WO2022262855A1 - 一种malt1抑制剂及其制备方法和用途 - Google Patents

一种malt1抑制剂及其制备方法和用途 Download PDF

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WO2022262855A1
WO2022262855A1 PCT/CN2022/099499 CN2022099499W WO2022262855A1 WO 2022262855 A1 WO2022262855 A1 WO 2022262855A1 CN 2022099499 W CN2022099499 W CN 2022099499W WO 2022262855 A1 WO2022262855 A1 WO 2022262855A1
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halogen
alkyl
cyano
nitro
cycloalkyl
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PCT/CN2022/099499
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English (en)
French (fr)
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李云飞
王艳辉
贾云静
刘彪
张瑱
林晓燕
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上海拓界生物医药科技有限公司
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Priority to CN202280027175.4A priority Critical patent/CN117120427A/zh
Publication of WO2022262855A1 publication Critical patent/WO2022262855A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the disclosure belongs to the field of medicine, and relates to a MALT1 inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and its use for preventing and/or treating autoimmune diseases, inflammatory diseases, cancer, and tumors.
  • Mucosa-associated-lymphoid-tissuelymphoma-translocation1 is an important protein molecule in the upstream of NF- ⁇ B signaling pathway, which is similar to B-cell chronic lymphocytic leukemia/lymphoma protein (B-cell Chronic lymphocyticleukemia/lymphoma10, BCL10) and membrane-associated guanylate kinase 1 (caspase-recruitment domain (CARD) containing membrane-associated guanylatekinase protein 1, CARMA1) with caspase recruitment structure form a complex CBM, which integrates the proximal antigen receptor protein signal Delivered to I ⁇ B kinase (IKK), which in turn activates the NF- ⁇ B signaling pathway. Excessive activation of MALT1-NF- ⁇ B signaling pathway is closely related to inflammation and tumorigenesis.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof
  • Ring A is selected from 9-15 membered heteroaryls containing 1-4 heteroatoms
  • ring A is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thio-1,2-dihydroisoquinolin-5-yl, quinolin-5-yl, iso Quinolin-5-yl, Thieno[2,3-c]pyridin-4-yl, Naphthyl,
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclyl, 3-6 membered heteroaryl; C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-
  • the 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Substituents of methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, 3-6 Heterocyclyl, 3-6 membered heteroaryl, -COR 2a , -SO 2 R 2b , -NHCOR 2c , hydroxyl; the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally selected from 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, normal Propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl, oxo substituents;
  • R 2a , R 2b , and R 2c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and hydroxyl;
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, 3-6 Heterocyclic group, 3-6 membered heteroaryl group, -COR 3a , -SO 2 R 3b , -NHCOR 3c ; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkane Oxygen, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl are optionally selected from 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl Substituents of base, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;
  • R 3a , R 3b , and R 3c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and hydroxyl;
  • R 4 and R 5 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group, methanesulfonyl group; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl Substituents of base, n-butyl, isobutyl, nitro, cyano, amino, hydroxyl;
  • the present disclosure also provides compounds represented by formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h or pharmaceutically acceptable salts thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 are as defined in formula I.
  • R is selected from hydrogen , C -6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, -COR 2a , -SO 2 R 2b , -NHCOR 2c , nitro, cyano, Halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group; said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n- But
  • R 2a , R 2b , and R 2c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and hydroxyl.
  • R is selected from hydrogen , C -6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, -COR 2a , -SO 2 R 2b , -NHCOR 2c , cyano, halogen, 3 -6-membered heterocyclic group; the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 heterocyclic group any Selected to be substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl, oxo ;
  • R 2a , R 2b , and R 2c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclic group.
  • R is selected from hydrogen , C -6 alkyl, cyano, halogen, 3-6 membered heterocyclic group, -COR 2a , -NHCOR 2c ; the C 1-6 alkyl, 3-6 membered heterocyclic group is optionally selected from 1-3 Substituted by halogen; R 2a and R 2c are each independently selected from amino, C 1-6 alkyl; preferably R 2 is selected from hydrogen, trifluoromethyl, cyano, halogen, 3-6 membered heterocyclyl, -CONH 2. -NHCOCH3 .
  • R is selected from hydrogen, C -6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl Substituents of base, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;
  • R is selected from hydrogen, C 1-6 alkyl , C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, ring Propyl, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl substituents.
  • R1 is selected from hydrogen, cyclopropyl, trifluoromethyl.
  • R is selected from hydrogen, C -6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, 3-6 heterocyclic, 3-6 Heteroaryl, -COR 3a , -SO 2 R 3b , -NHCOR 3c ; the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 ring Alkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl Substituents of base,
  • R 3a , R 3b , and R 3c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and hydroxyl.
  • R is selected from hydrogen, C -6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl; wherein The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are any Selected to be substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;
  • R is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl, C 1-6 alkoxy are optionally substituted by 1-3 selected from halogen;
  • R 3 is selected from halogen substituted C 1-6 alkyl
  • R3 is trifluoromethyl.
  • R and R are independently selected from From C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, amino, halogen, 3-6 membered heterocyclic group , 3-6 membered heteroaryl, hydroxyl, methanesulfonyl; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy , 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, iso Substitute
  • R and R are independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, amino, Halogen, hydroxyl, methanesulfonyl; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 Substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxyl;
  • R 4 and R 5 are independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, nitro, cyano, amino, halogen, hydroxyl, methanesulfonyl; wherein said C 1-6 Alkyl, C 3-6 cycloalkyl is optionally replaced by 1-3 selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, Substituents of cyano, amino, hydroxyl;
  • R and R are independently selected from methyl, ethyl, methoxy, cyclopropyl, nitro, cyano, amino, halogen, hydroxyl, methylsulfonyl; wherein said methyl, ethyl , methoxy, and cyclopropyl are optionally substituted by 1-3 substituents selected from halogen, nitro, cyano, amino, and hydroxyl.
  • R 4 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy.
  • the present disclosure also provides the following compound or a pharmaceutically acceptable salt thereof,
  • the present disclosure also provides a compound represented by formula II or a pharmaceutically acceptable salt thereof,
  • Ring B is selected from 9-15 membered heteroaryls containing 1-4 heteroatoms
  • ring B is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thio-1,2-dihydroisoquinolin-5-yl, quinolin-5-yl, iso Quinolin-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl, naphthyl,
  • R 6 and R 10 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group, methanesulfonyl group; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl Substituents of base, n-butyl, isobutyl, nitro, cyano, amino, hydroxyl;
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, hydroxyl, 3- 6-membered heterocyclic group, 3-6 membered heteroaryl group; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl Substituents of radical, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group; wherein said C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl Substituents of base, nitro, cyano, amino;
  • R 9 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heteroaryl, 3- 6-membered heterocyclic group, -O-3-6-membered heterocyclic group, -COR 9a , -SO 2 R 9b , -NH-CO-CH 3 ; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocycle Base, -O-3-6 membered heterocyclic group, 3-6 membered heteroaryl group, -NH-CO-CH 3 is optionally selected from 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, normal Propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, oxo substituents;
  • R 9a , R 9b and R 9c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl;
  • Ring B is selected from 9-15 membered heteroaryls containing 1-4 heteroatoms
  • ring B is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thio-1,2-dihydroisoquinolin-5-yl, quinolin-5-yl, iso Quinolin-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl, naphthyl,
  • R 6 and R 10 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group, methanesulfonyl group; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl Substituents of base, n-butyl, isobutyl, nitro, cyano, amino, hydroxyl;
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, hydroxyl, 3- 6-membered heterocyclic group, 3-6 membered heteroaryl group; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl Substituents of radical, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group; wherein said C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl Substituents of base, nitro, cyano, amino;
  • R 9 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heteroaryl, 3- 6-membered heterocyclyl, -COR 9a , -SO 2 R 9b , Wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl The group is optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino ;
  • R 9a , R 9b and R 9c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl;
  • the present disclosure also provides compounds represented by formulas II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h or pharmaceutically acceptable Salt,
  • R 6 , R 7 , R 8 , R 9 , R 10 are as defined in formula II.
  • R 9 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl , -COR 9a , -SO 2 R 9b , Wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group are optionally replaced by 1-3 Substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, oxo;
  • R 9a , R 9b and R 9c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl;
  • R 9 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy; said C 1-6 alkyl, C 1-6 alkoxy are optionally substituted by 1-3 halogens.
  • R 9 is selected from 3-6 membered heterocyclic groups, -COR 9a , -SO 2 R 9b , Wherein the 3-6 membered heterocyclic group is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino substituents are substituted;
  • R 9a , R 9b and R 9c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, and hydroxyl.
  • R 9 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heteroaryl, 3- 6-membered heterocyclyl, -COR 9a , -SO 2 R 9b , Wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl The group is optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino ;
  • R 9a , R 9b and R 9c are each independently selected from amino, C 1-6 alkyl, phenyl, p-methylphenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxyl;
  • R9 is selected from trifluoromethyl, triazole.
  • R9 is selected from
  • R 9 is selected from C 1-6 alkoxy, triazole, difluoromethyl, -NH-CO-CH 3 , Difluoromethoxy.
  • R 9 is selected from -NH-CO-CH 3 , -OCHF 2 , Difluoromethoxy, trifluoromethoxy,
  • R 9 is selected from -NH-CO-CH 3 , -OCHF 2 , Difluoromethoxy, trifluoromethoxy,
  • R9 is selected from trifluoromethyl.
  • R9 is selected from difluoromethyl.
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxyl; Wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heteroaryl are optionally replaced by 1-3 selected from halogen, methyl, ethyl , cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino substituents;
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl, 3-6 membered heteroaryl, hydroxyl; wherein The C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, ring Substituents of propyl, nitro, cyano, amino;
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, nitro, cyano, halogen, hydroxyl; wherein said C 1-6 alkyl, C 3-6 cycloalkane The group is optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, nitro, cyano, amino;
  • R is selected from hydrogen, 1-3 halogen substituted alkyl, halogen;
  • R8 is selected from chlorine.
  • R 6 and R 10 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano , amino, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, hydroxyl group, methylsulfonyl group; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally selected from 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, normal Propyl, isopropyl, n-butyl, isobutyl,
  • R and R are each independently selected from C 1-6 alkyl, C 1-6 alkoxy , C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, amino , halogen, hydroxyl, methanesulfonyl; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 Substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino, hydroxyl;
  • R 6 and R 10 are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, nitro, cyano, amino, halogen, hydroxyl, methylsulfonyl; wherein said C 1- 6 Alkyl, C 3-6 cycloalkyl are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro , cyano, amino, hydroxyl substituents are substituted;
  • R and R are each independently selected from methyl, ethyl, methoxy, cyclopropyl, nitro, cyano, amino, halogen, hydroxyl, methylsulfonyl ; wherein said methyl, ethyl
  • the radical, methoxy, and cyclopropyl are optionally substituted by 1-3 substituents selected from halogen, nitro, cyano, amino, and hydroxyl.
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen; wherein The C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl, ethyl , cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl substituents;
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, ring Propyl, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl substituents.
  • R7 is selected from hydrogen, cyclopropyl, trifluoromethyl.
  • R 7 is trifluoromethyl.
  • the present disclosure provides a compound represented by formula III or a pharmaceutically acceptable salt thereof,
  • Y 1 is CR 14 or N
  • Y 2 is CR 15 or N
  • Ring C is selected from the group optionally substituted by 1-3 R 13
  • Ring C is selected from 6-10 membered aryl and 5-10 membered heteroaryl optionally substituted by 1-3 R 13 ;
  • Ring C is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups that may be optionally substituted by 1-3 R 13 ;
  • Each R 13 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR 13a , -COR 13b , -SO 2 R 13c , -SOR 13c ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl , C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, Substituents of cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclyl, 3-6 membered heteroaryl; C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-
  • the 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Substituents of nitro, cyano, amino;
  • R 12 is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, which are optionally replaced by 1-3 R 12a is substituted, and the R 12a is selected from oxo, thio, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitr group, cyano group, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl Substituents of base, n-butyl, isobutyl, nitro,
  • R 13a , R 13b and R 13c are each independently selected from amino, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl;
  • R 14 and R 15 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;
  • Y 1 is CR 14 or N
  • Y 2 is CR 15 or N
  • Ring C is selected from the group optionally substituted by 1-3 R 13
  • Ring C is selected from 6-10 membered aryl and 5-10 membered heteroaryl optionally substituted by 1-3 R 13 ;
  • Ring C is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups that may be optionally substituted by 1-3 R 13 ;
  • Each R 13 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR 13a , -COR 13b , -SO 2 R 13c ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1- 6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heteroaryl are optionally selected from 1-3 halogen, methyl, ethyl, cyclopropyl, Substituents of n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclyl, 3-6 membered heteroaryl; C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-
  • the 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Substituents of nitro, cyano, amino;
  • R 12 is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, which are optionally replaced by 1-3 R 12a is substituted, and the R 12a is selected from oxo, thio, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitr group, cyano group, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group; the C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl Substituents of base, n-butyl, isobutyl, nitro,
  • R 13a , R 13b and R 13c are each independently selected from amino, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl;
  • R 14 and R 15 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;
  • Y 1 is CR 14 ;
  • Y2 is N
  • Ring C is selected from the group optionally substituted by 1-3 R 13
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclyl, 3-6 membered heteroaryl; C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-
  • the 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Substituents of nitro, cyano, amino;
  • R 12 is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, which are optionally replaced by 1-3 R 12a is substituted, and the R 12a is selected from oxo, thio, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitr group, cyano group, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl Substituents of base, n-butyl, isobutyl, nitro,
  • R 13 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclyl, 3-6 membered heteroaryl, -NHCOR 13a , -COR 13b , -SO 2 R 13c , -SOCH 3 ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl Substituents of base, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;
  • Y 1 is CR 14 ;
  • Y2 is N
  • Ring C is selected from the group optionally substituted by 1-3 R 13
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclyl, 3-6 membered heteroaryl; C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 5-
  • the 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Substituents of nitro, cyano, amino;
  • R 12 is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, which are optionally replaced by 1-3 R 12a is substituted, and the R 12a is selected from oxo, thio, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitr group, cyano group, halogen, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl Substituents of base, n-butyl, isobutyl, nitro,
  • R 13 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclic group, 3-6 membered heteroaryl group, -NHCOR 13a , -COR 13b , -SO 2 R 13c ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkane Oxygen, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl are optionally selected from 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl Substituents of base, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl;
  • the present disclosure also provides formula III-a, formula III-b, formula III-c, formula III-d, formula III-e, formula III-h or formula III-j, or formula III-k, formula The compound shown in III-m or its pharmaceutically acceptable salt,
  • n is an integer selected from 0-3,
  • R 11 , R 12 , R 13 , R 14 are as defined in formula III.
  • the compound represented by formula III or a pharmaceutically acceptable salt thereof is a compound represented by formula III-i or a pharmaceutically acceptable salt thereof
  • n is an integer selected from 0-3,
  • R 11 , R 12 , R 13 , R 14 are as defined in formula III.
  • R 14 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, nitro, cyano, hydroxyl; preferably R 14 is selected from hydrogen, methyl, cyclopropyl, halogen, nitro, cyano radical, hydroxyl; more preferably R is selected from hydrogen.
  • each R 13 is independently selected from trifluoromethyl, hydrogen, halogen; preferably R 13 is independently selected from trifluoromethyl.
  • each R 13 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3- 6-membered heteroaryl; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 heterocyclic,
  • the 3-6 membered heteroaryl is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, Amino substituents are substituted.
  • each R 13 is independently selected from nitro, cyano, halogen, -NHCOR 13a , -COR 13b , -SO 2 R 13c , -SO R 13c , wherein R 13a , R 13b and R 13c are independently selected from amino, C 1-6 alkyl, C 3-6 cycloalkyl.
  • each R 13 is independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, -SOCH 3 , halogen, cyano.
  • the present disclosure also provides a compound represented by formula III-f or formula III-g or a pharmaceutically acceptable salt thereof,
  • Ring C, R 11 , R 12 , R 15 are as defined in formula III.
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, nitric acid group, cyano group, hydroxyl group; preferably R 15 is selected from hydrogen, methyl, cyclopropyl, halogen, nitro, cyano group, hydroxyl group; more preferably R 15 is selected from hydrogen.
  • ring C is selected from 6-10 membered aryl and 5-10 membered heteroaryl optionally substituted by 1-3 R 13 ;
  • Each R 13 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR 13a , -COR 13b , -SO 2 R 13c , SOR 13c ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryl are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, ring Substituents of propyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • R 13a , R 13b and R 13c are each independently selected from amino, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl;
  • Ring C is selected from phenyl, naphthyl, 5-10 membered heteroaryl containing 1-3 heteroatoms optionally substituted by 1-3 R 13 ;
  • Each R 13 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, containing 1 - 3-6 membered heterocyclic group containing 3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms, -NHCOR 13a , -COR 13b , -SO 2 R 13c , SOR 13c ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group containing 1-3 heteroatoms, containing A 3-6 membered heteroaryl group with 1-3 heteroatoms is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl , nitro,
  • the heteroatom is selected from N, O, S;
  • R 13a , R 13b and R 13c are each independently selected from amino, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl.
  • ring C is selected from phenyl, pyridine, pyridazine, pyrazine , pyrimidine, Preferably ring C is selected from the group optionally substituted by 1-3 R 13
  • Each R 13 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, Tetrahydrofuranone, pyrrolidine, pyrrolidone, Triazole, -NHCOR 13a , -COR 13b , -SO 2 R 13c , SOR 13c ; the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3 -6 cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole, Optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino
  • R 13a , R 13b and R 13c are each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl.
  • R 12 is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms, said naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms
  • said R 12a is selected from oxo, thio, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3 -6 cycloalkyl, nitro, cyano, halogen, 3-6 membered heterocyclyl containing 1-3 heteroatoms, 3-6 membered heteroaryl containing 1-3 heteroatoms; said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group
  • the heteroatoms are selected from N, O, S.
  • R 12 is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thio-1,2-dihydroisoquinolin-5-yl, quino Lin-5-yl, isoquinolin-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl,
  • R 12a is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, Nitro, cyano, halogen, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms; the C 1-6 alkyl, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-membered heterocyclic group containing 1-3 heteroatoms -6-member
  • R 12 is selected from said Optionally substituted by 1-3 R 12a , said R 12a is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, Nitro, cyano, halogen, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms; the C 1-6 alkyl, C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-membered heterocyclic group containing 1-3 heteroatoms -6-membered heteroaryl is optionally replaced by 1-3 members selected from halogen, methyl,
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano , halogen; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 selected from halogen, methyl Substituents of radical, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl replaced by
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, ring Propyl, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl substituents.
  • R 11 is selected from hydrogen, cyclopropyl, trifluoromethyl.
  • the present disclosure also provides a compound represented by formula IV or a pharmaceutically acceptable salt thereof,
  • X 1 and X 2 are independently selected from C, O, N, and X 3 is selected from C, N or a bond; preferably X 1 is selected from N, X 2 is selected from C, and X 3 is selected from N;
  • Ring D is selected from naphthyl, 9-15 membered heteroaryl containing 1-4 heteroatoms;
  • R 18 is selected from oxo, thio, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, A 3-6-membered heterocyclic group containing 1-3 heteroatoms, a 3-6-membered heteroaryl group containing 1-3 heteroatoms; the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms
  • substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • the heteroatom is selected from N, O, S;
  • n is an integer selected from 0-3;
  • R 16 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3-6 Heterocyclyl, 3-6 membered heteroaryl; C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-
  • the 6-membered heterocyclic group and the 3-6-membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, Substituents of nitro, cyano, amino;
  • R 17 is selected from 6-10 membered aryl, 5-10 membered heteroaryl optionally substituted by 1-3 R 17a ;
  • Each R 17a is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR 17b , -COR 17c , -SO 2 R 17d, -SOR 17d ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl , C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, Substituents of cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • R 17b , R 17c and R 17d are each independently selected from amino, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl.
  • ring D is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl, 1-thio-1 ,2-Dihydroisoquinolin-5-yl, quinolin-5-yl, isoquinolin-5-yl, naphthyl, thieno[2,3-c]pyridin-4-yl,
  • R 18 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, containing 1-3 hetero Atomic 3-6 membered heterocyclic group, 3-6 membered heteroaryl group containing 1-3 heteroatoms; said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy Group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally selected by 1-3 Substituents from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • n is an integer selected from 0-3.
  • ring D is selected from 1-oxo-1,2-dihydroisoquinolin-5-yl
  • R 18 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, nitro, cyano, halogen, containing 1-3 hetero Atomic 3-6 membered heterocyclic group, 3-6 membered heteroaryl group containing 1-3 heteroatoms; said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy Group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group containing 1-3 heteroatoms, 3-6 membered heteroaryl group containing 1-3 heteroatoms are optionally selected by 1-3 Substituents from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • n is an integer selected from 0-3.
  • R 17 is selected from 6-10 membered aryl, 5-10 membered heteroaryl optionally substituted by 1-3 R 17a ;
  • Each R 17a is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, 3- 6-membered heterocyclic group, 3-6-membered heteroaryl group, -NHCOR 17b , -COR 17c , -SO 2 R 17d , -SOR 17d ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl , C 1-6 alkoxy group, C 3-6 cycloalkoxy group, 3-6 membered heterocyclic group, 3-6 membered heteroaryl group are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, Cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano, amino;
  • R 17b , R 17c and R 17d are each independently selected from amino, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl;
  • R 17 is selected from phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3 heteroatoms optionally substituted by 1-3 R 17a ;
  • Each R 17a is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, containing 1 -3-6 membered heterocyclic group with 3 heteroatoms, 3-6 membered heteroaryl group with 1-3 heteroatoms, -NHCOR 17b , -COR 17c , -SO 2 R 17d , -SOR 17d ; where The aforementioned C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, 3-6 membered heterocyclic group containing 1-3 heteroatoms, The 3-6 membered heteroaryl group containing 1-3 heteroatoms is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl Substitu
  • the heteroatom is selected from N, O, S;
  • R 17b , R 17c and R 17d are each independently selected from amino, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, p-methylphenyl.
  • R 17 is selected from phenyl, pyridine, pyridazine , pyrazine, pyrimidine,
  • Each R 17a is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, Tetrahydrofuranone, pyrrolidine, pyrrolidone, Triazole, -NHCOR 17b , -COR 17c , -SO 2 R 17d , -SOR 17d ; the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole, Optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano
  • R 17b , R 17c and R 17d are each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl.
