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WO2020082921A1 - Dérivé d'azote-hétéroarylamide, son procédé de préparation et son utilisation - Google Patents

Dérivé d'azote-hétéroarylamide, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2020082921A1
WO2020082921A1 PCT/CN2019/104957 CN2019104957W WO2020082921A1 WO 2020082921 A1 WO2020082921 A1 WO 2020082921A1 CN 2019104957 W CN2019104957 W CN 2019104957W WO 2020082921 A1 WO2020082921 A1 WO 2020082921A1
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group
deuterium
alkyl
cycloalkyl
membered
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Chinese (zh)
Inventor
赵保卫
寻国良
危明松
张鸣鸣
杨舒群
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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Abbisko Therapeutics Co Ltd
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and in particular relates to a azaarylamide derivative and a preparation method and application thereof.
  • the retinoic acid-related orphan receptor (ROR) family contains three members ROR ⁇ , - ⁇ and - ⁇ .
  • ROR ⁇ is indispensable in the development of the cerebellum, and ROR ⁇ is mainly expressed in the brain and retina, both of which play important functions in the normal development of the retina.
  • ROR ⁇ is divided into two subtypes of ROR ⁇ 1 and ROR ⁇ 2 (ROR ⁇ t) according to different transcriptional shear positions.
  • the former is mainly expressed in liver, skeletal muscle and kidney, while ROR ⁇ t is mainly expressed in immune organs.
  • the mice lacking ROR ⁇ t lack lymph nodes and Peyer's patches and other lymphoid organs.
  • the development and maturation of T cells is also affected. The number of various T cells is lower than that of normal mice.
  • T helper cells play an indispensable and important role.
  • CD4-positive T helper cells can differentiate into a series of regulatory helper cells such as Th1, Th2, Th17 and Treg under the induction of different cytokines in the microenvironment.
  • Th1 and Th2 play an important role in the process of antigen recognition, presentation and activation of T effector cells.
  • Treg is a type of regulatory cell that promotes immune suppression.
  • Th17 is a new type of T helper cell discovered in recent years, characterized by the secretion of interleukin 17 (IL-17) cytokine.
  • Th17 cells were originally thought to play a role in immune function by recruiting neutrophils in the fight against bacterial fungal infections.
  • ROR ⁇ t can directly affect the abundance and activity of Th17 cells by regulating ROR ⁇ t activity through small molecule compounds.
  • the level of cytokines (such as IL-17A) secreted by Th17 cells increases significantly, and the survival and immune activation capabilities of Th17 cells are greatly enhanced.
  • enhanced activation of Th17 cells can reduce the number of immunosuppressive Treg cells and reduce the expression of immunosuppressive receptors (such as PD-1) in tumor-infiltrating lymphocytes.
  • the small molecule ROR ⁇ t agonists that can be taken orally can enhance the ability of the immune system to recognize and kill tumor cells by activating Th17 cells, and may become a new class of anti-PD-1 and PD-L1 antibodies in clinical practice.
  • Tumor small molecule drugs can be taken orally to enhance the ability of the immune system to recognize and kill tumor cells by activating Th17 cells, and may become a new class of anti-PD-1 and PD-L1 antibodies in clinical practice.
