将上一步得到的2-溴-5-(4-乙氧基哌啶-4-基)吡啶盐酸盐溶于乙腈溶液(15mL)中，依次加入2-溴丙烷(800.0mg,6.5mmol)，碳酸钾(538mg,3.9mmol)。反应液在氮气保护下加热至80℃搅拌过夜。向反应液中加入水(50mL)，用乙酸乙酯(30mL x 3)萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩得到标题化合物(300mg,黄色固体)，收率：82％。MS(ESI):m/z 283.2[M+H]+.Dissolve 2-bromo-5-(4-ethoxypiperidin-4-yl)pyridine hydrochloride obtained in the previous step into acetonitrile solution (15 mL), and add 2-bromopropane (800.0 mg, 6.5 mmol) in sequence. , Potassium carbonate (538mg, 3.9mmol). The reaction solution was heated to 80°C under nitrogen protection and stirred overnight. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (300 mg, yellow solid), yield: 82%. MS(ESI):m/z 283.2[M+H] + .
(5)6'-氨基-5-(4-乙氧基-1-异丙基哌啶-4-基)-[2,3'-联吡啶]-5'-羧酸甲酯 (5)6'-Amino-5-(4-ethoxy-1-isopropylpiperidin-4-yl)-[2,3'-bipyridine]-5'-carboxylic acid methyl ester
将2-氯-5-(4-乙氧基-1-异丙基哌啶-4-基)吡啶(300mg,1.05mmol)溶于1,4-二氧六环/水(4mL/1mL)的混合溶液中，依次加入2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯(350mg,1.26mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(80mg,0.11mmol)和碳酸钾(435mg,3.15mmol)。反应液在氮气保护下加热至80℃搅拌18小时。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝10/1)纯化得到标题化合物(300mg,黑色油状物)，收率：71％。MS(ESI):m/z 399.2[M+H]+.Dissolve 2-chloro-5-(4-ethoxy-1-isopropylpiperidin-4-yl)pyridine (300mg, 1.05mmol) in 1,4-dioxane/water (4mL/1mL) To the mixed solution, methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate ( 350 mg, 1.26 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (80 mg, 0.11 mmol) and potassium carbonate (435 mg, 3.15 mmol). The reaction solution was heated to 80°C under nitrogen protection and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10/1) to obtain the title compound (300 mg, black oil), yield: 71%. MS(ESI):m/z 399.2[M+H] + .
(6)6'-氨基-5-(4-乙氧基-1-异丙基哌啶-4-基)-[2,3'-联吡啶]-5'-羧酸(6)6'-Amino-5-(4-ethoxy-1-isopropylpiperidin-4-yl)-[2,3'-bipyridine]-5'-carboxylic acid
将6'-氨基-5-(4-乙氧基-1-异丙基哌啶-4-基)-[2,3'-联吡啶]-5'-羧酸甲酯(300.0mg,0.75mmol)溶于甲醇/水(4mL/1mL)的混合溶剂中，加入氢氧化钠(91.0mg,2.27mmol)，体系在50℃条件下搅拌12小时。反应液减压浓缩，残留物经反相柱纯化得到标题化合物(130mg,黄色固体)，收率：45％。MS(ESI):m/z 385.2[M+H]+.6'-Amino-5-(4-ethoxy-1-isopropylpiperidin-4-yl)-[2,3'-bipyridyl]-5'-carboxylic acid methyl ester (300.0 mg, 0.75 mmol) was dissolved in a mixed solvent of methanol/water (4mL/1mL), sodium hydroxide (91.0mg, 2.27mmol) was added, and the system was stirred at 50°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase column to obtain the title compound (130 mg, yellow solid), yield: 45%. MS(ESI):m/z 385.2[M+H] + .
(7)6'-氨基-5-(4-乙氧基-1-异丙基哌啶-4-基)-N-(4-羟基双环[2.2.2]辛-1-基)-[2,3'-联吡啶]-5'-羧酰胺(7)6'-Amino-5-(4-ethoxy-1-isopropylpiperidin-4-yl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-[ 2,3'-bipyridyl]-5'-carboxamide
将6'-氨基-5-(4-乙氧基-1-异丙基哌啶-4-基)-[2,3'-联吡啶]-5'-羧酸(130.0mg,0.26mmol)溶于N,N-二甲基甲酰胺(2mL)中，依次加入4-氨基双环[2.2.2]辛烷-1-醇盐酸盐(51mg,0.29mmol)，HATU(198mg,0.52mmol)和N,N-二异丙基乙胺(101mg,0.78mmol)，体系在室温条件下搅拌1小时。反应液减压浓缩，残留物经Prep-HPLC纯化得到标题化合物(58.5mg,浅黄色固体)，收率：44％。MS(ESI):m/z 508.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.76(d,J＝2.0Hz,1H),8.62(d,J＝1.6Hz,1H),8.36(d,J＝2.4Hz,1H),7.89-7.81(m,3H),7.08(s,2H),4.30(s,1H),3.07(q,J＝6.8Hz,2H),2.71-2.54(m,5H),2.07-1.99(m,8H),1.92-1.85(m,2H),1.65-1.61(m,6H),1.08(t,J＝6.8Hz,3H),1.00(d,J＝6.8Hz,6H).6'-Amino-5-(4-ethoxy-1-isopropylpiperidin-4-yl)-[2,3'-bipyridine]-5'-carboxylic acid (130.0 mg, 0.26 mmol) Dissolve in N,N-dimethylformamide (2mL), add 4-aminobicyclo[2.2.2]octane-1-ol hydrochloride (51mg, 0.29mmol) and HATU (198mg, 0.52mmol) in sequence. and N,N-diisopropylethylamine (101 mg, 0.78 mmol), and the system was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain the title compound (58.5 mg, light yellow solid), yield: 44%. MS (ESI): m/z 508.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.76 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.6 Hz, 1H),8.36(d,J＝2.4Hz,1H),7.89-7.81(m,3H),7.08(s,2H),4.30(s,1H),3.07(q,J＝6.8Hz,2H), 2.71-2.54(m,5H),2.07-1.99(m,8H),1.92-1.85(m,2H),1.65-1.61(m,6H),1.08(t,J＝6.8Hz,3H),1.00( d,J＝6.8Hz,6H).
实施例80Example 80
化合物148：(R)-2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺Compound 148: (R)-2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)- 2,3-Dihydrospiro[indene-1,3'-pyrrolidin]-5-yl)nicotinamide
化合物115(90mg粗品,实施例57)经手性柱拆分得到标题化合物(16.6mg,白色固体)，对应保留时间8.022分钟，ee值为100％，绝对构型未确定。MS(ESI):m/z 517.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝2.4Hz,1H),7.96(d,J＝2.4Hz,1H),7.75(s,1H),7.45-7.43(m,2H),7.33(d,J＝8.4Hz,1H),6.88(s,2H),4.30(s,1H),3.88-3.85(m,2H),3.29-3.25(m,2H),2.89(t,J＝7.2Hz,2H),2.81-2.79(m,2H),2.75-2.62(m,2H),2.39-2.31(m,1H),2.17-2.10(m,1H),2.06-2.02(m,7H),1.99-1.90(m,2H),1.81-1.78(m,2H),1.64-1.60(m,6H),1.48-1.43(m,2H).Compound 115 (90 mg crude product, Example 57) was separated by chiral column to obtain the title compound (16.6 mg, white solid), with a corresponding retention time of 8.022 minutes, an ee value of 100%, and an undetermined absolute configuration. MS (ESI): m/z 517.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.31 (d, J = 2.4Hz, 1H), 7.96 (d, J = 2.4Hz, 1H),7.75(s,1H),7.45-7.43(m,2H),7.33(d,J＝8.4Hz,1H),6.88(s,2H),4.30(s,1H),3.88-3.85(m ,2H),3.29-3.25(m,2H),2.89(t,J＝7.2Hz,2H),2.81-2.79(m,2H),2.75-2.62(m,2H),2.39-2.31(m,1H ),2.17-2.10(m,1H),2.06-2.02(m,7H),1.99-1.90(m,2H),1.81-1.78(m,2H),1.64-1.60(m,6H),1.48-1.43 (m,2H).
实施例81Example 81
化合物149：(S)-2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(四氢-2H-吡喃-4-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺Compound 149: (S)-2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(tetrahydro-2H-pyran-4-yl)- 2,3-Dihydrospiro[indene-1,3'-pyrrolidin]-5-yl)nicotinamide
化合物115(90mg粗品,实施例57)经手性柱拆分得到标题化合物(14.7mg,白色固体)，对应保留时间12.402分钟，ee值为99.7％，绝对构型未确定。MS(ESI):m/z 517.1[M+H]+.1H NMR(400M Hz,DMSO-d6)δ8.31(d,J＝2.4Hz,1H),7.96(d,J＝2.4Hz,1H),7.75(s,1H),7.45-7.43(m,2H),7.33(d,J＝8.4Hz,1H),6.88(s,2H),4.30(s,1H),3.88-3.85(m,2H),3.29-3.25(m,2H),2.89(t,J＝7.2Hz,2H),2.84-2.76(m,2H),2.74-2.63(m,2H),2.39-2.31(m,1H),2.17-2.10(m,1H),2.06-2.02(m,7H),1.99-1.90(m,2H),1.81-1.78(m,2H),1.64-1.60(m,6H),1.48-1.43(m,2H).Compound 115 (90 mg crude product, Example 57) was separated by chiral column to obtain the title compound (14.7 mg, white solid), with a corresponding retention time of 12.402 minutes, an ee value of 99.7%, and an undetermined absolute configuration. MS (ESI): m/z 517.1[M+H] + . 1 H NMR (400M Hz, DMSO-d 6 ) δ8.31 (d, J = 2.4Hz, 1H), 7.96 (d, J = 2.4Hz ,1H),7.75(s,1H),7.45-7.43(m,2H),7.33(d,J＝8.4Hz,1H),6.88(s,2H),4.30(s,1H),3.88-3.85( m,2H),3.29-3.25(m,2H),2.89(t,J＝7.2Hz,2H),2.84-2.76(m,2H),2.74-2.63(m,2H),2.39-2.31(m, 1H),2.17-2.10(m,1H),2.06-2.02(m,7H),1.99-1.90(m,2H),1.81-1.78(m,2H),1.64-1.60(m,6H),1.48- 1.43(m,2H).