  • R 17 is selected from pyridine optionally substituted by 1-3 R 17a ;
  • Each R 17a is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen, tetrahydrofuran, Tetrahydrofuranone, pyrrolidine, pyrrolidone, Triazole, -NHCOR 17b , -COR 17c , -SO 2 R 17d , -SOR 17d ; the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, tetrahydrofuran, tetrahydrofuranone, pyrrolidine, pyrrolidone, triazole, Optionally substituted by 1-3 substituents selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, nitro, cyano
  • R 17b , R 17c and R 17d are each independently selected from amino, methyl, cyclopropyl, phenyl, p-methylphenyl;
  • R 17 is selected from the group optionally substituted by 1-3 R 17a
  • Each R 17a is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, nitro, cyano, 1-3 halogen substituted C 1-6 alkyl.
  • R 16 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkane Oxygen is optionally replaced by 1-3 members selected from halogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropoxy Substituents of radical, nitro, cyano, amino, hydroxyl;
  • R is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, nitro, cyano, halogen; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy are optionally replaced by 1-3 members selected from halogen, methyl, ethyl, ring Substituents of propyl, n-propyl, methoxy, ethoxy, cyclopropoxy, nitro, cyano, amino, hydroxyl;
  • R 16 is selected from hydrogen, cyclopropyl, trifluoromethyl.
  • the present disclosure also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the present disclosure also provides an isotope substitution of the compound shown in the first aspect to the tenth aspect, preferably, the isotope substitution is deuterium atom substitution.
  • the present disclosure also provides a pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt thereof as described in the first to eleventh aspects and a pharmaceutically acceptable excipient.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
  • the present disclosure also provides a method for preventing and/or treating disorders related to MALT1, which includes administering a therapeutically effective amount of the compound as described in the first to eleventh aspects to a subject in need or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in the twelfth aspect.
  • the diseases associated with MALT1 include but are not limited to autoimmune diseases, inflammatory diseases, cancers, tumors, etc., such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitis, primary hematopoietic disease Cancer or solid tumors, including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • autoimmune diseases inflammatory diseases, cancers, tumors, etc.
  • inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitis, primary hematopoietic disease Cancer or solid tumors, including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • the present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases, cancers, tumors, which includes administering to a subject in need a therapeutically effective amount of the The compound or its pharmaceutically acceptable salt or the pharmaceutical composition as described in the twelfth aspect.
  • the autoimmune diseases and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, the cancers or tumors, such as primary cancers or solid tumors of the hematopoietic system, including chronic Myeloid leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • the present disclosure also provides the compound or pharmaceutically acceptable salt thereof described in the first aspect to the eleventh aspect or the pharmaceutical composition described in the twelfth aspect in the preparation of medicines for preventing and/or treating diseases related to MALT1 use.
  • the present disclosure also provides the compound or pharmaceutically acceptable salt thereof from the first aspect to the eleventh aspect or the pharmaceutical composition described in the twelfth aspect for the prevention and/or treatment of autoimmune diseases and inflammatory diseases , cancer, tumor medicine purposes.
  • the autoimmune diseases and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, the cancers or tumors, such as primary cancers or solid tumors of the hematopoietic system, including chronic Myeloid leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • the present disclosure also provides the compounds according to the first aspect to the eleventh aspect or the pharmaceutically acceptable salt thereof or the pharmaceutical composition according to the twelfth aspect, which are used for preventing and/or treating diseases related to MALT1.
  • the present disclosure also provides the compounds described in the first aspect to the eleventh aspect or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the twelfth aspect, which are used for preventing and/or treating autoimmune diseases and inflammatory diseases , cancer, tumor purposes.
  • the autoimmune diseases and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, the cancers or tumors, such as primary cancers or solid tumors of the hematopoietic system, including chronic Myeloid leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • the compounds described in the present disclosure or their pharmaceutically acceptable salts or pharmaceutical compositions have a good inhibitory effect on MALT1, and the IC 50 value of the inhibitory activity on MALT1 is 0.01 to 1000nM, and the IC 50 of certain compounds on the inhibitory activity on MALT1
  • the value is from 0.01 to 500nM
  • the IC50 value of the inhibitory activity of some compounds on MALT1 is from 0.01 to 300nM
  • the IC50 value of the inhibitory activity of some compounds on MALT1 enzyme is from 0.01 to 200nM
  • the inhibitory activity of some compounds on MALT1 enzyme The IC 50 value ranges from 0.01 to 100nM
  • the IC 50 value of the inhibitory activity of some compounds on MALT1 enzyme is ⁇ 100nM
  • the IC 50 value of the inhibitory activity of some compounds on MALT1 enzyme is ⁇ 50nM.
  • compositions described in this disclosure may be selected from inorganic or organic salts.
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the disclosure. All such isomers and mixtures thereof are included within the scope of this disclosure.
  • Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure obtained Enantiomers are required.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • the bond If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.
  • the present invention may include all isomers such as tautomers, rotamers, geometric isomers, diastereoisomers body, racemate and enantiomer.
  • Tautomers are structural isomers of organic compounds that are readily interconvertible through a chemical reaction known as tautomerization. This reaction often results in the formal transfer of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds.
  • Some common tautomers are: keto-enol, lactam-lactim.
  • An example of a lactam-lactim equilibrium is between A and B as shown below,
  • Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. They can be replaced by isotopes 2 H(D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, respectively.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to mean deuterium having an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (ie, at least 45 % deuterium incorporation).
  • the present disclosure also includes various deuterated forms of the compounds.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound.
  • Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • C 1 -C 6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily be present, and this specification includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. And the case of cyano substitution.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, agent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
  • an “effective amount” or “therapeutically effective amount” as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dose of administration and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl, 2,2-dimethylpropyl and its various branched isomers, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxygen Generation, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl Oxygen, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl any substituted by one or more selected from halogen, deuterium, hydroxyl,
  • alkenyl includes branched and straight chain alkenes or alkenes containing aliphatic hydrocarbon groups having 2 to 12 carbon atoms.
  • C 2-6 alkenyl means alkenyl having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3 - methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • Alkenyl may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxygen Generation, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl Oxygen, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl any substituted by one or more selected from halogen, deuterium, hydroxyl,
  • Alkynyl includes branched and straight chain alkynyl groups or alkynes containing aliphatic hydrocarbon groups having 2 to 12 carbon atoms. For example ethynyl, propynyl (eg 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxygen Generation, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl Oxygen, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl any substituted by one or more selected from halogen, deuterium, hydroxy
  • cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.
  • multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, Oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl
  • the substituents may be substituted at any available point of attachment, preferably one
  • the cycloalkyl ring may be fused to an aryl or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzo Heptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy , C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 Alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl,
  • cycloalkenyl refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl.
  • Cycloalkenyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy , C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 Alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, o
  • heterocycloalkyl refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents containing from 3 to 20 ring atoms in which one or more Atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • m is an integer from 0 to 2
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperrolyl, Pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Multicyclic heterocycloalkyls include spiro, fused and bridged heterocycloalkyls.
  • Non-limiting examples of "heterocycloalkyl" include:
  • heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring bonded to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
  • Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano radical, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy group, C 3-8 cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2- 6 -alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally replaced by one or more Substituted by halogen, deuter
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated pi-electron system, such as benzene base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C -6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3 -8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy , C 3-6 cycloalkoxy, 3 to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl are optionally selected from one or more halogen, Deuterium, hydroxyl, oxo, nitro,
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group may be 5 to 12 membered or 5 to 10 membered, more preferably 5 or 6 membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, wait.
  • the heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy , C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 Alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, o
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy , C 3-8 cycloalkenyloxy, 5-6 membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 Alkynyloxy, C 3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C
  • alkenyloxy refers to -O-(alkenyl), wherein alkenyl is as defined above.
  • alkynyloxy refers to -O-(alkynyl), wherein alkynyl is as defined above.
  • cycloalkoxy refers to -O-(cycloalkyl), wherein cycloalkyl is as defined above.
  • heterocycloalkoxy refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.
  • cycloalkenyloxy refers to -O-(cycloalkenyl), wherein cycloalkenyl is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
  • High performance liquid chromatography was determined using Shimadzu LC-20A systems, Shimadzu LC-2010HT series, Shimadzu DGU-20A5R, Shimadzu LC-30AD, Shimadzu SIL-30AC or Agilent Agilent 1200 LC high pressure liquid chromatography (Ultimate XB -C18 3.0*150mm column or Xtimate C18 2.1*30mm column).
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um column.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the known starting materials of the present invention can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent
  • TLC thin-layer chromatography
  • the ratio is adjusted according to the polarity of the compound.
  • water and acetonitrile are used as the mobile phase, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Dissolve isoquinolin-5-amine (5.1g, 35.37mmol) in concentrated hydrochloric acid (50mL), add an aqueous solution (20mL) of sodium nitrite (3.66g, 53.06mmol) at 0°C, react for 30 minutes, dropwise Add a concentrated hydrochloric acid solution (20 mL) of stannous chloride (19.95 g, 88.43 mmol), react at room temperature for 3 hours, adjust the pH to 12-14 with 20% aqueous sodium hydroxide solution, extract with ethyl acetate (30 mL*3), The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with ethyl acetate to obtain the title compound 1b (2.33 g, yield: 40.0%).
  • reaction solution was poured into saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (22-42% acetonitrile-water) to obtain the title compound 13 (7.1 mg, yield: 9%).
  • reaction solution was diluted with 10ml of dichloromethane, washed with 2mmol/L sodium bisulfite (10mL), then washed with saturated sodium bicarbonate solution (10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed After concentration, the residue was purified by silica gel column chromatography with the eluent system ethyl acetate/n-hexane to obtain the title compound 14b (200 mg, yield: 76%). .
  • 1-Cyclopropylpyrazole-4-boronic acid pinacol esters 15a and 15b (200 mg, 0.85 mmol) were dissolved in dioxane (3 mL), and [1,1'-bis(diphenylphosphine) Ferrocene]palladium dichloride dichloromethane complex (70mg, 0.085mmol) and potassium carbonate (236mg, 1.71mmol), microwave reaction for 1 hour.
  • 2-Bromo-3-chloro-5-nitropyridine 19a (3.0g, 12.63mmol) was dissolved in 1,4-dioxane (25mL), and pyrrolidin-2-one (1.95mL, 25.27 mmol), methyl[2-(methylamino)ethyl]amine (0.27mL, 2.53mmol), potassium phosphate (5.36g, 25.27mmol) and copper iodide (0.086mL, 2.53mmol).
  • reaction solution was stirred at 60°C for another 1 hour, cooled to room temperature, slowly added saturated aqueous ammonium chloride solution (30 mL) to quench the reaction, and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the title compound 19 (55 mg, yield: 37%).
  • Methyl 6-iodopyridazine-4-carboxylate 600 mg, 2.273 mmol
  • 21c 639 mg, 2.046 mmol
  • the reaction mixture was quenched slowly with water (10 mL).
  • the aqueous layer was extracted with ethyl acetate (30 mL x 3).
  • the combined organic layers were washed with brine (30 mL x 2) and water (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • N-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(tri Fluoromethyl)-1H-pyrazole-4-carboxamide 23 (157mg, 0.31mmol) was dissolved in dioxane/water (12mL/4mL), and bisdibenzylideneacetone palladium (359.83mg, 0.63 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (26.57 mg, 0.063 mmol) and potassium hydroxide (35.11 mg, 0.63 mmol). Reaction was carried out at 115°C for 1 hour, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 24 (36 mg, yield: 23%).
  • 2-Chloro-1-methanesulfinyl-4-nitrobenzene 28a (300mg, 1.37mmol) was dissolved in ethanol/water (10mL/2mL), iron powder (381mg, 6.83mmol) and ammonium chloride ( 730mg, 13.66mmol), react at 90°C for 1 hour.
  • 3-Chloro-4-methylsulfinylaniline 28b (130mg, 0.68mmol) was dissolved in tetrahydrofuran (1mL), and diisopropylethylamine (0.34mL, 2.056mmol) and 1-(1- Oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride (281 mg, 0.82 mmol) in tetrahydrofuran (1 mL), room temperature After reacting overnight, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound 28 (100 mg, yield: 26.5%).
  • 3-Chloro-5-nitropyridin-2-ol 33a (354 mg, 2.03 mmol) was dissolved in acetonitrile (15 mL), and sodium hydride (219 mg, 5.48 mmol, 60%) was added at room temperature. Under nitrogen atmosphere, after reacting at room temperature for 10 minutes, 2,2-difluoro-2-(fluorosulfonyl)acetic acid 33b (632 mg, 3.55 mmol) was added, and the reaction was continued at room temperature for 20 minutes.
  • 5-trifluoromethylpyridin-3-amine 34a (0.15mL, 1.23mmol) was dissolved in tetrahydrofuran (3mL), di-tert-butyl dicarbonate (0.79mL, 3.70mmol) and p-dimethylaminopyridine (7.5 mg, 0.062mmol), react at room temperature for 16 hours, pour the reaction solution into water (20mL), extract with ethyl acetate (20mL*2), combine the organic phases, wash with saturated aqueous sodium chloride solution (20mL*2), anhydrous Dry over sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by silica gel column chromatography to obtain the title compound 34b (250 mg, yield: 77.2%).
  • 6-(oxolan-3-yl)-5-(trifluoromethyl)pyridin-3-amine 35d (35 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride ( 82mg, 2.06mmol), after 10 minutes, add 1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4- Formyl chloride 21h (88mg, 0.26mmol), under nitrogen atmosphere, react at 60°C for 1 hour, cool to room temperature, add saturated sodium bicarbonate solution (20mL) to the reaction solution, extract with dichloromethane (30mL*3), and combine the organic phases , dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by high performance liquid chromatography to obtain the title compound 35 (24.3 mg, yield: 17.5%).
  • reaction solution was adjusted to pH 12-14 with 20% aqueous sodium hydroxide solution, extracted with ethyl acetate (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 36f (240 mg, yield: 72.7%).
  • 2-Chloro-6-(trifluoromethyl)pyridin-4-amine 38a (440mg, 2.24mmol) was dissolved in 1,4-dioxane/water (15mL/5mL), and bis-dibenzylidene was added at room temperature Palladium acetonate (128.7 mg, 0.22 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (190 mg, 0.44 mmol) and potassium hydroxide (251 mg, 4.49 mmol).
  • reaction solution was adjusted to pH 2-3 with 1N hydrochloric acid solution, extracted with ethyl acetate (20mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 40h (22mg, yield : 66%).
  • In vitro assays include assays that determine cell morphology, protein expression and/or cytotoxicity, enzyme inhibitory activity, and/or subsequent functional consequences of treatment of cells with compounds of the invention. Alternatively or additionally to in vitro assays can be used to quantify the ability of an inhibitor to bind to a protein or nucleic acid molecule within a cell.
  • Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/target molecule complex, and determining the amount of radiolabel bound.
  • inhibitor binding can be determined by running competition experiments in which new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of an exemplary system for assaying compounds of the invention as inhibitors of MALT1 are set forth in the Biological Examples below.
  • Such assays are exemplary and not intended to limit the scope of the invention.
  • the skilled practitioner will understand that conventional assays can be modified to develop equivalent or other assays that can be used to equally assess activity or otherwise characterize compounds and/or compositions as described herein.
  • Test example 1 MALT1 biochemical protease assay
  • the composition of the final assay buffer was 5.625nM MALT1 protein, 2.5 ⁇ M Ac-LRSR-MCA, 20mM HEPES, 10mM KCl, 1.5mM MgCl 6H2O, 1mM 2Na (EDTA 2Na), 0.01% TritonX-100, 1M citric acid Trisodium Citrate Dihydrate, and 10 mM DTT.
  • Test compounds dissolved in 100% DMSO were added to a 384-well plate (Greiner-781086) at 200 nL per well using Echo. The highest concentration of each test compound was 10 ⁇ M or 1 ⁇ M, 3-fold serial dilution, and the tested concentration range was from 10 ⁇ M to 0.2 nM.
  • Control wells with assay buffer without enzyme were used as low controls (LC) and wells with vehicle (1% DMSO) reacted with enzyme but not treated with compound were used as high controls (HC).
  • Compounds were incubated with MALT1 enzyme and substrate for 15 hours at room temperature. Fluorescence was then measured using Envision at excitation 360 nm and emission 450 nm. XLfit was used to fit the inhibition curve and calculate the IC 50 value, which is shown in Table 1.

