WO2022095971A1 - Composé spiro hétérocyclique, son procédé de préparation et son utilisation - Google Patents

Composé spiro hétérocyclique, son procédé de préparation et son utilisation Download PDF

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WO2022095971A1
WO2022095971A1 PCT/CN2021/129049 CN2021129049W WO2022095971A1 WO 2022095971 A1 WO2022095971 A1 WO 2022095971A1 CN 2021129049 W CN2021129049 W CN 2021129049W WO 2022095971 A1 WO2022095971 A1 WO 2022095971A1
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independently
membered
alkyl
membered heterocycloalkyl
heteroatoms
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PCT/CN2021/129049
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Chinese (zh)
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王倩
张冰宾
石辰
舒思杰
霍国永
向志军
夏广新
吴国胜
梁涛
赵永新
李令文
柯樱
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上海医药集团股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
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    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Definitions

  • the present invention relates to a spiro heterocyclic compound, its preparation method and application.
  • RORs Retinoic acid receptor-related orphan receptors
  • RORs belong to the ligand-dependent transcription factor nuclear receptor superfamily and are involved in reproductive development, circadian rhythm regulation, metabolic disorders, inflammation, and It plays an important role in a series of physiological and pathological processes such as immune system regulation.
  • RORs mainly include three members, ROR ⁇ , ROR ⁇ , and ROR ⁇ .
  • ROR ⁇ is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood.
  • ROR ⁇ is mainly distributed in the central nervous system, including the brain, retina and pineal gland.
  • ROR ⁇ is highly expressed in the thymus, and is also distributed in the kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas. It is divided into ROR ⁇ 1 and ROR ⁇ t (also known as ROR ⁇ 2) according to different transcriptional splicing positions. The former is mainly expressed in thymus, testis, pancreas, heart, liver, skeletal muscle and kidney, while ROR ⁇ t is only expressed in immune organs.
  • Th17 cells are a subtype of T helper cells, which are characterized by the secretion of interleukin 17 (IL-17) cytokines. It was initially thought to play an immune function mainly by recruiting neutrophils in resisting bacterial and fungal infections. Subsequent studies found that Th17 cells Plays a key role in many mouse models of autoimmune diseases, including in some human autoimmune diseases including psoriasis (Psoriasis), multiple sclerosis (MS), rheumatoid arthritis (RA) and inflammatory bowel disease Elevated levels of IL-17 can also be detected in IBD. Increased numbers of Th17 cells were found in tissue and peripheral blood samples from patients with autoimmune disease. Therefore, Th17 cells or the cytokine IL-17 produced by them are closely related to the pathogenesis of autoimmune diseases and inflammation, inhibiting the differentiation of Th17 cells, and can be used for the treatment of related diseases.
  • IL-17 interleukin 17
  • ROR ⁇ t is a key regulator of Th17 cell differentiation. Littman et al. first reported that ROR ⁇ t is necessary for the differentiation of naive CD4+ T cells into Th17 cells. Mice lacking ROR ⁇ t lack lymphoid organs such as lymph nodes and Peyer's nodes, and the development and maturation of T cells is also affected, and the number of various T cells is lower than that of normal mice. Regulating the activity of ROR ⁇ t by small molecule compounds can directly affect the differentiation of Th17 cells, inhibiting ROR ⁇ t, and the level of cytokine IL-17 secreted by Th17 is significantly reduced. Therefore, ROR ⁇ t can be used as a new target for the treatment of autoimmune diseases, and it is of great significance to develop small molecule regulators of ROR ⁇ t for the treatment of ROR ⁇ t-mediated related diseases such as autoimmune diseases and inflammatory diseases.
  • patent applications CN107522634, WO2012158784, WO2018145653, etc. disclose some ROR ⁇ t small molecule modulators, but there are no related products on the market, and new ROR ⁇ t small molecule modulators with better activity and higher safety are still needed in this field.
  • the present invention provides a spiro heterocyclic compound different from the prior art, a preparation method and application thereof. These compounds have inhibitory activity on ROR ⁇ t and can effectively inhibit the ROR ⁇ t protein receptor, thereby regulating the differentiation of Th17 cells, inhibiting the production of IL-17, and then treating ROR ⁇ t-mediated related autoimmune diseases, especially for psoriasis, Multiple sclerosis, atopic dermatitis, inflammatory bowel disease and other diseases.
  • the present invention provides a spiroheterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite or a predrug thereof body:
  • n 0, 1 or 2;
  • u 0, 1, 2, 3 or 4;
  • v 0, 1, 2, 3, or 4;
  • p 1, 2, 3 or 4;
  • s is 1, 2, 3 or 4;
  • t 0, 1, 2 or 3;
  • W, Q, Y and Z are independently CH or N, and W, Q, Y and Z are not simultaneously CH or N;
  • Ring A and Ring B are independently C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heteroaryl
  • the heteroatoms in the cycloalkyl and the 5-10-membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1 1, 2, 3 or 4;
  • R 4 is independently halogen, -OR 4-1 , -CN, -NR 4-2 R 4-3 , C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl base, 5-10-membered heteroaryl, C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo; the 3-14-membered heterocycloalkyl and the The heteroatoms in the 5-10-membered heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • any two non-adjacent R 4 together with the carbon atoms to which they are connected form a 4-6-membered heterocycloalkyl group, and the heteroatom in the heterocycloalkyl group is N, and the number is 1;
  • R 1-1 , R 2-1 , R 3-1 and R 4-1 are independently hydrogen, "halogen substituted C 1 -C 7 alkyl", C 1 -C 7 alkyl, C 3 -C 14 Cycloalkyl, 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl
  • the heteroatoms in the base are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 1-2 , R 2-2 and R 3-2 are independently hydrogen, "halogen substituted C 1 -C 7 alkyl", C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3 -14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 1-3 , R 1-4 , R 2-3 , R 2-4 , R 3-3 , R 3-4 , R 4-2 and R 4-3 are independently hydrogen, C 1 -C 7 alkanes base, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heterocycloalkyl and the The heteroatoms in the 5-10-membered heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 1-3 and R 1-4 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R 1-3-1 substituted 3-14 membered heterocycloalkyl", a 3-14 membered heterocycloalkyl group Heterocycloalkenyl or "R 1-3-2 substituted 3-14-membered heterocycloalkenyl”; said 3-14-membered heterocycloalkyl, "R 1-3-1 substituted 3-14-membered heterocycle