实施例82Example 82
化合物56：2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)-5-(4-(7-(氧杂环丁烷-3-基)-2,7-二氮杂螺[3.5]壬烷-2-基)苯基)烟酰胺Compound 56: 2-amino-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5-(4-(7-(oxetane) -3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)nicotinamide
参照实施例30步骤(2)至步骤(4)的方法，以2-(4-溴苯基)-7-(氧杂环丁烷-3-基)-2,7-二氮杂螺[3.5]壬烷和(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸为原料，经类似的步骤得到标题化合物(1.1mg,白色固体)。MS(ESI):m/z 508.3[M+H]+.Referring to the method from step (2) to step (4) in Example 30, use 2-(4-bromophenyl)-7-(oxetan-3-yl)-2,7-diazaspiro[ Using 3.5]nonane and (6-amino-5-(methoxycarbonyl)pyridin-3-yl)boronic acid as raw materials, the title compound (1.1 mg, white solid) was obtained through similar steps. MS(ESI):m/z 508.3[M+H] + .
实施例83Example 83
化合物59：2-氨基-5-(4-(吗啉代甲基)苯基)-N-(哌啶-4-基)烟酰胺Compound 59: 2-amino-5-(4-(morpholinomethyl)phenyl)-N-(piperidin-4-yl)nicotinamide
参照实施例23的方法，第(3)步用4-氨基哌啶-1-羧酸叔丁酯替代四氢-2H-吡喃-4-胺进行缩合反应，再用盐酸脱去保护基，经Pre-HPLC纯化得到标题化合物(11.8mg,白色固体)。MS(ESI):m/z 396.4[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.37(d,J＝7.0Hz,1H),8.16(s,1H),7.62(d,J＝7.9Hz,2H),7.38(d,J＝7.9Hz,2H),7.14(s,2H),4.07-3.90(m,1H),3.90-3.76(m,1H),3.58(t,J＝3.6Hz,4H),3.49(s,2H),2.96(d,J＝11.9Hz,2H),2.66-2.53(m,2H),2.42-2.31(m,4H),1.77-1.73(m,2H),1.47-1.35(m,2H).Referring to the method of Example 23, in step (3), 4-aminopiperidine-1-carboxylic acid tert-butyl ester is used instead of tetrahydro-2H-pyran-4-amine to perform a condensation reaction, and then hydrochloric acid is used to remove the protecting group. Purification by Pre-HPLC gave the title compound (11.8 mg, white solid). MS (ESI): m/z 396.4[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.40 (s, 1H), 8.37 (d, J = 7.0Hz, 1H), 8.16 ( s,1H),7.62(d,J＝7.9Hz,2H),7.38(d,J＝7.9Hz,2H),7.14(s,2H),4.07-3.90(m,1H),3.90-3.76(m ,1H),3.58(t,J＝3.6Hz,4H),3.49(s,2H),2.96(d,J＝11.9Hz,2H),2.66-2.53(m,2H),2.42-2.31(m, 4H),1.77-1.73(m,2H),1.47-1.35(m,2H).
实施例84Example 84
化合物61：2-氨基-4-甲基-5-(4-(吗啉代甲基)苯基)-N-(四氢-2H-吡喃-4-基)烟酰胺Compound 61: 2-amino-4-methyl-5-(4-(morpholinomethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide
参照实施例23的方法，第(1)步用(6-氨基-5-(甲氧基羰基)-4-甲基吡啶-3-基)硼酸替代(6-氨基-5-(甲氧基羰基)吡啶-3-基)硼酸，经类似的步骤得到标题化合物(12.0mg,白色固体)。MS(ESI):m/z 411.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝7.9Hz,1H),7.79(s,1H),7.36(d,J＝7.9Hz,2H),7.24(d,J＝7.9Hz,2H),5.62(s,2H),4.07-3.96(m,1H),3.90-3.83(m,2H),3.59(t,J＝4.4Hz,4H),3.50(s,2H),3.41-3.32(m,J＝1.5Hz,2H),2.39-2.37(m,4H),2.08(s,3H),1.87-1.79(m,2H),1.54-1.42(m,2H).Referring to the method of Example 23, in step (1), (6-amino-5-(methoxycarbonyl)-4-methylpyridin-3-yl)boronic acid is used to replace (6-amino-5-(methoxy) Carbonyl)pyridin-3-yl)boronic acid, a similar procedure gave the title compound (12.0 mg, white solid). MS (ESI): m/z 411.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.47 (d, J = 7.9 Hz, 1H), 7.79 (s, 1H), 7.36 ( d,J＝7.9Hz,2H),7.24(d,J＝7.9Hz,2H),5.62(s,2H),4.07-3.96(m,1H),3.90-3.83(m,2H),3.59(t ,J＝4.4Hz,4H),3.50(s,2H),3.41-3.32(m,J＝1.5Hz,2H),2.39-2.37(m,4H),2.08(s,3H),1.87-1.79( m,2H),1.54-1.42(m,2H).
实施例85Example 85
化合物67：6-(4-(1-乙基哌啶-4-基)苯基)-N-(4-羟基双环[2.2.2]辛-1-基)-1H-吲唑-3-甲酰胺 Compound 67: 6-(4-(1-ethylpiperidin-4-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-1H-indazole-3- Formamide
参照实施例18的方法，第(3)步以1-乙基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)哌啶和6-溴-N-(4-羟基双环[2.2.2]辛-1-基)-1H-吲唑-3-甲酰胺(由6-溴-1H-吲唑-3-羧酸和4-氨基双环[2.2.2]辛烷-1-醇盐酸盐缩合得到)为原料，得到标题化合物(2.3mg,白色固体)。MS(ESI):m/z 473.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ13.60(brs,1H),8.17(d,J＝8.6Hz,1H),7.75(s,1H),7.67(d,J＝7.7Hz,2H),7.53(d,J＝8.9Hz,1H),7.37(d,J＝7.9Hz,2H),7.28(s,1H),4.36(s,1H),3.71-3.54(m,1H),3.04-3.00(m,2H),2.42-2.37(m,2H),2.13-2.06(m,6H),2.04-1.98(m,2H),1.83-1.76(m,2H),1.75-1.69(m,2H),1.68-1.64(m,6H),1.05(t,J＝7.0Hz,3H).Referring to the method of Example 18, in step (3), 1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)piperidine and 6-bromo-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-1H-indazole-3-carboxamide (from 6-bromo-1H -Indazole-3-carboxylic acid and 4-aminobicyclo[2.2.2]octane-1-ol hydrochloride (obtained from the condensation) were used as raw materials to obtain the title compound (2.3 mg, white solid). MS (ESI): m/z 473.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 13.60 (brs, 1H), 8.17 (d, J = 8.6Hz, 1H), 7.75 ( s,1H),7.67(d,J＝7.7Hz,2H),7.53(d,J＝8.9Hz,1H),7.37(d,J＝7.9Hz,2H),7.28(s,1H),4.36( s,1H),3.71-3.54(m,1H),3.04-3.00(m,2H),2.42-2.37(m,2H),2.13-2.06(m,6H),2.04-1.98(m,2H), 1.83-1.76(m,2H),1.75-1.69(m,2H),1.68-1.64(m,6H),1.05(t,J=7.0Hz,3H).
实施例86Example 86
化合物68：(R)-2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酰胺Compound 68: (R)-2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(tetrahydro-2H-pyran-4-yl) )pyrrolidin-3-yl)-1H-indazol-5-yl)nicotinamide
(1)(R)-3-(5-溴-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁酯(1)(R)-3-(5-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
将5-溴-1H-吲唑(1.00g,5.08mmol)溶于无水四氢呋喃(10mL)中，降温至0℃，加入(S)-3-羟基吡咯烷-1-羧酸叔丁酯(1.14g,6.09mmol)和三苯基膦(1.59g,6.09mmol)，在氮气氛围下加入偶氮二甲酸二乙酯(1.06g,6.09mmol)，混合物加热至50℃搅拌16小时。反应液冷却至室温，加水淬灭，水相用乙酸乙酯萃取。有机相合并，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物经柱层析(石油醚/乙酸乙酯＝5/1)纯化得到标题化合物(500mg,白色固体)，收率：26.9％。MS(ESI):m/z 366.2[M+H]+.Dissolve 5-bromo-1H-indazole (1.00g, 5.08mmol) in anhydrous tetrahydrofuran (10mL), cool to 0°C, add (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester ( 1.14g, 6.09mmol) and triphenylphosphine (1.59g, 6.09mmol), diethyl azodicarboxylate (1.06g, 6.09mmol) was added under a nitrogen atmosphere, and the mixture was heated to 50°C and stirred for 16 hours. The reaction solution was cooled to room temperature, quenched by adding water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the title compound (500 mg, white solid), yield: 26.9%. MS(ESI):m/z 366.2[M+H] + .
(2)(R)-5-溴-1-(吡咯烷-3-基)-1H-吲唑(2)(R)-5-bromo-1-(pyrrolidin-3-yl)-1H-indazole
参照实施例43步骤(2)的方法，以(R)-3-(5-溴-1H-吲唑-1-基)吡咯烷-1-羧酸叔丁酯为原料，得到标题化合物(320mg,白色固体)。MS(ESI):m/z 266.1[M+H]+.Referring to the method of step (2) in Example 43, using (R)-3-(5-bromo-1H-indazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester as raw material, the title compound (320 mg , white solid). MS(ESI):m/z 266.1[M+H] + .
(3)(R)-5-溴-1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑(3)(R)-5-bromo-1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazole
参照实施例43步骤(3)的方法，以(R)-5-溴-1-(吡咯烷-3-基)-1H-吲唑为原料，得到标题化合物(210mg,白色固体)。MS(ESI):m/z 350.1[M+H]+.Referring to the method of step (3) in Example 43, using (R)-5-bromo-1-(pyrrolidin-3-yl)-1H-indazole as raw material, the title compound (210 mg, white solid) was obtained. MS(ESI):m/z 350.1[M+H] + .