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Abstract

公开了一种MALT1抑制剂及其制备方法和用途。具体而言，公开了式III所示的化合物，其制备方法，含有其的药物组合物，以及其作为MALT1抑制剂用于预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤的用途。

Description

一种MALT1抑制剂及其制备方法和用途 技术领域
本公开属于医药领域，涉及一种MALT1抑制剂，其制备方法，含有其的药物组合物，以及其用于预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤的用途。
背景技术
黏膜相关组织淋巴瘤异位蛋白1(mucosa-associated-lymphoid-tissuelymphoma-translocation1，MALT1)是NF-κB信号通路上游一个重要的蛋白分子，同B细胞慢性淋巴细胞白血病/淋巴瘤蛋白(B-cell chronic lymphocyticleukemia/lymphoma10，BCL10)和含caspase募集结构的膜相关鸟苷酸激1(caspase-recruitment domain(CARD)containing membrane-associated guanylatekinase protein1，CARMA1)组成复合物CBM，将近端抗原受体蛋白信号传递给IκB激酶(IKK)，进而激活NF-κB信号通路。MALT1-NF-κB信号通路的过度活化与炎症及肿瘤的发生密切相关。
发明内容
第一方面，本公开提供式I所示的化合物或其可药用盐
Figure PCTCN2022099499-appb-000001
其中：
环A选自包含1-4个杂原子的9-15元杂芳基；
优选环A选自1-氧代-1,2-二氢异喹啉-5-基、1-硫代-1,2-二氢异喹啉-5-基、喹啉-5基、异喹啉-5-基、噻吩并[2,3-c]吡啶-4-基、萘基、
Figure PCTCN2022099499-appb-000002
Figure PCTCN2022099499-appb-000003
R 1选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙 基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
R 2选自氢、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-COR 2a、-SO 2R 2b、-NHCOR 2c、羟基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基、氧代的取代基所取代；
R 2a、R 2b、R 2c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基；
R 3选自氢、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-COR 3a、-SO 2R 3b、-NHCOR 3c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
R 3a、R 3b、R 3c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基；
R 4和R 5各自独立地选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
条件是，式I所示的化合物不包括以下化合物：
Figure PCTCN2022099499-appb-000004
Figure PCTCN2022099499-appb-000005
第二方面，本公开还提供式I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000006
Figure PCTCN2022099499-appb-000007
R 1、R 2、R 3、R 4、R 5如式I中定义。
在一些实施方案中，式I、I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h、I-i、I-j、I-k所示的化合物或其可药用盐中，R 2选自氢、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、-COR 2a、-SO 2R 2b、-NHCOR 2c、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、羟基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基、氧代的取代基所取代；
R 2a、R 2b、R 2c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基。
在一些实施方案中，式I、I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h、I-i、I-j、I-k所示的化合物或其可药用盐中，R 2选自氢、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、-COR 2a、-SO 2R 2b、-NHCOR 2c、氰基、卤素、3-6元杂环基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基任选被1-3个选自卤素、甲基、乙基、环丙基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基、氧代的取代基所取代；
R 2a、R 2b、R 2c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基。
在一些实施方案中，式I、I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h、I-i、I-j、I-k所示的化合物或其可药用盐中，R 2选自氢、C 1-6烷基、氰基、卤素、3-6元杂环基、-COR 2a、-NHCOR 2c；所述C 1-6烷基、3-6元杂环基任选被1-3个选自卤素取代；R 2a、R 2c各自独立地选自氨基、C 1-6烷基；优选R 2选自氢、三氟甲基、氰基、卤素、 3-6元杂环基、-CONH 2、-NHCOCH 3。
在一些实施方案中，式I、I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h、I-i、I-j、I-k所示的化合物或其可药用盐中，R 1选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
优选R 1选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代。
更优选R 1选自氢、环丙基、三氟甲基。
在一些实施方案中，式I、I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h、I-i、I-j、I-k所示的化合物或其可药用盐中，R 3选自氢、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-COR 3a、-SO 2R 3b、-NHCOR 3c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
R 3a、R 3b、R 3c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基。
在一些实施方案中，式I、I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h、I-i、I-j、I-k所示的化合物或其可药用盐中，R 3选自氢、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
优选R 3选自氢、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被1-3个选自卤素取代；
更优选R 3选自卤素取代的C 1-6烷基；
最优选R 3为三氟甲基。
在一些实施方案中，式I、I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h、I-i、I-j、I-k所示的化合物或其可药用盐中，R 4和R 5独立地选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、氨基、卤素、3-6元杂环基、3-6元杂芳基、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、 3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
优选R 4和R 5独立地选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、氨基、卤素、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
更优选R 4和R 5独立地选自C 1-6烷基、C 3-6环烷基、硝基、氰基、氨基、卤素、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
最优选R 4和R 5独立地选自甲基、乙基、甲氧基、环丙基、硝基、氰基、氨基、卤素、羟基、甲磺酰基；其中所述的甲基、乙基、甲氧基、环丙基任选被1-3个选自卤素、硝基、氰基、氨基、羟基的取代基所取代。
在某些实施方案中，R 4独立地选自卤素、C 1-6烷基、C 1-6烷氧基。
第三方面，本公开还提供了如下所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000008
第四方面，本公开还提供如式II所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000009
其中：
环B选自包含1-4个杂原子的9-15元杂芳基；
优选环B选自1-氧代-1,2-二氢异喹啉-5-基、1-硫代-1,2-二氢异喹啉-5-基、喹啉-5基、异喹啉-5-基、萘基、噻吩并[2,3-c]吡啶-4-基、萘基、
Figure PCTCN2022099499-appb-000010
Figure PCTCN2022099499-appb-000011
R 6和R 10各自独立地选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
R 7选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、羟基、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
R 8选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、羟基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 9选自氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂芳基、3-6元杂环基、-O-3-6元杂环基、-COR 9a、-SO 2R 9b、
Figure PCTCN2022099499-appb-000012
-NH-CO-CH 3；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、-O-3-6元杂环基、3-6元杂芳基、-NH-CO-CH 3任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、氧代的取代基所取代；
R 9a、R 9b和R 9c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基；
条件是，式II所示的化合物不包括以下化合物：
Figure PCTCN2022099499-appb-000013
Figure PCTCN2022099499-appb-000014
在某些实施方案中，式II所示的化合物或其可药用盐：
Figure PCTCN2022099499-appb-000015
其中：
环B选自包含1-4个杂原子的9-15元杂芳基；
优选环B选自1-氧代-1,2-二氢异喹啉-5-基、1-硫代-1,2-二氢异喹啉-5-基、喹 啉-5基、异喹啉-5-基、萘基、噻吩并[2,3-c]吡啶-4-基、萘基、
Figure PCTCN2022099499-appb-000016
Figure PCTCN2022099499-appb-000017
R 6和R 10各自独立地选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
R 7选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、羟基、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
R 8选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、羟基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 9选自氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂芳基、3-6元杂环基、-COR 9a、-SO 2R 9b、
Figure PCTCN2022099499-appb-000018
其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 9a、R 9b和R 9c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基；
条件是，式II所示的化合物不包括以下化合物：
Figure PCTCN2022099499-appb-000019
Figure PCTCN2022099499-appb-000020
Figure PCTCN2022099499-appb-000021
第五方面，本公开还提供如式II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000022
Figure PCTCN2022099499-appb-000023
优选式II-a；
R 6、R 7、R 8、R 9、R 10如式II中定义。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 9选自氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、-COR 9a、-SO 2R 9b、
Figure PCTCN2022099499-appb-000024
其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、氧代的取代基所取代；
R 9a、R 9b和R 9c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基；
优选R 9选自氢、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被1-3个卤素取代。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 9选自3-6元杂环基、-COR 9a、-SO 2R 9b、
Figure PCTCN2022099499-appb-000025
其中所述的3-6元杂环基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 9a、R 9b和R 9c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基。
在某些实施方案中，式II-d或式II-g所示的化合物或其可药用盐，其中
R 9选自氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂芳基、3-6元杂环基、-COR 9a、-SO 2R 9b、
Figure PCTCN2022099499-appb-000026
其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 9a、R 9b和R 9c各自独立地选自氨基、C 1-6烷基、苯基、对甲基苯基、C 3-6环烷基、3-6元杂环基、羟基；
优选R 9选自三氟甲基、三氮唑。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 9选自
Figure PCTCN2022099499-appb-000027
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 9选自C 1-6烷氧基、三氮唑、二氟甲基、
Figure PCTCN2022099499-appb-000028
Figure PCTCN2022099499-appb-000029
-NH-CO-CH 3、
Figure PCTCN2022099499-appb-000030
二氟甲氧基。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 9选自-NH-CO-CH 3、-OCHF 2、
Figure PCTCN2022099499-appb-000031
二氟甲氧基、三氟甲氧基、
Figure PCTCN2022099499-appb-000032
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 9选自-NH-CO-CH 3、-OCHF 2、
Figure PCTCN2022099499-appb-000033
二氟甲氧基、三氟甲氧基、
Figure PCTCN2022099499-appb-000034
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 9选自三氟甲基。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 9选自二氟甲基。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 8选自氢、C 1-6烷基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、羟基；其中所述的C 1-6烷基、C 3-6环烷基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
优选R 8选自氢、C 1-6烷基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、羟基；其中所述的C 1-6烷基、C 3-6环烷基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、硝基、氰基、氨基的取代基所取代；
更优选R 8选自氢、C 1-6烷基、C 3-6环烷基、硝基、氰基、卤素、羟基；其中所述的C 1-6烷基、C 3-6环烷基任选被1-3个选自卤素、甲基、乙基、环丙基、硝基、 氰基、氨基的取代基所取代；
更优选R 8选自氢、1-3个卤素取代的烷基、卤素；
最优选R 8选自氯。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 6和R 10各自独立地选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、氨基、卤素、3-6元杂环基、3-6元杂芳基、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
优选R 6和R 10各自独立地选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、氨基、卤素、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
更优选R 6和R 10各自独立地选自C 1-6烷基、C 3-6环烷基、硝基、氰基、氨基、卤素、羟基、甲磺酰基；其中所述的C 1-6烷基、C 3-6环烷基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基、羟基的取代基所取代；
最优选R 6和R 10各自独立地选自甲基、乙基、甲氧基、环丙基、硝基、氰基、氨基、卤素、羟基、甲磺酰基；其中所述的甲基、乙基、甲氧基、环丙基任选被1-3个选自卤素、硝基、氰基、氨基、羟基的取代基所取代。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 7选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
优选R 7选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代。
更优选R 7选自氢、环丙基、三氟甲基。
在某些实施方案中，式II、II-a、II-b、II-c、II-d、II-e、II-f、II-g、II-h所示的化合物或其可药用盐中，R 7为三氟甲基。
第六方面，本公开提供了一种式III所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000035
其中：
Y 1为CR 14或N；
Y 2为CR 15或N；
1)当Y 1为CR 14且Y 2为N时，
环C选自任选被1-3个R 13取代的
Figure PCTCN2022099499-appb-000036
2)当Y 1为N且Y 2为CR 15时，
环C选自任选被1-3个R 13取代的6-10元芳基、5-10元杂芳基；
3)当Y 1、Y 2均为N时，
环C选自可任选被1-3个R 13取代的6-10元芳基、5-10元杂芳基；
每个R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 13a、-COR 13b、-SO 2R 13c、-SOR 13c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 12选自萘基、包含1-4个杂原子的9-15元杂芳基，所述萘基、包含1-4个杂原子的9-15元杂芳基任选被1-3个R 12a所取代，所述R 12a选自氧代、硫代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基，所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异 丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 13a、R 13b和R 13c各自独立地选自氨基、C 1-6烷基、C 3-6环烷基、苯基、对甲基苯基；
R 14、R 15各自独立地选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；
条件是，式III所示的化合物不包括以下化合物：
Figure PCTCN2022099499-appb-000037
在某些实施方案中，式III所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000038
其中：
Y 1为CR 14或N；
Y 2为CR 15或N；
1)当Y 1为CR 14且Y 2为N时，
环C选自任选被1-3个R 13取代的
Figure PCTCN2022099499-appb-000039
2)当Y 1为N且Y 2为CR 15时，
环C选自任选被1-3个R 13取代的6-10元芳基、5-10元杂芳基；
3)当Y 1、Y 2均为N时，
环C选自可任选被1-3个R 13取代的6-10元芳基、5-10元杂芳基；
每个R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 13a、-COR 13b、-SO 2R 13c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧 基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 12选自萘基、包含1-4个杂原子的9-15元杂芳基，所述萘基、包含1-4个杂原子的9-15元杂芳基任选被1-3个R 12a所取代，所述R 12a选自氧代、硫代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 13a、R 13b和R 13c各自独立地选自氨基、C 1-6烷基、C 3-6环烷基、苯基、对甲基苯基；
R 14、R 15各自独立地选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；
条件是，式III所示的化合物不包括以下化合物：
Figure PCTCN2022099499-appb-000040
在某些实施方案中，式III所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000041
其中：
Y 1为CR 14；
Y 2为N；
环C选自任选被1-3个R 13取代的
Figure PCTCN2022099499-appb-000042
Figure PCTCN2022099499-appb-000043
R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 12选自萘基、包含1-4个杂原子的9-15元杂芳基，所述萘基、包含1-4个杂原子的9-15元杂芳基任选被1-3个R 12a所取代，所述R 12a选自氧代、硫代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基，所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 13a、-COR 13b、-SO 2R 13c、-SOCH 3；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 14选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；
条件是，式III所示的化合物不包括以下化合物：
Figure PCTCN2022099499-appb-000044
在某些实施方案中，式III所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000045
其中：
Y 1为CR 14；
Y 2为N；
环C选自任选被1-3个R 13取代的
Figure PCTCN2022099499-appb-000046
R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、5-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 12选自萘基、包含1-4个杂原子的9-15元杂芳基，所述萘基、包含1-4个杂原子的9-15元杂芳基任选被1-3个R 12a所取代，所述R 12a选自氧代、硫代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基，所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 13a、-COR 13b、-SO 2R 13c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 14选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；
条件是，式III所示的化合物不包括以下化合物：
Figure PCTCN2022099499-appb-000047
第七方面，本公开还提供式III-a、式III-b、式III-c、式III-d、式III-e、式III-h或式III-j、或式III-k、式III-m所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000048
Figure PCTCN2022099499-appb-000049
优选式III-h所示的化合物
Figure PCTCN2022099499-appb-000050
其中：
n选自0-3的整数，
R 11、R 12、R 13、R 14如式III中定义。
在某些实施方案中，式III所示的化合物或其可药用盐为式III-i所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000051
其中：
n选自0-3的整数，
R 11、R 12、R 13、R 14如式III中定义。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-h、III-i所示的化合物或其可药用盐中，R 14选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；优选R 14选自氢、甲基、环丙基、卤素、硝基、氰基、羟基；更优选R 14选自氢。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-h、III-i所示的化合物或其可药用盐中，其中每个R 13独立地选自三氟甲基、氢、卤素；优选R 13独立地选自三氟甲基。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-h、III-i所示的化合物或其可药用盐中，其中每个R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷 氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-h、III-i所示的化合物或其可药用盐中，其中每个R 13独立地选自硝基、氰基、卤素、-NHCOR 13a、-COR 13b、-SO 2R 13c、-SO R 13c，其中R 13a、R 13b和R 13c独立地选自氨基、C 1-6烷基、C 3-6环烷基。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-h、III-i所示的化合物或其可药用盐中，其中每个R 13独立地选自甲基、甲氧基、三氟甲基、三氟甲氧基、二氟甲氧基、-SOCH 3、卤素、氰基。
第八方面，本公开还提供式III-f或式III-g所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000052
环C、R 11、R 12、R 15如式III中定义。
在某些实施方案中，式III、式III-f所示的化合物或其可药用盐中，R 15选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；优选R 15选自氢、甲基、环丙基、卤素、硝基、氰基、羟基；更优选R 15选自氢。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-f、III-g、III-h所示的化合物或其可药用盐中，环C选自任选被1-3个R 13取代的6-10元芳基、5-10元杂芳基；
每个R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 13a、-COR 13b、-SO 2R 13c、SOR 13c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 13a、R 13b和R 13c各自独立地选自氨基、C 1-6烷基、C 3-6环烷基、苯基、对甲基苯基；
优选地，
环C选自任选被1-3个R 13取代的苯基、萘基、含1-3个杂原子的5-10元杂芳基；
每个R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、含1-3个杂原子的3-6元杂环基、含1-3个杂原子的3-6元杂芳基、-NHCOR 13a、-COR 13b、-SO 2R 13c、SOR 13c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6 烷氧基、C 3-6环烷氧基、含1-3个杂原子的3-6元杂环基、含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
所述杂原子选自N、O、S；
R 13a、R 13b和R 13c各自独立地选自氨基、C 1-6烷基、C 3-6环烷基、苯基、对甲基苯基。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-f、III-g、III-h所示的化合物或其可药用盐中，环C选自任选被1-3个R 13取代的苯基、吡啶、哒嗪、吡嗪、嘧啶、
Figure PCTCN2022099499-appb-000053
优选环C选自任选被1-3个R 13取代的
Figure PCTCN2022099499-appb-000054
每个R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、四氢呋喃、四氢呋喃酮、吡咯烷、吡咯烷酮、
Figure PCTCN2022099499-appb-000055
三氮唑、-NHCOR 13a、-COR 13b、-SO 2R 13c、SOR 13c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、四氢呋喃、四氢呋喃酮、吡咯烷、吡咯烷酮、三氮唑、
Figure PCTCN2022099499-appb-000056
任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 13a、R 13b和R 13c各自独立地选自氨基、甲基、环丙基、苯基、对甲基苯基。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-f、III-g、III-h、III-i所示的化合物或其可药用盐中，R 12选自萘基、包含1-4个杂原子的9-15元杂芳基，所述萘基、包含1-4个杂原子的9-15元杂芳基任选被1-3个R 12a所取代，所述R 12a选自氧代、硫代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
所述杂原子选自N、O、S。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-f、III-g、III-h、III-i所示的化合物或其可药用盐中，R 12选自1-氧代-1,2-二氢异喹啉-5-基、1-硫代-1,2-二氢异喹啉-5-基、喹啉-5基、异喹啉-5-基、萘基、噻吩并[2,3-c]吡啶-4-基、
Figure PCTCN2022099499-appb-000057
所述1-氧代-1,2-二氢异喹啉-5-基、1-硫代-1,2-二氢异喹啉-5-基、喹啉-5基、异喹啉-5-基、萘基、噻吩并[2,3-c]吡啶-4-基、
Figure PCTCN2022099499-appb-000058
任选被1-3个R 12a所取代，所述R 12a选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-f、III-g、III-h、III-i所示的化合物或其可药用盐中，R 12选自
Figure PCTCN2022099499-appb-000059
所述
Figure PCTCN2022099499-appb-000060
任选被1-3个R 12a所取代，所述R 12a选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代。
在某些实施方案中，式III、III-a、III-b、III-c、III-d、III-e、III-f、III-g、III-h、III-i所示的化合物或其可药用盐中，R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
优选R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代。
更优选R 11选自氢、环丙基、三氟甲基。
第九方面，本公开还提供式IV所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000061
其中：
X 1、X 2独立地选自C、O、N，X 3选自C、N或键；优选X 1选自N，X 2选自C，X 3选自N；
环D选自萘基、包含1-4个杂原子的9-15元杂芳基；
R 18选自氧代、硫代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
所述杂原子选自N、O、S；
m选自0-3的整数；
R 16选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 17选自任选被1-3个R 17a取代的6-10元芳基、5-10元杂芳基；
每个R 17a独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 17b、-COR 17c、-SO 2R 17d、-SOR 17d；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 17b、R 17c和R 17d各自独立地选自氨基、C 1-6烷基、C 3-6环烷基、苯基、对甲基苯基。
在某些实施方案中，式IV所示的化合物或其可药用盐中，环D选自1-氧代-1,2-二氢异喹啉-5-基、1-硫代-1,2-二氢异喹啉-5-基、喹啉-5基、异喹啉-5-基、萘基、噻吩并[2,3-c]吡啶-4-基、
Figure PCTCN2022099499-appb-000062
R 18选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
m选自0-3的整数。
在某些实施方案中，式IV所示的化合物或其可药用盐中，环D选自1-氧代-1,2-二氢异喹啉-5-基；
R 18选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
m选自0-3的整数。
在某些实施方案中，式IV所示的化合物或其可药用盐中，R 17选自任选被1-3个R 17a取代的6-10元芳基、5-10元杂芳基；
每个R 17a独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 17b、-COR 17c、-SO 2R 17d、-SOR 17d；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基所取代；
R 17b、R 17c和R 17d各自独立地选自氨基、C 1-6烷基、C 3-6环烷基、苯基、对甲基苯基；
优选地，R 17选自任选被1-3个R 17a取代的苯基、萘基、含1-3个杂原子的3-6元杂芳基；
每个R 17a独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、含1-3个杂原子的3-6元杂环基、含1-3个杂原子的3-6元杂芳基、-NHCOR 17b、-COR 17c、-SO 2R 17d、-SOR 17d；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、含1-3个杂原子的3-6元杂环基、含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
所述杂原子选自N、O、S；
R 17b、R 17c和R 17d各自独立地选自氨基、C 1-6烷基、C 3-6环烷基、苯基、对甲基苯基。
在某些实施方案中，式IV所示的化合物或其可药用盐中，R 17选自任选被1-3个R 17a取代的苯基、吡啶、哒嗪、吡嗪、嘧啶、
Figure PCTCN2022099499-appb-000063
每个R 17a独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、四氢呋喃、四氢呋喃酮、吡咯烷、吡咯烷酮、
Figure PCTCN2022099499-appb-000064
三氮唑、-NHCOR 17b、 -COR 17c、-SO 2R 17d、-SOR 17d；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、四氢呋喃、四氢呋喃酮、吡咯烷、吡咯烷酮、三氮唑、
Figure PCTCN2022099499-appb-000065
任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 17b、R 17c和R 17d各自独立地选自氨基、甲基、环丙基、苯基、对甲基苯基。
在某些实施方案中，式IV所示的化合物或其可药用盐中，R 17选自任选被1-3个R 17a取代的吡啶；
每个R 17a独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、四氢呋喃、四氢呋喃酮、吡咯烷、吡咯烷酮、
Figure PCTCN2022099499-appb-000066
三氮唑、-NHCOR 17b、-COR 17c、-SO 2R 17d、-SOR 17d；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、四氢呋喃、四氢呋喃酮、吡咯烷、吡咯烷酮、三氮唑、
Figure PCTCN2022099499-appb-000067
任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
R 17b、R 17c和R 17d各自独立地选自氨基、甲基、环丙基、苯基、对甲基苯基；
优选地，
R 17选自任选被1-3个R 17a取代的
Figure PCTCN2022099499-appb-000068
每个R 17a独立地选自卤素、C 1-6烷基、C 3-6环烷基、硝基、氰基、1-3个卤素取代的C 1-6烷基。
在某些实施方案中，式IV所示的化合物或其可药用盐中，R 16选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
优选R 16选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
更优选R 16选自氢、环丙基、三氟甲基。
第十方面，本公开还提供下式所示的化合物或其可药用盐，
Figure PCTCN2022099499-appb-000069
Figure PCTCN2022099499-appb-000070
Figure PCTCN2022099499-appb-000071
Figure PCTCN2022099499-appb-000072
Figure PCTCN2022099499-appb-000073
第十一方面，本公开还提供一种如第一方面至第十方面所示的化合物的同位素取代物，优选地，所述的同位素取代为氘原子取代。