  • the heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and “R 1-3-2 substituted 3-14-membered heterocycloalkenyl” are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 1-3-1 and R 1-3-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • R 2-3 and R 2-4 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl, "R 2-3-1 substituted 3-14-membered heterocycloalkyl", a 3-14-membered heterocycloalkyl Heterocycloalkenyl or "R 2-3-2 substituted 3-14-membered heterocycloalkenyl"; the 3-14-membered heterocycloalkyl, "R 2-3-1 substituted 3-14-membered heterocycloalkenyl”
  • the heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and “R 2-3-2 substituted 3-14-membered heterocycloalkenyl” are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 2-3-1 and R 2-3-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • R 3-3 and R 3-4 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R 3-3-1 substituted 3-14 membered heterocycloalkyl", a 3-14 membered heterocycloalkyl group Heterocycloalkenyl or "R 3-3-2 -substituted 3-14-membered heterocycloalkenyl"; the 3-14-membered heterocycloalkyl, "R 3-3-1 -substituted 3-14-membered heterocycloalkenyl”
  • the heteroatoms in cycloalkyl", 3-14-membered heterocycloalkenyl and “R 3-3-2 -substituted 3-14-membered heterocycloalkenyl” are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 3-3-1 and R 3-3-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • R 4-2 and R 4-3 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R 4-2-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkyl Heterocycloalkenyl or "R 4-2-2 substituted 3-14-membered heterocycloalkenyl”; said 3-14-membered heterocycloalkyl, "R 4-2-1 substituted 3-14-membered heterocycloalkenyl”
  • the heteroatoms in “cycloalkyl", 3-14-membered heterocycloalkenyl and “R 4-2-2 -substituted 3-14-membered heterocycloalkenyl” are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 4-2-1 and R 4-2-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • R 1-5 is independently hydrogen, -OR 1-5-1 , NR 1-5-2 R 1-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 2-5 is independently hydrogen, -OR 2-5-1 , NR 2-5-2 R 2-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 3-5 is independently hydrogen, -OR 3-5-1 , NR 3-5-2 R 3-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 1-6 is independently hydrogen, -OR 1-6-1 , NR 1-6-2 R 1-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 2-6 is independently hydrogen, -OR 2-6-1 , NR 2-6-2 R 2-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 3-6 is independently hydrogen, -OR 3-6-1 , NR 3-6-2 R 3-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 1-5-1 , R 2-5-1 , R 3-5-1 , R 1-6-1 , R 2-6-1 and R 3-6-1 are independently hydrogen, C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heterocycloalkyl and
  • the heteroatoms in the 5-10-membered heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1 or 2 , 3 or 4;
  • R 1-5-2 , R 1-5-3 , R 2-5-2 , R 2-5-3 , R 3-5-2 , R 3-5-3 , R 1-6-2 , R 1-6-3 , R 2-6-2 , R 2-6-3 , R 3-6-2 and R 3-6-3 are independently hydrogen, C 1 -C 7 alkyl, C 3 -C 14 -membered cycloalkyl, 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl
  • the heteroatoms in the aryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 1-5-2 and R 1-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "R 1-5-2-1- substituted 3-14-membered heterocycloalkyl ", 3-14-membered heterocycloalkenyl or "R 1-5-2-2 substituted 3-14-membered heterocycloalkenyl”; said 3-14-membered heterocycloalkyl, said "R 1 -5-2-1- substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R 1-5-2-2- substituted 3-14-membered heterocycle
  • the heteroatoms in "alkenyl” are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • Said R 1-5-2-1 and R 1-5-2-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 al
  • R 2-5-2 and R 2-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "R 2-5-2-1 substituted 3-14-membered heterocycloalkyl ", 3-14-membered heterocycloalkenyl or "R 2-5-2-2- substituted 3-14-membered heterocycloalkenyl”; said 3-14-membered heterocycloalkyl, said "R 2 -5-2-1- substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R 2-5-2-2- substituted 3-14-membered heterocycle
  • the heteroatoms in "alkenyl” are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • Said R 2-5-2-1 and R 2-5-2-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 al
  • R 3-5-2 and R 3-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "R 3-5-2-1 substituted 3-14-membered heterocycloalkyl ", 3-14-membered heterocycloalkenyl or "R 3-5-2-2- substituted 3-14-membered heterocycloalkenyl”; said 3-14-membered heterocycloalkyl, said "R 3 -5-2-1- substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R 3-5-2-2- substituted 3-14-membered heterocycle
  • the heteroatoms in "alkenyl” are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; Said R 3-5-2-1 and R 3-5-2-2 are independently hydroxyl, oxo, -CN, C 1 -
  • R 1-7 , R 2-7 , R 3-7 and R 4-4 are independently halogen, hydroxy, amino, mercapto, cyano, C 1 -C 7 alkoxy, C 3 -C 14 cycloalkyl , 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl
  • the heteroatoms are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 5 is independently C 1 -C 7 alkyl; alternatively, any two non-adjacent R 5 together with the carbon atom to which it is attached form a 4-10 membered cycloalkyl (ie, any two non-adjacent R 5 with One or more atoms to which they are bound together form a 4-10 membered cycloalkyl group; for example for When two non-adjacent R 5 together with the carbon atom to which they are attached form a 4-10 membered cycloalkyl group is a cycloheptyl group
  • the number of 1 and said R 3-5-2-2 is independently 1, 2 , 3, 4, 5, 6 or 7; when said R 1-7 , said R 2-7 , said Said R 3-7 , said R 4-4 , said R 1-3-1 , said R 1-3-2 , said R 2-3-1 , said R 2 -3-2 , said R 3-3-1 , said R 3-3-2 , said R 1-5-2-1 , said R 1-5-2-2 , said R 1-5-2-2 , said The number of said R 2-5-2-1 , said R 2-5-2-2 , said R 3-5-2-1 and said R 3-5-2-2 is When there are more than one, said R 1-7
  • n 0 or 1
  • Ring A and Ring B are independently C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heteroaryl
  • the heteroatoms in the cycloalkyl group and the 5-10-membered heteroaryl group are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 1-5 is independently hydrogen, -OR 1-5-1 , NR 1-5-2 R 1-5-3 or C 1 -C 7 alkyl;
  • R 2-5 is independently hydrogen, -OR 2-5-1 , NR 2-5-2 R 2-5-3 or C 1 -C 7 alkyl;
  • R 3-5 is independently hydrogen, -OR 3-5-1 , NR 3-5-2 R 3-5-3 or C 1 -C 7 alkyl;
  • R 1-6 is independently hydrogen, -OR 1-6-1 , NR 1-6-2 R 1-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 2-6 is independently hydrogen, -OR 2-6-1 , NR 2-6-2 R 2-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 3-6 is independently hydrogen, -OR 3-6-1 , NR 3-6-2 R 3-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 1-5-1 , R 2-5-1 , R 3-5-1 , R 1-6-1 , R 2-6-1 and R 3-6-1 are independently hydrogen, C 1 -C 7 alkyl or C 3 -C 14 cycloalkyl;
  • R 1-5-2 , R 1-5-3 , R 2-5-2 , R 2-5-3 , R 3-5-2 , R 3-5-3 , R 1-6-2 , R 1-6-3 , R 2-6-2 , R 2-6-3 , R 3-6-2 and R 3-6-3 are independently hydrogen, C 1 -C 7 alkyl, C 3 -C 14 -cycloalkyl or 3-14-membered heterocycloalkyl; the heteroatoms in the 3-14-membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independent 1, 2 or 3 lands.