(4)(R)-2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酸甲酯(4)(R)-2-amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazol-5-yl) smoke acid methyl ester
参照实施例43步骤(4)的方法，以(R)-5-溴-1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑和2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯为原料，得到标题化合物(160mg,白色固体)。MS(ESI):m/z 422.2[M+H]+.Referring to the method of step (4) in Example 43, use (R)-5-bromo-1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazole and 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinic acid methyl ester as raw materials to obtain the title compound ( 160mg, white solid). MS(ESI):m/z 422.2[M+H] + .
(5)(R)-2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酸(5)(R)-2-amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H-indazol-5-yl) smoke acid
参照实施例43步骤(5)的方法，以(R)-2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酸甲酯为原料，得到标题化合物(100mg,白色固体)。MS(ESI):m/z 408.2[M+H]+.Referring to the method of step (5) in Example 43, use (R)-2-amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H -Indazol-5-yl)nicotinic acid methyl ester was used as raw material to obtain the title compound (100 mg, white solid). MS(ESI):m/z 408.2[M+H] + .
(6)(R)-2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酰胺(6)(R)-2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(tetrahydro-2H-pyran-4-yl) )pyrrolidin-3-yl)-1H-indazol-5-yl)nicotinamide
参照实施例43步骤(6)的方法，以(R)-2-氨基-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酸和4-氨基双环[2.2.2]辛-1-醇盐酸盐为原料，得到标题化合物(36.4mg,白色固体)。MS(ESI):m/z531.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝2.3Hz,1H),8.10(s,1H),8.05(d,J＝2.3Hz,1H),7.98(s,1H),7.91(d,J＝8.9Hz,1H),7.79(s,1H),7.71(dd,J＝8.9,1.5Hz,1H),6.89(s,2H),5.44-5.33(m,1H),4.30(s,1H),3.91-3.81(m,2H),3.35-3.30(m,2H),3.16(t,J＝8.7Hz,1H),2.91-2.82(m,2H),2.80-2.74(m,1H),2.39-2.30(m,2H),2.26-2.16(m,1H),2.12-2.03(m,6H),1.80(d,J＝11.4Hz,2H),1.68-1.59(m,6H),1.52-1.36(m,2H).Referring to the method of step (6) in Example 43, use (R)-2-amino-5-(1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-1H -Indazol-5-yl)nicotinic acid and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride were used as raw materials to obtain the title compound (36.4 mg, white solid). MS (ESI): m/z531.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.40 (d, J = 2.3Hz, 1H), 8.10 (s, 1H), 8.05 (d,J＝2.3Hz,1H),7.98(s,1H),7.91(d,J＝8.9Hz,1H),7.79(s,1H),7.71(dd,J＝8.9,1.5Hz,1H) ,6.89(s,2H),5.44-5.33(m,1H),4.30(s,1H),3.91-3.81(m,2H),3.35-3.30(m,2H),3.16(t,J＝8.7Hz ,1H),2.91-2.82(m,2H),2.80-2.74(m,1H),2.39-2.30(m,2H),2.26-2.16(m,1H),2.12-2.03(m,6H),1.80 (d,J＝11.4Hz,2H),1.68-1.59(m,6H),1.52-1.36(m,2H).
实施例87Example 87
化合物69：(S)-2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-1H-吲唑-5-基)烟酰胺Compound 69: (S)-2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1-(1-(tetrahydro-2H-pyran-4-yl) )pyrrolidin-3-yl)-1H-indazol-5-yl)nicotinamide
参照实施例86的方法，以5-溴-1H-吲唑和(R)-3-羟基吡咯烷-1-羧酸叔丁酯为原料，经类似的步骤得到标题化合物(126.2mg,白色固体)。MS(ESI):m/z 531.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝2.4Hz,1H),8.10(s,1H),8.05(d,J＝2.4Hz,1H),7.99(d,J＝0.7Hz,1H),7.91(d,J＝8.8Hz,1H),7.80(s,1H),7.71(dd,J＝8.8,1.6Hz,1H),6.88(s,2H),5.46-5.33(m,1H),4.31(s,1H),3.89-3.82(m,2H),3.35-3.30(m,2H),3.16(t,J＝8.8Hz,1H),2.91-2.82(m,2H),2.80-2.74(m,1H),2.45-2.30(m,2H),2.27-2.18(m,1H),2.08-2.04(m,6H),1.81(d,J＝11.7Hz,2H),1.65-1.61(m,6H),1.50-1.38(m,2H).Referring to the method of Example 86, using 5-bromo-1H-indazole and (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as raw materials, the title compound (126.2 mg, white solid ). MS (ESI): m/z 531.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.40 (d, J = 2.4Hz, 1H), 8.10 (s, 1H), 8.05 ( d,J＝2.4Hz,1H),7.99(d,J＝0.7Hz,1H),7.91(d,J＝8.8Hz,1H),7.80(s,1H),7.71(dd,J＝8.8,1.6 Hz,1H),6.88(s,2H),5.46-5.33(m,1H),4.31(s,1H),3.89-3.82(m,2H),3.35-3.30(m,2H),3.16(t, J＝8.8Hz,1H),2.91-2.82(m,2H),2.80-2.74(m,1H),2.45-2.30(m,2H),2.27-2.18(m,1H),2.08-2.04(m, 6H),1.81(d,J＝11.7Hz,2H),1.65-1.61(m,6H),1.50-1.38(m,2H).
实施例88Example 88
化合物70：(R)-2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酰胺Compound 70: (R)-2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-(tetrahydro-2H-pyran-4-yl) )pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinamide
(1)(R)-3-(5-溴-2H-吲唑-2-基)吡咯烷-1-羧酸叔丁酯(1)(R)-3-(5-Bromo-2H-indazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
将5-溴-2-硝基苯甲醛(10.0g,43.48mmol)溶于异丙醇(100mL)中，加入(R)-3-氨基吡咯烷-1-羧酸叔丁酯(8.90g,47.83mmol)和三丁基膦(26.3g,130.44mmol)，混合物在氮气氛围下加热至80℃搅拌15小时。反应液冷却至室温，加水淬灭，水相用乙酸乙酯萃取。有机相合并，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物经柱层析(石油醚/乙酸乙酯＝5/1)纯化得到标题化合物(9.7g,白色固体)，收率：61.0％。MS(ESI):m/z 366.2[M+H]+.Dissolve 5-bromo-2-nitrobenzaldehyde (10.0g, 43.48mmol) in isopropanol (100mL), add (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (8.90g, 47.83mmol) and tributylphosphine (26.3g, 130.44mmol), the mixture was heated to 80°C under nitrogen atmosphere and stirred for 15 hours. The reaction solution was cooled to room temperature, quenched by adding water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain the title compound (9.7 g, white solid), yield: 61.0%. MS(ESI):m/z 366.2[M+H] + .
(2)(R)-5-溴-2-(吡咯烷-3-基)-2H-吲唑(2)(R)-5-bromo-2-(pyrrolidin-3-yl)-2H-indazole
参照实施例44步骤(1)的方法，以(R)-3-(5-溴-2H-吲唑-2-基)吡咯烷-1-羧酸叔丁酯为原料，得到标题化合物(7.1g,白色固体)。MS(ESI):m/z 266.2[M+H]+. Referring to the method of step (1) in Example 44, using (R)-3-(5-bromo-2H-indazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester as raw material, the title compound (7.1 g, white solid). MS(ESI):m/z 266.2[M+H] + .
(3)(R)-5-溴-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑(3)(R)-5-bromo-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazole
参照实施例44步骤(2)的方法，以(R)-5-溴-2-(吡咯烷-3-基)-2H-吲唑为原料，得到标题化合物(2.1g,白色固体)。MS(ESI):m/z 350.2[M+H]+.Referring to the method of step (2) in Example 44, using (R)-5-bromo-2-(pyrrolidin-3-yl)-2H-indazole as raw material, the title compound (2.1 g, white solid) was obtained. MS(ESI):m/z 350.2[M+H] + .
(4)(R)-2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸甲酯(4)(R)-2-amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazol-5-yl) smoke acid methyl ester
参照实施例44步骤(3)的方法，以(R)-5-溴-2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑和2-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)烟酸甲酯为原料，得到标题化合物(280mg,白色固体)。MS(ESI):m/z 422.2[M+H]+.Referring to the method of step (3) of Example 44, use (R)-5-bromo-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazole and 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinic acid methyl ester as raw materials to obtain the title compound ( 280mg, white solid). MS(ESI):m/z 422.2[M+H] + .
(5)(R)-2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸(5)(R)-2-amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazol-5-yl) smoke acid
参照实施例44步骤(4)的方法，以(R)-2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸甲酯为原料，得到标题化合物(200mg,白色固体)。MS(ESI):m/z 408.2[M+H]+.Referring to the method of step (4) of Example 44, use (R)-2-amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H -Indazol-5-yl)nicotinic acid methyl ester was used as raw material to obtain the title compound (200 mg, white solid). MS(ESI):m/z 408.2[M+H] + .
(6)(R)-2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酰胺(6)(R)-2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-(tetrahydro-2H-pyran-4-yl) )pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinamide
参照实施例44步骤(5)的方法，以(R)-2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸和4-氨基双环[2.2.2]辛-1-醇盐酸盐为原料，得到标题化合物(198.9mg,白色固体)。MS(ESI):m/z531.4[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.39(d,J＝2.4Hz,1H),8.03(d,J＝2.4Hz,1H),7.92(s,1H),7.82(s,1H),7.70-7.66(m,1H),7.57(dd,J＝9.0,1.7Hz,1H),6.87(s,2H),5.27-5.17(m,1H),4.31(s,1H),3.92-3.81(m,2H),3.35-3.30(m,2H),3.15-3.06(m,1H),3.02-2.89(m,2H),2.71-2.65(m,1H),2.48-2.41(m,1H),2.37-2.30(m,1H),2.28-2.18(m,1H),2.09-2.03(m,6H),1.82(d,J＝11.8Hz,2H),1.66-1.60(m,6H),1.50-1.36(m,2H).Referring to the method of step (5) of Example 44, use (R)-2-amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H -Indazol-5-yl)nicotinic acid and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride were used as raw materials to obtain the title compound (198.9 mg, white solid). MS (ESI): m/z531.4[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.47 (s, 1H), 8.39 (d, J = 2.4Hz, 1H), 8.03 (d,J＝2.4Hz,1H),7.92(s,1H),7.82(s,1H),7.70-7.66(m,1H),7.57(dd,J＝9.0,1.7Hz,1H),6.87( s,2H),5.27-5.17(m,1H),4.31(s,1H),3.92-3.81(m,2H),3.35-3.30(m,2H),3.15-3.06(m,1H),3.02- 2.89(m,2H),2.71-2.65(m,1H),2.48-2.41(m,1H),2.37-2.30(m,1H),2.28-2.18(m,1H),2.09-2.03(m,6H ),1.82(d,J＝11.8Hz,2H),1.66-1.60(m,6H),1.50-1.36(m,2H).