第十二方面，本公开还提供一种药物组合物，其包含第一方面至第十一方面所述的化合物或其可药用盐和可药用赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用盐。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
第十三方面，本公开还提供一种预防和/或治疗与MALT1相关病症的方法，其包括向有需要的受试者施用治疗有效量的如第一方面至第十一方面所述的化合物或其可药用盐或者如第十二方面所述的药物组合物。
所述与MALT1相关病症包括但不限于自身免疫性疾病、炎性疾病、癌症、肿瘤等，例如类风湿性关节炎、多重硬化症、系统性红斑狼疮或血管炎性疾病、造血系统原发性癌症或实体瘤，包括慢性髓性白血病、髓性白血病、非霍奇金淋巴瘤和其它B细胞淋巴瘤。
本公开还提供一种预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤的方法，其包括向有需要的受试者施用治疗有效量的如第一方面至第十一方面所述的化合物或其可药用盐或者如第十二方面所述的药物组合物。
所述自身免疫性疾病和炎性疾病，例如类风湿性关节炎、多重硬化症、系统 性红斑狼疮或血管炎性疾病，所述癌症或肿瘤例如造血系统原发性癌症或实体瘤，包括慢性髓性白血病、髓性白血病、非霍奇金淋巴瘤和其它B细胞淋巴瘤。
本公开还提供第一方面至第十一方面所述的化合物或其可药用盐或者第十二方面所述的药物组合物在制备用于预防和/或治疗与MALT1相关病症的药物中的用途。
本公开还提供第一方面至第十一方面所述的化合物或其可药用盐或者第十二方面所述的药物组合物在制备用于预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤的药物中的用途。
所述自身免疫性疾病和炎性疾病，例如类风湿性关节炎、多重硬化症、系统性红斑狼疮或血管炎性疾病，所述癌症或肿瘤例如造血系统原发性癌症或实体瘤，包括慢性髓性白血病、髓性白血病、非霍奇金淋巴瘤和其它B细胞淋巴瘤。
本公开还提供第一方面至第十一方面所述的化合物或其可药用盐或者第十二方面所述的药物组合物，其用于预防和/或治疗与MALT1相关病症的用途。
本公开还提供第一方面至第十一方面所述的化合物或其可药用盐或者第十二方面所述的药物组合物，其用于预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤的用途。
所述自身免疫性疾病和炎性疾病，例如类风湿性关节炎、多重硬化症、系统性红斑狼疮或血管炎性疾病，所述癌症或肿瘤例如造血系统原发性癌症或实体瘤，包括慢性髓性白血病、髓性白血病、非霍奇金淋巴瘤和其它B细胞淋巴瘤。
本公开所述的化合物或其可药用盐或药物组合物对MALT1具有很好的抑制作用，对MALT1的抑制活性的IC 50值在0.01至1000nM，某些化合物对MALT1的抑制活性的IC 50值在0.01至500nM，某些化合物对MALT1的抑制活性的IC50值在0.01至300nM，某些化合物对MALT1酶的抑制活性的IC 50值在0.01至200nM，某些化合物对MALT1酶的抑制活性的IC 50值在0.01至100nM，某些化合物对MALT1酶的抑制活性的IC 50值<100nM，某些化合物对MALT1酶的抑制活性的IC 50值<50nM。
本公开中所述化合物的可药用盐可选自无机盐或有机盐。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。所有这些异构体以及它们的混合物均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异 构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明所述化合物的化学结构中，键
Figure PCTCN2022099499-appb-000074
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022099499-appb-000075
可以为
Figure PCTCN2022099499-appb-000076
或者同时包含
Figure PCTCN2022099499-appb-000077
Figure PCTCN2022099499-appb-000078
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2022099499-appb-000079
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
虽然为简便起见将全部上述结构式画成某些异构体形式，但是本发明可以包括所有的异构体，如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。
互变异构体是有机化合物的结构异构体，通过被称为互变异构化的化学反应容易相互转化。这种反应常导致氢原子或质子的形式迁移，伴随着单键和邻近的双键的转换。一些常见的互变异构体为：酮-烯醇、内酰胺-内酰亚胺。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间，
Figure PCTCN2022099499-appb-000080
所有的互变异构形式在本发明的范围内。化合物的命名不排除任何互变异构体。
本公开所述化合物或其可药用盐、或其异构体的任何同位素标记的衍生物都被本公开所覆盖。能够被同位素标记的原子包括但不限于氢、碳、氮、氧、磷、氟、氯、碘等。它们可分别被同位素 2H(D)、 3H、 11C、 13C、 14C、 15N、 18F、 31P、 32P、 35S、 36Cl和 125I等代替。除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少3000倍的丰度的氘(即，至少45％的氘掺入)。
本公开还包括各种氘化形式的化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、 氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选被卤素或者氰基取代的C 1-C 6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法、途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
“烯基”包括具有2至12个碳原子的支链和直链烯烃或含有脂族烃基团的烯烃。例如“C 2-6烯基”表示具有2、3、4、5或6个碳原子的烯基。烯基的实例包括但不限于乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基。烯基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、 C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
“炔基”包括具有2至12个碳原子的支链和直链炔基或含有脂族烃基的炔烃。例如乙炔基、丙炔基(例如1-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基及1-甲基戊-2-炔基。炔基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至7个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“环烯基”指部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至8个碳原子。实例包括但不限于环戊烯基、环己烯基或环己二烯基。环烯基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6 烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。术语“杂环烷基”、“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至7个环原子。单环杂环烷基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“杂环烷基”非限制性实例包括：
Figure PCTCN2022099499-appb-000081
Figure PCTCN2022099499-appb-000082
等等。
所述杂环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为杂环烷基，其非限制性实例包括：
Figure PCTCN2022099499-appb-000083
等。
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2022099499-appb-000084
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基可以为5至12元或5至10元，更优选为5元或6元。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，
Figure PCTCN2022099499-appb-000085
等等。
所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2022099499-appb-000086
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
术语“烯氧基”指-O-(烯基)，其中烯基的定义如上所述。
术语“炔氧基”指-O-(炔基)，其中炔基的定义如上所述。
术语“环烷氧基”指-O-(环烷基)，其中环烷基的定义如上所述。
术语“杂环烷氧基”指-O-(杂环基)，其中杂环基的定义如上所述。
术语“环烯氧基”指-O-(环烯基)，其中环烯基的定义如上所述。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”指＝O取代基。
术语“硫代”指＝S取代基。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Shimadzu 2010 Mass Spectrometer或Agilent 6110A MSD质谱仪。
高效液相色谱法(HPLC)的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series、Shimadzu DGU-20A5R、Shimadzu LC-30AD、Shimadzu SIL-30AC或安捷伦Agilent 1200 LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3  150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，一般采用水和乙腈作为流动相，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(4-(三氟甲基)嘧啶-2-基)-1H-吡唑-4-甲酰胺1
Figure PCTCN2022099499-appb-000087
Figure PCTCN2022099499-appb-000088
第一步
5-肼基异喹啉1b
将异喹啉-5-胺(5.1g,35.37mmol)溶于浓盐酸(50mL)中，0℃加入亚硝酸钠(3.66g,53.06mmol)的水溶液(20mL)，反应30分钟后，逐滴加入氯化亚锡(19.95g,88.43mmol)的浓盐酸溶液(20mL)，室温反应3个小时，用20％氢氧化钠水溶液调pH至12～14，乙酸乙酯萃取(30mL*3)，有机相减压浓缩，残余物经硅胶柱层析色谱法以乙酸乙酯洗脱纯化，得到标题化合物1b(2.33g，产率：40.0％)。
MS(ESI)：m/z＝159.0[M+H] +。
第二步
1-(异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酸乙酯1d
将5-肼基异喹啉(2.33g,14.64mmol)和(Z)-2-(乙氧基亚甲基)-4,4,4-三氟-3-氧代丁酸乙酯1c(3.52g,14.64mmol)溶于乙醇(40mL)中，60℃反应3小时，减压浓缩得到粗产品，经硅胶柱层析色谱法以乙酸乙酯洗脱纯化，得到标题化合物1d(2.56g，产率：52.1％)。
MS(ESI)：m/z＝336.4[M+H] +。
第三步
5-(4-(乙氧羰基)-5-(三氟甲基)-1H-吡唑-1-基)异喹啉2-氧化物1e
将1-(异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酸乙酯(2.56g,7.64mmol)溶于二氯甲烷(30mL)，0℃加入间氯过氧苯甲酸(3.95g,22.9mmol)，室温反应过夜，依次用半饱和亚硫酸氢钠溶液(20mL*2)和碳酸钾溶液(20mL*2)洗涤，有机相干燥，真空浓缩，得到标题化合物1e(2.50g，产率：93.21％)。
MS(ESI)：m/z＝352.4[M+H] +。
第四步
1-(1-氯异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酸乙酯1f
将5-(4-(乙氧羰基)-5-(三氟甲基)-1H-吡唑-1-基)异喹啉2-氧化物(2.5g,7.12mmol)溶于氯仿(30mL)中，室温加入三氯氧磷(1.33mL,14.23mmol)，60℃反应3小时，冰浴下用水(20mL)淬灭，有机相真空浓缩，经硅胶柱层析色谱法以石油醚、 乙酸乙酯洗脱纯化，得到标题化合物1f(1.96g，产率：74.49％)。
MS(ESI)：m/z＝370.43[M+H] +。
第五步
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g
1-(1-氯异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯(1g,2.71mmol)溶于浓盐酸(15mL)，120℃反应3小时，真空浓缩得到标题化合物1g(864mg，产率：98.83％)。
MS(ESI):m/z＝324.4[M+H] +。
第六步
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(4-(三氟甲基)嘧啶-2-基)-1H-吡唑-4-甲酰胺1
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸(100mg,0.31mmol)和4-(三氟甲基)嘧啶-2-胺(50.46mg,0.31mmol)溶于吡啶(10mL)，室温加入三氯氧磷(0.058mL,0.62mmol)，120℃微波反应1小时。加入饱和碳酸氢钠水溶液(20mL)，二氯甲烷萃取(20mL*3)，有机相真空浓缩，经高效液相色谱法分离，得到标题化合物1(12mg，产率：8.28％)。
MS(ESI):m/z＝469.5[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.80(s,1H),11.62(s,1H),9.10(d,J＝5.0Hz,1H),8.44(d,J＝8.0Hz,1H),8.42(s,1H),7.93(d,J＝7.5Hz,1H),7.76(d,J＝5.0Hz,1H),7.68(t,J＝7.9Hz,1H),7.30-7.27(m,1H),5.71(d,J＝7.3Hz,1H)。
实施例2
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(6-(三氟甲基)嘧啶-4-基)-1H-吡唑-4-羧酰胺2
Figure PCTCN2022099499-appb-000089
第一步
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(6-(三氟甲基)嘧啶-4-基)-1H-吡唑-4-羧酰胺2
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸(120mg,0.37 mmol)和6-(三氟甲基)嘧啶-4-胺(60.55mg,0.37mmol)溶于吡啶(10mL)，室温加入三氯氧磷(0.069mL,0.74mmol)，120℃微波反应20min。加入饱和碳酸氢钠水溶液(20mL)，二氯甲烷萃取(20mL*3)，有机相减压浓缩，经高效液相色谱法分离，得到标题化合物2(11mg，产率：6.33％)。
MS(ESI)：m/z＝469.5[M+H] +。
1H NMR(400MHz,DMSO-d6)δ＝12.18(s,1H),11.63(d,J＝5.3Hz,1H),9.22(s,1H),8.56(d,J＝7.8Hz,2H),8.44(d,J＝8.0Hz,1H),7.95(d,J＝7.0Hz,1H),7.68(t,J＝7.9Hz,1H),7.34-7.25(m,1H),5.69(d,J＝7.3Hz,1H)。
实施例3
1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-5-(三氟甲基)-N-(2-(三氟甲基)吡啶-4-基)-1H-吡唑-4-甲酰胺3
Figure PCTCN2022099499-appb-000090
第一步
1-(1-肼基异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯3c
将1-(1-氯异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酸乙酯1f(200mg,0.54mmol)溶于二氧六环溶液中(12mL)，室温加入水合肼(3mL)，70℃反应5小时，反应液减压浓缩得到标题化合物3a(225mg，粗品)。
MS(ESI)：m/z＝366.5[M+H] +。
第二步
1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯3e
将1-(1-肼基异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯(225mg,0.62mmol)溶于原甲酸三乙酯(8mL)，100℃反应1小时，反应液减压浓缩得到标题化合物3e(220mg，产率：95.1％)。
MS(ESI)：m/z＝376.5[M+H] +。
第三步
1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-5-(三氟甲基)-1H-吡唑-4-羧酸3f
将1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯(220mg,0.58mmol)溶于浓盐酸(10mL)，120℃反应1小时，反应液减压浓缩得到标题化合物3f(240mg，粗品)。
MS(ESI)：m/z＝348.4[M+H] +。
第四步
1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-5-(三氟甲基)-N-(2-(三氟甲基)吡啶-4-基)-1H-吡唑-4-甲酰胺3
将1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-5-(三氟甲基)-1H-吡唑-4-羧酸(70mg,0.20mmol)和2-(三氟甲基)吡啶-4-胺3g(32.68mg,0.20mmol)溶于吡啶(6mL)中，逐滴加入三氯氧磷(0.038mL,0.40mmol)，室温反应1小时。加入水(10mL)，二氯甲烷萃取(3*15mL)，有机相减压浓缩，经高效液相色谱法分离，得到标题化合物2(27.1mg，产率：27.3％)。
MS(ESI)：m/z＝492.5[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ＝11.28(br s,1H),9.36(s,1H),8.83(d,J＝8.0Hz,1H),8.73(d,J＝5.5Hz,1H),8.60(s,1H),8.46(d,J＝7.5Hz,1H),8.26(s,1H),7.99(quin,J＝8.0Hz,3H),6.46(d,J＝7.5Hz,1H)。
实施例4
1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-N-(5-氯-6-甲氧基吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺4
Figure PCTCN2022099499-appb-000091
第一步
1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-N-(5-氯-6-甲氧基吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺4
将1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-5-(三氟甲基)-1H-吡唑-4-羧酸3f(71mg,0.20mmol)和5-氯-6-甲氧基吡啶-3-胺4a(32.42mg,0.20mmol)溶于吡啶(6mL)中，逐滴加入三氯氧磷(0.038mL,0.41mmol)，室温反应1小时。加入水(10mL)，二氯甲烷萃取(15mL*3)，有机相减压浓缩，经高效液相色谱法分离，得到标题化合物 4(5.5mg，产率：5.51％)。
MS(ESI)：m/z＝488.6[M+H] +。
实施例5
1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺5
Figure PCTCN2022099499-appb-000092
第一步
1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺5
将1-([1,2,4]三唑并[3,4-a]异喹啉-7-基)-5-(三氟甲基)-1H-吡唑-4-羧酸3f(70mg,0.20mmol)和5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-胺5a(39.43mg,0.20mmol)溶于吡啶(6mL)中，逐滴加入三氯氧磷(0.038mL,0.40mmol)，室温反应1小时，加入水(10mL)，二氯甲烷萃取(3*15mL)，有机相减压浓缩，经高效液相色谱法分离，得到标题化合物5(25mg，产率：23.6％)。
MS(ESI):m/z＝525.6[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ＝11.28(br s,1H),11.47-11.05(m,1H),9.35(s,1H),8.93-8.79(m,2H),8.71-8.66(m,1H),8.61(s,1H),8.46(d,J＝7.5Hz,1H),8.19(s,2H),8.08-7.92(m,2H),6.46(d,J＝7.5Hz,1H)。
实施例6
1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(2-(三氟甲基)吡啶-4-基)-1H-吡唑-4-甲酰胺6
Figure PCTCN2022099499-appb-000093
Figure PCTCN2022099499-appb-000094
第一步
1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯6b
将1-(1-氯异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯3a(200mg,0.54mmol)和硫脲(45.3mg,0.59mmol)溶于乙醇(10mL)中，80℃反应2小时，反应液加入水(10mL)，乙酸乙酯萃取(15mL*3)，有机相干燥，减压浓缩，得到标题化合物6b(214mg，粗品)。
MS(ESI)：m/z＝368.4[M+H] +。
第二步
1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸6c
将1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯(214mg,0.58mmol)溶于浓盐酸(10mL)，120℃反应1小时，反应液减压浓缩，得到标题化合物6c(198mg，粗品)。
MS(ESI)：m/z＝340.4[M+H] +。
第三步
1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(2-(三氟甲基)吡啶-4-基)-1H-吡唑-4-甲酰胺6
将1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸(51mg,0.15mmol)和2-(三氟甲基)吡啶-4-胺3g(24.37mg,0.15mmol)溶于吡啶(6mL)中，逐滴加入三氯氧磷(0.028mL,0.30mmol)，室温反应1小时。加入水(10mL)，二氯甲烷萃取(3*15mL)，有机相减压浓缩，经高效液相色谱法分离，得到标题化合物6(17.2mg，产率：23.6％)。
MS(ESI)：m/z＝484.5[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ13.62(s,1H),11.28(s,1H),9.02(d,J＝5.5Hz,1H),8.72(d,J＝5.5Hz,1H),8.56(s,1H),8.24(d,J＝2.0Hz,1H),8.08(dd,J＝7.7,1.2Hz,1H),7.98(dd,J＝5.4,2.0Hz,1H),7.80(t,J＝5.5Hz,1H),7.52(d,J＝7.2Hz,1H),6.15(d,J＝7.2Hz,1H)。
实施例7
N-(5-氯-6-甲氧基吡啶-3-基)-1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺7
Figure PCTCN2022099499-appb-000095
第一步
N-(5-氯-6-甲氧基吡啶-3-基)-1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺7
将1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸7a(65mg,0.19mmol)和5-氯-6-甲氧基吡啶-3-胺4a(30.38mg,0.19mmol)溶于吡啶(6mL)中，逐滴加入三氯氧磷(0.036mL,0.38mmol)，室温反应1小时，加入水(10mL)，二氯甲烷萃取(3*15mL)，有机相减压浓缩，经高效液相色谱法分离，得到标题化合物7(2mg，产率：2.18％)。
MS(ESI)：m/z＝480.6[M+H] +。
实施例8
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺8
Figure PCTCN2022099499-appb-000096
第一步
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺8
将1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸7a(60mg,0.18mmol)和5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-胺5a(34.59mg,0.18mmol)溶于吡啶(6mL)中，逐滴加入三氯氧磷(0.033mL,0.35mmol)，室温反应1小时。加入 水(10mL)，二氯甲烷萃取(15mL*3)，有机相减压浓缩，经高效液相色谱法分离，得到标题化合物8(4mg，产率：4.38％)。
MS(ESI)：m/z＝517.6[M+H] +。
实施例9
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-1-(异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-4-甲酰胺9
Figure PCTCN2022099499-appb-000097
第一步
5-叠氮异喹啉9b
将异喹啉-5-胺1a(1g,6.94mmol)溶于乙腈(14mL)中，0℃加入亚硝酸叔丁酯(1.1g,10.40mmol)和叠氮三甲基硅(1.2g,10.40mmol)，反应1小时后，将反应液浓缩后，经硅胶柱层析色谱法以乙酸乙酯和正己烷洗脱纯化，得到标题化合物9b(220mg，产率：19％)。
MS(ESI)：m/z＝171.2[M+H] +。
第二步
1-(异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-4-羧酸乙酯9c
将5-叠氮异喹啉9b(220mg,1.29mmol)和三氟乙酰乙酸乙酯(238mg,1.29mmol)溶于四氢呋喃(5mL)中，氮气氛下加热回流反应20个小时，减压弄多，经硅胶柱层析色谱法以乙酸乙酯和正己烷洗脱纯化，得到标题化合物9c(300mg，产率：69％)。
MS(ESI)：m/z＝337.4[M+H] +。
第三步
1-(异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-4-羧酸9d
1-(异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-4-羧酸乙酯9c(100mg,0.297 mmol)溶于乙醇(3mL)和水(1mL)，80℃反应2小时，反应液减压浓缩，残余物加入3毫升浓盐酸，再减压浓缩，得到标题化合物9d的粗品，产物不需要进一步纯化，直接用于下一步。
MS(ESI)：m/z＝309.1[M+H] +。
第四步
N-(5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-基)-1-(异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-4-甲酰胺9
将上一步粗品1-(异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-4-羧酸9d溶于吡啶(4mL)中，再加入5-氯-6-(2H-1,2,3-三唑-2-基)吡啶-3-胺5a(64mg,0.33mmol)，室温加入三氯氧磷(114mg,0.74mmol)，室温反应过夜。反应完成后，有机相减压浓缩，经C18反相柱色谱法纯化，冻干，得到标题化合物9(90mg，两步合并产率：62％)。
MS(ESI)：m/z＝486.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.82(br s,1H),9.59(s,1H),9.09(d,J＝2.4Hz,1H),8.80(d,J＝2.0Hz,1H),8.64(d,J＝6.0Hz,1H),8.56(d,J＝8.4Hz,1H),8.32(d,J＝6.8Hz,1H),8.20(s,2H),7.98(t,J＝8.0Hz,1H),7.29(d,J＝6.0Hz,1H)。
实施例10
N-(2-(二氟甲基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺10
Figure PCTCN2022099499-appb-000098
第一步
2-(二氟甲基)吡啶-4-胺10b
将4-溴-2-(二氟甲基)吡啶(300mg,1.44mmol)溶于氨水(2mL)和N-甲基吡咯烷酮(NMP)(1mL)中，加入氧化亚铜(41mg,0.29mmol，反应在微波140℃反应1小时。反应完成后，加入5ml乙酸乙酯，然后再用5ml水和5ml饱和NaCl水溶液分别洗涤两次，将有机相减压浓缩，得到标题化合物10b(210mg，粗品)，不需要进一步纯化，直接用于下一步。
MS(ESI)m/z：145.3[M+H] +。
第二步
N-(2-(二氟甲基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺10
将2-(二氟甲基)吡啶-4-胺10b(50mg,0.35mmol)溶于吡啶(3mL)中，再加入1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(112mg,0.35mmol),室温加入三氯氧磷(106mg,0.69mmol)，室温搅拌2小时。反应完成后，反应液减压浓缩，经C18反相柱色谱法纯化，冻干，得到标题化合物10(23.5mg，产率：15％)。
MS(ESI)m/z：450.6[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.64(s,1H),11.14(s,1H),8.63(d,J＝5.6Hz,1H),8.53(s,1H),8.45(d,J＝8.0Hz,1H),8.09(d,J＝2.0Hz,1H),7.95(d,J＝7.2Hz,1H),7.85(d,J＝5.6Hz,1H),7.68(t,J＝8.0Hz,1H),7.34-7.27(m,1H),7.13-6.79(m,1H),5.66(d,J＝7.6Hz,1H)。
实施例11
N-(苯并[c][1,2,5]噁二唑-5-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺11
Figure PCTCN2022099499-appb-000099
第一步
苯并[c][1,2,5]噁二唑-5-胺11b
将5-溴苯并[c][1,2,5]噁二唑11a(250mg,1.25mmol)溶于氨水(1.5mL)和N-甲基吡咯烷酮(1mL)中，加入氧化亚铜(36mg,0.25mmol，反应在微波140℃反应1小时。反应完成后，加入10ml乙酸乙酯，然后再用10ml水和10ml饱和NaCl水溶液分别洗两次，将有机相浓缩，得到标题化合物11b(180mg，粗品)，不需要进一步纯化，直接用于下一步。
MS(ESI)m/z：136.3[M+H] +。
第二步
N-(苯并[c][1,2,5]噁二唑-5-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺11
将苯并[c][1,2,5]噁二唑-5-胺11b(50mg,0.37mmol)溶于吡啶(3mL)中，再加入1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(119mg,0.37mmol)，室温加入三氯氧磷(113mg,0.74mmol)，室温反应2小时，反应液减压浓缩，经C18反相柱色谱法纯化，冻干，得到标题化合物11(8.3mg，产率：5％)。
MS(ESI)：m/z＝441.6[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.65(br s,1H),11.13(s,1H),8.54(s,2H),8.45(d,J＝8.0Hz,1H),8.13(d,J＝9.6Hz,1H),7.95(d,J＝7.2Hz,1H),7.76-7.64(m,2H),7.31(br s,1H),5.67(d,J＝7.6Hz,1H)。
实施例12
5-环丙基-1-(异喹啉-5-基)-N-(2-(三氟甲基)吡啶-4-基)-1H-吡唑-4-甲酰胺12
Figure PCTCN2022099499-appb-000100
第一步
(Z)-2-(环丙酰基)-3-乙氧基丙烯酸乙酯12c
室温，将3-环丙基-3-氧代丙酸乙酯(0.945mL,6.403mmol)溶于乙酸酐(1.8mL,19mmol)中，缓慢滴加原甲酸三乙酯(2mL,12mmol)，在130℃搅拌4h。反应完全后，将反应液减压浓缩，得到标题化合物12c(2.2g,产率：80％)，不经纯化，直接用于下一步反应。
第二步
5-环丙基-1-(异喹啉-5-基)-1H-吡唑-4-羧酸乙酯12d
将5-肼基异喹啉1b(0.60g,3.769mmol)和(Z)-2-(环丙酰基)-3-乙氧基丙烯酸乙酯12c(0.8g,3.769mmol)溶解于乙醇(10mL)，在60℃搅拌反应3小时至反应 完全。反应液冷却至室温，减压浓缩得到粗品，残余物用硅胶柱色谱法以洗脱剂体系(石油醚，乙酸乙酯)纯化，得到标题产物12d(120mg,产率：10％)。
MS(ESI)m/z：308.0[M+H] +。
第三步
5-环丙基-1-(异喹啉-5-基)-1H-吡唑-4-羧酸12e
室温，将化合物12d(50mg,0.163mmol)溶于甲醇(2mL)和水(1mL)，加入氢氧化钠(13mg,0.325mmol)。反应液加热到65℃，搅拌反应3小时至反应完全。反应液冷却至室温，反应液用水(10mL)稀释后，用1N盐酸调节pH＝5，水相用乙酸乙酯(15mL×3)萃取。合并有机相，用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物12e(40mg，产率：88％)。
MS(ESI)m/z：280.1[M+H] +。
1H NMR(400MHz,CD 3OD)δ＝9.43(s,1H),8.52(d,J＝6.0Hz,1H),8.37(d,J＝8.4Hz,1H),8.14(s,1H),8.01-7.94(m,1H),7.88(t,J＝7.6Hz,1H),7.30(d,J＝6.0Hz,1H),1.92-1.80(m,1H),0.80-0.55(m,4H)。
第四步
5-环丙基-1-(异喹啉-5-基)-N-(2-(三氟甲基)吡啶-4-基)-1H-吡唑-4-甲酰胺12
室温，将化合物12e(20mg,0.072mmol)、2-(三氟甲基)吡啶-4-胺3g(11.61mg,0.072mmol)和吡啶(56.64mg,0.716mmol)溶解于二氯甲烷(2mL)，加入三氯氧磷(11mg,0.072mmol)。在25℃搅拌反应1小时，然后升温至50℃继续反应1小时。反应液用饱和碳酸氢钠溶液(0.1mL)淬灭，减压浓度，得到粗品化合物。粗品化合物用制备HPLC(乙腈/水)纯化，得到标题化合物12(6mg，收率：29％)。
MS(ESI)m/z：424.1[M+H] +。
实施例13
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-(6-(2-氧代吡咯烷-1-基)-5-(三氟甲基)吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺13
Figure PCTCN2022099499-appb-000101
Figure PCTCN2022099499-appb-000102
第一步
5-硝基-3-(三氟甲基)吡啶-2-胺13b
将3-(三氟甲基)吡啶-2-氨13a(1g,6.169mmol)溶于浓H 2SO 4(10mL)中，冷却到0℃，缓慢滴加浓HNO 3(0.309mL,7.402mmol)。在0℃反应1小时，然后在25℃反应3h至反应完全。将反应液倒入冰水中(20mL)，用乙酸乙酯萃取(30mL x 3)。合并有机相并用水(30mL x 3)、盐水(30mL x 3)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经硅胶柱层析色谱法(0～20％乙酸乙酯/石油醚)纯化，得到标题化合物13a(1.0g，78％)。
1H NMR(400MHz,DMSO-d6)δppm 9.04(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H),7.91(s,2H)。
第二步
1-(5-硝基-3-(三氟甲基)吡啶-2-基)吡咯烷-2-酮13d
将5-硝基-3-(三氟甲基)吡啶-2-胺13b(500mg,2.414mmol)溶于乙腈(10mL)中，缓慢滴加氯丁酰氯(0.545mL,4.828mmol)和二异丙基乙胺(1.197mL,7.243mmol)，在25℃反应12小时。将反应液减压浓缩，残余物经硅胶柱层析色谱法(0～30％乙酸乙酯/石油醚)纯化，得到标题化合物13d(100mg，收率：15％)。
1H NMR(400MHz,CDCl 3)δppm 9.44(d,J＝2.4Hz,1H),8.83(d,J＝2.4Hz,1H),4.05(t,J＝7.2Hz,2H),2.67-2.59(m,2H),1.29-1.23(m,2H)。
第三步
1-[5-氨基-3-(三氟甲基)吡啶-2-基]吡咯烷-2-酮13e
将1-(5-硝基-3-(三氟甲基)吡啶-2-基)吡咯烷-2-酮13d(100mg,0.363mmol)溶于甲醇中(10mL)，在氩气氛下加入Pd/C 10％(39mg,0.363mmol)。氢气置换后，在氢气氛围中(15psi)室温反应至反应完全。滤除不溶物，减压浓缩，得到标题化合物13e(50mg，收率：56％)，产物不经纯化，直接用于下一步。
MS(ESI)m/z：246.1[M+H] +。
第四步
1-(1-氧代-1,2-1,2-二氢异喹啉-5-基)-N-(6-(2-氧代吡咯烷-1-基)-5-(三氟甲基)吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺13
将1-[5-氨基-3-(三氟甲基)吡啶-2-基]吡咯烷-2-酮13e(35mg,0.143mmol)、1-(1-氧代-1,2-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(46.14mg,0.143mmol)和吡啶(0.115mL,1.427mmol)溶于二氯甲烷(5mL)，缓慢滴加三氯氧磷(0.013mL,0.143mmol)。室温搅拌反应至反应完全。将反应液倒入饱和碳酸氢钠溶液(20mL)，用二氯甲烷(30mL x 3)萃取。将合并的有机相用无水硫酸钠干燥，过滤并减压浓缩。残余物用制备高效液相色谱法(22-42％乙腈-水)纯化，得到标题化合物13(7.1mg，收率：9％)。
MS(ESI)m/z：551.2[M+H] +。
1H NMR(400MHz,CD 3OD)δppm 9.06(d,J＝2.4Hz,1H),8.74(d,J＝2.4Hz,1H),8.57(d,J＝8.0Hz,1H),8.35(s,1H),7.87(d,J＝6.8Hz,1H),7.75-7.64(m,1H),7.25(d,J＝7.2Hz,1H),5.93(d,J＝7.6Hz,1H),3.96-3.83(m,2H),2.64-2.55(m,2H),2.30(quin,J＝7.6Hz,2H)。
19F NMR:(400MHz,CD 3OD)δppm-58.204,-63.608。
实施例14
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(2-(三氟甲基)吡啶-4-基)-1H-1,2,3-三唑-4-甲酰胺14
Figure PCTCN2022099499-appb-000103
第一步
5-(4-(乙氧羰基)-5-(三氟甲基)-1H-1,2,3-三唑-1-基)异喹啉2-氧化物14b
将1-(异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-4-甲酸乙酯14a(250mg,0.74mmol)溶于二氯甲烷(5mL)，加入间氯过氧苯甲酸(385mg,2.23mmol)，室温反应3小时。反应液加入10ml二氯甲烷稀释，再用2mmol/L的亚硫酸氢钠(10mL)洗涤，再加入饱和碳酸氢钠溶液(10mL)洗涤，有机相用无水硫酸钠干燥，过滤， 滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系乙酸乙酯/正己烷纯化，得到标题化合物14b(200mg，产率：76％)。.