  • n 0 or 1
  • n 0 or 1
  • u is 0 or 1
  • v 0, 1 or 2;
  • p 1 or 2;
  • s 1 or 2;
  • t 0 or 2;
  • Ring A and Ring B are independently C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heteroaryl
  • the heteroatoms in the cycloalkyl group and the 5-10-membered heteroaryl group are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 1 is "C 1 -C 7 alkyl substituted by R 1-7 ";
  • R 2 is independently halogen, "R 2-7 substituted C 1 -C 7 alkyl" or oxo;
  • R 3 is independently halogen, C 1 -C 7 alkyl, "R 3-7 substituted C 1 -C 7 alkyl" or oxo, or, any two non-adjacent carbon atoms to which R 3 is attached together form a 4-6 membered heterocycloalkyl;
  • R 4 is independently halogen, C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo;
  • R 1-7 , R 2-7 , R 3-7 and R 4-4 are independently halogen or hydroxy.
  • n 0 or 1
  • n 0 or 1
  • u is 0 or 1
  • v 0, 1 or 2;
  • p 1 or 2;
  • s 1 or 2;
  • t 0 or 2;
  • Ring A and Ring B are independently 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the heteroatoms in the 5-10-membered heteroaryl are independently selected From one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1, 2 or 3;
  • R 1 is C 1 -C 7 alkyl substituted by R 1-7 ;
  • R 2 is independently halogen, "R 2-7 substituted C 1 -C 7 alkyl" or oxo;
  • R 3 is independently halogen, C 1 -C 7 alkyl or oxo, alternatively, any two non-adjacent R 3 together with the carbon atom to which it is attached form a 4-6 membered heterocycloalkyl;
  • R 4 is independently halogen, -CN, -OR 4-1 , C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo;
  • R 1-7 , R 2-7 and R 4-4 are independently halogen or hydroxy
  • R 4-1 is hydrogen
  • n 0 or 1
  • n 0 or 1
  • u is 0 or 1
  • v 0, 1 or 2;
  • p 1 or 2;
  • s 1 or 2;
  • t 0 or 2;
  • Ring A and Ring B are independently C 6 -C 10 aryl or 5-10-membered heteroaryl; the heteroatoms in the 5-10-membered heteroaryl are independently selected from one of oxygen, sulfur and nitrogen. one or more, the number of heteroatoms is independently 1, 2 or 3;
  • R 1 is C 1 -C 7 alkyl substituted by R 1-7 ;
  • R 2 is independently halogen or "R 2-7 substituted C 1 -C 7 alkyl"
  • R 3 is independently halogen, C 1 -C 7 alkyl or oxo
  • R 4 is independently halogen, -CN, -OR 4-1 , C 1 -C 7 alkyl or oxo;
  • R 1-7 , R 2-7 and R 4-4 are independently halogen or hydroxy
  • R 4-1 is hydrogen
  • n 0 or 1
  • n 0 or 1
  • u is 0 or 1
  • v 0, 1 or 2;
  • p 1 or 2;
  • s 1 or 2;
  • t 0 or 2;
  • Ring A and Ring B are independently C 6 -C 10 aryl or 5-10-membered heteroaryl; the heteroatoms in the 5-10-membered heteroaryl are independently selected from one of oxygen, sulfur and nitrogen. one or more, the number of heteroatoms is independently 1, 2 or 3;
  • R 1 is "C 1 -C 7 alkyl substituted by R 1-7 ";
  • R 2 is independently halogen or "R 2-7 substituted C 1 -C 7 alkyl"
  • R 3 is independently halogen, C 1 -C 7 alkyl or oxo
  • R 4 is independently halogen, C 1 -C 7 alkyl or oxo
  • R 1-7 and R 2-7 are independently halogen or hydroxy.
  • the compound of formula I is as shown in formula II:
  • n 0 or 1
  • u is 0 or 1
  • v 0, 1 or 2;
  • p 1 or 2;
  • s 1 or 2;
  • t 0 or 2;
  • Ring A and Ring B are independently 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the heteroatoms in the 5-10-membered heteroaryl are independently selected From one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1, 2 or 3;
  • R 1 is C 1 -C 7 alkyl substituted by R 1-7 ;
  • R 2 is independently halogen, "R 2-7 substituted C 1 -C 7 alkyl" or oxo;
  • R 3 is independently halogen, C 1 -C 7 alkyl or oxo, alternatively, any two non-adjacent R 3 together with the carbon atom to which it is attached form a 4-6 membered heterocycloalkyl;
  • R 4 is independently halogen, -CN, -OR 4-1 , C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo;
  • R 1-7 , R 2-7 and R 4-4 are independently halogen or hydroxy
  • R 4-1 is hydrogen
  • the compound of formula I is as shown in formula II:
  • n 0 or 1
  • u is 0 or 1
  • v 0, 1 or 2;
  • p 1 or 2;
  • s 1 or 2;
  • t 0 or 2;
  • Ring A and ring B are independently C 6 -C 10 aryl or 5-10-membered heteroaryl; the heteroatom in the 5-10-membered heteroaryl is selected from one of oxygen, sulfur and nitrogen or Multiple, the number of heteroatoms is independently 1, 2 or 3;
  • R 1 is "C 1 -C 7 alkyl substituted by R 1-7 ";
  • R 2 is independently halogen or "R 2-7 substituted C 1 -C 7 alkyl"
  • R 3 is independently halogen or C 1 -C 7 alkyl; alternatively, any two non-adjacent R 3 and the carbon atoms to which they are attached together form a 4-6 membered heterocycloalkyl;
  • R 4 is independently C 1 -C 7 alkyl
  • R 1-7 and R 2-7 are independently halogen or hydroxy.