实施例89Example 89
化合物71：(S)-2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酰胺Compound 71: (S)-2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-(tetrahydro-2H-pyran-4-yl) )pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinamide
参照实施例88的方法，以5-溴-2-硝基苯甲醛和(S)-3-氨基吡咯烷-1-羧酸叔丁酯为原料，经类似的步骤得到标题化合物(195.2mg,白色固体)。MS(ESI):m/z 531.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.39(d,J＝2.2Hz,1H),8.03(d,J＝2.1Hz,1H),7.92(s,1H),7.82(s,1H),7.70-7.66(m,1H),7.58(dd,J＝9.0,1.4Hz,1H),6.88(s,2H),5.27-5.17(m,1H),4.31(s,1H),3.90-3.83(m,2H),3.35-3.30(m,2H),3.15-3.04(m,1H),3.03-2.92(m,2H),2.73-2.65(m,1H),2.48-2.41(m,1H),2.39-2.31(m,1H),2.28-2.20(m,1H),2.09-2.03(m,6H),1.81(d,J＝11.8Hz,2H),1.66-1.60(m,6H),1.48-1.39(m,2H).Referring to the method of Example 88, using 5-bromo-2-nitrobenzaldehyde and (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester as raw materials, the title compound (195.2 mg, white solid). MS (ESI): m/z 531.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.47 (s, 1H), 8.39 (d, J = 2.2Hz, 1H), 8.03 ( d,J＝2.1Hz,1H),7.92(s,1H),7.82(s,1H),7.70-7.66(m,1H),7.58(dd,J＝9.0,1.4Hz,1H),6.88(s ,2H),5.27-5.17(m,1H),4.31(s,1H),3.90-3.83(m,2H),3.35-3.30(m,2H),3.15-3.04(m,1H),3.03-2.92 (m,2H),2.73-2.65(m,1H),2.48-2.41(m,1H),2.39-2.31(m,1H),2.28-2.20(m,1H),2.09-2.03(m,6H) ,1.81(d,J＝11.8Hz,2H),1.66-1.60(m,6H),1.48-1.39(m,2H).
实施例90Example 90
化合物72：2-氨基-N-(反式-4-羟基环己基)-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酰胺Compound 72: 2-amino-N-(trans-4-hydroxycyclohexyl)-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H -indazol-5-yl)nicotinamide
参照实施例44的方法，第(5)步以2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸和反式-4-氨基环己烷-1-醇为原料，经类似的步骤得到标题化合物(1.5mg,白色固体)。MS(ESI):m/z505.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.44-8.41(m,1H),8.34(d,J＝7.8Hz,1H),8.17(d,J＝2.2Hz,1H),7.93(s,1H),7.69(d,J＝9.0Hz,1H),7.59(d,J＝9.0Hz,1H),7.09(s,2H),5.27-5.15(m,1H),4.59(d,J＝3.7Hz,1H),3.89-3.83(m,2H),3.80-3.68(m,1H),3.42-3.40(m,1H),3.31-3.29(m,1H),3.13-3.07(m,1H),3.02-2.89(m,3H),2.70-2.68(m,1H),2.49-2.41(m,1H),2.39-2.30(m,1H),2.28-2.17(m,1H),1.91-1.78(m,6H),1.48-1.35(m,4H),1.30-1.20(m,2H).Referring to the method of Example 44, in step (5), 2-amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazole -5-yl)nicotinic acid and trans-4-aminocyclohexan-1-ol were used as raw materials, and the title compound (1.5 mg, white solid) was obtained through similar steps. MS(ESI):m/z505.3[M+H] + . 1 H NMR(400MHz, DMSO-d 6 )δ8.48(s,1H),8.44-8.41(m,1H),8.34(d, J＝7.8Hz,1H),8.17(d,J＝2.2Hz,1H),7.93(s,1H),7.69(d,J＝9.0Hz,1H),7.59(d,J＝9.0Hz,1H) ,7.09(s,2H),5.27-5.15(m,1H),4.59(d,J＝3.7Hz,1H),3.89-3.83(m,2H),3.80-3.68(m,1H),3.42-3.40 (m,1H),3.31-3.29(m,1H),3.13-3.07(m,1H),3.02-2.89(m,3H),2.70-2.68(m,1H),2.49-2.41(m,1H) ,2.39-2.30(m,1H),2.28-2.17(m,1H),1.91-1.78(m,6H),1.48-1.35(m,4H),1.30-1.20(m,2H).
实施例91Example 91
化合物74：2-氨基-N-(四氢-2H-吡喃-4-基)-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酰胺Compound 74: 2-amino-N-(tetrahydro-2H-pyran-4-yl)-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl) )-2H-indazol-5-yl)nicotinamide
参照实施例44的方法，第(5)步以2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸和四氢-2H-吡喃-4-胺为原料，经类似的步骤得到标题化合物(1.8mg,白色固体)。MS(ESI):m/z 491.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.50-8.43(m,3H),8.21(d,J＝1.8Hz,1H),7.94(s,1H),7.72-7.68(d,J＝9.2Hz,1H),7.62-7.57(d,J＝9.2Hz,1H),7.10(s,2H),5.27-5.18(m,1H),4.07-3.98(m,1H),3.93-3.83(m,4H),3.43-3.39(m,2H),3.31-3.29(m,1H),3.14-3.07(m,1H),3.02-2.86(m,3H),2.71-2.68(m,1H),2.48-2.41(m,1H),2.37-2.30(m,1H),2.28-2.19(m,1H),1.82-1.78(m,4H),1.64-1.55(m,2H),1.50-1.36(m,2H).Referring to the method of Example 44, in step (5), 2-amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazole -5-yl)nicotinic acid and tetrahydro-2H-pyran-4-amine were used as raw materials, and the title compound (1.8 mg, white solid) was obtained through similar steps. MS (ESI): m/z 491.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.50-8.43 (m, 3H), 8.21 (d, J = 1.8Hz, 1H), 7.94(s,1H),7.72-7.68(d,J＝9.2Hz,1H),7.62-7.57(d,J＝9.2Hz,1H),7.10(s,2H),5.27-5.18(m,1H) ,4.07-3.98(m,1H),3.93-3.83(m,4H),3.43-3.39(m,2H),3.31-3.29(m,1H),3.14-3.07(m,1H),3.02-2.86( m,3H),2.71-2.68(m,1H),2.48-2.41(m,1H),2.37-2.30(m,1H),2.28-2.19(m,1H),1.82-1.78(m,4H), 1.64-1.55(m,2H),1.50-1.36(m,2H).
实施例92Example 92
化合物76：2-氨基-N-((3R,6S)-6-(羟甲基)四氢-2H-吡喃-3-基)-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酰胺Compound 76: 2-amino-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5-(2-(1-(tetrahydro-2H- Pyran-4-yl)pyrrolidin-3-yl)-2H-indazol-5-yl)nicotinamide
参照实施例44的方法，第(5)步以2-氨基-5-(2-(1-(四氢-2H-吡喃-4-基)吡咯烷-3-基)-2H-吲唑-5-基)烟酸和((2S,5R)-5-氨基四氢-2H-吡喃-2-基)甲醇盐酸盐为原料，经类似的步骤得到标题化合物(20.5mg,白色固体)。MS(ESI):m/z 521.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.44(d,J＝2.3Hz,1H),8.33(d,J＝7.3Hz,1H),8.19(d,J＝2.2Hz,1H),7.93(s,1H),7.70(d,J＝9.0Hz,1H),7.63-7.56(m,1H),7.11(s,2H),5.27-5.16(m,1H),4.68-4.63(m,1H),3.97-3.81(m,5H),3.43-3.38(m,2H),3.27-3.17(m,2H),3.16-3.08(m,2H),3.02-2.92(m,2H),2.28-2.22(m,1H),2.03-1.97(m,1H),1.86-1.70(m,4H),1.68-1.39(m,4H),1.36-1.21(m,2H).Referring to the method of Example 44, in step (5), 2-amino-5-(2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2H-indazole -5-yl)nicotinic acid and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride were used as raw materials. The title compound (20.5 mg, white solid ). MS (ESI): m/z 521.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.48 (s, 1H), 8.44 (d, J = 2.3Hz, 1H), 8.33 ( d,J＝7.3Hz,1H),8.19(d,J＝2.2Hz,1H),7.93(s,1H),7.70(d,J＝9.0Hz,1H),7.63-7.56(m,1H), 7.11(s,2H),5.27-5.16(m,1H),4.68-4.63(m,1H),3.97-3.81(m,5H),3.43-3.38(m,2H),3.27-3.17(m,2H ),3.16-3.08(m,2H),3.02-2.92(m,2H),2.28-2.22(m,1H),2.03-1.97(m,1H),1.86-1.70(m,4H),1.68-1.39 (m,4H),1.36-1.21(m,2H).