  • the object of the present invention is to provide a small molecule agonist of ROR ⁇ t.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof:
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl or 5-10 membered heteroaryl;
  • X 1 , X 2 and X 5 are each independently selected from C (R 8 ) or N;
  • X 3 and X 4 are each independently selected from C or N;
  • Y is selected from C (R 9 ) or N;
  • R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano , Nitro,
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0- 8- OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , or, R 3 and R 4 and the carbon directly connected to it Atoms together form C (O), 3-10 membered
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0-8 -OR 24 , -C 0 -8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8 -NR 26 R 27 , -C 0 -8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 )-C (O) R 25 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano , Nitro, azi
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 Heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -P (O) (R 28 ) 2 , -SF 5 , -C 0-8 -S (O) r R 23 ,- C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0 -8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further Or more selected from deuterium, halogen
  • Each R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S (O) r R 23 , -C 0- 8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O) R 25 , -C 0-8- NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , the above groups are optionally further substituted by one or more Selected from deuterium, halogen, cyan
  • R 10, R 11, R 13 , R 14, R 15, R 16 are each independently selected from hydrogen, deuterium, halo, cyano, nitro, azido, C 1- 10 alkyl group, C 2-10 chain, Alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S ( O) r R 23 , -C 0-8 -OR 24 , -C 0-8 -C (O) OR 24 , -C 0-8 -C (O) R 25 , -C 0-8 -OC (O ) R 25 , -C 0-8 -NR 26 R 27 , -C 0-8 -C (O) NR 26 R 27 or -C 0-8 -N (R 26 ) -C (O) R 25 , or , R 10 and R 11 , R 13 and R 14
  • R 21 and R 22 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aromatic Group or a 5-10 membered heteroaryl group, R 21 and R 22 together with the nitrogen atom directly connected thereto form a 4-10 membered heterocyclic group;
  • Each R 23 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered hetero Aryloxy or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclic group, C 5- 10 aryl group, C 5-10 aryloxy, 5-10 membered heteroaryl Substituted by aryl, 5-10 membered heteroaryloxy or -NR 26 R
  • Each R 24 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl Or 5-10 membered heteroaryl, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3 -10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclicoxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 Substituted by a heteroaryl group, a 5-10 membered heteroaryloxy group or a substituent of -NR 26 R 27 ;
  • Each R 25 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered hetero Aryl, 5-10 membered heteroaryloxy or -NR 26 R 27 , the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy
  • Each R 26 and R 27 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, methoxy group, sulfonyl group, methanesulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group , Monoalkylamino, dialkylamino or C 1-10 alkanoyl, the above groups are optionally further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-8 alkyl, C 1-10 alkoxy Group, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered hetero
  • R 26 and R 27 together with the nitrogen atom to which they are directly connected form a 4-10 membered heterocyclic group, and the above group is optionally further selected from one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
  • R 28 is each independently selected from C 1-10 alkyl or phenyl, and the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-8 alkyl, C 1-10 Substituted by substituents of alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group or phenyl group;
  • R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered hetero Aryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above groups are optional
  • R 2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl , Isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, methyl Sulfonyl, aminosulfonyl, methoxy, methoxyyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetamido, the above groups are optionally further selected by one or more Deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methanesulfonyl, hydroxy,
  • each of R 8 and R 9 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, cyano, Nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0- 4 -C (O) OR 24 , -C 0 -4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or- C 0-4 -N (R 26 ) -C (O) R 25 , the above
  • each of R 8 and R 9 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, Cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, phenyl, pyridyl, di Azole, triazole, mesyl, aminosulfonyl, hydroxy, methoxy, methoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetamido, the above groups
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro , Azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl , 5-8 membered heteroaryl, -C 0-4 -S (O) r R 23 , -C 0-4 -OR 24 , -C 0- 4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0 -4 -N (R 26 ) -C (O)
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, pyridyl, diazole, triazole, methanesulfonyl, aminosulfonyl, hydroxyl, methoxy, Methoxy, ethoxy, carboxy, acetyl, acetoxy, amino, dimethylamino, aminoacyl or acetylamino, or R 3 and R 4 together with the carbon atom to which they are directly attached form C (O) , 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, the above groups are optionally further selected from one or more selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl,
  • R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, phenyl, pyridyl, diazole, triazole, amino or dimethylamino, the above groups are optionally further selected by one or more groups A plurality of substituents selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, mesyl, hydroxy, methoxy, carboxy, or amino are substituted.