  • the compound of formula I is a compound of formula III:
  • ring A and ring B are independently C 3 -C 14 -membered cycloalkyl, 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the 3-14 The heteroatoms in the membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3 indivual;
  • the heteroatoms in the heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • the heteroatoms in the membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; or, any two non-adjacent heteroatoms R3 together with the carbon atom to which it is attached forms a 4-6 membered heterocycloalkyl;
  • R 1-1 , R 2-1 and R 3-1 are independently hydrogen, "halogen substituted C 1 -C 7 alkyl", C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl or 3 -14-membered heterocycloalkyl; the heteroatoms in the 3-14-membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 1-3 , R 1-4 , R 2-3 , R 2-4 , R 3-3 and R 3-4 are independently hydrogen, C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl and 3-14-membered heterocycloalkyl; the heteroatoms in the 3-14-membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1 , 2 or 3;
  • R 1-3 and R 1-4 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "3-14-membered heterocycloalkyl substituted by R 1-3-1 "; the 3-14-membered heterocycloalkyl group
  • the heteroatoms in -14-membered heterocycloalkyl and "R 1-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2 or 3;
  • the R 1-3-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • R 2-3 and R 2-4 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl or "3-14-membered heterocycloalkyl substituted by R 2-3-1 "; the 3-14-membered heterocycloalkyl group
  • the heteroatoms in -14-membered heterocycloalkyl and "R 2-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2 or 3; the R 2-3-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • the heteroatoms in -14-membered heterocycloalkyl and "R 3-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2, 3 or 4;
  • the R 3-3-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy base;
  • R 1-5 is independently hydrogen, -OR 1-5-1 , NR 1-5-2 R 1-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 2-5 is independently hydrogen, -OR 2-5-1 , NR 2-5-2 R 2-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 3-5 is independently hydrogen, -OR 3-5-1 , NR 3-5-2 R 3-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the heteroatoms the number of atoms is independently 1, 2 or 3;
  • R 1-6 is independently hydrogen, -OR 1-6-1 , NR 1-6-2 R 1-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 2-6 is independently hydrogen, -OR 2-6-1 , NR 2-6-2 R 2-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 3-6 is independently hydrogen, -OR 3-6-1 , NR 3-6-2 R 3-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;
  • R 1-5-1 , R 2-5-1 , R 3-5-1 , R 1-6-1 , R 2-6-1 and R 3-6-1 are independently hydrogen, C 1 -C 7 alkyl groups, C 3 -C 14 cycloalkyl groups or 3-14-membered heterocycloalkyl groups; the heteroatoms in the 3-14-membered heterocycloalkyl groups are independently selected from one of oxygen, sulfur and nitrogen or more, the number of heteroatoms is independently 1, 2, 3 or 4;
  • R 1-5-2 , R 1-5-3 , R 2-5-2 , R 2-5-3 , R 3-5-2 , R 3-5-3 , R 1-6-2 , R 1-6-3 , R 2-6-2 , R 2-6-3 , R 3-6-2 and R 3-6-3 are independently hydrogen, C 1 -C 7 alkyl, C 3 -C 14 -cycloalkyl or 3-14-membered heterocycloalkyl; the heteroatoms in the 3-14-membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independent 1, 2 or 3 lands;
  • R 1-5-2 and R 1-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R 1-5-2-1- substituted 3-14-membered heterocycloalkyl ";
  • the heteroatoms in the 3-14-membered heterocycloalkyl and the "R 1-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen
  • One or more of, the number of heteroatoms is independently 1, 2 or 3;
  • the R 1-5-2-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • R 2-5-2 and R 2-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R 2-5-2-1 substituted 3-14-membered heterocycloalkyl "; the heteroatoms in the 3-14-membered heterocycloalkyl and the "R 2-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen
  • One or more of, the number of heteroatoms is independently 1, 2 or 3;
  • the R 2-5-2-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • R 3-5-2 and R 3-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R 3-5-2-1 substituted 3-14-membered heterocycloalkyl ";
  • the heteroatoms in the 3-14-membered heterocycloalkyl and the "R 3-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen
  • One or more of, the number of heteroatoms is independently 1, 2 or 3;
  • the R 3-5-2-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;
  • R 1-7 , R 2-7 and R 3-7 are independently halogen, hydroxy, amino, mercapto, cyano, C 1 -C 7 alkoxy, C 3 -C 14 cycloalkyl and 3-14 membered Heterocycloalkyl; the heteroatoms in the 3-14-membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3 indivual.
  • the compound of formula I is a compound of formula IV:
  • v 0, 1 or 2;
  • Ring A is C 6 -C 10 aryl
  • Ring B is independently a C 6 -C 10 aryl group or a 5-10-membered heteroaryl group; the heteroatom in the 5-10-membered heteroaryl group is selected from one or more of oxygen, sulfur and nitrogen, The number of heteroatoms is 1, 2 or 3;
  • R 1 is "C 1 -C 7 alkyl substituted by R 1-7 ";
  • R 2 is independently halogen or "R 2-7 substituted C 1 -C 7 alkyl"
  • R 3 is independently halogen or C 1 -C 7 alkyl
  • R 1-7 and R 2-7 are independently halogen or hydroxy.
  • the heteroatom in the 3-14 membered heterocycloalkyl is not substituted by oxygen.
  • the heterocycloalkyl in the 3-14-membered heterocycloalkyl is a heteromonocycloalkyl or heterocycloalkyl Bridged cycloalkyl.
  • the 3-14 membered heterocycloalkyl is attached to the ring B through a heteroatom.
  • the ring A is a 3-14-membered heterocycloalkyl
  • the 3-14-membered heterocycloalkyl is a 5-, 6- or 7-membered heterocycloalkyl
  • a heteroatom for oxygen and/or nitrogen the number is 1 or 2.
  • the 3-14-membered heterocycloalkyl is piperidinyl or piperazinyl, more preferably
  • the C 6 -C 10 aryl group is a phenyl group or a naphthyl group, preferably a phenyl group.
  • the heteroaryl group is a monocyclic ring.
  • the heteroatom in the heteroaryl group is not substituted by oxygen.
  • the heteroatom is nitrogen, the heteroatom is not quaternized.
  • the ring A is a 5-10 membered heteroaryl group
  • the 5-10 membered heteroaryl group is attached to the ring B through a carbon atom.
  • the ring A is a 5-10-membered heteroaryl group
  • the 5-10-membered heteroaryl group is a 5- or 6-membered heteroaryl group
  • the heteroatom is sulfur and/or Nitrogen
  • the number is 1 or 2.
  • the ring A is a 5-10-membered heteroaryl group
  • the 5-10-membered heteroaryl group is a 5- or 6-membered heteroaryl group
  • the heteroatom is nitrogen. 1 or 2.
  • the 5-10-membered heteroaryl group is pyridyl, pyrimidinyl or thienyl, more preferably
  • the ring A is a 5-10 membered heteroaryl
  • the 5-10 membered heteroaryl is The right end is connected with methylene, and the left end is connected with ring B.
  • the heteroatom in the 3-14 membered heterocycloalkyl is not substituted by oxygen.
  • the heterocycle in the 3-14-membered heterocycloalkyl is a heteromonocycle.
  • the ring B is a 3-14 membered heterocycloalkyl
  • the 3-14 membered heterocycloalkyl is attached to the ring A through a heteroatom.
  • the ring B is a 3-14-membered heterocycloalkyl
  • the 3-14-membered heterocycloalkyl is a 5- or 6-membered heterocycloalkyl
  • the heteroatom is nitrogen
  • the number is 1 or 2.
  • the ring B is a 3-14-membered heterocycloalkyl group
  • the 3-14-membered heterocycloalkyl group is piperidinyl or piperazinyl, more preferably preferred
  • the left end is connected to ring A
  • the right end is connected to R1.
  • the C 6 -C 10 aryl group is phenyl or naphthyl, preferably phenyl.
  • the C 6 -C 10 aryl group is The left end is connected to ring A, and the right end is connected to R 1 .
  • the heteroaryl is a monocyclic heteroaryl.
  • the heteroatom in the heteroaryl group is not substituted by oxygen.
  • the heteroatom is nitrogen, the heteroatom is not quaternized.