实施例93 Example 93
化合物100：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-2H-吲唑-5-基)烟酰胺Compound 100: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-(tetrahydro-2H-pyran-4-yl)piperidine- 4-yl)-2H-indazol-5-yl)nicotinamide
参照实施例46的方法，第(2)步以5-溴-2-(哌啶-4-基)-2H-吲唑盐酸盐和四氢-4H-吡喃-4-酮为原料，经类似的步骤得到标题化合物(5.9mg,白色固体)。MS(ESI):m/z 545.4[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.38(d,J＝2.2Hz,1H),8.03(d,J＝2.1Hz,1H),7.90(s,1H),7.82(s,1H),7.67(d,J＝8.9Hz,1H),7.57(dd,J＝9.0,1.5Hz,1H),6.87(s,2H),4.53-4.41(m,1H),4.31(s,1H),3.91(dd,J＝10.5,3.3Hz,2H),3.31-3.26(m,2H),3.05(d,J＝11.5Hz,2H),2.69-2.67(m,1H),2.36-2.30(m,2H),2.17-2.08(m,4H),2.08-2.02(m,6H),1.72(d,J＝12.3Hz,2H),1.67-1.59(m,6H),1.55-1.40(m,2H).Referring to the method of Example 46, step (2) uses 5-bromo-2-(piperidin-4-yl)-2H-indazole hydrochloride and tetrahydro-4H-pyran-4-one as raw materials, A similar procedure gave the title compound (5.9 mg, white solid). MS (ESI): m/z 545.4[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.45 (s, 1H), 8.38 (d, J = 2.2Hz, 1H), 8.03 ( d,J＝2.1Hz,1H),7.90(s,1H),7.82(s,1H),7.67(d,J＝8.9Hz,1H),7.57(dd,J＝9.0,1.5Hz,1H), 6.87(s,2H),4.53-4.41(m,1H),4.31(s,1H),3.91(dd,J＝10.5,3.3Hz,2H),3.31-3.26(m,2H),3.05(d, J＝11.5Hz,2H),2.69-2.67(m,1H),2.36-2.30(m,2H),2.17-2.08(m,4H),2.08-2.02(m,6H),1.72(d,J＝ 12.3Hz,2H),1.67-1.59(m,6H),1.55-1.40(m,2H).
实施例94Example 94
化合物146：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉-7-基)烟酰胺Compound 146: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(tetrahydro-2H-pyran-4-yl)-1,2,3 ,4-tetrahydroisoquinolin-7-yl)nicotinamide
(1)7-溴-2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉(1)7-Bromo-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinoline
将7-溴-1,2,3,4-四氢异喹啉盐酸盐(1.0g,4.04mmol)，4-溴四氢-2H-吡喃(800mg,4.85mmol)和碳酸钾(2.79g,20.20mmol)溶于乙腈(20mL)中，混合物在氮气保护下加热至80℃搅拌反应16小时。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝20/1)纯化得到标题化合物(127mg,黄色油状物)，收率：10.1％。MS(ESI):m/z 296.0[M+H]+.7-Bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.0g, 4.04mmol), 4-bromotetrahydro-2H-pyran (800mg, 4.85mmol) and potassium carbonate (2.79 g, 20.20 mmol) was dissolved in acetonitrile (20 mL), and the mixture was heated to 80°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=20/1) to obtain the title compound (127 mg, yellow oil), yield: 10.1%. MS(ESI):m/z 296.0[M+H] + .
(2)2-(四氢-2H-吡喃-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2,3,4-四氢异喹啉(2)2-(Tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1,2,3,4-tetrahydroisoquinoline
将7-溴-2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉(80mg,0.27mmol)溶于1,4-二氧六环(10mL)中，加入联硼酸频那醇酯(76mg,0.30mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(100mg,0.14mmol)和乙酸钾(53mg,0.54mmol)。混合物在氮气保护下加热至90℃搅拌反应3小时。反应液直接用于下一步。MS(ESI):m/z 344.2[M+H]+.Dissolve 7-bromo-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinoline (80 mg, 0.27 mmol) in 1,4-dioxane (10 mL), add pinacol diborate (76 mg, 0.30 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (100 mg, 0.14 mmol) and potassium acetate ( 53 mg, 0.54 mmol). The mixture was heated to 90°C under nitrogen protection and stirred for 3 hours. The reaction solution was used directly in the next step. MS(ESI):m/z 344.2[M+H] + .
(3)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(四氢-2H-吡喃-4-基)-1,2,3,4-四氢异喹啉-7-基)烟酰胺(3)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(tetrahydro-2H-pyran-4-yl)-1,2,3 ,4-tetrahydroisoquinolin-7-yl)nicotinamide
将中间体5(149mg,0.44mmol)加入到第(2)步的反应液中，再加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(295mg,0.20mmol)，碳酸钾(165mg,1.20mmol)和纯水(1mL)。混合物在氮气保护下加热至100℃搅拌反应过夜。反应液经Pre-HPLC纯化得到标题化合物(14.8mg,白色固体)，收率：7.8％。MS(ESI):m/z477.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝2.4Hz,1H),7.96(d,J＝2.0Hz,1H),7.76(s,1H),7.40(d,J＝8.0Hz,1H),7.33(s,1H),7.14(d,J＝8.0Hz,1H),6.87(s,2H),4.29(s,1H),3.93(dd,J＝11.2,8.0Hz,2H),3.75(s,2H),3.39-3.36(m,2H),2.80-2.77(m,4H),2.64-2.57(m,1H),2.07-2.03(m,6H),1.81-1.78(m,2H),1.64-1.60(m,6H),1.57-1.48(m,2H).Add intermediate 5 (149 mg, 0.44 mmol) to the reaction solution in step (2), and then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (295 mg, 0.20 mmol) ), potassium carbonate (165 mg, 1.20 mmol) and pure water (1 mL). The mixture was heated to 100°C under nitrogen protection and stirred overnight. The reaction solution was purified by Pre-HPLC to obtain the title compound (14.8 mg, white solid), yield: 7.8%. MS (ESI): m/z477.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.32 (d, J = 2.4Hz, 1H), 7.96 (d, J = 2.0Hz ,1H),7.76(s,1H),7.40(d,J＝8.0Hz,1H),7.33(s,1H),7.14(d,J＝8.0Hz,1H),6.87(s,2H),4.29 (s,1H),3.93(dd,J＝11.2,8.0Hz,2H),3.75(s,2H),3.39-3.36(m,2H),2.80-2.77(m,4H),2.64-2.57(m ,1H),2.07-2.03(m,6H),1.81-1.78(m,2H),1.64-1.60(m,6H),1.57-1.48(m,2H).
实施例95Example 95
化合物150：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-异丙基哌啶-4-基)-2H-吲唑-5-基)烟酰胺Compound 150: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-isopropylpiperidin-4-yl)-2H-indazole- 5-yl)nicotinamide
(1)5-溴-2-(1-异丙基哌啶-4-基)-2H-吲唑(1)5-Bromo-2-(1-isopropylpiperidin-4-yl)-2H-indazole
将5-溴-2-(哌啶-4-基)-2H吲唑盐酸盐(220mg,0.79mmol,实施例46第1步)，2-溴丙烷(116mg,0.94mmol)和碳酸钾(543mg,3.93mmol)溶于乙腈(20mL)中，混合物在氮气保护下加热至80℃搅拌反应12小时。反应液减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝10/1)纯化得到标题化合物(80mg,白色固体)，收率：31.6％。MS(ESI):m/z 322.1[M+H]+.5-bromo-2-(piperidin-4-yl)-2H indazole hydrochloride (220 mg, 0.79 mmol, step 1 of Example 46), 2-bromopropane (116 mg, 0.94 mmol) and potassium carbonate ( 543 mg, 3.93 mmol) was dissolved in acetonitrile (20 mL), and the mixture was heated to 80°C under nitrogen protection and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=10/1) to obtain the title compound (80 mg, white solid), yield: 31.6%. MS(ESI):m/z 322.1[M+H] + .
(2)2-(1-异丙基哌啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2H-吲唑(2)2-(1-isopropylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -base)-2H-indazole
将5-溴-2-(1-异丙基哌啶-4-基)-2H-吲唑(80mg,0.25mmol)溶于1,4-二氧六环(10mL)中，加入联硼酸频那醇酯(69mg,0.27mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(92mg,0.12mmol)和乙酸钾(49mg,0.50mmol)。混合物在氮气保护下加热至90℃搅拌反应3小时。反应液直接用于下一步。MS(ESI):m/z 370.2[M+H]+.Dissolve 5-bromo-2-(1-isopropylpiperidin-4-yl)-2H-indazole (80 mg, 0.25 mmol) in 1,4-dioxane (10 mL), and add diboronic acid That ester (69 mg, 0.27 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (92 mg, 0.12 mmol) and potassium acetate (49 mg, 0.50 mmol). The mixture was heated to 90°C under nitrogen protection and stirred for 3 hours. The reaction solution was used directly in the next step. MS(ESI):m/z 370.2[M+H] + .
(3)2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-异丙基哌啶-4-基)-2H-吲唑-5-基)烟酰胺(3)2-Amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-isopropylpiperidin-4-yl)-2H-indazole- 5-yl)nicotinamide
将中间体5(91mg,0.27mmol)加入到第(2)步反应液中，再加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(90mg,1.22mmol)，碳酸钾(68mg,0.49mmol)和纯水(1mL)，混合物在氮气保护下加热至100℃搅拌反应过夜。反应液经Pre-HPLC纯化得到标题化合物(4.0mg,白色固体)，收率：3.3％。MS(ESI):m/z 503.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.37(d,J＝2.4Hz,1H),8.02(d,J＝2.4Hz,1H),7.90(s,1H),7.81(s,1H),7.68-7.66(m,1H),7.58-7.56(m,1H),6.86(s,2H),4.46(s,1H),4.29(s,1H),2.98-2.94(m,2H),2.78-2.75(m,1H),2.12-1.94(m,12H),1.64-1.60(m,6H),1.06-1.03(m,6H).Add intermediate 5 (91 mg, 0.27 mmol) to the reaction solution in step (2), and then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (90 mg, 1.22 mmol) , potassium carbonate (68 mg, 0.49 mmol) and pure water (1 mL), the mixture was heated to 100°C under nitrogen protection and stirred for overnight. The reaction solution was purified by Pre-HPLC to obtain the title compound (4.0 mg, white solid), yield: 3.3%. MS (ESI): m/z 503.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.44 (s, 1H), 8.37 (d, J = 2.4Hz, 1H), 8.02 ( d,J＝2.4Hz,1H),7.90(s,1H),7.81(s,1H),7.68-7.66(m,1H),7.58-7.56(m,1H),6.86(s,2H),4.46 (s,1H),4.29(s,1H),2.98-2.94(m,2H),2.78-2.75(m,1H),2.12-1.94(m,12H),1.64-1.60(m,6H),1.06 -1.03(m,6H).