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, -C 0-4 -S ( O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4 -OC (O ) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , above
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alky
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -OR 24 , -C ( O) OR 24 , -C (O) R 25 or -NR 26 R 27 , the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl , Vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-azetidinyl, piperidinyl, piper Azinyl,
  • each R 7 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1- 4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -P (O) (R 28 ) 2 , -SF 5 , -S (O) r R 23 , -C 0-4 -OR 24 , -C 0-4 -C (O) OR 24 , -C 0-4 -C (O) R 25 , -C 0-4- OC (O) R 25 , -C 0-4 -NR 26 R 27 , -C 0-4 -C (O) NR 26 R 27 or -C 0-4 -N (R 26 ) -C (O) R 25 , the above group is optionally further selected from one or more
  • each R 7 in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, -OR 24 , -C (O) R 25 , -C (O) OH, -C (O) NR 26 R 27 , amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl
  • R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, deuterium, fluorine, chlorine, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C 5-8 aryl group, 5-8 membered heteroaryl group, -C 0-4 -SR 23 , -C 0-4 -OR 24 or -NH 2 , or, R 10 and R 11 , R 13 Together with R 14 , R 15 and R 16 and the carbon atom to which they are directly connected, each independently forms C (O), a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, and the above groups are optionally further or more substituents selected from deuterium, fluoro, chloro, cyano, C 1-4 alkyl, halo-substituted C 1- 4 alkyl group, C 3-8 cycloalkyl, 3-8 membered heterocycly
  • R 17 and R 18 are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl or ethyl;
  • R 23 , R 24 , R 26 and R 27 are as described for the compound of formula (I).
  • the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure of the compound of formula (II) as follows:
  • X 1 and X 2 are each independently selected from C (R 8 ) or N;
  • Y is selected from CH or N;
  • R 1 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, amino or dimethylamino, the above groups are optionally further substituted by one or more Or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, hydroxyl, methoxy, carboxyl or amino;
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -P (O) (CH 3 ) 2 , -P (O) H 2 , -SF 5 , sulfonyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, -C (O) R 25 , -C (O) OH, -C (O) NR 26 R 27 , amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl , Ethyl, isopropyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, 3-a
  • Each R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, Hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, tri Substituted by substituents of fluoromethyl, cyclopropyl, phenyl, pyridyl, hydroxy, methoxy, carboxy, or amino;
  • Ring A, R 23 , R 24 , R 25 , R 26 , R 27 , and m2 are as described for the compound of formula (I).
  • the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure of the compound of formula (III) as follows:
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
  • Rings A, R 1 , R 6 , R 7 , R 8 and m2 are as described above.
  • the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof has the structure selected from the compound of formula (IV) as follows:
  • R 1 is independently selected from methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl or amino;
  • R 3 is each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, hydroxy, methoxy , Ethoxyl, carboxyl or amino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl, hydroxyl, methoxy, carboxyl or amino Substituted by a substituent;
  • R 6 is each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 3-oxetanyl, 3- Azetidinyl, methoxy, ethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyanide Group, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, trifluoromethoxy Substituted by the substituent of the group, trideuteromethoxy, carboxyl or amino;
  • Each R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, 3-azetidinyl, Hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino or dimethylamino, the above groups are optionally further selected by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, tri Substituted by substituents of fluoromethyl, cyclopropyl, hydroxy, methoxy, carboxy, or amino;
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
  • Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
  • Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents;
  • Rings A and m2 are as described above.
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
  • Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
  • Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents.
  • R 10 and R 11 are each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, cyclopropylmethyl, methoxymethyl, aminomethyl, benzyl, ethyl , Isopropyl, cyclopropyl, 3-oxetanyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, dideuteromethoxy or -NH 2 Or, R 10 and R 11 together with the carbon atom directly connected to them form C (O), cyclopropyl, cyclobutyl, 3-oxetanyl;
  • Each R 25 is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or isopropyl;
  • Each R 26 , R 27 is independently selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl, methoxy, sulfonyl, methanesulfonyl, amino, monoalkane Amino group, dialkylamino group or C 1-10 alkanoyl group, the above groups are optionally further selected from one or more selected from deuterium, halogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl, phenyl , Methoxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl substituents.
  • the aforementioned compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:
  • the second aspect of the present invention provides a method for preparing the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, comprising the following steps: the compound of formula Ia and the compound of formula Ib or its acid salt Coupling gives the compound of formula I:
  • a third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition in the preparation for the treatment of one or more tumors, cancers, and metabolites The application of drugs in diseases, autoimmune diseases or disorders.