  • the ring B is a 5-10 membered heteroaryl group
  • the 5-10 membered heteroaryl group is attached to the ring A through a carbon atom.
  • the heteroatom in the 5-10 membered heteroaryl group is located ortho to the point of attachment to ring A.
  • the ring B is a 5-10-membered heteroaryl group
  • the 5-10-membered heteroaryl group is a 5- or 6-membered heteroaryl group
  • the heteroatom is nitrogen. 1 or 2.
  • the 5-10-membered heteroaryl group is a pyridyl group, more preferably a pyridyl group
  • the ring B is a 5-10-membered heteroaryl
  • the 5-10-membered heteroaryl is The left end is connected to ring A, and the right end is connected to R 1 .
  • halogen is F, Br, Cl or I, preferably F.
  • R 1 is independently "C 1 -C 7 alkyl substituted by R 1-7 ", the number of said R 1-7 is 4, 5 or 6 or 7.
  • R 1 is independently "R 1-7 substituted C 1 -C 7 alkyl"
  • said C 1 -C 7 alkyl is C 1 -C 3 alkyl ( For example, methyl, ethyl, n-propyl or isopropyl), more preferably isopropyl.
  • R 1-7 when R 1-7 is halogen, the halogen is F, Br, Cl or I, preferably F.
  • R 1 is independently "R 1-7 substituted C 1 -C 7 alkyl"
  • R 1-7 substituted C 1 -C 7 alkyl is
  • halogen is F, Br, Cl or I, preferably F.
  • R 2 is independently "C 1 -C 7 alkyl substituted by R 2-7 ", the number of said R 2-7 is three.
  • R 2 is independently "R 2-7 substituted C 1 -C 7 alkyl"
  • said C 1 -C 7 alkyl is C 1 -C 3 alkyl ( For example, methyl, ethyl, n-propyl or isopropyl), more preferably methyl.
  • R 2-7 when R 2-7 is halogen, said halogen is F, Br, Cl or I, preferably F.
  • R 2 is independently "R 2-7 substituted C 1 -C 7 alkyl”
  • the "R 2-7 substituted C 1 -C 7 alkyl” is trifluoromethyl
  • halogen is F, Br, Cl or I, preferably F or Cl.
  • R 3 is independently C 1 -C 7 alkyl
  • said C 1 -C 7 alkyl is C 1 -C 3 alkyl (eg methyl, ethyl, n- propyl or isopropyl), more preferably methyl.
  • halogen is F, Br, Cl or I, preferably Cl.
  • said halogen is preferably F or Cl.
  • R 4 is independently C 1 -C 7 alkyl
  • said C 1 -C 7 alkyl is C 1 -C 3 alkyl (eg methyl, ethyl, n- propyl or isopropyl), more preferably methyl.
  • R 4 is independently "C 1 -C 7 alkyl substituted by R 4-4 ", the number of said R 4-4 is three.
  • R 4 is independently "R 4-4 substituted C 1 -C 7 alkyl"
  • said C 1 -C 7 alkyl is C 1 -C 3 alkyl ( For example, methyl, ethyl, n-propyl or isopropyl), more preferably methyl.
  • R 4-4 when R 4-4 is halogen, said halogen is F, Br, Cl or I, preferably F.
  • R 4 is independently "R 4-4 substituted C 1 -C 7 alkyl”
  • the “R 4-4 substituted C 1 -C 7 alkyl” is trifluoromethyl
  • the 4-10 membered cycloalkyl group is a 7-membered cycloalkyl group .
  • Ring B is a 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl group
  • the substitution site for R 1 is located at the para position to the bond to Ring A.
  • substitution site on Ring B on Ring A is Not adjacent.
  • m is 0 or 1, preferably 0.
  • n is 0 or 1, preferably 0.
  • u is 0 or 1.
  • v is 0, 1 or 2.
  • p is 1 or 2.
  • s is 1 or 2.
  • t is 0 or 2, preferably 0.
  • W is CH.
  • Z is CH.
  • Ring A is 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl, preferably C6 - C10 aryl or 5-10 membered Heteroaryl.
  • Ring B is a 3-14 membered heterocycloalkyl, a C6 - C10 aryl or a 5-10 membered heteroaryl, preferably a C6 - C10 aryl.
  • R 1 is independently halogen or "R 1-7 substituted C 1 -C 7 alkyl".
  • R 2 is independently halogen, "R 2-7 substituted C 1 -C 7 alkyl " or oxo, preferably halogen or "R 2-7 substituted C 1 -C 7 . alkyl".
  • R 3 is independently halogen, C 1 -C 7 alkyl or oxo, preferably halogen or "R 3-7 substituted C 1 -C 7 alkyl".
  • R 4 is independently halogen, -CN, -OR 4-1 , C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo , R 4-1 is H.
  • R 4 is independently halogen, C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo.
  • R 1-7 , R 2-7 , R 3-7 and R 4-4 are independently halogen or hydroxy.
  • the compound shown in formula I is optionally any of the following compounds:
  • the present invention also provides a compound I-a:
  • the compound I-a is preferably any one of the following compounds:
  • the retention time is 1.486min under the following chiral preparation conditions or with a retention time of 2.705min (i.e. compound );
  • chromatographic column chiral column CHIRALPAK IH-3; mobile phase A: n-hexane solution containing 0.1% ethylenediamine; mobile phase B: isopropanol; flow rate: 1ml/min; elution Conditions: eluted with 60% mobile phase A and 40% mobile phase B for 14min; flow rate: 1.0ml/min; detector wavelength: 220nm; temperature: room temperature, the "%" is volume percentage.
  • the present invention also provides the above-mentioned spiroheterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or
  • the preparation method of its prodrug, the preparation method is any of the following methods:
  • the preparation method of the compound shown in the formula I comprises the following steps: in a solvent, the compound I-a and the compound I-b are subjected to the reductive amination reaction of the following formula to obtain the compound shown in the formula I;
  • m, n, p, s, u, v, t, Y, Z, W, Q, R 1 , R 2 , R 3 , R 4 , R 5 , ring A and ring B are defined as above stated;
  • the preparation method of the compound shown in the formula I comprises the following steps: in the presence of a Pd catalyst, in a solvent, the compound I-d and the compound I-e are subjected to the Suzuki reaction of the following formula to obtain the compound I;
  • R6 is m, n, p, s, u, v, t, Y, Z, W, Q, R 1 , R 2 , R 3 , R 4 , R 5 , ring A and ring B are as defined above.
  • the conditions and operations of the reductive amination can be the conventional conditions and operations of this type of reaction in this area, and the present invention particularly preferably the following conditions and operations:
  • the solvent is preferably a halogenated hydrocarbon (eg, dichloromethane) and/or an amide solvent (eg, N,N-dimethylformamide).
  • a halogenated hydrocarbon eg, dichloromethane
  • an amide solvent eg, N,N-dimethylformamide
  • the reductive amination reaction is preferably carried out in the presence of a catalyst.
  • the catalyst is preferably one or more of triethylamine, acetic acid and trifluoroacetic acid.