实施例96Example 96
化合物151：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(2-(1-甲基哌啶-4-基)-2H-吲唑-5-基)烟酰胺Compound 151: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(2-(1-methylpiperidin-4-yl)-2H-indazole-5 -Nicotinamide
参照实施例95的方法，以5-溴-2-(哌啶-4-基)-2H吲唑盐酸盐(实施例46第1步)和碘甲烷为原料，经类似的步骤得到标题化合物(5.0mg,白色固体)。MS(ESI):m/z 475.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.41(d,J＝2.8Hz,1H),8.05(d,J＝3.2Hz,1H),7.92(s,1H),7.84(s,1H),7.71(d,J＝12.0Hz,1H),7.61-7.57(m,1H),6.89(s,2H),4.50-4.45(m,1H),4.33(s,1H),2.94-2.89(m,2H),2.26(s,3H),2.15-2.05(m,12H),1.67-1.62(m,6H).Referring to the method of Example 95, using 5-bromo-2-(piperidin-4-yl)-2H indazole hydrochloride (Step 1 of Example 46) and methyl iodide as raw materials, the title compound was obtained through similar steps. (5.0mg, white solid). MS (ESI): m/z 475.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.47 (s, 1H), 8.41 (d, J = 2.8Hz, 1H), 8.05 ( d,J＝3.2Hz,1H),7.92(s,1H),7.84(s,1H),7.71(d,J＝12.0Hz,1H),7.61-7.57(m,1H),6.89(s,2H ),4.50-4.45(m,1H),4.33(s,1H),2.94-2.89(m,2H),2.26(s,3H),2.15-2.05(m,12H),1.67-1.62(m,6H ).
实施例97Example 97
化合物147：2-氨基-N-(4-羟基双环[2.2.2]辛-1-基)-5-(1'-(氧杂环-3-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)烟酰胺Compound 147: 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(1'-(oxaheterocyclyl-3-yl)-2,3-dihydrospiro[ Inden-1,3'-pyrrolidin]-5-yl)nicotinamide
参照实施例67步骤(5)至步骤(8)的方法，第(5)步用3-氧杂环丁酮替代四氢-4H-吡喃-4-酮，第(8)步用 4-氨基双环[2.2.2]辛烷-1-醇替代四氢-2H-吡喃-4-胺，经类似的步骤得到标题化合物(2.2mg,白色固体)。MS(ESI):m/z 489.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.30(d,J＝2.0Hz,1H),7.96(d,J＝2.4Hz,1H),7.74(s,1H),7.44-7.42(m,2H),7.33(d,J＝7.6Hz,1H),6.87(s,2H),4.59-4.56(m,2H),4.51-4.47(m,2H),4.29(s,1H),3.66-3.63(m,1H),2.90-2.86(m,2H),2.72-2.63(m,3H),2.16-2.13(m,1H),2.05-1.94(m,10H),1.63-1.57(m,6H).Referring to the method from step (5) to step (8) in Example 67, use 3-oxetanone instead of tetrahydro-4H-pyran-4-one in step (5), and use 3-oxetanone in step (8). 4-Aminobicyclo[2.2.2]octane-1-ol was substituted for tetrahydro-2H-pyran-4-amine, and the title compound (2.2 mg, white solid) was obtained through a similar procedure. MS (ESI): m/z 489.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.30 (d, J = 2.0Hz, 1H), 7.96 (d, J = 2.4Hz, 1H),7.74(s,1H),7.44-7.42(m,2H),7.33(d,J＝7.6Hz,1H),6.87(s,2H),4.59-4.56(m,2H),4.51-4.47 (m,2H),4.29(s,1H),3.66-3.63(m,1H),2.90-2.86(m,2H),2.72-2.63(m,3H),2.16-2.13(m,1H),2.05 -1.94(m,10H),1.63-1.57(m,6H).
测试例1：激酶活性测试Test example 1: Kinase activity test
1.ALK2ADP-Glo测试方法1.ALK2ADP-Glo test method
化合物最终起始浓度为10uM，3倍梯度稀释共10个浓度。将化合物50倍稀释到1X激酶反应缓冲液中，在振荡器上震荡20分钟。用1X的酶反应缓冲液配制准备2X激酶。向反应板中每孔加入2μL激酶(Carna公司，货号09-134)。向每孔加入1μL在缓冲液中稀释好的化合物，用封板膜封住板子1000g离心30秒，25℃孵育10分钟。用1X的酶反应缓冲液配制4x ATP&Casein(Signalchem公司，货号C03-54BN-1MG)混合液，向反应板中加入1μL 4x ATP&Casein混合液。用封板膜封住板子1000g离心30秒，25℃孵育60分钟。转移4μL ADP-Glo(试剂盒来自Promega公司，货号V9102)到384反应板中1000rpm/min,离心1min，25℃孵育40min。转移8μL Detection溶液到384反应板中1000rpm/min,离心1min，25℃孵育40min。使用BGM酶标仪读取RLU信号。用Graphpad7.0软件进行数据分析并计算IC50。The final starting concentration of the compound was 10uM, and it was diluted 3-fold to a total of 10 concentrations. Dilute the compound 50-fold into 1X kinase reaction buffer and shake on a shaker for 20 minutes. Prepare 2X kinase using 1X enzyme reaction buffer. Add 2 μL of kinase (Carna, Cat. No. 09-134) to each well of the reaction plate. Add 1 μL of compound diluted in buffer to each well, seal the plate with sealing film, centrifuge at 1000 g for 30 seconds, and incubate at 25°C for 10 minutes. Use 1X enzyme reaction buffer to prepare 4x ATP&Casein (Signalchem Company, Cat. No. C03-54BN-1MG) mixture, and add 1 μL of 4x ATP&Casein mixture to the reaction plate. Seal the plate with sealing film, centrifuge at 1000g for 30 seconds, and incubate at 25°C for 60 minutes. Transfer 4 μL ADP-Glo (kit from Promega, Cat. No. V9102) to the 384 reaction plate at 1000 rpm/min, centrifuge for 1 min, and incubate at 25°C for 40 min. Transfer 8 μL of Detection solution to the 384 reaction plate at 1000 rpm/min, centrifuge for 1 min, and incubate at 25°C for 40 min. Read the RLU signal using a BGM microplate reader. Use Graphpad7.0 software for data analysis and calculation of IC 50 .
2.ALK5ADP-Glo测试方法2.ALK5ADP-Glo test method
化合物最终起始浓度为10uM，3倍梯度稀释共10个浓度。将化合物50倍稀释到1X激酶反应缓冲液中，在振荡器上震荡20分钟。用1X的酶反应缓冲液配制准备2X激酶。向反应板中每孔加入2μL激酶(ThermoFisher公司，货号1795372T)。向每孔加入1μL在缓冲液中稀释好的化合物，用封板膜封住板子1000g离心30秒，25℃孵育10分钟。用1X的酶反应缓冲液配制4x ATP混合液，向反应板中加入1μL 4x ATP混合液。用封板膜封住板子1000g离心30秒，25℃孵育180分钟。转移4μL ADP-Glo(试剂盒来自Promega公司，货号V9101)到384反应板中1000rpm/min,离心1min，25℃孵育40min。转移8μL Detection溶液到384反应板中1000rpm/min,离心1min，25℃孵育40min。使用BGM酶标仪读取RLU信号。用Graphpad7.0软件进行数据分析并计算IC50。The final starting concentration of the compound was 10uM, and it was diluted 3-fold to a total of 10 concentrations. Dilute the compound 50-fold into 1X kinase reaction buffer and shake on a shaker for 20 minutes. Prepare 2X kinase using 1X enzyme reaction buffer. Add 2 μL of kinase (ThermoFisher, Cat. No. 1795372T) to each well of the reaction plate. Add 1 μL of compound diluted in buffer to each well, seal the plate with sealing film, centrifuge at 1000 g for 30 seconds, and incubate at 25°C for 10 minutes. Prepare 4x ATP mixture with 1X enzyme reaction buffer, and add 1 μL of 4x ATP mixture to the reaction plate. Seal the plate with sealing film, centrifuge at 1000g for 30 seconds, and incubate at 25°C for 180 minutes. Transfer 4 μL ADP-Glo (kit from Promega, Cat. No. V9101) to the 384 reaction plate at 1000 rpm/min, centrifuge for 1 min, and incubate at 25°C for 40 min. Transfer 8 μL of Detection solution to the 384 reaction plate at 1000 rpm/min, centrifuge for 1 min, and incubate at 25°C for 40 min. Read the RLU signal using a BGM microplate reader. Use Graphpad7.0 software for data analysis and calculation of IC 50 .
采用分析软件XLfit5.5.5拟合量效曲线，得出各个化合物对酶活性的IC50值。The analysis software XLfit5.5.5 was used to fit the dose-effect curve and the IC50 value of each compound on the enzyme activity was obtained.
其中阳性化合物INCB-00928根据专利WO2018014829的实施例34制备。The positive compound INCB-00928 was prepared according to Example 34 of patent WO2018014829.
各化合物结果如表1所示，其中A表示＜5nM，B表示5-20nM，C表示20-100nM，D表示100-500nM，E表示500-1000nM，F表示＞1000nM。The results of each compound are shown in Table 1, where A represents <5nM, B represents 5-20nM, C represents 20-100nM, D represents 100-500nM, E represents 500-1000nM, and F represents >1000nM.
表1(红色标记为新添加的化合物激酶数据)

Table 1 (Red marks are newly added compound kinase data)

测试例2：细胞测试方法Test Example 2: Cell Test Method
采用qPCR方法测试化合物对HepG2细胞Hepcidin基因mRNA表达水平的抑制活性。将3.5x 105个HepG2细胞接种于12孔板中。贴壁培养24小时。不同浓度的化合物加入到12孔板中，化合物最大终浓度为10μM，2倍稀释，10个浓度点。将化合物孵育2小时，然后加入BMP6(来自R&D公司，货号507-BP-020)，BMP6终浓度为10ng/mL。细胞在化合物和BMP6存在下孵育6小时。弃除12孔板中培养基，用预冷的PBS洗涤孔后用胰蛋白酶消化细胞后，在4℃，1200rpm条件下离心5分钟收集细胞样品。得到的细胞样品提取RNA，用q-PCR方法进行测试，检测基因Hepcidin[HAMP](引物来自General Biosystems公司)的mRNA表达情况，并以GUSB为内参基因。利用Graph Pad软件对数据结果进行分析，并计算IC50。各化合物结果如表2所示，其中+++表示＜100nM，++表示100-1000nM，+表示＞1000nM。The qPCR method was used to test the inhibitory activity of the compound on the Hepcidin gene mRNA expression level in HepG2 cells. Seed 3.5x10 HepG2 cells in a 12-well plate. Adhere to culture for 24 hours. Compounds of different concentrations were added to the 12-well plate. The maximum final concentration of the compound was 10 μM, 2-fold dilution, and 10 concentration points. The compounds were incubated for 2 hours, then BMP6 (from R&D, Cat. No. 507-BP-020) was added to a final concentration of 10 ng/mL. Cells were incubated in the presence of compound and BMP6 for 6 hours. Discard the culture medium in the 12-well plate, wash the wells with pre-cooled PBS, digest the cells with trypsin, and centrifuge at 4°C, 1200 rpm for 5 minutes to collect cell samples. RNA was extracted from the obtained cell samples and tested using the q-PCR method to detect the mRNA expression of the gene Hepcidin [HAMP] (primers from General Biosystems), and GUSB was used as the internal reference gene. Use Graph Pad software to analyze the data results and calculate IC 50 . The results of each compound are shown in Table 2, where +++ means <100nM, ++ means 100-1000nM, and + means >1000nM.