  • the fifth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used for the treatment of one or more tumors, cancers, Drugs for metabolic diseases, autoimmune diseases or disorders.
  • the compound of the present invention has a strong inhibitory effect on ROR ⁇ t kinase activity, can be widely used in the preparation of therapeutic drugs, and is expected to be developed into a new generation of ROR ⁇ t agonist drugs. On this basis, the present invention has been completed.
  • Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group.
  • C 1-8 alkyl refers to a straight-chain alkyl group containing 1 to 8 carbon atoms and a branched-chain alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-eth
  • the alkyl group may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, "C 3-10 cycloalkyl” refers to a cycloalkyl group containing 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, where:
  • Monocyclic cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl, etc.
  • Polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has Completely conjugated ⁇ electron system. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups. Spirocycloalkyl groups include but are not limited to:
  • “Fused cycloalkyl” refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, where one or more rings (preferably 1 or 2) may contain one Or multiple double bonds (preferably 1, 2 or 3), but none of the rings has a completely conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups. Condensed cycloalkyl groups include but are not limited to:
  • Bridged cycloalkyl means an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more double bonds (preferably 1, 2 or 3), but none of them The ring has a completely conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , Benzocycloheptyl and so on.
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon.
  • ring r is an integer of 0, 1, 2
  • Monocyclic heterocyclic groups include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares an atom (called a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer) 0, 1, 2) heteroatoms, the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2, 3 or 4), but none of the rings has a completely conjugated ⁇ electron system.
  • Spiro heterocyclic groups are classified into mono-spiro heterocyclic groups, di-spiro heterocyclic groups, or poly-spiro heterocyclic groups according to the number of spiro atoms shared between rings.
  • Spiroheterocyclic groups include but are not limited to:
  • “Fused heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more (Preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2), and the remaining ring atoms are carbon.
  • the fused heterocyclic groups include but are not limited to:
  • Bridge heterocyclic group means a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but no one ring ⁇ electron system with complete conjugation, where one or more ring atoms (preferably 1, 2, 3 or 4) are selected from nitrogen, oxygen or S (O) r (where r is an integer of 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups.
  • the bridged heterocyclic groups include but are not limited to:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (that is, a ring sharing adjacent pairs of carbon atoms) group, a polycyclic ring having a conjugated ⁇ -electron system (that is, a ring with adjacent pairs of carbon atoms) ) Group, for example, "C 5-10 aryl” refers to an all-carbon aryl group containing 5-10 carbons, and “5-10 membered aryl” refers to an all-carbon aryl group containing 5-10 carbons, including but Not limited to phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • the aryl group may be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, including heteroatoms of nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), for example, 5-8 membered heteroaryl refers to heteroaromatic systems containing 5-8 ring atoms, 5-10 membered heteroaryl refers to heteroaromatic systems containing 5-10 ring atoms, including but not limited to furyl, thiophene Group, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • Alkenyl refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of an alkyl group, e.g., C 2- 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched Alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted.
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, C 2-8 alkynyl refers to a straight or branched chain containing 2-8 carbons Alkynyl. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted.
  • Alkoxy refers to -O- (alkyl), where alkyl is as defined above, for example, “C 1-8 alkoxy” refers to alkyloxy containing 1-8 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy, etc.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • Cycloalkoxy refers to -O- (unsubstituted cycloalkyl), where cycloalkyl is as defined above, for example, “C 3-10 cycloalkoxy” refers to those containing 3-10 carbons Cycloalkyloxy, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.
  • the cycloalkoxy group may be optionally substituted or unsubstituted.
  • 3-10 membered heterocyclic oxy means and -O- (unsubstituted 3-10 membered heterocyclyl), wherein the definition of 3-10 membered heterocyclyl is as described above, 3-10 membered heterocyclyloxy It may be optionally substituted or unsubstituted.