  • the reducing agent used in the reductive amination reaction is preferably sodium triacetyl borohydride and/or sodium acetyl borohydride.
  • the molar ratio of the reducing agent to the compound I-a is preferably 5:1-2:1, such as 3:1.
  • the molar ratio of the compound I-b to the compound I-a is preferably 0.9:1-3:1, for example, 1:1.
  • the temperature of the reductive amination reaction is preferably carried out at room temperature.
  • the progress of the reductive amination reaction can be monitored by conventional methods in the art (eg TLC or HPLC), and generally the end point of the reaction is that the compound I-a does not react or disappears.
  • the time of the reductive amination reaction is preferably 12-36 hours.
  • the post-processing steps after the reductive amination reaction are preferably as follows: concentration and column chromatography (for example, the eluent is methanol and dichloromethane with a volume content of 0-1:10).
  • condition and operation of described Suzuki can be the conventional condition and operation of this type of reaction in this area, and the present invention is particularly preferably the following condition and operation:
  • the Pd catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (Pd(dppf)Cl 2 ) and/or [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex.
  • the molar ratio of the Pd catalyst to the compound I-d is preferably 0.01:1-0.3:1, for example, 0.2:1.
  • the solvent is preferably an ether solvent (eg dioxane).
  • the alkaline reagent used in the Suzuki reaction is preferably an alkali metal carbonate (eg, potassium carbonate).
  • the molar ratio of the basic reagent to the compound I-d is preferably 1.2:1-5:1, for example, 3:1.
  • the molar ratio of the compound I-e to the compound I-d is preferably 1.1:1-2:1, for example, 1.5:1.
  • the temperature of the Suzuki reaction is preferably 80-110°C, for example, 100°C.
  • the progress of the Suzuki reaction can be monitored by conventional methods in the art (eg, TLC or HPLC), and generally, the end point of the reaction is that the compound I-d does not react or disappears.
  • the time of the Suzuki reaction is preferably 8-24 hours, such as 16 hours.
  • the post-processing steps after the Suzuki reaction is preferably the following steps: concentration and column chromatography (for example, the eluent is methanol and dichloromethane with a volume content of 0-1:10).
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned spiroheterocyclic compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable A solvate of a salt, its metabolite or its prodrug, with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a substance X in the preparation of a ROR ⁇ t protein receptor modulator; the substance X is the spiroheterocyclic compound shown in formula I, a pharmaceutically acceptable salt thereof, Its solvate, its solvate of a pharmaceutically acceptable salt, its metabolite, its prodrug or said pharmaceutical composition.
  • the present invention also provides the application of a substance X in the preparation of medicine; the substance X is the spiroheterocyclic compound shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, The solvate of its pharmaceutically acceptable salt, its metabolite, its prodrug or said pharmaceutical composition.
  • the present invention also provides the application of a substance X in the preparation of a medicine; the medicine is used for preventing or treating diseases related to the ROR ⁇ t protein receptor; the substance X is the spiro as shown in formula I.
  • the disease associated with the ROR ⁇ t protein receptor is preferably an autoimmune disease.
  • the autoimmune disease is preferably psoriasis (Psoriasis), multiple sclerosis (MS), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ankylosing spondylitis, systemic lupus erythematosus, One or more of Behçet's disease and chronic obstructive pulmonary disease.
  • Psoriasis psoriasis
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • ankylosing spondylitis systemic lupus erythematosus
  • Behçet's disease chronic obstructive pulmonary disease.
  • the present invention also provides the application of a substance X in the preparation of medicine;
  • the substance X is the spiroheterocyclic compound shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, The solvate of its pharmaceutically acceptable salt, its metabolite, its prodrug or said pharmaceutical composition;
  • said medicine is used for preventing or treating psoriasis, multiple sclerosis, rheumatoid joints one or more of inflammatory bowel disease, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, and chronic obstructive pulmonary disease.
  • the present invention also provides a method for preventing and/or treating a disease, the method comprising administering an effective amount of Substance X to a subject in need of treatment; wherein, the disease is a disease related to the ROR ⁇ t protein receptor, and the Substance X is the spiroheterocyclic compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its metabolite, its predrug body or the pharmaceutical composition.
  • the diseases related to the ROR ⁇ t protein receptor are the same as those described above.
  • the present invention also provides a method for preventing and/or treating a disease, the method comprising administering an effective amount of Substance X to a subject in need of treatment; wherein the disease is psoriasis, multiple sclerosis, rheumatoid One or more of arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease and chronic obstructive pulmonary disease; the substance X is the spiral as shown in formula I. Heterocyclic compounds, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, metabolites thereof, prodrugs thereof or the pharmaceutical composition thereof.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use.
  • patient is preferably a mammal, more preferably a human.
  • salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
  • base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • acids addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a salt is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • the pharmaceutically acceptable acid includes inorganic acids, and the inorganic acids include but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
  • solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
  • the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
  • “Pharmaceutically acceptable salt” and “solvate” in the term “solvate of a pharmaceutically acceptable salt” are as described above and refer to Compound 1 of the present invention, and a relatively non-toxic, pharmaceutically acceptable 2. A substance formed by combining with a stoichiometric or non-stoichiometric amount of a solvent.
  • the “solvates of pharmaceutically acceptable salts” include, but are not limited to, hydrochloric acid monohydrates of the compounds of the present invention.
  • crystal form means that the ions or molecules in it are arranged in a strictly periodic manner in three-dimensional space in a certain manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism.
  • amorphous means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.
  • stereoisomer refers to a cis-trans isomer or an optical isomer.
  • stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • Atoms in the terms “compound”, “pharmaceutically acceptable salt”, “solvate” and “solvate of a pharmaceutically acceptable salt” may exist in their natural or unnatural abundance. Taking a hydrogen atom as an example, its natural abundance form means that about 99.985% of it is protium and about 0.015% is deuterium; its unnatural abundance form, for example, about 95% of which is deuterium. That is, one or more atoms in the terms “compound”, “pharmaceutically acceptable salt”, “solvate” and “solvate of a pharmaceutically acceptable salt” may be present in unnatural abundance Atoms that exist in the form.
  • variable for example, R 1-1-1
  • R 1-1-1 When any variable (for example, R 1-1-1 ) appears multiple times in the definition of a compound, the definition that appears in each position of the variable is independent of the definitions that appear in other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2 or 3 R 1-1-1 groups, that is, the group may be substituted with up to 3 R 1-1-1 groups, the position R 1 The definition of -1-1 is independent of the definition of the remaining positions R 1-1-1 . Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a saturated straight or branched monovalent hydrocarbon radical having one to twelve carbon atoms (eg, C1 - C6 alkyl, eg, C1 - C4 alkyl).
  • alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2 -propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2 -Methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl , 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-di
  • alkenyl refers to a linear or branched monovalent hydrocarbon group of two to twelve carbon atoms having at least one position of unsaturation, ie, a carbon-carbon sp double bond (eg, C2 - C6 alkenyl, and such as C2 - C4 alkenyl), and includes groups having "cis” and “trans” orientations or "E” and “Z” orientations. Examples include, but are not limited to, vinyl, allyl.