表2
Table 2

Claims (24)

  1. 一种具有通式(I)所示结构的化合物、其氘代物、立体异构体或药学上可接受的盐：
    A compound having a structure represented by general formula (I), its deuterated product, stereoisomer or pharmaceutically acceptable salt:
    其中，in,
    环A为5-10元杂芳基，任选地被1-3个R3取代；Ring A is a 5-10 membered heteroaryl group, optionally substituted by 1-3 R 3 ;
    环B为6-15元环基，且任选1-3个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is a 6-15 membered ring group, and optionally 1-3 link carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
    L1选自化学键、C1-6烷基、亚氨基、羰基、-CO-NH-、苯基、5-6元杂芳基、-苯基-CO-NH-；L 1 is selected from chemical bond, C 1-6 alkyl, imino, carbonyl, -CO-NH-, phenyl, 5-6 membered heteroaryl, -phenyl-CO-NH-;
    L2选自化学键、-(CRaRb)n-、亚氨基、醚键、-C1-6烷基-O-；L 2 is selected from chemical bond, -(CR a R b ) n -, imino group, ether bond, -C 1-6 alkyl-O-;
    R1选自C1-6烷基、5-10元环烷基、5-10元杂环烷基，且任选地被1-3个R5取代；R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
    R2选自H、卤素、羟基、氰基、氨基，或R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
    R2选自4-10元杂环烷基或环烷基，且任选地被1-3个R6取代；R 2 is selected from 4-10 membered heterocycloalkyl or cycloalkyl, and is optionally substituted by 1-3 R 6 ;
    R3选自卤素、羟基、硝基、氰基、氨基、C1-6烷基；R 3 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl;
    R4选自卤素、羟基、硝基、氰基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基；R 4 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl;
    R5选自卤素、羟基、硝基、氰基、氨基、-CO-NRcRd、C1-6烷基、C1-6烷氧基、-(CRaRb)n-OH；R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, -CO-NR c R d , C 1-6 alkyl, C 1-6 alkoxy, -(CR a R b ) n -OH;
    R6选自卤素、羟基、氰基、-CO-Rc、-CO-NRcRd、-SO2-Rc，或R 6 is selected from halogen, hydroxyl, cyano, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
    R6选自C1-6烷基、C1-6烷氧基、4-8元环烷基、4-8元杂环烷基，且任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, C 1-6 alkoxy, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
    Ra、Rb独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基，或R a , R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl, or
    Ra、Rb与所连的碳原子形成3-6元环烷基；R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group;
    Rc、Rd独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基；R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
    Re选自卤素、羟基、硝基、氰基、氨基、C1-6烷氧基；R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
    n选自1-3的整数。n is selected from an integer from 1 to 3.
  2. 根据权利要求1所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于，具有式(II)所示结构：
    The compound according to claim 1, its deuterated product, stereoisomer or pharmaceutically acceptable salt, is characterized in that it has a structure represented by formula (II):
    X1、X2独立地选自CH或N；X 1 and X 2 are independently selected from CH or N;
    R1选自5-10元环烷基、5-10元杂环烷基，任选地被1-3个R5取代；R 1 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, optionally substituted by 1-3 R 5 ;
    R5选自卤素、羟基、硝基、氰基、氨基、C1-6烷基、-(CRaRb)n-OH；R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH;
    环B为Y1、Y2、Y3独立地选自CH或N，环C为并联的5-6元环基，环C中任选1个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is Y 1 , Y 2 , Y 3 are independently selected from CH or N. Ring C is a parallel 5-6 membered ring group. Any one carbon atom in ring C is substituted by oxygen; ring B is optionally substituted by 1- 3 R 4 substitutions;
    R4选自卤素、C1-3烷基、卤代C1-3烷基；R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
    R2为4-8元杂环烷基，含有1-3个选自N、O、S的杂原子，且任选地被1-3个R6取代；R 2 is a 4-8 membered heterocycloalkyl group, containing 1-3 heteroatoms selected from N, O, S, and optionally substituted by 1-3 R 6 ;
    R6选自-CO-Rc、-SO2-Rc，或R 6 is selected from -CO-R c , -SO 2 -R c , or
    R6选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
    Ra、Rb独立地选自H、卤素、羟基、硝基、氰基、氨基或C1-6烷基；R a and R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
    Rc独立地选自H、羟基、氨基或C1-6烷基；R c is independently selected from H, hydroxyl, amino or C 1-6 alkyl;
    Re选自卤素、羟基、硝基、氰基、氨基、C1-6烷氧基；R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
    n选自1-3的整数。n is selected from an integer from 1 to 3.
  3. 根据权利要求2所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 2, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    R1选自 R 1 is selected from
    R5选自羟基、卤素、C1-6烷基、-(CRaRb)n-OH；R 5 is selected from hydroxyl, halogen, C 1-6 alkyl, -(CR a R b ) n -OH;
    Ra、Rb独立地选自H、C1-3烷基；R a and R b are independently selected from H and C 1-3 alkyl;
    n选自1-3的整数。n is selected from an integer from 1 to 3.
  4. 根据权利要求3所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于： The compound according to claim 3, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    R1选自 R 1 is selected from
    R5选自羟基、卤素、C1-3烷基、-CH2OH、-C(CH3)2OH。R 5 is selected from hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH.
  5. 根据权利要求4所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于，具有式(II-1)所示结构：
    The compound according to claim 4, its deuterated product, stereoisomer or pharmaceutically acceptable salt, is characterized in that it has a structure represented by formula (II-1):
    环B为Y1、Y2、Y3独立地选自CH或N，环C为并联的5-6元环基，环C中任选1个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is Y 1 , Y 2 , Y 3 are independently selected from CH or N. Ring C is a parallel 5-6 membered ring group. Any one carbon atom in ring C is substituted by oxygen; ring B is optionally substituted by 1- 3 R 4 substitutions;
    R4选自卤素、C1-3烷基、卤代C1-3烷基；R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
    R2为5-7元杂环烷基，含有1-3个选自N、O、S的杂原子，且任选地被1-3个R6取代；R 2 is a 5-7 membered heterocycloalkyl group, containing 1-3 heteroatoms selected from N, O, S, and optionally substituted by 1-3 R 6 ;
    R6选自-CO-Rc、-SO2-Rc，或R 6 is selected from -CO-R c , -SO 2 -R c , or
    R6选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，任选地被1-3个Re取代；R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
    Rc独立地选自H、羟基、氨基或C1-6烷基；R c is independently selected from H, hydroxyl, amino or C 1-6 alkyl;
    Re选自卤素、羟基、硝基、氰基、氨基、C1-6烷氧基。R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy.
  6. 根据权利要求5所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 5, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B选自 Ring B is selected from
  7. 根据权利要求5所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 5, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B为环C为并联的5元碳环基或杂环基，环C中任选1个环节碳原子被氧取代；环B任选地被1-3个R4取代；Ring B is Ring C is a parallel 5-membered carbocyclyl or heterocyclyl, and any one carbon atom in Ring C is substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
    R4选自卤素、C1-3烷基、卤代C1-3烷基。R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  8. 根据权利要求7所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 7, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B选自 Ring B is selected from
    环B任选地被1-3个R4取代；Ring B is optionally substituted with 1-3 R 4 ;
    R4选自卤素、C1-3烷基、卤代C1-3烷基。R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  9. 根据权利要求8所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 8, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    R2选自优选 且任选地被1个R6取代；R 2 is selected from preferred and optionally substituted by 1 R 6 ;
    R6选自-CO-Rc、-SO2-Rc，或R 6 is selected from -CO-R c , -SO 2 -R c , or
    R6选自C1-3烷基、4-6元环烷基、4-6元杂环烷基，任选被1-3个Re取代；R 6 is selected from C 1-3 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
    Rc独立地选自H或C1-3烷基；R c is independently selected from H or C 1-3 alkyl;
    Re选自卤素、氰基、C1-3烷氧基。R e is selected from halogen, cyano, C 1-3 alkoxy.