MS(ESI)：m/z＝337[M+H] +。
第二步
1-(1-氯异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-羧酸乙酯14c
将化合物14b(200mg,0.57mmol)溶于三氯氧磷(5mL)，加热回流3小时。将反应液减压浓缩，得到标题化合物14c(210mg，产率：100％)，不需要进一步纯化，直接用于下一步。
MS(ESI)：m/z＝371[M+H] +。
第三步
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-1,2,3-三唑-4-羧酸14d
将化合物14c(200mg,0.54mmol)溶于浓盐酸中(8mL)，加热回流6小时。将反应液减压浓缩，残余物经C18反相柱色谱法纯化，冻干，得到标题化合物14d(95mg，产率：54％)。
MS(ESI)：m/z＝325[M+H] +。
1H NMR(400MHz,DMSO- d6)11.73(s,2H),8.74(d,J＝5.6Hz,1H),8.53(d,J＝8.0Hz,1H),8.45(d,J＝2.0Hz,1H),8.20-8.15(m,2H),7.75(t,J＝7.9Hz,1H),7.31(d,J＝7.2Hz,1H),5.80(d,J＝7.2Hz,1H)。
第四步
1-(1-羰基-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(2-(三氟甲基)吡啶-4-基)-1H-1,2,3-三唑-4-甲酰胺14
将化合物14d(30mg,0.09mmol)溶于吡啶(3mL)中，再加入2-(三氟甲基)吡啶-4-胺3g(15mg,0.09mmol)，室温下加入三氯氧磷(28mg,0.18mmol)，室温下反应2小时。反应液减压浓缩，经C18反相柱色谱法纯化，冻干，得到标题化合物14(10mg，产率：23％)。
MS(ESI)：m/z＝469[M+H] +。
实施例15
N-(5-氯-6-(1-环丙基-1H-吡唑-4-基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺15
Figure PCTCN2022099499-appb-000104
Figure PCTCN2022099499-appb-000105
第一步
5-氯-6-(1-环丙基-1H-吡唑-4-基)吡啶-3-氨基15c
将1-环丙基吡唑-4-硼酸频哪醇酯15a和15b(200mg,0.85mmol)溶于二氧六环(3mL)中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(70mg,0.085mmol)和碳酸钾(236mg,1.71mmol)，微波反应1小时。反应完成后，将加入10ml乙酸乙酯稀释，再用水(10mL)洗涤，再加入饱和NaCl水溶液(10mL)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析色谱法以洗脱剂体系乙酸乙酯/正己烷纯化，得到标题化合物15c(80mg，产率：40％).
MS(ESI)：m/z＝235[M+H] +。
第二步
N-(5-氯-6-(1-环丙基-1H-吡唑-4-基)吡啶-3-基)-1-(1-羰基-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺15
将化合物15c(30mg,0.13mmol)溶于吡啶(3mL)中，再加入1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(41mg,0.13mmol)，室温加入三氯氧磷(39mg,0.26mmol)，室温反应2小时。反应液减压浓缩，经C18反相柱色谱法纯化，冻干，得到标题化合物15(12mg，产率：17％)。
MS(ESI)：m/z＝540[M+H] +。
实施例16
N-[5-氯-6-(2,5-二氢呋喃-3-基)吡啶-3-基]-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺16
Figure PCTCN2022099499-appb-000106
第一步
N-[5-氯-6-(2,5-二氢呋喃-3-基)吡啶-3-基]-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟 甲基)-1H-吡唑-4-甲酰胺16
将1-(1-氧代-1，2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(59mL,0.18mmol)溶于二氯甲烷(3mL)中，室温加入2-氯-1-甲基吡啶-1-鎓碘化物(116mg,0.458mmol)、二异丙基乙基胺(0.25mL,1.53mmol)和5-氯-6-(2,5-二氢呋喃-3-基)吡啶-3-胺(30mg,0.15mmol)，45℃反应12小时，减压浓缩，残余物经高效液相色谱法纯化，得到标题化合物16(4.1mg，产率：5.3％)。
MS(ESI)：m/z＝502.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ11.63(d,J＝5.2Hz,1H),11.04(s,1H),8.77(d,J＝2.4Hz,1H),8.50(s,1H),8.46-8.40(m,3H),7.97-7.92(m,1H),7.94(d,J＝6.8Hz,1H),7.67(t,J＝8.0Hz,1H),7.32-7.27(m,1H),7.00(t,J＝2.0Hz,1H),5.65(d,J＝7.2Hz,1H),5.07-4.99(m,2H),4.86(t,J＝4.0Hz,2H)。
实施例17
N-(5-氯-6-(四氢呋喃-3-基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺17
Figure PCTCN2022099499-appb-000107
第一步
N-(5-氯-6-(四氢呋喃-3-基)吡啶-3-基)-1-(1-氧代-1，2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺17
将N-[5-氯-6-(2,5-二氢呋喃-3-基)吡啶-3-基]-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺16(50mg,0.1mmol)溶于甲醇(6mL)中，室温加入钯碳(10％,20mg)，氢气氛下，室温搅拌40分钟。通过硅藻土过滤。滤液减压浓缩，残余物经高效液相色谱法分离，得到标题化合物17(4.5mg，产率：8.9％)。
MS(ESI)：m/z＝503.4[M+H] +。
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.46-8.40(m,2H),8.34(d,1H),7.97-7.92(m,1H),7.68-7.64(m,1H),7.32-7.27(m,1H),5.65(d,1H),4.09-4.05(m,1H),3.91-3.75(m,5H),2.50-2.2.20(m,2H)。
实施例18
N-(5-氯-6-(四氢呋喃-2-基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺18
Figure PCTCN2022099499-appb-000108
第一步
3-[(N,N-二叔丁氧羰基)氨基]-1-氯-吡啶18b
将5-氯吡啶-3-胺18a(500mg,3.89mmol)溶于四氢呋喃(8mL)，室温加入二碳酸二叔丁酯(2.49mL,11.67mmol)和对二甲氨基吡啶(23mg,0.19mmol)，室温反应12小时。将反应液倒入水(15mL)，乙酸乙酯萃取(15mL*2)，有机相合并，经饱和氯化钠水溶液洗涤(20mL*2)，无水硫酸钠干燥，减压浓缩，经硅胶柱色谱分离，得到标题化合物18b(800mg，产率：62.5％)。
1H NMR(400MHz,CDCl 3)δ8.51(s,1H),8.33(s,1H),7.54(t,J＝2.0Hz,1H),1.45(s,18H)。
第二步
2-(2-环氧戊基)-3-氯-5-[(N,N-二叔丁氧羰基)氨基]-吡啶18c
将3-[(N,N-二叔丁氧羰基)氨基]-1-氯-吡啶18b(200mg,0.61mmol)溶于二甲基亚砜(2mL)，室温加入4-甲基苯-1-磺酸(0.078mL,0.49mmol)，室温搅拌20分钟，加入四氢呋喃(2mL,24.41mmol)、过氧二硫酸铵(0.35mL,3.04mmol)和二[2-(2,4-二氟苯基)-5-三氟甲基吡啶][2-2”-联(4-叔丁基吡啶)]铱二(六氟磷酸)盐(68mg,0.061mmol)，将反应液脱气10分钟并密封。蓝光照射下，反应混合物在室温搅拌3小时，加入水(20mL)，经乙酸乙酯萃取(20mL*2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，粗品经高效液相色谱法分离，得到标题化合物18c(40mg，产率：16％)。
1H NMR(400MHz,CDCl 3)δ8.34(d,J＝2.0Hz,1H),7.51(d,J＝2.0Hz,1H),5.40(t,J＝6.8Hz,1H),4.28-4.16(m,1H),4.08-3.94(m,1H),2.44-2.32(m,1H),2.19-1.95(m,3H),1.44(s,18H)。
第三步
5-氯-6-(四氢呋喃-2-基)吡啶-3-胺18d
将2-(2-环氧戊基)-3-氯-5-[(N,N-二叔丁氧羰基)氨基]-吡啶18c(30mg,0.075mmol)溶于二氯甲烷(1.5mL)中，冰浴下加入三氟乙酸(1.5mL,20.19mmol)。室温反应2小时，反应液减压浓缩，得到标题化合物18d(14mg，产率：93％)。
1H NMR(400MHz,CDCl 3)δ8.01(d,J＝2.4Hz,1H),6.98(d,J＝2.4Hz,1H),5.37-5.22(m,1H),4.14(q,J＝7.2Hz,1H),3.93(dt,J＝5.6,7.6Hz,1H),2.31-1.92(m,4H)。
第四步
N-(5-氯-6-(四氢呋喃-2-基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺18
将5-氯-6-(四氢呋喃-2-基)吡啶-3-胺18d(10mg,0.05mmol)溶于四氢呋喃(1mL)中，冰浴下加入氢化钠(10mL,0.25)，然后加入1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯21h(25mg,0.073mmol)的四氢呋喃溶液(1mL)，室温反应12小时，加入水(15mL)，经乙酸乙酯萃取(15mL*2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品经高效液相色谱法分离得到标题化合物18(1.8mg，产率：7.4％)。
MS(ESI)：m/z＝504.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ11.62(d,J＝5.2Hz,1H),10.96(s,1H),8.75(d,J＝2.0Hz,1H),8.49(s,1H),8.46-8.39(m,1H),8.34(d,J＝2.0Hz,1H),7.94(d,J＝7.2Hz,1H),7.67(t,J＝8.0Hz,1H),7.32-7.25(m,1H),5.65(d,J＝7.6Hz,1H),5.26(t,J＝6.8Hz,1H),3.93(q,J＝7.2Hz,1H),3.86-3.77(m,1H),2.22-2.15(m,2H),2.10-2.02(m,1H),2.00-1.92(m,1H)。
实施例19
N-(5-氯-6-(2-氧代吡咯烷-1-基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺19
Figure PCTCN2022099499-appb-000109
Figure PCTCN2022099499-appb-000110
第一步
1-(3-氯-5-硝基吡啶-2-基)吡咯烷-2-酮19b
将2-溴-3-氯-5-硝基吡啶19a(3.0g,12.63mmol)溶于1,4-二氧六环(25mL)中，室温加入吡咯烷-2-酮(1.95mL,25.27mmol)、甲基[2-(甲基氨基)乙基]胺(0.27mL,2.53mmol)、磷酸钾(5.36g,25.27mmol)和碘化铜(0.086mL,2.53mmol)。氮气氛下，110℃反应12小时，冷却至室温，加入水(50mL)，乙酸乙酯萃取(80mL*3)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱色谱分离得到标题化合物(1.0g，产率：32％)。
MS(ESI)：m/z＝242.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ9.18(d,J＝2.4Hz,1H),8.58(d,J＝2.4Hz,1H),4.05(t,J＝7.2Hz,2H),2.65(t,J＝8.0Hz,2H),2.30(q,J＝7.6Hz,2H)。
第二步
1-(5-氨基-3-氯吡啶-2-基)吡咯烷-2-酮19c
将1-(3-氯-5-硝基吡啶-2-基)吡咯烷-2-酮19b(1.0g,4.14mmol)溶于乙醇/水(20mL/5mL)，室温加入氯化铵(2.21g,41.3mmol)和铁粉(1.16g,20.6mmol)，90℃反应1小时，冷却至室温，经硅藻土抽滤，滤液减压浓缩，得到标题化合物19c(800mg，产率：91.3％)。
MS(ESI)：m/z＝212.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ7.75(d,J＝2.8Hz,1H),7.08(d,J＝2.8Hz,1H),5.79-5.67(m,2H),3.65(t,J＝7.2Hz,2H),2.41-2.33(m,2H),2.15-2.04(m,2H)。
第三步
N-(5-氯-6-(2-氧代吡咯烷-1-基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺19
将1-(5-氨基-3-氯吡啶-2-基)吡咯烷-2-酮19c(61mg,0.29mmol)溶于四氢呋喃(4mL)中，0℃加入氢化钠(58mg,1.46mmol)和1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯21h(100mg,0.29mmol)的四氢呋喃溶液(4mL)。室温反应1小时后，反应液60℃再搅拌1小时，冷却至室温，缓慢加入饱和氯化铵水溶液(30mL)淬灭反应，乙酸乙酯萃取(30mL*3)。有机相合并，无水硫 酸钠干燥，减压浓缩，残余物经高效液相色谱法分离得到标题化合物19(55mg，产率：37％)。
MS(ESI)：m/z＝571.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),11.02(s,1H),8.71(d,J＝2.4Hz,1H),8.50(s,1H),8.47-8.38(m,2H),7.94(d,J＝6.8Hz,1H),7.67(t,J＝7.6Hz,1H),7.29(d,J＝7.2Hz,1H),5.65(d,J＝7.2Hz,1H),3.86-3.77(m,2H),2.49-2.43(m,2H),2.16(q,J＝7.2Hz,2H)。
实施例20
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(4-(三氟甲基)吡啶-2-基)-1H-吡唑-4-甲酰胺20
Figure PCTCN2022099499-appb-000111
第一步
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(4-(三氟甲基)吡啶-2-基)-1H-吡唑-4-甲酰胺20
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(60mg,0.19mmol)和4-(三氟甲基)吡啶-2-胺3g(30mg,0.19mmol)溶于吡啶(6mL)中，逐滴加入三氯氧磷(0.035mL,0.37mmol)，室温反应1小时，加入水(10mL)，二氯甲烷萃取(15mL*3)，有机相减压浓缩，残余物经高效液相色谱法分离，得到标题化合物20(31mg，产率：35％)。
MS(ESI)：m/z＝468.6[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ＝11.68(s,1H),11.62(d,J＝5.0Hz,1H),8.71(d,J＝5.0Hz,1H),8.51(d,J＝7.0Hz,2H),8.44(d,J＝8.0Hz,1H),7.94(d,J＝7.5Hz,1H),7.67(t,J＝7.8Hz,1H),7.59(d,J＝5.0Hz,1H),7.30～7.27(m,1H),5.72(d,J＝7.3Hz,1H)。
实施例21
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(6-(三氟甲基)哒嗪-4-基)-1H-吡唑-4-甲酰胺21
Figure PCTCN2022099499-appb-000112
第一步
6-碘哒嗪-4-羧酸甲酯21b
向6-氯哒嗪-4-羧酸甲酯(2g，11.589mmol)的氢碘酸(20ml)的混合物加入碘化钠(2.61g，17.384mmol)。在氮气氛围下，于50℃搅拌12小时。将反应混合物冷却至室温，用水稀释(50毫升)。用饱和碳酸氢钠水溶液将混合物调节至pH＝7，并用二氯甲烷(50mL x 3)提取。合并的有机层用盐水(50毫升)洗涤，无水硫酸钠干燥，过滤并减压浓缩，得到标题化合物21b(740mg，收率：87％)。
MS(ESI)m/z＝264.9[M+H] +。
1H NMR(400MHz,CDCl 3)δppm 9.52(d,J＝1.6Hz,1H),8.30(d,J＝2.0Hz,1H),3.95(s,3H)。
第二步
6-(三氟甲基)哒嗪-4-羧酸甲酯21d
将6-碘哒嗪-4-羧酸甲酯(600mg，2.273mmol)和21c(639mg，2.046mmol)溶于N,N-二甲基甲酰胺(5毫升)中，混合物在氮气氛下微波加热至110℃，持续 4小时。用水(10mL)缓慢淬灭反应混合物。水层用乙酸乙酯(30mL x 3)提取。合并的有机层用盐水(30mL x 2)和水(30mL x 3)洗涤，无水硫酸钠干燥，过滤并减压浓缩。残余物用硅胶柱层析色谱法(流动剂为0～15％乙酸乙酯/石油醚梯度30ml/分钟)纯化，得到6-(三氟甲基)哒嗪-4-羧酸甲酯21d(210mg，收率：44.8％)。
MS(ESI)m/z：207.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.88(d,J＝1.6Hz,1H),8.35(d,J＝2.0Hz,1H),4.10(s,3H)。
第三步
6-(三氟甲基)哒嗪-4-羧酸21e
向6-(三氟甲基)哒嗪-4-羧酸甲酯(270mg,1.310mmol)在四氢呋喃(4mL)和水(2mL)中的混合物中加入氢氧化锂(164mg,3.930mmol)。混合物在20℃搅拌1小时，用1N盐酸将混合物调节至pH＝5。混合物用乙酸乙酯(20mL x 2)萃取。合并有机层，用盐水(30mL x 2)洗涤，用无水硫酸钠干燥，过滤并减压浓缩，得到6-(三氟甲基)哒嗪-4-羧酸21e(220mg，收率：87％)。
MS(ESI)m/z＝193.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δppm 9.84(d,J＝1.6Hz,1H),8.45(d,J＝2.0Hz,1H)。
第四步
N-[6-(三氟甲基)哒嗪-4-基]氨基羧酸叔丁酯21f
向6-(三氟甲基)哒嗪-4-羧酸(210mg，1.093mmol)的叔丁醇(5ml)混合物中，加入叠氮磷酸二苯酯(DPPA)(0.284ml，1.312mmol)和三乙胺(0.228ml，1.640mmol)。混合物在90℃搅拌12小时。反应混合物减压浓缩，加入水(10ml)，用乙酸乙酯(10mL x 3)萃取。合并有机层，用盐水(10mL)洗涤，无水硫酸钠干燥，过滤并减压浓缩。残余物用硅胶柱层析色谱法(溶剂为0～30％乙酸乙酯/石油醚)纯化，得到N-[6-(三氟甲基)哒嗪-4-基]氨基羧酸叔丁酯21f(140mg，收率：43.79％)。
MS(ESI)m/z＝264.1[M+H] +。
1H NMR(400MHz,CDCl 3)δppm 9.18(d,J＝2.4Hz,1H),8.31(d,J＝2.4Hz,1H),7.17(br s,1H),1.58(s,9H)。
第五步
6-(三氟甲基)哒嗪-4-胺21g
向N-[6-(三氟甲基)哒嗪-4-基]氨基羧酸叔丁酯(140mg，0.532mmol)在二氯甲烷(2ml)中的混合物加入三氟乙酸(1ml)。室温反应，TLC(PE/EA＝3:1)显示反应完全。用1N氢氧化钠水溶液将反应混合物调节至pH＝8，用二氯甲烷(10mL x 3)萃取，有机层用饱和盐水(10mL)洗涤，无水硫酸钠干燥，过滤，减压蒸发溶剂，得到6-(三氟甲基)哒嗪-4-胺21g(100mg，收率：97％)。
MS(ESI)m/z＝164.1[M+H] +。
1H NMR(400MHz,CDCl 3)δppm 8.70(d,J＝2.4Hz,1H),7.03(s,2H),6.97(d,J＝2.4Hz,1H)。
第六步
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯21h
0℃，向1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(100mg，0.309mmol)在二氯甲烷(2ml)中的混合物加入草酰氯(0.040ml，0.464mmol)和DMF(0.002ml，0.031mmol)。混合物在20℃搅拌1小时，减压浓缩，得到1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯(100mg，收率：94％)，无需进一步纯化，直接用于下一步骤。
MS(ESI)m/z＝338.0[M+H] +。
第七步
1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-[6-(三氟甲基)哒嗪-4-基]-1H-吡唑-4-甲酰胺21
在0℃，向6-(三氟甲基)哒嗪-4-胺21g(25mg，0.153mmol)的四氢呋喃(2ml)溶液中加入氢化钠(30.66mg，0.766mmol)。在0℃，加入1-(1-氧代-1，2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯21h(52.37mg，0.153mmol)的四氢呋喃(2ml)溶液。加入饱和氯化铵水溶液(10mL)使反应缓慢停止。水层用乙酸乙酯(20mL x 3)萃取。合并有机层，用盐水(20mL)洗涤，无水硫酸钠干燥，过滤并减压浓缩。残余物用制备高效液相色谱法纯化(条件：水(0.1％甲酸)-乙腈；)，得到1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-[6-(三氟甲基)哒嗪-4-基]-1H-吡唑-4-甲酰胺21(6mg，收率：15％)。
MS(ESI)m/z＝469.1[M+H] +。
1H NMR:(400MHz,DMSO-d 6)δppm 11.66(d,J＝5.6Hz,1H),11.57(s,1H),9.65(d,J＝2.0Hz,1H),8.57(s,1H),8.54-8.50(m,1H),8.45(d,J＝8.0Hz,1H),7.98(d,J＝7.6Hz,1H),7.73-7.64(m,1H),7.31(t,J＝6.8Hz,1H),5.65(d,J＝7.2Hz,1H)。
实施例22
1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(6-(三氟甲基)哒嗪-4-基)-1H-吡唑-4-甲酰胺22
Figure PCTCN2022099499-appb-000113
Figure PCTCN2022099499-appb-000114
第一步
1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-N-(6-(三氟甲基)哒嗪-4-基)-1H-吡唑-4-甲酰胺22
将1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸7a(60mg,0.18mmol)和6-(三氟甲基)哒嗪-4-胺22a(28.84mg,0.18mmol)溶于吡啶(6mL)中，室温加入三氯氧磷(0.033mL,0.35mmol)，60℃反应2小时，冷却至室温，加入饱和碳酸氢钠水溶液(15mL)，二氯甲烷萃取(15mL*3)，有机相减压浓缩，残余物经高效液相色谱法分离，得到标题化合物22(16mg，产率：18％)。