  • 5-10 membered heteroaryloxy refers to -O- (unsubstituted 5-10 membered heteroaryl), where 5-10 membered heteroaryl is as defined above, 5-10 membered heteroaryloxy It may be optionally substituted or unsubstituted.
  • C 1-8 alkanoyl refers to the monovalent radical remaining after removing the hydroxyl group of the C 1-8 alkyl acid, and is usually also expressed as "C 0-7 -C (O)-", for example, “C 1 -C (O)-"means acetyl;” C 2 -C (O)-"means propionyl;” C 3 -C (O)-"means butyryl or isobutyryl.
  • -C 0-8 -OR 24 means that the oxygen atom in -OR 24 is connected to a C 0-8 alkyl group, where C 0 alkyl refers to a bond, and C 1-8 alkyl is as defined above.
  • -C 0-8 -C (O) R 25 means that the carbonyl group in -C (O) R 25 is attached to C 0-8 alkyl, where C 0 alkyl refers to a bond, and C 1-8 alkyl Is defined as above.
  • Halo-substituted C 1-8 alkyl refers to 1-8 carbon alkyl groups on the alkyl optionally substituted by fluorine, chlorine, bromine, and iodine atoms, including but not limited to difluoromethyl, dialkyl Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • the hydrogen on the "halogen substituted C 1-8 alkoxy" alkyl group is optionally substituted with 1-8 carbon alkoxy groups substituted by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • DCM dichloromethane.
  • DMF means N, N-dimethylformamide.
  • THF means tetrahydrofuran.
  • PE means petroleum ether.
  • EA / EtOAc means ethyl acetate.
  • DMSO means dimethyl Sulfoxide.
  • MeCN means acetonitrile.
  • DME means dimethyl ether.
  • DIEA means N, N-diisopropylethylamine.
  • KAc means potassium acetate.
  • K 3 PO 4 is Refers to potassium phosphate.
  • NMP refers to N-methylpyrrolidone.
  • M-CPBA refers to m-chloroperoxybenzoic acid.
  • Pd / C refers to palladium carbon.
  • HATU refers to 2- (7-oxidation Benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate.
  • Pd (dppf) Cl 2 means [1,1'-bis (diphenylphosphine) di Ferrocene] Palladium dichloride.
  • DIBAL-H refers to diisobutylaluminum hydride.
  • LiBH (i-Bu) 3 refers to lithium triisobutylborohydride.
  • X-phos means 2-dicyclohexylphosphonium-2 ', 4 ', 6'-triisopropylbiphenyl.
  • heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more (preferably 1, 2, 3, or 4) hydrogen atoms in the group are substituted with a corresponding number of substituents independently of each other. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort.
  • an amino group or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an olefin).
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm). The measurement of NMR was performed by Bruker AVANCE-400 / 500 NMR instrument. The solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard. It is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • Liquid chromatography-mass spectrometry LC-MS was measured with an Agilent 6120 mass spectrometer. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized using or following methods known in the art.
  • Step 1 Synthesis of ethyl 3-bromo-2-carbonylvalerate
  • Step 2 Synthesis of ethyl 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylate
  • Step 3 Synthesis of (7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methanol
  • Step 4 Synthesis of 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carbaldehyde
  • Step 5 Synthesis of 3-ethyl-2-formylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 2 Synthesis of 2-((tert-butyldimethylsilyl) oxo) acetaldehyde
  • Oxalyl chloride (3.45g, 27.4mmol) was dissolved in anhydrous dichloromethane (100mL), the solution was cooled to -78 ° C, DMSO (4.23g, 54.7mmol) was slowly added, and the reaction solution was stirred at -78 ° C for 30 minutes After that, a solution of 2-((tert-butyldimethylsilyl) oxo) ethanol (4.02g, 22.8mmol) in anhydrous dichloromethane (50mL) was slowly added dropwise, and the reaction solution was stirred at -78 ° C for 1 After 1 hour, triethylamine (11.5g, 114.0mmol) was slowly added dropwise.
  • reaction solution was stirred at -78 ° C for 1 hour.