  10. 根据权利要求9所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 9, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    R2选自优选且被1个R6取代；R 2 is selected from preferred and replaced by 1 R 6 ;
    R6为4-6元杂环烷基，含有1个O原子，优选更优选 R 6 is a 4-6 membered heterocycloalkyl group, containing 1 O atom, preferably More preferred
  11. 根据权利要求1所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于，具有式(III)所示结构：
    The compound according to claim 1, its deuterated product, stereoisomer or pharmaceutically acceptable salt, is characterized in that it has a structure represented by formula (III):
    环B为环C为并联的5-6元环基，任选地含有1-2个选自N的杂原子；环B任选地被1-2个R4取代；Ring B is Ring C is a parallel 5-6 membered ring group, optionally containing 1-2 heteroatoms selected from N; Ring B is optionally substituted by 1-2 R 4 ;
    R4选自卤素、C1-3烷基、卤代C1-3烷基； R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
    R1选自4-8元环烷基、4-8元含有2个选自N、O、S杂原子的杂环烷基，优选 更优选R1任选地被1-3个R5取代；R 1 is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 2 heteroatoms selected from N, O, and S, preferably More preferred R 1 is optionally replaced by 1-3 R 5 ;
    R5选自卤素、羟基、硝基、氰基、氨基、C1-6烷基、-(CRaRb)n-OH，优选羟基、卤素、C1-3烷基、-CH2OH、-C(CH3)2OH；R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH, preferably hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH , -C(CH 3 ) 2 OH;
    L2选自化学键、-(CRaRb)n-；L 2 is selected from chemical bonds, -(CR a R b ) n -;
    R2为5-6元含有1-2个选自N、O杂原子的杂环烷基，任选地被1-2个R6取代；R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
    R6选自卤素、羟基、氨基、氰基，或R 6 is selected from halogen, hydroxyl, amino, cyano, or
    R6选自4-7元环烷基、4-7元含有1-2个选自N、O杂原子的杂环烷基、C1-3烷基，且任选地被1-3个Re取代；R 6 is selected from 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl containing 1-2 selected from N, O heteroatoms, C 1-3 alkyl, and is optionally replaced by 1-3 Re substitution ;
    Ra、Rb独立地选自H或C1-3烷基，或Ra、Rb与所连的碳原子形成3-6元环烷基；R a and R b are independently selected from H or C 1-3 alkyl, or R a , R b and the attached carbon atom form a 3-6 membered cycloalkyl group;
    Re为卤素；R e is halogen;
    n为1-3的整数。n is an integer from 1 to 3.
  12. 根据权利要求11所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 11, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B选自 Ring B is selected from
  13. 根据权利要求12所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 12, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B选自 Ring B is selected from
    L2选自化学键、C1-3亚烷基；L 2 is selected from chemical bond, C 1-3 alkylene;
    R2为5-6元含有1-2个选自N、O杂原子的杂环烷基，任选地被1-2个R6取代； R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
    R6选自卤素，或R 6 is selected from halogen, or
    R6选自4-6元环烷基、4-6元含有1-2个选自N、O杂原子的杂环烷基、C1-3烷基，且任选地被1-3个Re取代。R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1-2 selected from N, O heteroatoms, C 1-3 alkyl, and is optionally replaced by 1-3 R e replaced.
  14. 根据权利要求1所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于，包括以下化合物：
    The compound according to claim 1, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that it includes the following compounds:
    X1、X2独立地选自CH或N；X 1 and X 2 are independently selected from CH or N;
    R1选自4-8元环烷基、4-8元含有1-2个选自N、O、S杂原子的杂环烷基，优选 更优选 任选地被1-2个R5取代；R 1 is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, preferably More preferred optionally substituted by 1-2 R5 ;
    R5选自C1-3烷基、C1-3烷氧基、-C1-3烷基-OH、卤素、OH、氨基、酰胺基、氰基；R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkyl-OH, halogen, OH, amino, amide group, and cyano group;
    环B是r、p、q为1-3的整数；Z1、Z2、Z3独立地选自CH或N，且最多一个为N；为单键或双键；当为单键时，Z4为CH2或O，Z5为CH2或NH；当为双键时，Z4为CH，Z5为CH或N；Z6为NH或O；环B中任选1个环节碳原子被氧取代；环B任选地被1-2个R4取代；Ring B is r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH, Z 5 is CH or N; Z 6 is NH or O; any one carbon atom in ring B is replaced by oxygen; ring B is optionally replaced by 1-2 R 4 replace;
    R4选自卤素、C1-3烷基、C1-3烷氧基、羟基；R 4 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, and hydroxyl;
    L2为化学键、-(CRaRb)n-；L 2 is a chemical bond, -(CR a R b ) n -;
    R2选自H、卤素、羟基、氰基、氨基，或R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
    R2选自4-6元杂环烷基或4-6元环烷基，优选4-6元含有1-2个选自N、O、S杂原子的杂 环烷基或4-6元环烷基，更优选进一步优选且任选地被1-2个R6取代；R 2 is selected from 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, preferably 4-6 membered heteroatoms containing 1-2 selected from N, O, S heteroatoms Cycloalkyl or 4-6 membered cycloalkyl, more preferably Further preferred and optionally substituted by 1-2 R 6 ;
    R6选自卤素、羟基、C1-3烷基、C1-3烷氧基、氰基；R 6 is selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, and cyano;
    Ra、Rb独立地选自H或C1-3烷基，或Ra、Rb与所连的碳原子形成3-6元环烷基；R a and R b are independently selected from H or C 1-3 alkyl, or R a , R b and the attached carbon atom form a 3-6 membered cycloalkyl group;
    n为1-3的整数。n is an integer from 1 to 3.
  15. 根据权利要求14所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 14, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B选自 Ring B is selected from
  16. 根据权利要求14所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 14, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B是r或q为1-3的整数；Z1、Z2或Z3独立地选自CH或N，且最多一个为N；为单键或双键；当为单键时Z4为CH2或O；当为双键时Z4为CH；环B任选地被1-2个R4取代；Ring B is r or q is an integer from 1 to 3; Z 1 , Z 2 or Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O; when When it is a double bond, Z 4 is CH; Ring B is optionally replaced by 1-2 R 4 ;
    R4选自卤素、C1-3烷基、C1-3烷氧基、羟基。 R 4 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, and hydroxyl.
  17. 根据权利要求16所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 16, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    X1、X2为CH；X 1 and X 2 are CH;
    环B是r为1-2的整数，为单键或双键。Ring B is r is an integer from 1 to 2, be a single bond or a double bond.
  18. 根据权利要求17所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 17, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B是优选*端与吡啶连接，**端与L2连接，r为1-2的整数，为单键或双键。Ring B is preferred The * end is connected to pyridine, the ** end is connected to L 2 , r is an integer from 1 to 2, be a single bond or a double bond.
    L2为化学键或C1-3亚烷基；L 2 is a chemical bond or C 1-3 alkylene group;
    R2选自H、卤素、羟基、氰基、氨基，或R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
    R2选自4-6元杂环烷基或4-6元环烷基，优选4-6元含有1-2个选自N、O、S杂原子的杂环烷基或4-6元环烷基，更优选进一步优选 且任选地被1-2个R6取代；R 2 is selected from 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, preferably 4-6 membered heterocycloalkyl or 4-6 membered containing 1-2 heteroatoms selected from N, O, S Cycloalkyl, more preferably Further preferred and optionally substituted by 1-2 R 6 ;
    R6选自卤素、羟基、C1-3烷基、C1-3烷氧基、氰基。R 6 is selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, and cyano.
  19. 根据权利要求17所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 17, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    R1选自优选任选地被1-2个R5取代；R 1 is selected from preferred optionally substituted by 1-2 R5 ;
    R5选自卤素、-OH、C1-3烷基、C1-3烷氧基、-C1-3烷基-OH，优选F、Cl、-OH、甲基、-CH2-OH； R 5 is selected from halogen, -OH, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkyl-OH, preferably F, Cl, -OH, methyl, -CH 2 -OH ;
    更优选R1与R5形成如下结构： More preferably, R 1 and R 5 form the following structure:
  20. 根据权利要求17或19所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于：The compound according to claim 17 or 19, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that:
    环B选自 优选 进一步优选*端与吡啶连接，**端与L2连接；Ring B is selected from preferred Further preferred The * end is connected to pyridine, and the ** end is connected to L 2 ;
    L2为化学键、C1-3亚烷基，优选化学键或异丙基；L 2 is a chemical bond, C 1-3 alkylene group, preferably a chemical bond or isopropyl group;
    R2为H或优选H或 R2 is H or Preferably H or
  21. 根据权利要求1所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于，包括以下化合物：
    The compound according to claim 1, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that it includes the following compounds:
    M选自CH或N； M is selected from CH or N;
    R6a选自C1-3烷氧基，优选甲氧基、乙氧基、丙氧基；R 6a is selected from C 1-3 alkoxy, preferably methoxy, ethoxy, propoxy;
    R6b选自C1-6烷基、4-8元环烷基、4-8元杂环烷基，优选甲基、乙基、异丙基、更优选异丙基。R 6b is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, preferably methyl, ethyl, isopropyl, Isopropyl is more preferred.
  22. 根据权利要求1所述的化合物、其氘代物、立体异构体或药学上可接受的盐，其特征在于，包括以下化合物：







    The compound according to claim 1, its deuterated product, stereoisomer or pharmaceutically acceptable salt, characterized in that it includes the following compounds:







  23. 一种药物组合物，所述药物组合物含有权利要求1-22任意一项所述的化合物、其氘代物、立体异构体或药学上可接受的盐及其药物可接受的载体。A pharmaceutical composition containing the compound according to any one of claims 1 to 22, its deuterated product, stereoisomer or pharmaceutically acceptable salt and its pharmaceutically acceptable carrier.
  24. 根据权利要求1～22任意一项所述的化合物、其氘代物、立体异构体或药学上可接受的盐或根据权利要求23所述的药物组合物制备治疗和/或预防ALK2相关的疾病的药物中的用途；优选地，所述ALK2相关的疾病包括贫血、炎症、肿瘤及部分ALK2相关的遗传病，更优选地，所述ALK2相关的疾病包括进行性骨化性纤维发育不良、弥漫内生型桥脑胶质瘤、铁难治性缺铁性贫血、炎症性贫血，骨髓增生异常综合征、多发性骨髓瘤、骨髓增生性肿瘤相关的贫血；Preparation of the compound according to any one of claims 1 to 22, its deuterated product, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 23 for the treatment and/or prevention of ALK2-related diseases Use in medicine; Preferably, the ALK2-related diseases include anemia, inflammation, tumors and some ALK2-related genetic diseases. More preferably, the ALK2-related diseases include fibrodysplasia ossificans progressiva, diffuse Endogenous pontine glioma, iron-refractory iron deficiency anemia, inflammatory anemia, anemia related to myelodysplastic syndrome, multiple myeloma, and myeloproliferative neoplasms;
    优选地，所述药物单独使用或与其他治疗剂联合使用；更优选地，所述其他治疗剂为JAK2抑制剂，用于治疗骨髓增生性肿瘤相关的贫血。 Preferably, the drug is used alone or in combination with other therapeutic agents; more preferably, the other therapeutic agents are JAK2 inhibitors for the treatment of anemia associated with myeloproliferative tumors.
PCT/CN2023/087857 2022-04-13 2023-04-12 Alk2 kinase inhibitor WO2023198114A1 (en)

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