  • cycloalkyl refers to a saturated, non-aromatic, cyclic hydrocarbon radical (eg, C3 - C6 cycloalkyl) having three to twenty carbon atoms, including monocyclic cycloalkyls and polycyclic cycloalkanes base. Cycloalkyl groups contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl alkyl.
  • Polycyclic cycloalkyls are polycyclic (eg, bicyclic and tricyclic) cycloalkyl structures, including spiro, fused, and bridged cycloalkyls.
  • spirocyclic cycloalkyl refers to a polycyclic group with a single carbon atom (called a spiro atom) between 5 and 20 members, which may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl groups are divided into single spirocycloalkyl and double spirocycloalkanes. or polyspirocycloalkyl, preferably mono-spirocycloalkyl and double-spirocycloalkyl. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered Single/6-membered spirocycloalkyl.
  • spirocycloalkyl examples include, but are not limited to: "Fused-ring cycloalkyl” refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which may contain one or more double bonds , but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group with any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings has Fully conjugated pi electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged cycloalkyl preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include, but are not limited to:
  • heterocycloalkyl refers to a saturated carbocyclic group having 3 to 20 ring atoms, wherein at least one ring atom is a heteroatom independently selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus , and the remaining ring atoms are C.
  • the group may be a carbon group or a heteroatom group (ie it may be C-attached or N-attached, as long as it is possible).
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thi oxanyl and piperazinyl. Fused ring moieties, spiro ring moieties and bridged ring moieties are also included within the scope of this definition.
  • a group derived from tetrahydropyrrole can be tetrahydropyrrol-1-yl (N-attached) or tetrahydropyrrol-3-yl (C-attached).
  • heterocycloalkenyl refers to a monocyclic partially unsaturated (containing 1 or 2 double bond) non-aromatic cyclic hydrocarbon radical having three to twenty carbon atoms (eg C3 - C6cycloalkenyl) ).
  • aryl refers to any stable monocyclic or bicyclic carbocyclic ring of up to 10 atoms in each ring, at least one of which is aromatic.
  • aryl unit examples include phenyl, naphthyl, tetrahydronaphthyl, 2,3-indenyl, biphenyl, phenanthrenyl, anthracenyl, or acenaphthyl. It will be appreciated that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through the aromatic ring.
  • heteroaryl refers to stable monocyclic or bicyclic rings of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 atoms selected from the group consisting of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus heteroatoms.
  • Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline.
  • Heteroaryl should also be understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • the heteroaryl substituent is a bicyclic substituent and one ring is non-aromatic or contains no heteroatoms, it is understood that the attachment is through the aromatic ring, respectively.
  • Heteroaromatic and bicyclic heteroaromatic ring systems can be fused to form rings.
  • N, S, B, P or Se is optionally substituted with one or more oxygen atoms to give groups like NO, SO, SO2, BOH, PO, PO2 , SeO , the N atom can be quaternized .
  • Heteroaryl groups can be attached to the main structure at any heteroatom or carbon atom to form stable compounds.
  • a heteroaryl group can be a monoradical or a diradical, ie, a heteroarylene.
  • alkoxy refers to an alkyl group attached through an oxygen bridge; said alkyl group is as defined above.
  • alkylmercapto refers to an alkyl group attached through a sulfur bridge; said alkyl group is as defined above.
  • pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduced risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat the disease or disorder described herein.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.
  • patient refers to any animal, preferably a mammal, and most preferably a human, to whom the compound or composition is to be or has been administered according to embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • active ingredient refers to the active ingredient in the pharmaceutical composition or combination kit of the present invention, namely Compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, Its metabolites or prodrugs thereof, anticancer drugs, or the above-mentioned combinations formed by them.
  • room temperature refers to 15-35°C
  • overnight refers to 10-18 hours.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that: the compound of the present invention has inhibitory activity on ROR ⁇ t, and can effectively inhibit the ROR ⁇ t protein receptor, thereby regulating the differentiation of Th17 cells, inhibiting the production of IL-17, and then treating ROR ⁇ t-mediated related autoimmune diseases. disease.
  • the structures of all compounds of the present invention can be identified by nuclear magnetic resonance ( 1 HNMR) and/or mass spectrometry (MS).
  • LC-MS was determined by an Agilent 1200 HPLC/6120 mass spectrometer.
  • HPLC was determined by an Agilent 1260 high performance liquid chromatograph. HPLC specific conditions: mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; column time: 15 min; column type: Waters company Xselect, 5 ⁇ m, 4.6 ⁇ 250 mm.
  • the thin layer silica gel plate is Liangchen Silicon Source HSGF254 or Qingdao GF254 silica gel plate.
  • Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.
  • a chiral column model: CHIRALPAK IH-3, column diameter: 4.600, analytical method: mobile phase A: n-hexane solution containing 0.1% ethylenediamine; mobile phase B: isopropanol; flow rate: 1 ml/min; Elution conditions: use 60% mobile phase
  • the reaction mixture was quenched with saturated aqueous NaHCO 3 and water (200 ml) and extracted with ethyl acetate (3 ⁇ 200 ml). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to give the crude product (7.30 g). The crude product (1.00 g) was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM NH4HCO3 ) , 45% to 65%) to give compound 11 (0.55 g, 1.69 mmol) as a white solid.
  • 1,4-Dibromobenzene (I-17-a) (5.72 g, 24.2 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), the reaction solution was cooled to -78°C, and n-butyllithium was added dropwise to the reaction solution After the dropwise addition, the reaction solution was stirred at -78°C for 0.5 hours, and ethyl 2,2-difluoroacetate (6.62 g, 53.3 mmol) was added to the reaction solution, After the addition, the reaction solution was stirred at -78 °C for 1 hour, and the dot plate showed that the reaction raw materials disappeared.
  • reaction system was quenched with saturated aqueous NH4Cl (8 mL). Water (20 mL) and ethyl acetate (20 mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate .
  • N-Methoxy-N-methylpiperidine-4-carboxamide (I-41-c) (1.00 g, 5.81 mmol) was dissolved in 1,4-dioxane (20 ml), tert-butyl group was added ((1,1,1,3,3,3-Hexafluoro-2-(4-iodophenyl)propan-2-yl)oxy)dimethylsilane (3.37 g, 6.97 mmol), RuPhos Pd G3 (0.49 g, 0.58 mmol), RuPhos (0.27 g, 0.58 mmol) and cesium carbonate (3.78 g, 11.61 mmol). The protective system was replaced with nitrogen, and then the temperature was raised to 90° C. for 18 hours.