  • the resulting reaction solution was dichloromethane (50mL) ) Extraction, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give crude 2-((tert-butyldimethylsilyl) oxo) acetaldehyde (3.95 g, 95%).
  • Step 3 Synthesis of (R, E) -N- (2-((tert-butyldimethylsilyl) oxo) ethylene) -2-methylpropane-2-sulfinamide
  • Step 4 (R) -N-((R) -2-((tert-butyldimethylsilyl) oxo) -1- (4- (ethylthio) phenyl) ethyl) Synthesis of -2-methylpropane-2-sulfinamide
  • reaction solution was stirred at -78 ° C for 2 hours. LCMS showed that the reaction was complete.
  • the reaction solution was quenched with saturated ammonium chloride solution (50 mL). The mixture was concentrated to remove tetrahydrofuran, the remaining aqueous solution was extracted with dichloromethane (50 mL), the organic phase was dried and filtered, and the filtrate was concentrated.
  • Step 5 Synthesis of (R) -2-amino-2- (4- (ethylthio) phenyl) ethanol
  • Step 6 Synthesis of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol
  • Step 1 Synthesis of 4-ethylsulfonyl benzaldehyde
  • Step 3 Synthesis of 2-amino-2- (4-ethylsulfonylphenyl) ethanol
  • the mixed solution was extracted with ethyl acetate (200 mL), the organic phase was washed with H 2 O (100 mL) and discarded, and the aqueous phases were combined, and the pH was adjusted continuously to 9-10.
  • Step 4 Synthesis of (R) -2-amino-2- (4-ethylsulfonylphenyl) ethanol and (S) -2-amino-2- (4-ethylsulfonylphenyl) ethanol
  • the racemic mixture (15.0g, 65.2mmol) was resolved by chiral column to obtain:
  • Step 1 Synthesis of 1-bromo-4- (ethylsulfonyl) benzene
  • Step 3 Synthesis of (4- (ethylsulfonyl) phenyl) methylamine
  • Step 3 Synthesis of (5- (ethylsulfonyl) -pyridin-2-yl) methylamine hydrochloride
  • Step 1 Synthesis of methyl 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of 3-ethyl-2- (hydroxy (2- (trifluoromethyl) phenyl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 2 Synthesis of 3- (difluoromethoxy) -5-fluoro-N-methoxy-N-methylbenzamide
  • Step 3 Synthesis of 1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one
  • Step 4 Synthesis of 2-bromo-1- (3- (difluoromethoxy) -5-fluorophenyl) butane-1-one
  • Step 5 Synthesis of 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 6 Synthesis of 2- (3- (difluoromethoxy) -5-fluorophenyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of methyl 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of 3-ethyl-2-((2- (trifluoromethyl) piperidin-1-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of 7-bromo-3-ethylimidazo [1,2-a] pyridine-2-carboxylic acid
  • Step 2 Synthesis of (7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) (2- (trifluoromethyl) piperidin-1-yl) methanone
  • Step 3 Synthesis of 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carbonitrile
  • Step 4 Synthesis of 3-ethyl-2- (2- (trifluoromethyl) piperidine-1-carbonyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of N '-((7-bromo-3-ethylimidazo [1,2-a] pyridin-2-yl) methylene) benzenesulfonyl hydrazide
  • Step 2 Synthesis of 7-bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine
  • Step 3 Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 4 Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of methyl 3-ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of methyl 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 3 Synthesis of 3-ethyl-2-((2- (trifluoromethyl) phenoxy) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of methyl 3-ethyl-2- (hydroxymethyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of methyl 3-ethyl-2-((toluenesulfonyloxy) methyl) imidazo [1,2-a] pyridine-7-carboxylate
  • Step 3 Synthesis of methyl 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylate
  • Step 4 Synthesis of 2-((2-chloro-6-fluorophenoxy) methyl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of (2-chloro-6- (trifluoromethyl) phenyl) methanol
  • Step 2 Synthesis of 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene
  • Step 5 Synthesis of (E) -2- (2-chloro-6- (trifluoromethyl) styryl) -3-ethylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of ethyl 3-bromo-2-carbonylbutyrate
  • Step 2 Synthesis of ethyl 7-bromo-3-methylimidazo [1,2-a] pyridine-2-carboxylate
  • Step 3 Synthesis of (7-bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methanol
  • Step 4 Synthesis of 7-bromo-3-methylimidazo [1,2-a] pyridine-2-carbaldehyde
  • Step 5 Synthesis of N '-((7-bromo-3-methylimidazo [1,2-a] pyridin-2-yl) methylene) benzenesulfonyl hydrazide
  • Step 6 Synthesis of 7-bromo-2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine
  • Step 7 Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carbonitrile
  • Step 8 Synthesis of methyl 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylate
  • Step 9 Synthesis of 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-methylimidazo [1,2-a] pyridine-7-carboxylic acid
  • Step 1 Synthesis of ethyl 4-methyl-2-carbonylvalerate
  • the second step to the tenth step are prepared by referring to the synthetic method in Intermediate 15, 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-isopropylimidazo [1,2- a] Pyridine-7-carboxylic acid ESI-MS 397.2 [M + H] + .