MS(ESI)：m/z＝485.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.64(d,J＝2.4Hz,1H),9.02(d,J＝8.4Hz,1H),8.58(s,1H),8.52(d,J＝2.4Hz,1H),8.10～8.08(m,1H),7.80(t,J＝7.1Hz,1H),7.52(d,J＝7.1Hz,1H),6.15(d,J＝7.1Hz,1H)。
实施例23
N-(2-氯-6-(三氟甲基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺23
Figure PCTCN2022099499-appb-000115
第一步
N-(2-氯-6-(三氟甲基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺23
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(300mg,0.93mmol)和2-氯-6-(三氟甲基)吡啶-4-胺23a(182.43mg,0.93mmol)溶于吡啶(10mL)中，室温加入三氯氧磷(0.17mL,1.86mmol)，室温反应1小时，加入饱和碳酸氢钠水溶液(20mL)，二氯甲烷萃取(20mL*3)，有机相减压浓缩，残余物经高效液相色谱法分离，得到标题化合物23(300mg，产率：64％)。
MS(ESI)：m/z＝502.6[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.64(br d,J＝5.2Hz,1H),11.41(br s,1H),8.54(s,1H),8.44(d,J＝8.0Hz,1H),8.17～8.10(m,2H),7.99～7.93(m,1H),7.67(t,J＝8.0Hz,1H),7.32～7.27(m,1H),5.64(d,J＝7.2Hz,1H)。
实施例24
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-(2-氧代-6-(三氟甲基)-1,2-二氢吡啶-4-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺24
Figure PCTCN2022099499-appb-000116
第一步
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-(2-氧代-6-(三氟甲基)-1,2-二氢吡啶-4-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺24
将N-(2-氯-6-(三氟甲基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺23(157mg,0.31mmol)溶于二氧六环/水(12mL/4mL)中，室温加入双二亚苄基丙酮钯(359.83mg,0.63mmol)、2-二-叔丁膦基-2',4',6'-三异丙基联苯(26.57mg,0.063mmol)和氢氧化钾(35.11mg,0.63mmol)。115℃反应1小时，反应液经硅藻土滤过，滤液减压浓缩，残余物经高效液相色谱法纯化，得到标题化合物24(36mg，产率：23％)。
MS(ESI)：m/z＝484.3[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),11.07(s,1H),8.50(s,1H),8.44(d,J＝8.0Hz,1H),7.94(d,J＝6.8Hz,1H),7.67(t,J＝7.8Hz,1H),7.63(s,1H),7.36-7.25(m,2H),5.65(d,J＝7.3Hz,1H)。
实施例25
N-(苯并[c][1,2,5]噻二唑-5-基-1-(1-氧代-1,2-二氢异喹啉-5-基-5-三氟甲基)-1H-吡唑-4-甲酰胺25
Figure PCTCN2022099499-appb-000117
第一步
N-(苯并[c][1,2,5]噻二唑-5-基-1-(1-氧代-1,2-二氢异喹啉-5-基-5-三氟甲基)-1H-吡唑-4-甲酰胺25
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(50mg,0.16mmol)溶于吡啶(3mL)中，加入苯并[c][1,2,5]噻二唑-5-胺25a(28mg,0.19mmol)和三氯氧磷(47mg,0.31mmol)，室温反应2小时。将反应液减压浓缩，通过制备高效液相色谱法纯化，得到标题化合物25(24mg，产率：34％)。
MS(ESI)：m/z＝457.2[M+H] +。
1H NMR(400MHz,DMSO- d6)δ11.63(d,J＝5.8Hz,1H),11.01(s,1H),8.66(d,J＝1.6Hz,1H),8.53(s,1H),8.45(d,J＝8.0Hz,1H),8.12(d,J＝9.4Hz,1H),7.98-7.87(m,2H),7.68(t,J＝7.9Hz,1H),7.38-7.25(m,1H),5.68(d,J＝7.3Hz,1H)。
实施例26
N-(苯并[c][1,2,5]噁二唑-5-基)-1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺26
Figure PCTCN2022099499-appb-000118
第一步
N-(苯并[c][1,2,5]噁二唑-5-基)-1-(1-硫氧基-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺26
将1-(1-硫代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸7a(52mg,0.15mmol)和苯并[c][1,2,5]噁二唑-5-胺11b(31mg,0.23mmol)溶于吡啶(6mL)中，室温加入三氯氧磷(0.029mL,0.31mmol)，室温反应完全后，加入饱和碳酸氢钠水溶液(15mL)，二氯甲烷萃取(15mL*3)，有机相减压浓缩，残余物经高效液相色谱法纯化，得到标题化合物26(2.5mg，产率：3.5％)。
MS(ESI)：m/z＝457.2[M+H] +。
实施例27
N-(1,3-二氢异苯并呋喃-5-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-三氟甲基-1H-吡唑-4-甲酰胺27
Figure PCTCN2022099499-appb-000119
第一步
N-(1,3-二氢异苯并呋喃-5-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-三氟甲基-1H-吡唑-4-甲酰胺27
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(50mg,0.16mmol)溶于吡啶(3mL)中，加入1,3-二氢异苯呋喃-5-胺27a(25mg,0.19mmol)和三氯氧磷(47mg,0.31mmol)，室温反应2小时。将反应液浓缩，通过反相C18柱色谱法纯化，得到标题化合物27(30mg，产率：44％)。
MS(ESI)：m/z＝441.3[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.62(d,J＝5.0Hz,1H),10.60(s,1H),8.46-8.41(m,2H),7.91(d,J＝7.3Hz,1H),7.76(s,1H),7.67(t,J＝7.9Hz,1H),7.54(d,J＝8.0Hz,1H),7.33-7.26(m,2H),5.67(d,J＝7.3Hz,1H),5.00(d,J＝11.8Hz,4H)。
实施例28
N-(3-氯-4-(甲亚磺酰基)苯基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡 唑-4-甲酰胺28
Figure PCTCN2022099499-appb-000120
第一步
3-氯-4-甲基亚磺酰基苯胺28b
将2-氯-1-甲亚磺酰基-4-硝基苯28a(300mg,1.37mmol)溶于乙醇/水(10mL/2mL)，室温加入铁粉(381mg,6.83mmol)和氯化铵(730mg,13.66mmol)，90℃反应1小时。反应液经硅藻土过滤，滤液减压浓缩，残余物溶于乙酸乙酯(15mL)，经水(15mL)洗涤，有机相经无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱色谱法纯化，得到标题化合物28b(130mg，产率：50％)。
MS(ESI)：m/z＝190.0[M+H] +。
1H NMR(400MHz,DMSO-d6)δ7.45(d,J＝8.8Hz,1H),6.71(dd,J＝2.0,8.4Hz,1H),6.64(d,J＝2.0Hz,1H),5.95(s,2H),2.66(s,3H)。
第二步
N-(3-氯-4-(甲磺酰基)苯基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺28
将3-氯-4-甲基亚磺酰基苯胺28b(130mg,0.68mmol)溶于四氢呋喃(1mL)中，室温加入二异丙基乙基胺(0.34mL,2.056mmol)和1-(1-氧代-1，2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯(281mg,0.82mmol)的四氢呋喃溶液(1mL)，室温反应过夜，反应液减压浓缩，残余物经硅胶柱色谱法分离纯化，得到标题化合物28(100mg，产率：26.5％)。
MS(ESI)：m/z＝495.0[M+H] +。
1H NMR(400MHz,DMSO-d6)δ11.64(d,J＝5.6Hz,1H),10.98(s,1H),8.49(s,1H),8.44(d,J＝8.0Hz,1H),8.05(d,J＝2.0Hz,1H),7.96-7.90(m,2H),7.87-7.83(m,1H),7.67(t,J＝8.0Hz,1H),7.30(dd,J＝6.1,7.2Hz,1H),5.66(d,J＝7.2Hz,1H),2.80(s,3H)。
实施例29
N-(5-甲氧基-2-(三氟甲基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺29
Figure PCTCN2022099499-appb-000121
第一步
5-溴-2-(三氟甲基)吡啶-4-胺29a
将2-(三氟甲基)吡啶-4-胺3g(500mg,3.084mmol)溶于二氯甲烷(10mL)中，室温加入N-氯代丁二酰亚胺(NBS)(548mg,3.084mmol)，氮气氛下，室温反应16小时，反应液减压浓缩，残余物经硅胶柱层析色谱法分离纯化，得到标题化合物29a(790mg，产率：95.6％)。
MS(ESI)：m/z＝241.0[M+H] +。
1H NMR(400MHz,CDCl 3)8.41(s,1H),6.93(s,1H),4.84(s,2H)。
第二步
5-甲氧基-2-(三氟甲基)吡啶-4-胺29b
将2-溴-5-(三氟甲基)苯胺29a(190mg,0.792mmol)溶于甲醇(10mL)中，室温加入铜(123mg,1.95mmol)和甲醇钠(1216mg,8.333mmol)，100℃反应18小时，反应液减压浓缩，残余物经硅胶柱色谱法分离纯化，得到标题化合物29b(20mg,产率：5.3％)。
MS(ESI)：m/z＝193.1[M+H] +。
第三步
N-[5-甲氧基-2-(三氟甲基)吡啶-4-基]-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺29
将5-甲氧基-2-(三氟甲基)吡啶-4-胺29b(20mg,0.104mmol)和1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(33.65mg,0.104mmol)溶于吡啶(6mL)中，室温加入三氯氧磷(0.029mL,0.312mmol)，25℃反应16小时，减压浓缩，残余物经高效液相色谱法分离纯化，得到标题化合物29(7mg，产率：13.52％)。
MS(ESI)：m/z＝498.1[M+H] +。
1H NMR(400MHz,DMSO- d6)δ11.74-11.55(m,1H),10.60-10.29(m,1H),8.60(d,J＝4.8Hz,2H),8.50-8.36(m,2H),7.93(d,J＝7.2Hz,1H),7.68(t,J＝7.8Hz,1H), 7.34-7.21(m,1H),5.78-5.75(m,1H),4.09(s,3H)。
实施例30
N-(6-乙酰氨基-5-(三氟甲基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-三氟甲基-1H-吡唑-4-甲酰胺30
Figure PCTCN2022099499-appb-000122
第一步
5-硝基-3-(三氟甲基)吡啶-2-胺30b
将2-氯-5-硝基-3-(三氟甲基)吡啶30a(1g,4.41mmol)加入氨水的甲醇溶液(7M,9.46mL)，室温反应14小时，反应液减压浓缩，残留物用水稀释(40mL)，经乙酸乙酯萃取(40mL*3)，有机相合并，无水硫酸钠干燥，过滤，减压浓缩，得到标题化合物30b(900mg，产率：98.4％)。
1H NMR(400MHz,DMSO-d6)δ9.05(d,J＝2.4Hz,1H),8.39(d,J＝2.8Hz,1H),8.09(s,2H)。
第二步
N-(5-硝基-3-(三氟甲基)吡啶-2-基)乙酰胺30c
将5-硝基-3-(三氟甲基)吡啶-2-胺30b(0.19mL,1.45mmol)溶于二氯甲烷(3mL)中，室温加入三乙胺(0.40mL,2.90mmol)和对二甲氨基吡啶(194mL,1.59mmol)，然后冰浴下加入乙酰氯(0.11mL,1.59mmol)，室温反应1小时，反应液中加入水(30mL)，经乙酸乙酯萃取(30mL*2)，有机相合并，经无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶柱色谱分离纯化，得到标题化合物30c(300mg，产率：83％)。
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.47(d,J＝2.4Hz,1H),8.84(d,J＝2.8Hz,1H),2.14(s,3H)。
第三步
N-(5-氨基-3-(三氟甲基)吡啶-2-基)乙酰胺30d
将N-(5-硝基-3-(三氟甲基)吡啶-2-基)乙酰胺30c(240mg,0.96mmol)溶于乙醇/水(5mL/1.5mL)，室温加入氯化铵(0.042mL,1.20mmol)和铁粉(0.034mL,4.82mmol)，90℃反应1小时。冷却至室温，反应液中加入水(50mL)，乙酸乙酯萃取(50mL*2)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物30d(200mg，产率：94％)。
1H NMR(400MHz,DMSO-d6)9.62(s,1H),7.99(d,J＝2.8Hz,1H),7.25(d,J＝2.8Hz,1H),5.81(s,2H),1.91(s,3H)。
第四步
N-(6-乙酰氨基-5-(三氟甲基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-三氟甲基-1H-吡唑-4-甲酰胺30
将N-[5-氨基-3-(三氟甲基)吡啶-2-基]乙酰胺30d(35mg,0.16mmol)溶于四氢呋喃(3mL)中，冰浴下加入氢化钠(17mg,0.73mmol)，10分钟后，加入1-(1-氧代-1，2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯1g(50mg,0.15mmol)，氮气氛下，室温反应2小时，冰浴下加入氯化铵(10mL)，乙酸乙酯萃取(30mL*2)，有机相合并，经无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相色谱法分离，得到标题化合物30(8.6mg，产率：11％)。
MS(ESI)：m/z＝525.3[M+H] +。
1H NMR(400MHz,DMSO-d6)11.63(d,J＝6.0Hz,1H),11.09(s,1H),10.16(s,1H),8.99(d,J＝2.4Hz,1H),8.59(d,J＝2.4Hz,1H),8.51(s,1H),8.44(d,J＝8.0Hz,1H),7.95(d,J＝6.8Hz,1H),7.67(t,J＝8.0Hz,1H),7.36-7.23(m,1H),5.65(d,J＝7.6Hz,1H),2.03(s,3H)。
实施例31
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-(6-(吡咯烷-1-基)-5-(三氟甲基)吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺31
Figure PCTCN2022099499-appb-000123
第一步
5-硝基-2-(吡咯烷-1-基)-3-(三氟甲基)吡啶31c
将2-氯-5-硝基-3-(三氟甲基)吡啶31a(129mg,0.57mmol)溶于N,N-二甲基甲酰胺(7mL)，室温加入四氢吡咯31b(0.7mL,0.85mmol)和碳酸铯(371mg,1.14mmol)。室温反应3小时，反应液中加入水(15mL)，乙酸乙酯萃取(15mL*3)。有机相合并，饱和氯化钠水溶液洗涤，减压浓缩，残余物经硅胶柱层析色谱法分离纯化，得到标题化合物31c(100mg，产率：67％)。
MS(ESI)：m/z＝262.2[M+H] +。
第二步
6-(吡咯烷-1-基)-5-(三氟甲基)吡啶-3-胺31d
将5-硝基-2-(吡咯烷-1-基)-3-(三氟甲基)吡啶31c(100mg,0.38mmol)溶于乙醇/水(6mL/2mL)，室温加入铁粉(213mg,3.8mmol)和氯化铵(206mg,3.83mmol)。80℃反应2小时，反应液经硅藻土滤过，滤液加入水(15mL)，乙酸乙酯萃取(15mL*3)。有机相减压浓缩，残余物经硅胶柱色谱法分离纯化，得到标题化合物31d(49mg，产率：55％)。
MS(ESI)：m/z＝232.2[M+H] +。
第三步
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-(6-(吡咯烷-1-基)-5-(三氟甲基)吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺31
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸(68mg,0.21mmol)1g和6-(吡咯烷-1-基)-5-(三氟甲基)吡啶-3-胺31d(49mg,0.21mmol)溶于吡啶(5mL)中，室温加入三氯氧磷(0.42mmol,0.04mL)，室温反应1小时，加入饱和碳酸氢钠水溶液(10mL)，二氯甲烷萃取(10mL*3)，有机相减压浓缩，残余物经高效液相色谱法分离纯化，得到标题化合物31(5.6mg，产率：4.93％)。
MS(ESI)：m/z＝537.3[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),10.64(s,1H),8.61(d,J＝2.5Hz,1H),8.43(d,J＝5Hz,2H),8.32(d,J＝2.5Hz,1H),7.94～7.92(m,1H),7.67(t,J＝7.9Hz,1H),7.31～7.28(m,1H),5.64(d,J＝7.3Hz,1H),3.52～3.49(m,4H),1.93～1.89(m,4H)。
实施例32
N-(2-(1,1-二氟乙基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺32
Figure PCTCN2022099499-appb-000124
Figure PCTCN2022099499-appb-000125
第一步
4-氯-2-(1,1-二氟乙基)吡啶32b
将1-(4-氯吡啶-2-基)乙烷-1-酮32a(0.24mL,1.928mmol)溶于二氯甲烷(5mL)中，冰浴下加入二乙胺基三氟化硫DAST(2.54mL,19mmol)，25℃反应12小时。加入饱和碳酸氢钠水溶液(30mL)，用二氯甲烷萃取(20mL*3)，有机相合并，无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱色谱分离纯化，得到标题化合物32b(30mg，产率：8.7％)。
1H NMR(400MHz,CDCl 3)δ8.55(d,J＝5.2Hz,1H),7.68(d,J＝2.0Hz,1H),7.38(dd,J＝2.0,5.2Hz,1H),2.02(t,J＝18.8Hz,3H)。
第二步
N-[2-(1，1-二氟乙基)吡啶-4-基]氨基甲酸叔丁酯32c
将4-氯-2-(1，1-二氟乙基)吡啶32b(90mg,0.507mmol)和氨基甲酸叔丁酯(71mg,0.608mmol)溶于1,4-二氧六环(3mL)中，室温加入2-二环己基磷-2,4,6-三异丙基联苯(16mg,0.051mmol)、碳酸铯(247mg,0.76mmol)和醋酸钯(11mg,0.051mmol)。80℃微波反应2小时，冷却至室温，减压浓缩，残余物经硅胶柱层析色谱法分离纯化，得到标题化合物32c(130mg，产率：89％)。
1H NMR(400MHz,CDCl 3)δ8.46(d,J＝5.6Hz,1H),7.62(d,J＝2.0Hz,1H),7.46(dd,J＝2.0,5.6Hz,1H),7.14(br.s,1H),1.99(t,J＝18.8Hz,4H),1.46(s,9H)。
第三步
2-(1,1-二氟乙基)吡啶-4-胺32d
将N-[2-(1,1-二氟乙基)吡啶-4-基]氨基甲酸叔丁酯(70mg,0.271mmol)溶于二氯甲烷(3mL)中，冰浴下加入三氟乙酸(1mL,13.463mmol)，25℃反应12小时，减压浓缩，残余物倒入饱和的碳酸氢钠水溶液中(15mL)，用二氯甲烷萃取(15mL*3)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩，得到标题化合物32d(30mg，产率：69％)。
1H NMR(400MHz,CDCl 3)δ8.26(d,J＝6.0Hz,1H),6.89(d,J＝2.4Hz,1H),6.57(d,J＝3.2Hz,1H),2.07-2.01(m,3H)。
第四步
N-(2-(1,1-二氟乙基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺32
将2-(1,1-二氟乙基)吡啶-4-胺32d(45mg,0.285mmol)溶于四氢呋喃(2mL)中，氮气氛下，0℃加入氢化钠(56mg,1.423mmol)和1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯21h(97.22mg,0.285mmol)的四氢呋喃溶液，60℃反应12小时，缓慢滴加饱和氯化铵水溶液(10mL)淬灭反应，用乙酸乙酯萃取(20mL*3)，有机相合并，经无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相色谱法分离纯化，得到标题化合物32(11mg，产率：8.7％)。
MS(ESI)：m/z＝464.1[M+H] +。
1H NMR(400MHz,DMSO- d6)δ11.64(d,J＝5.2Hz,1H),11.11(s,1H),8.61(d,J＝5.6Hz,1H),8.52(s,1H),8.45(d,J＝8.0Hz,1H),8.08(d,J＝2.0Hz,1H),7.95(d,J＝6.4Hz,1H),7.85(dd,J＝2.0,5.6Hz,1H),7.68(t,J＝8.0Hz,1H),7.30(dd,J＝6.0,7.2Hz,1H),5.66(d,J＝7.2Hz,1H),2.01(t,J＝19.2Hz,3H)。
实施例33
N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺33
Figure PCTCN2022099499-appb-000126
第一步
3-氯-2-(二氟甲氧基)-5-硝基吡啶33c
将3-氯-5-硝基吡啶-2-醇33a(354mg,2.03mmol)溶于乙腈(15mL)，室温加入氢化钠(219mg,5.48mmol,60％)。氮气氛下，室温反应10分钟后，加入2,2-二氟-2-(氟磺酰基)乙酸33b(632mg,3.55mmol)，室温继续反应20分钟。冰浴下加入水(15mL)，乙酸乙酯萃取(20mL*3)，有机相减压浓缩，残余物经硅胶柱色谱法分离纯化，得到标题化合物33c(267mg，产率：58％)。
第二步
5-氯-6-(二氟甲氧基)吡啶-3-胺33d
将3-氯-2-(二氟甲氧基)-5-硝基吡啶33c(267mg,1.19mmol)溶于乙酸(10mL) 中，室温加入铁粉(664mg,11.89mmol)，室温反应3小时，反应液减压浓缩，二氯甲烷(15mL)溶解后经硅藻土滤过，饱和碳酸氢钠溶液洗涤，有机相减压浓缩，残余物经硅胶柱色谱法分离纯化，得到标题化合物33d(214mg，产率：92.5％)。