  • 2,6-Diisopropylaniline (6.32 g, 62.50 mmol) was dissolved in anhydrous tetrahydrofuran (160 mL), the reaction solution was cooled to -70°C, and n-butyllithium ( 25ml, 62.50mmol) the reaction solution was stirred at -70°C for 0.5 hours, 3-bromo-5-fluoropyridine (I-53-a) (10g, 56.82mmol) was added to the reaction solution, and the reaction solution was at -70°C After stirring for 0.5 hours, methyl iodide (9.68 g, 68.19 mmol) was added to the reaction solution, the reaction solution was slowly warmed to room temperature and stirred for 16 hours.
  • I-53-a 3-bromo-5-fluoropyridine
  • LC-MS 209.15 [M+1] + .
  • tert-butyl 4-((6-bromo-2-fluoropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-56-b) (2.5g, 6.42 mmol) was dissolved in dry tetrahydrofuran (50 ml), the system was cooled to 0°C, and NaH (60%, 513.4 mg, 12.84 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours.
  • Trimethyl sulfoxide (I-58-a) (66.27 g, 301.13 mmol) was dissolved in dry dimethyl sulfoxide (250 mL), and potassium tert-butoxide (33.79 g, 301.13 mmol) was added at room temperature , and stirred at this temperature for 30 minutes.
  • the system was cooled to 0°C, and a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (50 g, 250.94 mmol) in ethylene glycol dimethyl ether (DME) (250 mL) was added dropwise. After dropping, it was slowly warmed to room temperature and stirred for 6 hours.
  • DME ethylene glycol dimethyl ether
  • 3-bromo-2,6-difluoropyridine (3.34 g, 17.22 mmol) was dissolved in dry tetrahydrofuran (30 mL), cooled to -78 °C, and n-butyllithium (n-BuLi) was slowly added. ) (2.5M, 8.26 mL, 20.66 mmol).
  • tert-butyl 3-((2,6-difluoropyridin-3-yl)methyl)-3-hydroxypyrrolidine-1-carboxylate (1.9 g, 6.04 mmol) was dissolved in dry tetrahydrofuran (20 ml), the system was cooled to 0°C, and potassium tert-butoxide (678.3 mg, 6.04 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours.
  • tert-butyl 6'-fluoro-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylate (I-57- e) (1.00 g, 3.57 mmol) was dissolved in dry tetrahydrofuran (20 ml), cooled to 0°C, and sodium hydride (60%, 285.38 mg, 7.14 mmol) and benzyl alcohol (424.38 mg, 3.92 mmol) were added in portions at room temperature ). The reaction system was heated to 60°C for 2 hours. After completion of the reaction monitored by LCMS, it was cooled to room temperature and quenched by the addition of water (20 mL).
  • the compounds of the present invention use fluorescence resonance energy transfer (FRET) assay to determine the inhibitory activity of the compounds on ROR ⁇ t.
  • FRET fluorescence resonance energy transfer
  • Relative Ratio Calculate the relative ratio (response at 665 nm/response at 615 nm - response at blank background) for each well.
  • Inhibition rate% [1-(compound fluorescence detection value-positive compound fluorescence detection average value)/(negative control fluorescence detection average value-positive compound fluorescence detection average value)]x100
  • Calculate the IC50 and dose-response curve of the compound By calculating the inhibition rate of the compound and the log value of the compound concentration, use Graphpad 8.0 to obtain the IC50 and dose-response curve of the compound.
  • Compound number IC50 Compound number IC50 Compound number IC50 I-1 +++ I-2 +++ I-3 ++ I-6 + I-7 ++ I-8 +++ I-9 +++ I-10 ++ I-10A ++ I-10B ++ I-11 + I-12 +++ I-13 +++ I-14 ++ I-15 ++ I-16 +++ I-17 +++ I-18 ++ I-19 ++ I-20 ++ I-21 +++ I-22 +++ I-23 +++ I-24 ++ I-25 ++ I-27 ++ I-28A ++ I-28B ++ I-29 ++ I-30 + I-31 + I-32 ++ I-33 + I-34 + I-36 + I-41 + I-50 +++ I-51 + I-52 + I-53 +++ I-54 ++ I-56 + I-57 + I-58 + I-59 + I-60 +

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Abstract

L'invention concerne un composé spiro hétérocyclique, son procédé de préparation et son utilisation. Le composé spiro hétérocyclique est représenté par la formule I. Le composé a une activité inhibitrice sur RORγt, peut inhiber efficacement le récepteur de la protéine RORγt, ce qui permet de réguler la différenciation de cellules Th17, d'inhiber la génération d'IL-17, puis de traiter des maladies auto-immunes associées médiées par RORγt.
PCT/CN2021/129049 2020-11-06 2021-11-05 Composé spiro hétérocyclique, son procédé de préparation et son utilisation WO2022095971A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008088692A2 (fr) * 2007-01-12 2008-07-24 Merck & Co., Inc. Dérivés spirochromanone
CN101541809A (zh) * 2006-11-29 2009-09-23 辉瑞产品公司 螺环酮乙酰基-CoA羧化酶抑制剂
WO2011140425A1 (fr) * 2010-05-06 2011-11-10 Vertex Pharmaceuticals Incorporated Amides de chromène hétérocyclique-pipéridine spirocyclique utiles comme modulateurs des canaux ioniques
WO2013067248A1 (fr) * 2011-11-04 2013-05-10 Vertex Pharmaceuticals Incorporated Benzoxazines comme modulateurs des canaux ioniques
WO2018075959A1 (fr) * 2016-10-20 2018-04-26 Forma Therapeutics, Inc. Procédés utilisant des inhibiteurs de hdac11
WO2021086966A1 (fr) * 2019-10-29 2021-05-06 Biogen Ma Inc. Inhibiteurs spirocycliques d'o-glycoprotéine-2-acétamido-2-désoxy-3-d-glucopyranosidase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101541809A (zh) * 2006-11-29 2009-09-23 辉瑞产品公司 螺环酮乙酰基-CoA羧化酶抑制剂
WO2008088692A2 (fr) * 2007-01-12 2008-07-24 Merck & Co., Inc. Dérivés spirochromanone
WO2011140425A1 (fr) * 2010-05-06 2011-11-10 Vertex Pharmaceuticals Incorporated Amides de chromène hétérocyclique-pipéridine spirocyclique utiles comme modulateurs des canaux ioniques
WO2013067248A1 (fr) * 2011-11-04 2013-05-10 Vertex Pharmaceuticals Incorporated Benzoxazines comme modulateurs des canaux ioniques
WO2018075959A1 (fr) * 2016-10-20 2018-04-26 Forma Therapeutics, Inc. Procédés utilisant des inhibiteurs de hdac11
WO2021086966A1 (fr) * 2019-10-29 2021-05-06 Biogen Ma Inc. Inhibiteurs spirocycliques d'o-glycoprotéine-2-acétamido-2-désoxy-3-d-glucopyranosidase

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DATABASE REGISTRY 29 January 2017 (2017-01-29), ANONYMOUS : "INDEX NAME NOT YET ASSIGNED ", XP055928455, retrieved from STN Database accession no. 2061265-80-1 (+ 2060468-39-3 2060468-28-0) *

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