  • Step 1 Synthesis of ethyl 2- (cyclopropylmethyl) -1,3-disulfane-2-carboxylate
  • Step 2 Synthesis of ethyl 3-cyclopropyl-2-carbonylpropionate
  • the third step to the eleventh step are prepared by referring to the synthesis method in Intermediate 15, 2- (4-chloro-2- (trifluoromethyl) benzyl) -3-cyclopropylimidazo [1,2 -a] pyridine-7-carboxylic acid ESI-MS 395.2 [M + H] + .
  • Step 3 Synthesis of (R) -2-amino-2- (5- (ethylthio) pyridin-2-yl) ethane-1-ol
  • Step 4 Synthesis of tert-butyl (R)-(1- (5- (ethylthio) pyridin-2-yl) -2-hydroxyethyl) carbamate
  • Step 5 Synthesis of tert-butyl (R)-(1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) carbamate
  • Step 6 Synthesis of (R) -2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethane-1-ol
  • Step 1 Synthesis of ethyl 2- (4- (ethylthio) phenyl) -2-carbonylacetate
  • Step 2 Synthesis of ethyl R-2-((tert-butylsulfinyl) imino) -2- (4- (ethylthio) phenyl) ethyl acetate
  • Step 3 Synthesis of ethyl (R) -2-(((R) -tert-butylsulfinyl) amino) -2- (4- (ethylthio) phenyl) acetate
  • Step 4 Synthesis of (R) -2-amino-2- (4- (ethylthio) phenyl) ethyl acetate
  • Step 5 Synthesis of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethyl acetate
  • Butyric acid (10g, 118.3mmol), thionyl chloride (14.1g, 118.3mmol) were dissolved in 1,2-dichloroethane (100mL), the reaction solution was stirred at 80 ° C for 16 hours, cooled to room temperature, and reacted A solution of methyl 2-aminoisonicotinate (12.0 g, 78.9 mmol) and triethylamine (24.1 g, 236.7 mmol) in 1,2-dichloroethane (50 mL) was slowly added dropwise.
  • reaction solution was further stirred at room temperature for 1 hour, and the reaction solution was washed successively with saturated NaHCO 3 (100 mL), H 2 O (100 mL), and saturated brine (100 mL).