MS(ESI)：m/z＝195.1[M+H] +。
第三步
N-(5-氯-6-(二氟甲氧基)吡啶-3-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺33
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(73mg,0.23mmol)和5-氯-6-(二氟甲氧基)吡啶-3-胺33d(44mg,0.23mmol)溶于吡啶(7mL)，室温加入三氯氧磷(0.042mL,0.45mmol)，室温室温反应1小时，加入饱和碳酸氢钠水溶液(10mL)，二氯甲烷萃取(10mL*3)，有机相减压浓缩，残余物经高效液相色谱法分离，得到标题化合物33(10.8mg，产率：9％)。
MS(ESI)：m/z＝500.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),10.96(s,1H),8.50(d,J＝2.4Hz,1H),8.49(s,1H),8.47(d,J＝2.3Hz,1H),8.46～8.43(m,1H),7.95～7.93(m,1H),7.73(t,J＝66.6Hz,1H),7.68(t,J＝7.9Hz,1H),7.31～7.28(m,1H),5.64(d,J＝7.4Hz,1H)。
实施例34
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-(6-(四氢呋喃-2-基)-5-(三氟甲基)吡啶-3-基)-5-三氟甲基-1H-吡唑-4-甲酰胺34
Figure PCTCN2022099499-appb-000127
第一步
(5-(三氟甲基)吡啶-3-基)氨基羧酸叔丁酯34b
将5-三氟甲基吡啶-3-胺34a(0.15mL,1.23mmol)溶于四氢呋喃(3mL)，室温加入二碳酸二叔丁酯(0.79mL,3.70mmol)和对二甲氨基吡啶(7.5mg,0.062mmol)，室温反应16小时，将反应液倒入水(20mL)，乙酸乙酯萃取(20mL*2)，有机相合 并，经饱和氯化钠水溶液洗涤(20mL*2)，无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱层析色谱法分离纯化，得到标题化合物34b(250mg，产率：77.2％)。
1H NMR(400MHz,CDCl 3)δ8.61(d,J＝2.0Hz,1H),8.55(s,1H),8.39(s,1H),7.26(s,1H),1.54(s,9H)。
第二步
(6-(四氢呋喃-2-基)-5-(三氟甲基)吡啶-3-基)氨基甲酸叔丁酯34c
将(5-(三氟甲基)吡啶-3-基)氨基羧酸叔丁酯34b(180mg,0.69mmol)溶于二甲基亚砜(2mL)，室温加入4-甲基苯-1-磺酸(0.088mL,0.55mmol)、四氢呋喃(3.38mL,41.18mmol)、O-[(磺基过氧)磺基]氧化二铵(0.40mL,3.43mmol)和[4,4′-双(1,1-二甲基乙基)-2,2′-联吡啶N1,N1']双[3,5-二氟-2-[5-(三氟甲基)-2-吡啶基N]苯基-C]六氟磷酸铱(III)(77mg,0.069mmol)，蓝光照射下，反应混合物在室温搅拌12小时。反应液加入水(30mL)，乙酸乙酯萃取(30mL*2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析色谱法分离纯化，得到标题化合物34c(90mg，产率：39％)。
1H NMR(400MHz,CDCl 3)δ8.85-8.70(m,2H),8.42(d,J＝1.2Hz,1H),5.13(t,J＝7.6Hz,1H),4.03(t,J＝6.8Hz,2H),2.53-2.42(m,1H),2.41-2.31(m,1H),2.14-2.06(m,2H),1.54(s,9H)。
第三步
6-(四氢呋喃-2-基)-5-(三氟甲基)吡啶-3-胺34d
将(6-(四氢呋喃-2-基)-5-(三氟甲基)吡啶-3-基)氨基甲酸叔丁酯34c(80mg,0.24mmol)溶于二氯甲烷(1.5mL)中，冰浴下加入三氟乙酸(0.5mL,6.73mmol)。室温反应1小时，冰浴下加入饱和碳酸氢钠溶液(10mL)，二氯甲烷萃取(30mL*2)，有机相合并，反应液减压浓缩，得到标题化合物34d(50mg，产率：89％)。
MS(ESI)：m/z＝233.1[M+H] +。
第四步
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-(6-(四氢呋喃-2-基)-5-(三氟甲基)吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺34
将6-(四氢呋喃-2-基)-5-(三氟甲基)吡啶-3-胺34d(18mg,0.078mmol)和1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯21h(27.56mg,0.085mmol)溶于二氯甲烷(2mL)中，室温加入吡啶(0.063mL,0.77mmol)和三氯氧磷(0.022mL,0.23mmol)，室温反应1小时，加入饱和碳酸氢钠溶液(15mL)，经二氯甲烷萃取(15mL*2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相色谱法分离纯化，得到标题化合物34(4.9mg，产率：11％)。
MS(ESI)：m/z＝538.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ11.62(d,J＝5.6Hz,1H),10.61(s,1H),8.84(s, 1H),8.50(s,1H),8.47-8.42(m,2H),7.95(d,J＝7.6Hz,1H),7.67(t,J＝8.0Hz,1H),7.32-7.24(m,1H),5.69(d,J＝6.4Hz,1H),5.33(t,J＝6.8Hz,1H),4.04-3.96(m,1H),3.93-3.87(m,1H),2.33-2.22(m,2H),2.10-1.91(m,2H)。
实施例35
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-(6-(四氢呋喃-3-基)-5-(三氟甲基)吡啶-3-基)-5-三氟甲基-1H-吡唑-4-甲酰胺35
Figure PCTCN2022099499-appb-000128
第一步
2-(2,5-二氢呋喃-3-基)-5-硝基-3-(三氟甲基)吡啶35c
将2-溴-5-硝基-3-(三氟甲基)吡啶35a(0.27mL,1.85mmol)和2-(2,5-二氢呋喃-3-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷35b(397mg,2.03mmol)溶于二氧六环/水(4mL/0.6mL)，室温加入1,1’-二(二叔丁基膦)(240mg,0.369mmol)和碳酸钾(765mg,5.54mmol)，氮气氛下，70℃反应4小时，反应液中加入水(50mL)，经乙酸乙酯萃取(50mL*2)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱色谱法分离，得到标题化合物35c(300mg，产率：62％)。
MS(ESI)：m/z＝261.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ9.52(d,J＝2.4Hz,1H),8.81(d,J＝2.4Hz,1H),6.81-6.68(m,1H),5.19-5.15(m,2H),5.02-4.97(m,2H)。
第二步
6-(氧杂环戊烷-3-基)-5-(三氟甲基)吡啶-3-胺35d
将2-(2,5-二氢呋喃-3-基)-5-硝基-3-(三氟甲基)吡啶35c(270mg,1.04mmol)溶于甲醇(3mL)中，室温加入钯碳(10％,0.022mL，0.21mmol)，在氢气氛下于室温反应1小时，反应液经硅藻土过滤，滤液减压浓缩，得到标题化合物35d(200mg,，产率：82％)。
1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝2.4Hz,1H),7.18(d,J＝2.4Hz,1H), 5.69(s,2H),3.98-3.87(m,2H),3.84-3.77(m,1H),3.65-3.52(m,2H),2.21-2.05(m,2H)。
第三步
1-(1-氧代-1,2-二氢异喹啉-5-基)-N-[6-(氧代-3-基)-5-(三氟甲基)吡啶-3-基]-5-(三氟甲基)-1H-吡唑-4-甲酰胺35
将6-(氧杂环戊烷-3-基)-5-(三氟甲基)吡啶-3-胺35d(35mg,0.16mmol)溶于四氢呋喃(3mL)中，冰浴下加入氢化钠(82mg,2.06mmol)，10分钟后，加入1-(1-氧代-1，2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰氯21h(88mg,0.26mmol)，氮气氛下，60℃反应1小时，冷却至室温，反应液加入饱和碳酸氢钠溶液(20mL)，经二氯甲烷萃取(30mL*3)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩，经高效液相色谱法分离，得到标题化合物35(24.3mg，产率：17.5％)。
MS(ESI)：m/z＝538.2[M+H] +。
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),11.05(s,1H),9.08(d,J＝2.0Hz,1H),8.55-8.51(m,1H),8.49(s,1H),8.44(d,J＝8.0Hz,1H),7.94(d,J＝7.2Hz,1H),7.67(t,J＝7.6Hz,1H),7.29(d,J＝7.2Hz,1H),5.65(d,J＝7.6Hz,1H),4.10-4.02(m,1H),4.02-3.94(m,1H),3.90-3.82(m,1H),3.79-3.71(m,2H),2.28-2.20(m,2H)。
实施例36
1-(1-氧代-1,2-二氢酞嗪-5-基)-5-(三氟甲基)-N-(2-三氟甲基吡啶-4-基)-1H-吡唑-4-甲酰胺36
Figure PCTCN2022099499-appb-000129
第一步
3-羟基-4-硝基-2,3-二氢-1H-异吲哚-1-酮36b
将4-硝基-2,3-二氢-1H-异吲哚-1,3-二酮36a(5g,26.02mmol)溶于二氯甲烷/甲醇(50mL/50mL)，室温加入硼氢化钠(0.88g,26.02mmol)，室温反应6小时，加入饱和碳酸氢钠水溶液(40mL)淬灭反应，搅拌20分钟，水相用乙酸乙酯萃取(100mL*2)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩，得到标题化合物36b(3.8 g，产率：75％)。
MS(ESI)：m/z＝195.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.32(dd,J＝0.8,8.0Hz,1H),8.03(d,J＝6.8Hz,1H),7.84-7.80(m,1H),6.64(d,J＝8.8Hz,1H),6.35(d,J＝8.8Hz,1H)。
第二步
3-羟基-4-硝基-1,3-二氢-2-苯并呋喃-1-酮36c
将3-羟基-4-硝基-2,3-二氢-1H-异吲哚-1-酮36b(3.8g,19.57mmol)加入浓盐酸(30mL)，90℃反应12小时，冷却至室温，反应液减压浓缩，残余物经硅胶柱层析色谱分离纯化，得到标题化合物36c(2.6g，产率：68％)。
MS(ESI)：m/z＝196.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ8.53(dd,J＝0.7,8.0Hz,1H),8.49(s,1H),8.27(d,J＝7.2Hz,1H),7.96(t,J＝7.6Hz,1H),7.07(s,1H)。
第三步
5-硝基-1,2-二氢酞嗪-1-酮36d
将3-羟基-4-硝基-1,3-二氢-2-苯并呋喃-1-酮36c(2.6g,13.32mmol)溶于乙醇(20mL)中，室温加入水合肼溶液(186mL,3.54mmol)，80℃反应4小时，冷却至室温，过滤，滤液减压浓缩，得到标题化合物36d(1.6g，产率：62％)。
MS(ESI)：m/z＝192.1[M+H] +。
第四步
5-氨基-1,2-二氢酞嗪-1-酮36e
将5-硝基-1,2-二氢酞嗪-1-酮36d(1.6g,8.37mmol)溶于甲醇(20mL)中，氮气氛下，加入钯碳(10％,0.84mmol)，反应体系经氢气置换三次，并在15psi下室温反应12小时。反应液经硅藻土过滤，滤液减压浓缩，得到标题化合物36d(2.3g，产率：95％)。
MS(ESI)：m/z＝162.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),8.47(s,1H),7.49-7.39(m,1H),7.31(d,J＝7.8Hz,1H),6.99(dd,J＝1.0,8.0Hz,1H),6.26(s,2H)。
第五步
5-肼基-1,2-二氢酞嗪-1-酮36f
将5-氨基-1,2-二氢酞嗪-1-酮36e(300mg,1.86mmol)加入浓盐酸(5mL)中，冰浴下加入亚硝酸钠(0.149mL,2.792mmol)的水溶液(4mL)，冰浴下反应0.5小时，然后滴加二氯化锡(1050mg,4.65mmol)的浓盐酸溶液(8mL)，室温反应5小时。用20％的氢氧化钠水溶液将反应液调至pH为12-14，用乙酸乙酯萃取(50mL*3)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩，得到标题化合物36f(240mg，产率：72.7％)。
MS(ESI)：m/z＝177.1[M+H] +。
第六步
1-(1-氧代-1,2-二氢酞嗪-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯36h
将5-肼基-1,2-二氢酞嗪-1-酮36f(240mg,1.36mmol)溶于乙醇(6mL)中，室温加入(Z)-2-(乙氧基亚甲基)-4,4,4-三氟-3-氧代丁酸乙酯1c(0.26mL,1.36mmol)，60℃反应3小时，反应液减压浓缩，残余物经硅胶柱色谱法分离，得到标题化合物36h(50mg，产率：10％)。
MS(ESI)：m/z＝353.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),8.47(d,J＝7.6Hz,1H),8.45(s,1H),8.18-8.13(m,1H),8.06-8.00(m,1H),7.75(s,1H),4.35(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H)。
第七步
1-(1-氧代-1,2-二氢酞嗪-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸36i
将1-(1-氧代-1，2-二氢酞嗪-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯36h(40mg,0.11mmol)溶于四氢呋喃/水(6mL/2mL)中，室温加入氢氧化锂的水溶液(0.016mL，0.57mmol)，50℃反应6小时，反应液减压浓缩，然后加入1N盐酸溶液调节pH值至2-3，用乙酸乙酯萃取(20mL*2)，有机相合并，经无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物36i(30mg，产率：81％)。
MS(ESI)：m/z＝325.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ13.45(s,1H),13.02(s,1H),8.47(d,J＝8.0Hz,1H),8.39(s,1H),8.14(d,J＝7.0Hz,1H),8.06-7.99(m,1H),7.71(s,1H)。
第八步
1-(1-氧代-1,2-二氢酞嗪-5-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-羧酰胺36
将1-(1-氧代-1,2-二氢酞嗪-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸36i(20mg,0.062mmol)、2-(三氟甲基)吡啶-4-胺3g(10.0mg,0.062mmol)和吡啶(0.050mL,0.62mmol)溶于二氯甲烷(2mL)中，室温加入三氯氧磷(0.006mL,0.062mmol)，室温反应1小时，加入水(10mL)，用二氯甲烷萃取(10mL*3)，有机相合并，经无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相色谱法分离得到标题化合物36(2.6mg，产率：9％)。
MS(ESI)：m/z＝469.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),11.24(s,1H),8.72(d,J＝5.6Hz,1H),8.57(s,1H),8.50(d,J＝7.8Hz,1H),8.23(d,J＝1.6Hz,1H),8.19(d,J＝7.2Hz,1H),8.09-8.03(m,1H),7.97(dd,J＝1.6,5.6Hz,1H),7.64(s,1H)。
实施例37
1-(4-氧代-3,4-二氢喹唑啉-8-基)-5-(三氟甲基)-N-(2-三氟甲基吡啶-4-基)-1H-吡唑-4-甲酰胺37
Figure PCTCN2022099499-appb-000130
第一步
8-(2-(二苯基亚甲基)肼基)喹唑啉-4(3H)-酮37c
将8-溴-3,4-二氢喹唑啉-4-酮37a(500mg,2.22mmol)和(二苯基亚甲基)肼37b(436mg,2.22mmol)溶于甲苯(5mL)中，室温加入2-甲基丙-2-酸钠(355mg,3.70mmol)、1,1'-联萘-2,2'-双二苯膦(230mg,0.37mmol)和醋酸钯(41mg,0.19mmol)，氮气氛下，80℃反应12小时。反应液冷却至室温，经硅藻土过滤，滤液减压浓缩，残余物经硅胶柱色谱法分离，得到标题化合物37c(200mg，产率：31.7％)。
MS(ESI)：m/z＝341.1[M+H] +。
第二步
5-肼基-1,2-二氢喹唑啉-1-酮37d
将8-(2-(二苯基亚甲基)肼基)喹唑啉-4(3H)-酮37c(180mg，0.53mmol)溶于乙醇(5mL)，室温加入氯化氢(0.50mL，4.23mmol)，反应16小时。反应液过滤，减压浓缩，得到标题化合物37d(240mg)。
MS(ESI)：m/z＝177.1[M+H] +。
第三步
1-(4-氧代-3,4-二氢喹唑啉-8-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯37f
将5-肼基-1,2-二氢喹唑啉-1-酮37d(240mg,1.36mmol)溶于乙醇(6ml)中，室温加入(Z)-2-(乙氧基亚甲基)-4,4,4-三氟-3-氧代丁酸乙酯1c(0.14mL,0.74mmol)，60℃反应2小时，反应液减压浓缩，残余物经硅胶柱色谱法分离，得到标题化合物37f(100mg，产率：38％)。
MS(ESI)：m/z＝353.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ10.35-10.03(m,1H),8.50(dd,J＝1.6,8.4Hz,1H),8.27-8.24(m,1H),8.02(s,1H),7.92(dd,J＝1.6,7.6Hz,1H),7.70-7.66(m,1H), 4.45-4.38(m,2H),1.42(t,J＝7.2Hz,3H)。
第四步
1-(4-氧代-3,4-二氢喹唑啉-8-基)-5-(三氟甲基)-1H-吡唑-4-羧酸37g
将1-(4-氧代-3,4-二氢喹唑啉-8-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯37f(78mg,0.22mmol)溶于四氢呋喃/水(3mL/1mL)，室温加入氢氧化锂(0.031mL,1.11mmol)，50℃反应6小时，反应液中加入饱和碳酸氢钠水溶液(20mL)，并用二氯甲烷萃取(30mL*3)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩，得到标题化合物37g(60mg，产率：83％)。
MS(ESI)：m/z＝325.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.31-8.27(m,1H),8.17(s,1H),8.12-8.08(m,1H),7.57-7.52(m,1H),7.44-7.40(m,1H),7.02(s,1H)。
第五步
1-(4-氧代-3,4-二氢喹唑啉-8-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-甲酰胺37
将1-(4-氧代-3,4-二氢喹唑啉-8-基)-5-(三氟甲基)-1H-吡唑-4-羧酸37g(60mg,0.18mmol)、2-(三氟甲基)吡啶-4-胺3g(30mg,0.18mmol)和吡啶(0.150mL,1.85mmol)溶于二氯甲烷(8mL)，室温加入三氯氧磷(0.05mL,0.55mmol)，室温反应1小时，反应液加入饱和碳酸氢钠(15ml)中，并用二氯甲烷萃取(30mL*3)。有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相色谱法分离，得到标题化合物37(18.4mg，产率：21.2％)。
MS(ESI)：m/z＝469.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ11.26-11.07(m,1H),8.70(d,J＝5.6Hz,1H),8.51-8.46(m,1H),8.39-8.35(m,1H),8.24(d,J＝1.6Hz,1H),8.14(s,1H),8.11-8.07(m,1H),8.01-7.97(m,1H),7.72(t,J＝7.6Hz,1H)。
实施例38
N-(2-甲氧基-6-(三氟甲基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺38
Figure PCTCN2022099499-appb-000131
Figure PCTCN2022099499-appb-000132
第一步
2-甲氧基-6-(三氟甲基)吡啶-4-胺38b
甲醇钠的甲醇溶液(2mL，30％wt)加入到2-氯-6-(三氟甲基)吡啶-4-胺38a(100mg,0.51mmol)中，100℃微波反应1h，冷却到室温后，反应液中加入水(10mL)，乙酸乙酯萃取(10mL*3)，有机相减压浓缩，得到标题化合物38b(100mg,粗品)。
MS(ESI)：m/z＝193.1[M+H] +。
第二步
N-(2-甲氧基-6-(三氟甲基)吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺38
将1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(60mg,0.19mmol)和2-甲氧基-6-(三氟甲基)吡啶-4-胺38b(53mg,0.28mmol)溶于吡啶(7mL)中，室温加入三氯氧磷(0.035mL,0.38mmol)，反应2小时，加入饱和碳酸氢钠水溶液(15mL)，二氯甲烷萃取(15mL*3)，有机相减压浓缩，残余物经高效液相色谱法分离，得到标题化合物38(15mg，产率：16％)。
MS(ESI)：m/z＝498.3[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.56(s,1H),11.10(s,1H),8.45(s,1H),8.37(d,J＝8.0Hz,1H),7.94～7.81(m,1H),7.71(d,J＝1.6Hz,1H),7.60(t,J＝7.8Hz,1H),7.41(d,J＝1.6Hz,1H),7.22(m,1H),5.58(d,J＝7.4Hz,1H),3.85(s,3H)。
实施例39
N-(1-甲基-2-氧代-6-(三氟甲基)-1,2-二氢吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酰胺39
Figure PCTCN2022099499-appb-000133
第一步
4-氨基-6-(三氟甲基)吡啶-2-醇39a
将2-氯-6-(三氟甲基)吡啶-4-胺38a(440mg,2.24mmol)溶于1,4-二氧六环/水(15mL/5mL)中，室温加入双二亚苄基丙酮钯(128.7mg,0.22mmol)、2-二-叔丁膦基-2',4',6'-三异丙基联苯(190mg,0.44mmol)和氢氧化钾(251mg,4.49mmol)。115℃反应1小时，反应液减压浓缩，残余物加入水(20mL)，并用乙酸乙酯萃取(20mL*2)，水相用盐酸(3M)调pH值到2～3，并用乙酸乙酯萃取(20mL*2)，水相减压浓缩，得到标题产物39a(122mg，产率：30％)。