  • Step 2 Synthesis of methyl 2-chloro-3-ethylimidazo [1,2-a] pyridine-7-carboxylate
  • Step 2 Synthesis of 1- (4-bromo-2-fluorophenyl) -2-methylpropane-1-one
  • Step 1 Synthesis of 3-ethyl-2- (3-fluoro-4-isobutyrylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 2 Synthesis of 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Step 3 Synthesis of 3-ethyl-2- (3-fluoro-4-isobutylphenyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • the first step methyl 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate synthesis
  • Step 2 Synthesis of 3-ethyl-2- (hydroxy (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • the first step methyl 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylate synthesis
  • Step 2 Synthesis of 3-ethyl-2- (fluoro (3- (trifluoromethyl) pyridin-2-yl) methyl) imidazo [1,2-a] pyridine-7-carboxylic acid
  • Example 2 The preparation of Example 2 is obtained by referring to the synthesis method of Example 1:
  • the nuclear magnetic data of the compound prepared in Example 2 are as follows:
  • Example 4 The preparation of Example 4 is prepared by referring to the synthesis method of Example 3:
  • the nuclear magnetic data of the compound prepared in Example 4 are as follows:
  • Example 13 is prepared by referring to the synthesis method of Example 12:
  • the nuclear magnetic data of the compound prepared in Example 13 are as follows:
  • Examples 14-48 were prepared with reference to the synthesis method of Example 3 or 9:
  • the nuclear magnetic data of the compound prepared in Example 14 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 15 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 16 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 17 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 18 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 19 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 20 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 21 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 22 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 23 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 24 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 25 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 26 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 27 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 28 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 29 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 30 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 31 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 32 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 33 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 34 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 35 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 36 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 37 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 38 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 39 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 40 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 41 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 42 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 43 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 44 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 45 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 46 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 47 are as follows:
  • the nuclear magnetic data of the compound prepared in Example 48 are as follows:
  • TR-FRET Time-resolved fluorescence resonance energy transfer detection
  • This experiment is a TR-FRET compound screening experiment of ROR ⁇ t nuclear receptor agonist.
  • His-tagged ROR ⁇ t-LBD receptor When the His-tagged ROR ⁇ t-LBD receptor is combined with a receptor agonist, it may increase the recruitment of biotin-tagged co-activator peptides.
  • Europium-His-ROR ⁇ t-LBD is indirectly labeled by the donor (Eu) by binding to the Eu-anti-His antibody. Once Eu is activated by an energy source (such as a flash lamp or laser), the energy will be bound to the isophycocyanin-chain
  • an energy source such as a flash lamp or laser
  • the ROR ⁇ t reporter gene detection method was used to evaluate the activation and specificity of the compound to ROR ⁇ t.
  • the plasmid pfn26a-ROR ⁇ t-LBD and pGl4.35 (Promega, Cat.No.E1370) were co-transformed with HEK293 cells (Cell Bank of the Chinese Academy of Sciences, Cat. -100mg) In the presence of conditions, add compounds to evaluate its efficacy.
  • the specific experimental process is as follows:
  • test compound is evaluated by 4 times gradient dilution to evaluate the dose effect effect, starting from 50 ⁇ M;
  • the compounds of the present invention have obvious agonistic effects and specificity on ROR ⁇ t nuclear receptors, and are expected to be developed into a new generation of ROR ⁇ t agonists to meet the clinical application needs.

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  • Organic Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'azote-hétéroarylamide ayant une structure représentée par la formule (I), son procédé de préparation et son utilisation. Les définitions des différents substituants sont telles que décrites dans la spécification et les revendications. La série de composés peut être largement utilisée dans la préparation de médicaments pour traiter une ou plusieurs tumeurs, cancers, maladies métaboliques, et maladies auto-immunes ou troubles auto-immuns, et sont supposés être développés en tant que nouvelle génération de médicaments agonistes de RORγt.
PCT/CN2019/104957 2018-10-24 2019-09-09 Dérivé d'azote-hétéroarylamide, son procédé de préparation et son utilisation Ceased WO2020082921A1 (fr)

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WO2025060974A1 (fr) * 2023-09-18 2025-03-27 上海宇道生物技术有限公司 Composé de n-sulfonyl carboxamide, son procédé de préparation et son utilisation
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CN113717353B (zh) * 2021-08-27 2023-07-25 徐州工程学院 一种双氮杂晕苯二酰亚胺n-型聚合物及其制备方法和用途
CN115322128B (zh) * 2022-08-05 2024-06-18 南京师范大学 一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物及其制备方法与应用
WO2024217500A1 (fr) * 2023-04-18 2024-10-24 上海赛默罗生物科技有限公司 Composé d'isoquinoline et son procédé de préparation, composition pharmaceutique et utilisation associées

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