MS(ESI)：m/z＝179.4[M+H] +。
第二步
4-氨基-1-甲基-6-(三氟甲基)吡啶-2(1H)-酮39b
将4-氨基-6-(三氟甲基)吡啶-2-醇39a(122mg,0.62mmol)溶于乙醇(8mL)中，室温加入碳酸钾(128mg,0.93mmol)和碘甲烷(0.039mL,0.62mmol)。70℃反应3小时，冷却至室温，加入水(15mL)，用乙酸乙酯萃取(10mL*3)，有机相合并，减压浓缩，得到标题化合物39b(48mg，产率：40％)。
MS(ESI)：m/z＝193.0[M+H] +。
第三步
N-(1-甲基-2-氧代-6-(三氟甲基)-1,2-二氢吡啶-4-基)-1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酰胺39
将4-氨基-1-甲基-6-(三氟甲基)吡啶-2(1H)-酮39b(48mg,0.25mmol)和1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸1g(80mg,0.25mmol)溶于吡啶(6mL)中，室温滴加三氯氧磷(0.047mL,0.5mmol)，室温反应2小时。反应液加入水(10mL)，用二氯甲烷萃取(10mL*3)，有机相合并，减压浓缩，残余物用高效液相色谱法分离，得到标题化合物39(9.6mg，产率：7.7％)。
MS(ESI)：m/z＝498.2[M+H] +。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),10.90(s,1H),8.49(s,1H),8.44(d,J＝8.0Hz,1H),7.94(d,J＝7.5Hz,1H),7.68(t,J＝7.9Hz,1H),7.34–7.27(m,1H),7.24(d,J＝2.2Hz,1H),7.15(d,J＝2.2Hz,1H),5.64(d,J＝7.3Hz,1H),3.48(s,3H)。
实施例40
1-(8-氧代-7,8-二氢-2,7-萘啶-4-基)-5-(三氟甲基)-N-(2-三氟甲基吡啶-4-基)-1H-吡唑-4-甲酰胺40
Figure PCTCN2022099499-appb-000134
第一步
4-甲基-5-硝基吡啶-3-甲腈40b
将3-溴-4-甲基-5-硝基吡啶40a(3g,13.824mmol)溶于N,N-二甲基甲酰胺(6mL)中，室温加入氰化锌(1.5g,12.943mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.8g,1.383mmol)和三二亚苄基丙酮二钯(0.63g,0.691mmol)，氮气氛下，130℃微波反应1小时，冷却至室温，加入水(40mL)，用乙酸乙酯萃取(30mL*3)，有机相合并，经无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶柱色谱法分离，得到标题化合物40b(1.3g，产率：79％)。
MS(ESI)：m/z＝164.1[M+H] +。
第二步
4-[(E)-2-(二甲基氨基)乙烯基]-5-硝基吡啶-3-甲腈40c
将4-甲基-5-硝基吡啶-3-甲腈40b(1.3g,7.969mmol)溶于二氯甲烷(10mL)中，室温加入N,N-二甲基甲酰胺-二甲基缩醛(2mL,15.93mmol)，40℃反应12小时，反应液减压浓缩，得到标题化合物40c(1g，产率：57％)。
第三步
5-硝基-1,2-二氢-2,7-萘啶-1-酮40d
将4-[(E)-2-(二甲基氨基)乙烯基]-5-硝基吡啶-3-甲腈40c(1g,4.583mmol)加入乙酸(30mL)中，室温加入氢溴酸(18mL,4.383mmol)。氮气氛下，60℃反应5小时，反应液加入到饱和碳酸氢钠水溶液中(60mL)，用乙酸乙酯萃取(40mL*3)，有机相合并，经无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析色谱法分离纯化，得到标题化合物40d(460mg，产率：55％)。
MS(ESI)：m/z＝192.0[M+H] +。
1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),9.54(s,1H),9.43(s,1H),7.74(dd,J＝6.4,7.2Hz,1H),7.06(d,J＝7.2Hz,1H)。
第四步
5-氨基-1,2-二氢-2,7-萘啶-1-酮40e
将5-硝基-1,2-二氢-2,7-萘-1-酮40d(400mg,2.093mmol)溶于甲醇(6mL)中，室温加入钯碳(10％,221mg,0.208mmol)，氢气(15psi)氛围下，25℃反应3小时，经硅藻土过滤，滤液减压浓缩，得到标题化合物40e(200mg，产率：59％)。
MS(ESI)：m/z＝162.1[M+H] +。
1H NMR(400MHz,DMSO- d6)δ11.40(s,1H),8.54(s,1H),8.06(s,1H),7.28(d,J＝7.6Hz,1H),6.67(d,J＝7.2Hz,1H),5.79(s,2H)。
第五步
5-肼基-1,2-二氢-2,7-萘啶-1-酮40f
将5-氨基-1,2-二氢-2,7-萘啶-1-酮40e(100mg,0.621mmol)溶于浓盐酸(2mL)中，在0℃加入亚硝酸钠(0.05mg,0.931mmol)的水溶液(2mL)中，0℃搅拌0.5小时，然后滴加二水合氯化亚锡(350mg,1.551mmol)的浓盐酸(2mL)溶液，室温反应3小时，用20％的氢氧化钠水溶液将反应液调至pH＝12～14，用乙酸乙酯萃取(30mL*2)，水相冻干，得到标题化合物40f(100mg，产率：91％)。
MS(ESI)：m/z＝177.1[M+H] +。
第六步
1-(8-氧代-7,8-二氢-2,7-萘啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯40g
将5-肼基-1,2-二氢-2,7-萘啶-1-酮40f(80mg,0.454mmol)溶于乙醇(5mL)中，室温加入(Z)-2-(乙氧基亚甲基)-4,4,4-三氟-3-氧代丁酸乙酯1c(0.132mL,0.681mmol)，60℃反应3小时。反应液减压浓缩，残余物经硅胶柱层析色谱法分离纯化，得到标题化合物40g(36mg，产率：22％)。
MS(ESI)：m/z＝353.1[M+H] +。
1H NMR(400MHz,DMSO- d6)δ12.01(s,1H),9.48(s,1H),8.97(s,1H),8.47(s,1H),7.53(d,J＝7.2Hz,1H),5.82(d,J＝7.2Hz,1H),4.34(q,J＝7.2Hz,2H),1.32(t,J＝7.2Hz,3H)。
第七步
1-(8-氧代-7,8-二氢-2,7-萘啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧酸40h
将1-(8-氧代-7,8-二氢-2,7-萘啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧酸乙酯40g(36mg，0.102mmol)溶于四氢呋喃/水(3mL/1mL)，室温加入氢氧化锂(21mg,0.51mmol)，50℃反应4小时。反应液用1N盐酸溶液调节pH值至2-3，并用乙酸乙酯萃取(20mL*2)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩得到标题化合物40h(22mg，产率：66％)。
MS(ESI)：m/z＝325.1[M+H] +。
第八步
1-(8-氧代-7,8-二氢-2,7-萘啶-4-基)-5-(三氟甲基)-N-[2-(三氟甲基)吡啶-4-基]-1H-吡唑-4-羧酰胺40
将1-(8-氧代-7,8-二氢-2,7-萘啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧酸40h(20mg, 0.062mmol)、2-(三氟甲基)吡啶-4-胺3g(10mg,0.062mmol)和吡啶(0.05mL,0.617mmol)溶于二氯甲烷(4mL)中，室温加入三氯氧磷(0.006mL,0.062mmol)，室温反应1小时，加入水(10mL)，用二氯甲烷萃取(10mL*3)，有机相合并，经无水硫酸钠干燥，过滤，减压浓缩，残余物经高效液相色谱法分离，得到标题化合物40(1.7mg，产率：5.8％)。
MS(ESI)：m/z＝469.1[M+H] +。
1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),11.25(s,1H),9.50(s,1H),8.97(s,1H),8.71(d,J＝5.6Hz,1H),8.58(s,1H),8.22(s,1H),7.97(br d,J＝5.6Hz,1H),7.59(br d,J＝7.2Hz,1H),5.77(d,J＝7.2Hz,1H)。
生物学测试
体外测定法包括确定细胞形态、蛋白质表达和/或细胞毒性、酶抑制活性和/或用本发明化合物处理细胞的后续功能后果的测定法。体外测定法的替代或附加可用于定量抑制剂在细胞内结合至蛋白质或核酸分子的能力。
抑制剂结合可通过在结合之前放射性标记抑制剂、分离抑制剂/靶标分子复合物并确定放射性标记结合的量来测量。可选地或除此之外，抑制剂结合可通过运行竞争实验来确定，其中新抑制剂与经纯化的蛋白质或结合到已知放射性配体的核酸一起培养。用于测定本发明的作为MALT1抑制剂的化合物的示例性系统的详细条件在下文的生物学实施例中陈述。
此类测定是示例性的，并非旨在限制本发明的范围。熟练的从业人员能够理解，可以对传统的测定方法进行修改以开发等效的或其他的测定方法，其可用于同等的评估活性或以其他方式表征如本文所述的化合物和/或组合物。
测试例1 MALT1生物化学蛋白酶测定
使用作为底物的四肽(Ac-LRSR-MCA，PEPTIDE INSTITUTE)以及从哺乳动物细胞HEK293T纯化的全长MALT1蛋白(Strep-MALT1(1-824)-Myc/DDK，ORIGENE TP314639)，在体外测定中评估MALT1蛋白酶活性。四肽LRSR与AMC(7-氨基-4-甲基香豆素)偶联，并为MALT1蛋白酶提供淬灭的荧光底物。从精氨酸残基上切割AMC导致在450nm处测量的香豆素荧光增大(激发360nm)。最终的检测缓冲液的组成为5.625nM MALT1蛋白、2.5μM Ac-LRSR-MCA、20mM HEPES、10mM KCl、1.5mM MgCl·6H2O、1mM 2Na(EDTA·2Na)、0.01％TritonX-100、1M柠檬酸三钠二水合物(Trisodium Citrate Dihydrate)、和10mM DTT。使用Echo将溶于100％DMSO的测试化合物以每孔200nL的量添加到384-孔板(Greiner-781086)中。每个测试化合物的最高浓度为10μM或1μM，3倍梯度稀释，测试的浓度范围为10μM至0.2nM。不含酶的检测缓冲液的对照孔用作低对照(LC)，利用与酶反应但不加化合物处理的溶媒(1％DMSO)孔作为高对照(HC)。 将化合物与MALT1酶以及底物在室温下温育15小时。随后使用Envision中在激发360nm和发射450nm处测量荧光。使用XLfit进行抑制曲线的拟合并计算IC 50值，IC 50值如表1中所示。
使用下式计算IC 50值(Z prime>0.5)：
LC＝低对照值的中值
低对照：无MALT1酶的反应
HC＝高对照值的中值
高对照：没有化合物的溶媒对照
抑制％＝100-[(样品-LC)/(HC-LC)×100]
曲线拟合公式：fit＝(A+((B-A)/(1+((C/x)^D))))
A：Min(Bottom)，B：Max(Top)，C：IC 50(拐点)，D：斜率(Hill值)
实验结果：本公开化合物对MALT1生物化学蛋白酶的抑制的IC 50值，A：IC 50值＜100nm；B：100nm＜IC 50值＜600nm；C：600nm＜IC 50值＜1000nm；D：1000nm＜IC 50值。
表1
化合物编号 MALT1抑制IC 50(nM)
1 2689
2 199
3 4416
4 1114
5 624
6 131
7 78
8 22
9 951
10 46
11 34
12 388
13 37
14 608
15 39
16 117
17 69
18 44
19 166
20 127
21 41
22 129
23 76
24 27
25 383
26 236
27 477
28 39
29 170
30 76
31 62
32 184
33 12
34 221
35 205
36 512
37 725
38 75
39 350
40 119
对照化合物 43
对照化合物结构如下，可参照WO2018119036A制备获得：
Figure PCTCN2022099499-appb-000135
测试例2瘤内药物浓度的测定
将0.2mL(5x 10 6个)OCI-Ly3细胞(人弥漫大B细胞淋巴瘤细胞，药明康德医药科技有限公司)(加基质胶，体积比为1:1)皮下接种于每只雌性NOG小鼠(6-8周龄，体重18-22g，上海维通利华实验动物技术有限公司)的右后背，肿瘤平均体积达到230mm 3时开始分组给药。
表2体内药效实验动物分组及给药方案
Figure PCTCN2022099499-appb-000136
Figure PCTCN2022099499-appb-000137
注：N：每组小鼠数目；给药容积：根据小鼠体重10μl/g。如果体重下降超过15％停药，待恢复至10％以内恢复给药；BID：每天给药2次。
连续给药28天后，末次给药后0、2、4和8小时采集血浆和肿瘤样本。化合物的血浆和瘤内浓度用AB API4000质谱仪进行LC-MS/MS定量分析。(色谱柱：Raptor Biphenyl 2.7μm 50×2.1mm；流动相：A 0％乙腈水溶液(0.1％甲酸)、B 100％乙腈水溶液(0.1％甲酸)；定量方法：内标法)。
血浆样本制备：
用50％的乙腈水溶液稀释分析物原液，得到所需的工作溶液系列浓度。在空白NOG小鼠血浆30μL中加入工作液3μL(5、10、20、50、100、500、1000、5000、10000ng/mL)，达到0.5～1000ng/mL(0.5、1、2、5、10、50、100、500、1000ng/mL)的标定标准，总体积为33μL(标准样品)。分别制备1ng/mL、2ng/mL、50ng/mL和800ng/mL血浆质控样品，独立于用于校准曲线的质控样品。这些质控样品是在分析当天按照与校准标准相同的方法制备的。
在200μL含乙腈的内标混合物中，分别加入标准样品33μL、质控样品33μL和给药后采集的血浆样品33μL(血浆30μL，空白液3μL)用于沉淀蛋白。然后将样品涡旋30s。4℃ 4000rpm离心15分钟后，上清液加水稀释3倍，将稀释后的上清液20μL注入LC/MS/MS系统进行定量分析。
肿瘤样本制备：
用50％的乙腈水溶液稀释分析物原液，得到所需的工作溶液系列浓度。将3μL的工作液(5、10、20、50、100、500、1000、5000、10000ng/mL)添加到30μL空白NOG小鼠肿瘤，达到0.5～1000ng/mL(0.5、1、2、5、10、50、100、500、1000ng/mL)的校准标准，总量33μL(标准样品)。制备4个用于肿瘤的质量控制样品，分别为1ng/mL、2ng/mL、50ng/mL和800ng/mL，独立于用于校准曲线的样品。这些质控样品是在分析当天按照与校准标准相同的方法制备的。
在200μL含内标的乙腈混合物中，分别加入标准样品33μL、质控样品33μL和给药后采集的肿瘤样品33μL(肿瘤匀浆30μL，空白液3μL)用于沉淀蛋白。然后将样品涡旋30s。4℃4000rpm离心15min后，上清液加水稀释3倍，将稀释后的上清液20μL注入LC/MS/MS系统进行定量分析。结果汇总见表3和表4。
表3对比化合物药物浓度的测定结果
Figure PCTCN2022099499-appb-000138
Figure PCTCN2022099499-appb-000139
表4化合物11药物浓度的测定结果
Figure PCTCN2022099499-appb-000140
结果表明化合物11的肿瘤内/血浆浓度比值较高。

Claims (16)

  1. 式III所示的化合物或其可药用盐，
    Figure PCTCN2022099499-appb-100001
    其中：
    Y 1为CR 14；Y 2为N；
    环C选自任选被1-3个R 13取代的
    Figure PCTCN2022099499-appb-100002
    R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
    R 12选自萘基、包含1-4个杂原子的9-15元杂芳基，所述萘基、包含1-4个杂原子的9-15元杂芳基任选被1-3个R 12a所取代，所述R 12a选自氧代、硫代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基，所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
    R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 13a、-COR 13b、-SO 2R 13c、-SOCH 3；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
    R 14选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；
    条件是，式III所示的化合物不包括以下化合物：
    Figure PCTCN2022099499-appb-100003
  2. 式III所示的化合物或其可药用盐，
    Figure PCTCN2022099499-appb-100004
    其中：
    Y 1为CR 14；Y 2为N；
    环C选自任选被1-3个R 13取代的
    Figure PCTCN2022099499-appb-100005
    R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、5-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
    R 12选自萘基、包含1-4个杂原子的9-15元杂芳基，所述萘基、包含1-4个杂原子的9-15元杂芳基任选被1-3个R 12a所取代，所述R 12a选自氧代、硫代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基，所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代；
    R 13独立地选自C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素、3-6元杂环基、3-6元杂芳基、-NHCOR 13a、-COR 13b、-SO 2R 13c；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、3-6元杂环基、3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异 丁基、硝基、氰基、氨基的取代基所取代；
    R 14选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；
    条件是，式III所示的化合物不包括以下化合物：
    Figure PCTCN2022099499-appb-100006
  3. 根据权利要求1或2所述的式III所示的化合物或其可药用盐，其为式III-a、式III-b、式III-c、式III-d、式III-e、式III-h或式III-j所示的化合物或其可药用盐，
    Figure PCTCN2022099499-appb-100007
    优选式III-h所示的化合物
    Figure PCTCN2022099499-appb-100008
    其中：
    n选自0-3的整数，
    R 11、R 12、R 13、R 14如权利要求1中所定义。
  4. 根据权利要求1或2所述的式III所示的化合物或其可药用盐，其为式III-i所示的化合物或其可药用盐，
    Figure PCTCN2022099499-appb-100009
    其中：
    n选自0-3的整数，
    R 11、R 12、R 13、R 14如权利要求1中所定义。
  5. 根据权利要求1-4中任一项所述的式III所示的化合物或其可药用盐，其中R 14选自氢、C 1-6烷基、C 3-6环烷基、卤素、硝基、氰基、羟基；优选R 14选自氢、甲基、环丙基、卤素、硝基、氰基、羟基；更优选R 14选自氢。
  6. 根据权利要求1-5中任一项所述的式III所示的化合物或其可药用盐，其中每个R 13独立地选自三氟甲基、氢、卤素；优选R 13独立地选自三氟甲基。
  7. 根据权利要求1-5中任一项所述的式III所示的化合物或其可药用盐，其中每个R 13独立地选自硝基、氰基、卤素、-NHCOR 13a、-COR 13b、-SO 2R 13c、-SOCH 3；
    R 13a、R 13b和R 13c独立地选自氨基、C 1-6烷基、C 3-6环烷基、苯基、对甲基苯基。
  8. 根据权利要求1-5中任一项所述的式III所示的化合物或其可药用盐，其中每个R 13独立地选自甲基、甲氧基、三氟甲基、三氟甲氧基、二氟甲氧基、-SOCH 3、卤素、氰基；优选R 13选自三氟甲基。
  9. 根据权利要求1-8中任一项所述的式III所示的化合物或其可药用盐，其中n选自0-2的整数，优选n选自1-2的整数，更优选n为1。
  10. 根据权利要求1-9中任一项所述的式III所示的化合物或其可药用盐，其中：
    R 12选自1-氧代-1,2-二氢异喹啉-5-基、1-硫代-1,2-二氢异喹啉-5-基，优选1-氧代-1,2-二氢异喹啉-5-基；
    所述1-氧代-1,2-二氢异喹啉-5-基、1-硫代-1,2-二氢异喹啉-5-基任选被1-3个R 12a所取代，所述R 12a选自C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基、C 3-6环烷基、硝基、氰基、卤素、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6 元杂芳基；所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、包含1-3个杂原子的3-6元杂环基、包含1-3个杂原子的3-6元杂芳基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、硝基、氰基、氨基的取代基所取代。
  11. 根据权利要求1-9中任一项所述的式III所示的化合物或其可药用盐，其中：
    R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
    优选R 11选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基、硝基、氰基、卤素；其中所述的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 3-6环烷氧基任选被1-3个选自卤素、甲基、乙基、环丙基、正丙基、甲氧基、乙氧基、环丙氧基、硝基、氰基、氨基、羟基的取代基所取代；
    更优选R 11选自氢、环丙基、三氟甲基。
  12. 根据权利要求1-11中任一项所述的式III所示的化合物或其可药用盐，其选自：
    Figure PCTCN2022099499-appb-100010
    Figure PCTCN2022099499-appb-100011
  13. 根据权利要求1-12中任一项所述的式III所示的化合物或其可药用盐的同位素取代物，优选地，所述的同位素取代为氘原子取代。
  14. 一种药物组合物，其包含根据权利要求1-12中任一项所述的式III所示的化合物或其可药用盐或者根据权利要求13所述的同位素取代物和可药用赋形剂。
  15. 根据权利要求1-12中任一项所述的式III所示的化合物或其可药用盐或者根据权利要求13所述的同位素取代物或者根据权利要求14所述的药物组合物在制备用于预防和/或治疗与MALT1相关病症的药物中的用途。
  16. 根据权利要求1-12中任一项所述的式III所示的化合物或其可药用盐或者根据权利要求13所述的同位素取代物或者根据权利要求14所述的药物组合物在制备用于预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤的药物中的用途。
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